Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:41]=[CH:40][C:18]([C:19]([NH:21][C:22]4[CH:23]=[N:24][N:25]([CH:27]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]5)[CH:26]=4)=[O:20])=[CH:17][CH:16]=3)[CH:14]=2)=[N:2]1.[ClH:42]>O1CCOCC1.O>[ClH:42].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([NH:21][C:22]4[CH:23]=[N:24][N:25]([CH:27]5[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]5)[CH:26]=4)=[O:20])=[CH:40][CH:41]=3)[CH:14]=2)=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(NC(=O)c3ccc(-n4cc(-c5n[nH]c6ccccc56)nn4)cc3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1cnn(C2CCNCC2)c1)c1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Temperature: 25 °C
Yield: 72 %

Procedure:
To a solution of tert-butyl 4-[4-({4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoyl}amino)-1H-pyrazol-1-yl]piperidine-1-carboxylate (100 mg; 0.18 mmol; 1.0 eq.) in Dioxane (3 mL) was added HCl 4N solution in 1,4-dioxane (450 μl of a 4N solution in dioxane; 1.80 mmol; 10 eq.) and one drop of water. The resulting suspension was stirred at RT O/N. Solvent were removed under reduced pressure and the residue was suspended in ACN and filtered to afford the title compound as a beige solid (64 mg; 72%). 1H NMR (300 MHz, DMSO-d6) δ 13.45 (brs, 1H), 10.75 (s, 1H), 9.46 (s, 1H), 9.19-8.73 (m, 2H), 8.38 (d, J=8.1 Hz, 1H), 8.32-8.18 (m, 4H), 8.15 (s, 1H), 7.71 (s, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.52-7.39 (m, 1H), 7.27 (t, J=7.5 Hz, 1H), 4.64-4.42 (m, 1H), 3.48-3.30 (m, 2H), 3.05 (s, 2H), 2.27-2.05 (m, 4H). HPLC (Condition A): Rt 3.06 min (purity 95.7%). MS (ESI+): 454.4, MS (ESI−): 452.3.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][N:21](C3C=CC(C(OC)=O)=CC=3)[CH2:20][CH2:19]2)[CH2:14]1)=[O:11])=[O:7].Br[C:40]1[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=1>>[F:37][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:19][CH2:20][N:21]([C:42]3[CH:41]=[CH:40][CH:49]=[CH:48][C:43]=3[C:44]([O:46][CH3:47])=[O:45])[CH2:22][CH2:23]2)[CH2:14]1)=[O:11])=[O:7]
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: COC(=O)c1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1
Product: COC(=O)c1ccccc1N1CCC(N2CC[C@@H](NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1

Procedure:
The title compound was synthesized in similar fashion to methyl 4-(4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}piperidin-1-yl)benzoate, substituting methyl 2-bromobenzoate for methyl 4-bromobenzoate, and was isolated as a white solid. 1H-NMR (CD3OD) δ: 1.80-2.01 (m, 3H), 2.25-2.45 (m, 2H); 2.51-3.00 (m, 6H), 3.25-3.41 (m, 2H), 3.31-3.45 (m, 2H), 3.87 (s, 3H), 4.05-4.40 (m, 2H), 4.60-4.75 (m, 1H), 6.98-7.20 (m, 1H), 7.20-7.24 (m, 2H), 7.30-7.42 (m, 2H), 7.50-7.60 (m, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.98-8.10 (m, 1H), 8.16 (s, 1H), 8.18-8.30 (m, 1H). MS m/z: 533 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=2)[CH:17]=[C:16]1B(O)O)(OC(C)(C)C)=O>>[Cl:24][C:21]1[CH:22]=[C:23]2[C:18]([CH:17]=[C:16]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[NH:15]2)=[CH:19][CH:20]=1
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccc(Cl)cc21
Product: Clc1ccc2cc(-c3cccnc3)[nH]c2c1

