Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC=CC=1N1CC[N:12]([C:15]([C:17]2[O:18][C:19]3[C:24]([C:25](=[O:27])[CH:26]=2)=[CH:23][CH:22]=[CH:21][C:20]=3[N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:16])CC1.CN([C:38]([O:42]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.OS1C2C=CC=CC=2N=C1.[N:67]1([C:73]2[CH:79]=[CH:78][C:76](N)=[CH:75][CH:74]=2)[CH2:72][CH2:71][O:70][CH2:69][CH2:68]1>CN(C)C1C=CN=CC=1.CN(C)C=O.C(N(CC)CC)C>[N:67]1([C:73]2[CH:79]=[CH:78][C:76]([NH:12][C:15]([C:17]3[O:18][C:19]4[C:24]([C:25](=[O:27])[CH:26]=3)=[CH:23][C:22]([O:42][CH3:38])=[CH:21][C:20]=4[N:28]3[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]3)=[O:16])=[CH:75][CH:74]=2)[CH2:72][CH2:71][O:70][CH2:69][CH2:68]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COc1ccccc1N1CCN(C(=O)c2cc(=O)c3cccc(N4CCN(C)CC4)c3o2)CC1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: CN(C)c1ccncc1
Agent: F[B-](F)(F)F
Agent: O[SH]1C=Nc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
6-Methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 2) (3.0 g, 8.5 mmol), TBTU (5.5 g, 17 mmol), 1-hydroxybenzothiazole (2.6 g, 17 mmol), 4-dimethylaminopyridine (0.05 g, catalytic) and commercially available 4-morpholin-4-yl-aniline (1.66 g, 9.3 mmol) were dissolved in dimethylformamide (100 mL). Triethylamine (3.5 mL, 25 mmol was added and this mixture stirred at room temperature for 17 hours. The reaction mixture was concentrated under vacuum and the residue was partitioned between chloroform (400 mL) and saturated aqueous sodium bicarbonate (50 mL). The organic layer was separated, dried (Na2SO4), vacuum-filtered and concentrated under vacuum. The residue was purified by chromatography on silica eluted with 2–5% methanol in chloroform and then triturated with ether to yield a yellow powder. (1.6 g=39%) LCMS−m/z=479.5 mp=234–236° C.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=C[CH:8]=1.C1(CC([NH:22][CH:23]2[C:47](=[O:48])[N:25]3[C:26]([C:34]([O:36]CC4C=CC([N+]([O-])=O)=CC=4)=[O:35])=[C:27]([CH2:30]SC=C)[CH2:28][S:29][C@H:24]23)=O)C=CC=CC=1.CO.[C:51](=[O:54])(O)[O-:52].[Na+]>C(Cl)Cl>[CH3:8][C:51]([O:52][CH2:30][C:27]1[CH2:28][S:29][C@@H:24]2[C@H:23]([NH2:22])[C:47](=[O:48])[N:25]2[C:26]=1[C:34]([OH:36])=[O:35])=[O:54]
Reactant: c1ccncc1
Reactant: C=CSCC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Reactant: O=C([O-])O
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 0.33 h

Procedure:
To a suspension of phosphorus pentachloride-pyridine complex (prepared from phosphorus pentachloride (1.31 g) and pyridine (0.508 ml)) in methylene chloride was added p-nitrobenzyl 7-(2-phenylacetamido)-3-vinylthiomethyl-3-cephem-4-carboxylate (1.10 g) at -20° C. The mixture was stirred for 20 minutes under ice-cooling and poured into methanol (20 ml), and then an aqueous solution of sodium bicarbonate (2.1 g) was added thereto. The organic layer was separated at pH 4, washed with water, an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride successively and dried over magnesium sulfate. The inorganic material was filtered off, and to the filtrate was added bis(trimethylsilyl)urea (5.93 g). The mixture was stirred at 30° C. for 15 minutes to give a solution of the silylated 7-aminocephalosporanic acid derivative. On the other hand, phosphorus oxychloride (0.442 g) was added to a solution of N,N-dimethylformamide (0.207 ml) in ethyl acetate (0.65 ml) under ice-cooling. The mixture was stirred at the same temperature for 30 minutes. To the mixture were added 