Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:31]=[C:30]([C:32]([N:34]2[CH2:43][C:42]3[CH:41]=[N:40][N:39]([CH3:44])[C:38]=3[NH:37][C:36]3[CH:45]=[CH:46][CH:47]=[CH:48][C:35]2=3)=[O:33])[CH:29]=[CH:28][C:27]=1[CH2:49][CH2:50][CH2:51][CH2:52][C:53]([OH:55])=O.Cl.Cl.[CH3:58][C:59]([CH3:69])([CH3:68])[CH2:60][CH2:61][N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:58][C:59]([CH3:69])([CH3:68])[CH2:60][CH2:61][N:62]1[CH2:63][CH2:64][N:65]([C:53](=[O:55])[CH2:52][CH2:51][CH2:50][CH2:49][C:27]2[CH:28]=[CH:29][C:30]([C:32]([N:34]3[CH2:43][C:42]4[CH:41]=[N:40][N:39]([CH3:44])[C:38]=4[NH:37][C:36]4[CH:45]=[CH:46][CH:47]=[CH:48][C:35]3=4)=[O:33])=[CH:31][C:26]=2[CH3:25])[CH2:66][CH2:67]1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCCCC(=O)O
Reactant: CC(C)(C)CCN1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCCCC(=O)N1CCN(CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
HBTU (104 mg, 0.27 mmol) was added to a solution of 5-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-pentanoic acid from E83.2 (105 mg, 0.25 mmol) and 1-(3,3-dimethyl-butyl)-piperazine dihydrochloride from Example E4 (69 mg, 0.28 mmol) in DMF (10 ml) and DIEA (0.2 ml, 1.15 mmol). The mixture was stirred for 24 h at room temperature then concentrated in vacuo. The residue was dissolved in di-chloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 4% methanol:96% dichloromethane to 8% methanol:92% di-chloromethane) to give a white solid identified as the title compound (88 mg, 62%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[N:12]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:8]3[C:9]2=[C:4]([CH2:5][CH2:6][N:7]3[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[N:3]=1.[OH:42][C:43]([CH3:56])([CH3:55])[C@@H:44]([NH:51][C:52]([NH2:54])=[O:53])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C(Cl)Cl>[OH:42][C:43]([CH3:56])([CH3:55])[C@@H:44]([NH:51][C:52]([NH:54][C:2]1[CH:11]=[C:10]2[N:12]([C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:13]=[C:8]3[C:9]2=[C:4]([CH2:5][CH2:6][N:7]3[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[N:3]=1)=[O:53])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CC(C)(O)[C@@H](NC(N)=O)c1ccccc1
Reactant: COc1ccc(CN2CCc3nc(Cl)cc4c3c2nn4C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: COc1ccc(CN2CCc3nc(NC(=O)N[C@@H](c4ccccc4)C(C)(C)O)cc4c3c2nn4C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
7-chloro-3-(4-methoxybenzyl)-1-trityl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridine (40 mg, 0.072 mmol), (S)-1-(2-hydroxy-2-methyl-1-phenylpropyl)urea (22.4 mg, 0.108 mmol), cesium carbonate (82 mg, 0.25 mmol) and BrettPhos pre-catalyst (6.5 mg, 7.18 μM) were charged in a 1 dram vial, evacuated and backfilled with nitrogen and taken in 1,4-dioxane (0.4 mL) and heated reaction to 100° C. for 30 minutes. The reaction mixture was diluted with DCM, washed with water, brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-75% EtOAc-hexanes) gave (S)-1-(2-hydroxy-2-methyl-1-phenylpropyl)-3-(3-(4-methoxybenzyl)-1-trityl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridin-7-yl)urea. MS ESI calc'd. for C46H44N6O3 [M+H]+ 729. found 729.
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.[CH3:23]O>>[CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:23])=[O:16])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nccc2ccc(C(=O)O)cc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCCCc1nccc2ccc(C(=O)OC)cc12

Procedure:
A solution of 1-butylisoquinoline-7-carboxylic acid (325 mg, 1.41 mmol) in methanol (25 mL) containing concentrated sulfuric acid (800 μL) was refluxed overnight. The reaction mixture was then concentrated under reduced pressure, diluted with methylene chloride, washed with water, and saturated sodium chloride. The organic layer was then dried (sodium sulfate), filtered, and concentrated to yield methyl 1-butylisoquinoline-7-carboxylate (350 mg): ESI MS m/z 244 [M+H]+;
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:16]=[CH:15][C:9]2[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=2[CH:7]=1)[CH:3]=O.[CH3:17][O:18][C:19]1[N:24]=[N:23][C:22]([NH2:25])=[CH:21][CH:20]=1.O>C(O)CCC>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:2]([CH2:5][C:6]3[CH:16]=[CH:15][C:9]4[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=4[CH:7]=3)=[CH:3][N:25]=2)[N:24]=1
Reactant: CSc1nc2ccc(CC(Cl)C=O)cc2s1
Reactant: COc1ccc(N)nn1
Solvent: O
Solvent: CCCCO
Product: COc1ccc2ncc(Cc3ccc4nc(SC)sc4c3)n2n1
Temperature: 25 °C
Yield: 66.4 %

