Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:16])=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.BrC1C([NH:32][NH2:33])=NC(C)=CC=1C1C=CC(Cl)=CC=1>>[Br:1][C:2]1[C:3]([CH3:16])=[N:4][C:5]([NH:32][NH2:33])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)c(Br)c(NN)n1
Reactant: Cc1nc(Cl)cc(-c2ccc(Cl)cc2)c1Br
Product: Cc1nc(NN)cc(-c2ccc(Cl)cc2)c1Br
Yield: 92 %

Procedure:
The title compound (200 mg, 92% yield) as a white solid was prepared from 3-bromo-6-chloro-4-(4-chlorophenyl)-2-methylpyridine (220 mg, 0.7 mmol) by procedures analogous to those used for the preparation of 3-bromo-4-(4-chlorophenyl)-2-hydrazinyl-6-methylpyridine. HPLC/MS: retention time=2.87 min, [M+H]+=312.2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[F:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][N:22]2[CH:26]=[CH:25][C:24]([NH2:27])=[N:23]2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][N:22]2[CH:26]=[CH:25][C:24]([NH:27][C:2]3[CH:3]=[CH:4][C:5]([N:10]4[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]4)=[C:6]([CH:9]=3)[C:7]#[N:8])=[N:23]2)=[CH:19][CH:18]=1
Reactant: Nc1ccn(Cc2ccc(F)cc2)n1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3ccn(Cc4ccc(F)cc4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(4-fluoro-benzyl)-1H-pyrazol-3-ylamine. The title compound was obtained as a yellowish oil (Yield=75%). MS ISP (m/e): 373.2 (100) [(M+H)+].
Reaction SMILES: C(O[CH:5]([C:22]1[N:23]=[CH:24][N:25]([C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]=1[CH3:27])[CH:6]1[C:20](=[O:21])[N:10]2[C:11]3[C:16]([C:17]([CH3:18])=[C:9]2[CH2:8][CH2:7]1)=[CH:15][C:14]([Cl:19])=[CH:13][CH:12]=3)(=O)C.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[Cl:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]1[C:20](=[O:21])[C:6](=[CH:5][C:22]3[N:23]=[CH:24][N:25]([C:28]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:26]=3[CH3:27])[CH2:7][CH2:8][C:9]1=[C:17]2[CH3:18]
Reactant: CC(=O)OC(c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C)C1CCc2c(C)c3cc(Cl)ccc3n2C1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: Cc1c2n(c3ccc(Cl)cc13)C(=O)C(=Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Yield: 87.7 %

Procedure:
To a solution of 7-[(acetoxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-2-chloro-8,9-dihydro-10-methylpyrido[1,2-a]indol-6(7H)-one (1.40 g) in toluene (15 ml) was added 1.8-diazabicyclo[5.4.0]undec-7-ene (0.37 ml), and the mixture was refluxed for 2 hours. After being cooled, the solution was washed with water and brine, dried over sodium sulfate, evaporated, and triturated in diisopropyl ether, to give 2-chloro-8,9-dihydro-10-methyl-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methylene]pyrido[1,2-a]indol-6(7H)-one (1.11 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=O.OC(C(F)(F)F)=O.[NH2:36][CH2:37][C:38]([CH3:43])([CH3:42])[C:39]([OH:41])=[O:40].C[O-].[Na+]>CCO>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[C:7]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:6][C:5]=1[C:3]([NH:36][CH2:37][C:38]([CH3:43])([CH3:42])[C:39]([OH:41])=[O:40])=[O:2]
Reactant: COC(=O)c1nc(-c2ccccc2)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(C)(CN)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)c1nc(-c2ccccc2)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Temperature: 150 °C
Yield: 74.1 %

