Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: IC1C=CC=CC=1C(Cl)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([F:33])[CH:27]=1.[I:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42]>C1(C)C=CC=CC=1.C(O)C>[I:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:44]([NH:43][C:41](=[O:42])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[I:34])=[S:45])=[C:28]([F:33])[CH:27]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1ccccc1I
Agent: O=C(N=C=S)c1ccccc1I
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4I)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
2-Iodo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-iodo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-iodo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (86 mg, yield 90%).
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](Cl)=[N:18][N:17]=1.CCN(CC)CC.CN1C(=O)CCC1>O>[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=3)[CH2:6][CH2:5]2)=[N:18][N:17]=1
Reactant: N#Cc1ccc(N2CCNCC2)nc1
Reactant: Clc1nnc(Cl)c2ccccc12
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(N2CCN(c3nnc(Cl)c4ccccc34)CC2)nc1
Temperature: 80 °C
Yield: 51.1 %

Procedure:
To a 100-mL round-bottom flask is added 6-piperazin-1-yl-nicotinonitrile (9.60 g, 50 mmol), 1,4-dichlorophthalazine (11.2 g, 55.1 mmol, 1.1 eq), Et3N (3.5 mL, 250 mmol, 5 eq.), and NMP (100 mL). The mixture is heated to 80° C. for 2.5 h. Upon cooling to room temperature, the reaction is poured into H2O (500 mL) and the precipitate isolated by filtration, rinsing with additional H2O. Crude material is purified by recrystallization (CH2Cl2:heptanes) to afford 8.96 g title compound as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]([N:18]=[C:19]=[O:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:19]([NH:18][C:10](=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:20])#[N:5]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: N#Cc1ccccc1N
Product: N#Cc1ccccc1NC(=O)NC(=O)c1ccccc1

Procedure:
Prepared as in Example 1a from 2-aminobenzonitrile and benzoyl isocyanate as a white powder (661 mg, 59%). 1H NMR (400 MHz, DMSO-d6) δ7.27-7.29 (t, 1H), 7.52-7.56 (t, 1H), 7.64-7.74 (m, 2H), 7.82-7.85 (dd, 1H), 8.02-8.04 (m, 2H), 8.22-8.24 (d, 1H). MS 266 (MH+).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(Cc2ccc(F)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccc(F)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
A mixture of hydroxylammonium chloride (1.7 g), sodium hydrogen carbonate (2.74 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(4-fluorobenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.76 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.32 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.27 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.55 g, 65%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:35][OH:36])=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46].O>CN(C)C=O>[F:1][C:2]1[C:3]([CH2:35][O:36][S:45]([CH3:44])(=[O:47])=[O:46])=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:30])([CH3:32])[CH3:31]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(CO)c(F)c3o2)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(COS(C)(=O)=O)c(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
3.30 g (6.55 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-hydroxymethyl-5-pivaloylamino-4H-1-benzopyran-4-one obtained in Example 118 (4) was dissolved in 70 mL of dimethylformamide, 4.6 mL of triethylamine and 1.0 mL of methanesulfonyl chloride were added under ice-cooling and the mixture was stirred at room temperature for 10 minutes. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 3.57 g of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methanesulfonyloxymethyl-5-pivaloylamino-4H-1-benzopyran-4-one (yield: 94%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=2[F:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][CH:25]([NH2:27])[CH3:26].Cl.C(N=C=NCCCN(C)C)C.O.N1(O)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.O>[F:23][C:15]1[CH:16]=[C:17]([C:18](=[O:20])[NH:27][CH:25]([CH3:26])[CH3:24])[CH:21]=[CH:22][C:14]=1[N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2F)CC1
Reactant: CC(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)NC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-fluorobenzoic acid (1.1 g, 3.39 mmol), propan-2-amine (0.241 g, 4.07 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.975 g, 5.09 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol hydrate (0.779 g, 5.09 mmol) were suspended in DMF (Volume: 13.57 ml) and 4-methylmorpholine (1.864 ml, 16.96 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 h. It was diluted with water (50 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (3×50 mL), dried (MgSO4) and concentrated in vacuo to afford tert-butyl 4-(2-fluoro-4-(isopropylcarbamoyl)phenyl)piperazine-1-carboxylate (1.11 g, 3.04 mmol, 89% yield) as an off-white solid. ESI-MS: m/z 366 (M+H)+.
Reaction SMILES: [ClH:1].[OH:2][NH:3][C:4]([C:6]1([S:15]([C:18]2[CH:23]=[CH:22][C:21]([S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:11][CH2:10][N:9](CC#C)[CH2:8][CH2:7]1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[F:37]C1C=CC(S)=CC=1>CN(C=O)C.C(OCC)(=O)C>[ClH:1].[F:37][C:28]1[CH:29]=[CH:30][C:25]([S:24][C:21]2[CH:22]=[CH:23][C:18]([S:15]([C:6]3([C:4]([NH:3][OH:2])=[O:5])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]3)(=[O:17])=[O:16])=[CH:19][CH:20]=2)=[CH:26][CH:27]=1
Reactant: C#CCN1CCC(C(=O)NO)(S(=O)(=O)c2ccc(Sc3ccccc3)cc2)CC1
Reactant: Fc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NO)C1(S(=O)(=O)c2ccc(Sc3ccc(F)cc3)cc2)CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
Part A: To a solution of the sulfone of Example 9, part D (6.0 g, 14.4 mmol) in DMF (30 mL) were added potassium carbonate (2.39 mg, 17.3 mmol) and 4-fluorothiophenol (3.0 mL, 28.1 mmol), and the solution was stirred at ambient temperature for 18 hours. The solution was diluted with ethyl acetate and washed with 1N NaOH and saturated NaCl, and then dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfide as a solid (6.6 g, 87%).
Reaction SMILES: [CH:1]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].O>ClCCl>[CH3:17][S:18]([O:9][CH2:8][CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCC1CCCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103 %

