Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[CH3:25][CH:26]1[CH2:31][CH:30]([CH3:32])[CH2:29][NH:28][CH2:27]1>>[CH3:25][CH:26]1[CH2:31][CH:30]([CH3:32])[CH2:29][N:28]([CH2:22][C:17]2[CH:16]=[C:15]3[C:20]([CH:21]=[C:12]([C:10]4[N:11]=[C:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)[S:8][CH:9]=4)[C:13](=[O:24])[NH:14]3)=[CH:19][CH:18]=2)[CH2:27]1
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Reactant: CC1CNCC(C)C1
Product: CC1CC(C)CN(Cc2ccc3cc(-c4csc(-c5ccncc5)n4)c(=O)[nH]c3c2)C1

Procedure:
This compound was prepared according to the method described in example 8768 employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and 3,5-dimethylpiperidine to give a yellow solid. MS m/z: 431.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:16][CH:15]=1)[C:7]([OH:9])=[O:8])([O-])=O.[CH:30](O)=O>C(OC)(OC)OC.C(Cl)Cl.[Fe]>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[O:23][CH2:22][CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:12]3[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=3[N:1]=[CH:30]2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(Nc2ccc(OCCOc3ccccn3)cc2)c([N+](=O)[O-])c1
Reactant: O=CO
Agent: [Fe]
Solvent: COC(OC)OC
Solvent: ClCCl
Product: O=C(O)c1ccc2c(c1)ncn2-c1ccc(OCCOc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Nitro-4-({4-[2-(pyridin-2-yloxy)ethoxy]phenyl}amino)benzoic acid (6.00 g, 15.20 mmol), iron powder (8.49 g, 152.00 mmol), and formic acid (68 mL) were dissolved in dry trimethyl orthoformate (175 mL). The reaction was allowed to stir at rt. After 18 h, the reaction mixture was diluted with CH2Cl2 and filtered through Celite to give a bright orange solid. The crude mixture was recrystallized from methanol to give 1-{4-[2-(pyridin-2-yloxy)ethoxy]phenyl}-1H-benzimidazole-5-carboxylic acid as a yellow-tan powder. 1H NMR (d6-DMSO, 400 MHz): δ 8.61 (d, J=2.4 Hz, 1H), 8.32 (d, J=1.6 Hz, 1H), 8.19 (ddd, J=5.2, 1.6, 0.8 Hz, 1H), 7.93 (dd, J=8.8, 1.6 Hz, 1H), 7.73 (ddd, J=8.8, 6.8, 1.8, Hz, 1H), 7.61 (ddd, J=4.8, 2.8, 2.8 Hz, 2H), 7.58 (s, 1H), 7.24 (ddd, J=5.2, 3.2, 3.2 Hz, 2H), 7.01 (ddd, J=6.8, 5.2, 1.2 Hz, 1H), 6.88 (dd, J=8.4, .4.0 Hz, 1H), 4.64 (t, J=4.2 Hz, 2H), 4.43 (t, J=4.6 Hz, 2H). MS(ES+): m/z 376.47 (10) [MH+].
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH2:9]O)=[CH:5][CH:4]=1.P([N:29]=[N+:30]=[N-:31])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:29]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:11])[F:1])=[N:8][CH:7]=1)=[N+:30]=[N-:31]
Reactant: OCc1ccc(C(F)(F)F)nc1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1ccc(C(F)(F)F)nc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
A mixture of (6-(trifluoromethyl)pyridin-3-yl)methanol (2.0 g, 11.3 mmol) and diphenyl phosphorazidate (2.93 mL, 14 mmol) was dissolved in dry toluene (20 mL). The mixture was cooled to 0° C. under Argon, and neat DBU (2.1 mL, 14 mmol) was added. The reaction mixture was stirred for 2 h at 0° C. and then at rt for 16 h. The resulting two-phase mixture was washed with water and extracted with EtOAc. The combined organic layer was concentrated in vacuo and purified by silica gel chromotography afford 5-(azidomethyl)-2-(trifluoromethyl)pyridine (2.3 g, quantitative yield) of a light yellow oil: 1H NMR (300 MHz, CDCl3+CD3OD), d: 8.686 (m, 1H), 7.853 (m, 1H), 7.723 (d, J=8.1 Hz, 1H), 4.518 (s, 2H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[N:12]=[N:13][C:14]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH:16]=1)=[O:10].Cl.[CH3:31][O:32][NH2:33]>CO.O>[CH3:31][O:32]/[N:33]=[C:2]1/[C@H:3]([NH:8][C:9]([C:11]2[N:12]=[N:13][C:14]([O:24][CH2:25][C:26]([F:28])([F:29])[F:27])=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH:16]=2)=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7]/1
Reactant: CON
Reactant: O=C(N[C@@H]1CCCCC1=O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Agent: Cl
Solvent: CO
Solvent: O
Product: CO/N=C1\CCCC[C@H]1NC(=O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 85.2 %

