Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[C:17](=[C:18](C(O)=O)[CH:19]=[CH:20][CH:21]=3)[N:13]2[CH2:12][CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)(=O)O)C=CC=CC=1.C([N:42](CC)CC)C>C(O)(C)(C)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[C:17](=[C:18]([NH2:42])[CH:19]=[CH:20][CH:21]=3)[N:13]2[CH2:12][CH2:11][CH2:10]1
Reactant: O=C(O)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CCN(CC)CC
Agent: O=P(O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Product: Nc1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 90 °C
Reaction time: 12 h

Procedure:
A mixture of 1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylic acid (9.40 g, 25.9 mmol), diphenylphosphinic acid (7.85 g, 28.5 mmol) and triethylamine (4.0 mL) in t-butanol (250 mL) was stirred at 90° C. for 12 hr and concentrated in vacuo. A mixture of the residue and trifluoroacetic acid (100 mL) in dichloromethane (50 mL) was stirred at room temperature for 20 hr and concentrated in vacuo. The residue was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-60% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a yellow amorphous (440 mg, 1.32 mmol, 5%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH2:17])=[O:16])[OH:11])[CH3:3]>C(#N)C>[CH3:3][N:2]([CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@@:6]1([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH2:17])=[O:16])[OH:11])[CH3:1]
Reactant: CN(C)CC1CCCCC1(O)c1cccc(C(N)=O)c1
Solvent: CC#N
Product: CN(C)C[C@H]1CCCC[C@]1(O)c1cccc(C(N)=O)c1

Procedure:
The 3-[(1-RS,2RS)-2-[(dimethylamino)methyl]-1-hydroxycyclohexyl]-benzamide was then resolved using a Chiralpak AD column with 100% acetonitrile as the eluent and with 100% ethanol for rinsing the column in between each injection, to afford (−)-3-[(1R,2R)-rel-2-[(dimethylamino)methyl]-1-hydroxycyclohexyl]-benzamide (2.25 g): MS m/z 277.0 (MH+); [α]D25 −33.5 (c 1, CHCl3); Analytical reverse phase HPLC (gradient 10-90% MeCN, 0.1% aqueous TFA) tR=1.52 min, ˜99%; 1H NMR (CDCl3) δ 1.35-1.43 (s, 1H), 1.55-1.65 (m, 2H), 1.66-1.68 (m, 3H), 1.74-1.79 (m, 1H), 1.88 (d, 1H, J=13 Hz), 2.02-2.05 (m, 3H), 2.18 (s, 6H), 2.43-2.46 (m 1H), 5.69 (s, 1H), 6.44 (s, 1H), 7.43 (t, 1H, J=7.7 Hz), 7.69-7.72 (m, 2H), 8.0 (s, 1H).
Reaction SMILES: [SH-].[Na+].[CH3:3][C:4]1([CH3:13])[O:8][N:7]=[C:6]([S:9]([CH3:12])(=O)=O)[CH2:5]1.C(=O)([O-])[O-].[K+].[K+].C(S([O-])=O)O.[Na+].BrC[C:28]1[C:29]([C:38]([F:41])([F:40])[F:39])=[N:30][N:31]([C:34]([CH3:37])([CH3:36])[CH3:35])[C:32]=1[Cl:33]>CN(C)C=O.O>[C:34]([N:31]1[C:32]([Cl:33])=[C:28]([CH2:12][S:9][C:6]2[CH2:5][C:4]([CH3:13])([CH3:3])[O:8][N:7]=2)[C:29]([C:38]([F:39])([F:41])[F:40])=[N:30]1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC1(C)CC(S(C)(=O)=O)=NO1
Reactant: CC(C)(C)n1nc(C(F)(F)F)c(CBr)c1Cl
Agent: O=C([O-])[O-]
Agent: O=S([O-])CO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(SCc2c(C(F)(F)F)nn(C(C)(C)C)c2Cl)=NO1
Reaction time: 1 h
Yield: 49.8 %

