Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2(O)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2(O)CCc3ccccc32)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cccc(C2C=Cc3ccccc32)c1
Yield: 80.5 %

Procedure:
To a mixture of 23 g (0.095 mol) of 1-(3-methoxyphenyl)-indan-1-ol and 100 mg of p-toluene sulfonicacid was added 1 L of toluene and the mixture was placed on a Rotovap® and the solvent was distilled in vacuo (40 mm) until an oil residue was obtained. The oil was chromatographed (silica, 1:1 hexane/methylene chloride) to afford 17.0 g (80.1%) of 1-(3-methoxyphenyl)-indene as a pale yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:8]([O:10]C)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:8]([OH:10])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(CO)cc(C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(CO)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of methyl 3-tert-butyl-5-(hydroxymethyl)benzoate (3.0 g, 0.013 mol) in MeOH (20 mL) was added sodium hydroxide (0.54 g, 0.013 mol) in water (10 mL). The reaction mixture was allowed to stir at rt overnight and then concentrated. To the residue was added 1M HCl added (pH 5) and the resulting precipitate was collected by filtration to give 3-tert-butyl-5-(hydroxymethyl)benzoic acid (92%). LCMS ES−207.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]3[O:14][CH:8]3[C:7]=2[CH:15]=1)#[N:2].[C:16]([NH:19][NH2:20])(=[O:18])[CH3:17]>C(O)C>[C:16]([NH:19][NH:20][C@@H:8]1[C:7]2[CH:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11][C:10]([CH3:13])([CH3:12])[C@H:9]1[OH:14])(=[O:18])[CH3:17]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: CC(=O)NN
Solvent: CCO
Product: CC(=O)NN[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Yield: 77.5 %

Procedure:
6-Cyano-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (5.0 g) and 4.0 g of acetohydrazide were dissolved in 20 ml of ethanol and the solution was heated under reflux for 9 hours. After the reaction, the ethanol was distilled off under reduced pressure and the residue was crushed by adding ice water and filtered to obtain crystals. The crystals were dried and recrystallized from ethyl acetate-ethanol (7:1) to give 5.3 g of trans-4-(2-acetylhydrazino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol as white crystals, m.p. 209°-210° C.
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[NH:6][C:5]=1[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:24][O:25][CH2:26]Cl.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[N:6]([CH2:24][O:25][CH3:26])[C:5]=1[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)(=[O:3])[CH3:2]
Reactant: COCCl
Reactant: CC(=O)c1c(-c2ccncc2)[nH]c(-c2ccncc2)c1C
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCn1c(-c2ccncc2)c(C)c(C(C)=O)c1-c1ccncc1
Temperature: 75 °C
Reaction time: 15 h
Yield: 8.6 %

Procedure:
To a stirred solution of 3-acetyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole (1.0 g, 3.6 mmol) in DMF (5 mL) was added NaH (60% oil dispersion; 0.29 g, 7.2 mmol) at room temperature. The mixture was heated at 70-80° C. for 30 minutes, and after cooling to 0° C., chloromethyl methyl ether (0.41 mL, 5.4 mmol) was added. The mixture was stirred for 15 hours, and saturated aqueous NaHCO3 (30 mL) was added to the reaction mixture. The whole was extracted with ethyl acetate (50 mL×3). Combined organic layers were washed with water (50 mL), brine (50 mL), dried over MgSO4, and concentrated in vactio. The residual oil was purified by preparative TLC (1 mm×3) to give the title compound (0.1 g, 9% yield) as a light brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([SH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12][C:13]([CH3:15])=O.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:13]([CH3:15])([CH3:12])[O:8][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: CC(C)=O
Reactant: O=C(O)c1cc(Cl)ccc1S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC1(C)OC(=O)c2cc(Cl)ccc2S1
Yield: 25.4 %

