Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[S:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1>CC(O)(C)C>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[S:31][C:32]3[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=3[N:34]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCOc1ccccc1-c1nc2ccccc2s1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CC(C)(C)O
Product: c1ccc(C(c2ccccc2)N2CCN(CCOc3ccccc3-c3nc4ccccc4s3)CC2)cc1
Yield: 40.6 %

Procedure:
1-Benzhydryl-piperazine (2.26 g, 8.98 mmol) and 2-[2-(2-bromoethoxy)phenyl]-benzothiazole (0.75 g, 2.24 mmol) were stirred in t-BuOH (20 mL) at about 50° C. under N2 (g) for 24 hours. The mixture was concentrated in vacuo and flash chromatographed on silica (15% acetone/hexanes) to afford 460 mg (41%) of the free base of the product. mp 67-72° C.; LSIMS m/z 506 (MH+).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[O:2].[CH2:12]([Mg]Br)[CH2:13][CH3:14].Cl>O1CCCC1>[OH:2][CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCC[Mg]Br
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(C(=O)O)cc1
Reaction time: 0.25 h

Procedure:
6 g of 4-formylbenzoic acid is dissolved in 100 ml of tetrahydrofuran and mixed with 100 ml of a 1-molar solution of propyl magnesium bromide in tetrahydrofuran. After 6 hours of reaction time at room temperature the mixture is stirred into 100 ml of 2M of hydrochloric acid, extracted with ether and the ether phase is concentrated by evaporation. The crystalline material is filtered off with toluene on a suction filter and dissolved in 45 ml of dioxane and 5 ml of water and treated with 1.5 g of sodium boron hydride. After 15 minutes at room temperature, the mixture is added to 1M of hydrochloric acid, extracted with ethyl acetate, dried, concentrated by evaporation and chromatographed on 120 g of silica gel [toluene/acetic acid/water (10:10:1); upper phase after addition of a little water)]. 4.04 g of 4-(1-hydroxybutyl)-benzoic acid with a melting point of 109°-113° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].Cl.[CH3:22][N:23]([CH3:32])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([N:23]([CH3:32])[CH3:22])=[CH:25][CH:26]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CN(C)c1ccc(CN)cc1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Agent: Cl
Product: CN(C)c1ccc(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.41 mmol) and 4-(dimethylamino)benzylamine hydrogen chloride salt (60.9 mg, 0.49 mmol). The title compound was obtained as a solid (70 mg, 37% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.23 (1H, m), 8.99 (2H, s), 8.46 (1H, s), 7.1 (2H, dd), 6.7 (2H, dd), 4.26 (2H, m), 2.91 (6H, s). MS m/z: 483.05, 485.03 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH:11]([CH2:28][CH2:29][CH3:30])[C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[O:1][CH:11]([CH2:28][CH2:29][CH3:30])[C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5]
Reactant: CCCC(Br)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCC(Oc1ccccc1C=O)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 103.6 %

Procedure:
A mixture of 2-hydroxybenzaldehyde (2.44 g), diphenylmethyl 2-bromopentanoate (7.26 g), and potassium carbonate (3.45 g) in dimethylsulfoxide (20 ml) was stirred at room temperature for 5 hours. The mixture was diluted with water, neutralized with 1N hydrochloric acid, and was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated to give diphenylmethyl 2-(2-formylphenoxy)-pentanoate (8.04 g).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][OH:27].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][OH:27])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 63.9 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (10.0 g, 45 mmol), K2CO3 (10.0 g), 3-bromo-1-propanol (7.3 g, 46 mmol) and acetonitrile (200 ml) was refluxed for 3 hours. The reaction was poured into H2O and 7.1 g of a beige solid was collected. The filtrate was extracted with dichloromethane, and after concentration an additional 6.7 g of crude solid was harvested. The solids were combined and triturated with refluxing ethyl acetate to afford 8.0 g of 6-fluoro-3-[1-(3-hydroxypropyl)-4-piperidinyl]-1,2-benzisoxazole as an off-white solid. A sample (4.0 g) was recrystallized from ethanol-water (with charcoal treatment) to yield 2.4 g (40%) of the alcohol as a white solid, m.p.=140°-142° C. ANALYSIS: Calculated for C15H19FN2O2 : 64.73%C 6.88%H 10.06%N Found: 64.79%C 6.97%H 10.03%N
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[C:15]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:40])C=1>C(Cl)Cl.CCOC(C)=O>[O-:40][N+:4]1([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[C:15]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1C(c2cccnc2)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1C(c2cccnc2)=C(c2ccccc2)c2ccc(OCC[N+]3([O-])CCOCC3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.8 %

