Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:41])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][CH2:21][N:22]3[S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)(=[O:27])=[O:26])=[C:18]([O:38][CH3:39])[CH:17]=2)=[O:15])=[CH:9][C:8]=1[F:40])C.O1CCCC1>CO>[F:40][C:8]1[CH:9]=[C:10]([NH:13][C:14]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][CH2:21][N:22]3[S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:37])[F:36])[CH:29]=3)(=[O:26])=[O:27])=[C:18]([O:38][CH3:39])[CH:17]=2)=[O:15])[CH:11]=[CH:12][C:7]=1[C:6]([OH:41])=[O:5]
Reactant: CCOC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC3)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)Nc2ccc(C(=O)O)c(F)c2)cc2c1CCN2S(=O)(=O)c1cccc(C(F)(F)F)c1
Yield: 86 %

Procedure:
A 3 N aqueous KOH solution (2 mL) was added to a solution of 2-fluoro-4-{[4-methoxy-1-(3-trifluoromethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid ethyl ester (14.4 mg, 0.03 mmol, 1 equiv.) in 2:1 tetrahydrofuran:methanol (3 mL) and the mixture was shaken for 16 hours. The mixture was concentrated under a stream of N2 and the pH adjusted to 1 with 3 N aqueous HCl solution (2 mL). The mixture was extracted with 1:1 CHCl3:IPA (3×1 mL). The organic layers were combined, dried over Na2SO4 and the solvent was removed under reduced pressure to afford 2-fluoro-4-{[4-methoxy-1-(3-trifluoromethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, 12 mg (86% yield). LC @215 nm; Rt 2.27: 98%, m/z (ES+): 539 (M+H+.); δH (400 MHz; d6-Acetone) 10.69 (1H, br. s), 8.03 (2H, m), 7.90 (1H, d), 7.86-7.81 (3H, m), 7.82-7.72 (2H, m), 7.50 (1H, d), 7.21 (1H, s), 3.98 (2H, t), 3.74 (3H, s), 2.82 (2H, t).
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][O:6][C:7]1[C:16]([N:17]2[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][C:25]3[CH:29]=[CH:28][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:26]=3)[CH2:19][CH2:18]2)=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[CH3:36])C.[OH-].[Na+].Cl>C1COCC1>[CH3:36][C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([N:17]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][C:25]4[CH:29]=[CH:28][N:27]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:26]=4)[CH2:19][CH2:18]3)[C:7]=1[O:6][CH2:5][C:4]([OH:37])=[O:3])[N:14]=[CH:13][CH:12]=[CH:11]2
Reactant: CCOC(=O)COc1c(C)cc2cccnc2c1N1CCCN(Cc2ccn(-c3ccccc3)n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc2cccnc2c(N2CCCN(Cc3ccn(-c4ccccc4)n3)CC2)c1OCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
A mixture of {6-methyl-8-[4-(1-phenyl-1H-pyrazol-3-ylmethyl)-[1,4]diazepan-1-yl]-quinolin-7-yloxy}-acetic acid ethyl ester (500 mg, 1.0 mmol) and 2 N NaOH (1 ml, 2 mmol) in THF (3 ml) was stirred at rt for 3 hrs. The solution was then neutralized with 1 N HCl, extracted with mixed solvent (CH2Cl2:iPrOH 80:20) and purified by flash column chromatography on silica gel to give a light yellow solid (300 mg, 64%). MS (ES) m/z 472.2 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([SH:18])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][S:18][C:9]1[NH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1)[CH3:28]
Reactant: Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Yield: 68 %

