Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:10]=3[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:18][N:19]([CH2:21][CH2:22][CH2:23][Cl:24])[CH3:20].CCOCC>CN(C)C=O.O>[ClH:24].[ClH:24].[CH3:18][N:19]([CH3:20])[CH2:21][CH2:22][CH2:23][N:9]1[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8]1
Reactant: CN(C)CCCCl
Reactant: c1ccc(-c2n[nH]c3ccncc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CN(C)CCCn1nc(-c2ccccc2)c2cnccc21
Product: Cl
Reaction time: 1.5 h

Procedure:
3-Phenyl-1H-pyrazolo[4,3-c]pyridine (3.90 g) was suspended in 50 ml of dimethylformamide and 60% NaH (1.0 g) was added. After stirring for 90 minutes, dimethylaminopropyl chloride (3.0 g) was added, and stirring was continued for 1 hour. At the end of this time the reaction was warmed to 55° and, after an additional 2 hours, an additional 0.50 g of dimethylaminopropyl chloride was added. Warming and stirring was continued for 1 hour, after which time the reaction mixture was distributed between ether and H2O. The organic phase was dried, evaporated, and purified by flash chromatography (5% triethylamine-ethyl acetate), giving an oil upon evaporation of the product-containing fractions. The hydrochloride was formed in ethereal HCl and recrystallized from methanol-ether to give 3.76 g of product, m.p. 237°-239°.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:11])[C@H:6]([CH:8]([CH3:10])[CH3:9])[NH2:7])[CH3:3].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[O:21][C:20](=[O:22])[C:19]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[N:18]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:2]([O:4][C:5](=[O:11])[C@H:6]([CH:8]([CH3:10])[CH3:9])[NH:7][C:20]([C:19]1([NH:18][C:17]([C:13]2[O:12][CH:16]=[CH:15][CH:14]=2)=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)=[O:22])[CH3:3]
Reactant: CCOC(=O)[C@@H](N)C(C)C
Reactant: O=C1OC(c2ccco2)=NC12CCCCC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H](NC(=O)C1(NC(=O)c2ccco2)CCCCC1)C(C)C
Reaction time: 72 h

Procedure:
30 ml of dimethylformamide was added to a flask placed with 5 g (27 mmol) of L-valine ethyl ester hydrochloride and 5 g (22.8 mmol) of 2-(2-furanyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one. Then, 3.53 g (27.4 mmol) of diisopropylethylamine was added thereto, and the mixture was stirred for 3 days. After the solvent was distilled off under reduced pressure, ethyl acetate was added thereto, and the mixture was successively washed with a 10% aqueous potassium hydrogensulfate solution and saturated brine, followed by drying with sodium sulfate. After the solvent was distilled off under reduced pressure, it was purified by silica gel chromatography to obtain 8.3 g (quantitative) of the title compound.
Reaction SMILES: [CH:1]1([S:6][CH:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:25].[Na+]>CO.O>[CH:1]1([S:6]([CH:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])=[O:25])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1nccs1)C(SC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(Nc1nccs1)C(c1ccc(Cl)c(Cl)c1)S(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.8 %

Procedure:
To a solution of rac-2-cyclopentylsulfanyl-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide (Example 10; 34 mg, 0.088 mmol) in methanol (2 mL) was added a solution of sodium periodate (34 mg, 0.16 mmol) in water (1 mL) and the mixture was stirred at 25° C. After 6 h, the precipitate was filtered off and washed with dichloromethane (15 mL). The organic layer was set aside and the aqueous layer was extracted with dichioromethane (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure. Chromatography of the residue (Biotage Flash 12M column, 50 /50 hexanes/ethyl acetate) afforded rac-2-cyclopentanesulfinyl-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide (23 mg, 66% yield) as a colorless oil: EI- HRMS m/e calculated for C16H16N2O2S2Cl2 (M+) 402.0030, found 402.0035.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]2[N:12]=[C:13]([NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[C:14]([C:15]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[O:24][CH3:25])=[O:16])=[C:8]2[N:7]=1)C=C.CN1C(=O)CC(=O)N(C)C1=O.C(Cl)Cl.CO>C(Cl)Cl.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]2[N:12]=[C:13]([NH:26][C:27](=[O:32])[C:28]([F:30])([F:31])[F:29])[C:14]([C:15]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[O:24][CH3:25])=[O:16])=[C:8]2[N:7]=1
Reactant: C=CCOCc1ccn2nc(NC(=O)C(F)(F)F)c(C(=O)Nc3cnccc3OC)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Solvent: CO
Product: COc1ccncc1NC(=O)c1c(NC(=O)C(F)(F)F)nn2ccc(CO)nc12
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 84.2 %