Procedure:
To a solution of 100 mg of 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid ((R)-2-oxo-cyclohexyl)-amide in 0.5 ml methanol and 0.5 ml water, was added 98 mg O-methylhydroxylamine hydrochloride and the mixture was stirred at ambient temperature for 3.5 h. The solvents were evaporated and the residue was purified by chromatography on silica gel using a gradient of heptane:ethyl acetate=95:5 to 50:50 to yield 91 mg of the title compound as white foam. MS (EI): 457.3 (M+H).
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]2[O:9][CH2:10][O:11][C:3]=12.[CH3:12][O:13][CH2:14][CH2:15][C:16]#[CH:17].C(NC(C)C)(C)C>C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH3:12][O:13][CH2:14][CH2:15][C:16]#[C:17][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]2[O:9][CH2:10][O:11][C:3]=12
Reactant: C#CCCOC
Reactant: Nc1ccc(I)c2c1OCO2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COCCC#Cc1ccc(N)c2c1OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.8 %

Procedure:
A solution of 4-iodo-2,3-methylenedioxyaniline (1.32 g, 5.00 mmol) and 4-methoxybut-1-yne (0.84 g, 10.00 mmol) in ethyl acetate (25 ml) was cooled in ice-methanol, under an atmosphere of nitrogen, then treated with bis(triphenylphosphine) palladium(II) dichloride (350 mg, 10 mol %) followed by copper(I) iodide (95 mg, 10 mol %) and diisopropylamine (1.40 ml, 10.0 mmol). The reaction was stirred for 2 hours in the cooling bath and then allowed to warm to room temperature over 4 hours: The mixture was filtered through Celite and the filtrate was then purified by column chromatography on silica using a gradient of methanol in dichloromethane (0–2%) as eluent to give 4-(4-methoxybut-1-yn-1-yl)-2,3-methylendioxyaniline (524 mg, 82%) as a dark oil; LCMS: M+H+ 220 (82%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.CCN(CC)CC.[OH:19][CH2:20][CH:21]1[O:25][C:24](=[O:26])[NH:23][CH2:22]1>ClCCl>[S:7]([O:19][CH2:20][CH:21]1[O:25][C:24](=[O:26])[NH:23][CH2:22]1)([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1NCC(CO)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CNC(=O)O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
p-Toluenesulphonyl chloride (2.74 g, 14.36 mmol) and Et3N (1.45 g, 14.36 mmol) were added to 5-hydroxymethyl-1,3-oxazolidine-2-one (1.40 g, 11.97 mmol) dispersed in 20 mL of dichloromethane and stirred overnight at room temperature under N2. After completion of the reaction (TLC), the solvent in the reaction mixture was evaporated and the residue was purified by column chromatography employing EtOAc-hexane (70:30) as eluent to afford 5-tosyloxymethyl-1,3-oxazolidine-2-one in 80% yield. m.p. 96-99° C.; [α]27D=+45.40 CHCl3); IR (KBr) 3302, 2980, 2925, 2871, 1757, 1694, 1357, 1184, 1090, 996, 965 cm1; 1HNMR (200 MHz, CDCl3) δ 2.47 (s, 3H), 3.40-3.50 (m, 1H), 3.64-3.74 (m, 1H), 4.14 (d, 2H, J=4.4 Hz), 4.71-4.82 (m, 1H), 7.35 (d, 2H, J=8.2 Hz), 7.78 (d, 2H, J=8.2 Hz); Mass (EI) 271, 207, 173, 155, 139, 91.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26].[Br:48][C:49]1[CH:50]=[C:51]([CH:55]=[C:56]([Br:58])[CH:57]=1)[C:52](O)=[O:53].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH:38][C:52](=[O:53])[C:51]3[CH:50]=[C:49]([Br:48])[CH:57]=[C:56]([Br:58])[CH:55]=3)=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26]
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
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: C1CCOC1
Product: CC(=O)N1c2ccc(NC(=O)c3cc(Br)cc(Br)c3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
HATU condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 3,5-dibromobenzoic acid (10 mg) and N,N-diisopropylethylamine (22 l) in tetrahydrofuran (1 ml) was performed according to the method described in example 11.
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]21[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]2)(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>O>[CH3:26][S:27]([O:19][CH:16]1[CH2:17][CH2:18][C:6]2([CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]2[NH:4][C:1](=[O:3])[CH3:2])[CH2:14][CH2:15]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)NC1c2ccccc2CC12CCC(O)CC2
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NC1c2ccccc2CC12CCC(OS(C)(=O)=O)CC2
Temperature: 0 °C

