Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].C[O:5][C:6](=O)[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][C@H:13]1[C@@H:17]([OH:18])[CH2:16][C@@H:15]([OH:19])[C@@H:14]1[CH:20]=[CH:21][C@H:22]([OH:31])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH3:2][CH2:1][NH:3][C:6]([CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][C@@H:13]1[C@@H:14](/[CH:20]=[CH:21]/[C@@H:22]([OH:31])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:15]([OH:19])[CH2:16][C@@H:17]1[OH:18])=[O:5]
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](C=C[C@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Reactant: CCN
Solvent: O
Product: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Temperature: 23 °C
Reaction time: 48 h
Yield: 99.9 %

Procedure:
56 g of ethylamine (MW=45.08; 47.9 equivalents) in 24 mL of water were added to 8.08 g of crude (Z)-7 [(1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenyl-pent-1-enyl)-cyclo-pentyl]hept-5-enoic acid methylester (MW=402.54; 1 equivalents) and the resulting solution was stirred for 48 h at 23° C. The excess of ethylamine was removed by distillation in vacuo (25°, 100 mbar) after complete conversion. To the residue were added 400 mL of methylenechloride and 100 mL of water and the pH was adjusted to 1.5 by addition of 1M aqueous hydrochloric acid. After separation of the layers the organic layers were washed with 100 mL of saturated aqueous sodium bicarbonate, 100 mL of water, and 100 mL of brine. The solution was filtered and concentrated in vacuo yielding 8.33 g of oily bimatoprost crude. To the residue were added 25 mL of acetonitrile. After adding seeds the mixture was stirred for 30 minutes at ambient temperature, cooled to 0° C. and stirred for two hours at this temperature.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]2[N:21]([CH2:22][C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)[C:20]3[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=3[N:18]=2)[CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>O.CN(C)C(=O)C>[O:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[CH2:22][N:21]1[C:20]2[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=2[N:18]=[C:17]1[NH:16][CH:13]1[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][NH:7][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH2:11][CH2:12]1
Reactant: Brc1nccs1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccco2)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: c1coc(Cn2c(NC3CCN(CCNc4nccs4)CC3)nc3ccccc32)c1
Temperature: 140 °C
Reaction time: 3 h

Procedure:
A mixture of 2.7 parts of 2-bromothiazole, 5.1 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-(2-furanylmethyl)-1H-benzimidazol-2-amine, 5 parts of sodium carbonate, 0.1 parts of sodium iodide and 9 parts of N,N-dimethylacetamide was stirred for 3 hours at about 140° C. Water was added and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 3 parts of 1-(2-furanylmethyl)-N-[1-[2-(2-thiazolylamino)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 153.1° C. (compound 48).
Reaction SMILES: [CH:1]([C:4]1[NH:8][N:7]=[C:6]([CH2:9][C:10]([O:12]C)=O)[N:5]=1)([CH3:3])[CH3:2].[CH2:14]([C@@H:21]1[NH:26][CH2:25][CH2:24][N:23]([C:27]2[CH:35]=[C:34]3[C:30]([C:31]([CH2:40][CH3:41])=[N:32][N:33]3[CH:36]3[CH2:39][CH2:38][CH2:37]3)=[CH:29][CH:28]=2)[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([C@H:21]1[CH2:22][N:23]([C:27]2[CH:35]=[C:34]3[C:30]([C:31]([CH2:40][CH3:41])=[N:32][N:33]3[CH:36]3[CH2:37][CH2:38][CH2:39]3)=[CH:29][CH:28]=2)[CH2:24][CH2:25][N:26]1[C:10](=[O:12])[CH2:9][C:6]1[NH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[N:8][N:7]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)Cc1n[nH]c(C(C)C)n1
Reactant: CCc1nn(C2CCC2)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc12
Product: CCc1nn(C2CCC2)c2cc(N3CCN(C(=O)Cc4nnc(C(C)C)[nH]4)[C@@H](Cc4ccccc4)C3)ccc12

Procedure:
Prepared by the method outlined for Example 275 using methyl (5-isopropyl-1H-1,2,4-triazol-3-yl)acetate and 6-((S)-3-benzyl-piperazin-1-yl)-1-cyclobutyl-3-ethyl-1H-indazole as starting materials. Product as a light brown solid (35%). LC/MS (Method B) 3.72 min, [M+1]+ 526.
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11].OO.[CH3:29][OH:30]>O.OS(O)(=O)=O>[CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[C:14](=[C:15]([CH2:29][OH:30])[C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13]3)=[O:11]
Reactant: CO
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CO
Temperature: 0 °C
Yield: 99 %

