Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[ClH:16]>O>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH2:1][CH2:2][CH2:3][Cl:16])=[CH:7][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: Nc1ccc(C(=O)C2CC2)cc1[N+](=O)[O-]
Reactant: Cl
Solvent: O
Product: Nc1ccc(C(=O)CCCCl)cc1[N+](=O)[O-]
Yield: 84.5 %

Procedure:
A mixture of cyclopropyl (4-amino-3-nitrophenyl)methanone (80 g), prepared as described in U.S. Pat. No. 3,657,267, and concentrated HCl (420 ml) was stirred and refluxed for 30 minutes. The reaction mixture was cooled and water was added. The precipitate was filtered off, washed with water and dried, yielding 80 g (84.5%) of 1-(4-amino-3-nitrophenyl)-4-chloro-1-butanone; mp. 150° C. (intermediate 10).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH:17]=O)=[C:12]([O:19][CH3:20])[CH:11]=2)[CH:7]=[N:6]1.[CH:22]1([NH:28][C:29]2[C:34]3[N:35]=C(S(C)(=O)=O)[N:37]=[CH:38][C:33]=3[CH:32]=[CH:31][N:30]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([NH:28][C:29]2[C:34]3[N:35]=[C:17]([NH:16][C:13]4[CH:14]=[CH:15][C:10]([C:8]5[CH:7]=[N:6][N:5]([CH2:4][CH2:3][N:2]([CH3:21])[CH3:1])[CH:9]=5)=[CH:11][C:12]=4[O:19][CH3:20])[N:37]=[CH:38][C:33]=3[CH:32]=[CH:31][N:30]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CS(=O)(=O)c1ncc2ccnc(NC3CCCCC3)c2n1
Reactant: COc1cc(-c2cnn(CCN(C)C)c2)ccc1NC=O
Product: COc1cc(-c2cnn(CCN(C)C)c2)ccc1Nc1ncc2ccnc(NC3CCCCC3)c2n1
Yield: 25 %

Procedure:
The title compound was prepared according to Example 40 using N-(4-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-2-methoxyphenyl)formamide (Preparation 64) and N-cyclohexyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8-amine (Preparation 44). The residue was purified by silica gel column chromatography eluting with 0 to 10% MeOH in DCM to give the title compound (26 mg, 25%).
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].C[S+](C)(C)=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]3[C:23](=[CH:24][C:25]4[C@@:33]5([CH2:39][C:40]6C=CC=CN=6)[CH2:34][CH2:35][C:36](=[O:38])[CH2:37][C@H:32]5[CH2:31][CH2:30][CH2:29][C:26]=4[CH:27]=3)[CH:22]=[N:21]2)=[CH:16][CH:15]=1.F[C:47]1C=CC(N2C3C(=CC4[C@]5(CC6C=CC=CN=6)CCC(=O)C[C@@H]5CCCC=4C=3)C=N2)=CC=1>C1COCC1>[CH2:34]([C@:33]12[CH2:39][CH2:40][C@:36]3([CH2:35][O:38]3)[CH2:37][C@@H:32]1[CH2:31][CH2:30][CH2:29][C:26]1[C:25]2=[CH:24][C:23]2[CH:22]=[N:21][N:20]([C:17]3[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=3)[C:28]=2[CH:27]=1)[CH3:47]
Reactant: O=C1CC[C@]2(Cc3ccccn3)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCC[C@@H]2C1
Reactant: O=C1CC[C@@]2(Cc3ccccn3)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCC[C@H]2C1
Agent: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC[C@]12CC[C@]3(CO3)C[C@@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 65 °C
Reaction time: 5 h
Yield: 50 %

