Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Br:16])[CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1ccccc1OCc1ccccc1
Solvent: CC#N
Product: Oc1ccc(Br)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
12 g of 2-Benzyloxyphenol was dissolved in 300 ml of acetonitrile, 10.7 g of N-bromosuccinimide was added thereto, and the mixture was stirred at room temperature for 2 hours. Additional N-bromosuccinimide (1 g) was added thereto and the mixture was stirred for 1 hour, and further additional N-bromosuccinimide (1 g) was added thereto and the mixture was stirred for 2 hours. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography, to give 14.927 g of the title compound in the 10:1 hexane-ethyl acetate fraction.
Reaction SMILES: C[Si](C)(C)CC[O:5][CH2:6][C:7]1([C:20]([O:22][CH3:23])=[O:21])[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1.C(O)(C(F)(F)F)=O.C(N(C(C)C)C(C)C)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(Cl)Cl.O>[OH:5][CH2:6][C:7]1([C:20]([O:22][CH3:23])=[O:21])[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:8]1
Reactant: COC(=O)C1(COCC[Si](C)(C)C)CN(C(=O)OC(C)(C)C)CCO1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)C1(CO)CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.1 %

Procedure:
E2 (6.09 g, 16.22 mmol) was dissolved in DCM (100 mL), TFA (26.5 mL, 357 mmol) was added and the solution was stirred for 3 days at RT. The reaction mixture was concentrated and the residue was dissolved in DCM (100 mL). N-ethyl-N-isopropylpropan-2-amine (15 mL, 86 mmol) and di-tert-butyl dicarbonate (10.62 g, 48.7 mmol,) were added and the solution was stirred for 2 h at RT. Water was added and the mixture was extracted twice with DCM. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography from toluene:acetone 100:0 to 50:50 which gave the title compound (3.22 g, 72%). 1H NMR (400 MHz, CDCl3, 300K): δ 1.46 (9H, s), 2.24 (1H, m), 3.05 (2H, m), 3.64-4.14 (7H, m), 4.32 (1H, d, J=13.7 Hz); MS (ES) C12H21NO6 requires: 275. found: 298.2 [M+Na]+.
Reaction SMILES: NC1C([Br:12])=CC=CC=1C(OC)=O.[CH:13]([O:16][C:17]([N:19]1[CH2:25][CH2:24][CH2:23][CH:22]([N:26]([C:42](=[O:44])[CH3:43])[CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[C:21]2[CH:45]=[CH:46][CH:47]=[CH:48][C:20]1=2)=[O:18])([CH3:15])[CH3:14]>>[C:42]([N:26]([CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[C:30]([C:38]([F:39])([F:40])[F:41])[CH:29]=1)[CH:22]1[CH2:23][CH2:24][CH2:25][N:19]([C:17]([O:16][CH:13]([CH3:15])[CH3:14])=[O:18])[C:20]2[C:48]([Br:12])=[CH:47][CH:46]=[CH:45][C:21]1=2)(=[O:44])[CH3:43]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccccc21
Reactant: COC(=O)c1cccc(Br)c1N
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c(Br)cccc21

Procedure:
This compound was prepared utilizing the same methodology described in Example 1 wherein replacement of 2-amino-benzoic acid methyl ester with methyl 2-amino-3-bromobenzoate following the procedure of Example 1, Steps 1-8 for the synthesis of 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid isopropyl ester. CI MS 595 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[C:32]([O:1][CH2:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1)(=[O:34])[CH3:33]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(CO)c3ccccc32)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 5-hydroxymethyl-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.40 g) are added acetic anhydride (4.0 ml) and pyridine (0.5 ml), and the mixture is stirred at room temperature for 5 hours. After completion of the reaction, the reaction solution is poured into ice-water and extracted with ethyl acetate. The extract is washed successively with diluted hydrochloric acid and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is recrystallized from ethyl acetate/n-hexane to give 5-acetyloxymethyl-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.43 g) as colorless needles, m.p. 155-156° C.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][CH:7](O)[C:8]([OH:10])=[O:9])=[O:5].[Br:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1>CS(O)(=O)=O>[Br:17][C:18]1[S:19][C:20]([CH:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:15][CH:14]=[CH:13][C:12]=2[F:16])[C:8]([OH:10])=[O:9])=[CH:21][CH:22]=1
Reactant: O=C(NC(O)C(=O)O)c1c(F)cccc1F
Reactant: Brc1cccs1
Agent: CS(=O)(=O)O
Product: O=C(NC(C(=O)O)c1ccc(Br)s1)c1c(F)cccc1F
Temperature: 0 °C
Yield: 52.3 %

