Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+].Cl>O.CC(C)=O>[C:2]1([NH:1][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1)c1ccccc1
Reaction time: 1.5 h

Procedure:
N-phenylbenzamide (Structure II) is synthesized from aniline and benzoyl chloride using acetone as a reaction media and an aqueous solution of NaOH to neutralize the HCl generated. A 20 ml aqueous solution of NaOH (2.57 grams, 0.064 moles) and 6.0 grams (0.064 moles) of aniline are first added to a stirred 250 ml flask containing 75 ml of acetone. Benzoyl chloride (9.06 grams, 0.064 moles) is next added over a five minute period. This reaction mixture which now contains a white precipitate is stirred for 1.5 hours and then diluted with 50 ml of deionized water. This solution is next filtered and the filter cake obtained is sequentially washed with 50 ml of deionized water (two times) followed by 50 ml of methanol. The washed filter cake is recovered and DCS analysis of this product showed a sharp melting endotherm at 169° C. ##STR10##
Reaction SMILES: [F:1][CH:2]([F:30])[C:3]1[CH:8]=[C:7]([O:9][CH2:10][C@H:11]2[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[O:12]2)[CH:6]=[CH:5][C:4]=1[C:18]1[NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:26]([C:27](O)=[O:28])[C:20]=2[N:19]=1.S1C=CN=C1N.CN(C(ON1N=[N:52][C:47]2[CH:48]=[CH:49][CH:50]=[N:51]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:30][CH:2]([F:1])[C:3]1[CH:8]=[C:7]([O:9][CH2:10][C@H:11]2[CH2:15][O:14][C:13]([CH3:16])([CH3:17])[O:12]2)[CH:6]=[CH:5][C:4]=1[C:18]1[NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:26]([C:27]([NH:52][C:47]3[CH2:48][CH:49]=[CH:50][N:51]=3)=[O:28])[C:20]=2[N:19]=1
Reactant: CC1(C)OC[C@H](COc2ccc(-c3nc4c(C(=O)O)cccc4[nH]3)c(C(F)F)c2)O1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1nccs1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](COc2ccc(-c3nc4c(C(=O)NC5=NC=CC5)cccc4[nH]3)c(C(F)F)c2)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.8 %

Procedure:
(S)-2-(2-(difluoromethyl)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid (67; 100 mg, 0.239 mmol) was taken up in 10 ml of DMF along with 2-aminothiazole (4; 28.7 mg, 0.289 mmol), HATU (181.7 mg, 0.478 mmol) and DIEA (61.8 mg, 0.289 mmol). The resulting reaction mixture was stirred at room temperature for 12 h and diluted with water. The precipitated solids were collected by filtration and dried. Purification by chromatography (EtOAc/Hexane=2:1) afforded (S)-2-(2-(difluoromethyl)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide 68 (77 mg, 65%). MS (ESI) calcd for C24H22F2N4O4S: 500.13; found: 501 [M+H].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:24])[CH2:11][CH2:12][CH2:13][C:14]([O:16]N2C(=O)CCC2=O)=O)=[CH:5][CH:4]=1)#[CH:2].[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32]>C(Cl)Cl>[OH:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[CH:2])=[CH:8][CH:7]=1)=[O:24]
Reactant: NCCCCCCO
Reactant: C#Cc1ccc(NC(=O)CCCC(=O)ON2C(=O)CCC2=O)cc1
Solvent: ClCCl
Product: C#Cc1ccc(NC(=O)CCCC(=O)NCCCCCCO)cc1

Procedure:
A solution of (2,5-dioxopyrrolidin-1-yl) 5-(4-ethynylphenyl)amino-5-oxo-pentanate (0.2 g, 0.6 mmol) in CH2Cl2 (10 ml) is added slowly to a solution of 1-amino-6-hexanol (0.35 g, 3.0 mmol) in CH2Cl2 (50 ml) with vigorous stirring. The crude reaction solution is concentrated by rotary evaporation and the mixture is purified by silica column chromatography (10% methanol/5% TEA/CH2Cl2).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5]([C:7]1[C:16]2[C:11](=[C:12]([CH3:21])[CH:13]=[C:14]([N:18]=[C:19]=[S:20])[C:15]=2[CH3:17])[N:10]=[CH:9][CH:8]=1)#[N:6]>C1(C)C=CC=CC=1>[NH2:3][CH2:2][CH2:1][NH:4][C:19](=[S:20])[NH:18][C:14]1[C:15]([CH3:17])=[C:16]2[C:11](=[C:12]([CH3:21])[CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[C:5]#[N:6]
Reactant: Cc1cc(N=C=S)c(C)c2c(C#N)ccnc12
Reactant: NCCN
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=S)NCCN)c(C)c2c(C#N)ccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethylenediamine (2.93 mL) in toluene (30 mL) is slowly added a solution of 4-cyano-5,8-dimethyl-6-isothiocyanatoquinoline (2.1 g, 8.78 mmol) in toluene (100 mL). The reaction mixture is stirred at room temperature overnight. The solid which forms is filtered, washed well with toluene, and dried to afford 6-[N'-(2-aminoethyl)thioureido]-4-cyano-5,8-dimethylquinoline.
