Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:15]([O:17][CH3:18])=[O:16])[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[CH:4]=[C:3]([C:11]([O:13][CH3:14])=[O:12])[CH:2]=1.[C:19]([C:23]1[C:24]([OH:34])=[C:25]([CH2:30][CH2:31]CO)[CH:26]=[C:27]([CH3:29])[CH:28]=1)([CH3:22])([CH3:21])[CH3:20].[NH2-].[Na+]>CN(C)C=O>[C:19]([C:23]1[C:24]([OH:34])=[C:25]([CH2:30][CH2:31][CH2:18][O:17][C:15]([C:1]2[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH2:31][CH2:30][C:25]3[CH:26]=[C:27]([CH3:29])[CH:28]=[C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:24]=3[OH:34])=[O:8])[CH:4]=[C:3]([C:11]([O:13][CH2:14][CH2:31][CH2:30][C:25]3[CH:26]=[C:27]([CH3:29])[CH:28]=[C:23]([C:19]([CH3:20])([CH3:21])[CH3:22])[C:24]=3[OH:34])=[O:12])[CH:2]=2)=[O:16])[CH:26]=[C:27]([CH3:29])[CH:28]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)c1cc(C(=O)OC)cc(C(=O)OC)c1
Reactant: Cc1cc(CCCO)c(O)c(C(C)(C)C)c1
Agent: [NH2-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(CCCOC(=O)c2cc(C(=O)OCCCc3cc(C)cc(C(C)(C)C)c3O)cc(C(=O)OCCCc3cc(C)cc(C(C)(C)C)c3O)c2)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Yield: 52.7 %

Procedure:
Into a 100 ml reactor equipped with a condenser, thermometer and nitrogen introducing thin tube were charged 1.54 g (6.00 mmol) of trimethyl 1,3,5-benzenetricarboxylate, 4.00 g (18.00 mmol) of 3-(3-tert-butyl-2-hydroxy-5-methylphenyl)-1-propanol and 20 ml of N,N-dimethylformamide. The pressure of the reaction system was reduced to 20 mmHg and 75 vol% (15 ml) of N,N-dimethylformamide was distilled away to dry the reactants, solvent and apparatus. The reaction system was cooled to room temperature, and the vacuum was broken by introducing dry nitrogen. 0.07 g (1.8 mmol) of sodium amide was immediately added to initiate the ester exchange reaction. The reaction system was heated at 50° to 60° C. under 20 mmHg for 2 to 3 hours, and then heated at 60° to 80° C. under 20 mmHg for 2 to 3 hours while distilling N,N-dimethylformamide. Thereafter, the reaction mixture was further heated at 100° to 120° C. under 5 mmHg for 2 to 3 hours. When the reaction was completed, the reaction product was neutralized with dilute hydrochloric acid and then chloroform was added. After liquid separation and dehydration with anhydrous sodium sulfate, the organic solvent was removed under reduced pressure. After separation by silica gel chromatography (solvent: chloroform), 2.60 g (3.16 mmol) of the desired product was obtained. The yield was 53%. The physical properties of the product are shown below.
Reaction SMILES: [Cl:1][C:2]([Cl:10])([Cl:9])[C:3]([C:5](Cl)([Cl:7])[Cl:6])=[O:4].[Sb](F)(F)[F:12]>[Sb](Cl)(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]([Cl:10])([Cl:9])[C:3]([C:5]([Cl:7])([Cl:6])[F:12])=[O:4]
Reactant: O=C(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Reactant: F[Sb](F)F
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Product: O=C(C(F)(Cl)Cl)C(Cl)(Cl)Cl
Temperature: 140 °C
Yield: 128.1 %

Procedure:
A 2-liter round bottom flask equipped with a condenser and mechanical stirrer was charged with 1 liter (6.6 moles) of hexachloroacetone, 411.2 g (2.2 moles) of anhydrous antimony trifluoride and 30 ml of antimony pentachloride. The mixture was heated to 140° C. for a period of one hour then cooled to 0° C. The liquid portion of the reaction was decanted from the salts of the reaction and washed with 5×200 ml portions of 12N HCl dried over MgSO4 and distilled. The fraction boiling at 160°-167° C. afforded 700 g of product as a 3:1 mixture of pentachlorofluoro and tetrachlorodifluoro acetones, respectively, and was used without further purification.
