Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18](OC)=[O:19].[CH3:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=1>>[OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18]([NH:29][C:25]1[CH:24]=[C:23]([CH3:22])[CH:28]=[CH:27][N:26]=1)=[O:19]
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Reactant: Cc1ccnc(N)c1
Product: Cc1ccnc(NC(=O)C2=C(O)c3sc4ccccc4c3S(=O)(=O)N2C)c1
Yield: 31 %

Procedure:
Prepared analogous to Example 1 from methyl 4-hydroxy-2-methyl-2H-[1]benzothieno[2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 4-methyl-2-amino-pyridine with a yield of 31% of theory.
Reaction SMILES: [C:1]1([CH:13]2[CH2:18][CH2:17][CH2:16][N:15](C(OCC3C=CC=CC=3)=O)[CH2:14]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2>C(O)C.[C].[Pd]>[NH:15]1[CH2:16][CH2:17][CH2:18][CH:13]([C:1]2[N:2]=[N:3][N:4]3[C:9]=2[C:8]2[CH:10]=[CH:11][NH:12][C:7]=2[N:6]=[CH:5]3)[CH2:14]1
Reactant: O=C(OCc1ccccc1)N1CCCC(c2nnn3cnc4[nH]ccc4c23)C1
Agent: [Pd]
Solvent: CCO
Product: c1cc2c(ncn3nnc(C4CCCNC4)c23)[nH]1
Yield: 100.1 %

Procedure:
Benzyl 3-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidine-1-carboxylate (25.0 mg, 0.0664 mmol) in ethanol was stirred with 5% palladium-carbon (10 mg) under a hydrogen atmosphere at 50° C. for 2.5 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a light brown solid (16.1 mg, yield quantitative).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][C@H:18]3[CH3:24])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[O:25]1[CH2:28]C(=O)[CH2:26]1.[BH3-]C#N.[Na+].O>CO.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:28][O:25][CH2:26]4)[CH2:19][C@H:18]3[CH3:24])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: C[C@@H]1CN(C)CCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Reactant: O=C1COC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
A mixture of 115e (40.0 g, 106 mmol), oxetan-3-one (11.4 g, 159 mmol), NaBH3CN (10.0 g, 159 mmol), and zinc chloride (21.3 g, 159 mmol) in methanol (700 mL) was stirred at 50° C. for 5 hours. water (50 mL) was added to the mixture and concentrated under reduced pressure. The residue was extracted with dichloromethane (3×200 mL) and the combined organic layer was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 40:1 dichloromethane/methanol to afford 115f (35 g, 73%). MS: [M+H]+ 434.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:32]=[CH:31][C:9]3[C:10]4[C:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)=[CH:13][N:12]([C:18]2[N:19]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.[CH3:33][C:34]1([CH3:37])[CH2:36][O:35]1>>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[N:19]1[C:18]([N:12]2[N:11]=[C:10]3[C:14]([CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([CH:4]5[CH2:3][N:2]([CH2:33][C:34]([CH3:37])([OH:35])[CH3:36])[CH2:5]5)[CH:32]=[CH:31][C:9]=43)=[CH:13]2)=[N:22][CH:21]=[N:20]1
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2ccc(C4CNC4)cc2OCC3)c(F)c1
Reactant: CC1(C)CO1
Agent: Cl
Product: CC(C)(O)CN1CC(c2ccc3c(c2)OCCc2cn(-c4ncnn4-c4ccc(F)cc4F)nc2-3)C1

Procedure:
Following the procedure for 177, 8-azetidin-3-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride was reacted with 2,2-dimethyl-oxirane to give 183 as a white solid. 1H NMR (400 MHz, DMSO-d): δ 8.45 (s, 1 H); 8.31 (s, 1 H); 8.17 (s, 1 H); 7.84 (td, J=8.75, 5.92 Hz, 1 H); 7.66 (ddd, J=10.33, 9.02, 2.79 Hz, 1 H); 7.40-7.34 (m, 1 H); 7.31 (d, J=8.17 Hz, 1 H); 7.00 (d, J=1.69 Hz, 1 H); 6.93 (dd, J=8.25, 1.78 Hz, 1 H); 4.26 (t, J=5.06 Hz, 2 H); 3.79 (t, J=7.52 Hz, 2 H); 3.64 (t, J=7.75 Hz, 1 H); 3.35 (t, 2 H); 3.08 (t, J=5.05 Hz, 2 H); 2.35 (t, 2 H); 1.10 (s, 6 H). LCMS: RT=7.45 min, M+H+=493
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21](OCC)=[O:22])[N:9]=1.[CH3:26][O:27][CH2:28][CH2:29][NH2:30]>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21]([NH:30][CH2:29][CH2:28][O:27][CH3:26])=[O:22])[N:9]=1
Reactant: COCCN
Reactant: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Product: COCCNC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.0 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) are dissolved in 30 ml of 2-methoxyethylamine and the mixture is stirred at room temperature for 2 h. It is concentrated to dryness in vacuo and the residue is crystallized from isopropanol. After drying, 2-[3,5-Bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-(2-methoxyethyl)acetamide remains as colorless crystals of m.p. 184-186° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]([CH3:24])[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:11]2[C:16]=1[CH:15]=[CH:14][C:13]([Cl:17])=[CH:12]2)=[O:7].[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O>[N:25]([CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]([CH3:24])[C:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:11]2[C:16]=1[CH:15]=[CH:14][C:13]([Cl:17])=[CH:12]2)=[O:7])=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1c(C(=O)NCCCCl)c2ccc(Cl)cc2c1-c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(=O)NCCCN=[N+]=[N-])c2ccc(Cl)cc2c1-c1ccccc1
Temperature: 0 °C

