Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH:18]=[CH:17][N:16]=[N:15]2)=[CH:6][CH:5]=1)([O-])=O>CO.C1COCC1.[Pd]>[N:14]1([CH2:13][CH2:12][CH2:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[CH:18]=[CH:17][N:16]=[N:15]1
Reactant: O=[N+]([O-])c1ccc(CCCCn2ccnn2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(CCCCn2ccnn2)cc1

Procedure:
1-[4-(4-Nitro-phenyl)-butyl]-1H-[1,2,3]triazole (2.89 g, 11.74 mmol) is hydrogenated in a mixture of methanol/THF (1:1, 50 ml) in the presence of palladium on charcoal (10%, 0.5 g) for 5 h. After filtration solvents are removed in vacuo yielding 4-(4-[1,2,3]triazol-1-yl-butyl)-phenylamine as a yellow gum. Yield 2.03 g (80%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=2[O:19][CH3:20])[C:12]([NH2:23])=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([N:33]=[C:34]=[S:35])(=O)C1C=CC=CC=1>CC(C)=O>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=2[O:19][CH3:20])[C:12]([NH:23][C:34]([NH2:33])=[S:35])=[CH:11][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(N)c2c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(NC(N)=S)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.6 %

Procedure:
(4-Amino-6,8-dimethoxy-isoquinolin-1-ylmethyl)carbamic acid tert-butyl ester (225 mg, 0.675 mmol) was taken up in 10 mL of dry acetone, and benzoylisothiocyanate (121 mg, 0.742 mmol) was added dropwise. The reaction was stirred at room temperature for 2 h, and was then concentrated to a yellow solid. This solid was triturated with 50% aqueous EtOH, filtered, and suspended in 10% NaOH (5.0 mL). The reaction mixture was placed in an oil bath that was pre-heated to 98° C. for 1 h, (the solid was dissolved in 10 min). The mixture was cooled, acidified to pH 6-7 by 2.0 N aqueous HCl solution, and filtered. The yellow solid was washed with water, and dried in vacuo to give 126 mg (48%) of (6,8-dimethoxy-4-thioureido-isoquinolin-1-ylmethyl)carbamic acid tert-butyl ester. 1H-NMR (CDCl3): δ, 8.34 (s, 1H), 7.60 (s, 1H), 6.78 (d, 1H, J=2.1 Hz), 6.63 (d, 1H, J=1.9 Hz), 5.06 (d, 2H, J=3.7 Hz), 4.00 (s, 3H), 3.96 (s, 3H), 3.65 (s, 2H), 1.51 (s, 9H); MS: calculated for C18H24N4O4S+H 393.0; found: 393.0.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[NH2:25][CH2:26][CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([NH:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[N:3][C:4]=2[CH3:24])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: NCCN1CCCC1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Solvent: CCCCO
Product: Cc1nc(NCCN2CCCC2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 100 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 70 μL of 1-(2-aminoethyl)pyrrolidine in 1 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(2-(pyrrolidin-1-yl)ethylamino)nicotinamide. MS (Q1) 436.0 (M)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:13][NH2:14].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C1COCC1>CCOC(C)=O>[NH2:1][C:2]1[C:10]([Br:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:14][CH3:13])=[O:5]
Reactant: CN
Reactant: Nc1c(C(=O)O)ccc(F)c1Br
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(F)c(Br)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a slurry of 2-amino-3-bromo-4-fluorobenzoic acid (719; 0.690 g, 2.95 mmol) in 5 mL EtOAc was added methanamine (2.0 M in THF; Aldrich, St. Louis, Mo.; 5.90 mL, 11.79 mmol) to give a solution. 