Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C:12]1[NH:13][C:14](=[O:53])[C:15]2[N:16]=[CH:17][N:18]([C:51]=2[N:52]=1)[C@@H:19]1[O:50][C@H:24]([CH2:25][O:26][C:27]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C@@H:22]([OH:23])[C@H:20]1[OH:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.ClCC(C#N)[CH2:66][O:67][CH2:68][CH:69]([C:72]#[N:73])CCl.C(=O)(O)[O-].[Na+]>ClCCCl>[O:1]([CH2:8][C:9]([NH:11][C:12]1[NH:13][C:14](=[O:53])[C:15]2[N:16]=[CH:17][N:18]([C:51]=2[N:52]=1)[C@@H:19]1[O:50][C@H:24]([CH2:25][O:26][C:27]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C@@H:22]([OH:23])[C@H:20]1[O:21][CH2:66][O:67][CH2:68][CH2:69][C:72]#[N:73])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC(CCl)COCC(C#N)CCl
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)COc5ccccc5)nc43)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)COc5ccccc5)nc43)[C@H](OCOCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 47.8 %

Procedure:
N2-Phenoxyacetyl-5′-O-(4,4′-dimethoxytrityl)guanosine (720 mg, 1 mmol) was dissolved in 4 mL of 1,2-dichloroethane, and 452 mg of diisopropylethylamine (3.5 mmol) was added, and 365 mg of dibutylstannyl dichloride (1.2 mmol) was added subsequently. Then, the reaction was performed at room temperature for 1 hour. Then, the reaction was performed at 80° C., and 155.4 mg of chloromethyl 2-cyanoethylether (1.3 mmol) was added dropwise, and the solution was stirred for 60 minutes. After the reaction completed, the reaction solution was mixed with an aqueous saturated sodium bicarbonate solution, and was subjected to extraction with methylene chloride. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained mixture was purified by 30 g of silica gel column chromatography to obtain N2-phenoxyacetyl-5′-O-(4,4′-dimethoxytrityl)-2′-O-(2-cyanoethoxymethyl)guanosine (384 mg; yield 48%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:25])(=[O:24])[NH:11][C@H:12]([C:21](=O)[NH2:22])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]([O:26][CH2:27][CH2:28][C:29]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][CH:33]=[N:34]3)[CH:5]=1.CCN(CC)CC.O(C(C(F)(F)F)=O)C(C(F)(F)F)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:24])(=[O:25])[NH:11][C@H:12]([C:21]#[N:22])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]([O:26][CH2:27][CH2:28][C:29]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][CH:33]=[N:34]3)[CH:5]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(N)=O)c(OCCc2cccc3ncccc23)c1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: COC(=O)c1ccc(S(=O)(=O)N[C@H](C#N)CC(=O)OC(C)(C)C)c(OCCc2cccc3ncccc23)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
To a solution of 4-((S)-2-tert-butoxycarbonyl-1-carbamoyl-ethylsulfamoyl)-3-(2-quinolin-5-yl-ethoxy)-benzoic acid methyl ester (1.20 g, 2.20 mmol) in dry THF (10 mL) at 0° C. was added Et3N (0.80 mL, 5.50 mmol). A solution of (CF3CO)2O in THF (0.5 M, 0.37 mL, 2.60 mmol) was added to the solution dropwise. After 30 min of stirring at 0° C., the ice bath was removed. The reaction mixture was allowed to warm up to room temperature over 4 h. The reaction mixture was worked up by addition of EtOAc (100 mL) then followed by washing the organic phase with saturated NaHCO3 (50 mL). Drying and removal of solvents under vacuum gave 0.90 g (76%) of 4-((S)-2-tert-butoxycarbonyl-1-cyano-ethylsulfamoyl)-3-(2-quinolin-5-yl-ethoxy)-benzoic acid methyl ester as a tan solid. MS m/z 540.3 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH2:18][O:19][CH3:20])=[O:12])[S:10][C:3]=12.[CH3:21][NH:22][C:23]([C:25]1[C:26]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:27]=2[S:28][C:29]=1[CH3:30])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:21][NH:22][C:23]([C:25]1[C:26]2[CH:34]=[CH:33][C:32]([O:35][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH2:15][C@H:14]5[CH2:18][O:19][CH3:20])=[O:12])[S:10][C:3]=34)=[CH:31][C:27]=2[S:28][C:29]=1[CH3:30])=[O:24]
Reactant: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Cl)c2s1
Reactant: CNC(=O)c1c(C)sc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)sc2cc(Oc3ccnc4cc(C(=O)N5CCC[C@H]5COC)sc34)ccc12
Yield: 71.8 %

