Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.Br[CH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25]>C(#N)C.O>[C:24]([C:23]1[CH:22]=[C:21]([CH:28]=[CH:27][CH:26]=1)[CH2:20][NH:10][CH2:9][CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11])#[N:25]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCNCc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of β-alanine tert-butyl ester hydrochloride (7.1 g, 39.2 mmol) and triethylamine (14.2 mL, 107 mmol) in dry acetonitrile (100 mL) was added 3-(bromomethyl)benzonitrile (7.0 g, 35.7 mmol) in portions over 10 minutes at 0° C. After being stirred at RT for 5 hours, the reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (2×100 mL) The organic layers were combined, dried using sodium sulphate and concentrated under reduced pressure. The residue was purified by flash chromatography affording the title compound as a pale yellow liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.75 (s, 1H), 7.66 (m, 2H), 7.50 (m, 1H), 3.71 (s, 2H), 2.64 (t, 2H), 2.32 (m, 2H), 1.37 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O>>[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: N#Cc1cccnc1Cl
Product: N#Cc1cccnc1-c1ccccc1C(F)(F)F
Yield: 30 %

Procedure:
Prepared in 30% yield from 2-chloro-3-cyanopyridine and 2-trifluoromethylphenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 249.0 (M+H)+; 1H NMR (CDCl3) δ 7.45-7.50 (m, 2H), 7.62-7.72 (m, 2H), 7.83-7.86 (m, 1H), 8.09 (dd, J=7.8, 1.7 Hz, 1H), 8.87 (dd, J=5.7, 1.7 Hz, 1H).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[N+:9]([C:12]1[CH:13]=[C:14]([C:22](Cl)=[O:23])[C:15]2[O:20][CH2:19][CH2:18][O:17][C:16]=2[CH:21]=1)([O-:11])=[O:10].O>C(C(C)=O)C>[CH3:8][N:5]1[CH2:6][CH2:7][N:2]([NH:1][C:22]([C:14]2[C:15]3[O:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=2)=[O:23])[CH2:3][CH2:4]1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc2c1OCCO2
Reactant: CN1CCN(N)CC1
Solvent: O
Solvent: CCC(C)=O
Product: CN1CCN(NC(=O)c2cc([N+](=O)[O-])cc3c2OCCO3)CC1
Temperature: 10 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
33 g of 1-amino-4-methylpiperazine were dissolved in 630 ml of methyl ethyl ketone. The mixture was cooled to 10° C. and 61 g of 7-nitro-1,4-benzodioxane-5-carbonyl chloride were introduced by portions. The mixture was stirred for two hours and then the solid was filtered off and washed with 150 ml of methyl ethyl ketone. The obtained product was purified by transformation into the base (M.P.: 212° C.) and recrystallized by treatment with hydrochloric ethanol. 45 g of N-(4-methyl-1-piperazinyl)-7-nitro-1,4-benzodioxane-5-carboxamide were obtained (M.P.: 210° C. with one mole of water). The structue was confirmed by nuclear magnetic resonance and infrared analyses.
Reaction SMILES: C(C1C=C(CCC2C=CN3C(=O)C(/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])=C(N4CCOCC4)N=C3C=2)SC=1)C.[CH:32]([O:34][C@H:35]1[CH2:40][CH2:39][CH2:38][N:37]([C:41]2[N:42]=[C:43]3[CH:53]=[C:52]([C:54]([NH:56][C:57]4[S:58][CH:59]=[C:60]([C:62]([CH3:65])([CH3:64])[CH3:63])[N:61]=4)=[O:55])[CH:51]=[CH:50][N:44]3[C:45](=[O:49])[C:46]=2C=O)[CH2:36]1)=[O:33]>>[C:62]([C:60]1[N:61]=[C:57]([NH:56][C:54]([C:52]2[CH:51]=[CH:50][N:44]3[C:45](=[O:49])[C:46](/[CH:24]=[CH:25]/[C:26]([O:28][C:52]([CH3:54])([CH3:53])[CH3:51])=[O:27])=[C:41]([N:37]4[CH2:38][CH2:39][CH2:40][C@H:35]([O:34][CH:32]=[O:33])[CH2:36]4)[N:42]=[C:43]3[CH:53]=2)=[O:55])[S:58][CH:59]=1)([CH3:65])([CH3:64])[CH3:63]
Reactant: CC(C)(C)c1csc(NC(=O)c2ccn3c(=O)c(C=O)c(N4CCC[C@H](OC=O)C4)nc3c2)n1
Reactant: CCc1csc(CCc2ccn3c(=O)c(/C=C/C(=O)O)c(N4CCOCC4)nc3c2)c1
Product: CC(C)(C)OC(=O)/C=C/c1c(N2CCC[C@H](OC=O)C2)nc2cc(C(=O)Nc3nc(C(C)(C)C)cs3)ccn2c1=O
Yield: 100 %

