Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][CH2:6][C@@:7]([OH:12])([CH3:11])[C:8](O)=[O:9].CCN(CC)CC.[NH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=1>C1COCC1.O>[Br:5][CH2:6][C@@:7]([OH:12])([CH3:11])[C:8]([NH:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=1)=[O:9]
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: C[C@](O)(CBr)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: C[C@](O)(CBr)C(=O)Nc1ccc(C#N)c(Cl)c1
Reaction time: 3 h

Procedure:
Thionyl chloride (7.8 g, 65.5 mmol) was added dropwise to a cooled solution (less than 4° C.) of (R)-3-bromo-2-hydroxy-2-methylpropanoic acid (9.0 g, 49.2 mol) in 50 mL of THF under an argon atmosphere. The resulting mixture was stirred for 3 h under the same condition. To this was added Et3N (6.6 g, 65.5 mol) and stirred for 20 min under the same condition. After 20 min, 4-amino-2-chlorobenzonitrile (5.0 g, 32.8 mmol) and 100 mL of THF were added and then the mixture was allowed to stir overnight at room temperature. The solvent was removed under reduced pressure to give a solid which was treated with 100 mL of H2O, extracted with EtOAc (2×150 mL). The combined organic extracts were washed with saturated NaHCO3 solution (2×100 mL) and brine (300 mL), successively. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give a solid which was purified from column chromatography using EtOAc/hexane (50:50) to give 7.7 g (49.4%) of target compound as a brown solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]2[N:27]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[N:26]=[N:25][N:24]=2)=[CH:11][C:10]=1[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39](O)=[O:40])[CH:34]=1)C1C=CC=CC=1.[N:42]1([CH2:47][CH2:48][N:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[CH2:46][CH2:45][CH2:44][CH2:43]1>>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([C:23]2[N:27]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[N:26]=[N:25][N:24]=2)=[CH:11][C:10]=1[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([N:52]2[CH2:51][CH2:50][N:49]([CH2:48][CH2:47][N:42]3[CH2:43][CH2:44][CH2:45][CH2:46]3)[CH2:54][CH2:53]2)=[O:40])[CH:34]=1
Reactant: C1CCN(CCN2CCNCC2)C1
Reactant: COCCCn1nnnc1-c1cc(-c2cccc(C(=O)O)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Product: COCCCn1nnnc1-c1cc(-c2cccc(C(=O)N3CCN(CCN4CCCC4)CC3)c2)c(O)cc1O

Procedure:
This product was synthesized using template 2′,4′-bis-benzyloxy-5′-(1-butyl-1H-tetrazol-5-yl)-biphenyl-3-carboxylic acid (44) and 1-(2-pyrrolidinoethyl)-piperazine as described in general procedure D. LCMS: 536 [M+H].
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[N:18]=[C:19]([NH2:22])[S:20][CH:21]=3)=[C:12]([CH3:23])[CH:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[N:18]=[C:19]([NH:22][C:34](=[O:41])[C:35]4[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=4)[S:20][CH:21]=3)=[C:12]([CH3:23])[CH:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(Oc2ccc(OC(C)C)cc2)cc(C)c1-c1csc(N)n1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Oc2ccc(OC(C)C)cc2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a solution of 4-(4-(4-isopropoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-amine (16-6, 0.25 g, 0.72 mmol) in CH2Cl2 (5.0 mL) was added triethylamine (0.5 mL, 3.59 mmol) followed by isonicotinoyl chloride hydrochloride (0.35 g, 1.94 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with water. The resultant precipitate was filtered and recrystallized in toluene to give N-{4-(4-(4-isopropoxypherioxy)-2,6-dimethylphenyl)thiazol-2-yl}isonicotinamide (16, 0.26 g) as light yellow solids in 79% yield: 1H NMR (500 MHz, DMSO-d6) δ 8.80 (d, J=5.1 Hz, 2 H), 7.98 (d, J=5.7 Hz, 1 H), 7.16 (s, 1 H), 6.95 (m, 4 H), 6.69 (s, 2 H), 4.55 (t, J=6.0 Hz, 2 H), 2.05 (s, 6 H), 1.27 (s, 3 H), 1.26 (s, 3 H). ESI-MS: m/z 460.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[CH2:13][CH2:12]1>C(O)C>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)[CH2:13][CH2:12]2)=[C:2]([Cl:1])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(CCN2CCN(c3ccc([N+](=O)[O-])cc3Cl)CC2)cc1
Solvent: CCO
Product: Nc1ccc(CCN2CCN(c3ccc(N)cc3Cl)CC2)cc1
Yield: 70.9 %

