Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8].[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8]
Reactant: C1CCNC1
Reactant: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(Cl)c([N+](=O)[O-])c4)s3)cc2)CC1
Product: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(N5CCCC5)c([N+](=O)[O-])c4)s3)cc2)CC1

Procedure:
This compound was prepared from the compound of Example 15 and pyrrolidine by the procedure used in Example 57. Mass spectrum (ES) MH+=508.
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(O)(=O)C.[C:15]([O:19][CH3:20])(=[O:18])[NH:16][NH2:17]>CO>[CH3:20][O:19][C:15](=[O:18])[NH:16][N:17]=[C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)NN
Reactant: O=C1CCc2ccccc21
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)NN=C1CCc2ccccc21
Yield: 71.3 %

Procedure:
To a solution of 39.65 g (0.3 moles) of 1-indanone in 300 ml of methanol 3 ml of acetic acid and 27 g (0.3 moles) of methyl carbazate are added. The reaction mixture is boiled in a flask equipped with a reflux condenser for one hour, then clarified with bone coal, filtered and the filtrate is cooled with icy water. 43.7 g of the desired compound are obtained in the form of white crystals. M.p.: 155°-156° C.
Reaction SMILES: [C:1]([C:3]1[C:4]2[S:15][C:14]([CH3:16])=[CH:13][C:5]=2[NH:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:2].[Br:17]N1C(=O)CCC1=O.C(O)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:17][C:13]1[C:5]2[NH:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:3]([C:1]#[N:2])[C:4]=2[S:15][C:14]=1[CH3:16]
Reactant: CCOC(=O)c1[nH]c2cc(C)sc2c1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c2c(Br)c(C)sc2c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
Ethyl 6-cyano-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate (0.3 g), N-Bromosuccinimide (0.24 g) and acetic acid (2.5 mL) were dissolved in chloroform (5.0 mL) and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and concentrated under reduced pressure. The obtained residue was washed with diethyl ether, and dried under reduced pressure to give the title compound (0.20 g).
Reaction SMILES: C(OC([NH:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]([CH3:22])=[C:20]3[C:15]([C:16](=[O:31])[C:17]([C:26]([O:28]CC)=[O:27])=[CH:18][N:19]3[CH:23]3[CH2:25][CH2:24]3)=[C:14]([CH3:32])[C:13]=2[F:33])[CH2:8]1)=O)C.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[NH2:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]([CH3:22])=[C:20]3[C:15]([C:16](=[O:31])[C:17]([C:26]([OH:28])=[O:27])=[CH:18][N:19]3[CH:23]3[CH2:25][CH2:24]3)=[C:14]([CH3:32])[C:13]=2[F:33])[CH2:8]1
Reactant: CCOC(=O)NC1CCN(c2c(F)c(C)c3c(=O)c(C(=O)OCC)cn(C4CC4)c3c2C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1c(F)c(N2CCC(N)C2)c(C)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 29.5 %

Procedure:
To ethyl 7-(3-ethoxycarbonylamino-1-pyrrolidinyl)-cyclopropyl-6-fluoro-5,8-dimethyl-1, 4-dihydro-4-oxoquinoline-3-carboxylate (130 mg) is added 5% aqueous potassium hydroxide solution (3.2 ml) and the mixture is refluxed for 4 hours. After cooling, the reaction mixture is made acidic with acetic acid and then made weak alkaline with potassium carbonate. The resultant is extracted with dichloroethane and the extract is dried, followed by distillating the solvent under reduced pressure. To the residue is added diethyl ether and the precipitated crystals are filtered to give 7-(3-amino-l-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5, 8-dimethyl-l,4-dihydro-4-oxoquinoline-3-carboxylic acid (30 mg), m.p. 96°-98° C., as pale yellow needles.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1Br)([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:10]2[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1-c1ccc(Cl)cc1

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from example 1 step (i) and 4-chlorophenylboronic acid. Yield 0.63 g
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH:13]=O)=[C:11]([Cl:15])[N:10]=[C:9]1[C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:26]O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[CH2:1]([N:8]1[C:12]([C:13]#[N:26])=[C:11]([Cl:15])[N:10]=[C:9]1[C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)c1ccc(-c2nc(Cl)c(C=O)n2Cc2ccccc2)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(-c2nc(Cl)c(C#N)n2Cc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 62.3 %

