Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].O1CCCC1.[Cl:9][C:10]1[N:11]=[C:12]([C:17]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][C:21]2=O)=[O:18])[NH:13][C:14]=1[CH2:15][CH3:16].C([BH3-])#N.[Na+].C(O)(=O)C>>[Cl:9][C:10]1[N:11]=[C:12]([C:17]([NH:19][C@@H:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][C@H:21]2[NH:3][CH2:1][CH3:2])=[O:18])[NH:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCN
Reactant: CCc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2=O)nc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Temperature: 70 °C
Reaction time: 15 h
Yield: 46 %

Procedure:
A 2 N ethylamine/tetrahydrofuran solution (5 mL) was added to tert-butyl 4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-oxopiperidine-1-carboxylate obtained in Example (201c) (102 mg, 0.275 mmol), and the mixture was heated under reflux at 70° C. for four hours. The reaction solution was concentrated under reduced pressure, and then tetrahydrofuran (2 mL) and methanol (2 mL) were added. A 2 N ethylamine-tetrahydrofuran solution (138 μL), sodium cyanoborohydride (86.4 mg, 1.38 mmol) and acetic acid (110 μL, 1.93 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and aqueous saturated sodium bicarbonate solution was added to the residue, followed by extraction with chloroform. The resulting organic layer was dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform:methanol=10:1 v/v) to obtain 46 mg of the cis isomer of the title compound (42%) as a pale yellow oily substance and 51 mg of the trans isomer of the title compound (46%) as a pale yellow oily substance.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=1.[CH2:14]([O:16]CC)C.CN(C)C=O>C(OCC)(=O)C>[Br:6][C:7]1[N:8]=[C:9]([CH2:14][OH:16])[C:10]([F:13])=[CH:11][CH:12]=1
Reactant: CCOCC
Reactant: Fc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCc1nc(Br)ccc1F
Temperature: 0 °C
Yield: 42 %

Procedure:
Slowly add n-Butyllithium (2.5 M in hexanes, 9.40 mL, 23.3 mmol) to a −78° C. solution of 2-bromo-5-fluoro-pyridine (3.42 g, 19.4 mmol) and diethyl ether (200 mL). Stir the reaction at −78° C. for 1 h, then add dimethylformamide (2.00 mL, 25.5 mmol) and continue stirring for an additional hour. Warm the reaction to room temperature and remove the solvent under vacuum. Dissolve the crude material in methanol (50 mL) and cool to 0° C. Add sodium borohydride.(1.47 g, 38.9 mmol) and allow the reaction is to slowly warm to room temperature over 12 h. Quench the reaction with saturated aqueous sodium bicarbonate (20 mL) then add ethyl acetate (100 mL). Separate the layers and dry the resultant organic layer with magnesium sulfate, filter, and concentrate under vacuum to give a yellow solid. Purify the crude solid by column chromatography (silica gel; 10% to 50% ethyl acetate in hexanes) to give 1.66 g (42%) of the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 7.50-7.40m, 1H), 7.35-7.25 (m, 1H), 4.80 (s, 2H), 3.30 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]4[N:22]([CH:27]([CH3:29])[CH3:28])[C:23](=[O:26])[NH:24][CH2:25][C:19]4=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.CC(C)([O-])C.[K+]>O1CCCC1>[CH3:1][N:2]([CH3:30])[CH:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]4[N:22]([CH:27]([CH3:28])[CH3:29])[C:23](=[O:26])[N:24]=[CH:25][C:19]4=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1
Reactant: CC(C)N1C(=O)NCc2cnc(Nc3ccc(N4CCC(N(C)C)CC4)cc3)nc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)n1c(=O)ncc2cnc(Nc3ccc(N4CCC(N(C)C)CC4)cc3)nc21
Reaction time: 48 h
Yield: 19 %

Procedure:
Prepared from 200 mg (0.31 mmol) of 7-{4-[4-(dimethylamino)piperidin-1-yl]phenylamino}-1-isopropyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one, trifluoroacetic acid and 211 mg (1.88 mmol) of potassium tert-butoxide in 7 mL of tetrahydrofuran. The reaction mixture is stirred for 48 hours, and the workup is done as described in the general procedure, then the reaction is repeated for 72 hours. After the workup, the semi-solid is triturated in diethyl ether, and the powder is collected and dried to give 24 mg (18%) of the title compound:
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:24])[NH:12][CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][C:17](=[O:23])[NH:18]3)=[CH:8][C:9]=1[CH3:10])=[O:4].O[Li].O>C1COCC1.O>[CH3:10][C:9]1[CH:8]=[C:7]([C:11](=[O:24])[NH:12][CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][C:17](=[O:23])[NH:18]3)[S:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sc(C(=O)NCc2cccc3c2CC(=O)N3)cc1C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)NCc2cccc3c2CC(=O)N3)sc1C(=O)O
Yield: 92.8 %

