Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[CH3:19][C:20]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:22][C:21]=1[CH:31]=O.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:22][C:21]=2[CH3:31])[CH2:15][CH2:14]1
Reactant: c1ccc2oc(NC3CCNCC3)nc2c1
Reactant: Cc1nc(-c2ccccc2)[nH]c1C=O
Agent: Br
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1[nH]c(-c2ccccc2)nc1CN1CCC(Nc2nc3ccccc3o2)CC1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 15 %

Procedure:
To a solution of benzooxazol-2-yl-piperidin-4-yl-amine (65.2 mg, 0.3 mmol, 1.0 equiv; free amine of intermediate D) and 5-methyl-2-phenyl-3H-imidazole-4-carbaldehyde (61.5 mg, 0.33 mmol, 1.1 equiv; [CAS RN 68282-50-8] prepared as described in L. A. Reiter J. Org. Chem. 1987, 52, 2714-2726) in ethanol (2 mL) was added acetic acid (54.1 mg, 0.9 mmol, 3.0 equiv) and the reaction mixture heated under microwave irradiation to 100° C. After 10 min, sodium cyano borohydride (24.5 mg, 0.39 mmol, 1.3 equiv) was added and the mixture heated under microwave irradiation to 100° C. for an additional time period of 20 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 17.0 mg (15%) of the title compound. MS (ESI): 388.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][NH:9][C:10](=[O:13])[CH2:11][S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:16]I.O>CS(C)=O>[Cl:1][C:2]1[C:7]2[CH2:8][N:9]([CH3:16])[C:10](=[O:13])[CH2:11][S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CSc2cccc(Cl)c2CN1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN1Cc2c(Cl)cccc2SCC1=O
Reaction time: 0.5 h

Procedure:
A solution of 6-chloro-4,5-dihydro-1,4-benzothiazepin-3(2H)-one (5.33 g, prepared in a similar manner to example 11 of international patent application WO 92/21668) in dry dimethylsulphoxide (60 ml) was added slowly at room temperature to a stirred suspension of sodium hydride (0.6 g) in dimethylsulphoxide (20 ml). After the addition was completed, the mixture was stirred for 30 minutes before adding methyl iodide (6 ml) dropwise. The reaction mixture was stirred at room temperature for one hour, water (160 ml) was added and the mixture was extracted with diethyl ether. The organic layer was washed with water and the solvent was removed by evaporation. Purification of the residue by flash chromatography using dichloromethane/ethyl acetate (9.8:0.2) as eluent gave 6-chloro-4-methyl-4,5-dihydro-1,4-benzothiazepin-3(2H)-one. Yield 3.8 g (m.p. 122°-125° C.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.O>C(Cl)(Cl)Cl>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][CH:7]([N:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:12][CH2:11]3)[CH2:6][CH2:5]2)(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCN1CCC(N2CCc3ccccc32)CC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)NCCN2CCC(N3CCc4ccccc43)CC2)cc1
Yield: 23.6 %