Procedure:
5-(Allyloxymethyl)-N-(4-methoxy-3-pyridyl)-2-[(2,2,2-trifluoroacetyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxamide (70 mg, 0.1554 mmol), 1,3-dimethylbarbituric acid (48.53 mg, 0.3108 mmol) and Pd(PPh3)4 (17.96 mg, 0.01554 mmol) were suspended in DCM/MeOH (1.4 mL/0.35 mL) in a pressure tube. The mixture was stirred at 60° C. for ˜2.5 hrs. Further DCM (1.4 mL), MeOH (0.35 mL) and Pd(PPh3)4 (17.96 mg, 0.01554 mmol) were added and the resulting mixture was stirred at 60° C. overnight. The reaction was allowed to cool to RT, the suspended solid was collected by filtration and washed with DCM (2×1 mL) and ether (3×1 mL) to give a purple powder (53.7 mg, 84% Yield) which was used directly into next step without further purification. LC-MS (M+H)+ 411.2; 1H NMR (500 MHz, DMSO-d6) δ 11.66 (s, 1H), 10.34 (s, 1H), 9.45 (s, 1H), 9.37 (d, J=7.1 Hz, 1H), 8.29 (d, J=5.5 Hz, 1H), 7.46 (d, J=7.1 Hz, 1H), 7.23 (d, J=5.6 Hz, 1H), 5.93 (t, J=6.1 Hz, 1H), 4.81 (d, J=6.0 Hz, 2H), 4.06 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][C:8]([O:17][CH3:18])=[CH:7][C:5]=2[N:6]=1.C(N([CH2:24][CH3:25])CC)C.[OH-:26].[Na+]>ClCCl>[CH3:18][O:17][C:8]1[CH:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]2[S:3][C:2]([NH:1][C:10]([C:4]3[S:3][C:24]([CH3:25])=[CH:7][CH:5]=3)=[O:26])=[N:6][C:5]=2[CH:7]=1
Reactant: [OH-]
Reactant: CCN(CC)CC
Reactant: COc1cc(-c2ccccc2)c2sc(N)nc2c1
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(-c2ccccc2)c2sc(NC(=O)c3ccc(C)s3)nc2c1
Reaction time: 6 h
Yield: 5 %

Procedure:
2-Amino-5-methoxy-7-phenylbenzothiazol (45 mg, 0.18 mmol) is dissolved in dichloromethane (2 ml) and subsequently treated with triethylamine (0.073 ml, 0.53 mmol) and 5-methyll-thiophene-2-carbonyl chloride (56 mg, 0.35 mmol). After 6 h, further 0.073 ml, 0.53 mmol) and 5-methyll-thiophene-2-carbonyl chloride (56 mg, 0.35 mmol) are added and the mixture is stirred for additional 18 h at ambient. After addition of 0.1M aqueous sodium hydroxide, the mixture is stirred for additional 16 h. The organic layer is separated, dried and evaporated to dryness. Flash chromatography (silica, eluent ethyl acetate/cyclohexane 1:1, containing 0.5% of 25% aqueous ammonia) affords (10 mg, 5%) of the product as white solid. MS: m/e=380 (M+).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[Cl-].[Na+].O>[CH2:11]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc2c(c1)CCCN2
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(CN2CCCc3ccccc32)cc1
Temperature: 120 °C