Procedure:
A suspension of 14.4 g. of 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid (3-chloropropyl)amide in 80 ml. of dimethylformamide is treated with 5.2 g. of sodium azide and the mixture is stirred at 60° C. for 4 hours. The mixture is cooled and poured on to 500 ml. of ice-water. The separated product is removed by filtration under suction, washed with water and dissolved in methylene chloride. The organic solution is washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The solid residue is triturated with a small amount of ether and filtered, whereby there is obtained 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid (3-azidopropyl)amide having a melting point of 143°-146° C. (decomposition) which can be used in the process without further purification. An analytical sample is obtained by recrystallization from methanol and has a melting point of 148°-150° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:11][O:12][CH2:13][O:14][CH3:15])[C:6]=1[S:7]([NH2:10])(=[O:9])=[O:8].CS[C:18](SC)=[C:19]1[C:28](=[O:29])[C@@:27]([CH2:31][CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:30])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:37]>C1(C)C=CC=CC=1>[CH3:34][C:33]([CH3:36])([CH3:35])[CH2:32][CH2:31][C@:27]1([CH3:30])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([OH:37])=[C:19]([C:18]2[NH:1][C:2]3[S:3][CH:4]=[C:5]([CH2:11][O:12][CH2:13][O:14][CH3:15])[C:6]=3[S:7](=[O:8])(=[O:9])[N:10]=2)[C:28]1=[O:29]
Reactant: COCOCc1csc(N)c1S(N)(=O)=O
Reactant: CSC(SC)=C1C(=O)c2ccccc2[C@@](C)(CCC(C)(C)C)C1=O
Solvent: Cc1ccccc1
Product: COCOCc1csc2c1S(=O)(=O)N=C(C1=C(O)c3ccccc3[C@@](C)(CCC(C)(C)C)C1=O)N2
Yield: 84.7 %

Procedure:
A solution of the product of Example 10E (2.02 g, 7.9 mmol) and the product of Example 49E (2.49 g, 6.9 mmol) in 200 mL of toluene was warmed to reflux for 5 h, cooled, and concentrated in vacuo. The crude material was chromatographed on silica gel with methanol/dichloromethane (1:99) to afford the title compound (3.03 g, 85% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.39 (td, J=12.59, 3.13 Hz, 1 H) 0.72 (s, 9 H) 0.82 (m, 1 H) 1.57 (s, 3 H) 2.04 (m, 1 H) 2.22 (td, J=12.69, 4.41 Hz, 1 H) 3.33 (s, 3 H) 4.63 (s, 2 H) 4.71 (s, 2 H) 7.40 (s, 1 H) 7.53 (m, 1 H) 7.74 (d, J=4.04 Hz, 2 H) 8.13 (d, J=7.72 Hz, 1 H) 14.00 (s, 1 H); MS (APCI−) m/z 517 (M−H)−; Analysis calc'd for (C25H30N2O6S2): C, 57.89; H, 5.83; N, 5.40. Found: C, 57.82; H, 6.12; N, 5.05.
Reaction SMILES: [O:1]=[O+][O-].C1(C=[CH:11][C@@H:12]2[N:15]([C:16](=[O:18])[CH3:17])[C:14](=[O:19])[C@H:13]2[CH2:20][CH2:21][CH2:22][NH:23][C:24]([NH:36][C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])=[N:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])C=CC=CC=1>C(Cl)Cl>[CH:11]([C@@H:12]1[N:15]([C:16](=[O:18])[CH3:17])[C:14](=[O:19])[C@H:13]1[CH2:20][CH2:21][CH2:22][NH:23][C:24]([NH:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])=[N:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:1]
Reactant: CC(=O)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C=Cc1ccccc1
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: CC(=O)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 38 %

