Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7](=[O:16])[C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[N:3]=1.CC(C)([O-])C.[K+].[C:34]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36][CH2:35]1>C(O)(=O)C.C1COCC1>[NH2:1][C:2]1[N:6]([C:7](=[O:16])[C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:34](=[O:41])[CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])(=[O:25])=[O:26])=[CH:20][CH:19]=2)[N:3]=1
Reactant: O=C1CCCC(=O)O1
Reactant: Nc1nc(Nc2ccc(S(N)(=O)=O)cc2)nn1C(=O)c1c(F)cccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1nc(Nc2ccc(S(=O)(=O)NC(=O)CCCC(=O)O)cc2)nn1C(=O)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a nitrogen purged flask was added 4-[5-amino-1-(2,6-difluorobenzoyl)-1H-[1,2,4]triazol-3-ylamino]-benzenesulfonamide Compound 1a (2.0 g, 5.1 mmol) and THF (200 mL). The mixture was cooled to 0° C. and potassium tert-butoxide (6.1 mL, 1.0 M solu in THF) was added dropwise. After addition the mixture was stirred at 0° C. for 1 hr, then glutaric anhydride (0.69 g in 10 mL THF, 6.0 mmol) was added dropwise. The stirring was continued for 30 min, then the mixture was warmed to rt and stirred overnight. A few drops of acetic acid was added, then the mixture was concentrated. The residue was purified by flash chromatography (silica gel, CH2Cl2:MeOH/8:2) to afford the desired product Compound 11 (670 mg, 26%) as a white solid. NMR (300 MHz, CD3OD) δ 7.75 (d, J=7.0 Hz, 2H), 7.68 (m, 1H), 7.50 (d, J=6.9 Hz, 2H), 7.15 (t, J=6.9 Hz, 2H), 2.36 (t, J=6.8 Hz, 2H), 1.80 (t, J=6.8 Hz, 2H); MS (ESI) m/z: 493 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.Br[C:13]1[CH:18]=[CH:17]C(CC(OC2CCCCO2)=O)=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:9]([OH:11])=[O:10])[CH2:17][CH2:18][CH2:13][CH2:14][CH2:15]2)=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccc(Br)cc1)OC1CCCCO1
Reactant: O=C(O)Cc1ccc(Br)cc1
Product: O=C(O)C1(c2ccc(Br)cc2)CCCCC1
Yield: 25 %

Procedure:
The title compound was obtained in a manner analogous to that for 1-Phenylcyclohexanecarboxylic acid (1/3) starting with (4-bromophenyl)acetic acid (4d), via tetrahydro-2H-pyran-2-yl 2-(4-bromophenyl)acetate (5d). The crude product 1/9 was chromatographed on silica gel with petroleum ether-dioxane-acetic acid (85:15:2) and petroleum ether-tert-butylmethyl ether-acetic acid (8:2:0.1) as eluents to give 1-(4-bromophenyl)cyclohexanecarboxylic acid (1/9) in 25% yield. 1H NMR (CDCl3, HMDSO) δ: 1.17-1.92 (8H, m); 2.28-2.59 (2H, m); 7.33 (2H, d, J=8.8 Hz); 7.47 (2H, d, J=8.8 Hz); 10.34 (1H, br s).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.Cl[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14]>[OH-].[Na+].O1CCOCC1>[CH2:16]([O:15][C:13]([NH:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1)=[O:14])[CH:17]=[CH2:18]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=CCOC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 34.2 g (217.5 mmol) of trans 4aminomethylcyclohexanecarboxylic acid (Aldrich) in 217 mL of 2M aq. NaOH and 217 mL of dioxane was cooled to 15° C. To this solution was added 25 mL (235 mmol) of allyl chloroformate (Aldrich) in a slow stream. After the addition, the cold bath was removed, and the solution was stirred overnight at ambient temperature. The reaction mixture was poured slowly into a rapidly stirred mixture of 1L of 1M aq. citric acid and ice. The resulting mixture was stirred for 0.5 h and the precipitate collected by filtration, washed with water, and dried to a constant weight of 49.3 g (94%) of the title compound as a colorless solid.
