Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:38])([CH2:28][CH2:29][O:30]CC1C=CC=CC=1)[CH2:3][NH:4][C:5]([C:7]1[N:11]2[CH:12]=[C:13]([CH3:26])[CH:14]=[C:15]([O:16][CH2:17][C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[F:25])[C:10]2=[N:9][C:8]=1[CH3:27])=[O:6]>C(O)C.[Pd].[C]>[NH2:1][C:2]([CH3:38])([CH2:28][CH2:29][OH:30])[CH2:3][NH:4][C:5]([C:7]1[N:11]2[CH:12]=[C:13]([CH3:26])[CH:14]=[C:15]([O:16][CH2:17][C:18]3[C:19]([F:25])=[CH:20][CH:21]=[CH:22][C:23]=3[F:24])[C:10]2=[N:9][C:8]=1[CH3:27])=[O:6]
Reactant: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)NCC(C)(N)CCOCc3ccccc3)n2c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)NCC(C)(N)CCO)n2c1
Reaction time: 6.5 h

Procedure:
Under argon, 295 mg (0.52 mmol) of rac-N-[2-amino-4-(benzyloxy)-2-methylbutyl]-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide Example 262 were initially charged in 5.4 ml of ethanol, 56 mg of Pd/carbon (10%) were added and the mixture was hydrogenated under atmospheric pressure at room temperature for 6.5 h. The reaction mixture was left under hydrogen overnight. The reaction mixture was applied to silica gel, concentrated and purified by silica gel chromatography (mobile phase: dichloromethane/2N ammonia in methanol 10/1 isocratic). This gave 95 mg of the target compound (42% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Br)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.C([Sn](CCCC)(CCCC)[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)CCC>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: Nc1ccc(Br)c2c1C(=O)NC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: Nc1ccc(-c2cccs2)c2c1C(=O)NC2
Yield: 53.7 %

Procedure:
In a similar manner to Step 1 of Example 10, 7-amino-4-bromoisoindolinone (404 mg, 1.78 mmol) was dissolved in THF (20 mL), and the solution was treated with 2-(tributylstannyl)thiophene (1.13 mL, 3.56 mmol) and bis(triphenylphosphine)dichloropalladium (100 mg, 0.142 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=12/1) to obtain 7-amino-4-(thiophen-2-yl)isoindolinone (220 mg, yield 54%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[F-:13].[K+].O>CC#N>[C:8]([C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=[C:2]([F:13])[N:7]=1)#[N:9]
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#Cc1nc(F)ccc1[N+](=O)[O-]
Reaction time: 18 h

Procedure:
A mixture of 6-chloro-2-cyano-3-nitropyridine [Colbry, N. L.; Elslager, E. F.; Werbel, L. M.; J. Het. Chem., 1984, 21, 1521-1525] (10.0 g, 0.054 mol) and KF (9.48 g, 0.163 mol) in MeCN (200 mL) is heated under reflux with stirring for 18 h, then poured into water and extracted with EtOAc. The extract is washed with water and worked up, and the residue is chromatographed on silica gel, eluting with EtOAc/petroleum ether (3:7), to give after removal of the solvent under reduced pressure 2-cyano-6-fluoro-3-nitropyridine (7.2 g, 79%). 1H NMR (CDCl3) δ 8.79 (1H, dd, J=9.0, 6.0 Hz), 7.48 (1H, dd, J=9.0, 3.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:16][CH2:15][C:10]2([NH:14][CH2:13][CH2:12][CH2:11]2)[C:9]1=[O:17].C(N(CC)C(C)C)(C)C.[F:27][CH:28]([F:40])[O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:16][CH2:15][C:10]2([N:14]([S:36]([C:33]3[CH:32]=[CH:31][C:30]([O:29][CH:28]([F:27])[F:40])=[CH:35][CH:34]=3)(=[O:38])=[O:37])[CH2:13][CH2:12][CH2:11]2)[C:9]1=[O:17]
Reactant: O=C1N(c2ccccc2Cl)CCC12CCCN2
Reactant: O=S(=O)(Cl)c1ccc(OC(F)F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N(c2ccccc2Cl)CCC12CCCN2S(=O)(=O)c1ccc(OC(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
7-(2-Chlorophenyl)-1,7-diazaspiro[4.4]nonan-6-one (20 mg, 0.00008 mol) was dissolved in DCM. To this solution was added N,N-diisopropylethylamine (DIPEA) (42 μL, 0.00024 mol) and 4-(difluoromethoxy)benzenesulfonyl chloride (21 mg, 0.000088 mol) at 0° C. The solution was allowed to gradually warm to RT while stirring for 18 h. LC-MS: 457.1 (M+1H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:21](=O)[CH2:22][CH2:23][CH2:24][CH3:25])[C:17](OC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[CH3:27][CH:28]1[CH2:33][CH:32]([NH:34][C:35]2[NH:39][CH:38]=[N:37][N:36]=2)[CH2:31][CH2:30][O:29]1>>[CH2:22]([C:21]1[N:36]2[N:37]=[CH:38][N:39]=[C:35]2[N:34]([CH:32]2[CH2:31][CH2:30][O:29][CH:28]([CH3:27])[CH2:33]2)[C:17](=[O:18])[C:16]=1[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:14][CH:13]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Reactant: CC1CC(Nc2nnc[nH]2)CCO1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOC(C)C2)c2ncnn12
Temperature: 250 °C
Reaction time: 0.33 h

