Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][C@@H:6]1[CH2:8][C@@H:7]1[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][CH2:10]1.Br[C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][N:27]=1>CN(C)C=O.C(OCC)(=O)C.O>[CH3:35][S:32]([C:29]1[CH:30]=[CH:31][C:26]([O:3][CH2:4][CH2:5][C@@H:6]2[CH2:8][C@@H:7]2[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:11][CH2:10]2)=[N:27][CH:28]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Reactant: O=C(OCc1ccccc1)N1CCC([C@H]2C[C@H]2CCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCc3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (424 mg, 60% dispersion in mineral oil, 10.6 mmol) was added to a solution of benzyl 4-((1R,2S)-2-(2-hydroxyethyl)cyclopropyl)piperidine-1-carboxylate (1.07 g, 3.53 mmol) in N,N-dimethylformamide (10 mL) under nitrogen at RT. The mixture was stirred for 30 min at RT and 2-bromo-5-(methylsulfonyl)pyridine (1.25 g, 5.30 mmol) was added. The mixture was stirred overnight, diluted with ethyl acetate (100 mL) and water (50 mL), and the layers were separated. The organic layer was washed with brine (2×25 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (40 g RediSep, eluted with a gradient of hexanes to ethyl acetate, 9:1, 200 mL; 4:1, 500 mL; 1:1, 1 L) to provide the title compound as a light yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.71 (dd, J=0.5, 2.5 Hz, 1H), 8.03 (dd, J=2.5, 8.7 Hz, 1H), 7.40-7.28 (m, 5H), 6.84 (dd, J=0.6, 8.7 Hz, 1H), 5.13 (s, 2H), 4.48 (t, J=7.2 Hz, 2H), 4.30-4.10 (m, 2H), 3.07 (s, 3H), 2.90-2.60 (m, 2H), 2.20-2.00 (m, 1H), 1.85-1.65 (m, 2H), 1.60-1.45 (m, 1H), 1.45-1.20 (m, 2H), 1.10-0.85 (m, 2H), 0.75-0.50 (m, 2H), −0.12 (q, J=5.1 Hz, 1H). MS (Multimode) m/z 459 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[CH:34]=[CH:33][S:32][CH:31]=2)=[O:29])=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1>>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:18]=[CH:19][C:2]([C:22]2[CH:23]=[C:24]([NH:27][C:28]([C:30]3[CH:34]=[CH:33][S:32][CH:31]=3)=[O:29])[CH:25]=[CH:26][C:21]=2[CH3:20])=[N:3][CH:4]=1
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Product: COc1cccc(CNC(=O)c2ccc(-c3cc(NC(=O)c4ccsc4)ccc3C)nc2)c1