Reaction SMILES: ClC1C=C(Cl)C(Cl)=CC=1O[C:11](=[O:29])[C@H:12]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].Cl.[CH2:31]([O:38][C:39](=[O:47])[C@H:40]([CH3:46])[NH:41][C:42](=[O:45])[CH2:43][NH2:44])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CN1CCOCC1>C(Cl)Cl>[CH2:31]([O:38][C:39](=[O:47])[C@H:40]([CH3:46])[NH:41][C:42](=[O:45])[CH2:43][NH:44][C:11](=[O:29])[C@H:12]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=1)[NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: C[C@H](NC(=O)CN)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)Oc1cc(Cl)c(Cl)cc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
A solution of 17.6 parts N-t-butoxycarbonyl-L-tyrosine 2,4,5-trichlorophenyl ester, 9.0 parts glycyl-L-alanine benzyl ester hydrochloride and 1.2 parts N-methylmorpholine in 200 parts methylene chloride is stirred for 16 hours at room temperature. Removal of the solvent under reduced pressure affords a crude product which is purified by low pressure column chromatography to give N-t-butoxycarbonyl-L-tyrosylglycyl-L-alanine benzyl ester. The purified material is dissolved in 400 parts methanol. Then, 0.4 part palladium black metal catalyst is added and the mixture shaken with hydrogen at atmospheric pressure and room temperature for about 5 hours. The catalyst is removed by filtration, and the solvent is removed by evaporation under reduced pressure. The resulting material is purified by low-pressure chromatography to give N-t-butoxycarbonyl-L-tyrosylglycyl-L-alanine. This compound is represented by the following formula
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([NH:15][CH:16]1[CH2:44][CH2:43][CH:19]2[CH:20]([CH3:42])[NH:21][C:22]3[C:27]([CH:18]2[CH2:17]1)=[C:26]([O:28][C:29](=[O:31])[CH3:30])[CH:25]=[C:24]([S:32][CH:33]([CH:35]([CH3:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH3:34])[CH:23]=3)(=[O:14])[CH3:13].C(Cl)(Cl)Cl>C(O)(=O)C>[C:12]([NH:15][CH:16]1[CH2:44][CH2:43][CH:19]2[CH:20]([CH3:42])[NH:21][C:22]3[C:27]([CH:18]2[CH2:17]1)=[C:26]([O:28][C:29](=[O:31])[CH3:30])[CH:25]=[C:24]([S:32]([CH:33]([CH:35]([CH3:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH3:34])=[O:9])[CH:23]=3)(=[O:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCC(C)C(C)Sc1cc2c(c(OC(C)=O)c1)C1CC(NC(C)=O)CCC1C(C)N2
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCCCCC(C)C(C)S(=O)c1cc2c(c(OC(C)=O)c1)C1CC(NC(C)=O)CCC1C(C)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Equimolar amounts of m-chloroperbenzoic acid and dl-9-acetamido-1-acetoxy-6-methyl-3-(3-methyl-2-octylthio)5,6,6a,7,8,9,10,10a-octahydrobenzo[c]quinoline are added to a mixture of chloroform and acetic acid (2:1 v/v) and the mixture stirred at room temperature for one hour. The reaction mixture is washed with water, the organic phase dried over magnesium sulfate and evaporated to dryness at reduced pressure to give the title compound.
Reaction SMILES: [Cl:1][C:2]([F:13])([F:12])[C:3](=[O:11])[CH2:4][C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7].[CH:14]([O-])([O-])[O:15][CH2:16][CH3:17]>C(OC(=O)C)(=O)C>[Cl:1][C:2]([F:12])([F:13])[C:3](=[O:11])[C:4](=[CH:14][O:15][CH2:16][CH3:17])[C:5](=[O:10])[C:6]([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)C(=O)CC(=O)C(F)(F)Cl
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)C(C)(C)C)C(=O)C(F)(F)Cl
Yield: 43.4 %

Procedure:
12.4 g of 1-chloro-1,1-difluoro-5,5-dimethyl-2,4-hexanedione and 12.4 g of ethyl orthoformate were added to 50 ml of acetic anhydride, and the mixture was refluxed under heating for 2 hours. After the solvent was distilled off under reduced pressure, the residue was subjected to vacuum distillation to obtain 6.8 g of the desired product. (b.p. 105°-107° C./2 mmHg)
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Li+].[NH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([C:21](=O)[CH3:22])[CH:20]=1)[NH:17][CH:16]=[CH:15]2>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:21]([C:19]1[CH:20]=[C:12]([NH2:11])[CH:13]=[C:14]2[C:18]=1[NH:17][CH:16]=[CH:15]2)([CH3:22])=[CH2:1]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(=O)c1cc(N)cc2cc[nH]c12
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)c1cc(N)cc2cc[nH]c12