Procedure:
A mixture of 5-chloro-2-mercapto-benzoic acid (2.5 g, 13.25 mmol) (commercial available from Biogene Organics), acetone (7.9 g, 136 mmol), (+/−) camphor sulfonic acid (1.54 g, 6.63 mmol) and 4A moleculare sieves (1.5 g) in CHCl3 was heated to reflux for 3 days. Reaction mixture was diluted with CH2Cl2 (100 mL) and then washed with saturated NaHCO3 aqueous solution (2×50 mL). Organic layer was washed with brine, dried over MgSO4, filtered and concentrated. Crude residue was passed through a pad of silica gel and eluted with CH2Cl2. Filtrate was concentrated to provide the title compound (769 mg). 1H NMR (200 MHz, CDCl3): δ (ppm)=8.15 (d, J=2.4 Hz, 1H), 7.44 (dd, J=8.3, 2.0 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 1.83 (s, 6H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[O:12][C:13]=2[CH3:14])=[C:5]([O:25][CH3:26])[CH:4]=1.[CH2:27]([C:29]1[S:30][CH:31]=[C:32](/[CH:34]=[CH:35]/[C:36]2[C:37]([OH:47])=[N:38][N:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:40]=2)[N:33]=1)[CH3:28].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:27]([C:29]1[S:30][CH:31]=[C:32](/[CH:34]=[CH:35]/[C:36]2[C:37]([O:47][CH2:2][C:3]3[CH:24]=[CH:23][C:6]([O:7][CH2:8][C:9]4[N:10]=[C:11]([C:15]5[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=5)[C:18]#[N:19])[O:12][C:13]=4[CH3:14])=[C:5]([O:25][CH3:26])[CH:4]=3)=[N:38][N:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:40]=2)[N:33]=1)[CH3:28]
Reactant: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2O)cs1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4cccc(C#N)c4)oc3C)c(OC)c2)cs1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
A mixture of 3-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzonitrile (3.32 g), 4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol (2.95 g), potassium carbonate (1.37 g) and N,N-dimethylformamide (100 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with acetone-hexane (1:5-1:4, v/v) to give 3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzonitrile (4.10 g, yield 72%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 138-140° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][S:38][C:39]1[N:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:42]2[CH:43]=[N:44][C:39]([S:38][CH3:37])=[CH:40][CH:41]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CSc1ccc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CSc1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cn1
Yield: 87.6 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 0.5 g, 0.96 mmol), 6-methylsulfanyl-pyridine-3-boronic acid (370 mg, 2.2 mmol) and dichlorobis(triphenylphosphine)palladium (II) (67.4 mg, 0.096 mmol) in dioxane (6 mL) was added an aqueous sodium carbonate solution (2 M, 0.96 mL, 1.92 mmol). The resulting mixture was subjected to microwave irradiation for 3 h at 100° C. The mixture was diluted with ethyl acetate (80 mL), washed with a saturated aqueous sodium bicarbonate solution (2×20 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 25% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methylsulfanyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (400 mg, 88%) as a light yellow solid: LC/MS m/e calcd for C26H25N3O2S2 [M+H]+ 476.64, observed 476.0.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[CH3:22][O:23][C:24]([C:26]1[S:27][C:28]([C:48]([CH3:54])=[CH:49][CH:50]=[CH:51][CH:52]=[CH2:53])=[CH:29][C:30]=1[NH:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:34](=[O:47])[CH2:33]1)=[O:25]>ClCCCl>[CH3:22][O:23][C:24]([C:26]1[S:27][C:28]([C:48]([CH3:54])=[CH:49][CH:50]=[CH:51][CH:52]=[CH2:53])=[CH:29][C:30]=1[N:31]([CH:32]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)[C:34](=[O:47])[CH2:33]1)[C:8]([CH:5]1[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:7][CH2:6]1)=[O:10])=[O:25]
Reactant: C=CC=CC=C(C)c1cc(NC2CCN(Cc3ccc(OC)cc3)C(=O)C2)c(C(=O)OC)s1
Reactant: C[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C=CC=CC=C(C)c1cc(N(C(=O)C2CCC(C)CC2)C2CCN(Cc3ccc(OC)cc3)C(=O)C2)c(C(=O)OC)s1
Yield: 10.8 %

