Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:14](=[O:15])[CH2:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[S:10]1.CI.[C:22](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:22][CH:13]1[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[S:10][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:14]1=[O:15]
Reactant: O=C([O-])[O-]
Reactant: COc1ccccc1N1Sc2ccccc2CC1=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccccc1N1Sc2ccccc2C(C)C1=O

Procedure:
5.42 g (20 mmol) of 2,3-dihydro-2-(2-methoxyphenyl)benzothiazin-3-one are dissolved in 100 ml of acetone, and 6.9 ml of methyl iodide and 6.5 g of potassium carbonate are added, and the mixture is heated to reflux for 45 hours. After filtration, the filtrate is concentrated. The product crystallizes on trituration with isopropyl ether.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]([CH3:39])[O:37][CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]([CH3:39])[O:37][CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3coc(C)n3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(C)cc(-c3coc(C)n3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[C:3]([C:10](=[O:15])[C:11]([O:13]C)=[O:12])=[CH:2]1.C([O-])([O-])=O.[K+:20].[K+]>CO.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[C:3]([C:10](=[O:15])[C:11]([O-:13])=[O:12])=[CH:2]1.[K+:20]
Reactant: COC(=O)C(=O)c1c[nH]c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C([O-])C(=O)c1c[nH]c2ncccc12
Reaction time: 8 h
Yield: 89.7 %

Procedure:
Compound 2a (43 g, 0.21 mol) and K2CO3 (56.9 g, 0.41 mol) were dissolved in MeOH (200 ml) and H2O (200 ml). After 8 hours, product 3a precipitated out from the solution. Filtration afforded 43 g of compound 3a as a white solid in 90.4% yield.
Reaction SMILES: Cl.N[CH2:3][C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([S:13]([CH3:16])(=[O:15])=[O:14])[C:5]=1[OH:17].C1N2CN3CN(C2)CN1C3.FC(F)(F)C(O)=[O:31]>>[CH:3]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([S:13]([CH3:16])(=[O:15])=[O:14])[C:5]=1[OH:17])=[O:31]
Reactant: CC(C)c1cc(CN)c(O)c(S(C)(=O)=O)c1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: CC(C)c1cc(C=O)c(O)c(S(C)(=O)=O)c1

Procedure:
0.7 g (0.0025 mol) of 2-aminomethyl-4-isopropyl-6-methylsulfonylphenol hydrochloride are reacted with 0.45 g of urotropine in 8 ml of trifluoroacetic acid to give 2-formyl-4-isopropyl-6-methylsulfonylphenol in analogy to Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:31])[C:5]([O:11][C:12]2[C:13]([CH2:29]O)=[C:14]([CH:26](O)[CH3:27])[C:15]([O:18]CC3C=CC=CC=3)=[CH:16][CH:17]=2)=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[CH:3]=[C:4]([CH3:31])[C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:26][CH3:27])[C:13]=2[CH3:29])=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2
Reactant: Cc1cc(N)c2c(c1Oc1ccc(OCc3ccccc3)c(C(C)O)c1CO)CCC2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1c(O)ccc(Oc2c(C)cc(N)c3c2CCC3)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of 1-[-(7-amino-5-methylindan-4-yloxy)-6-benzyloxy-2-hydroxymethylphenyl]ethanol (40 mg) in dichloromethane (1 mL) was added triethylsilane (0.400 mL). Adding dropwise trifluoroacetic acid (1 mL), the mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness. To the residue were added ethyl acetate (3 mL) and a saturated aqueous solution of sodium hydrogen carbonate (10 mL). The reaction mixture was stirred for 15 min, and extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by thin layer chromatography on silica gel (developing solvent: hexane/ethyl acetate=1/1) to give the title compound (24 mg).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][C@H:36]([NH2:40])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][C@H:36]([NH:40][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([F:14])[C:10]([O:12][CH3:13])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c[nH]c23)cc1F
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CCCN(C(=O)OC(C)(C)C)C4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A80) and (S)-3-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[N:7]=1.B(O)(O)[C:13]1[CH:18]=[CH:17][C:16]2[NH:19][CH:20]=[CH:21][C:15]=2[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:13]3[CH:14]=[C:15]4[C:16](=[CH:17][CH:18]=3)[NH:19][CH:20]=[CH:21]4)=[CH:9][N:10]=2)[N:7]=1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: Clc1ccc2ncc(I)n2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1ccc2ncc(-c3ccc4[nH]ccc4c3)n2n1
Temperature: 150 °C
Yield: 90 %

