Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH3:2].[CH3:19][S:20](Cl)(=[O:22])=[O:21].[OH-].[Na+].ClCCl>O.C(OCC)(=O)C.C(N(CC)CC)C>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[N:11]([CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[S:20]([CH3:19])(=[O:22])=[O:21])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1cccc(CC)c1NCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1cccc(CC)c1N(Cc1cccnc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A 3.9 g. portion of 3-(2,6-diethylphenylaminomethyl)pyridine was suspended in about 10 ml. of methanesulfonyl chloride, and the mixture stood at ambient temperature for 3 days. It was then diluted with water, and made basic to about pH 10 with aqueous sodium hydroxide. It was extracted twice with 15 ml. portions of ethyl acetate, and the combined organic layers were washed twice with 15 ml. portions of water, and dried. The organic solution was evaporated under vacuum to obtain 4.5 g. of oily product. It was dissolved in ethyl acetate and purified over a short silica gel column in ethyl acetate. The product-containing fractions were combined and evaporated to obtain 3.5 g. of impure product. It was dissolved in 10 ml. of dichloromethane, and to it were added 1.26 ml. of triethylamine and 0.7 ml. of methanesulfonyl chloride. The mixture was stirred at ambient temperature for 3 days, and was then filtered, and the filtrate was evaporated under vacuum. The residue was dissolved in chloroform and purified over a silica gel column, eluting with 19:1 chloroform:methanol. The product-containing fractions were combined and evaporated under vacuum to obtain 3.7 g. of product, which was still only about 60% pure.
Reaction SMILES: CO[C:3]1C(O)=C[C:6]([O:10][CH3:11])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[CH2:15]1[O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23]CCOCCOC1.BrCC1OCCO1.C([O-])(O)=O.[Na+]>CCOCC.CN(C=O)C>[CH3:11][O:10][C:6]1[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=[C:31]([O:32][CH3:15])[C:30]=1[O:29][CH2:28][CH:27]1[O:23][CH2:24][CH2:25][O:26]1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: COc1cc(O)c(OC)c([N+](=O)[O-])c1
Agent: BrCC1OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cc([N+](=O)[O-])cc(OC)c1OCC1OCCO1
Temperature: 140 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
To a mixture of 2,5-dimethoxy-3-hydroxynitrobenzene (2.0 g, 8.43 mmol), 18-crown-6 (2.97 g, 8.43 mmol) and bromomethyl dioxolane (4.22 g, 25.3 mmol) was added DMF (60 ml). The solution was then heated for a total of 1.5 h in the CEM microwave at 140° C., initial voltage=300 W. The solution was poured on to a mixture of sat. NaHCO3 and Et2O, the layers separated and the aqueous extracted with Et2O. The combined organic layers were washed with water (4×50 ml), 1M HCl (50 ml) and brine (2×50 ml), dried over MgSO4 filtered and evaporated. Hexanes were added to the solid residue and the resulting suspension stirred for 1 h. The product was isolated by filtration and dried in a vacuum oven to afford the title compound (1.45 g, 57%). m/z 286 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:15])[C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5](O)=[O:6].C([N:18](CC)CC)C.ClC(OCC)=O>C1COCC1.O>[C:5]([C:4]1[CH:3]=[C:2]([Cl:1])[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([Cl:15])[CH:8]=1)(=[O:6])[NH2:18]
Reactant: COC(=O)c1c(Cl)cc(C(=O)O)cc1Cl
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(Cl)cc(C(N)=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80 %

Procedure:
To a solution of 3,5-dichloro-4-(methoxycarbonyl)benzoic acid (72 g, 289 mmol) and triethylamine (40 mL) in THF (240 mL) at room temperature was added ethyl chloroformate (40 mL). The reaction mixture was stirred for 20 min at room temperature and filtered. To the filtrate was added (NH4)2CO3 (28 g, 292 mmol) and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed with brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with petroleum-diethyl ether (5:1) to give methyl 4-carbamoyl-2,6-dichlorobenzoate (57 g, yield: 80%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 3.90 (s, 3H), 7.76 (s, 1H), 7.99 (s, 2H), 8.28 (s, 1H). LCMS (ESI) m/z: 248.0 [M+H+].
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([S:14]([NH:17][C:18]3[CH:19]=[C:20]([CH:33]=[CH:34][CH:35]=3)[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[O:22])(=[O:16])=[O:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.CSC1N=C(C2SC(S(Cl)(=O)=O)=CC=2)[CH:41]=[CH:40]N=1>>[CH2:40]([O:29][C:28](=[O:30])[C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21](=[O:22])[C:20]2[CH:33]=[CH:34][CH:35]=[C:18]([NH:17][S:14]([C:12]3[S:13][C:9]([C:7]4[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=4)=[CH:10][CH:11]=3)(=[O:15])=[O:16])[CH:19]=2)=[CH:32][CH:31]=1)[CH3:41]
Reactant: CSc1nccc(-c2ccc(S(=O)(=O)Cl)s2)n1
Reactant: CSc1nccc(-c2ccc(S(=O)(=O)Nc3cccc(C(=O)Nc4ccc(C(=O)O)cc4)c3)s2)n1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3ccc(-c4ccnc(SC)n4)s3)c2)cc1

