Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:4])(=[NH:3])[CH3:2].[Cl:5][C:6]1[CH:17]=[CH:16][C:9]([CH:10]=[CH:11][S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1>>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:10]=[CH:11][S:12]([NH:3][C:1](=[NH:4])[CH3:2])(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)cc1
Reactant: CC(=N)N
Product: CC(=N)NS(=O)(=O)C=Cc1ccc(Cl)cc1

Procedure:
Reaction of acetamidine with 4-chlorostyrylsulfonyl chloride according to the above procedure affords N-[(4-CHLOROSTYRYL)SULFONYL]ACETAMIDINE, m.p. 161°-163° C., crystallized from ethyl acetate.
Reaction SMILES: NC1C=CC(S(CC)(=O)=O)=C(C=1)C#N.[C:15]([S:19]([C:22]1[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][C:23]=1[C:24]#[N:25])(=[O:21])=[O:20])([CH3:18])([CH3:17])[CH3:16]>>[NH2:30][C:27]1[CH:28]=[CH:29][C:22]([S:19]([C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:21])=[O:20])=[C:23]([CH:26]=1)[C:24]#[N:25]
Reactant: CC(C)(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1C#N
Agent: CCS(=O)(=O)c1ccc(N)cc1C#N
Product: CC(C)(C)S(=O)(=O)c1ccc(N)cc1C#N
Yield: 96.1 %

Procedure:
Using a procedure analogous to that used to prepare 6B, 10A (609 mg, 2.27 mmol) was hydrogenated to give 10B (520 mg, 96%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 1.35 (s, 9 H), 6.91 (dd, J=8.79, 2.20 Hz, 1 H), 7.07 (d, J=2.20 Hz, 1 H), 7.66 (d, J=8.79 Hz, 1 H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([S:18][C:19]#N)=[CH: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.CI.[OH-].[K+].Cl>CO.O>[C:12]1([C:11]2[CH:10]=[C:9]([S:18][CH3:19])[NH:8][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#CSc1cc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: CO
Solvent: O
Product: CSc1cc(-c2ccccc2)c(-c2ccccc2)[nH]1
Temperature: 25 °C
Yield: 90.4 %

Procedure:
To a mixture of 1.4 g (0.005 mole) 2,3-diphenyl-5-thiocyanatopyrrole, 0.85 g (0.006 mole) methyl iodide in 10 ml methanol was added dropwise at 0° a solution of 0.8 g (~0.012 mole, 85%) potassium hydroxide in 5 ml water+5 ml methanol. The mixture was allowed to warm to room temperature, then was poured into 100 ml ice water and neutralized with hydrochloric acid. The aqueous mixture was extracted with methylene chloride, and the extracts dried and concentrated. The residue was chromatographed on 50 g Silic AR CC-7, eluting with toluene to give 1.2 g (90%) yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([NH:20][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:9]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)N
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CC(C)(C)NCc1cccc(-c2ccnc(Cl)n2)c1
Yield: 97 %

Procedure:
3-(2-Chloro-pyrimidin-4-yl)-benzaldehyde (intermediate 1) and tert butylamine were coupled by procedure B. The yield was 97%. LC-MS showed the product had the expected M+H+ of 276. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) 8.6 (d, 1H) 8.1 (s, 1H) 7.9 (d, 1H) 7.6 (d, 1H) 7.5 (m, 2H) 1.2 (s, 9H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][O:19][CH2:20][CH2:21][C:22]([NH2:25])([CH3:24])[CH3:23]>>[CH3:18][O:19][CH2:20][CH2:21][C:22]([NH:25][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:24])[CH3:23]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: COCCC(C)(C)N
Product: COCCC(C)(C)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 69 using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 50 mg, 0.214 mmol) and 3-methoxy-1,1-dimethyl-propylamine (CAN 889765-21-3, 50 mg, 0.32 mmol) as starting materials and isolated (40 mg, 56.14%) as white solid; LC-MS (UV peak area, ESI) 99.87%, 333.8 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:9][CH3:10])[CH:4]1[CH2:8][CH2:7][NH:6][CH2:5]1)[CH3:2].Cl[C:12]1[N:13]=[CH:14][C:15]([C:18]([NH:20][C:21]2[NH:22][N:23]=[C:24]([CH2:26][CH2:27][C:28]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=3)[CH:25]=2)=[O:19])=[N:16][CH:17]=1>CS(C)=O.CO>[CH2:1]([N:3]([CH2:9][CH3:10])[CH:4]1[CH2:8][CH2:7][N:6]([C:12]2[N:13]=[CH:14][C:15]([C:18]([NH:20][C:21]3[NH:22][N:23]=[C:24]([CH2:26][CH2:27][C:28]4[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=4)[CH:25]=3)=[O:19])=[N:16][CH:17]=2)[CH2:5]1)[CH3:2]
Reactant: CCN(CC)C1CCNC1
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Solvent: CO
Solvent: CS(C)=O
Product: CCN(CC)C1CCN(c2cnc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cn2)C1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 81.6 %

