Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.S(O)(O)(=O)=O.[CH3:7][S:8][C:9](=[NH:11])[NH2:10].C(=O)([O-])[O-].[Na+].[Na+].[Cl:18][CH2:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:7][S:8][C:9](=[NH:10])[NH:11][S:20]([CH2:19][Cl:18])(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)CCl
Reactant: CSC(=N)N
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CSC(=N)NS(=O)(=O)CCl
Yield: 90.6 %

Procedure:
Water (250 ml) is added with stirring to a slurry of S-methylisothiourea sulfate (77.3 g, 0.556 mol) and sodium carbonate (273 g, 2.58 mol) in methylene chloride (1100 ml). Chloromethanesulfonyl chloride (85% pure, 94.8 g, 0.542 mol) is then added slowly with stirring at such a rate as to maintain gentle reflux of the solvent. The mixture is then stirred at room temperature for 16 hr, and the organic solution is decanted from the inorganic residue. The residue is washed with additional methylene chloride (500 ml), and the combined organic solutions are dried with magnesium sulfate, filtered, and concentrated to leave crude II as a yellow oil (99.5 g, 90%). This crude material is adequate for preparing the thiadiazole compounds of the invention (e.g., see Example 4, below). Purification by chromatography on silica gel (2.5% ethyl ether in methylene chloride as eluant) provides the title compound as a colorless solid, mp 60°-62° C. (72 g, 65%).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@H:8]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH2:7][CH2:6][NH:5][CH2:4]1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C.[Br-].[CH3:36][CH:37]1[O:41][C:40](=[N+:42]([CH3:44])[CH3:43])[C:39]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:38]1>O>[CH3:1][O:2][C@H:3]1[C@H:8]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)[CH2:7][CH2:6][N:5]([CH:37]([CH3:36])[CH2:38][C:39]([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:40]([N:42]([CH3:43])[CH3:44])=[O:41])[CH2:4]1
Reactant: CO[C@@H]1CNCC[C@H]1NC(=O)c1cccc(C(F)(F)F)c1
Reactant: CC1CC(c2ccccc2)(c2ccccc2)C(=[N+](C)C)O1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CO[C@@H]1CN(C(C)CC(C(=O)N(C)C)(c2ccccc2)c2ccccc2)CC[C@H]1NC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.5 %

Procedure:
A mixture of 3.0 parts of trans-N-(3-methoxy-4-piperidinyl)-3-(trifluoromethyl)benzamide, 2.65 parts of sodium carbonate and 80 parts of 4-methyl-2-pentanone was stirred for 30 minutes at reflux temperature, using a water separator. After cooling 3.96 parts of N-(dihydro-5-methyl-3,3-diphenyl-2(3H)-furanylidene)-N-methylmethanaminium bromide were added and stirring was continued for 5 hours at reflux. After cooling overnight at room temperature, the reaction mixture was washed twice with 50 parts of water, dried, filtered and evaporated in vacuo. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 8 parts of acetonitrile. The product was filtered off and dried, yielding 1.3 parts (22.5%) of trans-3-methoxy-N,N,γ-trimethyl-α,α-diphenyl-4-[[3-(trifluoromethyl)benzoyl]amino]-1-piperidinebutanamide; mp. 197.8° C. (compound 52).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1>>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3ccccc32)cc1
Yield: 91 %

Procedure:
The title compound was prepared from toluene-4-sulfonyl chloride and 1H-indole, according to Method A, described above. Yield 91%; mp 60-62° C.; 1H NMR (CDCl3) δ 8.0-8.03 (dd, J=8 Hz, 1H), 7.78 (d, J=7 Hz, 2H), 7.57 (d, J=4 Hz, 1H), 7.52-7.56 (m, 1H), 7.26-7.36 (m, 2H), 7.20-7.23 (d, J=8 Hz, 2H), 6.66-6.68 (dd, J=4 Hz, 1H), 2.30 (s, 3H); 13C NMR (CDCl3) δ 145.4, 135.7, 135.3, 131.2, 130.3, 127.2, 126.8, 124.9, 123.7, 121.8, 113.9, 109.5, 21.9; MS (ES+) m/z 271.93 (M+).
Reaction SMILES: [C:1]1([C:7]([Mg]Br)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS([C:15]1[N:16]=[C:17]([O:31][CH2:32][CH2:33][CH3:34])[C:18]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=3)[O:21][C:19]=2[N:20]=1)(=O)=O.[Cl-].[Li+].C(OCC)(=O)C>O1CCCC1>[C:1]1([C:7]([C:15]2[N:16]=[C:17]([O:31][CH2:32][CH2:33][CH3:34])[C:18]3[N:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=4)[O:21][C:19]=3[N:20]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C([Mg]Br)c1ccccc1
Reactant: CCCOc1nc(S(C)(=O)=O)nc2oc(-c3cccc(C)c3)nc12
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(c1ccccc1)c1nc(OCCC)c2nc(-c3cccc(C)c3)oc2n1
Reaction time: 1 h