Procedure:
A mixture of sodium hydride (60 wt % in oil, 0.038 g, 1.594 mmol) and DMSO (5 mL) was heated to about 65° C. for about 30 min then cooled to rt and diluted with THF (2.5 mL). The reaction mixture was cooled in an ice water bath and trimethyl sulfoxonium iodide (0.149 g, 0.68 mmol) was added then stirred for about 15 min. (4aS,12bS)-12b-ethyl-9-(4-fluorophenyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3 (2H)-one (10, R1=4-Fluorophenyl, R2=Ethyl) was then added in one portion dissolved in THF (2.5 mL) and the mixture was stirred to rt for about 5 h. The solvents were removed and the residue was diluted with about 15 mL water and extracted with EtOAc (15 mL×3). The combined organics were washed with sat. aq. NaCl (15 mL). The organic layer was dried over MgSO4 filtered and concentrated to about 220 mg of a crude viscous oil. The sample was further purified on silica gel (12 g) using DCM/EtOAc with ramp conditions of 0-100% EtOAc in DCM over 20 min followed by 10 min at 100% EtOAc. The product fractions were concentrated to colorless viscous dried on a high vacuum to yield (2′R,4aS,12bS)-12b-ethyl-9-(4-fluorophenyl)-2,4,4a,5,6,7,9,12b-octahydro-1H-spiro[benzo[6,7]cyclohepta[1,2-f]indazole-3,2′-oxirane] (14, R1=4-Fluorophenyl, R2=Ethyl) (131 mg,50%) of a white crystalline solid. LC/MS, method 4, Rt=2.08 min, MS m/z 391 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.27 (s, 1H), 7.93 (s, 1H), 7.85-7.77 (m, 2H), 7.56 (s, 1H), 7.45-7.36 (m, 2H), 4.03 (q, J=7.1 Hz, 1H), 3.25-3.17 (m, 1H), 3.00-2.90 (m, 1H), 2.67 (d, J=4.7 Hz, 1H), 2.62 (d, J=4.7 Hz, 1H), 2.38-2.30 (m, 1H), 2.25-1.92 (m, 3H), 1.93-1.67 (m, 3H), 1.62-1.53 (m, 1H), 1.40-1.24 (m, 1H), 1.18 (t, J=7.1 Hz, 2H), 1.04-0.95 (m, 1H), 0.40 (t, J=7.3 Hz, 3H). Sign of rotation is negative.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH3:10])=[CH:4][N:3]=1.[C:11]([Zn]C#N)#[N:12].CN(C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:10][O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]#[N:12])=[N:3][CH:4]=1
Reactant: N#C[Zn]C#N
Reactant: COCc1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COCc1ccc(C#N)nc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
A mixture of 2-chloro-5-(methoxymethyl)pyridine (0.831 g, 5.27 mmol), tetrakis (1.219 g, 1.055 mmol), dicyanozinc (0.929 g, 7.91 mmol) and DMF (17.58 ml) was stirred at 100° C. for 3 hrs. The reaction was treated with water and extracted with EtOAc. The organic portion was dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by column chromatography, eluting with 10-40% EtOAc/Heptanes to give the title compound (550 mg, 3.71 mmol, 70.4%). MS m/z=149.1 (M+H).
Reaction SMILES: COC[O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]([CH2:32][CH:33]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[C:14]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[NH:27][C:26](=[O:31])[CH:25]=[CH:24]3)=[O:15])[CH2:7][CH2:6]1.Cl.[OH-].[K+]>CO>[OH:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]([CH2:32][CH:33]2[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]2)[C:14]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[NH:27][C:26](=[O:31])[CH:25]=[CH:24]3)=[O:15])[CH2:7][CH2:6]1
Reactant: COCOC1CCN(CCN(CC2CCCCCCC2)C(=O)CCCCOc2ccc3[nH]c(=O)ccc3c2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(CCCCOc1ccc2[nH]c(=O)ccc2c1)N(CCN1CCC(O)CC1)CC1CCCCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
In 30 ml of methanol is dissolved 12.10 g of 6-{4-[N-(4-methoxymethoxy-1-piperidinyl)ethyl-N-cyclooctylmethylaminocarbonyl]butoxy}carbostyril. Thereto is added 240 ml of 5% hydrochloric acid. The mixture is stirred for 8 hours at room temperature. To the mixture is added with a 10% aqueous potassium hydroxide solution under ice cooling to make the mixture alkaline. The resulting mixture is extracted with methylene chloride. The extract is washed with water and dried with anhydrous magnesium sulfate. The solvent is removed by evaporation. The residue is purified by means of a silica gel column chromatography (eluant; chloroform:methanol=8:1) and recrystallized from ethanol to obtain 6.50 g of 6-{4-[N-(4-hydroxy-1-piperidinyl)ethyl-N-cyclooctylmethylaminocarbonyl]butoxy}carbostyril.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[Cl:32][C:33]1[C:34]([CH3:43])=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl>[Cl:32][C:33]1[C:34]([CH3:43])=[C:35]([S:39]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([F:9])=[C:3]([NH:10][C:11]3[C:16]([C:17]4[N:25]=[CH:24][N:23]=[C:22]5[C:18]=4[N:19]=[CH:20][N:21]5[CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)=[CH:15][CH:14]=[CH:13][N:12]=3)[C:2]=2[F:1])(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 3-chloro-2-methyl benzene-1-sulfonyl chloride (16 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 26 mg of the target compound, 3-chloro-N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-2-methylbenzenesulfonamide (percentage yield: 90%), was obtained.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[CH:13][CH:12]=2)[CH2:6]1)=[O:4].Cl>O1CCOCC1>[F:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([N:7]2[C:8](=[O:10])[CH2:9][C@H:5]([C:3]([OH:4])=[O:2])[CH2:6]2)=[CH:16][CH:15]=1
Reactant: COC(=O)[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 50 °C
Yield: 82.6 %

