Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]([CH2:15][CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4]1.[OH:25][C:26]([CH3:41])([C:30]([NH:32][CH2:33][C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])=[O:31])[C:27](O)=[O:28].ON1C2C=CC=CC=2N=N1>>[CH2:18]([O:17][CH2:16][CH2:15][N:5]1[CH2:4][C@H:3]([NH:2][C:27](=[O:28])[C:26]([OH:25])([CH3:41])[C:30]([NH:32][CH2:33][C:34]([F:39])([F:40])[C:35]([F:36])([F:38])[F:37])=[O:31])[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]1=2)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(O)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Reactant: N[C@H]1CN(CCOCc2ccccc2)c2ccccc2NC1=O
Agent: Cl
Agent: On1nnc2ccccc21
Product: CC(O)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@H]1CN(CCOCc2ccccc2)c2ccccc2NC1=O

Procedure:
In an analogous manner to that described in Example 1e), the condensation of (S)-3-amino-5-(2-benzyloxy-ethyl)-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one hydrochloride and (RS)-2-hydroxy-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid with 1-hydroxy-benzotriazole and N-(3-dimethylaminpropyl)-N′-ethyl-carbodiimide hydrochloride as the condensating agents yielded a 1:1-mixture of the epimeric title compounds as a light yellow solid; MS (m/e) 559 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH3:23])[CH2:8][CH2:9][CH2:10][N:11]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([OH:21])[C:15]=3[O:14][CH2:13][C:12]2=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-:31].[K+].[K+].Br[CH2:37][C:38]([O:40][CH3:41])=[O:39].[Cl-].[NH4+]>CN(C=O)C>[C:24]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH3:23])[CH2:8][CH2:9][CH2:10][N:11]2[C:16]3[CH:17]=[CH:18][CH2:19][C:20]([OH:31])([O:21][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]=3[O:14][CH2:13][C:12]2=[O:22])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(CCCN1C(=O)COc2c(O)cccc21)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CBr
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)COC1(O)CC=CC2=C1OCC(=O)N2CCCC(C)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
4-(4,4-diphenylpentyl)-8-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine was dissolved in anhydrous DMF (15 ml), and anhydrous potassium carbonate (180 mg) and methyl bromoacetate (0.15 ml) were added to the resultant solution, and the mixture was stirred at room temperature overnight. The reaction solution was poured into a saturated ammonium chloride aqueous solution, and then extracted with ethyl acetate containing 15% n-hexane. The resultant organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The resultant residue was purified by medium-pressure column chromatography (solvent:ethyl acetate/cyclohexane=1/3) to obtain the colorless oily object compound (386 mg, yield 92%).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1)=[O:28].[CH2:40]([NH:42][CH2:43][CH2:44][OH:45])[CH3:41]>>[F:37][C:36]([F:39])([F:38])[C:33]1[CH:34]=[CH:35][C:30]([O:29][C:27](=[O:28])[N:2]([C@H:3]2[CH2:4][CH2:5][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:42]([CH2:40][CH3:41])[CH2:43][CH2:44][OH:45])[CH2:7][CH2:8]2)[CH3:1])=[CH:31][CH:32]=1
Reactant: CN[C@H]1CC[C@H](CCCCCOS(C)(=O)=O)CC1
Reactant: O=C(Cl)Oc1ccc(C(F)(F)F)cc1
Reactant: CCNCCO
Solvent: O=C(O)C(F)(F)F
Product: CCN(CCO)CCCCC[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to examples 29.10 and 29.11, trans-Methansulfonic acid 5-(4-methyl amino-cyclohexyl)-pentyl ester.trifluoroacetic acid salt and 4-trifluoromethyl-phenyl chloroformate were reacted, followed by treatment with 2-ethylamino-ethanol to yield trans-(4-{5-[Ethyl-(2-hydroxy-ethyl)-amino]-pentyl}-cyclohexyl)-methyl-carbamic acid 4-trifluoromethyl-phenyl ester, MS: 459 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][CH:33]([CH3:39])[CH2:34][C:35]([CH3:38])([OH:37])[CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CCOC(C)=O.C(#N)C>[OH:37][C:35]([CH3:38])([CH3:36])[CH2:34][CH:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[CH:19]=1)=[O:23])[CH3:39]
Reactant: CC(N)CC(C)(C)O
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(CC(C)(C)O)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (98 mg, 0.22 mmol), 4-amino-2-methylpentan-2-ol [prepared according to US 2003/0171584 A1] (27 mg, 0.23 mmol), and HATU (89 mg, 0.23 mmol). Then added acetonitrile (2 mL) followed by N,N-diisopropylethylamine (0.2 mL, 1.12 mmol). The yellow reaction mixture was stirred at room temperature overnight then diluted with EtOAc and washed with water (3×). The organic layer was combined, dried over Na2SO4, and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/heptanes (gradient: 5-90% EtOAc) to afford 75 mg (63%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-hydroxy-1,3-dimethyl-butyl)-amide as an off-white solid. MS: [M+H]+=541.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:13]([O-])=O)[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].O1CCOCC1.[ClH:22]>CCO.[Pd]>[ClH:22].[NH2:13][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([OH:1])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: COC(=O)c1cc(N)c(O)c(O)c1
Reaction time: 3 h
Yield: 98 %

