Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([C:12]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:13]=1[C:14](OC)=[O:15])(=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCO>[F:22][C:20]1[CH:21]=[C:12]2[C:13](=[CH:18][CH:19]=1)[C:14](=[O:15])[NH:3][N:2]=[C:4]2[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NN
Reactant: COC(=O)c1ccc(F)cc1C(=O)c1ccccc1
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(-c2ccccc2)c2cc(F)ccc12
Yield: 81.4 %

Procedure:
A solution of hydrazine hydrate (0.26 mL, 4.6 mmol) and the product of example 35C (0.390 g, 1.5 mmol) in EtOH (4.5 mL) was stirred at 80° C. for 3 hours, concentrated, and chromatographed on SiO2 (3% MeOH/CH2Cl2) to give 293.5 mg of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.42 (dd, 1H), 7.76 (ddd, 1H), 7.53-7.63 (m, 5H), 7.32 (dd, 1H).
Reaction SMILES: [C:1]1([O:7][S:8](=[O:11])(=[O:10])[NH2:9])[CH:6]=CC=[CH:3][CH:2]=1.[CH3:12][O:13]CC1(O)CC1>>[CH3:12][O:13][CH2:6][C:1]1([O:7][S:8](=[O:11])(=[O:10])[NH2:9])[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)Oc1ccccc1
Reactant: COCC1(O)CC1
Product: COCC1(OS(N)(=O)=O)CC1

Procedure:
Sulfamic acid 1-methoxymethyl-cyclopropyl ester was synthesized according to the method presented in the synthesis of sulfamic acid phenyl ester in Example 1 with the exception of utilizing 1-methoxymethyl cyclopropanol (synthesized by methods reported in European Journal of Chemistry 2006, 5069) to obtain sulfamic acid 1-methoxymethyl-cyclopropyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[C:15]([O:22][CH2:23][CH3:24])[CH:14]=3)[S:11][CH:12]=2)=[CH:4][C:3]=1[N+:25]([O-:27])=[O:26].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CS(C)=O>CN(C)C=O>[O:31]1[CH2:32][CH2:33][N:28]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]=[C:10]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[C:15]([O:22][CH2:23][CH3:24])[CH:14]=4)[S:11][CH:12]=3)=[CH:4][C:3]=2[N+:25]([O-:27])=[O:26])[CH2:29][CH2:30]1
Reactant: CCOc1ccc(-c2nc(-c3ccc(Cl)c([N+](=O)[O-])c3)cs2)cc1OCC
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CCOc1ccc(-c2nc(-c3ccc(N4CCOCC4)c([N+](=O)[O-])c3)cs2)cc1OCC
Yield: 91.5 %

Procedure:
A solution of 1 g of 4-(4-chloro-3-nitrophenyl)-2-(3,4-diethoxyphenyl)thiazole and 636 mg of morpholine dissolved in 20 ml of dimethylformamide and 20 ml of dimethyl sulfoxide was refluxed at 150° C. for 2-3.5 hours with heating. The reaction mixture was subjected to vacuum distillation. The residue was added to ice water, and an aqueous sodium hydrogencarbonate solution was added. The solution was extracted with dichloromethane three times. The combined extract was washed with an aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed by distillation. The residue was purified by silica gel column chromatography and recrystallized from ethyl acetate-n-hexane to obtain 1.03 g of 4-(4-morpholino-3-nitrophenyl)-2-(3,4-diethoxyphenyl)thiazole.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].C(O)(=O)C.N1CCCCC1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[C:13]([C:14]([CH3:16])=[O:15])[C:12]([O:18][CH2:19][CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:17])([O-:3])=[O:2]
Reactant: CC(=O)CC(=O)OCCOCc1ccccc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCCOCc1ccccc1
Yield: 113.6 %

