Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[C:9]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C@H:20]3[C:37](=[O:38])[N:36]([CH3:39])[CH2:35][C:34]4[CH:40]=[C:30]([CH:31]=[CH:32][C:33]=4[C@@H:41]([CH2:46][CH3:47])[C:42]([O:44]C)=[O:43])[NH:29][C:28](=[O:48])[O:27][CH2:26][C@H:25]([CH3:49])[C:24]4[CH:50]=[CH:51][C:21]3=[CH:22][C:23]=4[CH3:52])=[CH:16][CH:17]=2)[C:12]([F:53])=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1>[C:1]([O:5][C:6]([N:8]([C:54]([O:56][C:57]([CH3:59])([CH3:58])[CH3:60])=[O:55])[C:9]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C@H:20]3[C:37](=[O:38])[N:36]([CH3:39])[CH2:35][C:34]4[CH:40]=[C:30]([CH:31]=[CH:32][C:33]=4[C@@H:41]([CH2:46][CH3:47])[C:42]([OH:44])=[O:43])[NH:29][C:28](=[O:48])[O:27][CH2:26][C@H:25]([CH3:49])[C:24]4[CH:50]=[CH:51][C:21]3=[CH:22][C:23]=4[CH3:52])=[CH:16][CH:17]=2)[C:12]([F:53])=[CH:11][N:10]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@@H](C(=O)OC)c1ccc2cc1CN(C)C(=O)[C@H](Nc1ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c3c1)c1ccc(c(C)c1)[C@@H](C)COC(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC[C@@H](C(=O)O)c1ccc2cc1CN(C)C(=O)[C@H](Nc1ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c3c1)c1ccc(c(C)c1)[C@@H](C)COC(=O)N2
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.3 %

Procedure:
To a solution of 13G (62 mg, 0.075 mmol) in THF (2 mL) was added LiOH (2 mL, 2.000 mmol). The reaction mixture was stirred at rt for 2 days, concentrated and acidified with 1N HCl. The mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated to give 13H (60 mg, 98% yield).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[C:10]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:39])[CH:24]([NH:31]C(=O)OC(C)(C)C)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:18][CH:17]=3)=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>>[NH2:31][CH:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:23]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:10]2[C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([NH:2][CH3:1])[N:8]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:17][CH:18]=1)=[O:39]
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)C(NC(=O)OC(C)(C)C)c3ccccc3)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)C(N)c3ccccc3)cc2)n1
Reaction time: 16 h

Procedure:
Tert-butyl (rac)-2-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenylamino)-2-oxo-1-phenylethylcarbamate (0.040 g, 0.076 mmol) was treated with 1 mL TFA at ambient temperature. After 16 h, saturated aqueous sodium bicarbonate was added until pH=9, and the aqueous layer extracted once with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give (rac)-2-amino-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-2-phenylacetamide. MS m/z=441 [M+1]+. Calc'd for C25H24N6O2: 440.51.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[N:21]2[CH2:26][CH2:25][CH:24]([C:27]([O:29]C(C)(C)C)=[O:28])[CH2:23][CH2:22]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[N:21]2[CH2:22][CH2:23][CH:24]([C:27]([OH:29])=[O:28])[CH2:25][CH2:26]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: CC(C)(C)OC(=O)C1CCN(c2cnccc2NC(=O)c2c(N)nn3cc(F)cnc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nn2cc(F)cnc2c1C(=O)Nc1ccncc1N1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98 %