Procedure:
1-(2-Chloro-4-nitrophenyl)-4-(4-nitrophenethyl)piperazine (1.0 g), stannous chloride dihydrate (5.7 g) and ethanol (50 ml) were stirred under reflux for 1.25 hours, the mixture was evaporated to low bulk, and added to aqueous 5% sodium hydroxide (100 ml). The mixture was then extracted three times with dichloromethane and the combined organic extracts were dried (sodium sulphate) and evaporated to yield a yellow oil which solidified: yield of the title compound 0.6 g, m.p. 109°-112°. It was used in the next stage without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:22]=[C:21]([CH2:23][N:24]([CH3:35])[S:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:20]=[CH:19][C:9]=2[O:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[CH:4][C:3]=1[S:36]([CH3:39])(=[O:38])=[O:37]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:22]=[C:21]([CH2:23][N:24]([CH3:35])[S:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)(=[O:26])=[O:27])[CH:20]=[CH:19][C:9]=2[O:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[S:36]([CH3:39])(=[O:38])=[O:37]
Reactant: CN(Cc1ccc(OCC(=O)OC(C)(C)C)c(-c2ccc(F)c(S(C)(=O)=O)c2)c1)S(=O)(=O)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(Cc1ccc(OCC(=O)O)c(-c2ccc(F)c(S(C)(=O)=O)c2)c1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
To a solution of TFA/DCM (1:3, 10 mL) was added intermediate 31 (150 mg, 0.26 mmol, 1 eq) and the mixture was stirred at room temperature for 2 h. The organic solvent was removed in vacuo and the crude product was purified by reversed phase semi-preparative HPLC to afford 100 mg (73%) of 2-((4-fluoro-3-(methylsulfonyl)phenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)acetic acid (Example 28). 1HNMR (CD3CN, 300 MHz): δ 8.08 (m, 1H), 7.95 (m, 1H), 7.88 (m, 2H), 7.26-7.44 (m, 5H), 7.00 (d, 1H), 4.71 (s, 2H), 4.18 (s, 2H), 3.25 (s, 3H), 2.55 (d, 3H). MS (ES-API): MH−=524.1. HPLC (Method A) tR=2.02 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:13]([C:14]([NH2:16])=[O:15])=[C:12]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[NH:11][N:10]=2)=[CH:4][CH:3]=1.[C:26](O)(=[O:35])[C:27]1[C:28]([O:33][CH3:34])=[CH:29][CH:30]=[CH:31][CH:32]=1>CN(C=O)C>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][NH:17][C:12]2[NH:11][N:10]=[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:26](=[O:35])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])=[CH:7][CH:6]=3)[C:13]=2[C:14]([NH2:16])=[O:15])=[CH:20][CH:21]=1
Reactant: COc1ccccc1C(=O)O
Reactant: NC(=O)c1c(Nc2ccc(N)cc2)n[nH]c1NCc1ccc(O)cc1
Solvent: CN(C)C=O
Product: COc1ccccc1C(=O)Nc1ccc(Nc2n[nH]c(NCc3ccc(O)cc3)c2C(N)=O)cc1
Reaction time: 0.25 h
Yield: 12 %