Procedure:
This material was prepared by the reaction of 7-chloro-2-[(S)-2-(methoxymethyl)pyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 2a (153 mg, 0.5 mmole) with 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic acid methylamide 1d (164 mg, 0.7 mmole) and Cs2CO3 (868 mg, 2.7 mmole) in a manner as previously described for example 1 to give 178 mg (73%) of a yellow solid. 1H NMR (DMSO-d6): δ8.57 (1H, d, J=5.4 Hz, 8.29 (1H, q, J=4.5 Hz), 8.02 (1H, s), 7.95 (1H, d, J=2.2 Hz), 7.85 (1H, d, J=8.8 Hz), 7.32 (1H, dd, J=2.2, 8.8 Hz), 6.75 (1H, d, J=5.4 Hz), 4.37-4.23 (1H, m), 3.95-3.74 (2H, m), 3.60-3.48 (2H, m), 3.27 (3H, s), 2.83 (3H, d, J=4.5 Hz), 2.60 (3H, s), 2.08-1.81 (4H, m). Anal. Calcd. for C25H25N3O4S2: C, 60.58; H, 5.08; N, 8.48; S, 12.94. Found: C, 60.55; H, 5.33; N, 8.27; S, 12.68.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][C:12]([C:14]1[CH:19]=[CH:18][N:17]=[C:16](S(C)(=O)=O)[N:15]=1)=[O:13]>C1COCC1>[CH3:10][O:11][C:12]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:15]=1)=[O:13]
Reactant: Oc1ccccc1
Reactant: COC(=O)c1ccnc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(Oc2ccccc2)n1
Reaction time: 12 h
Yield: 25 %

Procedure:
NaH (3.5 g of a 60% suspension, 87.4 mmol) is added to a solution of phenol (8.23 g, 87.4 mmol) in THF (100 mL) at room temperature. 2-Methanesulfonyl-pyrimidine-4-carboxylic acid methyl ester, 15, (6.3 g, 29.1 mmol) is dissolved in THF (60 mL) and added dropwise to the solution of phenol. The reaction is allowed to stir for 12 hours then quenched by the addition of saturated aqueous NH4Cl. The aqueous phase is extracted with methylene chloride and the combined organic layers are dried, filtered, and concentrated in vacuo to afford a crude oil which is purified over silica (ethyl acetate/hexane 2:3) to afford 1.72 g (25% yield) of the desired product as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:33])=[C:9]([CH2:11][O:12][C:13]2[CH:30]=[CH:29][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([CH2:26][CH2:27][OH:28])[N:20]=3)=[CH:15][C:14]=2[O:31][CH3:32])[N:10]=1.[CH2:34]([P:43](=[O:50])([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:33])=[C:9]([CH2:11][O:12][C:13]2[CH:30]=[CH:29][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:34]/[P:43](=[O:50])([O:44][CH2:45][CH3:46])[O:47][CH2:48][CH3:49])=[CH:22][N:21]([CH2:26][CH2:27][OH:28])[N:20]=3)=[CH:15][C:14]=2[O:31][CH3:32])[N:10]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COc1cc(COc2nn(CCO)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(CCO)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 9.8 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-(2-hydroxyethyl)-1H-pyrazole-4-carbaldehyde (0.50 g), tetraethyl methylenediphosphonate (0.30 g) and N,N-dimethylformamide (15 mL) was added sodium hydride (60% in oil, 0.060 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol (100:1, v/v) to give diethyl (E)-2-[3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]ethenylphosphonate as colorless crystals (0.06 g, yield 15%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 95-96° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:35][CH2:34]2)=[CH:31][CH:32]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: Cc1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(N2CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)cc1
Temperature: 20 °C
Yield: 43 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (7 g), triethylamine (3.5 cc) and 4-(4-methylphenyl)piperazine (4.4 g) in toluene (100 cc). The mixture is heated for 6 hours at boiling point, then cooled to a temperature of about 20° C. After purification, flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane and ethyl acetate (80-20 vol) as eluant, and recrystallization from boiling acetonitrile (40 cc), 2-{3-[4-(4-methylphenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (4.5 g) is obtained, m.p. 136° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11][N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.C(OCC)(=O)C>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:30]2[CH2:31][CH2:32][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:28][CH:29]=2)=[N:3][C:4]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][N:10]=1
Reactant: Nc1ncc(Br)nc1-c1noc(-c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cnc(N)c(-c3noc(-c4ccccc4)n3)n2)CC1
Yield: 88.6 %

