Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[C:14]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[O:20])=[C:15]([OH:18])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[S:40](Cl)([CH3:43])(=[O:42])=[O:41].O>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[C:14]([C:19]([O:21][CH2:22][C:23]4[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=4)=[O:20])=[C:15]([O:18][S:40]([CH3:43])(=[O:42])=[O:41])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)OC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Reaction time: 1.5 h
Yield: 70.1 %

Procedure:
4-Nitrobenzyl 7-(2-phenylactamido)-3-hydroxy-3-cephem-4-carboxylate (100 g.) was dissolved in a mixture of N,N-dimethylformamide (0.4 l.) and tetrahydrofuran (0.4 l.), and thereto was added potassium carbonate (29 g.). To the mixture was added dropwise mesyl chloride (26.3 g. ) at 5° C. with stirring, and the stirring was continued at the same temperature for 1.5 hours. After the reaction mixture was poured into a mixture of water (3 l. ) and ethyl acetate (3 l.) the organic layer was separated out, washed with water (1 l.) and a saturated aqueous solution of sodium chloride (1 l.×2) and then dried over anhydrous magnesium sulfate, followed by treating with an activated charcoal. The filtrate was concentrated in vacuo, and the precipitated crystals were collected by filtration and washed with diisopropyl ether to give 4-nitrobenzyl 7-(2-phenylacetamido)-3-mesyloxy-3-cephem-4-carboxylate (81.8 g.).
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][C:8]1([OH:22])[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[CH:10]=[C:11]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[OH:5][CH2:6][CH2:7][C:8]1([OH:22])[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[CH:10]=[C:11]2[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)CC1(O)CC2CCC1C=C2c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC1(O)CC2CCC1C=C2c1ccccc1
Temperature: -15 °C
Yield: 109.1 %

Procedure:
295 mg of rac-(1R*,2R*,4R*)-(2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid tert.-butyl ester (intermediate K1A, major racemate) were dissolved in 6 mL THF and cooled to −15° C. To this solution were added dropwise 1.65 mL of a LiAlH4 solution (2.3M in THF). After complete addition the reaction mixture was allowed to warm to 0° C. over 3 h. Under cooling 1M aq. NaOH was added dropwise. The mixture was diluted with THF, filtrated over a pad of celite, washed with THF, EtOAc. The filtrate was evaporated to dryness to give 0.25 g of rac-(1R*,2R*,4R*)-2-(2-hydroxy-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol as white solid.
Reaction SMILES: I[C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][CH2:7][N:8]3[CH:19]=[CH:18][CH:17]=[C:9]3[C:10](=[CH:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[C:4]=2[CH:3]=1.Cl.[CH3:23][N:24](C)C=O>>[C:23]([C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][CH2:7][N:8]3[CH:19]=[CH:18][CH:17]=[C:9]3[C:10](=[CH:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[C:4]=2[CH:3]=1)#[N:24]
Reactant: CN(C)C=O
Reactant: CN(C)CCC=C1c2cc(I)ccc2CCn2cccc21
Agent: Cl
Product: CN(C)CCC=C1c2cc(C#N)ccc2CCn2cccc21
Reaction time: 0.5 h