Procedure:
4-{3-[5-(2-Methylsulfanyl-pyrimidin-4-yl)-thiophene-2-sulfonylamino]-benzoylamino}-benzoic acid, MS (ISP): m/e=525.2 (M−H), was prepared in analogy to example 1, steps A to D. Step C was performed using 5-(2-methylsulfanyl-pyrimidin-4-yl)-thiophene-2-sulfonyl chloride and yielded 4-{3-[5-(2-methylsulfanyl-pyrimidin-4-yl)-thiophene-2-sulfonylamino]-benzoylamino}-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: C(N(CCCC)C1C=CC([C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])=O)=C(O)C=1)CCC.CC1C=C(OC)C=CC=1NC1C=CC=CC=1.S(=O)(=O)(O)O>>[C:14]1([C:13]2[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][O:16]1)=[O:15]
Reactant: CCCCN(CCCC)c1ccc(C(=O)c2ccccc2C(=O)O)c(O)c1
Agent: COc1ccc(Nc2ccccc2)c(C)c1
Agent: O=S(=O)(O)O
Product: O=C1OCc2ccccc21

Procedure:
According to the method of the invention, 2-(4-dibutylamino-2-hydroxybenzoyl)benzoic acid is first reacted with 4-methoxy-2-methyldiphenylamine in the presence of concentrated sulfuric acid to provide a phthalide. In this condensation reaction, the amine is used in an amount of 0.8-1.2 mols per mol of the starting benzoic acid derivative, whereas concentrated sulfuric acid is used in an amount of 1.5-8 parts by weight per part by weight of the starting benzoic acid derivative. The reaction is carried out at temperatures usually of 0°-50° C. for 5-50 hours.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH2:24]([NH:31][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: OCCCSc1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(CNCCCSc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.1 %

Procedure:
In 150 ml of methylene chloride were dissolved 5.22 g (30.8 mmol) of 4-(3-hydroxypropylthio)pyridine and 5.16 ml (37.0 mmol) of triethylamine, methanesulfonyl chloride [2.86 ml (37.0 mmol)] was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried. Then the solvent was distilled off. 2.62 ml (24.0 mmol) of benzylamine was added to the residue, and the mixture was heated at 80° C. for 3 hours. After cooling, the mixture was purified by column chromatography (eluent: chloroform /methanol=25:1) to obtain 1.0 g of the desired compound (yield: 16.1%, yellow oil).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[C:28]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)(=[O:30])[CH3:29].C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:28]([C:31]1[CH:36]=[CH:35][C:34]([N:4]2[C:5](=[O:27])[C:6]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][CH:14]=3)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=[C:3]2[CH2:1][CH3:2])=[CH:33][CH:32]=1)(=[O:30])[CH3:29]
Reactant: CCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCc1nc(CC)n(-c2ccc(C(C)=O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h
Yield: 48.9 %

Procedure:
To a suspension of 4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.2 g), 4-acetylphenylboronic acid (1.1 g), triethylamine (2.2 mL), pyridine (1.3 mL) and molecular sieves 4 A (2.4 g) in dichloromethane (30 mL) was added copper(II) acetate (1.2 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.78 g, 51%).
Reaction SMILES: C([O-])(=O)C.[Na+].[Cl:6][C:7]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([Cl:17])[C:8]=1[NH2:9].CO[CH:20]1[CH:28]2[CH:23]([CH2:24][CH2:25][CH2:26][CH2:27]2)[CH:22](OC)O1.C(OCC)(=O)C>C(O)(=O)C.O>[Cl:6][C:7]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([Cl:17])[C:8]=1[N:9]1[CH:20]=[C:28]2[C:23]([CH2:24][CH2:25][CH2:26][CH2:27]2)=[CH:22]1
Reactant: COC1OC(OC)C2CCCCC12
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(Cl)c(-n2cc3c(c2)CCCC3)c(Cl)c1