Procedure:
To a solution of 3-nitrobenzaldehyde (4.53 g), 2-benzyloxyethyl acetoacetate (7.79 g) and acetic acid (360 mg) in benzene (15 ml), was added a solution of piperidine (306 mg) in benzene (5 ml), in a similar manner to the aforementioned Example 1-(i), and the mixture was heated to reflux for 2.5 hours under azeotropic dehydration. The reaction mixture was left to cool and diluted with benzene (50 ml), washed with water, diluted aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and then evaporated to dryness under reduced pressure to give brown oily 2-benzyloxyethyl 2-(3-nitrobenzylidene)acetoacetate (12.58 g). The mixture of the above obtained oil (12.58 g) and ethyl 3-amino-4,4-diethoxycrotonate (8.47 g) was heated at 100° to 102° C. for 4 hours and at 110° to 115° C. for 6.5 hours. After cooling, the reaction mixture was dissolved in ethyl acetate, washed twice with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residual brown oil (19.04 g) was chromatographed on a column of silica-gel (570 g) and eluted with a mixture of benzene and ethyl acetate (13:1, v/v) to give oily 2-benzyloxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate (9.64 g).
Reaction SMILES: C([NH:5][S:6]([CH2:9][CH2:10][CH:11]([O:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:12][CH3:13])(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:15]([O:14][CH:11]([CH2:12][CH3:13])[CH2:10][CH2:9][S:6]([NH2:5])(=[O:8])=[O:7])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCC(CCS(=O)(=O)NC(C)(C)C)OC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCC(CCS(N)(=O)=O)OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
A mixture of N-t-butyl-3-benzoyloxy-1-pentanesulfonamide (90.4 g) and trifluoroacetic acid (200 ml) was stirred overnight at room temperature. Trifluoroacetic acid was removed under reduced pressure and water and chloroform were added to the residue. A saturated aqueous solution of sodium hydrogencarbonate was added thereto with vigorously stirring until the aqueous layer became neutral. After extraction with chloroform, the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluate: hexane/ethyl acetate=2/1 to 1/1) to obtain 3-benzoyloxy-1-pentanesulfonamide (60.6 g) as oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.C1(P([N:33]=[N+:34]=[N-:35])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1COCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:33]=[N+:34]=[N-:35])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: COc1ccc(-c2cc(CO)ccc2OC)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(CN=[N+]=[N-])ccc2OC)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.8 %

Procedure:
A solution of 4-methoxy-3-(4-methoxyphenyl)benzyl alcohol (0.88 g, 3.59 mmol) and diphenylphosphoryl azide (1.18 g, 4.32 mmol) in anhydrous THF (15 mL) was cooled in an ice-bath prior to addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (0.87 g, 5.76 mmol). The resulting mixture was then stirred at room temperature for 48 hours. More diphenylphosphoryl azide was added (1.4 mol, 0.39 g) and the mixture stirred for further 16 hours. The solvent was then evaporated, the residue taken into dichloromethane and washed with acid. The organic layer was separated and the solvent removed under reduced pressure to afford 0.82 g of title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([N:13]([CH2:28][CH3:29])[CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH:26]=O)=[CH:20]2)[CH3:12].N1CCCCC1>C(O)C>[CH2:28]([N:13]([CH2:11][CH3:12])[CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH:26]=[C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]1=[O:10])=[CH:20]2)[CH3:29]
Reactant: CCN(CC)CCCc1ccc2[nH]c(C=O)cc2c1
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCCc1ccc2[nH]c(C=C3C(=O)Nc4ccccc43)cc2c1
Temperature: 95 °C
Yield: 18.3 %