Procedure:
A stirred mixture of 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal from Step 4 of Example 117 (600 mg, 2.2 mmol) and 6-methoxypyridazin-3-amine (550 mg, 4.4 mmol) in 1-butanol (20 mL) was heated at reflux overnight. The mixture was cooled to rt and water (40 mL) was added. The mixture was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 20:1 DCM/MeOH to afford 6-((6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole as a light brown solid (500 mg, 66%). 1H NMR (300 MHz, CDCl3) δ 7.79-7.73 (m, 2H), 7.67 (d, J=1.2 Hz, 1H), 7.43 (s, 1H), 7.38 (dd, J=1.5, 8.4 Hz, 1H), 6.64 (d, J=9.6 Hz, 1H), 4.33 (s, 2H), 3.94 (s, 3H), 2.78 (s, 3H). LCMS (ESI) m/z 343 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:19][CH3:20])=[C:7]([CH:18]=1)[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].P(Br)(Br)[Br:22]>CCOCC>[Br:22][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:19][CH3:20])=[C:7]([CH:18]=1)[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: BrP(Br)Br
Reactant: COc1ccc(CO)cc1C(=O)OCc1ccccc1
Solvent: CCOCC
Product: COc1ccc(CBr)cc1C(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 179.6 %

Procedure:
Benzyl 5-hydroxymethyl-2-methoxybenzoate (Patent Application No. Hei 11-162235) (15.5 g, 56.9 mmol) and 300 ml of dehydrated ether were mixed and phosphorus tribromide (2.0 ml, 21.1 mmol) was added dropwise under stirring and cooling with ice, which was further stirred for 1 hour. Ice water was added to the reaction mixture and ether layer was separated. The ether layer was washed with water, saturated sodium hydrogencarbonate and brine in sequence, then dried over anhydrous sodium sulfate and concentrated. The crystals obtained were recrystallized from diisopropyl ether to obtain 12.7 g (66%) of the aimed compound as colorless prisms.
Reaction SMILES: C1CO[C:3]2([C:9]3[CH:10]=[CH:11][C:12]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:13][C:8]=3[CH:7]=[CH:6][C:5]3[CH:19]=[CH:20][CH:21]=[CH:22][C:4]2=3)[O:2]1.CC(C)=O>O>[CH:13]1[C:8]2[CH:7]=[CH:6][C:5]3[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=3[C:3](=[O:2])[C:9]=2[CH:10]=[CH:11][C:12]=1[CH:14]([CH3:18])[C:15]([OH:17])=[O:16]
Reactant: CC(C(=O)O)c1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Solvent: CC(C)=O
Solvent: O
Product: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Yield: 90 %

Procedure:
2.0 Gm. of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid is dissolved in 20 ml. of acetone and to the solution is added 20 ml. of N-hydrochloric acid. The mixture is refluxed for one hour, then cooled, diluted with water, and extracted with ethyl acetate. The extract is washed, dried, and evaporated to give a 90% yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid, m.p. (chloroform-hexane) 138°-139°C.; m.p. (acetone-hexane) 113°-115°C. Use of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)acetic acid gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetic acid, m.p. (acetone-hexane) 148°-149.5°C.
Reaction SMILES: O[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.OS(O)(=O)=O.[OH-].[Na+].[CH:19]([OH:21])=[O:20]>>[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[C:19]([OH:21])=[O:20])[CH2:9]2
Reactant: O=CO
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1C2CC3CC(C2)CC1C3
Reaction time: 1.5 h

