Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][N:24]([C:27]2[S:28][C:29]([C:33](O)=[O:34])=[C:30]([CH3:32])[N:31]=2)[C:23](=[O:36])[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][N:24]([C:27]2[S:28][C:29]([C:33]([NH:1][CH2:2][C:3]3[O:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=3)=[O:34])=[C:30]([CH3:32])[N:31]=2)[C:23](=[O:36])[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Reactant: CCOC(=O)c1ccc(CN)o1
Product: CCOC(=O)c1ccc(CNC(=O)c2sc(-n3ccc(OCc4ccccc4)cc3=O)nc2C)o1
Yield: 67 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use ethyl 5-(aminomethyl)furan-2-carboxylate in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 67% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.85 (t, J=5.6 Hz, 1H), 8.61 (d, J=8.1 Hz, 1H), 7.45-7.33 (m, 5H), 7.20 (d, J=3.5 Hz, 1H), 6.45 (d, J=3.5 Hz, 1H), 6.39 (dd, J=8.1, 2.7 Hz, 1H), 6.23 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.45 (d, J=5.5 Hz, 2H), 4.23 (q, J=7.1 Hz, 2H), 2.54 (s, 3H), 1.24 (t, J=7.1 Hz, 3H); MS (ES+) m/z 494.2 (M+1).
Reaction SMILES: C1(C(=O)CCC(O)=O)C=CC=CC=1.[C:14]1([C:20]2([CH2:25][CH2:26]C(O)=O)[S:24]CC[S:21]2)C=CC=CC=1.[CH:30]([SH:33])([SH:32])[CH3:31]>>[CH2:20]([SH:24])[CH:25]([SH:32])[CH3:26].[CH3:14][CH:20]([SH:21])[CH:30]([SH:33])[CH3:31]
Reactant: CC(S)S
Reactant: O=C(O)CCC1(c2ccccc2)SCCS1
Agent: O=C(O)CCC(=O)c1ccccc1
Product: CC(S)C(C)S
Product: CC(S)CS

Procedure:
In the same manner, 4-phenyl-4-oxobutyric acid is converted to 2-phenyl-1,3-dithiolane-2-propionic acid using ethanedithiol; while the use of 1,2-propanedithiol and 2,3-butanedithiol affords 4-methyl- and 4,5-dimethyl-2-phenyl-1,3-dithiolane-2-propionic acid, respectively.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][O:21][C:22](=[O:39])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])=[O:18].[C:40](Cl)(=[O:56])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>C(OCC)C>[C:40]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][O:21][C:22](=[O:39])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][C:2](=[O:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:18])(=[O:56])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: O=C(CCCCCCCCCCCCCCCO)OCOC(=O)CCCCCCCCCCCCCCCO
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC(=O)OCOC(=O)CCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC
Yield: 88 %

Procedure:
A mixture of methylene bis(16-hydroxyhexadecanoate) (1.0 mmol) and palmitoyl chloride (7.0 mmol) was refluxed in diethyl ether (10 ml) for 24 hours before the solvent was evaporated. The residual material was purified on a silica gel flash column eluting first with hexane/chloroform (2:1) and then with chloroform. Yield 88%, white solid. 1H NMR (CDCl3): δ 0.88 (6 H, t, J 6.7 Hz), 1.2-1.4 (92 H, m), 1.5-1.7 (12 H, m), 2.28 (4 H, t, J 7.5 Hz), 2.35 (4 H, t, J 7.6 Hz), 4.05 (4 H, t, J 6.7 Hz), 5.75 (2 H, s). 13C NMR (CDCl3): δ 14.11, 22.70, 24.64, 25.06, 25.97, 28.70, 29.04, 29.19, 29.25, 29.29, 29.38, 29.47, 29.50, 29.56, 29.62, 29.67, 29.70, 29.71, 31.94, 34.00, 34.43, 64.39, 79.06, 172.59, 173.97.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]2[C:14](=[O:15])[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)[N:6]2[C:20]=1[CH2:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1)=O.[Cl-].[OH:28][NH3+:29].C([O-])(=O)C.[Na+].O>CO>[OH:28][N:29]=[CH:1][C:3]1[N:4]=[C:5]2[C:14](=[O:15])[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:16]([F:17])([F:18])[F:19])[CH:11]=3)[N:6]2[C:20]=1[CH2:21][C:22]1[NH:26][CH:25]=[CH:24][N:23]=1