Procedure:
N,N-diethylpyrrolidin-3-amine (142 mg, 1.00 mmol) was added to 5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (136 mg, 0.35 mmol) in anhydrous dimethylsulfoxide (1.75 ml) at 25° C. The resulting solution was stirred at room temperature for 50 mins. The reaction mixture was diluted with methanol (5.00 ml) and the crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford impure product as a brown dry film. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (141 mg, 82%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([B:17]3[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]3)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26]N1C(=O)CCC1=O>C1COCC1>[CH2:1]([N:8]1[C:16]([Cl:26])=[C:15]2[C:10]([CH:11]=[C:12]([B:17]3[O:18][C:19]([CH3:25])([CH3:24])[C:20]([CH3:23])([CH3:22])[O:21]3)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc3c(Cl)n(Cc4ccccc4)nc3c2)OC1(C)C
Temperature: 40 °C
Yield: 81.7 %

Procedure:
To a solution of 2-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-Indazole (200 mg, 0.598 mmol) in THF (2 mL), was added N-chlorosuccinimide (95.9 mg, 0.718 mmol). The mixture was heated at 40° C. for 4 hr, cooled to rt then concentrated to dryness. The crude material was purified by ISCO® chromatography using a gradient of 1-7% EtOAc in hexane to afford the desired product (180.1 mg, 82%). 1H NMR (400 MHz, DMF-d6) δ 7.98 (s, 1H), 7.59 (d, 1H), 7.38-7.28 (m, 4H), 7.22-7.19 (m, 2H), 5.74 (s, 2H), 1.34 (s, 12H); LC-MS m/z [M+H]+ 369.2, RT 3.94 min.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([CH3:13])=[N:6]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:10][C:8]1[C:7]([CH3:13])=[N:6][N:5]([CH2:4][CH2:3][OH:2])[CH:9]=1
Reactant: COC(=O)Cn1cc([N+](=O)[O-])c(C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nn(CCO)cc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To solution of 3-methyl-4-nitropyrazol-1-yl-acetic acid methylester (ChemCollect, Remscheid, Germany, 297 mg, 1.491 mmol) in THF (12 ml) cooled with an ice-bath was added a 1 M solution of lithium aluminium hydride in THF (1.5 ml, 1.5 mmol). The reaction mixture was stirred 1 h at rt then was added more of the reducing reagent (0.75 ml, 0.75 mmol), stirring 2 h at rt, (1.5 ml, 1.5 mmol), stirring 45 min, (2 ml, 2 mmol) and the reaction mixture was stirred 17 h at rt before being quenched with water and taken in EtOAc. The suspension was filtered and the solid washed with EtOAc. The filtrate was dried over Na2SO4, filtered and evaporated to give crude brown solid. (HPLC: tR 0.85 min (Method A); M+H=142 MS-ES)
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][C:38]#[CH:39])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH:20]([S:24][C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH2:21][CH2:22][OH:23])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][C:38]#[CH:39])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH:20]([S:24][C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH2:21][CH2:22][OH:23])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(CCO)Sc3nnn[nH]3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(CCO)Sc3nnn[nH]3)CS[C@H]12)c1csc(N)n1
Yield: 65.7 %

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (syn isomer, 1.9 g) was treated with conc. hydrochloric acid (0.67 g) in a similar manner to that of Example 1-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (syn isomer, 1.19 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([O:20]C)[C:8](=[O:22])[NH:7][C:6]=2[CH:23]=1.O.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([OH:20])[C:8](=[O:22])[NH:7][C:6]=2[CH:23]=1
Reactant: CCOC(=O)C=Cc1c(OC)c(=O)[nH]c2cc(Cl)ccc2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1c(O)c(=O)[nH]c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 68 h
Yield: 83.1 %