Procedure:
N-(3-Methoxybenzyl)-6-[5-(thiophen-3-ylcarbonylamino)-2-methyl-phenyl]-nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide (Intermediate 14) using General Method B. LCMS: retention time 3.27 min, MH− 458. NMR: δH [2H6]-DMSO 10.12,(1H, s), 9.29,(1H, t), 9.15,(1H, d), 8.35-8.32,(2H, m), 7.86,(1H, s), 7.78,(1H, d), 7.68-7.65,(3H, m), 7.32-7.24,(2H, m), 6.94,(2H, m), 6.84,(2H, d), 4.51,(2H, d), 3.75,(3H, s), 2.32,(3H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=4)=[N:16][C:17](=[O:18])[C:12]3=[C:11]([CH:28]([CH3:30])[CH3:29])[NH:10]2)=[C:4]([Cl:31])[CH:3]=1.C([Mg]Cl)(C)C.CN([CH:40]=[O:41])C>C1COCC1>[Cl:8][C:6]1[CH:7]=[C:2]([CH:40]=[O:41])[CH:3]=[C:4]([Cl:31])[C:5]=1[N:9]1[C:13]2=[N:14][C:15]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)=[N:16][C:17](=[O:18])[C:12]2=[C:11]([CH:28]([CH3:30])[CH3:29])[NH:10]1
Reactant: CN(C)C=O
Reactant: COc1cccc(Cc2nc3n(-c4c(Cl)cc(Br)cc4Cl)[nH]c(C(C)C)c-3c(=O)n2)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1cccc(Cc2nc3n(-c4c(Cl)cc(C=O)cc4Cl)[nH]c(C(C)C)c-3c(=O)n2)c1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
A two-neck flask was flame-dried, charged with 1-(4-bromo-2,6-dichlorophenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one (250 mg, 0.48 mmol) and 4 mL of THF, and placed under an argon atmosphere. The solution was cooled to 0° C. and isopropylmagnesium chloride (0.26 mL, 0.523 mmol) was added dropwise via syringe. The reaction was stirred at −78° C. for 2 min and DMF (0.08 mL, 1.06 mmol) was added via syringe. The reaction was stirred at −78° C. for 15 min and at RT for 30 min. The reaction was quenched with 10% aq. citric acid and extracted with EtOAc. The organic extract was washed with water then brine, dried (MgSO4), and evaporated. Purification by column chromatography on silica gel using 2:1 hexanes-EtOAc as eluent afforded 68 mg (30%) of the title as a white solid, mp 212-214° C. Mass Spec: 469 (M−H)−.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]1COCC1.[O:16]=[C:17]1[CH2:22][O:21][CH2:20][C@@H:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].IC>COCCOC>[CH3:11][C@@H:22]1[O:21][CH2:20][C@@H:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:17]1=[O:16]
Reactant: CC(C)(C)OC(=O)N1C(=O)COC[C@H]1c1ccccc1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: COCCOC
Solvent: CI
Product: C[C@@H]1OC[C@@H](c2ccccc2)N(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a 1 M solution of sodium bis(trimethylsilyl)amide in THF (0.79 mL, 0.79 mmol) at −78° C. was added dropwise a solution of tert-butyl (5R)-3-oxo-5-phenylmorpholine-4-carboxylate from Step C (200 mg, 0.72 mmol) in DME (5 mL) at −78° C. The resulting mixture was stirred at −78° C. for 10 min then iodomethane (0.049 mL, 0.79 mmol) was added. After stirring at −78° C. for a further 1 h, the reaction mixture was quenched with saturated aqueous NH4Cl (5 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was partially purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—90:10 to 60:40. Further purification was achieved by HPLC, using a ChiralPak AS column and eluting with hexane:i-PrOH—90:10, to give the title compound. MS: m/z=236 (M−C4H7).
Reaction SMILES: [H-].[Na+].[C:3]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19](OC)=[CH:18][CH:17]=3)[C:13](=[O:24])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[C:31](OC)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[C:41]1(C)C=CC=CC=1>>[C:31]([C@@H:12]1[CH2:11][CH:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:4][CH:5]=2)[N:14](/[CH:15]=[CH:16]/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:41]=2)[C:13]1=[O:24])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)c1ccccc1
Reactant: COc1ccc(CN2C(=O)CC[C@H]2Cc2ccc(-c3ccccc3)cc2)cc1
Reactant: Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: O=C(c1ccccc1)[C@@H]1CC(Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Temperature: 25 °C

Procedure:
Sodium hydride (2.03 g, 46.4 mmol) is suspended in 40-mL of anhydrous toluene, heat to reflux under nitrogen atmosphere, add a mixture solution of (S)-5-Biphenyl-4-ylmethyl-1-((E)-but-1-enyl)-pyrrolidin-2-one (3a, R1=1-butenyl) (11.02 g, 35.67 mmol) and methyl benzoate (4.86 g, 35.67 mmol) in anhydrous toluene dropwise, the reaction mixture is refluxed for 4 h, cool to ambient temperature, quench with saturated NH4Cl aqueous solution, extracted with toluene, the combined organic extracts are washed with saturated Na2CO3 and brine, dry over anhydrous Na2SO4, concentrate under vacuum to obtain (S)-3-Benzoyl-5-biphenyl-4-ylmethyl-1-((E)-but-1-enyl)-pyrrolidin-2-one (4a, R1=1-butenyl, R4=benzyl), which is directly used in the next step. 1HNMR (400 MHz, CDCl3): 1.07 (t, 3H, CH3H), 2.12 (m, 2H, CH2H), 2.20 (m, 2H, 3-CH2), 2.95 (m, 1H, 5-CH2), 3.13 (m, 1H, 5-CH2), 3.82 (m, H, 2-CH2H), 4.14 (m, 1H, 4-CH), 5.27 (m, 1H, CH═CH), 6.85 (d, 1H, HC═CH—N), 7.14˜8.20 (14H, m, aromatic). the ratio of (3S,5S) to (3R,5S) is 60:40 as determined by HPLC.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]3[CH2:15][CH2:14][CH:13]([N:16]([C:20]4[CH:37]=[CH:36][C:23](C(N[C@H](C(O)=O)CCC(O)=O)=O)=[CH:22][CH:21]=4)[CH2:17][C:18]#[CH:19])[C:7]=3[CH:8]=2)[N:3]=1.NC(CO)(CO)CO.[C:46]([OH:49])(=[O:48])C>[Cl-].[Zn+2].[Cl-]>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]3[CH2:15][CH2:14][CH:13]([N:16]([C:20]4[CH:37]=[CH:36][C:23]([C:46]([OH:49])=[O:48])=[CH:22][CH:21]=4)[CH2:17][C:18]#[CH:19])[C:7]=3[CH:8]=2)[N:3]=1
Reactant: CC(=O)O
Reactant: C#CCN(c1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)C1CCc2cc3nc(C)[nH]c(=O)c3cc21
Agent: NC(CO)(CO)CO
Agent: [Cl-]
Agent: [Zn+2]
Product: C#CCN(c1ccc(C(=O)O)cc1)C1CCc2cc3nc(C)[nH]c(=O)c3cc21
Temperature: 37 °C

