Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:10]=[C:9]([N:11]3[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12]3)[N:8]=[C:7]([NH:18][C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=3)[CH:6]=2)[CH2:2]1.ClCCl.C(N(C(C)C)C(C)C)C.[C:41](OC(=O)C)(=[O:43])[CH3:42]>CN(C1C=CN=CC=1)C>[F:16][C:13]1([F:17])[CH2:14][CH2:15][N:11]([C:9]2[CH:10]=[C:5]([CH:3]3[CH2:2][N:1]([C:41](=[O:43])[CH3:42])[CH2:4]3)[CH:6]=[C:7]([NH:18][C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[CH:21][N:20]=3)[N:8]=2)[CH2:12]1
Reactant: FC1(F)CCN(c2cc(C3CNC3)cc(Nc3cc(C(F)(F)F)ccn3)n2)C1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CC(c2cc(Nc3cc(C(F)(F)F)ccn3)nc(N3CCC(F)(F)C3)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.8 %

Procedure:
To a solution of 4-(azetidin-3-yl)-6-(3,3-difluoropyrrolidin-1-yl)-N-[4-(trifluoromethyl)-2-pyridyl]pyridin-2-amine (1-d, 180 mg, 0.4507 mmol) and DMAP (5.6 mg, 0.1 equiv., 0.04507 mmol) in dichloromethane (2 mL, 31.0 mmol) and N-ethyldiisopropylamine (0.47 mL, 6.0 equiv., 2.704 mmol) was added acetic anhydride (0.22 mL, 5.0 equiv., 2.253 mmol), and the brown solution was stirred at 25° C. for 2 h. DCM was removed, and the crude was submitted for HPLC purification to yield 9.5 mg (4.8%) off-white powder. 1H NMR (400 MHz, DMSO) δ (delta) 9.99-9.83 (s, 1H), 8.74-8.62 (s, 1H), 8.48-8.40 (d, J=5.1 Hz, 1H), 7.21-7.11 (d, J=5.2 Hz, 1H), 6.66-6.55 (s, 1H), 6.15-5.96 (s, 1H), 4.53-4.39 (t, J=8.6 Hz, 1H), 4.27-4.15 (t, J=9.2 Hz, 1H), 4.14-4.07 (dd, J=8.3, 6.1 Hz, 1H), 3.94-3.78 (m, 3H), 3.77-3.61 (m, 3H), 2.64-2.52 (dt, J=14.1, 7.0 Hz, 2H), 1.85-1.75 (s, 3H). LCMS: m/z 442 (M+H).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[OH:13]>O.C(O)(=O)C>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]([OH:13])=[C:6]([NH:5][C:2]([NH2:3])=[O:1])[CH:11]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.4 %

Procedure:
A solution of potassium cyanate (6.14 g, 75.6 mmol) in water (50 mL) was added dropwise to a stirred suspension of 2-amino-4-chlorophenol (5.00 g, 34.8 mmol) in a mixture of acetic acid (350 mL) and water (250 mL) and the resulting solution was stirred at room temperature for 3 hours. The reaction mixture was extracted three times with ethyl ether. The ether extracts were combined and concentrated to a thick oil. A 10% solution of sodium hydrogen carbonate (250 mL) was added to the above oil. The solid product was filtered and washed several times with water and recrystallized (toluene containing a little methanol) to afford the subtitle compound (3.27 g, 50.4%)
Reaction SMILES: [Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([OH:8])[CH2:4][C:5]([CH3:7])=[CH2:6].[C:11](OC(=O)C)(=[O:13])[CH3:12]>N1C=CC=CC=1>[Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([O:8][C:11](=[O:13])[CH3:12])[CH2:4][C:5]([CH3:7])=[CH2:6]
Reactant: C=C(C)CC(O)C(Cl)(Cl)Cl
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C=C(C)CC(OC(C)=O)C(Cl)(Cl)Cl
Yield: 80.1 %

