Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([CH2:10][C@H:11]([NH2:24])[C:12](=[O:23])[NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:7]=[CH:6][C:5]=1[O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28].[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([CH2:10][C@H:11]([NH:24][S:38]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:40])=[O:39])[C:12](=[O:23])[NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:7]=[CH:6][C:5]=1[O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)COc1ccc(C[C@H](N)C(=O)NCc2ccc(OC)cc2)cc1C(=O)OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)COc1ccc(C[C@H](NS(=O)(=O)c2ccccc2)C(=O)NCc2ccc(OC)cc2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-[(2S)-2-Amino-2-(4-methoxy-benzylcarbamoyl)-ethyl]-2-methoxycarbonylmethoxy-benzoic acid methyl ester of Step G (40 mg, 0.072 mmol) is stirred in pyridine (0.5 mL) at 0° C. under N2. Benzenesulfonyl chloride (20 mg, 0.11 mmol) is added and the reaction is stirred overnight at RT. The mixture is then diluted with CH2Cl2 (20 mL), washed with 2N HCl (2×20 mL) and then with saturated NaHCO3 (2×20 mL). The organics are dried over MgSO4, filtered, concentrated and purified by flash column chromatography to provide 5-[(2S)-2-benzenesulfonylamino-2-(4-methoxy-benzylcarbamoyl)-ethyl]-2-methoxycarbonylmethoxy-benzoic acid methyl ester.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([C:23]#[C:24][CH2:25][NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[O:33][CH2:34]SC)(C(C)(C)C)(C)C.C1CCCCC=1.S(Cl)(Cl)(=O)=O.N#N.[N-:50]=[N+:51]=[N-:52].[Na+]>C(Cl)Cl>[N:50]([CH2:34][O:33][C@@H:11]1[C@@H:10]([CH2:9][OH:8])[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([C:23]#[C:24][CH2:25][NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12]1)=[N+:51]=[N-:52]
Reactant: [N-]=[N+]=[N-]
Reactant: CSCO[C@H]1C[C@H](n2cc(C#CCNC(=O)C(F)(F)F)c(=O)[nH]c2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: N#N
Agent: [Na+]
Solvent: C1=CCCCC1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: [N-]=[N+]=NCO[C@H]1C[C@H](n2cc(C#CCNC(=O)C(F)(F)F)c(=O)[nH]c2=O)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36.7 %

Procedure:
To a solution of (3) (348 mg, 0.63 mmol) and cyclohexene (0.32 ml, 3.2 mmol) in dry CH2Cl2 (5 ml) at 4° C., sulfurylchloride (1M in CH2Cl2, 0.76 ml, 0.76 mmol) was added drop wise under N2. After 10 min TLC indicated the full consumption of the nucleoside (3). The solvent was evaporated and the residue was subjected to high vacuum for 20 min. It was then redissolved in dry DMF (3 ml) and treated with NaN3 (205 mg, 3.15 mmol). The resulting suspension was stirred under room temperature for 2 h. The reaction was quenched with CH2Cl2 and the organic layers were washed with sat aq. NaCl solution. After removing the solvent, the resulting yellow gum was redissolved in THF (2 ml) and treated with TBAF (1 M in THF, 0.5 ml) at room temperature for 30 min. The solvent was removed and the reaction worked up with CH2Cl2 and sat. aq. NaHCO3 solution. The aqueous layer was extracted three times with CH2Cl2. Purification by chromatography on silica (EtOAc:petroleum ether 1:1 to EtOAc) gave (4) (100 mg, 37%) as a pale yellow foam. 1H NMR (d6 DMSO) δ 2.15-2.26 (m, 2H, H-2′), 3.47-3.57 (m, 2H, H-5′), 3.88-3.90 (m, 1H, H-4′), 4.14 (d, J=4.7 Hz, 2H, CH2NH), 4.24-4.27 (m, 1H, H-3′), 4.75 (s, 2H, CH2N3), 5.14 (t, J=5.2 Hz, 1H, OH), 5.96-6.00 (m, 1H, H-1′), 8.10 (s, 1H, H-6), 10.00 (s, 1H, NHCOCF3)), 11.26 (s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:10][CH:9]2[N:21]([CH3:36])[C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=2)=[CH:4][CH:3]=1.[CH3:37][S:38][CH2:39][CH2:40][CH:41]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][N:18]([CH2:41][CH2:40][CH2:39][S:38][CH3:37])[CH2:17][CH2:16]3)=[O:14])[CH2:10][CH:9]2[N:21]([CH3:36])[C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:33])([F:32])[F:34])[CH:24]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCNCC3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F
Reactant: CSCCC=O
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCN(CCCSC)CC3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described for the synthesis of example 104, the title compound N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(3-methylsulfanyl-propyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 3-(methylthio)propionaldehyde instead of acetone and was obtained as a colorless oil. MS m/e: 612.1 [M]+.
Reaction SMILES: [O:1]1[CH:3]([CH3:4])[CH2:2]1.[CH3:5][NH:6][CH2:7][CH2:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO>[CH3:5][N:6]([CH2:7][CH2:8][CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:2][CH:3]([OH:1])[CH3:4]
Reactant: CNCCC(c1ccccc1)c1ccccc1
Reactant: CC1CO1
Solvent: CO
Product: CC(O)CN(C)CCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
6.38 g of 1,2-epoxypropane was added to a solution of 22.5 g of N-methyl-3,3-diphenylpropylamine in 60 ml of methanol. The solution was maintained at 15°-20° C. for 3 days, and then an additional 1.16 g of 1,2-epoxypropane was added. This solution was maintained for 24 hours at room temperature. The methanol was evaporated off and the product purified by chromatography on a silica gel column (methanol gradient in chloroform), to give 24 g of the title compound as colorless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.ClC1C=CC=CC=1.[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]Cl)#[N:15]>C(O)CO>[N:1]1([C:14]2[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[S:22][N:15]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccccc1SCl
Reactant: C1CNCCN1
Solvent: OCCO
Solvent: Clc1ccccc1
Product: c1ccc2c(N3CCNCC3)nsc2c1
Yield: 91 %

