Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14][OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][C:19](C)([O-])[CH3:20].[K+].C(Br)C=C>CS(C)=O>[CH2:20]([O:15][CH2:14][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1)[CH:19]=[CH2:18]
Reactant: CC(C)(C)[O-]
Reactant: OCCc1ccc(OCc2ccccc2)cc1
Agent: [K+]
Solvent: CS(C)=O
Solvent: C=CCBr
Product: C=CCOCCc1ccc(OCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A reaction flask was charged with 4-benzyloxy phenethyl alcohol of formula (6), (12 g, 0.052 mol), potassium tert-butoxide (8.842 g, 0.079 ml) and 50 ml and DMSO. The mixture was stirred under nitrogen at 50° C. for 30 minutes. A solution of allyl bromide (6.8 ml, 0.079 mol) was added drop wise to the reaction mixture with cooling about 20–25° C. The mixture was then stirred at 50° C. for 2 h. and cooled to room temperature. The reaction mixture was subsequently quenched with 150 ml of water. The desired product was extracted from neutralized aqueous mixture with toluene. The toluene extract was then washed with water and concentrated under vacuum to afford the title compound of formula (7), 13.9 g, (98%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1.S(Cl)([Cl:17])=O>>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([Cl:17])=[O:14])=[CH:7][CH:6]=1
Reactant: O=C(O)Cc1ccc(OCCBr)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccc(OCCBr)cc1
Yield: 86 %

Procedure:
4-Hydroxyphenylacetic acid (100 g, 0.6 mol) and cesium carbonate (250 g) were suspended in 300 mL of anhydrous acetonitrile followed by addition of 1,2-dibromoethane (300 mL). The suspension was brought to reflux for 24 hours in a 2L 3 neck round bottom flask fitted with a mechanical stirrer and reflux condenser then cooled to room temperature. The mixture was diluted to a volume of 2L by addition of ethyl ether and the suspension was filtered. Concentration of the filtrate in vacuo afforded a colorless oil which was purified by vacuum distillation (0.2 mm Hg, 140-145° C.) to give methyl 4-(2-bromoethoxy)-phenylacetate (93.14 g, 60% yield) as a colorless oil. The methyl 4-(2-bromoethoxy)-phenylacetate was taken into methanol (250 mL) and the resulting solution was cooled to 0° C. Sodium hydroxide (29 g) in a minimum of water was added to the methanol solution in portions and the mixture was stirred at 0° C. for an additional 30 minutes. The solution was warmed to room temperature then concentrated to a white solid. The residue was taken into water and the solution washed once with ethyl ether. The aqueous solution was then acidified to pH 1 by addition of concentrated aqueous hydrochloric acid to give a thick suspension. Filtration and drying afforded 4-(2-bromoethoxy)-phenylacetic acid (86 g, 97% yield) as a colorless solid. The 4-(2-bromoethoxy)-phenylacetic acid (50 g) was taken into thionyl chloride (70 mL) and brought to reflux under an atmosphere of nitrogen for 2 hours. Fractional vacuum distillation (0.2 mm Hg, 139-140° C.) afforded 4-(2-bromoethoxy)phenylacetyl chloride (46.0 g, 86% yield) as a colorless oil that quickly crystallized on cooling. 1H NMR (CDCl3) 6.95, 6.76, 6.60 (m, 11H, Ar—H), 4.68 (m, 1H), 4.24 (m, 2H), 3.80 (m, 1H), 3.41-3.63 (m, 3H), 3.07 (m, 1H), 2.87 (m, 2H), 2.61 (m, 1H); ES−MS (m/z) 458 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[S:12][C:8]=2[C:7]([C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36].C(=O)(O)[O-].[Na+]>C1COCC1.O>[C:35]([N:25]1[CH2:24][CH:23]=[C:22]([C:7]2[C:8]3[S:12][C:11]([NH:13][C:14]([N:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)=[O:15])=[N:10][C:9]=3[C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[CH2:27][CH2:26]1)(=[O:37])[CH3:36]
Reactant: COc1ccc(C2=CCNCC2)c2sc(NC(=O)N3CCOCC3)nc12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C2=CCN(C(C)=O)CC2)c2sc(NC(=O)N3CCOCC3)nc12
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
To a solution of 0.04 g (0.097 mMol) morpholine-4-carboxylic acid [4-methoxy-7-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzothiazol-2-yl]-amide hydrochloride in 2 ml THF were added 0.016 ml triethyl amine. At 0° C. 0.01 ml (0.11 mMol) acetic anhydride was added dropwise and stirred for 30 min. Then a mixture of 5 ml sat. aqueous sodium bicarbonate and 10 ml water were added. After extracting four times with 15 ml ethyl acetate the combined organic phases were dried over sodium sulfate and concentrated to dryness in vacuo to yield 0.031 g (76%) morpholine-4-carboxylic acid [7-(1-acetyl-1,2,3,6-tetrahydro-pyridin-4-yl)-4-methoxy-benzothiazol-2-yl]-amide as a white solid. ES-MS m/e (%): 417 ([M+H]+, 100).
Reaction SMILES: [N+:1]([C:4]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].C1(S(Cl)(=O)=O)C=CC=CC=1.[C:24](O)([CH3:27])([CH3:26])[CH3:25]>N1C=CC=CC=1>[C:24]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][CH:11]=[C:12]([CH3:13])[C:4]=1[N+:1]([O-:3])=[O:2])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)O
Reactant: Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Cc1cccc(C(=O)OC(C)(C)C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
200 mg (1.104 mmol) of 2-nitro-3-methyl benzoic acid was dissolved in 16 ml of pyridine. 468 mg (2.208 mmol) of benzene sulfonyl chloride was added thereto and stirred at room temperature for 2 hours. 329 mg (4.146 mmol) of t-butanol was added thereto and stirred at room temperature for 15 hours. The reaction mixture was extracted with dichloromethane and pyridine was removed by using 2N hydrochloric acid. The organic layer was then neutralized with sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The resulting mixture was concentrated under reduced pressure. The concentrated product was then purified by the column chromatography (ethylacetate:hexane=1:30) to obtain 2-nitro-3-methyl benzoic acid t-butyl ester (Intermediate compound 43, 194 mg, Yield of the first step: 74%). 190 mg (0.800 mmol) of the first intermediate compound 43 as a starting material was subjected to the third step in the reaction of Example 1 to obtain 3-bromomethyl-2-nitrobenzoic acid t-butyl ester (Intermediate compound 44, 160 mg, Yield of the second step: 63%). 154 mg (0.487 mmol) of the intermediate compound 44 was dissolved in 7 ml of dichloromethane, and trifluoroacetic acid was added thereto. The mixture was stirred for 6 hours. When the reaction was completed, the resulting mixture was concentrated under reduced pressure and 3-bromomethyl-2-nitrobenzoic acid (Intermediate compound 45, 121 mg, Yield of the third step: 96%) was obtained. The intermediate compound 45 as a starting material was subjected to the fourth through sixth steps in the reaction of Example 3 to obtain the title compound 14 (83 mg, Yield of the sixth step: 14%).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)=[O:8].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][N:9]([C:7]([C:6]2[C:5]([O:23][CH3:24])=[CH:4][C:3]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:2]([Cl:1])[CH:22]=2)=[O:8])[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COc1cc(I)c(Cl)cc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: OB(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: C1COCCO1
Solvent: O
Product: COc1cc(-c2ccccc2)c(Cl)cc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 90.8 %

