Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([F:14])([F:13])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C:10]([F:13])([F:14])[CH2:11][O:12][S:16]([CH3:15])(=[O:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC(F)(F)COCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC(F)(F)COCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
A solution of 3-benzyloxy-2,2-difluoropropan-1-ol (Compound 59H, 202 mg, 1 mmol) and methanesulfonyl chloride in DCM (3 mL) was cooled to 0° C. and treated with Et3N (0.28 mL, 2 mmol). The reaction mixture was allowed to warm at RT. After 12 h, the reaction mixture was diluted with DCM (5 mL) and washed with aq. K2CO3 (4×5 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give 220 mg (82%) of the title compound as yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.37-7.33 (m, 5H), 4.62 (s, 2H), 4.47 (t, J=12.4 Hz, 2H), 3.74 (t, J=12.4 Hz, 2H), 3.05 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH3:38])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH3:38][NH:37][S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35]
Reactant: CNS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CNS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-methyl-benzenesulfonamide [CAS 459434-40-3] according to general procedure II. Yellow solid. MS (ISP) 542.0 [(M−H)−]; mp 232° C.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:29])[CH2:12][S:13]([CH2:16][CH:17]([OH:28])[C:18]2[CH:23]=[CH:22][C:21]([NH:24]C(=O)C)=[CH:20][CH:19]=2)(=[O:15])=[O:14])=[CH:7][CH:6]=1)(=O)C.S(=O)(=O)(O)O>>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:29])[CH2:12][S:13]([CH2:16][CH:17]([OH:28])[C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)(=[O:15])=[O:14])=[CH:7][CH:6]=1.[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([O:29][C:11](=[O:29])[CH3:8])[CH2:12][S:13]([CH2:16][CH:17]([O:28][C:17](=[O:28])[CH3:16])[C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)(=[O:15])=[O:14])=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(C(O)CS(=O)(=O)CC(O)c2ccc(NC(C)=O)cc2)cc1
Agent: O=S(=O)(O)O
Product: CC(=O)OC(CS(=O)(=O)CC(OC(C)=O)c1ccc(N)cc1)c1ccc(N)cc1
Product: Nc1ccc(C(O)CS(=O)(=O)CC(O)c2ccc(N)cc2)cc1

Procedure:
247.5 Parts of 4-acetylaminophenyl-β-hydroxyethylsulfone (purity: 98.2%) and 205.8 parts of 50% sulfuric acid were fed into a two-shaft double-arm kneader (manufactured by Inoue Seisakusho) operated at 60 r.p.m., and the mixture was maintained at 100° to 105° C. under reduced pressure (400 mmHg) for 10 hours while distilling off the produced water and acetic acid. The reaction product was analyzed by liquid chromatography, obtaining 4-aminophenyl-β-sulfatoethylsulfone in a 96% yield, and 4-aminophenyl-β-hydroxyethylsulfone and 4-aminophenyl-β-acetoxyethylsulfone in small amounts.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:8]=[CH:7]2
Reactant: Ic1ccccc1
Reactant: Cc1cccc2cc[nH]c12
Product: Cc1cccc2ccn(-c3ccccc3)c12

Procedure:
Prepared by Procedure C and Scheme O using 7-methyl-1H-indole and iodobenzene: ESMS m/e: 208.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-:3])=[O:2].[N:12]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C.C(OCC)C>CN1C(=O)CCC1>[CH2:21]([O:20][C:18]([N:12]1[CH2:13][CH2:14][N:15]([CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:16][CH2:17]1)=[O:19])[CH3:22]
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCOC(=O)N1CCN(Cc2cccc([N+](=O)[O-])c2)CC1
Yield: 59 %

