Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[C:13](#N)[CH3:14].Cl.OO>O.[Fe].C1CCCCC1>[CH:14]1([O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]2([CH3:12])[CH3:11])[CH2:13][CH2:5][CH2:4][CH2:3][CH2:11]1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: CC#N
Agent: [Fe]
Agent: Cl
Agent: OO
Solvent: C1CCCCC1
Solvent: O
Product: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Yield: 75 %

Procedure:
Nanosized activated iron powder in mineral oil (0.042 g) is rinsed successively with two 2 ml portions of cyclohexane. Most of the solvent is removed with a pipette. The iron is added to a mixture of 5.00 g (29.0 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidin-4-ol, 44 ml of acetonitrile, and 32 ml of cyclohexane that has been heated to 40 degrees. To this mixture is carefully added over several minutes a solution of 0.548 g of concentrated hydrochloric acid in 3 ml of water. The reaction temperature is brought to reflux and a solution of 7.81 g (115 mmol) of 50% aqueous hydrogen peroxide is added dropwise over a period of 2.25 hours. After about one-half of the peroxide solution is added, a second portion of nanosized activated iron powder in mineral oil (0.039 g), rinsed twice with cyclohexane, and a solution of 0.166 g of concentrated hydrochloric acid in 1 ml of water are added to the reaction mixture. The reaction mixture is heated at 60-62 degrees for 1.5 hours after the peroxide has been added. After work up and purification according to the procedure of Example 54, the yield of the title compound is 5.53 g (75% yield), GC assay 96%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])/[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].[CH:10]1([NH:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:9])[CH2:4][C@@H:5]([C:6]([OH:8])=[O:7])[NH:20][CH2:19][CH2:18][CH2:17][NH:16][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COC(=O)/C=C\C(=O)O
Reactant: NCCCNC1CCCCC1
Solvent: CCN(CC)CC
Product: COC(=O)C[C@H](NCCCNC1CCCCC1)C(=O)O
Temperature: 0 °C

Procedure:
356 g (3.4 mols+14% excess) of maleic acid monomethyl ester are placed into a glass flask provided with stirrer, thermometer, condenser and dropping funnel, and, with vigorous stirring and ice-water cooling, 480 ml of triethylamine are added dropwise at 5°-8° C. internal temperature within 2 hours. 372.6 g (2.4 mols) of 3-cyclohexylaminopropylamine are then quickly introduced; the exothermic reaction is subsequently allowed to subside, and the reaction mixture is heated within 30 minutes to 85° C., in the course of which the reaction product crystallises out. After the reaction has finished, the temperature is lowered to room temperature; the product is mixed with 1100 ml of acetone and is filtered off; the filter residue is again mixed with 900 ml of acetone, and the suspension is filtered; the filter residue is then washed with acetone, and the product is dried at 60° C. and 53.2 mbars. The yield is 555.4 g (87.2% of theory) of a white crystalline aspartic acid derivative, which decomposes at 163° C.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15]C(C)(C)C)=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[O:22]1[CH2:27][CH2:26][CH:25]([CH2:28]C(O)=O)[CH2:24][CH2:23]1.C(O[C:40]([N:42]1[CH2:45][CH:44]([C:46]([OH:48])=O)[CH2:43]1)=O)C1C=CC=CC=1>>[N:10]1[CH:9]=[CH:8][CH:7]=[C:40]([N:42]2[CH2:43][CH:44]([C:46]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][CH:7]4[CH2:8][CH2:9][N:10]([C:13](=[O:15])[CH2:28][CH:25]5[CH2:24][CH2:23][O:22][CH2:27][CH2:26]5)[CH2:11][CH2:12]4)=[CH:20][CH:21]=3)=[O:48])[CH2:45]2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Reactant: O=C(O)CC1CCOCC1
Product: O=C(Nc1ccc(OC2CCN(C(=O)CC3CCOCC3)CC2)cc1)C1CN(c2cccnc2)C1

