Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:18])[C:8]([CH:10]1[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]1=O)=O)[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[C:10]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]=2[NH:3][N:2]=1)=[O:18])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)C1CCC(C)(C)C1=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1n[nH]c2c1CCC2(C)C
Yield: 70.9 %

Procedure:
Hydrazine hydrate (0.229 mL, 4.71 mmol) was added to a stirring room temperature solution of 1 (0.9961 g, 4.71 mmol) in EtOH (4.7 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by TLC (2 h). The reaction was concentrated and purified by silica gel chromatography (Combiflash column, 70:30:2 Hexanes:CH2Cl2:2N NH3 in EtOH). Only pure fractions were combined and concentrated to obtain 0.6955 g (71.2%) of 2. 1H (CDCl3, 400 MHz): δ 11.04 (1H, broad s), 4.33 (2H, q, J=7.3 Hz), 2.76 (2H, t, J=6.8 Hz), 2.26 (2H, t, J=6.8 Hz), 1.33 (3H, t, J=7.3 Hz), 1.31 (6H, s) ppm. 13C (CDCl3, 100 MHz): δ 168.08, 160.61, 128.73, 127.27, 61.15, 47.22, 38.64, 27.57, 22.00, 14.48 ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]#[N:19]>>[CH3:12][N:13]1[C:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=2)=[CH:16][CH:15]=[C:14]1[C:18]#[N:19]
Reactant: CCC(=O)c1ccc(Br)cc1
Reactant: Cn1cccc1C#N
Product: CCC(=O)c1ccc(-c2ccc(C#N)n2C)cc1

Procedure:
The title compound was prepared from 1-(4-bromophenyl)-propan-1-one and 1-methyl-2-cyanopyrrole according to the coupling procedure as described in example 1. MS (ES) m/z 239.2; HRMS: calcd for C15H14N2O+H+, 239.1179; found (ESI, [M+H]+), 239.1193.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[CH:13][C:14]([C:15](O)=[O:16])=[C:10]3[N:9]=[CH:8][CH:7]=2)=[CH:2]1.B#B>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[CH:13][C:14]([CH2:15][OH:16])=[C:10]3[N:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: O=C(O)c1cnn2c(-c3ccoc3)ccnc12
Agent: B#B
Product: OCc1cnn2c(-c3ccoc3)ccnc12

Procedure:
As described for Example 15 7-(3-furyl)pyrazolo-[1,5-a]pyrimidine-3-carboxylic acid is reduced with diborane to give the product of the example.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([N:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[OH-].[K+].[CH2:25](I)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CS(C)=O.O>[CH2:25]([O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([N:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCI
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3CC[C@@H]12
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 8 h

Procedure:
To a solution of 17β-hydroxy-4-methyl-5α-4-azaandrostan-3-one (102 mg, 0.336 mmol) in DMSO (3 ml) was added powdered KOH (300 mg) followed by n-hexyliodide (400 μl). After stirring the reaction mixture overnight, the reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, then brine, then dried (MgSO4), and concentrated in vacuo. The residue was then purified by preparative thin layer chromatography to afford the title compound, characterized by H1NMR.
Reaction SMILES: [CH2:1]([C:8]1[CH:25]=[CH:24][C:11]2[N:12]=[C:13]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=3[F:23])[S:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]1.C(O)(=O)C.[Na]>CO.C(Cl)Cl>[CH2:1]([C:8]1[CH:25]=[CH:24][C:11]2[N:12]=[C:13]([C:15]3[CH:22]=[CH:21][C:18]([CH2:19][N:26]4[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]4)=[CH:17][C:16]=3[F:23])[S:14][C:10]=2[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(-c2nc3ccc(Cc4ccccc4)cc3s2)c(F)c1
Reactant: O=C(O)C1CNC1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: O=C(O)C1CN(Cc2ccc(-c3nc4ccc(Cc5ccccc5)cc4s3)c(F)c2)C1
Reaction time: 1 h