2-(p-nitrobenzyloxycarbonylmethoxyimino)-2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]acetic acid (syn isomer) (1.14 g), methylene chloride (55 ml) and tetrahydrofuran (2 ml) at the same temperature and the mixture was stirred for 30 minutes to give an activated acid solution. This solution was added to the solution of the silylated 7-aminocephalosporanic acid derivative at -20° C. The mixture was stirred at -20°~-10° C. for 30 minutes, poured into ice-water and adjusted to pH 7 with an aqueous solution of sodium bicarbonate. The organic layer was separated, washed with a diluted aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel (25 g) column chromatography using a mixture of chloroform and methanol (50:1) as an eluent to give p-nitrobenzyl 7-[2-(p-nitrobenzyloxycarbonylmethoxyimino)-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3-vinylthiomethyl-3-cephem-4-carboxylate (syn isomer) (1.23 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 90 °C
Yield: 77.3 %

Procedure:
1-Fluoro-4-nitrobenzene (3.0 g, 0.021 mol) and 1-methylpiperazine (6.98 ml, 0.63 mol) were combined and heated neat at 90° C. for 48 h. Upon cooling to RT, the resulting brown oil solidified. The crude material was purified by re-crystallization from EtOAc/Hexane mixtures to leave the title compound as an orange solid (3.59 g). MS: (ES+) 222 (M+1)+; (ES−):220 (M−1)−. Calc'd for C11H15N3O2: 221.12.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCc2ccc(N)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of the crude 7-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (4.5 g, 16.2 mol) and 10% Pd—C (0.45 g) in MeOH (40 mL) was stirred under H2 (1 atm) at room temperature overnight. After filtration, the filtrate was concentrated and the residue was purified by column chromatography (petroleum ether—EtOAc, 5:1) to give tert-butyl 7-amino-3,4-dihydroquinoline-1(2H)-carboxylate (DC-1) as a brown solid (1.2 g, 22% over 2 steps). 1H NMR (CDCl3) δ 7.15 (d, J=2 Hz, 1 H), 6.84 (d, J=8 Hz, 1 H), 6.36-6.38 (m, 1 H), 3.65-3.68 (m, 2 H), 3.10 (br s, 2 H), 2.66 (t, J=6.4 Hz, 2 H), 1.84-1.90 (m, 2 H), 1.52 (s, 9 H); ESI-MS 496.8 m/z (2M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[C:4]=1/[CH:5]=[CH:6]/[S:7]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:22][CH3:23])=[C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])[CH:16]=1)(=[O:9])=[O:8].[OH-].[Na+:33]>C(O)C>[Na+:33].[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[C:4]=1/[CH:5]=[CH:6]/[S:7]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:22][CH3:23])=[C:15]([NH:17][CH2:18][C:19]([O-:21])=[O:20])[CH:16]=1)(=[O:8])=[O:9]
Reactant: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c(NCC(=O)O)c2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c(NCC(=O)[O-])c2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
(E)-2-(5-((2,4,6-Trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)acetic acid (15 g, 0.032 mol) is dissolved in ethanol (150 ml) and 1 N NaOH (1.28 g in 33 ml of water, 0.032 mol) is added, adjusted pH to 7.5-8.0 and stirred at room temperature for 1 h. The reaction is cooled to 0° C., and the precipitated solid is collected by filtration, washed with cold ethanol, and finally with hexane and dried under vacuum to give (E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)acetic acid sodium salt (13 g, 84%).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH2:15][C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]([N:23]([CH3:42])[C:24](=[O:41])[CH2:25][NH:26][C:27](=[O:40])[CH:28]=[CH:29][C:30]4[CH:35]=[CH:34][C:33]([C:36](=[O:39])[NH:37][CH3:38])=[CH:32][CH:31]=4)[C:17]=3Cl)[C:8]=2[N:7]=[C:6]1[CH2:44][CH3:45])(O)=[O:2].