Procedure:
A mixture of 1321 g of 1,1,1-trichloro-2-hydroxy-4-methyl-4-pentene, 695 g of acetic anhydride, and 32.6 ml of pyridine was heated at 95°-100° for 1 hour. The low boiling by-products were removed under vacuum, and the residue was then distilled, yielding 1276 g of 1,1,1-trichloro-2-acetoxy-4-methyl-4-pentene; bp, 87°/5.5 mm.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:24][CH2:23][CH:22]([C:25](OC)=[O:26])[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OCC)(=O)C.O>O1CCCC1>[C:7]1([CH:13]2[CH2:14][CH2:15][N:16]([CH:19]3[CH2:24][CH2:23][CH:22]([CH2:25][OH:26])[CH2:21][CH2:20]3)[CH2:17][CH2:18]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)C1CCC(N2CCC(c3ccccc3)CC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: OCC1CCC(N2CCC(c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.36 g (9.37 mM) of lithium aluminum hydride in 50 ml of tetrahydrofuran was added a solution of 2.825 g (9.372 mM) of methyl 4-(4-phenylpiperidino)cyclohexanecarboxylate in 50 ml of tetrahydrofuran dropwise with ice-cooling and the mixture was stirred at room temperature for one hour. To this reaction mixture was added ethyl acetate with ice-cooling to decompose the excess lithium aluminum hydride. Then, water was added until a white precipitate had formed. The precipitate was filtered off with the aid of celite and washed with ethyl acetate. The filtrate and washes were pooled and the solvent was distilled off under reduced pressure. The solid residue was rinsed with diethyl ether-hexane to provide the title compound.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)[CH3:2].[C:29](OC(=O)C)(=[O:31])[CH3:30]>ClC(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[NH:15][CH:16]1[CH2:17][CH2:18][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:21]1)[C:29](=[O:31])[CH3:30])[CH3:2]
Reactant: CCNCCn1c(NC2CCN(Cc3ccccc3)CC2)nc2cccnc21
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CCN(CCn1c(NC2CCN(Cc3ccccc3)CC2)nc2cccnc21)C(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
7.8 Parts of N-ethyl-2-[[1-(phenylmethyl)-4-piperidinyl]amino]-3H-imidazo[4,5-b]pyridin-3-ethanamine were taken up in 75 parts of trichloromethane. 1.51 Parts of acetic acid anhydride were added (exothermic reaction). The reaction mixture was stirred for 18 hours at room temperature. The whole was filtered over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was taken up in methylbenzene and the whole was evaporated again, yielding 8.5 parts (100%) of N-ethyl-N-[2-[2-[[1-(phenylmethyl)-4-piperidinyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]ethyl]acetamide as a residue (compound 176).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:36])[C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=2)=[O:21])[CH2:16]1>>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:36])[C:25]4[CH:26]=[C:27]([C:32]([F:35])([F:33])[F:34])[CH:28]=[C:29]([F:31])[CH:30]=4)=[O:21])[CH2:16]3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CNC(=O)c1cc(F)cc(C(F)(F)F)c1)NC1CNC1
Reactant: Nc1cccc(C2CCC(=O)CC2)n1
Product: Nc1cccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cc(F)cc(C(F)(F)F)c4)C3)CC2)n1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(6-amino-pyridin-2-yl)-cyclohexanone (as prepared in Example 22, Step C) and N-(azetidin-3-ylcarbamoylmethyl)-5-fluoro-3-trifluoromethyl-benzamide (analog synthesis by following the procedure described in Organic Synthesis XII, 40-2, 1932) using the procedure described in Step F of Example 1.
Reaction SMILES: [C:1]([OH:24])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].S(Cl)(Cl)=O.C(OC([NH:36][C@H:37]([C:41]([NH:43][C@H:44]([C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58])[CH2:45][CH2:46][C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48])=[O:42])[CH:38]([CH3:40])[CH3:39])=O)(C)(C)C.C1(OC)C=CC=CC=1.C(Cl)(=O)CCCCCCCCCCCCCCCCCCCCC>C1C=CC=CC=1.FC(F)(F)C(O)=O.O1CCCC1.C(N(CC)CC)C>[C:1]([NH:36][C@H:37]([C:41]([NH:43][C@H:44]([C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58])[CH2:45][CH2:46][C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48])=[O:42])[CH:38]([CH3:39])[CH3:40])(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: CCCCCCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)N[C@H](C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.3 %

