Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[O:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:14][CH2:13]1.C(N(CC)CC)C>C(O)CCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH2:20][CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: NCCCN1CCOCC1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Clc1nc(NCCCN2CCOCC2)c2cc[nH]c2n1
Yield: 123.2 %

Procedure:
A solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (105 mg, 0.56 mmol), 3-morpholinopropylamine (0.164 mL, 1.12 mmol) and triethylamine (0.150 mL, 1.08 mmol) in nBuOH (3 mL) was stirred at 60° C. overnight. It was then purified by HPLC to give 2-chloro-N-(3-morpholinopropyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a solid (204 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:5]=[CH:6][CH:7]=1.[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[S:35](Cl)(=[O:37])=[O:36]>>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:4]2[CH:3]=[C:2]([NH:1][S:35]([C:26]4[CH:27]=[CH:28][C:29]5[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH:25]=4)(=[O:37])=[O:36])[CH:7]=[CH:6][CH:5]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: Nc1cccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)c1
Product: O=C1CC(=O)N(c2cccc(NS(=O)(=O)c3ccc4ccccc4c3)c2)c2ccc3ccccc3c2N1
Yield: 100 %

Procedure:
By using 5-(3-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 53, (1), and naphthalene-2-sulfonyl chloride, the title compound (yield 100%) was obtained in the same manner as that of Example 150.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([SH:17])[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([S:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cnc2c(S)cccn2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc2c(SCc3ccccc3)cccn2c1=O
Yield: 95.3 %

Procedure:
To a suspension of 0.3 g of 3-ethoxycarbonyl-9-mercapto-4H-pyrido[1,2-a]pyrimidin-4-one II-1 in 4 ml of anhydrous DMF are added 0.3 g of benzyl bromide VI-1 and 0.5 g of K2CO3, and the resultant mixture is stirred at room temperature for 5 hours. The reaction mixture is diluted with water. The crystal precipitated is filtered and dissolved in CHCl3. The chloroform solution is dried over Na2SO4 and evaporated to give 0.389 g of the titled compound Ic-21.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C@H:4]([CH2:16][CH:17]=O)[CH2:5][C@H:6]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[O:7][CH3:8].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C@H:6]([O:7][CH3:8])[CH2:5][C@@H:4]([C:3]([O:2][CH3:1])=[O:19])[CH2:16][CH2:17][N:30]2[CH2:29][CH2:28][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:32][CH2:31]2)=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)[C@H](CC=O)C[C@@H](OC)c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)[C@@H](CCN1CCN(C(=O)OC(C)(C)C)CC1)C[C@@H](OC)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of 4(R)-(4-Fluoro-phenyl)-4-methoxy-2(S)-(2-oxo-ethyl)-butyric acid methyl ester (200 mg, 0.74 mmol) and piperazine-1-carboxylic acid tert-butyl ester (166 mg, 0.89 mmol) was added NaBH(OAc)3 (218 mg, 1.03 mmol) and AcOH (53.4 mg, 51 μL, 0.89 mmol) at room temperature. The mixture was stirred for 8 h at the room temperature. The reaction was quenched by pouring into 20 mL 5% aqueous NaOH and diluted with ethylacetate. The mixture was extracted with ethyl acetate (3×15 mL) and the combined organic layers washed with brine (2×10 mL) and dried over Na2SO4. The mixture was concentrated under reduced pressure and the product isolated by flash column chromatography eluting with 6% to 60% ethyl acetate/hexane to provide 270 mg of the title compound as an colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[S:19]1[CH2:23][CH2:22][NH:21][CH2:20]1.C(#N)C>CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:21]3[CH2:22][CH2:23][S:19][CH2:20]3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: C1CSCN1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCSC3)cc21
Temperature: 25 °C
Yield: 10.1 %

