Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([NH:10][C@H:11]([C@@H:24]([OH:26])[CH3:25])[C:12]([NH:14][NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].ClC1C(C)=C(N[C@H]([C@@H](O)C)[C:39](O)=[O:40])C=CC=1C#N.COC1C=C(C=CC=1)C(NN)=O>CO.CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([NH:10][C@H:11]([C@@H:24]([OH:26])[CH3:25])[C:12]([NH:14][NH:15][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([O:40][CH3:39])[CH:22]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)[C@H](C)O)ccc(C#N)c1Cl
Agent: COc1cccc(C(=O)NN)c1
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cccc(C(=O)NNC(=O)[C@H](Nc2ccc(C#N)c(Cl)c2C)[C@H](C)O)c1

Procedure:
Intermediate 6a was synthesized similarly to the procedure outlined for intermediate 1b described above using (2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 1a) (530 mg, 2.0 mmol) and 3-methoxy-benzohydrazide (329 mg, 2.0 mmol). After column chromatography (2% methanol/EtOAc) the title compound was isolated as a white solid (471 mg, 57%). 1H NMR (500 MHz, d6-acetone, δ in ppm) 9.88 (br s, 1H), 9.53 (br s, 1H), 7.47 (m, 3H), 7.38 (at, J=8.0 Hz, 1H), 7.12 (m, 1H), 6.66 (d, J=8.7 Hz, 1H), 5.55 (d, J=7.0 Hz, 1H), 4.88 (br s, 1H), 4.40 (m, 1H), 4.12 (dd, J=3.3, 7.0 Hz, 1H), 3.83 (s, 3H), 2.34 (s, 3H), 1.35 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH:1]1[NH:2][C:3]2[N:9]=[C:8]([NH2:10])[N:7]=[C:6](Cl)[C:4]=2[N:5]=1.C(N(CC)CC)C.C[O-:20].[Na+].O>C(O)C>[NH:7]1[C:6](=[O:20])[C:4]2[NH:5][CH:1]=[N:2][C:3]=2[N:9]=[C:8]1[NH2:10]
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: Nc1nc2nc[nH]c2c(=O)[nH]1

Procedure:
6-Chloroguanine derivative prepared in Preparation 6 (100 mg) was dissolved in 10 ml of ethanol, 32 ml of triethylamine and 53 mg of sodium methoxide were added, and the resulting mixture was refluxed for 4 hours. The reaction was stopped by adding 10 ml of water. The reaction solution was extracted with dichloromethane and distilled under reduced pressure. The residue was purified by silica gel column to give a compound wherein 6-position of guanine was substituted by ethoxy group.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[CH3:6][N:7]([O:20][CH3:21])[C:8](=[O:19])[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11](F)[CH:10]=1>C(#N)C>[CH3:6][N:7]([O:20][CH3:21])[C:8](=[O:19])[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])[CH:10]=1
Reactant: CON(C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)CN
Solvent: CC#N
Product: CON(C)C(=O)c1ccc([N+](=O)[O-])c(NCC(C)C)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
Add isobutylamine (8.7 mL) dropwise to a solution of N-[methyl]-N-[methoxy]-3-fluoro-4-nitrobenzamide (2 g, 8.77 mmol) in 80 mL dry acetonitrile at 0° C. Stir the resulting orange solution at room temperature over night. Concentrate under reduced pressure to provide the desired compound (90%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[C:21]([C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([NH:31][C:32](=[O:44])[CH2:33][N:34]2[CH2:39][CH2:38][NH:37][CH:36]([C:40]([NH:42][CH3:43])=[O:41])[CH2:35]2)=[C:26]([Cl:45])[CH:25]=1)(=[O:23])[CH3:22].C(N(CC)CC)C>COCCO>[C:21]([C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([NH:31][C:32](=[O:44])[CH2:33][N:34]2[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:7]3[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=3)[CH:36]([C:40]([NH:42][CH3:43])=[O:41])[CH2:35]2)=[C:26]([Cl:45])[CH:25]=1)(=[O:23])[CH3:22]
Reactant: CNC(=O)C1CN(CC(=O)Nc2c(Cl)cc(C(C)=O)cc2Cl)CCN1
Reactant: Fc1ccc(N(CCCCCl)c2ccc(F)cc2)cc1
Solvent: COCCO
Solvent: CCN(CC)CC
Product: CNC(=O)C1CN(CC(=O)Nc2c(Cl)cc(C(C)=O)cc2Cl)CCN1CCCCN(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 72 h
Yield: 19 %

