Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:34]([S:37][CH3:38])=[CH:33][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=2)[CH2:11][CH2:10]1)=[O:5].[C:39](N1C=CN=C1)(N1C=CN=C1)=[O:40]>O1CCCC1>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:20]2[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=[C:16]2[NH:15][CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][N:6]3[C:4](=[O:5])[C:3]4[C:2](=[CH:36][CH:35]=[C:34]([S:37][CH3:38])[CH:33]=4)[NH:1][C:39]3=[O:40])[CH2:14][CH2:13]2)=[CH:23][CH:24]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CSc1ccc(N)c(C(=O)NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)c1
Solvent: C1CCOC1
Product: CSc1ccc2[nH]c(=O)n(CCN3CCC(Nc4nc5ccccc5n4Cc4ccc(F)cc4)CC3)c(=O)c2c1
Yield: 85 %

Procedure:
A mixture of 6 parts of 2-amino-N-[2-[4-[[1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-5-(methylthio)benzamide, 1.78 parts of 1,1'-carbonylbis[1H-imidazole] and 90 parts of tetrahydrofuran was stirred and refluxed overnight. The reaction mixture was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 5.2 parts (85%) of 3-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-6-(methylthio)-2,4(1H,3H)-quinazolinedione; mp. 238° C. (compound 126).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)([N:3]1[CH:7]=[CH:6]N=[CH:4]1)=[O:2].C(N(C(C)C)CC)(C)C.O1CCCC1.Cl.Cl.N1CC[CH:32]([N:35]2[C:43]3[C:38](=[N:39][CH:40]=[CH:41][CH:42]=3)[NH:37][C:36]2=[O:44])[CH2:31]C1>C(#N)C>[N:8]1([C:1]([N:3]2[CH2:4][CH2:31][CH:32]([N:35]3[C:43]4[C:38](=[N:39][CH:40]=[CH:41][CH:42]=4)[NH:37][C:36]3=[O:44])[CH2:6][CH2:7]2)=[O:2])[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCC(n2c(=O)[nH]c3ncccc32)CC1)n1ccnc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
To a round bottom flask was added, 1,1′-carbonyldiimidazole (8.59 g, 51.4 mmol), diisopropylethylamine (12.6 mL, 72.2 mmol) and tetrahydrofuran (100 mL). This mixture was warmed to 40° C. and aged for 10 min, after which 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one dihydrochloride (10 g, 34.3 mmol) was added. The slurry was aged at 40° C. for 3 h, and then upon reaction completion, the solvent was swapped to acetonitrile which afforded an off white solid (9.19 g, 85.9%). LCMS: [M+H]=313; 1H NMR (400 MHz, d6-DMSO) δ 11.58 (1H, s), 8.09 (1H, s), 7.97 (1H, d, J=8.0 Hz), 7.73 (1H, d, J=4.0 Hz), 7.53 (1H, s), 7.05 (1H, s), 7.00 (1H, dd, J=4.0, 8.0 Hz), 4.52, (1H, dd, J=8.0, 12.0 Hz), 4.05 (2H, bd, J=8.0 Hz), 3.31 (2H, m), 2.34 (2H, m), 1.82 (2H, bd, J=12.0 Hz); 13C NMR (100 MHz, d6-DMSO) δ 153.0, 150.4, 143.4, 139.8, 137.2, 128.9, 123.0, 118.7, 116.4, 115.2, 49.3, 45.1, 28.5; mp 226° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8](=[NH:32])[C:9]1[S:10][C:11]([S:30][CH3:31])=[C:12]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[C:24]([CH3:29])=[N:25][CH:26]=[N:27][CH:28]=3)[CH:18]=2)(=[O:16])=[O:15])[CH:13]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.O>[CH3:29][C:24]1[C:23]([C:19]2[CH:18]=[C:17]([S:14]([C:12]3[CH:13]=[C:9]([C:8]([NH2:32])=[NH:7])[S:10][C:11]=3[S:30][CH3:31])(=[O:15])=[O:16])[CH:22]=[CH:21][CH:20]=2)=[CH:28][N:27]=[CH:26][N:25]=1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2cncnc2C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2cncnc2C)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 32 %