Procedure:
The title compound was prepared as described in Example 1A, substituting N-(4-(piperidin-4-yloxy)phenyl)-1-(pyridin-3-yl)azetidine-3-carboxamide for tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate and 2-(tetrahydro-2H-pyran-4-yl)acetic acid for 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.95 (bs, 1H), 7.93 (d, J=4.2 Hz, 1H), 7.88-7.83 (m, 1H), 7.55-7.47 (m, 2H), 7.26-7.08 (m, 1H), 7.01-6.78 (m, 3H), 4.14-4.04 (m, 2H), 4.02-3.62 (m, 6H), 2.37-1.73 (m, 6H), 1.66-1.00 (m, 8H); MS (ESI(+)) m/e 479 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[S:29][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:31][N:32]=1>>[S:33]([C:30]1[S:29][C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:25])([F:1])[F:26])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])=[N:32][CH:31]=1)(=[O:35])(=[O:34])[NH2:36]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1ncc(S(N)(=O)=O)s1
Product: NS(=O)(=O)c1cnc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 2-amino-thiazole-5-sulfonic acid amide [CAS-No. 63735-95-5] according to general procedure II. Yellow solid. MS (ISP) 535.2 [(M−H)−]; mp 309° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@@H:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+].[NH2:29]O.Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@@H:13]([C:15]3[O:22][NH:29][C:17](=[O:18])[CH:16]=3)[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(F)c(F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(F)c(F)c1
Temperature: -40 °C
Reaction time: 0.67 h
Yield: 71.2 %

