Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[CH2:4][CH2:5][CH2:6][CH:7](Br)[CH:8]1[O:38][C@H:11]2[CH2:12][C@@H:13]([O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[C@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[C@@H:18]([CH3:23])[CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9]1.C1CCN2C(=NCCC2)CC1.Cl.P([O-])([O-])([O-])=[O:54]>O1CCCC1.C(O)(=O)C.O>[CH3:1][O:2][C:3](=[O:40])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:38])[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C@@H:18]([CH3:23])[CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH2:12][C@@H:11]1[OH:54]
Reactant: O=P([O-])([O-])[O-]
Reactant: CCCC[C@H](C)[C@@H](/C=C/[C@@H]1[C@H]2CC(C(Br)CCCC(=O)OC)O[C@H]2C[C@H]1OC1CCCCO1)OC1CCCCO1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCC[C@H](C)[C@@H](/C=C/[C@@H]1[C@@H](CC(=O)CCCCC(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of nitrogen, a solution of 2.233 g of (13E)-(5RS,6RS,9α,11α,15S,16S)-5-bromo-6,9-epoxy-11,15-bis(tetrahydropyran-2-yloxy)-16-methylprost-13-enoic acid methyl ester [prepared as described in Reference Example 1(a)] and 7.4 ml of DBU was stirred at 70° C. for 3 hours, and then cooled to 0° C. To the reaction mixture were added 37 ml of 1 N hydrochloric acid and 37 ml of phosphate buffer solution (pH 6.68) with cooling to 0° C. The reaction mixture was extracted quickly with diethyl ether. The extract was dried over magnesium sulphate and concentrated under reduced pressure to give an oily product. To a solution of the oily product thus obtained in 40 ml of tetrahydrofuran were added dropwise 4 ml of water and 4 ml of 65% (v/v) aqueous acetic acid and the mixture was stirred at room temperature for 2 hours and then extracted with ethyl acetate. The extract was washed with water, an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (1:1) as eluent to give 1.323 g of the title compound having the following physical characteristics:
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)=[CH:13][CH:12]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.[C:24]([O:28][CH3:29])(=[O:27])[CH:25]=[CH2:26]>>[CH3:29][O:28][C:24](=[O:27])[CH2:25][CH2:26][N:20]1[CH2:21][CH2:22][CH2:23][C@@H:19]1[CH2:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([N:3]2[C:2]([Cl:1])=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]3)=[N:4]2)=[CH:16][CH:15]=1
Reactant: Clc1c2ccccc2nn1-c1ccc(OC[C@H]2CCCN2)cc1
Reactant: C=CC(=O)OC
Product: COC(=O)CCN1CCC[C@@H]1COc1ccc(-n2nc3ccccc3c2Cl)cc1
Yield: 81.3 %

Procedure:
The title compound was prepared from product from 3-chloro-2-[4-((R)-1-pyrrolidin-2-ylmethoxy)-phenyl]-2H-indazole (0.4 g, 1.1 mmol) and methyl acrylate (0.25 g, 3.4 mmol) using the procedure of step 5 of the Example 4 to provide the title compound (0.37 g, 79%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C@H:15]2[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.[OH-].[Li+].O>CO>[OH:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([N:9]2[C:10]([C:11]([F:12])([F:13])[F:14])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[CH2:16][CH2:17]1
Reactant: CCOC(=O)c1cnn([C@H]2CC[C@H](O)CC2)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnn([C@H]2CC[C@H](O)CC2)c1C(F)(F)F
Temperature: 80 °C

Procedure:
trans-1-(4-Hydroxy-cyclohexyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (62.3 mg, 0.203 mmol, prepared in Example 71, Step 1) was dissolved in methanol (0.3 mL). Lithium hydroxide (7.1 mg, 0.297 mmol) and water (0.3 mL) were added and the mixture was heated at 80° C. for 1 hour. After cooling to room temperature, the methanol was removed in vacuo. Tetrahydrofuran was added and removed in vacuo to insure complete removal of methanol. The residue was diluted with water and acidified with 6N HCl. Solid initially precipitated out of solution but quickly went to an oil/gum. The mixture was extracted with methylene chloride two times. The two organic phases were combined, washed with water, dried over sodium sulfate and concentrated to give trans-1-(4-hydroxy-cyclohexyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (35.8 mg; 63%). Mass spectrum: m/z: 277.1 (M−H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH:10]([CH2:12]O)[CH2:9][C:8]2=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.II.C(O)(=O)C>CN(C)C(=O)C.[Zn]>[CH:1]1([N:7]2[CH2:11][CH:10]([CH3:12])[CH2:9][C:8]2=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CC(CO)CN1C1CCCCC1
Agent: II
Agent: [Zn]
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: CC1CC(=O)N(C2CCCCC2)C1
Temperature: 75 °C
Yield: 43.4 %

