Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8]2)=[CH:4][CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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>[C:13]1([CH:9]2[NH:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:19]=[CH:20][C:2]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:22]([F:33])([F:32])[F:21])=[CH:3][CH:4]=3)[CH2:8]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Brc1ccc(CN2CCNC(c3ccccc3)C2)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: CCO
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccccc1-c1ccc(CN2CCNC(c3ccccc3)C2)cc1
Temperature: 120 °C
Yield: 41.4 %

Procedure:
100 mg of 1-(4-Bromo-benzyl)-3-phenyl-piperazine was combined with 136 mg of 2-(Trifluoromethyl)phenyl boronic acid, 17 mg of tetrakis(triphenylphosphine)palladium(0), 1.01 mL of 2M sodium carbonate solution, 2.7 mL toluene and 1.4 mL ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography eluting in a 0-20% methylene chloride/methanol gradient. The product fractions were pooled and concentrated to afford 49.5 mg of product. ES MS (+) m/z 397
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:13])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].OS(O)(=O)=O.[CH3:19]O>>[C:1]([C:4]1[C:5]([OH:13])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([O:9][CH3:19])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(C(=O)O)c1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C(C)=O)c1O
Yield: 20 %

Procedure:
To a solution of 3-acetyl-2-hydroxybenzoic acid 32 (3 g, 16.7 mmol) in MeOH (50 mL) was added conc. H2SO4 (3.0 mL. The reaction mixture was heated at reflux for 12 h. After concentration en vacuo, the crude residue was diluted with H2O, basified to pH=8 with aq NaHCO3 and extracted with EtOAc. The combined organic extracts were dried (MgSO4) and concentrated to give 38 as a white solid (550 mg, 20% yield).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][C@H:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@H:8]([OH:18])[CH2:7]2)=O)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH:1]1([CH2:4][N:6]2[CH2:11][CH2:10][C@H:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@H:8]([OH:18])[CH2:7]2)[CH2:2][CH2:3]1
Reactant: O=C(C1CC1)N1CC[C@H](c2ccccc2)[C@H](O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O[C@@H]1CN(CC2CC2)CC[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
cis-1-Cyclopropylcarbonyl-4-phenyl-3-piperidinol (10.01 g, 41.1 mmoles, described above) is suspended in dry tetrahydrofuran (250 ml) and added dropwise to a suspension of lithium aluminum hydride (5.0 g, 94.7 mmoles) in tetrahydrofuran. The mixture is stirred at room temperature for 2 hours. Water (60 ml) is added slowly to the cooled reaction mixture, followed by aqueous sodium hydroxide (60 ml, 3N). The gelatinous precipitate is removed by filtration and the filtrate evaporated. The solid residue is dissolved in methylene chloride, washed with brine, dried (MgSO4) and evaporated. The residue is crystallized from hexane to give the title compound, mp 98°-100° C.
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([Cl:25])=[C:12]([NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[C:22]([O-:24])=[O:23])[C:13]=1[Cl:14].[Na+].CN(C)C=O.CO>C(Cl)Cl>[Cl:14][C:13]1[C:8]([CH3:7])=[CH:9][CH:10]=[C:11]([Cl:25])[C:12]=1[NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=1[C:22]([O:24][CH3:1])=[O:23]
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(=O)[O-])c1Cl
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1Nc1c(Cl)ccc(C)c1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 70.5 %

Procedure:
Oxalyl chloride (9.50 g, 74.8 mmol) in 20 ml of methylene chloride is added dropwise to a 0° C. suspension of meclomen (10.20 g, 34.4 mmol) and dimethylformamide (2.70 ml, 34.7 mmol) in 50 ml of methylene chloride. The clear yellow solution is stirred at 0° C. for 90 minutes then added by cannula to 110 ml of methanol at room temperature. The white suspension is stirred at room temperature overnight. The white solid is collected providing 7.52 g of product. The filtrate is concentrated and the residue partitioned between ethyl acetate and water. The organic layer is washed with brine, dried over magnesium sulfate and concentrated, providing an additional 2.45 g of product (94% total), mp 130°-131° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:12]([O-])([OH:14])=[O:13].[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[N+:12]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)=[CH:6][CH:5]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: c1ccc(-c2c[nH]cn2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(-c2c[nH]cn2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 44.1 %

