Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12][CH2:13][C:14](Br)=[O:15]>CN(C=O)C.O1CCOCC1>[Br:12][CH2:13][C:14]([NH:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:15]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(Br)cc1C(=O)O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(CBr)Nc1ccc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 57 %

Procedure:
To a solution of 2-amino-5-bromobenzoic acid (11.2 g, 0.052 mol) in anhydrous DMF (40 mL) and anhydrous dioxane (40 mL) was added, dropwise, bromoacetyl bromide while keeping the internal temperature between 0° C. and 5° C. After the addition was completed (~25 min), the ice-bath was removed and the mixture was stirred for 20 h at rt. The reaction mixture was cooled in an ice-bath, water was added (100 mL), and then the mixture was poured into ice water. The precipitate which formed was filtered, washed with water, and then dried in a vacuum oven for 20 h at 40°-45° C., affording 9.9 g (57%) of the title compound: mp 203°-204° C.; 1H NMR (CDCl3) δ11.67 (s, 1H, NH), 8.64 (d, 1H, J=8.8), 8.55 (d, 1H, J=2.4), 7.71 (dd, 1H, J=2, J=6.8), 3.72 (s, 2H ); 13C NMR (CDCl3): 200.55, 138.06, 134.22, 134.20, 122.06, 107.46. 67.08; MS (EI, m/z) 337 (M+). HRMS (EI) calcd for C9H7NO3Br2 334.8792, found 334.8791.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH2:34]([O:36][C:37](=[O:42])[CH2:38][CH2:39][CH2:40][NH2:41])[CH3:35].C(N(CC)CC)C>O1CCCC1>[CH2:34]([O:36][C:37](=[O:42])[CH2:38][CH2:39][CH2:40][NH:41][C:18](=[O:20])[CH2:17][N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH3:35]
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CCOC(=O)CCCN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CCCNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole) and 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hrs. Then, under nitrogen atmosphere, 4-aminobutyric acid ethyl ester hydrochloride (3.19 g, 0.019 mole) and triethylamine (1.92 g, 0.019 mole) were added simultaneously and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated to dryness and the residue was partitioned between methylene chloride and water. The combined methylene chloride layers were extracted with dilute sodium hydroxide, then with water. The methylene chloride layer was separated, dried, and evaporated to dryness (5.3 g) (76% crude yield). A 2-g sample was recrystallized from absolute ethanol, and dried under high vacuum overnight to give 1.47 g, mp. 169°-71° C.
Reaction SMILES: Cl.[CH2:2]([C:9]1[NH:10][NH:11][C:12]2[CH:18]=[CH:17][N:16]=[CH:15][C:13]=2[N:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:19]([Cl:29])(=[O:28])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[ClH:29].[CH2:2]([C:9]1[NH:10][N:11]([C:19](=[O:28])[CH:20]=[CH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:12]2[CH:18]=[CH:17][N:16]=[CH:15][C:13]=2[N:14]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: c1ccc(CC2=Nc3cnccc3NN2)cc1
Agent: Cl
Product: O=C(C=Cc1ccccc1)N1NC(Cc2ccccc2)=Nc2cnccc21
Yield: 78 %

Procedure:
3-Benzyl-1,2-dihydropyrido[3,4-e]-as-triazine hydrochloride is reacted with cinnamoyl chloride as described in Example 1 to obtain 3-benzyl-1-cinnamoyl-1,2-dihydropyrido[3,4-e]-as-triazine hydrochloride with a yield of 78%; m.p.: 228° 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: N#CCC(N)=O
Reactant: O=Cc1cc(F)ccc1[N+](=O)[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 2 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: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.Cl.[OH:12][C:13]1[C:14]([CH:29]([CH3:32])[CH:30]=[CH2:31])=[CH:15][C:16]([CH3:28])=[C:17]2[C:25]=1[CH:24]([NH:26][CH3:27])[CH:23]1[CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]1>O>[OH:12][C:13]1[C:14]([CH:29]([CH3:32])[CH:30]=[CH2:31])=[CH:15][C:16]([CH3:28])=[C:17]2[C:25]=1[CH:24]([N:26]([CH3:27])[CH:8]=[O:10])[CH:23]1[CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: C=CC(C)c1cc(C)c2c(c1O)C(NC)C1CCCCC21
Reactant: O=CO
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: C=CC(C)c1cc(C)c2c(c1O)C(N(C)C=O)C1CCCCC21
Reaction time: 15 h

