Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=3)[N:11]=[C:12]2O)=[CH:7][C:6]=1[O:23][CH3:24])=[O:4].O=P(Cl)(Cl)[Cl:28]>>[CH3:1][N:2]([CH3:25])[C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=3)[N:11]=[C:12]2[Cl:28])=[CH:7][C:6]=1[O:23][CH3:24])=[O:4]
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(O)c2cc1C(=O)N(C)C
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1C(=O)N(C)C
Temperature: 130 °C
Yield: 70 %

Procedure:
A mixture of 1-Hydroxy-6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-7-carboxylic acid dimethylamide (0.1 g, 0.29 mmol) in POCl3 (4 ml) was sealed in microwave process vial (5 ml). The mixture was heated at 130° C. for 30 minutes under microwave irradiation. The mixture was concentrated, and the residue was treated with 1 ml MeOH. After stirred for half an hour at room temperature, the solid was collected and dried to give desired product (0.072 g, 70%). LC-MS: m/e 360 (MH+).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[NH:8][CH2:9][CH3:10])([O-:5])=[O:4].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C=O)C>[N+:3]([C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[N:8]([CH2:9][CH3:10])[S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25])([O-:5])=[O:4]
Reactant: CCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 64.6 %

Procedure:
To a suspension of sodium hydride (60%, 0.12 g (3.00 mmol)) in DMF (4.0 ml), 2,4-dinitro-N-ethylaniline (0.42 g (1.99 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, p-toluenesulfonyl chloride (0.57 g (2.99 mmol)) was added. After two hours' stirring at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography with ethyl acetate-hexane (1:2) as eluent, to give 0.47 g (65%) of the title compound as pale yellow crystals.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[Cl:39][C:35]1[CH:34]=[C:33]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH3:32])[CH:38]=[CH:37][CH:36]=1
Reactant: CN(C[C@@H](N)c1cccc(Cl)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1cccc(Cl)c1

Procedure:
Compound 64 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(3-chloro-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound. LC/MS [357 (M+H)]1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 9.20 (br s, 1H), 9.00 (d, 1H), 8.55 (s, 1H), 8.39 (d, 1H), 8.20 (s, 1H), 7.56 (m, 1H), 7.47-7.26 (m, 3H), 5.48 (s, 1H), 3.16 (dd, 1H), 2.92 (dd, 1H), 2.31 (s, 3H)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH:15]=[O:16])=[CH:12][C:11]([Br:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH:18]([O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([CH3:20])[CH3:19]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:25]2[CH:26]=[CH:27][C:22]([O:21][CH:18]([CH3:20])[CH3:19])=[CH:23][CH:24]=2)[C:8]2[C:13]([C:14]=1[CH:15]=[O:16])=[CH:12][C:11]([Br:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1C=O
Product: CCOC(=O)c1c(C=O)c2cc(Br)ccc2n1-c1ccc(OC(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 5-bromo-3-formylindole-2-carboxylic acid ethyl ester (4 g, 13.51 mmol; see step (a) above) and 4-isopropoxyphenylboronic acid (4.86 g, 27.02 mmol). Yield 4.1 g (710%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)O.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([Cl:19])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: OC(c1ccc(Cl)cc1)c1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Clc1ccc(C(Cl)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.3 %

Procedure:
A stirred solution of 9.0 grams (0.036 mole) of (2-chlorophenyl)(4-chlorophenyl)methanol in 90 mL of chloroform was cooled to 0° C., and 5.3 mL (0.072 mole) of thionyl chloride was added. Upon completion of the addition the reaction mixture was allowed to warm to ambient temperature, where it stirred for about 18 hours. After this time the reaction mixture was filtered and concentrated under reduced pressure. The filtrate was taken up in hexane and subjected to column chromatography on silica gel with hexane as eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 10.0 grams of (2-chlorophenyl)(4-chlorophenyl)methyl chloride. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[S:6][CH:5]=[C:4]([C:7]#[N:8])[C:3]=1[C:9]1[S:10][CH:11]=[CH:12][N:13]=1.[O:14]=[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:21]=2)[N:16]1[CH2:29][C:30](O)=[O:31]>>[C:7]([C:4]1[C:3]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[C:2]([NH:1][C:30](=[O:31])[CH2:29][N:16]2[C:17]3[C:22](=[CH:21][C:20]([C:25]([F:26])([F:28])[F:27])=[CH:19][CH:18]=3)[CH:23]=[CH:24][C:15]2=[O:14])[S:6][CH:5]=1)#[N:8]
Reactant: N#Cc1csc(N)c1-c1nccs1
Reactant: O=C(O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Product: N#Cc1csc(NC(=O)Cn2c(=O)ccc3cc(C(F)(F)F)ccc32)c1-c1nccs1