Procedure:
In 30 ml of pyridine were dissolved 3.4 g of 1-benzyl-4-chloro-2-(4-dimethylaminophenyl)-5-formylimidazole and 1.39 g of hydroxylamine hydrochloride, and 6 ml of acetic anhydride was added dropwise to the solution. After the addition was completed, the reaction solution was stirred at 100° C. for 3 hours, and evaporated to dryness under reduced pressure. The residue was dissolved in 100 ml of chloroform, washed with two 300 ml portions of water, and evaporated to dryness under reduced pressure. The residue was recrystallized twice from 30 ml of ethanol, yielding 2.1 g of 1-benzyl-4-chloro-2-(4-dimethylaminophenyl)-5-cyanoimidazole as slightly brown needles, m.p. 125°-127° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:40][O:41][CH2:42][CH3:43])[C:4]([CH3:39])=[C:5]([C:28]([O:30]COC(=O)C(C)(C)C)=[O:29])[CH:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:7]=1[C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:9]>C(OC(C)C)(C)C.O>[CH3:39][C:4]1[N:3]([CH2:40][O:41][CH2:42][CH3:43])[C:2]([CH3:1])=[C:7]([C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:15])([CH3:16])[CH3:17])=[O:9])[C@@H:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:5]=1[C:28]([OH:30])=[O:29]
Reactant: CCOCN1C(C)=C(C(=O)OCOC(=O)C(C)(C)C)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Solvent: CC(C)OC(C)C
Solvent: O
Product: CCOCN1C(C)=C(C(=O)O)[C@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.3 %

Procedure:
In 20 ml of isopropyl ether saturated with water was dissolved 1.2 g of bis(pivaloyloxymethyl) 1,4-dihydro-2,6-dimethyl-1-ethoxymethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate obtained in Example 14, and 200 mg of Lipase B was added thereto, followed by stirring at room temperature for 4 hours. Any insoluble matter was removed by filtration and washed with dichloromethane. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate/hexane=1/2) to obtain 840 mg (yield: 83%) of (S)-1,4-dihydro-2,6-dimethylethoxymethyl-4-(3-nitrophenyl)-5-pivaloyloxymethoxycarbonyl-3-pyridinecarboxylic acid as a pale yellow crystal.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([N:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc2c(c1)CCC21CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(CN2CCC3(CCc4ccccc43)CC2)cc1
Temperature: 100 °C
Yield: 18.9 %

Procedure:
To a stirred solution of spiro[indane-1,4'-piperidine] (110 mg, 0.59 mmol), in anhydrous DMF (10 ml), under an atmosphere of nitrogen, was added potassium carbonate (98 mg, 0.71 mmol) followed by benzyl bromide (0.08 ml, 0.65 mmol) dropwise. The mixture was heated at 100° C. for 2 hours, after which time the solution was cooled to ambient temperature. The solvent was removed in vacuo, then ether (20 ml) was added to the residue and the mixture was washed with water (2×20 ml). The organic layer was separated, dried (MgSO4) and the solvent evaporated in vacuo. The crude residue was chromatographed using 1:1 petrol (60/80):ether, to give 1'-benzylspiro[indane-1,4'-piperidine] as a viscous colourless oil (31 mg, 20%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[Br:8][C:9]1[C:14](Br)=[N:13][CH:12]=[CH:11][N:10]=1>C1COCC1>[Br:8][C:9]1[CH:14]=[N:13][C:12]([N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)=[CH:11][N:10]=1
Reactant: c1c[nH]cn1
Reactant: Brc1nccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1cnc(-n2ccnc2)cn1
Temperature: 0 °C

Procedure:
To sodium hydride (0.20 g) in THF (15 ml), imidazole (0.57 g) was added and cooled to 0° C. To the above mixture 2,3-dibromopyrazine (2 g) was added and entire reaction mixture was allowed to reflux for overnight. The reaction mixture was quenched with water 5 ml volatiles were removed under vacuum. The resulting crude mass was purified by column chromatography to afford 2-bromo-5-(1H-imidazol-1-yl)pyrazine as pure product.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][C:9](=[O:17])[NH:10][NH:11][C:12](OCC)=[O:13])=[C:6]([F:18])[C:5]([F:19])=[C:4]([F:20])[C:3]=1[F:21].C(=O)([O-])[O-].[K+].[K+]>O>[F:18][C:6]1[C:7]([N:8]2[C:9](=[O:17])[NH:10][NH:11][C:12]2=[O:13])=[C:2]([F:1])[C:3]([F:21])=[C:4]([F:20])[C:5]=1[F:19]
Reactant: CCOC(=O)NNC(=O)Nc1c(F)c(F)c(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=c1[nH][nH]c(=O)n1-c1c(F)c(F)c(F)c(F)c1F
Temperature: 70 °C