Procedure:
Cis-methyl 2-(3,4-difluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (5.23 g, 14.16 mmol) was dissolved in MeOH (50 mL) and cooled to −40° C. Sodium hydroxide (3.73 mL, 14.16 mmol) dissolved in water (5.00 mL) was added and the reaction stirred at −40° C. for 40 min. Hydroxylamine (0.868 mL, 14.16 mmol) was added and stirring continued for 3.5 h at −40° C. The reaction mixture was then added to a prewarmed 80° C. solution of 6 M hydrogen chloride (73.2 mL, 438.95 mmol) and stirred for 20 min. The solvent was concentrated in vacuo. DCM (200 mL) and water (150 mL) were added, shaken and the phases separated. The aqueous phase was extracted with DCM (150 mL). The combined organic phases were dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 20-60% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Cis-methyl 2-(3,4-difluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (3.41 g, 71.2%) was isolated as a white solid. 1H NMR (600 MHz, CDCl3) δ 1.81-1.88 (m, 1H), 2.08-2.18 (m, 1H), 2.19-2.28 (m, 1H), 2.30-2.38 (m, 1H), 3.02-3.11 (m, 1H), 3.32-3.40 (m, 1H), 3.67 (s, 3H), 4.09-4.18 (m, 1H), 5.02-5.08 (m, 1H), 5.56 (s, 1H), 6.86-6.92 (m, 1H), 6.95-7.01 (m, 1H), 7.03-7.10 (m, 1H). MS m/z 339 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:21])[C:19]=1[CH3:20].[CH:22]1([O:27][C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=2[O:36][CH3:37])[CH:31]=[O:32])[CH2:26][CH2:25][CH2:24][CH2:23]1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH:22]1([O:27][C:28]2[CH:29]=[C:30]([CH:31]([OH:32])[CH2:20][C:19]3[C:18]([Cl:21])=[CH:17][N:16]=[CH:15][C:14]=3[Cl:13])[CH:33]=[CH:34][C:35]=2[O:36][CH3:37])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COc1ccc(C(O)Cc2c(Cl)cncc2Cl)cc1OC1CCCC1
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
A stirred solution of diisopropylamine (9.75 mL) in dry tetrahydrofuran (200 mL) at -70° C. is treated dropwise with a solution of butyl lithium in hexane (27.2 mL; 2.5M) and the solution is stirred for 30 minutes. It is then treated with a solution of 3,5-dichloro-4-methylpyridine (10.25 g) in dry tetrahydrofuran (60 mL) during 30 minutes, while keeping the temperature below -75° C., and the solution is then stirred for a further 30 minutes. It is then treated with 3-cyclopentyloxy-4-methoxybenzaldehyde (13.92 g) in dry tetrahydrofuran (60 mL) during 15 minutes, and stirred for a further 1 hour 30 minutes at -75° C. The solution is treated with aqueous ammonium chloride solution and extracted with ethyl acetate (3×100 mL). The organic layers are combined, washed with brine, dried and concentrated to low volume. The resulting precipitate is filtered off, to give 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(3,5-dichloropyrid-4-yl)ethanol (20.5 g), m.p. 124-125° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10](Cl)(Cl)[CH:11]([OH:13])O.Cl.[NH2:17][OH:18].S([O-])([O-])(=O)=O.[Na+].[Na+].Cl>O>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:11](=[O:13])[CH:10]=[N:17][OH:18])[CH:6]=[CH:7][CH:8]=1
Reactant: NO
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: Nc1cccc(Br)c1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(C=NO)Nc1cccc(Br)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a 3000 mL round bottom flask, 3-bromoaniline (50 g, 0.2907 mol), water (1500 mL), chloral hydrate (57.7 g, 0.3488 mol), hydroxylamine hydrochloride (64.6 g, 0.9302 mol) and sodium sulphate (250 g) were added. To this reaction mixture was slowly added concentrated HCl (76 mL). The reaction mixture was stirred at 90° C. for 2 hours. The white precipitate was formed and was collected by filtration. The white solid was dried to provide the title compound [60 g, 85%]. 1H NMR (300 MHz, DMSO-d6): δ 12.28 (s, 1H), 10.38 (s, 1H), 8.03 (t, J=1.5 Hz, 1H), 7.62-7.65 (m, 2H), 7.29-7.31 (m, 2H). LC-MS (ESI): Calculated mass: 242.0; Observed mass [M+H]+: 243.0 (RT: 0.17 min).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2Cl)[CH2:5][CH2:4]1.[CH3:26][NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1.CC#N>O>[F:1][C:2]([F:25])([F:24])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[N:27]([CH3:26])[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:5][CH2:4]1
Reactant: CNc1cc(Cl)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Reactant: CNCc1ccc(F)cc1
Solvent: CC#N
Solvent: O
Product: CNc1cc(N(C)Cc2ccc(F)cc2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-2-chloro-4-methylamino-5-nitro-benzoic acid amide (60 mg, 0.158 mmol), N-methyl-N-(4-fluorobenzyl)amine (24 μL, 0.18 mmol) and MeCN (1 mL) is irradiated in a microwave oven for 45 min at 160° C., and after cooling diluted with water. The mixture is extracted with EtOAc, the combined organic phases are dried with Na2SO4, filtered and concentrated and directly used in the next step. Yield: 80 mg.
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[C:49]([O:55][CH3:56])[C:9]=1/[CH:10]=[CH:11]/[CH:12]([S:22]([CH:25](/[CH:35]=[CH:36]/[C:37]1[C:42]([O:43][CH3:44])=[CH:41][C:40]([O:45][CH3:46])=[CH:39][C:38]=1[O:47][CH3:48])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([NH2:34])[CH:27]=1)(=[O:24])=[O:23])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([NH2:21])[CH:14]=1>>[CH3:56][O:55][C:49]1[CH:50]=[C:51]([O:53][CH3:54])[CH:52]=[C:8]([O:7][CH3:6])[C:9]=1/[CH:10]=[CH:11]/[CH:12]([S:22]([CH:25](/[CH:35]=[CH:36]/[C:37]1[C:38]([O:47][CH3:48])=[CH:39][C:40]([O:45][CH3:46])=[CH:41][C:42]=1[O:43][CH3:44])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([NH:34][C:3]([O:2][CH3:1])=[O:4])[CH:27]=1)(=[O:24])=[O:23])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([NH:21][C:3]([O:2][CH3:1])=[O:4])[CH:14]=1
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(N)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Reactant: COC(=O)Cl
Product: COC(=O)Nc1cc(C(/C=C/c2c(OC)cc(OC)cc2OC)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)OC)c2)ccc1OC
Yield: 51 %