Procedure:
A solution of 8-Chloro-4-[2-(ethoxycarbonyl)ethenyl]-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.1009 g) in tetrahydrofuran (2.3 mL) was treated with a solution of lithium hydroxide monohydrate (0.0126 g) in tetrahydrofuran (2.3 mL) and water (0.5 mL) at room temperature. The solution was stirred at room temperature under argon for 68 hours. It was then added to 0.05N hydrochloric acid (10 mL). The resulting solid was filtered off, washed with water, and air-dried to give a light tan solid (0.0803 g). The solid was dissolved in hot ethanol (5 mL). The solution was filtered and treated with water (2 mL). The crystals were filtered off at room tempeature, washed with aqueous ethanol (1:1, v:v) and dried under vaccum to give a light tan solid (0.054 g); mp 177.5°-178.4° C.; 1H NMR (d6 -DMSO) 7.74 (d,1, J=16) 6.74 (d,1, J=16) for trans olefin protons; MS: m/z=276 (base peak), 322 (M+1). Analysis for C15H12ClNO5 : Calculated: C, 56.00; E, 3.78; N, 3.99; Found: C, 56.55; H, 3.78; N, 3.99.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([S:18][CH3:19])[N:13]=3)=[C:4]2[CH:3]=1.C(OCC)(=O)C.[CH:34]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:39][CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[N:5]2[N:9]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([S:18][CH3:19])[N:13]=3)=[C:4]2[CH:3]=1
Reactant: NC1CCCC1
Reactant: COc1ccc(-c2nn3c(Cl)cc(Cl)cc3c2-c2ccnc(SC)n2)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nn3c(NC4CCCC4)cc(Cl)cc3c2-c2ccnc(SC)n2)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of 5,7-dichloro-2-(4-methoxyphenyl)-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridine (148 mg, 0.35 mmol) in cyclopentylamine (5 mL) was heated at 80° C. for 3 hours. After cooling to room temperature, ethyl acetate was added to the reaction mixture. The organic phase was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration followed by chromatography (4:1 hexanes/ethyl acetate) gave N-{5-chloro-2-(4-methoxyphenyl)-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-yl}-N-cyclopentylamine (141 mg, 85%) as a yellow foam. 1H NMR (CDCl3) δ 8.15 (d, 1H), 7.84 (d, 1H), 7.51 (d, 2H), 6.99 (d, 2H), 6.65 (d, 1H), 6.09 (d, 1H), 6.02 (d, 1H), 3.96 (m, 1H), 3.88 (s, 3H), 2.63 (s, 3H), 2.15 (m, 2H), 1.81-1.69 (m, 6H). MS m/z 466 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].CS[C:10]1[N:11]=[N:12][C:13]([C:27]#[N:28])=[C:14]([N:16]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[CH2:18][CH2:17]2)[N:15]=1>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:10]1[N:11]=[N:12][C:13]([C:27]#[N:28])=[C:14]([N:16]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[CH2:18][CH2:17]2)[N:15]=1
Reactant: CSc1nnc(C#N)c(N2CCc3ccccc3CC2)n1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1nnc(C#N)c(N2CCc3ccccc3CC2)n1
Reaction time: 0.25 h
Yield: 9 %

Procedure:
Under an argon atmosphere at 0° C., a solution of 25.6 mg (0.34 mmol) of 2-methoxy-ethanol in 2 ml of tetrahydrofurane was treated with 15 mg (0.34 mmol) of sodium hydride (55% dispersion in refined oil) and stirred during 15 min. To this mixture, a solution of 100 mg (0.34 mmol) of 3-methylsulfanyl-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile in 3 ml of tetrahydrofurane was added and stirring continued for 18 h at 40° C. The yellow solution was evaporated under reduced pressure and the residue (141 mg) was chromatographed on silica gel with a 99:1 v/v mixture of dichloromethane and methanol as eluent. Thus were obtained 10 mg (9% of theory) of 3-(2-methoxy-ethoxy)-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile as a light yellow solid; MS: 326 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]([F:19])=[C:11]([CH:14]=[C:15]([CH2:17][CH3:18])[CH:16]=1)C=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[C:4]([Si:1]([O:8][C:9]1[CH:16]=[C:15]([CH2:17][CH3:18])[CH:14]=[CH:11][C:10]=1[F:19])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Yield: 254.7 %