Procedure:
hydroxyadamantane were dissolved in 30 mls of HCOOH 98-100 %, and this solution was added dropwise, while stirring vigorously, to 1.5 1. of H2SO4 96% cooled to 5°C. Stirring was then continued at the same temperature for 90 minutes and the mixture was finally poured out on ice. NaOH was added to the mixture until it has a pH of approximately 1 and the formed precipitate was extracted with diethyl ether. The extract was dried over Na2SO4 and the solvent was then evaporated. The cruse 2-adamantyl carboxylic acid was thus obtained, which was purified by two crystallizations from 70% ethanol. The purified acid had a melting point of 142-144°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH:10]([NH2:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[NH2:35][S:36]([C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1)(=[O:38])=[O:37].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:35][S:36]([C:39]1[CH:40]=[CH:41][C:42]([C:43]([NH:25][C@H:10]2[C@@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)=[O:44])=[CH:46][CH:47]=1)(=[O:37])=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)C(N)C1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)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)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](NC(=O)c2ccc(S(N)(=O)=O)cc2)C1
Reaction time: 8 h
Yield: 45.9 %

Procedure:
1-tert-butoxycarbonyl-3-amino-4-(benzyloxycarbonyl)amino-piperidine (151b) (300 mg) was dissolved in DMF (5 mL) prior to addition of Hunig's base (0.45 mL). 4-(aminosulfonyl)benzoic acid (210 mg) was added followed by BOP (420 mg). The solution was stirred for 8 h then quenched with aqueous NH4Cl. The mixture was partitioned between EtOAc and water. The organic layer was washed with NaHCO3, 5% LiCl (3×), and brine. The organic layer was dried, filtered, and concentrated. Flash chromatography of the residue provided tert-butyl (cis)-3-{[4-(aminosulfonyl)benzoyl]amino}-4-{[(benzyloxy)carbonyl]amino}-1-piperidinecarboxylate (210 mg). MS found: (M−H)−=531.3.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:23]=[CH:22][C:10]([O:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:9][CH:8]=1)=O.Cl.[O:28]1[C:32]2[CH:33]=[CH:34][C:35]([NH:37][NH2:38])=[CH:36][C:31]=2[O:30][CH2:29]1>>[O:28]1[C:32]2[CH:33]=[CH:34][C:35]([N:37]3[C:5]([C:7]4[CH:23]=[CH:22][C:10]([O:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:9][CH:8]=4)=[CH:4][C:3]([C:2]([F:26])([F:25])[F:1])=[N:38]3)=[CH:36][C:31]=2[O:30][CH2:29]1
Reactant: NNc1ccc2c(c1)OCO2
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Agent: Cl
Product: CC(C)(C)OC(=O)NCCOc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc3c(c2)OCO3)cc1
Yield: 56.7 %

Procedure:
The title compound (371.3 mg, 56.7%) was prepared from tert-butyl 2-[4-(4,4,4-trifluoro-3-oxobutanoyl)-phenoxy]ethylcarbamate obtained by Example 78-2 and 1-(1,3-benzodioxol-5-yl)hydrazine hydrochloride obtained by Example 83-1 in a similar manner to that of Example 78-3.
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([CH2:12][O:13][CH2:14][C@@H:15]1[CH2:19][C@@H:18]([O:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][N:16]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1)=[O:26])(O)=[O:10].C([N:40](CC)CC)C.O.N>O1CCCC1.O>[C:9]([CH2:12][O:13][CH2:14][C@@H:15]1[CH2:19][C@@H:18]([O:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][N:16]1[C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=1)=[O:26])(=[O:10])[NH2:40]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.5 h

Procedure:
A solution of isobutyl chloroformate (0.60 g) in tetrahydrofuran (1 ml) was dropwise added to a solution of (2S,4R)-2-(carboxymethyloxymethyl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.28 g) and triethylamine (0.82 ml) in tetrahydrofuran (13 ml) at -10°~-5° C., and the mixture was stirred at the same temperature for 30 minutes. The mixture was dropwise added to concentrated ammonia water (10 ml) at 0°-5° C. and the solution was stirred at the same temperature for 1 hour. The mixture was poured into water (50 ml) and extracted with chloroform (50 ml). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (25 g) and eluted with a mixture of methanol and chloroform (2:98 V/V) to give (2S,4R)-2-(carbamoylmethyloxymethyl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.00 g).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:14])=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:18]/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22]>CN(C=O)C.O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:14][CH2:18]/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(O)c(Br)cc21
Reactant: COC(=O)/C=C/CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)/C=C/COc1cc2c(cc1Br)N(C(C)=O)CC2
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 67.8 %

