Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][C:14]([C:16]2[N:17]=[CH:18][N:19]3[CH:23]=[CH:22][S:21][C:20]=23)=[O:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:26]([Sn:30](Cl)([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH3:29].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(OCC)(=O)C>C1COCC1.[Cl-].[Na+].O>[N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][C:14]([C:16]2[N:17]=[CH:18][N:19]3[CH:23]=[C:22]([Sn:30]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:26][CH2:27][CH2:28][CH3:29])[S:21][C:20]=23)=[O:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: O=C(NCC(=O)c1ncn2ccsc12)OCc1ccc([N+](=O)[O-])cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)CNC(=O)OCc3ccc([N+](=O)[O-])cc3)c2s1
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
7-(4-Nitrobenzyloxycarbonylamino)acetyl-imidazo[5,1-b]thiazole (2.52 g) was suspended in 50 ml of anhydrous THF. The suspension was cooled in an argon atmosphere to −70° C. Tri-n-butylstannyl chloride (3 ml) was added to the suspension. A solution (31.5 ml) of 1 N lithiumbis(trimethylsilyl)amide in THF was then added dropwise thereto over a period of 20 min. The mixture was allowed to react at the same temperature for one hr. The reaction solution was poured into a mixed solution composed of 250 ml of ethyl acetate and 150 ml of 15% brine. The organic layer was washed with 15% brine, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (ethyl acetate:dichloromethane=1:10) to give 1.41 g of the title compound.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=2[S:4][CH:3]=1.[CH:19]1(B(O)O)[CH2:21][CH2:20]1.CC(C)([O-])C.[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH:19]1([C:2]2[C:11]3[O:10][CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=3[S:4][CH:3]=2)[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)csc2C1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOc2c(C3CC3)csc2C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A mixture of tert-butyl 8-bromo-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (16.0 g) obtained in Example 1, steps 1-3, cyclopropylboronic acid (8.23 g), potassium tert-butoxide (12.5 g), tricyclohexylphosphine (1.88 g), palladium acetate (754 mg) and toluene (400 mL) was stirred at 100° C. for 8 hr, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→10% ethyl acetate/hexane) to give the title compound (10.6 g, 75.1%) as an oil.
Reaction SMILES: C([N:8]1[CH:30]=[N:29][C:28]2[N:13]([C@@H:14]3[O:27][C@H:17]([CH2:18][O:19]CC4C=CC=CC=4)[CH2:16][CH2:15]3)[CH:12]=[N:11][C:10]=2[C:9]1=[O:31])C1C=CC=CC=1.[OH-].[Na+].[H][H]>[OH-].[Pd+2].[OH-].[C].CN(C)C=O>[C@@H:14]1([N:13]2[C:28]3[N:29]=[CH:30][N:8]=[C:9]([OH:31])[C:10]=3[N:11]=[CH:12]2)[O:27][C@H:17]([CH2:18][OH:19])[CH2:16][CH2:15]1
Reactant: [H][H]
Reactant: O=c1c2ncn([C@H]3CC[C@@H](COCc4ccccc4)O3)c2ncn1Cc1ccccc1
Agent: [Pd+2]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: OC[C@@H]1CC[C@H](n2cnc3c(O)ncnc32)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
To a N,N-dimethylformamide solution (1 mL) of N1,5′-O-dibenzyl-2′,3′-dideoxyinosine (52 mg, 0.125 mmol), an aqueous solution of sodium hydroxide (0.3 mL) at a concentration of 1 mol/L was added, and the mixture was stirred at room temperature for 2 hours. To the obtained solution, 20% palladium hydroxide-carbon (10 mg) was added, and the mixture was stirred at room temperature for 2 hours in an atmosphere of hydrogen (1 atm) and thereafter stirred at 80° C. for 16 hours and at 100° C. for 6 hours. The palladium catalyst was removed from the obtained reaction mixture by filtration, and the resultant filtrate was concentrated under reduced pressure. After purification by chromatography (using 10 g of silica gel and a mixed solvent of dichloromethane and methanol (4:1) as an eluting solution), 21 mg of the intended product was obtained in a yield of 70% as a white solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)[CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][CH2:12]1.C[O:32][C:33](=[O:38])[CH:34]([OH:37])[CH2:35][NH2:36].