Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[O:19]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH:21]1[CH2:22][CH2:23][O:19][CH2:20]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: NC1CCOC1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCOC1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (300 mg, 1.13 mmol) was treated with tetrahydro-furan-3-ylamine following general procedure B to afford 8-methoxy-4-(tetrahydro-furan-3-ylamino)-quinoline-3-carboxylic acid ethyl ester (275 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (190 mg) following general procedure E. The above ethylamide (0.6 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 3-ethyl-7-methoxy-1-(tetrahydro-furan-3-yl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (10 mg). LCMS: m/z 342 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:31])=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:17][O:18]C(C)(C)C)=[CH:9][N:8](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[C:3]([Cl:31])=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:17][OH:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OCc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(Br)c(Cl)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OCc1ccccc1-c1c[nH]c2ncc(Br)c(Cl)c12
Temperature: 23 °C
Reaction time: 1 h

Procedure:
5-Bromo-3-(2-tert-butoxymethyl-phenyl)-4-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (66 mg, 0.12 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL) and stirred at 23° C. for 15 h. The solvent was evaporated and the resulting oil was dissolved in methanol (1 mL) and ethylenediamine (0.2 mL) and stirred at 23° C. for 1 h. The mixture was concentrated to afford [2-(5-Bromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl]-methanol which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH3:31][C:32]([CH3:34])=O>C(#N)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH:32]([CH3:34])[CH3:31])[CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=C(NC(COCC1CCNCC1)c1ccc(F)cc1)c1ccc2c(Cl)c[nH]c2c1
Solvent: CC#N
Product: CC(C)N1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccc(F)cc2)CC1
Yield: 75.7 %

Procedure:
Using alkylation method A, 3-chloro-N-[1-(4-fluoro-phenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (600 mg, 1.4 mmol) and acetone (10 mL, 135 mmol) afforded, after trituration (acetonitrile), 500 mg (76%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([C:13]([CH3:52])([CH3:51])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[C@H:41]([CH2:42][O:43][Si](C(C)(C)C)(C)C)[CH2:40][N:39]4[C@H:34]([CH2:35][O:36][CH2:37][CH2:38]4)[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[Cl:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl>CO>[F:54][C:2]([F:1])([F:53])[C:3]1[CH:4]=[C:5]([C:13]([CH3:52])([CH3:51])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[C@H:41]([CH2:42][OH:43])[CH2:40][N:39]4[C@H:34]([CH2:35][O:36][CH2:37][CH2:38]4)[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[Cl:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H]3COCCN3C[C@H]2CO[Si](C)(C)C(C)(C)C)cc1-c1ccc(F)cc1Cl
Agent: Cl
Solvent: CO
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H]3COCCN3C[C@H]2CO)cc1-c1ccc(F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(2-chloro-4-fluorophenyl)-6-[(7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-3-pyridinyl}-N,2-dimethylpropanamide (D58, 22 mg, 0.027 mmol) was dissolved in dry MeOH (2 mL), cooled in an ice-salt bath to ˜0° C. before adding c.HCl solution (˜0.1 mL), slowly. The reaction mixture was stirred at ˜0° C. for 1 hour before warming up and stirring at R.T. for 2 hours. Placed directly onto a 2 g SCX column, washing with MeOH (2×5 mL) before eluting the compound off with NH3 in MeOH (4×5 mL). Solvent evaporated under reduced pressure to afford the title compound as an off white solid. (10 mg)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=[O:12].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([O:13][CH2:19][CH3:20])=[O:12]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2ccccc2n1