Procedure:
A mixture of oxindole (26 mg, 0.19 mmol), 5-(3-diethylamino-propyl)-1H-indole-2-carbaldehyde (50 mg, 0.19 mmol) and piperidine(0.1 mL) in ethanol (1 mL) was heated in a sealed tube at 95° C. for 20 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 13 mg (18%) of the title compound as an orange crystalline solid.
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]([CH3:19])[C:5]2[C:10]([C:11]=1[N+:12]([O-:14])=[O:13])=[CH:9][C:8]([O:15][CH3:16])=[C:7]([O:17][CH3:18])[CH:6]=2.C(N(CC)CC)C.[CH2:27]([N:29]([CH2:33][CH3:34])[C:30](Cl)=[O:31])[CH3:28]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:27]([N:29]([CH2:33][CH3:34])[C:30]([O:1][C:2]1[N:3]=[C:4]([CH3:19])[C:5]2[C:10]([C:11]=1[N+:12]([O-:14])=[O:13])=[CH:9][C:8]([O:15][CH3:16])=[C:7]([O:17][CH3:18])[CH:6]=2)=[O:31])[CH3:28]
Reactant: COc1cc2c(C)nc(O)c([N+](=O)[O-])c2cc1OC
Reactant: CCN(CC)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)C(=O)Oc1nc(C)c2cc(OC)c(OC)cc2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a slurry of 3-hydroxy-6,7-dimethoxy-1-methyl-4-nitroisoquinoline (1.90 g, 7.19 mmol) in methylene chloride (100 mL) were added triethylamine (1.5 mL, 10.78 mmol), 4-dimethylaminopyridine (176 mg, 1.44 mmol) followed by diethylcarbamoyl chloride (0.81 mL, 8.62 mmol) in 5 mL of methylene chloride), added over a 10 minute period. The addition of each of the last three reagents was repeated twice two hours apart and then the mixture was stirred at room temperature overnight. The clear dark red-brown solution was washed with water (3×150 mL), saturated sodium bicarbonate solution and again with water. The organic phase was dried (Na2SO4), filtered and evaporated to dryness in vacuo. The tan residue was recrystallized from methylene chloride/ether to yield the title compound (2.04 g, 92.1%), mp 220°-221° C. (d). IR (KBr): 1738, 1520, 1260 cm-1. NMR (CDCl3): δ 1.24 and 1.28 [two t, J=7 Hz, total 6H, N(CH2CH3)2 ], 2.90 (s, 3H, 1-CH3), 3.20-3.80 (m, 4H, N(CH2CH3)2), 4.03 (s, 6H, 5,6-OCH3), 7.24 (s, 1H, 5- or 8-H), 7.28 (s, 1H, 5- or 8-H); MS (DCI): 364 (MH)+
Reaction SMILES: Br[CH:2]1[C:12](=[O:13])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3]1.[C-:14]#[N:15].[Na+].O.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>C1(C)C=CC=CC=1>[C:14]([CH:2]1[C:12](=[O:13])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3]1)#[N:15]
Reactant: [C-]#N
Reactant: O=C1C2=C(C=CC1Br)CCCCC2
Agent: [Na+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC1C=CC2=C(CCCCC2)C1=O
Temperature: 90 °C
Reaction time: 15 h

Procedure:
2-cyanobenzocycloheptan-1-one (compound Ia) was prepared by dissolving 2-bromobenzocycloheptan-1-one (30.2 g, 0.126 mol) in toluene (150 mL) in a 500 mL round bottom flask equipped with a condenser. NaCN (18.6g, 0.38 mol), water (50 g), and dibenzo-18-crown-6 (0.5 g) were added to the flask. The reaction mixture was stirred vigorously at 90° C. under a static blanket of nitrogen for 15 hours. The reaction mixture was cooled and washed three times with water (70 mL×2+100 mL). The toluene solution was dried over sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The residue was distilled under vacuum to give a yellow liquid (21.1 g, b.p. 158-162° C. at 17 mm Hg). The purity of the liquid was 96% by GC.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[F:17][C:18]([F:28])([F:27])[O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>C(O)C>[F:17][C:18]([F:27])([F:28])[O:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:24]=[CH:25][CH:26]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Reactant: Nc1cccc(OC(F)(F)F)c1
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1cccc(OC(F)(F)F)c1
Reaction time: 5 h
Yield: 56.4 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-3-quinolinecarbonitrile, 200 ml ethanol, and 3.4 ml (25.3 mmol) 3-trifluoromethoxyaniline was heated to reflux. At 5 hours, removed heat and made basic with saturated sodium bicarbonate. Stripped solvents, slurried residue with hexane, collected, and washed with water. Dissolved in ethyl acetate, stirred with Darco, filtered, stripped solvent, and dried in vacuo, giving 4.537 g of yellow-orange solid: mass spectrum (electrospray m/e): M+H=374.8.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:19]=[CH:18][C:8]([CH:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][C:11]([OH:13])=O)=[CH:7][CH:6]=1)([OH:3])=[O:2].C1(N)CCCCC1>>[CH2:14]([CH:9]1[C:8]2[C:18](=[CH:19][C:5]([CH2:4][C:1]([OH:3])=[O:2])=[CH:6][CH:7]=2)[C:11](=[O:13])[CH2:10]1)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)CC(CC(=O)O)c1ccc(CC(=O)O)cc1
Solvent: NC1CCCCC1
Product: CC(C)CC1CC(=O)c2cc(CC(=O)O)ccc21