Procedure:
Ozone was passed through a -78° C. methylene chloride solution of compound 27 (0.7 g, 1.2 mmol) until a blue color was maintained. Excess ozone was removed by purging the solution with N2. Dimethyl sulfide (1 mL) was added. The solution was warmed to room temperature, allowed to stand for 72 h, and concentrated. The residue was purified by silica gel chromatography (EtOAc:Et2O/1:3) to afford 230 mg (38%) of the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[CH3:12][C:13]1[CH:20]=[C:19]2[O:21][CH2:22][O:23][C:18]2=[CH:17][C:14]=1[CH:15]=[O:16]>>[CH3:12][C:13]1[CH:20]=[C:19]2[O:21][CH2:22][O:23][C:18]2=[CH:17][C:14]=1[CH:15]([C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][C:6]=1[C:8]([F:9])([F:10])[F:11])[OH:16]
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: Cc1cc2c(cc1C=O)OCO2
Product: Cc1cc2c(cc1C(O)c1c(C(F)(F)F)ccnc1Cl)OCO2
Yield: 74.1 %

Procedure:
Using 1.5 g (8.3 mmol) of 2-chloro-4-trifluoromethylpyridine and 1.4 g (8.2 mmol) of 2-methyl-4,5-(methylenedioxy)benzaldehyde, 2.1 g (yield 73%) of (2-methyl-4,5-(methylenedioxy)phenyl)(2-chloro-4-trifluoromethyl-3-pyridyl)methanol (m.p. 127-130° C.) was obtained by a process in accordance with step (a) of Synthesis Example 1.
Reaction SMILES: C1([CH:7]([SeH])[CH2:8][O:9][CH2:10][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])C=CC=CC=1.C(=O)(O)[O-].[Na+].I([O-])(=O)(=O)=O.[Na+].C(NC(C)C)(C)C>O1CCOCC1CO.O.C(Cl)Cl.C1C=CC=CC=1>[CH:8]([O:9][CH2:10][P:11]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:18])=[CH2:7]
Reactant: CCOP(=O)(COCC([SeH])c1ccccc1)OCC
Agent: O=C([O-])O
Agent: OCC1COCCO1
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CC(C)NC(C)C
Product: C=COCP(=O)(OCC)OCC
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a solution of 28 (30 g, 0.081 mol) in dioxane-methanol-water (6:2:1, 600 ml) was added sodium bicarbonate (34 g, 0.4 mol) followed by sodium periodate (51 g, 0.24 mol). After stirring for 30 minutes, the mixture was filtered. The filtrate was condensed to ca 100 ml volume diluted with CH2Cl2 (500 ml) and washed with brine. Evaporation of dried (MgSO4) solvent gave a colorless oil which was dissolved in benzene (200 ml). Diisopropylamine (30 g, 0.3 mol) was added and the solution was heated at 90° C. for 30 minutes. All volatiles were removed in vacuo and the residual oil was chromatographed on silica gel using CH2Cl2 -MeOH (3%) as eluent to give 18 (15.3 g, 95%) as a colorless oil. 1H-NMR (300 MHz CDCl3) δ 1.25 (T, J=7.2Hz, 6H), 3.86 (d, J=9 6Hz, 2H), 4.01-4.15 (m, 5H), 4.20 (dd, J=3.6, 14.7Hz, 1H), 6.42 (dd, J=6.6, 14.7Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([OH:8])[CH2:5][O:6][CH3:7].[H-].[Na+].Br.Cl[C:13]1[CH:14]=[C:15]([CH3:23])[C:16]2[N:17]([C:19]([NH2:22])=[N:20][N:21]=2)[N:18]=1.O>CN(C=O)C>[CH3:1][O:2][CH2:3][CH:4]([CH2:5][O:6][CH3:7])[O:8][C:13]1[CH:14]=[C:15]([CH3:23])[C:16]2[N:17]([C:19]([NH2:22])=[N:20][N:21]=2)[N:18]=1
Reactant: Cc1cc(Cl)nn2c(N)nnc12
Reactant: COCC(O)COC
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC(COC)Oc1cc(C)c2nnc(N)n2n1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
1,3-Dimethoxypropan-2-ol (12.96 ml) was initially charged in DMF (25 ml), admixed under argon with sodium hydride (681 mg) and stirred at 40° C. for 1 h. Subsequently, 6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.002; 1.5 g), dissolved in DMF (25 ml), was added dropwise within 20 min. After 1 h, the mixture was admixed with water and extracted by shaking four times with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated by rotary evaporation. The residue was triturated with MtB ether, filtered off with suction and dried. 764 mg of the title compound were isolated. LC-MS rt: 0.74 min [M+H]+: 268.1 (met. a)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([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:4][CH:3]=1.[CH:25]([C:27]1[C:28]([C:33](Cl)=[O:34])=[N:29][CH:30]=[CH:31][CH:32]=1)=[CH2:26].NC1C=CC(N2C(=O)CC(=O)NC3C(CC)=CC=CC2=3)=CC=1>>[CH:25]([C:27]1[C:28]([C:33]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:34])=[N:29][CH:30]=[CH:31][CH:32]=1)=[CH2:26]
Reactant: C=Cc1cccnc1C(=O)Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: CCc1cccc2c1NC(=O)CC(=O)N2c1ccc(N)cc1
Product: C=Cc1cccnc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 35 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 3-vinylpicolinic acid chloride, the title compound (yield 35%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[C:46]([NH2:47])=[CH:45][C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][N:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[NH2:47][C:46]1[CH:45]=[C:44]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:43]=[N:42][C:41]=1[O:40][CH3:39]
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ncc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)cc1N
Yield: 42.9 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (200 mg, 0.34 mmol) was treated with 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (202 mg, 0.81 mmol), sodium carbonate (86 mg, 0.81 mmols) and bis(triphenylphosphine)palladium(II) dichloride (31 mg, 0.04 mmol) in 1,2-dimethoxyethane (3.6 ml) and water (0.40 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 30%, hexane-ethyl acetate) to give 93 mg (40% yield) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:5](=[O:12])[CH2:4][S:3]1.[Br:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([CH:28]=O)=[CH:25][CH:26]=3)[CH:21]=[N:20]2)=[C:16]([C:32]([F:35])([F:34])[F:33])[CH:15]=1>>[Br:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24](/[CH:28]=[C:4]4/[C:5](=[O:12])[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:2](=[O:1])[S:3]/4)=[CH:25][CH:26]=3)[CH:21]=[N:20]2)=[C:16]([C:32]([F:33])([F:35])[F:34])[CH:15]=1
Reactant: CS(=O)(=O)NN1C(=O)CSC1=O
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Br)cc2C(F)(F)F)c1
Product: CS(=O)(=O)NN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Br)cc3C(F)(F)F)c2)C1=O

