Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[C:4]=1[C:16]([O:18]C(C)(C)C)=[O:17].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[C:4]=1[C:16]([OH:18])=[O:17]
Reactant: COc1ccccc1-c1noc(CF)c1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-c1noc(CF)c1C(=O)O

Procedure:
Treating tert-butyl 5-(fluoromethyl)-3-(2-methoxyphenyl)isoxazole-4-carboxylate with TFA/DCM (1:1) at room temperature for one hour followed by evaporation of DCM/TFA in vacuo provided the title compound. 1H-NMR (CD3OD, 400 MHz): δ 7.53-7.44 (1H, m), 7.42-7.35 (1H, m), 7.13-6.98 (2H, m), 5.74 (2H, d, J=47.2 Hz), 3.78 (3H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:32](=[O:33])[CH2:31][C:30](=[O:34])[NH:29][C:28]3[C:35]4[C:40]([CH:41]=[CH:42][C:27]2=3)=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:22][CH:21]=1>>[CH3:12][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:32](=[O:33])[CH2:31][C:30](=[O:34])[NH:29][C:28]3[C:35]4[C:40]([CH:41]=[CH:42][C:27]2=3)=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:22][CH:21]=1)=[O:8]
Reactant: CN(C)c1cccc(C(=O)O)c1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C(Cl)C(=O)Cl
Product: CN(C)c1cccc(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)c1
Yield: 36.6 %

Procedure:
3-Dimethylaminobenzoic acid (50 mg, 0.3 mmol) was treated oxalyl chloride with in the same manner as that of Example 40, and then by using the resultant together with 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.1 mmol) obtained in Example 1, (3), the title compound (17 mg, yield 37%) was obtained as pale brown crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]=O)=[CH:2]1.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1>N1C=CC=CC=1>[S:1]1[CH:2]=[C:3]([CH:10]=[CH:13][C:14]([OH:16])=[O:15])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1csc2ccccc12
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1csc2ccccc12
Temperature: 110 °C

Procedure:
A suspension of 1-benzothiophene-3-carbaldehyde (4.9 g, 0.03 mol), malonic acid (6.6 g, 0.06 mol) and piperidine (1 mL) in 100 mL anhydrous pyridine was heated at 110° C. overnight. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was taken up in 100 mL of water and 1 N hydrochloric acid was added to adjust the pH of this solution to ca. 3. The suspension was filtered and the yellow solid was collected, washed with water (3×50 mL) and concentrated in vacuo to give the indicated product with 95% purity (5.65 g, 91%).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([CH:7]([NH:15][CH3:16])[CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1.[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[CH:30][C:31]2[O:36][CH2:35][C:34](=[O:37])[N:33]([CH2:38][C:39]([OH:41])=O)[C:32]=2[CH:42]=1)=[O:27])[CH3:24].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.FC(F)(F)C(O)=O>C(Cl)Cl.CC#N.O>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:2]=[CH:3][C:4]([CH:7]([N:15]([CH3:16])[C:39](=[O:41])[CH2:38][N:33]2[C:32]3[CH:42]=[C:28]([C:26]([O:25][CH2:23][CH3:24])=[O:27])[CH:29]=[CH:30][C:31]=3[O:36][CH2:35][C:34]2=[O:37])[CH2:8][N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:5][CH:6]=1
Reactant: CNC(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)c1ccc2c(c1)N(CC(=O)O)C(=O)CO2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2c(c1)N(CC(=O)N(C)C(CN1CCOCC1)c1ccc(-c3ccccc3)cc1)C(=O)CO2
Reaction time: 0.25 h
Yield: 43.5 %

