Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11](O)[CH3:12].[CH:14]1([NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])(=[O:20])=[O:19])[CH2:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH:14]1([N:17]([CH:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH3:12])[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])(=[O:20])=[O:19])[CH2:16][CH2:15]1
Reactant: CC(O)c1ccc2ccccc2c1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1ccc2ccccc2c1)N(C1CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of 1-(2-naphthyl)ethanol (344 mg), N-cyclopropyl-2-nitrobenzenesulfonamide (581 mg) and triphenylphosphine (787 mg) in tetrahydrofuran (10 mL) was added dropwise diisopropyl azodicarboxylate (590 μL) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1→1/1), and then triturated with diethyl ether-n-hexane (1:1) to give N-cyclopropyl-N-[1-(2-naphthyl)ethyl]-2-nitrobenzenesulfonamide j[REx(1-1)] (499 mg) as a colorless powder.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[CH2:15](Br)[CH2:16][CH3:17].[H-].[Na+]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:15][CH2:16][CH3:17])[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: CCCBr
Reactant: Ic1ccc(Nc2ncccn2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCN(c1ccc(I)cc1)c1ncccn1

Procedure:
In the same manner as in Reference Example 13, N-(4-iodophenyl)pyrimidin-2-amine (300 mg) and propyl bromide (0.11 ml) were reacted in the presence of sodium hydride to obtain N-(4-iodophenyl)-N-propylpyrimidin-2-amine (348 mg).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[C:18]1([CH2:17][O:9][C:5]2[CH:6]=[C:7]([F:8])[C:2]([Br:1])=[CH:3][C:4]=2[F:10])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1cc(F)c(Br)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1cc(OCc2ccccc2)c(F)cc1Br

Procedure:
4-bromo-2,5-difluorophenol (2 g, 9.57 mmol) was dissolved in DMF (19 mL) and to this was added Cs2CO3 (4.37 g, 13.34 mmol) and the solution was stirred for 15 minutes before benzyl bromide (1.64 g, 9.57 mmol) was added. After 1 hour at room temperature the mixture was partitioned between ethyl acetate (100 mL)/water (100 mL), the layers were separated and the aqueous extracted with ethyl acetate. The combined organics were washed with saturated NH4Cl (100 mL), water (100 mL) and brine (2×100 mL) and dried over MgSO4. The crude material (2.74 g) was filtered through a pad of silica and eluted with 20% Et2O in hexane to afford 4-bromo-2,5-difluorophenyl phenylmethyl ether after evaporation of the solvent (2.51 g, 88%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]3[NH:14][C:13]4[CH2:18][CH2:19][N:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][C:12]=4[C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>CN(C)C=O>[C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]3[N:14]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:13]4[CH2:18][CH2:19][N:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][C:12]=4[C:11]=3[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)N1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCc2c(c3cc(OCc4ccccc4)ccc3n2Cc2ccccc2)C1
Temperature: 10 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
A mixture of intermediate (1) (0.09 mol) in N,N-dimethylformamide (200 ml) was stirred at 10° C. under a N2 flow. Sodium hydride (60%; 0.1 mol) was added portionwise. The mixture was stirred for 1 hour at room temperature, then it was cooled to 5° C. Benzylbromide (0.1 mol) was added dropwise. Stirring was continued for 2 hours. The mixture was cooled to 10° C. and poured out into cold water (500 ml). This mixture was extracted with CH2Cl2 (2×250 ml). The separated organic layer was washed with water (100 ml), dried, filtered and the solvent was evaporated. The solid residue was washed with CH3CN (50 ml), cooled and the resulting precipitate was filtered off and dried, yielding 30.0 g (76%) of ethyl 1,3,4,5-tetrahydro-8-(phenylmethoxy)-5-(phenyl-methyl)-2H-pyrido[4,3-b]indole-2-carboxylate (intermediate 2).
Reaction SMILES: C(O)(=O)C.[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([O:14]CC(Cl)(Cl)Cl)=[O:13])[N:9]2[C:20](=[O:28])[CH:21]([NH:22][C:23](=[O:27])[CH2:24][C:25]#[N:26])[C@H:8]2[S:7]1.C(OCC)(=O)C>CN(C)C=O.[Zn]>[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[N:9]2[C:20](=[O:28])[CH:21]([NH:22][C:23](=[O:27])[CH2:24][C:25]#[N:26])[C@H:8]2[S:7]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)CC#N)[C@H]2S1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)CC#N)[C@H]2S1
Yield: 105.4 %

