Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.IC.[CH3:26][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[C@H:15]([C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C(Cc1ccc(F)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: C[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 48.7 %

Procedure:
To a room-temperature solution of (S)-4-benzyl-3-(2-(4-fluorophenyl)acetyl)oxazolidin-2-one (5.1 g, 16.3 mmol, 1.0 equiv) in dry THF (100 mL) was added iodomethane (1.0 mL, 16.2 mmol, 1.0 equiv) by syringe. The resulting mixture was cooled to −78° C., and NaHMDS (8.15 mL, 2M in THF, 16.3 mmol, 1.0 equiv) was added dropwise by syringe. After stirring for 15 minutes at −78° C., the reaction mixture was allowed to warm to room temperature. The reaction was quenched with sat'd. aq. NH4Cl, and diluted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (7-20% EtOAc/Hexanes) provided the title compound (2.6 g, 49%). m/z=328.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:19][C:18](O)([CH3:20])[CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:22][CH3:23])[N:7]=1.C([N:32](C(C)C)CC)(C)C.CS(Cl)(=O)=O>C1COCC1>[NH2:32][C:18]1([CH3:20])[CH2:19][N:16]([S:13]([NH:12][C:10]2[CH:9]=[C:8]([O:22][CH3:23])[N:7]=[C:6]([S:5][CH2:4][C:3]3[CH:24]=[CH:25][CH:26]=[C:27]([F:28])[C:2]=3[F:1])[N:11]=2)(=[O:15])=[O:14])[CH2:17]1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(NS(=O)(=O)N2CC(C)(O)C2)nc(SCc2cccc(F)c2F)n1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: COc1cc(NS(=O)(=O)N2CC(C)(N)C2)nc(SCc2cccc(F)c2F)n1

Procedure:
A solution of N-{2-[(2,3-difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}-3-hydroxy-3-methylazetidine-1-sulfonamide (the product from example 129, 0.2 g) in THF (5 ml) was treated with diisopropylethylamine (0.45 ml) and methanesulfonylchloride (0.11 ml) under nitrogen.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)N(C2CC2)CCC3(C)C)=[CH:7][CH:6]=1)[CH3:2].[CH2:29]([O:31][C:32](=O)[C:33]1[CH:38]=CC(I)=CC=1)C>C(N(CC)CC)C.[Cu]I.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>[CH3:29][O:31][C:32]1([C:20]2[CH:15]=[CH:14][C:13]([C:12]#[C:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:28])=[CH:6][CH:7]=3)=[CH:22][CH:21]=2)[CH2:33][CH2:38]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCN3C2CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-methoxycyclopropyl)benzene (Intermediate 61, 100.0 mg, 0.47 mmol) and ethyl-4-iodo benzoate (Reagent A, 141.0 mg, 0.51 mmol) in triethyl amine (6 mL) was treated with copper(I)iodide (30.0 mg, 0.16 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (109 mg, 0.16 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-5% EtOAc-hexanes) afforded 135.0 mg (90%) of the title compound as an orange solid.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:14]([CH3:16])[CH3:15])=[C:10]([CH:13]=1)[CH:11]=O>CO>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:14]([CH3:16])[CH3:15])=[C:10]([CH:11]=[N:4][CH:1]2[CH2:3][CH2:2]2)[CH:13]=1
Reactant: NC1CC1
Reactant: CC(C)c1ccc(Cl)cc1C=O
Solvent: CO
Product: CC(C)c1ccc(Cl)cc1C=NC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
Cyclopropylamine (39.2 g, 0.69 mol) was added to a solution of 5-chloro-2-isopropylbenzaldehyde (II) (120 g, 0.65 mol, 99.6 GC-% by area) in methanol (1200 ml) and the mixture was stirred at room temperature for 2 hours. The solvent was subsequently removed under reduced pressure and N-[(5-chloro-2-isopropylphenyl)-methylene]cyclopropanamine (144 g, 99.2 GC-% by area, 98.5% of theory) was obtained as a light-yellow oil.
Reaction SMILES: [CH2:1](OC(=O)C1C=CN=C(C)C=1Cl)C.[CH3:14][O:15][N:16]=[C:17]1[C:25]2[C:20](=[CH:21][N:22]=[CH:23][C:24]=2Cl)[O:19][CH2:18]1>>[CH3:14][O:15][N:16]=[C:17]1[C:25]2[C:20](=[CH:21][N:22]=[CH:23][C:24]=2[CH3:1])[O:19][CH2:18]1
Reactant: CCOC(=O)c1ccnc(C)c1Cl
Reactant: CON=C1COc2cncc(Cl)c21
Product: CON=C1COc2cncc(C)c21

