Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N+:24]([O-])=O)=[C:13]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:14]=2)=[CH:4][CH:3]=1.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:24][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:14][C:13]=1[CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCc1cc(Oc2ccc(Cl)nc2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1cc(Oc2ccc(Cl)nc2)ccc1N
Yield: 100.7 %

Procedure:
The reaction and post-treatment were carried out according to Example (1b) using tert-butyl{5-[(6-chloropyridin-3-yl)oxy]-2-nitrophenyl}methylcarbamate produced in Example (18a) (8.0 g, 21 mmol), iron powder (5.6 g, 105 mmol), ammonium chloride (0.56 g, 11 mmol), ethanol (40 mL) and water (20 mL) to obtain the title compound (7.4 g, 99%) as a brown oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.I[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[N:13]([CH:21]([CH3:23])[CH3:22])[N:12]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[CH:21]([N:13]1[C:14]2=[N:15][CH:16]=[N:17][C:18]([NH2:20])=[C:19]2[C:11]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:12]1)([CH3:23])[CH3:22]
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2cccnc2)c2c(N)ncnc21
Temperature: 80 °C

Procedure:
A solution of 3-Pyridinylboronic acid (15 mg, 0.14 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.13 mmol) in DME (12 ml). Pd(PPh3)4 (15 mg, 0.015 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O) to yield BA52. ESI-MS (M+H)+ m/z calcd 255.1, found 255.0.
Reaction SMILES: FC(F)OC1C=C2C(=CC=1)N(CCCN(C)C)N=C2[C:19]1[N:24]=[C:23]2[C:25]([C:47]([NH:49][C:50]3([CH3:53])[CH2:52][CH2:51]3)=[O:48])=[CH:26][N:27](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:22]2=[N:21][CH:20]=1.[F:55][C:56]([F:61])([F:60])[C:57]([OH:59])=[O:58]>ClCCl>[F:55][C:56]([F:61])([F:60])[C:57]([OH:59])=[O:58].[CH3:53][C:50]1([NH:49][C:47]([C:25]2[C:23]3=[N:24][CH:19]=[CH:20][N:21]=[C:22]3[NH:27][CH:26]=2)=[O:48])[CH2:51][CH2:52]1
Reactant: CN(C)CCCn1nc(-c2cnc3c(n2)c(C(=O)NC2(C)CC2)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(OC(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(NC(=O)c2c[nH]c3nccnc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
To a solution of 2-(5-(difluoromethoxy)-1-(3-(dimethylamino)propyl)-1H-indazol-3-yl)-N-(1-methylcyclopropyl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (200 mg, 0.3 mmol) in 3 mL of dichloromethane was added trifluoroacetic acid (3 mL). The reaction mixture was stirred at room temperature overnight. After solvent evaporation, the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1% trifluoroacetic acid V/V) initially, and then proceed to 50% acetonitrile/50% water (0.1% trifluoroacetic acid V/V) in a linear fashion after just 9 min) to afford 245-(difluoromethoxy)-1-(3-(dimethylamino)propyl)-1H-indazol-3-yl)-N-(1-methylcyclopropyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide trifluoroacetate (20 mg, 7%) as a yellow solid. LCMS: (M+H)+=484; 1H NMR (300 MHz, CD3OD): δ 9.04 (s, 1H), 8.13 (s, 1H), 8.02 (s, 1H), 7.61 (d, 1H, J=9.0 Hz), 7.29 (dd, 1H, J1=9.0 Hz, J2=2.1 Hz), 6.78 (t, 1H, J=73.8 Hz), 4.56-4.52 (m, 2H), 3.19-3.12 (m, 2H), 2.79 (s, 6H), 2.39-2.33 (m, 2H), 1.47 (s, 3H), 0.93-0.89 (m, 2H), 0.76-0.72 (m, 2H).