Procedure:
1-[1-(2-Aminoethyl)piperidin-4-yl]indoline (113 mg) was dissolved in chloroform (3 ml). Under ice cooling, 4-methoxybenzenesulfonyl chloride (95 mg) was added thereto and the resultant mixture was stirred at room temperature overnight. After adding water, the reaction solution was extracted with chloroform. The organic layer was washed with brine and dried over magnesium sulfate. After evaporating the solvent, the resulting residue (80 mg) was purified by NH-silica gel column chromatography (methanol/methylene chloride system) to give the title compound (45 mg) as an oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[O:18][C:19]([CH3:35])=[C:20]([C:22]([NH:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[O:23])[N:21]=4)=[C:13]([NH:36][CH:37]([CH3:39])[CH3:38])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.CCOCC.Cl>C(Cl)Cl>[NH2:27][CH2:26][CH2:25][NH:24][C:22]([C:20]1[N:21]=[C:17]([C:14]2[CH:15]=[N:16][C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]4[N:3]=[CH:2][S:1][C:5]=4[CH:6]=3)=[CH:12][C:13]=2[NH:36][CH:37]([CH3:38])[CH3:39])[O:18][C:19]=1[CH3:35])=[O:23]
Reactant: Cc1oc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)nc1C(=O)NCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1oc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)nc1C(=O)NCCN
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl (2-(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxamido)ethyl)carbamate in DCM (5 mL) was treated with ether.HCl (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min. The reaction temperature was raised to room temperature and stirred for 30 min. The reaction mixture was concentrated to dryness. The material obtained was purified by prep. HPLC to afford N-(2-aminoethyl)-2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxamide 1H NMR: 400 MHz, DMSO-d6: δ 1.35 (d, J=6.40 Hz, 6H), 2.64 (s, 3H), 2.70-2.80 (m, 2H), 3.70-3.74 (m, 1H), 6.17 (s, 1H), 7.60 (dd, J=2.00, 9.00 Hz, 1H), 7.79 (d, J=7.20 Hz, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.02 (bs, 1H), 8.53 (s, 1H), 8.67 (d, J=2.00 Hz, 1H), 9.16 (s, 1H), 9.35 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm, 2.7 μm; Solvent A=2% ACN: 98% H2O: 10 mM NH4COOH; Solvent B=98% ACN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 1.5 min; retention time: 1.646 min; LCMS (ES-API), m/z 452.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 30 min (36 min run time); Flow rate: 1.0 μL/min; Retention time: 8.956 min; Purity: 91.1%.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[C:10]([F:16])=[C:9]([F:17])[C:8]=1[F:18])=[O:5])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:13][C:11]1[C:10]([F:16])=[C:9]([F:17])[C:8]([F:18])=[C:7]([O:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:12]=1
Reactant: [H][H]
Reactant: CCOC(=O)Oc1cc([N+](=O)[O-])c(F)c(F)c1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)Oc1cc(N)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
1.43 g (5.40 mmol) of the above O-ethoxycarbonyl-2,3,4-trifluoro-5-nitrophenol was dissolved in 20 mL of ethyl acetate under argon atmosphere, 200 mg of 10% palladium/carbon was added thereto, the gaseous phase in the reaction vessel was substituted with hydrogen and the mixture was stirred at room temperature for 4 hours. The reaction solution was filtered and the solvent was distilled off under reduced pressure to give 1.27 g of 5-amino-O-ethoxycarbonyl-2,3,4-trifluorophenol (yield: 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][C:11]1(C)C(C)(C)OB(C=C)O1.C([O-])([O-])=O.[K+].[K+]>CCO.C1COCC1.O.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:8][C:5]1[C:4]([F:9])=[CH:3][C:2]([CH:10]=[CH2:11])=[CH:7][N:6]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: Fc1cc(Br)cnc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: C=Cc1cnc(Cl)c(F)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a solution of 101 (5.00 g, 23.8 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (119, 21.39 mmol, Sigma-Aldrich) in a mixture of EtOH (30.0 mL) and THF (64.0 mL) under an argon atmosphere was added Pd(PPh3)2Cl2 (1.33 g, 1.90 mmol) and K2CO3 (8.20 g, 59.4 mmol). The resulting reaction mixture was heated to 60° C. and held for 16 hrs in a sealed bottle. The mixture was cooled to a temperature of about 25° C., diluted with water, and extracted with EtOAc. The organic layer was separated, washed with brine, and concentrated. The residue was chromatographed on a silica gel column eluted with EtOAc:hexanes to provide 112 as a colorless oil (85% yield). 1H NMR (CDCl3) δ: 5.48 (1H, d, J=10.97 Hz), 5.83 (1H, d, J=17.62 Hz), 6.68 (1H, dd, J=10.97, 17.62 Hz), 7.52 (1H, d, J=1.60 Hz), 8.20 (1H, d, J=1.60 Hz). LC/MS (M+1): m/z=158.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6](=[O:33])(SCC)[O:7][CH2:8][O:9][C:10](=[O:29])[C:11]1[CH:16]=[C:15]([S:17]([NH2:20])(=[O:19])=[O:18])[C:14]([Cl:21])=[CH:13][C:12]=1[NH:22][CH2:23][C:24]1[O:25][CH:26]=[CH:27][CH:28]=1>ClCCl>[C:6]([Cl:4])(=[O:33])[O:7][CH2:8][O:9][C:10](=[O:29])[C:11]1[CH:16]=[C:15]([S:17]([NH2:20])(=[O:19])=[O:18])[C:14]([Cl:21])=[CH:13][C:12]=1[NH:22][CH2:23][C:24]1[O:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CCSC(=O)OCOC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(C(=O)OCOC(=O)Cl)c(NCc2ccco2)cc1Cl
Reaction time: 0.25 h