Procedure:
A stirred mixture of 1 gm. of 9-iodo-11-(3-dimethylaminopropylidene)-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine, 1 gm. of cuprous cyanide, and 5 ml. of dimethylformamide is heated to reflux for 5 hr. The mixture is then poured into a solution of 4 gm. of ferric chloride hydrate in 25 ml. of 2 N hydrochloric acid. After stirring the resulting mixture at 60° for 30 min., it is extracted with 3 × 50 ml. of ethyl acetate. The aqueous acidic solution is then basified with sodium hydroxide and extracted with 3 × 50 ml. of ether. The combined ether extracts are then dried and evaporated to yield 9-cyano-11-(3-dimethylaminopropylidene)-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][C:6]=1[F:15])=[O:4].[CH3:16][C:17]1[NH:21][C:20](=[O:22])[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH2:23][CH2:24][CH3:25])[N:18]=1.C(=O)([O-])[O-].[K+].CC(C)=O.[K+].C1CCCCC1.C(OCC)(=O)C>C(OCC)(=O)C>[F:15][C:6]1[CH:7]=[C:8]([NH:11][C:12](=[O:14])[CH3:13])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][N:21]1[C:20](=[O:22])[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH2:23][CH2:24][CH3:25])[N:18]=[C:17]1[CH3:16]
Reactant: CC(=O)Nc1ccc(C(=O)CBr)c(F)c1
Reactant: CCCC1(c2ccccc2)N=C(C)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCCC1(c2ccccc2)N=C(C)N(CC(=O)c2ccc(NC(C)=O)cc2F)C1=O
Temperature: 70 °C
Yield: 93.4 %

Procedure:
To a mixture of N-[4-(2-bromo-acetyl)-3-fluoro-phenyl]-acetamide (1.1 g, 2.8 mmol) and (+/−)-2-methyl-5-phenyl-5-propyl-3,5-dihydro-imidazol-4-one (541 mg, 2.5 mmol) in 5 mL acetone potassium carbonate (698 mg, 5 mmol) is added and the reaction mixture is heated at 70° C. for 10 min in the microwave oven (Biotage Initiator). The mixture is cooled to room temperature, filtered and the filtrate evaporated to yield the crude product which is subjected to flash chromatography. ISCO Companion CombiFlash, 40 g silica gel, cyclohexane/ethyl acetate-gradient, ethyl acetate 0-100% to give (+/−)-N-{3-fluoro-4-[2-(2-methyl-5-oxo-4-phenyl-4-propyl-4,5-dihydro-imidazol-1-yl)-acetyl]-phenyl}-acetamide (956 mg, 71%). LC/MS at 254 nm; [M+H] 410; Rt 2.850 min
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C@@H:17]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][NH:18]2)[CH:12]=[CH:11][C:10]=1[N:27]1[S:31](=[O:33])(=[O:32])[N:30]([CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:29](=[O:40])[CH2:28]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C@@H:17]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][N:18]2[S:49]([CH3:48])(=[O:51])=[O:50])[CH:12]=[CH:11][C:10]=1[N:27]1[S:31](=[O:32])(=[O:33])[N:30]([CH2:34][CH2:35][Si:36]([CH3:38])([CH3:37])[CH3:39])[C:29](=[O:40])[CH2:28]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/[C@@H]3Cc4ccccc4CN3)cc2OCc2ccccc2)S1(=O)=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/[C@@H]3Cc4ccccc4CN3S(C)(=O)=O)cc2OCc2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-{2-benzyloxy-4-[(E)-(S)-2-(1,2,3,4-tetrahydroisoquinolin-3-yl)-vinyl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (0.12 g, 0.21 mmol) in CH2Cl2 (2 mL) is added triethylamine (0.15 mL, 1.0 mmol), followed by methanesulfonyl chloride (0.020 mL, 0.25 mmol). The mixture is stirred at RT for 1.5 h then is diluted with EtOAc (15 mL) and washed with 1N HCl (2×15 mL) and brine (1×15 mL). The organic layer is dried over Na2SO4, concentrated in vacuo and used directly in the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[CH:30]=[C:29]([CH2:31][CH2:32][O:33][CH2:34][CH3:35])[C:28](=[O:36])[N:27]([CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:42]>ClCCl.C(OCC)C>[ClH:42].[CH:37]1([N:27]2[C:25]3[N:26]=[C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:15][N:16]=4)[N:22]=[CH:23][C:24]=3[CH:30]=[C:29]([CH2:31][CH2:32][O:33][CH2:34][CH3:35])[C:28]2=[O:36])[CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: CCOCCc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCOCCc1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.7 %