Procedure:
6-chloro-3-iodoimidazo[1,2-b]pyridazine (1.00 g, 4.30 mmol, 1.0 equiv), in acetonitrile (20 mL), was added 1H-indol-5-yl-5-boronic acid (1.04 g, 6.45 mmol, 1.5 equiv), bis(triphenylphosphine)palladium(II) chloride (157 mg, 0.215 mmol, 0.05 equiv), then sodium carbonate (4.83 mL, 1.0 M aqueous solution, 2.0 equiv). The reaction mixture heated in the microwave at 150° C. for 20 min. Purification by column chromatography using 2% methanol in dichloromethane elutions gave 1.04 g of the white solid, 60%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17][C:18]#[N:19]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[C:17](=[CH:7]/[C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)/[C:18]#[N:19])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Product: COc1ccc(/C(C#N)=C/c2cccc([N+](=O)[O-])c2)cc1OC
Yield: 96.9 %

Procedure:
3-Nitrobenzaldehyde (3.02 g) and 3,4-dimethoxybenzyl cyanide (3.54 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (6.01 g, yield: 97%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][N:10]3[CH:13]=[CH:14][N:15]=[C:9]3[CH:8]=2)=[CH:3][CH:2]=1.Br[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([NH:26][C:27]2[S:28][C:29]([CH:33]([CH3:35])[CH3:34])=[C:30]([CH3:32])[N:31]=2)=[O:25])=[C:19]([F:36])[CH:18]=1.C([O-])(=O)C.[K+]>CS(C)=O>[F:36][C:19]1[CH:18]=[C:17]([C:13]2[N:10]3[CH:11]=[CH:12][C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[CH:8][C:9]3=[N:15][CH:14]=2)[CH:22]=[CH:21][C:20]=1[CH2:23][C:24]([NH:26][C:27]1[S:28][C:29]([CH:33]([CH3:35])[CH3:34])=[C:30]([CH3:32])[N:31]=1)=[O:25]
Reactant: c1cc(-c2ccn3ccnc3c2)ccn1
Reactant: Cc1nc(NC(=O)Cc2ccc(Br)cc2F)sc1C(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1nc(NC(=O)Cc2ccc(-c3cnc4cc(-c5ccncc5)ccn34)cc2F)sc1C(C)C
Yield: 11.3 %

Procedure:
Combine 7-pyridin-4-yl-imidazo[1,2-a]pyridine (0.242 g, 1.24 mmol), 2-(4-Bromo-2-fluoro-phenyl)-N-(5-isopropyl-4-methyl-thiazol-2-yl)-acetamide (0.460 g, 1.24 mmol), and potassium acetate (0.243 g, 2.48 mmol) in DMSO (5 mL). De-gas the mixture with N2 for 10 minutes, then add dichlorobis(triphenylphosphine) palladium(II) (0.087 g, 0.124 mmol). Stir the reaction at 100° C. under N2 for 14 hours. Purify using an SCX cartridge (10 g VARIAN bond elut), eluting with 1:1 methanol:dichloromethane, then 1:1 2 M NH3 in methanol:dichloromethane. The latter is purified via reverse phase chromatography using a 25 cm by 50.8 mm (i.d.) column w/10 micron particles (MeCN/0.03% HCl H2O (5:95) to 100% MeCN; 30 minutes). Compound obtained is extracted with ethyl acetate versus 1 N NaOH. The organic layer is washed with aqueous saturated sodium chloride. Dry the resulting organics over magnesium sulfate, filter, and concentrate to afford product (0.068 g, 11%). MS(ES), m/z 486 (M+1).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Cl:9][CH2:10][CH2:11][C:12](O)=O>Cl>[Cl:9][CH2:10][CH2:11][C:12]1[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1
Reactant: O=C(O)CCCl
Reactant: Nc1ccccc1N
Agent: Cl
Product: ClCCc1nc2ccccc2[nH]1
Yield: 32.3 %