Procedure:
3-((4-aminophenyl)amino)-5-((4-hydroxybenzyl)amino)-1H-pyrazole-4-carboxamide (150 mg) was dissolved in 8.0 mL of DMF and TEA (183 μL, 3.0 eq.) was then added to the reaction vessel. Reaction was then stirred on an ice bath for 15 min and o-Anisic acid (67 mg, 1.00 eq.) dissolved in DMF (2.0 mL) was slowly added into the reaction. The reaction continued stirring for 18 hrs and allowed to reach room temperature. The reaction was tracked via HPLC, once completed and no traces of starting material is present, the solvent was then removed via vacuo and column chromatography was used to purify the compound. A gradient of 0 to 20% MeOH in dichloromethane was used and the desired fractions were combined, evaporated and triturated with diisoproyl ether then filtered to yield product as an off white powder (0.025 g, 12.0% yield).
Reaction SMILES: Cl.[C:2]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]([C:18]([NH:20][C@@H:21]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[CH3:22])=[O:19])[NH2:17])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C(=O)(O)[O-].[Na+].[C:35]1([CH:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:42](Cl)=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[C:2]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]([C:18]([NH:20][C@@H:21]([C:23]1[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=1)[CH3:22])=[O:19])[NH:17][C:42](=[O:43])[CH:41]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:3]
Reactant: C[C@@H](NC(=O)[C@H](N)CCCNC(=O)OCc1ccccc1)c1ccc(O)cc1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)C(c1ccccc1)c1ccccc1)c1ccc(O)cc1

Procedure:
(R)-N5 -(Cbz)-(R)-N-[1-(4-hydroxyphenyl)ethyl]ornithine amide hydrochloride (28.1 g; 66.6 mmol; from step (c) above) was dissolved in THF (500 mL) and solid sodium bicarbonate (22.4 g; 266.4 mmol; 4 eq.) was slowly added. A solution of diphenylacetylchloride (21.4 g; 66.60 mmol) in THF was then slowly added dropwise over 30 minutes. The reaction was monitored by TLC analysis. After the reaction was judged complete, the solvent was removed under vacuum and the residue was dissolved in a mixture of THF, EtOAc and MeOH and washed with saturated aqueous sodium bicarbonate, water, saturated KHSO4 and brine. The organics were dried over Na2SO4, filtered and concentrated to dryness to yield 29.2 g (0.050 mol; 76%) of the sub-title compound.
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[CH:6][C:7]([F:10])=[N:8][CH:9]=1)[CH3:3].[CH3:11][C@@H:12]1[NH:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:10][C:7]1[N:8]=[CH:9][C:4]([C@H:2]([N:17]2[CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][C@@H:12]2[CH3:11])[CH3:3])=[CH:5][CH:6]=1
Reactant: CC(Br)c1ccc(F)nc1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H](c1ccc(F)nc1)N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C
Temperature: 70 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
A mixture of 5-(1-bromoethyl)-2-fluoropyridine (Example 146, Step 2; 8.95 g, 43.9 mmol) and (S)-tert-butyl 3-methylpiperazine-1-carboxylate (9.22 g, 46.1 mmol) (CNH Technologies Inc.) in acetonitrile (200 mL) was treated with K2CO3 (7.27 g, 52.6 mmol) and KI (1.456 g, 8.77 mmol). The mixture was placed into a pre-heated (70° C.)oil bath and allowed to stir under an inert atmosphere overnight. The heating bath was then removed and the reaction mixture was allowed to cool to ambient temperature. The reaction mixture was diluted with chloroform (200 mL) and water (300 mL). The organic layer was separated, and the aqueous layer was extracted with chloroform (1×100 mL). The combined organic layers were then washed with a saturated brine solution, dried over Na2SO4, filtered, and concentrated. The crude material was adsorbed onto silica gel and purified by column chromatography (120 g silica gel, 0% to 40% EtOAc/hexanes) to provide tert-butyl (3S)-4-((1R)-1-(6-fluoro-3-pyridinyl)ethyl)-3-methyl-1-piperazinecarboxylate (5.02 g, 15.52 mmol, 35.4% yield) (lower Rf diastereomer) as a viscous yellow-orange oil. m/z (ESI, +ve) 324.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.09-8.14 (m, 1H); 7.75 (td, J=8.0, 2.2 Hz, 1H); 6.90 (dd, J=8.5, 2.8 Hz, 1H); 3.94 (br. s., 1H, =); 3.55 (br. s., 1H); 3.37 (br. s., 2H); 3.20 (br. s., 1H); 2.71 (ddd, J=11.3, 7.6, 3.5 Hz, 1H); 2.43 (dd, J=9.6, 5.5 Hz, 2H); 1.43 (s, 9H); 1.38 (d, J=6.8 Hz, 3H); 0.99 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][P:4](Cl)[O:5][CH2:6][CH3:7])[CH3:2].[CH2:9]([Mg]Cl)[CH2:10][CH2:11][CH3:12]>CCOCC>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH3:12])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(Cl)OCC
Reactant: CCCC[Mg]Cl
Solvent: CCOCC
Product: CCCCP(OCC)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
Diethylchlorophosphite (18.8 gm, 0.12 moles) and 120 ml dry ether are combined in a round bottom flask equipped with a dropping funnel and under N2 atmosphere. With a double tipped canula, butyl magnesium chloride (60 ml; 2.0M, 0.12 moles; Aldrich Chemical Co., Milwaukee, Wis.) is added to the dropping funnel. The round bottom flask is cooled in a salt water/ice bath and the contents of the dropping funnel are slowly added to the cooled flask. After the addition is complete, the bath is removed and the solution is allowed to stir at room temperature for three hours. The precipitate which forms during the course of the reaction is then quickly filtered and washed with ether. The filtrate is concentrated by rotary evaporator to yield 21.17 gm of diethylbutylphosphonite. 31P NMR (CDCl3): 182 ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)([O:11][CH2:12][CH3:13])=[O:10].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[Br:8][C:4]1[N:3]=[C:2]([C:18]2[CH:19]=[C:14]([CH:15]=[CH:16][CH:17]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cccc(-c2cccc(Br)n2)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 19.3 %