Procedure:
Quinoline-2-carboxylic acid (Aldrich, 10.0 g, 57.7 mmol) was added to ethanol (500 mL) and sulfuric acid (25 mL) and refluxed for 7 hours. The mixture was concentrated under reduced pressure and dichloromethane (400 mL) was added. The organic layer was washed twice with saturated sodium bicarbonate (400 mL), dried with sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.39 (t, J=7.12 Hz, 3H), 4.43 (q, J=7.12 Hz, 2H), 7.76 (ddd, J=8.14, 6.95, 1.19 Hz, 1H), 7.88 (ddd, J=8.48, 6.95, 1.53 Hz, 1H), 8.11 (m, 2H), 8.18 (d, J=8.48 Hz, 1H), 8.58 (d, J=8.48 Hz, 1H). MS (DCI) m/z 202.05 (M+H)1.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.C[O-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[C:23]([CH:31]=O)[CH:22]=2)=[CH:17][CH:16]=1>COCCOC>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[C:23]([CH:31]=[C:5]3[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]3=[O:7])[CH:22]=2)=[CH:19][CH:20]=1
Reactant: CC1(C)CC(=O)C(C)(C)O1
Reactant: O=Cc1cc(-c2ccc(Cl)cc2)ccc1C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1(C)OC(C)(C)C(=Cc2cc(-c3ccc(Cl)cc3)ccc2C(F)(F)F)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To an ice-cold solution of 2,2,5,5-tetramethyldihydrofuran-3-one (0.887 g, 6.25 mmoles) in 1,2-dimethoxyethane (10 ml) is added sodium methoxide (0.405 g, 7.50 mmoles) in one portion. The reaction mixture is stirred at 0° C. for 30 minutes, followed by the dropwise addition of 4′-chloro-4-trifluoromethylbiphenyl-3-carbaldehyde (1.779 g, 6.25 mmoles) as a solution in 1,2-dimethoxyethane (10 ml). The reaction mixture is stirred at 0° C. for 30 minutes and then at ambient temperature for a further 1 hour after which it is partitioned between 1M hydrochloric acid and dichloromethane. The aqueous phase is extracted again with dichloromethane, than all organics are combined and evaporated to afford 4-[1-(4′-chloro-4-trifluoromethylbiphenyl-3-yl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (2.50 g) as a yellow gum. This material is used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[Cl:15])[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][S:19][CH2:18][CH2:17]2)[N:3]=1.OO.S([O-])([O-])=[O:25].[Na+].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[Cl:15])[N:5]=[C:4]([N:16]2[CH2:17][CH2:18][S:19](=[O:25])[CH2:20][CH2:21]2)[N:3]=1
Reactant: Nc1nc(-c2cc(Cl)ccc2Cl)nc(N2CCSCC2)n1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1nc(-c2cc(Cl)ccc2Cl)nc(N2CCS(=O)CC2)n1
Reaction time: 3 h

Procedure:
In 150 ml of acetic acid was dissolved 2.0 g of the compound synthesized in Example 38. To this solution was added 1.3 ml of 30% aqueous solution of hydrogen peroxide dropwise under ice-cooling and the mixture was stirred at the same temperature for 3 hours. The excess of hydrogen peroxide was decomposed with aqueous sodium sulfite solution and the mixture was concentrated. The crystals separated out were collected by filtration, rinsed with water, and dried to provide 1.86 g of the title compound as white crystals. m.p. 267-269° C.
Reaction SMILES: COC1C=C2C(CCC(=O)C2)=CC=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.N[C@H](C(O)=O)C.CC1N=CC(COP(O)(O)=O)=C(C=O)C=1O.[OH-].[Na+].[CH3:94][O:95][C:96]1[CH:105]=[C:104]2[C:99]([CH2:100][CH2:101][CH:102]([NH2:106])[CH2:103]2)=[CH:98][CH:97]=1>>[CH3:94][O:95][C:96]1[CH:105]=[C:104]2[C:99]([CH2:100][CH2:101][C@H:102]([NH2:106])[CH2:103]2)=[CH:98][CH:97]=1
Reactant: COc1ccc2c(c1)CC(N)CC2
Agent: COc1ccc2c(c1)CC(=O)CC2
Agent: C[C@H](N)C(=O)O
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Product: COc1ccc2c(c1)C[C@@H](N)CC2