Procedure:
Camptothecin (20.0 g) was dissolved in mixture of methanol (750 mL), water (500 mL), conc. H2SO4 (500 mL) and finely ground FeSO4 (16.0 g) and hydrogen peroxide (100 mL 30% solution) was added dropwise over the course of 2 h and the reaction mixture was allowed to stir for another hour. The reaction mixture was then filtered through a sintered glass funnel to remove all undissolved material. The resultant filtrate was then cooled to 0° C. and NaOH (375 g) in 1 L water was added slowly with vigorous stirring. The yellow-brown solid was then filtered, washed with water and pumped to dryness. The resultant crude product was then placed in a 1 L erlenmyer flask, DMF (300 mL) added and warmed to 110° C. Once the solid is dispersed into small particles, acetonitrile (500 mL) was added and the mixture heated until boiling. The mixture was then allowed to cool to room temperature then 0° C., filtered and the solid washed with chloroform to provide 7-hydroxymethylcamptothecin (21.50 g, 99%) as a pale yellow solid.
Reaction SMILES: O1CCOCC1.OS(O)(=O)=O.Cl.[NH2:13][CH2:14][CH2:15][CH2:16][CH:17]([CH2:21][CH2:22][CH3:23])[C:18]([OH:20])=[O:19].[CH3:24][C:25](=[CH2:27])[CH3:26]>C(=O)=O.O>[CH3:24][C:25]([O:19][C:18](=[O:20])[CH:17]([CH2:21][CH2:22][CH3:23])[CH2:16][CH2:15][CH2:14][NH2:13])([CH3:27])[CH3:26]
Reactant: CCCC(CCCN)C(=O)O
Reactant: C=C(C)C
Agent: Cl
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: CCCC(CCCN)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 49 %

Procedure:
To a cooled solution of 7 mL of dioxane was added 0.7 mL of conc. H2SO4 dropwise. The solution turned purple in color. To this solution, 700 mg (3.5 mmol) of 5-amino-2-propylpentanoic acid monohydrochloride (7) was slowly added and the resulting solution was transferred into a pressure bottle. To this solution was added 12 mL of isobutylene and the resulting solution was slowly stirred magnetically under pressure at room temperature for 20 hours. The reaction vessel was cooled in dry ice, pressure was released, and the reaction vessel warmed up to room temperature to vaporize the excess isobutylene. The reaction mixture was poured into 100 mL of cold water. The aqueous part was extracted with 2×150 mL of ether, basified with 4N sodium hydroxide to pH 10, and extracted with 3×100 mL of ethyl acetate to yield 380 mg (1.76 mmol, 49%) of rac-5-amino-2-propylpentanoic acid 1,1-dimethylethyl ester (8) as an oil. NMR, IR and MS data confirmed the compound identity.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH3:36][N:37]([CH3:50])[C:38]([C:40]1([C:43]2[CH:48]=[CH:47][C:46](Br)=[CH:45][N:44]=2)[CH2:42][CH2:41]1)=[O:39]>>[CH3:36][N:37]([CH3:50])[C:38]([C:40]1([C:43]2[CH:48]=[CH:47][C:46]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:45][N:44]=2)[CH2:42][CH2:41]1)=[O:39]
Reactant: CN(C)C(=O)C1(c2ccc(Br)cn2)CC1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(C3(C(=O)N(C)C)CC3)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 75 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 1-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid dimethylamide following a procedure analogous to that described in Example 1. Yield: 75% of theory; LC (method 1): tR=1.92 min; Mass spectrum (ESI+): m/z=542 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2].Br[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[Li+].[Br-].[H-].[Na+]>>[CH2:1]([C:3]1[N:4]([CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2]
Reactant: CCc1nc(C)cc(=O)[nH]1
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Product: CCc1nc(C)cc(=O)n1CCOc1ccc([N+](=O)[O-])cc1
Yield: 30.9 %

