Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1)=[O:4].[N-:16]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1COCC1>[NH2:16][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1ccc(F)c(C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCC(=O)c1ccc(F)c(C(F)(F)F)c1
Reaction time: 1 h
Yield: 150.4 %

Procedure:
Cool a solution of 2-bromo-1-(4-fluoro-3-(trifluoromethyl)phenyl)ethanone (93% pure by HPLC, 1000 g; 3.51 mol) and THF (5 L) to <5° C. in an ice bath. Add a solution of sodium azide (239 g; 3.68 mol, 1.05 eq) in water (800 mL) drop wise over one hour at <5° C. After stirring at <5° C. for one hour, separate and discard the aqueous layer. While still cold, add the organic layer slowly over 3 hours to a solution of triphenylphosphine (920.2 g, 3.51 mol, 1.0 eq), p-toluenesulfonic acid monohydrate (1335 g, 7.02 mol, 2.0 eq), and THF (5 L). Maintain the temperature at <15° C. throughout this addition and solids precipitate during the addition. Stir the reaction mixture at <20° C. for 2 hours and then filter the solid, wash with THF (3×2 L), and dry at 50° C. under vacuum to give 1167.4 g (85%, 92% corrected for starting material purity) of 2-amino-1-(4-fluoro-3-(trifluoromethyl)phenyl)ethanone, 4-methylbenzenesulfonate as a white crystalline solid. HRMS (ESI) m/z (M+H) 222.0531 calculated for C9H8F4NO 222.0537
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:7]([O:35][CH3:36])=[CH:8][C:9]2[CH2:10][CH2:11][N:12]3[C:18]4[C:19](=[O:29])[N:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=4[C:16]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)=[C:13]3[C:14]=2[CH:15]=1)=[O:4].[CH2:37]([N:39](CC)[CH2:40]C)C.CNC>CN(C=O)C.C1COCC1>[CH3:37][N:39]([CH3:40])[CH2:2][C:3]([NH:5][C:6]1[C:7]([O:35][CH3:36])=[CH:8][C:9]2[CH2:10][CH2:11][N:12]3[C:18]4[C:19](=[O:29])[N:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=4[C:16]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)=[C:13]3[C:14]=2[CH:15]=1)=[O:4]
Reactant: COc1cc2c(cc1NC(=O)CCl)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reactant: CCN(CC)CC
Agent: CNC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2c(cc1NC(=O)CN(C)C)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Temperature: 60 °C

Procedure:
A suspension of 392 mg of 22a in 3 ml of DMF was treated with 0.5 ml of triethylamine and 2 ml of a 2M solution of dimethylamine in THF. The reaction mixture was sealed and heated at an oil bath at 60° C. for 40 min. The clear solution was poured onto water and extracted with ethyl acetate. The extract was washed, dried and concentrated and the residue was purified by chromatography over silicagel, using a gradient of CH2Cl2-methanol. The material thus isolated was triturated with diethylether, to provide 438 mg of crystalline material.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1.[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][OH:30])=[CH:27][CH:26]=1>CCCCCC.C(OCC)(=O)C>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][O:30][C:3]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=3[Cl:16])[C:6]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[CH:5][N:4]=2)=[CH:27][CH:26]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: CSc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Clc1ccc(COc2ncc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)n2)cc1

