Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[C:15](Cl)[C:10]=1[C:11]([NH:13][NH2:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](OC1C=CC(C(NN)=O)=C(CC)C=1Cl)[C:29]1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[C:15]([CH2:28][CH3:29])[C:10]=1[C:11]([NH:13][NH2:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1c(Cl)cc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CCc1c(C(=O)NN)ccc(OCc2ccccc2)c1Cl
Product: CCc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1C(=O)NN

Procedure:
An analogous preparation procedure also gives 2,4-dibenzyloxy-6-chlorobenzohydrazide: yield 61%, m.p. 166-1670, and 4-benzyloxy-3-chloro-2-ethylbenzohydrazide: yield 85%, m.p. 182-1840.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[NH2:28][C@@H:29]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:30]([OH:34])[C:31]([OH:33])=[O:32]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:28][C@@H:29]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:30]([OH:34])[C:31]([OH:33])=[O:32])=[O:19])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Temperature: 4 °C
Reaction time: 48 h

Procedure:
2.26 g of the p-nitrophenyl ester of benzyloxycarbonyl-L-asparagine and 1.89 ml (13.6 mmol) of triethylamine were added, whilst ice-cooling, to a solution of 900 mg (3.9 mmol) of (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid hydrochloride in 15 ml of dimethylformamide, and the mixture was stirred at 4° C. for 2 days. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was mixed with 1N aqueous hydrochloric acid to cause crystallization. The crystals were collected by filtration and washed first with water and then with ethyl acetate, to give 1.52 g of the title compound as colorless crystals, melting at 225°-227° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:7].[Na+]>O>[N:1]1([CH:4]2[CH2:5][CH2:6][O:7][CH2:2][CH2:3]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: C1CCNCC1
Agent: [Na+]
Solvent: O
Product: C1CCN(C2CCOCC2)CC1
Yield: 72 %

Procedure:
Into a device similar to that used in Example 7 were charged 1.05 g (5.0 mmol) of tetrahydropyranyl-4-methanesulfonate synthesized in Example 5 and having a purity of 86% and 1.28 g (15.0 mmol) of piperidine, and the mixture was reacted at 100° C. for 4 hours. After completion of the reaction, 1.0 ml of 8 mol/l aqueous sodium hydroxide solution and 2.0 ml of water were added to the resulting reaction mixture to make the mixture basic (pH=11), the resulting mixture was extracted twice with each 30 ml of chloroform and the extract was dried over anhydrous magnesium sulfate. After filtration, the extract was concentrated under reduced pressure to obtain 0.74 g (yield: 72%) of 4-piperidinotetrahydropyrane having a purity of 82% (areal percentage according to gas chromatography) as a yellowish liquid.
Reaction SMILES: [N:1]([CH2:4][C:5]1([OH:14])[CH2:10][CH2:9][CH2:8][N:7]2[CH:11]=[N:12][CH:13]=[C:6]12)=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][CH2:4][C:5]1([OH:14])[CH2:10][CH2:9][CH2:8][N:7]2[CH:11]=[N:12][CH:13]=[C:6]12
Reactant: [H][H]
Reactant: [N-]=[N+]=NCC1(O)CCCn2cncc21
Agent: [Pd]
Solvent: CO
Product: NCC1(O)CCCn2cncc21

Procedure:
3 mmol of 8-azidomethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol are taken up in 10 ml of methanol and the solution is admixed with 0.30 mmol of 10% Pd/C. The reaction mixture is hydrogenated with a hydrogen pressure of 1 bar at 22° C. for 1-10 hours. The catalyst is filtered off over Hyflo and the filtrate is evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1B(O)O>>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Product: Cc1c2n(c3c(-c4ccc(Cl)cc4Cl)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, off-white solid (54 mg, 56%), MS (ISP) m/z=384.5 [(M+H)+], mp 257° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 2,4-dichloro-phenylboronic acid (62.0 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]=[C:14]=[O:15].[Br:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:18]=1[NH2:19]>C(#N)C.C(OC(C)C)(C)C>[Br:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:18]=1[NH:19][C:14]([NH:13][C:4]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:15]
Reactant: Nc1c(F)cccc1Br
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Solvent: CC#N
Solvent: CC(C)OC(C)C
Product: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1c(F)cccc1Br
Temperature: 81 °C
Reaction time: 45 h
Yield: 87.4 %