Procedure:
Sulfuric acid (95-98%, 250 mL) is placed in a 1 L 4-neck round bottomed flask equipped with mechanical stirrer, thermometer and cooled to 0° C. 4-Phenylimidazole (87.2 g, 0.606 mol) is added in portions to keep the temperature under 10° C. The starting material is dissolved completely after stirring for 20 minutes. The mixture is cooled to 0° C., fuming nitric acid (28.42 mL, 0.606 mol) is added dropwise to keep the temperature at 0-5° C. The addition took about 1.5 h. After stirring at 0° C. for 1 h, the reaction mixture is poured into ice (3 Kg) and stirred for 20 minutes, neutralized with sodium hydroxide (340 g) and then sodium carbonate (10%) to pH˜10. The mixture is filtered; the solid is washed with water (3×500 mL), methanol (500 mL) and air-dried. The crude product is recrystallized with ethanol (20 mL/g) to give 50.5 g product as tan crystals. The mother liquor is concentrated and the residue is recrystallized with ethanol to give another crop of the product (11.2 g) with a total yield of 61.7 g (53.9%); mp 226-228° C.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH2:37]=O>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][CH:24]5[CH2:25][CH2:26][N:27]([CH3:37])[CH2:28][CH2:29]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:34])[F:35])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CC1CCNCC1
Reactant: C=O
Product: CN1CCC(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(1-methylpiperidin-4-yl)methyl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(piperidin-4-ylmethyl)-1,3-thiazolidine-2,4-dione (Example 130) and formaldehyde following General Procedure R.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[Cl:13][CH2:14][C:15](Cl)=[O:16]>ClCCl>[Cl:13][CH2:14][C:15]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:16]
Reactant: C1COCCN1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(CCl)N1CCOCC1

Procedure:
Utilize a Quest 205 Parallel Synthesizer and to a mixture of morpholine (2.6 g, 30 mmol), dichloromethane (45 mL) and 2M K2CO3 slowly add chloroacetylchloride (3.73 g, 33 mmol) in dichloromethane (10 mL). Agitate the reaction overnight and filter off the organic layer. Extract the aqueous with dichloromethane (20 mL) and add it to the previously collected organic layer. Dry the organic phase (MgSO4) and concentrate under vacuum to obtain the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:25])[CH2:20][NH:21]C(C)C)=[CH:15][CH:14]=2)=[CH:9]1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:25])[CH2:20][NH:21][C:33]([NH:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:34])=[CH:15][CH:14]=2)=[CH:9]1
Reactant: CC(C)NCC(C)c1ccc(-c2ccsc2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(CNC(=O)Nc1ccccc1)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propyl-2-propyl amine trifluoroacetate (prepared in example 1) and phenyl isocyanate in a manner analogous to the procedure described in Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([O:17][CH2:18][O:19][CH3:20])[CH:13]=[CH:14][CH:15]=2)[CH:10]([CH2:21][OH:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([O:17][CH2:18][O:19][CH3:20])[CH:13]=[CH:14][CH:15]=2)[CH:10]([CH2:21][O:22][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: COCOc1cccc2c1C(CO)CN2C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOc1cccc2c1C(COS(C)(=O)=O)CN2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.3 %