Temperature: -78 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a solution of methyltriphenylphosponium bromide (3.8 g, 10 mmol) in 40 mL of THF was added 15 mL of a solution of lithium bis(trimethylsilyl)amide (15 mmol) and the resulting reaction mixture was stirred for 1 h at -78° C. A solution of 5-amino-7-acetylindole (0.55 g, 3.1 mmol) in 10 mL of THF was added into the solution slowly for 0.5 h period. The reaction mixture was slowly warmed to 25° C. and stirred for 12 h at the temperature. Column chromatographic separation of reaction mixture (50% EtOAc/n-Hexane) provided 0.45 g (2.6 mmol, 82%) of the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:25]([O:32][C:33](=[O:37])[C@@H:34]([CH3:36])[NH2:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:25]([O:32][C:33](=[O:37])[C@@H:34]([CH3:36])[NH:35][C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C[C@@H](N)C(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 23.0 g. (0.121 m) of N-t-butoxycarbonyl-L-alanine, 42.6 g. (0.121 m) of D-alanine benzyl ester p-toluenesulfonic acid salt and 17 ml. (0.121 m) of triethylamine in 400 ml. of cold (0° C.) methylene chloride was added dropwise 25.0 g. (0.121 m) of dicyclohexylcarbodiimide in 100 ml. of methylene chloride. After stirring overnight at room temperature the solids were filtered and the filtrate concentrated to an oil. The residue was dissolved in 400 ml. of ethyl acetate which was washed with a 1% hydrochloric acid solution, a 10% potassium carbonate solution, water and a brine solution. The organic phase was separated, dried over magnesium sulfate and concentrated to an oil. The residue was triturated with diethyl ether and the resulting solids filtered under nitrogen, 16.0 g. An additional 12.7 g. of the desired product crystallized from the filtrate.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:49])[CH2:19][C:20]3[NH:21][C:22]([CH2:42][CH2:43][C:44]4[S:45][CH:46]=[CH:47][N:48]=4)=[C:23]([C:38]([O:40][CH3:41])=[O:39])[CH:24]([C:30]4[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:37])[C:25]=3[C:26]([O:28][CH3:29])=[O:27])[CH2:14][CH2:13]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:50][S:51](Cl)(=[O:53])=[O:52].C(N(CC)CC)C>ClCCl>[Cl:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:37])[C:30]=1[CH:24]1[C:23]([C:38]([O:40][CH3:41])=[O:39])=[C:22]([CH2:42][CH2:43][C:44]2[S:45][CH:46]=[CH:47][N:48]=2)[NH:21][C:20]([CH2:19][C:18]([N:15]2[CH2:16][CH2:17][N:12]([CH2:11][C:5]3([CH2:4][NH:3][S:51]([CH3:50])(=[O:53])=[O:52])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]3)[CH2:13][CH2:14]2)=[O:49])=[C:25]1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)C1=C(CCc2nccs2)NC(CC(=O)N2CCN(CC3(CN)CCCCC3)CC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1=C(CCc2nccs2)NC(CC(=O)N2CCN(CC3(CNS(C)(=O)=O)CCCCC3)CC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of dimethyl 2-[2-[4-[[1-(aminomethyl)cyclohexyl]methyl]-1-piperazinyl]-2-oxoethyl]-4-(2,6-dichlorophenyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate dihydrochloride (230 mg/0.28 mmol) methansulfonylchloride (0.2 ml/2.5 mmol) and triethylamine (0.5 ml/3.5 mmol) in dichloromethane (5.0 ml) was stirred for 5 hours at ambient temperature. The mixture was diluted with dichloromethane (50 ml), and then washed with water (10 ml) and brine (10 ml) successively. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (NH2 gel/200-350 mesh/20 g/dichloromethane) to give a yellow film (122 mg/55%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([C@H:16]1[CH2:21][CH2:20][C@H:19]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:18][CH2:17]1)([O:8][Si](CC)(CC)CC)[C:4]([F:7])([F:6])[F:5].[Li]CCCC.[F:39][C:40]([F:51])([F:50])[CH2:41]OS(C(F)(F)F)(=O)=O>C1COCC1.CCCCCC>[F:39][C:40]([F:51])([F:50])[CH2:41][N:22]([C@H:19]1[CH2:18][CH2:17][C@H:16]([C:3]([OH:8])([C:2]([F:1])([F:33])[F:32])[C:4]([F:7])([F:5])[F:6])[CH2:21][CH2:20]1)[S:23]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:24])=[O:25]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC[Si](CC)(CC)OC([C@H]1CC[C@H](NS(=O)(=O)c2ccccc2)CC1)(C(F)(F)F)C(F)(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)N(CC(F)(F)F)[C@H]1CC[C@H](C(O)(C(F)(F)F)C(F)(F)F)CC1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.45 g (0.87 mmol) of trans N-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-benzenesulfonamide in 5 mL of dry THF was cooled to −78° C. and treated dropwise with 0.7 mL (1.13 mmol) of a 1.6M solution of nBuLi in hexane. The solution was warmed to −40° C., treated with 1.0 g (4.33 mmol) of trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester and then allowed to reach RT. The mixture was stirred for 30 min at RT and then refluxed for 2 hrs. The solvent was evaporated, the residue redissolved in 2 mL of THF and treated with an excess of TBAF. Distribution between a saturated aqueous solution of NH4Cl and Et2O, drying of the combined organic phases and chromatography on silica gel with heptane/EtOAc 2:1 gave 0.17 g (40%) of trans N-(2,2,2-trifluoro-ethyl)-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-benzenesulfonamide as a light yellow oil, MS: 486 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[C:4]([C:16]([OH:18])=O)=[N:3]1.C(Cl)(=O)C([Cl:22])=O.CN(C)C=O>ClCCl>[CH3:1][N:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[C:4]([C:16]([Cl:22])=[O:18])=[N:3]1