Procedure:
A mixture of docosanoic acid (500 mg) and thionyl chloride (2 ml) in benzene (5 ml) was refluxed for 1 hour. After removal of the solvent under reduced pressure, the residue was taken up in benzene and benzene was evaporated off. This operation was repeated three times to give crude docosanoyl chloride. Meanwhile, a solution of dibenzyl N-(N-tert-butoxycarbonyl-L-valyl)-L-glutamate (773 mg) and anisole (0.25 ml) in trifluoroacetic acid (1 ml) was stirred at 0° C. for 1 hour. Evaporation of trifluoroacetic acid under reduced pressure gave a residue which was taken up in benzene. Benzene was distilled off by using a high vacuum pump. This operation was repeated three times to leave crude dibenzyl N-(L-valyl)-L-glutamate, which was dissolved in tetrahydrofuran (5 ml). To this solution were added triethylamine (0.7 ml) and a solution of docosanoyl chloride prepared as mentioned above in tetrahydrofuran (3 ml). After the resulting mixture was stirred at room temperature for 3 hours, the solvent was removed under reduced pressure, and the residue was dissolved in chloroform. The chloroform solution was washed with 1N sodium hydroxide solution, 1N hydrochloric acid solution, and an aqueous solution of sodium bicarbonate successively, and then dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by being subjected to a silica gel column chromatography. Elution with chloroform and an usual work-up afforded dibenzyl N-(N-docosanoyl-L-valyl)-L-glutamate (520 mg, powder).
Reaction SMILES: C([O:8][C:9](=[O:25])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([NH:17][S:18]([CH2:21][CH2:22][CH3:23])(=[O:20])=[O:19])[C:11]=1[F:24])C1C=CC=CC=1.O.Cl>O1CCCC1.[OH-].[K+]>[Cl:16][C:15]1[C:10]([C:9]([OH:25])=[O:8])=[C:11]([F:24])[C:12]([NH:17][S:18]([CH2:21][CH2:22][CH3:23])(=[O:19])=[O:20])=[CH:13][CH:14]=1
Reactant: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)OCc2ccccc2)c1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)O)c1F
Yield: 85.6 %

Procedure:
To 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid benzyl ester (17, 6.00 g, 15.6 mmol) in 100 mL of tetrahydrofuran, 100 mL of 1.0 M aqueous potassium hydroxide was added. The reaction was heated to reflux overnight, then poured into water, acidified to pH 2 with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic portion was dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum to give the desired compound as a white solid (18, 3.95 g, 85.8%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:15].S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N+:3]=1[O-:15]
Reactant: Cc1ccc(C#N)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C#N)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Methylnicotinonitrile (3.68 g, 31.15 mmol) is dissolved in chloroform (60 ml). 3-Chloroperoxybenzoic acid (7.53 g, 32.71 mmol) is added dropwise as a solution in chloroform (60 ml), and the solution is stirred at room temperature overnight. Sodium sulphite (2.92 g, 23.17 mmol) is added, and the resulting mixture is stirred for one hour. The reaction is quenched with saturated sodium bicarbonate solution, and the product is extracted with chloroform (500 ml). The organic phase is washed with brine, dried over magnesium sulphate monohydrate, filtered and concentrated in vacuo. The residue is used without further purification.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1.[CH:27]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28]1>CN1C(=O)CCC1>[CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23]([NH:32][CH:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1)C1CC1
Solvent: CN1CCCC1=O
Product: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(NC4CCCC4)cc3)cc2s1)C1CC1

Procedure:
A solution of 4-fluorobenzenesulfonic 2-(cyclopropanecarbonylamino)benzo-thiazol-6-yl ester (example 7) (50 mg, 127.4 μmol) and cyclopentylamine (51 μl, 0.51 mmol) in 0.5 ml of NMP is heated at 150° C. by microwave for 5 minutes. The crude reaction product is purified by preparative LC/MS (basic medium (pH 9)) to give after freeze-drying 38 mg of 4-cyclopentylamino-benzenesulfonic 2-(cyclopropanecarbonylamino)benzothiazol-6-yl ester (white solid).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:29])[C:14]([CH3:28])([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.[OH-].[Na+:32]>O>[O:30]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:29])[C:14]([CH3:28])([CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[O-:22])=[N:3]1.[Na+:32]
Reactant: CC(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.6 %