Procedure:
At 24° C., a mixture of 4-(6-benzylbenzo[d]thiazol-2-yl)-3-fluorobenzaldehyde (190 mg, 547 μmol), azetidine-3-carboxylic acid (166 mg, 1641 μmol), acetic acid (0.095 mL, 1641 μmol) in MeOH (2 mL) and DCM (2 mL) was stirred for 1 h. The light yellow solution was treated with sodium borocyanohydride (34 mg, 547 μmol). The mixture was stirred for 12 h. The solids were filtered off and washed 3× with DCM, suspended in 4 mL of an aqueous buffered solution (phosphate buffer pH 6) and sonicated for 10 min. The mixture was filtered and the solids washed with water and dried in vacuo to yield 1-((4-(6-Benzylbenzo[d]thiazol-2-yl)-3-fluorophenyl)methyl)azetidine-3-carboxylic acid as a white solid [hS1P1 EC50=149 nM]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.27 (t, J=8.4 Hz, 1H), 8.04 (s, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.44 (d, J=6.6 Hz, 1H), 7.34-7.29 (m, 6H), 7.21-7.20 (m, 1H), 4.11 (s, 2H), 3.83-3.82 (br. m, 1H), 3.63 (s, 2H), 3.41 (t, J=6.8 Hz, 2H), 3.21 (t, J=7.0 Hz, 2H). MS (ESI) m/z: Calculated: 432.5; Observed: 433.2 (M++1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[F:21])=[C:9]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:8]=1)(=O)=O.[C:29](=[NH:42])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.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].O>[C:36]1([C:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[N:42][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=3[F:21])=[C:9]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:8]=2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COc1ccc(F)c(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2CC(C)(C)C)c1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(N=C(c3ccccc3)c3ccccc3)cc2CC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a solution of 2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl trifluoromethanesulfonate (1.77 g) in THF (28 mL) were added benzophenoneimine (1.06 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (244 mg), cesium carbonate (2.74 g) and tris(dibenzylideneacetone)dipalladium(0) (193 mg) at room temperature, and the mixture was stirred at 80° C. for 20 hr. The reaction mixture was poured into water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.90 g) as a crude yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:21][CH:20]([CH2:22][OH:23])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.Cl>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:21][CH:20]([CH:22]=[O:23])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(C=O)C1
Temperature: -78 °C
Yield: 37.5 %

Procedure:
Oxalyl chloride (2.1 mL; 24.0 mmol) was dissolved in methylene chloride (30 mL) and cooled to -78° C. Dimethyl sulfoxide (2.3 mL; 32.0 mmol) was added. A solution of 3-hydroxymethylazetidine-1-carboxylic acid tert-butyl ester (3.0 g; 16.0 mmol) in methylene chloride (20 mL) was added dropwise to the reaction mixture. Triethyl amine (11.1 mL; 80.1 mmol) was added and the reaction mixture was heated to room temperature. Methylene chloride (200 mL) and hydrochloric acid (200 mL; 1N) was added. The aqueous phase was extracted with methylene chloride (100 mL). The combined organic phases were washed with saturated sodium hydrogen carbonate (100 mL), dried (magnesium sulfate) and evaporated in vacuo. The residue was chromatographed on silica (3×30 cm) using ethyl acetate/heptane (4:1) as eluent to afford 1.11 g of 3-formylazetidine-1-carboxylic acid tert-butylester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:17])([C:13]([F:16])([F:15])[F:14])[O:8][CH2:7][CH2:6]2.[CH3:18][O:19]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:18]=[O:19])[C:9]([CH3:17])([C:13]([F:16])([F:14])[F:15])[O:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCOC2(C)C(F)(F)F
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc2c(cc1C=O)C(C)(C(F)(F)F)OCC2
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 48.3 %