Procedure:
Place 1-cyclohexyl-4-hydroxymethyl-pyrrolidin-2-one (Preparation 2) (2.5 g, 12.7 mmol) and triphenylphosphene (3.7 g, 13.9 mmol) in a flask and add dry N,N-dimethyl-acetamide (20 mL). Add a solution of iodine (3.2 g, 12.7 mol) in N,N-dimethyl-acetamide (3 mL). Stir reaction for 24 hours. Quench the reaction with saturated sodium bisulfite (20 mL) and extract with methylene chloride. Dry over sodium sulfate, filter, and concentrate. Dissolve crude material in acetonitrile (100 mL) and add glacial acetic acid (15 mL) and zinc (12.4 g, 190.1 mmol), then heat to 75° C. and stir for 6 hours. Cool to room temperature, filter, and partition between water and methylene chloride. Separate layers and wash methylene chloride with saturated sodium bicarbonate. Dry over sodium sulfate, filter, and concentrate. Purify by silica gel (30-40% ethyl acetate in hexane) to yield 1.0 g (45%) of the title compound. NMR (CDCl3) δ 3.94 (m, 1H), 3.45 (m, 1H), 2.88 (dd, 1H), 2.55 (dd, 1H), 2.38 (m, 1H), 2.02 (dd, 1H), 1.78 (m, 2H), 1.68 (m, 3H), 1.35 (m, 4H), 1.09 (m, 4H).
Reaction SMILES: [H-].[Na+].BrC[CH2:5][CH2:6][CH2:7][N:8]([CH2:21][CH2:22]C)[S:9]([C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20])(=[O:11])=[O:10].[C:24]1([CH3:79])[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:25]=1[S:32]([N:35]([CH2:60][CH2:61]CN(S(C1C(C)=CC(C)=CC=1C)(=O)=O)CCC)[CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=[O:34])=[O:33].C1(C)C=CC=CC=1.CCOC(C)=O>CN(C=O)C>[C:24]1([CH3:79])[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:25]=1[S:32]([N:35]([CH2:60][CH2:61][CH2:22][CH2:21][N:8]([S:9]([C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20])(=[O:10])=[O:11])[CH2:7][CH2:6][CH3:5])[CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=[O:33])=[O:34]
Reactant: CCCN(CCCCBr)S(=O)(=O)c1c(C)cc(C)cc1C
Reactant: CCCN(CCCN(CCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1)S(=O)(=O)c1c(C)cc(C)cc1C)S(=O)(=O)c1c(C)cc(C)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCN(CCCCN(CCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1)S(=O)(=O)c1c(C)cc(C)cc1C)S(=O)(=O)c1c(C)cc(C)cc1C
Yield: 85 %