Procedure:
A solution of 1.01 g (4.0 mmol) of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.79 ml (10 mmol) of thiazolidine, 20 ml of acetonitrile and 20 ml of N,N-dimethylformamide was heated at reflux for 16 hours. The reaction was cooled to room temperature and the solid which formed was removed by filtration. After triturating with hot methanol, the residue was recrystallized from N,N-dimethylformamide to give 0.13 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-thiazolidinyl)-3-quinolinecarboxylic acid; mp 270°-273° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([Cl:11])[C:7]=1[CH:8]([F:10])[F:9].Br[C:22]([C:24]([F:27])([F:26])[F:25])=[CH2:23].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:11][C:6]1[CH:5]=[C:4]([C:22]([C:24]([F:27])([F:26])[F:25])=[CH2:23])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH:8]([F:9])[F:10]
Reactant: C=C(Br)C(F)(F)F
Reactant: CC1(C)OB(c2cc(Cl)c(C(F)F)c(Cl)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)c(C(F)F)c(Cl)c1)C(F)(F)F
Temperature: 70 °C
Yield: 63 %

Procedure:
A mixture of 2-(3,5-dichloro-4-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxa-borolane (0.58 g, 1.8 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (0.45 g, 2.5 mmol), Cs2CO3 (1.8 mL, 2M, 3.6 mmol) and Pd(PPh3)2Cl2 (38 mg) in THF (10 mL) was heated at 70° C. in a sealed tube for 4 h. The mixture was cooled to rt and partitioned between ether and H2O. The aqueous layer was extracted with EA and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel eluted with hexanes to give 1,3-dichloro-2-(difluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (0.33 g; yield 62%) as colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.381 (s, 2H), 7.045 (t, J=53.0 Hz, 1 H), 6.049 (s, 1 H), 5.820 (s, 1 H) ppm.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].CCC[CH2-].[B:19](OC)([O:22]C)[O:20]C.Cl>O1CCCC1>[O:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[B:19]([OH:22])[OH:20])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COB(OC)OC
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: OB(O)c1ccccc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Diphenyl ether (0.85 g) was dissolved in anhydrous tetrahydrofuran (20 ml) and the reaction mixture was cooled to 0° C. N-butyllithium (1.6M, 3.1 ml) was delivered by drops thereto and the reaction mixture was stirred for 30 minutes at the same temperature. Trimethyl borate (0.68 ml) was added thereto and the reaction mixture was stirred for two hours at room temperature. 1N hydrochloric acid was added to the reaction mixture and the water layer was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the obtained residue was purified by column chromatography (ethyl acetate:hexane=1.5:1 to 1:3) to obtain the title compound (304 mg) having the following physical data.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:30][CH:29]=3)[CH:19]=[CH:20][C:21]=2[O:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[CH:8]=[CH:9][C:10]=1N1CCCC1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CS(C)=O.C(C1C=C(C2C=C(C3C=CC(C(OCC)=O)=CC=3)C=CC=2OCCCC=O)C=CC=1[N:59]1[CH2:63][CH2:62][CH2:61][CH2:60]1)(C)(C)C>C(N(CC)CC)C>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:21]([O:22][CH2:23][CH2:24][CH2:25][CH:26]=[O:27])([N:59]3[CH2:63][CH2:62][CH2:61][CH2:60]3)[CH2:20][CH:19]=[C:18]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][CH:33]=3)[CH:17]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCC=O)c(-c3ccc(N4CCCC4)c(C(C)(C)C)c3)c2)cc1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCO)c(-c3ccc(N4CCCC4)c(C(C)(C)C)c3)c2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(C2=CCC(OCCCC=O)(N3CCCC3)C(c3cccc(C(C)(C)C)c3)=C2)cc1
Yield: 78 %