Procedure:
A solution of Intermediate 368.2 (394 mg, 0.50 mmol) and 1 M TBAF (in THF) in THF (10 mL) was stirred for 2 h. The mixture was dilute with EtOAc and washed with H2O (3×50 mL) and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 60% EtOAc/hexanes gradient) to afford 324 mg of Intermediate 368.1. LCMS (2 min gradient) RT=2.06 min, 669.5 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[S:9][C:10]3[CH:16]=[C:15]([C:17]4[CH2:18][CH2:19][N:20]([S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])[CH2:21][CH:22]=4)[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:3][CH2:2]1.[C:29](Cl)(=[O:35])[O:30][CH2:31][CH2:32][O:33][CH3:34]>>[CH2:26]([S:23]([N:20]1[CH2:19][CH:18]=[C:17]([C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([O:7][CH:4]4[CH2:3][CH2:2][N:1]([C:29]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[O:35])[CH2:6][CH2:5]4)[S:9][C:10]=3[CH:16]=2)[CH2:22][CH2:21]1)(=[O:25])=[O:24])[CH2:27][CH3:28]
Reactant: CCCS(=O)(=O)N1CC=C(c2ccc3nc(OC4CCNCC4)sc3c2)CC1
Reactant: COCCOC(=O)Cl
Product: CCCS(=O)(=O)N1CC=C(c2ccc3nc(OC4CCN(C(=O)OCCOC)CC4)sc3c2)CC1

Procedure:
Example 25 was prepared from Compound 15A and 2-methoxyethyl carbonochloridate in a similar manner to the procedure described in Example 15. 1H NMR (599 MHz, DMSO-d6) δ ppm 8.22 (s, 1H), 7.88 (s, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 6.19 (br. s., 1H), 5.28-5.39 (m, 2H), 4.05-4.19 (m, 2H), 3.92 (br. s., 2H), 3.65-3.77 (m, 2H), 3.49-3.58 (m, 2H), 3.45 (t, J=5.6 Hz, 2H), 2.96-3.11 (m, 2H), 2.60 (br. s., 2H), 2.08 (d, J=8.8 Hz, 3H), 1.63-1.84 (m, 6H), 1.00 (t, J=7.3 Hz, 3H). LC/MS (m/z)=524 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C@H:15]([OH:26])[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CCO.[Pd]>[OH:26][C@@H:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=1)[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Reaction time: 4 h

Procedure:
A solution of carbamate (6) (41.0 g, 115 mmol) in EtOH (500 mL) was degassed by applying vacuum once. Pd/C (10% wt, 20.0 g) was added and the mixture was degassed by alternating vacuum/H2 three times. The reaction mixture was stirred under H2 pressure of 50 psi for 4 h. The reaction mixture was filtered through Celite, the filtrate was concentrated in vacuum and the residue was purified by crystallization (10% EtOAc in hexane) to give (R)-tert-butyl 3-hydroxy-3-(3-hydroxyphenyl)propylcarbamate (Intermediate I) as a white solid. Yield (24.0 g, 78%); 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 7.07 (t, J=7.6 Hz, 1H), 6.75-6.69 (m, 3H), 6.59 (d, J=8.0 Hz, 1H), 5.11 (d, J=4.0 Hz, 1H), 4.46-4.42 (m, 1H), 2.96 (t, J=6.8 Hz, 2H), 1.66-1.61 (m, 2H), 1.36 (s, 9H); RP-HPLC: tR=1.51 min, 98.13% (AUC); ESI MS m/z 266.28[M−H]+; Chiral HPLC 97.5% (R)-isomer.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:14]([NH2:20])[CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C[O:22][C:23](=O)[C:24]1[C:29]([NH:30][C:31]([CH:33]2[CH2:35][CH2:34]2)=[O:32])=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:36]Br.C(N(CC)CC)C>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:14]([N:20]3[C:23](=[O:22])[C:24]4[C:25](=[CH:26][CH:27]=[CH:28][C:29]=4[NH:30][C:31]([CH:33]4[CH2:35][CH2:34]4)=[O:32])[CH2:36]3)[CH2:15][S:16]([CH3:19])(=[O:17])=[O:18])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: COC(=O)c1c(CBr)cccc1NC(=O)C1CC1
Reactant: COc1ccc(C(N)CS(C)(=O)=O)cc1OCC1CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(CS(C)(=O)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)cc1OCC1CC1
Temperature: 90 °C
Yield: 3 %