Procedure:
This compound was prepared using a method analogous to that of 3-chloro-2-methylisonicotinic acid ethyl ester (A.2.5.2), 4-chlorofuro[2,3-c]pyridin-3(2H)-one O-methyl oxime replacing 2,3-dichloroisonicotinic acid ethyl ester. Purification by CC using Hept/EtOAc (9/1 to 1/1) gives a white solid;
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21].C(N(CC)C(C)C)(C)C>COCCOCCOC>[Cl:1][C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([NH:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][P:18]([O:19][CH2:20][CH3:21])([O:22][CH2:23][CH3:24])=[O:25])[N:5]=[CH:4][N:3]=1
Reactant: O=CNc1c(Cl)ncnc1Cl
Reactant: CCOP(=O)(CCCCON)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOCCOC
Product: CCOP(=O)(CCCCONc1ncnc(Cl)c1NC=O)OCC
Yield: 77.2 %

Procedure:
4,6-Dichloro-5-formamidopyrimidine (0.441 g, 2.3 mmol), diethyl 4-(aminooxy)butylphosphonate (0.4 g, 1.77 mmol) and N,N-diisopropylethylamine (0.8 ml, 4.6 mmol) in diglyme (15 ml) were stirred at 100° C. for 2.5 hr. The reaction mixture was then allowed to cool, the hydrochloride of N,N-diisopropylethylamine was filtered off and the filtrate was diluted with chloroform (150 ml). The resulting solution was washed with 4% aq. NaHCO3 (1×20 ml) and water (1×20 ml). The combined aqueous layers were extracted with chloroform (6×20 ml) and the combined chloroform solutions were concentrated to an oil. The residue was chromatographed on silica gel (eluted with chloroform: ethanol, 96:4) to yield the title compound (0.520 g, 77%). 1H NMR: δH [(CD3)2SO] 1.22 (6H, t, J=7Hz, (OCH2CH3)2), 1.68 (6H, m, CH2CH 2CH2P), 3.9 (2H, m, NOCH2), 3.97 (4H, m, (OCH2CH3)2), 8.14 (1H, s, H-2), 9.5 (1H, br.s, NHOCH2, D2O exchangeable), 11.0 (1H, NHCHO, D2O exchangeable).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([N+:14]([O-])=O)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])[CH3:2].CN(C=O)C>C(O)C.[Pd]>[NH2:14][C:5]1[C:4]([O:3][CH2:1][CH3:2])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([F:13])[CH:6]=1
Reactant: CCOc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOc1cc(C(=O)O)c(F)cc1N
Yield: 40.3 %

Procedure:
5-ethoxy-2-fluoro-4-nitrobenzoic acid (Intermediate 172; 1.24 g, 5.40 mmol) was stirred and dissolved in ethanol:DMF (50 mL:5 mL) over 5% Pd/C (125 mg) and hydrogenated at ambient temperature for 4 hours. The catalyst was filtered and washed with ethanol and the solvent evaporated. The resultant material was purified on a silica column, eluting with 0-5% MeOH/DCM. Product containing fractions were combined and evaporated to yield the title compound as a pale brown solid (433 mg, 40%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:2].[N:18]1([CH2:27][CH2:28][C:29](O)=[O:30])[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]1=[O:20].C(Cl)Cl.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:29](=[O:30])[CH2:28][CH2:27][N:18]1[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]1=[O:20])[CH3:2]
Reactant: Cc1cn(CCC(=O)O)c(=O)[nH]c1=O
Reactant: CCOC(=O)CNCCNC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)CCn1cc(C)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.3 %

