Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][N:16]([CH:21]4[CH2:24][O:23][CH2:22]4)[CH2:15][CH2:14][C:13]=3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:35]([N:36]2[CH2:47][CH2:46][N:45]3[C:38](=[CH:39][C:40]4[CH2:41][C:42]([CH3:49])([CH3:48])[CH2:43][C:44]=43)[C:37]2=[O:50])=[CH:34][C:33]([F:51])=[CH:32][C:31]=1B1OC(C)(C)C(C)(C)O1)(=[O:27])[CH3:26]>C([O-])([O-])=O.[Na+].[Na+].COCCOC.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>[F:51][C:33]1[CH:32]=[C:31]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:20]=[CH:19][C:18]4[CH2:17][N:16]([CH:21]5[CH2:24][O:23][CH2:22]5)[CH2:15][CH2:14][C:13]=4[N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[C:30]([CH2:29][O:28][C:25](=[O:27])[CH3:26])=[C:35]([N:36]2[CH2:47][CH2:46][N:45]3[C:38](=[CH:39][C:40]4[CH2:41][C:42]([CH3:48])([CH3:49])[CH2:43][C:44]=43)[C:37]2=[O:50])[CH:34]=1
Reactant: Cn1cc(Br)cc(Nc2ccc3c(n2)CCN(C2COC2)C3)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
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: [Na+]
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cc(Nc3ccc4c(n3)CCN(C3COC3)C4)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 125 °C
Reaction time: 0.17 h
Yield: 11.5 %

Procedure:
In a 10-mL microwave reaction vessel equipped with a magnetic stirring bar were placed 5-bromo-1-methyl-3-(6-(oxetan-3-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)pyridin-2(1H)-one 219a (250 mg, 0.64 mmol), 10-[2-(acetoxymethyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-fluorophenyl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-9-one 230a (635 mg, 1.3 mmol), Pd(PPh3)4 (37 mg, 0.03 mmol) in 2 N Na2CO3 (2 mL) and 1,2-dimethoxyethane (2 mL). After the reaction mixture was stirred at 125° C. for 10 minutes, it was purified by flash chromatography (dichloromethane:methanol, 3:1) to give 12% (50 mg) of 292a as a solid.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH3:30])([CH3:29])[CH2:21][CH2:20]1)=[S:11])(=O)C1C=CC=CC=1>CO>[CH3:29][C:22]1([CH3:30])[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:10]([NH2:9])=[S:11])[CH2:20][CH2:21]1
Reactant: CC1(C)CCN(c2ccccc2NC(=S)NC(=O)c2ccccc2)c2ccccc21
Solvent: CO
Product: CC1(C)CCN(c2ccccc2NC(N)=S)c2ccccc21
Reaction time: 0.07 h

Procedure:
1e was heated at 80° C. in the presence of MeOH (2.5 mL and 1N NaOH 0.5 mL) for 40 min. LC-MS showed completion of the reaction. The solvent was concentrated, and 1N HCl was added followed by the addition of Et2O. The Et2O layer was separated and was washed with H2O (2×), brine, dried over MgSO4, filtered, and concentrated to dryness. The resulting crude if was used directly in the next step: LC-MS (ESI) 312.1 (M+H) (10-90% MeOH in H2O with 0.1% TFA in a 4 min run, tR=3.51 min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:19][CH3:20])[C:5]2[C:6]3[N:14]=[C:13](Cl)[N:12]=[C:11]([O:16][CH2:17][CH3:18])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:19][CH3:20])[C:5]2[C:6]3[N:14]=[C:13]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[N:12]=[C:11]([O:16][CH2:17][CH3:18])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: C1CNCCN1
Reactant: CCOc1nc(Cl)nc2c1[nH]c1cc(Br)cc(OC)c12
Solvent: C1COCCO1
Product: CCOc1nc(N2CCNCC2)nc2c1[nH]c1cc(Br)cc(OC)c12
Yield: 76.2 %