Procedure:
To a solution of 3-nitrobenzylbromide (2.2 g; 10.0 mmol) in NMP (5 ml) was added ethyl piperazine-1-carboxylate dropwise with stirring. At the end of the addition the temperature had reached 35° C. Triethylamine (1.39 ml) was added causing the temperature to rise to 40° C. The mixture was stirred for additionally 30 min. prior to dilution with diethyl ether (25 ml). The mixture was filtered and the filtrate was washed with water, dried over magnesium sulphate and concentrated under reduced pressure. The concentrate was suspended in diethyl ether and filtered. The filtrate was diluted with ethyl acetate and extracted with diluted hydrochloric acid. The aqueous phase was rendered alkaline by addition of saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase was dried over magnesium sulphate and evaporated to dryness to leave 6a (1.72 g; 59%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11]C)=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:4][CH:3]=1.B(Br)(Br)Br.O.[Cl:24]CCl>C(OCC)(=O)C>[ClH:24].[NH2:1][C:2]1[C:10]([OH:11])=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:4][CH:3]=1
Reactant: COc1c(N)ccc2c1C(CCNC(C)=O)CC2
Reactant: ClCCl
Agent: BrB(Br)Br
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Product: Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a solution of N-[2-(6-amino-7-methoxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide (2.56 g, 10.3 mmol) in dichloromethane (80 mL) was added a solution of boron tribromide in dichloromethane (1M, 22.7 mL, 22.7 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1.5 hr. To the reaction solution was added water, and the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (80 mL), a solution of boron tribromide in dichloromethane (1M, 22.7 mL, 22.7 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 1.5 hr. To the reaction solution was added water, and the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and converted to hydrochloride with 4N hydrochloric acid/ethyl acetate solution. The solvent was evaporated under reduced pressure to give the title compound (2.51 g, yield 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](=O)[CH2:5]Cl.[CH3:13][NH:14][C:15](=[S:18])[NH:16][NH2:17]>CO>[ClH:1].[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]1[CH2:5][S:18][C:15]([NH:14][CH3:13])=[N:16][N:17]=1
Reactant: CNC(=S)NN
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Solvent: CO
Product: CNC1=NN=C(c2ccc(Cl)cc2Cl)CS1
Product: Cl

Procedure:
11.17 g of 2,4-dichlorophenacyl chloride and 5.755 g of 4-methyl-thiosemicarbazide are reacted in 200 ml of methanol using the procedure of Example 2. The initial crystallization is made from methanol/ethyl acetate. The solid is then recrystallized from methanol/ethyl acetate and dried at 65° C. under high vacuum to produce 5-(2,4-dichlorophenyl)-N-methyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride. m.p. 195° C.
Reaction SMILES: [C:1]([N:4]1[C:8]2=[N:9][C:10]3[N:11]([CH3:27])[C:12](=[O:26])[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([N:23]=[N+]=[N-])[CH3:22])[C:14](=[O:16])[C:15]=3[N:7]2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(O)C.[H][H]>[Pd].CO>[C:1]([N:4]1[C:8]2=[N:9][C:10]3[N:11]([CH3:27])[C:12](=[O:26])[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH2:23])[CH3:22])[C:14](=[O:16])[C:15]=3[N:7]2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCn2c1nc1c2c(=O)n(CCCC[C@@H](C)N=[N+]=[N-])c(=O)n1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CC(=O)N1CCn2c1nc1c2c(=O)n(CCCC[C@@H](C)N)c(=O)n1C

Procedure:
A mixture of (R)-8-acetyl-3-(5-azidohexyl)-7,8-dihydro-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (200 mg, 0.534 mmol) and 10% palladium on carbon (50% water, 150 mg) in a solution of ethanol (50 ml) and methanol (10 ml) was treated with hydrogen gas (50 psi) on a Parr sharker at room temperature for 18 hours. After filtering through a pad of celite, the filtrate was concentrated under reduced pressure to provide (R)-8-acetyl-3-(5-aminohexyl)-7,8-dihydro-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione as a white powder.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:20][Si:21]([CH2:24][CH2:25][O:26][CH2:27]Cl)([CH3:23])[CH3:22]>>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:27][O:26][CH2:25][CH2:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Product: C[Si](C)(C)CCOCn1cnc(-c2ccccc2)c1-c1ccccc1
Yield: 63.8 %

Procedure:
Reaction of 4,5-diphenyl-1H-imidazole (300 mg, 1.36 mmol), NaH (60%, 55 mg, 1.36 mmol), and SEMCl (289 uL, 1.63 mmol) followed by column chromatography on silica gel (hexane/EtOAC 3:2) gave the title compound (304 mg, 64%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.88 (t, 2H, J=7.5 Hz), 3.46 (t, 2H, J=9.0 Hz), 5.12 (s, 2H), 7.27-7.38 (m, 3H), 7.40-1.52 (m, 7H), 7.75 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25](=[O:38])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[F:39][C:40]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=1O>>[F:39][C:40]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=1[O:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25](=[O:38])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:10]
Reactant: Oc1ccc(F)cc1F
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COc3ccc(F)cc3F)CS[C@H]12