Procedure:
In a manner similar to that of Example 30a, by reacting 900 mg of ethyl 3″-tert-butyl-4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate obtained in Example 18e with 0.3 mL of oxalyl chloride, 0.54 mL of DMSO and 0.25 mL of triethylamine, 700 mg of ethyl 3″-tert-butyl-4′-(4-oxobutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate are obtained (yield=78%) in the form of a yellow oil.
Reaction SMILES: C(O[C@H:5]1[C@H:10]2[C@H:11]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@:7]([CH2:20][O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([CH2:8][O:9]2)[O:6]1)(=O)C.[C:29]([NH:37][C:38]1[N:46]=[CH:45][N:44]=[C:43]2[C:39]=1[NH:40][CH:41]=[N:42]2)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O>C(#N)C>[C:29]([NH:37][C:38]1[N:46]=[CH:45][N:44]=[C:43]2[C:39]=1[N:40]=[CH:41][N:42]2[C@@H:5]1[C@H:10]2[C@H:11]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@:7]([CH2:20][O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([CH2:8][O:9]2)[O:6]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Nc1ncnc2nc[nH]c12)c1ccccc1
Reactant: CC(=O)O[C@@H]1O[C@@]2(COCc3ccccc3)CO[C@@H]1[C@@H]2OCc1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: O=C(Nc1ncnc2c1ncn2[C@H]1O[C@@]2(COCc3ccccc3)CO[C@@H]1[C@@H]2OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
A solution of furanose 207 (167 mg, 0.434 mmol) and 6-N-benzoyladenine (194 mg, 0.813 mmol) in anhydrous acetonitrile (5.3 mL) was added BSA (0.43 mL, 1.76 mmol) and stirred at room temperature for 1 h. The solution was cooled to 0° C. and trimethylsilyl triflate (0.16 mL, 0.86 mmol) was added dropwise. After stiffing at 65° C. for 2 h, the reaction was quenched with a saturated aqueous solution of sodium hydrogen carbonate (40 mL) and the mixture was extracted with dichloromethane (2×50 mL). The combined extract was dried (MgSO4). The solvent was removed under reduced pressure and the residue was purified by chromatography over silica gel with dichloromethane:methanol (98:2) as eluent to give the product 208 as a solid (111 mg, 45%); 1H NMR (CDCl3): δ 8.82 (1H, s, H-8), 8.14 (1H, s, H-2), 7.59-7.26 (15H, m, Bz, Bn), 6.74 (1H, s, H-1′), 4.92 (1H, s, H-2′), 4.74-4.39 (4H, m, Bn), 4.42 (1H, s, H-3′), 4.19-4.10 (2H, m, H-5″), 3.92 (1H, d, J 11.8 Hz, H-5′), 3.88 (1H, d, J 11.5 Hz, H-5′); MS FAB: 564 (M+H, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([N:11]2[C:15]([CH:16]([CH3:18])[CH3:17])=[C:14](I)[C:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:12]2)=[CH:5][N:4]=1.[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[C:28]([F:34])[CH:27]=1>C1COCC1>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]([OH:31])[C:14]2[C:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:12][N:11]([C:6]3[C:7]([O:9][CH3:10])=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=3)[C:15]=2[CH:16]([CH3:18])[CH3:17])=[C:28]([F:34])[CH:27]=1
Reactant: O=Cc1ccc(Cl)cc1F
Reactant: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C(C)C)c1I
Solvent: C1CCOC1
Product: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C(C)C)c1C(O)c1ccc(Cl)cc1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 74.5 %