[ClH:46].[CH3:47][NH:48][CH3:49].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[Cl:46][C:17]1[C:18]([N:23]([CH3:42])[C:24](=[O:41])[CH2:25][NH:26][C:27](=[O:40])[CH:28]=[CH:29][C:30]2[CH:35]=[CH:34][C:33]([C:36](=[O:39])[NH:37][CH3:38])=[CH:32][CH:31]=2)=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[CH2:15][O:14][C:13]1[C:8]2[N:7]=[C:6]([CH2:44][CH3:45])[N:5]([CH2:4][C:1](=[O:2])[N:48]([CH3:49])[CH3:47])[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CCc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(C(=O)NC)cc4)c3Cl)cccc2n1CC(=O)O
Reactant: CNC
Reactant: Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(C(=O)NC)cc4)c3Cl)cccc2n1CC(=O)N(C)C
Yield: 73.6 %

Procedure:
A solution of 1-carboxymethyl-4-[2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]-benzyloxy]-2-ethyl-1H-benzimidazole (60 mg), dimethylamine hydrochloride (11.2 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (17.1 mg) and 1-hydroxybenzotriazole (18.6 mg) in dimethylformamide (1 ml) was stirred for 1 day at ambient temperature. To the reaction mixture was added water, and the mixture was extracted with chloroform. The organic layer was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (10% methanol-chloroform) to give 4-[2,6-dichloro-3-[N-methyl-N-[4-(methyl-carbamoyl)cinnamoylglycyl]amino]-benzyloxy]-2-ethyl-1-dimethylcarbamoylmethyl-1H-benzimidazole (46 mg) as amorphous.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:14].O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][O:8][CH3:14])=[CH:4][CH:3]=1
Reactant: CI
Reactant: OCCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In THF (100 ml) was dissolved 4-bromophenethyl alcohol (10 g). To the mixture was added under ice-cooling 65% sodium hydride (1.7 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added dropwise under ice-cooling iodomethane (3.7 ml), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=6/1) to give 1-bromo-4-(2-methoxyethyl)benzene (8.3 g). In THF (100 ml) was dissolved 1-bromo-4-(2-methoxyethyl)benzene (8.2 g). To the mixture was added dropwise at −78° C. 1.6M n-butyllithium/hexane (26.0 ml), and the mixture was stirred for 1 hour. To the mixture was added dropwise a solution of trimethyl borate (11.8 g) in THF (12 ml), and the mixture was stirred for 30 minutes and warmed to room temperature. To the mixture was added 10% sulfuric acid (40 ml), and the mixture was stirred for 15 minutes. The reaction mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was washed with hexane/isopropylether to give 4-(2-methoxyethyl)phenyl borate (3.7 g).
Reaction SMILES: ClC1C=C2C(=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.[I:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48]([O:50]CC)=O)=[C:33]2[S:53](Cl)(=[O:55])=[O:54].Cl.CN.[O:60]1[CH2:65][CH2:64][CH2:63][CH2:62][CH:61]1[CH2:66][NH:67][CH3:68]>>[I:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:48]([NH2:7])=[O:50])=[C:33]2[S:53]([N:67]([CH3:68])[CH2:66][CH:61]1[CH2:62][CH2:63][CH2:64][CH2:65][O:60]1)(=[O:54])=[O:55]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(I)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CNCC1CCCCO1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: CN
Agent: Cl
Product: CN(CC1CCCCO1)S(=O)(=O)c1c(C(N)=O)[nH]c2ccc(I)cc12