Procedure:
N—(N′—-BOC-aminoethyl)glycine ethyl ester (1 g, 0.0041 mol) was dissolved in DMF (12 mL). DhbtOH (0.73 g, 0.0045 mol) and 3-(1-thyminyl)propanoic acid (0.89 g, 0.0045 mol) were added. Methylene chloride (12 mL) was then added and the mixture was cooled to 0° C. in an ice bath. After addition of DCC (1.01 g, 0.0049 mol), the mixture was stirred at 0° C. for 2 h, followed by 1 h at room temperature. The precipitated DCU was removed by filtration, washed with methylene chloride (25 mL), and a further amount of methylene chloride (50 mL) was added to the filtrate. The organic phase was extracted with sodium hydrogen carbonate (1 volume saturated diluted with 1 volume water, 6×100 mL), potassium sulfate (1 volume saturated diluted with 4 volumes water, 3×100 mL), and saturated aqueous sodium chloride (1×100 mL), dried over magnesium sulfate, and evaporated to dryness, in vacuo. The solid residue was suspended in methylene chloride (15 mL), and stirred for 1 h. The precipitated DCU was removed by filtration and washed with methylene chloride. The filtrate was evaporated to dryness in vacuo, and the residue purified by column chromatography on silica gel, eluting with a mixture of methanol and methylene chloride (gradient from 1 to 6% methanol in methylene chloride). This afforded the title compound as a white solid (1.02 g, 59%). Anal. for C19H30N4O7, found (calc.) C: 53.15 (53.51) H: 6.90 (7.09) N: 12.76 (13.13). The compound showed satisfactory 1H and 13C-NMR spectra.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:16][NH:15][CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1.[F:26][C:27]([F:44])([F:43])[C:28]1[CH:29]=[CH:30][C:31]([N:34]2[CH2:39][CH2:38][CH:37]([C:40](O)=[O:41])[CH2:36][CH2:35]2)=[N:32][CH:33]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[CH2:16][N:15]([C:40]([CH:37]3[CH2:38][CH2:39][N:34]([C:31]4[CH:30]=[CH:29][C:28]([C:27]([F:44])([F:26])[F:43])=[CH:33][N:32]=4)[CH2:35][CH2:36]3)=[O:41])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(c2ccc(C(F)(F)F)cn2)CC1
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C(F)(F)F)cn3)CC2)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
A mixture of 125 mg (0.456 mmol) rac-[(3S,4R)-4-(4-Chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester, 198 mg (0.547 mmol) 1-(5-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxylic acid, 208 mg (0.547 mmol) HATU and 353 mg (2.73 mmol) DIPEA in 10 mL DMF and stirred for 1 h ar room temperature. The mixture was concentrated and DMF and DIPEA was added and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 187 mg (66%) of the title compound as light brown viscous oil. MS m/e: 619.4 [M+H]+.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[N:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7]>CC(O)=O.CCOCC>[NH2:3][C:4]1[N:11]=[CH:10][C:9]([Br:1])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1cccnc1N
Reactant: BrBr
Solvent: CCOCC
Solvent: CC(=O)O
Product: N#Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 22 h
Yield: 77.6 %

Procedure:
Bromine (1.1 mL, 21 mmol) in AcOH (3 mL) was added dropwise to a solution of 2-amino-nicotinonitrile (1.00 g, 8.4 mmol) in AcOH (20 mL) at 10° C. The orange mixture was stirred for 22 hours at ambient temperature then diluted with ether (100 mL). The resultant precipitated salt was filtered, washed with ether and dried on air. The precipitate was suspended in water (100 mL), neutralized with 1N NaOH, filtered, washed with water and dried on air to give 1.29 g (78%) title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.27 (d, J=2.5 Hz, 1H), 8.14 (d, J=2.5 Hz, 1H), 7.13 (s, br, 2H). MS (ESI) m/e: 197.9655 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:17][CH2:16][C@@H:15]([CH:18]([NH2:24])[C:19]3S[CH:21]=[CH:22][N:23]=3)[CH2:14]2)[C:9]([F:25])=[C:8]2[C:3]=1[C:4](=[O:33])[C:5]([C:30]([OH:32])=[O:31])=[CH:6][N:7]2[C@@H:26]1[CH2:28][C@@H:27]1[F:29].N[C:35]1C(F)=C(F)C(F)=C2[C:36]=1C(=O)C(C(O)=O)=CN2[C@@H]1C[C@@H]1F>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:17][CH2:16][C@@H:15]([CH:18]([NH2:24])[C:19]3[CH:36]=[CH:35][CH:21]=[CH:22][N:23]=3)[CH2:14]2)[C:9]([F:25])=[C:8]2[C:3]=1[C:4](=[O:33])[C:5]([C:30]([OH:32])=[O:31])=[CH:6][N:7]2[C@@H:26]1[CH2:28][C@@H:27]1[F:29]
Reactant: Nc1c(F)c(N2CC[C@@H](C(N)c3nccs3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Solvent: CC#N
Product: Nc1c(F)c(N2CC[C@@H](C(N)c3ccccn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Yield: 66.7 %