Procedure:
Part A. To a solution of 4,5-diphenyl-2-imidazolethiol (25.2 g, 0.1 mol) in N,N-dimethylformamide (250 mL) was added, dropwise, a solution of ethyl 5-bromopentanoate (23.73 mL, 31.35 g, 0.15 mol) in N,N-dimethylformamide (80 mL), and the reaction mixture was stirred at reflux under nitrogen for 18 hours. The reaction mixture was cooled, poured into 5% sodium bicarbonate and ice, and then extracted with ethyl acetate. The combined organic extracts were washed sequentially with 5% sodium bicarbonate, water, saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under vacuum. The residue was chromatographed with 7:3 hexane-ethyl acetate, and the resulting solid was recrystallized from acetonitrile and triturated with hexane to give 5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentanoic acid ethyl ester (25.95 g, 0.068 mol) as a white solid, mp 87°-89°. 1H NMR (DMSO-d6) δ7.55-7.15(m,11H), 4.0(q,2H,J=8Hz), 2.9(t,2H,J=7Hz), 2.3(t,2H,J=7Hz), 1.9-1.6(m,4H), 1.2(t,3H,J=8Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:26]2[CH2:28][CH2:27]2)[N:9]2[CH2:14][CH2:13][C:12]([CH2:21][C:22]([CH3:24])=[CH2:23])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:11][C:10]2=[O:25])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:34].[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:26]2[CH2:28][CH2:27]2)[N:9]2[CH2:14][CH2:13][C:12]([CH2:21][C:22]3([CH3:24])[CH2:23][O:34]3)([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:11][C:10]2=[O:25])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)CC1(c2ccccc2)CCN(C(c2ccc(Br)cc2)C2CC2)C(=O)O1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC1(CC2(c3ccccc3)CCN(C(c3ccc(Br)cc3)C3CC3)C(=O)O2)CO1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
3-[(4-Bromo-phenyl)-cyclopropyl-methyl]-6-(2-methyl-allyl)-6-phenyl-[1,3]oxazinan-2-one (diastereomer 2 from Step 3; 1.60 g) dissolved in dichloromethane (15 mL) was added to a solution of 3-chloroperoxybenzoic acid (77%, 0.94 g) in dichloromethane (15 mL) cooled to 5° C. The solution was stirred at room temperature for 3 h, before another portion of 3-chloroperoxybenzoic acid (77%, 0.13 g) was added. After stirring the solution at room temperature for another 1.5 h, aqueous 10% Na2S2O3 solution (10 mL) and aqueous saturated NaHCO3 solution (10 mL) were added and the resulting mixture was stirred for further 30 min. Dichloromethane (20 mL) was added and the organic phase was separated and washed with a 1:1 mixture of aqueous 10% Na2S2O3 solution and aqueous saturated NaHCO3 solution. Then the organic phase was washed with water, dried (MgSO4), and concentrated to furnish the title compound. Yield: 1.86 g (ca. 85-90% pure, quantitative); LC-MS (Method 1): tR=4.00 min; Mass spectrum (ESI+): m/z=456/458 (Br) [M+H]+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:10]([F:11])=[CH:9][C:8]([Br:12])=[CH:7][C:6]=1[F:13])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[Br:12][C:8]1[CH:7]=[C:6]([F:13])[C:5]([CH2:4][NH2:1])=[C:10]([F:11])[CH:9]=1
Reactant: [N-]=[N+]=NCc1c(F)cc(Br)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1c(F)cc(Br)cc1F
Temperature: 55 °C

Procedure:
To a mixture of the crude azide (330 mg, 1.33 mmol) in THF (12 mL) were added polymer-supported Ph3P (2.0 eq.) and water (2 mL). The reaction mixture was stirred at 55° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The aq. layer was extracted with EA and the combined org. extracts dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a yellow solid. LC-MS-conditions 02: tR=0.54 min; [M+CH3CN+H]+=263.45.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([OH:13])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:36][CH2:37][C:38]1[N:42]([C:43]2[S:44][C:45]([CH2:57][CH3:58])=[CH:46][C:47]=2[C:48](=[O:56])[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[Cl:55])[C:41]([CH3:59])=[N:40][N:39]=1.C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:55][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=1[C:48]([C:47]1[CH:46]=[C:45]([CH2:57][CH3:58])[S:44][C:43]=1[N:42]1[C:41]([CH3:59])=[N:40][N:39]=[C:38]1[CH2:37][NH:36][C:11]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[CH3:1])=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:13])=[O:56]
Reactant: Cc1c(C(=O)O)[nH]c2ccccc12
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)c2[nH]c3ccccc3c2C)s1
Reaction time: 6 h
Yield: 14.9 %

Procedure:
3-Methylindole-2-carboxylic acid (0.5 g) and 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (2.1 g) was dissolved in DMF (42 ml). Triethylamine (1.6 ml) and Bop reagent (1.32 g) were added under ice-cooling, and the mixture was stirred for 6 hours. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous citric acid solution, saturated brine, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate and methanol as an eluent and recrystallized from a mixed solvent of ethyl acetate and hexane to give 0.22 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-yl-methyl)-3-methyl-1H-indole-2-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:12]([C:20]#[N:21])=[CH:11][C:10]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1.[Cl:29][CH2:30][C:31](Cl)=[O:32]>>[Cl:29][CH2:30][C:31]([N:15]([C:13]1[C:12]([C:20]#[N:21])=[CH:11][C:10]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[N:14]=1)[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:32]
Reactant: CC(C)CNc1nc(-c2ccc(F)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Reactant: O=C(Cl)CCl
Product: CC(C)CN(C(=O)CCl)c1nc(-c2ccc(F)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N