Procedure:
3-Bromopyridine and N-Boc-6-chloro-indole-2-boronic acid are processed according to the procedure described in Example 91 to give 6-chloro-2-pyridin-3-yl-1H-indole. (ESI) m/z 229.0 (M+H)+.
Reaction SMILES: C(N(N1CCCC1)C1C=CC(F)=CC=1F)(=O)C(C)C.C([N:30]1[CH2:34][CH2:33][C@H:32]([N:35]([C:43](=[O:52])[C:44]([CH3:51])([CH3:50])[CH2:45][O:46][C:47](=[O:49])[CH3:48])[CH:36]2[CH2:41][CH2:40][CH:39]([F:42])[CH2:38][CH2:37]2)[CH2:31]1)(OCC1C=CC=CC=1)=O>>[C:47]([O:46][CH2:45][C:44]([CH3:51])([CH3:50])[C:43]([N:35]([CH:36]1[CH2:37][CH2:38][CH:39]([F:42])[CH2:40][CH2:41]1)[C@H:32]1[CH2:33][CH2:34][NH:30][CH2:31]1)=[O:52])(=[O:49])[CH3:48]
Reactant: CC(=O)OCC(C)(C)C(=O)N(C1CCC(F)CC1)[C@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: CC(C)C(=O)N(c1ccc(F)cc1F)N1CCCC1
Product: CC(=O)OCC(C)(C)C(=O)N(C1CCC(F)CC1)[C@H]1CCNC1

Procedure:
The title compound was prepared following the procedure described in Intermediate 64 using the product of Step B, (3S)-1-cbz-3-[acetyloxypivaloyl(4-fluoro-cyclohexyl)amino]pyrrolidine.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:6]([N:8]2[CH2:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]2=[O:15])[CH:7]=1.[CH3:32][CH:33]1[NH:37][C:36](=[O:38])[CH2:35][CH2:34]1>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C:5]3[CH:4]=[CH:3][C:2]([N:37]4[C:36](=[O:38])[CH2:35][CH2:34][CH:33]4[CH3:32])=[CH:7][C:6]=3[N:8]3[CH2:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]3=[O:15])=[O:17])[CH2:19][CH2:20]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CC(=O)N(C)C3=O)CC2)c(C)c1
Reactant: CC1CCC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3N3CC(=O)N(C)C3=O)CC2)c(C)c1
Yield: 11.9 %

Procedure:
Using 1-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-3-methylimidazolidine-2,4-dione (155 mg) described in Preparation Example 256 and 5-methylpyrrolidin-2-one (52 mg) and by the reaction and treatment in the same manner as in Example 666, the title compound (21 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:15][CH2:14][C:13](=O)[CH2:12]1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[OH-].[Na+]>[CH2:17]([NH:24][CH:13]1[CH2:14][CH2:15][CH:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][CH:6]=2)[CH2:12]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CCC(c2c[nH]c3ccc(F)cc23)C1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Fc1ccc2[nH]cc(C3CCC(NCc4ccccc4)C3)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 105.5 %

