Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:18]1C=C2C(=CC=1C)N(C(OC(C)(C)C)=O)N=C2.ClC1C(B2OC(C)(C)C(C)(C)O2)=CC=CN=1.C([O-])([O-])=O.[Na+].[Na+]>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:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][C:16]=2[CH3:18])[NH:13][N:12]=[CH:11]3)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccc1-c1ccc2[nH]ncc2c1
Reactant: Cc1cc2c(cnn2C(=O)OC(C)(C)C)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)OB(c2cccnc2Cl)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc2[nH]ncc2cc1-c1cccnc1Cl
Yield: 67 %

Procedure:
5-(2-Chloropyridin-3-yl)-6-methyl-1H-indazole was synthesized in the similar manner to the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole by heating the mixture of tert-butyl 5-bromo-6-methyl-1H-indazole-1-carboxylate (1.4 g, 4.5 mmol), 2-chloro-3-pyridine boronic acid pinacol ester (1.4 g, 5.9 mmol), Pd(PPh3)4 (370 mg, 0.32 mmol) and 2M aq.Na2CO3 (7 mL, 14 mmol) in 1,4-dioxane (40 mL). Upon work-up and purification procedure used in the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole provided 5-(2-chloropyridin-3-yl)-6-methyl-1H-indazole as a white solid (780 mg, 67%). 1H NMR (DMSO-d6): δ 13.02 (s, 1H), 8.44 (dt, 1H, J=1.7 and 4.7 Hz), 8.01 (s, 1H), 7.81 (dt, 1H, J=1.7 and 7.6 Hz), 7.53 (s, 1H), 7.51-7.48 (m, 1H), 7.45 (s, 1H), 2.12 (s, 3H).LCMS: rt 6.30 min (A), purity 98%, MS (m/e) 244.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:42]=[CH:41][C:40]=1[CH2:49]O.[OH-].[Na+]>O1CCOCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:49][C:40]3[CH:41]=[N:42][C:43]4[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=4)[N:39]=3)=[CH:15][CH:14]=2)=[N:3]1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(O)cc2)n1
Reactant: OCc1cnc2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3cnc4ccccc4n3)cc2)n1
Temperature: 60 °C
Yield: 69 %

Procedure:
To a solution of 4-(1-Methyl4-pyridin-4-yl-1H-pyrazol-3-yl)-phenol (50 mg) in dioxane (2 ml) was added triphenylphosphine (84 mg), quinoxaline-2-yl-methanol (48 mg) and di-t-butyl-aza-dicarboxylate (73 mg) and the reaction mixture was heated at 60° C. for 18 h. The reaction mixture was poured into 1N NaOH, extracted 3× methylene chloride, dried magnesium sulfate, filtered and concentration Purification via MPLC biotage chromatography provided the title compound (54 mg, 67%). 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.45 (d, J=6.2 Hz, 2H), 8.10 (m, 2 H), 7.77 (m, 2H), 7.55 (s, 1H), 7.37 (d, J=9.1 Hz, 2H), 7.10 (d, J=6.9 Hz, 2 H), 7.01 (d, J=8.7, 2H), 5.41 (s, 2 H), 3.94 (s, 3H); MS: (M+H m/z=394.4).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3(O)[C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)=[C:5]([CH3:23])[O:4][N:3]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH:10]3[C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)=[C:5]([CH3:23])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(O)(c1ccsc1)C(=O)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccsc1)C(=O)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
To a solution of 5-(3,5-dimethylisoxazol-4-yl)-3-hydroxy-3-(thiophen-3-yl)indolin-2-one (50 mg, 0.153 mmol) in trifluoroacetic acid (10 mL) was added triethylsilane (5 mL). The brown solution was stirred at ambient temperature for 3 h and concentrated in vacuo to dryness. The residue was diluted with dichloromethane (20 mL), washed with saturated ammonium chloride solution (10 mL), brine (3×20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified with chromatography on column to give the title compound (37 mg, 78.0%). 1H NMR (400 MHz, DMSO-d6): δH 10.62 (s, 1H), 7.53 (m, 1H), 7.31-7.32 (m, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.16 (s, 1H), 7.02-7.03 (m, 1H), 6.97 (d, J=8.0 Hz, 1H), 4.90 (s, 1H), 2.35 (s, 3H), 2.18 (s, 3H). MS (ESI) m/e [M+1]+ 311.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](O)=[O:6].S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([Cl:14])=[O:6]
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(Cl)c(Cl)c1
Yield: 91 %