Procedure:
A mixture of tert-butyl 4-(5-chloro-4-iodo-2-methoxybenzoyl)piperazine-1-carboxylate (300 mg, 0.56 mmol), phenylboronic acid (82 mg, 0.67 mmol), Pd(PPh3)4 (129 mg, 0.1 mmol), Na2CO3 (180 mg, 1.68 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was stirred at reflux under argon for 16 h. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=30:1) to afford the desired product (219 mg, 80% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[C:13]3([CH2:14][OH:15])[C:10]([CH3:16])([CH2:11][O:12]3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.CN1C=CN=C1.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:13]3([CH2:14][O:15][S:38]([C:35]4[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=4)(=[O:40])=[O:39])[C:10]([CH3:16])([CH2:11][O:12]3)[CH2:9][CH2:8]2)=[CH:17][CH:18]=1
Reactant: CC12CCC(Cc3ccc(Cl)cc3)C1(CO)OC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cn1ccnc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC23OCC2(C)CCC3Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.6 %

Procedure:
In 1 ml of toluene, 50 mg of Compound 8a-1 synthesized in Production Example 19 was dissolved. To the solution thus obtained, 39.5 μl of triethylamine, 22.2 μl of N-methylimidazole, and 53.6 mg of p-toluenesulfonyl chloride were added, and the resulting mixture was stirred at room temperature for 1.5 hours. After the reaction, water was added to the reaction solution thus obtained, and extraction with ethyl acetate was then carried out. The organic layer thus extracted was washed with an aqueous solution of hydrochloric acid, an aqueous solution of sodium hydrogen carbonate, and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was then purified by silica gel column chromatography to obtain 77.0 mg of Compound 9a-1-2.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:43])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][O:36]C3CCCCO3)=[CH:30][CH:29]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)Cl.O>CO>[CH3:1][C:2]1[NH:3][C:4]([CH3:43])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][OH:36])=[CH:32][CH:33]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCOc2ccc(CCOC3CCCCO3)cc2)C1c1cccc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCOc2ccc(CCO)cc2)C1c1cccc([N+](=O)[O-])c1
Reaction time: 24 h
Yield: 70.2 %