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[Li+].[OH-].C(O)(C(F)(F)F)=O>CN(C=O)C.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:36][CH2:35][C@@H:34]([OH:37])[C:33]([OH:32])=[O:38])=[O:27])=[CH:24][CH:23]=1)[CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([CH3:20])([CH3:18])[CH3:19])[CH2:13][CH2:12]1
Reactant: COC(=O)C(O)CN
Reactant: CC(C)(C)C1CCC(N(Cc2ccc(C(=O)O)cc2)c2nc3ccccc3[nH]2)CC1
Agent: On1nnc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)C1CCC(N(Cc2ccc(C(=O)NC[C@@H](O)C(=O)O)cc2)c2nc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the title compound of Example 1 Step D (0.04 mmol, 16 mg), the hydrochloride salt of 2-hydroxy β-alanine methyl ester (0.06 mmol, 9 mg), HOBt (0.1 mmol, 15 mg), and EDC (0.12 mmol, 23 mg) in 0.4 mL of DMF was added DIEA (0.2 mmol, 35 μL). After 3 h the reaction was partitioned into EtOAc/brine. The organic phase was dried with MgSO4 and concentrated under reduced pressure. The residue was taken up in 1 mL of dioxane and a solution of LiOH (1 mmol, 24 mg) in 0.5 mL of H2O was added. The reaction was stirred at ambient temperature overnight, acidified with TFA and the product was purified by reverse-phase chromatography (Condition A) and lyophilized, affording the title compound as a white solid. MS (ESI): m/z 493 (M+H). HPLC A: 1.73 min.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].C([O-])(O)=[O:12].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[O:12]1[CH2:3][CH:2]1[CH2:1][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: O=C([O-])O
Reactant: C=CCc1ccc(O)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(CC2CO2)cc1
Reaction time: 6 h
Yield: 37.9 %

Procedure:
4-allylphenol (8.9 g, 66.3 mmol) was dissolved in CH2Cl2 (180 ml). After addition of NaHCO3 (8.4 g, 99.5 mmol), m-chloroperbenzoic acid 70% (18 g, 73 mmol) was added portionwise. After 6 hours at room temperature, additional NaHCO3 (8.4 g, 99.5 mmol) and m-chloroperbenzoic acid 70% (18 g, 73 mmol) were added. After 17 hours, the reaction mixture was washed with sat. NaHCO3 (200 ml) and the resulting aqueous phases were extracted with CH2Cl2 (3×10 ml). The combined organic phases were washed with sat. Na2S2O3 (2×100 ml), dried over Na2SO4 and concentrated. The residue was chromatographed over silica gel (hexan-ethyl acetate 9:1 then 1:1) to provide (RS)-4-oxiranylmethyl-phenol (3.77 g, 38%) as yellow solid, m.p. 54°-57° C. and MS: m/e=150 (M+).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:5]=[C:6]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]2=[O:30])[CH:7]=[C:8]([F:19])[C:9]=1[N:10]1[CH2:16][C:15](=[N:17][OH:18])[C:12]2([CH2:14][CH2:13]2)[CH2:11]1.[CH2:31](Br)[CH3:32]>CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]2=[O:30])[CH:7]=[C:8]([F:19])[C:9]=1[N:10]1[CH2:16][C:15](=[N:17][O:18][CH2:31][CH3:32])[C:12]2([CH2:13][CH2:14]2)[CH2:11]1
Reactant: CCBr
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CC(=NO)C4(CC4)C3)c(F)c2)C(=O)O1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCON=C1CN(c2c(F)cc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC12CC2
Temperature: 0 °C
Reaction time: 3 h

Procedure:
While being maintained at 0° C., KOH (0.13 g, 2.4 mmol) was added to a solution of the (S)—N-{{3-[3,5-difluoro-4-(7-hydroxydimono?-5-azaspiro[2,4]heptan-5-yl)phenyl]-2-oxo-5-oxazolidinyl}methyl}acetamide (0.8 g, 1.4 mmol) obtained in Example 3 in 10 mL of DMF, and then slowly droplets of ethyl bromide (0.4 mL, 5.6 mmol) were added with stirring for 3 hours. After the reaction terminated, the reaction mixture was poured into cold water and extracted with ethyl acetate. The organic phase was washed with water and brine and dehydrated over anhydrous magnesium sulfate. Purification through flash column chromatography (n-hexane/ethyl acetate=1:4) afforded the target compound in a white pure form (0.52 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH:15]1([CH:20]=[CH:21][C:22]#[N:23])[CH2:19][CH2:18][CH2:17][CH2:16]1.N12CCCN=C1CCCCC2>C(#N)C>[CH:15]1([CH:20]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:21][C:22]#[N:23])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: N#CC=CC1CCCC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OB(c2cnn(C(CC#N)C3CCCC3)c2)OC1(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.00 g, 0.0103 mol) in acetonitrile (30 mL) was added 3-cyclopentylacrylonitrile (1.25 g, 0.0103 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (1.54 mL, 0.0103 mol). The resulting mixture was stirred at 60° C. overnight, then evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 50% EtOAc in hexanes, to give the desired product (2.36 g, 73%). LCMS (M+H) 316.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][SH:8])=[CH:5][CH:4]=1.Cl[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]#[N:19]>C[O-].[Na+].CO.C(#N)C>[C:18]([C:17]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[S:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)#[N:19]
Reactant: COc1ccc(CS)cc1
Reactant: N#Cc1ccncc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: COc1ccc(CSc2cnccc2C#N)cc1
Temperature: 25 °C
Yield: 59.5 %

Procedure:
A solution of 6.2 g (40 mmol) of p-methoxybenzylmercaptan in 9.8 mL of 4.4M sodium methoxide in methanol was added dropwise to a solution of 5.52 g (40 mmol) of 3-chloro-4-cyanopyridine in dry acetonitrile that has been cooled in an ice bath. After addition was complete the solution was allowed to warm to room temperature over 2 hours. The solvent was concentrated and the residue was partitioned between dichloromethane and water. The aqueous layer was extracted with two portions of dichloromethane and the combined extracts were washed with brine, dried (MgSO4) and concentrated to afford 6.1 g (60%) of a pale yellow crystalline solid, m.p. 80°-81° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]3([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH2:17][O:16]3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:26][NH:27][CH3:28]>C1COCC1>[CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)([OH:16])[CH2:17][N:27]([CH3:28])[CH3:26])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC2(c3cccnc3)CO2)CCN(C)C1
Reactant: CNC
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c1c(n2CC(O)(CN(C)C)c2cccnc2)CCN(C)C1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
2,8-Dimethyl-5-((2-(pyridin-3-yl)oxiran-2-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 0.6 mmol) was added to 2M dimethylamine solution in THF (5 mL) and the reaction mixture was allowed to stir at 40° C. overnight. The progress of reaction was monitored by LCMS. The solvent was removed under reduced pressure to obtain a crude oily product that was purified by reverse phase HPLC to afford 50 mg of 1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(dimethylamino)-2-(pyridin-3-yl)propan-2-ol as the TFA salt. 1H NMR (CDCl3, Free base) δ (ppm): 8.74 (s, 1H), 8.50 (d, 1H), 7.79 (d, 1H), 7.25 (dd, 1H), 7.16 (s, 1H), 7.1 (d, 1H), 6.97 (d, 1H), 4.08 (m, 2H), 3.83 (dd, 2H), 2.98 (m, 4H), 2.74 (d, 2H), 2.70 (s, 3H), 2.42 (s, 3H), 1.98 (s, 6H). Separation by chiral HPLC provided enantiomers II-265a-b.