Procedure:
A solution of 17 (80 mg, 0.26 mmol) in 5 mL anhydrous CH2Cl2 was cooled to 0° C. and treated with Et3N (79 μL, 0.57 mmol). After 10 min, MsCl (40 μL, 0.52 mmol) was added and the reaction mixture was subsequently warmed to 25° C. and stirred for 3 h. The reaction solution was concentrated under reduced pressure. Flash chromatography (SiO2, 2.5×10 cm, 30% EtOAc/hexane) yielded pure 18 (94 mg, 94%) as a colorless oil: 1H NMR (CDCl3, 250 MHz) δ7.49 (m, 1H), 7.15 (m, 1H), 6.68 (d, J=9.0 Hz, 1H), 5.19 (d, J=8.8 Hz, 1H), 5.17 (d, J=8.8 Hz, 1H), 4.58 (dd, J=3.6, 9.7 Hz, 1H), 4.21 (app t, J=8.9 Hz, 1H), 4.00 (m, 2H), 3.79 (m, 1H), 3.46 (s, 3H), 2,71 (s, 3H), 1.54 (s, 9H);13C NMR (CDCl3, 100 MHz) δ153.9, 152.1, 130.5, 110.2, 108.8, 107.7, 103.9, 94.4, 81.0, 69.9, 56.2, 51.1, 37.9, 37.2, 28.2; IR (film) νmax 2976, 1703, 1610, 1479, 1463, 1391, 1355, 1254, 1175, 1154, 1061, 952 cm−1; FABHRMS (NBA/CsI) m/z 520.0388 (C17H25NO7S+Cs+ requires 520.0406).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[O:26]([CH2:25][CH2:24][CH2:23][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCCCOc1ccccc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CCCOc3ccccc3)CC1)O2

Procedure:
Compound 144 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (3-bromopropoxy)benzene and conditions outlined in procedure V. LCMS: 436 [M+H]; Rt=1.05 min.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:19])[C:4]2[CH:9]=[CH:8][NH:7][C:6](=[O:10])[C:5]=2[O:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][O:27][CH2:28][CH2:29]Br>CN(C=O)C>[I:1][C:2]1[C:3](=[O:19])[C:4]2[CH:9]=[CH:8][N:7]([CH2:29][CH2:28][O:27][CH3:26])[C:6](=[O:10])[C:5]=2[O:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COCCBr
Reactant: O=c1c(I)c(-c2ccccc2)oc2c(=O)[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCn1ccc2c(=O)c(I)c(-c3ccccc3)oc2c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.6 %

Procedure:
To a solution of 3-iodo-2-phenyl-7H-pyrano[2,3-c]pyridine-4,8-dione (100 mg, 0.27 mmol) in DMF (3 mL) was added potassium carbonate (55 mg, 0.40 mmol), followed by 2-bromoethyl methyl ether (28 μL, 0.37 mmol). The reaction mixture was stirred at RT for 24 hours. The resulting mixture was partitioned between ethyl acetate (40 mL) and water (20 mL) and the phases were separated. The organic layer was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2, 60% ethyl acetate in cyclohexane) to give the title compound as a white solid (67 mg, 59%). LCMS (Method B): RT=3.94 min, [M+H]+=424.
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[C:16](=[O:18])[N:15]([CH:19]2[CH2:21][CH:20]2[C:22]2[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=2)[CH:14]=[CH:13]3)[CH:5]=[N:4][CH:3]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:1][C:13]1[C:12]2[C:17](=[C:8]([C:6]3[CH:5]=[N:4][CH:3]=[N:2][CH:7]=3)[CH:9]=[CH:10][CH:11]=2)[C:16](=[O:18])[N:15]([CH:19]2[CH2:21][CH:20]2[C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)[CH:14]=1
Reactant: O=c1c2c(-c3cncnc3)cccc2ccn1C1CC1c1ccc2ccccc2n1
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1c2c(-c3cncnc3)cccc2c(Cl)cn1C1CC1c1ccc2ccccc2n1
Yield: 7.89 %

Procedure:
Anti (+8-(pyrimidin-5-yl)-2-(2-(quinolin-2-yl)cyclopropyl)isoquinolin-1(2H)-one hydrochloride from example 240b was mixed with sodium hydrogencarbonate solution and DCM. The phases were separated and the organic phase dried. Purification by column chromatography (DCM/methanol) gave the title compound (7.89% yield) as white solid. LC-MS: m/e=425.1
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1Br)[CH3:2].[NH2:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][N:20]=[CH:21]2)=[CH:16][CH:15]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][N:20]=[CH:21]2)=[CH:16][CH:15]=1)[CH3:2]
Reactant: Nc1ccc2ccncc2c1
Reactant: CCOC(=O)c1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1Nc1ccc2ccncc2c1
Temperature: 105 °C
Reaction time: 16 h