Procedure:
To a solution of ethyl 1-(2,4-dimethoxypyrimidin-5-yl)-4-iodo-5-isopropyl-1H-pyrazole-3-carboxylate (product from step 184.4, 1.15 g, 2.55 mmol) in 14 ml THF, a solution of 1M isopropylmagnesium chloride lithium chloride complex (2.68 ml, 2.68 mmol) was added at 0° C. and the mixture was stirred for 15 min. Then the solution was cooled down to −78° C. and a solution of 4-chloro-2-fluorobenzaldehyde (405 mg, 2.55 mmol) in 3 ml THF was added. The reaction mixture was stirred for 30 min at temperatures between −78° C. to −20° C. The solution was quenched with 10 ml of 1M NH4Cl solution, washed with brine and extracted 3 times with EtOAc. The combined organic phases were dried (Na2SO4), filtered and evaporated. The crude product was purified by chromatography (Silicagel, heptane, heptane/EtOAc 1:4) to give 977 mg (1.901 mmol, 74.5% yield) of the title compound as a white foam. LCMS: (M+H)=479; tR=1.18 min (LC-MS 4). HPLC: tR=5.48 min (HPLC 7). TLC: Rf=0.35 (Heptane/EtOAc 1:2).
Reaction SMILES: FC1C=CC(N)=CC=1.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.[CH3:21][O:22][CH:23]([O:26][CH3:27])[CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:21][O:22][CH:23]([O:26][CH3:27])[CH2:24][NH:16][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([C:10]([F:19])([F:20])[F:9])=[CH:12][CH:13]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: COC(C=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Nc1ccc(F)cc1
Agent: [Na+]
Product: COC(CNCc1ccc(C(F)(F)F)cc1)OC
Yield: 67 %

Procedure:
Following the procedure as described in step A of Preparation 2, making variations as required to replace 4-fluoroaniline with 4-(trifluoromethyl)benzylamine to react with dimethoxyacetaldehyde followed by the imine reduction with sodium triacetoxyborohydride, 2,2-dimethoxy-N-(4-(trifluoromethyl)benzyl)ethanamine was obtained in 67% yield: 1H NMR (300 MHz, CDCl3) δ 7.52 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.1 Hz, 2H), 4.43 (t, J=2.7 Hz, 1H), 3.81 (s, 2H), 3.38 (s, 6H), 2.67 (dd, J=2.7, 2.5 Hz, 2H); MS (ES+) m/z 264.3 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19]C)=O)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:21][NH2:22]>C(O)C.CO>[CH3:21][NH:22][C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[C:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=1)=[O:19]
Reactant: COC(=O)c1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Reactant: CN
Solvent: CCO
Solvent: CO
Product: CNC(=O)c1ccc2[nH]cc(C3=CCN(C)CC3)c2c1

Procedure:
A solution of the product of stage (i) (0.5 g) in a mixture of methylamine in ethanol (40%, 20 ml) and methanol (10 ml) was heated at reflux for 10 h. The mixture was cooled, and partitioned between water (100 ml) and ethyl acetate (100 ml). The aqueous phase was separated, and extracted with ethyl acetate (50 ml). The organic layers were combined, dried and evaporated in vacuo to give a solid, (0.25 g) which was crystallized twice from ethyl acetate to give the title compound as microcrystals (0.1 g), m.p. 125°-135°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]([CH3:41])[CH2:14][CH2:15][N:16]([CH3:40])[C:17](=[O:39])/[CH:18]=[CH:19]/[C:20]1[C:28]2[C:23](=[CH:24][C:25]([CH:29]=O)=[CH:26][CH:27]=2)[N:22](COCC[Si](C)(C)C)[N:21]=1>>[CH3:41][N:13]([CH3:12])[CH2:14][CH2:15][N:16]([CH3:40])[C:17](=[O:39])[CH:18]=[CH:19][C:20]1[C:28]2[C:23](=[CH:24][C:25](/[CH:29]=[C:5]3/[C:6](=[O:11])[NH:7][C:8]4[C:4]/3=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=4)=[CH:26][CH:27]=2)[NH:22][N:21]=1
Reactant: CN(C)CCN(C)C(=O)/C=C/c1nn(COCC[Si](C)(C)C)c2cc(C=O)ccc12
Reactant: Cc1ccc2c(c1)CC(=O)N2
Product: Cc1ccc2c(c1)/C(=C\c1ccc3c(C=CC(=O)N(C)CCN(C)C)n[nH]c3c1)C(=O)N2