Procedure:
A solution of 3-methyl-5-[(2-oxo-2,3-dihydro-1H-indol-4-ylmethyl)-carbamoyl]-thiophene-2-carboxylic acid methyl ester (158 mg, 0.46 mmol) in THF/water (6 ml/3 ml) was treated with LiOH.H2O (206 mg, 4.6 mmol) at rt for 1 h. The reaction mixture was quenched with 1N HCl and extracted with EtOAc. The layers were separated. The organic layer was successively washed with water and brine, then dried over Na2SO4 and concentrated under reduced pressure to afford the desired product (141 mg, 95% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:12][C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1.[H-].[Na+].[CH3:15]I>CN(C)C=O>[CH3:15][N:12]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=[C:3]1[CH2:2][OH:1]
Reactant: Cc1ccnc2[nH]c(CO)nc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccnc2c1nc(CO)n2C

Procedure:
A procedure similar to that described in Preparation 15 was repeated, except that 5.00 g of 2-hydroxymethyl-7-methyl-3H-imidazo[4,5-b]pyridine, 1.34 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 2.0 ml of methyl iodide and 120 ml of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 10:1 by volume as the eluent, to give 4.4 g of the title compound, melting at >300° C.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([C:14]([C:20]#[N:21])=[C:15](C#N)[C:16]#[N:17])#[N:13]>CN(C)C=O>[N:7]1([C:1]2[CH:6]=[CH:5][C:4]([C:15]([C:16]#[N:17])=[C:14]([C:20]#[N:21])[C:12]#[N:13])=[CH:3][CH:2]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: N#CC(C#N)=C(C#N)C#N
Reactant: c1ccc(N2CCCC2)cc1
Solvent: CN(C)C=O
Product: N#CC(C#N)=C(C#N)c1ccc(N2CCCC2)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
4-(pyrrolidino) tricyanovinylbenzene was prepared by mixing 1-phenylpyrrolidine (1.0 g, 6.8 mmol) with tetracyanoethylene (0.9 g, 7 mmol) in 10 mL dimethylformamide at 0° C. The reaction mixture was stirred at room temperature for three hours and at 40° C. for another ten hours. The reaction mixture was quenched with 25 mL water and the dark red colored aqueous solution was extracted with 150 mL methylene chloride and washed several times with water (150 mL). The organic layer was then separated, dried over Na2SO4 and evaporated. The crude products were purified through a silica gel column. The column was eluted with a 1:1 ratio solution of methylene chloride and hexane to yield 1.7 g of the pure product 4 (90% yield).
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:16](N(CC)CC)[CH3:17].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33]([CH2:39][OH:40])([C:36]([OH:38])=O)[CH2:32][CH2:31]1)=[O:29])([CH3:26])(C)C>C(OCC)C>[CH2:23]([O:27][C:28]([N:30]1[CH2:31][CH2:32][C:33]2([C:36](=[O:38])[O:40][CH2:39]2)[CH2:34][CH2:35]1)=[O:29])[CH2:26][CH2:16][CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(C(=O)O)CC1
Reactant: CCN(CC)CC
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Product: CCCCOC(=O)N1CCC2(CC1)COC2=O
Temperature: 0 °C
Reaction time: 23 h
Yield: 81.5 %

Procedure:
Trifluoromethanesulfonic anhydride (2.60 mL, 15.39 mmol), followed by triethylamine (4.30 mL, 30.78 mmol) was added to a slurry of N-(tert-butoxycarbonyl)-4-hydroxymethylpiperidine-4-carboxylic acid (3.80 g, 14.65 mmol) in anhydrous diethyl ether (27 mL) cooled to 0° C. The biphasic solution was stirred for 23 hours, warmed to room temperature, stirred an addition 1 hour, and the upper diethyl ether layer separated by decantation. The lower was extracted with additional portions of diethyl ether (2×100 mL), and the combined organic extracts washed with aqueous sodium bicarbonate solution (2×50 mL), dried over magnesium sulfate, and concentrated in vacuo to afford 7-(butoxycarbonyl)-2-oxa-7-azaspiro[3.5]nonan-1-one as a pale yellow oil (2.88 g, 82%). 1HNMR (CDCl3) δ 1.48 (s, 9H), 1.79-1.89 (m, 2H), 2.02-2.10 (m, 2H), 3.48-3.66 (m, 4H), 4.13 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O-])([O-])=O.[Cs+].[Cs+].CI>C(#N)C>[C:24]([O:23][C:21]([NH:20][C:14]1([C:17]([O:19][CH3:28])=[O:18])[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.4 %

