Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH3:23])[CH:20]([CH3:22])[CH3:21])=[N:18][C:12]=2[O:11][C@@H:10]([CH2:24][O:25][CH3:26])[CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[ClH:33]>CO.[OH-].[OH-].[Pd+2]>[ClH:33].[CH3:26][O:25][CH2:24][C@H:10]1[CH2:9][NH:8][CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH3:23])[CH:20]([CH3:21])[CH3:22])=[N:18][C:12]=2[O:11]1
Reactant: COC[C@H]1CN(Cc2ccccc2)Cc2ncc(N(C)C(C)C)nc2O1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC[C@H]1CNCc2ncc(N(C)C(C)C)nc2O1
Temperature: 50 °C
Reaction time: 7 h
Yield: 61 %

Procedure:
To a solution of (6R)-8-benzyl-6-(methoxymethyl)-N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (261 mg) in methanol (7 mL) was added 20% Pd(OH)2/C (40 mg), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 7 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the obtained crude product in ethyl acetate (10 mL) was added a 4 N hydrogen chloride-ethyl acetate solution (200 μL), and the mixture was stirred for 30 min. The reaction mixture was filtered, and the obtained crystals were washed with ethyl acetate to give the title compound (136 mg, 61%).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:27])=[CH:12][C:13]([C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH3:19])[CH2:16][CH2:17][CH3:18])=[CH:14][C:4]=2[O:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[ClH:44].[N:45]1([CH2:51][CH2:52][CH2:53][C:54](O)=[O:55])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>C(Cl)Cl>[ClH:44].[CH3:28][C:2]1([CH3:1])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:27][C:54](=[O:55])[CH2:53][CH2:52][CH2:51][N:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)=[CH:12][C:13]([C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH3:19])[CH2:16][CH2:17][CH3:18])=[CH:14][C:4]=2[O:3]1
Reactant: CCCC(C)(c1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCC1
Reactant: O=C(O)CCCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCC(C)(c1ccc(F)cc1)c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2CCC1

Procedure:
5.0 g. (14.6 mmoles) of 4,4-dimethyl-9-hydroxy-7-(4-fluorophenyl-1-methylbutyl)-1,2,3,4-tetrahydrocyclopenta [c][1]benzopyran, prepared according to the method of Example 50, 3.14 g. (15.2 mmoles) of dicyclohexylcarbodiimide and 3.15 g. (15.2 mmoles) of γ-piperidinobutyric acid hydrochloride (m.p. 190°-192° ), Cruickshank & Sheehan, J. Am. Chem. Soc. 83, 2891 (1961), are combined with 250 ml. of methylene chloride and stirred for a total of 40 hours at room temperature. The insoluble by-product of dicyclohexylurea is separated by filtration and the methylene chloride is removed using a rotary evaporator. The brown residue is treated with approximately 75 ml. of benzene, and filtered to remove a small amount of insoluble material. The benzene is evaporated and the viscous residue is triturated with about 200 ml. of ether to give the crude product. Recrystallization from benzene yields the desired product.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH2:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:20]4=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]4[CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)=[CH:4][CH2:3]1>C1COCC1.CO.CC(O)=O.[Pt](=O)=O>[CH3:1][C:2]1([CH3:27])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[C:20]4=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]4[CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CC1(C)CC=C(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)CC1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1(C)CCC(Oc2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.9 %

Procedure:
Platinum(IV) oxide (40 mg) was added to a solution of 9-{4-[(4,4-dimethylcyclohex-1-en-1-yl)oxy]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (340 mg) in THF (dry) (30 mL), MeOH (30 mL) and AcOH (10 mL). The mixture was stirred at room temperature under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc, to remove catalytic poison). Platinum(IV) oxide (40 mg) was added and the mixture was stirred at 50° C. under hydrogen for 6 hr. Platinum(IV) oxide was added and the mixture was stirred 50° C. under hydrogen for 12 hr. The insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo with silica-gel. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo. The residue was crystallized from EtOAc/hexane. This was dissolved in THF, silica-gel was added to the solution and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc). The residue was crystallized from THF-EtOAc/IPE to give the title compound (37.6 mg) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6C(=O)C(NC(OC(C)(C)C)=O)C6C=CC=CC=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH2:65]([N:67]([CH:72]([C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)[C:73]([OH:75])=O)[C:68]([O:70][CH3:71])=[O:69])[CH3:66]>>[CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:73](=[O:75])[CH:72]([N:67]([CH2:65][CH3:66])[C:68]([O:70][CH3:71])=[O:69])[C:76]6[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC(C)(C)C)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: CCN(C(=O)OC)C(C(=O)O)c1ccccc1
Product: CCN(C(=O)OC)C(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Yield: 52 %