Procedure:
To a stirred solution of methyl 3,4-dihydroxy-5-nitrobenzoate (11.9 g, 55.8 mmol) in EtOH (200 mL), 4M HCl in dioxane (13.96 mL, 55.8 mmol) and 10% palladium on carbon (4.0 g, 3.76 mmol) were added. The reaction mixture was hydrogenated at atmospheric pressure of H2 for 3 hours (TLC-monitoring). The resulting mixture was filtered and concentrated with the use of a rotary evaporator. The residue was triturated with ether (100 mL). The precipitate was filtered off and vacuum-dried to afford methyl 3-amino-4,5-dihydroxybenzoate hydrochloride (12.0 g, 54.6 mmol, 98% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([SH:17])[CH2:14][C@H:13]2[CH2:18][NH2:19])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.C[Si](C)(C)Cl.[S:34](Cl)(=[O:37])(=[O:36])[NH2:35].Cl>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([SH:17])[CH2:14][C@H:13]2[CH2:18][NH:19][S:34](=[O:37])(=[O:36])[NH2:35])=[O:11])=[CH:20][CH:21]=1)([O-:3])=[O:2]
Reactant: NS(=O)(=O)Cl
Reactant: NC[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NS(=O)(=O)NC[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66.7 %

Procedure:
To a solution of crude (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-aminomethyl-4-mercaptopyrrolidine (3.3 g: 10.18 mmole) in dichloromethane (100 ml) at -78° C., triethylamine (2.84 ml: 2.2 eq.) and trimethylchlorosilane (3.12 ml: 2.2 eq.) are dropwise added. After stirring for 20 minutes, triethylamine (4.25 ml: 3 eq.) and 1M-sulfamoyl chloride in dichloromethane (25 ml: 2.5 eq.) are dropwise added to the mixture. After 20 minutes stirring, the reaction mixture is acidified with hydrochloric acid, warmed to room temperature, and extracted with dichloromethane. The extract is washed with water, and 1N-hydrochloric acid (10 ml) and methanol (30 ml) are added thereto. The solution is stirred at room temperature for 30 minutes. The reaction mixture is washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene: ethyl acetate) to give (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-sulfamoylaminomethyl-4-mercaptopyrrolidine (2.65 g). Yield: 66.7%. NMR δ(CDCl3 -CD3OD) ppm: 1.42(t, J=7 Hz, 1H), 1.65 to 1.93(m, 1H), 2.48 to 2.70(m, 1H), 3.05 to 3.63(m, 4H), 3.93 to 4.16(m, 2H), 5.22(s, 2H), 7.53(d, J=8 Hz, 2H), 8.23(d, J=8 Hz, 2H). IR ν (CHCl3) cm-1 : 3276br, 1692, 1607.
Reaction SMILES: C[N:2]([CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:13][CH:12]=1)[C:3](=O)OC(C)(C)C.C(O[K])(C)(C)C.[F:28][C:29]1[CH:30]=[C:31]([S:36]([Cl:39])(=[O:38])=[O:37])[CH:32]=[CH:33][C:34]=1[F:35]>O1CCCC1>[ClH:39].[F:28][C:29]1[CH:30]=[C:31]([S:36]([N:13]2[C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:15][C:11]([CH2:10][NH:2][CH3:3])=[CH:12]2)(=[O:37])=[O:38])[CH:32]=[CH:33][C:34]=1[F:35]
Reactant: CN(Cc1c[nH]c(-c2ccccc2)c1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(F)c(F)c2)c1
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32.8 %