Procedure:
A mixture of 1,2-Phenylenediamine (1.3 g, 12.0 mmol) and 3-chloropropionic acid (2.0 g, 18.5 mmol) were refluxed in 4N HCl (13 mL) for 16 hours to give the title compound as white solid (700 mg, 32%). 1H NMR (CD3OD) □3.35 (t, 2H, J=6.8 Hz), 4.00 (t, 2H, J=6.8 Hz), 7.18-7.25 (m, 2H), 7.49-7.55 (m, 2H); ES-MS m/z 181.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@H:19]([OH:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[C:37]([C:45]3[S:46][CH:47]=[CH:48][CH:49]=3)[CH:36]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.O.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>[C:13]([O:12][C:11]([N:10]([CH2:18][C@H:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[C:37]([C:45]3[S:46][CH:47]=[CH:48][CH:49]=3)[CH:36]=2)=[CH:3][CH:4]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1-c1cccs1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Br)cc1)C[C@H](O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3ccccc3)C(=O)OC(C)(C)C)cc2)cc1-c1cccs1
Temperature: 80 °C
Reaction time: 4 h
Yield: 51.4 %

Procedure:
To a solution of tert-butyl [2-(4-bromophenyl)ethyl]-[(2R)-2-hydroxy-2-phenylethyl]carbamate (280 mg) in 1,2-dimethoxyethane (4 ml) was added methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-thienyl)benzoate (275 mg), tetrakis(triphenylphosphine)palladium (62 mg) and aqueous solution of sodium carbonate (2M, 0.7 ml), and the mixture was stirred at 80° C. for 4 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3/1) to give methyl 4′-[2-[(tert-butoxycarbonyl) [(2R)-2-hydroxy-2-phenylethyl]amino]-ethyl]-3-(2-thienyl)-4-biphenylcarboxylate (191 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[OH:10][CH2:11][CH:12]([CH2:14]O)[OH:13].S(=O)(=O)(O)O.O>C1C=CC=CC=1>[OH:13][CH:12]1[CH2:11][O:10][CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([CH3:1])[CH:3]=2)[O:6][CH2:14]1
Reactant: OCC(O)CO
Reactant: Cc1cccc(C=O)c1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: Cc1cccc(C2OCC(O)CO2)c1
Yield: 64.6 %

Procedure:
A mixture of 3-methylbenzaldehyde (24.0 g, 0.2 mole), glycerol (18.4 g, 0.2 mole) and 40% sulfuric acid (2.0 ml) in 150 ml of benzene was heated under a Dean-Stark apparatus until no more water was collected (approximately 2.5 hours). The mixture was cooled, neutralized with potassium carbonate, diluted by the addition of 200 ml of ether and the ether solution washed with water (3 × 100 ml). The organic layer was dried over magnesium sulfate and concentrated to give a residue of 25.1 g of the desired 5-hydroxy-2-(3-methylphenyl)-1,3-dioxane nD25 1.5346.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[N:40][CH:39]=1.C(N(CC)CC)C>CN(C)C=O>[C:37]([NH:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[N:40][CH:39]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=O)c4cccnc4)cc3)cc21
Yield: 70.1 %

Procedure:
In a similar manner to that described in Example 47, a reaction was carried out using 5-{4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylmethoxy]benzyl}thiazolidine-2,4-dione dihydrochloride (400 mg), nicotinoylchloride (195 mg), triethylamine (354 mg) and anhydrous N,N-dimethylformamide (8 ml) and the reaction mixture was purified to give the title compound (297 mg).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15](C1NN=CC=1)[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:41]2[CH:42]=[N:43][NH:44][CH:45]=2)O1>>[C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([C:41]1[CH:42]=[N:43][NH:44][CH:45]=1)[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc2nc(-c3ccn[nH]3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Cc1cc2nc(-c3cn[nH]c3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reaction time: 1 h

