Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]12[C:10](=O)[O:9][C:7](=[O:8])[C@H:3]([CH2:4][CH2:5][CH2:6]1)[CH2:2]2.[CH:12]([O:17]C)([O:15][CH3:16])OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C@H:1]1([C:12]([O:15][CH3:16])=[O:17])[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]1
Reactant: COC(OC)OC
Reactant: O=C1OC(=O)[C@H]2CCC[C@@H]1C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)[C@@H]1CCC[C@H](C(=O)OC)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Anhydride 1 (3.85 g; 25 mmol) was combined with trimethyl orthoformate (4.10 mL; 37.5 mmol; 1.5 equiv) and methanol (8.2 mL). p-Toluenesulfonic acid (238 mg; 1.25 mmol; 0.05 equiv) was added and the reaction mixture was stirred overnight at ambient temperature to completely consume 1 and afford a single product by GC analysis. The solvent was removed at reduced pressure and the residue was dissolved in ethyl acetate (30 mL), washed with saturated aqueous NaHCO3 (10 mL), dried over MgSO4, and concentrated to afford 4.91 g (98%) of cis-2a which gave a single peak by GC analysis.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH:27]([O:40][C:41]([NH:43][C:44]1[NH:45][C:46](=[O:57])[C:47]2[N:48]=[CH:49][N:50]([CH2:53][C:54](O)=[O:55])[C:51]=2[N:52]=1)=[O:42])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:54](=[O:55])[CH2:53][N:50]2[CH:49]=[N:48][C:47]3[C:46](=[O:57])[NH:45][C:44]([NH:43][C:41]([O:40][CH:27]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:42])=[N:52][C:51]2=3)[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C(O)Cn1cnc2c(=O)[nH]c(NC(=O)OC(c3ccccc3)c3ccccc3)nc21
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nc2c(ncn2CC(=O)N2CCN(S(=O)(=O)c3nc4ccccc4s3)C(=O)C2)c(=O)[nH]1)OC(c1ccccc1)c1ccccc1

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [2-N-(benzhydryloxycarbonyl)-guanin-9-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 11.62 (bs, H), 11.24 (bs, 1H), 8.36 (m, 1H), 8.26 (m, 1H), 7.81 (s, 0.6H), 7.77 (s, 0.4H), 7.72 (m, 2H), 7.45 (d, 4H), 7.38 (t, 4H), 7.30 (t, 2H), 6.86 (s, 1H), 5.16 (s, 1.2H), 5.05 (s, 0.8H), 4.53 (s, 0.8H, 4.28 (s, 1.2H), 4.26 (t, 1.2H), 4.09 (t, 0.8H), 4.05 (t, 1.2H), 3.86 (t, 0.8H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[O:7][CH:6]=[C:5]2[C:13]([O:15][CH3:16])=[O:14].C([O-])(=O)C.[NH4+:21]>C(O)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:7])[NH:21][CH:6]=[C:5]2[C:13]([O:15][CH3:16])=[O:14]
Reactant: [NH4+]
Reactant: COC(=O)c1coc(=O)c2ccc(F)cc12
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1c[nH]c(=O)c2ccc(F)cc12
Temperature: 80 °C

Procedure:
A mixture of methyl 6-fluoro-1-oxo-1H-isochromene-4-carboxylate (1.53 g) and ammonium acetate (2.5 g) in 4 ml of glacial acetic acid was heated at 80° C. for 16 h. The reaction was cooled to 40° C., diluted with 8 ml of water and the solid collected by filtration (1.38 g).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.CS([Cl:32])(=O)=O>ClCCl>[Cl:32][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][O:7][C:6]2[CH:17]=[CH:18][C:3]([C:2]([F:20])([F:19])[F:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: OCc1ccc(COc2ccc(C(F)(F)F)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: FC(F)(F)c1ccc(OCc2ccc(CCl)cc2)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of [4-(4-trifluoromethyl-phenoxymethyl)-phenyl]-methanol (intermediate 14.1.2, 0.34 g, 1.2 mmol) in dichloromethane (10 mL) were added triethylamine (0.34 mL, 2.4 mmol) and methanesulfonyl chloride (0.19 mL, 2.4 mmol). The reaction mixture was stirred at room temperature for 36 h under nitrogen atmosphere. The reaction mixture was washed with water, the organic layer was dried over MgSO4 and the solvent was evaporated under reduced pressure.
Reaction SMILES: O[C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:14][CH:13]=3)=[O:11])=[C:8]([C:27]3[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=3)[S:7][C:6]=2[CH:34]=1.[CH2:35]([N:39]=[C:40]=[O:41])[CH2:36][CH2:37][CH3:38]>O1CCCC1>[CH2:35]([NH:39][C:40]([C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:14][CH:13]=3)=[O:11])=[C:8]([C:27]3[CH:32]=[CH:31][C:30]([C:40](=[O:41])[NH:39][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:29][CH:28]=3)[S:7][C:6]=2[CH:34]=1)=[O:41])[CH2:36][CH2:37][CH3:38]
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Reactant: CCCCN=C=O
Solvent: C1CCOC1
Product: CCCCNC(=O)c1ccc(-c2sc3cc(C(=O)NCCCC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Yield: 84.6 %