Procedure:
To a solution of 6-(2-morpholinoethoxy)-3-phenyl-2-(pyridin-3-yl)-1H-inden-1-one (100 mg, 0.24 mmol) obtained in Step 7 of Example 1 in CH2Cl2 (2 mL) at 10° C. was added MCPBA (21 mg, 1 eq). The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc and washed with sat. NaHCO3, H2O, and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MC/MeOH/NH4OH=92:7:1) to afford the title compound (14 mg, 13%).
Reaction SMILES: [Br:1]Br.[S:3]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[C:4]1[CH:10]=[O:11]>C(Cl)(Cl)Cl>[Br:1][C:7]1[S:3][C:4]([CH:10]=[O:11])=[C:5]([CH:8]=[O:9])[CH:6]=1
Reactant: O=Cc1ccsc1C=O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=Cc1cc(Br)sc1C=O
Reaction time: 8 h

Procedure:
Bromine (6.0 mL, 116.3 mmol) was added drop wise at room temperature to a solution of 2,3-thiophenedicarboxaldehyde (5.1 g, 36.38 mmol) in 100 mL of CHCl3. The reaction mixture was stirred overnight and then excess bromine was quenched with a saturated solution of Na2S2O3. The organic layer was extracted with CHCl3, dried over Na2SO4 and volatiles were removed in vacuo to obtain 1 as a brown solid. Spectroscopically pure compound was isolated by column chromatography using silica gel as stationary phase and a 4:1 mixture of CH2Cl2:hexanes. 1H NMR (500 MHz, CDCl3): δ1 0.37 (s, 1H), 10.26 (s, 1H), 7.59 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[C:6]([OH:14])[C:5]([NH:15][C:16]2[C:19](=[O:20])[C:18](=[O:21])[C:17]=2OCC)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:36][C@H:37]1[O:41][C@@H:40]([C@H:42]([NH2:45])[CH2:43][CH3:44])[CH2:39][CH2:38]1.CCN(CC)CC>CC#N>[Cl:1][C:2]1[C:7]([S:8]([N:11]([CH3:12])[CH3:13])(=[O:10])=[O:9])=[C:6]([OH:14])[C:5]([NH:15][C:16]2[C:19](=[O:20])[C:18](=[O:21])[C:17]=2[NH:45][C@@H:42]([C@H:40]2[CH2:39][CH2:38][C@@H:37]([CH3:36])[O:41]2)[CH2:43][CH3:44])=[CH:4][CH:3]=1
Reactant: CC[C@@H](N)[C@H]1CC[C@@H](C)O1
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)C)c2O)c(=O)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC[C@@H](Nc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)C)c2O)c(=O)c1=O)[C@H]1CC[C@@H](C)O1

Procedure:
To a stirred solution of 253 mg of 6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N,N-dimethyl-benzenesulfonamide in 5 ml of dry MeCN are added 362 mg of (R)-1-((2R,5R)-5-methyl-tetrahydrofuran-2-yl)-propylamine p-toluenesulfonate salt followed by 94 μl of Et3N at rt under an inert atmosphere of nitrogen. A reaction mixture obtained is heated at reflux for 45 minutes and solvent is evaporatedA residue obtained is purified by flash chromatography on silica eluting with 30-40% EtOAc in iso-hexane. The title compound is obtained. MH+ 472.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([C:19]2[S:23][C:22]([C:24]([OH:30])([CH3:29])[C:25]([F:28])([F:27])[F:26])=[N:21][CH:20]=2)[CH:15]=[C:16]([CH3:18])[CH:17]=1.C(O)(=O)C>O1CCOCC1>[CH3:18][C:16]1[CH:17]=[C:12]([NH:11][C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=2)[CH:13]=[C:14]([C:19]2[S:23][C:22]([C:24]([OH:30])([CH3:29])[C:25]([F:28])([F:27])[F:26])=[N:21][CH:20]=2)[CH:15]=1
Reactant: O=C(O)c1ccnc(Cl)n1
Reactant: Cc1cc(N)cc(-c2cnc(C(C)(O)C(F)(F)F)s2)c1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc(C(=O)O)n2)cc(-c2cnc(C(C)(O)C(F)(F)F)s2)c1
Temperature: 100 °C