Reactant: O=Cc1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1Cc1ncc[nH]1
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n2c(Cc3ncc[nH]3)c(C=NO)nc12
Temperature: 70 °C
Yield: 57.8 %

Procedure:
To a solution of 2-formyl-1-(1-imidazolylmethyl)-7-trifluoromethylimidazo[1,2-a]quinoxalin-4(5H)-one (250 mg, 0.69 mmol) in methanol (10 ml) was added a mixture of hydroxylammonium chloride (65 mg, 0.95 mmol) and sodiumacetate (150 mg, 1.10 mmol) in methanol (10 ml). The reaction mixture was heated at 70° C. for 1.5 h, followed by addition of water (10 ml). The precipitate was filtered off and washed with water. Recrystalization from isopropanol/petroleum ether gave 150 mg (58%) of the title compound. M.p. 227.5°-228° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:17])[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[OH:24][CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][C:29]=1[O:37][CH3:38]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:17][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([O:27][CH2:26][CH2:25][OH:24])=[C:29]([O:37][CH3:38])[CH:30]=2)[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)CC)c2c1N
Reactant: COc1cc(C(=O)O)ccc1OCCO
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](CC)NC(=O)c3ccc(OCCO)c(OC)c3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminobutoxy)-2-methylquinoline-3-carboxylate (Example 97b) and 4-(2-hydroxyethoxy)-3-methoxybenzoic acid (Uto, Y. et al. Bioorg. Med. Chem. Lett. 2009, 19, 4151) as brown solid (38%). MS 512 (MH+).
Reaction SMILES: C1(N=C=O)C=CC=CC=1.[CH:10]([P:12]([CH3:16])(=[O:15])[O:13][CH3:14])=[CH2:11].C(N(CC)CC)C.[C:24]1([CH2:30][CH2:31][N+:32]([O-])=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[CH2:30]([C:31]1[CH2:11][CH:10]([P:12]([CH3:16])(=[O:15])[O:13][CH3:14])[O:33][N:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=[N+]([O-])CCc1ccccc1
Reactant: C=CP(C)(=O)OC
Solvent: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COP(C)(=O)C1CC(Cc2ccccc2)=NO1
Yield: 79 %

Procedure:
Preparation is carried out in analogy to Example 23 from 37.1 ml (0.34 mol) of phenyl isocyanate, 22.5 g (0.187 mol) of methyl vinyl(P-methyl)phosphinate, 4 ml of triethylamine and 25.7 g (0.17 mol) of 2-phenylnitroethane in toluene, resulting in 34 g of brown oil.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[O:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[C:8](F)[CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>C(O)C.[Pd]>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[O:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCCCCc1ccc(C=Cc2ccc3c(c2)CCC(=O)O3)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: CCCCCc1ccc(CCc2ccc3c(c2)CCC(=O)O3)cc1
Yield: 68.9 %

Procedure:
Palladium-on-carbon (5%, 0.3 g) was added to a solution of 6-(2-(4-pentyl-2-fluorophenyl)ethenyl)-3,4-dihydrocoumarin (3.2 g) in ethanol (30 ml), and the mixture was stirred in a hydrogen atmosphere for 24 hours. The catalyst was removed from the reaction mixture by filtration, and the resulting solution was concentrated in vacuo and subjected to isolation and purification by silica gel column chromatography, thereby obtaining a while crystal (2.1 g) of a titled compound.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.B(F)(F)F.CCOCC.[OH:20][N:21]=[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[C:38]3[C:37]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[N:36][CH:35]=[N:34][C:33]=3[N:32](COCC[Si](C)(C)C)[CH:31]=2)[CH:25]=1)[NH2:23].O>O1CCCC1>[N:39]1([C:37]2[C:38]3[C:30]([C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([C:22]5[N:23]=[CH:1][O:20][N:21]=5)[CH:25]=4)=[CH:31][NH:32][C:33]=3[N:34]=[CH:35][N:36]=2)[CH2:40][CH2:41][O:42][CH2:43][CH2:44]1