Procedure:
A solution of methylchloroformate (10 mmol) and (E)-2,4,6-trimethoxy styryl-3-amino-4-methoxybenzylsulfone (10 mmol) was reacted according to General Method A. The product obtained was purified by recrystallization from 2-propanol. (yield 51%, m.p. 188-191° C.)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14].N1C=CC=CC=1.O1CCCC1>ClCCl>[CH:7]1[C:8]2[C:3](=[C:2]([NH:1][C:13](=[O:14])[O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cccc2cnccc12
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Nc1cccc2cnccc12)Oc1ccccc1
Reaction time: 3 h

Procedure:
To 5-aminoisoquinoline (2.7 g) were added phenyl chloroformate (2.85 ml), pyridine (2.0 ml) and tetrahydrofuran (50 ml), and the mixture was stirred for 3 hrs. The reaction mixture was diluted with dichloromethane, and washed with water and saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. Diethyl ether was added to the residue, and the precipitate was collected by filtration to give the title compound (3 g).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[C:17](OC)(OC)([O:21][CH3:22])[CH2:18][CH2:19][CH3:20]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:17]([O:21][CH3:22])[CH2:18][CH2:19][CH3:20])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: CCCC(OC)(OC)OC
Product: CCCC(OC)=C1C(=O)N(C(C)=O)c2ccc(C(C)=O)cc21

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and trimethyl orthobutyrate
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH2:36]([O:35][C:33]([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][N:9]1[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:12]=[C:8]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:34])[CH3:37]
Reactant: CCOC(=O)CCCCCCCBr
Reactant: CCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Product: CCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)n1CCCCCCCC(=O)OCC
Yield: 84.7 %

Procedure:
2-Heptyl-4,5-diphenylimidazole (1 g) was reacted with ethyl 8-bromooctanoate (1.6 g) in a method similar to Example 9 with a reaction time of 48 hours. Chromatography on silica gel (hexane/ethyl acetate) gave 1-(7-ethoxycarbonyl-heptyl)-2-heptyl-4,5-diphenylimidazole (1.3 g, 87%) as an oil. Found: C, 78.98; H, 9.22; N, 5.76%; C32H44N2O2 requires: C, 78.64; H, 9.08; N, 5.73%;
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12]CC)=O.[NH:15]1C2C(=CC=CC=2)C=C1C(OC)=O.CO.C(Cl)Cl>N(C)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH2:15])=[O:12]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: COC(=O)c1cc2ccccc2[nH]1
Agent: CNC
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: NC(=O)c1cc2ccccc2[nH]1

Procedure:
Stir ethyl indole-2-carboxylate 1 (X═H, 4.67 mmol) or methyl indole-2-carboxylate 2 (X═H, 4.67 mmol) in Me2NH/H2O (50 mL, 40%). Stir the reaction mixture at rt for 16 h monitoring by tlc (10% MeOH/CH2Cl2). Concentrate the mixture to minimum volume, dilute with H2O and collect the solid by filtration. Wash the filter cake with H2O and dry under vacuum at 60° C. to provide dimethyl amide 4 (X═H, R2═R3=Me), tlc Rf=0.65 (silica gel, 10% MeOH/CH2Cl2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N+:17]([O-])[CH:18]=[C:19]([Cl:21])[CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([N:25](CC)CC)C.C[Si](C#N)(C)C.[OH-].[Na+]>C(#N)C.C(OCC)(=O)C>[Cl:21][C:19]1[CH:20]=[C:15]([O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:16]([C:23]#[N:25])=[N:17][CH:18]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(Cl)c[n+]([O-])c1
Agent: C[Si](C)(C)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(Cl)cnc1C#N
Temperature: 80 °C
Reaction time: 15 h
Yield: 58.1 %