1-propanephosphonic acid cyclic anhydride 50 wt % in EtOAc (Matrix Scientific; 1.911 mL, 3.24 mmol) was added. The reaction became warm. The reaction was sealed and stirred rapidly at RT. After 30 min, additional methanamine 2.0 M in THF (Aldrich, St. Louis, Mo.; 5.90 mL, 11.79 mmol) was added. After 1 h, the reaction was partitioned between sat'd NaHCO3 and EtOAc. The organic layer was washed with sat'd NaHCO3 once, sat'd NaCl once, and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 2-amino-3-bromo-4-fluoro-N-methylbenzamide (0.57 g, 2.30 mmol, 78% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.36 (1H, d, J=3.9 Hz), 7.57 (1H, dd, J=8.8, 6.3 Hz), 6.89 (2H, br. s.), 6.57 (1H, t, J=8.6 Hz), 2.74 (3H, d, J=4.5 Hz). MS (ESI, pos. ion) m/z: 246.9/248.9 (M+1).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([Cl:15])[C:8]([Cl:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:27][C:26]([NH2:28])=[N:25][N:24]=2)=[CH:19][CH:18]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]([Cl:15])[C:8]([Cl:14])=[C:9]([CH:13]=1)[C:10]([NH:28][C:26]1[S:27][C:23]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)=[N:24][N:25]=1)=[O:12])(=[O:3])=[O:4]
Reactant: NS(=O)(=O)c1cc(Cl)c(Cl)c(C(=O)O)c1
Reactant: Nc1nnc(-c2ccc(F)cc2)s1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Product: NS(=O)(=O)c1cc(Cl)c(Cl)c(C(=O)Nc2nnc(-c3ccc(F)cc3)s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a 20 ml scintillation vial was added 5-(aminosulfonyl)-2,3-dichlorobenzoic acid (40 mg, 0.148mmol) and commercially available 5-(4-fluorophenyl)-1,3,4-thiadiazol-2-amine (28.9 mg, 0.148 mmol). To this was added EDC (28 mg, 0.148 mmol) and HOAt (20 mg, 0.148 mmol) followed by 3 ml DCM. The reaction mixture was stirred with a Teflon covered magnetic stir-bar at room temperature for overnight. The product was collected by vacuum filtration and air dried, yielding 5-(aminosulfonyl)-2,3-dichloro-N-[5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl]benzamide (31 mg, 47%) as light tan solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]1[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)=[O:4].[H-].[Na+].Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C=O)C.O>[F:25][C:2]([F:1])([F:24])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]1[C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:30][CH2:31][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:21][CH:22]=1)=[O:4]
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2c1ccc(O)cc1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
A solution of 2,2,2-trifluoro-1-[1-(4-hydroxyphenyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]ethanone (18.98 g, 54.0 mmol) in anhydrous DMF (200 ml) was added to a suspension of NaH (2.592 g, 108.0 mmol) in anhydrous DMF (400 ml) at rt under N2. After stirring at rt for 1 hr, a solution of 1-(2-chloroethyl)pyrrolidine hydrochloride (9.184 g, 54.0 mmol) in anhydrous DMF (200 ml) was added and the reaction mixture was heated to 100° C. for 4 hr. The reaction mixture was cooled to rt, diluted with H2O (2000 ml), and extracted with EtOAc (4×250 ml). The combined extracts were washed with H2O (3×250 ml), dried over MgSO4, and concentrated in vacuo to give 21.15 g of yellow oil. Purification by flash chromatography, eluting with EtOAc:MeOH (8:2) gave 10.503 g (43% yield) of yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccccc1C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 20 h

Procedure:
A mixture of 4-(2-methoxy-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (200 mg, 0.69 mmol), Pd—C 10% (30 mg) in EtOAc (5 mL) is hydrogenated at room temperature and atmospheric pressure for 20 h. The mixture is filtered over Celite, and the filtrate is evaporated to provide the title compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]=[N:9][OH:10])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[Cl:13]NC(=O)CCC(N)=O>CN(C)C=O>[OH:10][N:9]=[C:8]([Cl:13])[C:7]1[CH:11]=[CH:12][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1
Reactant: NC(=O)CCC(=O)NCl
Reactant: CCCc1ccc(C=NO)cc1
Solvent: CN(C)C=O
Product: CCCc1ccc(C(Cl)=NO)cc1
Reaction time: 0.17 h