Procedure:
215.4 g (2.50 mol) of piperazine, 50.0 g of chlorobenzene, 100.0 g of ethylene glycol were placed in a four-neck 1000 ml flask equipped with a stirrer, a thermometer, a dropping funnel and a condenser, 214.1 g (1.00 mol) of 2-cyanobenzenesulfenyl chloride was added dropwise in the melted state at about 120° C. over 1 hour while stirring, which was thereafter stirred for 2 hours to complete the reaction. After excess piperazine was removed with water, the reaction mixture was made acidic with hydrochloric acid, extracted into an aqueous layer, which was made alkaline with aqueous sodium hydroxide to obtain 199.5 g (m.p. 89-90° C.) of 3-(1-piperazinyl)-1,2-benzisothiazole as crystals. Yield from 2-cyanobenzenesulfenyl chloride was 91.1%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:17])[CH2:11][CH:12]([CH3:16])[CH2:13][CH:14]=O)=[CH:5][CH:4]=1)#[N:2].[NH2:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([CH2:32][CH3:33])[C:24]3[C:29]([C:30]=2[CH:31]=1)=[CH:28][CH:27]=[CH:26][CH:25]=3.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:17])[CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][NH:18][C:19]2[CH:20]=[CH:21][C:22]3[N:23]([CH2:32][CH3:33])[C:24]4[C:29]([C:30]=3[CH:31]=2)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CC(CC=O)CC(=O)Nc1ccc(C#N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCn1c2ccccc2c2cc(NCCC(C)CC(=O)Nc3ccc(C#N)cc3)ccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 40.2 %

Procedure:
A solution of the compound obtained in Step 2 (110 mg, 0.48 mmol) and 3-amino-N-ethylcarbazole (151 mg, 0.72 mmol) in TFA (1 mL) and toluene (1 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added sodium triacetoxyborohydride (304 mg, 1.43 mmol), and the mixture was stirred at room temperature for additional 14 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with 1N aqueous sodium hydroxide solution, water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 80% ethyl acetate/hexane) to give the title compound (82 mg, 0.193 mmol, 40.5%) as a pale-yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: COc1ccccc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1ccccc1NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 62 %