Procedure:
4-{6-[8-Cyclopentyl-6-(2-ethoxy-ethyl )-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (0.325 g, 0.577 mmol) was dissolved in dichloromethane (4 mL). 2 N HCl in diethyl ether (4 mL) was added and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated to give 8-cyclopentyl-6-(2-ethoxy-ethyl)-2-(5-piperazin-1-yl-pyridin-2ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride salt as a yellow solid (0.292 g, 97.7%). MS (APCl) Calc'd for M+H: 449.2. Found: 449.2. Anal. Calc'd for C25H33N7O22.6HCl,0.35H2O: C, 52.26; H, 6.56; N, 16.88. Found: C, 52.01; H, 6.96; N, 16.88.
Reaction SMILES: [CH2:1]([O:8]C1C=C(OCC2C=CC=CC=2)C(C(C)C)=CC=1C(O)=O)C1C=CC=CC=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.[Cl:50][C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][CH:59]=1)[CH2:56][NH:55][CH2:54]2>CN(C=O)C>[Cl:50][C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][CH:59]=1)[CH2:56][N:55]([CH:1]=[O:8])[CH2:54]2
Reactant: CC(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: Clc1ccc2c(c1)CNC2
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=CN1Cc2ccc(Cl)cc2C1

Procedure:
A solution of 2,4-bis-benzyloxy-5-isopropyl-benzoic acid (Preparation B10) (0.451 g, 1.2 mmol), EDC (0.276 mg, 1.44 mmol), HOAt (0.196 mg, 1.44 mmol), triethylamine (0.5 ml, 3.6 mmol) and 5-chloro-2,3-dihydro-1H-isoindole (0.187 g, 1.2 mmol) (Preparation C3) in DMF (5 ml) was stirred at room temperature for 16 hours, then evaporated under vacuum. The crude material was dissolved in ethyl acetate and extracted twice with saturated NaHCO3, organics washed with water three times, then evaporated under vacuum to give 0.5 g of 2,4-bis-benzyloxy-5-isopropyl-phenyl)-(5-chloro-1,3-dihydro-isoindol-2-yl)-methanone. MS: [M+H]+ 512
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18](O)=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[CH2:25][CH2:26][NH2:27].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[OH-].[Na+]>CN(C=O)C>[Cl:21][C:22]1[CH:23]=[C:24]([CH2:25][CH2:26][NH:27][C:18]([C:16]2[CH:15]=[CH:14][C:12]3[N:13]=[C:9]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])[NH:10][C:11]=3[CH:17]=2)=[O:19])[CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: NCCc1cccc(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1cccc(Cl)c1)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1

Procedure:
A solution of 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid (107.5 mg), 3-chlorophenethylamine (54.5 mg), BOP (186 mg) and DIEA (0.091 mL) in DMF (1 mL) was stirred at room temperature for 60 h. Then 1N NaOH aqueous solution was added. The aqueous layer was extracted with EtOAc, and the organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, EtOAc:Hexane=20:80 to 80:10) and prep-HPLC later to give 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid [2-(3-chloro-phenyl)-ethyl]-amide: MS (m/z) 446 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[O:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[BH4-].C([BH3-])#N.[Na+]>ClCCl.CO>[CH3:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]2[N:6]([CH:10]3[CH2:11][CH2:12][N:13]([CH:29]4[CH2:30][CH2:31][O:26][CH2:27][CH2:28]4)[CH2:14][CH2:15]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2[nH]c(=O)n(C3CCNCC3)c2cc1C
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH3-]C#N
Agent: [BH4-]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cc2[nH]c(=O)n(C3CCN(C4CCOCC4)CC3)c2cc1C
Reaction time: 8 h