Procedure:
The title compound was prepared from 5-amino-4-(thiazol-2-yl)thiophene-3-carbonitrile (271 mg, 1 mmol) and 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid (0.76 mmol) according to protocol A. The crude product was purified by column chromatography (35% EtOAc/hexanes) and HPLC to give N-(4-cyano-3-(thiazol-2-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide (24.mg) as a white solid with an m/z of 461.1 and retention of 7.348 min using the [7] LCMS method. 1H-NMR (300 MHz, CDCl3) δ 13.21 (s, 1H), 7.93 (m, 2H), 7.86 (dd, J=8.9, 1.8 Hz, 1H), 7.58 (s, 1H), 7.54 (d, J=3.4 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.31 (d, J=3.3 Hz, 1H), 7.00 (d, J=9.6 Hz, 1H), 5.35 (s, 2H). 13C-NMR (75 MHz, CDCl3) δ 165.3, 161.7, 161.0, 140.8, 140.0, 139.9, 129.4, 128.0, 126.5, 122.7, 120.4, 117.8, 115.9, 115.0, 114.7, 106.0, 46.3.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].[C:36]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)([CH3:39])([CH3:38])[CH3:37]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:43]4[CH2:44][CH2:45][N:40]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:41][CH2:42]4)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:31][C:32]([F:35])([F:34])[CH2:33]2)=[O:29])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Reactant: CC(C)(C)N1CCNCC1
Product: CC(C)(C)N1CCN(c2ccc(S(=O)(=O)[C@@H]3C[C@@H](C(=O)NC4(C#N)CC4)[C@H](C(=O)N4CC(F)(F)C4)C3)c(C(F)(F)F)c2)CC1

Procedure:
The title compound was prepared in analogy to Example 127 using (1R,2R,4R)-2-(3,3-Difluoro-azetidine-1-carbonyl)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 118) and 1-tert-butyl-piperazine. Light yellow foam. MS (EI): 646.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH3:10])=[CH:4][CH:3]=1.Cl.[NH2:13][OH:14].N1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:13][OH:14])[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCC(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCC(=NO)c1ccc(Cl)cc1
Yield: 54.5 %

Procedure:
1-(4-Chlorophenyl)propan-1-one (8.4 g, 50 mmol) was combined with hydroxylamine hydrochloride (4.0 g, 58 mmol), pyridine (4.6 g, 58 mmol), and ethanol (75 mL). The mixture was refluxed for 3 h. Solvent was evaporated and the residue diluted with water and extracted into diethyl ether/hexane (1:1). The organic extracts were washed with water, brine, and dried over anhydrous magnesium sulfate. Crystallization from cold hexane gave 5.0 g of 1-(4-chlorophenyl)propan-1-one oxime.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.C([O:16][C:17](=[O:19])[CH3:18])(=O)C>B(F)(F)F.CCOCC>[C:4]([O:12][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([O:11][C:1](=[O:12])[CH3:2])=[CH:3][C:2]=1[O:16][C:17](=[O:19])[CH3:18])(=[O:11])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: FB(F)F
Solvent: CCOCC
Product: CC(=O)Oc1cc(OC(C)=O)c2ccccc2c1OC(C)=O
Temperature: 25 °C

Procedure:
A solution of 1,4-naphthoquinone (79 g) in acetic anhydride (200 mL) and boron trifluoride etherate (10 mL) was heated overnight, then cooled to room temperature to give 1,2,4-triacetyloxynaphthalene, m.p. 136°-137° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([N:19]2[CH:23]=[CH:22][CH:21]=[CH:20]2)=[CH:10][C:9]=1[N+:24]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Ni]>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([N:19]2[CH:23]=[CH:22][CH:21]=[CH:20]2)=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1-n1cccc1
Agent: [Ni]
Product: COCCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1-n1cccc1

Procedure:
The title compound was prepared from [5-(2-methoxy-ethoxy)-2-nitro-4-pyrrol-1-yl-phenyl]-carbamic acid tert.-butyl ester (Example A3) by hydrogenation with Raney-Nickel according to the general procedure J (method a). Obtained as an orange solid (196 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[N:6]=[CH:5]2.C(Cl)Cl.[I:22]N1C(=O)CCC1=O>>[OH:1][C:2]1[C:3]([I:22])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[N:6]=[CH:5]2
Reactant: O=C1CCC(=O)N1I
Reactant: C[C@@]1(c2ncc3cc(O)ccc3n2)COC(=O)N1
Solvent: ClCCl
Product: C[C@@]1(c2ncc3c(I)c(O)ccc3n2)COC(=O)N1
Yield: 84.1 %

