Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[C:11]([CH2:13][N:14]([CH:22]2[CH2:24][CH2:23]2)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]([Cl:25])=[C:9]([Cl:26])[CH:8]=1)(=O)=O.[C-:27]#[N:28].[K+].[I-].[Na+]>CS(C)=O.CCOCC>[CH:22]1([N:14]([CH2:13][C:11]2[CH:12]=[C:7]([CH2:6][C:27]#[N:28])[CH:8]=[C:9]([Cl:26])[C:10]=2[Cl:25])[C:15](=[O:16])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:24][CH2:23]1
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N(Cc1cc(COS(C)(=O)=O)cc(Cl)c1Cl)C1CC1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N(Cc1cc(CC#N)cc(Cl)c1Cl)C1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of {3,4-dichloro-5-[(cyclopropyl{[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]phenyl}methyl methanesulfonate (1 eq.) from the previous step in DMSO (0.48 M) was added potassium cyanide (1.3 eq.) and sodium iodide (0.1 eq.). The resulting solution was stirred at RT for 3 h before it was diluted with ether and quenched with 1 N aq. NaOH. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 19:1 (v/v) Hex:EtOAc→3:7 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]([CH3:22])([CH3:21])[C@H:3]([NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:23]=[S:24](Cl)Cl.N1C=CC=CC=1>C1COCC1>[CH3:21][C:2]1([CH3:22])[O:1][S@:24](=[O:23])[N:10]([S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)(=[O:13])=[O:12])[C@@H:3]1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)C(C)(C)O)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)N2[C@H](c3ccccc3)C(C)(C)O[S@@]2=O)cc1
Reaction time: 2 h
Yield: 86.9 %

Procedure:
To a solution of (1R)-N-(2-hydroxy-2-methyl-1-phenyl-propyl)-4-methyl-benzene sulfonamide (2.0 g, 6.3 mmol) in THF 8 mL at −45° C. was added SOCl2 (1.12 g, 9.4 mmol), followed by slow addition of pyridine (1.24 g, 12.9 mmol) in THF (8 mL) over a period of 2 h. The reaction was monitored on TLC. The reaction was quenched by addition of saturated aqueous NaHCO3 and the mixture was extracted with EtOAc (30 ml), and organic phase washed with brine (20 mL) and evaporated to dryness. The residue was added hexane (40 mL) and stirred at ambient for 2 h. The precipitate formed was filtered and wet cake washed with hexane to afford the title compound (2.0 g, 87.5%) with 99% de.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][N:14](C(OC)=O)[CH2:13][C@@H:12]2[CH3:21])=[O:9])[NH:5][C:6]=1[CH3:7].[OH-].[K+].O.NN.O>C(O)CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][NH:14][CH2:13][C@@H:12]2[CH3:21])=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: COC(=O)N1CC[C@@H](NC(=O)c2cc(Cl)c(C)[nH]2)[C@@H](C)C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Cc1[nH]c(C(=O)N[C@@H]2CCNC[C@@H]2C)cc1Cl
Yield: 52.7 %