Procedure:
To a solution (7 mL) of tert-butyl methyl[(5-phenyl-1H-pyrrol-3-yl)methyl]carbamate (70 mg) in tetrahydrofuran was added tert-butoxy potassium (42 mg) at room temperature and the mixture was stirred for 30 min. 3,4-Difluorobenzenesulfonyl chloride (68 mg) was added at room temperature and the mixture was stirred for 1.5 hr. To the reaction mixture was added ice water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→4:1), and dissolved in methanol (15 mL). 4 mol/l Hydrogen chloride-ethyl acetate solution (1.5 mL) was added and the mixture was stirred at 65° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and crystallized from ethyl acetate to give the title compound as pale-brown crystals (yield 32 mg, 33%).
Reaction SMILES: ClC1C=CC=C(Cl)C=1N.C(C(=COCC)C(NC(OCC)=O)=O)#N.CCCCCC.[C:31]([C:33](=[CH:42][NH:43][C:44]1[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][C:45]=1[Cl:51])[C:34]([NH:36][C:37](OCC)=[O:38])=[O:35])#[N:32]>C(O)C.C1C2C(=CC=CC=2)CCC1>[C:31]([C:33]1[C:34](=[O:35])[NH:36][C:37](=[O:38])[N:43]([C:44]2[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][C:45]=2[Cl:51])[CH:42]=1)#[N:32]
Reactant: CCOC(=O)NC(=O)C(C#N)=CNc1c(Cl)cccc1Cl
Agent: CCOC=C(C#N)C(=O)NC(=O)OCC
Agent: Nc1c(Cl)cccc1Cl
Solvent: c1ccc2c(c1)CCCC2
Solvent: CCO
Solvent: CCCCCC
Product: N#Cc1cn(-c2c(Cl)cccc2Cl)c(=O)[nH]c1=O

Procedure:
2,6-Dichloroaniline and α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide in ethanol is refluxed 3 days and hexane added to prepare α-cyano-β-(2,6-dichloroanilino)-N-ethoxycarbonylacrylamide, which is cyclized by heating in tetralin to yield 5-cyano-1-(2,6-dichlorophenyl)uracil, m.p. 273°-274.5°.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH:9]([C:12]1[N:17]=[C:16]2[S:18][C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=[N:20][C:15]2=[CH:14][CH:13]=1)[C:10]#[N:11].[NH2:26][NH2:27]>CCO.CC(O)=O>[NH2:11][C:10]1[NH:27][N:26]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[C:9]=1[C:12]1[N:17]=[C:16]2[S:18][C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=[N:20][C:15]2=[CH:14][CH:13]=1
Reactant: CC(C)Nc1nc2ccc(C(C#N)C(=O)c3ccccc3F)nc2s1
Reactant: NN
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)Nc1nc2ccc(-c3c(-c4ccccc4)n[nH]c3N)nc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 1.4 %

