Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-:9].C([N+]1[CH:18]=[CH:17][N:16]([CH2:19][CH:20]([CH3:22])C)[CH:15]=1)C(C)C>>[Br-:9].[CH:1]1([N+:8]2[CH:18]=[CH:17][N:16]([CH:19]3[CH2:20][CH2:22][CH2:3][CH2:2][CH2:1][CH2:7]3)[CH:15]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCCC1
Reactant: CC(C)Cn1cc[n+](CC(C)C)c1
Agent: [Br-]
Product: c1c[n+](C2CCCCCC2)cn1C1CCCCCC1
Yield: 63 %

Procedure:
Using cycloheptylamine (2×110.4 mmol) the procedure used in Example 1 for synthesizing compound 1 was followed yielding 23.60 g white solids after drying under high vacuum (69.1 mmol, 63% yield). 1H NMR (300 MHz, DMSO-d6): 9.44, 7.93, 4.50, 2.08-1.97, 1.95-1.97, 1.77-1.69, 1.65-1.56, 1.54-1.46. 13C NMR (75 MHz, DMSO-d6): 133.5, 120.8, 61.1, 34.7, 26.8, 23.3. Analysis calculated for C17H29BrN2: C, 59.82; H, 8.56; N, 8.21 (C/N=7.29). Found: C, 59.45; H, 8.33; N, 8.08 (C/N=7.36).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:21])[NH:12][C:13]1[S:14][C:15]([S:18]([CH3:20])=[O:19])=[CH:16][N:17]=1)(=O)C.Cl>C1COCC1>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:12][C:13]1[S:14][C:15]([S:18]([CH3:20])=[O:19])=[CH:16][N:17]=1)=[O:21]
Reactant: CC(=O)Oc1ccccc1C(=O)Nc1ncc(S(C)=O)s1
Agent: Cl
Solvent: C1CCOC1
Product: CS(=O)c1cnc(NC(=O)c2ccccc2O)s1
Reaction time: 1 h

Procedure:
A solution of 11 (1.0 g, 3.1 mmol) is dissolved in THF (20 mL) and is added under stirring to 2M HCl (100 mL). The reaction is refluxed for one hour and is allowed to cool under stirring over one hour. The product is filtered using a sintered glass funnel, washed with distilled water and THF and dried in high vacuum and affords 12 as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([I:7])=[CH:5][N:6]=1.[C:8](Cl)(Cl)=[O:9]>C(OCC)(=O)C>[I:7][C:4]1[S:3][C:2]([N:1]=[C:8]=[O:9])=[N:6][CH:5]=1
Reactant: Nc1ncc(I)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C=Nc1ncc(I)s1
Reaction time: 3 h

Procedure:
2-Amino-5-iodothiazole (19.0 grams) and a saturated solution of phosgene in ethyl acetate (200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 3 hours. After this time the reaction mixture is cooled and filtered to recover the desired product 5-iodothiazol-2-yl isocyanate dimer.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:8][C:9]([OH:11])=[O:10])[C:5](O)=[O:6].[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[NH2:16].C(N(CC)CC)C.O>C1(C)C(C)=CC=CC=1>[Cl:12][C:13]1[CH:14]=[C:15]([N:16]=[C:5]([OH:6])[CH:4]([CH2:3][O:2][CH3:1])[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: COCC(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1C
Product: COCC(CC(=O)O)C(O)=Nc1cc(Cl)cc(Cl)c1