Procedure:
To 4-propylbenzaldehyde oxime (1.4 g, 8.58 mmol) in dimethylformamide (3 mL) was added N-chlorosuccinamide (1.145 g, 8.58 mmol) in batches over a period of 10 min. at room temperature. The reaction mixture was stirred at that temperature for an additional 10 min., and partitioned between ethyl acetate (20 mL) and brine (2×20 mL). The ethyl acetate layer was dried over sodium sulfate and purified by silica gel column chromatography using hexane and ethyl acetate. Fractions corresponding to the desired product were collected and concentrated to yield the title compound, which was immediately used for the subsequent step. LCMS M+1=198.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C([Li])CCC.[C:17](=[O:19])=[O:18].O>C1COCC1.CCCCCC>[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([C:17]([OH:19])=[O:18])=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2
Reactant: O=C=O
Reactant: Clc1ccc(Br)c2[nH]ccc12
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cl)c2cc[nH]c12
Temperature: -78 °C
Yield: 67 %

Procedure:
560 mg (2.43 mmol) of 7-bromo-4-chloro-1H-indole were dissolved in 15 ml THF. The reaction mixture was cooled to −78° C. and 4.55 ml of a 1.6 M butyl lithium solution in hexane were added under nitrogen in such a way, that the temperature did not exceed a maximum of −70° C. The yellow solution was stirred at 0 to 5° C. after complete addition for 30 min. The reaction mixture was cooled to −78° C. and dry ice was added. The reaction mixture was warmed to rt, stirred for 15 min and poured onto 100 ml water. The aqueous layer was washed twice with diethyl ether, acidified with 1N aqueous HCl solution and extracted twice with diethyl ether. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated. The crude residue was stirred with hexane for 15 min, filtered and dried to yield 319 mg (67%) of 4-chloro-1H-indole-7-carboxylic acid as an off-white solid. MS (ISP) 194.1 (M−H)−.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)[C:6]([O:8]C(C)(C)C)=[O:7]>CO>[F:24][CH:2]([F:1])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[CH2:16][N:17]1[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]1)[C:6]([OH:8])=[O:7]
Reactant: CN1CCN(Cc2ccc(C(=O)OC(C)(C)C)cc2C(F)F)CC1
Solvent: CO
Product: CN1CCN(Cc2ccc(C(=O)O)cc2C(F)F)CC1

Procedure:
This compound was prepared in the same manner as in Reference Example 1 (step 6), except that t-butyl 3-difluoromethyl-4-(4-methylpiperazin-1-ylmethyl)benzoate obtained in the step 5 was used, and that the resulting crude product was mixed with methanol, insolubles were removed by filtration, the filtrate was distilled off under reduced pressure, and then the residue was crystallized from acetonitrile.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([S:10][CH3:11])=[C:5]([CH3:9])[C:6]=1[CH:7]=[O:8].[BH4-].[Na+]>C(O)C>[CH3:1][C:2]1[S:3][C:4]([S:10][CH3:11])=[C:5]([CH3:9])[C:6]=1[CH2:7][OH:8]
Reactant: CSc1sc(C)c(C=O)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CSc1sc(C)c(CO)c1C
Temperature: 20 °C