Procedure:
The product of Step A was reacted with chloroacetyl chloride using conditions similar to EXAMPLE 62 Step A to afford the title compound. HPLC/MS: 489.9 (M+1), 491.8 (M+3); Rt=4.40 min.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[C:17](Cl)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]>ClCCl>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Reactant: CCCCC(=O)Cl
Solvent: ClCCl
Product: CCCCC(=O)Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 71.9 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.10 g, 0.46 mmol), valeryl chloride (0.055 mL, 0.46 mmol), and poly(vinylpyridine) (0.5 g) in dichloromethane (12 mL) provided N-6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-ylpentanamide (0.099 g). MS m/z 300 ([M+H]+); HRMS: calcd for C19H25NO2 +H+, 300.19581; found (ESI, [M+H]+), 300.1950.
Reaction SMILES: [Cl:1][CH2:2][C:3]#[C:4][CH2:5][Cl:6].[Cl:7][SiH:8]([Cl:10])[Cl:9]>C(O)(C)C>[Cl:1][CH2:2][C:3]([Si:8]([Cl:10])([Cl:9])[Cl:7])=[CH:4][CH2:5][Cl:6]
Reactant: Cl[SiH](Cl)Cl
Reactant: ClCC#CCCl
Solvent: CC(C)O
Product: ClCC=C(CCl)[Si](Cl)(Cl)Cl
Yield: 93.6 %

Procedure:
To a mixture of 15 ml (0.153 mol) of 1,4-dichloro-2-butyne and 13.6 ml (0.16 mol) of trichlorosilane (boiling point: 31°-32° C.) was added 0.15 ml (10 mmol) of an isopropyl alcohol solution of H2PtCl6.6H2O (0.05 g/ml), followed by heating for 8 hours. Thereafter, the mixture was directly distilled to obtain 37 g of 1,4-dichloro-2-(trichloro)silyl-2-butene. Yield: 94%. Boiling point: 70° C./1 mmHg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[N:13][OH:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:16][CH2:17][O:18][CH2:19][CH2:20]Br.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[F:10][C:9]([F:12])([F:11])[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:1]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:3]=1)=[N:13][OH:14]
Reactant: Nc1cccc(C(=NO)C(F)(F)F)c1
Reactant: BrCCOCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: ON=C(c1cccc(N2CCOCC2)c1)C(F)(F)F
Yield: 89.3 %

Procedure:
A mixture of 1-(3-aminophenyl)-2,2,2-trifluoroethanone oxime (1.7 g), bromoethyl ether (2.246 g), and i-Pr2NEt (2.57 g) in toluene (20 mL) was refluxed for 4 hours. After cooling, the reaction mixture was quenched with water. The aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over magnesium sulphate, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (50% ethyl acetate in hexane) to give the title compound as an oil (2.04 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[N:15]([C:16]=2[C:17](=[O:19])[CH3:18])[CH:14]=[CH:13][S:12]3)[CH:6]=[CH:7][CH:8]=1>COC(OC)N(C)C>[CH3:14][N:15]([CH3:16])[CH:11]=[CH:18][C:17]([C:16]1[N:15]2[C:11]([S:12][CH:13]=[CH:14]2)=[N:10][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:19]
Reactant: COc1cccc(-c2nc3sccn3c2C(C)=O)c1
Agent: COC(OC)N(C)C
Product: COc1cccc(-c2nc3sccn3c2C(=O)C=CN(C)C)c1
Temperature: 25 °C
Yield: 165.7 %