Procedure:
A solution of 4.76 g (20.6 mmol) of the product of Step A in 140 mL of methanesulfonic acid was immersed in an ice-water bath (temperature between 5°-10° C.). Then, 4.0 g (24.6 mmol) of 2-bromothiophene was added dropwise. It was stirred at the same temperature until a deep blue-black color formed. It was poured into ice-water and the resulting precipitate was filtered. The solid was triturated with methylene chloride to give 4.05 g of a tan solid: mp 198°-199° C. (dec.). 1H-NMR (DMSO-d6) δ9.80 (d,1H), 7.55 (m, 1H), 7.20 (m,3H), 7.00 (d, 1H), 5.80 (d, 1H).
Reaction SMILES: BrCC1C=CC(C2SC([C:14]([C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=3)=[O:15])=CC=2)=CC=1.C(=O)([O-])[O-].[K+].[K+].C(NC)C=C>CC(C)=O>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([CH:14]=[O:15])=[CH:17][CH:18]=1
Reactant: O=C(c1ccc(Br)cc1)c1ccc(-c2ccc(CBr)cc2)s1
Agent: C=CCNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(Br)cc1
Temperature: 0 °C

Procedure:
435 mg of [5-(4-bromomethyl-phenyl)-thiophen-2-yl]-4-bromophenyl-methanone are dissolved in 25 ml of acetone, 300 mg of potassium carbonate and 0.15 ml of N-allyl-methyl-amine are added and the mixture is held at reflux under argon for 4 hrs., treated with ice-water, extracted with ethyl acetate, dried and chromatographed on silica gel (ethyl acetate/hexane). 219 mg of 5-(4-[(allyl-methylamino)-methyl]-phenyl)-thiophen-2-yl)-(4-bromphenyl)-methanone, m.p. 131-133° C., are isolated.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1.[H-].[Na+].[CH:30]1([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCOCC1.CN(C=O)C>[CH:30]1([O:36][C:2]2[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]3[S:10][C:11]4[C:17]([N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=4[N:13]=3)=[O:7])=[CH:4][N:3]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: OC1CCCCC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(Cl)nc3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(OC4CCCCC4)nc3)nc12

Procedure:
From 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide with sodium hydride and cyclohexanol in dioxane and DMF. ES-MS m/e (%): 491 (M+Na+, 24), 469 (M+H+, 100).
Reaction SMILES: [Li+].[BH4-].CCOCC.C([O:10][C:11]([C:13]1[CH:20]=[C:19]2[N:15]([CH2:16][S:17][CH2:18]2)[N:14]=1)=O)C>CO>[N:14]1[N:15]2[C:19]([CH2:18][S:17][CH2:16]2)=[CH:20][C:13]=1[CH2:11][OH:10]
Reactant: CCOC(=O)c1cc2n(n1)CSC2
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CO
Product: OCc1cc2n(n1)CSC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
LiBH4 (cont. 90%) (459 mg) was added to the ether (126 mL) solution of 4H-5-thia-1,6a-diazapentalen-2-carboxylic acid ethylester (2.5 g) and MeOH (0.77 mL) under a nitrogen atmosphere at room temperature, then refluxed for 1.5 h. The mixture was quenched with 1 mol/L HCl (25 mL) and stirred for 1 h at room temperature. The mixture was neutralized by saturated sodium hydrogen carbonate solution and separated. The aqueous layer was extracted with dichloromethane (10×25 mL). The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with AcOEt. The titled compound was obtained as a pale yellow solid (1.7 g, 87.9%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:27][C@H:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:33](=[O:37])[CH2:34][C:35]#[N:36])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][C:12]=3[F:26])[C:3]=12.[CH:38]1([CH:41]=O)[CH2:40][CH2:39]1.N1CCCCC1>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:27][C@H:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:33]([C:34](=[CH:41][CH:38]3[CH2:40][CH2:39]3)[C:35]#[N:36])=[O:37])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][C:12]=3[F:26])[C:3]=12
Reactant: O=CC1CC1
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Reaction time: 0.33 h
Yield: 38 %