Procedure:
4.47 g (9 mmol) of [6-hydroxy-2-(4-hydroxyphenyl)benzo-[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone was dissolved in 250 ml of tetrahydrofuran and 4 g (40 mmol) of n-butylisocyanate was added. The reaction mixture, at room temperature and under nitrogen, was allowed to react for 72 hours. The reaction mixture had evaporated by the end of this time and the residue was dissolved in a minimal amount of chloroform. This solution was chromatographed (HPLC) on a silica gel column, eluted with a linear gradient of chloroform to chloroform-methanol (19:1) to afford 4.87 g of the title compound as a tan amorphous powder.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Cl:23][C:24]1[C:39]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:37]=[CH:36][C:25]=1[CH2:26][N:27]1[C@@H:32]([CH3:33])[CH2:31][NH:30][C:29](=O)[C:28]1=[O:35]>C1COCC1>[Cl:23][C:24]1[C:39]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:37]=[CH:36][C:25]=1[CH2:26][N:27]1[C@@H:32]([CH3:33])[CH2:31][NH:30][C:29](=[S:10])[C:28]1=[O:35]
Reactant: C[C@H]1CNC(=O)C(=O)N1Cc1cccc(C(F)(F)F)c1Cl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: C[C@H]1CNC(=S)C(=O)N1Cc1cccc(C(F)(F)F)c1Cl
Temperature: 55 °C
Yield: 176.3 %

Procedure:
To a heterogeneous mixture of Lawesson's reagent (650 mg, 1.6 mmol) in THF (30 mL) was added Intermediate 4 (1.0 g, 3.1 mmol) in one portion. The mixture was heated at 55° C. for 20 minutes and then concentrated to remove solvent. Purification by chromatography (SiO2; hexanes—100% EtOAc) afforded the desired product as a yellow solid (950 mg, 90%). MS (ESI): mass calcd. for C13H12ClF3N2OS, 336.0; m/z found, 337.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 9.78 (d, J=4.2 Hz, 1H), 7.65 (d, J=7.9 Hz, 2H), 7.38 (t, J=7.8 Hz, 1H), 5.17 (d, J=15.6 Hz, 1H), 4.53 (d, J=15.6 Hz, 1H), 3.84-3.66 (m, 2H), 3.40 (dd, J=11.7, 5.6 Hz, 1H), 1.38 (d, J=6.7 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[F:17][C:18]([F:28])([F:27])[O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>C(O)C>[F:17][C:18]([F:27])([F:28])[O:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1cccc(OC(F)(F)F)c1
Reaction time: 5 h
Yield: 56.4 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-3-quinolinecarbonitrile, 200 ml ethanol, and 3.4 ml (25.3 mmol) 3-trifluoromethoxyaniline was heated to reflux. At 5 hours, removed heat and made basic with saturated sodium bicarbonate. Stripped solvents, slurried residue with hexane, collected, and washed with water. Dissolved in ethyl acetate, stirred with Darco, filtered, stripped solvent, and dried in vacuo, giving 4.537 g of yellow-orange solid: mass spectrum (electrospray m/e): M+H=374.8.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:42])([F:41])[C:9]1[CH:10]=[C:11]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:12][NH:13][CH2:14][C:15]1[C:16]([N:25]([CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:26][CH3:27])=[N:17][C:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C:23]=2[CH:24]=1.[CH3:43][O:44][C:45](Cl)=[O:46]>C1COCC1>[CH3:43][O:44][C:45](=[O:46])[N:13]([CH2:12][C:11]1[CH:10]=[C:9]([C:8]([F:41])([F:7])[F:42])[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=1)[CH2:14][C:15]1[C:16]([N:25]([CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:26][CH3:27])=[N:17][C:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C:23]=2[CH:24]=1
Reactant: COC(=O)Cl
Reactant: CCN(CC1CCCC1)c1nc2c(cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCN(CC1CCCC1)c1nc2c(cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OC)CCCC2
Reaction time: 1 h