Procedure:
N-[(5Z)-5-({1-[4-Bromo-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methanesulfonamide was prepared from N-(2,4-dioxothiazolidin-3-yl)methanesulfonamide (from Example 360) and [4-bromo-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde following General Procedure E.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:29][CH2:30]C)[CH2:5][N:6]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]2[O:24][CH2:25][O:26][C:20]=2[C:19]=1[O:27][CH3:28])S(C1C=CC(C)=CC=1)(=O)=O)C.Cl.[CH2:33](O)C>[Pd]>[CH3:30][O:29][CH:4]([O:3][CH3:1])[CH2:5][N:6]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]2[O:24][CH2:25][O:26][C:20]=2[C:19]=1[O:27][CH3:28])[CH3:33]
Reactant: CCOC(CN(Cc1ccc2c(c1OC)OCO2)S(=O)(=O)c1ccc(C)cc1)OCC
Reactant: CCO
Agent: [Pd]
Agent: Cl
Product: COc1c(CN(C)CC(OC)OC)ccc2c1OCO2
Yield: 56 %

Procedure:
7.81 g (40 mmol) of 2-methoxy-3,4-methylenedioxybenzaldoxime (2) thus obtained, 3.67 ml (44 mmol) of concentrated hydrochloric acid and 500 mg of 5% palladium on carbon catalyst were added to 80 ml of ethanol to carry out hydrogenation at room temperature for 4 hours and 45 minutes. The catalyst was filtered out, the filtrate was concentrated and the residue is recrystallized from 60 ml of ethanol to obtain 4.86 g of 2-methoxy-3,4-methylenedioxybenzylamine hydrochloride (3). Yield 56%, m.p. 208°-210° C. IR and NMR spectra of the resultant product are listed below. ##STR29##
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:12][CH2:11][N:10]2[C:13](=[O:24])[C:14]3[C:19]4[CH2:20][CH2:21][CH2:22][CH2:23][C:18]=4[S:17][C:15]=3[N:16]=[C:9]2[CH2:8][CH2:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:3][CH2:4][CH:6]1[CH2:12][CH2:11][N:10]2[C:13](=[O:24])[C:14]3[C:19]4[CH2:20][CH2:21][CH2:22][CH2:23][C:18]=4[S:17][C:15]=3[N:16]=[C:9]2[CH2:8][CH2:7]1
Reactant: CCOC(=O)C1CCc2nc3sc4c(c3c(=O)n2CC1)CCCC4
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1c2c3c(sc2nc2n1CCC(CO)CC2)CCCC3
Reaction time: 0.33 h