Procedure:
1-Acetyl-6-bromo-5-hydroxyindoline (Tetrahedron, 1973, 29 (8), 1115) (2.54 g, 10 mmol) was stirred under Ar in dry DMF (50 ml) as sodium hydride (80%, 0.33 g, 11 mmol) was added over 10 min. After a further 10 min, methyl 4-bromocrotonate (1.75 ml, 15 mmol) was added. The mixture was stirred at 60° C. for 2 h, cooled, and diluted with water. The precipitated material was filtered off and washed with water and ether, affording the title compound (2.40 g, 68%) as a brown solid. NMR showed a mixture of isomers (ca. 1:1).
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N+:10]([C:13]1[CH:26]=[CH:25][C:16]([C:17]([O:19][CH2:20][C@:21]2([CH3:24])[CH2:23][O:22]2)=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11].C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[N:3]([CH2:24][C@@:21]([OH:22])([CH3:23])[CH2:20][O:19][C:17](=[O:18])[C:16]2[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:26][CH:25]=2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@]1(COC(=O)c2ccc([N+](=O)[O-])cc2)CO1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@](O)(COC(=O)c1ccc([N+](=O)[O-])cc1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 62.5 °C
Reaction time: 10 h
Yield: 87.2 %

Procedure:
2-Chloro-4-nitro-1H-imidazole (3 g, 20.34 mmol) and (S)-2-methyloxiran-2-ylmethyl 4-nitrobenzoate (5.31 g, 22.37 mmol) were dissolved in ethyl acetate (10 ml). Triethylamine (0.57 ml, 4.07 mmol) was added to the solution, and the resulting mixture was stirred at 60-65° C. for 10 hours. The reaction mixture was concentrated under reduced pressure. Ethyl acetate (3 ml) and toluene (30 ml) were added to the residue, and the resulting precipitates were filtered off to afford (S)-2-chloro-4-nitro-1-[2-hydroxy-3-(4-nitrobenzoyloxy)-2-methylpropyl]imidazole (6.82 g, yield 87%) as a yellow powder.
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([O:7][N:8]=[C:9]([C:12]1[C:13](=[O:31])[CH2:14][CH:15]([C:19]2[C:24]([CH3:25])=[C:23]([CH3:26])[C:22]([CH3:27])=[C:21]([CH3:28])[C:20]=2[O:29][CH3:30])[CH2:16][C:17]=1[OH:18])[CH2:10][CH3:11])[CH3:6].[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(O)C>[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([O:31][C:13]2[CH2:14][CH:15]([C:19]3[C:24]([CH3:25])=[C:23]([CH3:26])[C:22]([CH3:27])=[C:21]([CH3:28])[C:20]=3[O:29][CH3:30])[CH2:16][C:17](=[O:18])[C:12]=2[C:9](=[N:8][O:7][CH2:5][CH3:6])[CH2:10][CH3:11])(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: CCON=C(CC)C1=C(O)CC(c2c(C)c(C)c(C)c(C)c2OC)CC1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCON=C(CC)C1=C(OS(=O)(=O)c2ccc(C)cc2)CC(c2c(C)c(C)c(C)c(C)c2OC)CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.6 %

Procedure:
A solution of sodium ethoxide (1.10 mmole) in ethanol (8.2 ml) was added to a solution of 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(2-methoxy-3,4,5,6-tetramethylphenyl)cyclohex-2-en-1-one (0.40 g, 1.10 mmole) in ethanol (50 ml). The mixture was evaporated to dryness and the residue dissolved in acetone (50 ml). 4-Toluenesulfonyl chloride (0.21 g, 1.10 mmole) was added and the mixture was stirred at room temperature for 2 hours, then evaporated to dryness under reduced pressure. The residue was purified by column chromatography over silica gel (eluant dichloromethane) to give 3-(4-toluenesulfonyl)oxy-2-[1-(ethoxyimino)propyl]-5-(2-methoxy-3,4,5,6-tetramethylphenyl)cyclohex-2-en-1-one (0.59 g; 100%) as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([OH:6])[CH:3]([OH:5])[CH3:4].CCN(CC)CC.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:14][S:15]([O:5][CH:3]([CH:2]([O:6][S:15]([CH3:14])(=[O:17])=[O:16])[CH3:1])[CH3:4])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)C(C)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)C(C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
To a solution of butane 2,3-diol (15 g, 0.166 mol) and Et3N (57.7 mL, 0.415 mol) in CH2Cl2 (150 mL) at 0° C. was slowly added a solution of CH3SO2Cl (32.1 mL, 0.415 mol) in CH2Cl2 (75 mL). The mixture was stirred at 0° C. for 2 h and diluted with CH2Cl2. The mixture was washed with water, 1N HCl, 5% aqueous NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to afford butane-2,3-diyl dimethanesulfonate (40 g, 98%) as a light yellow oil. 1HNMR (CDCl3): δ4.9 (m, 2H, CH), 3.05 (s, 6H, H3), 1.4 (m, 6H, CH3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1.[F:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH2:26][C@@H:27]2[CH2:29][O:28]2)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH2:26][C@@H:27]([OH:28])[CH2:29][NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([NH:10][S:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)=[CH:23][CH:22]=1
Reactant: Fc1ccc(OC[C@@H]2CO2)cc1
Reactant: NCCc1ccc(NS(=O)(=O)c2ccccc2)cc1
Product: O=S(=O)(Nc1ccc(CCNC[C@H](O)COc2ccc(F)cc2)cc1)c1ccccc1