Procedure:
o-Anisidine (2.34 ml, 20 mmol) was dissolved in toluene (60 ml) to which were subsequently added, with cooling in an ice bath, pyridine (4.58 ml, 60 mmol), p-toluenesulfonyl chloride (3.89 g, 20 mmol) and a catalytically effective amount of 4-dimethylaminopyridine. After 2.5 hours of stirring at room temperature, the resulting reaction solution was mixed-with water (50 ml), extracted with ethyl acetate and then washed with water, 10% sodium hydroxide aqueous solution, 1N hydrochloric acid, water and saturated brine in that order. After drying on anhydrous magnesium sulfate and removing the solvent by evaporation, the resulting orange solid was dissolved in ethyl acetate (50 ml), adsorbed to anhydrous magnesium sulfate (20 g), eluted with ether and then subjected to evaporation to remove the solvent. The resulting colorless solid which was then washed with an ether-hexane (1:1) mixture solution to obtain 3.44 g (62.0%) of the title compound in the form of colorless prism crystals.
Reaction SMILES: [ClH:1].C[O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1.[CH3:29][NH2:30].CO.C(OCC)(=O)C.C(OCC)C>CO>[ClH:1].[ClH:1].[C:22]1([CH:18]2[CH2:17][N:16]([CH:14]([CH3:15])[CH2:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([NH:30][CH3:29])=[O:3])=[CH:8][CH:9]=3)[CH2:21][CH2:20][O:19]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN
Reactant: COC(=O)COc1ccc(CC(C)N2CCOC(c3ccccc3)C2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCOCC
Product: CNC(=O)COc1ccc(CC(C)N2CCOC(c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[2-(2-phenylmorpholino)propyl]phenoxyacetic acid methyl ester hydrochloride (3.0 g; obtained from the mother liquors of Example 1) in methanol (50 ml) was added a 30% aqueous solution of methylamine (10 ml). This mixture was heated under reflux for 3 hours during which time 3 further 10 ml portions of the methylamine solution were added. The solution was cooled to room temperature, a further 10 ml portion of methylamine solution added, and the reaction mixture allowed to stand at room temperature overnight. The solvent was removed under vacuum, aqueous sodium carbonate added to the residue and extracted with dichloromethane (X2). The combined extracts were washed with brine (X2), dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated to dryness. Chromatography of the residue on silica gel in 2% methanol-dichloromethane gave an oil, which, on treatment with an ethereal solution of hydrogen chloride, gave the title compound, m.p. 127°-130° C. (methanol-ethyl acetate-diethyl ether), as a 12:88 mixture of diastereoisomers.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[Cl:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=3)=[CH:13][CH:14]=2)[C:9]([NH:24][C:25]([NH2:27])=[NH:26])=[N:8][CH:7]=1>COCCOC.CN1C(=O)CCC1>[C:1]([O-:4])(=[O:3])[CH3:2].[Cl:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=3)=[CH:13][CH:14]=2)[C:9]([NH:24][C:25]([NH2:27])=[NH2+:26])=[N:8][CH:7]=1
Reactant: N#Cc1cccc(-c2ccc3c(Cl)cnc(NC(=N)N)c3c2)c1
Reactant: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: COCCOC
Product: CC(=O)[O-]
Product: N#Cc1cccc(-c2ccc3c(Cl)cnc(NC(N)=[NH2+])c3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 131.1 %

Procedure:
A solution of acetic acid (0.72 kg, mol) in DME (13.6 L) was added dropwise to a stirred solution of (4-chloro-7-(3-cyanophenyl)isoquinolin-1-yl)guanidine (4.4 kg, 13.7 mol) in NMP (14 kg) at 100° C. After addition the thick slurry was allowed to cool and was stirred overnight at room temperature. The solid was collected by filtration, washed with DME (4.9 L) and dried overnight in vacuo at 50° C. to give (4-chloro-7-(3-cyanophenyl)isoquinolin-1-yl)guanidinium acetate (6 kg, 143%) as an NMP wet off white solid.
Reaction SMILES: CON(C)[C:4]([CH2:6][C:7]1[N:8]=[CH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=O.[C:18]1([Mg]Br)C=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH2:26]>C1COCC1>[C:6]([C:7]1[N:8]=[CH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:26])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O
Reactant: CON(C)C(=O)Cc1cc2ccccc2cn1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1cc2ccccc2cn1
Yield: 77 %