Procedure:
A mixture of 4-hydroxy-7-phenoxy-1-phenyl-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.13 mmol), 3-amino-2,2-dimethyl-propionic acid TFA salt (125 mg, 0.54 mmol) and NaOMe (58 mg, 1.08 mmol) in EtOH (2 mL) was heated at 150° C. in a microwave reactor for 6 h. The solvent was evaporated, and the residue was partitioned between water (30 mL) and EtOAc (30 mL). 1 M HCl was added with vigorous stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-30% EtOAc/hexanes+2% AcOH) to give 44 mg of the title compound as a yellow solid. MS: (+) m/z 457.26 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[OH-].[Na+:17]>O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]\[C:12]([O-:14])=[O:13])=[CH:6][CH:7]=1.[Na+:17]
Reactant: Nc1ccc(NC(=O)/C=C\C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(NC(=O)/C=C\C(=O)[O-])cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
Under a nitrogen atmosphere, into a reaction vessel were charged 15.00 g (138.7 mmol) of 1,4-phenylenediamine and 255 ml of tetrahydrofuran. A solution prepared by dissolving 9.07 g (92.5 mmol) of maleic anhydride in 45 ml of tetrahydrofuran was dropped into this under cooling with ice over a period of about 3 hours, then, the mixture was stirred at room temperature overnight. After completion of the reaction, the deposited crystal was isolated by filtration, washed with 30 ml of tetrahydrofuran, and dried at 40° C. to obtain 18.14 g of coarse (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoic acid as an orange powder. To 18.14 g of coarse (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoic acid was added 36 ml of water and the mixture was cooled to 0 to 10° C., and 17.59 ml of a 5N sodium hydroxide aqueous solution was dropped. Thereafter, the solvent was distilled off under reduced pressure to obtain a residue to which 270 ml of ethanol was added, and the mixture was stirred at 70° C. for 1 hour, cooled down to room temperature, then, the solid was filtrated and washed twice with 25 ml of methanol. The resultant solid was dried at 45° C. for 2 hours, to obtain 16.2 g of sodium (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoate as a pale brown-white powder. Yield: 76.8%
Reaction SMILES: CS(O[CH2:6][C@H:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=O)=O.[N-:22]=[N+:23]=[N-:24].[Na+].O>CN(C=O)C>[C:16]1([C@H:7]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][N:22]=[N+:23]=[N-:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])c1ccccc1
Temperature: 55 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
(S)-2-Phenyl-2-tert-butoxycarbonylaminoethyl methanesulfonate (15.77 g, 0.05 mol) was dissolved in 50 mL DMF followed by the addition of sodium azide (19.5 g, 0.3 mol). The mixture was stirred for 24 hrs at 55° C., cooled to room temperature, poured into cold water (500 mL) and stirred vigorously for 20 minutes. Precipitate was collected by filtration, washed with water and dried, affording 9.97 g of the title compound as a white solid. Yield: 76%; (MH)+=263; 1H NMR (DMSO-d6): 1.37 (s, 9H), 3.36-3.50 (m, 2H), 4.69-4.75 (m, 1H), 7.23-7.36 (m, 5H), 7.65-7.68 (d, J=9.2 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:13]([CH3:14])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CNC
Product: CN(C)S(=O)(=O)c1ccc(Br)cc1
Yield: 77 %

Procedure:
Prepared by general procedure III from 4-bromobenzenesulfonyl chloride (9.59 g, 38 mmol) and excess aq. dimethylamine to give the title compound (7.61 g, 77%) as a white crystalline solid. MS (ISP) 266.1 [(M+H)+].
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:37])[C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH2:16][C@H:15]2[NH:25][C:26]([C:28]2[N:33]=[CH:32][C:31]3[CH2:34][NH:35][CH2:36][C:30]=3[CH:29]=2)=[O:27])=[O:12])=[N:7][CH:8]=1.[CH2:38]=O>>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:37])[C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([N:22]([CH3:23])[CH3:24])=[O:21])[CH2:16][C@H:15]2[NH:25][C:26]([C:28]2[N:33]=[CH:32][C:31]3[CH2:34][N:35]([CH3:38])[CH2:36][C:30]=3[CH:29]=2)=[O:27])=[O:12])=[N:7][CH:8]=1
Reactant: C=O
Reactant: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)C(=O)Nc2ccc(Cl)cn2)[C@H](NC(=O)c2cc3c(cn2)CNC3)C1
Agent: Cl
Product: CN1Cc2cnc(C(=O)N[C@@H]3C[C@@H](C(=O)N(C)C)CC[C@@H]3NC(=O)C(=O)Nc3ccc(Cl)cn3)cc2C1

Procedure:
In a manner similar to that employed in Example 18, the title compound was prepared from the compound obtained in Example 339 and formalin.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]#[CH:5].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH2:2]([N:16]1[CH2:15][CH2:14][N:13]([C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[CH2:18][CH2:17]1)[CH2:3][C:4]#[CH:5]
Reactant: C#CCCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C#CCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 6 h
Yield: 69.3 %