Procedure:
A mixture 3-(5-fluoro-1H-indol-3-yl)-cyclopentanone (1.0 g, 4.61 mmol), benzylamine (0.54 g, 5.05 mmol) and glacial acetic acid (0.7 mL, 1.08 mmol) were stirred at room temperature for 30 min. Sodium triacetoxyborohydride (1.5 g, 7.11 mmole) was added portionwise over a 10 min period. The reaction was stirred at room temperature for 24 hours. The reaction mixture was poured into 1 N aqueous NaOH (80 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with H2O (100 mL) and brine (100 mL), then were dried over anhydrous sodium sulfate, filtered and concentrated to give 1.5 g of a thick yellow oil. Flash chromatography on silica gel (7% 2 M NH3 in methanol/ethyl acetate) afforded 0.5 g of the cis isomer (first eluting) and 0.5 g of the trans isomer.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][C:20]=3[NH:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:37])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:25][CH:24]=3)[NH:15][C:14](=[O:38])[C:13]=12)=[O:7])C>C1COCC1>[C:30]([NH:29][C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:21]=2[C:12]2[C:13](=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[CH:10][CH:11]=2)[C:14](=[O:38])[NH:15]3)=[CH:28][CH:27]=1)(=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)c1cccc2c1c(=O)[nH]c1nccc(Nc3ccc(NC(=O)c4ccccc4)cc3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Nc2ccnc3[nH]c(=O)c4c(C(=O)O)cccc4c23)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
NaOH (4.2 mL, 1.00 M, 4.18 mmol) was added to a suspension of 423 (200 mg, 0.42 mmol) in THF (5 mL), and stirred overnight at room temperature. The crude reaction mixture was purified directly via HP-LC to provide 434 (17 mg) as a solid. LC-MS (M+H=451, obsd.=451). 1H NMR (400 MHz, DMSO-d6): δ 6.93 (d, 1H), 7.20 (d, 2H), 7.54 (m, 3H), 7.76 (m, 2H), 7.78 (d, 1H), 7.97 (d, 1H), 8.10 (d, 1H), 8.27 (s, 1H), 8.85 (d, 1H), 9.18 (s, 1H), 10.27 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:36]=[C:5]2[N:6]=[CH:7][C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:11]([C:20]4[CH:35]=[CH:34][C:23]([CH2:24][N:25]5[CH2:30][CH2:29][CH:28]([C:31](O)=[O:32])[CH2:27][CH2:26]5)=[CH:22][CH:21]=4)=[N:10][C:9]=3[N:4]2[N:3]=1.[CH:37]1[CH:38]=[CH:39][C:40]2N(O)N=[N:43][C:41]=2[CH:42]=1.C(Cl)CCl.C(N(C(C)C)CC)(C)C.NC1C=CC=CC=1>CN(C=O)C.C(Cl)Cl.O>[CH3:1][C:2]1[CH:36]=[C:5]2[N:6]=[CH:7][C:8]3[CH:13]=[C:12]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:11]([C:20]4[CH:35]=[CH:34][C:23]([CH2:24][N:25]5[CH2:26][CH2:27][CH:28]([C:31](=[O:32])[NH:43][C:41]6[CH:42]=[CH:37][CH:38]=[CH:39][CH:40]=6)[CH2:29][CH2:30]5)=[CH:22][CH:21]=4)=[N:10][C:9]=3[N:4]2[N:3]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1cc2ncc3cc(-c4ccccc4)c(-c4ccc(CN5CCC(C(=O)O)CC5)cc4)nc3n2n1
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc2ncc3cc(-c4ccccc4)c(-c4ccc(CN5CCC(C(=O)Nc6ccccc6)CC5)cc4)nc3n2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Compound (14-1) (20 mg, 0.042 mmol, 1.0 eq), HOBt (11 mg, 0.084 mmol, 2.0 eq), EDC (HCl salt, 12 mg, 0.063 mmol, 1.5 eq) and diisopropylethylamine (22 μL, 0.13 mmol, 3.0 eq) were dissolved in DMF (400 μL, anhydrous) and CH2Cl2 (400 μL, anhydrous). To this solution was added aniline (19 mg, 0.21 mmol, 5.0 eq) and the reaction stirred at room temperature for 16 hours. After that time water was added and the mixture extracted with CHCl3 (×3). The combined organic phases were dried with brine and Na2SO4, and then concentrated in vacuo. The residue was purified by silica gel chromatography by eluting with a gradient of CHCl3 to [CHCl3/MeOH/NH4OH 90:10:1]. The resulting solid was then dissolved in MeOH, added TFA (100 μL), and purified by reverse-phase chromatography (Solvent A H2O/CH3CN/TFA (95:5:0.05), Solvent B CH3CN/H2O/TFA (95:5:0.05)) with a gradient of 5% to 60% B over 5 minutes to give Compound (15-1)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[CH2:24][CH2:23]1.N#N.C(O[K])(C)(C)C.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>O1CCOCC1.C(Cl)(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:8]2[C:5]3=[N:6][CH:7]=[C:2]([NH:33][C:32]4[CH:31]=[CH:30][C:29]([CH2:28][N:25]5[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]5)=[CH:35][CH:34]=4)[CH:3]=[C:4]3[C:10]([CH3:11])=[N:9]2)=[CH:14][CH:15]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: COc1ccc(Cn2nc(C)c3cc(Br)cnc32)cc1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: N#N
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COc1ccc(Cn2nc(C)c3cc(Nc4ccc(CN5CCN(C)CC5)cc4)cnc32)cc1
Temperature: 90 °C