Procedure:
A solution of trans 4-methylcyclohexane carboxylic acid (56 mg, 0.399 mmol, 1.2 eq) in 1,2-dichloroethane (1 ml) at 0°, under N2, was treated with oxalyl chloride (2.0M solution in CH2Cl2) (231 μl, 0.46 mmol, 1.4 eq), followed by dimethylformamide (8 μl, 7 mg, 0.1 mmol, 30 mol %). After 1 h the reaction was treated with a solution of 3-[1-(4-Methoxy-benzyl)-2-oxo-piperidin-4-ylamino]-5-(1-methyl-hexa-1,3,5-trienyl)-thiophene-2-carboxylic acid methyl ester (150 mg, 0.33 mmol) in DCE (2 ml). The reaction was then placed in bath at 90° and left at reflux overnight for 21 h. The reaction was stripped-off solvent and the residue (212 mg) was purified by bond elute chromatography using (Hexane:CH2Cl2:EtOAc=1:1:1) as eluent to give 3-[[1-(4-Methoxy-benzyl)-2-oxo-piperidin-4-yl]-(4-methyl-cyclohexanecarbonyl)-amino]-5-(1-methyl-hexa-1,3,5-trienyl)-thiophene-2-carboxylic acid methyl ester (21 mg, 11%) as a yellow foam; (300 MHz, CDCl3) 0.55-0.73 (m, 1H), 0.77 (d, J=5.4 Hz, 3H), 1.26-1.30 (m, 12H), 1.94-2.12 (m, 1H), 2.14-2.19 (m, 1H), 2.40 (dd, J=9.0 Hz, J=12.0 Hz, 1H), 2.64-2.70 and 2.80 and 2.84 (m, 1H), 3.10-3.15 (m, 3H), 3.79-3.82 (m, 1H), 3.78 (s, 3H), 3.83 and 3.87 (s, 3H), 4.32 (t, J=12.0 Hz, 1H), 4.62 (dd, J=5.7 Hz, J=10.8 Hz, 1H)′ 4.50-5.0 (m, 1H), 6.79-6.83 (m, 2H), 6.99-7.14 (m, 2H), 7.26-7.48 (m, 3H), 7.61-7.65 (m, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]3[N:13]=[CH:14][CH:15]=[C:11]3[N:10]=[C:9]([NH2:16])[CH:8]=2)[CH2:3][CH2:2]1.[CH:17]1([C:20](O)=[O:21])[CH2:19][CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>N1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]3[N:13]=[CH:14][CH:15]=[C:11]3[N:10]=[C:9]([NH:16][C:20]([CH:17]3[CH2:19][CH2:18]3)=[O:21])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1cc(N2CCOCC2)n2nccc2n1
Reactant: O=C(O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(N2CCOCC2)n2nccc2n1)C1CC1

