Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6](Cl)[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:65]([SH:68])[CH2:66][CH3:67]>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([S:68][CH2:65][CH2:66][CH3:67])[N:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: CCCS
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCSc1cc(C(=O)OC)cc(Cl)n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
Add 2,6-dichloroisonicotinic acid methyl ester (4.12 g, 20.0 mmol), toluene (40 mL), palladium acetate (448 mg, 2.0 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.25 g, 2.0 mmol) and cesium carbonate (7.82 g, 24.0 mmol) into a sealed vessel flushed with nitrogen. Slowly add propanethiol (2.2 mL, 24 mmol,). Heat and stir the reaction mixture at 80° C. for 18 h. Cool to room temperature, dilute with diethyl ether and filter through a filtering agent. Concentrate the filtrate and purify (silica gel chromatography, 2:98 to 5:95 ethyl acetate:hexane) to give the title compound (55%).
Reaction SMILES: C([O:5][C:6](=[O:35])[CH:7]([CH2:11][NH:12][C:13]([C:15]1[N:16]=[C:17]([C:33]#[N:34])[C:18]2[C:23]([C:24]=1[OH:25])=[CH:22][CH:21]=[C:20]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:19]=2)=[O:14])[CH2:8][CH2:9][CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:33]([C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[C:20]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:19]=2)[C:24]([OH:25])=[C:15]([C:13]([NH:12][CH2:11][CH:7]([CH2:8][CH2:9][CH3:10])[C:6]([OH:35])=[O:5])=[O:14])[N:16]=1)#[N:34]
Reactant: CCCC(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A mixture of 2-{[(1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-methyl}-pentanoic acid tert-butyl ester (44 mg), TFA (2 mL) and DCM (2 mL) was stirred at rt overnight; then concentrated, the residue was dissolved in water and added 2 M HCl solution, solids were collected via filtration, washed with water and air dried to give the desired product (27 mg). LC MS ESI+: 420 (M+1)+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH:6]([CH3:8])[NH2:7])[CH3:3].[CH:10](=O)[C:11]([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl>[CH3:10][C:11]([CH3:14])([CH3:13])[CH:12]=[N:7][CH:6]([CH3:8])[C:5]([O:4][CH2:2][CH3:3])=[O:9]
Reactant: CCOC(=O)C(C)N
Reactant: CC(C)(C)C=O
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C(C)N=CC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A suspension of DL-alanine ethyl ester hydrochloride (10 g, 65.1 mmol) in DCM (150 mL) was washed with 2M aq. NaOH and the layers were separated. The organic phase was dried over Na2SO4, filtered and the filtrate was cooled to 0° C. before MgSO4 hydrate (11.3 g) followed by pivalaldeyde (7.72 g, 89.6 mmol) were added and the resulting mixture was warmed to RT and stirred for 16 h. The reaction mixture was filtered and evaporated in vacuo to give rac-ethyl 2-((2,2-dimethylpropylidene)amino)propanoate that was used further without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:12]([Si:15]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])Cl)([CH3:14])[CH3:13].[NH4+].[Cl-].CCOCC>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([Si:15]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:12]([CH3:14])[CH3:13])[CH:6]=[CH:5]2
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Fc1cc(F)c2[nH]ccc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(F)cc(F)c21
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
N-butyl lithium (2.7 ml, 2.5 M, 6.9 mmol) was added to 10 mL dry THF at −70° C. 5,7-difluoro-1H-indole (1.0 g, 6.5 mmol) in 5 mL THF was added in portions to the this solution and the mixture was stirred for 30 min at −75° C. Triisopropylchlorosilane (1.5 mL, 1.3 g, 6.9 mmol) was added, stirring was continued for 1 h at −75° C. and then the mixture was allowed to warm to −5° C. over 2 h. After treatment with 5 mL sat. NH4Cl, the mixture was mixed with 30 mL ether and the organic phase was washed with 5 mL sat. NaCl, dried (Na2SO4) and evaporated. The product was purified by flash chromatography (SiO2; hexanes) to provide the title compound as a clear oil (1.5 g; 74%): 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J=3.1 Hz, 1H), 7.07 (dd, J=8.7, 2.3 Hz, 1H), 6.69 (m, 1H), 6.59 (t, J=3.1 Hz, 1H), 1.67 (m, 3H), 1.13 (d, J=7.6 Hz, 18H). 19F NMR (376 MHz, CDCl3) δ −120.64, −120.65, −122.49, −122.49. EIMS m/z 309.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]3[C:22]([N:23]=[C:24]4C[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=24)=[CH:21][CH:20]=[N:19]3)=[CH:13][CH:12]=1.ClCCCOC1C=CC(C2N3N=CC=C3N=C3C=2CCCC3)=CC=1.CC1CCCN1>>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:18]3[N:19]=[CH:20][CH:21]=[C:22]3[N:23]=[C:24]3[C:25]=2[CH2:26][CH2:27][CH2:28][CH2:29]3)=[CH:15][CH:16]=1