Procedure:
150 g of 2-methoxymethylsuccinic acid, 150g of 3,5-dichloroaniline and 0.5 g of triethylamine are heated under reflux, for four hours, in 1.5 liters of xylene, and the water formed is separated off by means of a water separator. The solvent is then drawn off. 250 g of end product are obtained in crystalline form.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([CH2:27][CH3:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[N:21]1[CH:20]=[CH:19][C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[CH:26]=[C:25]([CH2:27][CH3:28])[S:24][C:14]=3[N:15]=2)=[CH:23][CH:22]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-4-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-dichlorobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:36])=[C:19]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:20]=[CH:21][C:22]=2[F:23])[CH:5]=[CH:4][N:3]=1.[NH4+:37].[OH-]>>[NH2:37][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:36])=[C:19]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:20]=[CH:21][C:22]=2[F:23])[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: CC(C)(C)c1nc(-c2c(F)ccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Agent: [OH-]
Product: CC(C)(C)c1nc(-c2c(F)ccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 21 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,6-difluorobenzenesulfonamide (150 mg, 0.269 mmol) and NH4OH (2.5 mL, 17.97 mmol) heated in the microwave at 130° C. for 15 min the title compound was obtained as a light yellow solid (135 mg, 89% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.86 (s, 1H), 8.05 (d, J=5.1 Hz, 1H), 7.62-7.73 (m, 1H), 7.44-7.59 (m, 1H), 7.17-7.34 (m, 3H), 6.79 (br. s., 2H), 5.83 (d, J=5.1 Hz, 1H), 1.39 (s, 9H). MS (ESI): 537 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([C:19](O)=[O:20])=[CH:7][C:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1.[F:22][C:23]1[CH:32]=[C:31]([NH2:33])[CH:30]=[C:29]([F:34])[C:24]=1[C:25]([O:27][CH3:28])=[O:26].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:22][C:23]1[CH:32]=[C:31]([NH:33][C:19]([C:6]2[C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]3[C:12]([CH3:16])([CH3:15])[CH2:11][CH2:10][C:9]([CH3:18])([CH3:17])[C:8]=3[CH:7]=2)=[O:20])[CH:30]=[C:29]([F:34])[C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: COCOc1cc2c(cc1C(=O)O)C(C)(C)CCC2(C)C
Reactant: COC(=O)c1c(F)cc(N)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COCOc1cc2c(cc1C(=O)Nc1cc(F)c(C(=O)OC)c(F)c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-methoxymethoxy-5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid (Compound K, as described in U.S. Pat. No. 5,856,490, 112mg, 0.38 mmol) in 6 ml of anhydrous methylene chloride was added 4-(dimethylamino)pyridine (DMAP, 100 mg, 0.46mmol), methyl 2,6-difluoro-4-aminobenzoate (Compound H1, as described in U.S. Pat. No. 5,856,490, 77mg, 0.38mmol ) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 110 mg, 0.57 mmol). The reaction mixture was stirred at room temperature for overnight then concentrated to dryness. The residue was purified by column chromatography with ethyl acetate: hexane (1:9) to yield the title compound as a clear oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:22])=[CH:4][C:5]([O:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:23][Si:24]([CH3:29])([CH3:28])[CH2:25][CH2:26]O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:23][Si:24]([CH3:29])([CH3:28])[CH2:25][CH2:26][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[C:3]([Cl:22])=[CH:4][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16]
Reactant: CC(C)(C)OC(=O)CCCOc1cc(Cl)c(Br)cc1C(=O)O
Reactant: C[Si](C)(C)CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCCOc1cc(Cl)c(Br)cc1C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 109.8 %

Procedure:
To a stirring dichloromethane solution (40 mL) containing 5-bromo-2-(3-tert-butoxycarbonyl-propoxy)-4-chloro-benzoic acid (2.3 g, 5.9 mmol) and 2-(trimethylsilyl)-ethanol (1.8 g, 8.9 mmol), dicyclohexyl-carbodiimide (1.83 g, 8.9 mmol) and DMAP (108 mg, 0.9 mmol) were added. The mixture was stirred at rt for 16 hrs and was concentrated. The residue was purified via silica gel flash chromatography (eluting with 20% ethyl acetate in hexane) to afford 5-bromo-2-(3-tert-butoxycarbonyl-propoxy)-4-chloro-benzoic acid 2-trimethylsilanyl-ethyl ester (3.2 g). MS ion (APCI): 482.0, 441.0, 410.9. tR=3.61 min (method 1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[C:10]1([CH:17]=[CH:16][CH:15]=[C:13]([OH:14])[CH:12]=1)[OH:11].[CH2:18]=[O:19].[OH-].[NH4+:21]>O>[NH3:21].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[C:10]1([CH:17]=[CH:16][CH:15]=[C:13]([OH:14])[CH:12]=1)[OH:11].[CH2:18]=[O:19]
Reactant: [NH4+]
Agent: C=O
Agent: COc1cccc(O)c1
Agent: Oc1cccc(O)c1
Solvent: O
Product: N