Procedure:
2-Methylthio-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (from Reference Example 3) was reacted with 4-chlorobenzyl alcohol according to the procedures described in Example 1 to afford 2-(4-chlorobenzyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine as the higher Rf product (95/5 hexane/ethyl acetate TLC). HPLC/MS: m/e=477 (M+1); Rt=4.91 min; 1H-NMR 500 MHz (CDCl3): δ 5.50 (s, 2H), 7.02 (d, J=9 Hz, 2H), 7.22 (d, J=9 Hz, 1H), 7.22-7.30 (m, 4H), 7.40 (d, J=9 Hz, 2H), 7.50 (d, J=9 Hz, 2H), 8.62 (s, 1H). 2-(4-Chlorobenzyloxy)-4-(2-chloro-4-thiomethyl phenyl)-5-(4-chlorophenyl)pyrimidine was obtained as the lower Rf by-product of the thiomethyl anion displacement of the 4-chloro substituent on the 4-(2,4-dichlorophenyl) ring. HPLC/MS: m/e=489 (M+1); Rt=4.81 min; 1H-NMR 500 MHz (CDCl3): δ 2.52 (s, 3H), 5.50 (s, 2H), 7.03 (m, 2H), 7.10-7.20 (m, 2H), 7.24-7.30 (m, 3H), 7.38 (d, J=9 Hz, 2H), 7.50 (d, J=9 Hz, 2H), 8.60 (s,1H).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[Cl:15][CH2:16][CH2:17][C@@H:18]1[CH2:24][N:23]([CH3:25])[C:22](=O)[C:21]2[CH:27]=[CH:28][CH:29]=[N:30][C:20]=2[O:19]1.C1(C)C=CC=CC=1>C(#N)C>[Cl:15][CH2:16][CH2:17][C@@H:18]1[CH2:24][N:23]([CH3:25])[C:22](=[S:2])[C:21]2[CH:27]=[CH:28][CH:29]=[N:30][C:20]=2[O:19]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN1C[C@@H](CCCl)Oc2ncccc2C1=O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CN1C[C@@H](CCCl)Oc2ncccc2C1=S

Procedure:
To a suspension of 9 g (0.02 mole) of phosphorus pentasulfide in 75 ml of acetonitrile was added 18 g (0.075 mole) of (R)-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido [3,2-f]-1,4-oxazepine-5(4H)-one and the mixture was stirred at reflux for 2.5 hr, cooled and treated with 60 ml of toluene. The mixture was filtered and the solid washed twice with 30 ml of 25% acetonitrile-75% toluene. The volume was made to about 400 ml with 50% toluene-50% acetonitrile and extracted with saturated aqueous potassium bicarbonate. The organic layer was separated, treated with magnesium sulfate and charcoal, and filtered. The filtrate was concentrated and the residue was recrystallized from isopropyl alcohol-chloroform. Yield of title compound was 13 g (68%), m.p. 168°-170° C.; [α]D25 =(-)47.4 (chloroform).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]2[NH:6][C:7]([C:9]3[CH:10]=[N:11][C:12]([NH:15][CH2:16][CH2:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[N:13][CH:14]=3)=[N:8][C:4]=2[C:3]=1[CH3:28].CO.[CH3:31]C1C(C=O)=CN=C(NCCCC2CCN(C)CC2)N=1.FC1C(C)=C(N)C(N)=CC=1>C1(C)C=CC=CC=1.O=[Mn]=O>[F:1][C:2]1[CH:27]=[CH:26][C:5]2[NH:6][C:7]([C:9]3[C:14]([CH3:31])=[N:13][C:12]([NH:15][CH2:16][CH2:17][CH2:18][CH:19]4[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]4)=[N:11][CH:10]=3)=[N:8][C:4]=2[C:3]=1[CH3:28]
Reactant: Cc1nc(NCCCC2CCN(C)CC2)ncc1C=O
Reactant: Cc1c(F)ccc2[nH]c(-c3cnc(NCCCC4CCN(C)CC4)nc3)nc12
Agent: O=[Mn]=O
Agent: Cc1c(F)ccc(N)c1N
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1nc(NCCCC2CCN(C)CC2)ncc1-c1nc2c(C)c(F)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
[5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine. To a mixture of 4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidin-5-yl}-methanol (0.14 g, 0.49 mmol) in toluene (3 mL) was added MnO2 (0.22 g, 2.48 mmol). After 30 min at 70° C., the mixture was filtered through diatomaceous earth. The filtrate was concentrated and immediately dissolved in DMF. A portion of this solution (corresponding to 0.05 g, 0.17 mmol of 4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbaldehyde) was then treated with 4-fluoro-3-methyl-benzene-1,2-diamine (1.1 equiv.) and Na2H2S2O5 (1.25 equiv.) at 90° C. for 12 h. The reaction mixture was purified by FCC to afford the title compound. MS: mass calcd. for C22H29FN6, 396.24; m/z found, 397.2 [M+H]+. 1H NMR (CD3OD): 8.62 (s, 1H), 7.55 (dd, J=8.0, 3.9 Hz, 1H), 7.17 (dd, J=10.3, 8.8 Hz, 1H), 3.60 (t, J=6.9 Hz, 2H), 3.10-2.99 (m, 2H), 2.71 (s, 3H), 2.66 (d, J=1.4 Hz, 3H), 2.44 (s, 3H), 2.26-2.17 (m, 2H), 1.98-1.88 (m, 2H), 1.87-1.77 (m, 2H), 1.55-1.36 (m, 5H).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH3:9][N:10]1C(=O)O[C:13](=[O:14])[C:12]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:11]12.CS(C)=O>O>[CH3:9][N:10]1[C:11]2[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=2[C:13](=[O:14])[N:1]2[CH2:8][CH2:7][CH2:6][CH:2]2[C:3]1=[O:5]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Solvent: CS(C)=O
Solvent: O
Product: CN1C(=O)C2CCCN2C(=O)c2ccccc21