Procedure:
A mixture of methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (1.2 g) and N-(2-methyltetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.3 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a mixture of 4 kinds of isomers (0.49 g, 62%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>[Ni]>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([OH:11])[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [Ni]
Product: CC(C)(C)C1CCC(O)CC1

Procedure:
PL 137 526 describes the hydrogenation of p-tert-butylphenol to form p-tert-butylcyclohexanol using a nickel catalyst.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10]C(OC(C)(C)C)=O)=[CH:5][CH:4]=1)#[N:2].[Cl:18][C:19]1[C:24]([C:25]([N:27]=[C:28]=[O:29])=O)=[C:23]([F:30])[C:22]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:21][CH:20]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:23]([F:30])[C:24]=1[C:25]1[NH:27][C:28](=[O:29])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:10]=1
Reactant: CC(C)(C)OC(=O)NNc1ccc(C#N)cc1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)N=C=O)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C#N)cc3)c(=O)[nH]2)c1F

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(4-cyanophenyl)hydrazinecarboxylate (step-2 of Intermediate 17, 0.060 g, 0.25 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate (Intermediate-51, 0.160 g, 0.51 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.020 g of pure product. 1H NMR (400 MHz, CDCl3): δ 1.20 (s, 9H), 4.45 (d, J=5.9 Hz, 2H), 6.19 (m, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H), 8.19 (d, J=8.4 Hz, 2H), 10.72 (br s, 1H); MS (m/z): 426.27 (M−H−).
Reaction SMILES: [CH2:1]([N:8]1[CH2:29][CH2:28][CH2:27][C:10]2([CH2:15][N:14]([C:16]3[CH:21]=[C:20]([N+:22]([O-])=O)[C:19]([NH2:25])=[C:18]([CH3:26])[CH:17]=3)[CH2:13][CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[Cl:34][C:35]1[C:40]([CH:41]=O)=[C:39]([I:43])[CH:38]=[CH:37][N:36]=1>CO.[Pd]>[CH2:1]([N:8]1[CH2:29][CH2:28][CH2:27][C:10]2([CH2:11][CH2:12][CH2:13][N:14]([C:16]3[CH:17]=[C:18]([CH3:26])[C:19]4[N:25]=[C:41]([C:40]5[C:35]([Cl:34])=[N:36][CH:37]=[CH:38][C:39]=5[I:43])[NH:22][C:20]=4[CH:21]=3)[CH2:15]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1c(I)ccnc1Cl
Reactant: Cc1cc(N2CCCC3(CCCN(Cc4ccccc4)C3)C2)cc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(N2CCCC3(CCCN(Cc4ccccc4)C3)C2)cc2[nH]c(-c3c(I)ccnc3Cl)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 9 %