Procedure:
A mixture of 2.07 parts of N-(4-chlorobutyl)-4-fluoro-N-(4-fluorophenyl)benzenamine, 2.5 parts of N-(4-acetyl-2,6-dichlorophenyl)-3-[(methylamino)carbonyl]-1-piperazineacetamide, 1.3 parts of N,N-diethylethanamine and 97 parts of 2-methoxyethanol was stirred for 3 days at 70° C. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The desired fraction was collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding a first fraction of 0.74 parts (19.0%) of N-(4-acetyl-2,6-dichlorophenyl)-4-[4-[bis(4-fluorophenyl)amino]butyl]-3-[(methylamino)carbonyl]-1-piperazineacetamide; mp. 87.1° C. The second fraction was collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding a second fraction of 0.78 parts (20.1%) of N-(4-acetyl-2,6-dichlorophenyl)-4-[4-[bis(4-fluorophenyl)amino]butyl]-3[(methylamino)carbonyl]-1-piperazineacetamide; mp. 85.0° C. Total yield: 1.52 parts (39.1%) of N-(4-acetyl-2,6-dichlorophenyl)-4-[4-bis(4-fluorophenyl)amino]butyl]-3-[(methylamino)carbonyl]-1-piperazineacetamide (compound 97).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:18][CH2:19][CH2:20][CH2:21]I.[Na+].[Cl-]>CN(C)C=O.O>[Cl:18][CH2:19][CH2:20][CH2:21][O:15][C:11]1[CH:10]=[C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:14]=[N:13][CH:12]=1
Reactant: ClCCCI
Reactant: Oc1cncc(OCc2ccccc2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCOc1cncc(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a solution of 5-(phenylmethoxy)-pyridine-3-ol (1.52 g, 7.56 mmol) in N,N-dimethylformamide (DMF) (10 mL) was added drop-wise over 5 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.238 g of an 80% dispersion in mineral oil, 7.94 mmol) in DMF (15 mL). The mixture was allowed to stir and warm to ambient temperature over 1 h. Next, 1-chloro-3-iodopropane (1.85 g, 9.07 mmol) was added drop-wise over 5 min. The resulting dark-brown mixture was stirred at ambient temperature for 4 h. Water (25 mL) was added, followed by saturated NaCl solution (25 mL), and the mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[C:37]1(C)[C:42](O)=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][C:26]2[CH:41]=[CH:42][CH:37]=[CH:38][C:39]=2[CH3:40])=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccccc1O
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)Oc4ccccc4C)cc3C)c2cc1OC
Yield: 87.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, o-cresol (25 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (62 mg, yield 84%).
Reaction SMILES: NC1C2CCOC=2C=CC=1.[CH2:11]([O:13][C:14]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:42][CH:41]3[CH:27]([C:28](=[O:48])[N:29]([CH3:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[CH:35][CH:36]4[C:38]([C:44]([OH:46])=[O:45])([NH:39][C:40]3=[O:43])[CH2:37]4)[CH2:26]2)[C:21]2[C:16](=[C:17]([CH3:51])[C:18]([O:49][CH3:50])=[CH:19][CH:20]=2)[N:15]=1)[CH3:12]>>[CH2:11]([O:13][C:14]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:42][CH:41]3[CH:27]([C:28](=[O:48])[N:29]([CH3:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[CH:35][CH:36]4[C:38]([C:44]([OH:46])=[O:45])([NH:39][C:40]3=[O:43])[CH2:37]4)[CH2:26]2)[C:21]2[C:16](=[C:17]3[CH2:51][CH2:50][O:49][C:18]3=[CH:19][CH:20]=2)[N:15]=1)[CH3:12]
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Agent: Nc1cccc2c1CCO2
Product: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc3c(c2n1)CCO3

