Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:4]([CH3:9])[CH:5]=[C:6]([NH2:8])[CH:7]=1)#[N:2].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl.Cl>[CH3:17][S:18]([NH:8][C:6]1[CH:7]=[C:3]([C:1]#[N:2])[N:4]([CH3:9])[CH:5]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(N)cc1C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(NS(C)(=O)=O)cc1C#N
Temperature: 0 °C
Reaction time: 24 h
Yield: 78.5 %

Procedure:
Compound 22-6 (310 mg) was dissolved in dichloromethane (30 ml) and cooled to 0° C. To the solution were added triethylamine (430 μl) and methanesulfonyl chloride (210 μl) successively through an injector, followed by stirring at room temperature for 24 hours. The resulting mixture was diluted with 1 N aqueous hydrochloric acid, and an organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by column-chromatography (ethyl aceate/hexane=1/1) to yield the compound 22-7 (400 mg, 78.5%)
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Mg]Br.[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:19]=1[C:20]#[N:21]>C1(C)C=CC=CC=1.C(OCC)C>[CH:8]1([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:20](=[NH:21])[C:19]2[C:18]([F:17])=[CH:25][CH:24]=[CH:23][C:22]=2[F:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: N#Cc1c(F)cccc1F
Reactant: C1CCC(NC2CCCCC2)CC1
Agent: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: N=C(c1c(F)cccc1F)N(C1CCCCC1)C1CCCCC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
Dicyclohexylamine (9.06 g, 50.1 mmol) was dissolved in toluene (125 mL). The solution was warmed to 50° C. and a solution of methylmagnesiumbromide was added (16.7 mL, 3.0 M in diethylether, 50.1 mmol) and the reaction mixture was stirred for 2 hours at 50° C. The mixture was cooled to 0° C. and 2,6-difluorobenzonitrile (6.80 g, 48.9 mmol). After 45 hours, the reaction mixture was quenched with a solution of ammoniumchloride in water (3.0 g in 80 mL). The water and organic phases were separated and the water layer was extracted 3 times with diethylether (40 mL). The combined organic solutions were dried over sodium sulphate. The sodium sulphate was filtered off and the filtrate was evaporated to dryness yielding 14.2 g (89%) of the product. The product was characterized by 1H NMR (300 MHz) (CDCl3) δ (ppm): 7.2 (pent, 1H), 6.8 (dd, 2H), 5.9 (bs, 1H), 3.5-2.3 (bm, 3H), 1.9-0.6 (bm, 19H), by 13C NMR (75 MHz) (CDCl3) δ (ppm): 158.9 (dd, J=248 Hz, J=8 Hz) 156.4, 130.1, 130.0, 129.8, 118.8, 118.4, 118.1, 12.1, 111.7, 61.3 (bs), 56.9 (bs), 32.0 (bs), 30.1 (bs), 26.8 (bs), 25.8 and by 19F NMR (282 MHz) (CDCl3) δ (ppm): −114.3 (s).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]([O:19]C)=O)[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][C:32]=1[O:39][CH3:40]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]([NH:36][CH2:35][C:34]2[CH:37]=[CH:38][C:31]([F:30])=[C:32]([O:39][CH3:40])[CH:33]=2)=[O:19])[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COc1cc(CN)ccc1F
Reactant: COC(=O)c1cc(CO[Si](C)(C)C(C)(C)C)nc(C)n1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CNC(=O)c2cc(CO[Si](C)(C)C(C)(C)C)nc(C)n2)ccc1F
Temperature: 70 °C
Yield: 81.2 %

Procedure:
To a stirred solution of methyl 6-((tert-butyldimethylsilyloxy)methyl)-2-methylpyrimidine-4-carboxylate (4.70 g, 15.86 mmol, Preparation #6) in MeOH (50 mL) were added DIEA (8.3 mL, 47.59 mmol Spectrochem) and 4-fluoro-3-methoxybenzylamine (3.8 g, 24.58 mmol, WO 2008/083056). The reaction mixture was heated to about 70° C. for about 15 h. The solvents were removed in vacuo and the crude material partitioned between EtOAc (300 mL) and 1N HCl solution (300 mL). The layers were separated and the aqueous layer extracted with EtOAc (1×150 mL). The combined organic layers were washed successively with 1N HCl solution (1×200 mL), water (1×200 mL) and brine (1×250 mL), dried over sodium sulphate and evaporated to dryness. The residue obtained was purified by silica gel (60-120 mesh) chromatography eluting with 25 to 35% of EtOAc in hexane. Relevant fractions containing the target compound were combined and evaporated to dryness under reduced pressure to afford 6-((tert-butyldimethylsilyloxy)methyl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide 5.4 g (81%); 1H NMR (400 MHz, DMSO): δ 9.431-9.400 (t, J=6.0 Hz, 1H), 7.884 (s, 1H), 7.173-7.112 (m, 2H), 6.897-6.860 (m, 1H), 4.794 (s, 2H), 4.468-4.452 (d, J=6.4 Hz, 2H), 3.814 (s, 3H), 2.68 (s, 3H), 0.934 (s, 9H), 0.118 (s, 6H), MS m/z: 420 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7](=O)[CH:8]=[CH:9][N:10](C)C)[S:5][CH:6]=1.O.[NH2:15]N>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:8]=[CH:9][NH:10][N:15]=2)[S:5][CH:6]=1
Reactant: NN
Reactant: CN(C)C=CC(=O)c1cc(Cl)cs1
Solvent: O
Solvent: CCO
Product: Clc1csc(-c2cc[nH]n2)c1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A mixture of 1-(4-chloro-2-thienyl)-3-(dimethylamino)prop-2-en-1-one (24.6 mmol) and hydrazine hydrate (49.2 mmol) in 25 mL ethanol was refluxed for 15 h and then allowed to cool to room temperature. The solvent was evaporated under reduced pressure and dried in vacuum to afford 4.5 g (99% yield) 3-(4-chloro-2-thienyl)-1H-pyrazole which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=[O:17])[CH2:4][C:5]1([CH3:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[O:8][CH2:7][CH2:6]1.[CH3:20][S+](C)(C)=O.[H-].[Na+].[I-].C[S+](C)(C)=O>CS(C)=O>[F:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2([CH3:16])[CH2:4][C:3]1([C:2]([F:1])([F:18])[F:19])[CH2:20][O:17]1
Reactant: C[S+](C)(C)=O
Reactant: CC1(CC(=O)C(F)(F)F)CCOc2ccc(F)cc21
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(CC2(C(F)(F)F)CO2)CCOc2ccc(F)cc21
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of 950 mg (3.45 mmol) of 1,1,1-trifluoro-3-(6-fluoro-4-methylchroman-4-yl)propan-2-one in 10 mL of anhydrous DMSO was added 3.5 mL (4.2 mmol) of a 1.2 M solution of trimethylsulfoxonium ylide, which was prepared by reacting 1.45 g (36.3 mmol) of sodium hydride (60% in mineral oil) with 8 g (36.3 mmol) of trimethylsulfoxonium iodide in 30 mL of DMSO. After 2 hours, the mixture was poured onto ice-cold saturated aqueous ammonium chloride and extracted with 150 mL of ether in several portions. The combined organic layers were washed with four portions of water, then washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 930 mg (93%) of 6-fluoro-4-methyl-4(2-trifloromethyloxiranylmethyl)chroman as a 1:1 mixture of diastereomers by 1H NMR.
