Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]1[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:13][CH:14]=[C:15]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:16]=1>ClCCCl>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][C:2]([NH:10][C:11]1[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:13][CH:14]=[C:15]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH:16]=1)=[O:9])[CH3:8]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Solvent: ClCCCl
Product: CCOC(=O)CC(=O)Nc1cc(Cc2ccc(F)cc2)cnc1C(=O)OCC

Procedure:
Ethyl 3-chloro-3-oxopropionate (1.32 g, 8.75 mmol) was added to a solution of ethyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate (2 g, 7.29 mmol) in DCE (20 mL) and the solution was heated at reflux for 1 h. The solvent was removed in vacuo and silica gel chromatography eluting with 0-5% MeOH/CH2Cl2 provide the product as an amber oil: 1H NMR (CDCl3) δ 8.96 (1H, br s), 8.32 (1H, d, J=1.8 Hz), 7.17 (2H, dd, J˜9, 6 Hz), 7.00 (2H, t, J˜9 Hz), 4.53 (2H, t, J=7 Hz), 4.29 (2H, t, J=7 Hz), 4.02 (2H, s), 3.54 (2H, s), 1.48 (3H, t, J=7 Hz), 1.33 (3H, t, J=7 Hz).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([N:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH3:17])=[C:11]([CH:14]=[CH2:15])[CH:12]=2)[O:7][C:6]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:4]>[OH-].[OH-].[Pd+2].C(OCC)(=O)C.CO>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([N:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH3:17])=[C:11]([CH2:14][CH3:15])[CH:12]=2)[O:7][C:6]=1[C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)=[O:4]
Reactant: C=Cc1cc2c(C(=O)NC)c(-c3ccc(F)cc3)oc2nc1N(C)S(C)(=O)=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1cc2c(C(=O)NC)c(-c3ccc(F)cc3)oc2nc1N(C)S(C)(=O)=O

Procedure:
To 2-(4-Fluoro-phenyl)-6-(methanesulfonyl-methyl-amino)-5-vinyl-furo[2,3-b]pyridine-3-carboxylic acid methylamide (11 mg, 0.027 mmol) was added 8 mg of 20% Pd(OH)2/C and ethyl acetate/methanol 5/1 (5 ml). The reaction flask was evacuated and filled with hydrogen gas from a balloon. After LCMS indicated conversion to product, the reaction mixture was filtered, evaporated to dryness and purified by HPLC to afford 5-Ethyl-2-(4-fluoro-phenyl)-6-(methanesulfonyl-methyl-amino)-furo[2,3-b]pyridine-3-carboxylic acid methylamide. MS (ESI) m/z 406.3 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.18 (s, 1H), 7.96-7.92 (m, 2H), 7.25-7.20 (m, 2H), 5.79 (br s, 1H), 3.32 (s, 3H), 3.19 (s, 3H), 2.99-2.98 (d, 3H), 2.96-2.91 (q, 2H), 1.33-1.29 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH2:9]2)=[C:4]([NH2:18])[CH:3]=1.C(N(CC)CC)C.C1(O[C:33](Cl)=[O:34])C=CC=CC=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>ClCCl.O>[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:33]([NH:18][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=2[N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH2:9]2)=[O:34])[CH2:39][CH2:38]1
Reactant: Nc1cc(Br)ccc1N1CCCc2ccccc21
Reactant: CN1CCNCC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)Nc2cc(Br)ccc2N2CCCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
1-(4-Bromo-2-aminophenyl)-1,2,3,4-tetrahydroquinoline (10.6 g, 0.035 mole) was dissolved on a steam bath in dichloromethane (150 ml). The solution was cooled to -5° C. in ice/methanol and triethylamine (5.01 g, 0.050 mole) was added in one portion, followed by a solution of phenylchloroformate (7.85 g, 0.050 mole) dissolved in dichloromethane (10 ml), dropwise over 15 minutes. The mixture was stirred 1 hour in the cold, 2 hours at room temperature, and an additional charge of phenylchloroformate (1.57 g, 0.010 mole) was added. After one hour, a solution of N-methylpiperazine (14.1 g, 0.14 mole) dissolved in dichloromethane (15 ml) was added over 0.5 hour. The reaction mixture was stirred under nitrogen at room temperature overnight. Water (100 ml) was added and the mixture was stirred 0.5 hour. The organic phase was separated, washed 4 times with water, dried over anhydrous sodium sulfate, and evaporated in a 100° C. bath in vacuo. The residue was dissolved in toluene (40 ml), adsorbed on a column of silica gel (500 g) packed in toluene and eluted with dichloromethane-methanol (98:2). The appropriate fractions were combined and evaporated to give 9.2 g (61%) of product, as an oil.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.Cl[CH2:6][CH2:7][N:8]([CH2:31][CH2:32]Cl)[C:9]1[CH:29]=[C:28]([Cl:30])[C:12]2[O:13][C:14]3[C:23]([CH3:24])=[CH:22][C:21]([C:25]([OH:27])=[O:26])=[CH:20][C:15]=3[S:16](=[O:19])(=[O:18])[CH2:17][C:11]=2[CH:10]=1.[CH3:34]O>>[CH3:34][O:27][C:25]([C:21]1[CH:22]=[C:23]([CH3:24])[C:14]2[O:13][C:12]3[C:28]([Cl:30])=[CH:29][C:9]([N:8]4[CH2:7][CH2:6][N:4]([CH:1]5[CH2:3][CH2:2]5)[CH2:32][CH2:31]4)=[CH:10][C:11]=3[CH2:17][S:16](=[O:19])(=[O:18])[C:15]=2[CH:20]=1)=[O:26]
Reactant: CO
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N(CCCl)CCCl)cc1CS2(=O)=O
Reactant: NC1CC1
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(C4CC4)CC3)cc(Cl)c1O2
Temperature: 110 °C