Reactant: Cn1nc(C(=O)O)c(=O)n(-c2ccccc2)c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1nc(C(=O)Cl)c(=O)n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.50 g (6.07 mmol) of 2-methyl-3,5-dioxo-4-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid and 1.16 g (9.10 mmol) of oxalyl chloride were dissolved in dichloromethane (30 ml). To the mixture, a drop of N,N-dimethylformamide was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 2-methyl-3,5-dioxo-4-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonyl chloride as a pale yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:4][C:5]([NH:16][CH:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]2)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC(C)Oc1cc(F)c([N+](=O)[O-])cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1Cl
Temperature: 80 °C
Reaction time: 17 h
Yield: 96.6 %

Procedure:
A solution of 5-chloro-2-fluoro-4-[(1-methylethyl)oxy]-1-nitrobenzene (D83, 153 mg, 0.65 mmol) in dimethylformamide (5 ml) was treated with 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (130 mg, 0.65 mmol) and diisopropylethylamine (0.113 ml, 0.65 mmol) and stirred at approx. 80° C. for 17 hrs. The mixture was concentrated under vacuum and the residue treated with water and extracted with diethyl ether (×2). The combined extract was dried (MgSO4) and concentrated under vacuum to afford the title compound as a yellow solid (260 mg, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:22][CH2:23]Br)[CH2:10][C:11]([N:13]([CH3:21])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.O.[NH:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]([CH3:21])[C:11](=[O:12])[CH2:10][CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:22][CH2:23][N:27]2[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]2)=[CH:15][CH:16]=1
Reactant: O=C1CCNCC1
Reactant: CN(C(=O)CC(CCBr)c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)CC(CCN1CCC(=O)CC1)c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 47 %

Procedure:
3,4-Dichloro-beta-(2-bromoethyl)-N-methyl-N-(4-chlorophenyl)benzene propanamide (4.6 g) in DMF (60 mL) was treated with 4-piperidone monohydrate hydrochloride (3.94 g) and K2CO3 (5.3 g). The mixture was stirred vigorously at ambient temperature for 120 hours. The reaction mixture was poured into H2O (100 mL) and extracted with EtOAc (2×100 mL). The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give an oil. Silica gel chromatography eluting with 95:5 (CH2Cl2 :MeOH) gave the title compound (2.25 g). Mass spectrum (FAB): 467.1.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[S:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[O:9])[CH2:3]1.[Br:16][CH2:17][C:18](Br)=[O:19]>C1COCC1>[Br:16][CH2:17][C:18]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[S:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[O:9])[CH2:3]1)=[O:19]
Reactant: O=C(Br)CBr
Reactant: O=C(N[C@@H]1CCNC1)c1ccc(Cl)s1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(N[C@@H]1CCN(C(=O)CBr)C1)c1ccc(Cl)s1

Procedure:
7.1 A solution of 400 mg 5-chloro-thiophene-2-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example 6.2) in 5 ml THF was treated with 0.31 ml TEA and 0.16 ml bromo acetylbromide. The reaction mixture was stirred over night. The precipitate was filtered and washed with THF. The filtrate was concentrated. The crude product was purified by chromatography (silica gel; gradient: CH2Cl2 to CH2Cl2/MeOH 98:2) to give 250 mg 5-chloro-thiophene-2-carboxylic acid [(R)-1-(2-bromo-acetyl)-pyrrolidin-3-yl]-amide. Off-white amorphous solid. 353.1 ([M+H]+)
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16](OCC)=[O:17])[C:11]2=[O:15])[CH:7]([CH3:21])[CH2:6][CH2:5][C:4]=3[CH:3]=1.[NH2:22][NH2:23]>CO>[F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([NH:22][NH2:23])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:21])[CH2:6][CH2:5][C:4]=3[CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1cn2c3c(cc(F)cc3c1=O)CCC2C
Solvent: CO
Product: CC1CCc2cc(F)cc3c(=O)c(C(=O)NN)cn1c23
Temperature: 25 °C

Procedure:
Ethyl 6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo-[ij]quinolizine-2-carboxylate (10 g., 0.0347 mole) is dissolved in methanol (200 ml.) containing 25 ml. of 97 percent hydrazine. The mixture is warmed to accelerate solution. The solution is stirred at room temperature, and solid begins to separate immediately. The solid is separated by filtration, washed with methanol and recrystallized from aqueous ethanol to provide 6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid hydrazide, m.p. 236°-238° C.