Procedure:
To 2-chloropyrimidine-4-carboxylic acid (175 mg, 1.104 mmol) in dioxane (2.201 mL) was added 2-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-1,1,1-trifluoropropan-2-ol (INTERMEDIATE 17, (334 mg, 1.104 mmol) and acetic acid (69.5 μL, 1.214 mmol). The reaction was heated to 100° C. overnight and was complete by LCMS analysis. The reaction was cooled to room temperature and the solvent was removed under reduced pressure. Remaining acetic acid was azeotroped with toluene (2×5 mL) to yield 2-({3-methyl-5-[2-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidine-4-carboxylic acid as a tan powder. MS ESI: [M+H]+ m/z 425.1. 1H NMR (500 MHz, dmso) δ 13.79-13.63 (m, 1H), 10.05 (s, 1H), 8.73 (d, J=5.0, 1H), 8.22-8.14 (m, 1H), 8.10 (s, 1H), 7.65 (s, 1H), 7.56 (s, 1H), 7.32 (d, J=5.0, 1H), 7.12 (s, 1H), 2.31 (s, 3H), 1.76 (s, 3H). rhSYK activity=+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:11]=[N:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:5]=[C:6](I)[C:7]=1[O:8][CH3:9].CC1(C)C(C)(C)OB([C:26]2[O:27][C:28]([CH3:31])=[CH:29][CH:30]=2)O1>>[Br:1][C:2]1[CH:3]=[C:4](/[N:11]=[N:12]/[N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:5]=[C:6]([C:26]2[O:27][C:28]([CH3:31])=[CH:29][CH:30]=2)[C:7]=1[O:8][CH3:9]
Reactant: COc1c(Br)cc(N=NN2CCCC2)cc1I
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)o1
Product: COc1c(Br)cc(/N=N/N2CCCC2)cc1-c1ccc(C)o1

Procedure:
1-((3-Bromo-5-iodo-4-methoxyphenyl)diazenyl)pyrrolidine (0.15 g, 0.366 mmol) and 4,4,5,5-tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxaborolane (0.076 g, 0.366 mmol), were reacted in the same manner as Example 1 Part B for 18 hours to give crude product which was purified on an Isco 12 g silica cartridge eluting with ethyl acetate/hexane (0% to 25%) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[C:15]([CH:18]=1)[C:16]#[N:17])#[CH:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cu]I.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:10]#[C:9][C:11]2[CH:12]=[CH:13][C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)=[C:15]([CH:18]=2)[C:16]#[N:17])[CH:5]=[CH:4][N:3]=1
Reactant: C#Cc1ccc(Oc2cccc(C(F)(F)F)c2)c(C#N)c1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1cc(C#Cc2ccnc(Cl)n2)ccc1Oc1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
A mixture of copper(I) iodide (117 mg, 0.613 mmol), dichloropalladium-triphenylphosphane (1:2) (215 mg, 0.306 mmol), 2,4-dichloropyrimidine (913 mg, 6.13 mmol), and 5-ethynyl-2-{[3-(trifluoromethyl)phenyl]oxy}benzonitrile (880 mg, 3.06 mmol) in a mixed solvents of TEA (18 mL, 129 mmol) and tetrahydrofuran (12 mL), was added triphenylphosphine (161 mg, 0.613 mmol) under Argon. The reaction mixture was stirred for 12 h at 60° C., filtered, washed with EA, concentrated. Purification via ISCO system (EtOAc=1:20 to 1:5) afforded the title compound as a brown solid. LC-MS (ESI): m/z 400 [M+H]+; 3.86 min (ret time).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15](=[O:17])[N:14]([CH3:18])[C:13]=3[CH:19]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:20]1[CH2:23][CH:22]([NH:24][C:25]([CH2:27][NH:28][C:29](=[O:40])[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)=[O:26])[CH2:21]1>>[OH:1][C:2]1([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15](=[O:17])[N:14]([CH3:18])[C:13]=3[CH:19]=2)[CH2:7][CH2:6][CH:5]([N:20]2[CH2:23][CH:22]([NH:24][C:25]([CH2:27][NH:28][C:29](=[O:40])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:37])[F:38])[CH:31]=3)=[O:26])[CH2:21]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: Cn1c(=O)oc2ccc(C3(O)CCC(=O)CC3)cc21
Product: Cn1c(=O)oc2ccc(C3(O)CCC(N4CC(NC(=O)CNC(=O)c5cccc(C(F)(F)F)c5)C4)CC3)cc21