Procedure:
The title compound was synthesized according to the method described in Example A57 from 5-methylindolin-2-one (8.0 mg, 0.0535 mmol) and (E)-N-(2-(dimethylamino)ethyl)-3-(6-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-N-methylacrylamide (23 mg, 0.0535 mmol) with a modified purification procedure. The product was extracted into EtOAc after the final deprotection step and washed with NaHCO3(sat) (2×), brine (2×) and the organic layer dried over MgSO4. After removal of solvent the resulting film was titurated with Et2O/hexanes to give after drying 9.4 mg, 41% yield of a yellow solid which was a 77:23 mixture of (E)/(Z) isomers. 1H NMR (400 MHz, CD3OD) δ 8.94, 7.91 (s, 1H), 8.20, 8.16 (d, J=8.7 Hz, 1H), 7.98-7.93 (m, 1H), 7.84 (s, 1H), 7.59, 7.43 (d, J=8.2 Hz, 1H), 7.52-7.42 (m, 2H), 7.08 (d, J=7.2 Hz, 1H), 6.82, 6.78 (d, J=7.6 Hz, 1H), 3.77-3.68 (m, 2H), 3.60, 3.13 (s, 3H), 2.68-2.61 (m, 2H), 2.37 (s, 6H), 2.19 (s, 3H); MS ESI 430.3 [M+H]+, calcd for [C25H27N5O2+H]+ 430.22.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[N:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)[N:3]=1.O.[NH2:30][NH2:31]>O1CCOCC1.O>[Cl:16][C:13]1[N:12]=[CH:11][C:10]([CH2:9][NH:8][C:6]2[N:5]=[C:4]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=3)[N:3]=[C:2]([NH:30][NH2:31])[N:7]=2)=[CH:15][CH:14]=1
Reactant: Fc1ccc(Nc2nc(Cl)nc(NCc3ccc(Cl)nc3)n2)cc1C(F)(F)F
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: NNc1nc(NCc2ccc(Cl)nc2)nc(Nc2ccc(F)c(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of 6-Chloro-N-(6-chloropyridin-3-ylmethyl)-N′-(4-fluoro-3-trifluoromethylphenyl)-[1,3,5]triazine-2,4-diamine (XVIII) (3.0 g, 6.9 mmol) in dioxane (30 mL) was added hydrazine hydrate (2 mL), and the mixture stirred at ambient temperature for 30 min. The mixture was diluted with water, the resulting slurry stirred for 10 min and filtered under vacuum to give a white solid. This solid was washed with water and dried under vacuum to give N-(6-chloro-pyridin-3-ylmethyl)-N′-(4-fluoro-3-trifluoromethylphenyl)-6-hydrazino-1,3,5-triazine-2,4-diamine (XIX) (2.89 g, 97% yield): 1H NMR (CDCl3); δ 9.40 (m, 1H), 8.5-7.5 (m, 4H), 7.45 (m, 2H), 7.33 (m, 2H), 4.49, m, 2H), 4.17 (bs, 2H); ESI/MS 429 (M+H), 427 (M−H).
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C:8]([NH2:10])=[O:9])=[CH:5][CH:4]=[C:3]([OH:11])[CH:2]=1.C1(C)C=CC(S(O[CH2:22][C@H:23]2[O:25][CH2:24]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:11][CH2:22][CH:23]2[O:25][CH2:24]2)=[CH:2][CH:1]=1)(=[O:9])[NH2:10]
Reactant: NC(=O)Cc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: NC(=O)Cc1ccc(OCC2CO2)cc1
Reaction time: 30 h