Procedure:
A solution of 3,4-dichlorobenzoic acid (20 g, 105.26 mmol) in thionyl chloride (200 ml) was stirred overnight at 90° C. The resulting mixture was concentrated under vacuum to afford 3,4-dichlorobenzoyl chloride as light yellow oil (20 g, 91%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[CH3:12]C1C=CC(S(O)(=O)=O)=CC=1.O>CO>[CH3:12][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[CH3:11]
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(Br)cc1C
Yield: 1135 %

Procedure:
To a solution of 4-bromo-2-methylbenzoic acid (2.0 g, 9.3 mmol) in methanol (20 mL) was added p-TsOH.H2O (90 mg, 0.50 mmol). The mixture was heated at reflux overnight. Methanol was evaporated and the residue was purified by chromatography on silica gel (3% ethyl acetate in petroleum ether) to afford 4-bromo-2-methyl-benzoic acid methyl ester (1.3 g, 61%). 1H NMR (CDCl3, 300 MHz) δ 7.78 (d, J=8.4 Hz, 1H), 7.41-7.36 (m, 2H), 3.89 (s, 3H), 2.57 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[CH3:14][O-].[Na+]>CO.CCOCC>[C:3]([CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][NH:1]1)([O:5][CH3:14])=[O:4]
Reactant: O=C(O)C1CCCCN1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCCCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
A slurry of 26 g (0.20 mole) of pipecolinic acid in 100 ml of methanol is cooled to -10° and 16.7 ml (0.22 mole) of thionyl chloride added over 5 minutes. The slurry is allowed to warm to ambient temperature and stirred overnight whereupon a thick slurry forms. Addition of 300 ml of methanol gives a solution which is evaporated in vacuo. The residue is suspended in 100 ml of methanol, treated with a solution of 10.8 g (0.2 mole) of sodium methoxide in 100 ml of methanol, and diluted with 400 ml of ether. The solid which forms is filtered and the filtrate evaporated and redissolved in ether. Filtration, evaporation and solution are repeated three times and the final residue distilled in vacuo to give 24.6 g (85%) of the above titled ester, bp. 70°-70.5° at 4.0 mm.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2].[NH2:19][CH2:20][CH2:21][CH2:22][S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[N+:1]([CH:4]=[C:5]([NH:19][CH2:20][CH2:21][CH2:22][S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Reactant: NCCCSc1ccccn1
Product: Cc1nc[nH]c1CSCCNC(=C[N+](=O)[O-])NCCCSc1ccccn1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene with 2-(3-aminopropylthio)pyridine according to the procedure of Example 1(a)(ii) yields the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]=[C:11]=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:13]([OH:17])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:11](=[O:12])[NH:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)O
Product: CC(C)(C)OC(=O)Nc1cccc([N+](=O)[O-])c1

Procedure:
3-Nitrophenylisocyanate was reacted with tert-butanol to form (3-nitro-phenyl)-carbamic acid tert-butyl ester. This was reacted with benzyl 2-bromoacetate, then the tert-butyloxycarbonyl group was removed and the resulting (3-nitro-phenylamino)-acetic acid benzyl ester was reduced with aluminium amalgam to afford (3-amino-phenylamino)-acetic acid benzyl ester. This was reacted with 5-(2-adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) according to the procedure of Example 20, step d. The benzyl ester was hydrogenolysed using the same procedure as in Example 1, step e to afford the title compound. 1H NMR (300 MHz, d6-DMSO/D2O) 7.02-6.86 (3H, m), 6.23 (1H, d), 3.55 (2H, s), 2.83 (2H, m), 2.61 (1H, m), 1.88-1.19 (27H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 59.09; H, 8.60; N, 9.41%. C37H57N5O8.3.0 mols H2O requires: C, 58.95; H, 8.42; N, 9.29%.
Reaction SMILES: [C:1]([CH2:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].C[O-].[Na+].C[O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18]C(CBr)=[CH:16][CH:15]=1.Cl>CC(O)=O>[O:3]=[C:1]([CH3:2])[CH2:4][CH2:5][C:6]1[CH:18]=[CH:19][C:14]([C:13]([OH:22])=[O:12])=[CH:15][CH:16]=1
Reactant: CC(=O)CC(C)=O
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)CCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of acetyl acetone (5.0 ml, 49 mmol) at room temperature NaOMe (25% wt, 10.8 ml, 47.3 mmol) was added followed by 4-bromomethyl-benzoic acid methyl ester 2 (9.0 g, 39.3 mmol). The reaction mixture refluxed 3 hours, cooled to the room temperature and acidified with HCl (pH 1-2). Evaporation of the resultant solution yielded a residue, which was refluxed in a mixture of glacial AcOH (50 ml) and conc. HCl (25 ml) for 4 hours. Acids were removed in vacuum and the residue was triturated with water to form a crystalline material, which was collected by filtration and dried to afford 278 (6.72 g, 80% yield). [M−1] 191.1.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(O)(=O)C.[NH2:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[N:24]1[CH:28]=[CH:27][CH:26]=[CH:25]1>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2([NH:15][C:16]3[C:17](=[CH:18][CH:19]=[C:20]([O:22][CH3:23])[CH:21]=3)[N:24]3[CH:25]=[CH:26][CH:27]=[C:28]23)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(-n2cccc2)c(N)c1
Reactant: CC(=O)N1CCC(=O)CC1
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2c(c1)NC1(CCN(C(C)=O)CC1)c1cccn1-2