Procedure:
The title compound was prepared as a white solid by reductive amination of 5-(1-hydroxy-4-oxo-cyclohexyl)-3-methyl-3H-benzooxazol-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[CH:15]([C:16]([O:18]C)=[O:17])[CH2:14][CH2:13][C:12]2=[O:20])[CH:7]=[CH:8][CH:9]=1>O>[F:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:12](=[O:20])[CH2:13][CH2:14][CH:15]2[C:16]([OH:18])=[O:17])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C1CCC(=O)N1Cc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CCC(=O)N1Cc1cccc(F)c1
Temperature: 25 °C
Yield: 66.2 %

Procedure:
A solution of 19.00 g of sodium hydroxide pellets in 225 ml of water was treated with 115.52 g of (±)-1-[(3-fluorophenyl)methyl]-5-methoxycarbonyl-2-pyrrolidinone and the mixture was heated for four hours (steam bath). The solution was cooled to the ambient temperature and extracted with diethyl ether (3×250 ml). The aqueous phase was acidified with concentrated hydrochloric acid to about pH=1. The aqueous phase was extracted with dichloromethane (2×300 ml) and the combined organic phase was dried over Na2SO4. The solution was vacuum filtered and the filtrate was concentrated to an oil which solidified on standing. The solid was recrystallized from 300 ml of toluene to yield 72.16 g of crystals, m.p. 114°-116.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[NH2:27][C:28]1[NH:29][CH:30]=[CH:31][N:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C:28]2[NH:29][CH:30]=[CH:31][N:32]=2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: Nc1ncc[nH]1
Product: O=C(Nc1ncc[nH]1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2-aminoimidazole via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(1H-imidazol-2-yl)terephthalamide. MS (Q1) 452 (m)+.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10](/[C:13](=[CH:22]\[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)/[C:14]([NH:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)=[O:15])=[CH:9][CH:8]=1.CN([CH:32]=[O:33])C.S(=O)(O)[O-]>C1COCC1.CCOC(C)=O>[CH:32]([C:19]1[S:18][C:17]([NH:16][C:14](=[O:15])/[C:13](/[C:10]2[CH:11]=[CH:12][CH:7]=[CH:8][CH:9]=2)=[CH:22]/[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:21][CH:20]=1)=[O:33]
Reactant: O=C(Nc1nccs1)/C(=C/C1CCOCC1)c1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: O=S([O-])O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1cnc(NC(=O)/C(=C/C2CCOCC2)c2ccccc2)s1
Temperature: 20 °C
Reaction time: 1.83 h

Procedure:
n-BuLi (17 mL of a 1.6M solution in hexanes, 27.2 mmol) was added to a stirred solution of (E)-2-(4-bromophenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylacrylamide (EXAMPLE 12, 4.00 g, 10.2 mmol) in anhydrous THF (100 mL) at −78° C. After 110 min, the mixture was treated with anhydrous DMF (5 mL, 64.6 mmol), before being allowed to warm to 20° C. over 30 min. The reaction was quenched with 1M HCl, then the THF was evaporated off under reduced pressure. The aqueous phase was extracted with CH2Cl2, then the CH2Cl2 extracts were dried (MgSO4), filtered, and concentrated. The residue was stirred with Na2S2O5 solution. The solid produced was collected and triturated with EtOAc. This material was then suspended in EtOAc, then saturated aqueous NaHCO3 was added with stirring. The layers were separated, then the aqueous phase was extracted with EtOAc and CH2Cl2. The combined organic layers were dried, filtered, concentrated, and subjected to column chromatography (CH2Cl2-THF, 93:7), to give EXAMPLE 125 (RTB=1.30 min; m/z (ES+)=371.2 [M+H]+) and EXAMPLE 126 (RTB=1.38 min; m/z (ES+)=343.4 [M+H]+). The EtOAc washings from the bisulfite addition complex were concentrated, then the residue was subjected to flash chromatography (CH2Cl2-THF, 24:1 to 93:7) to give EXAMPLE 124 (RTB=1.39 min; m/z (ES+)=315.3 [M+H]+) and an additional quantity of EXAMPLE 126.
Reaction SMILES: [C:1]1([CH:11]=[CH:12][C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>[Pd].O1CCCC1>[C:1]1([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C=Cc1cccc2ccccc12
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)CCc1cccc2ccccc12
Reaction time: 18 h
Yield: 99 %