Procedure:
Reactions were performed in the same manner as in Example 1, (J) by using (3S)-1-[8-({[4-(tert-butyl)-1,3-thiazol-2-yl]amino}carbonyl)-3-formyl-4-oxo-4H-pyrido-[1,2-a]pyrimidin-2-yl]hexahydro-3-pyridinyl formate (524 mg, 1.083 mmol), and the resulting residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=100:1→70:1→50:1) to obtain 742 mg (100% or more) of the title compound as a brown oily substance in a mixture containing byproducts.
Reaction SMILES: C1(S(Cl)(=O)=O)C=CC=CC=1.[CH2:11]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]2[CH:23]=[N:24][C:25]([C@H:28]3[CH2:33][CH2:32][C@H:31]([C:34]([NH2:36])=O)[CH2:30][CH2:29]3)=[N:26][CH:27]=2)[CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][CH3:15].N1C=CC=CC=1>C(Cl)Cl>[CH2:11]([C@H:16]1[CH2:17][CH2:18][C@H:19]([C:22]2[CH:27]=[N:26][C:25]([C@H:28]3[CH2:29][CH2:30][C@H:31]([C:34]#[N:36])[CH2:32][CH2:33]3)=[N:24][CH:23]=2)[CH2:20][CH2:21]1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCC[C@H]1CC[C@H](c2cnc([C@H]3CC[C@H](C(N)=O)CC3)nc2)CC1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC[C@H]1CC[C@H](c2cnc([C@H]3CC[C@H](C#N)CC3)nc2)CC1
Temperature: 55 °C

Procedure:
7.2 Ml. of benzenesulfonyl chloride are added dropwise while stirring to a suspension of 13.2 g. of crude trans-4-[5-(trans-4-n-pentylcyclohexyl)-2-pyrimidinyl]cyclohexane carboxamide in 150 ml. of pyridine. The mixture is then warmed to 55° C. for 3 hours in an oil-bath. The mixture is poured into 500 ml. of ice-water and the product is taken up in methylene chloride. The extract is washed successively with 3-N hydrochloric acid, saturated sodium bicarbonate solution and water, dried over sodium sulfate and evaporated. The crude product is chromatographed on a column of 500 g. of silica gel with toluene/5% acetate (v/v). The first fractions are mixtures and are discarded. The later fractions, which are uniform according to thin-layer chromatography, are dissolved in hexane, filtered hot with active carbon and recrystallized from the filtrate. There is obtained pure trans-4-[5-(trans-4-n-pentylcyclohexyl)-2-pyrimidinyl]cyclohexane carbonitrile; melting point 109.5° C., clearing point 175° C.
Reaction SMILES: C(O/[CH:4]=[C:5](\[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)/[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])C.Cl.[NH2:21]O>C(O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[CH:4]=[N:21][O:12][C:6]=2[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:14][CH:15]=1
Reactant: NO
Reactant: CCO/C=C(/C(=O)C(=O)OCC)c1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1oncc1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 25.7 %