Procedure:
2.0 Milliliters of acetic anhydride and 1.0 ml of 98% formic acid were mixed and the mixture was stirred under heating for 2 hours and left to stand of cooling. To the resulting solution were added 3.0 g of 8-hydroxy-5-methyl-9-methylamino-7-(1-methyl-2-propenyl)-1,2,3,4,4a,9a-hexahydrofluorene hydrochloride and 10 ml of acetic anhydride and reaction was carried out at 60° C. for 2 hours and at room temperature for 15 hours. To the reaction mixture was added water and the separated solid was collected by filtration, washed with water and once dissolved in chloroform and the solution was dried with magnesium sulfate. The solvent was distilled off and the residue was recrystallized from ethanol to obtain 1.42 g of 8-hydroxy-5-methyl-9-(N-methyl-N-formylamino)-7-(1-methyl-2-propenyl)-1,2,3,4,4a,9a-hexahydrofluorene.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:17]([OH:19])=[O:18])=[CH:8][N:9]2[CH:14]2[CH2:16][CH2:15]2)=[CH:4][C:3]=1[F:21].[C@H:22]12[CH2:30][NH:29][CH2:28][C@@H:27]1[NH:26][CH2:25][CH2:24][O:23]2.C(N(CC)CC)C>C(#N)C>[C:12]([C:11]1[C:2]([C@:22]23[CH2:30][NH:29][CH2:28][C@@H:27]2[NH:26][CH2:25][CH2:24][O:23]3)=[C:3]([F:21])[CH:4]=[C:5]2[C:10]=1[N:9]([CH:14]1[CH2:16][CH2:15]1)[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:6]2=[O:20])#[N:13]
Reactant: C1CO[C@H]2CNC[C@@H]2N1
Reactant: N#Cc1c(Cl)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1c([C@]23CNC[C@@H]2NCCO3)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
1.00 g (3.26 mmol) of 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid are stirred under argon at 40-45° C. for 25 hours with 501 mg (3.91 mmol) of (1S,6S)-2-oxa-5,8-diazabicyclo[4.3.0]nonane and 0.9 ml of triethylamine in 30 ml of acetonitrile. All volatile components are removed in vacuo and the residue is recrystallized from ethanol.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:15])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[Br:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19](F)[CH:18]=1.CCN(C(C)C)C(C)C>CC(O)C>[Br:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:1][CH2:2][CH:3]([OH:15])[CH2:4][N:5]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)[CH:18]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: Fc1cc(Br)ccn1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: OC(CNc1cc(Br)ccn1)CN1CCc2ccccc2C1
Temperature: 100 °C
Reaction time: 26 h
Yield: 58.3 %

Procedure:
A mixture of 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (14.0 g, 67.9 mmol), 4-bromo-2-fluoropyridine (10.0 g, 56.8 mmol) and DIPEA (11.0 g, 85.3 mmol) in i-PrOH (35 mL) were combined in a sealed tube and stirred at 100° C. for 26 h. The reaction mixture was then concentrated and the residue purified by column chromatography to give the desired product (12.0 g, 58.5%). LCMS (m/z): 362.0/364.0 [M+H]+/[M+2+H]+
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:39]=[C:38]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:27][CH2:28]2)=[O:22])[CH:37]=[CH:36][CH:35]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(C)(=O)=O)CC2)n3-c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 108 h
Yield: 42.7 %

Procedure:
A suspension of 0.20 g (0.43 mmol) [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone (example 1), 0.20 g (1.30 mmol) 3-chlorophenylboronic acid, 0.16 g (0.86 mmol) copper(II) acetate and 0.14 mL (0.14 g, 1.73 mmol) pyridine in 5 mL chloroform was stirred 4.5 days at room temperature. The volatile components were evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel with a gradient of dichloromethane:methanol (100:0 to 75:25 v/v) as eluant to afford 105 mg (42%) of the desired compound as a light-brown foam. MS (ISP): 572.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-])=O)[CH2:9][C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.[Cl:25]C1C=C2N(C3C=CC=CC=3[N+]([O-])=O)CC3(CCN(/C(/C([O-])=O)=C/C([O-])=O)CC3)C2=CC=1.C(O)C.Cl>[Fe].O>[ClH:1].[ClH:25].[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:8]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=2)[C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9]1
Reactant: O=[N+]([O-])c1ccccc1N1CC2(CCNCC2)c2ccc(Cl)cc21
Reactant: O=C([O-])/C=C(\C(=O)[O-])N1CCC2(CC1)CN(c1ccccc1[N+](=O)[O-])c1cc(Cl)ccc12
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccccc1N1CC2(CCNCC2)c2ccc(Cl)cc21