Reaction SMILES: C(OI1(OC(=O)C)(OC(=O)C)C2C=CC=CC=2C(=O)O1)(=O)C.[F:23][C:24]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:25]=1[CH2:26][O:27][C:28]1[C:29]2[N:30]([C:34]([C:38]([NH:40][CH2:41][CH2:42][OH:43])=[O:39])=[C:35]([CH3:37])[N:36]=2)[CH:31]=[CH:32][CH:33]=1>ClCCl.C(OCC)(=O)C>[F:23][C:24]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:25]=1[CH2:26][O:27][C:28]1[C:29]2[N:30]([C:34]([C:38]([NH:40][CH2:41][CH:42]=[O:43])=[O:39])=[C:35]([CH3:37])[N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NCCO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NCC=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 1.65 g 1,1,1-triacetoxy-1lambda5,2-benziodoxol-3(1H)-one (Dess-Martin periodinane, 3.9 mmol, 1.5 equivalents) were initially charged in 20 ml of dichloromethane. At −25° C., a solution of 1 g of 8-[(2,6-difluorobenzyl)oxy]-N-(2-hydroxyethyl)-2-methylimidazo-[1,2-a]pyridine-3-carboxamide (Example 175A, 2.6 mmol, 1 equivalent) in 32 ml of dichloromethane was slowly added dropwise. The reaction mixture was stirred overnight, warming to RT. The reaction solution was then diluted with about 160 ml of ethyl acetate and washed three times with 1 N aqueous sodium hydroxide solution. The organic phase was washed with saturated aqueous sodium chloride solution until neutral, dried over sodium sulphate, filtered and concentrated. This gave 879 mg (47% of theory; purity about 50%) of the title compound which was reacted further without purification.
Reaction SMILES: C1(OC([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][C:30]5[CH:35]=[CH:34][N:33]=[C:32]([NH:36][CH2:37][CH2:38][CH2:39][OH:40])[N:31]=5)=[CH:25][CH:24]=4)=[O:21])[CH:17]=3)[C:12]([CH3:42])([CH3:41])[CH2:11]2)=O)C=CC=CC=1>[Pd].C1COCC1>[CH3:41][C:12]1([CH3:42])[C:13]2[C:18](=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]4[CH:35]=[CH:34][N:33]=[C:32]([NH:36][CH2:37][CH2:38][CH2:39][OH:40])[N:31]=4)=[CH:27][CH:28]=3)=[O:21])=[CH:15][CH:14]=2)[NH:10][CH2:11]1
Reactant: CC1(C)CN(C(=O)Oc2ccccc2)c2cc(NC(=O)Nc3ccc(Oc4ccnc(NCCCO)n4)cc3)ccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: CC1(C)CNc2cc(NC(=O)Nc3ccc(Oc4ccnc(NCCCO)n4)cc3)ccc21
Reaction time: 10 h
Yield: 0 %

Procedure:
A mixture of 540 mg (927 mmol) 6-(3-{4-[2-(3-Hydroxy-propylamino)-pyrimidin-4-yloxy]-phenyl}-ureido)-3,3-dimethyl-2,3-dihydro-indole-1-carboxylic acid phenyl ester, 20 ml THF and 150 mg 10% Pd/C is hydrogenated at atmospheric pressure for 10 h. The catalyst is removed by filtration and the filtrate evaporated. The residue is purified by chromatography on silica (dichloromethane/methanol 95:5) and the obtained material (400 mg) stirred with dichloromethane for 1 h. the precipitate is isolated by filtration and washed with dichloromethane to give 150 mg (36%) of the title compound.