Procedure:
3-(R)-[1-Tert-butoxycarbonylamino-1-(2-pyridyl)methyl]pyrrolidine [F1] (339 mg, 1.22 mmol) was added to an acetonitrile suspension (10 ml) of 5-amino-6,7,8-trifluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (316 mg, 1.00 mmol), and the mixture was heated under reflux for 14 hours in the presence of triethylmine (0.5 ml). After cooling, the solvent of the reaction solution was evaporated under a reduced pressure. The resulting residue was dissolved in chloroform (150 ml), this was washed with 10% citric acid (80 ml) and saturated brine (80 ml) and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was mixed with concentrated hydrochloric acid (10 ml) under ice-cooling, further mixed with 1 mol/l hydrochloric acid aqueous solution (5 ml) at roan temperature and then washed with chloroform (50 ml×4), and the insoluble matter was removed by filtration. This hydrochloric acid aqueous solution was adjusted to an alkaline liquid property adding 10 mol/l sodium hydroxide aqueous solution. This suspension was adjusted to a liquid property of pH 7.4 by adding concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then extracted with chloroform (150 ml×4). The resulting organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under a reduced pressure to obtain the crude title compound as light yellow crystals. This was purified by recrystallizing from ethanol to obtain 316 mg (67%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[CH:5][CH:4]=1.C[C:15](OI(OC(C)=O)C1C=CC=CC=1)=[O:16].C([O-])(O)=O.[Na+]>>[CH3:1][O:2][C:3]1([O:16][CH3:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[CH:5]=[CH:4]1
Reactant: CC(=O)OI(OC(C)=O)c1ccccc1
Reactant: COc1ccc(O)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Product: COC1(OC)C=CC(=O)c2ccccc21

Procedure:
A solution of 4-methoxy-1-naphthol (2.76 g, 15.8 mmol) and DAIB (6.10 g, 18.9 mmol) on methanol (75 mL) was stirred at 25° C. under a nitrogen atmosphere for 1 h. The resultant dark blue solution was poured into a saturated NaHCO3 (aq) solution (75 mL), then the mixture concentrated to approx. 50 mL in vacuo. The blue oil was extracted with dichloromethane (3×75 mL) and the organic layer washed with water (2×75 mL) and brine (2×75 mL), then dried (MgSO4), filtered and concentrated in vacuo (water bath temperature <40° C.) to yield 4,4-dimethoxy-4H-naphthalen-1-one as a dark-blue semi-solid which was used without further purification; 1H NMR (CDCl3) δ 8.15 (1H, d, J 8.0 Hz, ArH), 7.40–7.85 (3H, m, ArH), 6.90 (1H, d, J 12.2 Hz, H-3), 6.55 (1H, d, J 12.2 Hz, H-2), 3.15 (6H, s, OCH3).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH2:12]Br)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[S:14]1(=[O:20])(=[O:19])[CH2:18][CH2:17][CH2:16][NH:15]1>>[Br:1][C:2]1[CH:11]=[C:10]([CH2:12][N:15]2[CH2:16][CH2:17][CH2:18][S:14]2(=[O:20])=[O:19])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(CBr)cc1Br
Reactant: O=S1(=O)CCCN1
Product: COC(=O)c1ccc(CN2CCCS2(=O)=O)cc1Br
Yield: 55.2 %