Procedure:
To a solution of 3-(2-fluorophenyl)-2-(2-(isopropylamino)thiazolo[5,4-b]pyridin-5-yl)-3-oxopropanenitrile (0.10 g, 0.282 mmol, 1.0 eq.) in EtOH (1 mL) and HOAc (2 mL) at 0° C. was added hydrazine (0.1 mL, 3.19 mmol, 11.3 eq.). After 10 min., the cold bath was removed, and the reaction mixture was stirred to room temperature for 10 min. It was then heated at 88° C. for 5 hr and at 100° C. overnight. After cooling to room temperature and then to 0° C., water was added followed by concentrated aqueous NH4OH until pH was 10 by litmus paper. The aqueous layer was extracted with EtOAc (3×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. MeOH was added to the residue, and the mixture was subjected to autoprep. The appropriate fractions were collected, and NaHCO3 (s) was added. The solution was then concentrated in vacuo not to dryness and extracted with CH2Cl2 (3×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo to give 5-(5-amino-3-phenyl-1H-pyrazol-4-yl)-N-isopropylthiazolo[5,4-b]pyridin-2-amine as a light yellow solid (0.0014 g, 1.3% yield). LC/MS (MH)=369.14.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.CON(C)[C:14](=[O:29])[C:15]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:17])[CH3:16].CO.Cl>C1COCC1.CCOCC>[CH3:17][C:15]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([CH3:16])[CH:14]=[O:29]
Reactant: CON(C)C(=O)C(C)(C)NC(=O)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C=O)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
Diisobutylaluminum hydride (1.77 mL, 1M solution in toluene, 0.708 mmol) was added to a stirred solution of benzyl {2-[methoxy(methyl)amino]-1,1-dimethyl-2-oxoethyl}carbamate (198.5 mg, 0.708 mmol) in dry THF (7.1 mL) at −78° C. under N2. The reaction was stirred at −78° C. for 4 h. MeOH (100 μL) and 1N HCl (250 μL) were added and the reaction was allowed to warm to room temperature. The mixture was diluted with Et2O (50 mL) and washed with 1N HCl (2×50 mL), 50% saturated NaHCO3 (50 mL) and water (50 mL), then dried (MgSO4) and concentrated in vacuo to give benzyl (1,1-dimethyl-2-oxoethyl)carbamate. Rf=0.40 (20% EtOAc in hexanes). LCMS calc.=244.1; found=244.1 (M+Na)+. 1H NMR (500 MHz, CDCl3) δ 9.43 (s, 1H), 7.38-7.30 (m, 5H), 5.34 (s, 1H), 5.09 (s, 2H), 1.37 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[C:23]([CH2:24][CH2:25][C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:27])=[C:22]([CH3:35])[NH:21][C:20]=1[CH:36]=O>C(O)C.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:36][C:20]2[NH:21][C:22]([CH3:35])=[C:23]([CH2:24][CH2:25][C:26]([N:28]4[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]4)=[O:27])[C:19]=2[CH3:18])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)N1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)c(C)c1CCC(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.7 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3,5-dimethyl-4-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrole-2-carbaldehyde (72.1 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-chloro-phenyl)-3-{3,5-dimethyl-4-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrol-2-ylmethylene}-1,3-dihydro-indol-2-one as a yellow solid (47.4 mg, 38%).
Reaction SMILES: [CH2:1]([N:5]([CH2:18][CH3:19])[C:6]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:7]=1[CH:8]=O)[CH2:2][CH2:3][CH3:4].[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:25][NH2:26].C(O)(=O)C.[OH-].[Na+]>ClCCCl.C(Cl)Cl>[F:20][C:21]([F:34])([F:35])[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=1)[CH2:25][NH:26][CH2:8][C:7]1[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:6]=1[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:18][CH3:19]
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCCCN(CC)c1ccc(C(F)(F)F)cc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCCN(CC)c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 88 %

Procedure:
2-(Butyl-ethyl-amino)-5-trifluoromethyl-benzaldehyde (6.5 g), 3,5-bis-trifluoromethyl-benzylamine (7.52 g), acetic acid (2.04 ml) are dissolved in 1,2-dichloroethane (50 ml), and thereto is added triacetoxy sodium borohydride (10.1 g) at room temperature and the mixture is stirred for 2 hours. To the reaction solution are added 1N-aqueous sodium hydroxide solution and methylene chloride, and the mixture is separated, and the organic layer is washed with a saturated brine and dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give {2-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-4-trifluoromethyl-phenyl}-butyl-ethyl-amine (10.48 g). MS (m/z): 501 [M+H]+
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:23][CH2:22][C:21]([C:31]([O:33]C)=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:23][CH2:22][C:21]([C:31]([OH:33])=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-phenyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.37 g). To the solution was added 1N sodium hydroxide solution (7.5 ml), and the mixture was stirred at room temperature overnight, concentrated, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-phenyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.27 g) as yellow crystals.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[S-:11][C:12]#[N:13].[NH4+].[CH2:15]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:22]([C:12]1[S:11][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:5])[N:13]=1)[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1ccc(NCc2ccccc2)cc1
Reactant: N#C[S-]
Reactant: O=C(Cl)c1cccnc1Cl
Agent: [NH4+]
Product: O=c1nc(N(Cc2ccccc2)c2ccc(C(F)(F)F)cc2)sc2ncccc12
Yield: 56.5 %