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]([OH:7])[C@H:5]([N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][C:11]([N:33]2[CH2:37][CH2:36][C@@H:35]([NH:38][C:39]([NH:41][C:42]4[CH:43]=NC=CC=4)=[O:40])[CH2:34]2)=[N:12][C:13]=3[NH:17][CH2:18][C:19]([OH:32])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:4][C@@H:3]1[NH:48][C:49](=[O:52])[CH2:50][OH:51].[C:53]1([O:59]C(=O)NC2C=NC=CC=2)[CH:58]=C[CH:56]=[CH:55][CH:54]=1>>[OH:1][C@H:2]1[C@@H:6]([OH:7])[C@H:5]([N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][C:11]([N:33]2[CH2:37][CH2:36][C@@H:35]([NH:38][C:39]([NH:41][CH2:42][C:43]4[CH:56]=[CH:55][CH:54]=[C:53]([OH:59])[CH:58]=4)=[O:40])[CH2:34]2)=[N:12][C:13]=3[NH:17][CH2:18][C:19]([OH:32])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:4][C@@H:3]1[NH:48][C:49](=[O:52])[CH2:50][OH:51]
Reactant: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(O)(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(O)(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)NCc5cccc(O)c5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to N-((1S,2R,3S,4R)-2,3-dihydroxy-4-{6-(2-hydroxy-2,2-diphenyl-ethylamino)-2-[(R)-3-(3-pyridin-3-yl-ureido)-pyrrolidin-1-yl]-purin-9-yl}-cyclopentyl)-2-hydroxy-acetamide (Example 192), by substituting (3-hydroxy-benzyl)-carbamic acid phenyl ester (Intermediate ZD) for pyridin-3-yl-carbamic acid phenyl ester (Intermediate ZB).
Reaction SMILES: [C:1]1([NH:11][C:12]2[C:13]3[CH:20]=[C:19]([C:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=4)[NH:18][C:14]=3[N:15]=[CH:16][N:17]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:27]([N:31]=[C:32]=[O:33])([CH3:30])([CH3:29])[CH3:28].C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CN(C)C=O>[C:27]([NH:31][C:32]([N:24]1[CH2:23][CH:22]=[C:21]([C:19]2[NH:18][C:14]3[N:15]=[CH:16][N:17]=[C:12]([NH:11][C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)[C:13]=3[CH:20]=2)[CH2:26][CH2:25]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: C1=C(c2cc3c(Nc4cccc5ccccc45)ncnc3[nH]2)CCNC1
Reactant: CC(C)(C)N=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)N1CC=C(c2cc3c(Nc4cccc5ccccc45)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension containing naphthalen-1-yl-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine (120 mg, 0.35 mmol), tert-butyl isocyanate (35 mg, 0.35 mmol) and N,N-diisopropylethylamine (122 μL, 0.70 mmol) in anhydrous N,N-dimethylformamide (2 mL) was stirred overnight at rt. The reaction mixture was poured into saturated NaHCO3 solution (50 mL) and extracted with EtOAc (3×50 ml). The combined organics were washed with brine (3×50 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (2 to 4% MeOH in DCM) gave the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ=8.13 (1H, s), 8.08-8.02 (2H, m), 7.89 (1H, d, J=8.1 Hz), 7.74-7.71 (1H, m), 7.63-7.54 (3H, m), 6.55 (1H, d, J=8.3 Hz), 6.43 (1H, s), 5.83 (1H, s), 4.04 (2H, s), 3.55 (2H, t, J=5.6 Hz), 2.42 (2H, s), 1.34 (9H, s); MS (ES+): m/z 441.08 [MH+], HPLC: tR=2.59 min (MicromassZQ, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=O)[C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[NH2:22][OH:23].N1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[C:3]([C:9](=[N:22][OH:23])[C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1ncc(Cl)cc1Cl
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=NO)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.7 %