Procedure:
A solution of (E)-ethyl 4-ethoxy-3-(4-fluorophenyl)-2-oxobut-3-enoate (1.5 g, 5.63 mmol, 1.00 equiv) and hydroxylamine hydrochloride (2 g, 28.99 mmol, 5.15 equiv) in ethanol (10 mL) was refluxed for 3 h. The reaction mixture was cooled to room temperature and then quenched by 15 mL of saturated sodium bicarbonate solution. The resulting mixture was extracted with 2×10 mL of ethyl acetate. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-10% of ethyl acetate in petroleum ether to yield 340 mg (26%) of ethyl 4-(4-fluorophenyl)-1,2-oxazole-5-carboxylate as a yellow oil. 1H-NMR (300 MHz, CDCl3): δ 8.57 (s, 1H), 7.47-7.43 (m, 2H), 7.11-7.03 (m, 2H), 4.43 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:15])=[C:9]([C:33](=[O:51])[NH:34][C:35]3[CH:40]=[N:39][C:38]([C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=4)=[CH:37][N:36]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:33](=[O:51])[NH:34][C:35]3[CH:40]=[N:39][C:38]([C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:48])[F:49])[CH:42]=4)=[CH:37][N:36]=3)[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3cccc(C(F)(F)F)c3)cn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3cccc(C(F)(F)F)c3)cn2)c1
Yield: 8.7 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-((4-(piperidin-1-yl)-2-((5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)carbamoyl)phenyl)carbamoyl)benzylthio)propanoate (140 mg, 0.19 mmol, 1.00 equiv) in dichloromethane (2 mL). This was followed by dropwise addition of 2,2,2-trifluoroacetic acid (1 mL) with stirring. The resulting solution was stirred for 2 h at 25° C. in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 11 mg (9%) of a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.47 (s, 1H), 11.01 (s, 1H), 9.47 (s, 1H), 9.23 (s, 1H), 8.44 (d, J=4.5 Hz, 2H), 8.10 (d, J=9 Hz, 1H), 7.80 (m, 4H), 7.51 (m, 3H), 7.36 (m, 1H), 3.83 (s, 2H), 3.41 (s, 4H), 2.60 (d, 2H), 1.60 (m, 6H). MS (ES, m/z): 644 [M+H]+.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].[OH-].[K+]>>[C:1]([OH:6])(=[O:7])[CH2:2][CH2:3][C:4]([OH:9])=[O:5].[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18]
Reactant: O=C1CCC(=O)O1
Agent: COCCOCCOCCO
Agent: [K+]
Agent: [OH-]
Product: O=C(O)CCC(=O)O
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
In a 3-L flask equipped with a stirrer, a thermometer and a dehydration tube, 500 g of succinic anhydride, 2,463 g of triethylene glycol monomethyl ether and 9.5 g of paratoluenesulfonic acid monohydrate were charged, and the mixture was reacted under reduced pressure of 4 to 10.7 kPa at 110° C. for 15 hours, while blowing nitrogen (500 mL/minute) into the space. The acid value of the reaction solution was 1.6 (KOH mg/g). To the reaction solution, 27 g of an adsorbent Kyoward 500SH (manufactured by Kyowa Chemical Industry Co., Ltd.) was added, stirred at 80° C. at 2.7 kPa for 45 minutes, and filtered. Thereafter, triethylene glycol monomethyl ether was distilled off at a liquid temperature of 115 to 200° C. at a pressure of 0.03 kPa. After cooling to 80° C., the residual liquid was filtered under reduced pressure, to give a diester of succinic acid and triethylene glycol monomethyl ether as a filtrate. The resultant diester had an acid value of 0.2 (KOH mg/g), a saponification value of 276 (KOH mg/g), a hydroxyl value of 1 or less (KOH mg/g) and a hue of APHA200.
Reaction SMILES: [OH-].[Na+].[NH:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([OH:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[NH2:4].[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)[CH3:16]>O>[C:18]1(/[C:15](=[N:4]/[NH:3][C:5]2[CH:10]=[CH:9][C:8]([S:11]([OH:14])(=[O:12])=[O:13])=[CH:7][CH:6]=2)/[CH3:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NNc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C/C(=N\Nc1ccc(S(=O)(=O)O)cc1)c1ccccc1
Temperature: 100 °C
Yield: 23.4 %

