Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:9][O:8][C:7]2[C:3](=[C:4]([CH:10]=O)[S:5][CH:6]=2)[O:2]1.[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[C:12]1([NH:18][N:19]=[CH:10][C:4]2[S:5][CH:6]=[C:7]3[O:8][CH2:9][CH2:1][O:2][C:3]=23)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NNc1ccccc1
Reactant: O=Cc1scc2c1OCCO2
Solvent: CO
Product: C(=NNc1ccccc1)c1scc2c1OCCO2
Temperature: 65 °C

Procedure:
In a 250 ml round bottomed flask, 3,4-ethylenedioxythiophene-2-carbaldehyde (5 g, 0.0294 mol) was dissolved in 120 ml of methanol by heat. A solution of N-phenylhydrazine (4.76 g, 0.0441 mol) in methanol was added to the cooled reaction mixture. After the reaction mixture was heated at 65° C. for 2.5 hours, the reaction mixture was concentrated and then placed in a freezer to form yellowish crystals of 3,4-ethylenedioxythiophene-2-carbaldehyde N-phenylhydrazone. The yellowish crystals were filtered off, washed with a large amount of cold methanol, and dried. The yield of 3,4-ethylenedioxythiophene-2-carbaldehyde N-phenylhydrazone was 4.73 g (62%). The melting point of the product was found to be 136–137° C. The 1H-NMR spectrum (100 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 7.81 (s, 1H, CH═N), 7.4–6.95 (m, 4H, Ar), 6.82 (t, 1H, J=5.3 Hz, 4-HPh), 6.26 (s, 1H, CH═S), and 4.4–4.1 (m, 4H, OCH2CH2). The infrared absorption spectrum of the product was characterized by the following absorption peaks (KBr window, cm−1): 3124, 3058 (arene C—H); 2976, 2922, 2869 (CH); 1595, 1500, 1442 (C═C in Ar, C═N); 1069, 935, 907 (C—O); 760 (Ar). The mass spectrum of the product was characterized by the following m/z peak: 261 (100%, M+1).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40]#[N:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].C([Li])CCC.C[Si]([CH:51]=[N+:52]=[N-:53])(C)C>C1COCC1.CCCCCC.[Cl-].[NH4+]>[NH:9]1[CH:10]=[C:6]([C:2]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([C:40]4[N:41]=[N:53][NH:52][CH:51]=4)[CH:36]=3)[CH:31]=2)([OH:1])[CH:3]([CH3:4])[CH3:5])[N:7]=[CH:8]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)C(O)(c1ccc2cc(C#N)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)C(O)(c1ccc2cc(-c3c[nH]nn3)ccc2c1)c1c[nH]cn1
Reaction time: 0.33 h

Procedure:
To an solution of 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthonitrile in THF (15 mL) was added a solution of n-butyllithium in hexane (1.6M:2.57 mL) under ice cooling, and the mixture was stirred for 20 min. A solution of trimethylsilyldiazomethane in THF (10% wt.:6.0 g) was added dropwise to the mixture and stirred for 90 min under ice cooling. The reaction mixture was diluted with saturated aq. ammonium chloride and extracted with ethyl acetate. The extract was washed with water and brine, dried and concentrated. The residue was purified by column chromatography (eluent; hexane:THF=1:1) and crystallized from ethyl acetate-hexane (1:1) to give the titled compound (881 mg) as a colorless powder.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:3]1.C[C@H]1CNCCN1>CO.C(Cl)(Cl)Cl>[CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:3]1
Reactant: C[C@@H]1CN(c2ccccn2)CCN1
Agent: C[C@H]1CNCCN1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H]1CN(c2ccccn2)CCN1

Procedure:
The title compound was prepared following the protocol used for the preparation of Intermediate 3, but starting from (S)-2-methyl piperazine (43%). TLC-Chloroform/MeOH (8/2); Rf=0.2.
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:52]=[CH:51][C:42]([C:43]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[O:44])=[C:41]([S:53]([CH:56]([CH3:58])[CH3:57])(=[O:55])=[O:54])[CH:40]=1>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:39]1[CH:52]=[CH:51][C:42]([C:43]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[O:44])=[C:41]([S:53]([CH:56]([CH3:58])[CH3:57])(=[O:54])=[O:55])[CH:40]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)S(=O)(=O)c1cc(Br)ccc1C(=O)N1CCOCC1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CC(C)S(=O)(=O)c1cc(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)ccc1C(=O)N1CCOCC1