Reactant: CCOC(OCC)OCC
Reactant: C[Si](C)(C)CCOCn1cc(-c2cccc(C(N)=NO)c2)c2c(N3CCOCC3)ncnc21
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: c1cc(-c2ncon2)cc(-c2c[nH]c3ncnc(N4CCOCC4)c23)c1
Temperature: 40 °C

Procedure:
Triethyl orthoformate (760 mg, 5.1 mol) and boron trifluoride diethyl etherate (370 mg, 2.6 mol) were added to a 0° C. solution of N′-hydroxy-3-[4-(morpholin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzenecarboximidamide (C35) (600 mg, 1.3 mmol) in tetrahydrofuran (25 mL). The reaction mixture was heated at 40° C. for 18 hours, then poured into water (50 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated. Purification via preparative reversed phase high-performance liquid chromatography (Column: Phenomenex Gemini C18, 8 μm; Mobile phase A: aqueous ammonia, pH 10; Mobile phase B: acetonitrile; Gradient: 30% to 50% B) provided the product as a yellow solid. Yield: 62 mg, 0.18 mmol, 14%. LCMS m/z 349.0 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.40 (s, 1H), 8.24 (br s, 1H), 7.98 (br d, J=7.5 Hz, 1H), 7.82 (br d, J=7.3 Hz, 1H), 7.63-7.70 (m, 2H), 3.39-3.45 (m, 4H), 3.13-3.20 (m, 4H).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:14][C:13]=2[Cl:27])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:29]([OH:32])[C:30]#[CH:31]>>[Cl:27][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:31]=[C:30]([CH2:29][OH:32])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:28])=[O:11]
Reactant: C#CCO
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Product: Cc1ccc(-n2cc(CO)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 434 (0.125 mmol) and prop-2-yn-1-ol (0.125 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 0:100 to 60:40 as the eluent to afford the title compound.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH2:21])[C:19]=3[N:20]=2)[CH2:6]1.[CH3:22][O:23][CH2:24][CH2:25][C:26](O)=[O:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[NH2:21][C:18]1[C:19]2[N:20]=[C:11]([N:7]3[CH2:8][CH2:9][CH2:10][C@H:5]([NH:4][C:26](=[O:27])[CH2:25][CH2:24][O:23][CH3:22])[CH2:6]3)[CH:12]=[CH:13][C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: COCCC(=O)O
Reactant: Nc1ncnc2ccc(N3CCC[C@H](N)C3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCC(=O)N[C@H]1CCCN(c2ccc3ncnc(N)c3n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
To an 8 mL screw-cap vial was added (S)-6-(3-aminopiperidin-1-yl)pyrido[3,2-d]pyrimidin-4-amine trihydrochloride 44 (0.15 mmol, 53 mg) followed by 3-methoxypropanoic acid (1.2 equiv., 0.18 mmol, 19 mg), HATU (1.2 equiv., 0.18 mmol, 68 mg), dimethylformamide (1 mL), then triethylamine (6 equiv., 0.90 mmol, 0.13 mL). The reaction was capped and shaken at room temperature overnight. The reaction was diluted with 3 mL DCM, and washed with 2 mL water. Organic was concentrated via GeneVac, then purified by reverse phase HPLC, yielding 15 mg of desired product. 