Procedure:
Sodium hydroxide (400 mg, 10 mmol) in 10 mL of water was added to a solution of 4-hydrazino-benzenesulfonic acid (1.88 g, 10 mmol) in 20 mL of water. Acetophenone (1.32 g, 11 mmol) was then added, and the mixture was heated to 100° C. overnight. The resulting mixture was then cooled and washed with ether. The pH of the aqueous solution was then adjusted to 4 with conc. HCl. Water was removed under vacuum, and methanol was added. The solution was filtered and concentrated to give product (680 mg) as a yellow solid (MS: (M+H)+=291.15).
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[NH:12]CC(O)COC1C=CC=C2C=1C(=O)OC2>C(O)C>[NH2:12][CH:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1
Reactant: O=C1OCc2cccc(OCC(O)CNC3CCc4ccccc4C3)c21
Agent: Cl
Solvent: CCO
Product: NC1CCc2ccccc2C1

Procedure:
Following the procedure described in Example 27, but starting from 7-(2,3-epoxypropoxy)phtalide (20.6 g), obtained from 7-hydroxyphtalide and epichlorohydrin according to the teaching of Belgian Patent 815,745, and 2-aminotetralin (14.81 g) in absolute ethanol (125 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-phtalid-7-yloxypropanamine hydrochloride is obtained ((iF): L"=H, E" and G" taken together, form a group --CO--O--CH2 --, R=H, and the chain is attached to position 2 of the tetralin moiety).
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][C:12]([OH:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[OH-].[Na+]>O>[CH2:1]([NH:9][CH2:10][CH2:11][C:12]([OH:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCC(O)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OC(CCNCc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
72.3 g of N-benzoyl-3-hydroxy-3,3-diphenylpropylamine are added portionwise to the suspension of 16.3 g of lithium aluminum hydride in 1.6 lt of diethyl ether while stirring and cooling with an ice-bath. The mixture is stirred for 2 hours while warming to room temperature and 3 hours while refluxing. It is cooled again and 16.3 g of water, 16.3 ml of 15% aqueous sodium hydroxide and 49 ml water was added in this order, filtered and the residue washed 3 times with 300 ml of warm chloroform. The combined filtrates are dried and evaporated, to yield the N-benzyl-3-hydroxy-3,3-diphenylpropylamine melting at 145°-146°.
Reaction SMILES: CN(CCN([CH2:8][CH2:9][N:10](C)C)C)C.O=[C:14]1O[C@H:19]([C@H:21]([CH2:23]O)O)[C:17]([O-])=[C:15]1O.[Na+]>O>[CH:14]1[CH:23]=[CH:21][C:19]([CH2:8][CH2:9][NH2:10])=[CH:17][CH:15]=1
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Reactant: CN(C)CCN(C)CCN(C)C
Agent: [Na+]
Solvent: O
Product: NCCc1ccccc1

Procedure:
A solution of Cu(I) catalyst at 1 mM and PHEA-MA at 1 mM (30 mg/mL) was prepared by dissolution of Cu(II)Br (2.35 mg, 10 μmol), PMDETA (6 μL, 30 μmol), sodium ascorbate (39.6 mg, 200 μmol) and PHEA-MA (300 mg, 10 μmol) in 10 mL of milli-Q water solution. The solution was then filtered with a 0.45 μm filter (Acrodisc Syringe Filter). Si wafers coated with the initiator layers were immersed vertically into the Cu(I) catalyst/PHEA-MA solution and allowed to polymerize for a predetermined time. To quench the reaction, the slides were washed 3 times with milli-Q water, soaked overnight in milli-Q water and then dried under air flow before ellipsometry or AFM analysis.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[CH:2].I[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([CH3:29])[CH:23]=1>>[OH:28][C:25]1[CH:26]=[CH:27][C:22]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=2)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[CH:23][C:24]=1[CH3:29]
Reactant: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Reactant: Cc1cc(I)ccc1O
Product: Cc1cc(C#Cc2cncc(C(=O)N=[S@@](C)(=O)c3ccccc3)c2)ccc1O
Yield: 73 %