Procedure:
The (imino-{4-[3-(4-methyl-pyrimidin-5-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester ((Example 293: step a) 15 mg, 0.03 mmol) was dissolved in dichloromethane (1 mL), water (1 drop) was added, followed by trifluoroacetic acid (1 mL). The solution was stirred for 1 h 40 min at rt. The solvents were removed in vacuo, the residue was co-evaporated with dichloromethane and methanol, then purified by preparative TLC (10% methanol in dichloromethane) which yielded the title compound as a pale yellow glass (4 mg, 32%). 1H-NMR (CD3OD): δ 9.05 (s, 1H), 8.61 (s, 1H), 8.13–8.08 (m, 2H), 8.04 (s, 1H), 7.78–7.76 (m, 2H), 2.66 (s, 3H), 2.49 (s, 3H). ESI-MS (m/z): Calcd. for C17H16N4O2S3: 404.5 (M+H); found: 405.1.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:32])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH2:30][CH3:31])[N:9]=3)[CH2:2]1.Br[C:34]([CH3:39])([CH3:38])[C:35]([NH2:37])=[O:36]>>[CH2:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([CH2:5][CH:3]4[CH2:2][N:1]([C:34]([CH3:39])([CH3:38])[C:35]([NH2:37])=[O:36])[CH2:4]4)[N:7]3[CH3:32])=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: CC(C)(Br)C(N)=O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(C)(C)C(N)=O)C3)n(C)c2n1

Procedure:
Following General Procedure C, 4-(8-(azetidin-3-ylmethyl)-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-9H-purin-6-yl)morpholine 530 was alkylated by 2-bromo-2-methyl-propionamide to give 531. LCMS m/z: 259.7 (2M+H+)
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[C:9]([Cl:17])[C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[N:11][CH:12]=2)[S:4][N:3]=1.[CH2:18]([C:20]1[C:25](/[CH:26]=[CH:27]/[O:28][CH3:29])=[CH:24][CH:23]=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1)[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:9]1[C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[N:11][CH:12]=[C:7]([C:5]2[S:4][N:3]=[C:2]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25](/[CH:26]=[CH:27]/[O:28][CH3:29])[C:20]=3[CH2:18][CH3:19])[N:6]=2)[CH:8]=1
Reactant: CCc1c(/C=C/OC)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Oc1ncc(-c2nc(Br)ns2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(/C=C/OC)cccc1-c1nsc(-c2cnc(OC(C)C)c(Cl)c2)n1
Yield: 123.6 %

Procedure:
5-(3-bromo-1,2,4-thiadiazol-5-yl)-3-chloro-2-[(1-methylethyl)oxy]pyridine (D109) (1.3 g, 3.89 mmol), 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.239 g, 7.77 mmol), tripotassium phosphate (2.474 g, 11.66 mmol) and Pd(Ph3P)4 (0.449 g, 0.389 mmol) in N,N-Dimethylformamide (DMF) (5 mL) and Water (5.00 mL) were heated by Biotage Initiator to 120° C. for 30 min. The reaction solution was concentrated and the slurry was diluted with ethyl acetate, washed with water, dried and purified by ISCO column chromatography to afford 3-chloro-5-(3-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,2,4-thiadiazol-5-yl)-2-[(1-methylethyl)oxy]pyridine (D110) (2 g). MS (ES): C21H22ClN3O2S requires 415.1. found 416.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([S:15][C:16]([F:19])([F:18])[F:17])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[C:6]=1[Br:7].ClC1C=C(C=CC=1)C(OO)=[O:25]>C(Cl)(Cl)Cl>[Br:1][C:2]1[NH:3][C:4]([S:15]([C:16]([F:19])([F:18])[F:17])=[O:25])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[C:6]=1[Br:7]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)Sc1[nH]c(Br)c(Br)c1-c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: O=S(c1[nH]c(Br)c(Br)c1-c1ccc(Cl)cc1)C(F)(F)F
Temperature: 0 °C
Yield: 38.5 %

Procedure:
A solution of 2,3-dibromo-4-(p-chlorophenyl)-5-[(trifluoromethyl)thio]pyrrole (1.0 g, 0.0023 mol) in chloroform (10 mL) is treated with 3-chloroperoxybenzoic acid (0.4 g, 60%, 0.0023 mol) with stirring at 0° C., warmed to room temperature with stirring for two hours, washed with saturated sodium metabisulfite solution, saturated sodium hydrogen carbonate solution, water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a yellow syrup. Flash chromatography of the syrup using silica gel and a 1:4 ethyl acetate/hexanes solution gives the title product as a yellow solid (0.4 g, mp 165.5°-167.5° C.) which is identified by 1HNMR, 19FNMR and 13CNMR spectral analyses.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:37]([NH2:40])[CH2:38][NH2:39]>COC(C)(C)C>[NH2:39][CH2:38][CH2:37][NH:40][C:21]1[N:20]=[CH:19][C:18]([N:16]([CH3:17])[C:14](=[O:15])[C:13]([C:5]2[CH:4]=[C:3]([C:2]([F:36])([F:35])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)([CH3:34])[CH3:33])=[C:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH:22]=1
Reactant: NCCN
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: COC(C)(C)C
Product: Cc1cc(F)ccc1-c1cc(NCCN)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 130 °C
Yield: 87 %