Procedure:
A solution of 25.61 g (74.6 mmol) of (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester in 650 ml of dioxane is treated with 175 ml of hydrochloric acid (37%). The mixture is heated at 50° C. for 18 h in a closed flask. For the working-up, the solution is evaporated under reduced pressure to yield the crude acid as a yellow solid. For purification, the crude acid is triturated at 0° C. in 50 ml of ethyl acetate. The solid is collected on a filter funnel and then dried under high vacuum to yield 20.3 g (82% of theory) of (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid as a yellowish solid; MS: m/e=330 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[CH:16][C:15]=2[Cl:33])=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1Cl)(=[O:3])[NH2:2].[NH3:34]>O1CCOCC1>[NH2:34][C:9]1[N:8]=[C:7]([S:11][CH3:12])[N:6]=[C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[CH2:24][CH2:25]3)=[CH:16][C:15]=2[Cl:33])[C:4]=1[C:1](=[O:3])[NH2:2]
Reactant: CSc1nc(Cl)c(C(N)=O)c(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2Cl)n1
Reactant: N
Solvent: C1COCCO1
Product: CSc1nc(N)c(C(N)=O)c(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2Cl)n1

Procedure:
A solution of the product of Example 59A (450 mg, 0.88 mmol) and 25% ammonia solution (1 mL) in dioxane (10 mL) was heated in a sealed tube at 100° C. for 16 hours. After cooling and concentration, the residue was purified by flash chromatography on silica gel eluting with 30:1 dichloromethane:methanol to give the title compound. MS: 493 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[Cl:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[CH:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)[CH2:9][NH:8][CH2:16]2
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(C3CCOCC3)cc2C1
Solvent: O=C(O)C(F)(F)F
Product: Clc1cc2c(cc1C1CCOCC1)CNC2