Procedure:
Cyclopropyl amine (0.819 g, 14.34 mmol) was added to a solution of Example 102j (0.5 g, 1.04 mmol) in methanol (5 mL), followed by addition of n-tetrabutylammonium iodide (0.010 g, 0.027 mmol) in an atmosphere of nitrogen, in a pressure reactor vessel and heated at 110° C. for 10 h. It was brought to room temperature, concentrated, treated with methanolic HCl solution, and refluxed at 70° C. for 2 h. The reaction mixture was concentrated, treated with aqueous sodium bicarbonate solution to neutral pH and extracted with n-butanol. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography (silica gel, 5% methanol/chloroform) to obtain the title compound. Yield: 0.220 g, (45%); 1H NMR (DMSO-d6): δ 0.4 (m, 4H, 2CH2), 1.65 (m, 1H, CH), 2.7 (s, 3H, CH3), 2.80 (d, 4H, 2CH2), 3.10 (m, 4H, 2CH2), 3.90 (s, 3H, OCH3), 5.2 (s, 2H, CH2), 7.05 (s, 1H, Ar), 7.1 (s, 1H, Ar), 8.1 (s, 1H, Ar), 8.15 (s, 1H, Ar); MS: m/e (EI+) 447 (M+).
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[CH2:14]([O:16][C:17]1[CH:25]=[C:24]([NH2:26])[C:23]([Cl:27])=[CH:22][C:18]=1[C:19]([OH:21])=O)[CH3:15].[O:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[CH2:33][N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1.[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]/[C:44]([OH:46])=[O:45]>O1CCCC1.C(O)C>[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]/[C:44]([OH:46])=[O:45].[O:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[CH2:33][N:34]1[CH2:35][CH2:36][CH:37]([NH:40][C:19](=[O:21])[C:18]2[CH:22]=[C:23]([Cl:27])[C:24]([NH2:26])=[CH:25][C:17]=2[O:16][CH2:14][CH3:15])[CH2:38][CH2:39]1
Reactant: NC1CCN(CC2CCCO2)CC1
Reactant: CCOc1cc(N)c(Cl)cc1C(=O)O
Agent: CCOC(=O)Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCCO2)CC1
Reaction time: 0.5 h

Procedure:
Triethylamine (5.6 ml; 0.04 moles) and ethyl chloroformate (3.84 ml; 0.04 moles) were added successively to a stirred suspension of 2-ethoxy-4-amino5-chlorobenzoic acid (8.6 g; 0.04 moles) in anhydrous tetrahydrofuran (300 ml) whilst maintaining the temperature between -5° and -10° C. After stirring at this temperature for 0.5 hours, a solution of 1-(2-tetrahydrofurylmethyl)-4-aminopiperidine (8.0 g; 0.04 moles) in anhydrous tetrahydrofuran (50 ml) was added, the temperature was maintained at -5° to -10° C. for 1 hour and then allowed overnight to reach room temperature. The solvent of the mixture was removed in vacuo, the residue poured into water, extracted with chloroform and the organic layers washed with water. The chloroformic solution was dried (Na2SO4) and the solvent removed in vacuo to give an oil which was treated with the stoichiometric amount of fumaric acid in boiling absolute ethanol. N-[1-(2-Tetrahydrofurylmethyl)-piperid-4-yl]-2-ethoxy-4-amino-5-chlorobenzamide hydrogen fumarate (10.6 g) was thus obtained, m.p. 199°-201° C. (d).
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([F:12])[CH:3]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([N:8]=[CH:15][N:16]([CH3:18])[CH3:17])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: Cc1cc(C(N)=O)c(F)cc1Br
Reactant: COC(OC)N(C)C
Product: Cc1cc(C(=O)N=CN(C)C)c(F)cc1Br
Yield: 95 %