Procedure:
A mixture of 1.0 g (1.9 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide and 5.0 ml (75 mmol) ethylenediamine was heated at 130° C. for 6 h. After cooling to room temperature the reaction mixture was diluted with 20 ml tert-butyl methyl ether and washed with 20 ml of a saturated aqueous solution of sodium carbonate, 20 ml of water and 20 ml of a saturated aqueous solution of sodium carbonate. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give 0.92 g (88%) of the title compound as a white foam.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[CH:31]=[CH:30][N:29]=[C:28]([NH2:32])[N:27]=4)=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:8][C:7]=1[C:33]([F:36])([F:35])[F:34]>C1COCC1.CCOC(C)=O.O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:3]([NH:2][CH3:1])=[O:4])[N:27]=4)=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:8][C:7]=1[C:33]([F:34])([F:36])[F:35]
Reactant: Nc1nccc(Oc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)cccc3c2)n1
Reactant: CN=C=O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)Nc1nccc(Oc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)cccc3c2)n1

Procedure:
130 μl (2.2 mMol) methyl isocyanate are added to a solution of 300 mg (0.68 mMol) 6-(2-amino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide (Step 10.3) in 10 ml THF in a sealed vessel. The mixture is stirred at 100° C. for 11 days (another 1.1 eq. of Me-NCO is added on day 8 and 9). Then the reaction mixture is diluted with EtOAc and water, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and partially concentrated. Precipitation with hexane, filtration and re-crystallization from boiling THF/CH3CN gives the title compound: m.p.: 233-234° C.
Reaction SMILES: [CH2:1]([C:5]([CH2:12][CH3:13])([CH2:8][CH2:9][C:10]#[N:11])[CH:6]=O)[CH2:2][CH2:3][CH3:4].[NH3:14].O=[Si]=O.[H][H]>>[CH2:1]([C:5]1([CH2:12][CH3:13])[CH2:8][CH2:9][CH2:10][NH:11][CH2:6]1)[CH2:2][CH2:3][CH3:4].[CH2:1]([C:5]([CH2:12][CH3:13])([CH2:8][CH2:9][CH2:10][NH2:11])[CH2:6][NH2:14])[CH2:2][CH2:3][CH3:4]
Reactant: N
Reactant: [H][H]
Reactant: CCCCC(C=O)(CC)CCC#N
Agent: O=[Si]=O
Product: CCCCC(CC)(CN)CCCN
Product: CCCCC1(CC)CCCNC1

Procedure:
41.6 g per hour of 2-butyl-2-ethyl-4-cyanobutanal (purity 90%, 37.4 g, 0.207 mol) and 1073 ml (646 g, 38.0 mol) per hour of liquid ammonia were pumped at 250 bar and 50° C. through a tubular reactor (diameter 16 mm, fill level 50 cm, oil-heated twin jacket) upstream of the hydrogenation reactor and filled with 43.3 g (96 ml) of a Y-zeolite pelleted with Aerosil 200 (HY-zeolite: Aerosil 200 =9:1, SiO2 :Al2O3 =6:1). The product stream was subsequently passed through the hydrogenation reactor from bottom to top at 250 bar and 120° C. while simultaneously passing 80 l(S.T.P.)/h (3.6 mol) of hydrogen through the reactor. The product stream was decompressed to atmospheric pressure and NH3 was removed by distillation. The product from 34.1 hours was separated by fractional distillation on a 30 cm packed column (3 mm glass rings), giving 358.3 g of 3-butyl-3-ethylpiperidine and 747.7 g of 2-butyl-2-ethylpentane-1,5-diamine. The diamine yield was 56.9% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([CH3:17])=[C:8]2[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[CH:32]=[CH2:33]>CC(C)=O.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:33][CH:32]=[CH2:31])=[CH:13][CH:14]=3)[C:9]([CH3:17])=[C:8]2[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:4][CH:3]=1
Reactant: C=CCBr
Reactant: Cc1c(CCC(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCOc1ccc2c(c1)c(C)c(CCC(=O)O)n2Cc1ccc(Cl)cc1