Procedure:
To a stirred solution of (R)-3-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-5-chloropyridine 1-oxide (610 mg, 1.855 mmol, EXAMPLE 29 Step 2) and triethylamine (1.56 mL, 11.13 mmol) in acetonitrile was added trimethylsilyl cyanide (TMSCN) (1.24 mL, 9.28 mmol) at ambient temperature and the mixture was heated at 80° C. After being stirred at 80° C. for 15 h, the mixture was cooled to room temperature. 1.24 mL of TMSCN (9.28 mmol) and 1.56 mL of triethylamine (11.13 mmol) were added to the mixture and the mixture was heated at 80° C. further 6 h. After cooling to room temperature, the mixture was concentrated in vacuo to give a dark brown oil. The residual oil was dissolved with ethyl acetate and 2 N aq. sodium hydroxide. The mixture was extracted with ethyl acetate twice and washed with water, 2 N hydrochloric acid, and brine. The extracts were combined and dried over sodium sulfate and concentrated in vacuo to afford an oil. The residual oil was purified by silica gel column chromatography (hexane to ethyl acetate/hexane 1:4) to afford 364 mg (58%) of the title compound as a waxy solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=O.O.C([O-])([O-])=O.[Na+].[Na+].S(Cl)([Cl:25])=O>CN(C)C=O.ClCCl>[Cl:25][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COc1cc2ncnc(Cl)c2cc1OC
Temperature: 25 °C
Yield: 79 %

Procedure:
A 6,7-dimethoxyquinazolin-4(3H)-one suspension (2a) (0.79 g, 3.83 mmol) in thionyl chloride (7.0 mL) containing 10 drops of N,N-dimethylformarnide (DMF) was agitated and heated under reflux for three hours, until a solution was obtained. The reaction mixture was left cooling at room temperature. The reaction environment was diluted in dichloromethane and water (160 mL) and left in ice bath. The material was treated under agitation with 30 mL of saturated Na2CO3 solution. Na2CO3 was carefully added until pH was adjusted to 7-8 range. Then, the aqueous phase was extracted with CH2Cl2 (2×30 mL), and the organic phase compound was washed with salt solution (2×10 mL), dried over magnesium sulfate, filtered, and the solvent was evaporated in a rotatory evaporator in order to provide 6,7-dimethoxy-4-chloroquinazoline (3a) as a yellow solid (0.68 g, 3.03 mmol, 79%), which was used without purification in the next stage: melting point 185-187° C.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:8]=2)[N:3]1[CH2:16][C:17]([OH:19])=O.[Cl:20][C:21]1[C:22]([C:27]2[N:31]=[CH:30][NH:29][N:28]=2)=[C:23]([NH2:26])[S:24][CH:25]=1>>[Cl:20][C:21]1[C:22]([C:27]2[N:31]=[CH:30][NH:29][N:28]=2)=[C:23]([NH:26][C:17](=[O:19])[CH2:16][N:3]2[C:4]3[C:9](=[N:8][C:7]([C:12]([F:13])([F:14])[F:15])=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[S:24][CH:25]=1
Reactant: O=C(O)Cn1c(=O)ccc2nc(C(F)(F)F)ccc21
Reactant: Nc1scc(Cl)c1-c1nc[nH]n1
Product: O=C(Cn1c(=O)ccc2nc(C(F)(F)F)ccc21)Nc1scc(Cl)c1-c1nc[nH]n1

Procedure:
The title compound was prepared from 2-(2-oxo-6-(trifluoromethyl)-1,5-naphthyridin-1(2H)-yl)acetic acid (160 mg, 0.588 mmol) and 4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-amine (59 mg, 0.294) mmol) according to protocol A. Retention time (min)=5.046, method [7], MS (ESI) 455.1 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.30 (d, J=8.9 Hz, 1H), 8.21 (d, J=9.8 Hz, 1H), 8.09 (d, J=8.9 Hz, 1H), 7.20 (s, 1H), 7.13 (d, J=9.8 Hz, 1H), 5.36 (s, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:26][CH2:25][C:15]3([CH:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16]3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:5])C.C1COCC1.CO.O.[OH-].[Li+]>O>[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[CH2:26][CH2:25][C:15]3([CH:17]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16]3)[CH2:14][CH2:13]2)=[CH:10][CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(C2CCC3(CC2)CC3C(=O)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)C1CC12CCC(c1ccc(C(=O)O)cc1)CC2
Reaction time: 16 h
Yield: 83.9 %

