Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:34][CH2:33]1>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:41]4[CH2:40][CH2:39][CH:38]([N:35]5[CH2:34][CH2:33][N:32]([CH3:31])[CH2:37][CH2:36]5)[CH2:43][CH2:42]4)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Reactant: CN1CCN(C2CCNCC2)CC1
Solvent: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N1CCC(N2CCN(C)CC2)CC1
Temperature: 105 °C
Yield: 66.3 %

Procedure:
Following the procedure of Example 11, a mixture of 110 mg (0.25 mmol) of 4-[3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)-phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile and 140 mg (0.76 mmol) of 1-methyl-4-piperidin-4-ylpiperazine in 0.8 mL of 1-methyl 2-pyrrolidinone is heated at 105° C. for 28 hours to yield the crude product. Purification by silica gel chromatography (gradient 94:6 methylene chloride/methanol to 84:15:1 methylene chloride/methanol/ammonium hydroxide) gives 100 mg of the 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-6-methoxy-7-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]quinoline-3-carbonitrile as a beige solid, mp 235-237° C.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:14]([O:16][CH3:17])=[O:15])=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:18]([N:37]1[C:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:48]2[CH:55]=[CH:54][C:51]([CH2:52]Br)=[CH:50][CH:49]=2)=[N:40][N:39]=[N:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:1]([C:5]1[N:9]([CH2:52][C:51]2[CH:50]=[CH:49][C:48]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[C:41]3[N:37]([C:18]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:38]=[N:39][N:40]=3)=[CH:55][CH:54]=2)[C:8]([C:10]([O:12][CH3:13])=[O:11])=[C:7]([C:14]([O:16][CH3:17])=[O:15])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(=O)OC)c(C(=O)OC)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 34.2 %

Procedure:
Following a procedure similar to that described in Example 35(a), but using 0.50 g of dimethyl 2-butylimidazole-4,5-dicarboxylate (prepared as described in Preparation 4) and 1.17 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide, 0.51 g of the title compound was obtained as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH:10]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH3:24])=[CH:17][CH:16]=1)[C:11]([O:13][CH3:14])=[O:12]>>[CH3:14][O:13][C:11](=[O:12])[CH:10]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH3:24])=[CH:17][CH:16]=1
Reactant: COC(=O)C(Br)c1ccc(OCC(C)Oc2ccc(Cl)cc2)cc1
Reactant: Oc1ccc(Cl)cc1
Product: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(OCC(C)Oc2ccc(Cl)cc2)cc1
Yield: 79.4 %

Procedure:
As described in Example 71, 2.19 g of p-chlorophenol is reacted with 7.0 g of methyl bromo{p-[2-(p-chlorophenoxy)propoxy]phenyl}acetate to give 6.2 g of product as a gum.
Reaction SMILES: [Cl:1][C:2]([F:6])=[C:3]([F:5])[F:4].[OH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12].[OH-].[K+]>CC(C)=O>[F:4][C:3]([F:5])([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])[CH:2]([F:6])[Cl:1]
Reactant: COC(=O)c1cccc(O)c1
Reactant: FC(F)=C(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OC(F)(F)C(F)Cl)c1