Procedure:
A mixture of 12.3 g. of L-proline, 17.7 g. of N-methyl isatoic anhydride and 100 ml. of dimethyl sulfoxide is heated on a steam bath for 6 hours, cooled and then diluted with 250 ml. of water. The reaction mixture is extracted three times with benzene. The combined benzene layers are washed twice with water and concentrated to remove the solvent. The residue is recrystallized from ethyl acetate yielding the pure dextrorotatory isomer.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=1.[NH:16]1[CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C(#N)C>[F:15][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=1)[O:4][CH2:3][CH2:2][N:16]1[CH2:19][CH2:18][CH2:17]1
Reactant: C1CNC1
Reactant: CS(=O)(=O)c1cc(F)cc(OCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CS(=O)(=O)c1cc(F)cc(OCCN2CCC2)c1
Temperature: 120 °C

Procedure:
1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.5 g, 1.6 mmol), azetidine (0.23 ml, 3.2 mmol) and potassium carbonate (0.58 g, 4.2 mmol) was dissolved in acetonitrile (10 ml). The mixture was heated in a sealed container at 120° C. for 2 h. The reaction mixture was cooled to room temperature, CH2Cl2 (100 ml) was added, solids was filtered off and the volatiles were evaporated. The amine was converted to the fumaric acid salt and re-crystallized from methanol/diethyl ether. MS m/z (relative intensity, 70 eV) 273 (M+, 1), 94 (5), 82 (3), 71 (5), 70 (bp).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[N:9][C:8]([Br:15])=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:6]=1)=[O:4].[OH-].[Li+]>O1CCCC1.O>[Br:15][C:8]1[N:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1
Reactant: COC(=O)c1nc(-c2ccc(Cl)cc2)c(Br)nc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc(-c2ccc(Cl)cc2)c(Br)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.6 %

Procedure:
To a solution of 7.7 g 5-bromo-6-(4-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid methyl ester in 50 ml tetrahydrofuran was added at 0° C. 20 ml of a 1M solution of lithium hydroxide in water. The cooling bath was removed and the mixture was stirred at ambient temperature for 20 min. The orange reaction mixture was partitioned between heptane and water. The phases were separated the aqueous phase was mixed with ethyl acetate and 10% aqueous citric acid whereby the yellow orange color almost disappeared. The phases were separated and the organic phase was washed with brine dried over sodium sulfate, evaporated and dried under high vacuum to yield 5.54 g of the title compound as yellow solid. This material was recrystallized from ethyl acetate/heptane before use. MS (M−H) at 381.1 and 379.1.
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[CH2:3][CH2:4][CH:5]([NH:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[OH:7].[H-].[Na+].S(C1C=CC(C)=CC=1)(O[CH3:31])(=O)=O.[ClH:39]>C1(C)C=CC=CC=1.CC(C)=O>[ClH:39].[ClH:39].[CH3:31][O:7][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:5]([NH:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)[CH2:4][CH2:3][CH:2]([CH3:24])[CH3:1]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)CCC(NCCCN1CCCCC1)C(O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: COC(c1ccccc1)C(CCC(C)C)NCCCN1CCCCC1
Yield: 21 %