Procedure:
The resulting m-methoxyphenol/resorcin/formaldehyde cocondensate was sampled in an amount of 15 parts in solid basis, and 10.5 parts of 28% aqueous ammonium hydroxide solution was added to the sampled cocondensate, and further water was added to the mixture to make the total amount of the resulting mixture up to 100 parts to obtain an aqueous ammonia solution of the m-methoxyphenol/resorcin/formaldehyde cocondensate. 75 parts of the aqueous ammonia solution of the cocondensate was mixed with 100 parts of an RFL having a composition shown in the following Table 1 to produce an adhesive liquid. This RFL had previously been produced by aging for 48 hours a mixture having the following composition.
Reaction SMILES: [CH3:1][N:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)=[CH:11][C:10]=2[S:9](=[O:26])[C:8]2[C:3]1=[CH:4][CH:5]=[C:6]([C:27]1[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=1)[CH:7]=2.ClC1C=CC=C(C(OO)=[O:45])C=1>>[CH3:1][N:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)=[CH:11][C:10]=2[S:9](=[O:45])(=[O:26])[C:8]2[C:3]1=[CH:4][CH:5]=[C:6]([C:27]1[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=1)[CH:7]=2
Reactant: CN1c2ccc(-c3cccc4ccccc34)cc2S(=O)c2cc(-c3cccc4ccccc34)ccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CN1c2ccc(-c3cccc4ccccc34)cc2S(=O)(=O)c2cc(-c3cccc4ccccc34)ccc21

Procedure:
For the preparation as a by-product in the synthesis of 10-methyl-3,7-bis(1-naphthyl)phenothiazine 5-oxide, see under Example 5. For a selective preparation of the sulfone, at least two molar equivalents of m-chloroperbenzoic acid are used.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]2[CH2:9][C@@H:4]([CH2:5][CH2:6][C@@H:7]2[NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:3]1.[Li+].[BH4-]>C1COCC1>[OH:3][C@@H:4]1[CH2:5][CH2:6][C@H:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:8]([CH2:2][OH:1])[CH2:9]1
Reactant: O=C(N[C@H]1CC[C@@H]2C[C@H]1C(=O)O2)OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(N[C@H]1CC[C@@H](O)C[C@H]1CO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A sample of benzyl (1R,2S,5R)-7-oxo-6-oxa-bicyclo[3.2.1]octan-2-ylcarbamate (2.8 g) was dissolved in anhydrous THF prior to the addition of LiBH4 (0.44 g) in one portion. The reaction mixture was stirred at rt overnight. The reaction was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with brine and dried (MgSO4). Filtered, concentrated and chromatographed to get benzyl (1S,2R,4R)-4-hydroxy-2-(hydroxymethyl)cyclohexylcarbamate as a white foamy solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C@:23]([S:35]([CH3:38])(=[O:37])=[O:36])([CH3:34])[C:24]([NH:26][O:27]C4CCCCO4)=[O:25])[C:17](=[O:39])[CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[ClH:40].O1CCOCC1>C(Cl)Cl.CO>[ClH:40].[OH:27][NH:26][C:24](=[O:25])[C@@:23]([S:35]([CH3:38])(=[O:37])=[O:36])([CH3:34])[CH2:22][CH2:21][N:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:11]=[CH:10][C:9]([N:6]3[CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5]3)=[CH:14][CH:13]=2)=[CH:16][C:17]1=[O:39]
Reactant: C[C@@](CCn1ccc(-c2ccc(N3CCC(CO)CC3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@](CCn1ccc(-c2ccc(N3CCC(CO)CC3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
(R)-4-{4-[4-(4-hydroxymethyl-piperidin-1-yl)-phenyl]-2-oxo-2H-pyridin-1-yl}-2-methanesulfonyl-2-methyl-N-(tetrahydro-pyran-2-yloxy)-butyramide (85.1 mg, 0.152 mmol) was dissolved in methylene chloride (5 mL) at ambient temperature. To this solution was added 4M HCl in 1,4-dioxane (0.304 mL, 1.22 mmol) and methanol (1 ml). The resulting solution was stirred at ambient temperature for 45 minutes. The solution was concentrated to a crude residue in vacuo. To the residue was added ethyl acetate (10 ml) and the resulting slurry was stirred overnight at ambient temperature. The slurry was filtered and washed with ethyl acetate/heptanes (1:1). The solid was dried in vacuo to afford (R)-N-Hydroxy-4-{4-[4-(4-hydroxymethyl-piperidin-1-yl)-phenyl]-2-oxo-2H-pyridin-1-yl}-2-methanesulfonyl-2-methyl-butyramide hydrochloride as an off-white solid. (72.7 mg). LCMS: M+1 478.6. 1H NMR (CD3OD, 400 MHZ) dppm, 7.82 (2H, d), 7.79 (1H, d), 6.84 (1H, d), 6.80-6.77 (1H, dd), 4.35-4.28 (1H, m), 4.00-3.93 (1H, m), 3.79-3.72 (4H, m), 3.55 (2H, d), 3.09 (3H, s), 2.64-2.56 (1H, m), 2.40-2.33 (1H, m), 2.16-2.13 (2H, d), 2.00-1.92 (1H, m), 1.87-1.76 (2H, m), 1.70 (3H, s).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:27])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][CH2:31][CH2:32][C:3]1=2.[ClH:40]>CO>[ClH:40].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[N:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:27])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:28][NH:29][CH2:30][CH2:31][CH2:32][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Agent: Cl
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)cc31)CNCCC2
Yield: 70 %