Procedure:
1-(4-biphenylyl)-N-methyl-2-(4-morpholinyl)ethanamine (0.68 g, 2.3 mmol) and {6-[(ethyloxy)carbonyl]-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl}acetic acid (0.8 g, 2.5 mmol) were dissolved in 12 mL of methylene chloride. Triethylamine (1.3 mL, 9.2 mmol) was delivered to the room temperature mixture, and the solution was allowed to stir for several minutes before a separate solution of 1H-1,2,3-benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 1.11 g, 2.5 mmol) dissolved in 5 mL of methylene chloride was added to the mixture at room temperature. The reaction was maintained at that temperature for 18 hours, before it was determined to be complete by LCMS (two Aquasil C18, 20×1 mm columns were run in sequence, 4 minutes at 0.1 mL/min, 1-99% CH3CN/H2O with 0.018% trifluoroacetic acid, ES) Rt=2.7 min and m/e 558 [M+1]+. Solvent was removed by rotary evaporation and the crude residue was purified by prep HPLC (Waters, 50×100 mm, 84 mL/min, A: acetonitrile B: water (pH=10, NH4OH), A: 10 to 99% over 15 min, UV detection at 214 nm) to give the title compound (0.58 g. 1.0 mmol, 43%) as an off-white amorphous solid. MS (ES) m/e 558 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][C:13]([C:15](Cl)=[O:16])=[CH2:14]>[OH-].[Na+].ClCCl>[C:15]([O:11][C:9]1[CH:10]=[C:2]([OH:1])[C:3](=[CH:7][CH:8]=1)[C:4]([OH:6])=[O:5])(=[O:16])[C:13]([CH3:14])=[CH2:12]
Reactant: O=C(O)c1ccc(O)cc1O
Reactant: C=C(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C=C(C)C(=O)Oc1ccc(C(=O)O)c(O)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2,4-dihydroxybenzoic acid (64.88 millimole, 10.0 g) was dissolved in an aqueous solution (300 g) of sodium hydroxide (1.7% by weight) to give an orange solution and the solution was cooled to 0° C. by ice bath. While stirring under a flow of nitrogen gas, a solution of methacryl chloride (8.0 g) in dichoromethane (100 ml) was added to the solution over a period of 60 minutes, and the solution was kept stirred at 0° C. for four hours after completing the addition. After the solution was stood to slowly warm to room temperature, the solution was further stirred overnight. The aqueous layer was separated from the organic layer, and to the aqueous layer was added an aqueous solution of 1N HCl so as to adjust its pH to 1. The solution was stood overnight to give colorless powder, and the powder was filtrated. The powder was washed by cold acidic water (100 ml) three times. After drying the powder under a reduced pressure at room temperature, the powder was recrystallized at 60° C. by an aqueous solution of methanol containing a small amount of hydroquinone to give colorless crystal having a needle shape: yield 10.11 g, 70.1%.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[C:17]2[C:22]([F:25])([F:24])[F:23])(=[O:10])=[O:9].N(OC(C)(C)C)=O>CC(O)=O>[F:25][C:22]([F:24])([F:23])[C:17]1[C:16]2[C:21](=[C:12]3[C:13](=[CH:14][CH:15]=2)[C:4]2[C:3](=[CH:2][CH:7]=[CH:6][CH:5]=2)[S:8](=[O:9])(=[O:10])[NH:11]3)[N:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1S(=O)(=O)Nc1cccc2c(C(F)(F)F)ccnc12
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Product: O=S1(=O)Nc2c(ccc3c(C(F)(F)F)ccnc23)-c2ccccc21
Yield: 20.9 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-N-(4-trifluoromethyl-quinolin-8-yl)-benzenesulfonamide (Intermediate 279) (300 mg, 0.82 mmol), t-butyl nitrite (0.14 ml, 1.22 mmol) and AcOH (4 ml) gave the title compound (60 mg, 16%) after purification by column chromatography with DCM/MeOH: aq.NH3 (99:1:2 drops) as the eluent.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCCC3N
Reactant: O=C(Cl)c1ccccc1
Product: Cc1ccc2[nH]c3c(c2c1)CCCC3NC(=O)c1ccccc1