Procedure:
This compound was prepared using the procedure used to prepare [1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using (Ethyl-methoxycarbonyl-amino)-phenyl-acetic acid (0.097 g, 0.410 mmol) to provide {1-[2-(5-{6-[4-(2-{1-[2-(Ethyl-methoxycarbonyl-amino)-2-phenyl-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (0.120 g, 52%) as a white solid. LCMS-ESI+: calc'd for C49H54N8O6: 840.38 (M+); Found: 851.91 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:32][CH2:31][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]4)=[CH:19][C:18]=3[F:30])[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:40][S:41](Cl)(=[O:43])=[O:42].CO>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][CH:26]([O:29][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:25][CH2:24]4)=[CH:19][C:18]=3[F:30])[CH2:13][CH2:12]2)[CH2:31][CH2:32]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccc(C3CCC(O)CC3)cc1F)C2=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccc(C3CCC(OS(C)(=O)=O)CC3)cc1F)C2=O
Temperature: 0 °C
Yield: 64.6 %

Procedure:
To a solution of 2-[2-fluoro-4-(4-hydroxy-cyclohexyl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (530 mg, 1.18 mmol) in DCM (8 mL) was added Et3N (179 mg, 0.3 mL, 1.77 mmol, 1.5 equiv.). The solution was cooled to an ice-water bath and then de-aerated by vacuum/nitrogen exchange. To this solution was transferred a solution of methanesulfonyl chloride (202 mg, 1.77 mmol, 1.5 equiv.) in DCM (2 mL). The clear solution was stirred with the ice-water bath on all the time for 1 h. TLC (5% MeOH in DCM indicated that the reaction was complete. The reaction was quenched by diluting with DCM (10 mL), followed by addition of NaHCO3 aq. (5 mL). The two layers were separated and the aqueous layer was extracted with DCM (2×5 mL). The combined extracts were washed with NaHCO3 aq. (5 mL), brine (5 mL) and dried (K2CO3). The solution was filtered through a silica gel pad, eluted with 5% MeOH in DCM. The filtrate was concentrated to dryness and purified again on a silica gel column, eluted with 5% MeOH in DCM to eliminate the minor component to afford 0.4 g (64% yield) of the title compound as an off-white wax-like solid material.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].FC(F)(F)S([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])(=O)=O.[N+:20]([C:23]1[CH:24]=[C:25](O)[C:26](=[CH:28][CH:29]=1)O)([O-:22])=[O:21]>CC(C)=O>[F:17][C:14]([F:15])([F:16])[CH2:13][O:12][C:28]1[CH:29]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=[CH:25][C:26]=1[O:4][CH2:1][C:14]([F:17])([F:16])[F:15]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCC(F)(F)F)c(OCC(F)(F)F)c1

Procedure:
To a refluxing mixture of 12.7 g (0.092 mole) of potassium carbonate, 21.3 g. (0.092 mole) of 2,2,2-trifluoroethyl trifluoromethanesulfonate and 62 ml. of acetone is added dropwise 6.2 g. (0.040 mole) of 4-nitrocatechol in 62 ml. of acetone over about 2.5 hours. Refluxing is continued for a total of 24 hours, then the solution is evaporated. The residue is mixed with equal volumes of water and diethyl ether. The ether layer is separated, washed with water and saturated sodium chloride solution and dried. Evaporation provides crude 3,4-bis(2,2,2-trifluoroethoxy)nitrobenzene. Chromatographic purification on a silica gel column is effected by eluting with mixtures of chloroform and hexane. Recrystallization from cyclohexane with a small amount of benzene provides solid product, m.p. 63°-65° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@:7]([CH2:21][O:22][SiH3])(C(C)(C)C)[C:6]1(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:3])[CH3:2].C(O)(=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[C@H:7]([CH2:21][OH:22])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CN(C(=O)OC(C)(C)C)[C@@](CO[SiH3])(C(C)(C)C)C1(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Reaction time: 24 h
Yield: 79.8 %

