Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.S(Cl)([Cl:15])(=O)=O.CCOCC>C(O)(=O)C>[NH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[C:4]([Cl:15])[CH:5]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccc(CCN)cc1
Solvent: CC(=O)O
Solvent: CCOCC
Product: NCCc1ccc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.1 mol of 2-(4-Methoxy-phenyl)-ethylamine was dissolved in 200 ml of acetic acid, followed by addition of 1.5 eq. of sulfuryl chloride at 0° to 5° C. The solution was stirred at room temperature for 1 hour. 250 ml of ether was added and the resulted solid was collected by filtration. The solid was heated in 48% aqueous HBr at 135° C. for 4 hours, cooled to 0° C., and the crystal was collected by filtration and washed with small amount of methanol then with ethyl acetate. LC-MS showed the product as HBr salt had the expected M+H+ of 186. 1H NMR (Varian 300 MHz, CD3OD shifts relative to the solvent peak at 3.3 ppm) δ 7.2 (d, 1H) 7.0 (m, 1H) 6.9 (d, 1H) 3.1 (m, 2H) 2.9 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:24]1[N:25]([CH2:32][C@:33]2([CH3:36])[CH2:35][O:34]2)[CH:26]=[C:27]([N+:29]([O-:31])=[O:30])[N:28]=1>CN(C=O)C>[CH3:35][C@@:33]1([CH2:36][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]3)=[CH:4][CH:3]=2)[O:34][C:24]2=[N:28][C:27]([N+:29]([O-:31])=[O:30])=[CH:26][N:25]2[CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)CC1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OC[C@@]3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 48.4 %

Procedure:
Tert-butyl 4-(4-hydroxyphenyl)piperidine-1-carboxylate (1.07 g, 3.86 mmol) was dissolved in DMF (10 ml). To the solution, sodium hydride (185 mg, 4.63 mmol) was added at room temperature, and the solution was stirred for 20 minutes at 80° C. To the solution, (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (923 mg, 4.24 mmol) was added with cooling on ice-bath, and the solution was stirred for further 20 minutes at 80° C. To the reaction mixture, ice-water was added, and the solution was stirred vigorously. The precipitates were filtered off, washed with water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=200/1) and then crystallized from ethyl acetate-diisopropyl ether to afford tert-butyl (R)-4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)phenyl]piperidine-1-carboxylate (857 mg, yield 48%) as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][CH2:12][NH:11][C:10]3[N:15]([CH3:24])[N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[C:9]2=3)=[C:4]([Cl:25])[CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:25][C:4]1[CH:3]=[C:2]([CH3:26])[CH:7]=[CH:6][C:5]=1[CH:8]1[S:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]([CH3:24])[N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:9]1=2
Reactant: Cn1nc(-c2ccccn2)c2c1NCCSC2c1ccc(Br)cc1Cl
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc(C2SCCNc3c2c(-c2ccccn2)nn3C)c(Cl)c1
Temperature: 100 °C
Yield: 16.3 %

Procedure:
To a degassed solution of 4-(4-bromo-2-chloro-phenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.4 g, 0.92 mmol, see Ex. #3 step D) in 1,4-dioxane (10 mL) was added potassium carbonate (0.4 g, 2.9 mmol), trimethylboroxine (0.200 g, 1.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.2 g, 0.18 mmol). The resulting mixture was heated, in a sealed microwave vessel, for about 1 h at about 100° C. in a microwave. After cooling to rt, the mixture was concentrated in vacuo. The residue was treated with water (25 mL) and ethyl acetate (150 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were washed with water (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, ethyl acetate/hexanes 1:1) to give 4-(2-chloro-4-methyl-phenyl)-1-methyl-3-(2 pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.055 g, 0.15 mmol, 60%) as an off white solid: LC-MS (Table 1, Method e) Rt=8.02 min; m/z 371 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.27 (3 H, s) 2.72 (1 H, ddd, J=15.0, 6.0, 2.5 Hz) 2.86 (1 H, ddd, J=15.0, 9.0, 2.5 Hz) 3.22-3.29 (1 H, m) 3.54-3.63 (1 H, m) 3.80 (1 H, br s) 3.84 (3 H, s) 6.75 (1 H, s) 6.89 (1 H, br.d, J=7.5 Hz) 7.07 (1 H, ddd, J=7.5, 5.0, 1.0 Hz) 7.16 (1 H, d, J=8.0 Hz) 7.22 (1 H, br.d, J=1.0 Hz) 7.58 (1H, td, J=7.5, 2.0 Hz) 7.70 (1 H, dt, J=8.0, 1.0 Hz) 8.53 (1 H, ddd, J=5.0, 2.0, 1.0 Hz).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([N:21]=[C:22]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:23]=2[C:24](=[O:27])[NH:25][CH3:26])[CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([CH3:20])=[N:10][C:11]([O:18][CH3:19])=[C:12]([CH:17]=1)[C:13]([O:15]C)=[O:14].[OH-].[Na+].Cl>O1CCOCC1>[F:1][C:2]1[C:3]2[N:4]([N:21]=[C:22]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[C:23]=2[C:24](=[O:27])[NH:25][CH3:26])[CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([CH3:20])=[N:10][C:11]([O:18][CH3:19])=[C:12]([CH:17]=1)[C:13]([OH:15])=[O:14]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(-c3cc(C(=O)OC)c(OC)nc3C)c(F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(-c3cc(C(=O)O)c(OC)nc3C)c(F)c12
Temperature: 25 °C