1H NMR (400 MHz, DMSO) δ 8.19-8.14 (s, 1H), 7.91-7.83 (d, J=7.0 Hz, 1H), 7.82-7.73 (d, J=9.3 Hz, 1H), 7.44-7.38 (d, J=9.3 Hz, 1H), 7.38-7.18 (m, 2H), 4.25-4.17 (d, J=12.7 Hz, 1H), 4.17-4.08 (d, J=13.8 Hz, 1H), 3.85-3.72 (m, 1H), 3.58-3.48 (m, 2H), 3.23-3.18 (s, 3H), 3.10-2.99 (m, 1H), 2.37-2.28 (m, 2H), 1.90-1.81 (m, 1H), 1.81-1.70 (m, J=8.7 Hz, 1H), 1.63-1.40 (m, 2H). LCMS M/Z (M+H)=331.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[CH:10]=[CH:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]=1.[N:21]#[C:22]Br.ClCCl>ClCCCl.O>[CH3:5][C:6]1[CH:10]=[CH:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:12])=[O:13])[C:7]=1[C:22]#[N:21]
Reactant: Cc1ccc(S(=O)(=O)n2ccc(C)c2)cc1
Reactant: N#CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)n2ccc(C)c2C#N)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Aluminium chloride (19.4 g, 0.15 mol) is added all at once to a solution of 3-methyl-1-(4-methylbenzenesulphonyl)-1H-pyrrole (13.0 g, 55.3 mmol) in 1,2-dichloroethane (230 mL) at ambient temperature. After stirring for 20 minutes, cyanogen bromide (11.11 g, 0.10 mol) is added in portions over a period of 20 minutes. After 4.5 hours, an additional amount of cyanogen bromide (1.94 g, 18.3 mmol) is added. After stirring for 17 hours at ambient temperature, the reaction mixture is poured slowly into a mixture of dichloromethane (300 mL) and water (600 mL) cooled to 0° C. The resulting mixture is stirred for 1 hour. Subsequently the phases are separated and the aqueous phase is extracted with dichloromethane (3×150 mL). The combined organic phases are washed with water (2×150 mL) and brine (150 mL). The organic phase is dried over Na2SO4, filtered and concentrated in vacuo to obtain the expected compound in the form of a solid.
Reaction SMILES: [S:1]1[C:5]2[C:6]([CH2:10][N:11]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH:12]3[CH2:17][CH2:16][N:15](C([O:20][C:21]([CH3:24])(C)C)=O)[CH2:14][CH2:13]3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C1([O:35]C)C=CC=CC=1.F[C:38](F)(F)[C:39]([OH:41])=[O:40]>ClCCl>[C:39]([OH:41])(=[O:40])/[CH:38]=[CH:24]/[C:21]([OH:20])=[O:35].[CH3:27][CH:26]([CH3:28])[CH2:25][N:11]([CH2:10][C:6]1[C:5]2[S:1][CH:2]=[CH:3][C:4]=2[CH:9]=[CH:8][CH:7]=1)[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)CN(Cc1cccc2ccsc12)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccccc1
Solvent: ClCCl
Product: CC(C)CN(Cc1cccc2ccsc12)C1CCNCC1
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
To a solution of 1,1-dimethylethyl 4-{[(1-benzothien-7-yl)methyl]-(2-methylpropyl)amino}-piperidine-1-carboxylate (0.66 g, 1.6 mmol, 1 eq) in dichloromethane (10 ml) is added anisole (2 ml) and trifluoroacetic acid (2 ml). The solution is stirred at room temperature for 16 h. The solvent and trifluoroacetic acid are removed in vacuo. The resulting oil is taken up in methanol and loaded onto an SCX-2 (10 g) column. The column is washed with methanol (50 ml). Basic material is then eluted using 2M ammonia in methanol (50 ml). Removal of solvent from the ammonia/methanol mixture under vacuum, gave the desired compound (0.34 g, 75%) as an oil. This is taken up in diethyl ether (5 ml) and a solution of fumaric acid (0.13 g, 1 eq) in hot methanol (1 ml) is added. The mixture is left at room temperature for 1 hr. The resulting precipitate is collected by filtration to give a white solid, which is dried in a vacuum oven at 40° C. for 16 hours. This gives the title product as a white solid (0.24 g, 35%); mass spectrum (LCMS): m/z=303.1 (M+30 1), Rt=4.72 (12 min gradient); 1H NMR (300 MHz, MeOD): δ=7.81-7.71 (1 H, m), 7.59-7.51 (1 H, m), 7.42-7.29 (3 H, m), 6.69 (2H, s), 3.97 (2 H, s), 3.46-3.38 (2 H, m), 2.96-2.75 (3 H, m), 2.35 (2 H, d), 2.18-2.01 (2 H, m), 1.95-1.65 (3 H, m) and 0.90 (6 H, d).