Procedure:
A solution of 4-bromo-1-butyne (0.500 g, 3.76 mmol) in acetonitrile (20 mL) was added with 1-tert-butoxycarbonylpiperazine (0.700 g, 3.76 mmol) and potassium carbonate (0.779 g, 5.64 mmol), and the mixture was stirred at 60° C. for 6 hours. The reaction mixture was added with water, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-(but-3-ynyl)piperazine-1-carboxylate (0.621 g, 69%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][O:6][C:7]1[N:12]=[C:11](S(C)(=O)=O)[C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])[N:8]=1.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][O:6][C:7]1[N:12]=[C:11]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])[N:8]=1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)c1nc(OCc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Product: Fc1ccc(COc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c(N3CCCC3)n2)cc1F

Procedure:
2-(3,4-Difluorobenzyloxy)-4-(methylsulfonyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-pyrimidine (Reference Example 7) (30 mg, 0.05 mmol) was reacted with pyrrolidine (37.7 mg, 0.53 mmol) by the same general procedure described in Example 103 to afford the title compound after flash column chromatography on silica gel (eluted with 90/10 hexanes/ethyl acetate): HPLC/MS: m/e=546 (M++1); Rt=3.70 min. 1H-NMR 400 MHz (CDCl3): δ 1.75-1.80 (br, 4H), 3.10-3.20 (br, 4H), 5.32-5.42 (m, 2H), 6.95 (d, J=9 Hz, 1H), 7.05-7.21 (m, 8H), 7.35-7.40 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16](Br)[CH:15]=2)[CH:7]=1)[CH3:2].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:14]2[CH:15]=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]([F:20])=[CH:18][CH:19]=2)=[O:22])[CH:7]=1)[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2ccc(F)c(Br)c2)c1
Product: CCOC(=O)Cc1cccc(NC(=O)c2ccc(F)c(-c3ccccc3)c2)c1
Temperature: 80 °C

Procedure:
[3-(3-Bromo-4-fluoro-benzoylamino)-phenyl]-acetic acid ethyl ester (190 mg, 0.50 mmol) was coupled to phenylboronic acid using Method E, except that the reaction mixture was heated at 80° C. for 25 min. The crude product was purified by column chromatography using 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-:5]C(C)C)C.[F:9][C:10]([F:17])([F:16])[C:11]([O:13]CC)=O.C(#N)C>C1COCC1>[F:17][C:10]([F:9])([F:16])[C:11](=[O:13])[CH2:2][C:3]#[N:5]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCOC1
Product: N#CCC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 56.7 %

Procedure:
To a cooled (−78° C.) solution of LDA (2M, 15 g, 39 mmol) in anhydrous THF (50 mL) was added drop-wise a solution of ethyl trifluoroacetate (2.5 g, 18 mmol) and acetonitrile (1.4 g, 35 mmol) in 15 ml THF. The reaction was kept at −78° C. for 45 min, warmed up to room temperature over 1 hour period and quenched with ice water. The reaction was concentrated under vacuum, the residue extracted with ethyl ether, the pH brought to 1 with concentrated HCl, extracted with dichloromethane. The aqueous solution was extracted with ethyl ether, the combined organic layers dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to afford 1.4 g of 4,4,4-trifluoro-3-oxobutanenitrile as a yellow oil, which was used as such in the next step.
Reaction SMILES: [CH3:1][Si](C)(C)N[Si](C)(C)C.[Na].[CH:11]([C:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:35])[C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[F:34])=[CH:21][CH:20]=1)=O>C1COCC1>[CH:11]([C:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:35])[C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[F:34])=[CH:21][CH:20]=1)=[CH2:1]
Reactant: O=CC1=C(c2ccc(NC(=O)c3c(F)cccc3F)cc2)CCCC1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Product: C=CC1=C(c2ccc(NC(=O)c3c(F)cccc3F)cc2)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
To the solution of Ph3PCH3Br (75 mg, 0.21 mmol) in THF (4 mL) was added sodium hexamethyldisilazane (NaHMDS) (1 N, 0.21 mL, 0.21 mmol) at −78° C. After stirring at this temperature for 30 min, Compound 100 (70 mg, 0.21 mmol) was added. The reaction solution was allowed to warm up to room temperature and stirred overnight. The solution was quenched with NH4Cl (20 mL) and extracted with EtOAc (30 mL). The organic portion was collected, dried and concentrated. Column chromatography afforded Compound 101 (42 mg, 60%). 1H NMR (300 MHz, CDCl3) δ 7.63-7.51 (m, 3H), 7.45-7.38 (m, 1H), 7.26-7.15 (m, 2H), 7.04-6.97 (m, 2H), 6.45 (dd, J=17.4 and 11.1 Hz, 1H), 5.14 (d, J=17.4 Hz, 1H), 4.86 (d, J=11.4 Hz, 1H), 2.37-2.29 (m, 4H), 1.79-1.72 (m, 4H); ESMS cacld (C21H13F2NO): 339.1; found: 340.1 (M+H).
Reaction SMILES: S1[C:5]([C:6](=[O:34])/[CH:7]=[CH:8]/[C@H:9]2[C@@H:13]([F:14])[CH2:12][C@H:11]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C@@H:10]2[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])=[CH:4][C:3]2[CH:35]=[CH:36][CH:37]=[CH:38][C:2]1=2.[BH4-].[Na+].[CH3:41]O>>[CH2:41]1[C:2]2[C:3](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:4][CH:5]1[C@H:6]([OH:34])/[CH:7]=[CH:8]/[C@H:9]1[C@@H:13]([F:14])[CH2:12][C@H:11]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C@@H:10]1[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29]
Reactant: CO
Reactant: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/C(=O)c2cc3ccccc3s2)[C@@H](F)C[C@@H]1OC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)C2Cc3ccccc3C2)[C@@H](F)C[C@@H]1OC1CCCCO1
Temperature: -40 °C