Reactant: CC1CCCN1CCCOc1ccc(-c2c3c(nc4ccnn24)CCCCC3)cc1
Agent: CC1CCCN1
Agent: ClCCCOc1ccc(-c2c3c(nc4ccnn24)CCCC3)cc1
Product: CC1CCCN1CCCOc1ccc(-c2c3c(nc4ccnn24)CCCC3)cc1

Procedure:
Using the method described for the preparation of 10-{4-[3-(2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene, the reaction of 9-[4-(3-chloro-propoxy)-phenyl]-5,6,7,8-tetrahydro-pyrazolo[5,1-b]quinazoline and 2-methyl-pyrrolidine provided the desired compound 9-{4-[3-(2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-5,6,7,8-tetrahydro-pyrazolo[5,1-b]quinazoline.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH:8]([CH3:11])[CH2:9][OH:10])=[CH:5][N:6]=1.N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C)C=O.O>[Si:17]([O:10][CH2:9][CH:8]([S:7][C:4]1[S:3][C:2]([NH2:1])=[N:6][CH:5]=1)[CH3:11])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(CO)Sc1cnc(N)s1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(CO[Si](C)(C)C(C)(C)C)Sc1cnc(N)s1
Temperature: 25 °C
Reaction time: 14.5 h
Yield: 87.4 %

Procedure:
2-((2-Aminothiazol-5-yl)thio)propan-1-ol (101 mg, 0.53 mmol) was dissolved in N,N-dimethylformamide (5 mL). Thereafter, imidazole (72 mg, 1.06 mmol) and t-butyldimethylsilyl chloride (100 mg, 0.64 mmol) were added to the above obtained solution, and the thus obtained mixture was then stirred at room temperature for 14.5 hours. Thereafter, the reaction solution was diluted with water, and was then extracted with ethyl acetate. The organic layer was washed with water and brine, and was then dried over anhydrous magnesium sulfate, followed by concentration in vacuo. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain 5-((1-((t-butyldimethylsilyl)oxy)propan-2-yl)thio) thiazole-2-amine (141 mg, 87%) in the form of a yellow oily product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])[N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1>>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([O:16][CH3:17])=[C:9]([C:4]2[N:3]=[C:2]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=3)[CH:7]=[C:6]([NH2:8])[CH:5]=2)[CH:14]=1
Reactant: COc1ccc(Cl)cc1-c1cc(N)cc(Cl)n1
Reactant: Nc1ccc(Cl)cc1
Product: COc1ccc(Cl)cc1-c1cc(N)cc(Nc2ccc(Cl)cc2)n1
Yield: 22 %

Procedure:
Following the method described in Example 3, 2-chloro-6-(5-chloro-2-methoxy-phenyl)-pyridin-4-yl-amine and 4-chloro-phenylamine, provided the title compound (22% yield). 1H NMR (acetone-d6) δ 3.90 (s, 3H, CH3), 5.39 (s, 2H, NH2), 6.90 (d, 1H, J=1.7 Hz, Ar), 7.12 (d, 1H, J=8.8 Hz, Ar), 7.24 (d, 2H, J=8.9 Hz, Ar), 7.34 (dd, 1H, J=8.8 Hz, J=2.8 Hz, Ar), 7.73 (d, 2H, J=8.9 Hz, Ar), 7.91 (d, 1H, J=2.8 Hz, Ar), 8.09 (s, 1H, NH).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([CH:13]2[CH2:21][CH2:20][C:16]3[N:17]=[CH:18][NH:19][C:15]=3[CH2:14]2)=[O:12])=[CH:3]1.[C:22]([C:30]([C:45]([OH:47])=[O:46])([OH:44])[C:31]([C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([OH:35])[C:32]([OH:34])=[O:33])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[C:36]([C:31]([C:32]([OH:34])=[O:33])([OH:35])[C:30]([C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([OH:44])[C:45]([OH:47])=[O:46])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([C@@H:13]2[CH2:21][CH2:20][C:16]3[N:17]=[CH:18][NH:19][C:15]=3[CH2:14]2)=[O:12])=[CH:3]1
Reactant: Cn1cc(C(=O)C2CCc3nc[nH]c3C2)c2ccccc21
Agent: O=C(O)C(O)(C(=O)c1ccccc1)C(O)(C(=O)O)C(=O)c1ccccc1
Solvent: CO
Product: Cn1cc(C(=O)[C@@H]2CCc3nc[nH]c3C2)c2ccccc21

Procedure:
In 60 ml of methanol was added 5.87 g of 5-[(1-methylindol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole obtained in Example 41, and a solution of 7.52 g of (+)-dibenzoyltartaric acid in 240 ml of methanol was added thereto to once form a clear solution. On leaving the solution to stand at room temperature for one night, there were precipitated crystals, which were collected by filtration and recrystallized three times from dimethylformamide/water to obtain 2.30 g of (R)-(-)-5-[(1-methylindol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole (+)-dibenzoyltartarate.