Procedure:
5,6-Dimethyl-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one (D32) (330 mg, 0.6 mmol) as suspension in dichloromethane (10 ml) was treated under argon at room temperature with triethylamine (4.2 mmol, 425 mg, 7 eq) and tetrahydro-4H-pyran-4-one (4.2 mmol, 420 mg, 7 eq). Then sodium triacetoxyborohydride (4.2 mmol, 890 mg, 7 eq) was added and the mixture was stirred overnight. Then 7 eq of fresh borohydride and the ketone were added again and stirred for 2 h 15 min. Methanol (3 mL) was added and stirred for 2 h. 7 eq of borohydride and the ketone were added again and stirred for 3.5 h. Then sodium cyanoborohydride (3 mmol, 188 mg, 5 eq) was added and the mixture was allowed to stand overnight. The mixture was loaded on an SCX cartridge, washed with methanol and eluted with 2M ammonia in methanol and dichloromethane. The eluate was concentrated under reduced pressure and chromatographed to give 5,6-dimethyl-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one as a white solid, which was transformed into the corresponding HCl salt. M+H=330.10,
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([CH3:12])[C:9](=[O:13])[NH:8][C:7]1=[O:14].[OH-].[K+].O.[CH3:18]S(C)=O>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([CH3:12])[C:9](=[O:13])[N:8]([CH3:18])[C:7]1=[O:14]
Reactant: Cc1cn(CCCCCl)c(=O)[nH]c1=O
Reactant: CS(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cn(CCCCCl)c(=O)n(C)c1=O

Procedure:
2.31 mmol (0.50 g) of 1-(4-chlorobutyl)-5-methylpyrimidine-2,4(1H,3H)-dione, 0.65 g (11.54 mmol) of KOH and 1.64 g (11.54 mmol) of methyl rodide in 20.5 ml of dimethyl sulfoxide (DMSO) were stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the aqueous mixture was extracted three times with methyl tert-butyl ether. The combined organic phase was then washed three times with saturated aqueous brine, and the organic phase was dried, filtered to remove the desiccant and concentrated. 0.53 g of a pale cloudy oil was obtained.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[S:14][CH:15]=[CH:16][N:17]=1.[Si:18]([O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=[O:30])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(OCC)C.C(OCC)(=O)C>[S:14]1[CH:15]=[CH:16][N:17]=[C:13]1[CH:29]([OH:30])[C:28]1[CH:31]=[CH:32][CH:33]=[C:26]([O:25][Si:18]([C:21]([CH3:23])([CH3:22])[CH3:24])([CH3:20])[CH3:19])[CH:27]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Reactant: Brc1nccs1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(O)c2nccs2)c1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 26.4 %

Procedure:
A solution of 1.6M n-butyllithium in hexane (206 mL, 0.33 mol) was cooled to -45° C. under nitrogen. A slurry of 2-bromothiazole (50 g, 0.30 mol) in 75 mL of diethyl ether was added in portions, maintaining a temp between -35° C. and -45° C. The resulting dark brown solution was stirred an additional 15 minutes at -40° C. before adding 3-(tert-butyldimethylsilyloxy)benzaldehyde (70.9 g, 0.30 mol, Example 54, infra) dropwise via syringe at a rate to maintain temperature between -25° C. and -35° C. The resulting mixture was stirred an additional 30 minutes at -15° C., then poured into a mixture of 1 L ice/600 mL 1M HCl. The organic phase was dried over sodium sulfate, and evaporated to give a brown oil. Chromatography on silica gel with hexane:ethyl acetate (gradient from 90:10 to 80:20) gave 25.5 g (26.4%) of a-(2-thiazolyl)-3-((tert-butyldimethylsilyl)oxy)benzyl alcohol as a viscous yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:12]([NH:14][C:15]2[NH:16][C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[C:18]([CH3:20])[N:19]=2)=[O:13])[C:6]([CH:9]([F:11])[F:10])=[N:7][CH:8]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39].[NH4+].[Cl-]>C(Cl)Cl>[C:38]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:12]([NH:14][C:15]2[NH:16][C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[C:18]([CH3:20])[N:19]=2)=[O:13])[C:6]([CH:9]([F:11])[F:10])=[N:7][CH:8]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)Cl
Reactant: Cc1nc(NC(=O)c2cc(CN)cnc2C(F)F)[nH]c1-c1ccc(C(F)(F)F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1cnc(C(F)F)c(C(=O)Nc2nc(C)c(-c3ccc(C(F)(F)F)cc3)[nH]2)c1
Reaction time: 8 h
Yield: 75.9 %