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 4-[4-bromo-2-(isopropylsulfonyl)benzoyl]morpholine (Intermediate 261), the title compound was obtained.
Reaction SMILES: O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:24][C:25]1[C:26]([CH:40]([C:52]2[CH:57]=[C:56]([F:58])[CH:55]=[CH:54][C:53]=2[F:59])[S:41]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[C:46]([F:51])[CH:45]=2)(=[O:43])=[O:42])=[CH:27][C:28]([N:31](S(C)(=O)=O)[S:32]([CH3:35])(=[O:34])=[O:33])=[N:29][CH:30]=1.CCCCCC>C(OCC)(=O)C>[Cl:24][C:25]1[C:26]([CH:40]([C:52]2[CH:57]=[C:56]([F:58])[CH:55]=[CH:54][C:53]=2[F:59])[S:41]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[C:46]([F:51])[CH:45]=2)(=[O:43])=[O:42])=[CH:27][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[N:29][CH:30]=1
Reactant: CS(=O)(=O)N(c1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)c(F)c2)c(Cl)cn1)S(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CS(=O)(=O)Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)c(F)c2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
Under a nitrogen atmosphere, a tetrahydrofuran solution (1M, 0.147 ml, 0.15 mmol) of tetrabutylammonium fluoride was added to a tetrahydrofuran (2 ml) solution of N-[5-chloro-4-[(2,5-difluorophenyl)(3,4-difluorophenylsulfonyl)methyl]pyridin-2-yl]-N-(methylsulfonyl)methanesulfonamide (72 mg, 0.12 mmol). The resulting mixture was stirred at room temperature for 2 hours. After the reaction mixture was concentrated under reduced pressure, the residue thus obtained was dissolved in ethyl acetate. The resulting solution was washed sequentially with 1N hydrochloric acid and a saturated aqueous solution of ammonium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated under reduced pressure. The residue thus obtained was washed with a mixed solvent of diethyl ether/hexane and collected by filtration to give the title compound (53 mg, 0.10 mmol, 84%) as a white solid.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[C:3](=[C:4]([CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=2)[CH2:2]1.CS(C)=O.C(Cl)(=O)C(Cl)=O>C(N(CC)CC)C>[CH2:1]1[CH2:10][O:9][C:8]2[C:3](=[C:4]([CH:11]=[O:12])[CH:5]=[CH:6][CH:7]=2)[CH2:2]1
Reactant: OCc1cccc2c1CCCO2
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1cccc2c1CCCO2
Yield: 100 %

Procedure:
(2H-3,4-Dihydrobenzopyran-5-yl)methanol was oxidized using DMSO, oxalyl chloride, and triethyl amine similar to the above procedures to give the product as a clear oil (100%).
Reaction SMILES: [CH:1]([C:4]1[O:8][C:7]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=2)=[N:6][N:5]=1)([CH3:3])[CH3:2].C(Cl)(=O)[C:19](Cl)=[O:20]>C(Cl)CCl>[CH:1]([C:4]1[O:8][C:7]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([N:15]=[C:19]=[O:20])=[O:14])=[CH:11][CH:10]=2)=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)c1nnc(-c2ccc(C(N)=O)cc2)o1
Solvent: ClCCCl
Product: CC(C)c1nnc(-c2ccc(C(=O)N=C=O)cc2)o1