Procedure:
A solution of methyl (3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidine-1-carboxylate (Intermediate 38, 2.2 g, 7.05 mmol), potassium hydroxide (2.76 g, 49.35 mmol), and hydrazine hydrate (2.5 mL, 49.35 mmol) in ethylene glycol (150 mL) was stirred for 40 h at 120° C. The reaction mixture was poured in to water (120 mL) and extracted with ethyl acetate (2×150 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered, concentrated in vacuo to yield the crude product which was triturated with water (30 mL) to afford 4-chloro-5-methyl-N-[(3S,4R)-3-methylpiperidin-4-yl]-1H-pyrrole-2-carboxamide 950 mg (52%) as brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:14]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH3:14])=[CH:4][CH:3]=1
Reactant: CI
Reactant: OCCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of 2-(4-bromophenyl)ethanol (1 g, 5 mmol) in anhydrous THF (10 mL) was added NaH (60% oil dispersion, 0.2 g, 5 mmol). The mixture was stirred at room temperature for 30 min and cooled to −0° C. Iodomethane (920 mg, 6.5 mmole) was added slowly to the mixture and stirred for 8 h. The reaction mixture was then quenched by adding water, extracted with ethyl acetate. The combined organic extracts were dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 5% ethyl acetate in hexane) to give the title compound as a colorless (1 g, 93% yield). 1H NMR (CDCl3, 400 MHz): 7.39 (d, 2H), 7.08 (d, 2H), 3.56 (t, 2H), 3.33 (s, 3H), 2.82 (t, 2H); MS (ESI) m/z. Calc. 215.1 (M+). Found: 216.3 (M′+1), 218.1 (M++3).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([S:31][CH3:32])=[N:26][CH:27]=[N:28]2)=[CH:23][CH:22]=1.[O:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]#[C:41][CH2:42]O)[CH2:35][CH2:34]1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[CH3:32][S:31][C:25]1[C:24]2[C:29](=[CH:30][C:21]([O:20][CH2:42][C:41]#[C:40][CH2:39][N:36]3[CH2:37][CH2:38][O:33][CH2:34][CH2:35]3)=[CH:22][CH:23]=2)[N:28]=[CH:27][N:26]=1
Reactant: OCC#CCN1CCOCC1
Reactant: CSc1ncnc2cc(O)ccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1ncnc2cc(OCC#CCN3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.1 %

Procedure:
Triphenylphosphine (4.09 g, 1.56 mmol) was added dropwise to a solution of 7-hydroxy-4-methylsulphanylquinazoline (1.2 g, 6.25 mmol), (prepared as described for the starting material in Example 8), in methylene chloride (30 ml), followed by 4-morpholinobut-2-yn-1-ol (1.26 g, 8.3 mmol), (J. Am. Chem. Soc. 1957, 79, 6184), in methylene chloride (5 ml) and diethyl azodicarboxylate (2.46 ml, 1.56 mmol) was added dropwise. After stirring for 3 hours at ambient temperature, the volatiles were removed under vacuum and the residue was purified by column chromatography eluting with methylene chloride/methanol (100/0 followed by 95/5). After removal of the solvent, the residue was triturated with ether, collected by filtration and dried under vacuum to give 4-methylsulphanyl-7-(4-morpholinobut-2-yn-1-yloxy)quinazoline (1.3 g, 63%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14](Cl)=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1.[CH3:19][OH:20]>>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14]([O:20][CH3:19])=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1
Reactant: CO
Reactant: O=C(Cl)c1csnc1-c1cccc(C(F)(F)F)c1
Product: COC(=O)c1csnc1-c1cccc(C(F)(F)F)c1