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]#[CH:9])=[CH:6][N:5]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[N:4]=1)#[N:2].[Br:22]N1C(=O)CCC1=O.CCOCC.O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:22][C:9]#[C:8][C:7]1[C:3]([C:1]#[N:2])=[N:4][N:5]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:18])[F:19])=[CH:12][C:11]=2[Cl:21])[CH:6]=1
Reactant: C#Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOCC
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C#CBr
Reaction time: 1 h

Procedure:
To a stirred solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-ethynylpyrazole (100 mg, the compound of Example C5) in acetone (5 ml) was added N-bromosuccinimide (54.9 mg) and silver nitrate (5 mg). Stirring was continued at room temperature for 60 minutes. The reaction mixture was then poured into ether (10 ml) and water (10 ml). The organic layer was separated, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel eluted with dichloromethane: hexane (2: 1) to provide the title compound as a white solid m.p. 166-8° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][O:15]C(=O)C)[N:13]=2)=[N:6][CH:7]=1.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=2)=[N:6][CH:7]=1
Reactant: CC(=O)OCc1csc(Nc2ccc(Br)cn2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCc1csc(Nc2ccc(Br)cn2)n1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 56 %

Procedure:
Acetic acid 2-(5-bromo-pyridine-2-yl amino)-thiazole-4-ylmethyl ester (0.29 mmol) is suspended in ethanol (1 ml) and 1 M NaOH (1 ml) is added. The suspension is stirred at RT for 75 min. The precipitate is filtered, washed with water and dried 16 h in vacuo at 40° C. “A6” is obtained as a colourless powder in a yield of 56%; mp. 207.0-209.0° C.; HPLC (method C): 1.41 min); LC-MS (method A): 1.222 min, 285.95 (M+H+);
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:23]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:34][CH2:35][NH2:36])[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]>C(#N)C>[CH2:20]([N:23]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:34][CH2:35][NH:36][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]
Reactant: CCCN(CCC)CC1CCCCN1CCN
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ncccc21
Solvent: CC#N
Product: CCCN(CCC)CC1CCCCN1CCNC(=O)N1c2ccccc2NC(=O)c2cccnc21
Yield: 66 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 2-[2-[(dipropylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 66% of theory. Colourless crystals, m.p. 149°-151° C. (acetonitrile).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH:19]=[O:20])[CH:15]=[CH:14][C:13]=2[C:12]2[N:21]([S:24]([N:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])[N:22]=[CH:23][C:11]=2[N:10]=1.[Mn]([O-])(=O)(=O)=[O:31].[K+]>CC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]([OH:31])=[O:20])[CH:15]=[CH:14][C:13]=2[C:12]2[N:21]([S:24](=[O:25])(=[O:26])[N:27]([CH3:29])[CH3:28])[N:22]=[CH:23][C:11]=2[N:10]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CN(C)S(=O)(=O)n1ncc2nc(-c3c(F)cccc3F)c3cc(C=O)ccc3c21
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CN(C)S(=O)(=O)n1ncc2nc(-c3c(F)cccc3F)c3cc(C(=O)O)ccc3c21
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A 250 ml round-bottomed flask is charged with 1.41 g of 5-(2,6-difluorophenyl)-7-formyl-N,N-dimethyl-1H-pyrazolo[4,3-c]isoquinoline-1-sulphonamide in 124 ml of acetone. 1.07 g of potassium permanganate in solution in 62 ml of water are added. After 1 h at RT, the acetone is evaporated and then the mixture is acidified to a pH of 1 by addition of 5N hydrochloric acid. The mixture is extracted with ethyl acetate and the organic phase is washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP to give 1.46 g of 5-(2,6-difluorophenyl)-1-(dimethylsulphamoyl)-1H-pyrazolo[4,3-c]isoquinoline-7-carboxylic acid (yellow solid). LC-MS-DAD-ELSD: 433 (+)=(M+H)(+).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:27])[N:14]([CH3:26])[C:15]([CH2:24][OH:25])=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[CH3:35][S:36]([O:25][CH2:24][C:15]1[N:14]([CH3:26])[C:13](=[O:27])[C:12]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=[CH:10][C:11]=2[C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)(=[O:38])=[O:37]