Procedure:
(R)-4-(6-Hydroxy-quinazolin-2-yl)-4-methyl-oxazolidin-2-one (330.0 mg, 0.001346 mol) was dissolved in methylene chloride (500 mL, 8 mol), (heterogeneous) followed by N-iodosuccinimide (302.8 mg, 0.001346 mol) at 23° C. The reaction mixture was then sonicated for 30 seconds, and all the solvent was removed under vacuum (rotavap). The residue was purified via chromatography (SiO2, 20 gm, 0-100% ethyl acetate/hexanes) to give 420 mg of desired product (84%). 1H NMR (MeOD) δ: 9.50 (s, 1H), 7.90 (d, J=9.0 Hz, 1H), 7.60 (d, J=9.0 Hz, 1H), 4.99 (d, J=8.8 Hz, 1H), 4.48 (d, J=8.8 Hz, 1H), 1.79 (s, 3H). MS (M+1): 372.00.
Reaction SMILES: [OH:1][CH:2]1[CH:19]([CH2:20][CH2:21][CH:22]([O:28]C2CCCCO2)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:5]2[CH2:6][C:7]3[C:12]([CH2:13][CH:4]2[CH2:3]1)=[C:11]([O:14][CH2:15][C:16]([OH:18])=[O:17])[CH:10]=[CH:9][CH:8]=3.O[CH2:36][CH2:37][C:38]([O:40]CC1C=CC=CC=1)=[O:39].CN(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl.CC(OC)(C)C>[OH:1][CH:2]1[CH:19]([CH2:20][CH2:21][CH:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:5]2[CH2:6][C:7]3[C:12]([CH2:13][CH:4]2[CH2:3]1)=[C:11]([O:14][CH2:15][C:16]([O:18][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:17])[CH:10]=[CH:9][CH:8]=3
Reactant: O=C(CCO)OCc1ccccc1
Reactant: CCCCCC(CCC1C(O)CC2Cc3c(cccc3OCC(=O)O)CC21)OC1CCCCO1
Agent: CN(C)C
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CCCCCC(O)CCC1C(O)CC2Cc3c(cccc3OCC(=O)OCCC(=O)O)CC21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Compound B (120 mg, 0.25 mmol), benzyl 3-hydroxypropionate (54 mg, 0.30 mmol) and trimethylamine (140 μL, 1.0 mmol) in DCM (4 mL) was added BOP—Cl (95 mg, 0.38 mmol). The reaction mixture was stirred at RT for 16 hr under nitrogen, diluted with MTBE, washed with brine, dried over sodium sulfate, and concentrated to an oil that was purified by silica gel chromatography. A solution of the THP-protected diester in ethanol (4 mL) was treated with PPTS (50 mg), stirred at 50° C. for 4 hr, and concentrated to an oil that was purified by silica gel chromatography. A solution of the THP-deprotected diester in dioxane (5 mL) was treated with wet 5% Pd/C (20 mg) and stirred for 24 hr under a balloon of hydrogen. The reaction mixture was filtered and concentrated to give crude Compound II-4. MS: m/z 485 [M+Na]+
Reaction SMILES: [Na].N.[C:3](#[N:5])[CH3:4].[C:6]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)#[N:7]>C(OCC)C>[NH2:7][C:6]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)=[CH:4][C:3]#[N:5]
Reactant: CC#N
Reactant: N#Cc1ccc2ccccc2c1
Agent: N
Agent: [Na]
Solvent: CCOCC
Product: N#CC=C(N)c1ccc2ccccc2c1
Yield: 22.2 %