Procedure:
Using methyl 2-bromo-4-bromomethylbenzoate (500 mg) and isothiazolidine 1,1-dioxide (216 mg) and by the reaction and treatment in the same manner as in Preparation Example 42, the title compound (312 mg) was obtained.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:31])[C@H:6]([N:24]1[CH2:28][CH2:27][C@H:26]([NH2:29])[C:25]1=[O:30])[CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][C:19]([F:22])([F:21])[F:20])[C:14]([NH2:23])=[N:13][CH:12]=[CH:11]2.C(N(C(C)C)CC)(C)C.[N:41]1([C:46]2[S:47][C:48]([S:51](Cl)(=[O:53])=[O:52])=[CH:49][N:50]=2)[CH2:45][CH2:44][CH2:43][CH2:42]1>C(Cl)Cl>[CH3:3][O:4][C:5](=[O:31])[C@H:6]([N:24]1[CH2:28][CH2:27][C@H:26]([NH:29][S:51]([C:48]2[S:47][C:46]([N:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)=[N:50][CH:49]=2)(=[O:53])=[O:52])[C:25]1=[O:30])[CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][C:19]([F:21])([F:22])[F:20])[C:14]([NH2:23])=[N:13][CH:12]=[CH:11]2
Reactant: O=S(=O)(Cl)c1cnc(N2CCCC2)s1
Reactant: COC(=O)[C@@H](Cc1cc2ccnc(N)c2cc1OC(F)(F)F)N1CC[C@H](N)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1cc2ccnc(N)c2cc1OC(F)(F)F)N1CC[C@H](NS(=O)(=O)c2cnc(N3CCCC3)s2)C1=O

Procedure:
To a suspension of 485 mg (1 mmol) of (R)-3-(1-Amino-7-trifluoromethoxy-isoquinolin-6-yl)-2-((S)-3-amino-2-oxo-pyrrolidin-1-yl)-propionic acid methyl ester bishydrochloride in 6 ml CH2Cl2, 873 μl (5 mmol) diisopropylethylamine and 379 mg (1.5 mmol) 2-Pyrrolidin-1-yl-thiazole-5-sulfonyl chloride, dissolved in 5 ml CH2Cl2, are added subsequently at 0° C. under stirring.
Reaction SMILES: [CH3:1][N:2]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=O)[CH2:5][CH2:4]1.C(Cl)(=O)C(Cl)=O.[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][NH:35][CH3:36]>C(Cl)Cl.CN(C=O)C>[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][N:35]([CH3:36])[C:9]([C@H:6]1[CH2:5][CH2:4][C@H:3]([N:2]([CH3:1])[S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=2)(=[O:13])=[O:14])[CH2:8][CH2:7]1)=[O:11]
Reactant: CN([C@H]1CC[C@H](C(=O)O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CNCCN(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)CCN(C)C(=O)[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Reaction time: 1.5 h