Procedure:
A stirred solution of 5-bromo-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine (7) (50 mg, 0.150 mmol) and 4-((4-methylpiperazin-1-yl)methyl)aniline (165) (30 mg, 0.165 mmol, 1.1 eq) in 1,4-dioxane (10 mL) was degassed and purged with N2 for 10 min. tert-BuOK (50 mg, 0.451 mmol, 3.0 eq) was added and the reaction mixture was purged and degassed again. To this reaction mixture was added ±BINAP (1.8 mg, 0.00301 mmol, 0.01 eq) and Pd2(dba)3 (5 mg, 0.0012 mmol, 0.04 eq) and the resulting reaction was heated at 90° C. for 12 hrs in sealed tube condition. After completion of the reaction the contents were cooled and diluted with CHCl3 and filtered through Celite bed. The CHCl3 layer was completely distilled off to get the crude product. The crude was passed through 100-200 mesh silica gel, eluting the pure compound 1-(4-methoxybenzyl)-3-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-5-amine 166 obtained with 6% MeOH in CH2Cl2 as an off-white coloured solid in 30 mg quantity.
Reaction SMILES: C([CH:3]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH2:16][C:10]3[C:11]2=[C:5]([CH2:6][N:7]=[CH:8][CH:9]=3)[CH2:4]1)#N>C(O)(=O)C.Cl>[CH2:13]1[CH:12]2[CH2:14][CH2:15][CH2:16][C:10]3[C:11]2=[C:5]([CH2:6][N:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]1
Reactant: N#CC1CC2=C3C(=CC=NC2)CCCC3C1
Agent: Cl
Solvent: CC(=O)O
Product: C1=NCC2=C3C(=C1)CCCC3CCC2
Yield: 70 %

Procedure:
A solution of 1.3 g (6.1 mmol) of 2-cyano-1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]azepine, an intermediate of Formula 8 prepared, for example, as described in Preparation 8A, in a mixture of 40 ml of acetic acid and 40 ml of 20% hydrochloric acid, was kept at reflux for 20 hours. The solution was concentrated to a small volume, approximately 30 ml of water was added and neutral materials were removed by extraction with ether. The aqueous layer was made basic by addition of NaOH, and the product was extracted with ether. After evaporation of the ether, 0.8 g of 1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]azepine was obtained as an oil (HCl salt, mp 207°-209° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]#[N:11].[NH2:12][C:13]1[C:18]([CH:19]=O)=[CH:17][N:16]=[C:15]([CH3:21])[N:14]=1.[Na]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:10]([NH2:11])=[N:12][C:13]2[N:14]=[C:15]([CH3:21])[N:16]=[CH:17][C:18]=2[CH:19]=1
Reactant: Cc1ncc(C=O)c(N)n1
Reactant: N#CCc1c(Cl)cccc1Cl
Agent: [Na]
Solvent: CCO
Product: Cc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Yield: 41.4 %

Procedure:
2,6-Dichlorophenylacetonitrile 8.1 g and 4-amino-2-methylpyrimidine-5-carboxaldehyde 6.9 g is added to a solution of 0.4 g of sodium metal in 60 ml of anhydrous ethanol. This mixture is heated at reflux for 3 hours. Upon cooling, the crude product precipitates and is collected by filtration. The solid is recrystallized from ethanol, with charcoal treatment, to give 5.5 g of 6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]pyrimidin-7-amine, mp 287°-289° C., which may occlude varying amounts of water, depending on the drying conditions.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH2:38][O:39][CH3:40])=[N:22][C:23]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)=[N:24][C:25]=1[CH3:26]>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH2:38][O:39][CH3:40])=[N:22][C:23]([C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=3)=[N:24][C:25]=2[CH3:26])=[CH:11][C:10]=1[CH3:16])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: COCc1nc(-c2ccc(OC(F)(F)F)cc2)nc(C)c1CCl
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(C)nc(-c3ccc(OC(F)(F)F)cc3)nc2COC)cc1C

Procedure:
In analogy to the procedure described in example 113A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 5-chloromethyl-4-methoxymethyl-6-methyl-2-(4-trifluoromethoxy-phenyl)-pyrimidine (example 149D]) to give the title compound as light yellow viscous oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[C:14]([OH:16])=[S:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:22]O>COC(OC)(C)C>[C:1]1([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[C:14]([O:16][CH3:22])=[S:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(=S)c1ccncc1Cc1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: COC(C)(C)OC
Product: COC(=S)c1ccncc1Cc1ccccc1
Yield: 96 %