Procedure:
298 mg of 1-phenyl-vinylmagnesium bromide were added to a solution of 500 mg of 5-methanesulfonyl-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine (example 5, step (f)) and 61 mg of lithium chloride in 20 ml of tetrahydrofuran. The reaction mixture was stirred for 1 h. Then 100 ml of ethyl acetate were added. The solution was extracted with 1 N hydrochloric acid, dried over sodium sulfate, filtered and evaporated in vacuo to give the crude title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:17].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]O)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:17][C:3]2[CH:4]=[CH:5][C:6]([O:8][C:9]3[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=3)=[CH:7][C:2]=2[Cl:1])=[CH:21][CH:20]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: Oc1ccc(Oc2cc(F)cc(F)c2)cc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1cc(F)cc(Oc2ccc(OCc3ccc(Cl)cc3)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.7 %

Procedure:
A mixture of 0.95 g of 2-chloro-4-(3,5-difluorophenoxy)phenol, 0.54 g of p-chlorobenzyl alcohol, 1.01 g of triphenylphosphine, 0.65 g of diethylazadicarboxylate and 90 ml of tetrahydrofuran was stirred at room temperature. After 48 hours, the reaction mixture was concentrated, and 50 ml of diethyl ether was added thereto. The precipitate were removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel chromatography to give 0.87 g of 4-chloro-1-[2-chloro-4-(3,5-difluorophenoxy)phenoxy]methylbenzene. Yield, 62%. m.p.: 95.3° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:15][CH2:16][CH2:17][CH3:18])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.Cl.Cl.[CH3:21][N:22]([CH2:24][CH:25]([OH:35])[CH2:26][O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[CH3:23].CO.N>C(O)CCC>[CH3:23][N:22]([CH2:24][CH:25]([OH:35])[CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([NH:32][C:2]2[N:7]=[C:6]([N:8]([CH2:15][CH2:16][CH2:17][CH3:18])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:33][CH:34]=1)[CH3:21]
Reactant: CCCCN(c1ccccc1)c1ccnc(Cl)n1
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Agent: Cl
Agent: N
Solvent: CO
Solvent: CCCCO
Product: CCCCN(c1ccccc1)c1ccnc(Nc2ccc(OCC(O)CN(C)C)cc2)n1
Temperature: 95 °C
Yield: 15.2 %

Procedure:
2-Chloro-4-(N-(n-butyl)anilino)pyrimidine (570 mg, 2.18 mmol) was dissolved in n-butanol (4 ml) and 4-[3-(N,N-dimethyl)amino-2-hydroxypropoxy]aniline dihydrochloride (Reference Example D-1; 554 mg, 1.97 mmol) was added. The resulting suspension was treated with methanol until all the solid dissolved. The reaction mixture was heated at 95° C. for 12 hours and allowed to cool to ambient temperature. The reaction mixture was then basified to pH 9–10 using methanolic ammonia and then evaporated onto silica (5 ml). The residue was purified by column chromatography eluting with methanol (15%):DCM:aqueous ammonia (1%). The resulting gum was re-evaporated from EtOAc twice to give the title product as a foam (130 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:17]([N:24]1[C:28](=[O:29])[CH:27]=[CH:26][C:25]1=[O:30])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O.C(Cl)Cl>[CH2:17]([N:24]1[C:28](=[O:29])[CH:27]2[CH:26]([C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)([OH:5])[C:3]3[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:2]=3[CH2:1]2)[C:25]1=[O:30])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccc(C)c(C(=O)c2ccccc2)c1
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1ccc2c(c1)C(O)(c1ccccc1)C1C(=O)N(Cc3ccccc3)C(=O)C1C2
Yield: 52.9 %