Reaction SMILES: Cl.[CH2:2]([NH2:4])C.C(N(CC)CC)C.Br[C:13]1[N:17]([C@H:18]2[O:30][C@@H:29]([CH2:31][O:32]C(=O)C)[C@H:24]([O:25]C(=O)C)[C@@H:19]2[O:20]C(=O)C)[C:16]2[CH:36]=[C:37]([Cl:41])[C:38]([Cl:40])=[CH:39][C:15]=2[N:14]=1.C(O)C>CN(C=O)C>[Cl:40][C:38]1[C:37]([Cl:41])=[CH:36][C:16]2[N:17]([C@H:18]3[O:30][C@@H:29]([CH2:31][OH:32])[C@H:24]([OH:25])[C@@H:19]3[OH:20])[C:13]([NH:4][CH3:2])=[N:14][C:15]=2[CH:39]=1
Reactant: CC(=O)OC[C@@H]1O[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CN(C)C=O
Product: CNc1nc2cc(Cl)c(Cl)cc2n1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Ethylamine hydrochloride (3.7 g, 46 mmol), triethylamine (7 mL), and 2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (0.60 g, 1.1 mmol) were combined with absolute ethanol (20 mL) and stirred at 80° C. for 24 h. The reaction mixture was separated between saturated sodium bicarbonate (2×50 mL) and ethyl acetate (200 mL). The organics were dried with sodium sulfate, concentrated, and purified on a silica gel column (2.5×18 cm, 230-400 mesh) with 1:20 methanol:dichloromethane. The main product off the column was a white solid (0.30 g, 0.96 mmol, 87%) m.p. 155-157° C.; [a]20D=(−) 20.6 (c=0.5 DMF).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:43])[C@H:6]([CH2:39][CH:40]([CH3:42])[CH3:41])[NH:7][C:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[CH:11][N:10](C(OC(C)(C)C)=O)[N:9]=1)#[N:2].CS(O)(=O)=O.C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([CH2:3][NH:4][C:5](=[O:43])[C@H:6]([CH2:39][CH:40]([CH3:41])[CH3:42])[NH:7][C:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)=[CH:17][CH:18]=2)=[CH:11][NH:10][N:9]=1)#[N:2]
Reactant: CC(C)C[C@H](Nc1nn(C(=O)OC(C)(C)C)cc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)NCC#N
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C[C@H](Nc1n[nH]cc1-c1ccc(N2CCNCC2)cc1)C(=O)NCC#N
Reaction time: 8 h

Procedure:
To N1-(cyanomethyl)-N2-(1-(tert-butoxycarbonyl)-4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-1H-pyrazol-3-yl)leucinamide (163 mg, 0.274 mmol) in dry THF (0.5 mL) under dry nitrogen was gradually added a total of 5 equivalents of MeSO3H (100 μL, 1.37 mmol) over a period of 3 hours in portions of 1–2 equivalents at a time and the reaction mixture was stirred overnight. Aqueous sat. NaHCO3 was added carefully and the product extracted with EtOAc (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel NH4OH/MeOH/CH2Cl2, 1/9/90) to afford N1-(cyanomethyl)-N2-[4-(4-piperazin-1-ylphenyl)-1H-pyrazol-3-yl]leucinamide. MS (+ESI): 398.4 [M+1]+.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Li+].C[Sn](C)(C)C.Br[C:28]1[C:37]2[C:32](=[CH:33][C:34]([O:38][CH3:39])=[CH:35][CH:36]=2)[N:31]=[CH:30][CH:29]=1.Cl.[OH-].[Na+]>CN(C=O)C.CCOC(C)=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][C:28]1[C:37]2[C:32](=[CH:33][C:34]([O:38][CH3:39])=[CH:35][CH:36]=2)[N:31]=[CH:30][CH:29]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc2c(Br)ccnc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Sn](C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(C)ccnc2c1
Temperature: 120 °C
Yield: 102.2 %

Procedure:
4 g of triphenylphosphine, 5.3 g of lithium chloride, 14 ml of tetramethyltin and 2.1 g of bis(triphenylphosphine)palladium(II) chloride are added to a solution of 6 g of 4-bromo-7-methoxyquinoline in 100 ml of DMF, under an inert atmosphere of argon at a temperature in the region of 20° C. The reaction medium is heated at a temperature in the region of 120° C. for 16 hours. After cooling, the insoluble material is filtered off. The filtrate is concentrated under reduced pressure. The residue obtained is taken up in 300 ml of EtOAc and 300 ml of water. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The oil obtained is taken up in 300 ml of EtOAc and 300 ml of water and then acidified with hydrochloric acid to pH 1. The aqueous phase is basified with sodium hydroxide to pH 10 and then extracted with 300 ml of EtOAc. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure to give 2.7 g of 4-methyl-7-methoxyquinoline, the characteristics of which product are as follows:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]([Cl:31])=[CH:19][C:18]=1[C:32]1[CH:36]=[CH:35][NH:34][N:33]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>ClCCl>[CH2:9]([O:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]([Cl:31])=[CH:19][C:18]=1[C:32]1[C:36]([Br:1])=[CH:35][NH:34][N:33]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1cc(-c2cc[nH]n2)c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: O