Procedure:
To a flask containing 300 mg of a substrate 7-methoxy-2-tetralone, 460 mg of D-glucose, 3 mg of NAD+, 910 mg of L-alanine, and 4.0 mg of pyridoxal phosphate, a culture fluid of the recombinant E. coli HB101 (pNMTA, pSTVPAG), obtained in Example 9, which expresses MTA, PALDH, and GDH was added so that total volume was 30 ml. The resultant product was stirred at 30° C. for 25 hours while being adjusted to a pH of 6.8 by drippage of 5 N aqueous solution of sodium hydroxide. The rate of conversion into 7-methoxy-2-aminotetraline after the reaction was 60.2%. The absolute configuration of 7-methoxy-2-aminotetraline was (S), and the optical purity was 97.1% e.e.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:24][C:25]1[CH:26]=[CH:27][C:28]2[S:33][CH2:32][CH:31]([CH2:34]I)[CH2:30][C:29]=2[CH:36]=1>CN(C)C=O>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]([CH:5]2[CH2:6][CH2:7][N:2]([CH2:34][CH:31]3[CH2:30][C:29]4[CH:36]=[C:25]([F:24])[CH:26]=[CH:27][C:28]=4[S:33][CH2:32]3)[CH2:3][CH2:4]2)=[O:9])=[CH:15][CH:14]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: Fc1ccc2c(c1)CC(CI)CS2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)C1CCN(CC2CSc3ccc(F)cc3C2)CC1
Temperature: 23 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 2.178 kg (10.5 mol) p-fluorophenyl 4-piperidinyl ketone hydrochloride (R. L. Duncan et al., J. Med. Chem. 13, 1 (1970)), 1.008 kg (9.96 mol) triethylamine and 25 1 dimethylformamide is added a solution of 3.053 kg (9.9 mol) (6-fluoro-3,4-dihydro-2H-1-benzothiopyran-3-yl)methyl iodide in 9 1 dimethylformamide with stirring at 23° C. over 45 min. The suspension is stirred for 3 days at ambient temperature. The reaction is filtered and the filtrate concentrated at 80° C./4 mbar. The resulting oil is poured into a mixture of 20 1 water and 24 1 ethyl acetate, cooled to 5° C. and basified to pH 10 with concentrated ammonium hydroxide. The organic layer is separated, the aqueous solution extracted further with ethyl acetate, and the combined organic solutions washed with water and brine, dried over sodium sulfate and activated carbon, filtered, and concentrated at 50° C./ 4 mbar. The residue is triturated with heptane, filtered, washed twice with heptane, dried in vacuo and dissolved in dichloromethane. The solution is filtered from the insolubles, stirred with 1.27 kg Kieselgel 60 for 30 min., then filtered and evaporated at 45° C./4 mbar to give the title compound as a solid, m.p. 121°-124° C.
Reaction SMILES: [OH:1][CH:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[N+:14]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:5]=1[NH:4][CH2:3][C:2](=[O:1])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:9]([OH:11])=[O:10])([O-:16])=[O:15]
Reactant: O=C(O)c1ccc(NCC(O)c2ccccc2)c([N+](=O)[O-])c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(O)c1ccc(NCC(=O)c2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A DCM (50 mL) suspension of 4-[(2-hydroxy-2-phenylethyl)amino]-3-nitrobenzoic acid (1.0 g, 3.3 mmol) was treated with Dess-Martin periodinane reagent (1.5 g, 3.5 mmol) at rt in one lot. The reaction mixture was stirred at rt for 2 h. The solid was filtered off and washed with DCM to afford the title compound as a yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 12.97 (br, 1H), 9.08 (t, J=4.4 Hz, 1H), 8.67 (d, J=2.0 Hz, 1H), 8.14 (d, J=8.0 Hz, 2H), 8.01 (dd, J=1.6 Hz, 8.8 Hz, 1H), 7.72 (t, J=7.6 Hz, 1H), 7.61 (t, J=7.6 Hz, 2H), 7.23 (d, J=8.8 Hz, 1H), 5.14 (d, J=4.8 Hz, 2H). MS (ES+): m/z 301.1 (40) [MH+]; HPLC: tR=3.10 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[CH3:15])=O.CNC(C1CC2C(C=1C)=CC=CC=2)=O>>[CH3:15][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[CH2:3][NH:2][CH3:1]
Reactant: CNC(=O)c1ccc2ccccc2c1C
Agent: CNC(=O)C1=C(C)c2ccccc2C1
Product: CNCc1ccc2ccccc2c1C
Yield: 36 %