Procedure:
A solution of 3-((R)-2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (240 mg, 0.47 mmol, 1.00 equiv), cyclopropanecarbaldehyde (98.7 mg, 1.41 mmol, 3.00 equiv) and piperidine (42 mg, 0.47 mmol, 1.00 equiv) in ethanol (15 mL) was stirred for 3 h at 65° C. The resulting mixture was concentrated under vacuum. The residue was purified on Prep-HPLC. Conditions: (1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (40% CH3CN up to 100% in 20 min); Detector, 254 nm. This resulted in 100 mg (36%) of the title compound as a white solid. MS (ESI, pos. ion) m/z: 560 (M+1) H-NMR (400 MHz, CD3OD, ppm): 8.36 (s, 1H), 7.68-7.65 (t, J=7.6 Hz, 1H), 7.30-7.20 (m, 2H), 7.14-7.11 (t, 1H), 7.03-7.00 (d, J=9.2 Hz, 2H), 6.58 (d, J=10.8 Hz, 1H), 4.92-4.87 (m, 1H) 3.65-3.60 (m, 1H), 3.50-3.46 (m, 1H), 2.14 (m, 1H), 1.99-1.81 (m, 4H), 1.24-1.23 (m, 2H), 0.93-0.77 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:41]>>[ClH:41].[ClH:41].[CH3:40][O:39][C:37]([CH2:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([N:26]2[CH2:27][CH2:28][CH:23]([N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:24][CH2:25]2)=[CH:34][CH:33]=1)=[O:38]
Reactant: COC(=O)COc1ccc(N2CCC(N(CCc3ccccc3)C3CCN(C(=O)OC(C)(C)C)CC3)CC2)cc1
Agent: Cl
Product: COC(=O)COc1ccc(N2CCC(N(CCc3ccccc3)C3CCNCC3)CC2)cc1

Procedure:
Prepared from 4-[(1-tert-butyloxycarbonylpiperidin-4-yl)-N-benzylmethylamino]-1-(4-methoxycarbonylmethyloxyphenyl)piperidine and ethereal hydrochloric acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]2)[N:19]=1.Cl>O1CCOCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]2)[N:19]=1
Reactant: COc1cc(-c2c[nH]c3ccc(-c4c(F)cccc4F)cc23)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)n1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(-c2c[nH]c3ccc(-c4c(F)cccc4F)cc23)nc(N[C@@H]2CCCNC2)n1
Temperature: 90 °C
Yield: 20.8 %

Procedure:
To solution of (R)-tert-butyl 3-((4-(5-(2,6-difluorophenyl)-1H-indol-3-yl)-6-methoxypyrimidin-2-yl)amino)piperidine-1-carboxylate (130 mg, 0.243 mmol) in dioxane (2 mL) was added HCl in dioxane (4 M, 2 mL) and the mixture was heated at 90° C. for overnight. The reaction was quenched with aq.NaHCO3 and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was washed with 50% EtOAc in petroleum ether to give (R)-4-(5-(2,6-difluorophenyl)-1H-indol-3-yl)-6-methoxy-N-(piperidin-3-yl)pyrimidin-2-amine (22 mg, 22%). MS (ESI, pos. ion) m/z: 436.1 (M+1); 1H-NMR (400 MHz DMSO-d6): δ ppm: 11.78 (brs, 1H) 8.66 (s, 1H), 8.25 (s, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.41-7.46 (m, 1H), 7.21-7.22 (m, 3H), 6.70 (s, 1H), 6.48 (s, 1H), 3.80-3.83 (brs, 4H), 2.89-2.99 (m, 1H), 2.33-2.41 (m, 2H), 1.98-1.99 (m, 2H), 1.43-1.50 (m, 2H), 1.12-1.24 (m, 2H).
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH:8]2[CH2:10][CH2:9]2)[N:5]=[N:4][N:3]=1.BrC1N=NN(C2CC2)N=1.[CH:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29])=[O:21]>>[CH:8]1([CH2:7][N:6]2[C:2]([C:24]3[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([CH:23]=3)[CH:20]=[O:21])=[N:3][N:4]=[N:5]2)[CH2:10][CH2:9]1
Reactant: COc1ccc(B(O)O)cc1C=O
Reactant: Brc1nnnn1CC1CC1
Agent: Brc1nnn(C2CC2)n1
Product: COc1ccc(-c2nnnn2CC2CC2)cc1C=O