Procedure:
52.4 Parts by weight of chlorotrifluoroethylene are introduced, over 10 hours, into a mixture of 46.5 parts by weight of methyl 3-hydroxybenzoate and 9.5 parts by weight of potassium hydroxide powder in 50 parts by weight of acetone, refluxing at 45°-52° C. After concentrating the reaction mixture on a rotary evaporator under reduced pressure, the residue is taken up in methylene chloride and the solution is extracted with sodium bicarbonate solution, dried and evaporated, giving 69.5 parts by weight of methyl 3-(1',1',2'-trifluoro-2'-chloroethoxy)-benzoate of nD25 =1.4710.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[CH3:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][C:25](=[O:31])[NH:26]2>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:24]3[C:23]4[C:27](=[CH:28][CH:29]=[CH:30][C:22]=4[CH3:21])[NH:26][C:25]3=[O:31])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cccc(C)c43)c(C)c2C1=O
Yield: 52.5 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-methyl-1,3-dihydro-indole-2-one (prepared according to U.S. Pat. No. 6,114,371) as starting materials to give 5-(2-diethylamino-ethyl)-3-methyl-2-(4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (40 mg, 52.5%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:32][CH:31]=2)[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][S:25][CH2:24][CH2:23]2)[C:19]=1[CH3:20])=[O:13].C1C=C(Cl)C=C(C(OO)=[O:51])C=1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)=[CH:32][CH:31]=2)[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][S:25](=[O:51])[CH2:24][CH2:23]2)[C:19]=1[CH3:20])=[O:13]
Reactant: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCSCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCS(=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
To a cooled solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-thiopyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide (200 mg, 0.34 mmol) in 2 ml of DCM, m-CPBA (70 mg, 0.41 mmol) was added at 0° C. and stirred at room temperature for 2 h (monitored by TLC). The reaction was quenched with sat. NaHCO3, compound was extracted in DCM, dried over Na2SO4, concentrated under reduced pressure and purified by silica gel (100-200) column chromatography to obtain the title compound (60 mg, 29.3%).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:14]=2)[N:9]([CH3:24])[C:8]=1[C:25]([O:27]CC)=[O:26])=[O:5])[CH3:2].C(O)C.[OH-].[K+]>O1CCCC1>[CH2:1]([O:3][C:4]([NH:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:14]=2)[N:9]([CH3:24])[C:8]=1[C:25]([OH:27])=[O:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)Nc1c(C(=O)OCC)n(C)c2cc(OCc3ccccc3)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)Nc1c(C(=O)O)n(C)c2cc(OCc3ccccc3)ccc12

Procedure:
A suspension of 28.1 g (0.0708 mol) of ethyl 3-[(ethoxycarbonyl)amino]-1-methyl-6-(phenylmethoxy)-1H-indole-2-carboxylate in 170 ml of 96° ethanol is brought to reflux. 64 ml of a 10% ethanolic potassium hydroxide solution and 50 ml of tetrahydrofuran are added to this mixture. The suspension is left at reflux for 150 min, is then concentrated under reduced pressure, diluted with a mixture of water and ice and acidified with 6N hydrochloric acid. The product is then extracted with a mixture of dichloromethane and tetrahydrofuran, the organic phase is washed with water and dried over sodium sulphate and the solvent is evaporated under reduced pressure. The residue is triturated in diisopropyl ether and 24.8 g of product are recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2[S:13][CH:14]=[CH:15][C:7]1=2)=[O:5].C(N(CC)CC)C.[C:28]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:29]([C:34](Cl)=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=1>ClCCl>[S:13]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][N:6]([C:4]([C:3]3[CH:16]=[CH:17][C:18]([NH:20][C:34]([C:29]4[C:28]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:35])=[CH:19][C:2]=3[Cl:1])=[O:5])[C:7]=2[CH:15]=[CH:14]1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Reactant: Nc1ccc(C(=O)N2CCCCc3sccc32)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2CCCCc3sccc32)c(Cl)c1)c1ccccc1-c1ccccc1