Reaction SMILES: C(O)(=[S:3])C.[OH-].[K+].Br[CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:17])[CH:14]=2)[C:9]1=[O:18].O>C(O)C>[Cl:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:18])[CH:8]([SH:3])[CH2:16]2
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Reactant: CC(O)=S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1c2ccc(Cl)cc2CC1S
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.37 g (18 mmoles) of thioacetic acid in 30 ml of ethanol is neutralized exactly, in a nitrogen atmosphere, by the dropwise addition of a 40% strength aqueous KOH solution, and 3.7 g (15 mmoles) of 2-bromo-5-chloro-1-indanone (Example 1 (a)) are added. The reaction mixture is stirred for 1 hour at room temperature and poured into 200 ml of water. The product which crystallizes after some time is filtered off and introduced, under nitrogen, into 35 ml of a 5% strength aqueous NaOH solution. After stirring for 1 hour at room temperature, the pH is adjusted to 1 with 2 N hydrochloric acid and the crystalline precipitate is filtered off. The resulting 5-chloro-2-mercapto-1-indanone decomposes at 173°-175° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([NH:17][C:18]1[C:19](=[O:25])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16].[C:26](Cl)(=[O:35])[CH:27]=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N1C=CC=CC=1.O>CN(C)C=O>[O:25]=[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=[C:18]1[NH:17][C:15]([C:3]1[N:4]([CH3:14])[S:5](=[O:12])(=[O:13])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:2]=1[O:1][C:26](=[O:35])[CH:27]=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:16]
Reactant: CN1C(C(=O)Nc2cccccc2=O)=C(O)c2ccccc2S1(=O)=O
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CN1C(C(=O)Nc2cccccc2=O)=C(OC(=O)C=Cc2ccccc2)c2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88 %

Procedure:
To a mixture of 4-hydroxy-2-methyl-N-(1-oxo-2,4,6-cycloheptatrien-2-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (2.0 g) and cinnamoyl chloride (1.3 g) in N,N-dimethylformamide (30 ml) was added pyridine (0.9 ml). The mixture was stirred at room temperature for 2.5 hours. The reaction mixture was poured into cooled water to give crystals, which were collected by filtration and washed with water. The crude crystals were dissolved in chloroform and the solution was washed successively with water and brine, dried over anhydrous magnesium sulfate, treated with activated charcoal and evaporated under reduced pressure to give crystals. The crystals were recrystallized from a mixture of ethyl acetate and hexane to give N-(1-oxo-2,4,6-cycloheptatrien-2-yl)-2-methyl-4-cinnamoyloxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (2.4 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH:21]3[CH2:23][CH2:22]3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24].C(OCC)(=O)C.C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:24].[CH:21]1([C:17]2[CH:18]=[C:19]([CH3:20])[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:15][CH:16]=2)[CH2:23][CH2:22]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(C2CC2)cnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (3.6 g), bis(tricyclohexylphosphine)palladium (II) dichloride (396 mg), tripotassium phosphate (12 g) and cyclopropylboronic acid (2.1 g) were added toluene (30 mL) and water (1.5 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give 4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (2.2 g). 4-(5-Cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (2.2 g) was dissolved in chloroform (5 mL), 4N hydrogen chloride/ethyl acetate (5 mL) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (20 mL) was added, and the mixture was filtered to give the title compound (1.3 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[N:11]2)=[CH:4][CH:3]=1.