Procedure:
4-carboxymethyl-β-isobutyl-dihydrocinnamic acid is cyclized in a manner analogous to that described in Example 1. The cyclohexylamine salt of the title compound has a M.P. of 140°-142° (from methanol/ether).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:18][CH2:19][C:20]#[N:21].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:19]([CH2:20][NH:21][C:10]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:12])#[N:18]
Reactant: CC(C)CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: N#CCN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CC(NC(=O)OC(C)(C)C)C(=O)NCC#N
Reaction time: 2 h

Procedure:
A solution comprised of 2-tert-butoxycarbonylamino-4-methylvaleric acid (5 g, 30 mmol) in DMF (20 mL) was cooled in an ice bath and then aminoacetonitrile hydrochloride (3 g, 30 mmol), PyBOP® (11.25 g, 21 mmol) and triethylamine (6 mL, 60 mmol) were added sequentially to the solution. The mixture was stirred for 2 hours and then concentrated under vacuum. The residue was partitioned between ethyl acetate (50 mL) and saturated sodium bicarbonate (40 mL). The organic layer was separated, washed with water, 1M hydrochloric acid (20 mL), water and brine, dried (MgSO4) and concentrated under reduced pressure. Product was purified from the residue using a plug of silica with ethyl acetate as the eluant to provide tert-butyl 1-cyanomethylcarbamoyl-3-methylbutylcarbamate.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1([NH2:12])[CH2:9][CH:8]1[CH:10]=[CH2:11])=[O:6])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:37]([N:43]([CH3:55])[C:44]([CH:46]1[CH2:50][CH:49]([OH:51])[CH2:48][CH:47]1[C:52](O)=[O:53])=[O:45])[CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:2]([O:4][C:5]([C:7]1([NH:12][C:52]([CH:47]2[CH2:48][CH:49]([OH:51])[CH2:50][CH:46]2[C:44](=[O:45])[N:43]([CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])[CH3:55])=[O:53])[CH2:9][CH:8]1[CH:10]=[CH2:11])=[O:6])[CH3:3]
Reactant: C=CC1CC1(N)C(=O)OCC
Reactant: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
1-(Amino)-2-(vinyl)cyclopropanecarboxylic acid ethyl ester hydrochloride (4.92 g, 31.7 mmol) and HATU (12.6 g, 33.2 mmol) were added to the acid (142) (8.14 g, 30.2 mmol). The mixture was cooled in an ice bath under argon, and then DMF (100 mL) and DIPEA (12.5 mL, 11.5 mmol) were added. After 30 min at 0° C., the solution was stirred at room temperature for an additional 3 h. Then, the reaction mixture was partitioned between EtOAc and water, washed successively with 0.5 N HCl (20 mL) and saturated NaCl (2×20 mL), and dried (Na2SO4). Purification by flash chromatography (EtOAc/CH2Cl2/Petroleum ether, 1:1:1) afforded the title compound (7.41, g 60%) as a colorless oil, m/z=407 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH-].[Na+]>>[CH3:1][C:2]1[CH:11]=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CC(=O)Nc1cc(C)nc2ccccc12
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1cc(C)nc2c1CCCC2
Yield: 78.6 %