Procedure:
To a solution of 4-(8-benzyl-2,8-diaza-spiro[5.5]undec-2-yl)-2-methyl-6-nitro-phenylamine (394 mg, 1.0 mmol) in MeOH (47.5 mL) were added Pd/C (10%, 40 mg) and acetic acid (2.5 mL). The mixture was stirred under atmospheric hydrogen (balloon) at the room temperature for 3 h and filter over Celite. The filtrate was mixed with 2-chloro-3-formyl-4-iodopyridine (267.5 mg, 1.0 mmol), stirred at the room temperature for 18 h, and evaporated to dryness under reduced pressure. The residue was dissolved in MeOH (10 mL) and 28% aqueous NH4OH solution (0.5 mL) was added. After it was stirred for 5 min, the mixture was concentrated and chromatographed (330:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (55 mg, 9%). 1H NMR (CDCl3) δ 1.22-1.36 (2H), 1.49-1.84 (6H), 1.95-2.59 (6H), 2.59 (s, 3H), 2.94-3.45 (6H), 6.82 (s, 1H), 6.87 (s, 1H), 7.16-7.33 (5H), 7.72 (d, J=6 Hz, 1H), 7.99 (d, J=6 Hz, 1H). ESI-MS m/z 612 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([O:18][CH2:19][C:20]3[CH:29]=[C:28]4[C:23]([C:24](Cl)=[CH:25][C:26]5[N:27]4[CH:30]=[N:31][N:32]=5)=[CH:22][CH:21]=3)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[N:34]1[CH:39]=[CH:38][CH:37]=[C:36](B(O)O)[CH:35]=1.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>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:12]=[C:13]([O:18][CH2:19][C:20]3[CH:29]=[C:28]4[C:23]([C:24]([C:36]5[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=5)=[CH:25][C:26]5[N:27]4[CH:30]=[N:31][N:32]=5)=[CH:22][CH:21]=3)[CH:14]=[C:15]([F:17])[CH:16]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2cc(F)cc(OCc3ccc4c(Cl)cc5nncn5c4c3)c2)CCOCC1
Reactant: OB(O)c1cccnc1
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: COC(=O)C1(c2cc(F)cc(OCc3ccc4c(-c5cccnc5)cc5nncn5c4c3)c2)CCOCC1
Temperature: 80 °C

Procedure:
To 5d (50 mg, 0.11 mmol) in DME:H2O (2:1, 2 mL) was added 3-pyridineboronic acid (20 mg, 0.16 mmol) and potassium carbonate (37 mg, 0.27 mmol). The mixture was degassed with N2 for 5 minutes, and then Pd(PPh3)4 (12 mg, 0.01 mmol) was added, and the mixture was degassed with N2 for an additional 5 minutes. The reaction was then heated to 80° C. overnight. After cooling to room temperature, the reaction was concentrated and purified by silica gel chromatography (10% MeOH in EtOAc) to give the desired product, 5e.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([SH:9])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH:22]([F:24])[F:23]>O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([S:9][CH:22]([F:24])[F:23])[N:3]=1
Reactant: FC(F)Cl
Reactant: Nc1nc(N)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(N)nc(SC(F)F)n1

Procedure:
To a mixture of 2.8 g of 2,4-diamino-6-mercapto-1,3,5-triazine, 5.5 g of potassium carbonate, and 20 ml of N,N-dimethylformamide is added and chlorodifluoromethane gas is aspirated at a temperature of 55°~65° C. for 2 hours in a 100 ml three-necked flask. After cooling, the mixture is mixed with water and extracted with ethyl acetate. The extract is evaported, and the resulting residue is purified by silica-gel chromatography to produce 0.8 g of 2,4-diamino-6-difluoromethylthio-1,3,5-triazine.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([O-:16])=O.P(Cl)(Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[C:12]([CH2:13][C:14]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10])=[O:16])([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CNc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)[O-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)CC(=O)N(C)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
75 g of N-methyl o-nitro aniline and 70 g. of monoethyl malonate (obtained according to M. Freund, Ber. 17, 780, 1884) are dissolved in 550 cc. of benzene, the solution is agitated and 106 g. of phosphorus pentachloride are added, while maintaining the temperature at 20°-23° C.; this is agitated for three hours at room temperature, then heated for 1 hour at 70° C.; a yellow precipitate forms, which dissolves again, giving an orange solution; a water-ice mixture is added, while agitating, to obtain a volume of 1,500 cc., keeping the temperature at 30° C.; the benzene phase is decanted off, washed with water, then with a saturated aqueous solution of sodium bicarbonate and finally with water, dried over sodium sulfate and evaporated under reduced pressure; the residue is purified by recrystallisation in the xylol-petroleum ether mixture (2.5-1). The compound melts at 54°-55° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH2:10][C:11]1[CH:12]=[C:13]2[C:17]3=[C:18]([CH2:20][S:21][CH2:22][CH2:23][N:16]3[C@H:15]3[CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][C@@H:14]23)[CH:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:10][C:11]1[CH:12]=[C:13]2[C:17]3=[C:18]([CH2:20][S:21][CH2:22][CH2:23][N:16]3[C@H:15]3[CH2:24][CH2:25][NH:26][CH2:27][C@@H:14]23)[CH:19]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Product: Clc1cccc(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c1