Procedure:
2-Methoxy-5-trifluoromethylphenyl isocyanate (1.19 kg) is fused at about 35° C. and dissolved in acetonitrile (4.2 l), then 2-bromo-6-fluoroaniline (870 g) is added and rinsed out with acetonitrile (380 ml). The resulting clear solution is stirred at 74-88° C. for 45 h, then concentrated in vacuo (200 mbar) at 50° C. to give a viscous magma (amount of distillate 4.4 l). This is diluted at room temperature with diisopropyl ether (1.5 l), filtered off with suction, washed with diisopropyl ether (1.15 l) and dried at 45° C. in the VDO using entraining nitrogen to constant mass (24 h). A total of 1.63 kg of N-(2-bromo-6-fluorophenyl)-N′-[2-methoxy-5-(trifluoromethyl)phenyl]urea is obtained as a solid, corresponding to 87.5% of theory.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]([O:23][C:24]1[CH:39]=[C:38](O)[CH:37]=[CH:36][C:25]=1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CC=CC=1.Cl>C(Cl)Cl.C(OCC)(=O)C>[CH2:16]([O:23][C:24]1[CH:39]=[C:38]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:37]=[CH:36][C:25]=1[C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1OCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1ccc(OS(=O)(=O)C(F)(F)F)cc1OCc1ccccc1
Temperature: 0 °C

Procedure:
Trifluoromethanesulfonic anhydride (0.22 mL) was added to an ice-cooled mixture of benzyl 2-benzyloxy-4-hydroxybenzoate (0.40 g) and pyridine (0.1 mL) in methylene chloride (1.5 mL) with stirring, and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into a mixture of hydrochloric acid and ethyl acetate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium-pressure liquid silica gel column chromatography (eluent: n-hexane/ethyl acetate=6/1) to afford benzyl 2-benzyloxy-4-trifluoromethanesulfonyloxybenzoate (0.56 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([O:13][CH3:14])[CH3:12].[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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:15][C:16]1[CH:21]=[C:20]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[C:5]3([O:13][CH3:14])[CH3:12])[CH:19]=[CH:18][CH:17]=1
Reactant: COC1(C)C(=O)Nc2ccc(Br)cc21
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC1(C)C(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Reaction time: 0.25 h
Yield: 29 %

Procedure:
A solution of 5-bromo-3-methoxy-3-methyl-1,3-dihydro-indol-2-one (0.52 g, 2.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.1 mmol) was dissolved in dimethoxyethane (22 cm3). After 15 min., 3-chlorophenylboronic acid (0.63 g, 4.1 mmol) and sodium carbonate (1.0 g) in water (10 cm3) was added and the reaction was heated under reflux. After 2 h the mixture was cooled, poured into water and extracted with EtOAc (×2), the combined organic extracts were washed with sodium hydroxide solution (1N, ×2) water, brine, dried (MgSO4) and evaporated. The residue was then purified by column chromatography (SiO2, EtOAc:hexane, 5:1) to afford 5-(3-chloro-phenyl)-3-methoxy-3-methyl-1,3-dihydro-indol-2-one (0.17 g, 0.58 mmol, 29%): 1H NMR (CDCl3) δ 1.65 (s, 3H), 2.91 (s, 1H), 3.24 (s, 3H), 6.92 (d, 1H, J=8.1 Hz), 7.26-7.38 (m, 2H), 7.43-7.46 (m, 1H), 7.52-7.55 (m, 1H), 7.62 (d, 1H, J=1.8 Hz); MS ((+) APCI) m/z 288 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([NH:11][C:12](=[O:14])[CH3:13])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[N:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]2[C:31]3[C:26](=[CH:27][C:28]([CH:32]=O)=[CH:29][CH:30]=3)[N:25](COCC[Si](C)(C)C)[N:24]=2)=[CH:17][CH:16]=1>>[O:1]=[C:2]1[NH:3][C:4]2[C:9](/[C:10]/1=[CH:32]\[C:28]1[CH:27]=[C:26]3[C:31]([C:23](/[CH:22]=[CH:21]/[C:18]4[CH:17]=[CH:16][N:15]=[CH:20][CH:19]=4)=[N:24][NH:25]3)=[CH:30][CH:29]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[NH:11][C:12](=[O:14])[CH3:13]
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2ccc(C=O)cc21
Reactant: CC(=O)Nc1cccc2c1NC(=O)C2
Product: CC(=O)Nc1cccc2c1NC(=O)/C2=C/c1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Yield: 94.9 %

