Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C2C=C(C#CC3C=CC(C(O)=O)=CC=3)C=CC=2C(C2C=CC=CC=2)=CC1.[CH3:30][C:31]1([CH3:62])[C:40]2[CH:39]=[C:38]([C:41]#[C:42][C:43]3[CH:53]=[CH:52][C:46]([C:47]([O:49]CC)=[O:48])=[CH:45][CH:44]=3)[CH:37]=[CH:36][C:35]=2[C:34]([C:54]#[C:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:33][CH2:32]1>>[CH3:30][C:31]1([CH3:62])[C:40]2[CH:39]=[C:38]([C:41]#[C:42][C:43]3[CH:53]=[CH:52][C:46]([C:47]([OH:49])=[O:48])=[CH:45][CH:44]=3)[CH:37]=[CH:36][C:35]=2[C:34]([C:54]#[C:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)=[CH:33][CH2:32]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3C#Cc2ccccc2)cc1
Agent: CC1(C)CC=C(c2ccccc2)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Product: CC1(C)CC=C(C#Cc2ccccc2)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl]benzoic acid (Compound 97), 22 mg (0.05 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(phenylethyn-1-yl)naphth-2-yl)ethynyl]benzoate (Compound 90) was converted to the title compound (pale yellow solid) using 11 mg (0.5 ml, 0.26 mmol) of LiOH (0.5M aqueous solution).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=3[CH3:22])[NH2:18])[N:9]=2)[CH:5]=[N:6][CH:7]=1.Cl.Cl.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[CH2:36][N:37]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]1)[C:30](Cl)=[O:31]>>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[CH2:36][N:37]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]1)[C:30]([NH:18][C:17]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:15]([NH:14][C:10]2[N:9]=[C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[CH:13]=[CH:12][N:11]=2)[CH:16]=1)=[O:31]
Reactant: COc1cc(C(=O)Cl)ccc1CN1CCN(C)CC1
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2cncc(Br)c2)n1
Agent: Cl
Product: COc1cc(C(=O)Nc2ccc(C)c(Nc3nccc(-c4cncc(Br)c4)n3)c2)ccc1CN1CCN(C)CC1
Reaction time: 17 h

Procedure:
This compound was prepared in the same manner as in Example 1, except that 3-[4-(5-bromopyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline (Reference Example 19) and 3-methoxy-4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride dihydrochloride (Reference Example 3) were used, and that the reaction was conducted at room temperature for 17 hours and the crude product was purified by silica gel column chromatography.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[O:7][C:6](=[O:8])[CH:5]([CH2:9][CH2:10][CH2:11][S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:4](=[O:32])[O:3]1.[CH3:34][O:35][C:36](=[O:40])[CH2:37][CH2:38]Br.C[O-].[Na+]>CO.CCCCCC.C(OC(=O)C)C>[CH3:34][O:35][C:36](=[O:40])[CH2:37][CH2:38][C:5]1([CH2:9][CH2:10][CH2:11][S:12][C:13]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:6](=[O:8])[O:7][C:2]([CH3:33])([CH3:1])[O:3][C:4]1=[O:32]
Reactant: COC(=O)CCBr
Reactant: CC1(C)OC(=O)C(CCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)CCC1(CCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)OC1=O
Yield: 76.9 %