Procedure:
To a solution containing Methyl 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl)-2-methoxy-6-methylnicotinate (0.041 g, 0.088 mmol) and dioxane (0.44 mL) was added aqueous sodium hydroxide (0.44 mL, 2.0 M). The solution was maintained at room temperature for 18 h. The solution was adjusted to below pH 4 with aqueous HCl (1.0 mL, 1.0 N). 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl)-2-methoxy-6-methylnicotinic acid precipitated as a white solid and was filtered off, washed with water (3×2 mL) and air dried. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.98 (1H, br. s.), 8.73 (1H, d, J=7.03 Hz), 8.44 (1H, q, J=4.52 Hz), 8.06 (1H, s), 7.87-7.98 (2H, m), 7.29-7.39 (2H, m), 7.04 (1H, t, J=7.03 Hz), 3.98 (3H, s), 2.76 (3H, d, J=4.52 Hz), 2.42 (3H, s). LCMS retention time: 1.798 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 3 micron, C18, 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH3CN/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% CH3CN/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 453 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.NC1C=CC=CC=1S(N)(=O)=O.Cl.[CH3:24][N:25]([CH2:27][C:28](Cl)=[O:29])[CH3:26].C(=O)(O)[O-].[Na+]>O.CC(C)=O>[CH3:24][N:25]([CH3:26])[CH2:27][C:28]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8](=[O:9])(=[O:10])[NH2:11])[CH:3]=1)=[O:29]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Agent: Nc1ccccc1S(N)(=O)=O
Agent: O=C([O-])O
Solvent: CC(C)=O
Solvent: O
Product: CN(C)CC(=O)Nc1cccc(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A flask was charged with 3-aminobenzene sulfonamide (3.3 g, 19 mmol), and 20 mL of 1:1 acetone:H2O. The solution was stirred at room temperature until the aminobenzene sulfonamide had dissolved. The flask was then cooled in an ice bath and dimethylamino-acetyl chloride HCl (4.6 g, 29 mmol) was added. To the resulting slurry sodium bicarbonate (4.8 g, 57 mmol) was added over a 15 m period. After 30 min the reaction was removed from the ice bath and allowed to stir at room temperature for 15 h. The reaction mixture was then filtered and washed with methanol and acetonitrile. The filtrate was dried on a rotary evaporator to yield 2-(dimethylamino)-N-(3-sulfamoyl-phenyl)acetamide, which was submitted to the next step without further purification. MS (EI) m/z C10H15N3O3S: 258.0 (MH+).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]([C:7]1[NH:8][S:9](=[O:23])(=[O:22])[C:10]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:11]=2[C:12]=1[OH:13])=[O:6].[CH2:24](I)[CH3:25]>C(O)C>[CH3:3][O:4][C:5]([C:7]1[N:8]([CH2:24][CH3:25])[S:9](=[O:23])(=[O:22])[C:10]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:11]=2[C:12]=1[OH:13])=[O:6]
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Reactant: CCI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN1C(C(=O)OC)=C(O)c2ccc3ccccc3c2S1(=O)=O
Temperature: 25 °C
Reaction time: 30 h