Procedure:
5-bromo-3-(5-phenyl-1,2,4-oxadiazol-3-yl)pyrazin-2-amine (150 mg, 0.4715 mmol), tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (189.5 mg, 0.6130 mmol) and sodium carbonate (707.0 μL of 2 M, 1.414 mmol) in DMF (1.500 mL) were heated to 120° C. for 45 min in the microwave. After this time the reaction mixture was diluted with water (5 mL) and ethyl acetate (5 mL) and the layers separated. Organic layer washed with water (3×5 mL), dried (MgSO4) and concentrated in vacuo to leave the title compound as a yellow/orange solid (175.6 mg, 88% yield). 1H NMR (400 MHz, DMSO) d 1.44 (s, 9H), 2.60 (m, 2H), 3.57 (m, 2H), 4.06 (m, 2H), 6.70 (s, 1H), 7.30 (br s, 2H), 7.69 (m, 2H), 7.77 (m, 1H), 8.25 (m, 2H) and 8.51 (1H, s) ppm; MS (ES+) 421.02
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7](Cl)=[O:8])[CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([C:17](=[O:19])[CH3:18])[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[C:17]([C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[NH:10][C:7]([C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)=[O:8])(=[O:19])[CH3:18]
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: CC(=O)c1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1cccc(NC(=O)c2cc(C)on2)c1

Procedure:
A solution of 5-methyl-3-isoxazolecarbonyl chloride (14.5 g) in acetone (30 ml) was added to a solution of m-aminoacetophenone (13.8 g) in acetone (280 ml) in the presence of anhydrous potassium carbonate (21.0 g). The mixture was stirred for 1/2hour, and then diluted with water. The precipitated product was filtered, washed with water and dried. Yield = 20.5 g (83%), m.p. 188°-190°.
Reaction SMILES: CCOCC.[CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:10]=1[N:18]=[CH:19][C:20]1[N:25]=[C:24]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][C:27]=2[CH2:36][NH:37][C:38]2[C:43]([CH3:44])=[CH:42][C:41]([CH3:45])=[CH:40][C:39]=2[CH3:46])[CH:23]=[CH:22][CH:21]=1)([CH3:8])[CH3:7].[CH:47]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[Li])([CH3:49])[CH3:48]>O>[CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:10]=1[NH:18][CH:19]([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=1[CH:47]([CH3:49])[CH3:48])[C:20]1[N:25]=[C:24]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][C:27]=2[CH2:36][NH:37][C:38]2[C:39]([CH3:46])=[CH:40][C:41]([CH3:45])=[CH:42][C:43]=2[CH3:44])[CH:23]=[CH:22][CH:21]=1)([CH3:8])[CH3:7]
Reactant: Cc1cc(C)c(NCc2ccc3ccccc3c2-c2cccc(C=Nc3c(C(C)C)cccc3C(C)C)n2)c(C)c1
Reactant: [Li]c1ccccc1C(C)C
Solvent: O
Solvent: CCOCC
Product: Cc1cc(C)c(NCc2ccc3ccccc3c2-c2cccc(C(Nc3c(C(C)C)cccc3C(C)C)c3ccccc3C(C)C)n2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Et2O (40 mL) was added to compound 6b (1.48 g, 2.74 mmol) to form a yellow suspension. At −80° C. an Et2O (5 mL) solution of 2-isopropylphenyllithium (0.690 g, 5.47 mmol) was added dropwise over 5 minutes. Upon the start of the addition the mixture became dark purple. The mixture was allowed to slowly warm to ambient temperature while stirring overnight. Then water was added (30 mL) and the yellow organic layer was separated and dried with brine. Further drying over MgSO4 followed by filtration and evaporation afforded crude diamine 7p as a yellow oil that was found by 1H NMR spectroscopy to be contaminated with about 10% of the imine 6b. The product was purified on basic alumina eluted with 5:1 hexanes:dichloromethane, gradually increasing the amount of ethyl acetate to 8%. The product eluted just before the imine impurity. Yield: 1.5 g, 83%. The 1H NMR spectrum of 7p in CD2Cl2 solution is complex due to the presence of more than one diastereoisomer.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[CH3:19].CS(O[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)(=O)=O>>[C:15]([C:10]1[C:11](=[O:14])[N:12]([CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=2)[CH:9]=1)([OH:17])=[O:16]
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Reactant: CS(=O)(=O)OCCCc1ccc(Cl)cc1
Product: Cc1cc(-c2cc(C(=O)O)c(=O)n(CCCc3ccc(Cl)cc3)n2)ccc1F
Yield: 80.8 %

Procedure:
Following the procedure of Example 1(6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3-(4-chlorophenyl)-1-propanol methanesulfonate were reacted. Without purification, the reaction product was reacted further following the procedure of Example 1(7) to yield the title compound as a yellow crystalline powder (yield: 80.8%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[Br:15][C:16]1[N:21]=[C:20]([CH:22]=O)[CH:19]=[CH:18][CH:17]=1.OS([O-])=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[Br:15][C:16]1[N:21]=[C:20]([C:22]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: O=Cc1cccc(Br)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(Br)n3)nc2c1
Temperature: 120 °C
Yield: 47.9 %