Procedure:
According to the procedure of Preparation 20 (b), except substituting N,1-dimethylnaphthalene-2-carboxamide (0.3 g, 1.5 mmole) for the N,3-dimethylindene-2-carboxamide, the title compound (0.1 g, 36%) was prepared as a colorless oil: MS (ES) m/e 186 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=1.[CH2:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[N:12]3[C:13]4[C:8]([CH2:9][CH2:10][CH2:11]3)=[CH:7][CH:6]=[CH:5][C:4]=4[N:3]=2)[CH2:23][CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Clc1nc2cccc3c2n1CCC3
Reactant: c1ccc(CN2CCNCC2)cc1
Product: c1ccc(CN2CCN(c3nc4cccc5c4n3CCC5)CC2)cc1
Yield: 70 %

Procedure:
A solution of 2-chloro-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline (3.00 g) in 1-benzylpiperazine (10 ml) was stirred at 100° C., under nitrogen, for four hrs. The reaction mixture was quenched with dilute sodium bicarbonate solution (300 ml) and extracted with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by high performance liquid chromatography (silica gel; 25:1 dichloromethane-methanol). The appropriate fractions were collected and evaporated. The residue was recrystallized from ethyl acetate to give 3.6 g (70%) of product, mp 157°-158° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][CH:26]=3)=O)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31].Cl.[O:35]([NH2:37])[CH3:36].CCN(CC)CC>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19](=[N:37][O:35][CH3:36])[C:21]3[CH:26]=[CH:25][N:24]=[C:23]4[NH:27][CH:28]=[CH:29][C:22]=34)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:30]([F:33])([F:31])[F:32]
Reactant: O=C(c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccnc2[nH]ccc12
Reactant: CON
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON=C(c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccnc2[nH]ccc12
Temperature: 25 °C

Procedure:
A solution of 4-chloro-N-[5-chloro-2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (41 mg), methoxyl amine hydrochloride salt (67 mg) and Et3N (0.14 mL) in THF (1 mL) was heated to 80° C. for 12 h. The mixture was cooled to room temperature, diluted with EtOAc (5 mL), filtered and evaporated in vacuo. The residue was purified by flash chromatography (silica) to afford the title compound as a white powder. MS (M+H)+: 544.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][N:13]1[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[NH:15][C:14]1=[O:24].S(OC)(O[CH3:29])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][N:13]1[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:29])[C:14]1=[O:24]
Reactant: COS(=O)(=O)OC
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1Cc1cc([N+](=O)[O-])cc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(Cc2cc([N+](=O)[O-])cc(Cl)c2Cl)c1=O
Yield: 20.8 %

Procedure:
By the method of Example 1, Step H, 24.5 grams (0.064 mole) of 3-(2,3-dichloro-5-nitrophenylmethyl)-6-trifluoromethyluracil, 12.07 grams (0.096 mole) of dimethyl sulfate, and 17.64 grams (0.127 mole) of potassium carbonate were reacted in 300 mL of acetone, yielding 5.30 grams of 3-(2,3-dichloro-5-nitrophenylmethyl)-1-methyl-6-trifluoromethyluracil as a bright yellow solid. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[N:12]=[C:11](OC2C=CC=CC=2)[N:10]=1.[C:30]1([CH:37]=[CH:36][CH:35]=[C:33]([OH:34])[CH:32]=1)[OH:31].[Cl-].[Al+3].[Cl-].[Cl-].C1S(=O)(=O)CCC1.Cl>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[N:12]=[C:11]([C:35]2[CH:36]=[CH:37][C:30]([OH:31])=[CH:32][C:33]=2[OH:34])[N:10]=1
Reactant: Cc1ccc(-c2nc(Oc3ccccc3)nc(-c3ccc(C)cc3C)n2)c(C)c1
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S1(=O)CCCC1
Product: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(O)cc3O)n2)c(C)c1
Temperature: 160 °C
Reaction time: 10.5 h
Yield: 68.7 %