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-iodo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and methylamine hydrochloride with (±)-N-(1-tetrahydro-2H-pyran-2-ylmethyl) -N-methylamine, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+ MS: 477.99 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:8]=[C:7]([N:9]2[CH:13]=[C:12]([C:14]([O:16]CC)=[O:15])[CH:11]=[N:10]2)[CH:6]=[N:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:20][C:2]([F:1])([F:19])[C:3]1[N:8]=[C:7]([N:9]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[N:10]2)[CH:6]=[N:5][CH:4]=1
Reactant: CCOC(=O)c1cnn(-c2cncc(C(F)(F)F)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cnn(-c2cncc(C(F)(F)F)n2)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Under N2, ethyl 1-(6-(trifluoromethyl)pyrazin-2-yl)-1H-pyrazole-4-carboxylate (155 mg, 542 μmol, Eq: 1.00) was dissolved in DMF (9.3 ml) and Water (9.3 ml). Potassium carbonate (150 mg, 1.08 mmol, Eq: 2) was added and the RM was stirred at 70° C. overnight. Control with LC-MS: Pr/SM: 74/26. Potassium carbonate (150 mg, 1.08 mmol, Eq: 2) was added and the RM was stirred at 70° C. overnight. Control with LC-MS: SM/Pr:4/96. At RT, the RM was partitioned between 1M K2CO3 and EtOAc; extracted; the water layer was acidified with 1M HCl; extracted with EtOAc; the organic phase was dried over MgSO4; filtered; concentrated in vacuo leading to 132 mg off-white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9]N)[CH2:5][CH2:4]1>C1(C)C=CC(C)=CC=1>[NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH3:9])[CH2:5][CH2:4]1.[CH3:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH2:1])=[CH:4][CH:5]=1
Reactant: NCC1CCC(CN)CC1
Solvent: Cc1ccc(C)cc1
Product: CC1CCC(CN)CC1
Product: Cc1ccc(CN)cc1

Procedure:
As a result of analysis by gaschromatography, it was found that the yield of 1,4-bis(aminomethyl)cyclohexane was 95.9 mol % and as other products 3.4 mol % of 4-aminomethyl-1-methylcyclohexane, 0.3 mol % of 4-methyl-benzylamine and 0.2 mol % of paraxylene were obtained.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>N1C=CC=CC=1>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: OC1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A round-bottomed flask (100 cc) was charged with cyclohexyl alcohol (5.01 9, 50.0 mmol) and p-toluenesulfonyl chloride (10.6 g, 55.6 mmol), followed by the addition of pyridine (20 mL) under ice cooling to form a solution. The solution was stirred for 8 h as it was warmed gradually to room temperature. After completion of the reaction, the reaction mixture was poured into ice water and stirred thoroughly. Following extraction with ether (50 mL×2), the organic layers were washed with 2N HCl, water and saturated brine and dried with anhydrous magnesium sulfate. After the desiccant was removed, the solvent was distilled off under vacuum to give cyclohexyl p-toluenesulfonate as a colorless clear oil (12.7 g; yield=99.0%). 1H-NMR(CDCl3,TMS,ppm): δ1.12-1.88(10H,m), 2.43(3H,s), 4.46(1H,m), 7.28(2H,d,J=8.9Hz), 7.76(2H,d,J=8.9Hz).
Reaction SMILES: CN(/[CH:4]=[C:5]1/[C:6](=O)[CH:7]=[CH:8][C:9]2([CH2:22]/1)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)C.[CH:24]([NH:27][NH2:28])([CH3:26])[CH3:25].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH:24]([N:27]1[C:6]2[CH:7]=[CH:8][C:9]3([CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:13][CH2:14]3)[CH2:22][C:5]=2[CH:4]=[N:28]1)([CH3:26])[CH3:25]
Reactant: CN(C)/C=C1\CC2(C=CC1=O)CCN(C(=O)OC(C)(C)C)CC2
Reactant: CC(C)NN
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)n1ncc2c1C=CC1(CCN(C(=O)OC(C)(C)C)CC1)C2
Temperature: 25 °C
Yield: 98.5 %

Procedure:
(E)-tert-Butyl 10-((dimethylamino)methylene)-9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate (107 g) was taken up in toluene (700 mL) and isopropyl hydrazine (44.4 g) was added. The reaction was stirred at reflux for 4 hours. The reaction was cooled to room temperature and ethyl acetate was added (500 mL). The reaction solution was washed with citric acid (2×300 mL, 10% aqueous), and water (400 mL). The organic layer concentrated in vacuo to afford tert-butyl 1-isopropyl-1,4-dihydrospiro[indazole-5,4′-piperidine]-1′-carboxylate as a yellow solid (109 g). 1H NMR (400 MHz, CDCl3) δ ppm 7.25 (s, 1H) 6.42 (dd, J=10.05, 0.49 Hz, 1H) 5.84 (d, J=9.95 Hz, 1H) 4.42-4.52 (m, 1H) 3.36-3.53 (m, 4H) 2.62 (s, 2H) 1.56-1.68 (m, 2H) 1.45-1.55 (m, 17H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:31]([Cl:34])=[CH:32][N:33]=1)[C:5]([NH:7][C:8]1[CH:30]=[CH:29][C:11]2[CH2:12][CH2:13][C:14]3[C:15]([C:26]([NH2:28])=[O:27])=[N:16][N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:18]=3[C:10]=2[CH:9]=1)=[O:6].[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][NH:39][CH3:40]>>[Cl:34][C:31]1[C:4]([C:5]([NH:7][C:8]2[CH:30]=[CH:29][C:11]3[CH2:12][CH2:13][C:14]4[C:15]([C:26]([NH2:28])=[O:27])=[N:16][N:17]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=5)[C:18]=4[C:10]=3[CH:9]=2)=[O:6])=[CH:3][C:2]([N:39]([CH2:38][CH2:37][N:36]([CH3:41])[CH3:35])[CH3:40])=[N:33][CH:32]=1
Reactant: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(NC(=O)c3cc(Cl)ncc3Cl)cc1-2
Reactant: CNCCN(C)C
Product: CN(C)CCN(C)c1cc(C(=O)Nc2ccc3c(c2)-c2c(c(C(N)=O)nn2-c2ccc(F)cc2)CC3)c(Cl)cn1
Reaction time: 24 h
Yield: 47.1 %

Procedure:
The title compound was synthesized by the same procedure as in Example 214 starting with the title compound of Example 248 (0.8 g, 0.0016 mol) and N,N,N′-trimethylethylene diamine (3.3 g, 0.032 mol). The reaction was run at 100° C. for 24 h. After removal of the volatiles under vacuum, the residue was partitioned between water and CH2Cl2. The organic layer was washed an additional time with water and dried over MgSO4. The crude product mixture was purified by preparative HPLC to give 0.424 g of the title product, yield: 47%. 1H NMR (400 MHz, d6-DMSO): 2.13 (s, 6H), 2.34 (t, 2H, J=6.7 Hz), 2.87-2.95 (m, 4H), 2.96 (s, 3H), 3.59 (t, 2H, J=6.7 Hz), 6.58 (s, 1H), 7.2 (d, 1H, J=2 Hz), 7.27 (s, 1H), 7.29-7.37 (m, 3H), 7.41-7.44 (dd, 1H, J=8 Hz, 2 Hz), 7.53-7.58 (m, 3H), 8.13 (s, 1H), 10.36 (s, 1H). M+1=563.
Reaction SMILES: [CH:1]([NH:4][C:5]1[NH:10][C:9]2[CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=[CH:14][C:8]=2[S:7](=[O:20])(=[O:19])[N:6]=1)([CH3:3])[CH3:2].[BrH:21].OO>O>[Br:21][C:13]1[C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][C:9]2[NH:10][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:6][S:7](=[O:19])(=[O:20])[C:8]=2[CH:14]=1
Reactant: CC(C)NC1=NS(=O)(=O)c2ccc(C(F)(F)F)cc2N1
Reactant: Br
Agent: OO
Solvent: O
Product: CC(C)NC1=NS(=O)(=O)c2cc(Br)c(C(F)(F)F)cc2N1
Temperature: 70 °C
Yield: 5.7 %

Procedure:
A solution of 3-isopropylamino-6-trifluoromethyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (307 mg; 1 mmol) in water (5 ml) was added 40% hydrobromic acid (0.44 ml; 3 mmol). The solution was then heated to 70° C. and 30% hydrogen peroxide (0.33 g; 3 mmol) was added. After 30 min the reaction mixture was cooled and extracted with ethyl acetate (20 ml) and purified by column chromatograpy (ethyl acetate:ethanol 9:1). Concentration of the appropiate fractions produced the title compound (22 mg); 1H-NMR (DMSO-d6) ppm; 7.60 (s, 1H), 7.10 (s, 1H), 6.65 (s, 1H), 3.95 (m, 1H) 1.11 (d, 6H).