Procedure:
To an ice cold solution of 1.21 g. of 1'-acetamidospiro(cyclohexane-1,2'-indan)-4-ol (isomer B)[27] (prepared in Example 61B) in 12 ml. of pyridine, 1.2 ml. of methane sulfonyl chloride is added. After about 5 hours in the cold the mixture is poured into ice: water. The solid that precipitates is recrystallized from acetone: Skellysolve B to give 1.21 g. of 1'-acetamidospiro(cyclohexane-1,2'-indan-4-ol methanesulfonate (isomer B)[28], melting at 161° to 163° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1Cl.[C:16]1([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)=[N:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[O:39][C:36]1[CH:35]=[CH:34][C:33]([NH:32][C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:22]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:23][N:24]=2)=[CH:38][CH:37]=1
Reactant: Clc1ccncc1Br
Reactant: Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Brc1cnccc1Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Temperature: 130 °C

Procedure:
A resealable reaction tube was charged with cesium carbonate (0.873 g, 0.268 mmol), 3-bromo-4-chloropyridine hydrochloride (0.205 g, 0.894 mmol) and 4-(4-phenylphthalazin-1-ylamino)phenol (0.280 g, 0.894 mmol) and purged with nitrogen for several minutes. 1.8 mL of DMSO was added, the tube was sealed, and the reaction mixture was heated to 130° C. for 3 h. Upon cooling the mixture was diluted with EtOAc and washed with water. The aqueous portion was extracted with EtOAc, and the combined organic portions were dried with MgSO4 and concentrated. N-(4-(3-bromopyridin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine was isolated as an orange solid. MS m/z=470 [M+H]+. Calc'd for C25H17BrN4O: 469.33.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[C:26]([CH:31]3[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]3)=N[CH:28]=[CH:29][N:30]=2)[CH2:20][CH2:19]1>C(Cl)Cl>[NH:34]1[CH2:33][CH2:32][CH:31]([C:26]2[C:25]([O:24][CH:21]3[CH2:20][CH2:19][N:18]([C:9]4[CH:10]=[CH:11][C:16]5[C:17](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:8]=4)[CH2:23][CH2:22]3)=[N:30][CH:29]=[CH:28][CH:2]=2)[CH2:36][CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccnc2OC2CCN(c3ccc4ccccc4n3)CC2)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cnc(OC2CCN(c3ccc4ccccc4n3)CC2)c(C2CCNCC2)c1
Temperature: 25 °C
Yield: 27 %

Procedure:
Trifluoroacetic acid (0.272 mL, 3.53 mmol) was added to a solution of tert-butyl 4-(3-(1-(quinolin-2-yl)piperidin-4-yloxy)pyrazin-2-yl)piperidine-1-carboxylate (1726 mg, 3.53 mmol) in DCM (2 mL) and stirred at RT until the starting material was completely consumed. The mixture was then diluted with ethyl acetate and neutralized with saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated. The brown solid was triturated with acetone and dried to give the title compound as a white solid (370 mg, 27% yield). [M+1] 390.2. IC50 (uM) 0.05444. 1H NMR (CDCl3, 400 MHz) δ (ppm): 1.53-1.69 (m, 1H) 1.86-2.00 (m, 2H) 2.12-2.34 (m, 6H) 3.03-3.14 (m, 2H) 3.23-3.32 (m, 1H) 3.53-3.71 (m, 4H) 4.13-4.22 (m, 2H) 5.35-5.43 (m, 1H) 7.06 (d, J=9.19 Hz, 1H) 7.20-7.26 (m, 1H) 7.52-7.59 (m, 1H) 7.62 (d, J=7.82 Hz, 1H) 7.67-7.82 (m, 1H) 7.89-7.95 (m, 1H) 7.97 (d, J=2.74 Hz, 1H) 8.06 (d, J=2.74 Hz, 1H)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:7]([CH2:21][CH2:22][N:23]=3)[C:8]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)=[N:9][C:10]=2[CH:11]=1.Cl[CH2:25][CH2:26][CH2:27][S:28]([N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1)(=[O:30])=[O:29]>>[CH3:37][N:34]1[CH2:33][CH2:32][N:31]([S:28]([CH2:27][CH2:26][CH2:25][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[N:7]([CH2:21][CH2:22][N:23]=4)[C:8]([NH:12][C:13](=[O:20])[C:14]4[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=4)=[N:9][C:10]=3[CH:11]=2)(=[O:30])=[O:29])[CH2:36][CH2:35]1
Reactant: CN1CCN(S(=O)(=O)CCCCl)CC1
Reactant: O=C(NC1=Nc2cc(O)ccc2C2=NCCN12)c1cccnc1
Product: CN1CCN(S(=O)(=O)CCCOc2ccc3c(c2)N=C(NC(=O)c2cccnc2)N2CCN=C32)CC1