Procedure:
Part A. A solution of 2,6-dibromopyridine (6.16 g, 26 mmol) and 3-carboethoxybenzeneboronic acid (0.5 g, 2.6 mmol) in acetonitrile (20 mL) is treated with a solution of sodium carbonate (0.88 g) in water (5 mL). The mixture is degassed twice, and a catalytic amount of tetrakis(triphenylphosphine)palladium is added. The reaction mixture is heated to 80° C. and stirred for 12 h., then cooled, filtered and evaporated. The residue is partitioned between water and ethyl acetate, and the organic phase is washed with satd. aq. brine, dried over sodium sulfate, filtered and evaporated. The residual material is separated by column chromatography to give ethyl 3-(6-bromo-pyridin-2-yl)-benzoate (154 mg, 20%).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]([F:28])([F:27])[C:23]([NH:25][NH2:26])=[O:24].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:26][NH:25][C:23](=[O:24])[C:22]([F:28])([F:27])[F:21])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)C(F)(F)F
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NNC(=O)C(F)(F)F)[C@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
To solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.25 g, 0.90 mmol) in dry DCM (20 mL) were added 2,2,2-trifluoroacetohydrazide 184 (0.17 g, 1.35 mmol, Aldrich), 1-hydroxybenzotriazole (0.19 g, 1.35 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4-(dimethylamino)pyridine (0.16 g, 1.35 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give (2R,5R)-6-(benzyloxy)-7-oxo-N′-(trifluoroacetyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 185 (0.224 g, 65%) as a white solid.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][C:21]=1[O:22]C(=O)C)[C:8]([NH:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:9])(=O)C>CO.O>[OH:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][C:21]=1[OH:22])[C:8]([NH:10][NH:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])=[O:9]
Reactant: CC(=O)Oc1ccc(C(=O)NNC(=O)OC(C)(C)C)cc1OC(C)=O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc(O)c(O)c1
Reaction time: 8 h