Procedure:
N-(6-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl)benzamide was prepared from 6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine and benzoyl chloride in a similar manner as described above to give a pale yellow solid (81% yield). 1H-NMR (CDCl3): δ 8.63 (s, 1H), 7.81-7.75 (m, 2H), 7.54-7.48 (m, 1H), 7.47-7.40 (m, 2H), 7.28 (m, 1H), 7.20 (d, 1H), 6.99 (dd, 1H), 6.40 (d, 1H), 5.36 (m, 1H), 2.75 (m, 2H), 2.44 (s, 3H), 2.31 (m, 1H), 2.02-1.91 (m, 3H); MS m/z 303 (M−1).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[C:21]=3[C:22]([F:25])([F:24])[F:23])[O:14][N:13]=2)=[CH:8][CH:7]=1.Cl>C1COCC1.O.O>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[N:20]1[C:21]([C:22]([F:23])([F:24])[F:25])=[C:17]([C:15]2[O:14][N:13]=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([CH:2]=[O:1])=[CH:11][CH:10]=3)[N:16]=2)[CH:18]=[N:19]1
Reactant: FC(F)(F)c1c(-c2nc(-c3ccc(C4OCCO4)cc3)no2)cnn1-c1ccccn1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2noc(-c3cnn(-c4ccccn4)c3C(F)(F)F)n2)cc1
Yield: 84.2 %

Procedure:
A solution of 3-(4-(1,3-dioxolan-2-yl)phenyl)-5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazole (25 g, 58.2 mmol) and con. HCl (500 mL) in THF/water (500 mL/500 mL) was stirred at RT for 3 hours. Upon completion of the reaction, as monitored by TLC, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine and then dried and concentrated under reduced pressure to afford 4-(5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (19 g, 49 mmol). The compound had an HPLC retention time=1.90 min.—CHROMOLITH® SpeedROD 4.6×30 mm. flow=5 mL/min (2 min. gradient); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=386.2.
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.CN1CC[C@@H]2C3C=CC=CC=3OC3C=CC=CC=3[C@@H]2C1.C(O)(=O)/C=C\C(O)=O.[CH3:37][N:38]1[CH2:43]C[C@@H:41]2[C:44]3[CH:56]=[CH:55][CH:54]=[CH:53][C:45]=3[CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[C@@H:40]2[CH2:39]1>>[CH3:43][N:38]1[CH2:39][CH:40]2[C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=3[CH2:46][C:45]3[CH:53]=[CH:54][CH:55]=[CH:56][C:44]=3[CH:41]2[CH2:37]1
Reactant: CN1CC[C@@H]2c3ccccc3Cc3ccccc3[C@@H]2C1
Agent: CN1CC[C@@H]2c3ccccc3Oc3ccccc3[C@@H]2C1
Agent: O=C(O)/C=C\C(=O)O
Product: CN1CC2c3ccccc3Cc3ccccc3C2C1

Procedure:
cis-2-methyl-1,2,3,4,4a,13b-hexahydro-dibenz[2,3;6,7] oxepino[4,5-c]pyridine maleate, m.p. 174°-175° C.; cis-2-methyl-2,3,4,4a,9,13b-hexahydro-1H-dibenzo[1,2;5,6] cyclohepta[3,4-c]pyridine maleate, m.p. 207°-209° C. and the corresponding trans isomer (maleate salt), m.p. 175°-176° C.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.NC1C(C)=C(C)C=CN=1.[NH2:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([CH3:25])=[CH:20][N:19]=1>>[C:5]([NH:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([CH3:25])=[CH:20][N:19]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cnc(N)cc1C
Agent: Cc1ccnc(N)c1C
Product: CC(=O)Nc1cc(C)c(C)cn1
Temperature: 137.5 °C