Procedure:
To a solution of 1.0 g of tert-butyl (S)—N-[2-(3,5-dichloropyridin-2-yl)-1-methyl-2-oxoethyl]carbamate and 239 mg of hydroxylamine hydrochloride in 5 ml of ethanol, 272 mg of pyridine was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, the resulting residue was mixed with 10 ml of water and extracted with ethyl acetate (10 ml×2), the resulting organic layers were combined, dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 40:60) as the eluent to obtain 740 mg of the desired product as pale yellow crystals.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][CH2:9][CH:10]1[CH2:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:13]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:12]=2[NH:11]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[NH:8]([CH2:9][CH:10]1[CH2:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:13]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:12]=2[NH:11]1)[C:5]([CH3:6])=[O:7]
Reactant: NCC1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCC1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1
Reaction time: 0.33 h

Procedure:
iv. 7 ml of acetic anhydride were added to a solution of 6.16 g of crude 2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine in 200 ml of methylene chloride. The solution was layered with 200 ml of saturated aqueous sodium bicarbonate and the mixture was stirred for 20 minutes. The organic layer was separated, washed with sodium bicarbonate solution, dried over sodium sulphate and evaporated to leave 6.2 g of resinous 2-acetaminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine. This material was heated with 40 g of polyphosphoric acid at 150° C for 10 minutes. The cooled mixture was dissolved in water, made alkaline with ammonia and ice and extracted with methylene chloride. The extracts were dried and evaporated and the residue (5.7 g) was chromatographed over 120 g of silica gel using 20% methanol in methylene chloride. The clear fractions were combined and evaporated to yield resinous 8-chloro-3a,4-dihydro-6-(2-fluorophenyl)-1-methy,-4H-imidazo-[1,5-a][1,4]benzodiazepine. A mixture of this material with 500 ml of toluene and 30 g of manganese dioxide was heated to reflux for 1.5 hours. The manganese dioxide was separated by filtration over Celite. The filtrate was evaporated and the residue crystallised from diethyl ether to yield 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine of melting point 152°-154° C. An analytical sample was recrystallised from methylene chloride/hexane.
Reaction SMILES: [OH-:1].[Na+].CN(C)[C:5](=[O:34])[CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:15]=2)[C:10]([OH:25])=[C:9]([C:26]([NH:28][CH2:29][CH2:30][O:31][CH3:32])=[O:27])[C:8]1=[O:33]>>[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C:14]2[CH:15]=[C:16]3[C:11]([C:10]([OH:25])=[C:9]([C:26]([NH:28][CH2:29][CH2:30][O:31][CH3:32])=[O:27])[C:8](=[O:33])[N:7]3[CH2:6][C:5]([OH:34])=[O:1])=[N:12][CH:13]=2)=[CH:23][CH:22]=1
Reactant: [OH-]
Reactant: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Agent: [Na+]
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)O)c1=O

Procedure:
A 4N NaOH solution (22 mL) was added dropwise to a 100° C. suspension of 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[2-(methyloxy)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (5 g, 11 mmol; the title compound in Example 89) in DMSO (50 mL). The mixture was stirred for 1 h at 100° C., cooled to 10° C., diluted with H2O (10 mL), acidified by dropwise addition of conc. HCl (7 mL), diluted with EtOH and filtered to give the product as a white solid: 1H NMR (d6-DMSO) δ 13.22 (1H, br s), 10.18 (1H, m), 8.55 (1H, s), 8.03 (1H, s), 7.35 (2H, m), 7.11 (2H, m), 4.98 (2H, s), 4.11 (2H, s), 3.52 (4H, m), 3.28 (3H, s).
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH:6]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7]1[CH:15]=[C:14]2[C:10]([C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][NH:13]2)=[CH:9][CH:8]=1)[C:3]([OH:5])=O.[NH2:29][C:30]1[S:31][CH:32]=[CH:33][N:34]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][C:2]([CH3:28])([CH:6]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:7]1[CH:15]=[C:14]2[C:10]([C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][NH:13]2)=[CH:9][CH:8]=1)[C:3]([NH:29][C:30]1[S:31][CH:32]=[CH:33][N:34]=1)=[O:5]
Reactant: Nc1nccs1
Reactant: CC(C)(C(=O)O)C(c1ccccc1)c1ccc2c(-c3ccccc3)n[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C(=O)Nc1nccs1)C(c1ccccc1)c1ccc2c(-c3ccccc3)n[nH]c2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 28.6 %

Procedure:
To a stirred solution of 2,2-dimethyl-3-phenyl-3-(3-phenyl-1H-indazol-6-yl)propanoic acid (26 mg, 0.07 mmol), 2-aminothiazole (28 mg, 0.28 mmol), and diisopropylethylamine (0.05 mL) in anhydrous DMF (0.2 mL) was added HATU (106 mg, 0.28 mmol) under argon. After stirring at rt for 2.5 hr and 80° C. for 1 hr, the mixture was concentrated. Purification using reverse phase HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA) gave 2,2-dimethyl-3-phenyl-3-(3-phenyl-1H-indazol-6-yl)-N-(thiazol-2-yl)propanamide (Example 112, 9 mg, 0.02 mmol, 28% yield) as a solid. MS found: (M+H)+=453. 1H-NMR (500 MHz, CDCl3) δ ppm 7.96 (1H, d, J=8.25 Hz) 7.86 (2H, d, J=8.25 Hz) 7.50 (1H, d, J=8.25 Hz) 7.46 (2H, d, J=8.25 Hz) 7.39-7.43 (2H, m) 7.35 (2H, d, J=7.70 Hz) 7.17-7.26 (4 H, m), 6.96 (1H, d, J=3.30 Hz) 4.62 (1H, s) 1.45 (6H, d, J=3.85 Hz).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:15]>N1C=CC=CC=1>[SH:15][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(C)CC(=O)c1ccc(O)nc1
Solvent: c1ccncc1
Product: CC(C)CC(=O)c1ccc(S)nc1
Temperature: 120 °C
Yield: 15 %