Procedure:
To a solution of 2.0 grams (0.087 mole) of sodium in 125 milliliters of liquid ammonia was added a solution of 3.67 grams (0.089 mole) of acetonitrile in 10 milliliters of diethyl ether over a period of about five minutes. The reaction mixture was then cooled in a dry ice-acetone bath and a solution of 10.0 grams (0.065 mole) of 2-cyanonaphthalene in a minimum of dry diethyl ether was rapidly added within about five minutes after completion of the acetonitrile addition. The reaction mixture was stirred for about one and one-half hours and the ammonia was then allowed to evaporate. Water was cautiously added to the reaction mixture under nitrogen and the resulting mixture was extracted with diethyl ether. The ether was separated and the residue recrystallized from a mixture of chloroform and hexane. There was obtained 2.8 grams (22% of theoretical) of β-amino-β-(2naphthyl)acrylonitrile, melting point 85°-90°C. By the process described in Dornow et al., Chemische Berichte 82, 254-6 (1949), the β-amino-β-(2-naphthyl)acrylonitrile was hydrolyzed to β-amino-β-(2-naphthyl)acrylamide.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([NH:20][C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:39])[CH2:25][CH2:24]2)=[O:22])[CH2:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([CH3:19])[CH:18]=2)[NH:15][N:14]=[CH:13]3)[CH:5]=[CH:4][CH:3]=1.[C:40]1(B(O)O)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>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.C(O)C>[CH3:19][C:17]1[CH:18]=[C:10]([CH2:9][CH:8]([NH:20][C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:39])[CH2:25][CH2:24]2)=[O:22])[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:7]=2)[CH:11]=[C:12]2[C:16]=1[NH:15][N:14]=[CH:13]2
Reactant: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2cccc(Br)n2)cc2cn[nH]c12
Reactant: OB(O)c1ccccc1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2cccc(-c3ccccc3)n2)cc2cn[nH]c12
Temperature: 140 °C
Yield: 81.7 %

Procedure:
To a microwave tube charged with (±)-N-(1-(6-bromopyridin-2-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl)-4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamide (24.6 mg, 0.0418 mmol, 1.0 equiv) was added phenyl boronic acid (7.1 mg, 0.0585 mmol, 1.4 equiv), Pd(PPh3)4 (4.8 mg, 0.1 equiv), toluene (1 mL), ethanol (0.2 mL), and potassium carbonate solution (2M, 0.085 mL). The vial was sealed and heated by microwave at 140° C. for 30 min. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. Flash column chromatography (10% methanol/methylene chloride) afforded the desired product (20 mg, 81.6%) as an off-white solid: MS (ESI) [M+H]+=586. 1H-NMR (400 MHz, CDCl3) δ 8.00-7.86 (m, 3H), 7.65-6.82 (m, 12H), 6.74 (d, J=7.2 Hz, 1H), 6.66 (d, J=8.0 Hz, 1H), 6.32 (br., 1H), 5.35-5.20 (m, 1H), 4.62-4.48 (m, 1H), 4.30-4.08 (m, 4H), 3.40 (dd, J=13.2 and 4.2 Hz, 1H), 3.13 (dd, J=13.2 and 8.4 Hz, 1H), 3.02-2.83 (m, 2H), 2.42 (s, 3H), 1.80-1.55 (m, 4H). HPLC tR=1.51 min.
Reaction SMILES: C(O[C@@:5]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25])([C@H:12]([S:14](Cl)(=[O:16])=[O:15])[CH3:13])[CH2:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1)(=O)C.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C:5]([CH2:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1)=[C:12]([S:14]([N:35]1[CH2:36][CH2:37][N:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:33][CH2:34]1)(=[O:15])=[O:16])[CH3:13]
Reactant: CC(=O)O[C@@](Cn1cncn1)(c1ccc(F)cc1F)[C@@H](C)S(=O)(=O)Cl
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Product: CC(=C(Cn1cncn1)c1ccc(F)cc1F)S(=O)(=O)N1CCN(c2ccccc2)CC1
Yield: 8.6 %

Procedure:
In dichloromethane (15 ml) was dissolved (2R 3R)-3-chlorosulfonyl-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butyl acetate (0.5 g). To the solution was added, under ice-cooling, 1-phenylpiperazine (0 27 g) The reaction mixture was stirred for 10 minutes under ice-cooling, which was then concentrated. The concentrate was subjected to a silica gel chromatography (eluent: hexane/ethyl acetate=1/2→ethyl acetate) for purification to give, as the first eluate, 1-[3-(2,4-difluorophenyl)-4-(1H-1,2,4-triazol-1-yl)-2-buten-2-ylsulfonyl]-4-phenylpiperazine (isomer B, Compound 31, 0.05 g) as a pale brown solid substance and, as the second eluate, 1-[3-(2,4-difluorophenyl)-4-(1H-1,2,4-triazol-1-yl)-2-buten-2-ylsulfonyl]-4-phenylpiperazine (isomer A, Compound 30, 0.18 g) as a pale brown solid substance.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][C@H:8]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][C:16]=1[O:24][CH2:25][CH2:26][C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[CH:29]=[CH:30][CH:31]=[N:32]2)(=[O:14])=[O:13])[CH:9]=[O:10])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:23][N:21]([CH3:22])[C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C@H:8]([CH:9]=[O:10])[CH2:7][C:6]([OH:37])=[O:5])(=[O:13])=[O:14])=[C:16]([O:24][CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][CH:31]=[N:32]3)[CH:17]=1
Reactant: CN(C)c1ccc(S(=O)(=O)N[C@H](C=O)CC(=O)OC(C)(C)C)c(OCCc2cccc3ncccc23)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1ccc(S(=O)(=O)N[C@H](C=O)CC(=O)O)c(OCCc2cccc3ncccc23)c1
Yield: 91.9 %