[NH2:15][C:16]1[S:17][C:18]([C:24]2[C:29]([F:30])=[CH:28][C:27]([C:31]([OH:34])([CH3:33])[CH3:32])=[CH:26][C:25]=2[F:35])=[CH:19][C:20]=1[C:21]([NH2:23])=[O:22]>>[F:35][C:25]1[CH:26]=[C:27]([C:31]([OH:34])([CH3:33])[CH3:32])[CH:28]=[C:29]([F:30])[C:24]=1[C:18]1[S:17][C:16]([NH:15][C:2]2[CH:3]=[CH:4][C:5]([CH2:9][N:10]3[CH:14]=[CH:13][N:12]=[N:11]3)=[C:6]([CH3:8])[N:7]=2)=[C:20]([C:21]([NH2:23])=[O:22])[CH:19]=1
Reactant: Cc1nc(Cl)ccc1Cn1ccnn1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1Cn1ccnn1

Procedure:
The title compound was synthesized from 6-chloro-2-methyl-3-(1H-1,2,3-triazol-1-ylmethyl)pyridine (83 mg, 0.40 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (130 mg, 0.42 mmol) according to the general procedure in Example 1.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=O)[O:4][C:2]2=[O:3].C(O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C)C=O.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(OCC)(=O)C.C(Cl)Cl>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([O:4][CH2:5][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:3]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1ccccc1C(=O)OCc1ccccc1

Procedure:
A mixture of isatoic anhydride (8.54 g), benzyl alcohol (6.0 g), 4-dimethylaminopyridine (6.7 g), dimethylformamide (17 ml), triethylamine (5.28 g), and methylene chloride (160 ml) is refluxed overnight, diluted with an equal volume of ethyl acetate and washed with water, brine, and water. The organic solution is dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product is purified by flash chromatography eluting with 30% ethyl acetate in hexane to give the desired product.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[O:36][CH:37]=[CH:38][N:39]=2)=[CH:31][C:30]=1[F:40].ClC1C=CC(S(N(CC2C=CC(C3OC=CN=3)=C(F)C=2F)[C@@H]2CCCC[C@H]2CO)(=O)=O)=CC=1>>[C:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[N:10]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[O:36][CH:37]=[CH:38][N:39]=2)=[CH:31][C:30]=1[F:40])[S:11]([C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1)(=[O:12])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Fc1cc(-c2ncco2)ccc1CBr
Agent: O=C([O-])[O-]
Agent: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncco2)c(F)c1F)[C@@H]1CCCC[C@H]1CO
Agent: [Cs+]
Product: CC(=O)[C@@H]1CCCC[C@H]1N(Cc1ccc(-c2ncco2)cc1F)S(=O)(=O)c1ccc(Cl)cc1
Yield: 70.2 %

Procedure:
The title compound was synthesized from N-((1R,2R)-2-acetylcyclohexyl)-4-chlorobenzenesulfonamide as a clear oil (550 mg, 1.74 mmol), cesium carbonate (700 mg, 2.15 mmol), and 2-(4-(bromomethyl)-3-fluorophenyl)oxazole (513 mg, 2.00 mmol) according to the procedure described for 4-chloro-N-(2,3-difluoro-4-(oxazol-2-yl)benzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (Example 20) to give N-((1R,2R)-2-acetylcyclohexyl)-4-chloro-N-(2-fluoro-4-(oxazol-2-yl)benzyl)benzenesulfonamide as a clear oil (600 mg, 70% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.66-7.78 (m, 4H), 7.63 (dd, J=10.83, 1.51 Hz, 1H), 7.51 (t, J=7.93 Hz, 1H), 7.36-7.43 (m, 2H), 7.21 (s, 1H), 4.41 (s, 2H), 3.93 (t, J=10.07 Hz, 1H), 2.74 (1, J=9.57 Hz, 1H), 1.79-1.91 (m, 4H), 1.58-1.71 (m, 3H), 1.43-1.55 (m, 1H), 1.10-1.22 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[NH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Reactant: NCCc1ccc(O)cc1
Solvent: COCCOC
Product: Nc1nc(NCCc2ccc(O)cc2)c([N+](=O)[O-])c(-c2ccco2)n1

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester and tyramine in DME. ES-MS m/e (%): 400 ([M+OAc]−, 20), 340 ([M—H]−, 100).