Procedure:
Compound 16 (0.72 mmol) in dry THF (6 ml) was added dropwise to LiAlH4 (1.95 mmol) in THF (2 ml) under argon at 0° C. The reaction mixture was stirred for 20 minutes. The reaction was quenched with water and 10% NaOH was added, and extracted with ether. The organic layer was washed with brine and dried over Na2SO4. After filtration the solvent was evaporated and the product purified by flash chromatography using EtOAc as an eluent.
Reaction SMILES: [C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[OH:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:32]1([CH2:38][CH2:39]O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C(O)C>[C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:25][CH2:39][CH2:38][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8][CH2:39][CH2:38][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCN1CCCCC1
Reactant: OB(c1ccccc1)C(OC(B(O)c1ccccc1)c1ccccc1)c1ccccc1
Solvent: CCO
Product: c1ccc(B(OCCN2CCCCC2)C(OC(B(OCCN2CCCCC2)c2ccccc2)c2ccccc2)c2ccccc2)cc1

Procedure:
The entitled compound (22 mg) was obtained by allowing 41 mg of bis(4,4′-(phenylhydroxyboryl)benzyl) ether and 13 mg of 1-piperidineethanol to act in 1 mL of ethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.C([Li])CCC.[C:21](OCC)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>C1COCC1>[O:28]=[C:21]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:3]=1
Reactant: CCOC(=O)c1ccncc1
Reactant: Cc1ccnc(NC(=O)OC(C)(C)C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(CC(=O)c2ccncc2)ccn1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 50 %

Procedure:
Tert-butyl 4-methyl-2-pyridinylcarbamate (Ihle, N. C.; Krause, A. E.; J. Org. Chem., 1996, 61(14):4810-4811; 10 g, 48.0 mmol) was dissolved in 100 mL THF and cooled to −78° C. under argon and was treated with n-butyllithium (2.5-M in hexanes, 48.0 mL, 120 mmol) such that the internal temperature did not exceed −50° C. The reaction was warmed to 20° C. for 20 min. then was recooled to −78° C. and ethyl isonicotinate (10.79 mL, 72.0 mmol) was added neat and the reaction again was warmed to 20° C. and stirred 45 minutes. The reaction was quenched with sat. NaHCO3 and extracted with ethyl acetate. The organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give a red-orange oil which was purified by silica gel chromatography, eluting from 50% ethyl acetate in hexanes to 100% ethyl acetate to afford 7.56 g (50%) of the titled compound as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:20])[C:7]([CH3:19])=[C:8]([C:17]#[N:18])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)(=[O:3])[CH3:2].[OH-:21].[K+].Cl>C(O)C>[C:1]([C:4]1[CH:5]=[C:6]([Cl:20])[C:7]([CH3:19])=[C:8]([C:17]([NH2:18])=[O:21])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(=O)c1cc(Cl)c(C)c(C#N)c1-c1cccc(F)c1
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CC(=O)c1cc(Cl)c(C)c(C(N)=O)c1-c1cccc(F)c1

Procedure:
A mixture of 6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-carbonitrile (0.87 g, 3.0 mmol) and potassium hydroxide (0.34 g, 6.1 mmol) in ethanol (4 mL) was refluxed for 2 hours. The mixture was cooled, acidified with 1 N HCl, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated to dryness under reduced pressure to yield the crude product. LCMS calculated for C16H14ClFNO2 (M+H)+: m/z=306.1. found: 306.0.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[C:17]1([C:23]2[O:27][C:26]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:25][N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]([N:31]2[CH2:30][CH2:29][CH:28]([C:26]3[O:27][C:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:24][N:25]=3)[CH2:33][CH2:32]2)=[O:16])[O:4][N:3]=1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Reactant: c1ccc(-c2nnc(C3CCNCC3)o2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: Cc1noc(NC(=O)N2CCC(c3nnc(-c4ccccc4)o3)CC2)c1C
Yield: 37.9 %

Procedure:
A solution of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (293 mg, 1.02 mmol), 4-(5-phenyl-1,3,4-oxadiazol-2-yl)piperidine (234 mg, 1.02 mmol), diisopropylethylamine (0.387 ml, 2.05 mmol) and dimethyl sulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 142 mg (37.9%) of the desired product as a solid.