Procedure:
To a solution of 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-(3-[4-(2-tetrahydropyran-2-yloxyethyl)phenoxy]propoxycarbonyl)-1,4-dihydropyridine (4.0 g, 6.7 mmoles) in methanol (50 mL) was added a catalytic amount of 4-toluenesulfonic acid. After 24 hours, 200 mL of CH2Cl2 and 100 mL of H2O were added. The organic extracts were dried over anhydrous Na2SO4 and the solvent evaporated. The residue (3.5 g) was purified by flash chromatography (80:20 CH2Cl2 :acetone). Evaporation of the pure fractions gave 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-(3-[4-(2-hydroxyethyl)phenoxy]propoxycarbonyl)-1,4-dihydropyridine (2.4 g, mp <50° C.). NMR (CDCl3)δppm: 8.1-6.5(m, 9H); 5.02(s, 1H); 4.13(t, 2H); 4.0-3.4(m, 7H); 2.68(t, 2H); 2.47(s, 1H); 2.27(s, 6 H); 2.3-1.8(m, 2H).
Reaction SMILES: [C:1](O)(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:8][NH:9][C:10]([NH2:12])=[S:11].P(Cl)(Cl)(Cl)=O.Cl>O1CCOCC1.O>[NH2:12][C:10]1[S:11][C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])=[N:8][N:9]=1
Reactant: CC(C)(C)C(=O)O
Reactant: NNC(N)=S
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1nnc(N)s1
Yield: 64.2 %

Procedure:
A three-liter reaction flask fitted with a power stirrer, heating mantle, dropping funnel, thermometer and water-cooled condenser was charged with 449 g (4.4 moles) of pivalic acid and 1500 ml of dioxane. To the stirred solution there was added 364 g (4.0 moles) of thiosemicarbazide. The dropping funnel was charged with 765 g (5.0 moles) of phosphorus oxychloride which was added to the well stirred solution in the reaction vessel. The reaction mixture was stirred and heated at 95°-100°. When the evolution of hydrogen chloride was complete, the mixture was cooled and the liquid phase was removed by decantation. Sufficient hot water was added to dissolve the pot residue. With ice-bath cooling and agitation, there was slowly added 450 ml of 50% aqueous sodium hydroxide. The mixture was cooled to 20° and the product was collected on a vacuum filter. The filter cake was washed with water and dried. There was obtained 404 g (64.2%) of 2-amino-5-tert-butyl-1,3,4-thiadiazole, m.p. 187°-88°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[F:28][C:29]([F:45])([F:44])[CH:30]1[CH:35]([NH2:36])[CH2:34][CH2:33][N:32]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:31]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH:36][C@H:35]4[CH2:34][CH2:33][N:32]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH2:31][C@H:30]4[C:29]([F:28])([F:44])[F:45])=[O:22])=[CH:19][N:18]=3)=[O:16])[CH2:13][CH2:14]2)=[O:8])=[CH:26][CH:27]=1
Reactant: COc1ccc(C(=O)C2CCN(C(=O)c3ccc(C(=O)O)cn3)CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C(C(F)(F)F)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)C2CCN(C(=O)c3ccc(C(=O)N[C@H]4CCN(C(=O)OC(C)(C)C)C[C@H]4C(F)(F)F)cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 65.4 %

