Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:17](=[O:18])[CH:11]3[CH2:12][C:13](=O)[CH2:14][CH2:15][CH:10]3[C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28]N)=[C:24]([CH3:30])[CH:23]=1>>[C:1]1([N:7]2[C:17](=[O:18])[CH:11]3[CH:10]([CH2:15][CH2:14][C:13]4[NH:28][C:25]5[C:26]([C:12]=43)=[CH:27][C:22]([O:21][CH3:20])=[CH:23][C:24]=5[CH3:30])[C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(NN)c(C)c1
Reactant: O=C1CCC2C(=O)N(c3ccccc3)C(=O)C2C1
Agent: Cl
Product: COc1cc(C)c2[nH]c3c(c2c1)C1C(=O)N(c2ccccc2)C(=O)C1CC3

Procedure:
Using N-phenyl-4-oxocyclohexane-1,2-dicarboximide instead of the N-benzyl-4-oxocyclohexane-1,2-dicarboximide and using 4-methoxy-2-methylphenyl-hydrazine hydrochloride instead of the phenylhydrazine, the same procedure as in Reference Example 1 (1) was repeated, to obtain N-phenyl-6-methoxy-8-methyl-1,2,3,4-tetrahydrocarbazole-3,4-dicarboximide.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([C:6](O)=[O:7])[CH2:5][CH2:4]1.[NH2:11][C:12]1[N:17]=[N:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[O:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[F:35][C:32]([F:33])([F:34])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:24]([N:21]1[CH2:20][CH2:19][N:18]([C:15]2[N:16]=[N:17][C:12]([NH:11][C:6]([C:3]3([C:2]([F:10])([F:9])[F:1])[CH2:5][CH2:4]3)=[O:7])=[CH:13][CH:14]=2)[CH2:23][CH2:22]1)=[O:25]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(NC(=O)C3(C(F)(F)F)CC3)nn2)CC1

Procedure:
Following the procedure of Example 2, making variations only as required to use 1-trifluoromethylcyclopropanecarboxylic acid in place of benzyloxyacetic acid to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)-methanone, the title compound was obtained as a white powder (16% yield). 1H NMR (300 MHz, CDCl3) δ 8.62, 8.18, 7.74, 7.63, 7.56, 7.34, 7.01, 4.03-3.89, 3.71-3.62, 3.60-3.58, 3.34-3.32, 1.54-1.52, 1.39-1.36. MS (ES+) m/z 487.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH:10]([CH3:18])[C:11]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH:10]([C:11](=[O:12])[C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH3:18])[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: CC(Br)C(=O)c1cccs1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C(=O)c1cccs1)n1cc(Cl)cnc1=O
Temperature: 25 °C
Yield: 29.8 %