Procedure:
A mixture of 2-bromo-benzoic acid ethyl ester (458 mg, 2.0 mmol), 7-aminoisoquinoline (144 mg, 1.0 mmol), Pd(OAc)2 (11 mg), BINAP (30 mg) and K2CO3 (414 mg) in 1 mL of toluene in a sealed tube was stirred for 16 h at 105° C. The reaction mixture was then allowed to cool to RT, diluted with 20 ml of CH2Cl2, filtered through a Celite® packed funnel and concentrated under reduced pressure. The concentrate was purified by flash column chromatography. The titled compound was obtained as oil. MS (ES+): 293.3 (M+H)+. Calc'd for C18H16N2O2—292.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].[CH2:25]([O:27][P:28]([CH2:33][C:34](O)=[O:35])([O:30][CH2:31][CH3:32])=[O:29])[CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:31]([O:30][P:28]([CH2:33][C:34]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:35])([O:27][CH2:25][CH3:26])=[O:29])[CH3:32]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: CCOP(=O)(CC(=O)O)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOP(=O)(CC(=O)Nc1ccccc1NC(=O)OC(C)(C)C)OCC
Reaction time: 6 h
Yield: 75.6 %

Procedure:
DIPEA (5.16 g, 6.90 mL, 40 mmol) and tert-butyl 2-aminophenylcarbamate (2.08 g, 10 mmol) were added to a solution of 2-(diethoxyphosphoryl)acetic acid (2.15 g, 11 mmol) in DCM (120 mL). After the mixture was stirred for ten minutes, HATU (4.56 g, 12 mmol) was added to the reaction and stirring was prolonged for 6 h at room temperature under a nitrogen atmosphere. After completion of the reaction as indicated by HPLC, the reaction mixture was washed with saturated NaHCO3 and brine. It was dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo to get the crude product, which was triturated with 30% v/v hexanes in EtOAc for 30 min. The solid was filtered, washed with 30% hexanes in EtOAc and dried to get 2.92 g of tert-butyl (2-(2-(diethoxyphosphoryl)acetamido)phenyl)carbamate as an off-white solid in 76% yield.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:14][O:15][C:16](=[O:34])[C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[NH:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29](I)[CH:28]=1)=[O:26].[N:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[C:37](B(O)O)[CH:36]=1>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.O.CO>[Cl:23][C:21]1[CH:20]=[CH:19][C:18]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:37]3[CH:36]=[N:35][C:44]4[C:39]([CH:38]=3)=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:28]=2)=[O:26])=[C:17]([CH:22]=1)[C:16]([O:15][CH3:14])=[O:34]
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(I)c1
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: CO
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(-c2cnc3ccccc3c2)c1
Temperature: 90 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
Under an Ar atmosphere, 9 mL of toluene, 2.5 mL of methanol, 2.5 mL of 2M aqueous sodium carbonate solution were added to 500 mg (1.20 mmol) of 5-chloro-2-{[(3-iodophenyl)carbonyl]amino}benzoic acid methyl ester and 330 mg (1.91 mmol) of quinolin-3-ylboronic acid, and the mixture was degassed. Further, 100 mg (0.087 mmol) of tetrakis(triphenylphosphine)palladium(0) was added, and the mixture was heated under stirring at 90° C. for 6 hours. After the mixture was cooled to room temperature, water was added thereto, followed by collection by filtration, water-washing, and drying. Thereafter, the resultant was dissolved in chloroform, followed by filtration. The filtrate was condensed, thereby giving 340 mg of methyl 5-chloro-2-({[3-(quinolin-3-yl)phenyl]carbonyl}amino)benzoate (yield: 67%).