Solvent: ClCCl
Product: Clc1cc(-c2n[nH]cc2Br)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
N-Bromosuccinimide (4.70 g, 26 mmol) was added in portions over 5 minutes to a stirred solution of 3-(2,4-Bis-benzyloxy-5-chloro-phenyl)-1H-pyrazole (10.29 g 26 mmol) in dichloromethane (200 ml). The reaction mixture was stirred at ambient temperature for 2 hours then water (200 ml) was added and vigorous stirring continued for 10 minutes. The phases were separated and the organic phase was washed with water (3×100 ml), saturated aqueous sodium chloride solution (2×100mi) and dried over sodium sulphate. The mixture was filtered and filtrate solvents were removed in vacuo to afford an off-white solid, which was triturated with ethyl acetate/hexane (1:20) mixture to give 3-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-bromo-1H-pyrazole (11.80 g, 97%) as off-white solid.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([OH:13])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:21]1[CH:26]=[C:25]([NH2:27])[CH:24]=[N:23][CH:22]=1>>[CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([NH:27][C:25]2[CH:26]=[N:21][CH:22]=[N:23][CH:24]=2)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Reactant: Nc1cncnc1
Product: O=C(Nc1cncnc1)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 9c) (100 mg, 0.35 mmol) and 5-pyrimidinamine (CAN 591-55-9, 39.5 mg, 0.41 mmol) as starting materials; off white solid (61 mg, 48.2%). MS (ESI): 367.2 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:21][CH2:20][C:19](=[CH:22][C:23]([O:25]CC)=[O:24])[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:28])[CH:16]=3)[N:11](C(OC(C)(C)C)=O)[C:10]=2[C:9]1=[O:36])=O)(C)(C)C.[Li+].[OH-]>CO.O>[F:28][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=[O:36])[NH:8][CH2:21][CH:20]=[C:19]([CH2:22][C:23]([OH:25])=[O:24])[C:18]2=1
Reactant: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)C(=O)c2c1c1cc(F)ccc1n2C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CC1=CCNC(=O)c2[nH]c3ccc(F)cc3c21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 5-ethoxycarbonylmethylene-7-fluoro-1-oxo-1,3,4,5-tetrahydro-azepino[3,4-b]indole-2,10-dicarboxylic acid di-tert-butyl ester, (1.31 g, 2.6 mmol) in MeOH—H2O (3:1 mixture, 150 mL) is added LiOH (0.312 g, 13 mmol). The mixture is stirred at room temperature for 2 days and concentrated. Water (100 mL) is added to the residue and it is acidified with 2M NaHSO4. The precipitate is collected by filtration and dried to give (7-fluoro-1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetic acid; 1H NMR (DMSO-d6) δ 2.26 (d, 2H, J=5.2 Hz), 2.79 (s, 2H), 5.00 (t, 1H, 6.4 Hz), 6.22 (dt, 1H, J1=2.4 Hz, J2=10.8 Hz), 6.56 (dd, 1H, J1=4.0 Hz, J2=8.8 Hz), 6.66 (dd, 1H, J1=2.4 Hz, J2=10.8 Hz), 7.26 (t, 1H, J=5.6 Hz), 11.10 (s, 1H); m/z [M++1] 275.0.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]4[CH2:24][CH2:23][CH2:22][C@H:21]4[CH3:25])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:26]([O:28]C)=[O:27])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[Na+].O>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]4[CH2:24][CH2:23][CH2:22][C@H:21]4[CH3:25])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:26]([OH:28])=[O:27])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4c(c3)OCO4)c(N3CCC[C@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a solution of (R)-methyl 2-(benzo[d][1,3]dioxol-5-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (120 mg, 0.31 mmol) in methanol (25 mL) was added sodium hydroxide (37.2 mg, 0.93 mmol) and water (2 mL). The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (20 mL) and adjusted pH to 5 with hydrochloric acid (3N). The solids were collected by filtration to afford (R)-2-(benzo[d][1,3]dioxol-5-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid (90 mg, 78%).