Procedure:
A solution of 2.92 g (0.010 mol) of 3-(α,α,α-trifluoro-m-tolyl)-4-isothiazolecarbonyl chloride prepared as in Example 29 and 10 ml of methanol was held at reflux for 0.5 hours and was concentrated under vacuum to 80° (0.3 torr) to 2.72 g of oil, nD23.4° =1.5404.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])#[N:2].[NH2:15][C:16]1[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=1>C(O)(=O)C>[CH3:14][O:13][C:11]1[CH:12]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:7])[NH:2][C:1]([NH:15][C:16]1[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=1)=[CH:3]2
Reactant: COc1ccc(C(=O)O)c(CC#N)c1
Reactant: Cc1cc(N)n[nH]1
Solvent: CC(=O)O
Product: COc1ccc2c(=O)[nH]c(Nc3cc(C)[nH]n3)cc2c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
2-Cyanomethyl-4-methoxy-benzoic acid (1.91 g, 0.01 mol), 3-amino-5-methylpyrazol (1 g, 0.01 mol) and acetic acid (15 ml) were sealed in bottle (20 ml). The mixture was heated at 130° C. for 20 minutes under microwave irradiation. The mixture was concentrated and the residue was dissolved in 5 ml MeOH. The solution was added dropwise to 200 ml water. After stirred for 1 hour, solid was collected and dried to give product (2.24 g, 82% yield). LC-MS: 271 (MH+)
Reaction SMILES: [CH:1]1([N:4]([CH:34]2[CH2:36][CH2:35]2)[C:5]([C:7]2[N:31]([CH2:32][CH3:33])[C:10]3=[N:11][C:12]([NH:19]/[C:20](/SC)=[CH:21]/[C:22](=[O:28])[CH:23]([O:26][CH3:27])[O:24][CH3:25])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:37]([N:39]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[NH2:40])[CH3:38]>C(O)(=O)C>[CH:1]1([N:4]([CH:34]2[CH2:36][CH2:35]2)[C:5]([C:7]2[N:31]([CH2:32][CH3:33])[C:10]3=[N:11][C:12]([NH:19]/[C:20](/[NH:40][N:39]([CH2:37][CH3:38])[C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])=[CH:21]/[C:22](=[O:28])[CH:23]([O:26][CH3:27])[O:24][CH3:25])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCN(N)C(=O)OC(C)(C)C
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N/C(=C/C(=O)C(OC)OC)SC)nc21
Solvent: CC(=O)O
Product: CCN(N/C(=C\C(=O)C(OC)OC)Nc1nc2c(cc(C(=O)N(C3CC3)C3CC3)n2CC)c2c1ncn2C)C(=O)OC(C)(C)C
Temperature: 35 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of (Z)—N,N-dicyclopropyl-4-(4,4-dimethoxy-1-(methylthio)-3-oxobut-1-enylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 101A, 160 mg, 0.312 mmol) and tert-butyl 1-ethylhydrazinecarboxylate (125 mg, 0.780 mmol) in acetic acid (2 mL) wan stirred at 35° C. overnight. Solvent was evaporated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 2-8% methanol/dichloromethane). (Z)-tert-Butyl 2-(1-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-4,4-dimethoxy-3-oxobut-1-enyl)-1-ethylhydrazinecarboxylate (195 mg, 0.312 mmol, 100% yield) was obtained as a yellow solid.
Reaction SMILES: [C:1]1([C@@H:7]([CH3:13])[CH2:8][NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:15]([CH2:19][CH3:20])[C:16](O)=[O:17]>>[CH2:19]([C@H:15]1[S:11][C:10]([NH:9][CH2:8][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:13])=[N:12][C:16]1=[O:17])[CH3:20]
Reactant: C[C@@H](CNC(N)=S)c1ccccc1
Reactant: CCC(Br)C(=O)O
Product: CC[C@H]1SC(NC[C@H](C)c2ccccc2)=NC1=O

Procedure:
Synthesis was performed from N-[(2R)-2-phenylpropyl]thiourea and 2-bromo-butyric acid according to Method D3.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][CH:17]=2)=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(CCO)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Nc2ccc(CCO)cc2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 33.6 %

Procedure:
A mixture of 2-chloro-5-methylsulfonylnitrobenzene (Kavalek, J.; et al. Collect. Czech. Chem. Commun, 1971, 36, 209., 2 g, 8.5 mmol), 4-aminophenylethyl alcohol (1.4 g, 10.2 mmol) and Na2CO3 (1.4 g, 12.7 mmol) in ethanol was stirred at 100° C. for 16 h. The insoluble matter was removed by filtration and washed with ethanol (100 mL). The filtrate was concentrated and the residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:4) to afford 960 mg (34%) of the title compound as yellow solids: 1H-NMR (CDCl3) δ 9.84 (1H, br.s), 8.82 (1H, d, J=2.1 Hz), 7.79 (1H, dd, J=2.1 Hz, 9.1 Hz), 7.36 (2H, d, J=8.4 Hz), 7.22–7.38 (3H, m), 3.94 (2H, br.s), 3.07 (3H, s), 2.93 (2H, t, J=6.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[N:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:31][N:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:31]1[C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][N:16]3[C:15](=[O:18])[N:4]4[N:5]=[CH:6][C:7]([C:8]5[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=5)=[C:2]([Cl:1])[C:3]4=[N:17]3)=[CH:22][CH:23]=2)=[CH:28][CH:29]=[N:30]1
Reactant: O=c1[nH]nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Reactant: BrCc1ccc(-c2ccno2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(-c3ccno3)cc2)nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Temperature: 50 °C
Yield: 79 %