Procedure:
A solution of 35 g of 2,5-dimethylbenzophenone and 31.5 g of N-benzylmaleimide in 500 cc of acetone or methylene chloride is irradiated with a mercury high pressure lamp through a pyrex filter, until all the material has reacted (20 to 130 hours), filtration and concentration by evaporation are then effected. After crystallization from ether, the residue yields 35 g of 2-benzyl-3a,4,9,9a-tetrahydro-6-methyl-4-phenyl-benz[f]isoindolin-4-ol-1,3-dione, having a M.P. of 162-164°, which are dissolved in 170 cc of trifluoroacetic acid. The solution is stirred at 25° for 3 hours and concentrated by evaporation. After crystallization from methylene chloride/methanol, the residue yields 30 g of (9aRS)-2-benzyl-9,9a-dihydro-6-methyl-4-phenyl-benz[f]isoindoline-1,3-dione, having a M.P. of 156°-158°.
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]([NH:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:17])[CH2:11][CH2:10]1>CN1CCCC1=O>[C:1]([NH:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:17])[NH:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N=C=O
Reactant: N[C@H]1CC[C@H](NC(=O)NC2CCCCC2)CC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)NC(=O)NC1CCC(NC(=O)NC2CCCCC2)CC1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
A solution of tert-butylisocyanate (1.17 g, 0.012 mol) in dry N-methyl-2-pyrrolidone (NMP) (50 mL) was added slowly to a solution of trans-1-(4-aminocyclohexyl)-3-cyclohexylurea (2.83 g, 0.012 mol) in dry NMP (100 mL) under inert atmosphere. The resulting mixture was heated to 70° C. and stirred for 24 h. The solution was precipitated in 1 M HCl and filtered off. The resulting white solid was washed with THF, recrystallized from DMF and dried under high vacuum.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:11](Br)=[C:10]2[C:6]=1[CH2:7][CH2:8][CH2:9]2)(=[O:3])[CH3:2].[C:15]([O:20][CH2:21][CH3:22])(=[O:19])/[CH:16]=[CH:17]/[CH3:18].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CCCC)CCCC)CCC>CN(C)C=O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:11]([C:17]([CH3:18])=[CH:16][C:15]([O:20][CH2:21][CH3:22])=[O:19])=[C:10]2[C:6]=1[CH2:7][CH2:8][CH2:9]2)(=[O:3])[CH3:2]
Reactant: C/C=C/C(=O)OCC
Reactant: CC(=O)Nc1ccc(Br)c2c1CCC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)C=C(C)c1ccc(NC(C)=O)c2c1CCC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-acetylamino-7-bromoindane (2.8 g, prepared according to the method of A. Courtin, Helv. Chim. Acta 1980, 63(8), pages 2280-2286), ethyl crotonate (2.51 g), palladium diacetate (150 mg), tri-ortho-tolyl phosphine (450 mg) and tributylamine (10 mL) in dimethylformamide (30 mL) was stirred at 120° C. for 4 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, then allowed to stand for 48 hours, then partitioned between ethyl acetate (500 mL) and aqueous hydrochloric acid (300 mL, 1M). The organic phase was washed with 5% aqueous sodium bicarbonate (150 mL) and then filtered. The clear yellow filtrate was dried over sodium sulfate then evaporated. The residue was subjected to normal phase HPLC on silica under gradient elution conditions using ethyl acetate, heptane and methanol mixtures (from 20:80:1 to 90/10/1, v/v/v) to give the title compound (1.9 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=2[S:5][C:6]=1[SH:7].S1C(S)=CC2C=CC=CC1=2.[S].Cl[CH2:24][C:25]([N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][CH2:28]1)=[O:26].S1C(SCC(N2C3C(=CC=CC=3)CCC2)=O)=CC2C=CC=CC1=2>>[N:27]1([C:25](=[O:26])[CH2:24][S:7][C:6]2[S:5][C:4]3[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=3[C:2]=2[CH3:1])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: Cc1c(S)sc2ccccc12
Reactant: O=C(CCl)N1CCCc2ccccc21
Agent: O=C(CSc1cc2ccccc2s1)N1CCCc2ccccc21
Agent: Sc1cc2ccccc2s1
Agent: [S]
Product: Cc1c(SCC(=O)N2CCCc3ccccc32)sc2ccccc12
Yield: 5 %