Procedure:
A mixture of 2.1 g of 6-chloro-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine], free base of Example 33, 95 ml of 95% ethyl alcohol, 7.5 ml of water and 4.4 g of iron powder is acidified with 0.2 ml of concentrated hydrochloric acid and then refluxed under nitrogen for 10 minutes. Thereafter, the mixture is permitted to cool before being filtered through celite. The filtrate is concentrated under vacuum leaving an oily residue which is basified. The alkaline mixture is extracted with ether and then dried. The product is converted to a solid dihydrochloric acid salt which is recrystallized from a methyl alcohol-ether mixture to provide off-white prisms, mp 270°-273° C. (after darkening) of 1-(2-aminophenyl)-6-chlorospiro[indoline-3,4'-piperidine]dihydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([NH2:6])=[C:4]([O:12][CH3:13])[CH:3]=1.C(=O)([O-])O.[Na+].[C:19](Cl)(=[O:21])[CH3:20].O>O1CCCC1>[Cl:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([NH:6][C:19](=[O:21])[CH3:20])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(Cl)c([N+](=O)[O-])cc1N
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cl)c([N+](=O)[O-])cc1NC(C)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 4-chloro-2-methoxy-5-nitroaniline (0.3 g) and sodium hydrogen carbonate (0.37 g) in tetrahydrofuran (4.5 mL) was added acetyl chloride (0.12 mL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=3/7) to give N-(4-chloro-2-methoxy-5-nitrophenyl)acetamide (0.24 g). This material was dissolved in N,N-dimethylformamide (5 mL). To the solution were added 2,3-difluoro-6-methoxybenzyl bromide (0.28 g) and sodium hydride (55%, 48 mg) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (4 mL). To the solution were added methanol (4 mL) and nickel(II) bromide (11 mg). To the mixture was added sodium borohydride (0.11 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=3/7) to give the title compound (0.27 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12]C)=[O:11])=[N:8][CH:9]=1)[CH3:2].[OH-].[Na+].Cl>CO.O>[CH2:14]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1)[CH3:15]
Reactant: CCN(CC)c1ccc(C(=O)OC)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCN(CC)c1ccc(C(=O)O)nc1
Temperature: 25 °C

Procedure:
To a stirred solution containing 2.5 g of methyl 5-diethylaminopicolinate in 40 ml methanol is added 40 ml water and 1.04 g of a 50% solution of NaOH in water. The mixture is heated to reflux and allowed to cool to room temperature. This is repeated. The base is neutralized with concentrated HCl, and the solvents removed in vacuo. The residue is dried azeotropically with dioxane. The residue is taken extracted into ethanol. Concentration of the ethanol gives 5-diethylaminopicolinic acid as a white crystalline solid, mp 145.5°-147.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]#[N:21])[CH:14]=2)[NH:9]1.[CH3:22][CH:23]([S:25](Cl)(=[O:27])=[O:26])[CH3:24]>N1C=CC=CC=1.O>[C:20]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:25]([CH:23]([CH3:24])[CH3:22])(=[O:27])=[O:26])[CH2:17][C:16]2([CH3:18])[CH3:19])#[N:21]
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(C#N)cc21
Reactant: CC(C)S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)S(=O)(=O)Nc1ccccc1C1CC(C)(C)c2cc(C#N)ccc2N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(2-aminophenyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile (500 mg, 1.8 mmol) in pyridine (3 mL) was added propane-2-sulfonyl chloride (201 μL, 1.8 mmol) at ice-bath under nitrogen. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, concentrated. The residue was purified by HPLC to give propane-2-sulfonic acid [2-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide LC/MS m/e obsd. (ESI+) [(M+H)+] 384.3.
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:20]([NH:22][C:23]1[S:24][C:25]([C:28]([OH:30])=O)=[CH:26][N:27]=1)=[O:21].[CH2:31]1[C:39]2[C:34](=[CH:35]C=CC=2)[CH2:33][N:32]1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH3:33][CH:34]([CH3:35])[CH2:39][CH2:31][NH:32][C:28]([C:25]1[S:24][C:23]([NH:22][C:20]([N:12]2[CH2:11][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:21])=[N:27][CH:26]=1)=[O:30]
Reactant: O=C(O)c1cnc(NC(=O)N2Cc3ccccc3C2)s1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Agent: NCCCc1ccccc1
Product: CC(C)CCNC(=O)c1cnc(NC(=O)N2Cc3ccccc3C2)s1