Procedure:
A solution of 4-bromo-2-fluoro-5-methylbenzamide (20 g, 86 mmol) in N,N-dimethyl-formamide dimethylacetal (200 mL) was stirred at 100° C. under nitrogen for 3 h. The resulting mixture was concentrated and dried to give the desired product (24.6 g, 95% yield) as a yellow oil, which was used in the next step without further purification. MS (ESI) m/z 287.0 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:13])[CH:10]=NO)=[C:4]([O:14][CH3:15])[CH:3]=1.[OH:16]S(O)(=O)=O>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([O:14][CH3:15])[CH:3]=1)[NH:8][C:9](=[O:13])[C:10]2=[O:16]
Reactant: COc1cc(Br)ccc1NC(=O)C=NO
Reactant: O=S(=O)(O)O
Product: COc1cc(Br)cc2c1NC(=O)C2=O
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To concentrated H2SO4 (30 ml) at 65° C. was added N-(4-bromo-2-methoxyphenyl)-2-(hydroxyimino)acetamide (5.55 g, 20 mmol) portionwise. The mixture was heated at 90° C. for 1.5 h. The mixture was cooled to room temperature, poured onto ice, and stirred for 10 min. The solid was collected by filtration, washed with water, and air dried to afford 5-Bromo-7-methoxyindoline-2,3-dione (3.6 g, crude, 70% yield). This material was used without further purification. 1H NMR (400 MHz, DMSO-d6): δH 7.93 (s, 1H), 7.38 (s, 1H), 3.94 (s, 3H). MS (ESI) m/e [M+1]+ 256, 258.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=O)=[O:13])=[C:4]1[CH3:23])[CH3:2].[C:24]([NH:27][C:28]1[CH:40]=[CH:39][C:31]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:30][CH:29]=1)(=[O:26])[CH3:25]>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2([N:32]([C:31]3[CH:39]=[CH:40][C:28]([NH:27][C:24](=[O:26])[CH3:25])=[CH:29][CH:30]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:14]3[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16](=[O:18])[O:13]2)=[C:4]1[CH3:23])[CH3:2]
Reactant: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Reactant: CC(=O)Nc1ccc(Nc2ccccc2)cc1
Product: CCn1c(C)c(C2(N(c3ccccc3)c3ccc(NC(C)=O)cc3)OC(=O)c3ccccc32)c2ccccc21
Yield: 50.3 %

Procedure:
Following a procedure similar to that described in Example 1A but employing 4.5 g of 2-(1-ethyl-2-methyl-3-indolylcarbonyl)benzoic acid and 3.4 g of 4-acetamido-N-phenylaniline there was obtained 3.8 g of 3-(1-ethyl-2-methyl-3-indolyl)-3-[N-(4-acetamidophenyl)-N-phenylamino]phthalide, m.p. 93°-116° C. A toluene solution of the product contacted with acidic clay or phenolic resin developed a yellow-colored image.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][CH2:8][C@:9]12[CH2:35][CH2:34][C@@H:33]([C:36]([CH3:38])=[CH2:37])[C@@H:10]1[CH:11]1[C@@:24]([CH3:27])([CH2:25][CH2:26]2)[C@@:23]2([CH3:28])[C@@H:14]([C@:15]3([CH3:32])[C@@H:20]([CH2:21][CH2:22]2)[C:19]([CH3:30])([CH3:29])[C@@H:18]([OH:31])[CH2:17][CH2:16]3)[CH2:13][CH2:12]1.C(N(CC)CC)C>C(Cl)Cl.CS(C)=O>[CH3:27][C@:24]12[C@@:23]3([CH3:28])[C@@H:14]([C@:15]4([CH3:32])[C@@H:20]([CH2:21][CH2:22]3)[C:19]([CH3:29])([CH3:30])[C:18](=[O:31])[CH2:17][CH2:16]4)[CH2:13][CH2:12][CH:11]1[C@H:10]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:9]1([CH:8]=[O:7])[CH2:26][CH2:25]2
Reactant: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)C(CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)C(CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.1 %