Procedure:
Compound 75 was obtained according to the procedure used to synthesize compound 72, except the addition of sulfur was done at 40° C. in an attempt to avoid significant formation of disulfide. The obtained crude material (75) was used for the next step without further purification. 1-(3,4-dihydroquinolin-1(2H)-yl)-2-(3-methylbenzo[b]thiophen-2-ylthio)-ethanone (76): Crude compound 75 (0.55 g, 3.0 mmol) was coupled with compound 4 (0.48 g, 2.3 mmol) according to procedure used to synthesize compound 73. The product was purified by column chromatography to yield compound 76 (95 mg, 5% for two steps): MS: m/z+354.1 [M+H]+; Anal. Calcd (found) for C20H19NOS2.0.1H2O: C, 67.61; (67.59), H, 5.45; (5.48), N, 3.94; (3.94), S, 18.05; (17.75).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:10]2[CH:9]=[C:8]3[N:11]=[C:12]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:13][C:7]3=[CH:6][C:5]=2[N:4]([CH2:23][C:24](=[O:27])[CH2:25][CH3:26])[C:3]1=[O:28].[BH4-].[Na+].Cl>C(Cl)Cl.CO>[OH:27][CH:24]([CH2:25][CH3:26])[CH2:23][N:4]1[C:5]2[CH:6]=[C:7]3[NH:13][C:12]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:11][C:8]3=[CH:9][C:10]=2[C:2]([CH3:1])([CH3:29])[C:3]1=[O:28]
Reactant: CCC(=O)CN1C(=O)C(C)(C)c2cc3nc(NC(=O)c4ccccc4)[nH]c3cc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCC(O)CN1C(=O)C(C)(C)c2cc3nc(NC(=O)c4ccccc4)[nH]c3cc21
Temperature: 25 °C
Yield: 44.4 %

Procedure:
To a cooled solution (0° C.) of N-[7,7-dimethyl-6-oxo-5-(2-oxo-butyl)-3,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl]-benzamide (150 mg) in CH2Cl2 (3.5 ml) and MeOH (1.5 ml) is added NaBH4 (29.1 mg; 0.77 mmol). The mixture is stirred and warmed to RT overnight. After completion hydrochloric acid (5 ml; 1 N) is added and the mixture extracted with EtOAc. The organic phase is washed with brine, dried over MgSO4 and evaporated to dryness to give N-[5-(2-hydroxy-butyl)-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl]-benzamide (67 mg) as a racemic mixture.
Reaction SMILES: C[Si]([N:5]=[N+:6]=[N-:7])(C)C.CN(C=O)C.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[Cu]I.CO>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[N:5]=[N:6][NH:7][CH:28]=2)=[CH:25][CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1ccc(OCc2ccccc2)cc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CO
Product: c1ccc(COc2ccc(-c3c[nH]nn3)cc2)cc1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
Trimethylsilyl azide (415 mg, 3.6 mmol) was added to a DMF (4.3 mL) and MeOH (0.48 mL) solution containing CuI (22.9 mg, 0.12 mmol) and 1-(benzyloxy)-4-ethynylbenzene (500 mg, 2.4 mmol) under Ar in a pressure tube (caution: build-up of pressure possible; use a safety shield). The reaction mixture was stirred at 100° C. for 12 h. The mixture was cooled to room temperature and filtered through a short silica gel pad and concentrated. The residue was purified by recrystallization from DCM.
Reaction SMILES: Cl.[CH:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][C@H:22]([C:26]([OH:28])=[O:27])[CH2:21]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:29](N(CC)CC)C.CS(Cl)(=O)=O.COC(=O)CC1CCNC1>C1COCC1>[CH3:29][O:28][C:26](=[O:27])[CH2:22][CH:23]1[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][N:7]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][C:12]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]2=3)[CH2:21]1
Reactant: CCN(CC)CC
Reactant: O=C(O)[C@H]1CCCN(CCCN2c3ccccc3CCc3ccccc32)C1
Agent: COC(=O)CC1CCNC1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)CC1CCN(CCCN2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 27 %