Reaction SMILES: [C:1]([C:3]1[CH:60]=[CH:59][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:51]=[C:52]([CH2:54][CH2:55][CH2:56][O:57][CH3:58])[CH:53]=2)[CH2:12][N:13]([CH:48]2[CH2:50][CH2:49]2)[C:14]([C@@H:16]2[C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][O:31][C:32]4[C:37]([Cl:38])=[CH:36][C:35]([CH3:39])=[CH:34][C:33]=4[Cl:40])=[CH:24][CH:23]=3)[CH2:20][CH2:19][N:18]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:17]2)=[O:15])=[CH:5][CH:4]=1)#[N:2].[N:61]([Si](C)(C)C)=[N+:62]=[N-:63].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH:48]1([N:13]([CH2:12][C:11]2[CH:10]=[C:9]([O:8][CH2:7][C:6]3[CH:59]=[CH:60][C:3]([C:1]4[NH:63][N:62]=[N:61][N:2]=4)=[CH:4][CH:5]=3)[CH:53]=[C:52]([CH2:54][CH2:55][CH2:56][O:57][CH3:58])[CH:51]=2)[C:14]([C@@H:16]2[C@@H:21]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][O:31][C:32]4[C:33]([Cl:40])=[CH:34][C:35]([CH3:39])=[CH:36][C:37]=4[Cl:38])=[CH:26][CH:27]=3)[CH2:20][CH2:19][N:18]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:17]2)=[O:15])[CH2:50][CH2:49]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCc2ccc(C#N)cc2)c1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCc2ccc(-c3nnn[nH]3)cc2)c1
Temperature: 105 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-([[3-[(4-cyanobenzyl)oxy]-5-(3-methoxy-propyl)benzyl](cyclopropyl)amino]carbonyl}-4-{4-[2-(2,6-dichloro-4-methylphen-oxy)ethoxy]phenyl}piperidine-1-carboxylate (1 eq.) from the previous step in toluene (0.04 M) was added azido(trimethyl)silane (3 eq.) and dibutyltin oxide (0.25 eq.). The reaction was heated to 105° C. and stirred for 16 h. The volatiles were removed in vacuo and the crude product was purified by flash column chromatography (SiO2, 95.9:3.9:0.2 (v/v/v) DCM/MeOH/AcOH) to afford the title compound as an oil.
Reaction SMILES: [NH2:1]/[C:2](=[N:14]\[OH:15])/[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=O.O>N1C=CC=CC=1>[F:16][C:17]([F:27])([F:28])[C:18]1[CH:19]=[C:20]([C:21]2[O:15][N:14]=[C:2]([CH2:3][N:4]3[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]3)[N:1]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1cnn(C/C(N)=N/O)c1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1cnn(Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1
Temperature: 115 °C
Yield: 22.4 %

Procedure:
A solution of the compound (2.2 g) obtained in Example 114a in pyridine (40 mL) was cooled in an ice bath and 3-(trifluoromethyl)benzoyl chloride (4.16 g) was added. The reaction mixture was heated to 110-120° C. overnight, cooled to room temperature, and poured into water. The mixture was extracted with ethyl acetate. The ethyl acetate layer was separated, washed successively with 1N aqueous hydrochloric acid solution, and saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-petroleum ether) to give the title compound (0.85 g) as a colorless solid.