Procedure:
Freshly distilled sulfuryl chloride (0.050 mole) in dichloromethane (25 mL) is added to O-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxymethyl) S-ethyl carbonothioate (1005) (0.050 mole) in dichloromethane (25 mL) at 0-5° C. with stirring during 15 minutes followed by stirring at ambient temperature for 45 minutes. The volatiles are removed by evaporation at ambient temperature and then at 20 millibar for 16 hours. The crude product is dissolved in ethyl acetate and applied to a column of silica gel. The column may be eluted with hexanes/ethyl acetate, and the fractions that contain pure product may be combined and spin evaporated in vacuo to give 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxymethyl carbonochloridate (1010). See eg., Folkmann, et al., Synthesis, 1159 (1990), Method G.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]3[NH2:23])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:24](Cl)(=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]3[NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H]1CCCC[C@H]1NC1CCCN(c2ccc([N+](=O)[O-])cc2)C1
Product: O=C(N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2ccc([N+](=O)[O-])cc2)C1)OCc1ccccc1

Procedure:
Benzyl (1R,2R)-2-((S)-1-(4-nitrophenyl)piperidin-3-ylamino)cyclohexylcarbamate was synthesized using (1R,2R)—N1-(1-(4-nitrophenyl)piperidin-3-yl)cyclohexane-1,2-diamine (from intermediate C, Example 2) (30 mg, 0.094 mmol) and benzyl carbonochloridate (16.07 mg, 0.094 mmol) according to General Procedure G to give 5 mg (12% yield) of the product as a yellow solid. Anal. Calcd. for C25H32N4O4 m/z 452.5, found: 453.3 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 8.08 (d, J=9.3 Hz, 2H), 7.36-7.29 (m, 5H), 6.77 (d, J=9.3 Hz, 2H), 5.05 (br. s., 2H), 4.91 (br. s., 1H), 3.75 (d, J=10.4 Hz, 1H), 3.66 (d, J=12.6 Hz, 1H), 3.31 (d, J=7.7 Hz, 1H), 3.04 (t, J=10.7 Hz, 1H), 2.83 (br. s., 2H), 2.54 (br. s., 1H), 2.15-2.03 (m, 2H), 1.99-1.91 (m, 1H), 1.83 (dd, J=9.1, 4.7 Hz, 2H), 1.79-1.69 (m, 3H), 1.32 (d, J=8.8 Hz, 2H), 1.48 (br. s., 1H), 1.62 (ddd, J=13.9, 10.4, 10.3 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ ppm 156.63, 154.71, 136.37, 128.52, 128.14, 126.12, 112.77, 66.77, 59.06, 50.93, 47.94, 32.19, 29.68, 24.53, 23.07.
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([O:21][C:22]3[C:23]([CH3:32])=[N:24][C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[O:33][CH3:34].C(=O)([O-])[O-].[K+].[K+].[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>O>[CH3:34][O:33][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:11]=1[O:10][CH2:9][CH2:8][CH2:7][N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[N:18]=[CH:17][CH:16]=[C:15]2[O:21][C:22]1[C:23]([CH3:32])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCCl
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCN1CCCCC1
Temperature: 75 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
N,N-Dimethylformamide (1 ml) was added to 7-(3-chloro-propoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 375) (40 mg), potassium carbonate (41 mg), and piperidine (25 mg), and the mixture was stirred at 75° C. overnight. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (32 mg, yield 72%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C[Mg+].[Br-].[C:14](=O)(O)[O-].[Na+].CC(C)=O>CCOCC.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([C:7](=[O:8])[CH3:14])[CH:9]=1
Reactant: O=C([O-])O
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=[Cr](=O)=O
Agent: C[Mg+]
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC(=O)c1cc(Br)ccc1F
Reaction time: 8 h
Yield: 87 %