Procedure:
Dissolve 5-(aminomethyl)-2-(difluoromethyl)-N-[4-methyl-5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]pyridine-3-carboxamide (0.047 g, 0.110 mmol) in DCM (3 mL). Add triethylamine (0.038 mL, 0.276 mmol) followed by acetyl chloride (9.830 μL, 0.138 mmol), and stir overnight. Pour the reaction into saturated aqueous NH4Cl (15 mL) solution, and extract with EtOAc (2×10 mL). Combine the organic extracts; dry the organic extracts over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure to dryness to give the title compound (0.039 g, 75% yield) as a light yellow solid. LCMS (m/z) 468 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:46])[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH2:34][O:35][Si](C(C)C)(C(C)C)C(C)C)[C@@H:31]([CH3:33])[N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[N:14][CH:15]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:1][O:2][CH2:3][C@H:4]([CH3:46])[O:5][C:6]1[CH:22]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH2:34][OH:35])[C@@H:31]([CH3:33])[N:32]=3)=[CH:26][CH:27]=2)[CH:20]=[C:8]([O:9][C:10]2[CH:15]=[N:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H](C)[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)O3)[nH]2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H](C)[C@H](CO)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(4R,5R)-4-methyl-5-{[(triisopropylsilyl)oxy]methyl}-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-2-(methylsulfonyl)pyridine (1.23 g, 1.83 mmol) synthesized in Example (89g) was dissolved in tetrahydrofuran (20 mL), and tetrabutylammonium fluoride (1.0 mol/L tetrahydrofuran solution, 2.11 mL, 2.11 mmol) is added at room temperature, followed by stirring at room temperature for 1 hour under nitrogen atmosphere. Water (20 mL) was added, and extraction was carried out with ethyl acetate (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=90%-100%) to afford the desired compound (715 mg, yield 76%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9]C(=O)C)[CH:5]=[N:6][C:7]=1Cl.[CH3:13][N:14](C=O)C>CC(OC)(C)C.O.[Ar].[Zn].[C-]#N.[C-]#N.[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].Cl[Pd]Cl>[Cl:1][C:2]1[C:7]([C:13]#[N:14])=[N:6][CH:5]=[C:4]([OH:9])[CH:3]=1
Reactant: CC(=O)Oc1cnc(Cl)c(Cl)c1
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Ar]
Solvent: COC(C)(C)C
Solvent: O
Product: N#Cc1ncc(O)cc1Cl
Temperature: 150 °C