Procedure:
A mixture of 5-chloropyrimidin-2-one (522 mg) and 2-(2-bromopropionyl)thiophene (965 mg) in triethylamine (0.84 ml) and ethanol (25 ml) was stirred at room temperature. After 3 h. the mixture was heated to 50° C. After a further 1 h. the solvent was removed and the residue dissolved in ethyl acetate (50 ml) which was washed with water (3×25 ml) and brine, dried (MgSO4) and evaporated to a yellow oil. The oil was triturated with diethyl ether and the resulting solid was crystallised twice from ethyl acetate to give the title pyrimidinone (320 mg), m.p. 128°-129° C., λmax (EtOH) 226 nm (ε 11,340), 263 nm (ε10,050), 290 nm (ε 8,950).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH:21]=[C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=3)[CH:23]=2)[CH:7]=[C:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([C:4]2[CH:23]=[C:22]([CH:21]=[C:6]([CH:7]=[C:8]3[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]3)[CH:5]=2)[O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][N:26]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cc(Oc3ccc(C(F)(F)F)cn3)cc(C3CC3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Oc2cc(C=C3CCNCC3)cc(C3CC3)c2)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of tert-butyl 4-(3-cyclopropyl-5-(5-(trifluoromethyl)pyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.408 g, 0.859 mmol) in dry CH2Cl2 (5 mL) was added trifluoroacetic acid (1.0 mL, 13.05 mmol) at 0° C. The reaction mixture was stirred for 30 min at 0° C. and at RT for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2 three times. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness to give the title compound (0.270 g, 84%) which was used in the next step.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([S:10][CH3:11])[C:7](Cl)=[O:8])(=[O:3])[CH3:2].Br.[O:13]=[C:14]1[CH2:18][NH:17][C@H:16]([C:19]([OH:21])=[O:20])[CH2:15]1.C(SCCC(N1CC(=O)C[C@H]1C(O)=O)=O)(=O)C>>[C:1]([S:4][CH2:5][CH:6]([S:10][CH3:11])[C:7]([N:17]1[CH2:18][C:14](=[O:13])[CH2:15][C@H:16]1[C:19]([OH:21])=[O:20])=[O:8])(=[O:3])[CH3:2]
Reactant: CSC(CSC(C)=O)C(=O)Cl
Reactant: O=C1CN[C@H](C(=O)O)C1
Agent: Br
Agent: CC(=O)SCCC(=O)N1CC(=O)C[C@H]1C(=O)O
Product: CSC(CSC(C)=O)C(=O)N1CC(=O)C[C@H]1C(=O)O