Procedure:
Acetic acid (4 ml) and zinc powder (3 g) were added under stirring and ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-(2-cyanoacetamido)-3-cephem-4-carboxylate (3.2 g) in anhydrous dimethylformamide (15 ml), and the mixture was stirred for 1 hour at the same temperature. After the reaction, ethyl acetate (100 ml) was added to the reaction mixture. The insoluble material was filtered off, and the filtrate was washed with 5% hydrochloric acid saturated with sodium chloride, and then extracted with a saturated sodium bicarbonate aqueous solution. The extract was acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. After the solvent was distilled off, the crystalline residue was recrystallized from a mixture of ethyl acetate and benzene to give 2-methyl-7-(2-cyanoacetamido)-3-cephem-4-carboxylic acid (2.3 g), mp 162° to 166° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.C(O)(C(F)(F)F)=O>O1CCCC1.[Ru]>[F:14][C:2]([F:1])([F:13])[CH:3]1[CH2:12][CH2:11][CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[NH:4]1
Reactant: FC(F)(F)c1ccc2ccccc2n1
Agent: [Ru]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: FC(F)(F)C1CCC2CCCCC2N1

Procedure:
15 g (0.076 mol) of 2-(Trifluoromethyl)quinoline [prepared from quinoline-2-carboxylic acid according to M. S. Raasch, J. Org. Chem. 27, 1406 (1962)] were hydrogenated in 100 ml of tetrahydrofuran on 2.5 g of ruthenium on alumina (about 10% RU content) at 180° C. for 8 h at an H2 pressure of 80-100 bar in a 0.3 1 V4A autoclave. After filtration, the THF was stripped off and the crude product was fractionated in a water pump vacuum by means of a microdistillation apparatus. B.p.16 (main fraction): 88° C. Yield: 12.5 g (0.061 mol) (80% of theory) The product was obtained as a diastereomer mixture. 19F--NMR: δ=+0.65 ppm(d, JH-F =7.1 Hz)(according to integral about 88%) 19F--NMR: δ=+0.90 ppm(d, JH-F =7.1 Hz)(according to integral about 12%) (against external CF3COOH).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:40][O:41][C:42](Cl)=[O:43]>O1CCCC1.[Cl-].[Na+].O>[CH3:40][O:41][C:42]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([O:19][CH:20]3[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]3)=[CH:14][CH:13]=2)[CH:18]=[C:10]1[C:8]([N:5]1[CH2:6][CH2:7][C:2]([F:1])([F:29])[CH2:3][CH2:4]1)=[O:9])=[O:43]
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: COC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(OC3CCN(C(C)C)CC3)ccc21
Yield: 15.7 %

Procedure:
A solution of (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1, 100 mg, 1.0 eq.), lithium bis-(trimethylsilyl)amide (1M solution in tetrahydrofuran, 271 ul, 1.1 eq.) and methylchloroformate (26 mg, 1.1 eq.) in tetrahydrofuran (2 mL) was stirred at room temperature for 48 h, then poured into brine, extracted with dichloromethane, dried over sodium sulfate, filtered, evaporated to dryness and purified on silica gel, eluting with a 98:2 to 97:3 gradient of dichloromethane/methanol, to yield 18 mg (15%) of the desired product as yellow oil. MS (m/e): 464.2 (MH+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:24]=[N:23][C:22]([NH:25][NH:26]C(=O)CC2CCOCC2)=[CH:21][C:20]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:26][NH:25][C:22]2[N:23]=[N:24][C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[Cl:12])=[C:20]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)[CH:21]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: O=C(CC1CCOCC1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1
Product: O=C(Cc1ccc(Cl)cc1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1
Yield: 62 %

Procedure:
The title compound (90 mg, 62%) as a white solid was prepared from 2-(4-chlorophenyl)acetic acid (62 mg, 0.36 mmol) and 1-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3)hydrazine (99 mg, 0.3 mmol) according to the procedures described for N′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)acetohydrazide (Example 9A). HPLC/MS (method A): retention time=3.57 min, (M+H)+=483.2.
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([NH:8][C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C@H:2]1[C@@H:7]([NH:8][C:9](=[O:10])[O:11][CH3:12])[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: COC(=O)N[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N[C@H]1CCNC[C@H]1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 140 %