Procedure:
To a solution of (1RS,2SR)-5-methyl-1-phenyl-2-(3-piperidinopropylamino)hexan-1-ol (1.66 g, 5 mmol) in toluene (25 ml) was added sodium hydride (0.14 g, 6 mmol) and the mixture was refluxed for 1 hour. To the reaction mixture was added methyl tosylate (1.12 g, 6 mmol) and the resulting mixture was refluxed for further 1 hour. After being cooled, the mixture was washed twice with water and once with brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by neutral alumina column chromatography (alumina: 40 g, eluent: chloroform) to give 1.1 g of oily matter. To a solution of the matter in acetone (20 ml) was added concentrated hydrochloric acid (0.1 ml) and the mixture was concentrated under reduced pressure. The residue was recrystallized from acetone (10 ml)-ethanol (0.2 ml) to obtain 0.45 g of the title compound as white crystals (yield: 21%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([CH3:15])=[CH:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].ClC(OCC)=O.[CH3:22][CH:23]([NH2:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>ClCCl.C(N(CC)CC)C>[CH3:22][CH:23]([NH:33][C:12](=[O:14])[CH:11]=[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:15])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCC(C)N
Reactant: CC(=CC(=O)O)c1cccc([N+](=O)[O-])c1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(C)NC(=O)C=C(C)c1cccc([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
To a stirred slurry of 5.2 g. of the 3-(3-nitrophenyl)-2-butenoic acid from Preparation 12 having a melting point of 208°-210° C., in 100 ml. of dichloromethane, was added 2.8 g. of triethylamine in 10 ml. of dichloromethane. This was followed by the addition of a solution of 3.0 g. of ethyl chloroformate in 20 ml. of dichloromethane, during 20 minutes. Stirring was continued for 30 minutes, and then a solution of 1-methyldecylamine in 20 ml. of dichloromethane was added dropwise during 25 minutes. Stirring was continued overnight, and the reaction mixture was washed successively with 1 N potassium carbonate, water and saturated sodium chloride. The resulting solution was dried using sodium sulfate, and then it was evaporated in vacuo leaving an oil which solidified on trituration under petroleum ether. This afforded 4.9 g. of the title compound, m.p. 72.5°-74° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:34])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=4)[CH2:22]3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:35]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[CH2:36][CH2:37][CH3:38]>>[CH2:35]([N:39]1[CH2:44][CH2:43][N:42]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:34])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([N:21]4[CH2:29][C:28]5[C:23](=[CH:24][CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=5)[CH2:22]4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:41][CH2:40]1)[CH2:36][CH2:37][CH3:38]
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)N3Cc4ccc(S(N)(=O)=O)cc4C3)cc2)c1
Reactant: CCCCN1CCNCC1
Product: CCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)N4Cc5ccc(S(N)(=O)=O)cc5C4)cc3)c2)CC1
Yield: 12 %