Procedure:
150 mg (0.42 mmol) 7-bromo-2-chloro-4-ethoxy-9-methoxy-5H-pyrimido[5,4-b]indole and 181 mg (2.1 mmol) piperazine were refluxed in 10 ml dioxan for 60 h. Then, the solvent was removed and the residue was suspended in water and sucked off. 130 mg (76%) 7-bromo-4-ethoxy-9-methoxy-2-(piperazin-1-yl)-5H-pyrimido[5,4-b]indole was obtained. ESI-MS [m/z]: 406, 408 [M+H]+
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:26]4[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=4)=[N:15][N:16]4[C:21]([NH:22][CH:23]5[CH2:25][CH2:24]5)=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:40][CH:41]1[CH2:43][CH2:42]1>CN(C)C=O>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:26]4[CH:27]=[CH:28][C:29]([O:32][CH2:40][CH:41]5[CH2:43][CH2:42]5)=[CH:30][CH:31]=4)=[N:15][N:16]4[C:21]([NH:22][CH:23]5[CH2:24][CH2:25]5)=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCC1CC1
Reactant: Oc1ccc(-c2nn3c(NC4CC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1cc(NC2CC2)n2nc(-c3ccc(OCC4CC4)cc3)c(-c3ccnc(NC4CCCC4)n3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To a solution of 4-[3-[2-(cyclopentylamino)-4-pyrimidinyl]-7-(cyclopropylamino)pyrazolo[1,5-a]pyridin-2-yl]phenol (146 mg, 0.34 mmol) in N,N-dimethylformamide (3 mL) was added cesium carbonate (0.22 g, 0.68 mmol) and (bromomethyl)cyclopropane (66 μL, 0.68 mmol). The reaction was stirred for 1 hour at room temperature, then partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (3:1 to 1:1 hexanes-ethyl acetate) provided 3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-[4-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-a]pyridin-7-amine (90.4 mg, 55%) as an off-white solid. 1H NMR (CDCl3): δ 7.99 (d, 1 H), 7.84 (d, 1 H), 7.55 (d, 2 H), 7.34 (t, 1 H), 6.98 (d, 2 H), 6.39–6.32 (m, 3 H), 5.08 (broad, 1 H), 4.37 (m, 1 H), 3.87 (d, 2 H), 2.68 (m, 1 H), 2.10 (m, 2 H), 1.80–1.27 (m, 6 H), 0.89 (m, 2 H), 0.78–0.65 (m, 4 H), 0.39 (m, 2 H); MS m/z 481 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=C)=[N:4][CH:3]=1.O.I([O-])(=O)(=O)=[O:18].[Na+]>O1CCOCC1.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=[O:18])=[N:4][CH:3]=1
Reactant: C=CCn1c(=O)ccc2ncc(F)cc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=CCn1c(=O)ccc2ncc(F)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
7-Fluoro-1-(2-propen-1-yl)-1,5-naphthyridin-2(1H)-one (1.683 g, 8.25 mmol) was dissolved in 1,4-dioxane (100 ml) and water (50 ml) was added. The solution was cooled to 0° C. and sodium periodate (5.29 g, 24.75 mmol) was added, followed by osmium tetroxide (9 mL of 4% aqueous solution). The stirred mixture was allowed to warm to rt, then stirred at rt for 1 h. The mixture was then treated with a further 100 ml of water and sodium periodate (10.58 g, 49.5 mmol) and stirred at rt for 1 h. The mixture was evaporated to approximately 50 ml and the residue was extracted with 20% methanol in DCM (3×300 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated to give (7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde (mainly as the methyl hemiacetal) as an off-white solid (1.531 g, 90%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:14])=[C:6]([O:12][CH3:13])[CH:7]=[C:8]([CH:11]=1)[CH:9]=O)([O-:3])=[O:2].[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>CO.[N+](C1C=CC=CC=1)([O-])=O>[N:21]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:22][C:9]=1[C:8]1[CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([OH:14])=[C:6]([O:12][CH3:13])[CH:7]=1
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: Nc1ccccc1N
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CO
Product: COc1cc(-c2nc3ccccc3[nH]2)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
aa) A solution of 4.93 g of 5-nitrovanillin and 2.7 g of 1,2-phenylenediamine in 45 ml of methanol and 15 ml of nitrobenzene is heated to boiling under reflux. After 15 minutes crystals begin to separate from the red solution. After 18 hours the reaction mixture is cooled to room temperature and diluted with 60 ml of methanol. The crystals are filtered under suction and washed with methanol. There is obtained 4-(2-benzimidazolyl)-2-methoxy-6-nitrophenol of m.p. 198°-200° (from N,N-dimethylformamide/methanol).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.[CH2:18]([Sn](CCCC)(CCCC)C=C)[CH2:19]CC.CC1C=CC=C(C)C=1CN1C2C(=CC=C(CC(O)=O)C=2)C(C)=N1>>[CH:18]([C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1)=[CH2:19]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Br)cc21
Agent: Cc1cccc(C)c1Cn1nc(C)c2ccc(CC(=O)O)cc21
Product: C=Cc1ccc2c(c1)N(C(=O)OC(C)(C)C)CC2