Procedure:
21.8 g of sodium hydrosulfide (purity: 70%, 272.5 mmoles) was added to a solution of 24.1 g (136.0 mmoles) of 5,5-dimethyl-3-methylsulfonyl-2-isoxazoline dissolved in 200 ml of N,N-dimethylformamide. The mixture was stirred for 1 hour. Thereto were added 18.8 g (136.2 mmoles) of anhydrous potassium carbonate and 21.0 g (136.2 mmoles) of Rongalit. The resulting mixture was stirred for 2 hours. Thereto was added, with ice-cooling, 40 g (125 mmoles) of 4-bromomethyl-1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole. The resulting mixture was stirred at room temperature for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 23.0 g (yield: 57.1%) of 3-(1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline as light pink crystals (melting point: 79.0 to 81.0° C.).
Reaction SMILES: CN(C=[N:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[C:17]([C:23]3[S:27][C:26]([C:28](N(OC)C)=[O:29])=[CH:25][C:24]=3[CH3:34])[CH:16]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])C.[CH2:35]1COC[CH2:36]1>>[CH3:22][O:21][C:20]1[CH:19]=[CH:18][C:17]([C:23]2[S:27][C:26]([C:28](=[O:29])[CH2:35][CH3:36])=[CH:25][C:24]=2[CH3:34])=[CH:16][C:15]=1[C:12]1[CH:11]=[CH:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:14][CH:13]=1
Reactant: COc1ccc(-c2sc(C(=O)N(C)OC)cc2C)cc1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Reactant: C1CCOC1
Product: CCC(=O)c1cc(C)c(-c2ccc(OC)c(-c3ccc(S(N)(=O)=O)cc3)c2)s1
Temperature: 82.5 °C

Procedure:
Grignard reagent (ethyl magnesium bromide, 1.32 g, 9.9 ml, 9.97 mmol) was added drop wise to a stirred solution of 5-(4′-(N-((dimethylamino)methylene)sulfamoyl)-6-methoxy-[1,1′-biphenyl]-3-yl)-N-methoxy-N,4-dimethylthiophene-2-carboxamide (1d, 1.0 g, 1.99 mmol) in anhydrous THF (20 ml) at 25° C. The reaction mixture was heated at 80-85° C. for 1 hour. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to 0° C. The cooled reaction mixture was then quenched by adding a saturated solution of ammonium chloride (10 ml). The mixture was then extracted with ethyl acetate (3×60 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product. The crude product so obtained was purified by flash chromatography using 30-40% ethyl acetate in hexane as an eluent to obtain the title compound. The compound was re-purified by dissolving 0.68 g of the compound in ethyl acetate (5 ml) and precipitating it by slow addition of diisopropyl ether. (0.180 g, 21.7%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][OH:11])[CH:9]=1)=[O:4].O[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][O:11][C:23]2[CH:24]=[CH:25][C:20]([C:17]3[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=3)=[CH:21][CH:22]=2)[CH:9]=1)=[O:4]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1cc(CO)c(C)o1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(COc2ccc(-c3ccccc3)cc2)c(C)o1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (1 g) in anhydrous tetrahydrofuran (20 mL) was cooled to 0° C. under a nitrogen atmosphere. 4-Hydroxybiphenyl (3 g) and triphenylphosphine (4.61 g) were added and the mixture was treated with diisopropylazodicarboxylate (3.46 mL) dropwise. The mixture was stirred at 0° C. for 10 min then cooling was removed and the mixture stirred for a further 3 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (50 mL) and water (100 mL). The organic phase was separated, dried and evaporated. The residue was purified by flash chromatography, eluting with pentane/ethyl acetate 9:1 by volume to give a mixture of the title compound and 4-hydroxybiphenyl (1.8 g). This material was purified further by flash chromatography eluting with dichloromethane/methanol 99:1 by volume to give compound 17 as a white solid (200 mg). LCMS System A: Rt=4.2 mins.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.[CH3:21][NH:22][C:23]([CH3:26])([CH3:25])[CH3:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:23]([N:22]([CH3:21])[C:18]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[N:8]=1)=[O:20])([CH3:26])([CH3:25])[CH3:24]
Reactant: CNC(C)(C)C
Reactant: O=C(O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1)C(C)(C)C

Procedure:
In analogy to the procedure described in Example 47 b), 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid was reacted with N,2-dimethylpropan-2-amine (CAN 94896-77-2) in the presence of TBTU and DIEA to give the title compound as colorless oil; MS (EI): m/e=341.1 [MH+].
Reaction SMILES: C([O:3][C:4](=[O:40])[CH:5]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:6][CH2:7][CH:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]([O:11]CC)=[O:10])C.[OH-].[K+]>O.CO>[C:34]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH2:27][CH:5]([CH2:6][CH2:7][CH:8]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]([OH:11])=[O:10])[C:4]([OH:40])=[O:3])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CCOC(=O)C(CCC(Cc1ccccc1-c1ccccc1)C(=O)OCC)Cc1ccccc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(CCC(Cc1ccccc1-c1ccccc1)C(=O)O)Cc1ccccc1-c1ccccc1
Yield: 85 %