Reaction SMILES: [NH2:1][CH:2]([C:4]([OH:6])=[O:5])[CH3:3].C(N(CC)CC)C.C[Si](Cl)(C)C.[CH2:19]([CH:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:22](Cl)=[O:23])[CH3:20]>ClCCl.O>[CH3:20][CH2:19][CH:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:22]([NH:1][CH:2]([CH3:3])[C:4]([OH:6])=[O:5])=[O:23]
Reactant: CC(N)C(=O)O
Reactant: CCCCCCC(CC)C(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCCCCC(CC)C(=O)NC(C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
18.6 g (0.211 mol) of D,L-alanine and 46.6 g (0.41 mol) of triethylamine are initially charged in 300 ml of dichloromethane. At 0° C. 50.09 g (0.461 mol) of trimethylsilyl chloride are added dropwise, and the mixture is stirred at room temperature for 1 h and then at 40° C. for 1 h. The solution is cooled to −10° C., and 40 g (0.21 mol) of 2-ethyloctanoyl chloride in 50 ml of dichloromethane are added dropwise. The mixture is stirred at room temperature overnight, 100 ml of water are then added dropwise with ice-cooling and the mixture is stirred for 10 minutes. The phases are separated, the aqueous phase is reextracted twice with in each case 100 ml of dichloromethane and the combined organic phases are dried over sodium sulfate and concentrated under reduced pressure. The residue is crystallized from toluene by adding n-hexane and is dried at 60° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O)#[N:21].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCCCCC>[F:8][C:6]1[CH:7]=[C:2]([C:23]2[C:22]([C:20]#[N:21])=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:10]2)[CH:5]=1
Reactant: Fc1cc(Br)cc(-n2ccc(-c3ccccn3)c2)c1
Reactant: N#Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: N#Cc1ccccc1-c1cc(F)cc(-n2ccc(-c3ccccn3)c2)c1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
2-[1-(3-Bromo-5-fluorophenyl)-1H-pyrrol-3-yl]pyridine (647 mg, 2.0 mmol), 2-cyanophenyl boronic acid (300 mg, 2.0 mmol), potassium carbonate (500 mg, 3.0 mmol) were combined in DME:H2O (10:3 mL) under argon and Pd(PPh3)4 (231 mg, 0.2 mmol) was added and the argon flow was continued for 10 min. The reaction mixture was heated at 80° C. overnight. The reaction mixture was allowed to cool to ambient temperature. TLC analysis showed no starting material present. The reaction mixture was diluted with EtOAc (100 mL), and washed with H2O (3×100 mL), brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford a dark oil. The crude product was purified by column chromatography eluting with 3.5:6.5 EtOAc:Hexane to afford 3′-fluoro-5′-(3-pyridin-2-yl-1H-pyrrol-1-yl)-1,1′-biphenyl-2-carbonitrile (480 mg, 70% yield) as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 8.94 (s, 1H), 8.70-8.72 (d, 1H), 8.46-8.49 (t, 1H), 8.33-8.35 (d, 1H), 8.03-8.05 (d, 1H), 7.83-7.95 (m, 4H), 7.79-7.81 (d, 1H), 7.64-7.74 (m, 2H), 7.51-7.53 (d, 1H), 7.40 (s, 1H). MS 340.0 (M++H).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[N:7]=[C:8]2[N:13]([CH:14]=1)[CH2:12][C@H:11]([OH:15])[CH2:10][O:9]2)([O-:5])=[O:4].[Cl:16][C:17]1[CH:22]=[N:21][C:20]([CH2:23]I)=[CH:19][N:18]=1>CN(C=O)C>[Cl:16][C:17]1[N:18]=[CH:19][C:20]([CH2:23][O:15][C@@H:11]2[CH2:10][O:9][C:8]3=[N:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:14][N:13]3[CH2:12]2)=[N:21][CH:22]=1
Reactant: Clc1cnc(CI)cn1