Procedure:
A suspension of the product of Example 31A (0.105 g) in water (2 mL) was treated with 0.997N sodium hydroxide solution (0.248 mL, 0.2247 mmol) and stirred at 25° C. for 1 hour. The solution was lyophilized to give the title compound (0.110 g, 99%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.47 (m, 1 H) 0.68 (m, 6 H) 0.80 (m, 1 H) 1.28 (m, 1 H) 1.39 (m, 3 H) 1.73 (m, 1 H) 2.15 (m, 1 H) 7.29 (m, 3 H) 7.50 (m, 3 H) 7.65 (m, 1 H) 8.05 (m, 1 H) 15.48 (m, 1 H). MS (ESI−) m/z 423 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[N:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>>[CH3:48][O:47][C:44]1[CH:45]=[CH:46][C:41]([CH2:40][N:8]([CH2:7][C:6]2[CH:49]=[CH:50][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([N:60]6[CH2:61][CH2:62][N:57]([C:52]7[CH:53]=[CH:54][CH:55]=[CH:56][N:51]=7)[CH2:58][CH2:59]6)=[O:36])=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:42][CH:43]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3F)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCN(c5ccccn5)CC4)cc3F)cn2)cc1
Yield: 143.1 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-benzoic acid (80.0 mg, 0.118 mmol) obtained in Step A in Example 1-D-21 and 1-(2-pyridyl)piperazine (38.5 mg, 0.236 mmol) instead of 1-pyridine-3-yl-piperazine, amidation was carried out in the same manner as Step B in Example 1-D-21, to obtain a crude product of {4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-3-fluoro-phenyl}-(4-pyridin-2-yl-piperazin-1-yl)-methanone as a yellow solid (139 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-285) as a yellow powder (54.8 mg, 80%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:38][C:39]1([F:45])[CH2:44][CH2:43][CH2:42][NH:41][CH2:40]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:41]3[CH2:42][CH2:43][CH2:44][C:39]([F:45])([F:38])[CH2:40]3)=[O:21])[N:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:8]=1
Reactant: FC1(F)CCCNC1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)N1CCCC(F)(F)C1
Temperature: 0 °C
Reaction time: 1.75 h
Yield: 15.5 %

Procedure:
A cold (0° C.) solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (4) (1.0 g, 1.0 eq.) in CH2Cl2 (20 mL) was treated sequentially with EDC HCl (0.656 g, 1.2 eq.), 3,3-difluoropiperidine hydrochloride (0.540 g, 1.2), DIPEA (435 mg, 1.2 eq) and HOBT (25.92 g, 1.2 eq.). The clear reaction mixture was stirred at 0° C. for 1.5-2 h then quenched with 50 mL ice-water slurry and extracted with CH2Cl2 (2×25 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 0.70 g of crude compound. No trans compound was formed as confirmed by LCMS and 1H NMR. Purification by column chromatography afforded 0.20 g of material that was further recrystallized/triturated using ether: petroleum ether to remove aliphatic impurity affording 0.180 g (14.1% yield) of desired pure compound.
Reaction SMILES: C([O-])=O.[NH4+].C([N:12]1[CH2:17][CH2:16][C:15]2([C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:19]([C:38]3[C:39]4[C@H:46]([CH3:47])[CH2:45][CH2:44][C:40]=4[N:41]=[CH:42][N:43]=3)[CH2:18]2)[CH2:14][CH2:13]1)C1C=CC=CC=1>[Pd].CO>[CH3:47][C@H:46]1[C:39]2[C:38]([N:19]3[C:20]4[C:25](=[C:24]([C@H:26]5[CH2:30][CH2:29][CH2:28][N:27]5[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH:23]=[CH:22][CH:21]=4)[C:15]4([CH2:16][CH2:17][NH:12][CH2:13][CH2:14]4)[CH2:18]3)=[N:43][CH:42]=[N:41][C:40]=2[CH2:44][CH2:45]1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c([C@H]5CCCN5C(=O)OC(C)(C)C)cccc43)c21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: C[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4c([C@H]5CCCN5C(=O)OC(C)(C)C)cccc43)c21
Yield: 62.8 %