Procedure:
NaH (60%, 0.12 g, 2.90 mmol), 71 (1.24 g, 2.42 mmol) in DMF (30 mL), and 67 (0.91 g, 2.42 mmol) in DMF (10 mL) were reacted and worked up following the method of 72. Column chromatography (25:1 toluene/EtOAc) gave 1.67 g (85%) of 74 as an oil: NMR δ 0.74 (t, 3 H, J=7), 1.35-1.45 (m, 11 H), 2.00 (t, 2 H, J=7), 2.25 (s, 3 H), 2.28 (s, 3 H), 2.55 (s, 6 H), 2.56 (s, 6 H), 2.98-3.08 (m, 8 H), 6.90 (s, 2 H), 6.91 (s, 2 H), 7.15-7.44 (m, 15 H). Anal. (C48H61N3O4S2) C, H, N.
Reaction SMILES: [C:1]1([C@H:11]([N:13]([CH2:21][C@@H:22]2[C@@H:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][N:24](C(=O)C(F)(F)F)[CH2:23]2)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1.CO>[C:1]1([C@H:11]([N:13]([CH2:21][C@@H:22]2[C@@H:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:25][NH:24][CH2:23]2)[C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)C(F)(F)F)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A 9.27 g portion of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenyl-1-(trifluoroacetyl)pyrrolidin-3-yl]methyl}carbamate was dissolved in 105 ml of THF-methanol (2:1), mixed with 35 ml of 1 M sodium hydroxide aqueous solution and stirred at room temperature for 1Hour. The reaction solution was concentrated under a reduced pressure, the residue was mixed with water and extracted with chloroform, and the organic layer was dried with anhydrous sodium sulfate. This was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol-aqueous ammonia) to obtain 6.97 g of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate as a colorless oily substance. FP: 431, NMR 1 (80° C.): 1.42 (9H, s), 1.45-1.55 (1H, m), 1.48 (3H, d, J=6.8 Hz), 2.23-2.30 (1H, m), 2.30-2.38 (1H, m), 2.48-2.57 (2H, m), 2.82-2.88 (1H, m), 2.87-2.92 (1H, m), 2.96-3.03 (1H, m), 5.95 (1H, q, J=6.8 Hz), 6.70-6.76 (2H, m), 7.04-7.17 (3H, m), 7.37 (1H, t, J=7.6 Hz), 7.39 (1H, m), 7.47-7.54 (2H, m), 7.81 (1H, m), 7.88-7.94 (1H, m), 8.02-8.09 (1H, m).
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([OH:13])=O)=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[C:61]([F:63])[CH:60]=[C:59]([F:64])[CH:58]=2)=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:50]=[CH:51][C:52]([CH2:53][N:54]([CH2:55][CH2:56][C:57]2[CH:58]=[C:59]([F:64])[CH:60]=[C:61]([F:63])[CH:62]=2)[C:11]([C:10]2[C:2]([F:1])=[CH:3][CH:4]=[C:5]3[C:9]=2[NH:8][CH:7]=[CH:6]3)=[O:13])=[CH:65][CH:66]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)c1ccc(CNCCc2cc(F)cc(F)c2)cc1
Reactant: O=C(O)c1c(F)ccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2cc(F)cc(F)c2)C(=O)c2c(F)ccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.4 %

Procedure:
To a solution of 80 mg (0.45 mmol) of 6-fluoro-1H-indole-7-carboxylic acid and 143 mg of TBTU (0.45 mmol) in 5 ml DMF, were added 0.38 ml (2.23 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 176 mg (0.58 mmol) of (4-tert-butyl-benzyl)-[2-(3,5-difluoro-phenyl)-ethyl]-amine were added. After stirring for 17 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:4) to give 166 mg light brown foam (78%). MS 464.1 (M)
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[C@@H:54]([NH2:56])[CH3:55]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:56][C@H:54]([C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=4[F:47])[CH3:55])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](N)c1ccccc1F
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N[C@@H](C)c2ccccc2F)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with (S)-1-(2-fluoro-phenyl)-ethylamine (Matrix) to give the title compound. HR-MS (ES, m/z) calculated for C44H51Cl2FN5O3 [(M+H)+] 786.3348, observed 786.3343.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[C:10]=1[CH2:26][CH2:27][CH2:28][CH:29]=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:31]OS([O-])=O.[K+].Cl.C(OC(C)C)(=O)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[C:10]=1[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C)c(OCc2ccccc2)c(CCCC=O)c(C)c1OCc1ccccc1
Reactant: O=S([O-])OO
Agent: Cl
Agent: [K+]
Solvent: CC(=O)OC(C)C
Solvent: CN(C)C=O
Product: Cc1c(C)c(OCc2ccccc2)c(CCCC(=O)O)c(C)c1OCc1ccccc1
Reaction time: 8 h
Yield: 92.8 %