Reactant: O=[N+]([O-])c1cn2c(n1)OC[C@@H](O)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cn2c(n1)OC[C@@H](OCc1cnc(Cl)cn1)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
Triethylamine (4.17 mL, 3.0 mmol) and mesyl chloride (1.57 mL, 2.00 mmol) were added to a solution of (5-chloro-2-pyrazinyl)methanol (1.44 g, 10.0 mmol) in anhydrous THF (20 mL) at 0° C. The mixture was stirred at 0° C. for 0.5 h then partitioned between EtOAc/water. The organic fraction was dried (MgSO4) and the solvent was removed under reduced pressure to give the crude mesylate. The mesylate was dissolved in acetone (40 mL), sodium iodide (7.5 g, 50 mmol) was added and the mixture was refluxed for 1 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc/water. The residue was chromatographed on silica gel (DCM) to give 2-chloro-5-(iodomethyl)pyrazine. Sodium hydride (60% w/w, 0.36 g, 9.0 mmol) was added to a solution of (S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxa-zin-6-ol (0.93 g, 5.02 mmol) and 2-chloro-5-(iodomethyl)pyrazine (1.54 g, 6.05 mmol) in DMF (10 mL) at −78° C. The mixture was stirred at 0° C. for 1 h and then quenched with ice. EtOAc (200 mL) was added, the organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with a gradient (0-5%) MeOH/EtOAc to give the title compound (1.015 g, 65%) as a white solid. APCI MS m/z 312.6 (M+H). 1H NMR (400 MHz, (CD3)2SO) δ 8.76 (d, J=1.4 Hz, 1H), 8.50 (d, J=1.4 Hz, 1H), 8.02 (s, 1H), 4.85 (d, J=13.7 Hz, 1H), 4.81 (d, J=13.7 Hz, 1H), 4.70 (td, J=12.1, 2.6 Hz, 1H), 4.49 (bd, J=12.0 Hz, 1H), 4.29-4.38 (m, 2H), 4.25 (dd, J=13.5, 3.3 Hz, 1H).
Reaction SMILES: [OH:1][CH:2]([C:7]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[S:15][C:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[C:9]=2[C:8]=1[C:22]1[C:23]([CH3:32])=[C:24]2[C:29](=[CH:30][CH:31]=1)[O:28][CH2:27][CH2:26][CH2:25]2)[C:3]([O:5][CH3:6])=[O:4].C([O-])(O)=O.[Na+]>C(OC(C)(C)C)(=O)C>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:1][C:8]([CH3:22])([CH3:9])[CH3:7])[C:7]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[S:15][C:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[C:9]=2[C:8]=1[C:22]1[C:23]([CH3:32])=[C:24]2[C:29](=[CH:30][CH:31]=1)[O:28][CH2:27][CH2:26][CH2:25]2
Reactant: COC(=O)C(O)c1c(-c2ccc3c(c2C)CCCO3)c2c3c(sc2c(=O)n1C)CCCC3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2C)CCCO3)c2c3c(sc2c(=O)n1C)CCCC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 118.9 %

Procedure:
To a solution of compound methyl 2-hydroxy-2-(2-methyl-4-(5-methylchroman-6-yl)-1-oxo-1,2,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-c]pyridin-3-yl)acetate (30 mg, 0.066 mmol) in t-Butyl acetate (3 mL) was added HClO4 (6.64 mg, 0.066 mmol). The mixture was stirred at room temperature for 30 min. The reaction mixture neutralized with saturated aqueous NaHCO3 (10 mL). The resulting solution was extracted with ethyl acetate (15 mL×3). The combined ethyl acetate were dried over Na2SO4 and concentrated to dryness to give crude product, which was purification with prep-TLC afford title product (20 mg, 59% yield) as a solid. LCMS (m/z) ES+=510 (M+1)