Procedure:
The titled compound (207 mg) as a white solid was prepared from tert-butyl 6-bromo-2,3-dihydro-1H-indole-1-carboxylate obtained by the method described in the document (WO 1998/43956 A) and tributyl(vinyl)tin according to the method of the process (2) of Example 66.
Reaction SMILES: [CH2:1](O)/[CH:2]=[CH:3]/[CH3:4].C(O[C:9]([O:14]CC)([O:11][CH2:12][CH3:13])[CH3:10])C.C(O)(=O)C>>[CH3:4][CH:3]([CH:2]=[CH2:1])[CH2:10][C:9]([O:11][CH2:12][CH3:13])=[O:14]
Reactant: CCOC(C)(OCC)OCC
Reactant: C/C=C/CO
Solvent: CC(=O)O
Product: C=CC(C)CC(=O)OCC
Temperature: 125 °C
Yield: 71 %

Procedure:
To a solution of (E)-but-2-en-1-ol (50 g, 693 mmol) in 1,1,1-triethoxyethane (890 mL 4854 mmol) was added acetic acid (5 g, 83 mmol) at room temperature. The reaction was heated to 125° C. for 4 h. The by-product ethanol was distilled by normal distillation to get crude compound ethyl 3-methylpent-4-enoate (70 g, 71.0%) as color less oil. This was taken to next step without further purification; 1H NMR (DMSO-d6) δ ppm 5.82-5.73 (m, 1H), 5.03-4.92 (m, 2H), 4.08-4.02 (m, 2H), 2.50 (m, 1H), 2.31-2.26 (m, 2H), 1.17 (t, J=8 Hz, 3H), 1.00 (d, J=8 Hz, 3H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:10]([NH2:13])([CH3:12])[CH3:11]>>[CH:10]([NH:13][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])([CH3:12])[CH3:11]
Reactant: CC(C)N
Reactant: N#Cc1ccccc1F
Product: CC(C)Nc1ccccc1C#N

Procedure:
According to a similar manner to that in Reference Example 3, the title compound was synthesized from 2-fluorobenzonitrile and isopropylamine.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][NH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18]([F:21])([F:20])[F:19].FC1C=CC=C(OC)C=1C1C=CN=CC=1N(CC(F)(F)F)[C:40](=[O:55])[C:41]1[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[C:43]([S:51]([CH3:54])(=[O:53])=[O:52])[CH:42]=1>>[CH3:54][S:51]([C:43]1[CH:42]=[C:41]([CH:46]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:44]=1)[C:40]([N:4]([CH2:3][C:2]([F:1])([F:22])[F:23])[C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18]([F:19])([F:20])[F:21])=[O:55])(=[O:53])=[O:52]
Reactant: COc1cccc(F)c1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Reactant: FC(F)(F)CNc1cnccc1-c1ccccc1OC(F)(F)F
Product: CS(=O)(=O)c1cc(C(=O)N(CC(F)(F)F)c2cnccc2-c2ccccc2OC(F)(F)F)cc(C(F)(F)F)c1
Yield: 20 %