Procedure:
To a 0° C. stirred solution of 5-bromo-2 fluoro-benzaldehyde (5.00 g, 24.6 mmol) in anhydrous ether (100 mL) under nitrogen gas was added via syringe MeMgBr (3M solution in ether, 10 mL, 30 mmol) over 3 min. The mixture was poured into a saturated solution of sodium bicarbonate (100 mL), the organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give a viscous oil. The oil was mixed with acetone (100 mL) and treated with Jones reagent (1.1 M, 40 mL, 1.79 mmol). The mixture was stirred overnight, acetone was evaporated and the residue was extracted with ethyl acetate (60 mL×2). The extracts were washed with water (50 mL) and then a saturated aqueous solution of sodium bicarbonate (50 mL). Evaporation gave the ketone as an oil (4.63 g, 87%) that was used in the next reaction without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH3:23])[CH:18]=[CH:17]3)[C:3]=1[CH3:24].[CH3:25][C:26]1([CH3:41])[C:30]2=[N:31][CH:32]=[C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:34]=[C:29]2[NH:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:25][C:26]1([CH3:41])[C:30]2=[N:31][CH:32]=[C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:34]=[C:29]2[N:28]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH3:23])[CH:18]=[CH:17]4)[C:3]=2[CH3:24])[CH2:27]1
Reactant: Cc1c(-c2ccc3c(ccn3C)c2)nc2cc(F)cc(F)c2c1Cl
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc3c(ccn3C)c2)nc2cc(F)cc(F)c2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21

Procedure:
4-Chloro-5,7-difluoro-3-methyl-2-(1-methyl-1H-indol-5-yl)quinoline (44.1 mg, 0.129 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-morpholine (30 mg, 0.129 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (12.3 mg, 0.026 mmol), Pd2dba3 (11.8 mg, 0.013 mmol), sodium tert-butoxide (37.1 mg, 0.386 mmol), and toluene (1.29 mL) were stirred at 105° C. for 2 h. The reaction mixture was then concentrated and the resulting residue partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine and water, then dried (MgSO4) and concentrated. Purification of the crude product by reverse-phase HPLC (0-70% acetonitrile in water) gave 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-3-methyl-2-(1-methyl-1H-indol-5-yl)-quinoline. 1H NMR (400 MHz, chloroform-d) δ ppm 7.90 (1H, dd, J=1.6, 0.8 Hz), 7.69 (1H, ddd, J=9.6, 2.5, 1.4 Hz), 7.56 (1H, d, J=2.3 Hz), 7.43-7.53 (2H, m), 7.15 (1H, d, J=2.9 Hz), 6.95 (1H, ddd, J=11.8, 8.9, 2.6 Hz), 6.59 (1H, dd, J=3.1, 0.6 Hz), 5.77 (1H, d, J=2.3 Hz), 3.88 (3H, s), 3.84-3.86 (1H, m), 3.77 (4H, dd, J=5.1, 4.5 Hz), 3.72 (1H, d, J=9.4 Hz), 2.94-3.10 (4H, m), 2.36 (3H, s), 1.56 (3H, s), 1.50 (3H, s). Mass Spectrum (ESI) m/e=540.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[O:8][C:9](=[O:12])[CH:10]=[CH:11][C:5]2=[CH:4][CH:3]=1.[O:13]1CCOCC1>C(Cl)Cl>[O:12]=[C:9]1[O:8][C:6]2=[N:7][C:2]([CH:1]=[O:13])=[CH:3][CH:4]=[C:5]2[CH:11]=[CH:10]1
Reactant: Cc1ccc2ccc(=O)oc2n1
Reactant: C1COCCO1
Solvent: ClCCl
Product: O=Cc1ccc2ccc(=O)oc2n1
Temperature: 160 °C
Yield: 40 %