Procedure:
Reaction of N-(2-methyl-quinolin-4-yl)acetamide (136 mg, 0.679 mmol) using the general procedure for small scale hydrogenations (workup with NaOH in place of saturated NaHCO3) provided N-(2-methyl-5,6,7,8-tetrahydroquinolin-4-yl) acetamide (109 mg, 78%): 1H NMR δ 1.83-1.90 (m, 4H), 2.21 (s, 3H), 2.47 (s, 3H), 2.46-2.2.53 (m, 2H), 2.84-2.87 (m, 2H), 7.18 (br s, 1H), 7.82 (br s, 1H); 13C NMR δ 22.7, 22.8, 23.5, 24.6, 25.3, 33.1, 112.3, 117.3, 143.7, 156.4, 157.3, 169.0; MS m/z: 205 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][N:21]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24][CH:23]=1>>[N:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][N:21]=2)[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[O:6])[CH:25]=[N:24][CH:23]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccnc(Br)c1
Reactant: OB(O)c1cncnc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccnc(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 69 using 2-bromo-N-(4-(trifluoromethoxy)phenyl)isonicotinamide and 5-pyrimidine boronic acid to afford a grey solid. UPLC-MS (Condition 1) tR2.31 min, m/z=361.0 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.43 (d, J=8.56 Hz, 2H) 7.92 (d, J=9.29 Hz, 3H) 8.58 (s, 1H) 8.96 (d, J=5.14 Hz, 1H) 9.31 (s, 1H) 9.53 (s, 2H) 10.74 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5](C(O)=O)[CH:4]=[N:3]1.CC(O)(C)C.CC[N:24](C(C)C)C(C)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCOCC1>[CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([NH2:24])[CH:4]=[N:3]1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cn1ncc(C(=O)O)c1Oc1ccccc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: Cn1ncc(N)c1Oc1ccccc1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a stirred mixture of 1-Methyl-5-phenoxy-1H-pyrazole-4-carboxylic acid (16.00 g; 73.32 mmol), t-BuOH (51.20 g; 690.77 mmol) in 1,4-dioxane under argon was added DIPEA (37.44 g; 289.69 mmol) and Diphenylphosphoryl azide (41.60 g; 151.16 mmol). After 10 minutes at ambient temperature it was heated up to 110° C. and stirred there for 3 hours. The solvent was evaporated and the crude material purified by column chromatography. This compound was dissolved in DCM and treated with 4 M HCl in 1,4-dioxane. It was stirred for 2 days at ambient temperature. The solvent was evaporated and the residue dissolved in water and washed with EtOAc. The aqueous layer was basified with NaHCO3 solution and extracted with EtOAc. The organic layer was dried and concentrated to dryness.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:75]=[CH:74][CH:73]=[C:72]3[C:68]=2[CH:69]=[CH:70][N:71]3[CH3:76])[C:56]=1[CH3:77].CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:75]=[CH:74][CH:73]=[C:72]5[C:68]=4[CH:69]=[CH:70][N:71]5[CH3:76])[C:56]=3[CH3:77])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2cccc3c2ccn3C)nc2cc(F)cc(F)c2c1Cl
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(-c2cccc3c2ccn3C)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.020 g, 0.042 mmol), 2,5-dimorpholinopyridin-3-amine (0.083 g, 0.32 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(1-methyl-1H-indol-4-yl)quinoline (0.090 g, 0.26 mmol), Pd2dba3 (9.62 mg, 10.50 mmol) and sodium tert-butoxide (0.068 g, 0.71 mmol) in toluene (2.6 mL) at 120° C. for 3.5 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(1-methyl-1H-indol-4-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 7.79 (3H, d, J=11.5 Hz), 7.65 (1H, m), 7.63 (1H, d, J=2.7 Hz), 7.45 (1H, d, J=8.2 Hz), 7.38 (1H, app t, J=8.2 Hz), 7.22 (1H, d, J=0.6 Hz), 7.09 (1H, d, J=3.1 Hz), 7.02 (3H, ddd, J=13.5, 8.6, 2.5 Hz), 6.41 (1H, d, J=2.3 Hz), 6.25 (1H, d, J=3.1 Hz), 3.93 (4H, br. s), 3.87 (3H, s), 3.84 (4H, m), 3.25 (4H, br. s), −3.07 (4H, br. s.), 2.03 (3H, s). Mass Spectrum (ESI) m/e=571.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.[OH-].[Na+].Br[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].Cl>CN(C)C=O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:21][CH:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:6]=2[N:14]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1CBr
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.4 %

Procedure:
To a solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 50 mg, 0.2 mmol) in N,N-dimethylformamide (0.5 mL) was added powdered sodium hydroxide (12 mg, 0.31 mmol) and tetrabutylammonium hydrogen sulfate (3 mg, 0.009 mmol). The mixture was stirred at room temperature for 30 min then tert-butyl 2-(bromomethyl)pyrrolidine-1-carboxylate (67 mg, 0.25 mmol) was added. The resulting mixture was stirred at room temperature for 4 days. Water (5 ml) was added to the mixture, followed by HCl (3% aqueous, 1 mL). The mixture was extracted with ethyl acetate (3×30 ml). The extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (12 g silica, methylene chloride to 90/10 methylene chloride/methanol gradient) to yield tert-butyl 2-{[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]methyl}pyrrolidine-1-carboxylate (xvi-e, 20 mg, 20%). NH4OAc QC conditions. M+1=410.