Procedure:
33 ml of 1 N sodium hydroxide were added dropwise over a period of 25 minutes to a suspension of 10.1 gm (0.033 mol) of 4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide and 20 gm (0.12 mol) of ethyl iodide in 400 ml of aqueous 75% ethanol, whereby the starting material went completely into solution. The reaction mixture was then stirred at room temperature for 30hours. Thereafter, the crystals which had formed were collected by filtration and washed with a small quantity of ethanol, yielding 8.7 gm (79% of theory) of the desired compound, m.p. 179° C (from ethanol).
Reaction SMILES: C([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)C1C=CC=CC=1.Cl[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15]>C1C=CC=CC=1>[Cl:19][C:18]([Cl:21])([Cl:20])[CH2:17][O:16][C:14]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)=[O:15]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: C1=CCN(Cc2ccccc2)C1
Solvent: c1ccccc1
Product: O=C(OCC(Cl)(Cl)Cl)N1CC=CC1
Reaction time: 1 h

Procedure:
40.0 g (0.25 mol) of N-benzyl-3-pyrroline are dissolved in 400 ml of benzene. 53.0 g (0.25 mol) of 2,2,2-trichloroethyl chloroformate are introduced into this solution in the course of 30 minutes, at 0° and under a nitrogen atmosphere. The reaction mixture is stirred for a further 1 hour at 0°, then washed at room temperature twice with, in each case, 100 ml of a mixture of water and 2 N hydrochloric acid (3:1) and then twice with water, dried over sodium sulphate and evaporated under a water pump vacuum. The oily residue is distilled under a high vacuum and, after 24 g of benzyl chloride has been separated off, N-(β,β,β-trichloroethoxycarbonyl)-3-pyrroline with a boiling point of 84°-85° C./0.12 mm Hg is obtained.
Reaction SMILES: N1C=CN=C1CN1C(=O)COC2N=C(C3C=CC(C4(N)CCC4)=CC=3)C(C3C=CC=CC=3)=CC1=2.[CH3:35][N:36]1[C:41]2[CH:42]=[C:43]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[C:44]([C:46]3[CH:51]=[CH:50][C:49]([C:52]4([NH:56]C(=O)OC(C)(C)C)[CH2:55][CH2:54][CH2:53]4)=[CH:48][CH:47]=3)=[N:45][C:40]=2[CH2:39][NH:38][C:37]1=[O:70]>>[NH2:56][C:52]1([C:49]2[CH:48]=[CH:47][C:46]([C:44]3[C:43]([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)=[CH:42][C:41]4[N:36]([CH3:35])[C:37](=[O:70])[NH:38][CH2:39][C:40]=4[N:45]=3)=[CH:51][CH:50]=2)[CH2:53][CH2:54][CH2:55]1
Reactant: CN1C(=O)NCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3ncc[nH]3)C(=O)CO4)cc2)CCC1
Product: CN1C(=O)NCc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Yield: 20.3 %

Procedure:
Following the procedure for 1-((1H-imidazol-2-yl)methyl)-6-(4-(1-aminocyclobutyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one, tert-butyl 1-(4-(1-methyl-2-oxo-7-phenyl-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-6-yl)phenyl)cyclobutylcarbamate (31 mg, 0.064 mmol) was reacted to afford the title compound (5 mg, 20%).
Reaction SMILES: C(OC(=O)[N:7]([CH2:32][CH:33]=[CH2:34])[C@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:18]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH3:19])[CH:14]=2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C>[CH2:32]([NH:7][C@H:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([N:18]([CH3:19])[S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]([CH3:30])[CH3:31])=[CH:25][CH:24]=3)(=[O:21])=[O:22])[CH:12]=[CH:11][C:10]=2[CH2:9]1)[CH:33]=[CH2:34]
Reactant: C=CCN(C(=O)OC(C)(C)C)[C@H]1CCc2cc(N(C)S(=O)(=O)c3ccc(C(C)C)cc3)ccc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCN[C@H]1CCc2cc(N(C)S(=O)(=O)c3ccc(C(C)C)cc3)ccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
Allyl-{(S)-6-[(4-isopropyl-benzenesulfonyl)-methyl-amino]-1,2,3,4-tetrahydronaphthalen-2-yl}-carbamic acid tert-butyl ester (672 mg, 1.35 mmol) was dissolved in dichloromethane (30 ml). Trifluoroacetic acid (1 ml) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness. Ethyl acetate (100 ml) was added and extracted with NaOH (2M). The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness to yield 1.05 g of crude product. The crude product was dissolved in ethyl acetate (20 ml) and the precipitate was collected to yield the desired compound (270 mg, 50%). The mother liquid was reduced in vacuo to yield an oil (840 mg, 54% purity).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]3[C:21]([C:29]([F:32])([F:31])[F:30])([O:24][Si](C)(C)C)[CH2:22][CH2:23][C:5]=3[C:4]=2[C:3]=1[Cl:33].[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:21]([C:29]([F:31])([F:30])[F:32])([OH:24])[CH2:22][CH2:23][C:5]=3[C:4]=2[C:3]=1[Cl:33]
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4c(Cl)c(Cl)ccc42)CCC3(O[Si](C)(C)C)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OC1(C(F)(F)F)CCc2c1[nH]c1ccc(Cl)c(Cl)c21
Yield: 62.3 %