Procedure:
To a solution of 7-methyl-2H-pyrano[2,3-b]pyridin-2-one (160 mg, 0.98 mmol) in 1,4-dioxane (12 mL) in a microwave reaction vial was added SeO2 (328 mg, 3.0 mmol). The reaction vial was capped and the mixture was heated in a microwave at 160° C. for 90 minutes. The reaction was diluted with DCM, filtered through a pad of Celite® and concentrated. The resulting material was dissolved in DCM and loaded onto a plug of silica gel and evaporated. Purification by column chromatography (silica gel) using a DCM/MeOH gradient (0-10% MeOH) provided the desired product as a pale yellow solid (120 mg, 40%). LCMS (ES+) m/z 176 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[CH3:28][O:29][C:30]1[CH:38]=[C:37]2[C:33]([C:34](=[O:44])[C:35](=[O:43])[N:36]2[CH2:39][C:40](O)=[O:41])=[CH:32][CH:31]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:40](=[O:41])[CH2:39][N:36]1[C:37]2[C:33](=[CH:32][CH:31]=[C:30]([O:29][CH3:28])[CH:38]=2)[C:34](=[O:44])[C:35]1=[O:43]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: COc1ccc2c(c1)N(CC(=O)O)C(=O)C2=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc2c(c1)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C(=O)C2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.6 %

Procedure:
A mixture of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.200 g, 0.476 mmol), 2-(6-methoxy-2,3-dioxoindolin-1-yl)acetic acid (0.112 g, 0.476 mmol), DMAP (0.029 g, 0.238 mmol) and EDC (0.274 g, 1.428 mmol) in DCM (10 ml) was stirred at room temperature for 4 hours; then the reaction mixture was washed with 1N HCl, aqueous 5% NaHCO3 and brine. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography on silica gel (ethyl acetate:DCM=7:3) to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(6-methoxy-2,3-dioxoindolin-1-yl)acetoxy)ethyl)pyridine 1-oxide (0.166 g, 0.260 mmol, 55% yield). MS/ESI+ 637.19 [MH]+; [αD]=+67.91 c=0.22 in DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.37 (s, 2H), 7.61 (d, 1H), 7.17 (d, 1H), 7.05 (d, 1H), 6.94 (dd, 1H), 7.07 (t, 1H), 6.69 (dd, 1H), 6.66 (d, 1H), 6.02 (dd, 1H), 4.60 (s, 2H), 3.89 (d, 2H), 3.86 (s, 3H), 3.38 (dd, 1H), 3.19 (dd, 1H), 1.07-1.33 (m, 1H), 0.48-0.67 (m, 2H), 0.18-0.48 (m, 2H)
Reaction SMILES: C(OC([CH2:6][CH2:7][N:8]([CH3:27])[CH2:9][CH:10]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([CH2:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)[C:11]([O:13]C)=O)=O)C.[H-].[Na+].Cl>C1(C)C=CC=CC=1>[CH2:23]([C:18]1[C:17]([O:25][CH3:26])=[CH:16][C:15]([CH:10]2[C:11](=[O:13])[CH2:6][CH2:7][N:8]([CH3:27])[CH2:9]2)=[CH:20][C:19]=1[O:21][CH3:22])[CH3:24]
Reactant: CCOC(=O)CCN(C)CC(C(=O)OC)c1cc(OC)c(CC)c(OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCc1c(OC)cc(C2CN(C)CCC2=O)cc1OC
Temperature: 25 °C
Yield: 88.4 %