Reaction SMILES: [S:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]Cl)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])(=[O:3])=[O:2].[OH-].[Na+]>O>[S:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[CH:11][CH:10]=1)(=[O:7])=[O:8])([CH3:4])(=[O:2])=[O:3]
Reactant: CS(=O)(=O)NS(=O)(=O)c1ccc(CCCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=Cc1ccc(S(=O)(=O)NS(C)(=O)=O)cc1

Procedure:
The N-mesyl-4-(2-chloroethyl)-benzenesulfonamide intermediate was then reacted with sodium hydroxide and water as in Example I to yield 0.28 mols of the N-mesyl-4-vinylbenzenesulfonamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4](=[C:9]([NH2:11])[CH3:10])[C:5](OC)=[O:6].C[C:14]1(C)[CH2:18][CH2:17][CH2:16][N:15]1[CH3:19].CC(C)([O-])C.[Na+].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C(O)(C)(C)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([OH:6])=[C:18]2[CH2:17][CH2:16][N:15]([CH3:19])[C:14]2=[N:11][C:9]=1[CH3:10])=[O:12]
Reactant: COC(=O)C(C(=O)OC)=C(C)N
Reactant: CN1CCCC1(C)C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: COC(=O)c1c(C)nc2c(c1O)CCN2C
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 100 mg of 2-(1-Amino-ethylidene)-malonic acid dimethyl ester (57.7 μmol) and 168 mg of 2,2-dimethyl-1-methylpyrrolidine (115.4 μmol) in 2 mL of toluene was heated at reflux for 3 h then 160 mg of sodium tert butoxide (2.9 eq) and 1 mL of tert butanol was added. The resulting reaction mixture was heated at 90° C. and stirred for 16 h then cooled to room temperature. To this solution was added 5 mL of aqueous saturated ammonium chloride and was extracted with three portions of 10 mL of ethyl acetate. The combined organic layer was washed with brine and dried (MgSO4). After the solvent was removed under diminished pressure, the residue was purified by flash chromatography on a silica gel column (15×2 cm). Elution with 1:20 to 1:10 EtOAc-hexanes gave product 28 as white solid: yield 115 mg, (90%); Silica gel TLC Rf 0.46 (1:4 EtOAc-Hexane); 1H NMR (CDCl3, ppm): δ 2.62 (s, 3H), 2.93 (t, J=8.4 Hz, 2H), 2.98 (s, 3H), 3.55 (t, J=9.0 Hz, 2H), 3.90 (s, 3H), 11.79 (s, 1H). 13C NMR (CDCl3, ppm): δ 22.48, 27.82, 31.90, 51.98, 52.35, 101.09, 102.20, 162.20, 163.75, 165.64, 172.38; HRMS (ESI+) calculated for C11H14N2O3 223.1077. found 223.1082.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([O:16][C:17]([NH:19][C:20]1[C:21]([C:31]([NH:33][C:34]2[CH:35]=[N:36][CH:37]=[CH:38][C:39]=2[N:40]2[CH2:45][C@H:44]([CH3:46])[C@H:43]([NH:47][C:48](=[O:51])[O:49][CH3:50])[C@H:42]([NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56])[CH2:41]2)=[O:32])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[C:25](Br)[CH:24]=2)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:60][C:61]1(C)C(C)(C)OB(C=C)O1.O>O1CCOCC1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[CH2:9]([O:16][C:17]([NH:19][C:20]1[C:21]([C:31]([NH:33][C:34]2[CH:35]=[N:36][CH:37]=[CH:38][C:39]=2[N:40]2[CH2:45][C@H:44]([CH3:46])[C@H:43]([NH:47][C:48](=[O:51])[O:49][CH3:50])[C@H:42]([NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56])[CH2:41]2)=[O:32])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[C:25]([CH:60]=[CH2:61])[CH:24]=2)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)N[C@H]1[C@@H](C)CN(c2ccncc2NC(=O)c2nc3cc(Br)ccc3cc2NC(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)Nc3cnccc3N3C[C@H](C)[C@H](NC(=O)OC)[C@H](NC(=O)OC(C)(C)C)C3)nc2c1
Temperature: 60 °C
Yield: 49.5 %

Procedure:
A vial was charged with dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (40 mg, 0.051 mmol), and K3PO4 (179 mg, 0.844 mmol) were added. The vial was sealed with a septum, then purged with nitrogen three times. A mixture of tert-butyl methyl [(3R,4S,5S)-1-(3-{[(3-{[(benzyloxy)carbonyl]amino}-7-bromoquinolin-2-yl)carbonyl]amino}pyridin-4-yl)-5-methylpiperidine-3,4-diyl]biscarbamate (200 mg, 0.262 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (87 mg, 0.56 mmol) in 1,4-dioxane (2.0 mL) was added, followed by deoxygenated water (0.50 mL, 28 mmol). The resulting reaction mixture was heated at 60° C. for 2 h. The mixture was purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a yellow solid (92 mg, 49%). LCMS calc. for C38H44N7O7 (M+H)+: m/z=710.3. Found: 710.3.