Procedure:
The title compound (8) was prepared from 4-amino-2,3-dihydrobenzofurane following the procedure (Steps A-J) reported for synthesis of 17-[2-ethoxy-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.046]-octadec-7-ene-4-carboxylic acid (2): m/z=564 (M+H)+.
Reaction SMILES: C1([C@]2(O)[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])[CH3:10])CC1.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([O:22][CH3:23])[CH:15]=1.[C:24](=[O:27])([O-])[O-].[Li+].[Li+].O>CS(C)=O>[OH:27][C@H:24]1[C:9]([CH3:11])([CH3:10])[CH2:5][N:6]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([O:22][CH3:23])[CH:15]=2)[C@@H:7]1[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: COc1cc(F)ccc1C#N
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(N2CC(C)(C)[C@H](O)[C@H]2C)ccc1C#N
Yield: 44.1 %

Procedure:
A suspension (5 mL) of (2R,3S)-2,4,4-trimethylpyrrolidin-3-ol 0.5 oxalate (152 mg), 4-fluoro-2-methoxybenzonitrile (183 mg) and lithium carbonate (155 mg) in DMSO was stirred at 100° C. for 15 hr, added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→2/3) to give the title compound as a colorless solid (yield: 103 mg, yield: 45%).
Reaction SMILES: [CH:1]1([O:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:11]1(C)C=CC(S(O)(=O)=O)=CC=1.CO>O>[CH:1]1([O:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)COC1CCCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)COC1CCCC1
Temperature: 25 °C
Yield: 4424.1 %

Procedure:
In a three necks 500 ml flask were introduced, in the following order, 65 g (451 mmol) of (cyclopentyloxy)acetic acid (obtained according to U.S. Pat. No. 4,735,932), 1.4 g of para-toluenesulfonic acid and 280 ml of MeOH. After 6 hours at reflux, the reaction mixture was cooled at room temperature diluted into 300 ml of water and extracted with 300 ml of ether. The organic phase thus obtained was washed twice with water, dried over MgSO4 and concentrated. It was thus obtained 56.9 g of product (yield=80%) having a GC purity of 99%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[N:7][N:6]=[CH:5]4)[CH:25]=2)[CH2:20][CH2:21]1
Reactant: CN1CCN(c2nncc3cc(Br)ccc23)CC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCN(C)CC3)nncc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
A mixture of 6-bromo-1-(4-methylpiperazin-1-yl)phthalazine (0.13 g, 0.42 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide (0.13 g, 0.42 mmol), tetrakis(triphenylphosphine)palladium (24mg, 0.021 mmol) and 2 M potassium carbonate (0.7 mL, 1.4 mmol) in 5 mL DME/EtOH (4: 1) was stirred at 90° C. for 2 h. The mixture was directly purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 10% 2 M ammonia in MeOH/DCM to give the title compound (0.15g) as a yellow solid. Found MS (ES+): 402(M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[CH3:2].[Li]CCCC.CCCCCC.[C:29](=O)([O:33]CC)[O:30][CH2:31][CH3:32]>C1COCC1.O>[CH2:31]([O:30][C:29]([C:7]1[N:3]([CH2:1][CH3:2])[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)=[N:5][CH:6]=1)=[O:33])[CH3:32]
Reactant: CCn1ccnc1-c1cccc2ccccc12
Reactant: CCOC(=O)OCC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1cnc(-c2cccc3ccccc23)n1CC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-ethyl-2-naphthalen-1-yl-1H-imidazole (1.11 g, 5 mmol) in anhydrous THF (30 ml) at −78° C. under nitrogen is added a solution of n-BuLi in hexane (1.6 M, 3.44 ml, 5.5 mmol, 1.1 eq.) dropwise. The resulting mixture is stirred at −78° C. for 1 hr, followed by the addition of diethyl carbonate (1.77 g, 15 mmol, 3.0 eq.). The resulting solution is stirred at −78° C. for 30 min, warmed to rt slowly, and stirred for an additional 30 min at rt. Water (30 ml) is added to quench the reaction, and THF is evaporated under reduced pressure. The residue is extracted with EtOAc (30 ml×2) and the combined organic layers are washed with water and brine, dried over sodium sulfate, and concentrated. The crude product is purified through silica gel chromatography (hexanes/EtOAc, from 8:1 to 4:1) to give 3-ethyl-2-naphthalen-1-yl-3H-imidazole-4-carboxylic acid ethyl ester. LCMS 295 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C@@H:7]2[CH2:12][CH2:11][NH:10][CH2:9][C@H:8]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31].[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37]>CCOCC.C(O)C.CN(C)C=O>[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37].[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C@@H:7]2[CH2:12][CH2:11][N:10]([CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])[CH2:9][C@H:8]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:19][CH:20]=1
Reactant: CC(C)=CCBr
Reactant: Fc1ccc(O[C@@H]2CCNC[C@H]2c2ccccc2)cc1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCOCC
Product: CC(C)=CCN1CC[C@@H](Oc2ccc(F)cc2)[C@H](c2ccccc2)C1
Temperature: 79 °C