Procedure:
According to the method of A57B, N-(2-oxoindolin-7-yl)acetamide (30 mg, 0.16 mmol) was reacted with (E)-3-(2-(pyridin-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (60 mg, 0.16 mmol) to give the title compound as an orange solid (64 mg, 72%). MS ESI 552.3 [M+H]+, calcd for [C31H33N5O3Si+H]+ 552.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[N:7]([CH2:9][CH2:10][CH2:11][OH:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:8][N:7]([CH2:9][CH2:10][CH:11]=[O:12])[C:6](=[O:13])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCCO)C(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(CCC=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Commercially available tert-butyl(3-hydroxypropyl)(methyl)carbamate (1.858 g, 9.82 mmol) was solubilised in DCM (40 ml) and treated with sodium bicarbonate (4.12 g, 49.1 mmol) followed by Dess-Martin reagent (5.21 g, 12.28 mmol). The reaction mixture was stirred at RT for 2 hrs and then partitioned between DCM and sodium bicarbonate solution. Sodium thiosulphate was added and the organic portion was separated. The aqueous layer was extracted with DCM (×2) and the combined organic extracts were dried over MgSO4 (anh), filtered and evaporated under reduced pressure to afford the title compound without further purification;
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][CH2:2]1.[Cl:11][C:12]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:21](N1C2C(=CC=CC=2)CCC1)=[O:22]>>[Cl:11][C:12]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:21]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][CH2:2]1)=[O:22]
Reactant: c1ccc2c(c1)NCCN2
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Product: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21

Procedure:
The title compound was prepared in analogy to Example 1, from 1,2,3,4-tetrahydro-quinoxaline (commercially available; CAS RN 3476-89-9) and 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate). Light yellow foam (99%). MS (ESI): m/z=400.06 [M+H]+.
Reaction SMILES: [C:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:20]3[N:19]([CH3:23])[C:18]4[CH2:24][CH:25]5[NH:29][CH:28]([C:17]=4[C:16]=3[C:15]=2C(OC(C)(C)C)=O)[CH2:27][CH2:26]5)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[ClH:37]>C(OCC)C>[ClH:37].[C:1]1([S:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH3:23])[C:18]2[CH2:24][CH:25]4[NH:29][CH:28]([C:17]3=2)[CH2:27][CH2:26]4)(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4cccc5ccccc45)ccc31)C1CCC(C2)N1
Agent: Cl
Solvent: CCOCC
Product: Cn1c2c(c3cc(S(=O)(=O)c4cccc5ccccc45)ccc31)C1CCC(C2)N1

Procedure:
The product of step A was subjected to Boc-deprotection with 2 M HCl in diethyl ether following the procedure of Example 28, step C. The crude material was purified by flash column chromatography (SiO2, 80:18:2 chloroform/methanol/ammonium hydroxide) followed by semi-preparative HPLC. The free base was treated with 1.25 M HCl in methanol (0.5 mL) and lyophilized to give 2-(1-napthyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (5 mg, 12%, AUC HPLC 97.9%) as a white solid: mp 229-231° C.; 1H NMR (DMSO-d6, 300 MHz) δ 9.38 (br s, 1H), 9.02 (br s, 1H), 8.63 (d, J=8.7 Hz, 1H), 8.48 (s, 1H), 8.43 (dd, J=7.2, 1.2 Hz, 1H), 8.28 (d, J=8.1 Hz, 1H), 8.03-8.09 (m, 1H), 8.76 (t, J=7.8 Hz, 1H), 7.57-7.65 (m, 4H), 5.38 (d, J=3.9 Hz, 1H), 4.47 (br s, 1H), 3.64 (s, 3H), 3.34-3.40 (m, 1H), 2.49 (d, J=17.4 Hz, 1H), 2.18-2.33 (m, 2H), 2.03-2.12 (m, 1H), 1.71-1.89 (m, 1H); ESI MS m/z 403 [M+H]+.
Reaction SMILES: CN(C)[CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[C:14]1(=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[C:7]1([C:5](=[O:6])[CH2:4][CH2:3][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:14]2=[O:20])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)CCC(=O)c1ccccc1
Reactant: O=C1CCCCC1
Product: O=C(CCC1CCCCC1=O)c1ccccc1
Yield: 39.9 %