Procedure:
A solution of 5.1 g (20 mmol) of 3-phenylmethylthiopyridine-4-carboxylic acid in 150 mL of methanol, 1.6 mL of 2,2-dimethoxypropane, and 5 mL of sulfuric acid was heated at reflux for 18 hours. The solution was cooled, concentrated to 25 mL, then partitioned between ether and sodium bicarbonate solution. The ether layer was washed with sodium bicarbonate solution, then brine, then dried and concentrated to afford 5.0 g (96%) of white crystals, m.p. 79°-80° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].F[C:17]1[CH:22]=[C:21]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])[C:20]([F:36])=[CH:19][C:18]=1[N+:37]([O-:39])=[O:38].Cl>CN(C)C=O>[F:36][C:20]1[C:21]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:22][C:17]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[C:18]([N+:37]([O-:39])=[O:38])[CH:19]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Reactant: COc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2[N+](=O)[O-])c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
The mixture of 3.53 g of 3-methoxyphenol, 5.12 g of anhydrous potassium carbonate, 10 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzen (described above, produced in Intermediate Production Example 4) and 40 ml of N,N-dimethylformamide was stirred at 60 to 70° C. for 2 hours. The reaction mixture was poured into the mixture of aqueous hydrochloric acid solution and ice water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 4.17 g of 5-fluoro-2-(3-methoxyphenoxy)-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[I:17])=[CH:14][C:13]([F:18])=[CH:12][CH:11]=2)=[O:7].[C:19]([CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH2:22][CH3:23])=[O:20]>C1COCC1>[CH2:22]([O:21][C:19](=[O:20])[CH:24]=[CH:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[I:17])=[CH:14][C:13]([F:18])=[CH:12][CH:11]=2)=[O:7])[CH3:23]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCCNC(=O)c1[nH]c2ccc(F)cc2c1I
Solvent: C1CCOC1
Product: CCOC(=O)C=CCCNC(=O)c1[nH]c2ccc(F)cc2c1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-fluoro-3-iodo-1H-indole-2-carboxylic acid (3-oxo-propyl)-amide, prepared as in reference 13, (5.86 g, 16.3 mmol) in THF (200 mL) is added (carbethoxymethylene) triphenylphosphorane (18 g, 51.7 mmol) at 0° C. The reaction is stirred at room temperature overnight. It is washed with saturated NH4Cl (200 mL) and extracted with Et2O (200 mL×2). The combined organic layers are washed with brine and dried. It is concentrated and purified by silica gel column chromatography and eluted with EtOAc-Hexanes to give 5-[(5-fluoro-3-iodo-1H-indole-2-carbonyl)-amino]-pent-2-enoic acid ethyl ester as the trans isomer; 1H NMR (DMSO-d6) δ 1.25 (t, 3H, J=6.8 Hz), 2.52 (t, 2H, J=6.8 Hz), 3.48 (q, 2H, J=5.6 Hz), 4.10 (q, 2H, 6.8 Hz), 5.96 (d, 1H, J=15.6 Hz), 6.96 (dt, 1H, J1=5.8 Hz, J2=15.6 Hz), 7.06-7.18 (m, 2H), 7.46 (dd, 1H, J1=4.0 Hz, J2=8.8 Hz), 8.11 (t, 1H, J=6.4 Hz), 12.10 (s, 1H); m/z [M++1] 431.0.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=O)[CH3:2].[N:12]1[NH:13][C:14](=[O:18])[CH:15]=CC=1>>[O:18]=[C:14]1[NH:13][N:12]=[C:1]([C:4]2[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=2)[CH:2]=[CH:15]1
Reactant: O=c1cccn[nH]1
Reactant: CC(=O)c1ccc(C#N)cc1
Product: N#Cc1ccc(-c2ccc(=O)[nH]n2)cc1