Procedure:
To an ice-cold solution of 1-((benzyloxy)carbonyl)-4-((tert-butoxycarbonyl)amino)piperidine-4-carboxylic acid (0.50 g, 1.32 mmol) in ACN (15 mL) was added Cs2CO3 (0.52 g, 1.59 mmol) and the resulting reaction mixture stirred at the same temperature for 10 min followed by addition of MeI (0.4 mL, 4.2 mmol). The reaction mixture was stirred for 1 h at rt. After completion of reaction (by TLC), the mixture was passed through celite and solvent was evaporated under reduced pressure to obtain a white solid compound (0.52 g, 96% yield). MS: 393.31 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]([CH2:21][NH2:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:23][S:24]([NH:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)(=[O:26])=[O:25]>>[NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:10]([CH2:21][NH:22][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([NH:27][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:29][CH:30]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: NCC1CN(c2cccc(N)c2)CCN1Cc1ccccc1
Product: CS(=O)(=O)Nc1ccc(C(=O)NCC2CN(c3cccc(N)c3)CCN2Cc2ccccc2)cc1

Procedure:
In a manner similar to Preparation 3, react 4-(3-aminophenyl)-1-(phenylmethyl)-2-piperazinemethanamine (4.8 g, 16 mmol) with 4-[(methylsulfonyl)amino]benzoyl chloride (3.8 g, 16 mmol) to obtain the title compound.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]2[CH2:11][C@H:9]2[C@H:8]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:6]12[CH3:7])[C@:20]1([CH3:21])[C@@:15]2([O:34][C@@H:14]2[C@H:13]3Cl)[CH2:16][C@@H:17]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:18][CH2:19]1)(=[O:3])[CH3:2].CC(O)C>C(O)(=O)C.[Zn]>[C:1]([O:4][C@H:5]1[C@H:10]2[CH2:11][C@H:9]2[C@H:8]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:6]12[CH3:7])[C@:20]1([CH3:21])[C@@:15]([OH:34])([CH2:16][C@@H:17]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:18][CH2:19]1)[CH:14]=[CH:13]3)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H]2C[C@H]2[C@H]2[C@@H]3[C@H](Cl)[C@H]4O[C@]45C[C@@H](OC(=O)c4ccccc4)CC[C@]5(C)[C@H]3CC[C@@]21C
Agent: [Zn]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1[C@H]2C[C@H]2[C@H]2[C@@H]3C=C[C@]4(O)C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@@]21C
Yield: 72.5 %

Procedure:
200 mg of 17β-acetoxy-3β-benzoyloxy-7α-chloro-5,6β-epoxy-15β,16β-methylene-5β-androstane is stirred in 4 ml of acetic acid and 4 ml of propan-2-ol with 800 mg of zinc dust for 1 hour at 80° C. The mixture is filtered off from the zinc, washed with diethyl ether, and worked up analogously to Example 1. After chromatography and recrystallization from diisopropyl ether-acetone, 135 mg of 17β-acetoxy-3β-benzoyloxy-15β,16β-methylene-5β-androst-6-en-5-ol is obtained, mp 212°-212.5° C.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13]Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[NH:18][CH:19]=[N:20]2.C(N(CC)CC)C.Cl.C(N(CC)CC)C>CN(C)C=O>[Cl:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH2:13][O:12][CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCCOCCl)c1ccccc1
Reactant: Clc1ncnc2nc[nH]c12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OCCOCn1cnc2c(Cl)ncnc21)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Following substantially the procedure of Schaeffer, et al. supra but with minor modifications, 1-benzoyloxy-2-chloromethoxyethane (4.4g) was added with stirring to a dry solution of 6-chloropurine (3.1g) and triethylamine (6.5ml) in dimethylformamide (50ml). The reaction was exothermic, immediately precipitating triethylamine hydrochloride. The reaction mixture was stirred at room temperature for 24 hours and filtered. The filtrate was evaporated on a rotary evaporator at 70° C. The remaining thick amber oil was dissolved in the minimum amount of benzene and purified by column chromatography using a silica gel column. Benzene elution removed a trace of an unidentified material. Elution with ether first removed a small amount of ethylene glycol monobenzoate and then 6-chloro-9-(2-benzoyloxyethoxymethyl)purine. Recrystallization from ether gave a white material, m.p. 108.5°-111° C.
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C[N:28](C)[CH:29]=[O:30].[NH4+].[Cl-]>C1COCC1>[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH:26]=[CH:25][N:24]=[C:23]2[C:29]([NH2:28])=[O:30])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN(C)C=O
Reactant: c1ccc(CCCCn2ccnc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: NC(=O)c1nccn1CCCCc1ccccc1
Temperature: -78 °C