Procedure:
1-[3,4-bis(Acetyloxy)benzoyl]-2-[(t-butyloxy)carbonyl]hydrazine (2.6 g) was dissolved in 50 ml of methanol and 5 ml of water. At 0° C., ammonia (gas) was bubbled into the solution for 10 minutes. After standing overnight in a refrigerator, the solution was evaporated, and to the remaining oil, 10 ml of dichloromethane was added. This yielded 1.5 g of the title compound, melting point 148° C.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][C:12]([CH2:21][N:22]2[CH2:27][CH2:26][N:25]([S:28]([C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[C:36]([Cl:41])[CH:37]=4)[CH:32]=3)(=[O:30])=[O:29])[CH2:24][C:23]2=[O:42])([NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][CH2:10]1)=O)(C)(C)C>C(OCC)(=O)C.C(O)C>[ClH:41].[CH2:19]([O:18][C:16]([NH:15][C:12]1([CH2:21][N:22]2[CH2:27][CH2:26][N:25]([S:28]([C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[C:36]([Cl:41])[CH:37]=4)[CH:32]=3)(=[O:29])=[O:30])[CH2:24][C:23]2=[O:42])[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1)=[O:17])[CH3:20]
Reactant: CCOC(=O)NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 159 %

Procedure:
A 4N hydrochloric acid solution in ethyl acetate (30 ml) and ethanol (6 ml) were added to 1-[1-(tert-butoxycarbonyl)-4-ethoxycarbonylamino-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (5.21 g), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, the precipitated crystals were filtered, washed with ethyl acetate-ethanol, and dried to obtain 1-[4-ethoxycarbonylamino-4-piperidinylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone hydrochloride (3.71 g). Ethyl acetimidate hydrochloride(148 mg) and triethylamine (0.337 ml) were added to a solution of 1-[4-ethoxycarbonylamino-4-piperidinylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone hydrochloride (218 mg) in methanol (10 ml) under ice-cooling, and the mixture was stirred at room temperature overnight. After distillation of the solvent, purification by CHP20 column chromatography (water:acetonitrile:1N hydrochloric acid=100:0:0→60:40:0.5) afforded the colorless amorphous title compound (190 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([CH3:25])([O:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:26].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[CH3:17][C:16]([O:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])([CH3:25])[CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:26])[C:11]=2[N:12]=[CH:13]1
Reactant: CC(C)(Cn1cnc2c(Cl)nc3ccccc3c21)OCCS(C)(=O)=O
Reactant: N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(Cn1cnc2c(N)nc3ccccc3c21)OCCS(C)(=O)=O
Temperature: 150 °C

Procedure:
A suspension of 4-chloro-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinoline (4.30 g, 11.3 mmol) in a solution of ammonia in methanol (7 M, 43 mL) in a high pressure vessel was heated at 150° C. for 12 hours. The vessel was allowed to cool to room temperature. The mixture was concentrated under reduced pressure to afford a solid that was slurried in water (50 mL), saturated aqueous sodium carbonate, and methanol. The solid was isolated by filtration, washed with water, and purified by flash chromatography (silica gel, eluted with 10% methanol in dichloromethane) to provide a white solid. The solid was heated in methanol (200 mL) at reflux, isolated by filtration, washed with methanol, and dried to yield 2.2 g of 1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 261-264° C.
Reaction SMILES: [C:1]1([CH2:11][NH:12][C:13]([NH:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[N:19][N:20]3C(OC)=O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[NH:20]1[C:21]2[C:17](=[C:16]([NH:15][C:13]([NH:12][CH2:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)=[O:14])[CH:24]=[CH:23][CH:22]=2)[CH:18]=[N:19]1
Reactant: COC(=O)n1ncc2c(NC(=O)NCc3cccc4ccccc34)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(NCc1cccc2ccccc12)Nc1cccc2[nH]ncc12
Reaction time: 0.5 h