Procedure:
As described for Example 1, a solution of 2 mmol of 4-(2-chloro-4-aminobenzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine and 5 mmol of triethylamine in 10 ml of dichloromethane under argon is reacted with [1,1'-biphenyl]-2-carbonyl chloride for 16 hours at room temperature to give the product as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[NH2:8].[CH3:13][O:14][C:15]1[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[CH:23]=[CH:22][C:16]=1[CH:17]=[CH:18][C:19](O)=O>>[CH3:13][O:14][C:15]1[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[CH:23]=[CH:22][C:16]=1/[CH:17]=[CH:18]/[C:19]1[NH:1][C:2]2[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=2[N:8]=1
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1C
Product: COc1ccc(/C=C/c2nc3c([nH]2)c(=O)n(C)c(=O)n3C)c(OC)c1C
Yield: 27.7 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 1.0 g (5.88 mmol) of 5,6-diamino-1,3-dimethyluracil and 1.44 g (6.45 mmol) of 2,4-dimethoxy-3-methylcinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 581 mg (yield 28%) of Compound 94 as pale yellow needles.
Reaction SMILES: [N:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N+:2]=[N-:3].[CH2:19]([OH:22])[C:20]#[CH:21]>>[OH:22][CH2:19][C:20]1[N:3]=[N:2][N:1]([C:4]2[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=2[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:21]=1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1N=[N+]=[N-]
Reactant: C#CCO
Product: CC(C)(C)OC(=O)NCc1ccccc1-n1cc(CO)nn1
Temperature: 90 °C
Reaction time: 18 h
Yield: 38 %

Procedure:
tert-butyl 2-azidobenzylcarbamate, 12, (5.4 g, 21.7 mmol) was dissolved in neat propargyl alcohol (10 mL). The reaction mixture was stirred at 90° C. for 18 h. The reaction mixture was then concentrated in vacuo and the resulting residue dissolved in diethyl ether. Upon standing, triazole 13 crystallized. The crystals were collected by filtration yielding 2.5 g (38%) of 13: 1H NMR (400 MHz, CDCl3) δ 7.82, (s, 1H), 7.64-7.35 (m, 3H), 7.34-7.30 (m, 1H), 5.35, (bs, 1H), 4.87, (s, 2H), 4.15 (s, 2H), 1.42 (s, 9H); ESI+ MS: m/z (rel intensity) 249 (100, M-tBu).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:22][C:23]1[CH:27]=[N:26][N:25]([CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH:24]=1)[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Reactant: BrCC1CCCCC1
Product: COc1ccc(N(Cc2cnn(CC3CCCCC3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(4-methoxyphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.56 g) and (bromomethyl)cyclohexane (0.20 mL) as starting materials, 5-benzyloxy-N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.55 g) was obtained. By the reaction and treatment in the same manner as in Example 133 using this compound (0.45 g), N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.36 g) was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][S:9][C:8]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:7]1=2.I.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](SC)=[NH:25]>C(O)C.C([O-])(O)=O.[Na+]>[CH3:17][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][S:9][C:8]2[CH:12]=[C:13]([NH:16][C:24]([C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)=[NH:25])[CH:14]=[CH:15][C:7]1=2
Reactant: CN(C)CCCN1CCSc2cc(N)ccc21
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN(C)CCCN1CCSc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.6 %

Procedure:
A solution of 4-(3-(dimethylamino)propyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-amine (0.22 g, 0.875 mmol) in dry ethanol (10 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.499 g, 1.750 mmol) at room temperature, and the resulting mixture was stirred over night (18 hours) at room temperature. The reaction was diluted with saturated NaHCO3 solution (25 mL), and the product was extracted into CH2Cl2 (3×20 mL). The combined CH2Cl2 layers were washed with brine (15 mL) and dried (Na2SO4). The solvent was evaporated, and the crude material was purified by column chromatography (5:95 (2M NH3 in MeOH):CH2Cl2) on silica gel to obtain the title product 22 (0.27 g, 86%) as a solid. 1H NMR (DMSO-d6) δ 7.68 (d, 1H, J=3.0 Hz), 7.56 (d, 1H, J=5.1 Hz), 7.06 (dd, 1H, J=3.9, 4.8 Hz), 6.69 (d, 1H, J=8.7 Hz), 6.52-6.45 (m, 2H), 6.33 (brs, 2H), 3.51-3.48 (m, 2H), 3.25 (t, 2H, J=7.2 Hz), 3.04-3.01 (m, 2H), 2.25 (t, 2H, J=6.9 Hz), 2.14 (s, 6H), 1.70-1.61 (m, 2H); ESI-MS (m/z, %): 361 (MH+, 93), 276 (100); HPLC purity: 98.23% by area.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]3[S:15][CH:16]=[CH:17][C:13]=3[C:12](=[O:18])[NH:11][N:10]=2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[CH:26]([CH3:28])[CH3:27]>CN(C=O)C>[CH:26]([N:11]1[C:12](=[O:18])[C:13]2[CH:17]=[CH:16][S:15][C:14]=2[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[N:10]1)([CH3:28])[CH3:27]
Reactant: COc1ccc(-c2n[nH]c(=O)c3ccsc23)cc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nn(C(C)C)c(=O)c3ccsc23)cc1
Temperature: 80 °C
Yield: 65 %