Procedure:
2-(3'-Phenyl-3'-oxopropyl)cyclohexanone was prepared according to the method of W. Hahn and J. Epsztain (Roczniki Chem. 1963, 37, 403-12): A mixture of β-dimethylaminopropiophenone (27 gm.) amd cyclohexanone (37.5 g.) were heated at reflux for 5 hours under nitrogen and the solvent removed in vacuo. The residual oil was distilled giving 2-(3'-phenyl-3'-oxopropyl)cyclohexanone (14 g.) which was cyclised to the title compound according to the method of Hahn and Epsztain by dissolving the diketone (12 g.) in ethanol (65 ml.), treating with hydroxylamine hydrochloride (9 g.) and heating under reflux for 1 hour. The cooled reaction mixture was poured onto water (300 ml.), extracted with ether (2 × 50 ml.) and the extracts discarded. The aqueous solution was made basic with K2CO3 and extracted with ether (3 × 50 ml.). The combined ether extracts were dried and the solvent removed in vacuo. The residual oil was distilled to give the title compound as a colourless oil (7 g.) b.p. 134°-8° C/15 mm. Found: C, 85.40; H, 7.5; N, 6.9%, C15H15N requires: C, 86.00; H, 7.2; N, 6.7%.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH:13]=[CH:14][CH:15]=2)[C:10]([C:27](=[O:33])[C:28]([O:30]CC)=[O:29])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=3)[CH:13]=[CH:14][CH:15]=2)[C:10]([C:27](=[O:33])[C:28]([OH:30])=[O:29])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2cccc(-c3ccc(C(F)(F)F)cc3)c12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2cccc(-c3ccc(C(F)(F)F)cc3)c12

Procedure:
2-{1-Benzyl-4-[4-(trifluoromethyl)phenyl]-1H-indol-3-yl}-2-oxoacetic acid was prepared from ethyl {1-benzyl-4-[4-(trifluoromethyl)phenyl]-1H-indol-3-yl}(oxo)acetate (0.064 g, 0.142 mmol), and potassium hydroxide (0.0471 g, 0.839 mmol) in THF (2.5 mL) and water (2.5 mL) according to the procedure described in Step 4 of Example 5. The title compound was obtained as a light yellow solid (0.0497 g, 89%), mp: 183-184° C. Mass spectrum (+APCI, [M+H]+) m/z 424; 1HNMR (400 MHz, DMSO-d6): δ 13.5-14.0 (br s, 1H), 8.65 (s, 1H), 7.65-7.7 (m, 3H), 7.25-7.45 (m, 8H), 7.2 (dd, 1H, J=7.3 Hz and 0.73 Hz), and 5.65 ppm (s, 2H).
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O.N1CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:3]([C:2](=[CH:12][C:11]1[CH:14]=[CH:15][CH:16]=[C:9]([Cl:8])[CH:10]=1)[C:1]([NH2:7])=[O:6])(=[O:4])[CH3:5]
Reactant: CC(=O)CC(N)=O
Reactant: O=Cc1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1cccc(Cl)c1)C(N)=O