Procedure:
Reaction under N2 atmosphere. A mixture of DIPA (0.455 mol) in THF (500 ml) was stirred at −78° C. Butyllithium, 2.5M/hexane (0.390 mol) was added dropwise at −40° C. The mixture was stirred for 15 min, then re-cooled to −78° C. A solution of 1-(4-phenylbutyl)-1H-imidazole, prepared according to the procedure described in J. Chem. Soc., Perkin Trans., 1 (1975), 17, 1670-1671, (0.325 mol) in THF (350 ml) was added dropwise at −60° C. The mixture was stirred for one hour, then re-cooled to −78° C. This mixture was added dropwise to a mixture of N,N-dimethylformamide (0.390 mol, dry, p.a.) in THF (500 ml), stirred at −78° C. The reaction mixture was stirred for one hour at −78° C., then allowed to warm to room temperature while stirring overnight. A saturated aqueous NH4Cl solution (400 ml) was added and this mixture was extracted with THF. The separated organic layer was dried, filtered and the solvent evaporated, yielding 74.2 g of 1-(4-phenylbutyl)-1H-imidazole-2-carboxamide (interm. 18).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@H:7]1[CH2:12][C:11](=[O:13])[CH2:10][CH2:9][C@H:8]1[C:14]([OH:16])=[O:15].[CH2:18](O)[CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[CH3:17][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]1[C@H:8]([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][C:11]2([O:20][CH2:19][CH2:18][O:13]2)[CH2:12]1
Reactant: Cc1ccccc1[C@@H]1CC(=O)CC[C@H]1C(=O)O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1[C@@H]1CC2(CC[C@H]1C(=O)O)OCCO2