Procedure:
Combine 2-hydroxy-5-(3-methyl-butyryl)-pyridine (742 mg, 4.1 mmol) and phosphorus pentasulfide (1.88 g, 4.2 mmol) in pyridine (5 mL). Heat the mixture at 120° C. for 5 h under a nitrogen atmosphere. Cool the mixture to room temperature and partition between water and EtOAc. Collect the aqueous layer, wash with additional EtOAc and DCM. Acidify the aqueous layer with 1M aqueous HCl and extract with DCM (4×30 mL). Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo to obtain the title compound (120 mg, 15%). MS (ES+) m/z: 196.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH3:7][C:5]1[O:4][N:3]=[C:2]([NH:1][S:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:16])=[O:15])[CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(N)no1
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccccc2)no1
Yield: 83.9 %

Procedure:
3-Amino-5-methylisoxazole (0.196 g, 2.0 mmol) was dissolved in dry pyridine (3 ml). Benzenesulfonyl chloride (0.352 g, 2.0 mmol) was added and the resultant solution stirred at room temperature for 16 h. Pyridine was removed under reduced pressure. The residue was dissolved in dichloromethane (75 ml) and washed with 1N HCl (2×50 ml). The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to give N-(5-methy-3-isoxazolyl)benzene-sulfonamide (0.40 g, 84% yield). The product was purified by recrystallization using ethyl acetate/hexanes to give a white solid, m.p. 107°-8° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1.[CH3:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]>>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:3][C:4]=1[CH3:10])=[O:7]
Reactant: Cc1cc(Br)ccc1C=O
Reactant: CNC(=O)OC(C)(C)C
Product: Cc1cc(CNC(=O)OC(C)(C)C)ccc1C=O

Procedure:
The title compound was prepared from crude 4-bromo-2-methylbenzaldehyde (D91) and 1,1-dimethylethyl methylcarbamate (D83) using a method similar to that described for D84 in Description 84. δH (CDCl3, 400 MHz) 10.20 (1H, s), 7.76 (1H, d), 7.28 (1H, dd), 7.19 (1H, d), 3.31 (3H, s), 2.66 (3H, s), 1.49 (9H, s).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[CH2:11]([O:17][C@H:18]([CH3:22])[C:19](Cl)=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:11]([O:17][C@H:18]([CH3:22])[C:19]([O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1)=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C(O)[C@H]1CC[C@H](O)CC1
Reactant: CCCCCCO[C@H](C)C(=O)Cl
Product: CCCCCCO[C@H](C)C(=O)O[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Using trans-4-hydroxycyclohexane carboxylic acid (1.01 g, 7 mmol) and (R)-2-n-hexyloxypropanoyl chloride (1.35 g, 7 mmol), the reaction was carried out in the same manner as described in Example 4, (1), to give the title compound as a pale yellow oil; yield: 750 mg.
Reaction SMILES: [S:1]([C:5]1[S:9][C:8]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20]C(=O)C)=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[N:7][N:6]=1)(=[O:4])(=[O:3])[NH2:2]>Cl>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([NH:10][C:8]2[S:9][C:5]([S:1]([NH2:2])(=[O:3])=[O:4])=[N:6][N:7]=2)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(S(N)(=O)=O)s2)cc1
Agent: Cl
Product: Nc1ccc(S(=O)(=O)Nc2nnc(S(N)(=O)=O)s2)cc1
Yield: 57.7 %