Procedure:
In a manner analogous to that of Example 7, the title compound was prepared from the amine from Example 6 and the epoxide from Example 141: 1H NMR (300 MHz, CD3OD): 2.93 (m, 2H), 3.1-3.28 (m, 4H), 3.96 (m, 2H), 4.2 (m, 1H), 6.9-7.16 (m, 8H), 7.5 (m, 3H), 7.74 (d, J=7Hz, 1H); FAB-MS m/z 445 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[N:6]=[C:5]2Cl.[NH:20]1[C:28]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[CH:22]=[CH:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[N:6]=[C:5]2[N:20]1[C:28]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[CH:22]=[CH:21]1
Reactant: c1cc2[nH]ccc2cn1
Reactant: Fc1ccccc1-c1nc(Cl)c2cc(Br)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccccc1-c1nc(-n2ccc3cnccc32)c2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.7 %

Procedure:
6-Bromo-4-chloro-2-(2-fluoro-phenyl)-quinazoline from Step D (1 g, 2.9 mmol) was dissolved in N,N-dimethyl formamide (3 ml) and to it was added 1H-Pyrrolo[3,2-c]pyridine (0.346 g, 2.9 mmol) followed by cesium carbonate (0.961 g, 2.9 mmol). The mixture was magnetically stirred at room temperature for 1 hr. Water was added and the product filtered to yield title compound (1.236 g, 98%). MS (ES) 420 (M+H)+
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.Cl[C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][N:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1(C)C=CC=CC=1>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][N:20]=2)=[CH:13][CH:12]=1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: Oc1ccc(CCNC2CCCCC2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc(Oc2ccc(CCNC3CCCCC3O)cc2)nc1
Temperature: 25 °C

Procedure:
Heat a mixture of 4-[2-(2-hydroxycyclohexylamino)ethyl]phenol (152.6 mg, 0.65 mmol), 6-chloronicotinamide (84.6 mg, 0.54 mmol) and K2CO3 (186.7 mg, 1.35 mmol) in 3:1 DMF/toluene (4.0 mL) at 160° C. for 2 hours. Cool to room temperature and filter with thorough MeOH and CH2Cl2 wash. Concentrate the filtrate and remove DMF azeotropically with xylenes. Purify by flash chromatography, eluting with 75:15:10 EtOAc/CH2Cl2/2.0 M NH3 in MeOH (56.3 mg, 29%): MS ES+ 356.1 (M+H)+, HRMS calcd for C20H26N3O3 356.1974 (M+H)+, found 356.1966, time 0.37 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=1.23 min, 100% purity; Chiralpak AD 225 min, 60:40 EtOH/heptane at 1.0 mL/min, tR=5.55 min, 50% and tR=7.17 min, 50%; Anal. Calcd for C20H25N3O3.0.2CH2Cl2.0.2MeOH: C, 64.68; H, 6.97; N, 11.09. Found: C, 64.46; H, 6.84; N, 11.11.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([B:8]([OH:10])[OH:9])=[CH:5][CH:4]=1)=O.Cl.[CH3:12][NH:13][CH3:14].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:12][N:13]([CH2:1][C:3]1[S:7][C:6]([B:8]([OH:10])[OH:9])=[CH:5][CH:4]=1)[CH3:14]
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(C)Cc1ccc(B(O)O)s1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 5-formyl-2-thiopheneboronic acid (500 mg, 3.2 mmol) in DCE (30 mL) was added dimethylamine hydrochloride (520 mg, 6.3 mmol) followed by triethylamine (0.9 mL, 6.5 mmol). The reaction mixture was stirred for 10 min before sodium triacetoxyborohydride (1.36 g, 6.3 mmol) was added in one portion. After the reaction mixture was stirred at room temperature for 5 h, it was quenched with 30 mL of MeOH, stirred briefly, then concentrated under vacuum. Introduction of a CH2Cl2/Et2O mixture to this residue revealed a solid, which was filtered and washed with Et2O. The resulting organic filtrate was concentrated to a viscous oil, which was used without further purification.