Procedure:
To the 2,5-bis(2-phenyl-benzyl) adipic acid diethylester, obtained as described above, were added 180 mL of a solution of 6 M KOH in H2O/MeOH and the reaction mixture was refluxed for 16 hours. MeOH was removed on a rotary evaporator and the aqueous layer was washed with Et2O (2×200 mL). The alkaline aqueous layer was acidified, at 0° C., with HCl 37% to pH 1. A white/yellow powder was formed, filtered off and washed with water and a little hexane. Said powder was thoroughly dried, to afford 77.0 g of 2,5-bis(2-phenyl-benzyl) adipic acid (85% yield).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[Cu](C#N)[C:14]#[N:15]>CN(C)C=O.O>[O:12]=[C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:14]#[N:15])[CH:11]=2)[CH:6]=[CH:7][NH:8]1
Reactant: O=c1[nH]ccc2ccc(Br)cc12
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2cc[nH]c(=O)c2c1
Temperature: 180 °C
Yield: 70.1 %

Procedure:
To a suspension of 7-bromoisoquinolin-1 (2H)-one (70 g, 0.31 mol) in N,N-dimethylformamide (1 L) was added copper cyanide (56 g, 0.63 mol). The reaction was heated to 180° C. for 2 hours. The reaction was cooled to room temperature and was diluted with water (1 L). The solution was extracted with ethyl acetate (3×). The organics were dried over sodium sulfate, filtered, and concentrated to give crude 1-oxo-1,2-dihydroisoquinoline-7-carbonitrile (37 g). This crude material was taken up in ethanol (500 mL) and 1 N aqueous sodium hydroxide (400 mL) was added. The mixture was heated to reflux and stirred for 2 hours. The reaction was cooled to room temperature and the pH was adjusted to ˜2 with 1 N aqueous hydrochloric acid. The solids were collected by filtration, rinsed with water, and dried under vacuum to give the title compound (35 g, 85%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6, δ): 13.15 (br. s., 1H), 11.49 (s, 1H), 8.75 (s, 1H), 8.17-8.14 (m, 1H), 7.75 (d, 1H), 7.34-7.29 (m, 1H), 6.62 (d, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH:15](C)[CH2:14]2)[CH:3]=1.[CH3:27][C:28]1([NH:33][C:34](=[O:36])[CH3:35])[CH2:32][CH2:31][NH:30][CH2:29]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([N:30]3[CH2:31][CH2:32][C:28]([NH:33][C:34](=[O:36])[CH3:35])([CH3:27])[CH2:29]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: CC(=O)NC1(C)CCNC1
Reactant: Cc1ccc2nc(N3Cc4ccccc4S(=O)(=O)C(C)C3)cc(Cl)c2c1
Product: CC(=O)NC1(C)CCN(c2cc(N3CCS(=O)(=O)c4ccccc4C3)nc3ccc(C)cc23)C1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 26 by using 4-(4-chloro-6-methylquinolin-2-yl)-2-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and N-(3-methylpyrrolidin-3-yl)acetamide.
Reaction SMILES: [CH:1]1[C:2]([C:23]([F:26])([F:25])[F:24])=[CH:3][C:4]([Cl:22])=[C:5]([N:8]2[N:12]=[C:11]([C:13]#[N:14])[C:10]([S+:15]([O-:20])[C:16]([F:19])([F:18])[F:17])=[C:9]2[NH2:21])[C:6]=1[Cl:7].[CH:27](OCC)(OCC)[O:28][CH2:29][CH3:30]>O>[C:13]([C:11]1[C:10]([S:15]([C:16]([F:19])([F:17])[F:18])=[O:20])=[C:9]([N:21]=[CH:27][O:28][CH2:29][CH3:30])[N:8]([C:5]2[C:4]([Cl:22])=[CH:3][C:2]([C:23]([F:24])([F:26])[F:25])=[CH:1][C:6]=2[Cl:7])[N:12]=1)#[N:14]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1[S+]([O-])C(F)(F)F
Reactant: CCOC(OCC)OCC
Solvent: O
Product: CCOC=Nc1c(S(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C