Procedure:
The reaction procedure of Example 57 was followed except that 190 mg of 2-chloronicotinoyl chloride, 83 mg of ammonium thiocyanate and 271 mg of 4-(benzylamino)benzotrifluoride were used. As a result, 252 mg of 2-[N-benzyl-N-(4-trifluoromethylphenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[NH2:10][C:11]([NH2:13])=[S:12].S(Cl)(Cl)(=O)=O>>[C:4]1([C:1]2[N:10]=[C:11]([NH2:13])[S:12][CH:2]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NC(N)=S
Reactant: CC(=O)c1ccccc1
Solvent: O=S(=O)(Cl)Cl
Product: Nc1nc(-c2ccccc2)cs1

Procedure:
Carefully mix 360 g (3 mols) of acetophenone and 455 g (6 mols) of thiourea; then add 264 ml (3.3 mols) of sulfuryl chloride in small fractions. The reaction is exothermic and the sulfuryl chloride is added over the course of two hours.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([CH2:13][CH2:14][CH:15]2[CH:20]=[CH:19][C:18](OC)=[CH:17][C:16]2=C=O)[N:7]=1.Br[CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]/[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]/[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[CH:10][CH:9]=[C:8]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:3]([O:2][CH3:1])=[O:25])=[CH:19][CH:20]=2)[N:7]=1
Reactant: COC(=O)CCc1nc(CCC2C=CC(OC)=CC2=C=O)ccc1O
Reactant: COc1ccc(/C=C/CCCCBr)cc1
Product: COC(=O)CCc1nc(CCc2ccc(C(=O)OC)cc2)ccc1OCCCC/C=C/c1ccc(OC)cc1
Yield: 106.1 %

Procedure:
Under the conditions of example 1 D, 280 mg of 3-{6-[2-(4-methoxy-carbonylphenyl)-ethyl]-3-hydroxy-2-pyridyl}-propionic acid methyl ester is reacted with 220 mg of (1E)-6-bromo-1-(4-methoxyphenyl)-1-hexene, worked up, and the crude product is chromatographed on silica gel with hexane/0-10% ethyl acetate. 230 mg of 3-{6-[2-(4-methoxycarbonylphenyl)-ethyl]-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester of melting point 59°-61° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20](OC(C)(C)C)(=[O:25])[CH2:21][C:22]([CH3:24])=[O:23].C(OCC)(=O)C.CCCCCC>C1(C)C(C)=CC=CC=1>[C:12]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][C:20](=[O:25])[CH2:21][C:22](=[O:23])[CH3:24])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Reactant: CC(=O)CC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Product: CC(=O)CC(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Temperature: 120 °C
Yield: 31.2 %

Procedure:
A mixture of 3-amino-2-benzoyl-6-chloroindole (Example 1) (850 mg, 4.07 mmol) and tert-butyl acetoacetate (1.3 ml, 8.15 mmol) in xylene (10 ml) was heated at 120° C. for 5 h. The mixture was concentrated and purified by flash column chromatography eluting with hexane/ethyl acetate (2/1) to give a yellow amorphous solid. Recrysalization from ethyl acetate/hexane afforded 450 mg (31%) of the titled compound as a pale yellow solid. m.p.: 170-173° C. 1H-NMR (CDCl3) δ: 10.22 (1H, br s), 8.47 (1H, br s), 8.01 (1H, d, J=8.8 Hz), 7.83-7.77 (2H, m), 7.65-7.50 (3H, m), 7.32 (1H, d, J=1.5 Hz), 7.11 (1H, dd, J=1.5, 8.8 Hz), 3.56 (2H, s), 2.32 (3H, s).