Procedure:
5 mmol of 2,2-dimethyl-5-[3-[(triphenylmethyl)thio]-propyl]-1,3-dioxane-5-propanoic-4,6-dione (I) (2.3 g), was dissolved with 20 mmol methyl-3-bromopropionate (3.34 g=2.18 ml) and 4.6 ml of 4.37 M methanolic solution of sodium methoxide (20 mmol) in 10 ml of methanol. The reaction mixture was heated to 60° C. overnight after which TLC in hexane/ethylacetate 1:1 detected no starting material. The mixture was then evaporated to dryness and mixed with 40 ml of aqueous 10% KHSO4. The organic material was extracted by 3 portions of EtOAc, the organic layers were combined dried with MgSO4 and evaporated. The residue was crystallized from hexane/ethylacetate to yield 2.1 g (77%) of 2,2-dimethyl-4,6-dioxo-5-[3-[(triphenylmethyl)thio]propyl]-1,3-dioxane-5-propanoic acid methyl ester (II), 13C-NMR (CDCl3) δ24.6, 29.4, 29.5, 29.6, 31.4, 32.6, 37.7, 51.9, 52.8, 66.8, 105.7, 126.7, 127.9, 129.5, 144.7, 168.4, 172.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[NH:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:35][S:36]([O:19][CH2:18][CH2:17][CH2:16][C@:13]1([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:14][CH2:15][N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH3:9])[C:11](=[O:27])[NH:12]1)(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)NC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCOS(C)(=O)=O)(c2ccc(F)cc2)NC1=O
Temperature: 25 °C
Yield: 94.1 %

Procedure:
To a solution of (R)-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)-4-(3-hydroxypropyl)tetrahydropyrimidin-2(1H)-one (50 mg, 0.12 mmol) and triethylamine (161 mg, 1.59 mmol) in CH2Cl2 (5 mL) was added methanesulfonyl chloride (91 mg, 0.8 mmol) at 0° C., and the reaction mixture was stirred at rt till the reaction was over. The reaction was quenched with H2O, and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give crude 3-((R)-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)-2-oxohexahydropyrimidin-4-yl)propyl methanesulfonate (58 mg, 95%), which was used for the next step without further purification.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]2[CH:27]([OH:28])[C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:29][CH3:30])[CH:24]=4)[N:19]=[CH:18][C:17]=3[O:16][CH2:15]2)[CH2:10][CH2:9]1)(C)(C)C.[O:32]=[C:33]1[NH:38][C:37]2[CH:39]=[C:40](C(O)=O)[CH:41]=[CH:42][C:36]=2[S:35][CH2:34]1>>[OH:28][CH:27]1[C:26]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:29][CH3:30])[CH:24]=3)[N:19]=[CH:18][C:17]=2[O:16][CH2:15][CH:14]1[C@H:11]1[CH2:10][CH2:9][C@H:8]([NH:7][C:6]([C:40]2[CH:41]=[CH:42][C:36]3[S:35][CH2:34][C:33](=[O:32])[NH:38][C:37]=3[CH:39]=2)=[O:5])[CH2:13][CH2:12]1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: COc1ccc2ncc3c(c2c1)C(O)C([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)CO3
Product: COc1ccc2ncc3c(c2c1)C(O)C([C@H]1CC[C@H](NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1)CO3

Procedure:
The titled compound is prepared as a white lyophilizated powder following Scheme 6 and in analogy to Example 15 using [trans-4-(4-hydroxy-6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-cyclohexyl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[N:15]([C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][N:22]=[CH:23]2)=[C:16]=[O:17]>C(OCC)C>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:10][CH2:11][N:12]([C:16]([NH:15][C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH:20]=[CH:21][N:22]=[CH:23]4)=[O:17])[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(N2CCNCC2)cc1C
Reactant: O=C=Nc1cccc2cnccc12
Solvent: CCOCC
Product: Cc1ccc(N2CCN(C(=O)Nc3cccc4cnccc34)CC2)cc1C