Procedure:
4-(Pentafluorophenyl)-1-carbethoxysemicarbazide, 2.13 g (0.0068 M), and potassium carbonate, 0.938 g (0.0068 M), are added to 75 ml of water. The mixture is heated at 70° C. under N2 about 12 hours. The solution is cooled in an ice bath and filtered to remove a trace of starting material. The pH of the solution is adjusted to pH 7 with concentrated HCl and extracted with ethyl acetate to remove a product which is less polar than the urazole in the TLC system, chloroform/ethyl acetate/acetic acid (5/5/1). The pH of the solution is reduced to 1 or 2 with concentrated HCl and then extracted with ethyl acetate. About 1/3 of a volume of toluene is added to the ethyl acetate and the solvents evaporated. The resulting crude solid weighs 0.569 g. The product is purified by two crystallizations from ethyl acetate/toluene (1/3 by vol). The yield of purified material is 0.476 g. It is recrystallized from H2O, mp 223°-226°.
Reaction SMILES: [OH-].[Na+].Cl[CH2:4][CH:5]([OH:9])[CH2:6][CH2:7][Cl:8].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1>O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:4][CH:5]([OH:9])[CH2:6][CH2:7][Cl:8])=[CH:13][CH:12]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OC(CCl)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OC(CCCl)COc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
To a rapidly stirring solution of 22.5 g (0.56 mole) of sodium hydroxide in 400 ml of water was added, dropwise, 73.8 g (0.52 mole) of freshly distilled 1,4-dichloro-2-butanol. The mixture was stirred for 15 min at ambient temperature. To this mixture was added, over a 45 min period, a solution obtained by adding 75.0 g (0.43 mole) of 4-bromophenol to a solution of 18.0 g (0.47 mole) of sodium hydroxide in 430 ml of water. The mixture was stirred vigorously for 30 hr and then cooled to an ice bath. The suspended solid was collected by filtration, rinsed with water several times and air dried. Recrystallization from ethyl ether-petroleum ether (b.p. range 30°-60° C.) gave 44.2 g (37%) of white solid, m.p. 75°-78° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:8])[CH:7]=1.[Mg].Cl.[OH2:12]>C1COCC1.C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:2]2[CH2:3][CH2:4][C:5](=[O:12])[CH2:6][CH2:7]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O
Reactant: Fc1cc(F)cc(Br)c1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O=CO
Product: O=C1CCC(c2cc(F)cc(F)c2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Grignard reagent was prepared from 50.0 g (259 mmol) of 3,5-difluorobromobenzene and 6.32 g (260 mmol) of dried magnesium in 350 ml of THF, and cooled down to 0° C. Solution of 40.6 g (260 mmol) of a commercially available cyclohexanedionemonoethylene ketal in 300 ml of THF was added dropwise thereto. After finishing of the dropping, the reaction product was warmed up to room temperature and stirred for 3 hours. The reaction product was added to 500 ml of 6N hydrochloric acid, the product was extracted with toluene, washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, and the solvent was distilled off. To the residue was added 100 ml of toluene and 5 g of p-toluene sulfonic acid (hereinafter abbreviated to PTS) and refluxed for 5 hours with the water formed by the reaction being removed by a Dean and Stark. Subsequently, 2 g of ethylene glycol was added and refluxed for 2 hours. To the reaction product was added 200 ml of water, the organic layer was washed with saturated aqueous sodium bicarbonate solution and water in turn, dried over magnesium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography treatment using toluene/ethyl acetate (4/1) as eluent, and then subjected to hydrogenation in ethanol using 2.02 g of 5% Pd/C as catalyst. After termination of the reaction, the catalyst was filtered off, and the ethanol was distilled off. After the concentrated product thus obtained was refluxed in 150 ml of formic acid for 3 hours, 400 ml of water was added to the reaction product, the product was extracted with toluene, the extract was washed with saturated aqueous sodium bicarbonate solution and water in turn, the toluene layer was dried over magnesium sulfate, and then the toluene was distilled off to obtain 20.2 g (96.1 mmol) of 4-(3,5-difluorophenyl)cyclohexanone. Yield of this product from 3,5-difluorobromobenzene was 37.1%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]([C:18](F)=[O:19])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]#[N:17])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]([C:26]1[N:27]=[C:28]([NH2:31])[S:29][CH:30]=1)=[O:25]>O1CCOCC1>[CH3:22][O:23][C:24]([C:26]1[N:27]=[C:28]([NH:31][C:18](=[O:19])[C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]#[N:17])[S:29][CH:30]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C#N)C(=O)F
Reactant: COC(=O)c1csc(N)n1
Solvent: C1COCCO1
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2C#N)NC(=O)OC(C)(C)C)n1
Temperature: 120 °C
Yield: 95.3 %