Procedure:
The 3-(acetylthio)-2-(methylthio)propionic acid chloride is reacted with 4-keto-L-proline, hydrobromide according to the procedure of Example 1 (d) to yield 1-[3-(acetylthio)-2-methylthio-1-oxopropyl]-4-oxo-L-proline.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:9][CH:8]=1)=[O:6])[CH3:3].CC(C)([O-])C.[K+].[N:39]1([CH2:44][C:45](=O)[CH2:46][O:47][CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[CH:43]=[CH:42][N:41]=[CH:40]1>O1CCCC1>[N:39]1([CH2:44]/[C:45](/[CH2:46][O:47][CH2:48][C:49]2[CH:50]=[CH:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=2)=[CH:13]\[C:10]2[CH:9]=[CH:8][C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])=[CH:12][CH:11]=2)[CH:43]=[CH:42][N:41]=[CH:40]1
Reactant: CCOC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(COCC(=O)Cn2ccnc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(/C=C(/COCc2ccc(OC)cc2)Cn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A stirred suspension containing [[4-(ethoxycarbonyl)phenyl]methyl]triphenylphosphonium bromide (11.8 g, 0.0234 mol) in dry tetrahydrofuran (25 ml) at 0° C. under a nitrogen atmosphere was treated with potassium t-butoxide (2.58 g, 0.023 mol). The mixture was allowed to warm up to room temperature and stirred for an additional 90 minutes. The resulting orange mixture was treated with a solution of 1-(1H-imidazol-1-yl)-3-[(4-methoxyphenyl)methoxy]-2-propanone (7.1 g, 0.0273 mol) in dry tetrahydrofuran (25 ml) and stirred for 2 hours. The solvent was evaporated off under reduced pressure and the residue was dissolved in ethyl acetate (300 ml) washed with water (3×150 ml) and extracted into hydrochloric acid (3×200 ml of 5M). The acid solution was basified (K2CO3) and extracted with ethyl acetate (3×250 ml). The extracts were combined, dried over sodium sulfate and the solvent was evaporated off under reduced pressure to yield a crude product. The crude product was purified by column chromatography (silica gel 10% hexane in chloroform). The less polar isomer, ethyl 4-[3-(1H-imidazol-1-yl)-2-[[(4-methoxyphenyl)methoxy]methyl]-1E-propenyl]benzoate was obtained as a colourless oil having the following structural characteristics:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:20][C:21](=[O:39])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33](Br)[CH:32]=2)=[CH:26][C:25]=1[CH3:38]>>[CH3:38][C:25]1[CH:26]=[C:27]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:18][C:9]3[CH:10]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:12]=[CH:13][C:8]=3[O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:32]=2)[CH:28]=[CH:29][C:24]=1[CH2:23][CH2:22][C:21]([OH:39])=[O:20]
Reactant: Oc1cc(C(F)(F)F)ccc1Oc1ccccc1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Br)c2)cc1C
Product: Cc1cc(Oc2cccc(Oc3cc(C(F)(F)F)ccc3Oc3ccccc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared according to Example 85 by using 2-phenoxy-5-trifluoromethyl-phenol and 3-[4-(3-bromo-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester to afford about 35 mg (11%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C29H23O5F3 508, found 509 (M+1, 100%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:20](=[O:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[F:27][C:28]1[CH:29]=[C:30]([CH2:35][C:36]([NH2:39])([CH3:38])[CH3:37])[CH:31]=[CH:32][C:33]=1[F:34].[BH4-].[Li+].ClCCl>O1CCCC1.O>[F:27][C:28]1[CH:29]=[C:30]([CH2:35][C:36]([NH:39][CH2:21][CH:20]([C:11]2[C:12]3[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=3[CH:19]=[C:9]([OH:8])[CH:10]=2)[OH:26])([CH3:37])[CH3:38])[CH:31]=[CH:32][C:33]=1[F:34]
Reactant: CCOC(O)C(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Reactant: CC(C)(N)Cc1ccc(F)c(F)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(Cc1ccc(F)c(F)c1)NCC(O)c1cc(O)cc2c1OCC(=O)N2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
357 mg (1 mmol) of 6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 185 mg (1 mmol) of 2-(3,4-difluorophenyl)-1,1-dimethylethylamine are stirred for 30 minutes in 5 mL tetrahydrofuran at ambient temperature. It is cooled to 0° C. and, under an argon atmosphere, 1.5 mL of a 2 molar solution of lithium borohydride in tetrahydrofuran is added dropwise. The mixture is stirred for 30 minutes at ambient temperature, combined with 10 mL dichloromethane, and 3 mL water, stirred for a further hour and then filtered through an EXTRELUT® column. The eluate containing the ethanol amine is freed from solvent. The residue is dissolved in methanol and hydrogenated with palladium on charcoal (10%) as catalyst at 2.5 bar and ambient temperature. Then the catalyst is separated off and the crude product is purified by chromatography. White solid. Yield: 31 mg (6%, trifluoroethyl acetate); mass spectroscopy: [M+H]+=393.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.C([Li])CCC.[CH3:17][CH:18]([CH2:20][C:21](=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH3:19]>C(OCC)C>[S:4]1[CH:5]=[CH:6][C:2]([C:21]([OH:26])([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][CH:18]([CH3:19])[CH3:17])=[C:3]1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)CC(=O)CC(C)C
Reactant: Brc1ccsc1-c1cccs1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)CC(O)(CC(C)C)c1ccsc1-c1cccs1
Reaction time: 0.25 h
Yield: 18.1 %