Procedure:
To a mixture of sodium acetate (14.0 g) in 225 ml of acetic acid heated to refluxing is first added 2,6-dichloro-4-nitroaniline (6.40 g, 30.8 mmol), followed by 1,3-dimethoxyoctahydroisobenzofuran (5.73 g, 30.8 mmol). The reaction mixture is heated under reflux for 16 hours, after which the acetic acid is stripped off by rotoevaporation and the residue is poured into ethyl acetate and water. The aqueous layer is extracted with ethyl acetate, and the combined organic layers are washed with water and with brine and dried. The residue is purified by column chromatography to give 2-(2,6-dichloro-4-nitrophenyl)-4,5,6,7-tetrahydroisoindole, which is then reduced with stannous chloride according to Example 9 procedures to give 3,5-dichloro-4-(4,5,6,7-tetrahydroisoindol-2-yl)aniline.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31]Br)[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH2:31][CH:28]3[CH2:29][CH2:30][N:25]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:26][CH2:27]3)[N:7]=2)[C:3]=1[CH3:11]
Reactant: Cc1c(Br)ccc2[nH]ncc12
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Br)ccc2nn(CC3CCN(C(=O)OC(C)(C)C)CC3)cc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
5 g of 5-bromo-4-methyl-1H-indazole was dissolved in 110 ml DMF and treated with 11.5 g of caesium carbonate and 7.9 g of N-Boc-4-(bromomethyl)piperidine. The mixture was stirred for 3 hrs at 60° C. and overnight at RT. The reaction mixture was next diluted with ethyl acetate, and the organic phase was washed twice with water, dried over sodium sulphate, filtered and concentrated. The residue was purified chromatographically on the Biotage SP4 via a 65i-Si column Gradient: hexane/ethyl acetate 0-100%. Yield: 3.53 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)/[C:8]([O:10]CC)=[O:9])[N:6]=1.O.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\OC1CCCCC1)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nc(/C(=N/OC2CCCCC2)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(cyclohexyloxyimino)acetate (0.536 g) was dissolved in ethanol (15 ml), and water (5 ml) and aqueous sodium hydroxide (1N, 6.4 ml) added. The mixture was stirred at room temperature for 24 h. Ethanol was removed and the residue diluted with water (25 ml), washed with ethyl acetate, and acidified to pH 2.8. The precipitate was collected by filtration, washed with cold water and dried in vacuo to give the title compound as a cream solid (0.335 g; 69%), νmax (nujol) 1630 cm-1 δH (D6DMSO) 1.2-2.0 (10H, br m), 6.78 (1H, d), and 7.14 (2H, s, exch. D2O).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:13][C:12]3[CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C:11]=3[CH2:10]2)=[N:6][CH:5]=1)(O)=[O:2].[CH2:24]([NH2:29])[CH2:25][CH:26]([CH3:28])[CH3:27].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:27][CH:26]([CH3:28])[CH2:25][CH2:24][NH:29][C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:10][C:11]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:14][C:12]=3[CH2:13]2)=[N:6][CH:5]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC2=C(C1)CN(c1ncc(C(=O)O)s1)C2
Reactant: CC(C)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CCNC(=O)c1cnc(N2CC3=C(CN(C(=O)OC(C)(C)C)C3)C2)s1