Procedure:
A solution of tert-butyl 6-methyl-8-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (67 mg, 0.13 mmol) in 1.25 M HCl in MeOH (16 mL) was stirred at ambient temperature for 18 h. The mixture was concentrated to dryness under reduced pressure and diluted with MeOH (2.0 mL) and Et2O (25 mL). The resulting solids were collected by filtration and dried to yield the title compound (42 mg, 70%) as a yellow powder: mp 274-280° C. decomp; 1H NMR (500 MHz, DMSO-d6) δ 9.50 (s, 2H), 9.20 (d, J=2.0 Hz, 1H), 8.50 (dd, J=8.0, 2.0 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.86 (d, J=7.0 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.09 (dd, J=8.5, 2.0 Hz, 1H), 7.00 (d, J=2.0 Hz, 1H), 6.80 (d, J=7.5, 2.0 Hz, 1H), 4.42-4.41 (m, 2H), 3.73 (s, 3H), 3.43-3.41 (m, 2H), 3.11 (t, J=6.0 Hz, 2H), 2.10-2.08 (m, 2H); ESI MS m/z 439 [M+H]+; HPLC (Method A) 99.0% (AUC), tR=13.7 min.
Reaction SMILES: [CH2:1]([NH:8][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:20].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([N:8]([CH3:9])[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCc1ccccc1
Reactant: O=C(CCl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CC(=O)c1ccc(F)cc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a solution of benzyl-methyl-amine (28.9 g) and triethylamine (33.8 mL) in dimethylformamide (600 mL) was added in 5 portions 2-chloro-1-(4-fluorophenyl)-ethanone (40 g) on an ice bath. After stirring at room temperature for 2 hours, ethyl acetate was added, and the salt that precipitated was removed by filtration, and the filtrate was concentrated. A crude purification was carried out by silica gel column chromatography (hexane/ethyl acetate), and the title compound (56.9 g) was obtained as a colorless oily matter.
Reaction SMILES: Cl.Cl.COC1C=CC([C:11]2[CH:12]=[C:13]3[C:18]4=[C:19]([CH2:21][CH2:22][CH2:23][N:17]4[CH2:16][C@@H:15]4[CH2:24][NH:25][CH2:26][C@@H:14]34)[CH:20]=2)=C(C(F)(F)F)C=1.[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1B(O)O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C2C(=CC=CC=2)CC1.FC(F)(F)C(O)=O>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl>[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[C:11]1[CH:12]=[C:13]2[C:18]3=[C:19]([CH2:21][CH2:22][CH2:23][N:17]3[CH2:16][C@@H:15]3[CH2:24][NH:25][CH2:26][C@@H:14]23)[CH:20]=1
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNC[C@H]2CN4CCC3)c(C(F)(F)F)c1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: Clc1ccc(-c2cc3c4c(c2)[C@@H]2CNC[C@H]2CN4CCC3)c(Cl)c1
Temperature: 25 °C