Procedure:
To a stirring suspension of 8-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one prepared as described in example 354G, and 5-(4-(bromomethyl)phenyl)isoxazole (122 mg, 0.51 mmol), prepared as described as in Example 250A in DMF (5 mL) at RT under argon was added K2CO3 (119 mg, 0.86 mmol). The resulting mixture was heated at 50° C. for 3 h. HPLC/MS analysis indicated complete reaction. The reaction mixture was concentrated under vacuum with co-evaporation of toluene (10 mL×2) to obtain a dark yellow solid. The crude product was purified by silica gel column chromatography (ISCO) eluting with hexanes/EtOAc to obtain pure title compound, 2-(4-(isoxazol-5-yl)benzyl)-8-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (149 mg, 79%) as a yellow solid. MS [M+H]+ 438; HPLC retention time=3.55 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:23][S:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[CH3:23][S:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:22][N:12]4[C:13](=[O:21])[NH:14][C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=5[C:11]4=[N:10][CH2:9]3)=[CH:4][CH:3]=2)=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: CSc1cccc(N=C=O)c1
Reactant: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Product: CSc1cccc(NC(=O)Nc2ccc(C3CN=C4c5ccccc5NC(=O)N4C3)cc2)c1
Yield: 46.9 %

Procedure:
In a manner similar to the procedure described in Example 7, 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (20.2 mg, 0.069 mmol) and 3-(methylthio)phenyl isocyanate (0.0105 mL, 0.076 mmol) were reacted to give the title compound as an off-white solid (14.8 mg, 47%). 1H NMR (DMSO-d6) δ: 10.68 (s, 1H), 8.69 (s, 1H), 8.66 (s, 1H), 7.98 (d, J=7.9 Hz, 1H), 7.41-7.47 (m, 4H), 7.19-7.26 (m, 3H), 7.13-7.15 (m, 1H), 7.06 (t, J=7.5 Hz, 1H), 7.01 (d, J=7.9 Hz, 1H), 6.84-6.87 (m, 1H), 4.22 (dt, J=12.7, 3.0 Hz, 1H), 3.70-3.75 (m, 1H), 3.51-3.59 (m, 2H), 2.93-2.99 (m, 1H), 2.45 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Cl[C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][N:14]=1>CN(C)C=O>[Cl:19][C:18]1[C:13]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1cccnc1Cl
Reactant: Oc1cccc(C(F)(F)F)c1
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Oc2ncccc2Cl)c1
Temperature: 120 °C

Procedure:
7.68 g of sodium hydride dispersion (ca. 50 percent in mineral oil) was washed with pentane under nitrogen and 100 ml of N,N-dimethylformamide was then added. 21.92 g (135 mmol) of 3-(trifluoromethyl)phenol was added dropwise over 30 minutes at room temperature. The resultant phenate solution was added dropwise over 2 hours, under nitrogen, to a solution of 20.1 g (136 mmol) of 2,3-dichloropyridine in 80 ml of N,N-dimethylformamide, heated to 120° C. After a reaction time of 3 hours, the mixture was cooled to room temperature, the precipitate of sodium chloride was filtered off and the filtrate was concentrated. The residue was extracted with toluene and 0.1 N hydrochloric acid and the organic phase was washed with saturated sodium chloride solution and concentrated. The oily residue was distilled under vacuum. The yield of the title compound was 24.75 g (67 percent) of a colorless oil, content (GC) 99.7 percent. Other data concerning the title compound was:
Reaction SMILES: [C:1]([NH:11][CH:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[C:1]([NH:11][CH:12]([C:17]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:28])=[O:29])=[CH:23][CH:22]=1)=[O:19])[CH2:13][CH:14]([CH3:15])[CH3:16])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)O
Product: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)Nc1ccc(S(N)(=O)=O)cc1