Procedure:
To a suspension of potassium carbonate (0.269 g, 1.949 mmol) in dry THF (5 mL) was added a THF solution (10 mL) of {3-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-5,6,7,8-tetrahydro-quinolin-2-yl}-cyclopentylmethyl-ethylamine (0.25 g, 0.3 mmol), which was then stirred for 1 h. Methylchloroformate (0.137 g, 1.46 mmol) was then added and stirring was was continued at RT for 8 h. The solvent was then evaporated, water was added, and the product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was evaporated to afford a residue. This crude residue was purified over silica gel (100-200 mesh) and eluted with 2% ethyl acetate and petroleum ether to afford (3,5-bis-trifluoromethyl-benzyl)-[2-(cyclopentylmethyl-ethyl-amino)-5,6,7,8-tetrahydro-quinolin-3-ylmethyl]-carbamic acid methyl ester as light green, pasty compound (0.05 g, yield: 15%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:10][CH3:11])[C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].[Cl:12][C:13]1[CH:14]=[C:15]([S:20](Cl)(=[O:22])=[O:21])[CH:16]=[CH:17][C:18]=1[Cl:19]>>[Cl:12][C:13]1[CH:14]=[C:15]([S:20]([NH:9][C:5]2[C:4]([O:10][CH3:11])=[N:3][C:2]([Cl:1])=[C:7]([Cl:8])[N:6]=2)(=[O:21])=[O:22])[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: COc1nc(Cl)c(Cl)nc1N
Product: COc1nc(Cl)c(Cl)nc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5,6-dichloro-3-methoxy-2-pyrazinamine (0.1 g) and 3,4-dichlorobenzenesulphonyl chloride (0.15 g). Yield 0.11 g.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([N:13]([CH3:15])[CH3:14])[N:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[O:25])=[CH:19][CH:18]=2)[N:3]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.O>CN1C(=O)N(C)CCC1>[CH3:14][N:13]([CH3:15])[C:6]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:2]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[N:3]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[O:25])=[CH:19][CH:18]=2)[N:5]=1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N(C)C
Reactant: C1COCCN1
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)Cc1c(N(C)C)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N1CCOCC1
Temperature: 150 °C
Yield: 93.6 %

Procedure:
A mixture of methyl {4-chloro-6-(dimethylamino)-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetate (0.094 g, 0.19 mmol) and morpholine (0.048 mL, 0.55 mmol) in DMPU (2 mL) was heated at 150° C. in a sealed tube for 15 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc. The combined organic extracts was washed sequentially with 1N HCl, saturated NaHCO3, and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product thus obtained was chromatographed over silica gel eluting with 5% EtOAc in CH2Cl2 to give methyl {4-(dimethylamino)-6-morpholin-4-yl-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetate (0.096 g, 95% yield) as an oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[S:10][C:11](Br)=[CH:12][N:13]=2)[CH:5]=[CH:4][CH:3]=1.[C:15]([C:18]1[CH:19]=[C:20]([SH:25])[CH:21]=[CH:22][C:23]=1[CH3:24])([OH:17])=[O:16].C[O-].[Na+]>CO.C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[S:10][C:11]([S:25][C:20]3[CH:21]=[CH:22][C:23]([CH3:24])=[C:18]([CH:19]=3)[C:15]([OH:17])=[O:16])=[CH:12][N:13]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(Nc2ncc(Br)s2)n1
Reactant: Cc1ccc(S)cc1C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(Sc2cnc(Nc3cccc(Br)n3)s2)cc1C(=O)O
Temperature: 54 °C
Yield: 81.3 %