Procedure:
A solution of 53.51 g (140.3 mmol) of methyl 3-[(2-ethoxycarbonyl-ethyl)-methyl-amino]-2-(4-ethyl-3,5-dimethoxyphenyl)-propionate in 150 ml of toluene was added dropwise at 80° to a suspension of 11.62 g (266.3 mmol) of sodium hydride (55% in mineral oil) in 150 ml of toluene and the mixture was subsequently heated at reflux for 15 hours. The solution was cooled to room temperature and adjusted to pH 1 with 6N hydrochloric acid. The toluene was separated and extracted once with 150 ml of 6N hydrochloric acid. The acidic phases were heated at reflux for 20 hours. After cooling to room temperature the mixture was adjusted to pH 14 with 28% NaOH and extracted three times with 250 ml of methylene chloride. The organic phases were washed once with 200 ml of water and once with 200 ml of saturated sodium chloride solution, dried (MgSO4), filtered and evaporated. Chromatography (silica gel, methylene chloride/methanol 19:1) and recrystallization from hexane yielded 34.4 g (88%) of 3-(4-ethyl-3,5-dimethoxy-phenyl)-1-methyl-piperidin-4-one as pale yellow crystals of m.p. 84-85°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:8]=1)([O-])=O>CO.[Pd]>[O:12]1[CH2:11][CH2:10][CH:9]([N:7]2[CH:8]=[C:4]([NH2:1])[CH:5]=[N:6]2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1cnn(C2CCOCC2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cnn(C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
To the above 4-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (0.45 g) in MeOH (5 mL) was added 5% Pd/C (0.045 g). The reaction vessel was evacuated and filled with H2 (3×). The reaction was stirred under H2 (1.1 KPa) at room temperature overnight. The mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by column chromatography (CH2Cl2/MeOH=6/1 then 1/1) to give 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine (0.17 g, 78% yield for 2 steps). 1H NMR (500 MHz, CDCl3): δ 7.17 (s, 1H), 7.06 (s, 1H), 4.22 (m, 1H), 4.10-4.06 (m, 2H), 3.53-3.49 (m, 2H), 2.06-1.99 (m, 4H). LCMS (ESI) m/z: 168.1 [M+H+].
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[N+:14]([O-])([OH:16])=[O:15].[OH-].[NH4+]>>[CH3:8][C:3]1[C:2]([OH:1])=[CH:7][CH:6]=[C:5]([N+:14]([O-:16])=[O:15])[N:4]=1
Reactant: Cc1ncccc1O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1nc([N+](=O)[O-])ccc1O
Yield: 9.7 %

Procedure:
While maintaining a temperature of 0-5° C. with external ice cooling, 3-hydroxy-2-methyl pyridine (10.00 g, 91.63 mmol) was added gradually to concentrated sulfuric acid (65.00 ml). A mixture of concentrated sulfuric acid (8.50 ml) and nitric acid (6.50 g, 103.16 mmol) was added over 2 h. The resulting mixture was poured onto ice. Addition of a few milliliters of saturated ammonium hydroxide caused precipitation of crude 2-methyl-6-nitro-pyridin-3-ol. This was collected by filtration and recrystallized from methanol/water to yield pure 2-methyl-6-nitro-pyridin-3-ol (1.37 g, 10%). Basification of the mother liquors to pH 3-4 triggered precipitation of the isomeric 2-methyl-4-nitro-pyridin-3-ol (major component), which was discarded.