Procedure:
The title compound (5.2 g, 25%) was prepared from 2-ethyl-4-methyl-1,6-dihydro-6-pyrimidone (7.65 g, 55.43 mmol), 4-[2-bromoethoxy]nitrobenzene (15.0 g, 60.97 mmol), LiBr (11.09 g, 127.49 mmol) and 60% NaH (2.76 g, 72.06 mmol) as base by a similar procedure to that described in preparation 1.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:21]=1[NH2:22]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:22][C:21]1[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:20]=1[O:19][CH3:18])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(C)cccc2c1Cl
Reactant: COc1ccc(C)cc1N
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(C)cccc2c1Nc1cc(C)ccc1OC
Yield: 53.1 %

Procedure:
3-Butyryl-4-chloro-8-methylquinoline (1.77 g, 7.14 mmol) and 2-methoxy-5-methylaniline (1.47 g, 10.7 mmol) in dioxan (10 ml) were heated at reflux for 30 minutes, then evaporated and converted to free base. Recrystallisation from methanol and then from ethyl acetate/petroleum ether gave 3-butyryl-4-(2-methoxy-5-methylphenylamino)-8-methylquinoline (1.32 g), m.p. 136°-138°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=2[O:15][CH3:16])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[Cl:21][S:22](O)(=[O:24])=[O:23]>C(Cl)Cl>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([N:4]2[CH2:5][CH2:6][O:1][C:2]3[CH:20]=[C:19]([S:22]([Cl:21])(=[O:24])=[O:23])[CH:18]=[CH:17][C:3]2=3)=[C:8]([O:15][CH3:16])[CH:9]=1)#[N:12]
Reactant: COc1cc(C#N)ccc1N1CCOc2ccccc21
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1cc(C#N)ccc1N1CCOc2cc(S(=O)(=O)Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.4 %

Procedure:
To a solution of 4-(2H-benzo[b][1,4]oxazin-4(3H)-yl)-3-methoxybenzonitrile (790 mg, 2.96 mmol) in DCM (10 mL) was added chlorosulfonic acid (0.79 mL, 11.8 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h. After completion, reaction mixture was poured into ice water (15 mL), quenched with solid sodium bicarbonate (pH˜9-10) and the aqueous layer was extracted with ethyl acetate (2×20 mL). The organic layer was dried over sodium sulfate and concentrated to get 4-(4-cyano-2-methoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride as a sticky yellow solid (220 mg, 20.3%) which was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:13][CH:14]=2)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: c1ccc2[nH]ccc2c1
Product: FC(F)(F)c1cnc(Cl)nc1-c1c[nH]c2ccccc12

Procedure:
Starting materials: 2,4-dichloro-5-(trifluoromethyl)pyrimidine and 1H-indole. m/z 298.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[CH:24][CH:23]=3)[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.ClC1C=CC=C(C(OO)=[O:43])C=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:33]=[CH:32][N+:31]([O-:43])=[CH:30][CH:29]=4)=[CH:26][CH:27]=3)=[O:34])[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(c1ccc(-c2ccncc2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccc(-c2cc[n+]([O-])cc2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: -20 °C
Reaction time: 21 h

Procedure:
In dichloromethane (10 ml), 1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine (300 mg) obtained in Example 1 was dissolved, followed by the addition of 3-chloroperbenzoic acid (382 g) at −20° C. The resulting mixture was stirred at −20° C. for 21 hours. An aqueous solution of sodium sulfite was added to decompose an excess peroxide. Dichloromethane and a saturated aqueous solution of sodium bicarbonate were added to separate an organic layer. After drying the organic layer over anhydrous magnesium sulfate, the residue obtained by distilling off the solvent was purified by chromatography on a silica gel column (2-5% methanol-dichloromethane). After the solvent was distilled off, ether was added to the residue to solidify it, followed by collection through filtration, whereby the title compound (200 mg, 63%) was obtained as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][OH:11])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][N:16]=1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][O:11][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][N:16]=2)[CH2:4][CH2:3]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CN1CCN(CCCO)CC1
Agent: [H-]
Agent: [Na+]
Product: CN1CCN(CCCOc2ccc(C#N)cn2)CC1
Yield: 47.2 %