Procedure:
To a 2M solution of oxalyl chloride (47.0 mL, 94 mmol) in CH2Cl2, was added a solution of DMSO (13.7 mL, 192 mmol) in CH2Cl2 (20 mL) dropwise at −15° C. After 5 min, a solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13bR)-3a-(hydroxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-ol (4.43 g, 10.01 mmol) in a mixture of DMSO (30 mL) and CH2Cl2 (50 mL) was added at −15° C. Triethylamine (56 mL) was added 15 minutes later and the stirring was continued for another 10 min. The reaction mixture was allowed to warm up to RT. The reaction was quenched by addition of water (100 mL), and the reaction mixture was extracted with CH2Cl2 (70 mL×3). The combined organic layers were washed with brine (30 mL×3), dried over MgSO4, filtered and concentrated. The crude material was purified using silica gel chromatography eluted with a mixture of ethyl acetate and hexanes, to give the product as a solid (3.3 g 75%). LCMS: m/e 461.15 (M+Na)+, 2.91 min (method 2).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:10]([O:13]C(=O)C)(=O)[CH3:11].C(=O)([O-])[O-].[Na+].[Na+].C(=O)=O.[Cl:26]Cl>O.C(Cl)(Cl)Cl>[Cl:26][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[N:1]([C:10](=[O:13])[CH3:11])[CH2:2][CH2:3]2
Reactant: c1ccc2c(c1)CCN2
Reactant: ClCl
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)N1CCc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1428 g (12 moles) of indoline and 3000 ml of chloroform were admixed with stirring with 1350 g (132 moles) of acetic acid anhydride with cooling to keep the temperature at 20° to 30° C. and the mixture was stirred for one hour. Then, 600 ml of water were added thereto followed by addition in portions over 71/2 hours to the mixture of 702 g (6.6 moles) of sodium carbonate with vigorous stirring and external cooling during which carbon dioxide evolved. Within 7.5 hours 937 g (13.2 moles) of chlorine were added to the mixture held at no more than 30° C. and the mixture was stirred for 30 minutes. 3000 g of water were added to the mixture which was stirred for 15 minutes after which the organic phase was separated and evaporated to dryness under reduced pressure at 130° C. At 70° to 75° C. 2400 ml of isopropanol were added to the residue and the mixture was stirred with heating until total dissolution occured and the mixture was cooled to room temperature and was stirred at 20° to 25° C. for one hour. The mixture was vacuum filtered to obtain 5-chloro-1-acetyl-indoline melting at 115° to 116° C. which was washed with 1500 ml of isopropanol.
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: CCO
Solvent: CC(=O)O
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: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.FC(F)(F)S(O[C:38]1[CH:43]([CH3:44])[CH2:42][CH2:41][CH2:40][C:39]=1[CH3:45])(=O)=O>>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:38]4[CH:43]([CH3:44])[CH2:42][CH2:41][CH2:40][C:39]=4[CH3:45])=[CH:21][CH:22]=3)=[O:16])[CH2:6][C:5]=12
Reactant: CC1=C(OS(=O)(=O)C(F)(F)F)C(C)CCC1
Reactant: CC1(C)OB(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)OC1(C)C
Product: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)C(C)CCC1

Procedure:
(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone of Step B (0.300 g, 0.746 mmol) and 2,6-dimethyl-cyclohex-1-en-1-yl trifluoromethanesulfonate (0.255 g, 0.821 mmol) were reacted by the procedure described in Example 1, Step F. Purification by flash column chromatography on silica gel, eluting with a solvent gradient of from 30 to 60% ethyl acetate in hexane, followed by recrystallization from petroleum ether (−20° C.) afforded the title compound as white crystals, m.p. 153–154° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1)[CH:5]=O.[C:13]([CH2:15][C:16]([NH2:18])=[O:17])#[N:14].N1CCCCC1>C(O)C>[C:13]([C:15](=[CH:5][C:4]1[CH:3]=[C:2]([F:1])[CH:9]=[CH:8][C:7]=1[N+:10]([O-:12])=[O:11])[C:16]([NH2:18])=[O:17])#[N:14]
Reactant: O=Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: N#CCC(N)=O
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CC(=Cc1cc(F)ccc1[N+](=O)[O-])C(N)=O