Procedure:
[(S)-2-(2-Cyano-phenyl)-1-fluorocarbonyl-ethyl]-carbamic acid tert-butyl ester (2.4 g, 8.2 mmol) and 2-amino-thiazole-4-carboxylic acid methyl ester (1.24 g, 7.8 mmol) were dissolved in p-dioxane (40 mL). The mixture was heated in a sealed tube under microwave irradiation at 120° C. for 15 minutes The solution was concentrated, and the residue was purified by chromatography over silica gel eluted with 1:1 ethyl acetate/hexanes to give 2-[(S)-2-tert-butoxycarbonylamino-3-(2-cyano-phenyl)-propionylamino]-thiazole-4-carboxylic acid methyl ester as a white solid (3.2 g, 95%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15](=O)[C:14](=[CH:17][N:18](C)C)[CH2:13][CH2:12][CH2:11][C:8]=2[NH:9][CH:10]=1)=[O:5])[CH3:2].C(O)(=O)C.[NH2:25]N>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]3=[N:25][NH:18][CH:17]=[C:14]3[CH2:13][CH2:12][CH2:11][C:8]=2[NH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c1C(=O)C(=CN(C)C)CCC2
Reactant: NN
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]c2c1-c1n[nH]cc1CCC2

Procedure:
The title compound is prepared in analogous fashion to Example 8 using 5-dimethylaminomethylene-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxylic acid ethyl ester and hydrazine acetate. The crude product mixture is carried into the next step without purification. Electrospray mass spectrum: m/z 246 [M+1]; 1H NMR (DMSO-d6, 300 MHz) δ>13.0 (br s, 1H), 11.65 (br s, 1H), 7.49 (s, 1H), 7.20 (s, 1H), 4.25 (q, J=7.2 Hz, 2H), 2.91 (m, 2H), 2.76 (m, 2H), 1.84 (m, 2H), 1.28 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=O)[CH2:17]Br)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[C:26]([Br:27])=[CH:25][CH:24]=[CH:23][N:22]=1>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[N:20]=[C:21]2[C:26]([Br:27])=[CH:25][CH:24]=[CH:23][N:22]2[CH:17]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: Nc1ncccc1Br
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCC[C@H]1c1cn2cccc(Br)c2n1
Temperature: 78 °C
Reaction time: 8 h
Yield: 153.7 %

Procedure:
(S)-benzyl-2-(2-bromoacetyl)pyrrolidine-1-carboxylate (1.771 g, 5.4 mmol), 2-amino-3-bromo-pyridine (0.9412 g, 5.4 mmol), and ethanol (20 mL) were combined under nitrogen. The reaction mixture was heated to 78° C. and stirred overnight. The sample was concentrated and saturated sodium bicarbonate (50 mL) was added. The mixture was extracted with ethyl acetate (3×50 mL). The ethyl acetate extracts were dried over magnesium sulfate and filtered. The crude material was adsorbed onto silica gel and purified by flash chromatography (40 g SiO2, 0-100% ethyl acetate in hexanes) to give (S)-benzyl-2-(8-bromoimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate (0.869 g, 8.3 mmol, 2.2 mmol, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[CH3:17][N:18]([CH3:31])[C:19]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(O)(=O)C>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:12][CH2:13][N:14]([CH:22]2[CH2:21][CH2:20][C:19]([N:18]([CH3:31])[CH3:17])([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:24][CH2:23]2)[CH2:15][CH2:16]1
Reactant: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: CN(C)C1(c2ccccc2)CCCCC1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C)C1(c2ccccc2)CCC(N2CCC(c3c[nH]c4ccc(Cl)cc34)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-chloro-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (218 mg, 1 mmole) and 4-dimethylamino-4-phenylcyclohexane (217 mg, 1 mmole) were dissolved in dry 1,2-dichloroethane (20 ml). Glacial acetic acid (1 mmole) and sodium triacetoxy boron hydride (300 mg, 1.4 mmole) were added to this mixture. The reaction mixture was then stirred for 24 hours at RT. The reaction mixture was worked up by distilling off the 1,2-dichloroethane and diluted with water (10 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The product was a mixture of two diastereoisomeric compounds, which were separated by chromatography with methanol. The non-polar diastereoisomer was obtained as a colourless oil in a yield of 210 mg (48%), and the polar diastereoisomer was obtained as a colourless oil in a yield of 80 mg (18%).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]([C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=2)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]([C:26]1[CH:31]=[N:30][C:29](Cl)=[CH:28][N:27]=1)=[O:25]>O1CCOCC1>[CH2:1]([C:8]1[N:9]=[N:10][C:11]([C:16]2[CH2:17][CH2:18][N:19]([C:29]3[N:30]=[CH:31][C:26]([C:24]([O:23][CH3:22])=[O:25])=[N:27][CH:28]=3)[CH2:20][CH:21]=2)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(Cc2ccccc2)nnc(C2=CCNCC2)c1C
Reactant: COC(=O)c1cnc(Cl)cn1
Solvent: C1COCCO1
Product: COC(=O)c1cnc(N2CC=C(c3nnc(Cc4ccccc4)c(C)c3C)CC2)cn1
Temperature: 160 °C
Yield: 29.9 %