Procedure:
50 g of 4-acetylbenzonitrile is converted into the pyridazinone in accordance with GWP 1.
Reaction SMILES: [Br:1]Br.O[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([CH3:14])=[CH:9][CH:10]=2)[C:5]=1[CH2:15][C:16]([OH:18])=[O:17]>C(O)(=O)C>[Br:1][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[CH3:14])[C:5]1[CH2:15][C:16](=[O:17])[O:18][C:4]=1[CH:13]=[CH:12]2
Reactant: BrBr
Reactant: Cc1ccc2ccc(O)c(CC(=O)O)c2c1
Solvent: CC(=O)O
Product: Cc1cc2c3c(ccc2cc1Br)OC(=O)C3

Procedure:
A solution of bromine (0.05 ml) in acetic acid (2 ml) was added over 5 minutes to a solution of 2-hydroxy-7-methyl-1-naphthylacetic acid (0.21 g) in acetic acid (5 ml). The solid which precipitated was collected and washed with acetic acid to give 7-bromo-8-methyl-2(1H)-naphtho[2,1-b]furanone, m.p. 238°-240°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17](O)=[O:18])=[CH:13][C:12]=2[C:20]#[CH:21])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:46][C@@H:47]([NH2:57])[CH2:48][CH2:49][CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1>CN(C)C=O.C(OCC)(=O)C>[C:20]([C:12]1[CH:13]=[C:14]([C:17]([NH:57][C@H:47]([CH3:46])[CH2:48][CH2:49][CH2:50][C:51]2[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=2)=[O:18])[CH:15]=[CH:16][C:11]=1[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)#[CH:21]
Reactant: C[C@@H](N)CCCc1cccnc1
Reactant: C#Cc1cc(C(=O)O)ccc1-c1ccc(OC)c(OC)c1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#Cc1cc(C(=O)N[C@H](C)CCCc2cccnc2)ccc1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 459 mg of 3',4'-dimethoxy-2-ethynyl[1,1'-biphenyl]-4-carboxylic acid in 8 mL of dimethylformamide was cooled in an ice bath and treated with 0.25 mL of triethylamine and 0.38 mL of diphenylphosphoryl azide. After 1 hour. 0.3 mL of (R)alpha-methyl-3-pyridinebutanamine was added and the reaction mixture was allowed to warm to room temperature over 48 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried and concentrated. The residue was chromatographed over 50 g of silica gel eluting with ethyl acetate and the product was crystallized from ethyl acetate-hexane to give 576 mg of (R)-2-Ethynyl-3',4'-dimethoxy-N-[1-methyl-4-(3-pyridinyl)butyl][1.1'-biphenyl]-4-carboxamide, mp 135°-137° C.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][NH:5][C:6](=[O:21])[CH:7]=[C:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.CO.[Li+].[OH-].Cl>O>[CH:10]1[C:9]2[C:8](=[CH:7][C:6]([NH:5][CH2:4][C:3]([OH:22])=[O:2])=[O:21])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)CNC(=O)C=C1c2ccccc2-c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CNC(=O)C=C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.7 %

Procedure:
2-(2-(9H-fluoren-9-ylidene)acetamido)acetic acid methyl ester (293 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 5 hours at room temperature. The mixture is neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (259 mg, 93% yield) as a white solid. LC-MS (m/z) 280 (M+1).
Reaction SMILES: [CH2:1]1[CH:10]2[C:5](=[CH:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][O:2]1.C1C=C(Cl)C=C(C(OO)=[O:19])C=1>C(Cl)Cl>[O:19]1[CH:6]2[C:5]31[CH:10]([CH2:9][CH2:8][CH2:7]2)[CH2:1][O:2][CH2:3][CH2:4]3
Reactant: C1=C2CCOCC2CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C1CC2COCCC23OC3C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3,4,6,7,8,8a-hexahydro-1H-isochromene (0.120 g, 0.868 mmol) in CH2Cl2 (6 mL) at 0° C. was added MCPBA (˜77%, 0.300 g, 1.30 mmol). The mixture was stirred at rt for 1 hr. It was quenched with sat'd. aq. sodium sulfite. The mixture was diluted with CH2Cl2 and said. aq. NaHCO3 then extracted with CH2Cl2. The combined organics were dried (anhd. Na2—SO4), filtered, and concentrated. The residue was purified by column chromatography to give the title compound.