Procedure:
1-(3,4-Dimethylphenyl)piperazine (194 mg, 1.02 mmol) in diethyl ether (20 mL) was treated with an ethereal solution of 5-isocyanatoisoquinoline. The precipitate that formed was collected by filtration, washed with diethyl ether, and air-dried to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.29 (d, 1H, J=0.7 Hz), 8.82 (s, 1H), 8.49 (d, J=6.2 Hz, 1H), 7.90-7.93 (m, 1H), 7.76-7.79 (m, 1H), 7.61-7.71 (m, 2H), 7.00 (d, 1H, 8.5 Hz), 6.83 (d, 1H, J=2.4 Hz), 6.73 (dd, 1H, J=83 Hz, 2.5 Hz), 3.67 (m, 4H), 3.15 (m, 4H), 2.19 (s, 3H), 2.13 (s, 3H); MS (ESI+) m/z 361 (M+H).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)=[C:4]([F:20])[CH:3]=1.[CH2:21]([C:24]1[CH:29]=[CH:28][C:27]([C:30]#[CH:31])=[CH:26][CH:25]=1)[CH2:22][CH3:23].Cl>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:17]([C:14]1[CH:15]=[CH:16][C:11]([C:10]#[C:9][C:5]2[CH:6]=[C:7]([F:8])[C:2]([C:31]#[C:30][C:27]3[CH:28]=[CH:29][C:24]([CH2:21][CH2:22][CH3:23])=[CH:25][CH:26]=3)=[CH:3][C:4]=2[F:20])=[CH:12][CH:13]=1)[CH2:18][CH3:19]
Reactant: CCCc1ccc(C#Cc2cc(F)c(Br)cc2F)cc1
Reactant: C#Cc1ccc(CCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Product: CCCc1ccc(C#Cc2cc(F)c(C#Cc3ccc(CCC)cc3)cc2F)cc1
Temperature: 0 °C
Yield: 44.8 %

Procedure:
4-Bromo-2,5-difluoro-4'-propyltolane (5.0 g), 4-propylphenylacetylene (2.1 g), triphenylphosphine (0.06 g) and bis(triphenylphosphine)palladium(II) chloride (0.04 g) were dissolved in triethylamine (33 ml) under nitrogen atmosphere, and then copper(I) iodide (0.01 g) was added thereto, followed by refluxing for 5 hours. The reaction solution was poured into a mixture of concentrated hydrochloric acid (16 ml) and ice (30 g), and then extracted with chloroform. After washing the resultant with water twice, chloroform was distilled off therefrom. The residue was purified using silica gel-chloroform column chromatography, and then recrystallized from acetone to give 1,4-bis(4'-propylphenylethynyl)-2,5-difluorobenzene (2.6 g). The C-N point and the N-I point of the compound were 153.4° C. and 197.7° C., respectively.
Reaction SMILES: [CH2:1]1[O:5][C@@H:4]2[C@@H:6]([OH:9])[CH2:7][O:8][C@@H:3]2[C@@H:2]1[OH:10].[N+:11]([O-])([OH:13])=[O:12].C(OC(=O)C)(=O)C>C(Cl)CCl.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)C.O>[CH2:1]1[O:5][C@@H:4]2[C@H:6]([O:9][N+:11]([O-:13])=[O:12])[CH2:7][O:8][C@@H:3]2[C@H:2]1[OH:10]
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Reactant: O=[N+]([O-])O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=[N+]([O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Temperature: 10 °C
Yield: 42 %