Procedure:
A mixture of 1,2,3,4-tetrahydroquinoline (0.5 g, 3.75 mmol), benzyl bromide (0.67 mL, 5.63 mmol) and diisopropylethyl amine (0.98 mL, 5.63 mmol) in DMF (5 mL) was heated in an oil bath (T˜120° C.) for 16 hours. Reaction mixture was cooled, added to brine (75 mL) and extracted with ethyl acetate (100 mL). Organic layer was washed with brine (4×) and decolorized with activated charcoal. Upon filtering, it was dried with MgSO4, filtered again and evaporated to dryness to provide Compound 5 as an oily residue (420 mg) with the structure given below:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[Cl:14])[N:4]([CH3:15])[N:3]=1.[I:16]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:6]([I:16])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[Cl:14])[N:4]([CH3:15])[N:3]=1
Reactant: Cn1nc(Br)cc1-c1ccc(F)cc1Cl
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nc(Br)c(I)c1-c1ccc(F)cc1Cl
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-bromo-5-(2-chloro-4-fluorophenyl)-1-methyl-1H-pyrazole (i.e. the product of Step C) (620 mg, 2.14 mmol) in N,N-dimethylformamide (8 mL) at 60° C. was added N-iodosuccinimide (963 mg, 4.28 mmol). The reaction mixture was stirred at 60° C. for 3 h, and then diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The material was purified by silica gel chromatography (5 to 30% gradient of ethyl acetate in hexanes as eluant) to provide the title compound as a pale yellow solid (515 mg) melting at 139-141° C.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1.Br[C:14]1C=C(C)C=CC=1OC.COB(OC)OC>>[CH3:12][O:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:14])=[CH:7][C:6]=1[B:8]([OH:10])[OH:9]
Reactant: COc1ccc(C)cc1Br
Reactant: COc1ccc(F)cc1B(O)O
Agent: COB(OC)OC
Product: COc1ccc(C)cc1B(O)O
Yield: 96 %

Procedure:
This compound was prepared in a manner similar to that of 5-fluoro-2-methoxyphenylboronic acid (EXAMPLE 107) from 2-bromo-4-methylanisole (2.00 g, 9.94 mmol), n-BuLl (2.5M in hexanes; 4.00 mL, 10 mmol), and trimethylborate (3.4 mL, 30 mmol) to afford 1.60 g (96%) of 2-methoxy-5-methylphenylboronic acid which was used without further purification.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[C:5]([O-])(=O)[CH3:6].[Na+].BrCC(O)=O.[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-:17])=[O:16]>C(O)C>[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([C:5]2[N:1]=[C:2]([NH2:4])[S:3][CH:6]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CC(=O)[O-]
Reactant: NC(N)=S
Agent: O=C(O)CBr
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Temperature: 25 °C

Procedure:
1.0 g (13.2 mmol) of thiourea, sodium acetate (2.2 g 26.4 mmol), and 25 mL of dry ethanol were combined in a 25 mL round bottom flask. To this suspension was added nitrobenzene bromoacetate (4.2 g, 1.72 mmol). Reaction mixture was heated under reflux overnight. This suspension was cooled to room temperature. The solid was collected by suction filtration and washed using water. The resulting solid was dried to yield 4-(4-nitro-phenyl)-thiazol-2-ylamine. MS: 222.1 (M+H+).
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH+:14]=[CH:13]1)([OH:10])=O.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[N:12]1([CH2:11][C:8]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=2)=[O:10])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1
Reactant: O=C(O)Cn1c[nH+]c2ccccc21
Reactant: NCc1ccc(Cl)cc1
Agent: O=C([O-])C(F)(F)F
Product: O=C(Cn1cnc2ccccc21)NCc1ccc(Cl)cc1