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(1H-pyrazol-4-yl)quinolin-6-yl)acetic acid (77) was prepared following the procedure for (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(1H-pyrazol-5-yl)quinolin-6-yl)acetic acid of Example 70 except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 1H-pyrazol-5-ylboronic acid and the in the final step the reaction was stirred for 1 hour. 1H-NMR: 400 MHz, (CD3CN) δ: 8.45 (s, 2 H), 8.08 (s, 1 H), 7.89 (d, J=8.8 Hz, 1 H), 7.73 9 (d, J=8.8 Hz, 1 H), 7.59 (m, 3 H), 7.34 (d, J=7.2 Hz, 1H), 5.22 (s, 1 H), 2.63 (s, 3 H), 0.97 (s, 9 H). LCMS-ESI+ (m/z): [M+H]+ calcd for C25H25ClN3O3: 450.15. found: 450.53.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:36]=[CH:35][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([O:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:18]=2)[NH:15][C:14]([C:26]2[S:27][CH:28]([CH2:31][C:32]([OH:34])=O)[CH2:29][N:30]=2)=[CH:13]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.C[N:39](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.N>CCCCCC.C(OCC)(=O)C.CO.O.CN(C)C=O>[CH3:1][S:2]([C:5]1[CH:36]=[CH:35][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([O:19][CH:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[CH:18]=2)[NH:15][C:14]([C:26]2[S:27][CH:28]([CH2:31][C:32]([NH2:39])=[O:34])[CH2:29][N:30]=2)=[CH:13]3)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(N)=O)S4)cc3c2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
A mixture of (2-{5-[4-(methylsulfonyl)phenoxy]-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (370 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (268 mg), 1-hydroxybenzotriazole (189 mg), and N,N-dimethylformamide (20 mL) was stirred at 50° C. for 30 min. The reaction solution was cooled to room temperature, 10% aqueous ammonia solution (1.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (methanol:ethyl acetate:hexane=0:50:50 to 10:90:0, volume ratio) to give the title compound (200 mg, yield 54%) as a white amorphous solid. The white amorphous solid was crystallized from diethyl ether and the obtained crystals were recrystallized from ethyl acetate-diethyl ether to give the title compound as colorless crystals.
Reaction SMILES: Br[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:3]=1[C:4]#[N:5].CCOC(C)=O.[NH4+:17].[OH-]>C1COCC1>[NH2:17][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:3]=1[C:4]#[N:5]
Reactant: [NH4+]
Reactant: N#Cc1c(Br)ccnc1Br
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1c(Br)ccnc1N
Temperature: 100 °C
Yield: 26.8 %

Procedure:
A mixture of compound D7 (32 g, 122.2 mmol) in NH4OH (200 ml, 30% in water) and THF (200 ml) was heated at 100° C. for 12 h. in a PARR pressure vessel. After cooling, EtOAc was added. The organic layer was separated, washed with brine, dried (Na2SO4) and evaporated in vacuo. The solid residue thus obtained was triturated with DCM and then filtered off. The filtrate was evaporated in vacuo to yield compound D8 (6.5 g, 26.8%) as a white solid.
Reaction SMILES: C[Mg]I.[CH2:4]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:22]=[CH:21][C:18](C#N)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH:7]=[CH2:8].C1(C)C=CC=CC=1.C([O:32][CH2:33][CH3:34])C>>[CH2:4]([C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[CH:16]=[CH:17][C:18]([C:33](=[O:32])[CH3:34])=[CH:21][CH:22]=2)[CH2:13][CH2:14]1)[CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: C=CCCC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Reactant: CCOCC
Agent: C[Mg]I
Solvent: Cc1ccccc1
Product: C=CCCC[C@H]1CC[C@H](c2ccc(C(C)=O)cc2)CC1