Procedure:
The procedure used for the preparation of Example 24 was used to prepare the title compound from N-(8-hydroxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (Example 2-5 in WO2004029055) and 1-[(3-chloropropyl)sulfonyl]-4-methylpiperazine (Intermediate D) (70 mg, 16%). TLC: Rf=0.08 in 10% MeOH/CH2Cl2, HPLC MS RT=1.06 min, MH+=512.1; 1H NMR (DMSO-d6) δ: 2.12-2.37 (2H, m), 2.37 (3H, s), 3.15-3.23 (6H, m), 3.30-3.33 (4H, m), 4.00-4.20 (6H, m), 6.84 (1H, d), 7.29 (1H, s), 7.51 (1H, dd), 7.75 (1H, d), 8.41 (1H, d), 8.70 (1H, m), 9.28 (1H, s), 12.29 (1H, s).
Reaction SMILES: [OH:1][CH:2]([C:5]([O:18][CH3:19])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]#[N:4].C([O-])([O-])=O.[K+].[K+].CS([C:30]1[N:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[N:31]=1)(=O)=O.O>CN(C=O)C>[CH3:39][O:38][C:32]1[CH:33]=[C:34]([O:36][CH3:37])[N:35]=[C:30]([O:1][CH:2]([C:5]([O:18][CH3:19])([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]#[N:4])[N:31]=1
Reactant: COC(c1ccccc1)(c1ccccc1)C(O)C#N
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)nc(OC(C#N)C(OC)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
7.3 g (28.8 mmol) of 2-hydroxy-3-methoxy-3,3-diphenylpropionitrile were dissolved in 90 ml of DMF, and 4 g (28.8 mmol) of K2CO3 and 6.3 g (28 mmol) of 2-methanesulfonyl-4,6-dimethoxypyrimidine were added. The mixture was stirred at room temperature for about 12 h, then poured into water and extracted with ethyl acetate. The combined organic phases were washed again with H2O, dried and concentrated. The residue obtained in this way was then purified by chromatography on silica gel (n-hepane/ethyl acetate).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2=[O:14].[B:15]1(B2OC(C)(C)C(C)(C)O2)[O:19]C(C)(C)C(C)(C)[O:16]1.C([O-])(=O)C.[K+].O>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][C:7]1([CH3:13])[CH2:6][C:5](=[O:14])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([B:15]([OH:19])[OH:16])[CH:3]=2)[O:8]1
Reactant: CC1(C)CC(=O)c2cc(Br)ccc2O1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)c2cc(B(O)O)ccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
A solution of 6-bromo-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (21 g), pinacol diborane (25 g), palladium acetate (0.92 g) and potassium acetate (2.4 g) in N,N-dimethylformamide (250 mL) was stirred at 90° C. for 2 hr under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (80 mL), and 0.5 M hydrochloric acid (40 mL) and sodium periodate (7.0 g) were added at 0° C. The reaction mixture was stirred at room temperature for 2 hr and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate and hexane to give the title compound (15 g, 84%) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[F:8].C(B(CC)[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)C.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[F:8][C:7]1[CH:6]=[CH:5][C:4]([NH2:9])=[CH:3][C:2]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCB(CC)c1cccnc1
Reactant: Nc1ccc(F)c(Br)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: [K+]
Solvent: O
Solvent: COCCOC
Product: Nc1ccc(F)c(-c2cccnc2)c1
Temperature: 80 °C
Yield: 46.4 %