Procedure:
The title compound was prepared from 2-(4-(3-(3-cyanophenyl)ureido)phenylsulfonyl)isoindoline-5-sulfonamide following procedure C and using 3 equivalents of n-butylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH:21]=O)=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[NH2:25][CH2:26][CH2:27][CH2:28][P:29](=[O:32])([OH:31])[OH:30].[BH3-]C#N.[Na+]>CO>[C:15]1([C:14]2[N:13]=[C:12]([CH2:21][NH:25][CH2:26][CH2:27][CH2:28][P:29](=[O:30])([OH:32])[OH:31])[CH:11]=[CH:10][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:24])([F:23])[F:1])=[CH:4][CH:5]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCCP(=O)(O)O
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=P(O)(O)CCCNCc1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure M, 5-(4-trifluoromethylphenyl)-6-phenyl-pyridine-2-carbaldehyde (Compound 57, 58 mg, 0.18 mmol), (3-amino-propyl)-phosphonic acid (25 mg, 0.18 mmol), Bu4NOH (0.18 ml, 0.18 mmol, 1 M in MeOH) and NaCNBH3 (11 mg, 0.18 mmol) in MeOH (3 ml) were reacted to produce the title compound as a white solid.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C@@H:13]([OH:28])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[N+](=[CH2:32])=[N-].CC1C=CC(S(N(N=O)C)(=O)=O)=CC=1>C1COCC1.CCOCC>[CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C@@H:13]([OH:28])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([O:7][CH3:32])=[O:6]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: C=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Yield: 100 %

Procedure:
Cholic acid (1a) (2.0 g, 4.9 mmol) in THF (40 ml) at 0° C. was treated dropwise with freshly prepared diazomethane in ether (prepared in the usual manner from diazald: diazald is N-methyl-N-nitroso-p-toluenesulphonamide) until the yellow colour persisted. After 15 minutes at 0° C. the solvent was evaporated to yield a white foam (2.1 g, 100%). Recrystallisation from methanol afforded pure methyl cholate1 (1.3 g, 63%): m.p. 158°-159° C. (crystals began to melt 86°-88° C. and then resolidified--this was probably due to the retention of methanol in the crystals, see NMR data) [Lit1 156°-158° C.]; 1H NMR (60 MHz; CDCl3) δ0.66 (3H, s, 18-CH3), 0.87 (3H, s, 19-CH3), 3.0-3.6 (1H, m. 3β-H), 3.2-3.5 (3H, m [exchanges on adding D2O], 3α, 7α and 12α OH's), 3.48 (s, MeOH of crystallisation [ca. 1 mol equiv.]), 3.65 (3H, s, 24-OMe), 3.7-3.9 (1H, m, 7β-H), 3.8-4.0 (1H, m, 12β-H); IR (nujol mull) 3392, 3300 (OH's), 1734 (C=O) cm-1.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].C(Cl)Cl.[CH3:9][N:10]1[C:14]2[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[S:17][C:13]=2[C:12]([NH2:22])=[N:11]1>N1C=CC=CC=1>[CH3:9][N:10]1[C:14]2[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[S:17][C:13]=2[C:12]([NH:22][C:1](=[O:4])[CH2:2][CH3:3])=[N:11]1
Reactant: CCC(=O)Cl
Reactant: Cn1nc(N)c2sc3ccccc3c21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)Nc1nn(C)c2c1sc1ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.8 g. of propionyl chloride in 10 ml. of methylene chloride was added to a stirred solution of 0.01 mole of the above-referred amine in 50 ml. of methylene chloride containing 2.0 ml. of pyridine. The resulting clear solution was stirred overnight at room temperature and then washed with water, 5% aqueous hydrochloric acid, water, 10% aqueous sodium bicarbonate and finally with water. The upper organic layer was dried over magnesium sulfate and concentrated in vacuo to give a solid residue. This residue was recrystallized from ethanol to give N-(1-methyl-1H-(1)-benzothieno[3,2-c]pyrazol-3-yl)propanamide, m.p. 88°-89° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1.C=O.[CH:27](O)=O.C([O-])([O-])=O.[Na+].[Na+]>O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][N:23]([CH3:27])[CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1
Reactant: O=CO
Reactant: Fc1cccc(F)c1-c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCC2
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CN1CC[C@H]2[C@@H](C1)c1cc(-c3c(F)cccc3F)cc3c1N2CCC3
Temperature: 80 °C
Yield: 62.7 %