Procedure:
A solution of the product from step 1 in 10 mL of DMF was added Cs2CO3 (2 eq. 1.95 g) and 2-iodopropane (1.2 eq., 360 uL). The reaction was heated to 80° C. for 2 h, and then filtered through celite, washed with MeOH:CH2Cl2 (95:5). The filtrate was concentrated and purified by silica gel flash chromatography (MeOH:CH2Cl2, 97:3) to afford 585 mg (65%) of the product: Mp 124-6° C.; MS m/z 301 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[N:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[N:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:23][CH:22]=1
Reactant: OB(O)c1ccncc1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccncc3)ccn2c1=O
Yield: 70 %

Procedure:
Methyl 8-(pyridin-4-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (500 mg, 1.71 mmol) and pyridin-4-yl-boronic acid (253 mg, 2.05 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (400 mg, 69%).
Reaction SMILES: Cl[C:2]1([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH3:14].[CH2:22]([SH:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)(=O)C>CO>[CH2:22]([S:29][C:2]1([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH3:14])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCN1C(=O)c2ccccc2C1(Cl)c1ccc(Cl)cc1
Reactant: SCc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCN1C(=O)c2ccccc2C1(SCc1ccccc1)c1ccc(Cl)cc1

Procedure:
Distilled THF was added to 3-chloro-3-(4-chlorophenyl)-2-propylisoindolin-1-one (1.06 g, 3.31 mmol) followed by benzyl mercaptan (0.855 mL, 7.29 mmol) as for general procedure C. On addition of the benzyl mercaptan, a pale pink precipitate formed which turned white over time. The ethyl acetate was mostly removed under vacuum. On leaving overnight in the fridge, clear crystals formed. The crude product was purified by flash column chromatography (20:80, EtOAc:petrol) and recrystallised in the minimum amount of hot ethyl acetate giving large colourless crystals of 3-benzylsulfanyl-3-(4-chlorophenyl)-2-propyl-2,3-dihydroisoindolin-1-one (918 mg, 2.25 mmol, 68%). Rf 0.68 (40:60 EtOAc:petrol). Mp. 131.5-133.4° C. λmax (CH3OH)/nm 223.0, Abs 0.964. IR: 3161, 2968, 1665, 1608, 1467, 1435, 1402 cm−1. 1H NMR (300 Hz, CDCl3); δ 0.72 (t, 3H, J=7.5 Hz, N(CH2)2—CH3), 1.37 (m, 1H, N—CH2—CH2—CH3), 1.57 (m, 1H, N—CH2—CH2—CH3), 2.80 (d, 1H, J=12 Hz, S—CH2), 3.10 (d, 1H, J=12 Hz, S—CH2), 3.17 (m, 1H, N—CH2), 3.36 (m, 1H, N—CH2), 6.92-7.81 (m, 13H, Ar). 13C NMR (75 Hz, CDCl3); 111.8 (N—(CH2)2—CH3), 21.5 (N—CH2—CH2), 33.4 (S—CH2), 42.6 (N—CH2), 78.2 (S—C—N), 123.2, 123.4, 127.3, 128.0, 128.5, 128.9, 128.9, 131.0, 132.8, 134.9, 135.8, 137.1, 148.3 (Ar), 167.9 (C═O). LC/MS-ES+ m/z 410.6, 408.7, 286.1, 287.1. Anal. Calcd. for C24H22ClNOS: C, 70.66; H, 5.44; N, 3.43%. Found C, 70.60; H, 5.51; N, 3.51%.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([CH3:28])[CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1.[H-].[Na+].Br[CH2:33][CH2:34][O:35][CH2:36][CH3:37]>>[CH2:34]([O:35][CH2:36][CH2:37][N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[C:19]([CH:16]2[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][O:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:2])=[O:29])[CH2:14][CH2:15]2)=[CH:20]1)[CH3:33]
Reactant: CCOCCBr
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3c(C)cccc23)CC1
Agent: [H-]
Agent: [Na+]
Product: CCOCCn1cc(C2CCN(CCOc3ccccc3C(=O)O)CC2)c2cccc(C)c21