Procedure:
To a suspension of tert-butyl 1-[4-[(2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]-3-pyridyl]piperidine-4-carboxylate trifluoroacetic acetate (prepared according to a methodology similar to the one described in Example 1) (101 mg, 0.1773 mmol) in DCM (5 mL) was added TFA (1 mL, 12.98 mmol). The mixture was stirred at room temperature for 20 hours. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and diethyl ether (×2) to give title compound as a beige solid (98% Yield, di-TFA salt). 1H NMR (500 MHz, DMSO) δ 11.10 (s, 1H), 9.58 (dd, 1H), 8.91 (d, 1H), 8.86 (d, 1H), 8.68 (s, 1H), 8.56 (d, 1H), 6.92 (s, 2H), 3.10 (d, 2H), 2.99-2.82 (m, 2H), 2.53-2.50 (m, 1H), 2.15-1.93 (m, 4H); 19F NMR (471 MHz, DMSO) δ −74.10, −151.83; LC-MS ES+: 400.0.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([CH:34]([C:36]2[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][CH:37]=2)[CH3:35])=[CH:4][N:3]=1.[NH2:46][C:47]1[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[N:51][CH:52]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C(Cl)Cl>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:10]2[N:9]=[C:8]([C:7]3[C:2]([NH:46][C:47]4[CH:52]=[N:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=4)=[N:3][CH:4]=[C:5]([CH:34]([C:36]4[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:43])=[O:44])=[CH:38][CH:37]=4)[CH3:35])[CH:6]=3)[N:13]=[C:12]([CH3:14])[N:11]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)c4ccc(S(C)(=O)=O)cc4)cnc3F)n2)cc1
Reactant: COc1ccc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)c4ccc(S(C)(=O)=O)cc4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 51.5 %

Procedure:
4-(2-Fluoro-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (764.7 mg, 1.218 mmol) and 5-amino-2-methoxypyridine (162.9 mg, 1.312 mmol) were dissolved in THF (12 mL) and the flask was cooled in an ice water bath while being stirred under nitrogen. Then, lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran/ethyl benzene, 3.6 mL, 3.6 mmol) was added via syringe, and the reaction was stirred at 0° C. After 40 min, the reaction was treated with ice water (1.5 mL), diluted with DCM, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted funnel with about 2 inches of silica gel; DCM to 100:1 DCM/MeOH to 75:1 DCM/MeOH to 40:1 DCM/MeOH). The fractions with product were collected, concentrated, and dried under high vacuum in a water bath (about 40° C.) to give N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (459.4 mg). 1H NMR (CDCl3, 400 MHz) δ 11.57 (s, 1H), 8.65 (d, J=2.35 Hz, 1H), 8.25 (d, J=2.35 Hz, 1H), 8.14 (d, J=2.35 Hz, 1H), 7.89 (dd, J=8.71 Hz, 2.45 Hz, 1H), 7.81 (d, J=8.22 Hz, 2H), 7.40 (d, J=8.02 Hz, 2H), 7.24-7.14 (m, 4H), 6.90-6.81 (m, 4H), 6.70 (d, J=8.80 Hz, 1H), 4.87 (d, J=4.89 Hz, 2H), 4.77 (d, J=5.09 Hz, 2H), 4.23-4.16 (m, 1H), 3.92 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H), 2.98 (s, 3H), 2.57 (s, 3H), 1.66 (d, J=7.24 Hz, 3H). m/z (ESI, pos. ion) 732 (M+H)+.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@@H:2]([C:4]([NH:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5])[CH3:3].[NH:22]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[C@H:23]([C:32]([OH:34])=O)[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CO.C1COCC1.[Pd]>[NH:22]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[C@H:23]([C:32]([NH:1][C@@H:2]([C:4]([NH:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5])[CH3:3])=[O:34])[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=1
Reactant: COC(=O)CNC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CNC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94212.5 %