Procedure:
A mixture of (7aS,11aR)-2-(2,6-difluorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (0.050, 0.15 mmol), HCHO (0.20 mL, 2.9 mmol) and formic acid (1.0 mL, 2.9 mmol) was heated at 80° C. for 4 h and cooled to room temperature. Water (5.0 mL) was added and the solution was basified with saturated Na2CO3 until pH>8. The mixture was extracted with CH2Cl2 (3×10 mL), dried (Na2SO4) and flash column chromatography (1-5% MeOH in CHCl3) gave the title compound (0.032 g, 62%) as a white foam. 1H NMR (CDCl3, 300 MHz) δ2.00-2.20 (m, 5H), 2.20-2.50 (m, 4H), 2.55-2.68 (m, 1H), 2.68-2.82 (m, 3H), 2.86-2.98 (m, 1H), 3.28-3.42 (m, 3H), 6.90-7.08 (m, 4H), 7.14-7.25 (m, 1H) ppm. MS (ESI): 341 (base, M+H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:11]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]([NH2:28])=[O:27])(=[O:24])=[O:23])=[CH:18][CH:17]=1)=[O:12].[CH2:29](N)[CH2:30][CH2:31][CH3:32]>O1CCOCC1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:11]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27])(=[O:24])=[O:23])=[CH:18][CH:17]=1)=[O:12]
Reactant: CCCCN
Reactant: NC(=O)NS(=O)(=O)c1ccc(CCNC(=O)N2Cc3ccccc3C2=O)cc1
Solvent: C1COCCO1
Product: CCCCNC(=O)NS(=O)(=O)c1ccc(CCNC(=O)N2Cc3ccccc3C2=O)cc1

Procedure:
4 g of N-(4-[2-(-1-oxo-isoindoline-2-carboxamido)ethyl]-benzenesulfonyl-urea (melting point 207°-209° C., prepared from 4-[2-(1-oxo-isoindoline-2-carboxamido)-ethyl]-benzenesulfonamide and potassium cyanate in 80% ethanol) and 0.73 g of butylamine in 100 ml of dioxane are refluxed for 1 hour. The solvent is then distilled off under reduced pressure, the residue is reprecipitated from very dilute ammonia and recrystallized from dilute acetone. The N-(4-[2-(1-oxo-isoindoline-2-carboxamido)-ethyl]-benzenesulfonyl)-N'-butyl urea obtained melts at 188° to 190° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]([C:24]1[NH:28][N:27]=[N:26][N:25]=1)[C:20]([O:22][CH3:23])=[O:21].N1C(CC(OCC)=O)=NN=N1>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:24]2[NH:28][N:27]=[N:26][N:25]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)C(N)c1nnn[nH]1
Agent: CCOC(=O)Cc1nnn[nH]1
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1nnn[nH]1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(1H-tetrazol-5-yl)acetate (prepared from ethyl 1H-tetrazole-5-acetate [CAS 173367-99-2] using procedures essentially the same as those described in S. Kukolja, J. Med. Chem., 1985, 28, 1886-1896), the title compound was prepared as a solid. The reaction was product was purified by tituration using EtOAc/hexanes.
Reaction SMILES: C([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:19]1[C:24]([Br:25])=[CH:23][CH:22]=[CH:21][N:20]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)(C)(C)C.CCN(C(C)C)C(C)C.ClC(O[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=O>C(Cl)Cl>[CH2:40]([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:19]1[C:24]([Br:25])=[CH:23][CH:22]=[CH:21][N:20]=1)[C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:13][CH:14]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1Br)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an ice bath cooled solution of (S)-(3-bromopyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamine hydrochloride (Intermediate 40) (1.20 g, 2.2 mmol), DIPEA (1.50 mL, 8.6 mmol), and DCM (20 mL) was added benzyl chloroformate (0.40 mL, 2.8 mmol). The resulting mixture was allowed to warm to rt as the bath warmed. After 16 h, the reaction was eluted through a cartridge of silica gel (25 g) with DCM. The filtrate was concentrated in vacuo to give the title compound as a light yellow oil. MS (ESI pos. ion) m/z: 464.9, 466.9 (M+H).