Procedure:
To 7,8-dichloro-4-tosyl-3-(trifluoromethyl)-3-(trimethylsilyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indole (0.2 g, 0.3 mmol) in THF (10 mL), KOH (104 mg, 1.8 mmol) in H2O (10 mL) was added and the resulting mixture was refluxed for 18 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude compound which was purified by column chromatography (10% EtOAc-hexane) to afford the title compound as a white solid (58 mg, 53%). 1H NMR (500 MHz, DMSO-d6, δ in ppm) 11.70 (s, 1H), 7.35 (d, 8.5 Hz, 1H), 7.28 (d, J=9.0 Hz, 1H), 6.90 (s, 1H), 3.12-3.07 (m, 1H), 2.97-2.88 (m, 2H), 2.88-2.50 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[C:15]2[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=2)[C:5]([F:21])=[CH:4][C:3]=1[S:22]([N:25]([C:33]1[N:34]=[CH:35][S:36][CH:37]=1)C(=O)OC(C)(C)C)(=[O:24])=[O:23].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[C:15]2[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=2)[C:5]([F:21])=[CH:4][C:3]=1[S:22]([NH:25][C:33]1[N:34]=[CH:35][S:36][CH:37]=1)(=[O:23])=[O:24]
Reactant: Cn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)N(C(=O)OC(C)(C)C)c2cscn2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2cscn2)cc1F
Yield: 179.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the tert-butyl [(2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}phenyl)sulfonyl](1,3-thiazol-4-yl)carbamate (177 mg, 0.319 mmol) prepared in Example 5a, trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (260 mg, 87%) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[CH3:17])[CH2:4][CH2:3]1>C(O)C.[Pd].C(O)C.O.ClCCl>[CH3:17][C:9]1[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:8]=1[N:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1CCN(C)CC1
Agent: [Pd]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(N)cc1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.2 %

Procedure:
A solution of the product of step (a) (4.5 g) in ethanol was added under vacuum to a prehydrogenated suspension of palladium on charcoal (10% Pd on C, 50% paste with water, 1.4 g) in ethanol:water (5:2., 50 ml). The suspension was stirred at room temperature under an atmosphere of hydrogen for 2 hours. The suspension was filtered through a pad of hyflo, the filter pad washed well with ethanol:water (4:1,200 ml) and the combined filtrates evaporated in vacuo to give a gummy solid which was dissolved in dichloromethane, dried and concentrated in vacuo to give the title compound as a pale green crystalline solid (4.052 g) m.p. 82°-83° C. Analysis Found: C, 70.2; H, 9.5; N,20.4 C12H19N3 requires: C, 70.2; H, 9.3; N, 20.5%
Reaction SMILES: [C:1]([O:5][C:6]([C@:8]1([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][C@@H:12](Br)[C@@H:11]2[C@H:9]1[C@H:10]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:30]1[CH:34]=[N:33][C:32]([SH:35])=[N:31]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([C@:8]1([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][C@H:12]([S:35][C:32]2[N:33]=[CH:34][NH:30][N:31]=2)[C@@H:11]2[C@H:9]1[C@H:10]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Sc1nc[nH]n1
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@@H](Br)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@H](Sc2nc[nH]n2)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
Add to a solution of ditert-butyl(1R,2S,4R,5R,6R)-4-bromo-2-(tert-butoxycarbonylamino)bicyclo[3.1.0]hexane-2,6-dicarboxylate (2 g, 4.20 mmol) in dimethylformamide (10 mL), 1H-1,2,4-triazole-3-thiol (525 mg, 5.04 mmol) and potassium carbonate (1.16 g, 8.4 mmol). Stir the mixture at 80° C. overnight. Cool to room temperature and dilute with ethyl acetate, wash with 10% citric acid and brine, dry over anhydrous sodium sulfate, filter and concentrate to dryness. Purify by silica gel chromatography (80 g silica column) eluting with hexane:ethyl acetate (80:20 to 0:100) to obtain the title compound (1.64 g, 78%). MS (m/z): 497 (M+1).
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:5].[NH2:16][C:17]([NH2:19])=[S:18].C([O-])(=O)C.[Na+]>C(O)C>[NH2:19][C:17]1[S:18][CH:2]=[C:3]([C:4](=[O:5])[C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)[N:16]=1
Reactant: NC(N)=S
Reactant: O=C(CCl)C(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(C(=O)c2ccc([N+](=O)[O-])cc2)cs1
Temperature: 50 °C
Yield: 32.4 %