Procedure:
This compound was prepared by the method described in General Procedure 5 in Example 27 using 3-(4-methyl-piperazin-1-yl)-propan-1-ol (1.0 g, 6.32 mmol), 60% sodium hydride (379 mg, 9.48 mmol), and 6-chloronicotinonitrile (876 mg, 6.32 mmol). The reaction mixture was partitioned between satd. aq. NaHCO3 (30 mL) and CHCl3 (60 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. Purification by Method 1 afforded 776 mg (47%) of a beige solid. MS (ESI): mass calcd for C14H20N4O, 260.16; m/z found, 261.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.47 (dd, J=2.3, 0.8, 1H), 7.77 (dd, J=8.6, 2.3, 1H), 6.80 (dd, J=8.6, 0.8, 1H), 4.41 (t, J=6.6, 2H), 2.76-2.35 (m, 10H), 2.29 (s, 3H), 2.01-1.95 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1.[CH:15]1([CH2:18][NH:19][C:20](=[O:37])[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[C:23](B3OC(C)(C)C(C)(C)O3)[CH:22]=2)[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][NH:19][C:20]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[C:25]([C:2]3[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]4[CH2:12][CH2:11]4)=[O:7])=[CH:4][N:3]=3)[CH:26]=2)=[O:37])[CH2:17][CH2:16]1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nc1
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)NCC2CC2)cc1-c1ccc(C(=O)NCC2CC2)cn1

Procedure:
6-[5-(Cyclopropylmethyl)carbamoyl-2-methyl-phenyl]-N-cyclopropylmethyl-nicotinamide was prepared from 6-chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) and N-(cyclopropylmethyl)-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 10) using General Method B. LCMS: retention time 2.87 min, MH+ 364. NMR: δH [2H6]-DMSO 9.10,(1H, s), 8.83,(1H, t), 8.60,(1H, t), 8.30,(1H, dd), 7.92,(1H, s), 7.84,(1H, d), 7.71, (1H, d), 7.41,(1H, d), 3.19,(2H, t), 3.13,(2H, t), 2.37,(3H, s), 1.03,(2H, m), 0.44, (4H, m), 0.23,(4H, m).
Reaction SMILES: S(=O)(=O)(O)O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[CH:21]=[CH:22][N+:23]([O-])=O.[OH-].[Na+]>C1COCC1.O>[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[CH2:21][CH2:22][NH2:23]
Reactant: COc1ccc(F)c(C=C[N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)c(CCN)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.5 %

Procedure:
Cautiously add sulfuric acid (14.7 mL, 265 mmol) dropwise at 0° C. to lithium aluminum hydride (1M solution in THF, 565 mL) with efficient stirring. Warm the mixture to ambient temperature for 20 min and then cool back to 0° C. Add a solution of 1-fluoro-4-methoxy-2-(2-nitro-vinyl)-benzene (18.7 g, 95 mmol) in THF (150 mL) by cannula and stir 2.5 h at ambient temperature. Cool the mixture to 0° C., cautiously add water (4.6 mL) followed by 2N aqueous NaOH (4.6 mL) and water (6.5 mL). Remove the precipitate by filtration and evaporate the filtrate to give the desired intermediate (16 g, 100%). MS (ES+) m/z: 170 (+H)+.
Reaction SMILES: C(O)[C@@H](O)C(O)=[O:4].NC1C=CC(C=C)=CC=1.[CH:17]1([N:23]=[C:24]=[N:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.NC=CC1C=CC=CC=1>C(#N)C>[CH:26]1([NH:25][C:24]([NH:23][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:4])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)[C@H](O)CO
Agent: C=Cc1ccc(N)cc1
Agent: NC=Cc1ccccc1
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
Alternatively D-glyceric acid -(p-vinylanilide) can be prepared directly from D-glyceric acid and p-aminostyrene on treatment with N,N'-dicyclohexylcarbodiimide as condensing agent: To a solution (cooled to 0° C) of 5.3 g (0.05 mole) D-glyceric acid in 150 ml of acetonitrile, there was added 8.9 g (0.075 mole) β aminostyrene and 10.3 g (0.05 mole) N.N'-dicyclohexylcarbodiimide. A precipitate of N.N'-dicyclohexylurea is formed immediately, but the reaction was allowed to proceed for 15 hours at room temperature. After filtration and removal of the acetonitrile by distillation under reduced pressure, the residue was taken up in ethyl acetate and extracted with HCl, bicarbonate and water. After drying and removal of the solvent the residue was crystallized from chloroform, yielding 7.5 g (73%), m.p. 135 - 136° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31].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+]>O1CCOCC1.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]>[CH3:18][C:14]1[CH:13]=[C:12]([C:10](=[O:11])[CH2:9][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([N:26]3[CH2:30][CH2:29][CH2:28][C:27]3=[O:31])=[CH:3][CH:4]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH:17]=[CH:16][N:15]=1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(Br)cc2)c2ccccc2C)ccn1
Reactant: O=C1CCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(C(=O)C[C@H](c2ccc(N3CCCC3=O)cc2)c2ccccc2C)ccn1