Reactant: Cn1c(CO)c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(COS(C)(=O)=O)c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c1=O
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
A suspension of 1-benzyl-4-(4-chlorophenyl)-5-(hydroxymethyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (4 g, 10.6 mmol) in Dichloromethane (DCM) (50 mL) was treated with Et3N (4.38 mL, 31.5 mmol) and MsCl (1.839 mL, 23.60 mmol) at 0° C. and then stirred for 30 min. The mixture was diluted with Dichloromethane, washed with 0.1N HCl and NaHCO3, dried over Na2SO4, filtered and concentrated to afford (1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl methanesulfonate as a pale yellow solid (4.8 g, 10.5 mmol, 95% yield) which was used for in next step without any further purification. A solution of (1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl methanesulfonate (4.8 g, 10.5 mmol) in N,N-Dimethylformamide (DMF) (30 mL) was treated with KCN (6.15 g, 94 mmol) and the resultant was stirred at ambient temperature overnight. The mixture was quenched with water and then extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (0-70% ethyl acetate/hexanes) to afford 2-(1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetonitrile (2.7 g, 7.0 mmol, 67% yield) as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.47-7.52 (m, 2H) 7.31-7.35 (m, 3H) 7.27-7.30 (m, 4H) 7.04-7.09 (m, 1H) 5.94-5.98 (m, 1H) 5.83-5.88 (s, 2H) 3.81 (s, 3H) 3.64 (s, 2H); LCMS (m/z) ES+=388 (M+1).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].Cl.[NH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1.Cl.[C:17]1(=[O:23])[O:22][CH2:21][CH2:20][CH2:19][CH2:18]1>ClCCCl.ClC(Cl)C.CCN(CC)CC>[CH2:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:15][CH:7]1[NH:6][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][OH:23]
Reactant: NC1Cc2ccccc2C1
Reactant: O=C1CCCCO1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(CCCCO)NC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.7 mL (18.75 mmol) of Et3N in 5 mL of 1,2-dichloroethane was added drop by drop under ice cooling to a suspension of 1.85 g (13.75 mmol) AlCl3 in 10 mL of dichloroethane. At room temperature a solution of 2.33 g (13.75 mmol) 2-aminoindane HCl (and Et3N for the solvation of the hydrochloride) and 1.16 mL (12.5 mmol) delta-valerolactone in 7.5 mL 1,2-dichloroethane was added to the mixture. After one hour of stirring at room temperature the mixture was quenched with ice water and stirred for another 30 minutes. The suspension was filtered by Celite. After adding of dichloromethane, separating of the organic layer, washing it with water, drying it with Na2SO4 and evaporating of the solvent, followed.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[OH:18].C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][N:27]=[N:26][CH:25]=1)CCC.[F-].[Cs+].C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.[Cu](I)I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:26]1[CH:25]=[CH:24][C:29]([C:2]2[CH:7]=[C:6]([C:8]3[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=3)[CH:5]=[CH:4][C:3]=2[OH:18])=[CH:28][N:27]=1
Reactant: Oc1ccc(-c2ccc(C(F)(F)F)nc2)cc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Product: Oc1ccc(-c2ccc(C(F)(F)F)nc2)cc1-c1ccnnc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
2-Iodo-4-(6-(trifluoromethyl)pyridin-3-yl)phenol (Preparation 60, 840 mg, 2.30 mmol) was dissolved in acetonitrile (20 mL) and 4-(tributylstannyl)pyridazine (1.10 g, 2.99 mmol), caesium fluoride (698 mg, 4.60 mmol), copper iodide (87 mg, 0.46 mmol) and tetrakis(triphenylphosphine)palladium (0) (266 mg, 0.23 mmol) were added. The reaction mixture was stirred at 80° C. for 18 hours and then partitioned between ethyl acetate and water containing 0.88 ammonia. The resulting mixture was stirred for 15 minutes and then filtered through a pad of celite. The aqueous phase was separated and extracted with ethyl acetate (2×20 mL) and the combined organic phases were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified on silica gel by Biotage (10% to 100% EtOAc in heptane over 25 CV) to give a mixture of the title compound and triphenylphosphine oxide. The residue was triturated with dichloromethane to give the title compound (360 mg, 50%) as a white solid.