Procedure:
To a solution of cycloheptylmethanol (1.0 g, 7.81 mmol) in dichloromethane (20 ml) at 0° C. under nitrogen was added triethylamine (1.63 ml, 1.5 mol. equiv.) Methanesulphonyl chloride (0.73 ml, 1.2 mol. equiv.) was added, dropwise, and the reaction allowed to stir for two hours at room temperature. Water (50 ml) and dichloromethane (50 ml) were added. The organic phase was separated, washed with water (2×50 ml) and then dried over anhydrous magnesium sulphate. The solution was then filtered and the solvent removed under reduced pressure to give the title compound as an oil (1.66 g).
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4]CCCCCCCC/C=C\CCCCCCCC.[CH:25](=[O:34])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(=[O:48])CCCCCCCCCCCC>>[C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C:25]([OH:48])=[O:34]
Reactant: CCCCCCCCCCCCC=O
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCC=O
Product: O=C(O)CCCCCCCCCCCC(=O)O

Procedure:
338.58 g (1 mol) of erucic acid (purity 95%) were ozonized in analogy to Example 1 and then hydrogenation was carried out. The hydrogenation solution obtained in this way contained nonanal and tridecanealdehyde acid and was divided by distillation. For oxidation, the corresponding aldehyde fraction was employed and was oxidized at 14 bar in analogy to Example 1. 185 g of tridecanedioic acid per cycle were obtained with a purity of 95%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:40])([CH2:32][Si](OC(C)C)(C)C)[C@H:10]([N:12]1[C:16](=[O:17])[N:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])=[CH:20][CH:19]=2)[CH:14]=[N:13]1)[CH3:11].C(=O)([O-])[OH:42].[Na+]>CO.O1CCCC1.OO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:40])([CH2:32][OH:42])[C@H:10]([N:12]1[C:16](=[O:17])[N:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])=[CH:20][CH:19]=2)[CH:14]=[N:13]1)[CH3:11]
Reactant: CC(C)O[Si](C)(C)C[C@](O)(c1ccc(F)cc1F)[C@@H](C)n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(CO)c1ccc(F)cc1F
Yield: 90.5 %

Procedure:
2-[(1R,2S)-2-(2,4-Difluorophenyl)-2-hydroxy-3-(isopropoxydimethylsilyl)-1-methylpropyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (11 g) was dissolved in a mixture of methanol and tetrahydrofuran (1:1, 90 ml), to which 19.2 ml of 30% aqueous hydrogen peroxide and 1.57 g of sodium hydrogencarbonate were added. Then, the mixture was heated at 70° to 80° C. for 90 minutes. The reaction solution was cooled and extracted with a mixture of 500 ml of ethyl acetate and 100 ml of diisopropyl ether. The extract was washed with 100 ml of water, an aqueous solution of Na2S2O3 (50 ml×2) and 50 ml of an aqueous solution of sodium chloride successively, and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was recrystallized from 50 ml of diisopropyl ether to give 8.27 g of 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-dihydroxy-1-methylpropyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone as colorless prisms. The mother liquor of recrystallization was submitted to silica gel chromatography (silica gel: 40 g, eluent; hexane:ethyl acetate=1:1). The resultant was recrystallized from diisopropyl ether to give 0.33 g of the above compound (total yield: 93.7%).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18](=[O:29])[CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1.[C:32](Cl)(=[O:34])[CH3:33].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:31][C:2]([F:1])([F:30])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18](=[O:29])[CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([C:32](=[O:34])[CH3:33])[CH:21]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)Cl
Reactant: O=C(Nc1cccc(OC(F)(F)F)c1)[C@@H]1CCCN1C(=O)Cc1c[nH]c2ccccc12
Agent: CN(C)c1ccncc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Product: CC(=O)n1cc(CC(=O)N2CCC[C@H]2C(=O)Nc2cccc(OC(F)(F)F)c2)c2ccccc21
Temperature: 80 °C