Procedure:
From a mixture of 5bromo-1-cyclopropylmethyl-1H-tetrazole with 5bromo-2-cyclopropyl-2H-tetrazole (1.91 g) and 3-formyl-4-methoxy-phenyl-boronic acid (1.86 g) to give the title compound (657 mg) as a yellow solid.
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)=[C:27]([C:32]2[N:36]([CH3:37])[N:35]=[N:34][N:33]=2)[CH:28]=[CH:29][CH:30]=[O:31])=[CH:22][CH:21]=1.Cl>O1CCCC1.CCCCCC>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)=[C:27]([C:32]2[N:36]([CH3:37])[N:35]=[N:34][N:33]=2)[CH:28]=[CH:29][CH:30]([OH:31])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[CH:24][CH:25]=1
Reactant: Cn1nnnc1C(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1nnnc1C(C=CC(O)CC(=O)CC(=O)OC(C)(C)C)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 2.3 h

Procedure:
A solution of 144 g (0.91 mol) of t-butyl acetoacetate in 400 mL of tetrahydrofuran was added dropwise over 1.5 hours to a mixture of 44.0 g (1.10 mol) of sodium hydride (60% in mineral oil) in 100 mL of hexane and 500 mL of tetrahydrofuran under nitrogen at 0° C. After the addition, this mixture was stirred for 2.3 hours. A solution 2.5M n-butyllithium in hexane (360 mL, 0.91 mol) was added dropwise over 1 hour. After stirring at 0° C. for 1 hour, 200 g (0.57 mol) of the aldehyde prepared in Step A was added all at once and the temperature rose to 20° C. After stirring for 1 hour in an ice-water bath, 1200 mL of 10% aqueous hydrochloric acid was added over 1 hour. The organic layer was washed with 2×300 mL of water, 300 mL of saturated sodium chloride solution, dried with anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to give the title compound which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]([N:20]([CH2:21][CH3:22])[CH2:18][CH3:19])=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Reactant: CCNCC
Product: CCN(CC)C(=O)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Yield: 13 %

Procedure:
The amide was synthesized from 1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (232 mg, 0.85 mmol) and diethyl amine using General Procedure G and was isolated in 13% yield as a white solid. HPLC Rt=12.0 min; 1H NMR (400 mHz, CDCl3) 7.38-7.26 (m, 2H), 7.08 (dd, J=2.2, 8.4 Hz, 1H), 3.29 (bs, 2H), 2.84 (bs, 2H), 2.26 (d, J=12.1 Hz, 2H), 1.73-1.54 (m, 7H), 1.29-1.24 (m, 2H), 1.08 (bs, 3H), 0.82 (bs, 3H); 13C NMR (100 mHz, CDCl3) 172.9, 147.2, 133.0, 130.8, 130.4, 127.5, 125.2, 51.2, 42.0, 40.9, 37.3, 26.0, 23.7, 13.4, 12.4; GC-MS (SCOUT) 13.2 min, M+ 327.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([F:21])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+].O.Cl>O1CCCC1.C(OCC)(=O)C>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([F:21])[CH:12]=2)[C:3]([OH:22])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-propionic acid methyl ester (110 mg, 0.335 mmol) in tetrahydrofuran (1 mL) was treated with a 0.8M aqueous lithium hydroxide solution (630 μL, 0.502 mmol). The reaction mixture was stirred at 25° C. for 2 h and then treated with water (30 mL), a 1N aqueous hydrochloric acid solution (2 mL), and ethyl acetate (30 mL). The layers were separated, and the resulting aqueous layer was back-extracted with ethyl acetate (30 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-propionic acid as a pale yellow oil which solidified to a pale yellow solid upon sitting at 25° C. The pale yellow solid corresponding to 3-cyclopentyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-propionic acid (106 mg, 98%) was used without further purification: mp 115-117° C.; EI-HRMS m/e calcd for C15H19FO4S (M+) 314.0988, found 314.0986.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[C:3]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=O)[CH:28]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)O)=[CH:23][CH:22]=1.[ClH:38]>C(O)C>[ClH:38].[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[NH:1][C:2]3[N:6]([C:28]=2[C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[C:3]=3[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:25][CH:26]=1
Reactant: O=C(c1ccc(F)cc1)C(O)c1ccc(F)cc1
Reactant: Nc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Agent: Cl
Solvent: CCO
Product: Fc1ccc(-c2nn3c(-c4ccc(F)cc4)c(-c4ccc(F)cc4)[nH]c3c2-c2ccncc2)cc1