Procedure:
A solution of (±)-trans tert-butyl 2-bromo-5,6,8a,9,11,11a-hexahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline-10(8H)-carboxylate from EXAMPLE 7, Part A (55 mg, 0.139 mmol), Ba(OH)2-8 H2O (70 mg, 0.222 mmol), and 2,4-dichlorophenyl boronic acid (35 mg, 0.181 mmol) in DME (3 mL) and water (2 mL) were degassed with argon at near reflux temperature. The solution was cooled to rt, and a mixture of solid PPh3 (5.5 mg, 20.9 mmol) and Pd(PPh3)2Cl2 (5 mg, 6.95 μmol) was added in a single portion. The solution was stirred at reflux under a positive pressure of argon for 4 h. After the starting bromide was consumed, the DME was removed under reduced pressure. The residue was diluted with EtOAc and washed with water followed by brine. The organic layer was dried over Na2SO4, and evaporated under reduced pressure to a golden oil (80 mg crude weight). The crude product was purified on a Redipak (5 g) silica column using a gradient elution of 5%-33% EtOAc in hexanes. Evaporation of the fractions containing product as identified by TLC gave N-Boc protected biaryl intermediate as a white foam (44 mg, 69%). The N-Boc protected indoline (44 mg, 95.8 μmol) was dissolved into CH2Cl2 (9.0 mL) and cooled to 0° C. under N2. Neat trifluoroacetic acid (TFA) was added via syringe in a single portion to the stirred, cooled solution. The reaction was stirred at 0° C. for 2 h and followed by TLC analysis. When all of the N-Boc protected material had been consumed, the solution was basified to pH>10 with 3 N NaOH. The product was extracted into CH2Cl2, washed with brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure to give crude free-base. The crude free-base was purified by semi-preparative HPLC (Dynamax 60 Å, C-18) using an isocratic mobile phase of 50:50:0.05 v/v/v water:acetonitrile:TFA. The title compound of EXAMPLE 34 was obtained as a yellow semi-solid (26 mg, 76%). 1H NMR (500 MHz, CDCl3) δ 0.88 (m, 1H), 1. 26 (broad s, 2H), 1.91-1.94 (m, 1H), 2.00-2.06 (m, 1H), 2.28 (m, 1H), 2.72 (broad s, 1H), 2.95 (m, 1H), 3.0-3.5 (m, 4H), 3.59 (m, 2H), 3.83 (broad s, 1H), 6.68 (s, 1H), 6.91 (s, 1H), 7.21 (m, 2H), 7.42 (s, 1H). LRMS (ES)+: 359 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:10][CH3:11])=[C:4]([CH2:8]O)[CH:5]=[CH:6][CH:7]=1.C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Br:13])[C:3]=1[CH2:10][CH3:11]
Reactant: BrC(Br)(Br)Br
Reactant: CCc1c(Br)cccc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1c(Br)cccc1CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
To a solution of (3-bromo-2-ethylphenyl)methanol (D133) (3 g, 13.95 mmol) in Dichloromethane (DCM) (50 mL) was added CBr4 (5.55 g, 16.74 mmol). To the reaction solution was added triphenylphosphine (5.49 g, 20.92 mmol) portionwise at 0° C. The reaction solution was warmed to room temperature and stirred at the temp overnight. The solvent was removed in vacuo and the residue was purified by ISCO column chromatography to afford 1-bromo-3-(bromomethyl)-2-ethylbenzene (D134) (1.3 g) as an oil.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]3[C:26](=[O:33])[C:27]([CH3:32])=[C:28]([CH3:31])[C:29](=[O:30])[C:24]=3[N:23]=[C:22]2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([CH2:20][N:21]2[C:25]3[C:26](=[O:33])[C:27]([CH3:32])=[C:28]([CH3:31])[C:29](=[O:30])[C:24]=3[N:23]=[C:22]2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:18][CH:19]=1)([OH:7])=[O:5]
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)C(=O)C(C)=C(C)C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)O)cc1)C(=O)C(C)=C(C)C2=O
Yield: 104.5 %