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[CH:5]=1.[CH3:13][S:14]([NH2:17])(=[O:16])=[O:15].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[C:27]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:36])[CH2:26]2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]2[C@:27]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]([CH2:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([NH:17][S:14]([CH3:13])(=[O:16])=[O:15])=[O:12])[C:28]3=[O:36])[CH2:26]2)=[CH:23][CH:24]=1
Reactant: CS(N)(=O)=O
Reactant: O=C1Nc2ccccc2C12CC2c1ccc(Cl)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Product: CS(=O)(=O)NC(=O)c1cccc(CN2C(=O)[C@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 60 starting from 3-bromomethyl-benzoic acid methyl ester, methylsulfonamide (commercially available), (1R,2S) and 1S, 2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C25H21ClN2O4S: 480, observed (M+H)+: 481.2 1HNMR (400 MHz, DMSO-d6) δppm 2.08-2.18 (m, 1 H) 2.35-2.42 (m, 1 H) 2.92 (s, 3 H) 3.13-3.25 (m, 2 H) 4.95-5.13 (m, 2 H) 6.15 (d, 1 H) 6.70 (t, 1 H) 6.87 (d, 1 H) 7.02-7.10 (m, 2 H) 7.30-7.44 (m, 6H) 7.81-7.89 (m, 2 H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[C:5]([Cl:15])[C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1.[F:16][C:17]([F:24])([F:23])[C:18]1[CH:22]=[CH:21][NH:20][N:19]=1>>[Cl:12][C:10]1[C:9]2[C:4](=[C:5]([Cl:15])[C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=[C:2]([N:20]2[CH:21]=[CH:22][C:18]([C:17]([F:24])([F:23])[F:16])=[N:19]2)[CH:11]=1
Reactant: COc1ccc2c(Cl)cc(Cl)nc2c1Cl
Reactant: FC(F)(F)c1cc[nH]n1
Product: COc1ccc2c(Cl)cc(-n3ccc(C(F)(F)F)n3)nc2c1Cl
Temperature: 120 °C
Yield: 50.9 %

Procedure:
A mixture of compound 45d (5 g, 19 mmol) and 3-trifluoromethylpyrazole 86a (7.76 g, 57 mmol) was heated at 120° C. for 4-6 hrs and the reaction was followed by LCMS and TLC. The reaction mixture was purified by silica gel column (mono and dipyrazole were separated) using DCM and heptane as mobile phase to yield compound 119b (3.5 g) in 51% yield.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[C-:18]#[N:19].[Na+].CS(C)=O>O>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14][C:18]#[N:19])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: [C-]#N
Reactant: CCC[C@H]1CC[C@H](c2ccc(CCl)cc2)CC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCC[C@H]1CC[C@H](c2ccc(CC#N)cc2)CC1
Temperature: 140 °C

Procedure:
114 g (0.45 mol) of 4-(trans-4'-propylcyclohexyl) benzyl chloride, 27 g (0.55 mol) of NaCN and 113 cm3 of DMSO were mixed and while stirring, the mixture was heated to a temperature of 140° C. by a mantle heater. The product of the reaction was cooled to room temperature. 400 cm3 of water was added and extracted three times with 100 cm3 of chloroform. The chloroform layers were combined and washed with 10% hydrochloric acid and water. The chloroform was distilled off under reduced pressure and the residue was distilled under reduced pressure (155° C./2.5 mmHg) to yield 106 g (0.44 mol) of 4-(trans-4'-propylcyclohexyl) benzyl cyanide.