Procedure:
The title compound was prepared as described in Example 1C, substituting 3-methylbutan-1-amine for 3-phenylpropan-1-amine and 2-(isoindoline-2-carboxamido)thiazole-5-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.01-11.16 (bs, 1H), 8.27 (t, J=5.6 Hz, 1H), 7.96 (s, 1H), 7.29-7.36 (m, 4H), 4.73-4.88 (bs, 4H), 3.18-3.28 (m, 2H), 1.52-1.69 (m, 1H), 1.34-1.44 (m, 2H), 0.90 (d, J=6.6 Hz, 6H); MS (ESI(−)) m/e 357 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12][Si](C(C)(C)C)(C)C)[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[C@H:31]1[CH2:36][CH2:35][C@H:34]([NH:37][C:38]2[N:43]=[CH:42][C:41](Br)=[CH:40][N:39]=2)[CH2:33][CH2:32]1)(=O)=O>CN1C(=O)CCC1.CCOC(C)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12][C@@H:31]2[CH2:36][CH2:35][C@H:34]([NH:37][C:38]3[N:39]=[CH:40][CH:41]=[CH:42][N:43]=3)[CH2:33][CH2:32]2)[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Br)cc2nccnc12
Reactant: CS(=O)(=O)O[C@H]1CC[C@H](Nc2ncc(Br)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Brc1cc(O[C@H]2CC[C@@H](Nc3ncccn3)CC2)c2nccnc2c1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
As shown in step 8-i of Scheme 8, to a mixture of 7-bromoquinoxalin-5-ol (compound 1018, 200 mg, 0.89 mmol) and cesium carbonate (579 mg, 1.78 mmol) in NMP (4.0 mL) was added (trans)-4-(pyrimidin-2-ylamino)cyclohexyl methanesulfonate (compound 1014, 241.1 mg, 0.8887 mmol). The mixture was stirred for 18 hours at 90° C., at which time an additional 0.5 eq of compound 1014 (241 mg, 0.89 mmol) was added. After stirring at 90° C. for an additional 6 hours, the reaction mixture was diluted with EtOAc, washed with H2O, dried over Na2SO4, concentrated, and purified by medium pressure silica gel chromatography (0-5% MeOH/DCM) to provide N-((cis)-4-((7-bromoquinoxalin-5-yl)oxy)cyclohexyl)pyrimidin-2-amine (compound 1025): 1H-NMR (300 MHz, CDCl3) δ 9.01-8.77 (m, 2H), 8.29 (d, J=4.8 Hz, 2H), 7.89 (d, J=1.9 Hz, 1H), 7.25 (d, J=2.0 Hz, 1H), 6.53 (t, J=4.8 Hz, 1H), 5.43-5.22 (m, 1H), 4.79 (td, J=5.2, 2.5 Hz, 1H), 4.18-3.95 (m, 1H), 3.51 (s, 1H), 2.22 (td, J=10.2, 9.6, 5.4 Hz, 2H), 2.09-1.86 (m, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=O)[CH2:10][CH2:11][O:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][O:18][NH2:19]>N1C=CC=CC=1>[CH3:17][O:18][N:19]=[C:9]1[C:8]2[C:13](=[CH:14][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[O:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)c1ccc2c(c1)OCCC2=O
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CCOc2cc(C(C)(C)C)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.8 %