Procedure:
To a stirred mixture of (2S,4S)-4-acetoxy-1-tert-butoxycarbonyl-2-tert-butyldiphenyl silyloxy methypyrrolidine (23.3 g, 46.9 mmol) and acetic acid (6.0 ml, 104.8 mmol) in THF (470 ml) was added TBAF (93.8 ml, 93.8 mmol) at 0° C. After 24 h stirring, the mixture was concentrated in vacuo. The resulting residue was diluted with EtOAC and aq. NH4Cl and extracted with EtOAc. The combined extracts were washed with brine, which were dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel [700 g, CHCl3/EtOAc (4/1)], to give (2S,4S)-4-acetoxy-1-tert-butoxycarbonyl-2-pyrrolidinemethanol (9.70 g, 8%) as a colorless oil. 1H-NMR (CDCl3) δ 1.47 (s, 9H), 1.63 (m, 1H), 1.81 (m, 1H), 2.07 (s, 3H), 2.34 (m, 1H), 3.42 (dd, J=12.7, 0.9 Hz, 1H), 3.62–3.85 (m, 31H), 4.48 (br, 1H), 5.20 (br, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:16]([CH3:19])([O-:18])=[O:17].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:19]/[N+:16]([O-:18])=[O:17])[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1ccc(C=O)cc1C
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(/C=C/[N+](=O)[O-])cc1C
Yield: 66.2 %

Procedure:
A solution of 3,4-dimethylbenzaldehyde (20 mL, 0.15 mol), ammonium acetate (12.5 g, 0.16 mol), glacial acetic acid (65 mL), nitromethane (34 mL, 0.63 mol), and acetic anhydride (3.0 mL, 0.032 mol) is refluxed for 2 hours. The reaction is concentrated to an oil, then dichloromethane (100 mL) is added, and the solution is washed with water (2×) and brine. The organic phase is dried (MgSO4), and concentrated to a dark green solid. This material is re-crystallized (treated with Darco) from 50% cyclohexane/hexanes to afford 17.6 g (66% yield) of the desired compound. 1H NMR (CDCl3) δ 8.08 (dd, J=2.4 Hz, 13.5 Hz, 1H), 7.61 (dd, J=2.4 Hz, 13.5 Hz, 1H), 7.31-7.36 (m, 2H), 7.25 (d, J=7.8 Hz, 1H), 2.36 (s, 3H), 2.35 (s, 3H); MS 329 (MH+).
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].[CH:17](=[O:22])/[CH:18]=[CH:19]/[CH2:20][CH3:21]>CCO>[C:2]([N:5]1[CH:17]([OH:22])[CH2:18][CH:19]([CH2:20][CH3:21])[C:6]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CC/C=C/C=O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)C(CC)CC(O)N1C(C)=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Sodium (4.02 g, 0.175 mol) was dissolved in a stirred solution of diethyl acetamidomalonate (235.4 g, 1.19 mol) in abs EtOH (1.4 L) at ambient temperature under argon. The reaction mixture was cooled to 0° C., and trans-2-pentenal (100 g, 1.08 mol) was added dropwise maintaining the reaction temperature at <5° C. After the addition, the reaction was allowed to warm to room temperature, stirred for 4 h, then quenched with acetic acid (28 mL). The solution was concentrated in vacuo, and the residue dissolved in EtOAc (1.5 L), washed with 10% NaHCO3 solution (2×300 mL), brine, and dried (MgSO4). The solution was filtered and concentrated to 700 mL, then heated to reflux and treated with hexane (1 L). On cooling, the title compound precipitated and was collected to give 287 g. 1H NMR (CD3OD) δ 5.65 (d, 1H, J=5 Hz), 4.1-4.25 (m, 4H), 2.7-2.8 (m, 1H), 2.21 (s, 3H), 2.10 (dd, 1H, J=6, 13, Hz), 1.86-1.97 (m, 2H), 1.27 (t, 3H, J=7 Hz), 1.23 (t, 3H, J=7 Hz), 1.1-1.25 (m, 1H), 0.97 (t, 3H, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:18])=[CH:5][C:6]=1[CH:7]1[CH2:15][C:14]2[NH:13][N:12]=[C:11]([CH3:16])[C:10]=2[C:9](=O)[CH2:8]1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[S:3][C:4]([Cl:18])=[CH:5][C:6]=1[CH:7]1[CH2:15][C:14]2[NH:13][N:12]=[C:11]([CH3:16])[C:10]=2[C:9](=[N:23][NH:22][C:19]([NH2:21])=[NH:20])[CH2:8]1
Reactant: Cc1n[nH]c2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1n[nH]c2c1C(=NNC(=N)N)CC(c1cc(Cl)sc1Cl)C2
Yield: 209.1 %