Procedure:
Using 845 mg of the product of Example 23 as starting material, diluted in 23 ml of dimethyl ketone, 476 mg of potassium carbonate and 225 μl of allyl bromine was added. The reaction was refluxed overnight. The reaction was then diluted with water and the acetone removed in vacuo. Then the reaction was extracted with CH3CO2Et and the organic phase was dried and concentrated to yield after flash chromatography (hexane 8, ethyl acetate 2) 790 mg of the compound, which was then hydrolyzed following the procedure of Example 2.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.[H][H].C(C1C=CC=CC=1)(=O)C.[C:24](=O)([O:28]CC)[O:25][CH2:26][CH3:27]>CCCCCC>[CH2:26]([O:25][C:24](=[O:28])[CH2:11][C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=1)=[O:12])[CH3:27]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1cccc(F)c1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(=O)c1ccccc1
Product: CCOC(=O)CC(=O)c1cccc(F)c1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
A 60%-in-oil dispersion of sodium hydride, 21.7 g (0.543 moles), was placed in a three-neck 2 L round-bottom flask equipped with an addition funnel, nitrogen inlet, magnetic stirrer, heating mantle, thermocouple and condenser with dry hexane (1 L). The resulting suspension was stirred for 15 minutes, stirring was halted and the solids were allowed to settle. The clear supernatant containing the hexane and dissolved oil was then removed via a cannula. Diethyl carbonate (1 L) was added and the suspension was heated to 120° C. To this suspension was cautiously added dropwise, over 40 minutes, a solution of 100 g (0.494 moles) of m-fluoro acetophenone dissolved in 250 mL of diethyl carbonate. As addition proceeded a reaction initiated, hydrogen was evolved and the color changed to tan. After the acetophenone derivative addition was complete, the reaction was heated for 1 additional hour. The reaction mixture was cooled and was poured into a 2 L separatory funnel. The diethyl carbonate layer was twice washed with 10% acetic acid solution and then purified by vacuum distillation (bp 114-117° C. at 0.8-0.9 mm Hg) in 91% yield.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[C:12]([N:20]=[C:21]=[S:22])(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:20][C:21]([SH:22])=[N:11]2)=[CH:6][CH:5]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(S)nc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
A mixture of 17 parts of (4-methoxyphenyl)hydrazine hydrochloride, 16.3 parts of benzoyl isothiocyanate, 10 parts of N,N-diethylethanamine and 130 parts of dichloromethane is stirred for 1 hour at room temperature. The mixture is washed with water and the solvent is evaporated. Then there are added 4.5 parts of sodium hydroxide solution 50% and 80 parts of ethanol to the residue and the whole is stirred and refluxed for 30 minutes. The mixture is neutralized with concentrated hydrochloric acid and diluted with water. The precipitated product is filtered off and crystallized from 1-butanol, yielding 13 parts (46%) of 1-(4-methoxyphenyl)-5-phenyl-1H-1,2,4-triazole-3-thiol; mp. 260° C.
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ClC(C1C=CC=CC=1)C1C=CC=CC=1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:2]([N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc2c(c1)CCN2
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: ClC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1ccc(C(c2ccccc2)N2CCc3ccccc32)cc1

Procedure:
A mixture of 49.4 g (0.2 mole) of bromodiphenylmethane (an equimolar quantity of chlorodiphenylmethane may be used instead), 23.8 g (0.2 mole) of indoline, 55.2 g (0.4 mole) of anhydrous potassium carbonate, and 200 ml of toluene is refluxed for 16 hrs under nitrogen with good stirring. The salts are removed by filtration, and the solvent is evaporated. The residue is chromatographed on silica gel with 30:70 toluene-hexane as the eluent. The product is a viscous oil, which can be crystallized from ethanol to give 1-benzhydryl-indoline, m.p. 62°-63.5°. The structure is confirmed by nmr spectroscopy and elemental analysis:
Reaction SMILES: CN(C(N[C@H](C(O)=O)C(C)C)=O)[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1.[NH2:22][C@H:23]([C:27]([NH:29][C@@H:30]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH2:31][C@H:32]([OH:51])[C@@H:33]([NH:41][C:42]([O:44][CH2:45][C:46]1[S:50][CH:49]=[N:48][CH:47]=1)=[O:43])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:28])[CH:24]([CH3:26])[CH3:25].N[C@@H](CC1C=CC=CC=1)C[C@H](O)[C@@H](NC([O:74][CH2:75][C:76]1SC=NC=1)=O)CC1C=CC=CC=1>>[CH:9]([C:6]1[S:7][CH:8]=[C:4]([CH2:3][CH2:76][C:75]([NH:22][C@H:23]([C:27]([NH:29][C@@H:30]([CH2:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:31][C@H:32]([OH:51])[C@@H:33]([NH:41][C:42]([O:44][CH2:45][C:46]2[S:50][CH:49]=[N:48][CH:47]=2)=[O:43])[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:28])[CH:24]([CH3:26])[CH3:25])=[O:74])[N:5]=1)([CH3:10])[CH3:11]
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Reactant: CC(C)[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Product: CC(C)c1nc(CCC(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1