Procedure:
The procedure described in Example 1(a) was repeated, but using 2.00 g of diphenylmethyl 3-hydroxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylate and 2,4-difluorophenol, to afford 500 mg of the title compound as a powder.
Reaction SMILES: [C:1]([O:6][C:7]12[CH2:16][C:11]3([OH:17])[CH2:12][CH:13]([CH2:15][C:9]([OH:18])([CH2:10]3)[CH2:8]1)[CH2:14]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH:19](=[O:21])[CH3:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:33]1CC[CH2:35][CH2:34]1>>[C:1]([O:6][C:7]12[CH2:16][C:11]3([O:17][CH:19]([OH:21])[CH3:20])[CH2:12][CH:13]([CH2:15][C:9]([O:18][CH:34]([OH:33])[CH3:35])([CH2:10]3)[CH2:8]1)[CH2:14]2)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C1CCOC1
Reactant: C=C(C)C(=O)OC12CC3CC(O)(CC(O)(C3)C1)C2
Reactant: CC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=C(C)C(=O)OC12CC3CC(OC(C)O)(C1)CC(OC(C)O)(C3)C2
Temperature: 30 °C
Reaction time: 6 h

Procedure:
To 30 ml of tetrahydrofuran were added 5 mmol of 1-methacryloyloxy-3,5-dihydroxyadamantane, 15 mmol of acetoaldehyde, and 1 mmol of p-toluenesulfonic acid, and the mixture was stirred at 30° C. for 6 hours. The reaction mixture was condensed under acidic conditions and crystallized by adding to diethyl ether dropwise to give the object compound 1-methacryloyloxy-3,5-di(1-hydroxyethoxy)adamantane (acetal compound) represented by the following formula:
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:12][C:13](=[O:38])[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2(O)[NH:34][C:33]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([O:35][CH3:36])[N:31]=4)[N:26]=[CH:25][C:24]=3[O:23][CH2:22]2)[CH2:17][CH2:16]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([BH3-])#N.[Na+]>ClCCl.CO>[CH2:5]([O:12][C:13](=[O:38])[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH:21]2[NH:34][C:33]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([O:35][CH3:36])[N:31]=4)[N:26]=[CH:25][C:24]=3[O:23][CH2:22]2)[CH2:17][CH2:16]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COc1ccc2ncc3c(c2n1)NC(O)([C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1)CO3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2ncc3c(c2n1)NC([C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1)CO3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic acid (10 μL, 0.17 mmol, 5.4 eq) is added at room temperature to a stirred solution of [trans-4-(3-hydroxy-6-methoxy-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-carbamic acid benzyl ester (15 mg, 0.03 mmol, 1.0 eq) in dichloromethane (3 mL) and methanol (3 mL), followed by sodium cyanoborohydride (10 mg, 0.16 mmol, 5.0 eq). After 30 minutes stirring at room temperature, the reaction mixture is extracted with ethyl acetate (3×10 mL) and a saturated ammonium chloride aqueous solution (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 10:1, v/v) to afford [trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-4,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-carbamic acid benzyl ester as a white solid (11 mg, 76% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[N:5]=[C:4]([CH3:17])[N:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C(O)C>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH3:16])=[C:8]([C:6]2[N:5]=[C:4]([CH3:17])[N:3]=[C:2]([NH:23][C:22]3[CH:24]=[CH:25][C:19]([Cl:18])=[CH:20][CH:21]=3)[CH:7]=2)[CH:13]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COc1ccc(Cl)cc1-c1cc(Cl)nc(C)n1
Solvent: CCO
Product: COc1ccc(Cl)cc1-c1cc(Nc2ccc(Cl)cc2)nc(C)n1
Yield: 61.7 %

Procedure:
Alternatively, a solution of 4-chloro-6-(5-chloro-2-methoxy-phenyl)-2-methyl-pyrimidine (50 mg, 0.18 mmol) and 4-chloroaniline (23 mg, 0.18 mmol) in ethanol (10 ml) was stirred at 80° C. under an argon atmosphere for 5 hours. After concentration under vacuum the crude product was crystallized (ethyl acetate) to give the title compound (40 mg, 60% yield). 1H NMR (DMSO-d6) δ 2.53 (s, 3H, CH3), 3.33 (s, 3H, CH3), 7.23 (d, 1H, J=8.9 Hz, Ar), 7.33 (s, 1H, Ar), 7.41 (d, 2H, J=8.9 Hz, Ar), 7.51 (dd, 1H, J=8.9 Hz, J=2.8 Hz, Ar), 7.79 (d, 2H, J=8.9 Hz, Ar), 8.0 (d, 1H, J=2.8 Hz, Ar), 9.75 (s, 1H, NH).
Reaction SMILES: Cl.[Cl:2][C:3]1[S:7][C:6]([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:5][CH:4]=1.O=[CH:17][CH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:28])[CH3:27])[CH2:21][CH2:20]1>>[Cl:2][C:3]1[S:7][C:6]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:28])[CH3:27])[CH2:21][CH2:20]3)[CH2:12][CH2:11]2)=[O:9])=[CH:5][CH:4]=1
Reactant: CC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: O=C(c1ccc(Cl)s1)C1CCNCC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(Cl)s3)CC2)CC1