Procedure:
To a stirring mixture consisting of (Z)-isopropyl 7-((1R,2R,3S,5S)-2-((E)-3-(benzo[b]thiophen-2-yl)-3-oxoprop-1-enyl)-3-fluoro-5-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoate (prepared in Step H, 13.4 g) in methanol (325 mL) cooled to −40° C. was added CeCl3 heptahydrate (9.46 g). The reaction mixture was further cooled to −78° C. and was stirred for an additional hour. Sodium borohydride (1.89 g) was added and the reaction mixture was stirred for one hour at −78° C. Upon completion (as visualized by TLC), the reaction was quenched by the addition of acetone and the mixture was warmed to room temperature. The mixture was subsequently acidified with 5% KHSO4, extracted with DCM, and the organic layers were washed twice with brine. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude title intermediate (15.2 g). The crude intermediate was carried on with no further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][C@H:3]1[CH2:4][OH:5].[OH-].[Na+].Cl[C:12]1[N:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=2)[N:15]=[C:14]([NH:28][CH:29]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[N:13]=1>C1C=CC=CC=1>[Cl:27][C:21]1[CH:20]=[C:19]([NH:18][C:16]2[N:15]=[C:14]([NH:28][CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)[N:13]=[C:12]([O:5][CH2:4][CH:3]3[CH2:6][CH2:7][CH2:8][N:2]3[CH3:1])[N:17]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: CN1CCC[C@H]1CO
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(OCC3CCCN3C)n2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of N-methyl prolinol (0.226 g, 1.96 mmol) and sodium hydroxide (79 mg, 1.96 mmol) in benzene (10 mL) was heated to reflux for 2 hours with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.25 g, 0.65 mmol) at same temperature. The mixture was heated to reflux for 6 hours, concentrated under vacuum and diluted with water (3 mL). The gum which separated was collected (by decanting out the liquid portion) and purified by column chromatography (1-3% MeOH—CHCl3) to afford the title compound E25 as a semi-solid (0.06 g, 20%). HPLC: Symmetry shield RP18 (250×4.6 mm) 5 microns [solvent A=0.01 M K2PO4 (pH 3.0); solvent B=CH3CN], Gradient elution program: T/% B=0/35, 10/35, 40/80, 50/80, 55/35, 60/35; 270 nm, Rt 15.51 min, 99.55% purity; MS (CI): m/z 461 (M+H, 100).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1>[OH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:13]1[CH2:14][CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:10])[CH2:12]1
Reactant: O=C(O)CCCC1CCCN(C(=O)OCc2ccccc2)C1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCCC(CCCCO)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(1-{[(phenylmethyl)oxy]carbonyl}-3-piperidinyl)butanoic acid (commercially available, for example, from Astatech) (5.01 g, 16.41 mmol) in dry THF (40 mL) at 0° C. under nitrogen was added a solution of Borane-THF complex, (1M solution in THF) (49.2 mL, 49.2 mmol), dropwise over 1 hour. The mixture was allowed to stir at 0° C. and gradually allowed to warm to room temperature over 20 hours. The mixture was cooled in an ice bath and cautiously quenched with dropwise addition of MeOH (20 mL), stirred in the cold bath for 2 hours, then quenched further with 10% 2N HCl/MeOH (20 mL), stirred for 1 hour at room temperature and evaporated under reduced pressure. The residue was co-evaporated with methanol several times. The sample was purified by chromatography on silica (100 g, loaded in dichloromethane/EtOAc) using a gradient of 0-100% ethyl acetate-cyclohexane over 30 minutes collecting all 45 mL fractions on the Flashmaster II. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a colourless oil (4.55 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)=[CH:21][CH:20]=3)[C:16]([C:17]#[N:18])=[C:12]2[NH:11][CH2:10][CH2:9]1.[OH-:30].[Na+].OO>CCO.CS(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)=[CH:23][CH:24]=3)[C:16]([C:17]([NH2:18])=[O:30])=[C:12]2[NH:11][CH2:10][CH2:9]1
Reactant: N#Cc1c(-c2ccc(OCC3CC3)cc2)nn2c1NCCC2c1ccccc1N
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1c(-c2ccc(OCC3CC3)cc2)nn2c1NCCC2c1ccccc1N
Temperature: 60 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
To a solution of 7-(2-aminophenyl)-2-(4-(cyclopropylmethoxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (350 mg, 0.91 mmol) in EtOH (4 mL) and DMSO (4 mL) was added NaOH aqueous solution (5 N, 2 mL) and H2O2 (2 mL). After stirring at 60° C. for 3 hr, the mixture was partitioned between 100 mL of H2O and 100 mL of EA. The organic layer was separated from aqueous layers, washed with saturated brines (100 mL×2), dried over Na2SO4 and concentrated. The residue was purified by chromatography column on silica gel (elution with DCM/MeOH) to afford 150 mg (41%) of desired product as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.37 (d, J=8.8 Hz, 2H), 6.97-6.92 (m, 3H), 6.75 (br s, 1H), 6.67 (d, J=8.0 Hz, 1H), 6.49 (t, J=7.6 Hz, 1H), 6.27 (d, J=7.6 Hz, 1H), 5.58-5.54 (m, 1H), 5.16 (s, 2H), 3.83 (d, J=7.2 Hz, 2H), 3.27-3.24 (m, 1H), 3.01-2.92 (m, 1H), 2.23-2.13 (m, 1H), 2.13-2.07 (m, 1H), 1.24-1.18 (m, 1H), 0.59-0.54 (m, 2H) and 0.34-0.30 (m, 2H). MS (ESI) m/e [M+1]+ 404.0.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2.[C:18]1([CH3:27])[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1>>[CH3:27][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2
Reactant: Cc1cccc(B(O)O)c1
Reactant: BrC=C1c2ccccc2CCc2ccccc21
Product: Cc1cccc(C=C2c3ccccc3CCc3ccccc32)c1