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from (2,2,2-trifluoro-ethyl)-[4-(2-trifluoromethoxy-phenyl)-pyridin-3-yl]-amine (37) and 3-methanesulfonyl-5-trifluoromethyl-benzoyl chloride (example 223, intermediate d) after a reaction time of 12 hours at 25° C. The crude product was purified by preparative HPLC (ammonium acetate/acetonitrile) to give the desired compound as an off-white solid (12 mg, 20%). MS (ESI): m/z=587.2 [M+H]+.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH2:14][CH2:15][C:16]1[N:17]2[CH:23]=[N:22][CH:21]=[C:18]2[S:19][CH:20]=1.[CH2:24]([O:27][C:28]([NH:30][S:31]([NH2:34])(=[O:33])=[O:32])=[O:29])[CH:25]=[CH2:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.O1CCCC1>[CH2:24]([O:27][C:28]([N:30]([CH2:14][CH2:15][C:16]1[N:17]2[CH:23]=[N:22][CH:21]=[C:18]2[S:19][CH:20]=1)[S:31]([NH2:34])(=[O:33])=[O:32])=[O:29])[CH:25]=[CH2:26]
Reactant: C=CCOC(=O)NS(N)(=O)=O
Reactant: OCCc1csc2cncn12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCOC(=O)N(CCc1csc2cncn12)S(N)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
Under an argon atmosphere at -38° C., 0.77 ml of diethyl azodicarboxylate was added dropwise to 10 ml of an anhydrous tetrahydrofuran solution containing 550 mg of 3-(2-hydroxyethyl)imidazo[5,1-b]thiazole, 884 mg of N-allyloxycarbonyl-N-aminosulfonylamine and 1286 mg of triphenylphosphine, and the mixture was then stirred at -38° C. to -32° C. for 30 minutes and further stirred for 10 minutes while the solution was heated up to 0° C. The solvent was evaporated under reduced pressure to obtain an oil, and this oil was then dissolved in 50 ml of dichloromethane. Further, extraction was carried out with 2N hydrochloric acid (20 ml×2), and the combined aqueous layer was then washed with 10 ml of dichloromethane. Afterward, the solution was adjusted to pH 9 with anhydrous potassium carbonate, and then subjected to extraction with dichloromethane (30 ml×2). The dichloromethane extract was dried (anhydrous magnesium sulfate:anhydrous potassium carbonate=1:1) and then filtered, and the solvent was evaporated under reduced pressure. Afterward, the resulting oil was purified by a silica gel column chromatograph to obtain 548 mg of the title compound as a milky white amorphous.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[N:7]=1>C(N(CC)CC)C.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>[OH:4][CH2:1][C:2]#[C:3][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:3]#[C:2][CH2:1][OH:4])[N:7]=1
Reactant: Brc1cccc(Br)n1
Reactant: C#CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: OCC#Cc1cccc(C#CCO)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 134.8 %