Procedure:
Acetic anhydride (2.0 mL, 21 mmol) and 500 mg (4.09 mmol) of a 4:1 mixture of 2-amino-3,4-dimethylpyridine and 2-amino-4,5-dimethylpyridine (prepared by the method of W. O. Siegl, J. Heterocycl. Chem. 1981, 18, 1613-1618) were heated in a 135-140° C. oil bath for 2 h. The solution was concentrated on a rotary evaporator and the residue was chromatographed twice on silica gel, eluted with 30-50% ethyl acetate in dichloromethane to give 71 mg of pure 2-acetamido-4,5-dimethylpyridine.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8](F)[N:7]=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[N:5]=1.[CH2:16]([OH:18])C>>[NH2:3][C:4]1[N:9]=[C:8]([O:18][CH3:16])[N:7]=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[N:5]=1
Reactant: CCO
Reactant: Nc1nc(F)nc(OC(F)(F)F)n1
Agent: [H-]
Agent: [Na+]
Product: COc1nc(N)nc(OC(F)(F)F)n1
Reaction time: 0.25 h

Procedure:
2.3 g (0.093 mol) of 97% strength sodium hydride were added a little at a time to 300 ml of ethanol at from 20 to 35° C. and stirring was carried out until dissolution was complete, which took 15 minutes. 18.5 g (0.093 mol) of 2-amino-4-fluoro-6-trifluoromethoxy-1,3,5-triazine were then added at 0° C. in the course of 10 minutes, while stirring and stirring was continued for 1 hour at 0° C. and overnight at 22° C. The mixture was evaporated down under reduced pressure, after which the residue was taken up in methylene chloride and the solution was extracted with water and dried. Evaporation gave 17.9 g (85.9% of theory) of the title compound of melting point 69°-91° C.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([OH:10])=[O:9].[CH2:17](O)C>>[Br:6][CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([O:10][CH3:17])=[O:9]
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: COC(=O)C(Br)c1ccccc1
Yield: 79 %

Procedure:
Concentrated sulfuric acid (0.5 mL) was added to a solution of α-bromophenylacetic acid (3.00 g, 13.9 mmol) in ethanol (30 mL) at room temperature, and the mixture was heated under reflux for 1 hour. The reaction mixture was cooled, and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, then dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (2.50 g, yield 79%). This was oily.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:23][C:24]([F:27])([F:26])[F:25])[C:16]=3[NH:15][C:14](=O)[C:13]=2[CH2:12][CH2:11]1>P(Cl)(Cl)(Cl)=O>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:23][C:24]([F:26])([F:25])[F:27])[C:16]=3[N:15]=[C:14]([NH:15][CH2:16][CH2:17][OH:23])[C:13]=2[CH2:12][CH2:11]1
Reactant: COc1ccc(N2CCc3c2c2cccc(OC(F)(F)F)c2[nH]c3=O)c(C)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(N2CCc3c(NCCO)nc4c(OC(F)(F)F)cccc4c32)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 129.2 %

Procedure:
1-(2-Methyl-4-methoxyphenyl)-4-oxo-6-trifluoromethoxy-2,3,4,5-tetrahydropyrrolo[3,2-c]quinoline(4.0 g, 10 mmol) was dissolved in phosphoryl chloride(10 ml). The reaction mixture was refluxed for 2 hours, and cooled. After removing the excess phosphoryl chloride by simple distillation, the residue was poured into iced water, neutralized with aqueous solution of sodium hydroxide (1N), and stirred at room temperature for 30 minutes. It was extracted with dichloromethane(20 ml) for 3 times, and the organic layer was washed with water (15 ml) for 3 times, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 2.8 g of desired compound as solid in 70% of yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([C:17]([NH:20]C(=O)CCl)([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.NC(N)=S.C(O)C.C(=O)(O)[O-].[Na+]>O.C(O)(=O)C>[NH2:20][C:17]([C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:4]2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([Br:1])[CH:3]=2)=[N:16][CH:15]=1)([CH3:18])[CH3:19]
Reactant: Cn1cc(Br)cc(Nc2ccc(C(C)(C)NC(=O)CCl)cn2)c1=O
Agent: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Cn1cc(Br)cc(Nc2ccc(C(C)(C)N)cn2)c1=O
Temperature: 25 °C
Yield: 90.6 %