Procedure:
To a mixture of 6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinic acid (0.094 g, 0.257 mmol, 1.0 eq), and 3-trifluoromethyl-4-amino-1-Boc-piperidine (0.257 mmol, 1.0 eq) was added dimethylformamide (2.5 mL) and triethylamine (0.054 mL, 0.386 mmol, 1.5 eq). HATU (0.107 g, 0.283 mmol, 1.1 eq) was added and the reaction was stirred at room temperature for 14 hours and partitioned between EtOAc (120 mL) and NaHCO3-water (1:1, 120 mL). The organics were further washed with brine (100 mL), water (100 mL) and brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (0→10% MeOH—CH2Cl2) yielded the coupled product (0.104 g, 68%) as a colourless oil; 1H nmr (CDCl3) δ 8.90 (1H, br s, pyH-6), 8.08 (1H, br d, J 7.0 Hz, pyH-4), 7.92 (2H, d, J 9.0 Hz, 2H of C6H4OMe), 7.50 (2H, m, pyH-3, NH), 6.94 (2H, d, J 9.0 Hz, 2H of C6H4OMe), 4.61 (2H, m, 1H of pipH-2, H-4, H-6, 1H of BzpipH-2, H-6), 3.86 (3H, s, OCH3), 3.86-3.74 (2H, m, 1H of pipH-2, H-4, H-6, 1H of BzpipH-2, H-6), 3.52 (1H, m, BzpipH-4), 3.52-3.38 (2H, m, 2H of pipH-2, H-4, H-6), 3.26-3.04 (1H, m, 1H of pipH-2, H-3, H-4, H-6), 3.22 (1H, m, 1H of BzpipH-2, H-6), 3.12 (1H, t, J 11.5 Hz, 1H of BzpipH-2, H-6), 2.76 (1H, m, 1H of pipH-2, H-3, H-4, H-6), 2.00 (1H, m, 1H of BzpipH-3, H-5), 1.90-1.65 (5H, m, pipH-5, 3H of BzpipH-3, H-5), 1.45 (9H, s, C(CH3)3); 19F nmr (CDCl3) δ −62.7; m/z 619 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:22][C@H:23]2[CH2:28][CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]1[NH:20][C:19]2[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=2[CH:13]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[C:3]([NH:22][C@H:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:11]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@H]1CCCNC1
Yield: 44 %

Procedure:
Prepared according to Example 53, using tert-butyl (3S)-3-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-2-quinoxalinyl)amino)-1-piperidinecarboxylate (Ex. 51) and (2.5:1) DCM:TFA. Purification by reverse-phase preparative HPLC (Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in ACN/H2O, gradient 5% to 80%) and free-base generation by elution of a solution of the product in MeOH through a pre-washed column of Si-carbonate (SiliaPrep, Silicyle) provided 2-(2-methyl-3-((3S)-3-piperidinylamino)-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (105 mg, 44%). 1H NMR (CDCl3) δ: 7.87-7.95 (m, 1H), 7.59-7.67 (m, 1H), 7.31-7.42 (m, 1H), 7.09 (s, 1H), 5.29 (s, 1H), 4.06 (br. s., 1H), 3.59-3.66 (m, 2H), 3.20-3.28 (m, 1H), 2.84-3.06 (m, 5H), 2.59 (s, 3H), 2.15-2.33 (m, 2H), 2.03 (m, 2H), 1.73-1.85 (m, 1H), 1.51-1.69 (m, 1H). m/z (ESI, +ve) 377.2 (M+H)+.
Reaction SMILES: [CH:1]1([CH:4]2[CH:9]=[CH:8][C:7]3=[C:10]([CH:18]=O)[CH:11]=[C:12]([O:16][CH3:17])[C:13]([O:14][CH3:15])=[C:6]3[O:5]2)[CH2:3][CH2:2]1.[NH:20]([CH2:27][CH2:28][C:29]#[N:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CS(C)=O>[NH:20]([CH:27]=[C:28]([CH2:18][C:10]1[C:7]2[CH:8]=[CH:9][CH:4]([CH:1]3[CH2:2][CH2:3]3)[O:5][C:6]=2[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=1)[C:29]#[N:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N#CCCNc1ccccc1
Reactant: COc1cc(C=O)c2c(c1OC)OC(C1CC1)C=C2
Solvent: CS(C)=O
Product: COc1cc(CC(C#N)=CNc2ccccc2)c2c(c1OC)OC(C1CC1)C=C2
Temperature: 10 °C
Reaction time: 1 h