Reaction SMILES: [C:1]1(=[C:8]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCO.[OH-].[Na+].Cl>C1COCC1>[C:1]1(=[C:8]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([CH3:23])([CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(Oc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1)C(=O)O
Yield: 74.6 %

Procedure:
The hydrolysis procedure described for 191 was employed. Ethyl 2-({4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)-2-methylpropanoate (225) (0.150 g, 0.37 mmol) was dissolved in THF and EtOH (1:1, 6 mL) and then treated with 1 N NaOH (3 mL, excess) at 70° C. for 1 h. The reaction mixture was cooled and poured into 20% aqueous HCl (40 mL). Standard work-up and purification afforded 0.105 g (75%) of the title compound 226 as an off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 13.06 (br s, 1H), 9.26 (s, 1H), 6.98 (d, J=8.4 Hz, 2H), 6.90 (d, J=7.8 Hz, 2H), 6.72 (d, J=8.4 Hz, 2H), 6.67 (d, J=8.1 Hz, 2H), 2.21 (br s, 4H), 1.52 (br s, 8H), 1.48 (s, 6H). LCMS (ESI): m/z 379 (M−H)−. Anal. Calcd for C24H28O4, C, 75.76; H, 7.42; Found: C, 75.07, H, 7.52.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([NH2:8])[CH2:5][CH:4]([NH2:9])[CH2:3]1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[C:14]([F:18])=[CH:13][N:12]=1>C(O)(C)C.C(#N)C>[Cl:10][C:11]1[N:16]=[C:15]([NH:8][CH:6]2[CH2:7][CH:2]([CH3:1])[CH2:3][CH:4]([NH2:9])[CH2:5]2)[C:14]([F:18])=[CH:13][N:12]=1
Reactant: CC1CC(N)CC(N)C1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CC(C)O
Solvent: CC#N
Product: CC1CC(N)CC(Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-methylcyclohexane-1,3-diamine, 76a, (2.2 g, 17.2 mmol) in isopropyl alcohol (40 ml) and acetonitrile (40 ml) was added 2,4-dichloro-5-fluoropyrimidine (1.4 g, 8.6 mmol). The mixture was stirred at room temperature overnight, concentrated to dryness, and purified on silica gel eluted with 1-20% methanol/dichloromethane, to give 0.6 g of racemic N1-(2-chloro-5-fluoropyrimidin-4-yl)-5-methylcyclohexane-1,3-diamine: 1H NMR (300 MHz, MeOD) δ 7.85 (d, J=3.5 Hz, 1H), 4.07 (ddd, J=11.9, 7.9, 4.1 Hz, 1H), 3.54 (qd, J=11.3, 4.2 Hz, 1H), 2.82 (tt, J=11.4, 3.7 Hz, 1H), 2.16 (dd, J=15.0, 13.0 Hz, 1H), 1.89 (t, J=13.4 Hz, 2H), 1.50 (dd, J=76.0, 21.9 Hz, 2H), 1.10 (dt, J=17.9, 9.0 Hz, 1H), 0.99 (dd, J=8.5, 5.0 Hz, 3H), 0.81 (ddd, J=23.8, 12.0, 8.2 Hz, 1H); LCMS RT=1.24 (M+1) 259.1.