Procedure:
N-{1-[6-(5-Bromo-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino)-pyridin-3-yl]-1-methyl-ethyl}-2-chloro-acetamide (2.97 g, 7.2 mmol) and thiourea (0.655 g, 8.6 mmol) were suspended in an ethanol (35 ml)/acetic acid (8 ml) mixture and refluxed overnight. The reaction mixture was allowed to cool to room temperature. Water was added and the mixture was cooled to 0° C. Sodium bicarbonate was added (ph=8) and then it was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated to give 3-[5-(1-Amino-1-methyl-ethyl)-pyridin-2-ylamino]-5-bromo-1-methyl-1H-pyridin-2-one (2.2 g, 91%) as a yellow solid. MS (H+)=339.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:15](=[O:26])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:27]=1.[Cl:28][C:29]1[N:34]=[C:33](Cl)[CH:32]=[CH:31][N:30]=1.C(N(C(C)C)CC)(C)C>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:21][CH2:22][N:23]([C:31]5[CH:32]=[CH:33][N:34]=[C:29]([Cl:28])[N:30]=5)[CH2:24][CH2:25]4)[C:15](=[O:26])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:27]=1
Reactant: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1CC1CCNCC1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1CC1CCN(c2ccnc(Cl)n2)CC1
Temperature: 110 °C

Procedure:
To a solution of 4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-1-piperidin-4-ylmethyl-piperazin-2-one (40 mg, 0.094 mmole) in n-butanol (1.0 mL) is added 2,4-dichloropyrimidine (14, 0.094 mmole) and diisopropylethylamine (0.016 mL, 0.094 mmole) and this mixture is heated at 110° C. for 4 hours. The reaction is concentrated and purified by column chromatography (silica, 25% ethyl acetate/dichloromethane) to yield 4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-1-[1-(2-chloro-pyrimidin-4-yl)-piperidin-4-ylmethyl]-piperazin-2-one. 1H NMR (300 MHz, CDCl3) d 8.01 (d, 1H), 7.89-7.87 (m, 3H), 7.48 (dd, 1H), 6.35 (d, 1H), 4.41-4.20 (m, 2H), 3.87 (s, 2H), 3.48 (s, 4H), 3.28 (dd, 2H), 2.05-1.95 (m, 1H), 1.67 (d, 2H), 1.31-1.20 (m, 2H); MS (Ion spray) 542 (M+H)+.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][NH:13][C:12](=[O:16])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].CO>CN(C=O)C.C(Cl)Cl>[CH2:24]([O:23][C:21]([CH2:20][N:13]1[CH:14]=[CH:15][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:11][C:12]1=[O:16])=[O:22])[CH3:25]
Reactant: O=C(Nc1cc[nH]c(=O)n1)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)Cn1ccc(NC(=O)c2ccccc2)nc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
To a stirred suspension of 6 (1.92 g, 9 mmol) in dry DMF (100 mL) at 0° C., NaH (0.43 g, 18 mmol) was added and the mixture was stirred at room temperature for 1 h. Ethyl bromoacetate (1.5 g, 9 mmol) was added dropwise at 0° C. and stirred for 1 h. Methanol (2 mL) was added to quench the reaction, and the solvents were removed under reduced pressure. The residue obtained was dissolved in DCM, washed with water (3×50 mL), dried over Na2SO4, and the solvent was evaporated to give 7 as a white solid (1.38 g, 54%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1/[CH:8]=[C:9]1/[C:10](=[O:23])[C:11]2[C:16]([CH2:17][CH2:18]/1)=[CH:15][C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2>[Pt]>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]1=[O:23]
Reactant: COc1cc2c(cc1OC)C(=O)/C(=C/c1ccncc1F)CC2
Agent: [Pt]
Product: COc1cc2c(cc1OC)C(=O)C(Cc1ccncc1F)CC2