Procedure:
A solution of 0.137 g (0.375 mmol) of trans-4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexanecarboxylic acid in 2 mL of CH2Cl2 was treated at RT with 1 drop of DMF, followed by 0.035 mL (0.412 mmol, 1.1 eq) of oxalyl chloride within 5 min, and stirring was continued for 90 min. The solution was evaporated, redissolved in 2 mL of CH2Cl2 and treated with 0.058 mL (0.450 mmol, 1.2 eq) of N,N,N′-trimethylethylenediamine at 0° C. The reaction was kept at RT for 2 h, then partitioned between Et2O (×3)/aqueous saturated NaHCO3. The organic phases were washed once with 10% aqueous NaCl, dried over Na2SO4 and evaporated. Purification by flash-chromatography on 8 g of silica gel (CH2Cl2:MeOH 99:1 to 9:1) gave 0.088 g (53%) of pure trans-4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexanecarboxylic acid (2-dimethylamino-ethyl)-methyl-amide, MS: 450 (MH+), MP: 83° C.
Reaction SMILES: BrBr.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[CH3:17])=[CH:6][CH:5]=1.C(=O)([O-])[O-:19].[Ca+2]>O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[CH:17]=[O:19])=[CH:8][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(F)cc1-c1ccc(Cl)cc1
Agent: BrBr
Agent: [Ca+2]
Solvent: O
Product: O=Cc1ccc(F)cc1-c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
Bromine (67 g) is added slowly to a stirred solution of 4-chloro-5'-fluoro-2'-methylbiphenyl (of 46.9 g) while being illuminated. The temperature is kept between 105-110° C. for 1 hour. Water (120 ml) and calcium carbonate (90 g) are then added to this product with stirring at reflux for 20 hours. The organics are extracted with chloroform (400 ml.), and the organic phase is washed with water, separated and dried (MgSO4). The chloroform is evaporated. The residue is recrystallized from hexane.
Reaction SMILES: ICI.[CH2:4]([Zn]CC)C.[CH2:9]([O:11][C:12](=[O:40])[CH2:13][N:14]1[C:22]2[CH2:21][CH2:20][CH2:19][C@@H:18]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([CH3:39])=[CH2:38])[CH:28]=3)(=[O:26])=[O:25])[C:17]=2[CH:16]=[N:15]1)[CH3:10].[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH2:9]([O:11][C:12](=[O:40])[CH2:13][N:14]1[C:22]2[CH2:21][CH2:20][CH2:19][C@@H:18]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:30]=[C:29]([C:37]4([CH3:4])[CH2:39][CH2:38]4)[CH:28]=3)(=[O:26])=[O:25])[C:17]=2[CH:16]=[N:15]1)[CH3:10]
Reactant: CC[Zn]CC
Reactant: C=C(C)c1cc(C(F)(F)F)cc(S(=O)(=O)N[C@@H]2CCCc3c2cnn3CC(=O)OCC)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: ICI
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2NS(=O)(=O)c1cc(C(F)(F)F)cc(C2(C)CC2)c1
Reaction time: 0.25 h
Yield: 17.9 %

Procedure:
To a solution of diiodomethane (1.0 mL, 16 mmol) in toluene (10 mL) was added diethylzinc (15% in hexane, 10 mL, 8.8 mmol) under an argon atmosphere at 0° C. and the mixture was stirred for 15 minutes. To the mixture was added [(R)-4-(3-isopropenyl-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (0.2 g, 0.46 mmol) in toluene (4 ml) and the mixture was stirred at 0° C. and then room temperature for 4 hours. The mixture was poured into aqueous ammonium chloride (20 mL) and extracted with dichloromethane (30 mL×3). The combined organic layers were washed with water (20 mL×3), then brine (30 mL), dried over sodium sulfate, concentrated and purified by preparative HPLC to afford {(R)-4-[3-(1-methyl-cyclopropyl)-5-trifluoromethyl-benzenesulfonylamino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (40 mg, 18%) as a white solid. MS calcd. for C22H26F3N3O4S 485, obsd. (ESI+) [(M+H)+] 486.
Reaction SMILES: C[O:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([C:9]2[CH:10]=[C:11]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:12]3[C:17]=2[CH:16]=[CH:15][CH:14]=[CH:13]3)=[O:8])=[CH:5][CH:4]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[CH:10]=[C:11]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:12]3[C:17]=2[CH:16]=[CH:15][CH:14]=[CH:13]3)=[O:8])=[CH:26][CH:27]=1
Reactant: CCOC(=O)CCCc1cc(C(=O)c2ccc(OC)cc2)c2ccccn12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: CCOC(=O)CCCc1cc(C(=O)c2ccc(O)cc2)c2ccccn12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 55.9 %

Procedure:
To a mixture of ethyl 4-[1-(4-methoxybenzoyl)-indolizin-3-yl]butyrate (640 mg) and ethanethiol (2.5 ml) in dichloromethane (8 ml) was added aluminum chloride (700 mg) at 0° C. After stirred at 0° C. for 10 minutes, the solvent was evaporated and the residue was poured into a mixture of ethyl acetate and ice-water. The organic layer was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel column eluting with a mixture of chloroform and ethyl acetate (4:1) to give ethyl 4-[1-(4-hydroxybenzoyl)indolizin-3-yl]butyrate (344 mg) as yellow solid.