Procedure:
An admixture of 146 g of isosorbide, 60 g of glacial acetic acid and 5 g of p-toluenesulphonic acid in 700 ml of ethylene chloride are boiled under reflux, with the interposition of a water separator, until no more water is split off. The reaction mixture is then concentrated; the residue is taken up in 400 ml of methylene chloride and extracted by shaking twice with 100 ml of aqueous concentrated sodium bicarbonate solution. The aqueous phases are extracted by shaking twice with 200 ml of methylene chloride. The methylene chloride phases are combined and dried with sodium sulphate. The methylene chloride solution is then cooled to approximately 10° C. The nitration mixture--prepared by adding 61 g of 100% strength nitric acid dropwise at from -5° to 0° C. to acetic anhydride (108 g) and glacial acetic acid (64 g) which have been cooled to -5° C.--is pre-cooled to -5° C. and is then added dropwise, while stirring, the internal temperature being kept below 20° C. After stirring for a further 2 hours at 20° C., the mixture is poured into approximately 1.2 l of ice water, the organic phase is separated off, the aqueous phase is extracted by shaking once with 200 ml of methylene chloride, and the combined organic phases are extracted by shaking with 300 ml of water and are concentrated (thin-layer chromatography confirms that no explosive isosorbide dinitrate is present). The residue is dissolved in 700 ml of ethanol and warmed to 50° C., a solution of 10 g of potassium hydroxide in 100 ml of ethanol is added, and the mixture is stirred for 10 minutes at 50° C. After cooling to 20° C., the mixture is neutralized with dilute hydrochloric acid and concentrated. The residue is taken up in 500 ml of water and extracted by shaking four times with 100 ml of methylene chloride. The methylene chloride phases are combined, dried over sodium sulphate and concentrated. The residue is recrystallized from a mixture of 3 parts of chloroform and 1 part of carbon tetrachloride and gives 80.2 g of isosorbide-5-nitrate in the form of colorless, felted needles of melting point: 90° to 91° C.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][C:12]=2[N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:20]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[OH:30][NH3+:31].C([O-])(=O)C.[Na+].[Cl-].[NH4+]>C(OCC)(=O)C.O.C(O)C>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[N:31][OH:30])=[CH:13][C:12]=2[N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:20]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH3+]O
Reactant: CCCCN1CCN(c2cc(C=O)ccc2C2CCC(C(C)(C)C)CC2)CC1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCN1CCN(c2cc(C=NO)ccc2C2CCC(C(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.6 %

Procedure:
To a mixture of the crude product of 4-(4-t-butylcyclohexyl)-3-(4-butylpiperazine-1-yl)benzaldehyde produced in Example (101b) (247 mg), hydroxylammonium chloride (134 mg, 1.93 mmol) and ethanol (10 mL) were added sodium acetate (193 mg, 2.35 mmol) and water (1.5 mL), followed by stirring for 2 hours at room temperature. The reaction mixture was poured into ice water, and then ethyl acetate and saturated aqueous solution of ammonium chloride were added and extraction was performed with ethyl acetate. The separated organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give 271 mg of a crude product of the title compound as a light yellow solid. This product was directly used without purification for the following reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].S(S([O-])=O)([O-])=O.[Na+].[Na+]>CCOCC>[C:25]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:5]1[C:4](=[O:29])[C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[C:7](=[O:11])[C:6]=1[CH3:12])([OH:27])=[O:26]
Reactant: COC(=O)CCCCCCCCCCCCC1=C(C)C(=O)C(OC)=C(OC)C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCCC(=O)O)=C(C)C1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
In 200 ml of ether is dissolved 1.5 g of 2,3-dimethoxy-6-(12-methoxycarbonyldodecyl)-5-methyl-1,4-benzoquinone (I:n=12, R=CH3) and the solution is shaken with 75 ml of a 20% aqueous solution of sodium hydrosulfite. The ether layer is separated and concentrated. To the residue are added, under ice-cooling and in a nitrogen gas stream, 5 ml of a 30% aqueous solution of sodium hydrosulfite and 3.5 ml of a 30% aqueous solution of potassium hydroxide. The mixture is warmed at 50° C. for 2.5 hours. After cooling, the reaction mixture is made acidic with cold hydrochloric acid and extracted with ether. The ether is distilled off under reduced pressure, the residue dissolved in 75 ml of methanol and a solution of 15 g of ferric chloride in 60 ml of water added. The mixture is stirred at room temperature for 1 hour, at the end of which time it is diluted with water and extracted with ethyl acetate. The extract is washed with water and dried, and the solvent is distilled off under reduced pressure. The residue is crystallized from ether-hexane to obtain 1.09 g of 6-(12-carboxydodecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (I:n=12, R=H), m.p. 62° C.
Reaction SMILES: [CH3:1][CH:2]=[CH:3][CH2:4][CH3:5]>[Ni]>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CC=CCC
Agent: [Ni]
Product: C=CCCCCCCCC