Reaction SMILES: CCN(C(C)C)C(C)C.F[C:11]1[C:12]([CH3:31])=[N:13][C:14]2[C:19]([N:20]=1)=[C:18]([C:21]1[NH:29][C:28]3[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=3[CH:22]=1)[CH:17]=[CH:16][CH:15]=2.[NH2:32][CH:33]1[CH2:36][CH:35]([OH:37])[CH2:34]1>CS(C)=O>[OH:37][CH:35]1[CH2:36][CH:33]([NH:32][C:11]2[C:12]([CH3:31])=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]([C:21]2[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=2)[CH:17]=[CH:16][CH:15]=3)[CH2:34]1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: NC1CC(O)C1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CC(O)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Prepared according to Example 127, using DIPEA (141 μl, 0.803 mmol), 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4 (5H)-one (Example 126; 40 mg, 0.135 mmol), 3-aminocyclobutanol (35.3 mg, 0.405 mmol, Sigma Aldrich; mixture of cis- and trans-isomers), and DMSO (1.4 mL) stirring at 80° C. for 2 h. Purification by high throughput parallel purification (Rilas Technologies, Woburn, Mass.) provided 2-(3-((3-hydroxycyclobutyl)amino)-2-methyl-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (mixture of cis- and trans-isomers): 1H NMR (DMSO-d6) δ: 12.31-12.44 (m, 1H), 7.86-7.95 (m, 1H), 7.51-7.61 (m, 1H), 7.26-7.40 (m, 2H), 7.04-7.11 (m, 1H), 6.91-7.02 (m, 1H), 5.12-5.26 (m, 1H), 4.37-4.53 (m, 1H), 3.86-4.07 (m, 1H), 3.41-3.48 (m, 1H), 2.88-3.01 (m, 2H), 2.75-2.85 (m, 1H), 2.55-2.59 (m, 4H), 2.26-2.48 (m, 2H), 1.94-2.09 (m, 1H). m/z (ESI, +ve) 364.1 (M+H)+.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=2)=[CH:18][C:17]=1[C:33]1[CH:42]=[CH:41][C:40]2[C:39]([CH3:44])([CH3:43])[CH2:38][CH2:37][C:36]([CH3:46])([CH3:45])[C:35]=2[CH:34]=1.O>C(#N)C>[CH:1]([NH:4][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:27]=2)=[CH:18][C:17]=1[C:33]1[CH:42]=[CH:41][C:40]2[C:39]([CH3:44])([CH3:43])[CH2:38][CH2:37][C:36]([CH3:46])([CH3:45])[C:35]=2[CH:34]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCI)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Reactant: CC(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1ccc(-c2ccc(OCCCNC(C)C)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Yield: 30.3 %

Procedure:
430 μl (5 mmol) of isopropylamine and 420 mg (3 mmol) of potassium carbonate are added to a solution of 600 mg (1 mmol) of ethyl 4′-(3-iodopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate in 50 ml of acetonitrile. The reaction mixture is stirred at reflux overnight. The reaction is stopped by adding water and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then purified by chromatography on silica gel (50/50 heptane/ethyl acetate). 160 mg of ethyl 4′-(3-isopropylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a yellowish solid (m.p.=171° C., yield=30%).