Procedure:
Prepared in analogy to Example A2(c) from 5-chloro-6-(tetrahydro-pyran-4-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Yellow oil. MS (m/e): 240.2 ({37Cl}[M+H]+, 39%), 238.1 ({35Cl}[M+H]+, 100%).
Reaction SMILES: [CH3:1][N:2]1[CH:9]=[CH:8][C:6](=[O:7])[N:5]([CH3:10])[C:3]1=[O:4].[Cl:11][S:12](O)(=[O:14])=[O:13]>>[CH3:1][N:2]1[CH:9]=[C:8]([S:12]([Cl:11])(=[O:14])=[O:13])[C:6](=[O:7])[N:5]([CH3:10])[C:3]1=[O:4]
Reactant: O=S(=O)(O)Cl
Reactant: Cn1ccc(=O)n(C)c1=O
Product: Cn1cc(S(=O)(=O)Cl)c(=O)n(C)c1=O
Temperature: 25 °C
Yield: 79.2 %

Procedure:
1,3-Dimethyluracil (411 g, 2.93M) was added portionwise over 30 minutes to chlorosulfonic acid (5480 g, 47.0M) with stirring at room temperature. The exotherm was allowed to proceed to 50° C. without cooling. Upon completion of addition, the reaction was heated gradually to reflux (~154° C.) for 2 hours. Upon cooling the reaction was cautiously poured onto ice. The resultant solid was filtered off, washed thoroughly with water and dried in vacuo at 40° C. for 16 hours. An off-white solid (554 g, 79.2%), m.p. 225°-230° C. (dec.) was obtained.
Reaction SMILES: C([O:5][C:6]([C@@:8]12[CH2:15][CH2:14][CH2:13][C@:12]1([Cl:16])[C:11](=[O:17])[N:10]([C@@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[CH2:9]2)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:16][C@:12]12[CH2:13][CH2:14][CH2:15][C@@:8]1([C:6]([OH:7])=[O:5])[CH2:9][N:10]([C@@H:18]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:19])[C:11]2=[O:17]
Reactant: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)CCC[C@]2(Cl)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](c1ccccc1)N1C[C@]2(C(=O)O)CCC[C@]2(Cl)C1=O
Temperature: 25 °C
Reaction time: 14.5 h
Yield: 87.3 %

Procedure:
A mixture of tert-butyl (1S,5R)-5-chloro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octan-1-ylcarboxylic acid (332 mg, 0.912 mmol) and trifluoroacetic acid (2 mL) in dichloromethane (4 mL) was stirred for 14.5 hours at room temperature. The solvent was distilled off under reduced pressure. To the residue was added diethyl ether (3 mL), and then the precipitate was collected by filtration to afford 245 mg of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([O:7][CH3:17])=[O:6]
Reactant: CO
Reactant: Cc1cc(C(=O)O)ccc1I
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(I)c(C)c1

Procedure:
24.4 g (0.093 mol) of 3-methyl-4-iodobenzoic acid and 250 ml of methanol were introduced into a round-bottomed flask and 2.5 ml of concentrated sulfuric acid were added dropwise. Heating was carried out at reflux for twelve hours, the reaction mixture was evaporated and the residue taken up in ethyl acetate and water. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue was triturated in methanol and filtered. 21.9 g (85%) of the expected methyl ester, with a melting point of 58°-59° C., were recovered.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[C:13]([Cl:14])=[CH:12][CH:11]=[C:4]([C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6])[CH:3]=2)=[CH:18][CH:17]=1
Reactant: CON(C)C(=O)c1ccc(Cl)c(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CON(C)C(=O)c1ccc(Cl)c(-c2ccc(Cl)cc2)c1
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
3-Bromo-4-chloro-N-methoxy-N-methylbenzamide (1.0 mg, 3.8 mmol, 1.0 eq) and 4-chloro phenyl boronic acid (787 mg, 5 mmol, 1.3 eq) was dissolved in toluene and stirred for 10 minutes. The solution was purged with nitrogen for 10 minutes and degassed under vacuum. Tetrakis triphenylphosphinepalladium (223 mg, 0.19 mmol, 0.05 eq) and K2CO3 (696 mg, 5 mmol, 1.3 eq) were added to the reaction. The mixture was refluxed for 12 h under nitrogen and the volatiles were removed under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic layer was dried with anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (60-120) eluting with 5-10% ethyl acetate/hexane to afford the desired compound (1 g, 90%). 1H NMR (400 MHz, CD3OD) δ 3.37-3.39 (s, 3H), 3.60-3.64 (s, 3H), 7.10-7.13 (t, 1H), 7.25-7.27 (t, 1H), 7.43-7.48 (m, 3H), 7.60-7.63 (m, 3H). MS (ESI): 310.2 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[O:4][N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:22]1[NH:27][CH2:26][CH2:25][N:24]2[C:28](=[O:31])[CH2:29][CH2:30][C@@H:23]12>CC#N>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]([N:27]2[CH2:26][CH2:25][N:24]3[C:28](=[O:31])[CH2:29][CH2:30][C@H:23]3[CH2:22]2)=[O:9])[O:4][N:3]=1
Reactant: Cc1cc(C(=O)O)on1
Reactant: O=C1CC[C@H]2CNCCN12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: Cc1cc(C(=O)N2CCN3C(=O)CC[C@H]3C2)on1
Reaction time: 1 h
Yield: 81.3 %