Procedure:
Under an argon gas stream, 168 mg of N-methoxy-N-methylisoquinoline-3-carboxyamide was dissolved in 1 mL of anhydrous THF, followed by stirring under cooling with ice. To the reaction liquid was slowly added 0.8 mL of phenyl magnesium bromide (1 mol/L THF solution), followed by continuously stirring for 30 minutes. Water was added to the reaction liquid, followed by extraction with chloroform. The organic layer was washed with diluted hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (chloroform alone) to obtain 154 mg (yield 77%) of a title compound as a yellow oily substance.
Reaction SMILES: [Cl-:1].[Zr+4:2].[Cl-].[Cl-].[Cl-].[CH2:6]1[CH2:10][O:9][CH2:8][CH2:7]1.C1(C)C=CC=CC=1.C([Li:22])CCC>CCCCCC>[O:9]1[CH2:10][CH2:6][CH2:7][CH2:8]1.[O:9]1[CH2:10][CH2:6][CH2:7][CH2:8]1.[Cl-:1].[Zr+2:2].[Cl-:1].[Cl-:1].[Li+:22]
Reactant: [Zr+4]
Reactant: [Li]CCCC
Agent: [Cl-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: [Li+]
Product: [Zr+2]
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Under argon and moisture-free conditions, 6.32 (27.1 mmol) of zirconium (IV) chloride were cooled to −78° C., and 175 mL of THF were slowly added. After addition the milky slurry was allowed to warm up to room temperature and was stirred for 45 minutes. At this point, 50 mL of toluene were added and the mixture was cooled again to −78° C. Then, over a period of 30 min, 36 mL of a 1.6 M solution of n-butyllithium in hexane was gradually introduced. The suspension turned from white to yellow and then gradually to dark brown. The reaction mixture was allowed to warm up to room temperature and was stirred for 18 hours. The removal of the lithium chloride was accomplished as follows : As much of the THF as possible was evaporated under reduced pressure and collected in a cooled dry ice trap. During this process the flask with the zirconium (II) chloride solution was kept at about 25° C. The amount of solvent removed was 194 mL.
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:5][CH:4]([C:6]#N)[CH2:3]1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl.C1C[O:20]CC1>[Zn].CS(O)(=O)=O>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][C:6]([CH:4]1[CH2:5][C:2]([F:8])([F:1])[CH2:3]1)=[O:20])[CH3:15]
Reactant: N#CC1CC(F)(F)C1
Reactant: C1CCOC1
Reactant: CCOC(=O)CBr
Agent: CS(=O)(=O)O
Agent: Cl
Agent: [Zn]
Product: CCOC(=O)CC(=O)C1CC(F)(F)C1
Temperature: 76 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
Zinc metal (0.558 g, 10 micron dust, 8.5 mmol) was stirred in THF (2.5 ml) and methane sulphonic acid (0.04 mmol) was added and refluxed at 76° C. for 10 minutes. To this was added 3,3-difluoro-cyclobutanecarbonitrile (500 mg, 4.3 mmol, prepared according to Elend et al. Synth Comm, 2005, 35, 657) and the reaction mixture was heated for a further 10 minutes. Ethyl bromoacetate (0.751 ml, 6.8 mmol) dissolved in THF (0.5 mL) was then injected over a 2 hour period with the aid of a syringe pump and after the addition the mixture was stirred for a further 30 minutes. Aqueous HCl (3 ml of 3 M solution) was added drop-wise at 0° C. and the reaction mixture was then stirred for 17 hours between 0 and 20° C. The reaction mixture was analyzed by MS and TLC which showed the formation of the product and the consumption of the starting material and the reaction was worked up with (2×20 ml) water and (2×20 ml) ethyl acetate, the organic portion was then dried (Na2SO4) and reduced in vacuo. The product was isolated and purified using flash chromatography (AcOEt 7:93 heptane) and 3-(3,3-difluoro-cyclobutyl)-3-oxo-propionic acid ethyl ester (599 mg, 68% yield) was obtained as a colourless liquid. MS (ESI+): 207.1 ([M+H]+).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(#N)C>O>[N:13]1([C:2]2[N:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: C1COCCN1
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1ccc(N2CCOCC2)nc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Ethyl 6-chloronicotinate (5.0 g) and morpholine (10 ml) were mixed and then heated to 100° C. In less than 5 minutes at this temperature, a thick paste formed. Acetonitrile (15 ml) was added and heating was continued overnight at 90° C. The mixture was cooled, diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo to give ethyl 6-morpholin-4-ylpyridine-3-carboxylate as a white solid.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH2:22])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:9]=[N:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH:1]([O:4][C:5]([C:7]1[N:8]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:22][S:30]([CH3:29])(=[O:32])=[O:31])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:9]=[N:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1cncn1C1CCCc2ccc(N)cc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)OC(=O)c1cncn1C1CCCc2ccc(NS(C)(=O)=O)cc21
Reaction time: 2.5 h