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 4-(5-isopropyl-1,3,4-oxadiazol-2-yl)benzamide (0.200 g), oxalyl chloride (0.012 mL) and EDC (15 mL) to afford 0.150 g of the desired product.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[C:33]([F:40])=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:35][C:34]3[CH:37]=[CH:38][CH:39]=[C:32]([Cl:31])[C:33]=3[F:40])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: Fc1c(Cl)cccc1CBr
Product: Cc1nc2c(ccn2Cc2cccc(Cl)c2F)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 3-chloro-2-fluorobenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.49-7.42 (m, 1 H), 7.38-7.31 (m, 1 H), 7.24-7.11 (m, 3 H), 7.06-7.00 (m, 1 H), 6.94 (dd, J=4.5, 8.4 Hz, 1 H), 6.30 (dd, J=3.5, 11.5 Hz, 1 H), 5.71-5.52 (m, 3H), 4.33-4.26 (m, 2 H), 2.95-2.81 (m, 2 H), 2.76 (s, 3 H), 2.14-2.03 (m, 2 H), 1.01-0.91 (s, 9 H); LC/MS (m/z) ES+=537.4 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:7]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][C:8]=2[S:9][CH:10]=1)[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:7]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:8]=2[S:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)Cc1csc2cc(OC)ccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)Cc1csc2cc(O)ccc12
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of (6-Methoxy-benzo[b]thiophen-3-yl)-acetic acid ethyl ester (2.4 g, 9.6 mmol) in methylene chloride (60 mL) is added BBr3 (1.0 M, heptane, 29.4 mL, 29.4 mmol) at −20˜−30° C. The reaction mixture is allowed to warm to room temperature over 2 hrs, and TLC indicated clean conversion. The reaction is quenched by ice water, extracted with methylene chloride, dried over sodium sulfate, concentrated. Column chromatography on silica gel eluted with hexanes/ethyl acetate yields the title compound (2.2 g).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[C:53]([NH:61][C:62]1[CH:74]=[C:73](Br)[CH:72]=[CH:71][C:63]=1[C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])(=[O:60])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:53]([NH:61][C:62]1[CH:74]=[C:73]([N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)[CH:72]=[CH:71][C:63]=1[C:64]([O:66][C:67]([CH3:69])([CH3:70])[CH3:68])=[O:65])(=[O:60])[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1NC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
86 mg of 4-phenylpiperidine, 0.22 g of cesium carbonate, 2.4 mg of tris(dibenzylideneacetone)dipalladium(0), 1.2 mg of palladium acetate and 6.3 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl were added to 3.0 mL of toluene solution containing 0.10 g of tert-butyl 2-(benzamido)-4-bromobenzoate, and the resulting mixture was heated to reflux for 2 hours. After the reaction mixture was cooled to room temperature, 2.4 mg of tris(dibenzylideneacetone)dipalladium(0), 1.2 mg of palladium acetate and 6.3 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl were added and the resulting mixture was heated to reflux for 6 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane:ethyl acetate=10:1] to obtain tert-butyl 2-(benzamido)-4-(4-phenylpiperidin-1-yl)benzoate as pale yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[C:9]([C:15]([OH:17])=O)[NH:10]3)[CH2:3][CH2:2]1.Cl.Cl.Cl.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C@@H:29]([N:31]2[CH2:36][CH2:35][C@H:34]([OH:37])[C@@H:33]([CH3:38])[CH2:32]2)[CH3:30])[CH2:24][CH2:23]1>>[OH:37][C@H:34]1[CH2:35][CH2:36][N:31]([C@@H:29]([CH3:30])[CH2:28][N:25]2[CH2:24][CH2:23][CH:22]([NH:21][C:15]([C:9]3[NH:10][C:11]4[C:7]([CH:8]=3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH:14]=[CH:13][CH:12]=4)=[O:17])[CH2:27][CH2:26]2)[CH2:32][C@@H:33]1[CH3:38]
Reactant: C[C@H]1CN([C@@H](C)CN2CCC(N)CC2)CC[C@@H]1O
Reactant: O=C(O)c1cc2c(OCC3CC3)cccc2[nH]1
Agent: Cl
Product: C[C@H]1CN([C@@H](C)CN2CCC(NC(=O)c3cc4c(OCC5CC5)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-cyclopropylmethoxy-1H-indole-2-carboxylic acid, 77 (see example 4) and amine 56.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.[I-].[Na+].O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].C(OCC)(=O)C>C(#N)C.O>[OH:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2OC)cc1
Agent: [Ce+3]
Agent: [Cl-]
Agent: [I-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(CC(=O)c2ccc(OC)cc2O)cc1
Yield: 93.9 %