Procedure:
Methyl 4-({[(1-naphthylmethyl)amino]carbonyl}amino)-1H-indazole-1-carboxylate in methanol was treated with 5M sodium hydroxide (8 equivalents) (prepared by dissolution of 1 gram of sodium hydroxide in 20 μL of methanol). After stirring for 30 minutes, the mixture was diluted with water (10 mL) and filtered. The filter cake was washed with water (10 mL), water:methanol (1:1), and dried under reduced pressure to provide the title compound. MS (M+H)+ 317.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[CH:11][CH:10]=1.O>N1C=CC=CC=1>[C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccc(CCc2ccco2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(CCc2ccco2)cc1

Procedure:
Acetic anhydride (0.28 ml) was added dropwise to a solution of 2-[2-(4-aminophenyl)ethyl]furan (0.50 g) in pyridine (5 ml) at ambient temperature with stirring. After being stirred for 1 hour, the mixture was poured into water (50 ml) and the resulting precipitate was collected by filtration to give 2-[2-(4-acetamidophenyl)ethyl]furan (0.58 g).
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:8]([OH:9])=[CH:7][CH:6]=[N:5]1.[Cl:10][C:11]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>C(Cl)(Cl)Cl>[CH3:3][N:4]1[C:8]([O:9][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:11]=2[Cl:10])=[CH:7][CH:6]=[N:5]1
Reactant: Cn1nccc1O
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cn1nccc1OC(=O)c1ccc(Cl)cc1Cl
Temperature: 10 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
In 30 ml of an aqueous solution containing 4.0 g (0.1 mol) of sodium hydroxide was dissolved 9.8 g (0.1 mol) of 1-methyl-5-hydroxypyrazole at room temperature. To the resulting aqueous solution maintained at 10° C. was added dropwise a solution prepared from 23.0 g (0.11 mol) of 2,4-dichlorobenzoyl chloride and 100 ml of chloroform with stirring over 1 hour, followed by additional stirring for 2 hours at a temperature below about 20° C. Then the chloroform layer was separated and washed successively with water, 5% aqueous sodium bicarbonate and saturated brine and, after drying, solvent was distilled off under reduced pressure to give 23.5 g of 1-methyl-5-(2,4-dichlorobenzoyloxy)-pyrazole (yield: 86%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][C:25]([F:28])([F:27])[F:26])[CH:15]=[CH:16][CH:17]=2)[N:7]=1)=O)C.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>ClCCl>[CH3:11][C:9]1[N:8]([C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][C:25]([F:27])([F:28])[F:26])[CH:15]=[CH:16][CH:17]=2)[N:7]=[C:6]([CH:4]=[O:3])[CH:10]=1
Reactant: CCOC(=O)c1cc(C)n(-c2cccc(-c3ccccc3OC(F)(F)F)c2)n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1cc(C=O)nn1-c1cccc(-c2ccccc2OC(F)(F)F)c1
Reaction time: 0.33 h

Procedure:
To a solution of ethyl 5-methyl-1-[2′-(trifluoromethoxy)-1,1′-biphenyl-3-yl]-1H-pyrazole-3-carboxylate (from EXAMPLE 3) (1.1 g, 2.82 mmol) in anhydrous dichloromethane (10 mL) was added DIBAL-H in toluene solution (1.0M, 6.8 mL, 6.8 mmol) at −78° C. After stirring for 20 min at that temperature, the reaction was quenched with methanol as described above in EXAMPLE 123. Further work-up and purification, as described in EXAMPLE 123, produced the titled compound.