Procedure:
In a manner similar to that describe in Example 434, a mixture of (S)-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 4-iodo-2-methylphenol were reacted to give the title compound as a light yellow solid (43 mg, 73%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:3]1=[O:13].[H-].[Na+].O[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][C:23]3[CH2:40][C@:30]4([C:38]5[C:33](=[N:34][CH:35]=[CH:36][CH:37]=5)[NH:32][C:31]4=[O:39])[CH2:29][C:24]=3[CH:25]=2)[N:20]=1>CN(C=O)C>[CH3:1][C:2]1([CH3:14])[CH2:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]([CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][C:23]4[CH2:40][C@:30]5([C:38]6[C:33](=[N:34][CH:35]=[CH:36][CH:37]=6)[NH:32][C:31]5=[O:39])[CH2:29][C:24]=4[CH:25]=3)[N:20]=2)[C:3]1=[O:13]
Reactant: CC1(C)CC(c2ccccc2)NC1=O
Reactant: O=C1Nc2ncccc2[C@@]12Cc1cc3ccc(CO)nc3cc1C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(c2ccccc2)N(Cc2ccc3cc4c(cc3n2)C[C@]2(C4)C(=O)Nc3ncccc32)C1=O
Reaction time: 0.5 h

Procedure:
To a solution of (±)-3,3-dimethyl-5-phenylpyrrolidin-2-one (221 mg, 0.893 mmol, described in Intermediate 51) in DMF (0.5 mL), at ambient temperature, was added sodium hydride (60% dispersion in mineral oil; 37 mg, 0.923 mmol). The resulting mixture was stirred for 30 min, then (S)-2-(chloromethyl)-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (100 mg, 0.298 mmol, described in Intermediate 7) was added and the resulting mixture was stirred at ambient temperature for 2 h. The reaction mixture was quenched with H2O (0.1 mL) and purified directly by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 95:5, to give the title compound. MS: m/z=547 (M+1). HRMS: m/z=547.2466; calculated m/z=547.2452 for C32H31N6O3.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]([CH3:11])[N:4]=1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[F:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[CH:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:43]=[CH:44][C:45]([F:46])=[C:24]([NH:23][C:8]([C:6]5[N:5]([CH3:11])[N:4]=[C:3]([CH2:1][CH3:2])[CH:7]=5)=[O:10])[CH:25]=4)=[CH:33][N:32]3[N:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1F
Reactant: CCc1cc(C(=O)O)n(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2F)n(C)n1
Yield: 81.2 %

Procedure:
In the same manner as in Example 18-4 and using 3-ethyl-1-methyl-1H-pyrazole-5-carboxylic acid (188 mg, 1.22 mmol), tetrahydrofuran (7 mL), oxalyl chloride (160 μL, 1.83 mmol), N-[6-(3-amino-4-fluorophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.611 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (230 mg, 81%) was obtained as a white solid.
Reaction SMILES: C([O:8][C:9]([N:11]1[CH2:16][C@H:15]([C:17](=[O:19])[NH2:18])[N:14]([CH2:20][CH2:21][CH2:22][C:23]([N:25]2[CH2:32][CH2:31][C:28]3([CH2:30][CH2:29]3)[C@H:27]([OH:33])[CH2:26]2)=[O:24])[C:13](=[O:34])[C@@H:12]1[CH3:35])=O)C1C=CC=CC=1.[Cl:36][C:37]1[CH:42]=[C:41]([N:43]=C=O)[CH:40]=[CH:39][C:38]=1[C:46]([F:49])([F:48])[F:47]>[Pd]>[Cl:36][C:37]1[CH:42]=[C:41]([NH:43][C:9]([N:11]2[C@@H:12]([CH3:35])[C:13](=[O:34])[N:14]([CH2:20][CH2:21][CH2:22][C:23]([N:25]3[CH2:32][CH2:31][C:28]4([CH2:30][CH2:29]4)[C@H:27]([OH:33])[CH2:26]3)=[O:24])[C@@H:15]([C:17]([NH2:18])=[O:19])[CH2:16]2)=[O:8])[CH:40]=[CH:39][C:38]=1[C:46]([F:48])([F:49])[F:47]
Reactant: O=C=Nc1ccc(C(F)(F)F)c(Cl)c1
Reactant: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)[C@@H](C(N)=O)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)[C@@H](C(N)=O)CN1C(=O)Nc1ccc(C(F)(F)F)c(Cl)c1
Yield: 73 %