Procedure:
A 12-L three-necked flask fitted with an overhead stirrer, heating mantle, water separator (e.g. Dean Stark trap) with condenser was placed under a nitrogen atmosphere and charged with 1.475 kg (3.37 moles) of fipronil and 6 L of triethyl orthoformate. The suspension was heated to reflux over 2.5 h, then at reflux for 3 h with collection and removal of the distillate. The mixture was cooled to room temperature, then evaporated under reduced pressure at a bath temperature of 60-80° C., then at 50° C. overnight. The resulting beige solid, 1.717 kg (95.8% by HPLC, 3.335 moles, 99% purity corrected yield) was used without further purification. (m.p. about 63° C.)
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21](O)[CH2:20][CH2:19]2>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([O:1][C:2]1[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=1)[CH2:20][CH2:19]2
Reactant: OC1CCc2cc(Cl)ccc21
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OC2CCc3cc(Cl)ccc32)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 5-chloro-2,3-dihydro-1H-inden-1-ol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.36-2.44 (1H, m), 2.57-2.66 (1H, m), 2.90-2.98 (1H, m), 3.12-3.20 (1H, m), 5.73-5.75 (1H, m), 5.85 (1H, d, J=2.0 Hz), 7.20 (1H, d, J=8.0 Hz), 7.29 (1H, s), 7.32 (1H, d, J=8.0 Hz), 7.36 (1H, dd, J=1.8 Hz, 4.8 Hz), 7.63 (1H, d, J=2.0 Hz), 7.87 (1H, s), 8.65 (1H, d, J=4.8 Hz). [M+H] Calc'd for C18H13ClN4O, 337; Found, 337.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C1(=O)[O:11][CH:9]([CH3:10])[CH2:8]O1>>[OH:11][CH:9]([CH3:10])[CH2:8][C:2]1[NH:1][CH:5]=[CH:4][N:3]=1
Reactant: CC1COC(=O)O1
Reactant: c1c[nH]cn1
Product: CC(O)Cc1ncc[nH]1
Temperature: 140 °C

Procedure:
Mix 6.8 g imidazole and 15.3 g propylene carbonate and heat at 140° C. for 1 hour. Chromatograph the resultant residue on silica gel, eluting with methylene chloride:ethyl acetate (1:1), then with 5→10% methanol in methylene chloride to obtain the title compound of step A.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[C:15]([CH:16]=2)=[N:14][N:13]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:12]=3[C:24]([NH:26][CH3:27])=[O:25])[CH:5]=[CH:6][CH:7]=1.[C:28]1(=[O:38])[O:33][C:31](=[O:32])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12>C(#N)C>[F:23][C:20]1[CH:21]=[CH:22][C:17]([N:13]2[C:12]([C:24](=[O:25])[NH:26][CH3:27])=[C:11]3[C:15]([CH:16]=[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:28]([C:29]5[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=5[C:31]([OH:33])=[O:32])=[O:38])[CH:7]=[CH:6][CH:5]=4)[CH:9]=[CH:10]3)=[N:14]2)=[CH:18][CH:19]=1
Reactant: CNC(=O)c1c2ccc(-c3cccc(N)c3)cc2nn1-c1ccc(F)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC#N
Product: CNC(=O)c1c2ccc(-c3cccc(NC(=O)c4ccccc4C(=O)O)c3)cc2nn1-c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 51.3 %