Procedure:
In analogy to example 39, from (R)-3-(4-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (example 142, step 2) and pyrrolidin-2-one in the presence of tris(dibenzylideneacetone)dipalladium(0), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and cesium carbonate in 1,4-dioxane was prepared the title compound as a white semisolid, MS (ESI+): m/z=399.1 ([M+H]+).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]([NH:12][C@@H:13]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[N:48]=[CH:47][C:46]([C:49]4[CH:54]=[CH:53][C:52]([O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])=[CH:51][CH:50]=4)=[CH:45][N:44]=3)=[CH:39][CH:38]=2)[C:14]([NH:16][C@H:17]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:18][C:19]([O:21]CC2C=CC=CC=2)=[O:20])=[O:15])=[O:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Pd]>[C:32]([O:31][C:29](=[O:30])[C@@H:17]([NH:16][C:14](=[O:15])[C@@H:13]([NH:12][C:10]([C:8]1[S:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)=[O:11])[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[N:48]=[CH:47][C:46]([C:49]3[CH:54]=[CH:53][C:52]([O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])=[CH:51][CH:50]=3)=[CH:45][N:44]=2)=[CH:41][CH:42]=1)[CH2:18][C:19]([OH:21])=[O:20])([CH3:33])([CH3:34])[CH3:35]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)s4)C(=O)N[C@@H](CC(=O)OCc4ccccc4)C(=O)OC(C)(C)C)cc3)nc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)s4)C(=O)N[C@@H](CC(=O)O)C(=O)OC(C)(C)C)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
Prepared using General Procedures 18: To 4-benzyl 1-(tert-butyl) ((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-L-aspartate INT-47 (345 mg, 0.4 mmol) in THF (5 mL) was added 10% Pd/C (60 mg). The reaction vessel was flushed with hydrogen gas and the reaction was stirred vigorously under hydrogen overnight at room temperature. The reaction mixture was filtered to remove the catalyst, the solvent was removed, and the crude product was purified by chromatography 0-100% EA in hexane to afford 228 mg (66%) of (S)-4-(tert-butoxy)-3-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)-4-oxobutanoic acid INT-44 as a white solid. LCMS-ESI (m/z) calculated for C43H54N4O7S: 770.4. found 771.3 [M+H]+, tR=4.21 min (Method 16).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[C:10]([NH:16][C:17](=[O:19])[CH3:18])[CH:9]=2)=[C:4]([F:20])[C:3]=1[O:21][CH3:22].[BH4-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14][OH:15])=[CH:12][N:11]=[C:10]([NH:16][C:17](=[O:19])[CH3:18])[CH:9]=2)=[C:4]([F:20])[C:3]=1[O:21][CH3:22]
Reactant: COc1c(Cl)ccc(-c2cc(NC(C)=O)ncc2C=O)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(Cl)ccc(-c2cc(NC(C)=O)ncc2CO)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a stirred solution of N-(4-(4-chloro-2-fluoro-3-methoxyphenyl)-5-formylpyridin-2-yl)acetamide (1.7 g, 2.370 mmol) in a mixture of THF (15 mL) and methanol (5 mL) was added sodium borohydride (0.090 g, 2.370 mmol) in two portions and the reaction mixture was stirred at room temperature for 30 min. The volatiles were removed, water (15 mL) was added and the solution extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulphate, and concentrated under reduced pressure to afford N-(4-(4-chloro-2-fluoro-3-methoxyphenyl)-5-(hydroxymethyl)pyridin-2-yl)acetamide (1.6 g, 1.88 mmol, 38% yield) as a brown solid. The compound was carried into the next step without further purification. LCMS (ESI) m/e 324.9 [(M+H)+, calcd for C15H15ClFN2O3 325.1]; LC/MS retention time (Method F): tR=0.97 min.