Procedure:
2-Pentene from the raffinate II metathesis was dimerized continuously as in example 2 over an Ni heterogeneous catalyst. Fractional distillation of the product gave a decene fraction with a purity of 99.5%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][CH2:15][C:11]2([CH2:14][NH:13][CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:28][CH2:27][N:26]([CH2:29][C:30](O)=[O:31])[C:25]2=[O:33])=[CH:20][CH:19]=1.C(N=C=NCCCN(C)C)C.CN1CCOCC1>ClCCl>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]2([CH2:14][N:13]([C:30](=[O:31])[CH2:29][N:26]3[CH2:27][CH2:28][C:24]([C:21]4[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=4)([C:34]4[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=4)[C:25]3=[O:33])[CH2:12]2)[CH2:15][CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: c1ccc(CN2CCC3(CC2)CNC3)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CC2(CCN(Cc3ccccc3)CC2)C1
Reaction time: 8 h

Procedure:
7-Benzyl-2,7-diazaspiro[3.5]nonane (0.237 g, 0.749 mmol), 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.248 g, 0.749 mmol; Example 58D), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.199 mL, 1.123 mmol) and N-methylmorpholine (0.247 mL, 2.247 mmol) were stirred together in dichloromethane (2 mL). After stirring overnight, the reaction was diluted with dichloromethane (20 mL) and washed with 1 N HCl (10 mL) and brine (10 mL), dried over magnesium sulfate and concentrated. The residue was loaded onto a GraceResolv™ 40 g silica gel column (Grace Davison Discovery Sciences) and the title compound eluted with a gradient of 0.4% methanol/dichloromethane containing 0.2 N NH3 to 6% methanol/dichloromethane containing 0.2 N NH3 (Flow=40 mL/minute) over 40 minutes. 1H NMR (300 MHz, CDCl3) δ 7.39-7.15 (m, 9H), 6.99 (t, J=8.2, 4H), 3.97 (s, 2H), 3.72 (d, J=20.0, 4H), 3.53 (t, J=6.5, 2H), 3.46 (s, 2H), 2.75 (t, J=6.4, 2H), 2.32 (s, 4H), 1.73 (s, 4H); MS (ESI+) m/z 530.2 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[F:22][C:23]1[CH:28]=[C:27]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:26]=[CH:25][C:24]=1[OH:37].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:37][C:24]3[CH:25]=[CH:26][C:27]([CH2:29][CH2:30][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[CH:28][C:23]=3[F:22])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Oc1ccc(CCN2CCOCC2)cc1F
Reactant: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Oc2ccc(CCN3CCOCC3)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (270 mg, 0.84 mmol) and 2-fluoro-4-(2-morpholin-4-yl-ethyl)-phenol (225 mg, 0.84 mmol) in DMF (5 mL), was K2CO3 (137 mg, 0.84 mmol) added. The reaction mixture was irradiated under microwave for 1 hour at 150° C. The reaction was cooled to room temperature and poured into H2O (50 mL) and extracted with ethyl acetate (50 mL). The ethyl acetate was dried over MgSO4, and concentrated under vacuum and purified over SiO2 to afford Compound C146 (380 mg, 90%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.09˜7.02 (m, 1H), 6.93˜6.91 (m, 2H), 5.12 (m, 1H), 4.61 (m, 1H), 3.46˜3.37 (m, 6H), 3.18˜3.13 (m, 2H), 2.61˜2.57 (m,2H), 2.38˜2.26 (m, 2H), 2.25 (b, 2H), 1.96 (s, 3H), 1.79˜1.74 (m, 2H), 1.49˜1.45 (m, 2H), 1.03 (d, 6H). LCMS 503.5 [M+1].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:32])[NH:21][C:22]3[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)=[CH:16][C:15]=1[CH3:33])[O:9][CH2:8][CH2:7][CH:6]2[C:34]([O:36]C)=[O:35])#[N:2].O[Li].O>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:32])[NH:21][C:22]3[CH:23]=[N:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=3)=[CH:16][C:15]=1[CH3:33])[O:9][CH2:8][CH2:7][CH:6]2[C:34]([OH:36])=[O:35])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(C(F)(F)F)nc4)cc3C)c(C#N)cc21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(C(F)(F)F)nc2)ccc1Oc1cc2c(cc1C#N)C(C(=O)O)CCO2
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.3 %