Procedure:
The product of Example 1A (1.50 g, 7.3 mmol) and methoxyamine hydrochloride (0.69 g, 8 mmol) were dissolved in 7 mL of pyridine. The reaction mixture was stirred at ambient temperature for 16 hours, and the pyridine removed under reduced pressure. The residue was taken in diethyl ether and sequentially washed with water and 1N aqueous hydrochloric acid. The isolated organic layer was then dried with magnesium sulfate, filtered and the solvent removed under reduced pressure to give 1.53 g of the title compound, which was used without further purification. MS (DCI) m/e 234 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[CH2:8]Br)#[N:2].[CH3:12][NH:13][CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[CH2:8][N:13]([CH3:12])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])#[N:2]
Reactant: N#Cc1ccc(F)c(CBr)c1
Reactant: CNCCC(=O)OC(C)(C)C
Product: CN(CCC(=O)OC(C)(C)C)Cc1cc(C#N)ccc1F

Procedure:
The title compound was prepared following the general procedure 10 starting from 5-cyano-2-fluorobenzylbromide (1.5 g, 7.0 mmol) and tert-butyl N-methyl-beta-alaninate (1.3 g, 8.4 mmol, prepared as described in Biorg. Med. Chem. (11) 2003, 3083-3099). It was isolated as a pale yellow oil (1.9 g, 92%). 1H NMR (CDCl3, 300 MHz) δ 7.79 (dd, J=6.7, 2.1 Hz, 1H), 7.57-7.52 (m, 1H), 7.11 (m, 1H), 3.57 (s, 2H), 2.74 (t, J=7.1 Hz, 2H), 2.43 (t, J=7.1 Hz, 2H), 2.22 (s, 3H), 1.45 (s, 9H). LC/MS (Method B): 293.2 (M+H)+. HPLC (Method A) Rt 2.44 min (Purity: 86.4%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH:23]2[CH2:25][CH2:24]2)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[CH3:22])=[O:4].[OH-].[K+]>C(O)C.O>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH3:22])[CH:10]=1)[N:7]=[C:6]([CH:23]1[CH2:25][CH2:24]1)[C:5]([C:3]([OH:4])=[O:2])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1c(C2CC2)nc2c(C)cc(Cl)cc2c1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(Cl)cc2c(-c3ccccc3)c(C(=O)O)c(C3CC3)nc12

Procedure:
The title compound was prepared in analogy to example 6 step B from a mixture of 6-chloro-2-cyclopropyl-8-methyl-4-phenyl-quinoline-3-carboxylic acid methyl ester and KOH in a mixture of ethanol/water. White solid. MS (ESI): 338.2 (M+H)+.
Reaction SMILES: [N+:1](=[CH2:3])=[N-].[CH:4](=[C:11]1[NH:15][C:14](=[O:16])[C:13]([N+:17]([O-:19])=[O:18])=[C:12]1O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CN>CCOCC.CO>[CH:4](=[C:11]1[NH:15][C:14](=[O:16])[C:13]([N+:17]([O-:19])=[O:18])=[C:12]1[NH:1][CH3:3])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C=[N+]=[N-]
Reactant: O=C1NC(=Cc2ccccc2)C(O)=C1[N+](=O)[O-]
Agent: CN
Solvent: CCOCC
Solvent: CO
Product: CNC1=C([N+](=O)[O-])C(=O)NC1=Cc1ccccc1
Yield: 45 %

Procedure:
An excess of diazomethane in ether is added to a suspension of 0.46 g (2 mmol) benzylidene-4-hydroxy-3-nitro-3-pyrrolin-2-one (prepared by the method of H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, vol. 331, pp. 389-394) and Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in 20 ml methanol. When the evolution of nitrogen has subsided, the solvent is stripped off, the residue is dissolved in methanol and the solution is heated under reflux with an excess of methylamine solution for five minutes, whereupon yellow crystals precipitate out, which are filtered off with suction and washed with methanol. 5-Benzylidene-4-methylamino-3-nitro-1,5-dihydropyrrol-2-one was obtained with a melting point of 238° C. in a yield of 45%.
Reaction SMILES: C[N:2](/[CH:4]=[CH:5]/[C:6]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=O)C.O.[NH2:18]N>C(O)C>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][NH:2][N:18]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: CN(C)/C=C/C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(-c2cc[nH]n2)cc1
Yield: 78.9 %

Procedure:
A solution of 1-(4-nitrophenyl)-3-N,N-dimethylamino-2-propen-1-one (27.3 g) and 85% hydrazine hydrate (23.6 g) in ethanol was heated at 60° C. for one hour. The crystallized solid was filtered to give 18.5 g of 3-(4-nitrophenyl)-pyrazole; M.p. 196°-197° C.