Procedure:
The title compound 102 is prepared according to the procedure reported in Example 36.1 with compound 86 (313 mg, 1 mmol) and Pt/C (5 wt % loading, 93 mg) as reactants. White solid. (Yield 188 mg, 60%).
Reaction SMILES: [CH:1](/O)=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Br-].[Na+].[C:13](=[O:16])(O)[O-:14].[Na+]>ClCCl.O.[O-]Cl.[Na+]>[CH2:5]([C@H:6]1[CH2:7][C@H:8]1[CH2:9][C:13]([OH:14])=[O:16])[CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: O=C([O-])O
Reactant: CCCCCCC/C=C\O
Agent: [Br-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: ClCCl
Product: CCCCC[C@H]1C[C@H]1CC(=O)O

Procedure:
Cis-nonen-1-ol (10.0 g) is subjected to the cyclopropanation conditions as described in the preparation of Example 52. The resulting residue is taken up in 100 mL of dichloromethane at 0° C., followed by the addition of 800 mg of sodium bromide in 2 mL of water and 150 mg of 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical. To this mixture is added 1.50 g of Aliquot 336 followed by the dropwise addition of 9.2 g of sodium bicarbonate in 230 mL of 5% NaOCl. The aqueous phase is made basic, separated from the organic phase and acidified with concentrated HCl, and then extracted three times with dichloromethane. The combined organic layers are washed with water, dried over MgSO4, and concentrated in vacuo to give cis-2-(2'-pentylcyclopropyl)acetic acid.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:27]#[N:28])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.C([O:33][C:34](=[O:40])[C:35]([CH3:39])([CH3:38])[CH2:36][NH2:37])(C)(C)C.Cl>CO.O>[C:27]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:37][CH2:36][C:35]([CH3:39])([CH3:38])[C:34]([OH:40])=[O:33])=[O:7])[N:9]=1)#[N:28]
Reactant: CCCCOC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3)ccc2c1O
Reactant: CC(C)(C)OC(=O)C(C)(C)CN
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 1-cyano-7-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (80 mg, 0.21 mmol) (prepared according to U.S. Pat. No. 7,928,120) and 3-Amino-2,2-dimethyl-propionic acid tert-butyl ester (71 mg, 0.41 mmol) in MeOH (1.5 mL) was microwaved at 120° C. For 1 h. Reaction mixture was diluted with water (80 mL), acidified by 1 N HCl and then extracted with EtOAc. Organic layer was washed with brine, dried over MgSO4, filtered and concentrated. Residue was then treated with 3 mL of (½) TFA/CH2Cl2. Resultant mixture was stirred at room temperature for 5 h and concentrated to provide the title compound 90 mg (0.21 mmol) in 100% yield. LC-MS ESI−: 422.07 (M−1)−.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[C:8]([N+:15]([O-])=O)[CH:7]=1.[NH4+].[Cl-]>C1COCC1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[C:8]2[C:7]=1[CH:1]=[CH:2][NH:15]2
Reactant: C=C[Mg]Br
Reactant: CC(C)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)c1ccc(Br)c2cc[nH]c12
Reaction time: 1 h

Procedure:
Vinyl magnesium bromide (1 M in THF) (98 mL, 98 mmol) was added to 4-bromo-1-isopropyl-2-nitrobenzene (4 g, 16.39 mmol) in THF (60 mL) at −40° C. The reaction mixture was stirred for 1 h, then poured into saturated aqueous NH4Cl and extracted with ether. The combined ethereal extracts were dried (MgSO4) and concentrated. Chromatography over silica eluting with 1-20% EtOAc/hexanes afforded the title compound. LC-MS: calculated for C11H12BrN 237.02, observed m/e 238.2 (M+H)+ Rt (1.96/4 min.).