Procedure:
15.0 G. of 2,4-dimethyl-5-(methylthio)thiophene-3-carboxaldehyde was dissolved in 150 ml. fo dry ethanol with stirring at 20° C. 0.8 G. of sodium borohydride was added and the mixture was stirred for 30 minutes, then poured into ice water and extracted with ethyl ether. The combined ether extracts were washed with a solution of 5% sodium carbonate and saturated sodium chloride solution, dried over sodium sulfate, filtered, and evaporated to yield 2,4-dimethyl-3-hydroxymethyl-5-(methylthio)thiophene.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:36])[N:9]([C:25]2[CH:26]=[C:27]([CH:33]=[CH:34][CH:35]=2)[C:28]([O:30]CC)=[O:29])[CH2:10][CH2:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:4][C:3]=1[C:37]1[CH:42]=[CH:41][C:40]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])=[CH:39][CH:38]=1.O.[OH-].[Li+]>CO>[Cl:1][C:2]1[S:6][C:5]([NH:7][C:8]([N:9]([CH2:10][CH2:11][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[CH:26]=[C:27]([CH:33]=[CH:34][CH:35]=2)[C:28]([OH:30])=[O:29])=[O:36])=[N:4][C:3]=1[C:37]1[CH:38]=[CH:39][C:40]([NH:43][S:44]([CH3:47])(=[O:45])=[O:46])=[CH:41][CH:42]=1
Reactant: CCOC(=O)c1cccc(N(CCC(c2ccccc2)c2ccccc2)C(=O)Nc2nc(-c3ccc(NS(C)(=O)=O)cc3)c(Cl)s2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(-c2nc(NC(=O)N(CCC(c3ccccc3)c3ccccc3)c3cccc(C(=O)O)c3)sc2Cl)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 3-(3-(5-chloro-4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)-1-(3,3-diphenylpropyl)ureido)benzoate 73 (0.366 g, 0.531 mmol) in MeOH (20 mL) was added lithium hydroxide hydrate (0.440 g, 10.5 mmol). The reaction mixture was heated to 60° C. After 3 h, the reaction mixture was partially concentrated, neutralized with 1 M HCl, and diluted with EtOAc. The organic phase was washed with brine (1×), dried over MgSO4, filtered, and concentrated to give 3-(((5-chloro-4-(4-((methylsulfonyl)amino)phenyl)-1,3-thiazol-2-yl)carbamoyl)(3,3-diphenylpropyl)amino)benzoic acid 74. Mass spectrum, calculated for C33H29ClN4O5S2 660.1; found 661.1 (M++1).
Reaction SMILES: CC(C)([O-])C.[K+].CCOP(OCC)([CH2:12][C:13]#[N:14])=O.[C:18]([O:22][C:23](=[O:33])[NH:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([CH:31]=O)[CH2:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19]>C1COCC1>[C:18]([O:22][C:23](=[O:33])[NH:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([CH:31]=[CH:12][C:13]#[N:14])[CH2:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=CC#N)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of potassium tert-butoxide (5.54 g, 49.5 mmol) in dry THF (110 mL) at 0° C., diethyl cyanomethyl phosphonate (8.00 mL, 49.5 mmol) was added slowly dropwise and the mixture was stirred at 0° C. for 1 hour. A solution of trans (4-formyl-cyclohexyl)-carbamic acid tert-butyl ester (9.36 g, 41.2 mmol) in dry THF (290 mL) was added slowly over ˜15 mins, then the cooling bath was removed and the mixture was stirred at ambient temperature for 1 hour. Ethyl acetate and water were added and the phases were separated. The aqueous phase was extracted with ethyl acetate (×2) and the combined organic phase was washed with 10% aqueous citric acid solution, saturated sodium hydrogen carbonate solution, and brine, dried with sodium sulfate and concentrated under vacuum to give 12.6 g (>quant) of trans [4-(2-cyano-vinyl)-cyclohexyl]-carbamic acid tert-butyl ester as a−1:2 mixture of E- and Z-isomers which was contaminated with some phosphonate residues. The golden oil crystallized almost immediately and was used in the next step without further purification.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[C:8]([CH3:16])[CH:7]=1>C(O)(=O)C>[F:5][C:6]1[CH:11]=[C:10]([N+:1]([O-:4])=[O:2])[C:9]([NH:12][C:13](=[O:15])[CH3:14])=[C:8]([CH3:16])[CH:7]=1
Reactant: CC(=O)Nc1ccc(F)cc1C
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(=O)Nc1c(C)cc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 87 %