Procedure:
A suspension of 2-[(6-bromo-2-pyridinyl)amino]-5-bromothiazole (100 mg, 0.3 mmol), 3-carboxy-4-methylthiophenol (170 mg, 0.98 mmol) and sodium methoxide (210 μL, 25% w/w solution in methanol, 0.9 mmol) in methanol (4.9 mL) and THF (2 mL) was heated to 54° C. for 5.5 h. Supplemental sodium methoxide solution (1.42 mL) was added in portions over a period of 5 h. The mixture was heated to 54° C. for 16 h and concentrated. The residue was diluted with 1 N aqueous HCl solution at 0° C. and stirred for several minutes. The precipitated solid was filtered, washed several times with water and ether, and dried in vacuo over P2O5. Trituration with ether afforded the titled compound (103 mg, 81%) as an off-white solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[N:10]([CH3:24])[C:11]2[C:16]([CH:17]=1)=[C:15]([O:18][CH3:19])[C:14]([O:20][CH3:21])=[C:13]([O:22][CH3:23])[CH:12]=2)(=O)=O.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:24][N:10]1[C:11]2[C:16](=[C:15]([O:18][CH3:19])[C:14]([O:20][CH3:21])=[C:13]([O:22][CH3:23])[CH:12]=2)[CH:17]=[C:9]1[CH2:8][CH2:7][CH2:6][N:25]1[CH2:30][CH2:29][N:28]([CH2:6][CH2:7][CH2:8][C:9]2[N:10]([CH3:24])[C:11]3[C:16]([CH:17]=2)=[C:15]([O:18][CH3:19])[C:14]([O:20][CH3:21])=[C:13]([O:22][CH3:23])[CH:12]=3)[CH2:27][CH2:26]1
Reactant: C1CNCCN1
Reactant: COc1cc2c(cc(CCCOS(C)(=O)=O)n2C)c(OC)c1OC
Product: COc1cc2c(cc(CCCN3CCN(CCCc4cc5c(OC)c(OC)c(OC)cc5n4C)CC3)n2C)c(OC)c1OC