Procedure:
A 100 ml round bottom flask was charged with the 1-[6-(3-methoxyphenyl)imidazo [2,1-b][1,3]thiazol-5-yl]ethanone (17.95 g, 62 mmol) and dimethylformamide dimethylacetal (120 ml). The mixture was refluxed for 72 hours and then cooled to room temperature. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (ethyl acetate), giving a pale yellow solid (16.82 g). 300 MHz 1H NMR (DMSO-d6) δ: 8.40 (d, J=4.4 Hz, 1H), 7.59 (d, J=12.5 Hz, 1H), 7.41 (d, J=4.4 Hz, 1H), 7.37 (t, J=7.7 Hz, 1H), 7.17-7.21 (m, 2H), 6.99-7.03 (m, 1H), 5.15 (d, J=12.5 Hz, 1H), 3.79 (s, 3H), 3.04 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)([CH:9]([CH3:11])[CH3:10])[CH2:5][CH2:6][CH2:7]Br.[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][CH2:30][CH2:31][NH:32][CH3:33].N1C2C=CC=CC=2NC=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)([CH:9]([CH3:11])[CH3:10])[CH2:5][CH2:6][CH2:7][N:32]([CH2:31][CH2:30][CH2:29][C:21]1[NH:20][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=1)[CH3:33]
Reactant: CNCCCc1nc2ccccc2[nH]1
Reactant: COC(=O)C(CCCBr)(c1ccc(Br)cc1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc2[nH]cnc2c1
Solvent: CCO
Product: COC(=O)C(CCCN(C)CCCc1nc2ccccc2[nH]1)(c1ccc(Br)cc1)C(C)C

Procedure:
After the 5-bromo-2-(4-bromophenyl)-2-isopropylpentanoic acid methyl ester (1 g, 1 eq) was dissolved in ethanol, [3-(1H-benzimidazole-2-yl)propyl]methylamine (0.66 g, 1 eq) as a benzimidazole derivative, and potassium carbonate (0.58 g, 1.2 eq) were added into the solution and heated and refluxed for 3 hours. When the reaction was completed, the precipitate was filtrated and the solvent was removed at low pressures. The target compound 5-{[3-(1H-benzimidazole-2-yl)propyl]methylamino}-2-(4-bromophenyl)-2-isopropyl pentanoic acid methyl ester was obtained by separation and purification of the mixture using a column chromatography (ethyl acetate:methanol=10:1) (635 mg, 36%).
Reaction SMILES: [O:1]1[C:5]2([CH2:9][CH2:8][CH:7](/[CH:10]=[C:11](\[C:22]3[NH:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[CH:23]=3)/[C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH2:6]2)[O:4][CH2:3][CH2:2]1>[Pd].CO>[O:4]1[C:5]2([CH2:9][CH2:8][CH:7]([CH2:10][CH:11]([C:22]3[NH:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[CH:23]=3)[C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CS(=O)(=O)c1ccc(/C(=C/C2CCC3(C2)OCCO3)c2cc3cccnc3[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCC3(C2)OCCO3)c2cc3cccnc3[nH]2)cc1
Temperature: 50 °C
Yield: 56.9 %

Procedure:
A mixture of (Z)-2-[2-(1,4-dioxa-spiro[4.4]non-7-yl)-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (enantiomer 2, 150 mg, 0.35 mmol) and 10% palladium on activated carbon (45 mg) in methanol (250 mL) was heated at 50° C. under hydrogen (50 psi) for 5 h. The mixture was cooled to 25° C., the catalyst filtered off, washed with ethyl acetate and concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[2-(1,4-dioxa-spiro[4.4]non-7-yl)-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (85 mg, 56%): LC/MS m/e calcd for C23H26N2O4S [M+H]+ 427.54, observed 427.1.
Reaction SMILES: Br[CH:2]([CH3:37])[C:3]([C:5]1[CH:6]=[C:7]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[C:8](=[O:22])[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:10]=1[CH3:11])=O.[NH2:38][C:39]([NH2:41])=[S:40].CC([O-])=O.[Na+]>CCO>[CH3:36][S:33]([C:30]1[CH:29]=[CH:28][C:27]([CH2:26][NH:25][C:23]([C:7]2[C:8](=[O:22])[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)[C:10]([CH3:11])=[C:5]([C:3]3[N:38]=[C:39]([NH2:41])[S:40][C:2]=3[CH3:37])[CH:6]=2)=[O:24])=[CH:32][CH:31]=1)(=[O:34])=[O:35]
Reactant: Cc1c(C(=O)C(C)Br)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1sc(N)nc1-c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Temperature: 90 °C
Yield: 67.3 %

Procedure:
5-(2-Bromopropanoyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (Example 53 (b), 0.04 g, 0.067 mmol), thiourea (0.0067 g, 0.086 mmol), NaOAc (0.011 g, 0.136 mmol), EtOH (2 ml) and a magnetic stirrer bar were placed in a tube designed for microwave synthesis. The vial was sealed and the mixture was heated in a CEM Discover Microwave apparatus (100 W, 90° C.) for 20 minutes, giving complete conversion of the starting material to a single product according to LC-MS. The solvents were evaporated to give a crude mixture which was purified on preparative HPLC, giving the title compound (0.026 g, 66%) as a slightly yellowish solid after freeze-drying the pure fractions.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-:2].CC(C)([O-])C.[K+].[CH:15]1([C:18](Cl)=[O:19])[CH2:17][CH2:16]1>C1COCC1>[CH:15]1([C:18]2[O:19][CH:2]=[N:1][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:17][CH2:16]1
Reactant: O=C(Cl)C1CC1
Reactant: [C-]#[N+]CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncoc1C1CC1