Procedure:
To a stirred solution of 6-methoxy-1-methyl-1trifluoromethylisochroman (460 mg) in dry dichloromethane (5 ml) was added titanium(IV) chloride under nitrogen at −78° C. After 15 minutes, to the yellow solution was added a solution of dichloromethyl methyl ether in dry dichloromethane at the same temperature. The reaction mixture was stirred at −78° C. for one hour, poured onto ice water, and stirred at room temperature for 30 minutes. The aqueous layer was extracted with methylene chloride. The extracts were washed with brine, dried over magnesium sulfate, and concentrated to give a crude product. This was purified by silica-gel column chromatography eluted with a gradient of hexane and ethyl acetate (10:1, 8:1, 6:1) to give the title compound (179 mg, 48.3% from 1,1,1-Trifluoro-2-(4-methoxy-2-(2-(tetrahydropyran-2-yloxy)ethyl)phenyl)-propan-2-ol). 1H-NMR(CDCl3): 10.41 (s, 1H), 7.82 (s, 1H), 6.78 (s, 1H), 4.19-4.11 (m, 1H), 3.94 (s, 3H), 3.94-3.87 (m, 1H), 2.91 (t, J=4.4 Hz, 2H), 1.67 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:5][C:6]([C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1)=[O:7].[OH-].[Na+].Cl>CC(C)=O>[N:9]1[CH:10]=[CH:11][N:12]=[CH:13][C:8]=1[C:6]([NH:5][C@H:4]([C:3]([OH:21])=[O:2])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1cnccn1
Reaction time: 2 h
Yield: 93.5 %

Procedure:
The product N-pyrazineformyl-L-phenylalanine methyl ester (1.0 g, 3.51 mmol) in Preparation example 2 was dissolved with 10 ml of acetone, 2N NaOH was added dropwise slowly until a pH value of 12˜13 was obtained, and the solution was kept reacting under the condition of ice water bath, the reaction was monitored by TLC and completed after 2 h. Hydrochloric acid was add dropwise under the condition of ice water bath until a pH value of 2˜3 was obtained, a large amount of white solid was produced, the generated precipitate was filtered, washed with water and diethyl ether followed by airing to dry and gave 0.89 g of white product with a yield of 93.6%, m.p.: 166-169° C. 1H-NMR (DMSO-d6, 300 MHz): δ 3.23 (—CH2, m, 2H), 4.74 (—CH, m, 1H), 7.16˜7.25 (-Ph, m, 5H), 8.74 (—CONH, t, 1H), 8.86˜8.89 (-Pyz, t, 2H), 9.14 (-Pyz, d, 1H), 13.06 (—COOH, s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[S:22]1C2C(=CC=CC=2)C(N)CC1>>[S:22]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]([NH:11][C:4]2[C:3]([CH2:1][CH3:2])=[N:8][CH:7]=[C:6]([CH2:9][CH3:10])[N:5]=2)[CH2:13][CH2:14]1
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: NC1CCSc2ccccc21
Product: CCc1cnc(CC)c(NC2CCSc3ccccc32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,4-dihydro-2H-thiochromen-4-ylamine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.71, 7.30, 7.15, 7.05, 5.44, 4.51, 3.17, 2.98, 2.68, 2.64, 2.56, 2.14, 1.31; HRMS (FAB) calcd for C17H21N3S+H 300.1534, found 300.1532.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][C:16]1[N:17]=[CH:18][N:19]([CH2:21][CH2:22][S:23]([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:20]=1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([S:23]([CH2:22][CH2:21][N:19]3[CH:20]=[C:16]([CH3:15])[N:17]=[CH:18]3)(=[O:25])=[O:24])=[CH:27][CH:28]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: Cc1cn(CCS(=O)(=O)c2ccc(C(=O)O)cc2)cn1
Product: Cc1cn(CCS(=O)(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)cn1