Procedure:
To a solution of (S)-1-(2-1H-indol-3-yl-acetyl)-pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl)-amide (100 mg, 0.232 mmol) in DMF (1.5 mL) under nitrogen atmosphere were added acetyl chloride (148 μl, 2.09 mmol) followed by DMAP (85 mg, 0.7 mmol) and the reaction mixture was heated at 80° C. for 18 h. After completion of the reaction, the mixture was poured into citric acid (10% solution), and extracted three times with EtOAc. The combined organic layers were washed twice with water, dried over Na2SO4, filtered and concentrated. The crude material was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19×50 mm, 20% CH3CN/H2O 2.5 min, 20-100% CH3CN/H2O in 10 min, CH3CN/H2O containing 0.1% HCOOH flow: 20 mL/min) to give after lyophilization of the purified fractions the desired compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](Cl)=[O:32])=[CH:26][CH:25]=1>C1COCC1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[O:32])=[CH:26][CH:25]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)Cc3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and (4-fluorophenyl)acetyl chloride: ESMS m/e: 440.3 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:6]1[C:14]2[C:9](=[C:10]([CH2:15][CH2:16][CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=O.[CH3:30][C:31]1([CH3:47])[C:40]2[C:35]3=[C:36]([C:41]([CH2:43][C:44]([NH2:46])=[O:45])=[CH:42][N:34]3[CH2:33][CH2:32]1)[CH:37]=[CH:38][CH:39]=2>>[CH:26]([Si:19]([CH:20]([CH3:22])[CH3:21])([CH:23]([CH3:25])[CH3:24])[O:18][CH2:17][CH2:16][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[NH:8][CH:7]=[C:6]2[C:4]1[C:3](=[O:2])[NH:46][C:44](=[O:45])[C:43]=1[C:41]1[C:36]2=[C:35]3[C:40](=[CH:39][CH:38]=[CH:37]2)[C:31]([CH3:47])([CH3:30])[CH2:32][CH2:33][N:34]3[CH:42]=1)([CH3:27])[CH3:28]
Reactant: COC(=O)C(=O)c1c[nH]c2c(CCCO[Si](C(C)C)(C(C)C)C(C)C)cccc12
Reactant: CC1(C)CCn2cc(CC(N)=O)c3cccc1c32
Product: CC(C)[Si](OCCCc1cccc2c(C3=C(c4cn5c6c(cccc46)C(C)(C)CC5)C(=O)NC3=O)c[nH]c12)(C(C)C)C(C)C

Procedure:
Beginning with 7-((triisopropylsilyloxy)propyl)indole-3-glyoxylic acid methyl ester and 2-(6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:18]([F:27])[CH:17]=2)[CH:9]=1)([CH3:7])[CH3:6])C.[OH-].[Li+]>C(O)C.O1CCCC1>[F:27][C:18]1[CH:17]=[C:16]([C:15]#[C:14][C:10]2[CH:9]=[C:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:28])=[O:3])[CH:13]=[CH:12][CH:11]=2)[CH:21]=[CH:20][C:19]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: CCOC(=O)C(C)(C)c1cccc(C#Cc2ccc(CC(=O)OC)c(F)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)Cc1ccc(C#Cc2cccc(C(C)(C)C(=O)O)c2)cc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 103.7 %

Procedure:
A solution of 2-[3-(3-fluoro-4-methoxycarbonylmethyl-phenylethynyl)-phenyl]-2-methyl-propionic acid ethyl ester (Intermediate 134, 0.13 g, 0.34 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was treated with 2M lithium hydroxide (1 mL, 2 mmol) and the resulting reaction mixture was stirred at ambient temperature for 45 minutes. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product (0.125 g, ˜100%).
Reaction SMILES: [Br:1]Br.[CH:3]([CH:6]1[C:14]2[C:9](=[CH:10][C:11]([CH3:15])=[CH:12][CH:13]=2)[C:8]([CH3:17])([CH3:16])[CH:7]1[CH3:18])([CH3:5])[CH3:4].N1C=CC=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:1][C:12]1[CH:13]=[C:14]2[C:9]([C:8]([CH3:17])([CH3:16])[CH:7]([CH3:18])[CH:6]2[CH:3]([CH3:5])[CH3:4])=[CH:10][C:11]=1[CH3:15]
Reactant: BrBr
Reactant: Cc1ccc2c(c1)C(C)(C)C(C)C2C(C)C
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cc2c(cc1Br)C(C(C)C)C(C)C2(C)C
Reaction time: 1 h