Procedure:
The title compound was synthesized by referring to Chem. Lett., 2000, (7), 738. To a solution of 1-(2,4-dimethoxyphenyl)-2-(4-methoxyphenyl)ethanone (2.8 g) in acetonitrile (150 ml) were sequentially added sodium iodide (3.0 g) and cerium(III) chloride heptahydrate (5.7 g), and the solution was refluxed for 20 hours and 30 minutes. Sodium iodide (760 mg) and cerium(III) chloride heptahydrate (1.9 g) were added thereto, and the solution was further refluxed for 22 hours 30 minutes. To the reaction solution were added ethyl acetate and water, the solution was filtered through celite pad, extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was adsorbed onto silica gel and purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (2.5 g).
Reaction SMILES: [NH3:1].[Cl-].[NH4+].Cl[C:5]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][N:8]=[CH:7][N:6]=1>C(O)C>[NH2:1][C:5]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][N:8]=[CH:7][N:6]=1
Reactant: Clc1ncncc1Oc1ccccc1
Reactant: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ncncc1Oc1ccccc1
Yield: 66 %

Procedure:
To a solution of 125 ml. of absolute ethanol saturated with ammonia was added 2.0 g. ammonium chloride and 25.7 g. (0.124 mol) of 4-chloro-5-phenoxy pyrimidine and the mixture was heated in a 250 ml. stainless steel pressure bomb at 160° for six hrs. The bomb was cooled and the contents poured into a 1000 ml. rb flask. The bomb was rinsed with 4 × 100 ml. boiling ethanol and the combined ethanol solutions were stripped to an oily mixture on the rotary evaporator. The residues were extracted with 4 × 150 ml ether and the ether solution concentrated on the steam bath until a solid began to precipitate. Cooling gave a yellow solid which was collected by vacuum filtration. The solid was taken up in hot ethyl acetate and treated with activated charcoal filtered and concentrated on the steam bath. Careful addition of hexane and cooling gave 15.3 g (66%) white crystals mp 118°-120°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[OH:9][C@@H:10]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([O:9][C@@H:10]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccnc(Cl)n2)C1
Temperature: 140 °C

Procedure:
2,4-Dichloropyrimidine (3.95 g, 26.5 mmol), tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (4.14 g, 22.11 mmol), and cesium carbonate (18 g, 55.3 mmol) were taken up in DMSO (44 ml). The reaction mixture was heated to 140° C. for 40 min, cooled to room temperature, and diluted with ethyl acetate. The mixture was washed with water (×2) and brine. The combined organics were dried over sodium sulfate, concentrated, and purified by Combiflash (ethyl acetate/hexanes) to afford tert-butyl (3R)-3-[(2-chloropyrimidin-4-yl)oxy]pyrrolidine-1-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.CCO.[OH-].[Na+].Cl>C1COCC1>[CH3:1][C:2]1[C:3]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:4]([O:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:19][CH:20]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: CCOC(=O)COc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(Oc3ccc(OCC(=O)O)cc3)c(-c3ccccc3)c(C)cc2c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
Ethyl [(4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}phenyl)oxy]acetate (234) (0.170 g, 0.39 mmol) was dissolved in 1:1 THF:EtOH (6 mL). To the above mixture was added 1 N NaOH (0.5 mL) at room temperature and heated to 50° C. The reaction mixture was kept at that temperature for 0.5 h and cooled at RT. Reaction mixture was acidified with 25% aqueous HCl, and then extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure to afford 0.155 g (97%) the crude product (235). 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J=10.0 Hz, 1H), 7.54 (s, 1H), 7.28-7.03 (m, 4H), 6.64 (d, J=9.0 Hz, 2H), 6.50 (d, J=8.9 Hz, 2H), 4.54 (s, 2H), 3.93 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:41])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[C:37]([NH:39][CH3:40])[N:36]=[CH:35][N:34]=2)[CH:28]=1)=O)(C)(C)C>>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:38]=[C:37]([NH:39][CH3:40])[N:36]=[CH:35][N:34]=4)[CH:28]=3)[CH2:24][C:23](=[O:41])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CNc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ncn1
Product: CNc1cc(-c2cccc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)c2)ncn1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (128 mg, 0.5 mmol) and 3-[3-(6-methylamino-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K54) (180 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (132 mg).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:37]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>C(Cl)Cl>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)=[CH:19][CH:18]=3)[C:43]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:44])=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: c1cc(OC2CCCCO2)ccc1CNc1ccc(OCCN2CCCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CCCCC1)N(Cc1ccc(OC2CCCCO2)cc1)c1ccc(OCCN2CCCC2)cc1
Reaction time: 1 h