Procedure:
A mixture of palladium on carbon (10% degussa typed, 10 mg), ammonium formate (50 mg, 0.80 mmol) and (R)-tert-butyl 2-(1′-benzyl-1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)pyrrolidine-1-carboxylate (15 mg, 0.026 mmol) in MeOH (5 mL) was heated to reflux for 5 hours. The reaction was filtered with a pad of celite and eluted with EtOAc (100 mL), and the filtrate was washed with water (10 mL). The organic layer was dried with Na2SO4, filtered and concentrated. The residue was purified with flash chromatography (eluted with 10% MeOH/ethyl acetate, 10% 7N NH3 in MeOH/ethyl acetate) to afford the product (R)-tert-butyl 2-(1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)pyrrolidine-1-carboxylate (8 mg, 63%) as a solid. 1H NMR (CDCl3, 400 MHz) δ 8.80 (s, 1H), 7.13 (t, 1H), 6.86-6.92 (m, 1H), 7.40 (d, 1H), 5.30-5.40 (m, 1H), 4.20-4.30 (m, 1H), 3.58-4.00 (m, 1H), 3.70-3.80 (m, 1H), 3.55-3.65 (m, 1H), 3.40-3.50 (m, 1H), 3.00-3.20 (m, 2H), 2.80-3.00 (m, 211), 2.65-2.80 (m, 1H), 2.40-2.50 (m, 2H), 2.30-2.40 (m, 1H), 2.10-2.20 (m, 1H), 2.00-2.10 (m, 1H), 1.80-1.95 (m, 211), 1.55-1.75 (m, 3H), 1.40-1.50 (m, 1H), 1.20 (s, 911), 0.80-0.90 (m, 3H). MS (APCI+) [M+H]+ 490.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]([O:18][C:19]([C:21]1[S:22][C:23]([CH3:27])=[C:24]([NH2:26])[CH:25]=1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.C(OCC)C>[CH2:11]([O:18][C:19]([C:21]1[S:22][C:23]([CH3:27])=[C:24]([NH:26][C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH:25]=1)=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C=NCc1ccccc1
Reactant: Cc1sc(C(=O)OCc2ccccc2)cc1N
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1sc(C(=O)OCc2ccccc2)cc1NC(=O)NCc1ccccc1
Reaction time: 0.33 h
Yield: 65.7 %

Procedure:
Benzyl isocyanate (0.29 g, 2.2 mmol) was added to a stirred solution of 5-methyl-4-amino-thiophene-2-carboxylic acid benzyl ester from Example 9, Step 2 (0.5 g, 2.0 mmol) in toluene (10-15 mL) at room temperature under an inert atmosphere. After 20 minutes, the mixture was heated to reflux for 10 minutes, allowed to cool, then diluted with an equal volume of diethyl ether. After 10 minutes, the precipitate was filtered off, rinsed with ether, and dried to afford 0.5 g of 4-(3-benzyl-ureido)-5-methyl-thiophene-2-carboxylic acid benzyl ester; mp 208-209° C.
Reaction SMILES: [F:1][C:2]([CH:4]([OH:16])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([CH3:8])[CH3:7])=[CH2:3].[CH2:17]([Zn]CC)C.ICI.O>C(OCC)(=O)C>[F:1][C:2]1([CH:4]([OH:16])[CH2:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)([CH3:8])[CH3:7])[CH2:17][CH2:3]1
Reactant: CC[Zn]CC
Reactant: C=C(F)C(O)CC(C)(C)c1ccc(F)cc1
Solvent: ICI
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(CC(O)C1(F)CC1)c1ccc(F)cc1
Reaction time: 0.08 h

Procedure:
To the above crude 2-fluoro-5-(4-fluorophenyl)-5-methylhex-1-en-3-ol (1.73 g, 7.65 mmol) stirred under nitrogen gas and cooled on ice, was added diethyl zinc (1.1 M in toluene, 8.0 mL). After 5 minutes, 1.0 mL of diiodomethane was added dropwise over 20 minutes and the mixture was stirred and allowed to come to room temperature and then stirred at room temperature for 4 days. 0.5 mL of water was then added to the reaction mixture, followed by ethyl acetate. The resulting mixture was then filtered through diatomaceous earth and the solvent was removed in vacuo and the residue was fractionated over silica gel (hexanes-dichloromethane (1:1) to dichloromethane gradient) to give 1-(1-fluorocyclopropyl)-3-(4-fluorophenyl)-3-methylbutan-1-ol as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][CH2:27][CH2:28][C:29](OCC)=[O:30])[N:20]=1.[Li+].CC([N-]C(C)C)C>>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:28]([CH2:27][CH2:26][CH2:25][C:21]3[N:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[C:29]2=[O:30])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CCCCc1cccnn1
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: O=c1c(CCCc2cccnn2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1
Yield: 4.9 %

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-(pyridazin-3-yl)pentanoate (1.2 eq., prepared in Synthetic Example 6) and LDA (1.2 eq.) to obtain 1-(3-nitrophenyl)-3-[3-(pyridazin-3-yl)propyl]-1,8-naphthyridin-2(1H)-one (yield, 4.9%). The product was purified through flash column chromatography and recrystallization (mp 234–235° C./DMF).