Procedure:
7-Morpholinopyrazolo[1,5-a]pyrimidin-5-amine (9A, 0.10 mmol) in pyridine (0.4 ml), cyclopropanecarboxylic acid (0.15 mmol) in pyridine (0.4 ml), HATU (0.17 mmol) in pyridine (0.4 ml) and DIEA (0.34 mmol) are mixed together before microwave irradiation at 150° C. for 6 minutes. The crude product was then purified by preparatory HPLC to give the titled compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.00-1.09 (m, 2 H) 1.09-1.16 (m, 2 H) 1.99-2.09 (m, 1 H) 3.91-3.98 (m, 4 H) 4.12-4.21 (m, 4 H) 6.47 (d, J=2.26 Hz, 1 H) 7.27 (s, 1 H) 7.51 (s, 1 H) 7.98 (d, J=2.07 Hz, 1 H) 13.03 (br. s., 1 H); ESI-MS: m/z 288 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][N:11](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[F:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([C:10]#[N:11])=[N:3][CH:4]=1
Reactant: Cc1cc(Cl)ncc1F
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cc(C#N)ncc1F
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
A microwave tube was charged with 2-chloro-5-fluoro-4-methylpyridine (5.5 mmol), Zn(CN)2 (16.6 mmol), Pd(PPh3)4 (1.1 mmol) in DMF (20 mL). The mixture was stirred at 150° C. for 5 min in a microwave reactor. The mixture was combined with other crudes obtained following the procedure described above. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc, washed (sat. NH4Cl), dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (SiO2, 5:95 to 15:85 EtOAc/petroleum ether) to yield the desired product.
Reaction SMILES: [F:1][C:2]1[C:8]([OH:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[OH:4].[Cl:11][CH2:12][C:13](=O)[CH2:14][C:15](OCC)=[O:16].O>CS(O)(=O)=O>[Cl:11][CH2:12][C:13]1[C:5]2[C:3](=[C:2]([F:1])[C:8]([OH:9])=[C:7]([F:10])[CH:6]=2)[O:4][C:15](=[O:16])[CH:14]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Oc1ccc(F)c(O)c1F
Agent: CS(=O)(=O)O
Solvent: O
Product: O=c1cc(CCl)c2cc(F)c(O)c(F)c2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
A solution of 2,4-difluororesorcinol (0.8 g) in 8 mL of methyl sulfonic acid is introduced into a flask and then 1.3 equivalents (963 μL) of ethyl 4-chloroacetoacetate are added dropwise. After 3 hours of stirring at room temperature, the mixture is cooled to 0° C. and then 100 mL of water are added. The residue is then filtered, dried and washed with diethyl ether in order to obtain 0.34 g (25%) of the compound 1.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[I:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:21])=[C:18]([CH:20]=1)[NH2:19].Cl>C(N(CC)CC)C>[I:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:21])=[C:18]([NH:19][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(I)cc1N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(I)cc1NC(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
2.1 mL of benzoyl chloride was added to 70 mL of a methylene chloride solution containing 3.5 g of 5-iodo-2-methylaniline and 2.5 mL of triethylamine at room temperature and stirred at the same temperature for 30 minutes. 1.0 mol/L hydrochloric acid was added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution, and the solvent was evaporated under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue and a solid substance was separated by filtration to obtain 4.2 g of N-(5-iodo-2-methylphenyl)benzamide as pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][NH2:8].[CH3:9][NH:10][S:11]([C:14]1[CH:15]=[C:16]([C:24](Cl)=[O:25])[C:17]2[O:22][CH2:21][CH2:20][O:19][C:18]=2[CH:23]=1)(=[O:13])=[O:12].O>C(Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][NH:8][C:24]([C:16]1[C:17]2[O:22][CH2:21][CH2:20][O:19][C:18]=2[CH:23]=[C:14]([S:11](=[O:13])(=[O:12])[NH:10][CH3:9])[CH:15]=1)=[O:25]
Reactant: CN1CCCC1CN
Reactant: CNS(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2
Solvent: O
Solvent: ClC(Cl)Cl
Product: CNS(=O)(=O)c1cc2c(c(C(=O)NCC3CCCN3C)c1)OCCO2
Yield: 78.5 %

Procedure:
61 g of dextrorotatory 1-methyl-2-aminomethyl-pyrrolidine, 465 ccm of chloroform and, in portions, 155 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride, with the temperature being maintained at 5°-10° C., were introduced into a balloon flask provided with an agitator and a thermometer. After agitation of the mixture and the addition of 1,850 cm3 of water, chloroform was distilled and the remaining solution was filtered. The base was precipitated by the addition of 65 cm3 of 20% ammonia. The crystals formed were dried off, washed and dried. 154 g of dextrorotatory-N-(1-methyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide was produced (M.P.: 187°-188° C.; yield: 78.5%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]1[C:10](=[O:11])[N:9]([CH2:12][CH:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[N:7]1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:8]2[N:9]([CH2:12][CH:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[C:10](=[O:11])[N:6]([CH2:5][C:4]3[CH:3]=[C:2]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[C:30]([F:41])([F:40])[F:29])[CH:28]=[CH:27][CH:26]=3)[N:7]=2)=[CH:20][CH:21]=1
Reactant: O=c1n(Cc2cccc(Br)c2)nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: O=c1n(Cc2cccc(-c3ccccc3C(F)(F)F)c2)nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F