Procedure:
The title compound was synthesized according to a procedure described in Example 98 starting from 3-carboxymethyl-3H-benzoimidazol-1-ium trifluoro-acetate (Example 92, Part B) and 4-chloro-benzylamine. Calculated for C16H14ClN3O m/z: 299.76, found 301.1 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:33][N:34]([CH3:52])[C:35]1([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[CH:46]=2)[CH2:40][CH2:39][C:38](=[CH:41][C:42](O)=[O:43])[CH2:37][CH2:36]1.[OH-].[Na+]>CN(C)C=O.O>[CH3:52][N:34]([CH3:33])[C:35]1([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[CH:46]=2)[CH2:40][CH2:39][C:38](=[CH:41][C:42]([NH:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:43])[CH2:37][CH2:36]1
Reactant: CN(C)C1(c2cccc(F)c2)CCC(=CC(=O)O)CC1
Reactant: NCCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN(C)C1(c2cccc(F)c2)CCC(=CC(=O)NCCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 29 %

Procedure:
3-phenylpropylamine (768 mg, 5.68 mmol), N-methylmorpholine (1.15 g, 11.36 mmol) and dicyclohexylcarbodiimide (2.34 g, 11.36 mmol) were added to a solution of [4-dimethylamino-4-(3-fluoro-phenyl)-cyclohexylidene]acetic acid (1.5 g, 5.68 mmol) in dry dimethylformamide (35 ml) under argon and the mixture was stirred at RT for 3 d. The urea which had precipitated out was separated off and the filtrate was introduced into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Still further urea thereby precipitated out and was separated off. The aqueous phase was diluted with water (300 ml), 5 M sodium hydroxide solution (7 ml, 35 mmol) was added and the mixture was stored at 5° C. for 20 h. The crude product thereby precipitated out as a beige-coloured solid (2.16 g). After chromatography on silica gel G [100 g; EtOAc/MeOH (10:1)], the amide was obtained in a yield of 29% (648.5 mg) with an m.p. of 129-131° C.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][NH2:35])[CH2:28]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.N>ClCCl.CO>[N:20]1([CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][NH:35][C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:28]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: NCCN1CCCC(CN2CCCCC2)C1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCCC(CN3CCCCC3)C2)c2ccccc21
Yield: 38 %

Procedure:
Prepared analogously to Example 46 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[3-[(piperidin-1-yl)methyl]-piperidin-1-yl]ethanamine in a yield of 38% of theory. Colourless amorphous substance, RF 0.16 (Macherey-Nagel, Polygram® SIL G/UV254, pre-coated plastic sheets for TLC, eluant: dichloromethane/methanol/conc. ammonia 90/10/1 v/v).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=3)[NH:13][C:12]2=[O:21])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>C1COCC1>[Cl:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:21])[C:11]2=[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][S:29]([CH3:28])(=[O:31])=[O:30])[CH:10]=2)[CH2:6][O:7]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccc(Cl)cc31)OC2
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=C1C(=O)Nc3ccc(Cl)cc31)OC2
Reaction time: 16 h
Yield: 80.4 %

Procedure:
A mixture of 3-(6-amino-3H-isobenzofuran-1-ylidene)-5-chloro-1,3-dihydro-indol-2-one (100 mg, 0.33 mmol), pyridine (1 ml) and methanesulfonyl chloride (76 mg, 0.66 mmol) in THF (3.5 ml) was stirred for 16 hours, and was then poured into water (100 ml). The solid was filtered, washed with water and dried under vacuum to give a crude product. The crude product was triturated with MeOH/water to provide N-[3-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-5-yl]-methanesulfonamide as a yellow solid (100 mg, 81%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]=[C:5]([CH:7]1[CH:12]([C:13]([OH:15])=[O:14])[CH:11]2[CH2:16][C:8]1([CH2:17][CH:18]=[CH2:19])[CH:9]=[CH:10]2)[OH:6].C(N(CC)CC)C.[S:27](Cl)([OH:30])(=O)=[O:28].[CH4:32].Cl>C1(C)C=CC=CC=1>[CH3:32][S:27]([O:1][CH2:2][CH2:3][N:4]=[C:5]([CH:7]1[CH:12]([C:13]([OH:15])=[O:14])[CH:11]2[CH2:16][C:8]1([CH2:17][CH:18]=[CH2:19])[CH:9]=[CH:10]2)[OH:6])(=[O:30])=[O:28]
Reactant: O=S(=O)(O)Cl
Reactant: C
Reactant: C=CCC12C=CC(C1)C(C(=O)O)C2C(O)=NCCO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCC12C=CC(C1)C(C(=O)O)C2C(O)=NCCOS(C)(=O)=O
Temperature: 5 °C