Procedure:
To a solution of 1-(3-cyclopropylmethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (1.0 g, 3.3 mmol) in DMF (18 mL), were added 2-bromomethyl-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (1.0 g, 3.3 mmol) and triethylamine (1.3 mL, 9.8 mmol). The mixture was heated at 90° C. overnight. The solvent was removed in vacuo. The resulting oil was extracted with ethyl acetate (50 mL) and water (30 mL). The organic layer was washed with water (30 mL×4) and brine (30 mL), and dried over magnesium sulfate. The solvent was removed in vacuo and the resulting oil was purified by silica gel column to give cyclopropanecarboxylic acid {2-[1-(3-cyclopropylmethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (50 mg, 5%): mp 224-226° C.; 1H NMR (CDCl3) δ 0.35-0.39 (m, 2H, c-CH2), 0.60-0.63 (m, 2H, c-CH2), (0.88-0.93 (m, 2H, c-CH2), 1.08-1.12 (m, 2H, c-CH2), 1.25-132 (m, 1H c-CH), 1.63-1.69 (m, 1H, c-CH), 2.95 (s, 3H, CH3), 3.69 (dd, J=5, 15 Hz, 1H, CHH), 3.82 (d, J=4 Hz, 2H, c-CH), 3.86 (s, 3H, CH3), 4.19 (dd, J=10, 17 Hz, 1H, CHH), 4.20 (d, J=17 Hz, 1H, CHHN), 4.43 (d, J=17 Hz, 1H, CHHN), 5.72 (dd, J=5, 10 Hz, 1H, NCH), 6.84-7.02 (m, 4H, Ar), 7.45 (t, J=8 Hz, 1H, Ar), 8.43 (d, J=8 Hz, 1H, Ar), 10.46 (s, 1H, NHCO); 13C NMR (CDCl3) δ 3.3, 3.4, 8.3, 10.2, 16.2, 41.5, 47.9, 51.7, 55.9, 56.0, 74.3, 77.2, 111.8, 113.0, 116.7, 117.1, 117.9, 119.6, 129.4, 133.6, 138.2, 141.3, 149.1, 150.0, 170.1, 172.6. Analy. Calculated for C26H3oN2O6S: C, 62.63; H, 6.06; N, 5.62. Found: C, 62.41; H, 5.95; N, 5.43.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:59])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[CH:46]([OH:58])[CH2:45]2)[CH:7]([CH3:60])[CH2:6][CH2:5][C:4]1=[O:61])[CH3:2].[CH2:62](OC(=N)C(Cl)(Cl)Cl)[CH:63]=[CH2:64].FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:59])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:52])[CH3:53])[CH:46]([O:58][CH2:64][CH:63]=[CH2:62])[CH2:45]2)[CH:7]([CH3:60])[CH2:6][CH2:5][C:4]1=[O:61])[CH3:2]
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"(tert-butyldimethylsiloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (186 mg in 6 ml 33% methylene chloride in cyclohexane) allyltrichloroacetimidate (62 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (5 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 24 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×5 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate: hexane (1:4)+1% methanol) gave the title compound (80 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.C(OC(=O)[NH:25][C:26]([CH3:34])([CH3:33])[CH2:27][C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)(C)(C)C.Cl>O1CCOCC1>[NH2:25][C:26]([CH3:34])([CH3:33])[CH2:27][C:28]1[S:29][C:30]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)=[CH:31][CH:32]=1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: CC(C)(Cc1cccs1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(N)Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1

Procedure:
The title compound was prepared analogous to Method C, starting from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and (1,1-Dimethyl-2-thiophen-2-yl-ethyl)-carbamic acid tert-butyl ester (prepared by BOC protection of 1,1-Dimethyl-2-thiophen-2-yl-ethylamine), followed by BOC cleavage with HCl in dioxane.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[CH2:8]([N:16]=[C:17]=[S:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:16]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:17]1=[S:18])[CH3:2]
Reactant: CCNCC(=O)O
Reactant: S=C=NCCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(CCc2ccccc2)C1=S

Procedure:
A mixture of the crude N-ethyl glycine (18.4 g), phenethyl-isothiocyanate (16.3 g), triethyl amine (20.2 g) and chloroform (300 mL) was heated at reflux for 18 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (400 mL) and water (300 mL). The organic phase was washed with 1N HCl (2×300 mL), then evaporated to dryness. Purification was achieved by flash chromatography on silica gel (20% ethyl acetate in hexane) The title compound (15.0 g) was obtained as an off-white solid, m.p. 66°-68° C. Anal. Calcd. for. C13H16N2 O S: C, 62.87; H, 6.49; N, 11.28. Found: C, 63.03; H, 6.49; N, 11.32. Mass spectrum (EI, M.+) m/z 248.