Procedure:
A suspension of Z-D-Ala-Gly-OMe (26) (5.88 g, 0.02 mmol) and 10% Pd-C (0.4 g) in methanol (300 ml) was stirred under a hydrogen atmosphere at room temperature for 1.5 hr. The catalyst was filtered and the filtrate was evaporated in vacuo. The residue and Z-Tyr (6.30 g, 0.02 mol) was dissolved in dry THF (300 ml), cooled to 0° C. and HOBt (2.70 g, 0.02 mol) and DCC (4.12 g. 0.02 mol) were added successively at 0° C. The solution was stirred for 3 hr at 0° C. and overnight at room temperature. The precipitated crystals were filtered. The filtrate was evaporated under reduced pressure, the residual crystals were dissolved in EtOAc and the solution was washed with 5% NaHCO3, 0.2 N Hcl and water, and dried over anhyd. Na2SO4. The solvent was removed in vacuo and the resulting solid was purified by silica gel column chromatography using CHCl3 --CH3OH (98:2) as eluant to give Z-Tyr-D-Ala-Gly-OMe (27) (8.62 g, 94.3%), mp 154°-155° C. (AcOEt-hexane); [α]D22 33.4° (C=1.0, MeOH); NMR (CDCl3 -DMSO-d6 (4:1) δ: 1.25 (3H, d, J=7 Hz, CH3), 2.82-3.03 (2H, m, CH2,), 3.70 (3H, s, CH3O), 3.80-3.95 (2H, m, CH2PhOH), 4.15-4.60 (2H, m, 2 CH), 5.05 (2H, s, CH2O), 6.70-7.25 (4H, m, ArH), 6.70-6.90 (1H, br, NH), 7.36 (5H, s, ArH), 7.70-8.10 (2H, br, NH). Rf (I)=0.48; Rf (VI)=0.08.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:9]=2[O:10][C:11]=1[CH3:12])(=[O:5])[CH3:4].I[CH2:21][CH3:22].O>CN(C)C=O>[C:3]([N:6]([C:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:9]=2[O:10][C:11]=1[CH3:12])[CH2:21][CH3:22])(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1c(C)oc2c([N+](=O)[O-])cccc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(C)=O)c1c(C)oc2c([N+](=O)[O-])cccc12
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
Sodium hydride (60%, 54 mg) was added to a solution of 3-acetylamino-2-methyl-7-nitrobenzo[b]furan (280 mg) in N,N-dimethylformamide (3 ml) at 4° C. The mixture was stirred for 30 minutes and to the mixture was added iodoethane (240 mg). The mixture was stirred at ambient temperature for 2 hours. The reaction mixture was poured into cold water and the separated oil was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 3-(N-acetyl-N-ethylamino)-2-methyl-7-nitrobenzo[b]furan as a crystalline solid (310 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)O)c(Cl)c1
Temperature: 50 °C
Yield: 99.7 %

Procedure:
To methyl 2-chloro-4-methylbenzoate (1.00 g, 5.42 mmol) in tetrahydrofuran (10 mL) methyl alcohol (5 mL) and water (2.5 mL) is added 2N lithium hydroxide (8.12 mL, 16.2 mmol). The reaction mixture is heated at 50° C. for 2.5 hr, cooled to room temperature, and then quenched with 5N hydrochloric acid (3.24 mL). The mixture is concentrated to remove the tetrahydrofuran and methyl alcohol. A white precipitate is formed and is filtered. After drying, 0.922 g (100%) of 2-chloro-4-methylbenzoic acid is isolated. ES(−)MS m/z 169, (M−H)− consistent with 1 Cl.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:30])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](F)(F)F)=[CH:21][CH:20]=3)=[CH:14][C:13]=2[Cl:29])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].NC1C=CC(C)=C(C(C2C=CC(NC3C=CC([Cl:53])=CC=3C)=CC=2Cl)=O)C=1>>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:30])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([Cl:53])=[CH:25][C:24]=3[CH3:23])=[CH:14][C:13]=2[Cl:29])=[O:11])[CH:9]=1)=[N+:2]=[N-:3]
Reactant: Cc1cc(Cl)ccc1Nc1ccc(C(=O)c2cc(N)ccc2C)c(Cl)c1
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Product: Cc1cc(Cl)ccc1Nc1ccc(C(=O)c2cc(N=[N+]=[N-])ccc2C)c(Cl)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 416, using compound 444 (0.09 mmol). The crude product was used without any further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].C(N(C(C)C)C(C)C)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:17]=[C:2]([NH:1][S:43]([CH3:42])(=[O:45])=[O:44])[CH:3]=[CH:4][C:5]=2[NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2ccc(N)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1ccc(NCC2CCNCC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Reaction time: 8 h
Yield: 55.2 %

Procedure:
A suspension of 5-amino-N-(5-chloropyridin-2-yl)-2-[(1-Boc-piperidin-4-yl)methylamino]benzamide (0.55 g, 1.2 mmol) in 12 mL of dichloromethane at 0° C. was treated with ethyldiisopropylamine (231 μL, 1.3 mmol) followed by methanesulfonyl chloride (93 μL, 1.2 mmol). The reaction mixture was allowed to reach room temperature overnight, then it was concentrated in vacuo to a crude residue. The residue was directly applied to an SCX column, which was washed with methanol and allowed to stand overnight. Elution with 1:1 dichloromethane-1 N ammonia in methanol provided yellow fractions, which were combined and concentrated in vacuo to a crude residue. Purification by silica gel chromatography, eluting with 9:1 dichloromethane-2 N ammonia in methanol, afforded solid material which was taken up in ac tonitrile and sonicated for several minutes. The resulting suspension was filtered, giving rise to the title compound (0.29 g, 56%) as a pale-yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH2:24])[CH:21]([CH3:23])[CH3:22]>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([NH:24][CH2:20][CH:21]([CH3:23])[CH3:22])[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: CC(C)CN
Solvent: CS(C)=O
Product: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl

Procedure:
The title compound was prepared from (4,5-dichloro-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example A20) (3.0 g, 9.77 mmol) and isobutylamine (3.57 g, 48.8 mmol) in DMSO (20 mL) at 55° C. according to the general procedure C. Obtained as a brown solid (2.26 g, 67%).
Reaction SMILES: P(=O)([O-])O[C:3]([CH2:19][CH3:20])(CC)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([CH2:12][CH2:13][CH3:14])=[C:6]([O:15][CH3:16])[CH:5]=1.[F:23][C:24]1[CH:31]=[CH:30]C(C=O)=[CH:26][CH:25]=1>>[CH3:11][O:10][C:8]1[CH:9]=[C:4]([CH:3]=[CH:19][C:20]2[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=2)[CH:5]=[C:6]([O:15][CH3:16])[C:7]=1[CH2:12][CH2:13][CH3:14]
Reactant: CCCc1c(OC)cc(C(CC)(CC)O[PH](=O)[O-])cc1OC
Reactant: O=Cc1ccc(F)cc1
Product: CCCc1c(OC)cc(C=Cc2ccc(F)cc2)cc1OC

Procedure:
This material was prepared from diethyl(3,5-dimethoxy-4-1-propylbenzyl) phosphonate and 4-fluorobenzaldehyde in the same procedure as described in Example 21.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH:5]1[CH:9]=[CH:8][NH:7][C:6]1=[O:10].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](Cl)=[O:17]>[N+](C1C=CC=CC=1)([O-])=O>[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]([C:9]1[NH:5][C:6](=[O:10])[NH:7][CH:8]=1)=[O:17]
Reactant: O=C(Cl)c1cccs1
Reactant: O=c1[nH]cc[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(c1c[nH]c(=O)[nH]1)c1cccs1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
In 50 ml of nitrobenzene is combined 13.3 g of aluminum chloride, 4.2 g of 1,3-dihydro-2H-imidazol-2-one and 8.1 g of thienoyl chloride. The mixture is stirred at 60° C. for 3 hours and poured over ice water. The solids are filtered, washed with ether and recrystallized twice from ethanol-water to afford the title compound. M.P. 339°-42° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[CH:17]([O:30][Si](C(C)(C)C)(C)C)[CH2:18][CH2:19][C:20]2[S:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[C:21]=2[Cl:29])[CH2:13][CH:12]([OH:38])[C:11]1=[O:39].C1C=CN=CC=1.F.C([O-])(O)=O.[Na+]>C(#N)C>[CH3:1][O:2][C:3](=[O:40])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[CH:17]([OH:30])[CH2:18][CH2:19][C:20]2[S:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[C:21]=2[Cl:29])[CH2:13][CH:12]([OH:38])[C:11]1=[O:39]
Reactant: COC(=O)CCC/C=C\C[C@H]1C(=O)C(O)C[C@@H]1/C=C/C(CCc1sc2ccccc2c1Cl)O[Si](C)(C)C(C)(C)C
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Product: COC(=O)CCC/C=C\C[C@H]1C(=O)C(O)C[C@@H]1/C=C/C(O)CCc1sc2ccccc2c1Cl
Reaction time: 2 h