Procedure:
tert-Butyl 5-(5-carboxythiazol-2-yl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-2-carboxylate (186 mg, 0.55 mmol), isoamylamine (0.42 ml, 2.6 mmol), triethylamine (153 μl, 1.1 mmol) and HATU (209 mg, 0.55 mmol) were stirred at room temperature in 20 ml of DMF for 2 h. The solvent was evaporated off, and the residue was admixed with water and ethyl acetate. The organic phase was removed and concentrated, and the crude product was converted further directly. Yield: 225 mg, M+H+: 407.20.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35](O)=[O:36])[CH:12]=[CH:13][CH:14]=1.[NH2:39][C:40]1[C:41]([CH3:46])=[N:42][CH:43]=[CH:44][CH:45]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:46][C:41]1[C:40]([NH:39][C:35]([CH:16]2[CH:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:38])[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17]2)=[O:36])=[CH:45][CH:44]=[CH:43][N:42]=1
Reactant: Cc1ncccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ncccc1NC(=O)C1NC(CC(C)(C)C)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Yield: 55.2 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 52c (0.3 g, 0.52 mmol) was reacted with 3-amino-2-methyl-pyridine (Aldrich) (0.11 g, 1.1 mmol), HATU (0.36 g, 0.94 mmol) and iPr2NEt (0.27 g, 1.6 mmol) in CH2Cl2 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-methyl-pyridin-3-yl)-amide as a yellow solid (0.16 g, 55%).
Reaction SMILES: [C:1]1(=O)[CH:5]2[CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH:4]2[CH2:3][NH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]1[NH:2][CH2:3][CH:4]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[CH2:6][CH:5]12
Reactant: O=C1NCC2c3ccccc3CC12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)CC1CNCC21
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A solution of 3,3a,8,8a-tetrahydro-2H-2-aza-cyclopenta[a]inden-1-one (1.5 g, 8.8 mmol) in THF (44 mL) was cannulated to a solution of LAH in THF (26.4 mL, 1.0 M solution in THF). The resulting solution was stirred for 4 hours at 70° C., then overnight at room temperature. The reaction was quenched via the stepwise addition of H2O (1 mL), aqueous NaOH (1 mL, 2.0 M solution), and H2O (3 mL). The resulting mixture was filtered through celite, the celite washed with warm MeOH (200 mL), and the filtrate concentrated to give the subtitle compound and its regioisomer, which were used without further purification. MS calculated for C11H13N+H: 160, observed: 160.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][C:6](=[O:10])[CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[C:13]([O:17][C:18](=[O:39])[N:19]([CH2:21][C:22]1[CH:27]=[C:26]([CH2:28]Cl)[CH:25]=[CH:24][C:23]=1[O:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1)[CH3:20])([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[C:13]([O:17][C:18](=[O:39])[N:19]([CH2:21][C:22]1[CH:27]=[C:26]([CH2:28][N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][C:6]2=[O:10])[CH:25]=[CH:24][C:23]=1[O:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1)[CH3:20])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)N1CCNC(=O)C1
Reactant: CN(Cc1cc(CCl)ccc1Oc1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(Cc2ccc(Oc3ccc(Cl)c(Cl)c3)c(CN(C)C(=O)OC(C)(C)C)c2)C(=O)C1
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
To a solution of 4-isopropyl-piperazin-2-one (32 mg, 0.22 mmol) in DMF (2.2 mL) at 0° C. was added NaH (90%, 11 mg). After 30 min, a solution of [5-chloromethyl-2-(3,4-dichloro-phenoxy)-benzyl]-methyl-carbamic acid tert-butyl ester (96 mg, 0.22 mmol) in DMF (2.2 mL) was added and the reaction was allowed to come to rt and stir overnight. The mixture was quenched with satd. aq. NaHCO3 and extracted with DCM. The combined organic layers were dried (Na2SO4) and concentrated. The crude product was purified by FCC to provide the desired product (94 mg, 79%). MS (ESI): mass calcd. for C27H35Cl2N3O4, 535.20; m/z found, 536.2 [M+H].
Reaction SMILES: [CH:1]1([CH2:4]/[C:5](=[N:7]/[S:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])/[CH3:6])[CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.CO>ClCCl>[CH:1]1([CH2:4][CH:5]([NH:7][S:8]([C:10]([CH3:11])([CH3:13])[CH3:12])=[O:9])[CH3:6])[CH2:2][CH2:3]1
Reactant: C/C(CC1CC1)=N\S(=O)C(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CO
Product: CC(CC1CC1)NS(=O)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 41.3 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-methyl-propane-2-sulfinic acid [2-cyclopropyl-1-methyl-eth-(E)-ylidene]-amide (120 mg, 0.596 mmol) and dichloromethane (2 ml) under an argon atmosphere. The reaction mixture was cooled in a −78° C. bath. DIBAL-H (0.80 ml, 0.800 mmol) was added slowly dropwise. The reaction mixture was allowed to stir for 45 min after which the cooling bath was removed. The reaction mixture was stirred for 15 min at room temperature, after which the reaction mixture was returned to the cooling bath. The reaction was quenched with MeOH (0.08 mL, 1.98 mmol). The reaction mixture was diluted with dichloromethane (8 mL) and 1.0 M aqueous Na+K+ tartrate solution (5 mL). After stirring at room temperature overnight, the mixture was extracted with dichloromethane. The organic layer was concentrated to afford 50 mg of 2-methyl-propane-2-sulfinic acid (2-cyclopropyl-1-methyl-ethyl)-amide which was used in the next step directly without purification.
Reaction SMILES: Br[C:2]1[C:3](=[O:30])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCO[C:40]2[CH:48]=[C:47]3[C:43]([C:44](C4C=CC=CC=4)=C(Br)C3=O)=[CH:42][CH:41]=2)CC1.B(O)(O)C1C=CC(C)=CC=1>>[F:17][C:15]1[CH:16]=[C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][S:25](=[O:29])(=[O:28])[CH2:26][CH2:27]4)=[CH:7][CH:8]=3)[C:3](=[O:30])[C:2]=2[C:40]2[CH:48]=[CH:47][C:43]([CH3:44])=[CH:42][CH:41]=2)[CH:12]=[C:13]([F:18])[CH:14]=1
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Reactant: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(OCCN3CCS(=O)(=O)CC3)cc21
Agent: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCN4CCS(=O)(=O)CC4)cc3C2=O)cc1
Yield: 71 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-[2-(1,1-dioxothiomorpholin-4-yl)ethoxy]-1H-inden-1-one obtained in Step 1 of Example 92 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, p-tolylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (EtOAc/hexanes=1:1) to obtain the title compound (71%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.P(OCC)(OCC)OCC.[C:27]([C:29]1[CH:30]=[C:31]([C:35]2C=CC=C(CP(=O)(OCC)OCC)C=2)[CH:32]=[CH:33][CH:34]=1)#[N:28].[H-].[Na+].C(C1C=C(C=CC=1)C=O)#N>COCCOC>[C:27]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:2][C:3]2[CH:4]=[C:5]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=3)[CH:6]=[CH:7][CH:8]=2)[CH:32]=[CH:33][CH:34]=1)#[N:28]
Reactant: N#Cc1cccc(-c2cccc(CBr)c2)c1
Reactant: CCOP(=O)(Cc1cccc(-c2cccc(C#N)c2)c1)OCC
Agent: CCOP(OCC)OCC
Agent: N#Cc1cccc(C=O)c1
Agent: [H-]
Solvent: COCCOC
Product: N#Cc1cccc(C=Cc2cccc(-c3cccc(C#N)c3)c2)c1
Reaction time: 6 h
Yield: 16.5 %