Reaction SMILES: [Na+].[C:2]1([S:8]([O-:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][C:17](=[CH2:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].II.C(N(CC)CC)C>C(OCC)(=O)C.O>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16]/[C:17](=[CH:25]\[S:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:10])=[O:9])/[C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19]
Reactant: O=S([O-])c1ccccc1
Reactant: C=C(COCCOC)C(=O)OC(C)(C)C
Agent: II
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: COCCOC/C(=C\S(=O)(=O)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 72 h

Procedure:
To a suspension of benzenesulphinic acid sodium salt (7.59 g, 46.2 mmol) and tert-butyl 2-(2-methoxyethoxymethyl)acrylate (10.0 g, 46.2 mmol) in ethyl acetate (50 mL) under a nitrogen atmosphere at room temperature was added, in one portion, iodine (11.3 g, 46.2 mmol) and the mixture stirred for 3 days. An additional 50 mL of ethyl acetate was added after 2 days. The reaction mixture was cooled to 0° C. and triethylamine (9.67 mL, 69.3 mmol) added dropwise. The reaction was stirred at 0° C. for 2 hours and at room temperature for 16 hours and diluted with distilled water (100 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous layer further extracted with ethyl acetate (25 mL). The combined ethyl acetate extracts were washed with a 1.0M aqueous hydrochloric acid solution and 5% aqueous sodium thiosulphate solution (2×100 mL), filtered to remove solids and the filter pad washed with ethyl acetate. The combined filtrate and washings were washed with distilled water (50 mL), and concentrated under reduced pressure to give a brown oil, (14.85 g). The crude product was purified by chromatography on silica by eluting with hexane/ethyl acetate (2:1) to give, after combination and evaporation of appropriate fractions, the title compound as an oil, (5.09 g, 30.8%) which crystallised on standing, m.pt.=46°-48° C., Rf =0.25 (silica, hexane/ethyl acetate, 2:1), (MH+ 357.05, 1.7%).
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].[NH2:6][C@@H:7]([CH:11]([CH3:13])[CH3:12])[C:8]([OH:10])=[O:9].[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][O:2][C:3]([NH:6][C@@H:7]([CH:11]([CH3:13])[CH3:12])[C:8]([OH:10])=[O:9])=[O:4]
Reactant: COC(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
Methylchloroformate (14.5 mL, 0.188 mol) was added over 15 min to a cooled (0-6° C.) mixture of (S)-2-amino-3-methyl-butyric acid (20.0 g, 0.171 mol), NaOH (6.80 g, 0.171 mol) and sodium carbonate (18.1 g, 0.171 mol) in water (200 mL). The cooling bath was removed and the mixture was stirred at ambient temperature overnight. Conc. aqueous HCl (30 mL) was added to the reaction mixture to adjust pH to ˜1. A solid formed and the mixture was stirred for 90 min. The mixture was filtered and the solid was dried overnight under reduced pressure at 40° C. to provide the title intermediate (27.8 g, 93% yield). 1H NMR (CD3OD, 400 MHz) δ (ppm) 4.87 (br. s, 4H), 4.05 (d, J=5.49, 1 H), 3.65 (s, 3H), 2.25-2.05 (m, 1H), 0.98 (d, J=6.87, 3H), 0.94 (d, J=6.87, 3H).
Reaction SMILES: [C:1](=[S:9])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16]C)=[O:14]>C1COCC1>[C:2]1([C:1]2[S:9][CH:11]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1csc(-c2ccccc2)n1

Procedure:
A solution of benzothioamide (4.0 g, 29.2 mmol) in THF (80 mL) was treated dropwise with ethyl bromopyruvate (7.6 g, 39 mmol) and heated at reflux for 18 hours. The reaction was then concentrated under vacuum, diluted with ethyl acetate, washed with water (1×), brine (1×) and dried over anhydrous magnesium sulfate. The residue obtained after concentration was purified by silica gel chromatography (4.5×11 cm, 20% AcOEt/toluene), followed by a second purification with 20% AcOEt/hexane. The title material was obtained after concentration as a yellow oil (5.25, 77%). 1H NMR (CDCl3, 400 MHz): 8.14 (s, 1H) 8.00 (m, 2H) 7.46-7.42 (m, 3H) 4.43 (q, J=7.0 Hz, 2H) 1.42 (t, J=7.3 Hz, 3H).