Procedure:
Observing the procedure of Example I, N-carbobenzyloxy-DL-leucine is reacted with 4-amino-benzenesulfonamide to yield the desired product, 4-(N-carbobenzyloxy-DL-leucylamino)benzene-sulfonamide having a mp. of 167°-8° C.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:7]=[C:8]([C:12]2([NH2:22])[CH2:21][CH2:20][C:15]3(OCC[O:16]3)[CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+]>C(O)(=O)C.O>[NH2:22][C:12]1([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH:7]=2)[CH2:13][CH2:14][C:15](=[O:16])[CH2:20][CH2:21]1
Reactant: CC(C)(C)c1cccc(C2(N)CCC3(CC2)OCCO3)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cccc(C2(N)CCC(=O)CC2)c1

Procedure:
A solution of 8-(3-tert-Butyl-phenyl)-1,4-dioxa-spiro[4.5]dec-8-ylamine hydrochloride (337 mg, 1.03 mmol) in glacial acetic acid (9 mL) and water (4 mL) was heated to 75° C. for 21 h, whereupon the reaction was deemed complete by HPLC analysis. The reaction mixture was basified with 2.5 N NaOH solution, then extracted with ethyl acetate (3×25 mL). The combined organic layers were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. Material was pure by HPLC/MS: retention time=1.18 min, method [7]; mass spec (ESI) 246 (MH+, 33), 229 (M−NH2+, 100), 228 (28), 173 (47).
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[CH3:15][O:16][C:17](=[O:43])[C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([C:36]3(O)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:28]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>CCOC(C)=O>[CH3:15][O:16][C:17](=[O:43])[C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([CH:36]3[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]3)=[CH:28]2)(=[O:25])=[O:26])=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(C3(O)CCCCC3)c3ccccc32)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(S(=O)(=O)n2cc(C3CCCCC3)c3ccccc32)cc1
Reaction time: 1.5 h
Yield: 87 %

Procedure:
Under N2, add triethylsilane (676 mg, 0.929 ml, 5.82 mmol, 2.6 eq) followed by trifluoroacetic acid (4.08 g, 2.7 ml, 35.79 mmol, 16.0 eq) to a CH2CL2 solution (20 ml) of 4-[3-(1-Hydroxy-cyclohexyl)-indole-1-sulfonyl]-benzoic acid methyl ester (925 mg, 2.24 mmol, 1 eq). Stir for 1.5 hours and then remove volatiles on rotovap. Add EtOAc to crude mix and workup with sat aqueous sodium bicarbonate. Extract product into organics, separate organics, dry over MgSO4, and concentrate on rotovap to give crude product as a pink oil. Purify by silica gel chromatography to give 4-(3-Cyclohexyl-indole-1-sulfonyl)-benzoic acid methyl ester (775 mg, 87% yield) as a white solid. Mass Spectrum (m/e): 397.99 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:4]([OH:13])=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2].S(Cl)([Cl:17])(=O)=O>C(#N)C>[Cl:17][C:12]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([OH:13])[C:3]=1[C:1]#[N:2]
Reactant: N#Cc1cc2c(cc1O)CCCC2
Reactant: O=S(=O)(Cl)Cl
Solvent: CC#N
Product: N#Cc1c(O)cc2c(c1Cl)CCCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 100 mL round-bottom flask was placed 5,6,7,8-tetrahydro-3-cyano-2-naphthol (1.0 g, 5.77 mmol, 1 eq, from Method II-2) in 20 mL of dry acetonitrile under argon. Sulfuryl chloride (6.09 mL, 28.85 mmol, 5.0 eq) was added dropwise. The reaction was stirred at rt for 18 h. The reaction mixture was concentrated and purified on silica gel (flash column chromatography) eluting with 20% ethyl acetate-hexane. A 1:1 diastereomeric mixture of 4-Chloro-3-hydroxy-5,6,7,8-tetrahydro-naphthalene-2-carbonitrile and 1-Chloro-3-hydroxy-5,6,7,8-tetrahydro-naphthalene-2-carbonitrile was obtained as a yellow liquid (887 mg, 66.6%, isomer ratio: 1:1). 1H-NMR (CD3CN) δ 7.81 (s, 1H), 3.24 (m, 1H), 2.66 (m, 1H), 2.33 (m, 1H), 2.07(m, 2H), 1.88 (m, 2H), 1.43 (m, 1H). GC-MS (M+=207).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:13]2[C:8](=[C:9]([O:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[O:7][C:6](=[O:22])[CH:5]=1.CS(C)=O.[Br:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([Cl:35])[C:33]=1Cl>[Cl-].[Na+].O>[Br:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([Cl:35])[C:33]=1[NH:3][C:4]1[C:13]2[C:8](=[C:9]([O:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[O:7][C:6](=[O:22])[CH:5]=1
Reactant: COc1ccc2c(N)cc(=O)oc2c1OC1CCCC1
Reactant: Clc1cncc(Br)c1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(Nc3c(Cl)cncc3Br)cc(=O)oc2c1OC1CCCC1
Reaction time: 0.17 h