Procedure:
420 mg (0.8 mmol) Of the ester was dissolved in 20 ml of chloroform, and to this was added 4 ml of trifluoroacetic acid and the mixture was heated under reflux for 2 hours. After the reaction mixture was cooled, an aqueous saturated solution of sodium bicarbonate was added to adjust pH to 8. The organic layer was washed with an aqueous saturated saline solution and dried over anhydrous sodium sulphate, and the solvent was distilled off under the reduced pressure to obtain 370 mg of 1-[(2'-carboxybiphenyl-4-yl)methyl]-2-n-butyl-5,6-dimethyl-1H-benzimidazol-4,7-dione (Compound No. 26) as yellow powder (yield 99% ). This has the following NMR spectrum. δ ppm (CDCl3): 0.83 (3H, t, J=7 Hz), 1.27-1.35 (2H, m), 1.57-1.70 (2H, s), 2.09 (3H, s), 2.71 (2H, t, J=8 Hz), 5.61 (2H, s), 7.10 (2H, d, J=8 Hz), 7.31 (3H, d, J=8 Hz), 7.40-7.46 (1H, m), 7.55 (1H, dd, J=8, 1 Hz), 7.95 (1H, dd, J=8, 1 Hz)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1/[CH:10]=[CH:11]/[C:12]1[CH:17]=CC=CC=1.C1(=O)NC(=O)C=C1>C1(C)C=CC=CC=1>[CH:10]1[C:2]2[NH:1][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]=2[CH:17]=[CH:12][CH:11]=1
Reactant: C(=C/c1cc2ccccc2[nH]1)\c1ccccc1
Agent: O=C1C=CC(=O)N1
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)[nH]c1ccccc12

Procedure:
1.3 g (5.9 mmole) (E)-1-(2-indolyl)-2-phenylethylene and 0.7 g (7.2 mmole) maleic acid imide are heated under reflux for 16 hours in 25 ml toluene. After the addition of 0.1 g (1 mmole) maleic acid imide, it is refluxed for a further 8 hours After cooling, the crystals formed are filtered off and chromatographed on silica gel with toluene/ethyl acetate 4:1. The fraction with the Rf of 0.1 is isolated and recrystallized from toluene. One obtains 1,2,3,3a,4,5,6,10c-octahydro-1,3-dioxo-4-phenylpyrrolo3,4-c]carbazole in the form of colorless crystals of the mp 212°-215° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([CH2:14][CH2:15][CH3:16])[CH:11]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:10]([OH:24])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]([CH2:43]Cl)[CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:1]([N:8]1[CH2:13][CH:12]([CH2:14][CH2:15][CH3:16])[CH:11]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:10]([O:24][CH2:43][C:35]2[CH:34]=[C:33]([O:32][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC1CN(Cc2ccccc2)CC(O)C1c1ccc(F)cc1
Reactant: ClCc1cc(OCc2ccccc2)c2ccccc2c1
Product: CCCC1CN(Cc2ccccc2)CC(OCc2cc(OCc3ccccc3)c3ccccc3c2)C1c1ccc(F)cc1

Procedure:
In an analogous manner to that described in Example 62(h), by alkylating (3RS,4RS,5SR)-1-benzyl-4-(4-fluoro-phenyl)-5-propyl-piperidin-3-ol with 1-benzyloxy-3-chloromethyl-naphthalene there was obtained (3RS,4RS,5SR)-1-benzyl-3-(4-benzyloxy-naphthalen-2-ylmethoxy)-4-(4-fluoro-phenyl)-5-propyl-piperidine as a yellow resin, MS (ISP): 574 (M+H)+.