Reaction SMILES: [ClH:1].C(OC(OCC)[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH2:28][CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[CH:17][N:16]=2)[C:7]1=[O:36])C>C(O)C>[ClH:1].[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH2:28][CH2:29][CH2:30][N:31]1[CH2:32][CH2:33][CH2:34][CH2:35]1)[N:18]=[CH:17][N:16]=[C:15]2[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:7]1=[O:36]
Reactant: CCOC(OCC)N1C(=O)C(c2ncnc3cc(OCCCN4CCCC4)c(OC)cc23)c2ccccc21
Agent: Cl
Solvent: CCO
Product: COc1cc2c(C3C(=O)Nc4ccccc43)ncnc2cc1OCCCN1CCCC1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 113.7 %

Procedure:
2M Hydrochloric acid (1.5 ml, 3 mmol) was added to a solution of 4-(1-diethoxymethyloxindol-3-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (151 mg, 0.29 mmol), (prepared as described in Example 24), in ethanol (15 ml) at 80° C. and the mixture was stirred at 80° C. for 1.5 hours. The reaction mixture was allowed to cool, the solvent was removed by evaporation and the residue was purified by reverse phase C18 chromatography eluting with a gradient of acetonitrile in water (0-40%). The acetonitrile was removed by evaporation from the fractions containing product and concentrated hydrochloric acid (0.1 ml) was added to the aqueous phase. The solution was freeze dried to give 6-methoxy4-(oxindol-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline hydrochloride (150 mg, 100%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1N.Br[CH2:13][CH:14]=[CH2:15].N(OC(C)(C)C)=O>CC#N>[CH2:15]([C:3]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[F:1])[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: C=CCc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
2-Fluoro-4-nitroaniline (5 g, 32.0 mmol) was added to a solution of 3-bromoprop-1-ene (41.5 mL, 480 mmol) and tert-butyl nitrite (5.76 mL, 48.0 mmol) in 32 mL of degassed anhydrous CH3CN at 18-19° C. under nitrogen. At the end of the addition of the arylamine, another half-equivalent of tert-butyl nitrite (1.180 mL, 16.01 mmol) was added; the reaction was stirred at room temperature for 1 hr. The reaction was concentrated under reduced pressure to remove the volatile material. The residue was purified by silica gel flash chromatography, 100% Heptane-5% Ethyl Acetate/95% Heptane, to give 1-allyl-2-fluoro-4-nitrobenzene (2.98 g). 1H NMR (400 MHz, DMSO-d6) δ 3.51 (dd, J=6.4, 1.1 Hz, 2H), 5.05-5.16 (m, 2H), 5.96 (ddt, J=16.8, 10.2, 6.6, 6.6 Hz, 1H), 7.56-7.62 (m, 1H), 8.03-8.11 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[CH2:22][CH2:23][CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.FC(O)(F)F>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[CH2:22][CH2:23][C:24](=[O:29])[C:25]([F:26])([F:27])[F:28])[CH2:13]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=S(=O)(NC1CCc2c(CCC(O)C(F)(F)F)cccc2C1)c1ccc(Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: OC(F)(F)F
Solvent: ClCCl
Product: O=C(CCc1cccc2c1CCC(NS(=O)(=O)c1ccc(Cl)cc1)C2)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
4-Chloro-N-((R/S)-5-((R/S)-4,4,4-trifluoro-3-hydroxybutyl)-1,2,3,4-tetrahydronaphthalen-2-yl)benzenesulfonamide, designated as (+/−)-22/(+/−)-22 in FIG. 10, was prepared as follows. Dess-Martin periodinane (128.8 mg, 0.30 mmol) was added to a solution of the trifluoromethyl alcohol (67.6 mg, 0.15 mmol) in dichloromethane (4 mL) and the reaction was stirred at room temperature for 2 hour. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was separated, dried over magnesium sulfate and concentrated to dryness. Silica gel chromatography (20% ethyl acetate in hexanes), gave the purified product, (R/S)-4-chloro-N-(5-(4,4,4-trifluoro-3-oxobutyl)-1,2,3,4-tetrahydronaphthalen-2-yl)benzenesulfonamide, as colorless oil (51.1 mg). Yield 76%.