Procedure:
From (5-chloro-thiophen-2-yl)-piperidin-4-yl-methanone hydrochloride (10 mg) and N-[trans-4-(2-oxo-ethyl)-cyclohexyl]-acetamide (7 mg, intermediate AG) by procedure A.1. Yield: 9 mg (59%). White solid. MS (m/z): 397.4 ([M+H]+).
Reaction SMILES: Cl[C:2](OCC)=[O:3].[NH2:7][N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([NH2:15])=[O:14].N1C=CC=CC=1>O1CCOCC1>[NH:7]1[C:2](=[O:3])[NH:15][C:13](=[O:14])[C:9]2=[CH:10][CH:11]=[CH:12][N:8]12
Reactant: NC(=O)c1cccn1N
Reactant: CCOC(=O)Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)c2cccn2[nH]1
Temperature: 155 °C
Yield: 62.8 %

Procedure:
Ethyl chloroformate (4.9 ml, 51 mmol) was added dropwise to a stirred mixture of 1-amino-1H-pyrrole-2-carboxamide (5.85 gm, 46.7 mmol, Journal of Heterocyclic Chemistry, 1994, 31, 781) and dry pyridine (4.2 mL, 51 mmol) in dry dioxane (48 mL) under N2 at RT. The mixture was heated at reflux for 1 hr and then the solvent was removed. The residue was heated at 155° C. for 17 hr and then allowed to cool to RT. The cooled residue was triturated with MeOH. The solid precipitate was collected by filtration and washed with cold MeOH to give 4.43 g 1A (63% yield). 1H NMR (DMSO-d6): 6.34 (br. s, 1H), 6.75 (br. s, 1H), 7.12 (br. s, 1H); MS: 152 (M+H)+; and RP HPLC ret. t.: 0.36 min (YMC Xterra S 7: 3.0×50 mm column, 2 min gradient, 5 mL/min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9]1.[Br:30][C:31]1[S:32][CH:33]=[C:34]([C:36](O)=[O:37])[N:35]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[Br:30][C:31]1[S:32][CH:33]=[C:34]([C:36]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][C@@H:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9]2)=[O:37])[N:35]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2N)CC[C@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1csc(Br)n1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2NC(=O)c2csc(Br)n2)CC[C@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 60 h

Procedure:
A solution containing 1 eq each of tert-butyl (3R,4R)-1-(3-aminopyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate, 2-bromothiazole-4-carboxylic acid, HOAT and EDC in DMF, at a concentration of 0.5 M, was stirred for 60 hours. The solution was diluted with EtOAc and was washed with H2O (4×), NaCl(sat.), was dried over MgSO4, was filtered and the volatiles were removed in vacuo yielding tert-butyl (3R,4R)-1-(3-(2-bromothiazole-4-carboxamido)pyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate, LCMS (m/z): 612.2/614.2 (MH+); LC Rt=4.26 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:26])[N:11]([CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH2:1]([O:8][C:9]1[C:10](=[O:26])[N:11]([CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:32]3[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(OCc2ccccc2)cccn1CS(=O)(=O)c1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)Cn3cccc(OCc4ccccc4)c3=O)cc2)cc1