Reaction SMILES: [N:1]#[C:2][NH2:3].C[O-].[Na+].CO[C:9]([CH:13]1[CH2:15][CH2:14]1)=[N:10][C:11]#[N:12]>CO>[C:2]([NH:3][C:9]([CH:13]1[CH2:15][CH2:14]1)=[N:10][C:11]#[N:12])#[N:1]
Reactant: N#CN
Reactant: COC(=NC#N)C1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#CN=C(NC#N)C1CC1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
At 0° C. 8,4 g of cyanamide in 50 ml methanole are added to 36 g of a 30% solution of sodium methylate in methanol and stirred for 30 min. at 10° C. The resulting solution is then cooled to -20° C. and mixed with a solution of 22 g N-cyano-cyclopropanecarboximidic acid methylester in 60 ml methanole. The reaction mixture is then stirred for 30 min. at 20° C. and then evaporated. 100 ml of dioxane is added to the resulting residue which is then concentrated by evaporation. Then again 100 ml of toluene is added and the solution is concentrated at an ambient temperature of 60° C. up to a residual weight of 33 g.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:21]=[CH:20][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH2:17][C:11]=3[CH:10]=2)[C:5]([Cl:22])=[CH:4][N:3]=1.[CH2:23]([N:25]1[CH2:31][CH2:30][C:29]2[CH:32]=[C:33](N)[CH:34]=[CH:35][C:28]=2[CH2:27][CH2:26]1)[CH3:24].[C:37]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[CH:21]=[CH:20][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[CH:37][C:2]([NH:7][C:33]2[CH:34]=[CH:35][C:28]3[CH2:27][CH2:26][N:25]([CH2:23][CH3:24])[CH2:31][CH2:30][C:29]=3[CH:32]=2)=[N:3][CH:4]=1
Reactant: CCN1CCc2ccc(Nc3nc(Cl)ncc3Cl)cc2CC1
Reactant: CCN1CCc2ccc(N)cc2CC1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CCN1CCc2ccc(Nc3cc(Nc4ccc5c(c4)CCN(CC)CC5)c(Cl)cn3)cc2CC1
Yield: 74.8 %

Procedure:
(2,5-dichloro-pyrimidin-4-yl)-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-amine (50 mg, 0.15 mmol) and 3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (29 mg. 0.15 mmol) were combined with camphorsulfonic acid (74 mg, 0.32 mmol) in 5 mL isopropyl alcohol and subjected to microwave irradiation at 120° C. for 80 minutes. 35 mg addition camphorsulfonic acid was added and microwave irradiation was continued for an additional hour. The mixture was concentrated and the organics were partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was separated, was dried (sodium sulfate), and was concentrated. The solid was obtained was triturated with ether. The ether was separated and concentrated and the solid obtained was purified by reverse phase chromatography (0% to 30% acetonitrile:water on C8) to afford 55 mg (76%) of 5-Chloro-N*2*,N*4*-bis-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-pyridine-2,4-diamine as a white solid. Mp: 132-4° C.; MS: 493.41 (M+2H); 1H NMR (chloroform-d): δ 8.04 (s, 1H), δ 7.41 (d, J=8 Hz, 1H), δ 7.28 (m, 2H), δ 7.09 (d, J=8 Hz, 1H), δ 7.02 (m, 2H), δ 6.90 (br s, 1H), δ 3.00-2.85 (m, 8H), δ 2.76-2.54 (m, 12H), δ 1.17 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[C@@:6]([CH3:13])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:5][C:4](=[O:14])[CH:3]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:23][C:24]1[C:32]2[C:27](=[CH:28][C:29]([CH3:33])=[CH:30][CH:31]=2)[NH:26][CH:25]=1>>[CH3:23][C:24]1[C:32]2[C:27](=[CH:28][C:29]([CH3:33])=[CH:30][CH:31]=2)[NH:26][C:25]=1[CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]1[C:4](=[O:14])[NH:5][C@:6]([CH3:13])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]=1[OH:1]
Reactant: C[C@]1(c2ccccc2)NC(=O)C=C1O
Reactant: Cc1ccc2c(C)c[nH]c2c1
Reactant: O=Cc1ccccc1
Product: Cc1ccc2c(C)c(C(C3=C(O)[C@@](C)(c4ccccc4)NC3=O)c3ccccc3)[nH]c2c1

Procedure:
Using general procedure D, (R)-4-hydroxy-5-methyl-5-phenyl-1,5-dihydro-pyrrol-2-one (prepared according to Lit. 11, see also Lit. 19) was reacted with benzaldehyde and 3,6-dimethyl-1H-indole (Lit. 22) to give the title compound as a yellow foam. MS: 423.3 ([M+H]+).