Procedure:
This compound was prepared following the procedure described in Example 138 (part B) starting with 0.068 g (0.172 mmol) of 2-{2-[4-(7-methyl-1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester (prepared as in Example 138, part A), 0.010 g (0.26 mmol) of NaH in 60% of mineral oil and 0.023 mL (0.22 mmol) of bromoethylethyl ether. The crude mixture was hydrolised following the procedure described in Example 138 (part C) and purified by chromatography over silica gel affording 0.074 g (93% of yield) of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:44])[C:5]([O:8][C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([C:18]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)=[CH:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[N:15](S(C3C=CC=CC=3)(=O)=O)[C:12]2=[N:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:44])[C:5]([O:8][C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([C:18]([C:25]3[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=3)=[CH:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[NH:15][C:12]2=[N:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Yield: 99.2 %

Procedure:
A solution of 2-{1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-2-methyl-propionic acid ethyl ester (1.34 g, 2.11 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 8.0 mL, 8.0 mmol) was stirred at room temperature for 12 h. The resulting mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous ammonium chloride solution and brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-2-methyl-propionic acid ethyl ester (1.04 g, quant.) as a white solid: LC/MS m/e calcd for C27H32N2O5S [M+H]+ 497.63, observed 497.4.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([N:29]3[CH2:30][CH2:31][N:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=4)[CH2:27][CH2:28]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: c1ccc(N2CCNCC2)nc1
Product: O=C(N1CCN(c2ccccn2)CC1)N1Cc2ccccc2Oc2ccc(Cl)cc21
Yield: 81.1 %

Procedure:
The title compound of Example 2 (1.0 g, 3.4 mmol) was combined with 1-(2-pyridyl)piperazine (0.56 g, 3.4 mmol) and the reaction was carried out by the method of Example 4. Following chromatographic purification, 1.16 g of the title product was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=O)[CH2:4][NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(Cl)(Cl)Cl.[SH2:19]>>[CH3:1][O:2][C:3]1[S:19][C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][CH:4]=1
Reactant: S
Reactant: COC(=O)CNC(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1cnc(-c2ccccc2)s1
Temperature: 80 °C

Procedure:
1.0 g (5.2 mmol) of benzoylglycin methyl ester and 1.4 g (6.4 mmol) of diphosphorous pentasulfide was added quickly into a reaction vessel. After that, anhydrous chloroform (15 ml) was also added and heated to around 80° C. When decrease in hydrogen sulfide generation and white precipitate formation in the reaction solution were observed, an argon balloon was attached and the solution was refluxed for 24 hours. After completion of reaction, the precipitate was dissolved by adding an aqueous solution of strong alkali to the solution, and the organic phase was extracted with dichloromethane, followed by drying with addition of magnesium sulfate and removal of solvent. The product was developed with ethyl acetate:hexane=5:5 solvent on a silica column to give 5-methoxy-2-phenylthiazole (Rf=0.40). The yield was 566 mg in weight and 57% in percentage.