Procedure:
40 ml Bromine is added at 10° C. to a solution of 100 g 1-isopropyl-2,3,3,5-tetramethyl indan (obtained according to Example I or II) and 1 ml pyridine in 50 ml carbon tetrachloride. Then the reaction mixture is stirred during one hour and poured out into an aqueous solution of approximately 25 g sodium thiosulphate. The organic layer is separated, washed with 25% sodium hydroxide and evaporated. The residue is distilled under diminished pressure yielding 105 g 6-bromo-1-isopropyl-2,3,3,5-tetramethyl indan. B.p. 145°-150° C./1 mm Hg. 25 g Dimethyl formamide is added to a solution of 1-isopropyl-2,3,3,5-tetramethyl-6-indanyl magnesium bromide, prepared from 9 g magnesium and 100 g of the 6-bromo indan obtained above. The reaction mixture is then heated to reflux during 30 min., poured out into a mixture of ice and diluted sulphuric acid and extracted with ether. The solution in ether is washed neutral, dried and evaporated. The residue is distilled under diminished pressure yielding 30 g 6-formyl-1-isopropyl-2,3,3,5-tetramethyl indan. B.p. 135° C./1 mm Hg.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([CH:9]2[CH2:13][CH2:12][CH:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][CH2:12][C@@H:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)C2CCC(S(=O)(=O)c3ccc(F)cc3Cl)C2)CC1
Reactant: C1COCCN1
Product: N#CC1(NC(=O)[C@@H]2CC[C@@H](S(=O)(=O)c3ccc(N4CCOCC4)cc3Cl)C2)CC1

Procedure:
The title compound was synthesized in analogy to Example 80, from Rac-(1S,35)-3-(2-chloro-4-fluoro-benzenesulfonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide and morpholine to afford the desired product as a light yellow oil. MS (EI): 438.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)=[CH2:6])[CH3:3].[CH3:14][N:15]=[C:16]=[O:17].C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC>C(OCC)C>[CH3:1][N:2]([CH2:4][C:5]([C:7]1[CH:13]=[CH:12][C:10]([NH:11][C:16](=[O:17])[NH:15][CH3:14])=[CH:9][CH:8]=1)=[CH2:6])[CH3:3]
Reactant: CN=C=O
Reactant: C=C(CN(C)C)c1ccc(N)cc1
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCOCC
Product: C=C(CN(C)C)c1ccc(NC(=O)NC)cc1
Temperature: 25 °C

Procedure:
To 9.3 g (0.053 Mol) 4(1-dimethylaminomethyl-ethenyl)-aniline in 220 ml absolute diethylether are added 5 ml (0.085 Mol) methylisocyanate and the reaction solution, after addition of 0.3 ml dibutyl tin diacetate, stirred over night, at room temperature. The crystals that precipitated after 18 hours are filtered off and washed with petrol ether to give the analytically pure title compound, m.p. 123°-124°.
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[C:9]([O-:12])([O-])=O.[K+].[K+].CI.[CH3:17][N:18](C=O)C>O>[NH2:8][C:1]1[C:6]([CH3:7])=[C:5]([O:12][CH3:9])[CH:4]=[CH:3][C:2]=1[C:17]#[N:18]
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: C=CCCCCCN
Agent: [K+]
Solvent: CI
Solvent: O
Product: COc1ccc(C#N)c(N)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
A mixture of compound 76 (12 g, 0.08 mol), K2CO3 (11 g, 0.08 mol) in dry DMF (200 mL) was stirred for 15 min at RT. To this was added MeI (13.6 g, 0.096 mol) and the mixture was stirred for 4 h at RT. The reaction mixture was diluted with water (800 mL), extracted with 30% ethyl acetate in pet. ether (3×300 mL). The combined organic layers were washed with water and brine, dried and concentrated to give a crude product. The crude product was washed with pet. ether to give pure title compound (12 g, 93%).
Reaction SMILES: [NH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[CH2:6][CH2:5][C:4]=2[C:3]([C:14]2[CH:19]=[CH:18][N+:17]([O-])=[CH:16][CH:15]=2)=[N:2]1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:18]1[CH:19]=[C:14]([C:3]2[C:4]3[CH2:5][CH2:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[NH:1][N:2]=2)[CH:15]=[CH:16][N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1ccc(-c2n[nH]c3c2CCc2ccccc2-3)cc1
Product: Clc1cc(-c2n[nH]c3c2CCc2ccccc2-3)ccn1

Procedure:
The N-oxide product from Example 14 (150 mg) was dissolved in phosphorus oxychloride (6 ml). The mixture was boiled under reflux for 4 hours. Excess phosphorus oxychloride was removed under reduced pressure and the residue was washed with saturated sodium carbonate solution and the product was extracted into chloroform, washed, dried and evaporated to give 3-(2-chloro-4-pyridyl)-4,5-dihydro-1H-benzo[g]indazole.