Procedure:
Pd(Ph3P)4 (99 mg, 2%), CuBrSMe2 (38 mg) and propargyl alcohol (1.3 ml, 21 mmol) are added successively to a solution of 2,6-dibromopyridine (5.0 g, 21.1 mmol) in triethylamine (120 ml), and the mixture is stirred at RT for 10 min and then under reflux at 80° C. for 2 h. After cooling, the reaction mixture is filtered off through kieselguhr, and the filter cake is washed with ethyl acetate (20 ml). The organic phase is concentrated under reduced pressure. Further purification is carried out by chromatography [toluene/acetone (7:3)] on a silica gel column. This gives the title compound (2.65 g) as a colorless solid. TLC, silica gel (glass plates) [toluene/acetone (7:3)], Rf=0.15.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[N:9][NH:10][CH:11]=1)=[O:5].FC1C=CC=C(F)C=1C(NC1C=NN(CC2C=CC=CC=2COC2C=CC=CC=2)C=1)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:55][C:56]1[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][C:57]=1[O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CN(C=O)C>[Cl:62][C:59]1[CH:60]=[CH:61][C:56]([CH2:55][N:10]2[CH:11]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:15][CH:14]=[CH:13][C:12]=3[F:16])[CH:8]=[N:9]2)=[C:57]([O:63][CH2:64][C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:58]=1
Reactant: O=C(Nc1cn[nH]c1)c1c(F)cccc1F
Reactant: Clc1ccc(CBr)c(OCc2ccccc2)c1
Agent: O=C(Nc1cnn(Cc2ccccc2COc2ccccc2)c1)c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1cnn(Cc2ccc(Cl)cc2OCc2ccccc2)c1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2,6-difluoro-N-1H-pyrazol-4-ylbenzamide (for a preparation see intermediate 2, 52 mg, 0.23 mmol) and potassium carbonate (65 mg, 0.47 mmol) was added a solution of 1-(bromomethyl)-4-chloro-2-[(phenylmethyl)oxy]benzene (74 mg, 0.27 mmol) in DMF (1 ml). The reaction was stirred overnight, under nitrogen and at ambient temperature. The suspension was filtered using a hydrophobic frit and the residue washed with methanol (1 ml). The filtrate was purified by MDAP (Method A) on Supelcosil ABZ+Plus column using acetonitrile-water with a formic acid modifier. The solvent was evaporated in vacuo to give the title compound (33 mg) as a white solid; LCMS (System 1): MH+=454, tRET=3.60 min.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[S:9](=[O:14])(=[O:13])[CH2:8][CH2:7][CH2:6]2)=[O:2].C1(C)C=CC=CC=1.[CH2:22](O)[CH2:23][OH:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[O:2]1[CH2:22][CH2:23][O:24][CH:1]1[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[S:9](=[O:14])(=[O:13])[CH2:8][CH2:7][CH2:6]2
Reactant: OCCO
Reactant: O=Cc1ccc2c(c1)CCCS2(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=S1(=O)CCCc2cc(C3OCCO3)ccc21

Procedure:
To a mixture of 3.0 g (14.3 mmole) 6-formyl-1,1dioxothiachroman and 140 ml toluene was added 15.9 ml ethylene glycol and 0.66 g (3.5 mmole) p-toluenesulfonic acid hydrate. The mixture was heated at reflux for 18 hours or until no further water was collected in the attached water separator (Dean-Stark trap). The reaction mixture was cooled, diluted with ethyl acetate, washed with water, sodium bicarbonate, water again, brine and dried (MgSO4). Evaporation of solvent in vacuo gave 3.73 g of residual oil which solidified on standing. Mass spectrum (m/e): 254 (M+).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:21])[C:9]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:10]([CH3:14])[C:11]=2[NH2:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].C(OCC)(=O)C>ClCCl>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:21])[C:9]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:10]([CH3:14])[C:11]=2[NH:13][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cc1c(C)c(N)c2c(c1C)CCN2C(C)=O
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1c(C)c2c(c(NC(=O)C(C)(C)C)c1C)N(C(C)=O)CC2
Yield: 76 %