Procedure:
A mixture of N-{p-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoyl}-L-glutamic acid (6 g), carboxypeptidase G2 (2000 units) and tris buffer [prepared by mixing 2-amino-2-hydroxymethyl-1,3-propanediol (12.11 g), zinc chloride (0.035 g) and distilled water (950 ml), by adjusting the basicity of the mixture to pH 7.3 by the addition of 2N aqueous hydrochloric acid and by adding sufficient distilled water to give a final volume of 1 L; 750 ml] was stirred and heated to 37° C. for 30 hours. A second portion of carboxypeptidase G2 (2000 units) was added and the mixture was heated to 37° C. for a further 24 hours. The mixture was cooled to 0° C. and acidified to pH 4 by the addition of glacial acetic acid. The precipitate was isolated, washed with water and dried under vacuum. There was thus obtained p-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[a]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoic acid as a solid (4 g), m.p. 264° C.;
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:4]1([CH3:18])[C:3](=[O:19])[C:2]([C:32]2[CH:31]=[CH:30][C:29]([O:28][C:27]([F:26])([F:38])[F:39])=[CH:34][CH:33]=2)=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[O:5]1
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2ccc(OC(F)(F)F)cc2)C1=O
Temperature: 90 °C
Reaction time: 24 h
Yield: 32.4 %

Procedure:
To a stirred solution of 4-bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone (150 mg) in 15 ml toluene and 5 ml ethanol, were added 30 mg of tetrakis(triphenylphosphine)palladium(0), 5 ml of saturated aqueous sodium carbonate, and 100 mg of 4-(trifluoromethoxy)benzeneboronic acid. The reaction solution was stirred at 90° C. for 24 hours. Then the solvent was removed under reduced pressure. The resulting residue was extracted with water and dichloromethane. The organic layer was concentrated in vacuo and the resulting residue was separated by column chromatography (hexane/ethylacetate) to yield 60 mg of 2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-4-{4-(trifluoromethoxy)phenyl}-3(2H)-furanone as a solid. mp: 118-120° C. NMR: δ1.58 (s, 6H), 3.08 (s, 3H), 7.20-7.26 (m, 2H), 7.31-7.34 (m, 2H), 7.82-7.85 (m, 2H), 7.95-7.98 (m, 2H). IR (cm−1): 2931, 1698, 1510, 1387, 1258, 1150, 960, 846, 770.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH2:9][C:10]([OH:12])=O)[N:7]=[N:8][C:4]=2[C:3]=1[O:15][C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Cl:24])[CH:17]=1.C(Cl)(=O)C(Cl)=O.[Cl:31][C:32]1[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=1[NH2:34]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH2:9][C:10]([NH:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[Cl:31])=[O:12])[N:7]=[N:8][C:4]=2[C:3]=1[O:15][C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Cl:24])[CH:17]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3CC(=O)O)c1
Reactant: Nc1ccccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3CC(=O)Nc2ccccc2Cl)c1
Reaction time: 0.17 h

Procedure:
To a suspension of [5-chloro-4-(3-chloro-5-cyanophenoxy)-1H-1,2,3-benzotriazol-1-yl]acetic acid (15 mg, 0.041 mmol) (see step 2 in Example 16) in DCM (0.5 mL) was added oxalyl chloride (58 mg, 0.454 mmol). This was followed by addition of DMF (1 drop) and then, following bubbling cessation, by addition of 2-chloroaniline (158 mg, 1.239 mmol). After 10 minutes, the reaction mixture was concentrated, taken up in DMF/MeOH and purified by reverse phase chromatography, eluting with 30-95% MeCN/H2O+0.1% TFA. The product fraction was lyophilized to yield the title compound. 1H NMR (DMSO-d6) δ 10.2 (s, 1H), 7.90 (d, J=9.0 Hz, 1H), 7.83 (m, 2H), 7.75 (d, J=8.3 Hz, 1H), 7.55 (m, 3H), 7.34 (m, 1H), 7.24 (m, 1H), 5.85 (s, 2H). HRMS (M+1)=472.0152.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([NH:12][NH2:13])=[N:4][N:3]=1.C(O)(=O)C.[N:18]([O-])=O.[Na+]>O>[Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][N:13]=[N:18][N:4]2[N:3]=1
Reactant: NNc1nnc(Cl)c2c1CCCC2
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Clc1nn2nnnc2c2c1CCCC2