Procedure:
208 mg (2.06 mmol) of acetoacetamide, 0.23 ml (2.00 mmol) of 3-chlorobenzaldehyde and 0.02 ml (0.20 mmol) of piperidine were heated under reflux in the presence of a catalytic amount of p-toluenesulfonic acid in 30 ml of benzene overnight while removing water. Ethyl acetate was added to the reaction mixture and they were washed with 1 N hydrochloric acid and then with saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 2-acetyl-3-(3-chlorophenyl)acrylamide. 10 ml of 2-propanol and 486 mg (1.65 mmol) of (3,3-diphenylpropane-1-yl)3-aminocrotonate were added to the obtained product, and they were stirred under heating at 80° C. overnight. 2-Propanol was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (hexane/ethyl acetate=1/2) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=1)(=[O:20])=[O:19].C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C(O)(CC)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH:1][C:2]2[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:12])([CH3:13])[CH3:14])[N:5]=[CH:4][C:3]=2[C:15]#[N:16])=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Reactant: C[Si](C)(C)CCOCn1ncc(C#N)c1N
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: C[Si](C)(C)CCOCn1ncc(C#N)c1Nc1ccc(S(C)(=O)=O)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
5-amino-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile (1.27 g, 5.33 mmol), 4-bromophenyl methyl sulfone (1.253 g, 5.33 mmol), Pd2 dba3 (0.244 g, 0.266 mmol), K2CO3 (0.810 g, 5.86 mmol) and X-Phos (0.635 g, 1.332 mmol) were taken up in tert-amyl alcohol (15 mL). The flask was evacuated and back-filled with N2 (×3) and the resulting mixture was stirred at 100° C. overnight. MeOH was added and the solvent removed in vacuo while loading onto silica. Purification of the residue by MPLC (12-100% EtOAc-hexanes) followed by MPLC (6-100% EtOAc-hexanes) gave 5-{[4-(methylsulfonyl)phenyl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile as a hygroscopic yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([N:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12][CH2:11][CH2:10]1)=O.[ClH:19]>C1COCC1.CCOC(C)=O>[ClH:19].[S:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:9]([NH2:7])[CH2:10][CH2:11]1
Reactant: O=NN1CCSc2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NN1CCSc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a solution of lithium aluminum hydride in THF (1 M) (331 mL, 331 mmol) was added 4-nitroso-3,4-dihydro-2H-1,4-benzothiazine (59.6 g, 330.8 mmol) in 150 mL of THF at −15° C. over 2 hours under nitrogen atmosphere. After the addition, the mixture was slowly warmed to room temperature. After 4 hours, the reaction was complete (TLC, 70:30 hexanes, ethyl acetate) and hydrated sodium sulfate (approximately 150 g) was added carefully until bubbling ceased. The resulting slurry mixture was filtered and washed with THF (5×50 mL). The organic filtrate was concentrated under reduced pressure to give a red oil. This residue was taken in EtOAc (300 mL), cooled to 0° C., and treated with 1 M solution of ethereal hydrochloric acid (230 mL). The precipitate obtained was collected by filtration, washed with EtOAc (50 mL) and dried under vacuum to give 2,3-dihydro-4H-1,4-benzothiazin-4-amine hydrochloride as a white solid (48.8 g, 73%). 1H NMR (300 MHz, CDCl3) δ3.21-3.32 (m, 2H), 3.69-3.78 (m, 2H), 4.70-5.11 (br-s, 2H), 6.98-7.36 (m, 4H) ppm.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[S:12])[NH:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]=O>>[CH2:1]([NH:8][C:9](=[S:12])[NH:10][N:11]=[CH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccn1
Reactant: NNC(=S)NCc1ccccc1
Product: S=C(NCc1ccccc1)NN=Cc1ccccn1

Procedure:
The title compound was prepared from a mixture of 4-benzylthiosemicarbazide (100 mg, 0.552 mmol) and 2-pyridinecarboxaldehyde (52 μL, 0.552 mmol) similar to Example 3 and isolated as a pale white solid (83 mg, 59%). 1H NMR (DMSO-d6): 11.84 (s, 1H), 9.27 (t, J=5.7 Hz, 1H), 8.57 (d, J=4.8 Hz, 1H), 8.30 (d, J=8.1 Hz, 1H), 8.13 (s, 1H), 7.83 (t, J=7.7 Hz, 1H), 7.40-7.31 (m, 3H), 7.26 (d, J=4.8 Hz, 1H), 4.86 (d, J=6.0 Hz, 2H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[N:12][O:13][N:14]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:26][C:27]1[CH:36]=[CH:35][C:30]([C:31](=[O:34])[CH2:32]Br)=[CH:29][CH:28]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:26][C:27]1[CH:36]=[CH:35][C:30]([C:31](=[O:34])[CH2:32][N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=[C:2]2[C:10]2[C:11]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[N:12][O:13][N:14]=2)=[CH:29][CH:28]=1
Reactant: OCCCNc1nonc1-c1nc2ccccc2[nH]1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cn1c(-c2nonc2NCCCO)nc2ccccc21)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 4-(1H-benzimidazol-2-yl)-furazan-3-yl-N-(3-hydroxypropyl)-amine (0.70 g, 0.27 mmol), potassium carbonate (0.472 g, 3.42 mmol) and 4-chlorophenacyl bromide (0.069 g, 0.29 mmol) in DMF (5 ml) is stirred at room temperature for 16 hours. The reaction mixture is diluted with ethyl acetate, washed with water and dried over sodium sulphate. Filtration of the sodium sulphate, concentration of the filtrate under reduced pressure and chromatography of the residue on silicagel using hexane-ethyl acetate as eluent gives the title compound as a yellowish solid, m.p. 166-169° C.