Procedure:
3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-propanol (2.0 g, 0.0079 mol, prepared as described in example 10) was dissolved in dry THF (25 ml) under an atmosphere of nitrogen, and triethylamine (2.75 ml) was added. Methanesulfonyl chloride (0.61 ml, 0.0079 mol) was added dropwise and when addition was complete the reaction mixture was stirred for 45 minutes. The mixture was filtered and 3-pyrrolidinacetic acid methyl ester (2.4 g, 0.012 mol) was added to the filtrate. The mixture was heated at reflux temperature for 4 h and then stirred at room temperature for 48 h. Triethylamine (2.2 ml) was added and the mixture was heated at reflux temperature for 24 h. After cooling to room temperature the solvent was removed by evaporation in vacuo. The residue was purified by column chromatography on silica gel (125 g) using a mixture of dichloromethane and methanol (9:1) as eluent, affording 0.9 g (27%) of 1-(3-(10,11-dihydro-5H-dibenzo [b,f]azepin-5-yl)-1-propyl)-3-pyrrolidinacetic acid methyl ester as an oil. Rf : 0.15 (SiO2 ; dichloromethane/methanol/acetic acid=20:2:1).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[CH:9]=[CH:8][C:7]([C:12]2[S:13][CH:14]=[C:15]([CH3:17])[CH:16]=2)=[N:6]1.Cl[C:19]1[CH:20]=[CH:21][N:22]=[C:23]2[C:28]=1[N:27]=[CH:26][C:25]([O:29][CH3:30])=[CH:24]2>CC(O)C>[CH3:30][O:29][C:25]1[CH:24]=[C:23]2[C:28]([C:19]([N:2]([CH3:1])[CH2:3][CH2:4][N:5]3[C:10](=[O:11])[CH:9]=[CH:8][C:7]([C:12]4[S:13][CH:14]=[C:15]([CH3:17])[CH:16]=4)=[N:6]3)=[CH:20][CH:21]=[N:22]2)=[N:27][CH:26]=1
Reactant: CNCCn1nc(-c2cc(C)cs2)ccc1=O
Reactant: COc1cnc2c(Cl)ccnc2c1
Solvent: CC(C)O
Product: COc1cnc2c(N(C)CCn3nc(-c4cc(C)cs4)ccc3=O)ccnc2c1
Temperature: 100 °C

Procedure:
A suspension of 2-(2-(methylamino)ethyl)-6-(4-methylthiophen-2-yl)pyridazin-3(2H)-one (275 mg, 1103 μmol) and 8-chloro-3-methoxy-1,5-naphthyridine (193 mg, 993 μmol) in iPrOH (5 mL) was heated to 100° C. for 18 h in an appropriately sealed vial. The mixture was partitioned between CH2Cl2 (30 mL) and 1M NaOH (10 mL), and the organic dried over MgSO4. After concentration under reduced pressure, the organic residue was dissolved in iPrOH (2 mL) and the resulting crystallized solid was washed with iPrOH (2×0.5 mL) then dried under reduced pressure. MS (ESI pos. ion) m/z (MH+): 408. Calc'd exact mass for C21H21N5O2S: 407. 1H NMR (400 MHz, Chloroform-d) δ ppm 2.26 (s, 3 H) 3.22 (s, 3 H) 3.83 (s, 3 H) 4.51 (t, J=5.77 Hz, 2 H) 4.75 (t, J=5.77 Hz, 2 H) 6.55 (d, J=5.52 Hz, 1H) 6.60 (d, J=9.54 Hz, 1 H) 6.91 (s, 1 H) 6.97 (s, 1 H) 7.19 (d, J=9.54 Hz, 1 H) 7.32 (d, J=3.01 Hz, 1 H) 8.32 (d, J=5.52 Hz, 1 H) 8.46 (d, J=2.51 Hz, 1 H).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]#[N:15])[C:10]=2[O:12][CH3:13])[N:5]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=1)=[CH2:2].Br[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1.C1(C)C=CC(P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:13][O:12][C:10]1[C:9]([C:14]#[N:15])=[CH:8][CH:7]=[C:6]2[C:11]=1[C:3](/[CH:1]=[CH:2]/[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)=[N:4][N:5]2[C:16]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Brc1cccnc1
Reactant: C=Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(C#N)c(OC)c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Solvent: CCN(CC)CC
Product: COc1c(C#N)ccc2c1c(/C=C/c1cccnc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 110 °C