Procedure:
To a solution of 3-(7-amino-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester, which can be prepared as described as in Example 45, (0.408 g, 1.36 mmol) and pyridine (0.162 g, 2.04 mmol) in dichloromethane (4 mL) at 0° C. is added methanesulfonyl chloride (0.168 g, 1.47 mmol) and the reaction is stirred for 2.5 hours. The solution is then washed with 10% aqueous HCl and water and the combined aqueous phases are extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated to give a residue, which is purified by silica gel chromatography (dichloromethane-methanol mixtures) to give 3-(7-methanesulfonylamino-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; MS: (ESI) m/z 378.2 (M+H)+; 1H NMR (400 MHz, MeOD) δ ppm 1.38 (d, J=6.3 Hz, 3 H), 1.40 (d, J=6.3 Hz, 3 H), 1.84-1.93 (m, 2 H), 2.19-2.33 (m, 2 H), 2.87 (dt, J=16.9, 6.6 Hz, 1 H), 2.88 (s, 3 H), 3.01 (dt, J=16.9, 6.3 Hz, 1 H), 5.24 (sept, J=6.3 Hz, 1 H), 6.32 (t, J=6.1 Hz, 1 H), 6.81 (d, J=2.0 Hz, 1 H), 7.21 (dd, J=8.3, 2.0 Hz, 1 H), 7.26 (d, J=8.3 Hz, 1 H), 7.51 (s, 1 H), 7.75 (d, J=1.0 Hz, 1 H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15]1([N:18]2[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]2)[CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>O1CCCC1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH:15]1([N:18]2[CH2:23][CH2:22][CH:21]([NH:24][C:2]3[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=3[N+:12]([O-:14])=[O:13])[CH2:20][CH2:19]2)[CH2:17][CH2:16]1
Reactant: NC1CCN(C2CC2)CC1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(NC2CCN(C3CC3)CC2)c([N+](=O)[O-])c1

Procedure:
To a solution of 4-fluoro-3-nitrobenzenesulfonamide (1.26 g) and 1-cyclopropylpiperidin-4-amine (0.802 g) in tetrahydrofuran (20 mL) was added N,N-diisopropylethylamine (2.22 g) and 4-dimethylaminopyridine (35 mg). The mixture was stirred at reflux overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with aqueous NaHCO3, water, and brine and dried over Na2SO4. After filtration and concentration, the residue was dissolved in dichloromethane and loaded on a column and eluted with dichloromethane (500 mL), 5% 7N NH3 in 10% methanol in dichloromethane (1.5 L) to give the product.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].ClCCl.[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=1)[NH:16][CH:15]=[CH:14]2.[CH3:23][CH2:24][O:25]CC>>[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=1)[NH:16][CH:15]=[C:14]2[C:1](=[O:5])[C:2]([O:25][CH2:24][CH3:23])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)c1cc(Br)cc2cc[nH]c12
Reactant: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1c[nH]c2c(C(C)C)cc(Br)cc12
Reaction time: 4.5 h
Yield: 67 %

Procedure:
A 2.0 M solution of oxalyl dichloride in dichloromethane (60 ml, 0.12mol) was added dropwise during 10 min to a solution of 5-Bromo-7-isopropyl-1H-indole (14.5 g, 0.061 mol) in Et2O (220 ml) at room temperature under a nitrogen atmosphere. The mixture was stirred for 4.5 hr. The Et2O was removed by evaporation and absolute EtOH (220 ml) was added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. The EtOH was evaporated, and EtOAc was added to the residue and washed with sat. NaHCO3 and brine. The organic layers were dried over MgSO4, concentrated, and dried under vaccume to give a crude product (13.8 g, 67%). 1H NMR (300 MHz, CDCl3) δ 8.85 (b, NH), 8.46 (dd, 2H), 7.33 (d, 1H), 4.42 (qrt, 2H), 3.21 (m, 1H), 1.44 (t, 3 H), 1.38 (d, 6H), ESI (+) MS m/e=339 (MH+), ESI (−) MS m/e=337 (MH−).