Procedure:
In analogy to the procedure described in the example 120 step E, (2S,5R)-5-carbamoyl-4-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (example 147 step B) was first deprotected using 10% palladium on charcoal and then subsequently reacted with 2-chloro-4-isocyanato-1-trifluoromethyl-benzene (intermediate 16) to give the titled compound in 73% yield as a colorless solid. MS: 574.3 (MH+, 1Cl).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=[C:4]([CH3:18])[N:3]=1.[ClH:19].[C:20]1([CH2:26][C:27](=[NH:31])OCC)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[ClH:19].[F:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:27](=[NH:31])[CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3][C:4]([CH3:18])=[CH:5][CH:6]=1
Reactant: CCOC(=N)Cc1ccccc1
Reactant: Cc1ccc(OCc2c(F)cccc2F)c(N)n1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(OCc2c(F)cccc2F)c(NC(=N)Cc2ccccc2)n1
Yield: 6.9 %

Procedure:
A mixture of 2-amino-3-(2,6-difluorobenzyloxy)-6-methyl-pyridine (5.0 g, 20 mmol) and ethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was purified by chromatography (silica, chloroform/methanol) and recrystallisation from ethanol/ether to obtain the product (0.56 g), m.p. 173°-177° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5](=O)[CH2:6][C:7]([O:9][CH3:10])=[O:8].[Cl-].ClC1N(C)C=C[N+]=1C.C(N(CC)CC)C.CCCCCC>ClCCl.O>[CH3:10][O:9][C:7](=[O:8])[CH:6]=[C:5]=[CH:4][C:3]([O:2][CH3:1])=[O:12]
Reactant: COC(=O)CC(=O)CC(=O)OC
Agent: Cn1cc[n+](C)c1Cl
Agent: [Cl-]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O
Product: COC(=O)C=C=CC(=O)OC
Temperature: 0 °C
Reaction time: 4 h
Yield: 40.1 %

Procedure:
3-Oxopentanedioic acid dimethyl ester (11 mL, 75 mmol) was dissolved in dichloromethane (100 mL), and cooled to 0° C. The obtained solution was added with 2-chloro-1,3-dimethylimidazolium chloride (14 g, 83 mmol) and triethylamine (31 mL, 0.23 mol), warmed up to a room temperature and stirred for 4 hours. The reaction mixture was added with hexane (200 mL) and water and extracted with hexane 3 times. The organic layers were combined and sequentially washed with water and saturated brine, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain penta-2,3-dienedioic acid dimethyl ester (4.7 g, 40%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][CH2:11][C@H:12]1[CH2:14][O:13]1)[CH3:9].[C:15]([O:19][CH3:20])(=[O:18])[C:16]#[CH:17].C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[O:13]1[CH2:14][C@@H:12]1[CH2:11][O:10][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:17]#[C:16][C:15]([O:19][CH3:20])=[O:18])[CH3:9]
Reactant: CC(OC[C@H]1CO1)c1ccccc1I
Reactant: C#CC(=O)OC
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C#Cc1ccccc1C(C)OC[C@H]1CO1
Temperature: 65 °C
Reaction time: 8 h
Yield: 3.3 %

Procedure:
(R)-2-[[1-(2-Iodophenyl)ethoxy]methyl]oxirane (1.50 g) obtained in Step 1 was dissolved in tetrahydrofuran (15 ml), methyl propynoate (1.66 g), tetrakis(triphenylphosphine)palladium(0) (69.2 mg), copper iodide (37.5 mg) and potassium carbonate (2.72 g) were successively added, and the mixture was stirred overnight at 65° C. The reaction mixture was cooled to room temperature, water was added and, after filtration through celite, the filtrate was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (43 mg).