Procedure:
A mixture of 3-fluoro-6-nitrobenzaldehyde (10.0 g., 0.0592 mole), 2-cyanoacetamide (5.24 g., 0.0622 mole), piperidine (0.37 g., 4.36 millimole) and ethanol (92 ml.) is heated to reflux on a steam bath for two hours. It is then cooled in an ice-bath whereupon the product precipitates and is recovered by filtration, washed with cold ethanol and dried. Yield = 9.1 g. (65%) of crude product. M.P. 162°-166° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([O:26][CH3:27])[O:24][CH3:25])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CC(N(C)C)=O.CCOC(C)=O>[C:8]([C:7]1[C:2]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:3][C:4]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([O:26][CH3:27])[O:24][CH3:25])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:5][CH:6]=1)#[N:9]
Reactant: C1COCCN1
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(Cl)c(C#N)cn1)CCC2
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(N3CCOCC3)c(C#N)cn1)CCC2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
N-(4-chloro-5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2J, 60 mg, 0.155 mmol) and morpholine (500 μl, 5.74 mmol) were dissolved in DMA (1 ml) under argon. The mixture was stirred at 100° C. for 1 h. The reaction mixture was cooled to room temperature, diluted in EtOAc and washed 2× with NH4Cl aq sat and 1× with brine. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) followed by reverse phase chromatography (4.3 g C18 cartridge, 0.1% TFA in water/acetonitrile 90:10 to 0:100) to give the title compound as a white solid. (UPLC-MS 3) tR 1.13 min; ESI-MS 439.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([OH:17])([CH3:16])[C:3]#[C:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[OH:6].C([O-])(O)=O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[OH:17][C:2]([CH3:16])([CH3:1])[C:3]#[C:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:6]
Reactant: CC(C)(O)C#CC(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(O)C#CC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.7 %

Procedure:
To a room temperature solution of 4-methyl-1-(4-nitrophenyl)pent-2-yne-1,4-diol (2 g, 8.51 mmol, 1 eq) in dry DCM (100 mL) was added NaHCO3 (680 mg, 8.51 mmol, 1 eq) followed by Dess Martin Periodinane (9.2 g, 21.27 mmol, 2.5 eq). The reaction mixture was stirred at RT for 16 h. After completion of the reaction (as monitored by TLC), the reaction mixture was quenched with a saturated sodium bisulfite solution and extracted with DCM (2×100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 20% EtOAc hexanes to afford 4-hydroxy-4-methyl-1-(4-nitrophenyl)pent-2-yn-1-one (1.7 g, 86%) as an oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[O:7][C:8]1[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=1.[C:23]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl>[CH:23]1([NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:7][C:6]3[CH:15]=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:4]([CH:3]([O:2][CH3:1])[O:21][CH3:22])[CH:5]=3)[CH:9]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COC(OC)c1cc(Oc2cccc(N)c2)ccc1[N+](=O)[O-]
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: COC(OC)c1cc(Oc2cccc(NC3CCCCC3)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(3-Dimethoxymethyl-4-nitro-phenoxy)-phenylamine (0.0125 mol) was dissolved in DCE (150 mL), and cyclohexanone (0.0125 mol) was added, followed by NaBH(OAc)3 (0.0187 mol). The reaction mixture was stirred overnight at room temperature. Some extra NaBH(OAc)3 was added, and the reaction mixture was stirred overnight at room temperature. A 10% NaOH solution (150 mL) was added, and this mixture was extracted with diisopropyl ether. The separated organic layer was dried (MgSO4) and filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: 20:80 up to 5:95 hexane:CH2Cl2). The product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[S:15][C:14]([CH2:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])=[CH:13][CH:12]=2)[C:8]([O:22][CH3:23])=[CH:7][N:6]=1)(=O)=O.[CH3:24][C:25]1([CH3:34])[CH2:30][CH:29]([NH2:31])[CH2:28][C:27]([CH3:33])([CH3:32])[NH:26]1.CCN(C(C)C)C(C)C>CO>[CH3:23][O:22][C:8]1[C:9]([C:11]2[S:15][C:14]([CH2:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])=[CH:13][CH:12]=2)=[N:10][C:5]([NH:31][CH:29]2[CH2:30][C:25]([CH3:34])([CH3:24])[NH:26][C:27]([CH3:33])([CH3:32])[CH2:28]2)=[N:6][CH:7]=1
Reactant: COc1cnc(S(C)(=O)=O)nc1-c1ccc(CCC(C)(C)O)s1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1cnc(NC2CC(C)(C)NC(C)(C)C2)nc1-c1ccc(CCC(C)(C)O)s1
Temperature: 120 °C

Procedure:
4-[5-(2-Methanesulfonyl-5-methoxy-pyrimidin-4-yl)-thiophen-2-yl]-2-methyl-butan-2-ol (240 mg, 0.673 mmol) was mixed with 2,2,6,6-Tetramethyl-piperidin-4-ylamine (0.5 ml, 2.86 mmol) and DIEA (0.5 ml, 2.92 mmol) and heated to 120° C. in a closed flask for 2 hours. The residue was then diluted with MeOH and purified by preparative HPLC to give the title compound. Yield: 8 mg (3%).