Procedure:
To a solution of 3-methyl-isoxazole-5-carboxylic acid (100 mg, 0.79 mmol) in CH3CN (10 ml), carbonyldiimidazole (140 mg, 0.87 mmol) was added at room temperature. After stirring for 1 hour, a solution of (S)-(−)-hexahydropyrrolo[1,2-a]pyrazin-6(7H)-one (compound of Description 5, 121 mg, 0.86 mmol) in CH3CN (2 ml), was added dropwise at room temperature. After stirring the solution for 20 hours, the solvent was removed under vacuum and the residue purified by flash chromatography (DCM/MeOH 95/5 respectively) to afford the title compound as an oil (160 mg, 82% yield).
Reaction SMILES: B#B.[F:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17]>O1CCCC1>[F:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[CH2:16][OH:17]
Reactant: O=C(O)c1cccc(-c2cc([N+](=O)[O-])ccc2F)c1
Agent: B#B
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(-c2cccc(CO)c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.7 %

Procedure:
A 1M solution (200 ml) of diborane in tetrahydrofuran was added to a stirred solution of 3-(2-fluoro-5-nitrophenyl)-benzoic acid (6.6 g) in 500 ml tetrahydrofuran. The reaction mixture was stirred at room temperature for 12 hours and then quenched with water and extracted with ethyl acetate. The organic extracts were dried and evaporated to yield a yellow solid which was purified by elution on silica gel with 40% ethyl acetate/hexanes. This gave the pure required product as a yellow solid (4.04 g, 65% yield), m.p. 113°-114° C. NMR (CDCl3, 250 MHz): 8.42 (four line multiplet, 1H), 8.25 (8 line multiplet, 1H), 7.55 (m, 4H), 7.3 (four line multiplet, 1H), 4.8 (d, 2H, J=4.5 Hz), 0.9 (t, 1H).
Reaction SMILES: [F:1][C:2]1[N:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[F:1][C:2]1[N:9]=[C:8]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C1CCNC1
Reactant: N#Cc1cc(F)c(F)nc1F
Product: N#Cc1cc(F)c(N2CCCC2)nc1F
Yield: 57 %

Procedure:
Prepared in 57% yield from 2,5,6-Trifluoro-nicotinonitrile and pyrrolidine according to the procedure described for Example 178A. 1H NMR (DMSO-d6) δ 1.85-1.93 (m, 4H), 3.55-3.62 (m, 4H), 8.01 (dd, J=12.2, 6.8 Hz, 1H).
Reaction SMILES: [OH-].[Na+].CO.[SH2:5].Br[CH2:7][CH:8]=[C:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14]>O>[CH3:16][C:9]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:8][CH2:7][SH:5]
Reactant: S
Reactant: CC(C)=CCCC(C)=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)=CCCC(C)=CCS