Procedure:
49.26 g of allylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid N-(2'-hydroxyethyl)imide (prepared according to Example 3a) and 22.26 g of triethylamine are dissolved in 160 g of toluene, and the solution is cooled under nitrogen to 5° C. With stirring, 22.91 g of methane sulfochloride are added dropwise for 1 hour, while keeping the temperature in the range from 5° to 10° C. by external cooling. The mixture is subsequently stirred for a further 18 hours at room temperature. The pH is adjusted with 1N HCl to 5 and the mixture is washed with water and dried. The product is isolated as described in Example 7. Yield: 54 g (83.0% of theory); η40°C. =2138.4 mPa.s; n25D =1.5238.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][CH2:4][CH:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[OH:6].[NH2-].[Na+].F[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.O>CS(C)=O.C(O)(=O)C>[CH3:12][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]([O:6][C:24]1[C:25]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][CH:23]=1)[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN(C)CCC(O)c1cccs1
Reactant: Fc1cccc2ccccc12
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CN(C)CCC(Oc1cccc2ccccc12)c1cccs1
Temperature: 87.5 °C

Procedure:
N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine (2, racemic hydroxy compound) (50 gm) was dissolved in dimethyl sulfoxide (250 ml). To the clear solution sodamide (13.7 gm) was added at 20-25° C. in small lots within 10-15 minutes under nitrogen atmosphere. The resulting reaction mass was stirred for half an hour to get a clear solution. To this solution 1-fluoronaphthalene (3) (43.4 gm) was added in 20-25 minutes. The temperature was raised to 80-95° C. and stirred for 3-5 hours, then cooled to 25-30° C. Reaction mass added into cold-water (500 ml), pH was adjusted to 5.5-6.0 with acetic acid. Aqueous reaction mass washed with cyclohexane followed by pH adjustment between 10.5-11.0 with caustic solution. Reaction mixture was extracted with cyclohexane and organic layer concentrated under reduced pressure to provide thick oily mass of (±)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine (4). The oily mass was dissolved in ethyl acetate (250 ml) and oxalic acid (30 gm) was added. Stirred at 50-60° C. for 1 hour then at 25-30° C. for 2 hours. Solid was filtered and dried to give racemic N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine oxalate (5, HA=oxalic acid) as white solid. Yield: 75 gm.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][C:9]([NH:11][C:12]([C:14]3[N:15]=[CH:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:13])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.N1([C:29]([N:31]2[CH:35]=[CH:34]N=C2)=[O:30])C=CN=C1.[F:36][C:37]1[CH:42]=CC(N)=[CH:39][CH:38]=1>CN(C=O)C>[F:36][C:37]1[CH:42]=[CH:34][C:35]([NH:31][C:29](=[O:30])[NH:1][C:2]2[C:7]3[NH:8][C:9]([NH:11][C:12]([C:14]4[N:15]=[CH:16][C:17]5[C:22]([CH:23]=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[O:13])=[N:10][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:39][CH:38]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(F)cc1
Reactant: Nc1cccc2nc(NC(=O)c3cc4ccccc4cn3)[nH]c12
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)Nc1cccc2nc(NC(=O)c3cc4ccccc4cn3)[nH]c12
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 38.6 %