Reaction SMILES: [CH3:1][NH2:2].[C:3]1([CH3:13])[CH:8]=[CH:7][CH:6]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:4]=1>C(O)C.CCOC(C)=O.O>[CH3:1][NH:2][S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH3:13])[CH:4]=1)(=[O:11])=[O:10]
Reactant: CN
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNS(=O)(=O)c1cccc(C)c1
Temperature: 0 °C
Yield: 90 %

Procedure:
A RBF was charged with methylamine (0.9 mL, 40%, 28 mmol) in ethanol (2 mL). The mixture was chilled to 0° C. in an ice bath while stirred under an inert atmosphere. Then, m-toluenesulfonyl chloride (0.8 mL, 6 mmol) was added dropwise into the mixture. The resulting mixture was allowed to stir at 0° C. under an inert atmosphere for 30 minutes. The mixture was diluted with EtOAc and water and then the aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give N,3-dimethylbenzenesulfonamide (1.0 g, 98% yield) as a colorless oil. MS (ESI pos. ion) m/z: 173 (MH+). Calculated exact mass for C7H10NO2S: 172.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH3:17])[CH:3]=1.CI.[C:20](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:20][O:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[C:4]([CH3:17])[CH:3]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(C)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(C)c(NC(=O)OC(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a solution of tert-butyl (4-hydroxy-2,5-dimethylphenyl)carbamate (1.25 g) and methyl iodide (1.12 g) in N,N-dimethylformamide (10.5 mL) was added potassium carbonate (1.46 g), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (1.32 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:16][CH2:17][CH3:18])=[CH:13][C:12]([CH:19]=O)=[CH:11][CH:10]=2)=[O:5])[CH3:2].[C:21]1([C@@H:27]2[CH2:29][C@H:28]2[NH:30][C:31]2[S:32][CH2:33][C:34](=[O:36])[N:35]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:16][CH2:17][CH3:18])=[CH:13][C:12](/[CH:19]=[C:33]1/[C:34](=[O:36])[N:35]=[C:31]([NH:30][C@@H:28]3[CH2:29][C@H:27]3[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[S:32]/1)=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2ccc(C=O)cc2c1OCC
Reactant: O=C1CSC(N[C@@H]2C[C@H]2c2ccccc2)=N1
Product: CCOC(=O)c1cnc2ccc(/C=C3\SC(N[C@@H]4C[C@H]4c4ccccc4)=NC3=O)cc2c1OCC

Procedure:
Similar procedure as described in example 1g was used, starting from 6-formyl-4-ethoxy-quinoline-3-carboxylic acid ethyl ester (example 9b) and 2-((1R,2S)-2-phenyl-cyclopropylamino)-thiazol-4-one (example 1f) to give 4-ethoxy-6-[4-oxo-2-((1R,2S)-2-phenyl-cyclopropylamino)-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carboxylic acid ethyl ester. LC-MS m/e 488 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])=[CH:18][N:17]=1)([OH:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH3:11][O:10][CH2:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[CH2:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])=[CH:18][N:17]=3)([CH3:14])[O:15][C:2]=2[CH:7]=1
Reactant: COCOc1ccc(CC(C)(O)c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cn2)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COCOc1ccc2c(c1)OC(C)(c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cn1)C2
Yield: 98.5 %

Procedure:
A mixture of 1-(2-bromo-4-(methoxymethoxy)phenyl)-2-(5-(triisopropylsilyloxy)pyridin-2-yl)propan-2-ol (9.6 g), copper iodide(I) (3.5 g), cesium carbonate (5.1 g) in toluene (60 mL, containing ca. 0.6 mL DMF) was heated to reflux overnight. The mixture was filtrated and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to afford the title compound (8 g).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[S:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([OH:25])[CH:21]=3)[O:16][C:15]=2[CH3:26])[CH:8]=1)(=[O:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:36][C:37]1[S:38][C:39]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:40]=2[N:41]=1.Cl>CN(C)C=O.CCOCC.O>[F:28][C:2]([F:27])([F:1])[S:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH2:36][C:37]4[S:38][C:39]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:40]=5[N:41]=4)[CH:21]=3)[O:16][C:15]=2[CH3:26])[CH:8]=1)(=[O:4])=[O:5]
Reactant: Cc1oc2ccc(O)cc2c(=O)c1Cc1cccc(NS(=O)(=O)C(F)(F)F)c1
Reactant: Fc1ccc2sc(CCl)nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1oc2ccc(OCc3nc4cc(F)ccc4s3)cc2c(=O)c1Cc1cccc(NS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a stirred solution of 1.8 g (4.4 mmole) of the product from Example 126 in 50 mL dimethylformamide was added 2.4 g (17.4 mmole) potassium carbonate. The mixture was stirred at room temperature for 1 hour then 1.2 g (5.72 mmole) 2-(chloromethyl)-5-fluorobenzothiazole was added. The mixture was stirred for 18 hours, poured into water, acidified to ph 1-4 with 1N HCl, and extracted with ethyl acetate. The ethyl acetate extract was washed with water and brine and then dried (MgSO4), and concentrated to give a solid. Trituration with ether afforded 2.45 g (97%) of the title product as a solid, mp 218°-220° C. Analysis calculated for C26H18N2S2O5F4 : C, 53.98; H, 3.14; N, 4.84. Found: C, 53.94; H, 2.91; N, 4.55.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44](O)=[O:45])=[CH:41][CH:42]=3)[C:37]([CH3:47])=[C:36]2[CH3:48])=[CH:30][CH:29]=1)=[O:21])(C)(C)C>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([CH2:11][NH:12][C:44]([C:40]2[CH:39]=[C:38]3[C:43](=[CH:42][CH:41]=2)[N:35]([CH2:34][C:31]2[CH:30]=[CH:29][C:28]([C:23]4[C:22]([C:20]([OH:21])=[O:19])=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:33][CH:32]=2)[C:36]([CH3:48])=[C:37]3[CH3:47])=[O:45])=[CH:13][CH:14]=1
Reactant: NCc1ccc(-c2ccccc2)cc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3ccc(-c4ccccc4)cc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 4-phenylbenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [CH2:1]([C@@H:8](/[CH:24]=[CH:25]/[C@H:26]([CH3:42])[C:27]([N:29]1[C@@H:33]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:32][O:31][C:30]1=[O:41])=[O:28])[C:9]([N:11]1[C@@H:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][O:13][C:12]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[CH2:1]([C@@H:8]([CH2:24][CH2:25][C@H:26]([CH3:42])[C:27]([N:29]1[C@@H:33]([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:32][O:31][C:30]1=[O:41])=[O:28])[C:9]([N:11]1[C@@H:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][O:13][C:12]1=[O:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](/C=C/[C@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@@H](CC[C@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of (2S,5S,E)-2-benzyl-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)-5-methylhex-3-ene-1,6-dione (250 mg, 0.440 mmol) in EtOAc (5 mL) was added 10% Pd/C (73 mg, 0.069 mmol). The reaction mixture was purged with nitrogen and stirred under an atmosphere of hydrogen (balloon) overnight. The reaction mixture was filtered through CELITE® and concentrated to afford (2R,5S)-2-benzyl-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)-5-methylhexane-1,6-dione (223 mg, 0.392 mmol, 89% yield) which was used without further