Procedure:
A mixture of 5-amino-3-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole (100 mg), 1,2-bis-(4-fluorophenyl)-2-hydroxyethan-1-one (167 mg) and concentrated hydrochloric acid (1 ml) in ethanol was refluxed for 5 hours. The reaction mixture was concentrated in vacuo and the obtained crystalline was washed with hot ethanol to give 2,3,6-tris-(4-fluorophenyl)-7-(pyridin-4-yl)-1H-imidazo[1,2-b]pyrazole hydrochloride (50 mg).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][C@H:11]([OH:23])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[OH-].[Na+]>C(Cl)Cl.O1CCCC1.C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC.O.CO>[CH2:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][C@@H:11]([OH:23])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H]1C[C@@H](COCc2ccccc2)[C@@H](OCc2ccccc2)C1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O[C@@H]1C[C@@H](COCc2ccccc2)[C@@H](OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of (1S,3S,4S)-3-(benzyloxy)-4-(benzyloxymethyl)cyclopentanol (23) (340.00 g, 1088.3 mmol) in methylene chloride (3400 mL) and triethylamine (455.08 mL, 3265.0 mmol) at 0° C., was added methanesulfonyl chloride (92.661 mL, 1197.2 mmol) slowly under a blanket of nitrogen, maintaining a temperature of less than 10° C. The reaction was allowed to warm to ambient temperature and stirred for 1 hour. HPLC indicated complete consumption of starting material. The reaction mixture was cooled to 0° C. and quenched with water (1700 mL) maintaining a temperature of less than 10° C. The organics were separated and extracted twice with water (1700 mL) and twice with saturated sodium bicarbonate in water (1700 mL). Sodium sulfate (50 g) was added and the mixture stirred for 10 minutes. The slurry was filtered and the filtrate concentrated to give a brown oil. The oil was taken up in tetrahydrofuran (3400 m) to which tetrabutylammonium acetate (656.28 g, 2176.7 mmol) was added and the mixture was stirred at ambient temperature for 20 hours. HPLC analysis indicated complete consumption of starting material. The reaction mixture was concentrated to ˜2 volumes (700 mL), and ethyl acetate (3400 mL) was added and mixture was extracted three times with water (1700 mL) and once with saturated sodium chloride in water (1700 mL). The organics were concentrated and the resulting residue was eluted through a plug of silica gel (1 kg) with 0-20% ethyl acetate/hexane [ethyl acetate (4 L)+hexane (16 L)]. The desired fractions were combined and concentrated to give a brown residue. To the resulting residue, methanol (4000 mL) was added followed by a mixture of sodium hydroxide (130.59 g, 3265.0 mmol) in water (2000 mL), and the reaction mixture was stirred at ambient temperature for 1 hour. HPLC analysis indicated complete consumption of starting material. The majority of the methanol in the reaction mixture was concentrated and water (1700 mL) was added. The mixture was extracted three times with ethyl acetate (3×1700 mL). The combined organics were washed with saturated sodium chloride in water (1700 mL) and dried over sodium sulfate (50 g). The resulting slurry was filtered and concentrated to give a light brown oil (238 g, 70%). 1H NMR (300 MHz, CD3OD, δ): 7.28 (m, 10H), 4.50 (m, 3H), 4.38 (m, 2H), 4.12 (t, 1H), 3.70 (m, 1H), 3.45 (m, 1H), 2.52 (m, 1H), 2.11 (m, 1H) and 1.75 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C@H:11]1[CH2:16][NH:15][CH2:14][CH2:13][N:12]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]2[CH2:14][CH2:13][N:12]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[C@@H:11]([CH3:10])[CH2:16]2)=[CH:4][CH:3]=1
Reactant: C[C@H]1CNCCN1C(=O)OCc1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: C[C@H]1CN(Cc2ccc(Br)cc2)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
A mixture of 4-bromobenzaldehyde (1.19 g, 6.42 mmol), phenylmethyl (2S)-2-methyl-1-piperazinecarboxylate (1.505 g, 6.42 mmol) and sodium triacetoxyborohydride (2.04 g, 9.63 mmol) in 1,2-DCE (15 ml) was stirred at room temperature overnight. Saturated aq. NaHCO3 solution was added and the mixture stirred for 30 mins. Product was extracted and the extracts dried (Na2SO4). Chromatography (0-30% EtOAc in pentane) gave the title compound (2.18 g). MS (ES): MH+ 403/405.