Procedure:
To a solution of 30 mg (0.1 mmol) of above isoquinoline-3-carboxylic acid (7-amino-1H-benzoimidazol-2-yl)-amide in dry DMF (1 mL) was added 24 mg (0.15 mmol) of di-imidazol-1-yl-methanone in one portion. The mixture was heated at 50° C. for 30 min. After cooling to room temperature, 16 mg (0.15 mmol) of 4-fluoro-phenylamine was added to the reaction. The reaction mixture was stirred at 45° C. for 45 min. After cooling to room temperature, the organic solvent was removed under reduced pressure, and the residue was purified by column chromatography eluting with DCM/methanol (v/v=10:0.5 to 10:1) to provide 17 mg (39%) of isoquinoline-3-carboxylic acid {7-[3-(4-fluoro-phenyl)-ureido]-1H-benzoimidazol-2-yl}-amide. LCMS: 441 (M+1)+.
Reaction SMILES: Cl[Si:2]([CH3:9])([CH3:8])[CH2:3][CH:4]([CH3:7])[CH2:5]Cl.[CH2:10]([NH2:13])[CH:11]=[CH2:12]>>[CH3:8][Si:2]1([CH3:9])[CH2:3][CH:4]([CH3:7])[CH2:5][N:13]1[CH2:10][CH:11]=[CH2:12]
Reactant: CC(CCl)C[Si](C)(C)Cl
Reactant: C=CCN
Product: C=CCN1CC(C)C[Si]1(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The 2,2,4-trimethyl-1-allyl-1-aza-2-silacyclopentane was prepared as follows. Chlorodimethyl(3-chloro-2-methylpropyl)silane (100 g, 0.54 mol) was slowly added to 211.73 g (3.71 mol, 6.87 eq) of undistilled allyl amine resulting in an exothermic reaction. This reaction mixture was stirred at room temperature for 15 hours, heated to reflux at atmospheric pressure for 72 hours, and heated to 120° C. under about 50 psig pressure for 16 hours. The following GC-MS ratios shown in the Table exemplified the reactions progression and the spectra observed were as shown.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][NH:8][C:9]2[C:10]([N+:24]([O-])=O)=[C:11]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.[CH3:29]O>[Ni]>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:9]3=[N:19][C:18]([C:20]([F:23])([F:22])[F:21])=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]3[N:24]=[CH:29]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cc(C(F)(F)F)nc(NCc2ccc(OC)cc2)c1[N+](=O)[O-]
Reactant: CO
Agent: [Ni]
Product: CCOC(=O)c1cc(C(F)(F)F)nc2c1ncn2Cc1ccc(OC)cc1
Temperature: 150 °C
Reaction time: 6 h
Yield: 60 %

Procedure:
Ethyl 2-[(4-methoxybenzyl)amino]-3-nitro-6-(trifluoromethyl)isonicotinate x193 (2.6 g, 6.5 mmol) is dissolved in methanol (100 ml), and Raney nickel (0.8 g) is added. The starting compound is hydrogenated in a Parr apparatus under a hydrogen pressure of 3 atm until the conversion of x193 is complete (1.5-2 h). The catalyst is filtered off and washed with methanol. The filtrate is evaporated to dryness. Triethyl orthoformate (100 ml) and p-toluene sulfonic acid (0.15 g) are added. The flask is equipped with a reflux condenser. The apparatus is flushed with argon, and the obtained reaction mixture is heated under vigorous stirring to 150° C. for 6 h. The reaction solution is evaporated in vacuum. The residue is partitioned between dichloromethane and a saturated aqueous solution of NaHCO3. The organic layer is dried with anhydrous sodium sulfate and evaporated. The target product is purified by chromatography on silicagel (dichloromethane/acetone) to afford 1.5 g of ethyl 3-(4-methoxybenzyl)-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine-7-carboxylate x196.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8]O.P(Br)(Br)[Br:11].C(=O)(O)[O-]>C(OCC)C>[Br:11][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: OCCc1ccccn1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Solvent: CCOCC
Product: BrCCc1ccccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 173.2 %

Procedure:
To an ice-cold solution of 2-pyridin-2-yl-ethanol (1 g, 8.1 mmol) in diethyl ether (20 mL) was added freshly distilled phosphorous tribromide (0.75 g, 2.7 mmol) over 15 min. The reaction mixture was warmed to r.t. and stirred for a further 5 hours. The reaction mixture was poured into an excess of cooled bicarbonate solution and extracted with dichloromethane (×2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to afford 2-(2-bromo-ethyl)-pyridine (0.87 g, 58%) as a liquid.