Procedure:
With cooling with ice, fuming nitric acid (25 ml) was dropwise added to an acetic acid (100 ml) solution of N-(4-fluoro-2-methylphenyl)acetamide (I-259) (10.0 g, 59.8 mmol), taking 50 minutes. After the addition, then restoration to room temperature and stirring for 23 hours, the reaction liquid was poured into ice. The precipitated solid was collected by filtration, washed with water, then dried to obtain the entitled compound (11.1 g, 87%) as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27](Cl)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1.[C:38]([NH:42][C:43](=[O:51])[CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)([CH3:41])([CH3:40])[CH3:39]>>[C:38]([NH:42][C:43](=[O:51])[CH2:44][N:45]1[CH2:46][CH2:47][N:48]([C:27]([N:9]2[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:12]=[C:8]2[C:6]2[CH:7]=[C:2]([Cl:1])[C:3]([C:33]([C:36]#[N:37])([CH3:34])[CH3:35])=[CH:4][C:5]=2[O:30][CH2:31][CH3:32])=[O:28])[CH2:49][CH2:50]1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(C)(C)NC(=O)CN1CCNCC1
Product: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NC(C)(C)C)CC1

Procedure:
N-tert-Butyl-2-{4-[(4S,5R)-2-[5-chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetamide was prepared from (4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12k) and N-tert-butyl-2-piperazin-1-yl-acetamide (example 16g) in an analogous manner as described in example 25. LR-MS: 737.4 [(M+H)+]
Reaction SMILES: [Cl-].[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][C:13]2[N:14]=[CH:15][NH2+:16][CH:17]=2)=[CH:5][CH:4]=1.[C:18]([Cl:23])(=[O:22])[CH2:19][CH2:20][CH3:21]>C(O)(C(F)(F)F)=O>[Cl-:23].[C:18]([O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][C:13]2[N:14]=[CH:15][NH2+:16][CH:17]=2)=[CH:5][CH:4]=1)(=[O:22])[CH2:19][CH2:20][CH3:21]
Reactant: CCCC(=O)Cl
Reactant: Oc1ccc2c(c1)C(CC1=C[NH2+]C=N1)CC2
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Product: CCCC(=O)Oc1ccc2c(c1)C(CC1=C[NH2+]C=N1)CC2

Procedure:
4-(6-hydroxy-indan-1-ylmethyl)-1H-imidazol-1-ium chloride (100 mg, 0.399 mmol) and butyric acid chloride (510 mmol) were reacted in TFA (1 ml) and purified as described in example 1. Yield 90 mg (77%) of a white hygroscopic solid. 1H NMR (CDCl3, TMS): δ 1.02 (t, 3H), 1.70-1.79 (m, 3H), 2.18-2.24 (m, 1H), 2.52 (t, 2H), 2.73-2.86 (m, 3H), 3.18 (dd, 1H), 3.53 (qui, 1H), 6.84 (dd, 1H), 6.87 (s, 1H), 6.92 (s, 1H), 8.66 (s, 1H), 11.28 (s (broad), 2H). 13C NMR (CDCl3, TMS): δ 13.66, 18.45, 29.68, 30.52, 31.68, 36.24, 43.98, 115.79, 117.05, 120.36, 125.36, 132.32, 132.59, 141.32, 146.36, 149.51, 172.85.-HPLC-MS (EI): m/z=285.2 ((M+H)+—Cl−). Anal.—Calc. for C17H20N2O2.HCl.0.2CH2Cl2: C, 61.16; H, 6.39; N, 8.29. Found C, 61.30; H, 6.46; N, 8.22.
Reaction SMILES: CC1(C)[O:7][CH2:6][CH:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])[CH:10]=2)[CH2:4][O:3]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[OH:7][CH2:6][CH:5]([CH2:4][OH:3])[CH2:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21]
Reactant: Cc1oc(-c2ccccc2)nc1Cc1cccc(CC2COC(C)(C)OC2)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1Cc1cccc(CC(CO)CO)c1
Yield: 106.6 %