Procedure:
A mixture of 3-bromo-4-fluorophenylamine (7.92 g, 41.7 mmol), diethyl(3-pyridyl)borane (6.74 g, 45.9 mmol), tetrakis(triphenylphosphine)palladium(0) (0.96 g, 0.83 mmol) and potassium carbonate (17.26 g, 125 mmol) in 1,2-dimethoxyethane (30 mL) and water (15 mL) was heated at 80° C. for 20 h. After cooling to ambient temperature the reaction was partitioned between ethyl acetate (500 mL) and water (500 mL). The organics were washed with brine (400 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel, eluting with dichloromethane on a gradient of ethyl acetate (0%-20%) gave 4-fluoro-3-(pyridin-3-yl)phenylamine (3.64 g, 46%) as a colourless oil that solidified on standing to afford a white solid: δH (360 MHz, CDCl3) 3.65 (2H, s), 6.65-6.72 (2H, m), 6.99 (1H, dd, J 9 and 9), 7.33-7.37 (1H, m), 7.84-7.86 (1H, m), 8.58 (1H, d, J 4), 8.76 (1H, m).
Reaction SMILES: O=C(C)C[N:4]1[C:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:7][C:6]([NH2:28])=[N:5]1.Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].O1[CH2:46][CH2:45][CH2:44]C1>CO>[CH3:44][C:45]1[NH:28][C:6]2[N:5]([CH:46]=1)[N:4]=[CH:8][CH:7]=2
Reactant: C1CCOC1
Reactant: CC(=O)Cn1nc(N)cc1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cn2nccc2[nH]1
Reaction time: 2 h

Procedure:
To a solution of 1-(2-oxopropyl)-5-triphenylmethyl-aminopyrazole (0.75 g) in methanol was added conc. hydrochloric acid (0.75 ml). The mixture was stirred for 2 hours. The reaction mixture was added to a mixture of ethyl acetate, tetrahydrofuran and ice-cold water, and the mixture was adjusted to pH 8 with sodium bicarbonate. The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure The residue was pulverized with diisopropyl ether to give 2-methyl-1H-imidazo[1,2-b]pyrazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.BrBr>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccccc1
Reactant: CC(=O)Cc1cccc(F)c1
Agent: BrBr
Product: CC(=O)C(c1ccc(F)cc1)c1cccc(F)c1
Reaction time: 1 h

Procedure:
A solution of 16.5 g. of m-fluorophenyl-2-propanone [Z. Eckstein and J. Plenkiewicz, Rocznik, Chem., 37, 907 (1963)]in 70 ml. of p-fluorobenzene is cooled and stirred as 5.5 ml. of bromine are added dropwise. Argon gas is bubbled through the mixture for one hour. The solution is then added dropwise to a mixture of 29.6 g. of aluminum chloride and 70 ml. of p-fluorobenzene, stirred at 80°-90° C. Stirring is continued at this temperature for one hour then the mixture is poured into ice and 45 ml. of concentrated hydrochloric acid. Toluene is added, the organic layer is separated, washed with dilute sodium hydroxide and then water and distilled, giving the desired product as a liquid, b.p. 106°-112° C. (0.15 mm.).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([OH:30])=[C:11]([CH:29]=1)[C:12]([NH:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)=[O:13].O>O1CCCC1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:30][C:2]([O:4][CH3:5])=[O:3])=[C:11]([CH:29]=1)[C:12]([NH:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:26])([F:27])[F:28])[CH:16]=1)=[O:13]
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)Oc1ccc(Cl)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
Methyl chloroformate(42 μL, 0.54 mmol) was added to a solution of 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide 1 sodium salt(200 mg, 0.49 mmol) in tetrahydrofuran(5 mL) under ice cooling, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was washed with n-hexane under suspension to give the title compound(171.2 mg, 78.6%) as a white solid.
Reaction SMILES: [CH2:1]([N:5]([C:23]1[CH:24]=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH:26]=[CH:27][CH:28]=1)[S:6]([C:9]1[CH:21]=[CH:20][C:12]([O:13][CH2:14][C:15]([O:17]CC)=[O:16])=[C:11]([CH3:22])[CH:10]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([N:5]([C:23]1[CH:24]=[C:25]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:34]=2)[CH:26]=[CH:27][CH:28]=1)[S:6]([C:9]1[CH:21]=[CH:20][C:12]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:11]([CH3:22])[CH:10]=1)(=[O:7])=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(c1cccc(-c2ccc(C(F)(F)F)cc2)c1)S(=O)(=O)c1ccc(OCC(=O)OCC)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCN(c1cccc(-c2ccc(C(F)(F)F)cc2)c1)S(=O)(=O)c1ccc(OCC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a solution of ethyl [4-({butyl[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amino}sulfonyl)-2-methylphenoxy]acetate (100 mg, 0.18 mmol) in methanol (4 mL) and tetrahydrofuran (4 mL), was added 2M NaOH aq. (2 mL). After stirring for 1 h at room temperature the solvent was removed in vacuo and the residue acidified with 2M HCl, before extraction into ethyl acetate (2×20 mL). The organic solution was dried (MgSO4) and the solvents removed in vacuo to afford the title compound as a white solid (85 mg).