Procedure:
10% Palladium on carbon (1.00 g) was added to a suspension of 3-(1-naphthyl)acrylic acid (50.0 g) in tetrahydrofuran (500 ml). The mixture was hydrogenated at 6 atmospheres for 18 hours then filtered through a kieselguhr pad washing with ethyl acetate (3×100 ml). The filtrate was evaporated under reduced pressure to give the subtitle compound (50.0 g) as a solid.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:9].C(N(CC)CC)C>C(Cl)Cl>[C:8](=[O:9])([O:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)[O:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
To a mixture of cyclopentanol (0.5 g, 6 mol), p-nitrophenyl chloroformate (1.3 g, 6.4 mmol) in methylene chloride (10 mL) was added triethylamine (1.2 mL, 8.7 mmol). The mixture was stirred at r.t. for 2 h. After removal of solvent, the crude residue was purified by flash chromatography on a silica gel column eluted with 20% EtOAc in hexane to yield the desired product (0.86 g, 59%).
Reaction SMILES: C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:19]12([OH:29])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2.[C:30](O)(=[O:34])[C:31]([CH3:33])=[CH2:32]>O>[C:30]([O:29][C:19]12[CH2:26][CH:25]3[CH2:24][CH:23]([CH2:22][CH:21]([CH2:27]3)[CH2:20]1)[CH2:28]2)(=[O:34])[C:31]([CH3:33])=[CH2:32]
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: C=C(C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)C(=O)OC12CC3CC(CC(C3)C1)C2

Procedure:
200 ml of toluene and 1 g of p-toluenesulfonic acid were added to 70 g of 1-adamantanol and 50 g of methacrylic acid. They were subjected to a reaction with heating and stirring, while water was distilled off using a Dean-Stark trap. The resulting organic phase was washed with water, a 10 mass % aqueous sodium hydrogencarbonate solution and water in this order and distilled to obtain crude 1-adamantyl methacrylate (a crude product) having a purity of 91 mass %.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:30])[CH:28]=[CH2:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[C:27](=[O:30])[CH2:28][CH2:29][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Ic1ccccc1
Reactant: C=CC(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(=O)CCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 39, Step 1, using 1-{4′-[4-(1-hydroxy-allyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and iodobenzene. The crude material was purified on silica gel (0-60% EtOAc in hexanes) to give a separable mixture of two compounds, one of which was the title compound.
Reaction SMILES: Cl.[OH:2][CH2:3][CH:4]1[CH2:12][CH:11]2[CH:7]([CH2:8][NH:9][CH2:10]2)[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])([OH:13])[CH2:5]1.[N:21]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][C:33](O)=[O:34])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[OH:2][CH2:3][CH:4]1[CH2:12][CH:11]2[CH:7]([CH2:8][N:9]([C:33](=[O:34])[CH2:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:10]2)[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])([OH:13])[CH2:5]1
Reactant: OCC1CC2CNCC2C(O)(c2ccccc2F)C1
Reactant: O=C(O)Cc1ccccc1N1CCCC1
Agent: Cl
Product: O=C(Cc1ccccc1N1CCCC1)N1CC2CC(CO)CC(O)(c3ccccc3F)C2C1
Yield: 18.3 %

Procedure:
The procedure is as described for Example 14, starting from 0.73 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-fluorophenyl)perhydroisoindol-4-ol hydrochloride and 0.68 g of 2-(1-pyrrolidinyl)phenylacetic acid, and gives 0.2 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-fluorophenyl)-2-[2-(1-pyrrolidinyl)phenylacetyl]perhydroisoindol-4-ol in the form of a thick white foam.