Procedure:
Analogously to the preparation of Example 122, 72 mg (0.15 mmol) of the compound from Example 101A were reacted with 43 mg (0.23 mmol) of 2-(trifluoromethyl)phenylboronic acid. This gave 49 mg (58% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:14][CH:15]=O)[C:10](=[O:13])[CH:11]=[CH:12][C:6]2=[N:5][CH:4]=1.[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CO>[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][N:39]([CH2:15][CH2:14][N:9]4[C:7]5=[N:8][C:3]([O:2][CH3:1])=[CH:4][N:5]=[C:6]5[CH:12]=[CH:11][C:10]4=[O:13])[CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cnc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A suspension of [3-(methyloxy)-6-oxopyrido[2,3-b]pyrazin-5(6H)-yl]acetaldehyde (185 mg 0.84 mmol) and 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinylcarbamate (for a synthesis see WO2004/058144 Example 99(h) (283 mg, 0.84 mmol) in chloroform (10 mL) and methanol (1.5 mL) was stirred at room temperature under argon for 1 h before addition of sodium triacetoxyborohydride (515 mg, 2.52 mmol). The reaction was stirred at rt overnight. A saturated solution of sodium bicarbonate (20 mL) was added to the reaction and the aqueous phase was extracted with 10% MeOH/DCM (3×50 mL).The combined organic phases were dried (MgSO4), filtered and evaporated and the residue was subjected to column chromatography on silica gel eluting with 0-10% methanol-DCM to afford 252 mg of the title compound (60%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1.[H][H]>[Ni].CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1
Reactant: [H][H]
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1nc(-c2cccnc2)cs1
Agent: [Ni]
Solvent: CO
Product: Cc1ccc(N)cc1Nc1nc(-c2cccnc2)cs1

Procedure:
In a reactor, a mixture of (2-methyl-5-nitro-phenyl)-(4-pyridin-3-yl-thiazol-2-yl)-amine (40 kg, 128.06 mol), Raney Nickel (2.7 kg, 46.00 mol) and methanol (600 L), was warmed to 40-45° C. and hydrogenated under hydrogen pressure (5 kg/cm2) for 2 hours. The reaction mixture was filtered and concentrated. Water was added to the residue under stirring. The product was then filtered and dried in a tray drier at 45-50° C.
Reaction SMILES: [CH:1]([C@@H:4]1[C:9]([O:10][CH3:11])=[N:8][CH2:7][C:6]([O:12][CH3:13])=[N:5]1)([CH3:3])[CH3:2].[Li]CCCC.Br[CH2:20][C:21]1[CH:25]=[C:24]([C:26]2[S:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[O:23][N:22]=1>C1COCC1>[Cl:31][C:28]1[S:27][C:26]([C:24]2[O:23][N:22]=[C:21]([CH2:20][C@H:7]3[C:6]([O:12][CH3:13])=[N:5][C@H:4]([CH:1]([CH3:3])[CH3:2])[C:9]([O:10][CH3:11])=[N:8]3)[CH:25]=2)=[CH:30][CH:29]=1
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Commercially available (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazine (2.0 g, 10.86 mmol) in dry THF (12 ml) under argon was cooled to −75° C. n-BuLi (8 ml, 13.03 mmol, 1.6M solution in hexanes) was added slowly and stirring was continued for 30 min. After that 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole (3.628 g, 13.03 mmol), (preparation described in J. Med. Chem. 2005, 4511-4525; Bioorg. Med. Chem. Lett. 2004, 4191-4195), in THF (15 ml) was added dropwise under stirring and stirring was continued for 30 min at −75° C. Then the mixture was warmed to 0° C. and stirred for 1 h before it was quenched with sat. aq. NaHCO3-solution. The mixture was extracted with ethyl acetate, the organic layers were combined and dried with MgSO4, filtered and evaporated to dryness. A crude oil was obtained (4.1 g) and the diastereomeric excess (d.e.: 88%) was determined by H-NMR from that crude mixture. The mixture was separated by column chromatography on silica gel (n-heptane-ethyl acetate 6:1). Yield: 3.3 g, 80%.