Procedure:
A mixture of 4.34 g trans-4-(4-fluorophenoxy)-3-phenylpiperidine, 4.8 g of anhydrous potassium carbonate, 2.62 g of 1-bromo-3-methyl-2-butene and 64 ml of dry dimethylformamide is heated and vigorously stirred overnight at 79° C. under nitrogen. The mixture is cooled to room temperature and partitioned between water (300 ml) and ether (500 ml). The phases are separated and the ether phase is washed with water (3×300 ml), followed by 300 ml of saturated sodium chloride solution. After drying over anhydrous sodium sulfate the ether extracts are filtered and concentrated in vacuo to a brown oil which crystallized upon standing. The crystalline solid is dissolved in 50 ml of boiling hexane and filtered to remove a dark brown gummy residue. Evaporation of the solvent in vacuo afforded an oil which crystallized under high vacuum to afford a dark orange solid. The solid is dissolved in ether (50 ml) and treated dropwise with a solution of 1.53 g of fumaric acid in a mixture of 100 ml of ether and 25 ml of absolute ethanol. The crude salt is filtered, washed with ether, dried and recrystallized from 325 ml of isopropanol to give product as colorless, fluffy platelets, mp 215°-217° C. dec.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([S:17](Cl)(=[O:19])=[O:18])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][S:29]([C:32]1[S:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[CH:33]=1)(=[O:31])=[O:30].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([S:17](=[O:19])(=[O:18])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][S:29]([C:32]3[S:36][C:35]4[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=4[CH:33]=3)(=[O:31])=[O:30])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2sc(S(=O)(=O)Cl)cc2C1
Reactant: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCc2sc(S(=O)(=O)Nc3ccccc3NS(=O)(=O)c3cc4ccccc4s3)cc2C1
Yield: 312.3 %

Procedure:
2-[2-(Benzo[b]thiophene-2-sulfonylamino) -phenylsulfamoyl]-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (280 mg) was prepared by using 2-chlorosulfonyl-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.049 g, 0.148 mmol) and benzo[b]thiophene-2-sulfonic acid (2-amino-phenyl)-amide (0.045 g, 0.148 mmol, prepared as in Example 1) using pyridine in DCM following procedure as in Example 2.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][CH2:4][C:3]1([C:11]([CH3:13])=[CH2:12])[CH:9]=[O:10].Br[CH:15]([CH3:17])[CH3:16]>>[CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][CH2:4][C:3]1([CH:9]([OH:10])[CH:15]([CH3:17])[CH3:16])[C:11]([CH3:13])=[CH2:12]
Reactant: CC(C)Br
Reactant: C=C(C)C1(C=O)CCC(C)=CC1C
Product: C=C(C)C1(C(O)C(C)C)CCC(C)=CC1C
Reaction time: 24 h
Yield: 72 %

Procedure:
To a mixture of Mg (1.2 g, 50 mmol), Li (0.35 g, 50 mmol) and 2,4-dimethyl-1-(prop-1-en-2-yl)cyclohex-3-enecarbaldehyde (8.9 g, 50 mmol) was added 2-bromopropane (7.5 g, 60 mmol). The mixture was stirred for 24 h under an argon atmosphere and was then poured on ice-cold sat. NH4Cl solution. The mixture was extracted with MTBE (3×50 ml). The combined org. phases were washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was distilled in a Kugelrohr oven to yield 8.0 g (72%) of a colorless oil.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][O:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][CH2:21][C:22]2=O)=[CH:18][CH:17]=1.O>C1COCC1>[CH3:14][O:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][CH2:21][C:22]2=[CH:5][C:3]#[N:4])=[CH:18][CH:17]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)C(=CC#N)CC2
Reaction time: 15 h
Yield: 52.5 %