Procedure:
To a solution of 4-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)butanal (450 mg, 1.12 mmol) in DMF (11.5 mL) was added Oxone (350 mg, 1.12 mmol) giving a cloudy white solution. The suspension was stirred vigorously overnight and poured over 10 mL 2.5 M HCl and stirred until the solution clarified. Isopropyl acetate (iPrOAc) (25 mL) was added after the exotherm subsided. The organics were washed 2×10 mL 2.5 M HCl, 1×10 mL saturated aqueous NaCl and dried over Na2SO4. Concentration gave 435 mg of 4-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)butanoic acid as a white solid. MS M++H at 419 m/z;
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19](Cl)[C:14]3=[CH:13][N:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[C:21](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.ClCCl>O1CCOCC1>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([CH3:21])[C:14]3=[CH:13][N:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@H](c2ncc3c(Cl)nccn32)CC1
Reactant: O=C([O-])[O-]
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)O[C@H]1CC[C@@H](c2ncc3c(C)nccn32)CC1
Temperature: 95 °C
Reaction time: 1 h

Procedure:
To (cis)-4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl acetate (48.0 mmol, 14.09 g) in dry dioxane (275 ml) under a nitrogen atmosphere were added dry potasium carbonate (71.9 mmol, 9.94 g), trimethylboroxine (144 mmol, 20.03 ml, 50 wt % solution in tetrahydrofuran) and 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride complex with dichloromethane (4.80 mmol, 3.88 g) and the reaction mixture was stirred at 95° C. for one hour. The reaction mixture was cooled to room temperature, filtered over decalite, the filter rinsed with dioxane and the filtrate concentrated in vacuo. The residue was purified by column chromatography (silica gel; dichloromethane with gradient 0 to 6% of methanol) to give (cis)-4-(8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl acetate (12.8 g).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[Cl:38])=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=3[Cl:38])=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: Cc1ccc(C(=O)CCCCCBr)c(Cl)c1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc(C)cc2Cl)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(2-chloro-4-methylphenyl)-1-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(2-chloro-4-methylphenyl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[NH:4][C:5]1[CH:17]=[C:16]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:6]=1[C:7]([O:9]C(C)(C)C)=[O:8]>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[NH:4][C:5]1[CH:17]=[C:16]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1Nc1ccc(F)cc1F
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(CCc2ccccc2)cc1Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid 10 mL was added to the obtained tert-butyl 2-(2,4-difluoroanilino)-4-phenethylbenzoate, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, methanol was added to the obtained residue, and solid matter was filtrated to give 2-(2,4-difluoroanilino)-4-phenethylbenzoic acid 59 mg of white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH:23]12[O:29][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28]2>C1(C)C=CC=CC=1>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]2[OH:29])=[C:3](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C1CCC2OC2C1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1N
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1NC1CCCCC1O
Temperature: 80 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
A 100-mL pressure vessel was charged with (E)-ethyl 3-(2-amino-5-(benzylthio) phenyl)acrylate (3 g, 9.57 mmol), toluene (31.9 ml), cyclohexene oxide (2.91 ml, 28.7 mmol), and activated Al2O3 (24 g, 9.57 mmol) (dried at 150° C. for 16 h). The reaction vessel was sealed with a Teflon cap and the yellow reaction mixture was warmed to 80° C. After 16 h, additional cyclohexene oxide (2.91 ml, 28.7 mmol) and activated Al2O3(10 g, 3.98 mmol) was added and the reaction vessel was sealed with a Teflon cap and warmed to 80° C. After 48 h, the reaction mixture was allowed to cool to RT then filtered through a fritted funnel and the pad of Al2O3 was eluted with EtOAc (2×100 mL). The filtrate was concentrated under reduced pressure to furnish a yellow residue which was purified by flash column chromatography (100-g Biotage column, eluent: gradient, 0 to 50% EtOAc in heptane) to afford (±)-(E)-ethyl 3-(5-(benzylthio)-2-((2-hydroxycyclohexyl)amino) phenyl)acrylate (3.5 g, 8.50 mmol, 89% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ=7.84 (d, J=15.7 Hz, 1H), 7.37 (d, J=2.3 Hz, 1H), 7.31-7.18 (m, 6H), 7.14 (dd, J=2.2, 8.7 Hz, 1H), 6.65 (d, J=8.9 Hz, 1H), 6.27 (d, J=15.5 Hz, 1H), 5.48 (d, J=6.8 Hz, 1H), 4.75 (d, J=5.0 Hz, 1H), 4.03 (s, 1H), 3.52-3.39 (m, 1H), 3.20-3.11 (m, 1H), 3.07 (d, J=8.9 Hz, 1H), 1.90 (d, J=9.7 Hz, 1H), 1.80 (d, J=2.5 Hz, 1H), 1.70-1.50 (m, 2H), 1.21-1.05 (m, 2H). m/z (ESI) 412.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[N:11]1([CH2:16][C:17]2[CH:18]=[CH:19][C:20](Br)=[N:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:20]2[CH:19]=[CH:18][C:17]([CH2:16][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)=[CH:22][N:21]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: Fc1ccc(-c2ccc(Cn3ccnc3)cn2)cc1