Reaction SMILES: C(O)(=O)C(O)=O.C(O)(=O)C(O)=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:16][CH2:15]1.C(N(CC)CC)C.[C:44](Cl)(=[O:49])[CH2:45][CH2:46][CH2:47][CH3:48]>O1CCCC1>[C:44]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:18][CH2:19]1)(=[O:49])[CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Reactant: CCCCC(=O)Cl
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC(=O)NC1CCN(CCNC(=O)c2nn(C(C)C)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 23, as the free base (0.330 g, 1 mmol) and triethylamine (0.15 mL, 1.05 mmol) were stirred in 10.0 mL tetrahydrofuran and cooled briefly in an ice bath. To the mixture was added dropwise valeryl chloride (0.12 mL, 1 mmol) and the resulting mixture was stirred 18 h at room temperature and filtered, and the filtrate was evaporated to 0.385 g oil. Crystallization from diethyl ether provided 0.176 g colorless crystals. Mp 107°-109° C. Mass spectrum, m+ =413. Anal (C23H35N5O2) theory C, 66.80; H, 8.53; N, 16.93; found C, 66.59; H, 8.66; N, 17.04.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1([C:31](Cl)=[O:32])[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH:7][C:31]([C:18]1([CH2:17][CH2:16][CH2:15][CH2:14][Br:13])[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:32]
Reactant: COc1ccc(CN)cc1OC
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: COc1ccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)cc1OC

Procedure:
Prepared analogously to Example 1 from 3,4-dimethoxybenzylamine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: [OH:1][C:2]1([CH2:14][CH2:15][OH:16])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[OH:1][C:2]1([CH2:14][CH2:15][O:16][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CCO)C1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2(O)CCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
Under cooling with a cryogen (−10° C. to 0° C.), to a solution of tert-butyl 3-hydroxy-3-(2-hydroxyethyl)pyrrolidine-1-carboxylate (4.72 g) in pyridine (10 mL) was added p-toluene sulfonylchloride (1.68 g), followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure, and 1 M hydrochloric acid was added thereto, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane: EtOAc) to obtain tert-butyl 3-hydroxy-3-(2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)pyrrolidine-1-carboxylate (3.25 g) as a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([F:10])[C:5]([O:11]C)=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([F:10])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)c(C=O)c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1c(Br)ccc(O)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
A solution of 6-bromo-2-fluoro-3-methoxybenzaldehyde (2 g, 8.58 mmol) in dichloromethane (43 mL) under a nitrogen balloon was cooled to −78° C. in an acetone dry ice bath. 1 M boron tribromide solution in dichloromethane (9.5 mL) was added drop wise under nitrogen balloon. The reaction was stirred at room temperature overnight. The reaction was then put on an ice water bath and the excess boron tribromide was quenched with ice chips. Water was added and the solution was extracted with dichloromethane. The aqueous layer was extracted two times with dichloromethane. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure to give 6-bromo-2-fluoro-3-hydroxybenzaldehyde (1.61 g, 86% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH3:42][O:43][C:44]([CH:46]1[CH2:51][CH2:50][CH:49](CN2C=CC(N)=N2)[CH2:48][CH2:47]1)=[O:45]>C(Cl)Cl>[CH3:42][O:43][C:44]([CH:46]1[CH2:51][CH2:50][CH:49]([CH2:21][N:18]2[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=3)[CH2:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[N:17]2)[CH2:48][CH2:47]1)=[O:45]
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: COC(=O)C1CCC(Cn2ccc(N)n2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)C1CCC(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.3 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 125 mg, 0.38 mmol) was dissolved in methylene chloride (2 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (190 μL, 0.38 mmol) was added and the reaction stirred at 25° C. for 15 min. The solution was chilled to 0° C. and 2,6-lutidine (89 μL, 0.76 mmol) was added dropwise. The reaction continued to stir at 0° C. for 15 min. The 4-(3-amino-pyrazol-1-ylmethyl)-cyclohexanecarboxylic acid methyl ester (90 mg, 0.38 mmol) was added as a pre-dissolved reaction in methylene chloride (2 mL), the ice bath was removed and the reaction continued to stir at 25° C. for 25 min. The reaction was diluted with methylene chloride (100 mL), washed with water (2×30 mL), saturated aqueous brine solution (1×20 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 15% ethyl acetate/methylene chloride) afforded 4-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-cyclohexanecarboxylic acid methyl ester (80 mg, 38%) as a white foam: ESI-LRMS m/e calcd for C27H36ClN3O5S [M+] 549.21, found 550.36 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.91-1.07 (m, 2H, CH2), 1.06-1.21 (m, 2H, CH2), 1.32-1.47 (m, 2H, CH2), 1.46-1.56 (m, 2H, CH2), 1.56-1.93 (m, 9H, CH and 4×CH2), 1.93-2.04 (m, 2H, CH2), 2.11-2.32 (m, 2H, 2×CH), 3.26 (s, 3H, SO2CH3), 3.54 (t, J=7.5 Hz, 1H, CH), 3.66 (s, 3H, CO2CH3), 3.80 (d, J=7.0 Hz, 2H, NCH2), 6.64 (d, Jo=2.2 Hz, 1H, Ar), 7.21 (d, Jo=2.2 Hz, 1H, Ar), 7.46 (dd, Jo=8.1, Jm=1.7 Hz. 1H, Ar), 7.59 (d, Jm=1.7 Hz, 1H, Ar), 7.58 (s, 1H, NH), 8.09 (d, Jo=8.1 Hz, 1H, Ar).