Procedure:
To 4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (170 mg, 0.358 mmol) is added 50% TFA in DCM. The reaction mixture is stirred for 10 min and concentrated to afford 3-benzyl-4,5-dimethyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazine as a yellow sticky solid (125 mg, 100%). To a solution of 3-benzyl-4,5-dimethyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazine (180 mg, 0.644 mmol) in dioxane is added methyl-5-chloropyrazine-2-carboxylate (222 mg, 1.29 mmol) and TEA (0.45 mL, 3.22 mmol) in a microwave tube. The reaction mixture is heated at 160° C. for 40 min in a microwave reactor. The mixture is concentrated to afford a brown oil and purified by prep HPLC, eluting with 10%-100% acetonitrile:water (both mobile phases modified by 3% n-PrOH). Fractions containing the desired product are combined and freeze-dried to afford a white solid (80 mg, 30%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[C:12]([OH:14])=[O:13].S(=O)(=O)(O)O.O.[CH3:21]O>>[CH3:21][O:9][C:8]([C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([C:12]([OH:14])=[O:13])=[C:4]([CH3:11])[CH:5]=1)=[O:10]
Reactant: Cc1cc(C(=O)O)cc(C)c1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cc(C)c(C(=O)O)c(C)c1

Procedure:
2,6-Dimethyl-1,4-benzenedicarboxylic acid (from Preparation 7) (5.0 g, 26mmol) was suspended in methanol (40 mL), concentrated sulfuric acid (5 mL) was added, and the mixture was heated at reflux for 2 hours. The solution was cooled, and water was added to precipitate the product. Filtration, followed by washing with water (3×) and petroleum ether (3×), and drying at high vacuum gave 2.05 g of the product as a white powder, m.p. 191°-192° C. (ref. W. A. Noyes, cited above).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8].[NH3:13]>CO>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:13])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Br)c1
Reactant: N
Solvent: CO
Product: NS(=O)(=O)c1cnc(Cl)c(Br)c1
Reaction time: 8 h

Procedure:
5-Bromo-6-chloropyridine-3-sulfonyl chloride (8.2 g) in methanol (20 mL) was cooled to 0° C. To this mixture was added 7N NH3 in methanol (80 mL). The reaction mixture was stirred overnight. The solvent was removed at low temperature, and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. The solid was purified by flash column chromatography on silica gel using 10-50% ethyl acetate in hexanes to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[Br:16])([CH3:4])([CH3:3])[CH3:2].[C:18](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[C:1]([O:5][C:6](=[O:17])[N:7]([C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[Br:16])[CH3:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1Br
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C(=O)OC(C)(C)C)c1cc(F)c(F)cc1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of Example 144A (12.37 g, 40.1 mmol) in anhydrous N,N-dimethylformamide (100 mL) was added cesium carbonate (19.62 g, 60.2 mmol) and iodomethane (5.02 mL, 80 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours, and was partitioned between ethyl acetate and brine. The organic phase was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated and the residue was separated by flash chromatography on silica gel (Teledyne CombiFlash Rf, 40% to 100% ethyl acetate in hexane) to provide the title compound. MS (ESI+) m/z 322 (M+1).