Procedure:
To a solution of 2-amino-4,6-dimethoxybenzamide (0.40 g, 2.04 mmol) and 6-bromopyridine-2-carbaldehyde (0.379 g, 2.04 mmol) in N,N-dimethylacetamide (24 mL) was added NaHSO3 (0.544 g, 3.06 mmol) and p-toluenesulfonic acid monohydrate (0.078 g, 0.408 mmol) at rt. The reaction mixture was heated at 120° C. for 6 h. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with water (10 mL). The precipitated solids were collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 95:5 dichloromethane/methanol) to give 2-(6-bromopyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.354 g, 48%) as a light yellow solid: 1H NMR (400 MHz, DMSO-d) δ 11.25 (br s, 1H), 8.36 (d, J=7.81 Hz, 1H), 7.87-8.04 (m, 2H), 6.81 (s, 1H), 6.62 (s, 1H), 3.91 (s, 3H), 3.87 (s, 3H); ESI MS m/z 362 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][OH:39]>C(#N)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([CH2:36][CH2:37][CH2:38][OH:39])[S:25]([CH3:28])(=[O:27])=[O:26])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCCO)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
To a solution of Compound (1) (50 mg, 0.11 mmol) in ACN (4 mL) was added potassium carbonate (30 mg, 0.22 mmol) followed by 3-bromo-1-propanol (38 μL, 0.32 mmol). The mixture was heated to 80° C. and stirred for 16 h at which time no starting material was observed. The mixture was cooled to RT, diluted with EtOAc (10 mL), washed with water (3 mL), brine (3 mL) and dried (MgSO4). The solvent was removed in vacuo to give the crude mixture which was purified by flash column chromatography eluting with EtOAc/hexane (5-100%) to give 2-(4-bromophenyl)-5-cyclopropyl-6-[(3-hydroxypropyl)(methylsulfonyl)amino]-N-methyl-2H-indazole-3-carboxamide (4) (28 mg, 50%). ESI-MS m/z calculated for [M+H]+: 521.09/523.08; found: 521.03/523.03.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][CH:12]([F:27])[C:13]1[CH:17]=[CH:16][NH:15][C:14]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19].C1(P(C2C=CC=CC=2)(=O)[NH2:35])C=CC=CC=1.O>CN(C=O)C>[NH2:35][N:15]1[CH:16]=[CH:17][C:13]([CH:12]([F:11])[F:27])=[C:14]1[C:18]([NH:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:19]
Reactant: NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(Nc1ccccc1)c1[nH]ccc1C(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: Nn1ccc(C(F)F)c1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
1.1 ml (1.1 mmol) of a 1M solution of lithium bis(trimethylsilyl)amide was added to a solution of 3-(difluoromethyl)-N-phenyl-1H-pyrrole-2-carboxamide (100 mg, 0.42 mmol) and DPPONH2 (P,P-diphenylphosphinic amide, available from Sigma Aldrich®, cat. no. 5994-87-6) (250 mg, 1,1 mmol) in DMF (4 mL) at room temperature. A thick suspension formed and additional 4 mL of DMF were added. The mixture was stirred at room temperature for 1 hour and then it was poured into 50 mL of water and extracted with ethyl acetate. The aqueous layer was further extracted with ethyl acetate (2×). The combined organic layer was washed with water and brine and was dried over sodium sulphate, filtered and concentrated. The crude product was purified by flash chromatography (0% to 33% AcOEt/Hexanes) to yield 40 mg (38% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]=O)[CH:27]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:32][C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)=[CH:9][C:8]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1cccnc1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NCc2cccnc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
(4-Amino-2-phenylbenzoyl)methionine methyl ester (1.15 g, 3.21 mmol), prepared as in Example 192B, and 3-pyridine carboxaldehyde (361 mg, 3.37 mmol) were combined in 15 mL methanol and sodium cyanoborohydride (302 mg, 4.81 mmol) was added followed by crushed molecular sieves. The reaction was adjusted to pH=6 with acetic acid and stirred at 25° C. for 3 hours. The reaction was concentrated and transferred directly to a column of silica gel and purified by flash chromatography (5%methanol-ethyl acetate) to give [4(3-pyridylmethylamino)-2-phenylbenzoyl]methionine methyl ester (1.38 g, 95%) as an oil that solidified after standing. 1H NMR (300 mHz, CDCl3) δ 8.6 (d, 1H), 8.52 (dd, 1H), 7.72-7.65 (m, 2H), 7.45-7.30 (m, 6H), 6.62 (dd, 1H), 6.48 (d, 1H), 5.72 (bd, 1H), 4.64 (dq, 1H), 4.42 (bs, 2H), 3.64 (s, 3H), 2.25-2.05 (m, 3H), 2.00 (s, 3H), 1.95-1.80 (m, 1H), 1.72-1.60 (m, 1H); CIMS MH+ 450.