Procedure:
300 mg of 3-vinyl-4-methoxy-1-trityl-1H-indazole-5-carbonitrile and 180 μl of 3-bromopyridine were dissolved in a mixed solvent of 1 mL triethylamine/5 mL acetonitrile, added with 40 mg of tri-p-tolylphosphine and 27 mg of palladium acetate (II), and heated at 110° C. for 24 hours. The reaction solution was added with silica gel, the solvent was evaporated, and the resultant residue was purified by column chromatography (hexane:ethyl acetate=7:3), to afford 120 mg of the title compound as a pale yellow oil.
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@@H:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]2)=[O:2].OO.[O-:20]Cl=O.[Na+].OS([O-])=O.[Na+]>C(#N)C.O>[C:1]([C:3]1[C:4]([CH3:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@@H:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]2)([OH:20])=[O:2]
Reactant: COC(=O)C[C@H]1CCc2c1ccc(C=O)c2C
Reactant: [O-][Cl+][O-]
Agent: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C[C@H]1CCc2c1ccc(C(=O)O)c2C
Temperature: 25 °C
Yield: 91.5 %

Procedure:
To an ice-cold solution of methyl (R)-(5-formyl-4-methyl-indan-1-yl)acetate (872 mg, 3.76 mmol, from Step C), NaH2PO4 (150 mg) and 30% H2O2 (500 μL) in acetonitrile (10 mL) and H2O (2.5 mL), a solution of NaClO2 (615 mg) in H2O (4 mL) was added dropwise and the reaction mixture was allowed to warm to ambient temperature over 1 hr. After another hour, NaHSO3 (1.0 g) was added and the mixture was partitioned between EtOAc (30 mL) and 2.0 N HCl (15 mL). The layers were separated and the organic layer was washed with H2O (2×15 mL), brine (1×15 mL) dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to give 854 mg of the title compound as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.74-1.82 (m, 1H), 2.40-2.50 (m, 2H), 2.56 (s, 3H), 2.78 (dd, 1H, J=5.5, 15.5 Hz), 2.82-2.93 (m, 1H), 2.94-2.99 (m, 1H), 3.61-3.66 (m, 1H), 3.73 (s, 3H), 7.07 (d, 1H, J=7.8 Hz), 7.89 (d, 1H, J=8.0 Hz), 10.8-12.0 (br, s 1H); HPLC A: rt=2.74 min, m/z=249 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[Cl:13][C:14]1[C:21]([F:22])=[CH:20][CH:19]=[C:18]([F:23])[C:15]=1[CH2:16]Br>>[Cl:13][C:14]1[C:21]([F:22])=[CH:20][CH:19]=[C:18]([F:23])[C:15]=1[CH2:16][N:9]1[C:8](=[O:10])[CH2:7][NH:6][C:5]2[N:11]=[CH:12][C:2]([I:1])=[CH:3][C:4]1=2
Reactant: Fc1ccc(F)c(CBr)c1Cl
Reactant: O=C1CNc2ncc(I)cc2N1
Product: O=C1CNc2ncc(I)cc2N1Cc1c(F)ccc(F)c1Cl

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (300 mg) was reacted with 2-chloro-3,6-difluorobenzyl bromide as in General Procedure 1. The title compound was obtained as an off white solid (63% yield). M.p. 237° C., LCMS: m/z=436.17 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 4.01 (s, 2H), 5.24 (s, 2H), 7.05 (d, J=1.5 Hz, 1H), 7.23-7.32 (m, 1H), 7.41-7.48 (m, 1H), 7.79 (d, J=1.5 Hz, 1H).