Procedure:
To a solution of 2 g. of sodium hydroxide in 40 ml. of methanol saturated with hydrogen sulfide is added 14 g. of 1-bromo-3,7-dimethylocta-2,6-diene. The mixture is stirred at about 25° for about five hours with continued introduction of hydrogen sulfide. The mixture is diluted with water and then extracted with petroleum ether. The organic phase is washed well with water, dried over sodium sulfate and evaporated under reduced pressure to yield 3,7-dimethylocta-2,6-dienylmercaptan which is purified by chromatography.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:20][O:21][C:22](=[O:62])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[C:38]([Cl:41])[CH:39]=3)[N:34]([CH:42]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:33]=2[CH2:55][CH2:56][N:57]=[N+]=[N-])=[CH:25][C:24]=1[O:60][CH3:61].O>C1COCC1>[CH3:20][O:21][C:22](=[O:62])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[C:38]([Cl:41])[CH:39]=3)[N:34]([CH:42]([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:33]=2[CH2:55][CH2:56][NH2:57])=[CH:25][C:24]=1[O:60][CH3:61]
Reactant: COC(=O)c1ccc(OCCc2c(CCN=[N+]=[N-])n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 11.7 %

Procedure:
Ph3P (polymer support: 3 mmol Ph3P/gram) (0.110 g, 0.33 mmol) was added to a solution of the azide from step 7 (0.110 g, 0.18 mmol) in THF (2 mL). Reaction was stirred at room temperature for 24 hours. Then water (0.5 mL) was added and reaction was stirred at room temperature overnight. Reaction solution was filtered and the filtrate was concentrated by rotary evaporation. The resulting residue was purified with silica gel prep plates and 2% MeOH in dichloromethane as eluent. Obtained 0.012 g of 4-{2-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-methoxy-benzoic acid methyl ester in 12% yield.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][CH2:14][C:15]([OH:17])=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O/[N:19]=[C:20](/[C:22]1[CH:39]=[CH:38][C:25]([CH2:26][N:27]2[CH2:30][CH:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]2)=[CH:24][CH:23]=1)\[NH2:21].C(N=C=NC(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(#N)C.CCOC(C)=O>[C:1]1([C:7]2([CH2:13][CH2:14][C:15]3[O:17][N:21]=[C:20]([C:22]4[CH:23]=[CH:24][C:25]([CH2:26][N:27]5[CH2:28][CH:29]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:30]5)=[CH:38][CH:39]=4)[N:19]=3)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCC1(c2ccccc2)CCCCC1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Agent: CC(C)N=C=NC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(CCC4(c5ccccc5)CCCCC4)n3)cc2)C1
Reaction time: 1.5 h

Procedure:
To a stirred solution of the 3-(1-phenylcyclohexyl)propanoic acid (0.118 g, 0.508 mmol) and the (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (Intermediate 1, 0.155 g, 0.508 mmol) in acetonitrile (5.0 mL) at room temperature was added the 1,3-diisopropylcarbodiimide (0.095 mL, 0.609 mmol). The stirring was continued at room temperature and followed by LC/MS. After 90 min., TBAF (0.609 mL, 0.609 mmol) was added to the reaction. The reaction was found to be over after 2 h. The reaction mixture was diluted with EtOAc and washed with water followed by brine. It was then concentrated and purified by preparative HPLC to give the tert-butyl 1-(4-(5-(2-(1-phenylcyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate as a glassy solid. LCMS of the tert-butyl 1-(4-(5-(2-(1-phenylcyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (Conditions: Start % B═O; Final % B=100; Gradient Time=2 min; Flow Rate=5 ml/min; Wavelength=220; Solvent A=10% MeOH—90% H20—0.1% TFA; Solvent B=90% MeOH—10% H2O—0.1% TFA and Column 4=Phenomenex Luna 5u C18 4.6×30 mm (2 min. grad)) (M+H)+=502.39. Retention time=1.927.