Procedure:
To a suspension of 9.9 g of 1-chloro-4-hydrazino-5,6,7,8-tetrahydrophthalazine in 35 ml of aqueous 12% acetic acid was added a solution of 3.5 g of sodium nitrite in 30 ml of water. The mixture was kept at room temperature (about 22°-25° C.) for about 20 minutes. The solid present was then separated by filtration, air dried and recrystallized to give 6-chloro-7,8,9,10-tetrahydrotetrazolo[5,1-a]phthalazine melting at about 109°-110° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)=[O:26])=[CH:20][CH:19]=1>CC(O)C.C(N(CC)CC)C>[CH3:13][N:12]([CH3:14])[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([NH:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:29][CH:28]=3)=[O:26])=[CH:22][CH:23]=2)[N:11]=1
Reactant: NCc1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CN(C)c1nc(NCc2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc2)nc2ccccc12
Yield: 15.1 %

Procedure:
A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in step B of example 1 (42 mg, 0.2 mmol) and biphenyl-4-carboxylic acid (4-aminomethyl-phenyl)-amide hydrochloride (49 mg, 0.14 mmol) in 2-propanol (1 mL) and triethylamine (200 μL) was stirred at reflux for 2 days. The resulting mixture was concentrated and purified by column chromatography (silica gel, CH2Cl2 to 10% 2 M NH3/MeOH in CH2Cl2) to give biphenyl-4-carboxylic acid {4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-phenyl}-amide (10 mg, 15%) as a white solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C@H:9]([C:14]([OH:16])=[O:15])[C:10]([SH:13])([CH3:12])[CH3:11]>N1C=CC=CC=1.C(O)C>[C:1]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[C:10]([SH:13])([CH3:12])[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(S)[C@H](N)C(=O)O
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=O)N[C@H](C(=O)O)C(C)(C)S
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (96 mmol, 9.80 g) was added dropwise to a well stirred solution of D-(−) penicillamine (40 mmol, 5.97 g) in pyridine (50 mL) at 0° C. After 30 min, the flask was removed from ice and allowed to stir at room temperature for 15 h. The resultant orange solution was partitioned between chloroform and dilute HCl and washed 4× with dilute HCl. After drying over MgSO4, the organic phase was evaporated to yield an orange residue. The residue was first dissolved in absolute ethanol (20 mL), and then precipitated in pentane at −78° C. The light yellow crystalline product was isolated by filtration (2.07 g, 30%). 1H NMR (CDCl3) δ 1.65 (s, CH3), 1.86 (s, CH3), 2.05 (s, NHCOCH3), 5.68-5.70 (d, CH(CH3)2), 6.56 (NHCOCH3). 13C NMR (CDCl3) δ 22.52 (NHCOCH3), 26.20 (CH(CH3)2), 30.22 (CH(CH3)2), 51.23 (CH), 169.37 (NHCOCH3), 192.21 (SCO).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[CH3:9].[CH3:10][S-:11].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:11][CH3:10])[C:3]=1[CH3:9]
Reactant: Cc1c(F)cccc1Br
Reactant: C[S-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cccc(Br)c1C
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 57.8 %