Procedure:
70 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-(4-methyl-1H-imidazole-1-yl)ethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-(4-methyl-1H-imidazol-1-yl)ethylsulfonyl)benzamide. MS (Q1) 481.0 (M)+.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][C@H:24]([C:35]([NH:37][C:38]1[CH:39]=[N:40][N:41]([CH3:63])[C:42]=1[NH:43][C:44]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:36])[CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>C(Cl)Cl>[CH3:63][N:41]1[C:42]([NH:43][C:44]([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[C:38]([NH:37][C:35](=[O:36])[C:24](=[O:23])[CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:32])[CH3:33])[CH:39]=[N:40]1
Reactant: Cn1ncc(NC(=O)[C@@H](O)CCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cn1ncc(NC(=O)C(=O)CCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
Dess-Martin periodinane (4.2 g) was dissolved in methylene chloride (75 ml), and tert-butyl ((3S)-3-hydroxy-4-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-4-oxobutyl)carbamate (5 g) was added to the solution. The whole mixture was stirred at room temperature for 30 minutes and quenched with 1N aqueous sodium hydroxide solution (70 ml) with stirring for 30 minutes. The whole mixture was extracted with ethyl acetate. The extract was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel (ethyl acetate:methylene chloride=1:4) to give tert-butyl (4-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3,4-dioxobutyl)carbamate (3.4 g).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7](O)=[O:8].ClC(OCC(C)C)=O.[F:19][C:20]1[CH:21]=[C:22]([NH:26][C:27]2[N:32]=[C:31]([NH:33][CH2:34][CH2:35][CH3:36])[C:30]([C:37]#[C:38][CH2:39][CH2:40][CH2:41][NH:42][C:43](=[O:48])[C@@H:44]([NH:46][CH3:47])[CH3:45])=[CH:29][N:28]=2)[CH:23]=[CH:24][CH:25]=1>CN(C)C=O.CN1CCOCC1.C(=O)([O-])O.[Na+]>[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7]([N:46]([C@@H:44]([CH3:45])[C:43]([NH:42][CH2:41][CH2:40][CH2:39][C:38]#[C:37][C:30]1[C:31]([NH:33][CH2:34][CH2:35][CH3:36])=[N:32][C:27]([NH:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=2)=[N:28][CH:29]=1)=[O:48])[CH3:47])=[O:8]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1C#CCCCNC(=O)[C@H](C)NC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1C#CCCCNC(=O)[C@H](C)N(C)C(=O)/C=C/CN(C)C
Reaction time: 0.08 h
Yield: 54.6 %

Procedure:
To a solution of 4-dimethylaminocrotonic acid hydrochloride (307 mg) in N,N-dimethylformamide (9 mL), N-methylmorpholine (682 μL) was added under ice cooling, and the mixture was stirred at the same temperature for 5 minutes. Then, isobutyl chloroformate (204 μL) was added to the mixture under ice cooling, and the mixture was stirred at the same temperature for 3 minutes. To the reaction mixture, (S)—N-(5-(2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)-2-(methylamino)propanamide (F6) dihydrochloride (300 mg) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour and 30 minutes. To the reaction mixture, saturated aqueous sodium hydrogencarbonate (10 drops) were added, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent, 100 to 90% ethyl acetate in methanol) to obtain (S,E)-4-(dimethylamino)-N-(1-((5-(2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-1-oxopropan-2-yl)-N-methyl-2-butenamide (7-1, 208 mg).
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7](=[O:11])[NH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].Br[CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17]>CN(C=O)C>[Br:1][C:2]1[C:6]2[C:7](=[O:11])[NH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:3]=1
Reactant: O=c1[nH]ccc2[nH]cc(Br)c12
Reactant: CCC(Br)CC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CC)n1cc(Br)c2c(=O)[nH]ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.8 %