Procedure:
7.06 g (0.05 mole) of 1-acetyl-4-piperidone and 5 ml. of glacial acetic acid are added to a solution of 9.41 g (0.05 mole) of 1-(2-amino-4-methoxy-phenyl)pyrrole [Example 19(b)] in 150 ml. of absolute ethanol. The solution is refluxed for 12 hours. The volume of the solvent is reduced to about one fifth and the solution is cooled. A solid precipitates and is filtered, dried, and recrystallized from ethanol to give 1'-acetyl-4,5-dihydro-7-methoxyspiro[pyrrolo(1,2-a) quinoxaline-4,4'-piperidine], m.p. 211°-213° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:16][C:17]([C:20]3[N:29]=[CH:28][CH:27]=[CH:26][C:21]=3[C:22]([O:24]C)=[O:23])=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(O)=O.CCOC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:16][C:17]([C:20]3[N:29]=[CH:28][CH:27]=[CH:26][C:21]=3[C:22]([OH:24])=[O:23])=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccnc1-c1cnc(C(=O)CCCCCCc2ccccc2)o1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(CCCCCCc1ccccc1)c1ncc(-c2ncccc2C(=O)O)o1
Yield: 39.6 %

Procedure:
The title compound was prepared from methyl 2-(2-(7-phenylheptanoyl)oxazol-5-yl)nicotinate (8 mg, 0.020 mmol) following General Procedure E. Preparative thin layer chromatography (2% AcOH/EtOAc) yielded the title compound as a white solid (3 mg, 38%): 1H NMR (THF-d8, 600 MHz) δ 8.71 (d, 1H, J=4.8 Hz), 8.09 (d, 1H, J=7.8 Hz), 7.79 (s, 1H), 7.45-7.44 (m, 2H), 7.22-7.19 (m, 2H), 7.16-7.14 (m, 2H), 7.11-7.08 (m, 1H), 3.05 (t, 2H, J=7.8 Hz), 2.60 (t, 2H, J=7.2 Hz), 1.73-1.69 (m, 2H), 1.66-1.61 (m, 2H), 1.43-1.39 (m, 4H); 13C NMR (THF-d8, 150 MHz) δ 185.5, 165.6, 156.4, 150.9, 149.5, 142.7, 141.1, 135.7, 127.0, 126.7, 126.5, 125.9, 123.9, 121.9, 37.1, 24.3, 30.0, 27.6, 27.5, 22.2; MALDI-FTMS m/z 379.1646 (M+H+, C22H23N2O4, requires 379.1652).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:22])[CH2:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=O)[CH2:31][S:32][C:33]#[N:34])=[CH:26][CH:25]=1>C(O)CCC>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:34]=[C:33]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14](=[O:22])[CH2:15][C:16]([CH3:20])([CH3:21])[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)[S:32][CH:31]=2)=[CH:26][CH:25]=1
Reactant: N#CSCC(=O)c1ccc(Cl)cc1
Reactant: CC(C)(CC(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)O
Solvent: CCCCO
Product: CC(C)(CC(=O)c1ccc(-c2ccc(Nc3nc(-c4ccc(Cl)cc4)cs3)cc2)cc1)C(=O)O
Temperature: 90 °C
Yield: 6.9 %