Procedure:
To a solution of 1-bromo-3-fluoro-2-methylbenzene (2.0 g, 10.6 mmol) in N,N-dimethylformamide (10 ml) was added sodium methanethiolate (0.85 g, 11.7 mmol) and the mixture was stirred for 15 min at 150° C. After cooling, aqueous sodium carbonate (10%, 50 ml) was added and the phases were separated. The aqueous phase was extracted with ethylacetate (2×50 ml) and the combined organic phases was dried (MgSO4) and evaporated under reduced pressure to give an oil. The residue was purified by flash column chromatography (isooctane) to give the title compound (1.33 g). MS m/z (relative intensity, 70 eV) 218 (M+, 98), 216 (M+, 92), 202 (26), 200 (26), 122 (bp), 121 (56).
Reaction SMILES: C[O-].[Na+].[CH2:4]([CH:6]([CH2:10][CH3:11])[C:7](=O)[CH3:8])[CH3:5].[CH:12](OCC)=O.O.[NH2:18][NH2:19]>C(OCC)C>[CH2:4]([CH:6]([C:10]1[CH:11]=[CH:12][NH:19][N:18]=1)[CH2:7][CH3:8])[CH3:5]
Reactant: NN
Reactant: CCOC=O
Reactant: CCC(CC)C(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCC(CC)c1cc[nH]n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
To a stirred suspension of sodium methoxide (23.6 g, 0.437 mol) in diethyl ether (˜800 mL) was added dropwise a solution of 3-ethyl-2-pentanone (49.9 g, 0.437 mol) and ethyl formate (32.4 g, 0.437 mol) in diethyl ether (˜200 mL) at temperatures between 10° C. and 20° C. After the addition, the reaction mixture was allowed to warm up to room temperature, and stirred at room temperature for 2 hours. Additional diethyl ether (˜800 mL) was then added. The reaction mixture was stirred at room temperature for one additional hour and then concentrated. The residue was suspended in a solution of ethanol (950 mL) and acetic acid (30 mL). To this suspension was added hydrazine monohydrate (24 mL, 0.49 mol). The reaction mixture was heated at reflux for 60 hours and was then allowed to cool slowly to room temperature. The reaction mixture was then concentrated. To the residue was added 200 mL of 1N hydrochloric acid, followed by ˜75 mL of concentrated hydrochloric acid until pH ˜0. The acidic aqueous solution was then washed twice with diethyl ether (˜250 mL each). The pH of the aqueous solution was then adjusted to 9–10 by addition of aqueous 50% sodium hydroxide solution. The aqueous solution was then extracted twice with diethyl ether (˜300 mL each). The diethyl ether extracts were combined, dried over MgSO4 and concentrated to give the title compound as a pale yellow oil (41 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19](O)=[O:20])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([NH:30][NH2:31])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[C:22]([NH:30][NH:31][C:19](=[O:20])/[CH:18]=[CH:17]/[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:9]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)NNC(=O)c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (200 mg, 0.7 mmol), benzohydrazide (142.2 mg, 1.04 mmol) and HATU (397.02 mg, 1.04 mmol) dissolved in DMF (7.0 ml), N,N-diisopropylethylamine (DIPEA)(0.1819 ml, 1.04 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc=3:1) and dried so that ivory (E)-tert-butyl 3-(3-(2-benzoyl hydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (223.5 mg, 79.2%).
Reaction SMILES: C(OC([N:8]([C:41](OC(C)(C)C)=O)[C:9](=[O:40])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([CH3:37])=[CH:35][C:34]([CH2:38][CH3:39])=[CH:33][N:32]=2)[CH2:27][CH2:26]1)=[O:24])=O)(C)(C)C.N1C[CH2:51][CH2:50][CH2:49]1>>[O:22]=[S:17]1(=[O:21])[CH2:18][CH2:19][CH2:20][N:16]1[C:14]1[CH:13]=[CH:12][C:11]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([C:31]3[C:36]([CH3:37])=[CH:35][C:34]([CH2:38][CH3:39])=[CH:33][N:32]=3)[CH2:29][CH2:30]2)=[O:24])=[C:10]([C:9]([N:8]2[CH2:41][CH2:51][CH2:50][CH2:49]2)=[O:40])[CH:15]=1
Reactant: C1CCNC1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C(=O)N3CCCC3)CC2)c(C)c1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzamide (202 mg) described in Example 785 and pyrrolidine (30 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (118 mg) was obtained.
Reaction SMILES: CS([O:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=2)[O:16][CH2:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([O:22]C)=[O:21])=[CH:8][CH:7]=1)(=O)=O.[OH-].[Li+].Cl>C1COCC1.O>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=2)[O:16][CH2:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([OH:22])=[O:21])=[CH:31][CH:32]=1
Reactant: COC(=O)c1ccccc1COc1cccc(CCOc2ccc(OS(C)(=O)=O)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1COc1cccc(CCOc2ccc(O)cc2)c1
Yield: 18.3 %

Procedure:
Methyl 2-{[3-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenoxy]methyl}benzoate (0.109 g, 0.24 mmol) was dissolved in a mixture of THF/water (7/1, 2.5 ml). Lithium hydroxide (23 mg, 0.96 mmol) was added. The reaction was performed in a single node microwave oven (7 min, 150° C.). The mixture was acidified (HCl, 1 ml, 1 M) and the water phase was extracted with two portions of EtOAc. The organic phases were combined, dried (MgSO4) and the solvent was removed by evaporation and gave 16 mg of 2-({3-[2-(4-hydroxyphenoxy)ethyl]phenoxy}methyl)benzoic acid (yield 18%)