Procedure:
A solution of 5.0 g of 3′-bromomethylbiphenyl-3-carbonitrile and 5 ml of triethyl phosphite are mixed together and slowly heated to 150°. The mixture is stirred at 150° for 6 h and after customary working up 6.05 g of diethyl 3′-cyanobiphenyl-3-ylmethylphosphonate (“BA”) are obtained. 150 mg of sodium hydride are added with ice-cooling and under nitrogen to a solution of 1.0 g of “BA” and 3-cyanobenzaldehyde in 20 ml of ethylene glycol dimethyl ether. The mixture is stirred for 4 hours, worked up in the customary manner and 0.93 g of 3′-[2-(3-cyanophenyl)vinyl]biphenyl-3-carbonitrile (“BB”) is obtained. After hydrogenation of 360 mg of “BB” with Pd-C, 5% in methanol, 360 mg of 3′-[2-(3-cyanophenyl)ethyl]biphenyl-3-carbonitrile (“DC”) are obtained. After reaction with hydroxylammonium chloride and hydrogenation with Raney nickel, the compound 3,-[2-(3-amidinophenyl)ethyl]biphenyl-3-carboxamidine, FAB 343
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[Cl:5][S:6]([N:9]=[C:10]=[O:11])(=[O:8])=[O:7]>ClCCl>[O:11]=[C:10]1[N:9]([S:6]([Cl:5])(=[O:8])=[O:7])[CH2:2][CH2:3][O:4]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: OCCBr
Solvent: ClCCl
Product: O=C1OCCN1S(=O)(=O)Cl
Reaction time: 0.5 h

Procedure:
A solution of 1.13 ml of 2-bromoethanol (15.9 mmol, 1.0 eq) in dichloromethane (20 ml) was slowly added to a solution of 2.25 g of chlorosulfonyl isocyanate (15.9 mmol, 1.0 eq) in dichloromethane (100 ml) under argon at 0° C. in such a way that the temperature did not exceed 10° C. After the addition was complete, stirring was continued at 0° C. for 30 min. The product obtained in this way was directly reacted further in the next step.