Procedure:
A solution of methylmagnesium iodide in diethyl ether (prepared from 195 mg of magnesium shavings and 0.495 ml of methyl iodide in 15 ml of diethyl ether) was treated dropwise at room temperature with a solution of 1.0 g of p-[trans-4-(4-pentenyl)cyclohexyl]benzonitrile. The mixture was heated to reflux for 15 minutes. Subsequently, 15 ml of toluene were added to the reaction mixture, the diethyl ether was distilled off and the mixture was heated to reflux for a further 1.5 hours. Thereafter, the reaction mixture was treated cautiously at 0° C. with saturated ammonium chloride solution and partitioned three times in diethyl ether/washed twice with water, dried over magnesium sulphate, filtered and evaporated. Chromatographic separation of the yellow crystalline residue (1.1 g) on silica gel with ethyl acetate/petroleum ether (vol. 5:95) gave 0.96 g (90%) of p-[trans-4-(4-pentenyl)cyclohexyl]acetophenone as light yellow crystals; m.p. 47.6° C.
Reaction SMILES: C(O[C:4](=[O:22])[CH2:5][C:6]1[NH:10][C:9]2[CH:11]=[C:12]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:13]=[CH:14][C:8]=2[N:7]=1)C.[NH2:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:25]=1[C:26]#[N:27].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[K]>C1COCC1>[NH2:27][C:26]1[C:25]2[C:24](=[CH:31][CH:30]=[CH:29][C:28]=2[F:32])[NH:23][C:4](=[O:22])[C:5]=1[C:6]1[NH:10][C:9]2[CH:11]=[C:12]([N:15]3[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]3)[CH:13]=[CH:14][C:8]=2[N:7]=1
Reactant: N#Cc1c(N)cccc1F
Reactant: CCOC(=O)Cc1nc2ccc(N3CCN(C)CC3)cc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Agent: [K]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc3nc(-c4c(N)c5c(F)cccc5[nH]c4=O)[nH]c3c2)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
[6-(4-Methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-acetic acid ethyl ester (250 g, 820 mmol) (dried with ethanol as described above) was dissolved in THF (3800 mL) in a 5000 mL flask fitted with a condenser, mechanical stirrer, temperature probe, and purged with argon. 2-Amino-6-fluoro-benzonitrile (95.3 g, 700 mmol) was added to the solution, and the internal temperature was raised to 40° C. When all the solids had dissolved and the solution temperature had reached 40° C., solid KHMDS (376.2 g, 1890 mmol) was added over a period of 5 minutes. When addition of the potassium base was complete, a heterogeneous yellow solution was obtained, and the internal temperature had risen to 62° C. After a period of 60 minutes, the internal temperature decreased back to 40° C., and the reaction was determined to be complete by HPLC (no starting material or uncyclized intermediate was present). The thick reaction mixture was then quenched by pouring it into H2O (6000 mL) and stirring the resulting mixture until it had reached room temperature. The mixture was then filtered, and the filter pad was washed with water (1000 mL 2×). The bright yellow solid was placed in a drying tray and dried in a vacuum oven at 50° C. overnight providing 155.3 g (47.9%) of the desired 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one.
Reaction SMILES: Cl[C:2]1[C:3]2[C:4](=[CH:15][S:16][CH:17]=2)[C:5](=[CH:12][C:13]#[N:14])[C:6]2[C:7](=[CH:9][S:10][CH:11]=2)[N:8]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[C:13]([CH:12]=[C:5]1[C:4]2=[CH:15][S:16][CH:17]=[C:3]2[C:2]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)=[N:8][C:7]2=[CH:9][S:10][CH:11]=[C:6]12)#[N:14]
Reactant: CN1CCNCC1
Reactant: N#CC=C1c2cscc2N=C(Cl)c2cscc21
Product: CN1CCN(C2=Nc3cscc3C(=CC#N)c3cscc32)CC1
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 85 %

Procedure:
50 ml of N-methyl-piperazine are added to 14.4 g (52 mmoles) of 5-chloro-9-cyanomethylene-dithieno[3,4-b:4',3'-e]azepine and the mixture is stirred under nitrogen at 110° C. for 2 to 3 hours. After having been cooled, the dark homogeneous reaction mixture is poured onto ice-water and the yellowish crude 9-cyanomethylene-5-(4-methyl-piperazin-1-yl)-dithieno[3,4-b:4',3'-e]azepine is filtered off with suction. After the crude product has been dried in an oven under reduced pressure, it is recrystallized from ethanol, with the addition of active charcoal, or purified by column chromatography (silica gel, mobile phase: a 95/5 mixture of methylene chloride and methanol). 13.6 g (85%) of yellowish 9-cyanomethylene-5-(4-methyl-piperazin-1-yl)-dithieno[3,4-b:4',3'-e]azepine are obtained in the form of a cis/trans-isomer mixture of melting point 148°-151° C.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1>>[Br:10][C:11]1[CH:12]=[C:13]([O:19][CH3:20])[C:14]([O:17][CH3:18])=[CH:15][C:16]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: COc1ccc(Br)cc1OC
Reactant: O=C(O)c1ccccc1
Product: COc1cc(Br)c(C(=O)c2ccccc2)cc1OC

Procedure:
By reaction of benzoic acid with 1-bromo-3,4-dimethoxybenzene, in a manner analogous to that of Example 3(a), there is obtained (2-bromo-4,5-dimethoxyphenyl)-phenylmethanone, m.p. 71°-72° C.