Procedure:
30 g of (RS)-2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-carbaldehyde and 17.5 g of 3-anilinopropionitrile were dissolved in 300 ml of dimethyl sulphoxide under argon, cooled to 10° C. and treated portionwise with 13.5 g of potassium tert.butylate. Subsequently, the mixture was stirred at 10° C. for a further 1 hr. and at 20° C. for 5 hrs. For the working up, the mixture was poured on to 3 l of ice/water and extracted: 2×3 l of ethyl acetate, 2×3 l of water. The crude product was purified by silica gel chromatography with hexane/ethyl acetate 5:1 to 2:1 and crystallized from hexane/ethyl acetate. (RS)-3-Anilino-2-(2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl-methyl)acrylonitrile was obtained as white crystals, m.p. 140° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([F:24])[C:7]([C:10]2([F:23])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH:2]=[CH2:3].[OH2:25].C([OH:30])(C)(C)C>>[OH:25][C@@H:2]([CH2:3][OH:30])[CH2:1][C:4]1[CH:5]=[C:6]([F:24])[C:7]([C:10]2([F:23])[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15]2)=[N:8][CH:9]=1
Reactant: O
Reactant: C=CCc1cnc(C2(F)CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Reactant: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCC(F)(c2ncc(C[C@@H](O)CO)cc2F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
To a solution of 24 (1.60 g, 4.7 mmol) in t-butanol (20 mL) and H2O (20 mL) AD-mix-beta (5.0 g) was added portion wise at 5° C. The reaction was slowly warmed to room temperature and further stirred at this temperature for 16 hrs. The reaction mixture was cooled down to 5° C. and then quenched by adding excess sodium sulfite and stirred for 20 min. The resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL×2). The organic layers were combined which was washed with brine, dried over Na2SO4, and concentrated. The obtained residue was and chromatographed on silica gel eluted with hexane/ethyl acetate (20%-100%) to afford 1.70 g (97%) of 25 as a colorless oil which was use directly for the next step. LC/Ms (M+1) 373.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.[H-].[Na+].[CH3:16]I>CN(C=O)C>[CH3:16][O:1][CH2:2][CH2:3][S:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc(SCCO)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCSc1ccc(C(=O)O)cc1
Temperature: 27.5 °C
Reaction time: 0.25 h
Yield: 60.2 %

Procedure:
To a stirred solution of 4-(2-Hydroxy-ethylsulfanyl)-benzoic acid (7 g, 0.0352 mol) in DMF (140 mL) was added Sodium hydride (4.2 g, 0.088 mmol) at 5-10° C. under nitrogen atmosphere. Reaction mixture was stirred for 15 min at 25-30° C. and then Methyl iodide (6.6 mL, 0.1057mol) was added to at 10-15° C. Stirring continued for 3 hr after removing cooling. Reaction mixture was then quenched in aqueous NaOH solution and stirred for 30 min. Aqueous layer was washed with ethyl acetate (200 mL). Aqueous layer was then acidified using dil.HCl. Product obtained was filtered which on drying afforded 4.5 g of desired product in 60% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([F:33])[CH:32]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:10]=[CH:9][C:8]=1[CH2:26][C:27]([NH2:29])=[O:28].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:52]([NH:59][CH2:60][CH:61]=O)([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53]>C(Cl)(Cl)Cl>[C:55]([O:54][C:52]([NH:59][CH2:60][CH2:61][N:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:11]3[N:10]=[CH:9][C:8]([CH2:26][C:27]([NH2:29])=[O:28])=[C:7]([NH:6][CH2:5][C:4]4[CH:3]=[C:2]([F:1])[CH:32]=[C:31]([F:33])[CH:30]=4)[CH:12]=3)=[CH:19][CH:18]=2)[CH2:21][CH2:22]1)=[O:53])([CH3:58])([CH3:57])[CH3:56]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCNCC3)cc2)cc1NCc1cc(F)cc(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCN1CCN(c2ccc(Nc3cc(NCc4cc(F)cc(F)c4)c(CC(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
20 mg of 4-[(3,5-difluorobenzyl)amino]-6-{[4-(piperazin-1-yl)phenyl]amino}pyridine-3-carboxyamide (the compound of Example 221) was dissolved in 0.5 mL of chloroform, to which 1.4 mg of acetic acid, 15 mg of sodium triacetoxyborohydride and 8.7 mg of N-Boc-2-aminoacetaldehyde were added, and stirred overnight at room temperature. The reaction mixture was washed with water and saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=5:1) to obtain 19 mg (71%) of the title compound as a light yellow solid.
Reaction SMILES: S(Cl)([Cl:3])=O.C(OC([NH:12][C@@H:13]1[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:15][CH2:14]1)=O)(C)(C)C.[CH3:24]O>>[ClH:3].[NH2:12][C@@H:13]1[CH2:14][CH2:15][C@H:16]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:18]1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CCC(=O)O)CC1
Reactant: O=S(Cl)Cl
Product: COC(=O)CC[C@H]1CC[C@@H](N)CC1
Product: Cl
Reaction time: 0.17 h

Procedure:
At −5° C., 2.9 ml (40.5 mmol) of thionyl chloride were slowly added dropwise to 100 ml of methanol, and the mixture was stirred at this temperature for 10 min. 5 g (18.4 mmol) of 3-{cis-4-[(tert-butoxycarbonyl)amino]cyclohexyl}propanoic acid were then added in one portion, and the reaction mixture was stirred at room temperature overnight. After the reaction had gone to completion, the solvent was evaporated under reduced pressure. This gave 3.95 g (17.8 mmol, 96.7% of theory) of a colorless solid.