Procedure:
To a mixture of 6-(2,5-dichlorothiophen-3-yl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (0.3 g) and aminoguanidine hydrochloride (122 mg) were added ethanol (5 ml) and concentrated hydrochloric acid (0.1 ml), and the mixture was refluxed for 4 hours and cooled. Precipitated crystals were filtered, washed with ethanol and dried to give 6-(2,5-dichlorothiophen-3-yl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 127) (0.41 g) as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH3:2].[C:17](=O)([O-])[O-].[Cs+].[Cs+].IC>C(#N)C.ClCCl>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]([S:12]([CH3:15])(=[O:13])=[O:14])[CH3:17])[CH3:2]
Reactant: CCOC(=O)c1ccccc1NS(C)(=O)=O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CI
Product: CCOC(=O)c1ccccc1N(C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
195 b) To a stirred suspension of 2-methanesulfonylamino-benzoic acid ethyl ester (1.0 g, 4.1 mmol) and cesium carbonate (1.5 g, 4.5 mmol) in acetonitrile (10 mL) was added iodomethane (0.28 mL, 4.5 mmol). The mixture was stirred at room temperature for 18 hours then diluted with dichloromethane (30 mL), filtered through a plug of diatomaceous earth and evaporated. 2-(Methanesulfonyl-methyl-amino)-benzoic acid ethyl ester was isolated as a clear viscous oil (1.08 g, 100%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.90 (d, J=7.7 Hz, 1H), 7.55 (t, J=7.7 Hz, 1H), 7.47-7.38 (m, 2H), 4.38 (q, J=7.0 Hz, 2H), 3.32 (s, 3H), 2.96 (s, 3H), 1.41 (t, J=7.1 Hz, 3H). MS=280 (M+Na)+.
Reaction SMILES: Cl[N:2]1[C:6](=O)[CH2:5][CH2:4][C:3]1=[O:8].[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[CH:24]=[CH:23][N:22]=[C:21](SC)[N:20]=2)=[N:11]1.O.CN1C(=O)C[CH2:31][CH2:30]1>>[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:2][C@H:6]3[CH2:31][CH2:30][C@H:3]([OH:8])[CH2:4][CH2:5]3)[N:20]=2)=[N:11]1
Reactant: CSc1nccc(-c2nn(C)c3ccccc23)n1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1CCCC1=O
Solvent: O
Product: Cn1nc(-c2ccnc(N[C@H]3CC[C@H](O)CC3)n2)c2ccccc21
Reaction time: 1 h

Procedure:
N-Chlorosuccinimide (239 mg, 1.77 mmol) was added to a solution of 1-methyl-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-indazole (413 mg, 1.6 mmol) in NMP, and the resulting mixture was stirred at 85° C. for 15 min. trans-Aminocyclohexanol was then added, the reaction mixture stirred for 1 h, then poured into water and extracted twice with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude residue was purified by preparative TLC to give trans-4-[4-(1-methyl-1H-indazol-3-yl)-pyrimidin-2-ylamino]-cyclohexanol. MS=324 [M+H]+; MP=180-183.3° C. (Compound 77).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][CH3:6].[NH2:8][C:9]1[N:10]=[C:11]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:12]([C:19]2[CH:20]=[CH:21][C:22](=[O:28])[N:23]([CH:25]([CH3:27])[CH3:26])[N:24]=2)=[N:13][C:14]=1S(C)(=O)=O.Cl>CCCCCC>[NH2:8][C:9]1[N:10]=[C:11]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:12]([C:19]2[CH:20]=[CH:21][C:22](=[O:28])[N:23]([CH:25]([CH3:27])[CH3:26])[N:24]=2)=[N:13][C:14]=1[O:7][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(C)n1nc(-c2nc(S(C)(=O)=O)c(N)nc2-c2ccccc2)ccc1=O
Reactant: CCCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: CCCCOc1nc(-c2ccc(=O)n(C(C)C)n2)c(-c2ccccc2)nc1N
Temperature: 27.5 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60% in oil suspension) (31.1 mg) in 1,2-dimethyl-2-imidazolidinone (0.6 ml) was added to 1-butanol (0.0716 ml) and the mixture was stirred at 25-30° C. for 30 minutes. 6-[5-Amino-6-(methylsulfonyl)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (150 mg) was added and the mixture was heated at 100-105° C. for 15 hours. After addition of 0.1N HCl (3 ml) was added to the mixture and a precipitate was collected by filtration. The precipitate was dissolved in CHCl3, dried over MgSO4, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (80:20 v/v) to give a solid. The solid was suspended in hexane and collected by filtration to give 6-(5-amino-6-butoxy-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (83 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[CH2:7][CH2:8][C:9]#[N:10])[CH3:2].[OH-:16].[Na+]>O>[CH2:14]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[CH2:7][CH2:8][C:9]([NH2:10])=[O:16])[CH3:15]
Reactant: CCN(CC)c1cccc(CCC#N)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CCN(CC)c1cccc(CCC(N)=O)c1
Temperature: 60 °C