Procedure:
To a solution of 3-bromo-1,5-dihydro-4H-pyrrolo[3,2-c]pyridin-4-one (1.00 g) in DMF (30 mL) was added sodium hydride (60% dispersion in mineral oil, 0.207 g), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 3-bromopentane (0.851 g), and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate to ethyl acetate) to give the title compound (90.5 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:16])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:17]([N:11]1[CH2:12][CH2:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([OH:16])[C:9]([CH3:14])([CH3:15])[CH2:10]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: CC1(C)CNCCC1(O)c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CN(Cc2ccccc2)CCC1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
A suspension of 4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol (540 mg, 2.252 mmol) and benzaldehyde (0.274 mL, 2.70 mmol) in methylene chloride (15 mL) was treated with sodium triacetoxyborohydride (716 mg, 3.38 mmol), and the mixture was stirred overnight at room temperature. The mixture was concentrated in-vacuo. The residue was taken up in ethyl acetate, washed 3× with 1 N NaOH, once with brine, dried over sodium sulfate, and concentrated in-vacuo to yield the title compound (696 mg, 2.110 mmol, 94% yield) as a colorless oil. MS (ESI+)=330.14, (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[S:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C([C:26]1[C:27]([N:32]=[CH:33][N:34]([CH3:36])C)=[N:28][CH:29]=[CH:30][CH:31]=1)#N.NC1C=C(OCC2C=CC=C(F)C=2)C=CC=1SC1C=CC(O)=CC=1>>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([S:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[C:2]([NH:1][C:36]2[C:26]3[CH:31]=[CH:30][CH:29]=[N:28][C:27]=3[N:32]=[CH:33][N:34]=2)[CH:7]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CN(C)C=Nc1ncccc1C#N
Reactant: Nc1cc(OCc2ccccc2)ccc1Sc1ccc(O)cc1
Agent: Nc1cc(OCc2cccc(F)c2)ccc1Sc1ccc(O)cc1
Product: Oc1ccc(Sc2ccc(OCc3ccccc3)cc2Nc2ncnc3ncccc23)cc1

Procedure:
The product from Example 27A and the product from Example 57A were reacted according to the procedure in Example 57E substituting the product of Example 27A for the product of Example 57D to provide the title compound which was isolated as the acetic acid salt (79 mg, 48%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 5.10 (s, 3H), 6.61-6.72 (m, 2H), 6.93 (d, J=9.56 Hz, 1H), 7.11 (d, J=8.46 Hz, 4H), 7.24 (s, 1H), 7.32-7.47 (m, 5H), 7.59-7.68 (m, 1H), 8.54 (s, 1H), 8.83 (d, J=9.56 Hz, 1H), 9.04 (s, 1H); ESI+ m/z 453 (M+H)+, ESI− m/z 451 (M−H)−.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Ca+2:13]>O>[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5].[Ca+2:13]
Reactant: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: O=C([O-])/C=C/C(=O)[O-]

Procedure:
A calcium fumarate sample was prepared by combining 580 g (5 moles) of fumaric acid (Pfizer, fine granular, F.C.C.) with 1650 g (92 moles) of water and 500 g (5 moles) of calcium carbonate (Baker Reagent grade) at ambient temperature. Dry calcium carbonate was added to the fumaric acid suspension in ten equal portions of 50g, one portion every 5 min. while stirring the mixture continuously using a Lightning mixer at high speed. The mole ratio of fumaric acid to CaCO3 to water was 1:1:18.4. After the final addition of calcium carbonate, the pH of the mixture was 4.95. It was found that the addition of CaCO3 to the fumaric acid proceeded through an endothermic reaction, the final temperature of the reaction vessel was 17.3° C. (63° F.) while the starting solution temperature was 19.8° C. (68° F.).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15]C)[CH:10]=3)[O:8][C:4]=2[CH:3]=1.B(Br)(Br)Br.O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=3)[O:8][C:4]=2[CH:3]=1
Reactant: COc1cccc(-c2nc3ccc(Br)cc3o2)c1
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: Oc1cccc(-c2nc3ccc(Br)cc3o2)c1
Temperature: 65 °C
Reaction time: 9 h
Yield: 88.7 %

Procedure:
To a solution of 6-bromo-2-(3-methoxyphenyl)benzoxazole (Compound of Example 242) (19.45 g) in chloroform (800 ml) was added dropwise boron tribromide (100.05 g) at 0° C., and the mixture was stirred at room temperature for 4 hours and 65° C. for 9 hours. The reaction mixture was poured into water, and the mixture was stirred at room temperature for 30 minutes and extracted with chloroform-tetrahydrofuran (4:1, v/v). The organic layer was washed with water and dried over MgSO4, and the solvent was distilled off under reduced pressure. The resulting crystals were collected by filtration to obtain 3-(6-bromobenzoxazol-2-yl)phenol (16.46 g, 89%).