Procedure:
To a solution of methyl 6-cyano-7-(2-methyl-4-(6-(trifluoromethyl)pyridin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylate (0.097 g, 0.190 mmol) in 2 mL of THF containing 200 μL methanol was added LiOH—H2O (0.379 mL, 0.379 mmol) and the solution was stirred at ambient temperature for 12 hours. The reaction was quenched with 1 drop of glacial acetic acid and then concentrated to dryness. The crude material was purified by silica gel column chromatography, eluting with 2-5% methanol/dichloromethane+0.1% acetic acid to provide the desired product (0.04 g, 42%). MS (APCI)=498.1 (M+1).
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1.O>CN(C)C(=O)C.CCOC(C)=O>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[S:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:8])=[O:7])=[CH:21][CH:20]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(C)(C)NS(=O)(=O)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)N(Cc1ccc(Br)cc1)S(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
To a solution of N-tert-butyl-1-phenyl-methanesulfonamide (1 g, 4.39 mmol) in N,N-dimethylacetamide (15 mL) was added sodium hydride (60% in mineral oil) (211 mg, 5.3 mmol) and the reaction was stirred at ambient temperature for 30 minutes. 1-Bromo-4-(bromomethyl)benzene (1.21 g, 4.83 mmol) was then added and the reaction was stirred at 80° C. for 16 hours. Water was added and the reaction was diluted with EtOAc and washed with water (×2) and brine, dried with MgSO4, concentrated and purified by silica gel column chromatography (0-30% EtOAc in heptane) to give N-[(4-bromophenyl)methyl]-N-tert-butyl-1-phenyl-methanesulfonamide (1.18 g, 68% yield). LCMS (m/z) ES+ 397 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:20][CH2:19][C:5]2[N:6]([CH2:14][CH2:15][C:16]([OH:18])=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.CCN=C=NCCCN(C)C.[CH:32]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>ClCCl>[CH:32]1([NH:38][C:16](=[O:18])[CH2:15][CH2:14][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:20][CH2:19][C:5]2=3)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: NC1CCCCC1
Reactant: Cc1ccc2c(c1)c1c(n2CCC(=O)O)CCN(C)C1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CCC(=O)NC2CCCCC2)CCN(C)C1
Reaction time: 16 h

Procedure:
3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoic acid was mixed with EDCI (78 mg, 0.4 mmol) and cyclohexylamine in dichloromethane and the reaction mixture was stirred for 16 h to obtain N-cyclohexyl-3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanamide after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:16][C:15](=[O:17])[O:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[C:6]=2[CH:7]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:24]=[C:23]([C:2]2[CH:3]=[CH:4][C:5]3[NH:16][C:15](=[O:17])[O:14][C:8]4([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]4)[C:6]=3[CH:7]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=C1Nc2ccc(Br)cc2C2(CCCCC2)O1
Reactant: OB(O)c1cccc(Cl)c1
Product: O=C1Nc2ccc(-c3cccc(Cl)c3)cc2C2(CCCCC2)O1

Procedure:
Prepared according to Procedure A from 6-bromo-spiro[4H-3,1-benzoxazine-4,1′-cyclohexane]-2(1H)-one and 3-chlorophenyl boronic acid. Off-white solid: mp 165-168° C. 1H-NMR (DMSO-d6) δ 10.25 (s, 1H), 7.74 (t, 1H, J=1.9 Hz), 7.50-7.67 (m, 3H), 7.42-7.49 (m, 1H), 7.35-7.38 (m, 1H), 6.93-6.95 (d, 1H, J=4.2 Hz), 1.91-1.98 (m, 4H), 1.64-1.76 (m, 3H), 1.60 (m, 2H), 1.29-1.39 (m, 1H); MS (APCI) m/z 328 ([M+H]+, 80%).