Procedure:
p-Hydroxyphenylacetamide (1 g) and (S)-glycidyl p-toluenesulfonate (1.51 g, 99.3% e.e.) were dissolved in acetone (30 ml). Potassium carbonate (1.19 g) was added to the solution and the solution was stirred for 30 hours under refluxing. After the reaction, inorganic materials were filtered off and acetone was removed to give 1.43 g of crude (S)-1-[p-(carbamoylmethyl)phenoxy-2,3-epoxypropane. The optical purity of it was 62.8% e.e. by measurement of Chiral column OD (Daisel Chemical industries Ltd.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15](Br)=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])#[CH:20].C(NC(C)C)(C)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([C:20]#[C:19][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cnc2c(OCc3ccccc3)cccn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#Cc1cnc2c(OCc3ccccc3)cccn12
Temperature: 25 °C
Yield: 63.7 %

Procedure:
A mixture of 8-(benzyloxy)-3-bromoimidazo[1,2-a]pyridine (10.0 g, 33.0 mmol), 9.39 mL (66.0 mmol) of ethynyltrimethylsilane, 0.580 g (0.825 mmol) of Pd(PPh3)2Cl2, 0.230 g (1.19 mmol) of Cul, and 5.09 mL (36.3 mmol) of diisopropylamine in 100 mL of acetonitrile was heated at reflux for 3 h under an atmosphere of N2. Upon cooling to ambient temperature, the reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 20-50% EtOAc/hexanes) to provide 6.74 g of product: 321 m/z (M+H).
Reaction SMILES: O.[CH2:2]([N:9]1[C@H:13]2[CH2:14][S:15]/[C:16](=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])/[C@H:12]2[N:11]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:10]1=[O:33])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H]>[OH-].[OH-].[Pd+2].CO>[CH2:2]([N:9]1[C@H:13]2[CH2:14][S:15][C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C@H:12]2[N:11]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:10]1=[O:33])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCC/C=C1\SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCC[C@@H]1SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 117 °C
Reaction time: 4 h
Yield: 72.4 %

Procedure:
400 ml of purified water, 12.85 g of 20% palladium hydroxide on carbon (50% wet), 900 ml of a methanol solution containing 249.5 g of ethyl (5Z)-5-[(3aS,6aR)-1,3-dibenzyl-hexahydro-2-oxo-4H-thieno[3,4-d]imidazol-4-yliden]pentanoate were added successively in this order, and the atmosphere was replaced with 490 kPa hydrogen three times. Moreover, 627 kPa hydrogen pressure was applied at 6.5° C., and the mixture was stirred at 500 rpm. The reaction temperature and the pressure became 92.5° C. and 843 kPa at 50 minutes after initiation of heating, 117° C. and 921 kPa after 4 hours, and 116° C. and 853 kPa after 11 hours, so that hydrogen was charged up to 882 kPa. After 24 hours, the reaction mixture was cooled at 115° C. and 892 kPa, washed with methanol, and the catalyst was filtered off. The filtrate was concentrated, 400 ml of toluene was added to the residue, and replacement and concentration were carried out three times with an outer bath at 65° C. To the above-mentioned residue were added 1206 ml of methanol, 402 ml of water and 53.3 g of sodium hydroxide, the resulting mixture was stirred at 40° C. for 2 hours. To the reaction mixture was added 300 g of 10% aqueous hydrochloric acid, the mixture was neutralized to pH 7, 6 g of activated charcoal was added to the mixture and the resulting mixture was stirred at room temperature for 40 minutes. The reaction mixture was subjected to precoat filtration with 6 g of activated charcoal. Methanol was distilled of under reduced pressure, and 600 ml of ethyl acetate was added. 10% aqueous hydrochloric acid was added to the mixture to carry out extraction (pH of the aqueous layer was 0.7), and the organic layer was washed with 10% brine. The organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and when no ethyl acetate was distilled off, the residue was subjected to replacement with 170 ml of mesitylene and concentration two times to give 170.1 g of (3aS,4S,6aR)-1,3-dibenzyl-hexahydro-2-oxo-4H-thieno[3,4-d]imidazol-4-pentanoic acid as colorless oily product.