Procedure:
To a solution of Compound (16) (10 mg, 0.03 mmol) in ACN (3 mL) was added phthalic anhydride (8.2 mg, 0.06 mmol) and the reaction mixture was heated to 70° C. and stirred for 15 h. The reaction mixture was then cooled to RT and the resulting precipitate was collected by filtration. The residue was washed with cold ACN (5 mL) to afford Compound (17) as an off-white amorphous solid (7.83 mg, 55%). ESI-MS m/z calculated for [M+H]+: 509.15; found: 509.08. 1H NMR (400 MHz, d6-DMSO) δ 13.07 (brs, 1H), 10.47 (s, 1H), 8.77-8.71 (m, 1H), 7.99-7.87 (m, 3H), 7.77-7.38 (m, 12H), 2.85 (d, J=4.5 Hz, 3H).
Reaction SMILES: COC[O:4][C:5]([CH2:7][N:8]([S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34])[C:9]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:10]=1[O:11][CH2:12][C:13]1[CH:24]=[CH:23][C:16]([C:17]([O:19][CH2:20][O:21][CH3:22])=[O:18])=[CH:15][CH:14]=1)=O.[CH3:42][NH:43][CH3:44]>C1COCC1>[CH3:42][N:43]([C:5]([CH2:7][N:8]([S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:34])=[O:35])[C:9]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:10]=1[O:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][CH2:20][O:21][CH3:22])=[O:18])=[CH:23][CH:24]=1)=[O:4])[CH3:44]
Reactant: CNC
Reactant: COCOC(=O)CN(c1ccc(C(F)(F)F)cc1OCc1ccc(C(=O)OCOC)cc1)S(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Product: COCOC(=O)c1ccc(COc2cc(C(F)(F)F)ccc2N(CC(=O)N(C)C)S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-[2-(N-methoxymethoxycarbonylmethyl-phenylsulfonylamino)-5-trifluoromethylphenoxymethyl]benzoic acid. methoxymethyl ester (476 mg; prepared in Reference Example 35) in THF (2 ml), dimethylamine(0.8 ml) was added. The mixture was stirred for 3 days at room temperature. The solvent was distilled off. The residue was purified on silica gel column chromatography (hexane:AcOEt=2:1→1:1) to give the title compound (290 mg) having the following physical data.
Reaction SMILES: [OH-].[Na+].CO.[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([O:36]C)=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[CH:11]=[C:10]([O:39][CH2:40][CH2:41][CH3:42])[C:9]=2[C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[CH2:7][CH2:6]1.Cl>C(OCC)(=O)C.C1COCC1>[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([OH:36])=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[CH:11]=[C:10]([O:39][CH2:40][CH2:41][CH3:42])[C:9]=2[C:43]2[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=2)[CH2:6][CH2:7]1
Reactant: CCCOc1cc(CN2CCC(N3CCc4nc(CCC)c(C(=O)OC)cc4C3=O)CC2)cc(C2CC2)c1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCOc1cc(CN2CCC(N3CCc4nc(CCC)c(C(=O)O)cc4C3=O)CC2)cc(C2CC2)c1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.50 mL) was added at room temperature to a methanol (5 mL)-THF (5 mL) solution of methyl 6-(1-((2-cyclopropyl-4′-fluoro-6-propoxybiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (475 mg), and the mixture was stirred at 60° C. for 30 minutes. The reaction mixture was neutralized with hydrochloric acid at room temperature. Then, ethyl acetate was added thereto, and the solvent was distilled off under reduced pressure. The deposited solid was collected by filtration and washed with diethyl ether. The obtained solid was recrystallized (DMSO/ethanol/hexane) to obtain the title compound (360 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[C:4]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[N:3]=1.O.[NH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(COC)OC.C(O)C>[CH3:14][C@H:9]1[CH2:10][O:11][CH2:12][CH2:13][N:8]1[C:6]1[CH:5]=[C:4]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[N:3]=[C:2]([C:26]2[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=2)[NH2:21])[N:7]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(-c2cccc(N)c2)n1
Temperature: 90 °C
Yield: 90.5 %

Procedure:
2-Chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidine (1.50 g, 4.91 mmol) was dissolved in 18% DMF in 7:3:2 dimethoxyethane:water:ethanol (15 mL). (3-Aminophenyl)boronic acid (1.01 g, 7.36 mmol), 2M sodium carbonate (5 mL) and dichlorobis(triphenylphosphine) palladium (173 mg, 0.25 mmol) were added to the solution. The reaction was refluxed at 90° C. for 18 hours under a nitrogen atmosphere then the reaction allowed to cool and partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was dried over magnesium sulphate, filtered and vacuumed to dryness. The resultant brown oil was dissolved in DCM and filtered to remove insoluble material then the filtrate chromatographed on silica, eluting with 0-4% methanol in DCM, to give the desired product as a yellow oil (1.61 g).
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([N:5]=[C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=[C:8]2O)=[N:3]1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:8]1[C:9]2[C:4](=[N:3][N:2]([CH3:1])[CH:10]=2)[N:5]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1cc2c(O)cc(-c3ccccc3)nc2n1
Product: Cn1cc2c(Cl)cc(-c3ccccc3)nc2n1

Procedure:
39 g. of 2-methyl-6-phenyl-2H-pyrazolo[3,4-b]pyridin-4-ol (0.17 mol.) are refluxed in 195 ml. of phosphorus oxychloride for 90 minutes. The excess phosphorus oxychloride is removed in vacuo and the residue is poured onto ice. Concentrated aqueous ammonia is added under external cooling to adjust the mixture to pH 8-9. Stirring is continued for one additional hour. The collected 4-chloro-2-methyl-6-phenyl-2H-pyrazolo[3,4-b]pyridine is washed with water and dried at 70°, yield: 41 g. (100%); m.p. 177°-179°. Recrystallization from ethyl acetate gives a melting point of 189°-190°.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][C:11]=1C.BrC1C=CC(C(Cl)=O)=CC=1>>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:14](=[O:15])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:17][CH:18]=1
Reactant: Cc1cc(C(=O)Cl)ccc1Br
Reactant: BrCc1ccccc1
Agent: O=C(Cl)c1ccc(Br)cc1
Product: O=C(Cc1ccccc1)c1ccc(Br)cc1

Procedure:
The title compound was prepared according to the procedure of step 1 in the Example 169 using benzyl bromide and 4-bromo-3-methylbenzoyl chloride, instead of 4-bromobenzoyl chloride.