Procedure:
A mixture solution of 320 mg of 2,2-dimethyl-5-{3-[(5-methyl-2-phenyloxazol-4-yl)methyl]benzyl}-1,3-dioxane, 21 ml of ethanol and 21 mg of pyridinium p-toluenesulfonate (PPTS) was stirred for 2 hours at 55-60° C. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (Wakogel® C-200, chloroform) to provide 305 mg of the objective compound as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.C1(N[S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([O:14][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reaction time: 0.5 h

Procedure:
A solution of t-butyl-4-oxopiperidine-1-carboxylate (6.50 g, 32.6 mmol) in THF (50 mL) was added dropwise to a stirred solution of LDA (24 mL, 35.8 mmol, 1.1 eq., 1.5 M in hexanes) in THF (50 mL) at −78° C. After stirring for 30 min, a solution of N-phenyltrifluoromethanesulfonamide (12.48 g, 35.0 mmol, 1.07 eq.) in THF was added. The reaction mixture was stirred under inert atmosphere for 6 h at 0° C. The reaction was concentrated in vacuo and filtered over a pad of alumina (hexanes/EtOAc 9:1) to afford 2 as a pale yellow oil which was used without further purification (10.26 g, 95%).
Reaction SMILES: Cl.O1C=C[CH2:4][C:3]1=O.[C:8]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:9][C:10]([CH3:12])=[O:11]>>[C:10]([CH:9]1[CH2:16][CH:15]([CH2:3][CH3:4])[O:14][C:8]1=[O:13])(=[O:11])[CH3:12]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C1CC=CO1
Agent: Cl
Product: CCC1CC(C(C)=O)C(=O)O1
Reaction time: 8 h

Procedure:
The mixture was allowed to stand overnight and was transferred to a separatory funnel and acidified with 125 ml concentrated hydrochloric acid. The organic layer was separated and the water layer extracted three times with 50 ml diethyl ether. The extracts were combined with the organic layer, dried through sodium sulfate, and the diethyl ether was removed by means of a Rotovap. 182 Grams of product were obtained which when analyzed by GC indicated 83.6% lactone and 7.8% ethyl acetoacetate.
Reaction SMILES: S(O)(O)(=O)=O.[CH2:6]1[C:15]2[C:10](=[C:11]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][NH:7]1.[CH2:21]1C2C(=C(NS(C)(=O)=O)C=CC=2)CC[NH:22]1.S(=O)(=O)(O)O.Cl.C(N(CC)C(C)C)(C)C.N#CBr>C(#N)C.O>[C:21]([N:7]1[CH2:8][CH2:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:6]1)#[N:22]
Reactant: CS(=O)(=O)Nc1cccc2c1CCNC2
Agent: Cl
Agent: N#CBr
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: CS(=O)(=O)Nc1cccc2c1CCN(C#N)C2
Temperature: 20 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
To a stirred slurry of N-(1,2,3,4-tetrahydro-5-isoquinolyl)methanesulfonamide hemisulfate (prepared analogously to the compound of Example 19(b) in WO 98/30560, but using sulphuric acid in the final step in place of hydrochloric acid; 240 g, 0.88 mol) in acetonitrile (2400 ml) at 0° C. was added N,N-diisopropylethylamine (326 ml, 1.88 mmol). Cyanogen bromide (99.2 g, 0.94 mol) was added over a period of 20 minutes keeping the temperature below 10° C. The resulting slurry was allowed to warm to 20° C. and stirred at this temperature for 18 hrs. After this time, water (2400 ml) was added and the resulting mixture extracted with CH2Cl2 (2×2500 ml). The combined organic phases were washed with water (2000 ml) and evaporated to dryness. The resulting solid was reslurried in CH2Cl2 (360 ml) and the solid collected by filtration to yield 158 g (72%) of the title compound.