Procedure:
3-Bromo-2,2′-bithiophene (IIIa) (3.00 g, 12 mmol) in dry diethylether (100 mL) was added slowly to a solution of n-butyllithium (1.6 M in hexane, 7.50 mL, 12 mmol) in dry diethylether (100 mL) at −78° C. over 2 h under N2. The mixture was stirred for 15 minutes at the same temperature. Freshly distilled 2,6-dimethyl-4-heptanone (2.17 mL, 12 mmol) was added via a syringe to the mixture at −78° C., followed by stirring overnight at room temperature. The reaction was quenched with an aqueous NH4Cl-solution (2.5 M, 50 mL) and water (50 mL) at 0° C. The organic phase was separated and the aqueous phase was extracted with diethylether. The combined organic phases were washed with brine, dried over MgSO4 and evaporated under reduced pressure to give a crude oil. The oily residue was purified by column chromatography (eluent hexane/EtOAc 90:10) to afford the title compound (IIb) as a green oil (0.67 g, 18%). 1H-NMR (CDCl3): δ=7.35 (dd, J=1.1 Hz, J=5.1 Hz, 1H), 7.22 (d, J=4.7 Hz, 1H), 7.08 (dd, J=1.1 Hz, J=3.6 Hz, 1H), 6.97 (d, J=4.7 Hz, 1H), 6.92 (dd, J=3.6 Hz, J=5.1 Hz, 1H), 1.85 (d, J=5.8 Hz, 4H), 1.08-0.78 (m, 2H), 0.50 (d, J=7.1 Hz, 12H). 13C-NMR (CDCl3): δ=146.24, 136.18, 130.09, 129.31, 128.92, 127.85, 127.35, 125.48, 79.83, 53.28, 25.10, 24.93.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:27])[NH:4][C:5]1[CH:21]=[CH:20][C:19]2[C:10]3[NH:11][C:12](=[O:18])[C:13]4[N:14]([CH:15]=[CH:16][N:17]=4)[C:9]=3[CH:8]([CH2:22][C:23]([O:25]C)=[O:24])[C:7]=2[CH:6]=1.[ClH:28]>O1CCOCC1>[ClH:28].[CH3:1][NH:2][C:3](=[O:27])[NH:4][C:5]1[CH:21]=[CH:20][C:19]2[C:10]3[NH:11][C:12](=[O:18])[C:13]4[N:14]([CH:15]=[CH:16][N:17]=4)[C:9]=3[CH:8]([CH2:22][C:23]([OH:25])=[O:24])[C:7]=2[CH:6]=1
Reactant: CNC(=O)Nc1ccc2c(c1)C(CC(=O)OC)c1c-2[nH]c(=O)c2nccn12
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)Nc1ccc2c(c1)C(CC(=O)O)c1c-2[nH]c(=O)c2nccn12
Temperature: 40 °C

Procedure:
A mixture of 1.4 g of enantiomer A which is methyl [8-(3-methylureido)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl]acetate, 13 ml of 8N hydrochloric acid and 65 ml of dioxane is heated at a temperature in the region of 40° C. for 33 hours. The reaction mixture is filtered and the solid is washed with ethyl ether and dried under vacuum (1 mmHg; 0.13 kPa). 0.9 g of (+)-[8-(3-methylureido)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl)acetic acid hydrochloride is obtained in the form of a yellow solid melting above 260° C. (Analysis, % calculated C: 52.38, H: 4.14, Cl: 9.10, N: 17.97, O: 16.42, % found C: 52.4, H: 3.7, N: 17.8; [α]20D =+94.2°).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:31])[CH2:15][NH:16][CH2:17]C(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:3].[CH3:32][N:33]([CH3:43])[C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[S:42])=[CH:36][CH:35]=1>>[CH3:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:31])[CH2:15][N:16]([C:41]([NH:40][C:37]1[CH:38]=[CH:39][C:34]([N:33]([CH3:43])[CH3:32])=[CH:35][CH:36]=1)=[S:42])[CH2:17][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:1]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNCC(c1ccccc1)c1ccccc1
Reactant: CN(C)c1ccc(N=C=S)cc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN(Cc1ccccc1)C(=S)Nc1ccc(N(C)C)cc1

Procedure:
When in the procedure of Example 80 an appropriate amount of the product of Example 71 was substituted for the product of Example 70 and an appropriate amount of 4-dimethylaminophenylisothiocyanate was substituted for ethyl isocyanato acetate the title compound was obtained. Total yield, 0.84 g (80%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH:12]=O)[C:6]=2[CH:5]=[CH:4]1)[CH3:2].[CH3:14][NH2:15].[BH4-].[Na+].O>CO>[CH2:1]([N:3]1[C:11]2[C:6](=[C:7]([CH2:12][NH:15][CH3:14])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)[CH3:2]
Reactant: CCn1ccc2c(C=O)cccc21
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCn1ccc2c(CNC)cccc21
Reaction time: 3 h
Yield: 90.8 %