Procedure:
The titled compound was prepared from 3-benzyloxy-1-(4-bromo-benzenesulfonylmethyl)-1H-pyridin-2-one (obtained from Example 65) and 4-methoxy-phenylboronic acid according to the procedure described in Example 52 Step A. MS: 462 (M+H).
Reaction SMILES: N1C=NN=N1.[C:6]([O:10][P:11](N(C(C)C)C(C)C)[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:9])([CH3:8])[CH3:7].[OH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C@@:39]([CH3:49])([S:45]([CH3:48])(=[O:47])=[O:46])[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1.S([O-])([O-])=[O:51].[Na+].[Na+]>O1CCCC1>[C:13]([O:12][P:11]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C@@:39]([CH3:49])([S:45]([CH3:48])(=[O:47])=[O:46])[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)([O:10][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:51])([CH3:14])([CH3:15])[CH3:16]
Reactant: CCOC(=O)[C@@](C)(CCc1ccc(-c2ccc(O)cc2)cc1)S(C)(=O)=O
Reactant: CC(C)N(C(C)C)P(OC(C)(C)C)OC(C)(C)C
Reactant: O=S([O-])[O-]
Agent: [Na+]
Agent: c1nnn[nH]1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@](C)(CCc1ccc(-c2ccc(OP(=O)(OC(C)(C)C)OC(C)(C)C)cc2)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
A solution of 1H-tetrazole (2.37 g, 33.9 mmol, 3.0 equiv), di-tert-butyl-N,N-diisopropylphosphoramidite (7.42 mL, 22.6 mmol, 2.0 equiv), and ethyl(2R)-4-(4′-hydroxybiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanoate (4.25 g, 11.3 mmol, 1.0 equiv) in tetrahydrofuran (113 mL) was allowed to stir overnight at room temperature. A solution of saturated sodium sulfite (330 mL) was added, and the mixture was extracted with dichloromethane (3×440 mL). The combined organic layers were washed with water (3×330 mL), brine (3×330 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (50% ethyl acetate in heptane) to provide a colorless oil (5.84 g, 91%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (t, J=7.13 Hz, 3H) 1.50-1.52 (m, 18H) 1.71 (s, 3H) 2.17-2.30 (m, 1H) 2.46-2.61 (m, 2H) 2.72-2.85 (m, 1H) 3.04 (s, 3H) 4.26 (qd, J=7.13, 1.27 Hz, 2H) 7.21-7.28 (m, 4H) 7.45-7.53 (m, 4H).
Reaction SMILES: [CH:1]([S:4][CH2:5][C@@H:6]1[CH2:11][C:10](=[O:12])[CH2:9][CH2:8][C@@H:7]1[NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:3])[CH3:2].[C:24]12(CS(O)(=O)=O)C(C)(C)C(CC1)[CH2:27][C:25]2=[O:26].[CH3:39][CH:40](O)[CH3:41]>C(OC(C)C)(OC(C)C)OC(C)C>[CH:40]([O:12][C:10]1([O:26][CH:25]([CH3:27])[CH3:24])[CH2:9][CH2:8][C@H:7]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:6]([CH2:5][S:4][CH:1]([CH3:3])[CH3:2])[CH2:11]1)([CH3:41])[CH3:39]
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: CC(C)O
Reactant: CC(C)SC[C@@H]1CC(=O)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: CC(C)OC(OC(C)C)OC(C)C
Product: CC(C)OC1(OC(C)C)CC[C@H](NC(=O)OCc2ccccc2)[C@H](CSC(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A sample of benzyl (1S,2R)-2-(isopropylthiomethyl)-4-oxocyclohexylcarbamate (8.66 g, 25.81 mMol) was dissolved in a mixture of iPrOH (50 mL) and triisopropyl orthoformate (50 mL) prior to the portionwise addition of camphorsulfonic acid (1.2 g, 5.16 mMol). After overnight stirring at rt, the reaction was quenched by addition of saturated sodium bicarbonate. Partitioned between EtOAc and water. The aq. layer was re-extracted with EtOAc. Combined organic layer was washed with brine and dried (MgSO4). Filtered, concentrated and flash chromatographed to yield benzyl (1S,2R)-4,4-diisopropoxy-2-(isopropylthiomethyl)cyclohexylcarbamate as a foamy solid (8.376 g, yield=74%)
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[S:29]1[CH2:33][C:32](=[O:34])[NH:31][C:30]1=[O:35].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[C:33]2[S:29][C:30](=[O:35])[NH:31][C:32]2=[O:34])=[CH:23][CH:22]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(OCCN(Cc2ccccc2)c2nc3ccccc3s2)cc1
Reactant: O=C1CSC(=O)N1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(=Cc2ccc(OCCN(Cc3ccccc3)c3nc4ccccc4s3)cc2)S1

Procedure:
4-(2-(N-(2-Benzothiazolyl)-N-benzylamino)ethoxy) benzaldehyde (3 g) and 2,4-thiazolidinedione (1 g) were dissolved in toluene (200 ml) containing piperidine (0.2 ml) and benzoic acid (0.2 g) and heated to reflux for 4h. in a Dean and Stark apparatus. On cooling, the solution was concentrated under vacuum to 50% of its volume and the title compound, which crystallised, was collected by filtration and dried in vacuo (m.p. 185°-188° C.). It was used in Example 27 without further purification.