Procedure:
Synthesized using 4-fluorophenylboronic acid (230 mg, 1.68 mmol) and 1a (200 mg, 0.84 mmol) according to Method C. Yellow solid. Yield: 160 mg, 0.63 mmol, 75%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=5.18 (s, 2H), 6.92 (s, 1H), 7.12 (brs, 1H), 7.15 (t, J=8.8 Hz, 2H), 7.48 (dd, J=8.2, 2.2 Hz, 1H), 7.60 (s, 1H), 7.67 (d, J=8.2 Hz, 1H), 7.97 (dd, J=8.8, 5.4 Hz, 2H), 8.57 (d, J=1.9 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.1, 115.7 (d, J=22.1 Hz), 119.0, 120.2, 128.7 (d, J=8.6 Hz), 130.0, 130.4, 134.7 (d, J=3.9 Hz), 135.8, 137.3, 148.6, 156.6, 163.7 (d, J=249.5 Hz); MS (ESI): m/z=254.18 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:19])[C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([CH3:17])[C:10]=1[CH3:18].[Al+3].[Cl-].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:19])[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH3:17])[C:10]=1[CH3:18]
Reactant: COc1ccc(C(=O)c2ccccc2F)c(C)c1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: Cc1c(O)ccc(C(=O)c2ccccc2F)c1C

Procedure:
To a solution of 42 g (0.163 m) of 2'-fluoro-4-methoxy-2,3-dimethylbenzophenone of Example 1A in 350 ml of dry benzene, 43.5 g (0.326 m) of AlCl3 is added. The mixture is refluxed 21 hours, poured onto 120 ml concentrated HCl and ice and extracted with ether. The ether extract is washed with water, dried (Na2CO3) and evaporated to give pure 2'-fluoro-4-hydroxy-2,3-dimethylbenzophenone, 39.4 g (98%). An analytical sample is recrystallized from ethanol/H2O, m.p. 131°-132° C.
Reaction SMILES: Br[C:2]1[C:3]([NH:18][C@@H:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][C@@H:20]2[OH:28])=[N:4][C:5]([O:16][CH3:17])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:7]=1.[CH2:29]([Sn](CCCC)(CCCC)C=C)[CH2:30]CC.[F-].[K+]>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>[Cl:15][C:9]1[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[C:6]1[N:7]=[C:2]([CH:29]=[CH2:30])[C:3]([NH:18][C@@H:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][C@@H:20]2[OH:28])=[N:4][C:5]=1[O:16][CH3:17]
Reactant: COc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(Br)nc1-c1ccc(Cl)cc1Cl
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=Cc1nc(-c2ccc(Cl)cc2Cl)c(OC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: 120 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a solution of (1R,2S)-1-{[3-bromo-5-(2,4-dichlorophenyl)-6-methoxypyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol (150 mg, 0.31 mmol) in DMF (1.6 mL) is added Pd(PPh3)4 (7 mg, 6 μmol), and tributyl vinyl tin (114 mg, 0.36 mmol). The reaction is heated at 120° C. overnight. Sat. aq. KF (15 mL) is added and the mixture is stirred at rt for 1 hr. Extract with CH2Cl2 (5×30 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated. Purify by biotage MPLC (90 g column, 15% ethyl acetate/hexanes) to afford 132 mg (38%) of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-6-methoxy-3-vinylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol as a solid: 1H NMR (CDCl3) δ 3.08–3.12, 3.28–3.34, 3.93, 4.82, 5.46–5.49, 5.54–5.67, 6.09–6.13, 6.77–6.84, 7.28–7.50; MS (ESI+) for C20H17Cl2N3O2 m/z 402 (M+H)+.