purification. Anal. Calcd. for C34H36N2O6 m/z 568.3. found: 569.0 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.33-7.29 (m, 4H), 7.24-7.21 (m, 8H), 7.04-7.02 (m, 3H), 4.64-4.62 (m, 2H), 4.19-4.11 (m, 4H), 4.04 (m, 1H), 3.66 (bs, 1H), 3.32 (m, 1H), 3.01-2.9 (m, 2H), 2.78 (m, 1H), 2.61 (m, 1H), 2.40 (m, 1H), 1.71-1.62 (m, 4H), 0.91 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:23])[C:14]3[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=3[O:21][CH3:22])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:23])[C:14]3[CH:19]=[C:18]([NH:20][S:25]([CH3:24])(=[O:27])=[O:26])[CH:17]=[CH:16][C:15]=3[O:21][CH3:22])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(N)cc1C(=O)NC1CCN(C2CCCCC2)C1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc(NS(C)(=O)=O)cc1C(=O)NC1CCN(C2CCCCC2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68.7 %

Procedure:
To a solution of N-(1-cyclohexyl-3-pyrrolidinyl)-2-methoxy-5-aminobenzamide (1.0 g) in dry pyridine (5 ml), methanesulfonyl chloride (308 mg) is added with ice cooling, and the reaction mixture is stirred at room temperature for 20 minutes. The reaction mixture is worked up as in Example 1 to give N-(1-cyclohexyl-3-pyrrolidinyl)-2-methoxy-5-methanesulfonamidobenzamide (731 mg) as crystals melting at 170° to 171.5° C.
Reaction SMILES: [CH3:1][S:2]([O:5][C@@H:6]1[CH2:10][C@H:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[C@H:8]([CH2:19][O:20]CC2C=CC=CC=2)[CH2:7]1)(=[O:4])=[O:3].CO>[OH-].[Pd+2].[OH-].[Pd]>[CH3:1][S:2]([O:5][C@H:6]1[CH2:7][C@@H:8]([CH2:19][OH:20])[C@@H:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:14])[CH2:10]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](OS(C)(=O)=O)C[C@H]1COCc1ccccc1
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](OS(C)(=O)=O)C[C@H]1CO
Reaction time: 2 h

Procedure:
A suspension of (1S,3S,4S)-3-[(benzyloxy)methyl]-4-{[tert-butyl(dimethyl)silyl]-oxy}cyclopentyl methanesulfonate (690 mg, 0.0017 mol) and Palladium hydroxide, 20 wt. % Pd on carbon (160 mg, 0.00012 mol) in methanol (10 mL, 0.2 mol) was stirred under an atmosphere of hydrogen for 2 hours. The reaction was purged with nitrogen and filtered the mixture through celite with DCM. The filtrate was concentrated to obtain 350 mg (65%).
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[N:10]=[C:9]([NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[CH3:13])[C:8]([C:21]([O:23]CC)=[O:22])=[CH:7][N:6]=1>O.CO.O1CCCC1>[Cl:4][C:5]1[N:10]=[C:9]([NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[CH3:13])[C:8]([C:21]([OH:23])=[O:22])=[CH:7][N:6]=1
Reactant: CCOC(=O)c1cnc(Cl)nc1N[C@@H](C)c1ccc(F)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(Cl)ncc1C(=O)O)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.9 %

Procedure:
A solution of lithium hydroxide monohydrate (633 mg, 15.09 mmol) in water (6 mL) was added to a solution of (S)-ethyl 2-chloro-4-(1-(5-fluoropyridin-2-yl)ethylamino)pyrimidine-5-carboxylate (Preparation 5a, 490 mg, 1.51 mmol) in a mixture of methanol (6 mL) and tetrahydrofuran (2 mL) and the reaction mixture was stirred at ambient temperature for 3 hours. The solvents were evaporated under reduced pressure and water was added to the resulting residue. The pH was then adjusted to ca. 6 with 2M aqueous hydrochloric acid and the aqueous suspension was extracted with diethyl ether (×3). The organic phase was washed with water and brine, dried (MgSO4), filtered and the solvent evaporated under reduced pressure to give the title compound (0.21 g, 41%) as a semi-solid.