Procedure:
A mixture of ethyl isocyanoacetate (13.4 g) in THF (65 ml) was added dropwise to a stirred solution of potassium tert-butoxide (14.5 g) in THF (97 ml) at 0° C. Cyclopropanecarboxylic acid chloride (5.4 ml) was added dropwise at below 10° C. and the solvent evaporated. Water (68 ml) and acetic acid (3.4 ml) was added to the mixture, then diisopropyl ether (2×150 ml) was added and the layers separated. The aqueous layer was further extracted with diisopropyl ether (2×150 ml) and the combined organic extracts were dried. Evaporation of the solvent afforded the title compound as a yellow oil (8.3 g).
Reaction SMILES: [C:1](Cl)(=[O:14])[O:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1.[NH:16]1[CH2:20][CH:19]=[CH:18][CH2:17]1.C1COCC1>C([O-])(O)=O.[Na+]>[N:16]1([C:1]([O:2][CH2:3][C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=2)=[O:14])[CH2:20][CH:19]=[CH:18][CH2:17]1
Reactant: O=C(Cl)OCc1ccc2ccccc2c1
Reactant: C1=CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccc2ccccc2c1)N1CC=CC1
Reaction time: 12 h
Yield: 75 %

Procedure:
Naphthalen-2-ylmethyl carbonochloridate (31.93 g, 144.7 mmol) was added to a solution of 2,5-dihydro-1H-pyrrole (10 g, 144.7 mmol) in a 1:1 mixture of saturated NaHCO3 (400 mL) and THF (400 mL). The reaction was stirred for 12 hours, condensed to a small volume, diluted with saturated NaHCO3, extracted with CH2Cl2, wash with 1 N HCl, dried over sodium sulfate, filtered and condensed to afford 27.5 g of the desired product as a solid.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[N+:21]([O-])=O)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([F:34])[CH:33]=1)[C:28](Cl)=[O:29].Cl>N1C=CC=CC=1>[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([F:34])[CH:33]=1)[C:28]([NH:21][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[CH:19]=[CH:20][C:11]([NH:10][C@H:1]1[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]1)=[N:12]2)=[O:29]
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: O=[N+]([O-])c1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-Indan-1-yl-(5-nitro-quinolin-2-yl)-amine (0.15 g, 0.545 mmol) was dissolved in 1.5 mL pyridine and 3,5-difluorobenzoylchloride (0.98 g, 0.554 mmol) was added. The reaction mixture was stirred at room temperature overnight. 1 N HCl was added until pH5. The mixture was extracted three times with ethyl acetate (50 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The crude product was recrystallized from isopropanol and diisopropylether. The title compound was obtained as a brown solid (44 mg, 19%), MS: m/e=416.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:14][CH2:15][CH2:16]Br>CS(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2([C:7]#[N:8])[CH2:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CC1(c2ccc(Cl)cc2)CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
4-Chlorobenzyl cyanide (10 g) in dry DMSO (20 ml) was added over 5 min to a stirred suspension of sodium hydride (4.4 g) in DMSO at 25° C. under argon. The mixture was stirred for 30 minutes then a solution of 1,3-dibromopropane (27 g) in dry DMSO (50 ml) was added over 30 minutes while maintaining the temperature of the reaction mixture at 25°-30° C. After stirring an additional 40 minutes at this temperature the reaction mixture was added to ice water (500 ml) and extracted with dichloromethane (3×75 ml). The extracts were evaporated and the residue extracted with diethyl ether (4×50 ml). The ether extracts were washed with water, dried over anhydrous sodium sulphate and evaporated to yield an oil (10.8 g) which on distillation gave the nitrile [bp 90°/10-6Torr.] yield 5.4 g (43%).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>>[N:17]1([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:16]3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(N3CCCC3)cc2C1
Agent: Cl
Product: c1cc2c(cc1N1CCCC1)CNC2

Procedure:
Prepared in analogy to Example A3 (e) from 5-Pyrrolidin-1-yl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and HCl. Brown oil. MS (m/e): 189.6 (M+H+, 100%).