Procedure:
A mixture of 40 parts of 3-diethylamino-hydrocinnamonitrile, 34 parts by volume of 66° Be sulphuric acid and 6 parts of water was heated at 100°-105° C. for an hour. The reaction mixture was then left to cool to about 60° C., then poured on 500 parts of ice. It was neutralized by addition of about 160 parts by volume of a 35° Be solution of sodium hydroxide, while assuring that the temperature of the mixture did not exceed 20° C. After filtering and washing with water, 3-diethylamino-hydrocinnamamide was obtained of the formula: ##STR15## which melted at 59° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[CH:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].[CH2:11]([O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[C:12]#[C:13][CH3:14]>>[CH3:2][O:3][C:4](=[O:10])[CH:5]([NH:6][S:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:11][C:12]#[C:13][CH3:14])=[CH:21][CH:20]=1)(=[O:24])=[O:23])[CH:7]([CH3:9])[CH3:8]
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C(N)C(C)C
Agent: Cl
Product: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)C(C)C)cc1

Procedure:
According to the procedure of Example 20, 1.500 g (8.95 mmol) of D,L-valine methyl ester hydrochloride and 2.19 g (8.95 mmol) of 4-but-2-ynyloxy-benzenesulfonyl chloride provided 2.15 g of the NH-sulfonamide ester, 2-(4-but-2-ynyloxy-benzenesulfonylamino)-3-methyl-butyric acid methyl ester, as a white solid.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N:15]([C:20]3[CH:30]=[CH:29]C=C[C:21]=3[C:22](OCC)=O)[CH2:16][CH:17]3[CH2:19][CH2:18]3)=[C:11]([CH3:14])[CH:12]=2)[C:7]([CH3:32])([CH3:31])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[OH-:33].[K+].[CH2:35]([OH:37])[CH3:36]>>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N:15]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[C:20]3[CH:30]=[CH:29][C:36]([C:35]([OH:33])=[O:37])=[CH:22][CH:21]=3)=[C:11]([CH3:14])[CH:12]=2)[C:7]([CH3:32])([CH3:31])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccccc1N(CC1CC1)c1cc2c(cc1C)N(C(C)C)CCC2(C)C
Reactant: CCO
Reactant: [OH-]
Agent: [K+]
Product: Cc1cc2c(cc1N(CC1CC1)c1ccc(C(=O)O)cc1)C(C)(C)CCN2C(C)C
Temperature: 40 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
4 Ethyl [(1-isopropyl-4,4,7-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl)(cyclopropylmethyl)amino]benzoate (Compound 25, 0.1 g, 0.2 mmol) was dissolved in ethanol (4.0 mL) and the solution treated with 1.7 M KOH (1.0 mL). The solution was heated to 40° C. and stirred for 24 hours. The solution was cooled and concentrated under reduced pressure. The residue was diluted with water, acidified with 10% HCl, and extracted with ether (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. Purification by recrystallization in ethanol gave the title compound (63 mg, 67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C(N(CC)CC)C.[C:32](Cl)(Cl)=[S:33].[NH2:36][CH2:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:32]([NH:36][CH2:37][CH2:38][CH2:39][N:40]2[CH2:41][CH2:42][N:43]([CH3:46])[CH2:44][CH2:45]2)=[S:33])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: S=C(Cl)Cl
Reactant: CN1CCN(CCCN)CC1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=S)NCCCN4CCN(C)CC4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 12.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (51 mg) was dissolved in N,N-dimethylformamide (2 ml) and triethylamine (1 ml) to prepare a solution. Thiophosgene (51 mg) was then added to the solution, and the mixture was stirred at room temperature for 6 hr. Next, 1-(3-aminopropyl)-4-methylpiperazine (50 mg) was added thereto, and the mixture was further stirred at room temperature for 16 hr. Ethyl acetate was added to the reaction solution, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (10 mg, yield 11%).