Procedure:
In a 8-mL screw-cap vial, a mixture of 4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoic acid (60 mg, 0.20 mmol) and 2-(4-chlorophenyl)-2-oxoethyl thiocyanate (64 mg, 0.30 mmol) in 4 mL n-butanol was heated at 90° C. overnight. The solvent was removed under reduced pressure. The mixture was dissolved in 5 mL 1:4 MeOH/DMF and purified by reverse-phase HPLC to provide 6.8 mg (7%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 11.90 (br s, 1 H), 10.50 (s, 1 H), 7.75–8.00 (m, 10 H), 7.50 (m, 3 H), 3.30 (m, 2 H), 1.05 (s, 6 H); LC-MS m/z 491.2 (MH+), ret. time 3.83 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].C1(N=[C:20]=[O:21])CCCCC1.N12CCN(CC1)CC2.C(Cl)(Cl)=O>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([N:12]=[C:20]=[O:21])(=[O:10])=[O:11]
Reactant: NS(=O)(=O)c1cc(Cl)ccc1Cl
Reactant: O=C=NC1CCCCC1
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Solvent: Clc1ccccc1
Product: O=C=NS(=O)(=O)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Yield: 75 %

Procedure:
A suspension of 452 g of 2,5-dichlorobenzene sulfonamide, 260 g of cyclohexylisocyanate and 10.0 g of "Dabco" (1,4-diazabicyclo[2,2,2]octane) in 2000 ml chlorobenzene was heated for one hour to reflux in a flask fitted with a water condenser and dry-ice condenser in series, a stirrer and a thermometer. Phosgene was then added into the vapor space of the flask at such a rate that the temperature of the reaction mass was maintained at 123°-125° C. due to refluxing phosgene. During 3 hours of operation a total of 260 g of phosgene was added. The dry-ice condenser was then removed and the reaction mass refluxed to drive off excess phosgene until the temperature reached 134° C. After cooling to room temperature and filtration, the solvent and cyclohexylisocyanate were recovered by distillation at 100 mm pressure. The resulting residue was then distilled at lower pressure. Obtained were 378 g (75% yield) of 2,5-dichlorobenzenesulfonylisocyanate (B.P. 105° C./0.35 mm).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:15]=[C:14]3[CH:16]=[CH:17][C:18](=[O:20])[N:19]=[C:13]3[NH:12][C:11]2=[O:21])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[C:22]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(#N)C=C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C@@H:1]1([N:10]2[CH:15]=[C:14]3[CH:16]=[CH:17][C:18](=[O:20])[N:19]([CH3:22])[C:13]3=[N:12][C:11]2=[O:21])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=c1ccc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c(=O)[nH]c-2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: C=CC#N
Solvent: CCN(CC)CC
Product: Cn1c(=O)ccc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c(=O)nc21
Yield: 396.6 %

Procedure:
A solution was prepared by dissolving 460 mg of 5-iododeoxyuridine (a) in 20 ml of absolute dioxane, to which 22 mg of palladium acetate, 34 mg of triphenylphosphine, 0.3 ml of triethylamine, and 0.13 ml of acrylonitrile were added and the mixture was made to undergo a reaction at 100° C. for 12 hours. After the removal of the precipitate by filtration, a hydrogen sulfide gas bubbled into the filtrate and the resulting precipitate was removed by filtration with Calite. The filtrate was concentrated under reduced pressure and the residue was refined by column chromatography on silica gel to obtain 159 mg of (E)-5-(2-cyanoethenyl)deoxyuridine (b).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:20])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]3[OH:13])[C:6]=2[N:7]=1.[H-].[Na+].I[CH3:24]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([Cl:20])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]3[O:13][CH3:24])[C:6]=2[N:7]=1
Reactant: Nc1nc(Cl)c2ccn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(Cl)nc(N)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of the compound from Step B (1.0 g, 3.3 mmol) in dry DMF (100 mL) at 15° C. was treated with 60% NaH (0.14 g, 3.5 mmol). After 30 min., iodomethane (47 g, 3.3 mmol) was added portionwise to the stirred solution. The reaction was stirred at room temperature for 16 hrs. and then evaporated at a temperature below 40° C. The resulting solid was chromatographed on silica gel to afford the product as a white solid; yield 0.81 g. 1H NMR (DMSO-d6): δ 3.25 (s, 3H), 3.54 (m, 2H), 3.87 (m, 1H), 4.07 (m, 1H), 4.22 (m, 1H), 5.01 (m, 1H), 5.16 (d, 1H), 6.07 (d, 1H), 6.37 (d, 1H), 6.70 (s br, 2H), 7.40 (s, 1H). Mass spectrum: m/z 316 (M+1)+.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)=[O:4].[CH3:22][S:23]([NH:26][C:27]1[CH:42]=[CH:41][C:30]2[NH:31][C:32]([CH2:37][C:38](O)=[O:39])=[N:33][S:34](=[O:36])(=[O:35])[C:29]=2[CH:28]=1)(=[O:25])=[O:24].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[O-]CC.[Na+].Cl>CN(C)C=O.C(OCC)(=O)C.C(O)C>[OH:4][C:3]1[C@H:5]2[C@H:6]([CH2:7][CH2:8][CH2:9]2)[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:16][CH:17]=2)[C:38](=[O:39])[C:37]=1[C:32]1[NH:31][C:30]2[CH:41]=[CH:42][C:27]([NH:26][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:28][C:29]=2[S:34](=[O:36])(=[O:35])[N:33]=1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: COC(=O)C1CCCC1NCc1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3CCC[C@@H]3N(Cc3ccc(C(F)(F)F)cc3)C1=O)N2
Temperature: 60 °C
Yield: 51.8 %