Procedure:
To a solution of [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (1.70 g, 4.29 mmol) and triethylamine (2.40 mL, 17.2 mmol) in methylene chloride (8–10 mL) at 0° C. was added cyclohexanecarbonyl chloride (1.72 mL, 12.87 mmol) in methylene chloride (30 mL) dropwise. The reaction mixture was stirred for 1 hr. and was quenched with water/saturated sodium bicarbonate (1/1, 40–50 mL). The layers were separated and the aqueous solution was washed with methylene chloride (2×25 mL). The combined organic solutions were dried (magnesium sulfate), filtered, and concentrated. Medium pressure chromatography using a solvent gradient (methylene chloride to 10% methanol/methylene chloride) afforded the title compound of Step A. MS 507 (M+1)+
Reaction SMILES: CC[O-].[Na+].[CH2:5]([O:7][C:8](=[O:21])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[CH:19][N:18]=[N:17]2)=[CH:12][CH:11]=1)[CH3:6].[O:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1.CC(O)=O>CCO.CS(C)=O.CCOC(C)=O>[O:22]1[CH2:27][CH2:26][CH:25]([CH:28]=[C:9]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH:20]=[CH:19][N:18]=[N:17]3)=[CH:14][CH:15]=2)[C:8]([O:7][CH2:5][CH3:6])=[O:21])[CH2:24][CH2:23]1
Reactant: CCOC(=O)Cc1ccc(-n2ccnn2)cc1
Reactant: O=CC1CCOCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CC1CCOCC1)c1ccc(-n2ccnn2)cc1
Temperature: 80 °C

Procedure:
NaOEt (0.63 mL of a 0.5M solution in EtOH, 0.32 mmol) was added dropwise to a stirred solution of ethyl(4-[1,2,3]triazol-1-ylphenyl)acetate (730 mg, 3.16 mmol) and tetrahydropyran-4-carboxaldehyde (396 mg, 3.47 mmol) in anhydrous DMSO (3 mL). The mixture was heated at 80° C. for 16 h, before being treated with AcOH to adjust the pH to 7. EtOAc (30 mL) was added, then the solution was washed with H2O (2×10 mL) and brine (10 mL), before being dried (MgSO4). Filtration, solvent evaporation, and column chromatography (IH-EtOAc, 1:1) yielded ethyl 3-(tetrahydropyran-4-yl)-2(4-[1,2,3]triazol-1-ylphenyl)acrylate: m/z (ES+)=328.2 [M+H]+. This ester (404 mg, 1.23 mmol) was saponified as described above in Preparation 25 to give the title compound: m/z (ES+)=300.2 [M+H]+.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[C:2]#[CH:3].[N:6]([CH:9]([CH3:17])[C:10]([O:12]C(C)(C)C)=[O:11])=[N+:7]=[N-:8]>>[NH2:5][C:1]([C:2]1[N:8]=[N:7][N:6]([CH:9]([CH3:17])[C:10]([OH:12])=[O:11])[CH:3]=1)=[O:4]
Reactant: C#CC(N)=O
Reactant: CC(N=[N+]=[N-])C(=O)OC(C)(C)C
Product: CC(C(=O)O)n1cc(C(N)=O)nn1

Procedure:
2-[4-(Aminocarbonyl)-1H-1,2,3-triazol-1-yl]propanoic acid was prepared from commercially available propiolamide and tert-butyl 2-azidopropanate using a procedure analogous to that used to prepare Intermediate 52. 1HNMR (500 MHz, CD3OD) δ: 8.48 (s, 1H), 5.50 (q, J=7.3 Hz, 1H), 1.85 (d, J=7.3 Hz, 3H). LC-MS: m/z (ES) 185 (MH)+.