Procedure:
Sodium hydride (7 mg, 60%, 0.18 mmol) was added to a solution of 4-amino-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one (77 mg, 0.28 mmol, Example 3, Step 1) and anhydrous DMSO (3 mL) under N2. After 10 min, 3-bromo-4,5-dichloropyridine (69 mg, 0.31 mmol) was added, and the reaction was stirred for 20 h, poured into brine, and extracted with EtOAc. The organic extract was dried, filtered, concentrated, and purified by reverse-phase HPLC (20→100% MeCN/H2O) to give 4-(3-bromo-5-chloropyridin-4-ylamino)-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one: 1H NMR (400 MHz, DMSO-d6): δ 9.54 (s, 1H), 8.91 (s, 1H), 8.84 (s, 1H), 7.95 (d, 1H), 7.21 (d, 1H), 4.85 (m, 1H), 4.59 (s, 1H), 3.92 (s, 3H), 1.87-1.79 (m, 4H), 1.68-1.54 (m, 4H); MS (ESI): 464.7.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH2:10][C:11](O)=[O:12])=[CH:5][CH:4]=1)#[N:2].[NH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([F:54])[C:28]=1[CH2:29][CH2:30][C@H:31]1[O:36][CH2:35][C@H:34]([CH2:37][O:38][C:39]([NH:41][CH2:42][C:43]([F:46])([F:45])[F:44])=[O:40])[N:33]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:32]1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH2:10][C:11]([NH:22][C:23]2[CH:24]=[N:25][CH:26]=[C:27]([F:54])[C:28]=2[CH2:29][CH2:30][C@H:31]2[O:36][CH2:35][C@@H:34]([CH2:37][O:38][C:39](=[O:40])[NH:41][CH2:42][C:43]([F:46])([F:44])[F:45])[N:33]([C:47]([O:49][C:50]([CH3:51])([CH3:53])[CH3:52])=[O:48])[CH2:32]2)=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cncc2F)OC[C@@H]1COC(=O)NCC(F)(F)F
Reactant: N#Cc1ccc([C@@H](CC(=O)O)c2ccc(F)c(F)c2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)C[C@H](c2ccc(C#N)cc2)c2ccc(F)c(F)c2)OC[C@H]1COC(=O)NCC(F)(F)F
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
The product from step 1 (50 mg, 0.16 mmol) and the product from step 4 of Example 89 (78 mg, 0.16 mmol) were dissolved in pyridine (1 mL) and the stirred solution was cooled to −10° C. in an ice/acetone bath. To the cold solution was added POCl3 dropwise (0.02 mL, 0.18 mmol). The mixture was stirred at −10° C. for 30 min. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution (1 mL) and the mixture was allowed to warm to ambient temperature. The mixture was diluted with water (10 mL) and extracted with dichloromethane (3×10 mL). The combined dichloromethane phases were dried (Na2SO4), filtered, and the filtrate solvents were removed in vacuo. The residue was purified on a 12 g silica gel column using a gradient elution of 0-100% EtOAc:hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give the title compound as a gum. (M+H-Boc)+=650.