Procedure:
Combine 5-bromomethylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (0.5 g, 1.75 mmol) and m-tolylboronic acid (0.238 g, 1.75 mmol) using procedures essentially as described in Example 219, below. Pass through a plug of silica gel equilibrated with hexanes. Concentrate the filtrate to give the title product: MS (m/e): 296 (M+); HPLC (ISO80-10M)) t=17.78 min (95%).
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([O:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[C:25]4[C:21]([C:22]([CH2:27][CH2:28][C:29]([O-:31])=[O:30])=[CH:23][NH:24]4)=[CH:20][CH:19]=3)[N:14]=2)=[CH:9][C:8]=1[O:32][CH3:33])[CH3:5].Cl>C1COCC1.O>[CH3:5][CH:4]([O:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[C:25]4[C:21]([C:22]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:23][NH:24]4)=[CH:20][CH:19]=3)[N:14]=2)=[CH:9][C:8]=1[O:32][CH3:33])[CH3:3]
Reactant: COc1cc(-c2nc(-c3ccc4c(CCC(=O)[O-])c[nH]c4c3)no2)cnc1OC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2nc(-c3ccc4c(CCC(=O)O)c[nH]c4c3)no2)cnc1OC(C)C
Temperature: 90 °C
Yield: 61.1 %

Procedure:
Sodium hydroxide (50 mg) was added to a solution of 3-(6-{5-[6-[(1-methylethyl)oxy]-5-(methyloxy)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D112) (258 mg) in THF (3 mL) and water (3 mL). The resulting mixture was heated at 90° C. for 1 hour. Then 0.5 M HCl solution was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-(6-{5-[6-[(1-methylethyl)oxy]-5-(methyloxy)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoic acid (E87) (158 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.35 (6H, d), 2.61 (2H, t), 2.97 (2H, t), 3.94 (3H, s), 5.42 (1H, m), 7.34 (1H, d), 7.72 (2H, m), 7.82 (1H, d), 8.13 (1H, s), 8.54 (1H, d), 11.18 (1H, s), 12.08 (1H, br s). MS (ES): C22H22N4O5 requires 422; found 423.2.