Procedure:
1-Ethyl-1H-indole-4-carbaldehyde (2.40 mg, 13.8 mmol) was dissolved in anhydrous methanol (62 mL). Methylamine (6.00 mL of 33% solution in ethanol, 48.2 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to a greenish brown oil and then dissolved in anhydrous methanol (62 mL). Sodium borohydride (539 mg, 14.3 mmol) was added and the mixture was stirred overnight at room temperature. Water (90 mL) was added and the solution was concentrated. Sodium hydroxide (15 mL, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×50 mL). Combined organic layers were dried over Na2SO4, filtered and concentrated to afford the title compound ((1-ethyl-1H-indol-4-yl)-N-methylmethanamine) (2.36 g, 91%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.33-7.30 (m, 2H), 7.10-6.97 (m, 2H), 6.52 (d, J=3.0 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 3.88 (s, 2H), 2.30 (s, 3H), 1.33 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)/[C:8](=[CH:16]/[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)/[C:7]1=[O:23])=[O:5])[CH3:2].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]=[N:32][C:33]([O:35][Si](C)(C)C)=[CH2:34])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C:8]2([CH:16]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[CH2:35][C:33](=[O:34])[NH:32][CH:31]2[C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=2)[C:7]1=[O:23])=[O:5])[CH3:2]
Reactant: C=C(N=Cc1ccc(Cl)cc1)O[Si](C)(C)C
Reactant: CCOC(=O)N1C(=O)/C(=C\C2CCCCC2)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1ccc(Cl)cc1)NC(=O)CC2C1CCCCC1
Yield: 72 %

Procedure:
In a manner similar to the method described in example 4c, E/Z-6-chloro-3-cyclohexylmethylene-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.40 g, 1.20 mmol) prepared in example 6b was reacted with 1-(4-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 7a, in toluene to give racemic (2′S,3S,4′R)-6-chloro-2′-(4-chlorophenyl)-4′-cyclohexyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a white solid (Yield 0.45 g, 72%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH2:9]Br)[CH:3]=1.[C-:11]#[N:12].[Na+].CCOC(C)=O.O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH2:9][C:11]#[N:12])[CH:3]=1
Reactant: [C-]#N
Reactant: Fc1ccc(Br)cc1CBr
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1cc(Br)ccc1F
Temperature: 90 °C
Reaction time: 2 h

Procedure:
4-Bromo-2-bromomethyl-1-fluoro-benzene (1.2 g, 3.7 mmol) and sodium cyanide (2.0 g, 4.1 mmol) were combined in DMSO (15 mL) and stirred at 90° C. for 2 hours. Once no starting material was seen by analytical tlc, the mixture was worked-up with EtOAc and H2O to give the title compound.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[C:14]([C:19](O)=[O:20])=[N:15][N:16]([CH3:18])[CH:17]=3)=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:60][C:61]1([CH3:66])[CH2:65][CH2:64][CH2:63][NH:62]1>CN(C=O)C>[CH:1]1([C:4]2[N:9]=[C:8]([C:10](=[N:12][C:13]3[C:14]([C:19]([N:62]4[CH2:63][CH2:64][CH2:65][C:61]4([CH3:66])[CH3:60])=[O:20])=[N:15][N:16]([CH3:18])[CH:17]=3)[OH:11])[C:7]([NH:22][C:23]3[CH:28]=[N:27][CH:26]=[N:25][CH:24]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC1(C)CCCN1
Reactant: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cn1cc(N=C(O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)N2CCCC2(C)C)n1
Reaction time: 8 h
Yield: 7.2 %