Procedure:
A solution of (S)-3-[4-dimethylamino-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid tert-butyl ester (0.33 g, 0.60 mmol) in TFA (2 mL) and CH2Cl2 (20 mL) was stirred for 3 h. After the solvent was removed under vacuum, the residue was subjected to preparative reverse-phase HPLC (VYDAC, C18) using a linear gradient of (A) water containing 0.1% TFA and (B) acetonitrile containing 0.1% TFA (20-65% B, in 120 min) at a flow rate of 15 mL/min. Fractions containing the major peak were pooled and lyophilized to yield 0.260 g (92%) of (S)-3-[4-dimethylamino-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid. MS (APCI) m/z 470.1 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH:16]=O.[CH3:18][NH:19][CH3:20].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][N:19]([CH3:20])[CH3:18]
Reactant: CNC
Reactant: O=CC1CCCN1c1ccc([N+](=O)[O-])cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)CC1CCCN1c1ccc([N+](=O)[O-])cc1F
Reaction time: 0.5 h
Yield: 69 %

Procedure:
1-(2-Fluoro-4-nitro-phenyl)-pyrrolidine-2-carbaldehyde (100 mg, 0.42 mmol) and dimethylamine (large excess) is stirred at room temperature in CH2Cl2 for 5 min and NaBH(OAc)3 (120 mg, 0.57 mmol) is added. The reaction is stopped after 30 min as TLC suggested complete conversion and the desired product (77 mg, 69%) is isolated after chromatography.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:14]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([I:25])=[C:21]([O:26][CH3:27])[CH:20]=4)[N:16]=[N:15]3)[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O>C1COCC1.O>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:14]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([I:25])=[C:21]([O:26][CH3:27])[CH:20]=4)[N:16]=[N:15]3)[C:11](=[O:13])[N:12]([CH2:40][C:41]([F:44])([F:43])[F:42])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2cn(C3CCc4c(F)cccc4NC3=O)nn2)ccc1I
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-c2cn(C3CCc4c(F)cccc4N(CC(F)(F)F)C3=O)nn2)ccc1I
Temperature: 25 °C
Yield: 90.9 %

Procedure:
6-Fluoro-3-[4-(4-iodo-3-methoxy-phenyl)-1,2,3-triazol-1-yl]-1,3,4,5-tetrahydro-1-benzazepin-2-one (20 g, 41.8 mmol) was suspended in THF and stirred at room temperature. Cesium carbonate (24.53 g, 75 mmol) was added, followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (14.56 g, 62.7 mmol). The mixture was heated to gentle reflux for 2 h. The reaction was diluted with water, and the aqueous layer was extracted with EtOAc. The combined organic fractions were dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel, gradient to 100% EtOAc/hexanes. 6-Fluoro-3-[4-(4-iodo-3-methoxy-phenyl)-1,2,3-triazol-1-yl]-1-(2,2,2-trifluoro-ethyl)-1,3,4,5-tetrahydro-1-benzazepin-2-one (21.3 g) was obtained as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:7]([NH2:9])[CH:8]=1.[OH:20][C:21]1[CH:22]=[C:23]([C:30](O)=[O:31])[C:24](=[CH:28][CH:29]=1)[C:25](O)=[O:26]>>[OH:20][C:21]1[CH:22]=[C:23]2[C:24](=[CH:28][CH:29]=1)[C:25](=[O:26])[N:9]([C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[C:30]2=[O:31]
Reactant: COc1ccc(CCc2ccc(OC)cc2N)cc1
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Product: COc1ccc(CCc2ccc(OC)cc2N2C(=O)c3ccc(O)cc3C2=O)cc1
Yield: 110.6 %

Procedure:
Synthesized from 5-methoxy-2-[2-(4-methoxyphenyl)ethyl]phenylamine (1.5 g) and 4-hydroxyphthalic acid (1.6 g) according to an analogous synthetic method to Preparation Example 112, the title compound (2.6 g) was obtained.