Procedure:
To a 250 mL round-bottomed flask equipped with a magnetic stirrer, a condenser and a nitrogen atmosphere are added 6.00 g (0.0157 mol) of the product of Example 2, 2.08 g (0.0189 mol) of resorcinol, 2.09 g (0.0157 mol) of aluminum chloride and 6 mL of tetramethylene sulfone (sulfolane). The mixture is stirred at 138° C. for six hours, 147° C. for seven hours, 160° C. for 10.5 hours and then allowed to cool to room temperature. A portion of 2N hydrochloric acid is added and the mixture is refluxed for two hours and then allowed to cool to room temperature. The solids formed are collected by vacuum filtration and then washed with portions of water and heptane. The crude solid is taken up in ethyl acetate and passed through a plug of silica gel. The solvent is removed under reduced pressure to give 5.25 g of crude product. The crude product is recrystallized from methanol to afford 4.29 g (69% yield) of the title compound as a yellow solid melting at 199-201° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])O.[Na+].C(O)(C)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C.O>[N+:17]([C:4]1[C:5]2[C:9]([CH:10]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([O:26][CH:21]4[CH2:22][CH2:23][CH2:24][CH2:25][O:20]4)=[CH:28][CH:29]=3)[CH:3]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cc(Br)cc2nn(C3CCCCO3)cc12
Reactant: OB(O)c1ccc(OC2CCCCO2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(-c2ccc(OC3CCCCO3)cc2)cc2nn(C3CCCCO3)cc12
Temperature: 150 °C

Procedure:
6-Bromo-4-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (500 mg, 1.53 mmol), Pd(dppf)Cl2 (125 mg, 0.153 mmol), [4-(tetrahydro-2H-pyran-2-yloxy)phenyl]boronic acid (511 mg, 2.3 mmol), saturated sodium hydrogen carbonate (aq) (3 ml) and isopropyl alcohol (12 ml) were added to each of 5 microwave vessels. All 5 reactions were heated at 150° C. for 10 mins in a Biotage microwave. The reaction mixtures were combined and water (250 ml) and ethyl acetate (250 ml) were added. The mixture was filtered and the organic layer collected. The organic layer was washed with water, then brine, dried over magnesium sulphate, filtered and dried in vacuo. The residue was purified using silica gel chromatography, eluting with 0-25% ethyl acetate in cyclohexane. Appropriate fractions were combined and the solvent was removed in vacuo to give the title compound, 2.3 g.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][O:6][C:7](=[O:25])[CH:8]([OH:24])[CH2:9][NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([F:21])[CH:20]=1)[N:17]([CH3:22])[C:16](=[O:23])[CH2:15][CH2:14]2.C(N(CC)CC)C>ClCCl>[CH3:5][O:6][C:7]([C@@H:8]1[O:24][C:1](=[O:2])[N:10]([C:11]2[CH:12]=[C:13]3[C:18](=[C:19]([F:21])[CH:20]=2)[N:17]([CH3:22])[C:16](=[O:23])[CH2:15][CH2:14]3)[CH2:9]1)=[O:25]
Reactant: O=C(Cl)Cl
Reactant: COC(=O)C(O)CNc1cc(F)c2c(c1)CCC(=O)N2C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1CN(c2cc(F)c3c(c2)CCC(=O)N3C)C(=O)O1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
Phosgene (20% solution in toluene, 4.07 ml, 7.69 mmol) is added dropwise at 0° C. to 3-(8-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylamino)-2-hydroxypropionic acid methyl ester (Step 4, 1.81 g, 6.41 mmol) and triethylamine (2.23 ml, 16.0 mmol) in dichloromethane (25 ml). The mixture is allowed to warm. to room temperature and stirred for an additional hour. The reaction is washed with 2N aqueous hydrochloric acid and saline, dried (MgSO4) and evaporated. The residue is purified by flash column chromatography (50% ethyl acetate/hexane) to give the title compound as a white solid (1.71 g, 83%); MS (m/z): [M+H]+=323.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:23][C@@H:24]([CH3:27])[CH2:25][OH:26])=[C:7]([CH:22]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:9])#[N:2].[CH3:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:23][C@@H:24]([CH3:27])[CH2:25][O:26][S:29]([CH3:28])(=[O:31])=[O:30])=[C:7]([CH:22]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:9])#[N:2]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)CO)cc1OC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)COS(C)(=O)=O)cc1OC
Temperature: 0 °C
Yield: 112.1 %

Procedure:
To a solution of (S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)benzamide (4 g) in pyridine (20 mL) was added methanesulfonyl chloride (1.36 g), and the mixture was stirred for an hour at 0° C. The resulting mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give (S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-[2-(methanesulfonyloxy)-1-methylethylamino]benzamide (5.43 g) as an oil.