Procedure:
A mixture of chloromethyl-(4-nitrophenyl)diketone (2 g), thiourea (1.5 g) and sodium acetate (1.6 g) in ethanol (20 ml) was heated at 50° C. for 4 hours with stirring. The mixture was concentrated in vacuo and the residue was triturated with water. The precipitates were collected by filtration, washed with water and dried in vacuo to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 100 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-4-(4-nitrobenzoyl)thiazole (0.71 g, yield: 32.4%). mp: 194°-198° C. (dec.) IR (Nujol): 3300-3450, 1660, 1600, 1520, 1350 cm-1
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[Br-].[Li+].C(=O)(O)[O-].[Na+].Cl[CH2:20][CH:21]=O>CC(C)=O>[CH:3]1[C:2]2[N:1]([CH:20]=[CH:21][C:7]=2[C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][N:4]=1
Reactant: O=CCCl
Reactant: COC(=O)Cc1cnccn1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: COC(=O)c1ccn2ccncc12

Procedure:
To a solution of 10 g (65.7 mmol) of methyl pyrazin-2-ylacetate in 263 mL of anhydrous acetone (4 mL/mmol) there are added in succession 5.7 g of lithium bromide (65.7 mmol), 22.1 g of sodium bicarbonate (263 mmol) and then 9.4 mL of chloroacetaldehyde (50% solution in water) (72.6 mmoles). The whole is subsequently heated at reflux overnight. The reaction mixture is subsequently concentrated to dryness and then taken up in ethyl acetate. The organic phase is washed with a saturated sodium chloride solution, dried over magnesium sulphate, filtered and then concentrated to dryness. There is obtained an oil, which is purified by chromatography over silica gel (CH2Cl2/ethyl acetate gradient). After concentration, the title product is obtained in the form of a solid.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([CH3:11])[CH2:9][N:8]([C:12]2[C:17]([NH2:18])=[CH:16][N:15]=[C:14]3[CH:19]([O:22]C(=O)C)[CH2:20][CH2:21][C:13]=23)[CH2:7][C@H:6]1[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=O)C.[C:34]([O:38][C:39]([NH:41][C:42]1[C:43]([C:57](O)=[O:58])=[N:44][C:45]([C:49]2[C:54]([F:55])=[CH:53][CH:52]=[CH:51][C:50]=2[F:56])=[C:46]([F:48])[CH:47]=1)=[O:40])([CH3:37])([CH3:36])[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.[OH-].[Na+].CO>[C:34]([O:38][C:39]([NH:41][C:42]1[C:43]([C:57]([NH:18][C:17]2[C:12]([N:8]3[CH2:9][C@H:10]([CH3:11])[C@@H:5]([OH:4])[C@H:6]([NH:26][C:27](=[O:28])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:7]3)=[C:13]3[CH2:21][CH2:20][CH:19]([OH:22])[C:14]3=[N:15][CH:16]=2)=[O:58])=[N:44][C:45]([C:49]2[C:54]([F:55])=[CH:53][CH:52]=[CH:51][C:50]=2[F:56])=[C:46]([F:48])[CH:47]=1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)[C@@H](OC(C)=O)[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)c(F)cc3NC(=O)OC(C)(C)C)cnc3c2CCC3O)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (3R,4R,5S)-1-[7-(acetyloxy)-3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-4-yl acetate (11.0 mg, 0.024 mmol), 3-[(tert-butoxycarbonyl)amino]-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (12 mg, 0.03 mmol), HATU (33 mg, 0.09 mmol) in DMF (0.09 mL) and DIPEA (23 mg, 0.18 mmol) was stirred at room temperature for 16 h. The reaction mixture was diluted with 1N NaOH solution (0.5 mL) and MeOH (0.5 mL). The reaction mixture was stirred at room temperature for 1 h. After concentration under vacuum, the aqueous layer was extracted with DCM three times. The combined organic layers were dried, filtered and concentrated under reduced pressure to give the crude product, which was purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a white powder. LCMS calc. for C36H44F3N6O7 (M+H)+: m/z=729.3. Found: 729.4.