Procedure:
To a solution of 60% sodium hydride (2.71 g, 67.9 mmol) in THF (150 ml) was added dropwise, under ice-cooling, diethyl cyanomethylphosphonate (11.5 g, 64.8 mmol). The mixture was stirred for 15 hours, to which was then added dropwise a solution of 6-methoxy-1-indanone (10.0 g, 61.7 mmol) in THF (30 ml). The reaction mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into water, and the organic layer was subjected to extraction with ethyl acetate. The extract solution was washed with brine and water, followed by drying over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (hexane:ethyl acetate=8:2). Recrystallization of the product-from ethyl acetate/hexane afforded the above-titled compound (6.00 g, yield 53%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:10]2=[O:19])=[CH:5][CH:4]=1)[CH3:2].Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])=[O:23].C(N(CC)CC)C>C(Cl)Cl>[Cl:31][C:25]1[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:24]=1[C:22](=[O:23])[CH2:21][N:16]1[CH2:17][CH2:18][C:11]2([C:10](=[O:19])[N:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:13][CH2:12]2)[CH2:14][CH2:15]1
Reactant: CCc1ccc(N2CCC3(CCNCC3)C2=O)cc1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(N2CCC3(CCN(CC(=O)c4ccc(Cl)cc4Cl)CC3)C2=O)cc1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
A mixture of 320 mg (1.24 mmol) 2-(4-ethylphenyl)-2,8-diazaspiro[4.5]decan-1-one, 431 mg (1.61 mmol) 2-bromo-1-(2,4-dichlorophenyl)ethanone and 376 mg (3.72 mmol) triethylamine in 50 mL DCM was stirred at 22° C. for 16 h. The crude reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography on silica eluting with a gradient formed from ethyl acetate and heptane to yield after evaporation of the product containing fractions 435 mg (79%) of the title compound as orange solid. MS m/e: 445.2 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:15]([C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[C:21]([CH3:28])[N:22]=[CH:23]2)=[C:16]=[O:17].N(C1C=CC=C2C=1C=CN=C2)=C=O>>[CH3:28][C:21]1[N:22]=[CH:23][C:24]2[C:19]([CH:20]=1)=[C:18]([NH:15][C:16]([NH:12][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:8][CH:9]=1)=[O:17])[CH:27]=[CH:26][CH:25]=2
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Reactant: NCc1ccc(N2CCCCC2)cc1
Agent: O=C=Nc1cccc2cnccc12
Product: Cc1cc2c(NC(=O)NCc3ccc(N4CCCCC4)cc3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 61B using 4-(1-piperidinyl)benzylamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 1H NMR (300 MHz, DMSO-d6) δ 9.69 (s, 1H), 9.60 (s, 1H), 8.68 (s, 1H), 8.57 (d, 1H, J=7.5 Hz), 8.00 (d, 1H, J=7.5 Hz), 7.85-7.55 (m, 4H), 7.43 (m, 2H), 4.40 (d, 2H, J=6 Hz), 3.44 (m, 4H), 2.77 (s, 3H), 1.90 (m, 4H), 1.65 (m, 2H); MS (ESI) 375 (M+H)+; Anal. Calcd for C23H26N4O.2.4HCl: C, 59.80; H, 6.20; N, 12.13. Found: C, 59.91; H, 6.45; N, 11.78.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([CH:25]2[CH:34]3[CH:29]([CH:30]=[CH:31][C:32]([NH2:35])=[CH:33]3)[CH2:28][CH2:27][CH2:26]2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.CO>C(O)(C)C.C(OCC)C>[NH:20]1[CH:24]=[C:23]([CH:25]2[CH:34]3[CH:29]([CH:30]=[CH:31][C:32]([NH2:35])=[CH:33]3)[CH2:28][CH2:27][CH2:26]2)[N:22]=[CH:21]1
Reactant: NC1=CC2C(C=C1)CCCC2c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Solvent: CO
Product: NC1=CC2C(C=C1)CCCC2c1c[nH]cn1

Procedure:
A mixture of 7.7 g of the product obtained in Step 3, 4.2 ml of concentrated hydrochloric acid and 100 ml of methanol is heated at reflux for 2 hours. After concentration of the solvent, the residue is taken up in an isopropanol/diethyl ether mixture. The expected product is obtained by filtering off the precipitate.