Procedure:
Using 3-chlorobenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 156. 1H NMR (CDCl3) δ: 7.37 (s, 1H), 7.29-7.20 (m, 2H), 6.34 (d, 1H, J=2.2 Hz), 6.24 (d, 1H, J=2.6 Hz), 4.25 (broad s, 2H), 3.67 (s, 2H), 3.57-3.50 (m, 1H), 3.42-3.31 (m, 2H), 3.20-2.85 (m, 6H), 2.60 (dd, 1H, J=12.8, 9.9 Hz), 2.15-1.97 (m, 2H). LRMS (ES)+: 386.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][C:44]=1[Cl:45]>>[CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:31])([F:30])[F:32])[CH:26]=[C:25]([C:33]([F:34])([F:35])[F:36])[CH:24]=2)[CH:12]=[C:13]([C:41]2[CH:42]=[CH:43][C:44]([Cl:45])=[C:39]([F:38])[CH:40]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Product: COC(=O)C(CC(C)C)c1cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc(-c2ccc(Cl)c(F)c2)c1
Yield: 65 %

Procedure:
The title compound was prepared in 65% yield from 4-methyl-2-(5-trifluoromethanesulfonyloxy-3′,5′-bis-trifluoromethyl-biphenyl-3-yl)-pentanoic acid methyl ester (prepared in Intermediate A) and 3-fluoro-4-chlorophenylboronic acid under the conditions described in Example 26, step (d).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:34][CH3:35])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH:15][C:16]([C:18]1[C:19]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:17])=[CH:10][CH:9]=2)=[O:5])C.O.[OH-].[Li+]>CO.O>[CH2:34]([N:7]1[C:8]2[C:13](=[CH:12][C:11]([NH:15][C:16]([C:18]3[C:19]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:26][CH:25]=4)=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:17])=[CH:10][CH:9]=2)[CH:14]=[C:6]1[C:4]([OH:5])=[O:3])[CH3:35]
Reactant: CCOC(=O)c1cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2n1CC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCn1c(C(=O)O)cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21

Procedure:
1-Ethyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid ethyl ester (4.5 g, 9.37 mmol) was added to MeOH/H2O (110 mL, 10/1). Lithium hydroxide monohydrate (1.5 g, 35.7 mmol) was added to the above mixture. The mixture which resulted was heated to reflux overnight. The solvent was removed under reduced pressure and the residue was dissolved in H2O (500 mL). The solution was acidified with 6N HCl to pH 2. The solid was collected by filtration and dried under vacuum (4.0 g, 94.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([CH3:23])=[CH:18][CH:19]=2)[N:14]=1.C(#N)C>O>[CH3:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: Cc1ccc2ccc(N)nc2n1
Solvent: O
Solvent: CC#N
Product: COc1ccc(C(=O)Nc2ccc3ccc(C)nc3n2)cc1
Temperature: 4 °C
Yield: 72.6 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (12.2 g), N,N'-carbonyldiimidazole (10.3 g) and 2-amino-7-methyl-1,8-naphthyridine (9.5 g). The product produced by precipitation in water (14.4 g; m.p. 110° C.) is dissolved in boiling acetonitrile (150 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (2×10 cc) and dried at 45° C. under reduced pressure (0.067 kPa). N-(7-methyl-1,8-naphthyridin-2-yl)-4-methoxybenzamide (12.7 g) is produced, m.p. 119° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:16]4=[O:23])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:24]=1.CC1(C)C(C)(C)OB([C:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH:34]=2)O1>>[CH3:20][C:19]1([CH3:21])[N:15]([C:13]2[S:14][C:10]3[CH2:9][CH2:8][O:7][C:6]4[CH:24]=[C:2]([C:33]5[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH:34]=5)[CH:3]=[CH:4][C:5]=4[C:11]=3[N:12]=2)[C:16](=[O:23])[NH:17][C:18]1=[O:22]
Reactant: CC1(C)C(=O)NC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)OCCc2sc(N4C(=O)NC(=O)C4(C)C)nc2-3)CC1
Yield: 19 %