Procedure:
To stirred solution of 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid (70 mg, 0.18 mmol) in DMF were sequentially added N-methylmorpholine (0.12 ml, 0.9 mmol), HBTU (210 mg, 0.55 mmol), and 2,2-dimethylpyrrolidine (35 mg, 0.36 mmol) at rt, and the reaction mixture was allowed to stirr overnight. The solvent was removed in vacuo, and the residue was dissolved in EtOAc (10 ml), and was washed with aqueous NaHCO3 solution and water. The aqueous layer was back-extracted with EtOAc, and the combined organic layer was dried (Na2SO4), filtered, and evaporated in vacuo. The crude product was purified by prep. HPLC (column: Gemini C18 (250×21.2 mm, 5μ); elution with a gradient of 0.05% aqueous TFA solution/acetonitrile) to give the title compound (6 mg, 6%) as sticky yellow solid.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[C:8]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]2[O:15][C:16]([CH2:19][N:20]([CH3:22])[CH3:21])=[CH:17][CH:18]=2)=[N:7][C:6]([NH2:23])=[N:5]1.[C:24](=O)([O-])[O-:25].[K+].[K+]>CC(C)=O>[CH3:3][N:4]1[C:8]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]2[O:15][C:16]([CH2:19][N:20]([CH3:21])[CH3:22])=[CH:17][CH:18]=2)=[N:7][C:6]([NH:23][CH:24]=[O:25])=[N:5]1
Reactant: O=C([O-])[O-]
Reactant: CN(C)Cc1ccc(CSCCNc2nc(N)nn2C)o1
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)Cc1ccc(CSCCNc2nc(NC=O)nn2C)o1
Temperature: 5 °C
Yield: 13.9 %

Procedure:
A stirred suspension of 1-methyl-N5 -[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-1H-1,2,4-triazole-3,5-diamine, dihydrochloride (3.83 g) and potassium carbonate (3.04 g) in acetone (60 ml) was heated at reflux for 30 min, and then cooled to 5° C. Aceticformic anhydride (1.32 g) was added and the suspension was allowed to warm up to room temperature. The inorganic material was filtered off and the solution evaporated to give an oil which was chromatographed. The resulting oil was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and evaporated to afford the title compound (0.47 g) as a colourless oil. tlc System B, Rf 0.61. Nmr. (CDCl3) 0.28 brd, (1H); 0.93 d, (1H); 3.81,s, (2H); 5.25, brt (1H); 6.28,s, (2H); 6.47,s, (3H); 6.52 s+m (2H); 7.16,t, (2H) 7.74,s, (6H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.O1CCOCC1.[BH4-].[Na+].Cl>O.CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: OCc1ccc(Cl)cc1F
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
First, 25 g of 4-chloro-2-fluorobenzaldehyde was dissolved in a mixed solvent consisting of 250 ml of 1,4-dioxane and 25 ml of methanol, to which 2.4 g of sodium borohydride was added under ice cooling, and the mixture was stirred for 30 minutes. After completion of the reaction, a small amount of diluted aqueous hydrochloric acid was added, and the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 25 g of 4-chloro-2-fluorobenzyl alcohol.
Reaction SMILES: [Na].FS(O)(=O)=O.[CH2:7]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH2:16])=[NH:15])[CH:8]([CH3:10])[CH3:9].C([O:23][CH:24]=[C:25]([C:31](OCC)=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27])C.C(O)(=O)C>C(O)C>[O:23]=[C:24]1[NH:16][C:14]([C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][CH2:7][CH:8]([CH3:10])[CH3:9])=[N:15][CH:31]=[C:25]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CC(C)COc1ccccc1C(=N)N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: O=S(=O)(O)F
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc(-c2ccccc2OCC(C)C)[nH]c1=O
Temperature: 0 °C
Yield: 84.9 %

Procedure:
To a solution of sodium (161 mg., 7 mg-atoms) in ethanol (10 ml.) was added 2-isobutoxybenzamidine fluorosulfonate (1.02 g., 3.5 mmole). The mixture was warmed to give a clear solution to which was added a solution of diethyl ethoxymethylenemalonate (756 mg., 3.5 mmole) in ethanol (2 ml.). The solution was heated under reflux for 3 hours. The cooled mixture was added to ice-water (50 ml.) and was acidified to pH 5 with glacial acetic acid. After brief stirring, the solid was collected by filtration, washed with water, and dried to give the title compound (0.94 g., 86%), m.p. 90°-91°.