Procedure:
2-(3-Methanesulfonyloxypropyl)-N-methyl-4,5,6-trimethoxyindole (160 mg) and piperazine (17 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][C:18]3[NH:19][CH:20]=[CH:21][N:22]=3)=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[OH:25]O.[OH-].[Na+].O>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][C:18]3[NH:19][CH:20]=[CH:21][N:22]=3)=[CH:9]2)=[CH:23][CH:24]=1)(=[O:25])[NH2:2]
Reactant: N#Cc1ccc(Cn2cc(Cc3ncc[nH]3)c3ccccc32)cc1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccc(Cn2cc(Cc3ncc[nH]3)c3ccccc32)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1-(4-Cyanobenzyl)-3-(1-imidazolylmethyl)indole (1.0 g) was dissolved in ethanol (10 ml) and 30% hydrogen peroxide (5 ml) and 6 N sodium hydroxide (5 ml) were added. The resulting mixture was stirred for 2 hours at 50° C. and then poured into water. The solid product was filtered off, washed with water and crystallised from ethanol to give 1-(4-carbamoylbenzyl)-3-(1-imidazolylmethyl)indole (0.65 g), m.p. 173°-175° C. Found: C, 72.63; H, 5.54; N, 16.29. C20H18N4O4 requires: C, 72.71; H, 5.49; N, 16.96.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[CH:4][C:5]2[C:9]([CH3:10])=[CH:8][S:7][C:6]=2[C:11]=1[Cl:12].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].CC(=O)CC>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:13][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][C:5]2[C:9]([CH3:10])=[CH:8][S:7][C:6]=2[C:11]=1[Cl:12]
Reactant: Cc1csc2c(Cl)c(Cl)c(O)cc12
Reactant: CCOC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cc2c(C)csc2c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
A mixture of 3.7 g of 6,7-dichloro-5-hydroxy-3-methylbenzo[b]thiophene, 4.3 g of ethyl bromoacetate and 20 ml of 2-butanone containing 5 ml of dimethylformamide is stirred at 60°-70° for 2 hours. The cooled mixture is diluted with ice-water and extracted 3 times with ether. The combined ether extract is dried over anhydrous magnesium sulfate and concentrated under vacuum to a brownish oil. Purification of the crude product is effected by column chromatography (alumina/ether). The purified ester is recrystallized from ether-pentane to give 4.3 g of ethyl [(6,7-dichloro-3-methylbenzo[b]thien-5-yl)oxy]acetate as fluffy needles, mp 115°-117°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[N:19]=1)[OH:17])[CH2:13][CH2:14][CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[N:19]=1)=[O:17])[CH2:13][CH2:14][CH3:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC1(C(O)c2ccc(Cl)c(Cl)n2)CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CCCC1(C(=O)c2ccc(Cl)c(Cl)n2)CCCN1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a stirred solution of 2-[(5,6-dichloro-pyridin-2-yl)-hydroxy-methyl]-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.288 g, 0.742 mmol) in DCM (12 mL) at 0° C. under nitrogen was added DMP (0.315 g, 0.742 mmol) in a single portion. The reaction mixture was stirred for one hour, then was quenched with a 1:1 mixture of 10% aqueous Na2S2O3 and saturated aqueous NaHCO3 (50 mL), and extracted with DCM (3×30 mL). The combined oraganic phases were concentrated in vacuo to give 2-(5,6-dichloro-pyridine-2-carbonyl)-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.280 g, 0.725 mmol, 98%) as a yellow solid that was used directly without further purification.
Reaction SMILES: [CH3:1][C:2](=O)[CH:3]([S:7][C:8]1[N:12]=[CH:11][NH:10][N:9]=1)[C:4](=O)[CH3:5].[C:14]1([NH:20][NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH3:1][C:2]1[C:3]([S:7][C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[C:4]([CH3:5])[N:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:21]=1
Reactant: CC(=O)C(Sc1nc[nH]n1)C(C)=O
Reactant: NNc1ccccc1
Solvent: CCO
Product: Cc1nn(-c2ccccc2)c(C)c1Sc1nc[nH]n1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 3-(2,4-pentanedion-3-yl)thio-1H-1,2,4-triazole (Example 46-a) (2 g), phenylhydrazine (1 ml) and ethanol (10 ml) was heated and stirred for 4 hours on an oil bath at 100° C. The reaction solution was concentrated under reduced pressure, and then the residue was crystallized from ethanol-ethyl acetate to yield the title compound (1.42 g).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([C:31]2[N:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:26][CH2:27][N:28]([C:31]2[N:36]=[CH:35][C:34]([NH:37][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:33][CH:32]=2)[CH2:29][CH2:30]1
Reactant: Nc1ccc(N2CCN(c3ncccn3)CC2)nc1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCN(c3ncccn3)CC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (100 mg, 0.39 mmol) in methylene chloride (15 mL) was added 6-(4-pyrimidin-2-yl-piperazin-1-yl)-pyridin-3-ylamine (100 mg, 0.39 mmol) and diisopropylethylamine (0.35 mL, 1.90 mmol). To this solution was added bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (PyBrOP) in one portion (280 mg, 0.59 mmol). The mixture was stirred at room temperature overnight. The residue was purified by HPLC to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4-pyrimidin-2-yl-piperazin-1-yl)-pyridin-3-yl]-amide as a light yellow powder. The NMR spectrum obtained on the sample is compatible with its structure. LCMS calcd for C24H20F3N7O2 (m/e) 495, obsd 496 (M+H).
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]3[CH2:22][C@@H:21]([C:23](=[O:32])[NH:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]([C:33](=[O:55])[C@@H:34]([NH:41][C:42](=[O:54])[C@@H:43]([N:45]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH3:46])[CH3:44])[CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)[CH2:19]3)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[C:50]([O:49][C:47](=[O:48])[N:45]([C@H:43]([C:42](=[O:54])[NH:41][C@@H:34]([CH:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)[C:33]([N:20]1[CH2:19][C@@H:18]([NH2:17])[CH2:22][C@H:21]1[C:23](=[O:32])[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:55])[CH3:44])[CH3:46])([CH3:51])([CH3:52])[CH3:53]
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)NCc1ccccc1)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](N)C[C@H]1C(=O)NCc1ccccc1)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
((3S,5S)-5-Benzylcarbamoyl-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-2-cyclohexyl-acetyl}-pyrrolidin-3-yl)-carbamic acid 9H-fluoren-9-ylmethyl ester (100 mg, 0.13 mmol) was dissolved in DMF (0.9 mL) at room temperature and piperidine (0.1 mL) was added. The mixture was stirred at room temperature for 30 minutes, concentrated and the residue purified by silica gel chromatography to give the title compound as a white foam (71 mg, 52%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.Cl[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([N:14]3[CH2:15][CH2:16][N:17]([CH2:22][C:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]=4)[CH2:18][CH2:19]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc([C@H]2CC[C@H](N3CCNCC3)CC2)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Product: Fc1ccc([C@H]2CC[C@H](N3CCN(Cc4ccc5ccccc5n4)CC3)CC2)cc1

Procedure:
This compound was prepared from trans 1-[4-(4-fluorophenyl)-1-cyclohexyl]piperazine (2.4 mmole) and 2-chloromethylquinoline hydrochloride (2.4 mmole) by the method described in Example 45 to give the product (82%, mp 160-162° C.). Calc'd for C26H30FN3.0.2H2O: C, 76.70%; H, 7.53%; N, 10.32% Found: C, 76.68%; H, 7.49%; N, 10.32%.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][C:3]1([CH3:27])[CH3:26].[BH4-].[Na+]>CO>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][C:3]1([CH3:27])[CH3:26]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)C(C)(C)C3)c(F)c2)C(=O)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)C(C)(C)C3)c(F)c2)C(=O)O1
Yield: 78 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(4-oxo-3,3-dimethyl-piperidin-1-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.0 mmol), with sodiumborohydride (1.2 mmol)) methanol (10 ml) at a temperature 0-25° C. for 2 hours in 78% yield.