Procedure:
An acetonitrile (0.35 mL) solution of 7 (9 mg, 0.015 mmol) was treated with HF-pyridine (0.07 mL). The solution was allowed to stir for 2 h and then 20 mL of saturated NaHCO3 solution was added. The mixture was extracted with dichloromethane (3×15 mL) and the combined dichloromethane solution dried (Na2SO4), filtered and evaporated. Purification by preparative thin layer chromatography (50% ethyl acetate/hexanes) gave two diastereomers of diol 8 (2 mg each, 0.004 mmol each, 27% for each).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([NH:18][C:2]2[N:7]=[C:6]([NH:18][C:17]3[CH:19]=[CH:20][C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:15][CH:16]=3)[C:5]([F:9])=[CH:4][N:3]=2)=[CH:19][CH:20]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)c1ccc(N)cc1
Product: CC(C)(C)c1ccc(Nc2ncc(F)c(Nc3ccc(C(C)(C)C)cc3)n2)cc1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-tert-butylaniline were reacted to yield N2,N4-bis(4-tert-butylphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.77 (d, 1H, J=3.9 Hz), 7.47 (d, 2H, J=9 Hz), 7.38 (m, 4H), 7.30 (d, 2H, J=8.7 Hz), 1.34 (s, 9H), 1.32 (s, 9H); LCMS: ret. time: 34.09 min.; purity: 93%; MS: 393 (MH+).
Reaction SMILES: O1CCCC1.[CH:6]([OH:9])([CH3:8])[CH3:7].[H-].[Na+].[Br:12][C:13]1[N:30]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:16]2[CH:17]=[N:18][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20](=[O:21])[C:15]=2[C:14]=1[CH2:39]Br>O>[Br:12][C:13]1[N:30]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:16]2[CH:17]=[N:18][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20](=[O:21])[C:15]=2[C:14]=1[CH2:39][O:9][CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)O
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CBr)c(Br)n2COCC[Si](C)(C)C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)OCc1c(Br)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67 %

Procedure:
To 2 ml of dehydrated tetrahydrofuran solution containing 1 ml of isopropanol was added 155 mg of sodium hydride (55% dispersed material in mineral oil), the mixture was stirred at room temperature for 20 minutes, then, 272 mg (0.48 mmol) of 2-bromo-3-bromomethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 25-(a) was further added to the mixture, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed successively with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 176 mg of the title compound as a colorless oil. (Yield: 67%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[C:17]([CH:21]3[C:30]([CH3:32])([CH3:31])[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:33](O)=[O:34])[CH:27]=4)[NH:22]3)[CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10]1.[CH:36]1([S:39]([NH2:42])(=[O:41])=[O:40])[CH2:38][CH2:37]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[C:17]([CH:21]3[C:30]([CH3:31])([CH3:32])[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:33]([NH:42][S:39]([CH:36]5[CH2:38][CH2:37]5)(=[O:41])=[O:40])=[O:34])[CH:27]=4)[NH:22]3)[CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10]1
Reactant: Cc1ccc(N2CCN(c3cccc(C4Nc5ccc(C(=O)O)cc5CC4(C)C)c3)CC2)c(C)c1
Reactant: NS(=O)(=O)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(N2CCN(c3cccc(C4Nc5ccc(C(=O)NS(=O)(=O)C6CC6)cc5CC4(C)C)c3)CC2)c(C)c1
Yield: 24.9 %

Procedure:
A mixture of 2-{3-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.21 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (61 mg, 0.32 mmol), 4-dimethylaminopyridine (39 mg, 0.32 mmol), cyclopropane sulfonamide (76 mg, 0.63 mmol) in dichloromethane (10 mL) was refluxed for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid (2-{3-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl)-amide (30 mg, 25%) as a light yellow solid: LC/MS m/e calcd for C33H40N4O3S (M+H)+: 573.8, observed: 573.3.
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C:9]1[C:10]([CH3:28])=[CH:11][C:12]2[O:16][CH2:15][C@H:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[C:13]=2[C:26]=1[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29](OCC)(=[O:31])C.CCCCCC>C(Cl)(Cl)Cl>[C:1]([NH:5][C:6]([NH:8][C:9]1[C:10]([CH3:28])=[C:11]([CH:29]=[O:31])[C:12]2[O:16][CH2:15][C@H:14]([C:17]3[CH:18]=[CH:19][C:20]([CH:23]([CH3:24])[CH3:25])=[CH:21][CH:22]=3)[C:13]=2[C:26]=1[CH3:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(C)=O
Reactant: Cc1cc2c(c(C)c1NC(=O)NC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: Cc1c(C=O)c2c(c(C)c1NC(=O)NC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Yield: 78 %

Procedure:
Using (+)-N-(tert-butyl)-N′-((3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)urea, the title compound was synthesized in the same manner as in Example 20. Yield: 78%. Melting point: 209-210° C. (ethyl acetate-hexane). [α]D20=−31.2° (c=0.48, chloroform).