Procedure:
0.159 g of tert-butyl 6-(4-ethoxycarbonylphenyl)spiro[2.5]octane-1-carboxylate (0.44 mmol, 1 eq.) is placed in 4 mL of a 3/1 mixture of THF/methanol in a 50 mL round-bottomed flask. 0.075 g of lithium hydroxide monohydrate (1.78 mmol; 4 eq.) dissolved in 1 mL of water is added with stirring. After 16 hours at room temperature, the reaction medium is evaporated and aqueous 6% sulfur dioxide solution is added. The precipitate is filtered off to give 0.122 g of tert-butyl 6-(4-carboxyphenyl)-spiro[2.5]octane-1-carboxylate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][C@@H:12]([CH3:14])[NH:11][CH2:10][C@@H:9]2[CH3:15])[CH:5]=[N:4][CH:3]=1.[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][C@@H:12]([CH3:14])[NH:11][CH2:10][C@@H:9]2[CH3:15])[CH:5]=[N:4][CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCc1ccccc1
Reactant: C[C@@H]1CN(c2cncc(Cl)n2)[C@@H](C)CN1
Product: C[C@@H]1CN(c2cncc(OCc3ccccc3)n2)[C@@H](C)CN1
Temperature: 95 °C

Procedure:
The title compound was prepared according to the procedure of example 20, starting from 1-(6-chloro-2-pyrazinyl)-trans-2,5-dimethylpiperazine (1.23 g, 5.40 mmol; obtained in step 1 above), benzyl alcohol (8.36 g, 77.3 mmol), and K-t-BuO (1.99 g, 17.7 mmol). The reaction mixture was heated at 95° C. for 5.5 h. The yield of the title compound was 0.47 g (29%) which was obtained as an oil. Purity 99% (HPLC). MS m/z 298 (M)+. HRMS m/z calcd for C17H22N4O (M)+ 298.1794, found 298.1798.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[C:6]([N:10]=[N:11][C:12]([C:15]#[N:16])([CH3:14])[CH3:13])([CH3:9])([CH3:8])[CH3:7].O>CO.CCCCC>[C:6]([N:10]=[N:11][C:12]([CH3:14])([CH3:13])[C:15](=[N:2][OH:3])[NH2:16])([CH3:9])([CH3:7])[CH3:8]
Reactant: NO
Reactant: CC(C)(C)N=NC(C)(C)C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCC
Solvent: CO
Solvent: O
Product: CC(C)(C)N=NC(C)(C)C(N)=NO
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.1 %

Procedure:
To a mixture of 8.35 grams (0.12 moles) of hydroxylamine hydrochloride and 9.6 grams (0.12 moles) of 50% NaOH in 110 ml of 90% aqueous methanol in a 250 ml round bottom flask equipped with a magnetic stirrer and condenser was added 15.3 grams (0.1 moles) of 2-t-butylazo-2-cyanopropane (from Example I). The mixture was stirred for 72 hours at room temperature, poured into 400 ml of water and extracted with 100 ml of methylene chloride, the organic layer separated, dried over anhydrous sodium sulfate, filtered and the methylene chloride evaporated under reduced pressure leaving a soft solid. The residue was slurried in 100 ml of pentane to remove any unreacted 2-t-butylazo-2-cyanopropane, filtered and the filter cake air dried. The yield was 12.5 grams (67% yield) of a white solid having a melting point of 105°-109°C (dec.). The infrared spectrum of the product was in agreement with the structure of the desired amidoxime.