Procedure:
Using the procedure of Example 1 U but replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine with the resultant compound of Example 31 D and replacing (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with the resultant compound of Example 31 F provided, after purification by silica gel chromatography, the desired compound.
Reaction SMILES: [CH3:1][CH:2]([SH:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.F[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>O>[CH:2]([S:4][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25])([CH3:3])[CH3:1]
Reactant: CC(C)S
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(SC(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of propane-2-thiol (3.30 mL), potassium carbonate (6.60 g) and DMF (40 mL), 1-fluoro-4-methyl-2-nitrobenzene (4.85 g) was added and stirred at room temperature for 5 hours. After addition of water, the reaction liquid was extracted with ethyl acetate, and the extract was washed with water and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give 1-(isopropylsulfanyl)-4-methyl-2-nitrobenzene (6.60 g) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][N:10]=[C:11]2[C:15](=O)[O:14][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:12]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH4+:23].[OH-].Cl.O>CC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:12][C:11]([C:15]([NH2:23])=[O:14])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(NN=C2N=C(c3ccccc3)OC2=O)ccc1F
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(-n2nc(C(N)=O)nc2-c2ccccc2)ccc1F
Yield: 55.2 %

Procedure:
3.0 g (0.01 mole) of 4-(3-methyl-4-fluorophenylhydrazono)-2-phenyl-oxazoline-5-one (R1 =3--CH3, R2 =4--F and R3 =H in the formula II) was suspended in 16 ml of acetone. To the suspension, 1.57 ml of 29% solution of NH4OH (0.013 mole) was added dropwise at room temperature. After refluxing the reaction mixture for 25 minutes, heating was stopped and 1.57 ml of concentrated hydrochloric acid was added dropwise. After the addition was over, the reaction mixture was refluxed again for 5 minutes. Then 40 ml of water was added to the reaction mixture, and the resulting crystal was filtered out, washed with acetone containing water and dried. The obtained crystal was recrystallized from a mixture of 20 ml of ethanol and 5 ml of water to obtain 1.7 g of almost colorless crystal, m.p. 123°-126° C., with a yield of 55.2%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:25])=[N:8][C:9]2[C:14]([C:15]=1[NH2:16])=[C:13]([O:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].[C:26](O)(=[O:30])[CH2:27][CH2:28][CH3:29]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:25])=[N:8][C:9]2[C:14]([C:15]=1[NH2:16])=[C:13]([O:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([C:26](=[O:30])[CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24]1)[CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC3CCNCC3)c2c1N
Reactant: CCCC(=O)O
Product: CCCC(=O)N1CCC(COc2cccc3nc(C)c(C(=O)OCC)c(N)c23)CC1

Procedure:
Prepared as in Example 24a from ethyl-4-amino-2-methyl-5-(piperidin-4-ylmethoxy)-quinoline-3-carboxylate (Example 35b) and butyric acid as a yellow oil (50%). MS 414 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].[CH2:9]([Li])[CH2:10][CH2:11][CH3:12].BrCCC=C.O>O1CCCC1>[CH3:2][CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH2:12][CH2:11][CH:10]=[CH2:9]
Reactant: [Li]CCCC
Reactant: CCc1ccccn1
Agent: C=CCCBr
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(C)c1ccccn1
Temperature: -20 °C

Procedure:
A solution of 8.46 ml (0.074 mol) of 2-ethylpyridine in 35 ml of tetrahydrofuran was cooled to −20° C. and 47 ml of n-butyllithium (15 w.-% in hexane, 0.074 mol) were subsequently added while stirring. The mixture was allowed to come to room temperature, stirred for another one hour and subsequently cooled back down to −20° C. A solution of 7.52 ml (0.074 mol) of 4-bromo-1-butene in 10 ml of tetrahydrofuran was then added at such a rate that the temperature remained at −20° C. The mixture was allowed to warm to room temperature, stirred for a further 14 hours and hydrolyzed with 50 ml of water. The organic phase was separated off and the aqueous phase was extracted three times with 30 ml each time of diethyl ether. The organic phases were combined; dried over magnesium sulfate, the magnesium sulfate was filtered off and the solvent was distilled off. The residue obtained in this way was distilled at 98-100° C./14 torr. This gave 8.95 g (75%) of 2-(1-methyl-4-pentenyl)pyridine.