Procedure:
To a solution of acetic acid 5,6-dichloro-pyridin-3-yl ester (CA 110861-18-2, Synthesis, 1990, 499) (4.88 g, 23.6 mmol) in anhydrous DMF (45 ml) was added after degasing with argon Zn-dust (70 mg, 1.07 mmol), Zn(CN)2 (1.28 g, 10.9 mmol) and DPPF PdCl2 (966 mg, 1.18 mmol) and the reaction mixture was heated for 6 h at 130° C. and 18 h at 150° C. The reaction mixture was diluted with TBME and H2O, filtered over Celite, and the product was extracted with TBME. Combined extracts were washed with water and brine, dried over MgSO4, filtered and concentrated. The title compound was obtained as a beige solid after crystallization from EtOAc-hexane: TLC(CH2Cl2-MeOH 19:1): Rf=0.22;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([CH3:16])[C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.Cl.Cl[CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.[H-].[Na+].[Na+].[I-]>CC(N(C)C)=O.O.CCOCC>[Br:1][C:2]1[CH:7]=[N:6][C:5]([N:8]([CH3:16])[C@H:9]2[CH2:10][CH2:11][C@H:12]([O:15][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:13][CH2:14]2)=[N:4][CH:3]=1
Reactant: ClCCN1CCCC1
Reactant: CN(c1ncc(Br)cn1)[C@H]1CC[C@H](O)CC1
Agent: Cl
Agent: [H-]
Agent: [I-]
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(c1ncc(Br)cn1)[C@H]1CC[C@H](OCCN2CCCC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.2 g (0.7 mmol) of trans-4-[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-cyclohexanol and 0.24 g (1.4 mmol) 1-(2-chloroethyl)pyrrolidine hydrochloride in 3.5 ml of DMA was treated at 0° C. with 0.24 g (5.59 mmol) of NaH (55% in oil) in small portions. The reaction was stirred for 30 min at 0° C. After warming up to RT a catalytic amount of NaI was added to the reaction and stirred for 1 h at 80° C. The reaction was cooled and poured into water/Et2O (3×). The organic phase was dried over Na2SO4 evaporated and purified by flash silica gel column (CH2Cl2/MeOH 99:1 to 9:1) to yield 13 g (5%) of trans-(5-Bromo-pyrimidin-2-yl)-methyl-[4-(2-pyrrolidin-1-yl-ethoxy)-cyclohexyl]-amine, MS: 383 (MH+, 1Br).
Reaction SMILES: C(OC(C(CC(O)=O)C(O)=O)=O)C.C([C:16](CC)([OH:51])[C:17]([CH2:23][CH2:24][C:25]1([CH2:31][CH2:32][O:33][Si:34]([C:47]([CH3:50])([CH3:49])[CH3:48])([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)([CH2:21][OH:22])[CH2:18][CH2:19][OH:20])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[O:33]([CH2:32][CH2:31][C:25]1([CH2:24][CH2:23][C:17]([CH2:21][OH:22])([CH2:18][CH2:19][OH:20])[CH2:16][OH:51])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[Si:34]([C:47]([CH3:49])([CH3:50])[CH3:48])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CCC(O)(CC)C(CO)(CCO)CCC1(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCCCC1
Agent: CCOC(=O)C(CC(=O)O)C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)[Si](OCCC1(CCC(CO)(CO)CCO)CCCCC1)(c1ccccc1)c1ccccc1
Reaction time: 1.5 h
Yield: 34 %

Procedure:
To a solution of diethyl 2-[2-[1-[2-(tert-Butlydiphenylsiloxy)ethyl]cyclohexyl]ethyl]-2-hydroxymethylbutane-1,4-diol ethoxycarbonylsuccinate (1.0 g) in diethyl ether (20 mL) was added lithium aluminum hydride (178 mg) under ice cooling. After stirring the solution under ice cooling for 1.5 hours, water (0.18 mL) and a 15% aqueous sodium hydroxide solution (0.18 mL) were successively added thereto. The solution was stirred at room temperature for 15 minutes. Water (0.54 mL) was then added to the solution, and it was stirred at room temperature for additional 30 minutes. The solution was dried over anhydrous magnesium sulfate and filtered. Chloroform was added to the solid, and the solution was stirred at room temperature for 2 hours, followed by filtration. The combined filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, hexane:ethyl acetate=1:4) to give the title compound (230 mg)
Reaction SMILES: C(O[C:6](=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[OH:14])(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH3:6][NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[OH:14]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN[C@@H]1CCCC[C@H]1O
Reaction time: 0.75 h

Procedure:
3.51 g racemic trans-(2-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester were added to a suspension of 3.09 g lithium aluminium hydride in THF. The reaction mixture was heated at reflux over night. After that time subsequently 3.1 ml water, 3.1 ml sodium hydroxide solution (2M) and 3.1 ml water were added. The mixture was then stirred for 45 minutes and then filtered through celite. The celite was washed with EtOAc. The solvent was evaporated.