Procedure:
Compound 138 (1.0 g, 2.6 mmol) was heated at reflux with aqueous HCl (6 M, 10 mL) for 50 min. The homogeneous solution was evaporated to dryness and the residue was taken up in distilled water (10 mL). The pH was adjusted to 9 with 25% aqueous ammonia, the resulting solution was filtered to remove insoluble matter, and the solution acidified to pH 4 with glacial acetic acid. Cooling the solution overnight gave a solid, which was collected by filtration, washed with cold water, and air-dried. Recrystallization from 20% ethanol/H2O gave the pure product (500 mg, 1.5 mmol, 57%), mp 241-242° C. (lit17 mp 247-248° C.); 1H NMR (300 MHz, DMSO-d6) δ 6.58 (d, 2H, J=7.8 Hz), 7.43 (d, 2H, J=8.1 Hz), 8.43 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ 112.8, 125.9, 128.0, 153.1, 157.6, 166.0; LRMS (LCQ, ESI+) calcd for C8H10N5O4S3 336.0, found 335.8 (M+H)+; HRMS (ESI+, m/z) calcd for C8H10N5O4S3 335.9889, found 335.9883 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:32][NH:33][C:34]([NH:36][OH:37])=[NH:35].Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:32][NH:33][C:34](=[NH:35])[NH:36][OH:37])[CH2:10]1
Reactant: Cc1ccnc2c1C(=O)CC(c1c(Cl)cccc1Cl)C2
Reactant: N=C(NN)NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)NO)CC(c1c(Cl)cccc1Cl)C2
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
A mixture of 7-(2,6-dichlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (153 mg), 1-amino-3-hydroxyguanidine p-toluenesulfonate (262 mg) and concentrated hydrochloric acid (0.1 ml) in ethanol (3 ml) was stirred at 90° C. (bath temperature) for 1.5 hours. The reaction solution was concentrated under reduced pressure, and to the residue were added ethyl acetate (30 ml), tetrahydrofuran (20 ml) and 0.2 N sodium hydroxide (15 ml). The mixture was shaken, and the separated upper layer was washed with 0.2 N sodium hydroxide (10 ml) and water (10 ml, thrice). To the upper layer was added 2 N hydrochloric acid (0.5 ml), and the mixture was concentrated under reduced pressure. The residue was washed with a mixture of ether (3 ml) and ethanol (1.5 ml) and dried to give 7-(2,6-dichlorophenyl)-5-(1-hydroxyguanidin-3-yl)imino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 96) as pale yellow crystals.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][C:12]2[C:20]3[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=3[CH:15]=[C:14]([C:23]([OH:25])=O)[CH:13]=2)[CH2:3][CH2:2]1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][C:12]2[C:20]3[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=3[CH:15]=[C:14]([C:23]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)=[O:25])[CH:13]=2)[CH2:3][CH2:2]1
Reactant: Cc1nc2c(OC3CCOc4ccccc43)cc(C(=O)O)cc2n1C
Reactant: CN1CCNCC1
Product: Cc1nc2c(OC3CCOc4ccccc43)cc(C(=O)N3CCN(C)CC3)cc2n1C
Yield: 34 %

Procedure:
The title compound was prepared as a white solid in 34% yield (30 mg) from 4-(3,4-dihydro-2H-chromen-4-yloxy)-1,2-dimethyl-1H-benzimidazole-6-carboxylic acid (70 mg, 0.21 mmol, STEP 2 of Example 11) and 1-methylpiperazine (41 mg, 0.42 mmol) by the same manner in STEP 3 of Example 11:
Reaction SMILES: [Na].[CH2:2]([OH:14])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13].[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH:16]=[CH2:17].[Cl-].[NH4+]>O1CCCC1>[C:20]([O:19][C:15]([CH2:16][CH2:17][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:14][CH2:17][CH2:16][C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: OCCOCCOCCOCCO
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCOCCOCCOCCOCCOCCC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
0.4 g of sodium is added to a solution of 91 g of tetraethylene glycol in 250 ml of tetrahydrofuran, and the mixture is stirred at room temperature. Once the sodium has dissolved, 145 ml of tert-butyl acrylate are added. The mixture is stirred for 12 h. The reaction solution is neutralized with ammonium chloride, concentrated, taken up in aqueous sodium chloride solution and extracted with ethyl acetate. The organic phase is concentrated. The residue is 39.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:22][C:21]([C:23]([NH2:25])=O)=[C:20]([CH3:26])[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>O1CCCC1>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:22][C:21]([C:23](=[S:36])[NH2:25])=[C:20]([CH3:26])[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cc(C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)[nH]c1C(N)=O
Solvent: C1CCOC1
Product: Cc1cc(C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)[nH]c1C(N)=S
Temperature: 55 °C
Reaction time: 3 h
Yield: 85.2 %

Procedure:
To a solution (10 mL) of 5-{2-cyclopentyl-1-[4-(methylsulfonyl)phenyl]ethyl}-3-methyl-1H-pyrrole-2-carboxamide (135 mg) in tetrahydrofuran was added Lawesson's reagent (156 mg), and the mixture was stirred for 3 hr at 55° C. After cooling to room temperature, the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and the title compound (120 mg, yield 86%) was m obtained as yellow amorphous crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 391 (MH+).