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([CH3:20])([CH3:19])[C:15]([F:18])([F:17])[F:16])[CH:9]=2)=[C:5]([CH3:7])[N:6]=1.C([Sn](CCCC)(CCCC)[C:26]([O:28]CC)=[CH2:27])CCC.[F-].[K+].Cl.[OH-].[Na+]>O1CCOCC1.CCOC(C)=O.C1COCC1.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>[CH3:7][C:5]1[N:6]=[C:2]([C:26](=[O:28])[CH3:27])[S:3][C:4]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:14]([CH3:20])([CH3:19])[C:15]([F:18])([F:17])[F:16])[CH:9]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1nc(Cl)sc1-c1ccnc(C(C)(C)C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)c1nc(C)c(-c2ccnc(C(C)(C)C(F)(F)F)c2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
To a solution of 2-chloro-4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazole (3.3 g, 10.3 mmol) and Pd(PPh3)2Cl2 (0.72 g, 1.03 mmol) in 50 mL dioxane under nitrogen, tributyl(1-ethoxyvinyl)stannane (3.82 ml, 11.32 mmol) was added. The mixture was heated to 100 C for 16 h. The reaction was cooled to r.t. and diluted with 25 mL EtOAc. 2M KF (15.4 ml) solution was added and stirred for 1 h. Copious precipitate formed. The reaction was filtered through Celite and chased with EtOAc. The organic layer was rinsed with 60 mL water, and concentrated to give grey solid. Crude solid was dissolved in THF (50 mL) and 1N HCl (20.58 mL) was added. The reaction was stirred at r.t. for 2 h. The mixture was neutralized by addition of 1 N NaOH. THF was removed in vacuo. Extracted aqueous with 2×50 mL EtOAc. The organic layers were washed with 50 mL brine, and dried over Na2SO4. Filtered and concentrated on silica gel. Flash chromatography using 10-50% EtOAc in heptane gave 1.65 g (49%) 1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)ethanone as a yellow oil. MS m/z 329.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.72 (dd, J=5.2, 0.9 Hz, 1H), 7.60 (dq, J=1.8, 0.9 Hz, 1H), 7.34 (dd, J=5.1, 1.6 Hz, 1H), 2.74 (s, 3H), 2.63 (s, 3H), 1.69 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.CO.B(F)(F)F.[CH3:18]COCC.C>C(Cl)Cl.O>[CH3:18][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=1[OH:11]
Reactant: CCOCC
Reactant: Nc1ccc(O)c(C(=O)O)c1
Agent: FB(F)F
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(N)ccc1O

Procedure:
To a stirred solution of 76.6 g (0.5 mole) of 5-aminosalicyclic acid in 252.0 g (8 mole) of methanol was added 150.0 g (1.06 mole) of borontrifluoride etherate (Aldrich) and the mixture was heated at reflux overnight. The reaction mixture was treated with 150 mL of water and filtered. The filtrate pH was adjusted to 8.4 with sodium bicarbonate, and the resulting solid was collected by filtration and air dried to give 43.0 g (51%) of crude title compound as a solid. A sample was dissolved in methylene chloride, treated with charcoal and filtered. The filtrate was concentrated under reduced pressure to give a solid. The solid was recrystallized from methylene chloride-petroleum ether (30°-60° C.) to give title compound as golden-brown needles, mp 95°-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:27]#[N:28])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]([O:24][CH3:25])[CH2:22][CH3:23])[C:17]([OH:19])=O)[C:10](=[O:26])[CH:9]=2)[CH:7]=1.[NH2:29][C:30]1[CH:40]=[CH:39][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][CH:31]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:27]#[N:28])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]([O:24][CH3:25])[CH2:22][CH3:23])[C:17]([NH:29][C:30]3[CH:31]=[CH:32][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:39][CH:40]=3)=[O:19])[C:10](=[O:26])[CH:9]=2)[CH:7]=1