Procedure:
1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2,4-dione was coupled with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate to give tert-butyl 4-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate. Yield 19%. MS (ESI+):511.3
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([N:17](C)[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]([CH3:26])[C:13](=[N:27][C:28]3[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=3[CH3:36])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:37]I>O1CCCC1>[CH2:18]([N:17]=[C:15]1[N:14]([CH3:26])[C:13](=[N:27][C:28]2[C:29]([CH3:36])=[CH:30][C:31]([CH3:35])=[CH:32][C:33]=2[CH3:34])[CH:12]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:16]1[CH3:37])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(N(C)Cc3ccccc3)n2)cc1OC
Reactant: CI
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=NCc3ccccc3)n2C)cc1OC
Temperature: 25 °C

Procedure:
To a solution of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-2-(N-methyl-N-benzylamino)-4-(2,4,6-trimethylphenylimino)pyrimidine (1.0 g) in tetrahydrofuran (20 ml) was added methyl iodide (2.58 ml). The solution was refluxed for 10 hours and cooled to ambient temperature. The reaction mixture was evaporated in vacuo and the residue was chromatographed on silica gel using chloroform to give 2-benzylimino-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-1,2,3,4-tetrahydro-4-(2,4,6-trimethylphenylimino)pyrimidine (0.62 g).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH:11]=[CH:10]2.CN([CH:32]=[O:33])C>>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][CH:20]=1)[CH:11]=[C:10]2[CH:32]=[O:33]
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)c1ccc(Cn2ccc3cc(Br)ccc3c2=O)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(Cn2cc(C=O)c3cc(Br)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DMF (10 mL) was cooled in an ice bath and phosphorus oxychloride (1.4 mL) added over 20 seconds. The solution was stirred for 10 minutes at room temperature then a solution of the product of step i) (2.0 g) in DMF (4 mL) was added over 5 minutes. The mixture was heated at 95° C. for 16 hours then allowed to cool and poured onto ice/water. The mixture was then extracted into ethyl acetate (100 mL) the organics combined and evaporated under reduced pressure. The residue was purified (SiO2 chromatography, eluting with 1:1 ethyl acetate:isohexane) to give the sub-titled compound (1.5 g).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1.C([Li])(CC)C.[C:21](=[O:23])=[O:22]>C(OCC)C>[CH2:12]([C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:21]([OH:23])=[O:22])[CH:11]=2)[CH:6]=[CH:7][N:8]=1)[CH2:13][CH2:14][CH3:15]
Reactant: O=C=O
Reactant: CCCCc1nccc2ccc(Br)cc12
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CCCCc1nccc2ccc(C(=O)O)cc12
Temperature: 25 °C

Procedure:
To a −60° C. solution of 7-bromo-1-butylisoquinoline prepared in step 1 (940 mg, 3.55 mmol) in diethyl ether (15 mL) was added sec-butyl lithium (3.0 mL, 1.3 M cyclohexanes, 3.90 mmol) to yield a dark green solution. The reaction mixture was stirred at −60° C. for an additional 15 minutes at which time carbon dioxide gas was bubbled through the solution for 20 minutes with the aid of a gas dispersion tube. The resulting solution was then allowed to warm to room temperature and concentrated under reduced pressure to yield a pink solid. The residue was partitioned between ethyl acetate and water and then acidified to pH 7 with 1 N hydrochloric acid. The aqueous phase was extracted again with ethyl acetate and the combined organic phases were washed with saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated to yield 1-butylisoquinoline-7-carboxylic acid (299 mg). ESI MS m/z 230 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH2:9][CH2:10][CH2:11][NH:12][C:5]=2[CH:4]=[N:3]1.[H-].[Na+].[Cl:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=2)=[O:21])=[CH:18][CH:17]=1>CN(C=O)C.O>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26][N:12]3[C:5]4[CH:4]=[N:3][N:2]([CH3:1])[C:7](=[O:8])[C:6]=4[CH2:9][CH2:10][CH2:11]3)=[CH:24][CH:23]=2)=[O:21])=[CH:30][CH:31]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Cn1ncc2c(c1=O)CCCN2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2c(c1=O)CCCN2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
In DMF (5 ml) was dissolved 6-methyl-1,2,3,4-tetrahydropyrido[2,3-d]pyridazin-5(6H)-one (116 mg) followed by addition of sodium hydride (60%) (56 mg), and the mixture was stirred at room temperature for 30 minutes. Then, 4-(4-chlorobenzoyl)benzyl bromide (341 mg) was added and the mixture was further stirred at room temperature for 1 hour. This reaction mixture was diluted with water and extracted with ethyl acetate-THF. The organic layer was serially washed with water and saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography (ethyl acetate) to provide 165 mg of the title compound as yellow amorphous solid.