Procedure:
To a solution of 1-acetyl-7-amino-5-ethoxycarbonylmethyl-4,6-dimethylindoline obtained in Example 7 (4.0 g) in dichloromethane (40 ml) was added diisopropylethylamine (2.14 g, 1.2 equivalent) with stirring, and the resulting mixture was cooled to 0–5° C. Subsequently, to the reaction mixture was added dropwise pivaloyl chloride (1.74 g, 1.05 equivalent) at 0–5° C., and the resulting mixture was stirred for 1.0 hour at this temperature. The reaction mixture was washed with water (40 ml), and the resulting mixture was partitioned. The separated organic layer was washed twice with a saturated sodium hydrogen carbonate solution (20 ml each) and concentrated under reduced pressure. To the residue obtained was added ethyl acetate (20 ml), and the resulting mixture was concentrated under reduced pressure to about 12 ml. This addition and evaporation of ethyl acetate was repeated once again, and the resulting mixture was stirred at room temperature. After stirring, ethylcyclohexane (28 ml) was added, and the resulting mixture was stirred for more than 10 minutes at room temperature and then for more than 30 minutes at 0–5° C. Crystals precipitated were separated by filtration, washed with a mixed solvent of ethyl acetate and ethylcyclohexane (1:4)(40 ml) and dried under reduced pressure (50° C.) to afford the title compound (3.92 g, yield: 76%) as colourless crystals.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])=[CH:23][CH:22]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:33]([C:28]3[N:29]=[C:30]([CH3:32])[O:31][C:27]=3[C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COc1ccc(-c2oc(C)nc2C(=O)O)cc1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: COc1ccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)c2)cc1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(4-methoxy-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: Br[CH:2]([C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=1)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:18]([NH2:26])(=[S:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1.C(OCC)(=O)C>O1CCCC1>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:18]2[S:25][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=3)[N:26]=2)[CH:20]=1
Reactant: NC(=S)c1cccnc1
Reactant: CCOC(=O)C(Br)C(=O)c1cccc(C#N)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(-c2cccnc2)nc1-c1cccc(C#N)c1
Temperature: 65 °C
Reaction time: 16 h
Yield: 22.8 %

Procedure:
To a solution of ethyl 2-bromo-3-(3-cyanophenyl)-3-oxopropionate (1.0 g, 3.4 mmol) in 20 mL of tetrahydrofuran was added thionicotinamide (0.46 g, 3.4 mmol). The resulting mixture was stirred at 65° C. for 16 h. The reaction was allowed to cool and the solvent was evaporated in vacuo. The residue was triturated with chloroform, taken up in ethyl acetate, washed with saturated aq Na2CO3 and brine, dried (MgSO4) and concentrated in vacuo to yield a solid. Trituration with ethyl acetate left the title compound as an off-white solid (0.26 g, 23%). MS (ESI) 336.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:12](O)[CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[C:24]1(=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[NH:25]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:34]=[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[N:25]1[C@@H:12]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([F:1])[CH:3]=1)[CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCC[C@H](O)c1ccc(C(F)(F)F)c(F)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC[C@H](c1ccc(C(F)(F)F)c(F)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 42.2 %

Procedure:
To a solution of 286 (0.600 g, 1.78 mmol) and THF (15 mL) cooled to 0° C. was added isoindoline-1,3-dione (0.288 g, 1.96 mmol) and PPh3 (0.700 g, 2.67 mmol) followed by the dropwise addition of a THF (6 mL) solution of DEAD (0.420 mL, 2.67 mmol). The reaction was warmed to RT and stirred for 20 h. The reaction was concentrated, triturated with ether and filtered. The resulting filtrate was poured into water and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with hexane/EtOAc (4:1) to afford 0.350 g (42.4%) of (R)-tert-butyl 3-(1,3-dioxoisoindolin-2-yl)-3-(3-fluoro-4-(trifluoromethyl)phenyl)propylcarbamate (288).
Reaction SMILES: [CH2:1]([Cl:4])[CH:2]=[CH2:3].[CH3:5][NH2:6].[OH2:7]>>[CH2:1]([CH:2]1[O:7][CH2:3]1)[Cl:4].[CH2:1]([Cl:4])[CH:2]=[CH2:3].[CH3:5][NH2:6]
Reactant: O
Agent: CN
Solvent: C=CCCl
Product: ClCC1CO1

Procedure:
10 parts by weight of water are added to the mixture of poly(methylamine allyl chloride) copolymer and hydrated silica, then filtered to remove the hydrated silica; then 1.5 parts by weight of epichlorohydrin is gradually added while agitating and keeping the temperature below 70° C. for 10 to 60 minutes thereby producing a liquid poly(methylamine allyl chloride epichlorohydrin) resinous product. It is then heated to 80° to 100° C. for 10 to 60 minutes thereby producing a solid resinous product.