Reactant: CCC(CC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O)OC
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)C(CC(CC)OC)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1

Procedure:
620 mg (1.53 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxyhexanoic acid (mixture of racemic diastereomers), 253 mg (1.53 mmol) of ethyl 4-aminobenzoate, 218 mg (1.53 mmol) of Oxima and 239 μl (1.53 mmol) of DIC in 15.3 ml of dimethylformamide were reacted according to General Method 5B. The crude product was purified by flash chromatography (120 g cartridge, 85 ml/min, cyclohexane/ethyl acetate gradient). Yield: 634 mg (70% of theory)
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH:17]3OC(=O)N[CH2:18]3)[CH:14]=2)[NH:9][CH:8]=1)[CH3:4].Cl.NC1C=CC(CC2[O:34][C:33](=[O:35])[NH:32]C2)=CC=1.CN1CCC(C2C3C(=CC=C(CC4COC(=O)N4)C=3)NC=2)CC1.Cl.C(N)C>>[CH3:4][N:3]([CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][C@H:17]3[CH2:18][O:35][C:33](=[O:34])[NH:32]3)[CH:14]=2)[NH:9][CH:8]=1)[CH3:2]
Reactant: CN(C)CCc1c[nH]c2ccc(CC3CNC(=O)O3)cc12
Reactant: Nc1ccc(CC2CNC(=O)O2)cc1
Agent: CCN
Agent: CN1CCC(c2c[nH]c3ccc(CC4COC(=O)N4)cc23)CC1
Agent: Cl
Product: CN(C)CCc1c[nH]c2ccc(C[C@H]3COC(=O)N3)cc12

Procedure:
By steps identical to steps (d) to (f) of Synthetic Example 1 and Synthetic Example 2 or steps (d) and (e) of Synthetic Example 1 and Synthetic Example 3 and steps (e) to (h) of Synthetic Example 4, the product from step (a) was converted to (S)-N,N-dimethyl-2-[5-(2-oxo-l,3-oxazolidin-4-ylmethyl)-1H. indol-3-yl]ethylamine.
Reaction SMILES: [Li]CCCC.Br[C:7]1[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=1.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([C:27]3[N:31]([CH3:32])[C:30]([CH3:33])=[N:29][CH:28]=3)=[O:26])[CH:23]=2)[N:18]=[C:17]([O:34][CH3:35])[C:16]=1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1>C1COCC1>[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([C:27]3[N:31]([CH3:32])[C:30]([CH3:33])=[N:29][CH:28]=3)([C:7]3[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=3)[OH:26])[CH:23]=2)[N:18]=[C:17]([O:34][CH3:35])[C:16]=1[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=1
Reactant: Cc1ncc(Br)n1C
Reactant: COc1nc2ccc(C(=O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3cnc(C)n3C)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.24 mL, 0.6 mmol) was added dropwise by syringe to a solution of 5-bromo-1,2-dimethyl-1H-imidazole (107.8 mg, 0.616 mmol) in dry THF (6 mL) in a dry ice-acetone bath. After 1-2 minutes, (4-chloro-3-(4-fluorobenzyl)-2-methoxyquinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanone (0.217 g, 0.512 mmol, Intermediate 46: step b) in dry THF (2 mL) was added to the mixture via syringe. After 5 minutes, the reaction was removed from the cold bath and was allowed to warm to ambient temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride. Water was added and the aqueous mixture was extracted with dichloromethane. The combined organic layers were dried (Na2SO4), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (silica gel, 0-10% MeOH-DCM) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J=2.2 Hz, 1H), 7.63 (d, J=8.7 Hz, 1H), 7.37 (dd, J=8.8, 2.1 Hz, 1H), 7.30-7.25 (m, 2H), 6.97-6.92 (m, 2H), 6.19 (s, 1H), 6.12 (s, 2H), 4.22 (s, 2H), 4.07 (s, 3H), 3.37 (s, 6H), 2.24 (s, 6H); MS m/e 520.2 [M+H]+.