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[N:11]([CH3:30])[C:12]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[N:14]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CI.[H-].[Na+].[C:35](=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:35][N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:8]([C:10]1[N:11]([CH3:30])[C:12]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[N:14]=1)=[O:9]
Reactant: Cn1c(C(=O)NC2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1C)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-cyclohexyl-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1-methylimidazole-2-carboxamide (15 mg, 0.033 mmol) from Example 36, (Method A) and methyl iodide (0.003 mL, 0.049 mmol) in DMF (2 mL) was added sodium hydride (60% in mineral oil, 2 mg, 0.049 mmol). The mixture was stirred at rt for 2 hr and then poured into aq. sodium bicarbonate and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by Prep TLC (0.5 mm, silica) (25% ethyl acetate in hexanes) to afford the title compound.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[NH:11][N:10]=[N:9][C:8]=1[C:12](=[O:14])[NH2:13].C(O)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([NH:6][C:7]1[NH:11][N:10]=[N:9][C:8]=1[C:12](=[O:14])[NH2:13])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC(=O)c1nn[nH]c1N
Reactant: O=C(Cl)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: NC(=O)c1nn[nH]c1NC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
Concentrated sulphuric acid (1.5 ml.) was added dropwise, under anhydrous conditions, to an ice-cooled, stirred suspension of 5-amino-4-carbamoyl-1H-1,2,3-triazole (1.27 g.) in benzoyl chloride (15 ml.), and the reaction mixture then stirred at room temperature overnight. The mixture was poured into ice-water, whereupon a gummy precipitate was formed. The aqueous solution was decanted off, and the gum triturated thoroughly with diethyl ether. The remaining solid was then filtered off, and washed well with diethyl ether, to give crude 5-benzamido-4-carbamoyl-1H-1,2,3-triazole (2.26 g.), m.p. 280° C. (with decomposition). An aliquot was heated in boiling ethanol, and the solid filtered off, while still hot, to give pure 5-benzamido-4-carbamoyl-1H-1,2,3-triazole, m.p. 306° C. (with decomposition).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([CH3:13])[N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:49][CH2:50][C:51]([N:53]1[CH2:58][CH2:57][CH:56]([NH:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[Cl:66])[CH2:55][CH2:54]1)=[O:52]>CN(C=O)C.O>[Cl:66][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=1[NH:59][CH:56]1[CH2:55][CH2:54][N:53]([C:51](=[O:52])[CH2:50][NH:49][C:14]([C:10]2[CH:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:12]([CH3:13])[N:11]=2)=[O:16])[CH2:58][CH2:57]1
Reactant: Cn1nc(C(=O)O)cc1-c1ccccc1O
Reactant: NCC(=O)N1CCC(Nc2ccccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(C(=O)NCC(=O)N2CCC(Nc3ccccc3Cl)CC2)cc1-c1ccccc1O
Reaction time: 8 h
Yield: 40.2 %

Procedure:
To a stirred solution of 5-(2-hydroxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (0.13 g, 0.0006 mol) in DMF (2 mL) was added DIPEA (0.308 g, 0.00234 mol), HOBt (0.101 g, 0.00075 mol) and EDCI.HCl (0.143 g, 0.00075 mol) at ambient temperature. After 5 minutes 2-amino-1-[4-(2-chloro-phenylamino)-piperidin-1-yl]-ethanone hydrochloride (0.181 g, 0.00060 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and recrystallized from ethyl acetate to afford 0.113 g (41%) of 5-(2-hydroxy-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 468.18 (M+1)+, 96.98%. 1H NMR (DMSO-d6): δ 10.2 (s, 1H), 8.7 (t, 1H), 7.7 (d, 1H), 7.4 (s, 1H), 7.1 (m, 3H), 6.8 (m, 3H), 6.6 (m, 1H), 4.9 (m, 1H), 4.3 (d, 1H), 4.1 (m, 4H), 3.9 (m, 1H), 3.6 (m, 1H), 3.1 (m, 1H), 2.7 (m, 1H), 1.9 (m, 2H), 1.4 (m, 2H).