Procedure:
(1R,2R)-2-(o-tolyl)-4-oxo-cyclohexanecarboxylic acid (500 mg, 2.153 mmol) in THF (6.0 ml) was reacted with ethylene glycol (0.600 ml, 10.76 mmol) and p-toluenesulfonic acid (82 mg, 0.431 mmol), and then aged at rt until the reaction was complete. The mixture was poured into water and extracted with EtOAc. The combined organic portions were dried (Na2SO4), filtered and concentrated to afford the title compound. HPLC/MS: 231.0 (M-CO2H+1), Rt=1.04 min (LC-2).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1Br.[OH:14][CH2:15][CH:16]1[CH2:24][CH:23]2[CH:19]([CH2:20][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]2)[C:18](=[O:32])[CH2:17]1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[OH:14][CH2:15][CH:16]1[CH2:24][CH:23]2[CH:19]([CH2:20][N:21]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:22]2)[C:18]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[F:6])([OH:32])[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC2CC(CO)CC(=O)C2C1
Reactant: Fc1ccccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CC2CC(CO)CC(O)(c3ccccc3F)C2C1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
94.4 cm3 of a 1.6M solution of butyllithium in hexane are added dropwise to a solution of 16.5 cm3 of 2-fluorobromobenzene in 200 cm3 of tetrahydrofuran, cooled to -78° C. The reaction mixture is stirred at -78° C. for 2 hours, and then a solution of 8.1 g of (3aRS,6SR,7aSR)-6-hydroxymethyl-2-tert-butyloxycarbonylperhydroisoindol-4-one in 20 cm3 of tetrahydrofuran is added. The reaction mixture is subsequently stirred at room temperature for 48 hours, then treated with 50 cm3 of saturated aqueous ammonium chloride solution and subjected to extraction with 200 cm3 of ethyl acetate, and the organic phase is washed with 100 cm3 of saturated sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 6 cm, height 35 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (50:50 by volume) and collecting fractions of 75 cm3. Fractions 21 to 45 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 6.35 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-fluorophenyl)-2-tert-butyloxycarbonylperhydroisoindol 4-ol are obtained in the form of a thick white foam.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br)([O-:16])=[O:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2ccn(Cc3cccc([N+](=O)[O-])c3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
To a solution of 1H-indole-6-carboxylic acid methyl ester (1.0 g, 5.7 mmol) and 3-nitrobenzyl bromide (1.48 g, 6.8 mmol) in DMF (15 mL) was added K2CO3 (1.6 g, 11.4 mmol). After stirring at room temperature for 16 hr, the solution was diluted with ethyl acetate (100 ml) and washed with water (3×50 ml). The organic layer was dried (MgSO4), filtered and concentrated. The remaining residue was recrystallized with ethyl acetate/hexane to provide 1.34 g (76% yield) of 1-(3-nitrobenzyl)-1H-indole-6-carboxylic acid methyl ester as light orange crystals. 1H NMR (300 MHz, DMSO) δ 8.13 (m, 2H), 8.03 (s, 1H), 7.81 (d, 1H, J=3.0 Hz), 7.67-7.54 (m, 4H, J=9.0 Hz), 6.65 (d, 1H, J=3.0 Hz), 5.73 (s, 2H), 3.81 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:11][CH2:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:5])[CH3:2].[CH3:18][S:19]([NH:22][C:23]1[CH:38]=[CH:37][C:26]2[NH:27][C:28]([CH2:33][C:34](O)=[O:35])=[N:29][S:30](=[O:32])(=[O:31])[C:25]=2[CH:24]=1)(=[O:21])=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.ClCCl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[N:11]([CH2:12][CH2:13][C:14]([CH3:16])([CH3:15])[CH3:17])[C:34](=[O:35])[CH2:33][C:28]1[NH:27][C:26]2[CH:37]=[CH:38][C:23]([NH:22][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:24][C:25]=2[S:30](=[O:31])(=[O:32])[N:29]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1NCCC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CCC[C@@H]1N(CCC(C)(C)C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of cis-2-(3,3-dimethylbutylamino)-cyclopentanecarboxylic acid ethyl ester (54.5 mg, 0.226 mmol) in N,N-dimethylformamide (5.0 mL) was added (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 150.6 mg, 0.452 mmol) and a 1.0 M solution of N,N′-dicyclohexylcarbodiimide in dichloromethane (0.23 mL, 0.23 mmol). After stirring at 25° C. for 12 h, the mixture was diluted with dichloromethane and the precipitated N,N′-dicyclohexylurea byproduct was removed by filtration. The filtrate was concentrated and dried in vacuo to afford the crude product, cis-2-{(3,3-dimethylbutyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)acetyl]amino}-cyclopentanecarboxylic acid ethyl ester as a yellowish oil. The crude product was used in the next step without further purification. LC-MS (ESI) calcd for C24H36N4O7S2 556.20, found 557.3 [M+H+].
Reaction SMILES: Cl.[C:2]([O:5][C@H:6]1[C@H:11]([NH2:12])[C@@H:10]([O:13][C:14](=[O:16])[CH3:15])[C@H:9]([O:17][C:18](=[O:20])[CH3:19])[C@@H:8]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:7]1)(=[O:4])[CH3:3].C(N(CC)CC)C.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>C(Cl)Cl>[C:2]([O:5][C@H:6]1[C@H:11]([NH:12][C:36](=[O:37])[CH2:35][O:34][CH3:33])[C@@H:10]([O:13][C:14](=[O:16])[CH3:15])[C@H:9]([O:17][C:18](=[O:20])[CH3:19])[C@@H:8]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:7]1)(=[O:4])[CH3:3]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
To a suspension of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-amino-tetrahydro-2H-pyran-2,4,5-triyl triacetate hydrochloride (0.500 g, 1.31 mmol) in CH2Cl2 (20 mL) was added triethylamine (0.544 mL, 3.915 mmol), followed by 2-methoxyacetyl chloride (0.13 mL, 1.44 mmol). The reaction was stirred at room temperature for 18 h. The reaction mixture was washed once with saturated aqueous NaHCO3 (3 mL) and once with brine (3 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Purification of the crude material by flash chromatography on silica gel (5:1 EtOAc:hexanes) afforded (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(2-methoxyacetamido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate as a white solid (0.380 g, 70% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11]CC)=[O:10])=[CH:4][N:3]=1.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([OH:11])=[O:10])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(Cl)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(Cl)ncc1C(=O)O
Yield: 77.7 %

Procedure:
A solution of ethyl 2-chloro-4-methylpyrimidine-5-carboxylate (1.0 g, 5 mmol), NaOH (0.24 g, 6 mmol) in H2O (30 mL) was stirred at room temperature for 3 h. The solution was acidified with 6N HCl and the resulting solid was filtered and dried to give the title compound (0.67 g 78%), 1HNMR (DMSO-d6) δ 9.01 (s, 1H), 2.75 (s, 3H).