Procedure:
2-(4-Trifluoromethyl-benzylamino)-cyclopentanecarboxylic acid methyl ester (0.1 g, 0.33 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL). (7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.108 g, 0.33 mmol) was added followed by N-methylmorpholine (0.087 mL, 0.66 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.069 g, 0.36 mmol) was added and the mixture was stirred at 25° C. for 3 h. The solution was diluted with ethyl acetate (25 mL) and washed with 1.0 M aqueous hydrochloric acid solution (2×25 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. The oil was dissolved in ethanol (4 mL) and a 21% w/w solution of sodium ethoxide in ethanol (1.3 mL, 3.6 mmol) was added, and the reaction mixture was heated to 60° C. for 2 h. Upon cooling to 25° C., the reaction mixture was acidified to pH 2-3 with 2.0 M aqueous hydrochloric acid solution, upon which the product precipitated while stirring. The solid was collected by vacuum filtration and purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 50%-70% in 8 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, (4aR,7aS)-N-{3-[4-hydroxy-2-oxo-1-(4-trifluoromethyl-benzyl)-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.1 g, 0.171 mmol, 52%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.42-1.62 (3H, m), 1.96-2.15 (3H, m), 3.06 (3H, s), 3.90 (1H, d, J=7.2 Hz), 4.58 (1H, d, J=14.8 Hz), 5.00 (1H, d, J=15.6 Hz), 7.49 (4H, q, J=2.4 Hz), 7.57 (4H, m), 7.68 (2H, m), 10.18 (1H, s). LC-MS (ESI) calcd for C24H23F3N4O6S2 584.10, found 585.1 [M+H+]. [α]D=−50.6863.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH2:8])=[CH:6][CH:5]=[N:4]1)[CH3:2].N1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17].O>O1CCCC1>[CH2:1]([N:3]1[C:7]([NH:8][C:16](=[O:17])[O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[CH:6][CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1nccc1N
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: CCn1nccc1NC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.1 %

Procedure:
To a solution of 1-ethyl-1H-pyrazole-5-amine (500 mg, 4.50 mmol) and pyridine (0.440 ml, 5.40 mmol) in tetrahydrofuran (15 ml) was added 2,2,2-trichloroethyl chloroformate (0.747 ml, 5.40 mmol) with ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give 646 mg (50.1%) of the desired product as an oil.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[C:20]3[O:19][CH2:18][CH2:17][O:16][C:15]=3[CH:14]=[CH:13][CH:12]=1)=[O:10])[NH:2]2.[CH3:21][C:22]1[S:23][C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]([F:39])([F:38])[F:37])=[C:25]([C:27](O)=[O:28])[N:26]=1>>[CH3:21][C:22]1[S:23][C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]([F:39])([F:37])[F:38])=[C:25]([C:27]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[C:20]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:14]=[CH:13][CH:12]=3)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:28])[N:26]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2C(F)(F)F)s1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2c1OCCO2
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4c3OCCO4)C[C@@H]3C[C@@H]32)c(-c2ccccc2C(F)(F)F)s1

Procedure:
prepared by reaction of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-methyl-5-(2-trifluoromethyl-phenyl)-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.40 min; [M+H]+=544.1.