Procedure:
(3R,4S)-tert-butyl 3-fluoro-4-((methoxycarbonyl)amino)piperidine-1-carboxylate (127 mg, 0.460 mmol) was taken up in DCM (5 mL) and TFA (0.708 mL, 9.19 mmol) was added. The reaction was stirred at rt for 1 h. The solvent was removed in vacuo and the material was dissolved in MeOH. The solution was loaded onto an SCX column (5 g, benzenesulfonic acid sorbent) and the column was rinsed with MeOH, followed by 7N NH3/MeOH to obtain the product. The solvent was removed in vacuo to obtain methyl ((3R,4S)-3-fluoropiperidin-4-yl)carbamate (113.5 mg) as a colorless gum. The crude material was taken onto the next step without further purification.
Reaction SMILES: [NH:1]([C:5]1[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:27])[NH:10]2)[C:2]([CH3:4])=[O:3].[OH:28]O>>[NH:1]([C:5]1[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:28])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:27])[NH:10]2)[C:2]([CH3:4])=[O:3]
Reactant: OO
Reactant: CC(=O)Nc1c(OCCCCSc2ccccc2)ccc2[nH]c(=O)ccc12
Product: CC(=O)Nc1c(OCCCCS(=O)c2ccccc2)ccc2[nH]c(=O)ccc12

Procedure:
Prepared analogous to Example 123 from 5-acetamino-6-(4-phenylmercapto-butoxy)-carbostyril and hydrogen peroxide.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][C:9]=1[O:18][CH3:19].[Li+].[OH-]>O1CCOCC1.C(OCC)(=O)C>[OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[O:18][CH3:19]
Reactant: COC(=O)c1ccc(O[C@@H]2CCC[C@H]2O)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)O)ccc1O[C@@H]1CCC[C@H]1O

Procedure:
A solution of methyl 4-[(1R,2R)-2-hydroxycyclopentoxy]-3-methoxy-benzoate (2.8 g, 11 mmol) and LiOH (21 mL of 2.0 M, 42 mmol) in dioxane (20 mL) was stirred at 50° C. overnight. The mixture was diluted with ethyl acetate and was washed with water. The aqueous layer was acidified with 1N HCl and the product was extracted into ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated to give 4-((1R,2R)-2-hydroxycyclopentyloxy)-3-methoxybenzoic acid. ESI-MS m/z talc. 252.1, found 253.5 (M+1)+; Retention time: 1.07 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@H:11]3[C@:15]([C:17]#[CH:18])([OH:16])[C@H:14]([O:19]CC4C=CC(Cl)=CC=4Cl)[C@@H:13]([CH2:29][O:30]CC4C=CC(Cl)=CC=4Cl)[O:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.B(Cl)(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@H:11]3[C@:15]([C:17]#[CH:18])([OH:16])[C@H:14]([OH:19])[C@@H:13]([CH2:29][OH:30])[O:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C#C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: C#C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(Cl)ncnc21
Temperature: -78 °C
Reaction time: 5 h

Procedure:
To a cold (−78° C.) solution of (2R,3R,4R,5R)-2-(4-Chloro-pyrrolo[2,3-d]pyrimidin-7-yl)-4-(2,4-dichlorobenzyloxy)-5-(2,4-dichlorobenzyloxymethyl)-3-ethynyl-tetrahydrofuran-3-ol I-5 (150 mg, 0.24 mmol, 1 equiv.) in dry DCM (20 ml) is added 1M solution of BCl3 in DCM (2.4 ml, 2.4 mmol, 10 equiv.) drop-wise and stirred at −78° C. for about 5 h. The reaction mixture is quenched with MeOH (15 mL) at 0° C. and stirred for 30 min. Solvent is evaporated and dried together with silica gel (4 ml), the crude product on silica gel is purified by flash chromatography (DCM:methanol=90:10) to give (2R,3R,4R,5R)-2-(4-Chloro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-ethynyl-5-hydroxymethyl-tetrahydrofuran-3,4-diol I-6 as a brown foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[N:11]([CH2:19][C:20]2[O:21][CH:22]=[CH:23][N:24]=2)[C:10]=1[CH:25]([CH3:27])[CH3:26])=[O:8].[CH:32](I)([CH3:34])[CH3:33]>>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:32]([CH3:34])[CH3:33])=[CH:15][CH:16]=2)[N:11]([CH2:19][C:20]2[O:21][CH:22]=[CH:23][N:24]=2)[C:10]=1[CH:25]([CH3:27])[CH3:26])=[O:8]
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ncco1
Reactant: CC(C)I
Product: CC(C)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ncco3)c2c1

Procedure:
The title compound was prepared from N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-3-carboxamide (Compound 210) and isopropyl iodide by General Procedure N.
Reaction SMILES: [Si:1]([N:8]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:9][CH:10]=[CH2:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:16]([O:18][SiH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[CH3:17]>[Pt].C([Si](C)(C)O[Si](C=C)(C)C)=C.C1(C)C=CC=CC=1>[Si:1]([N:8]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:9][CH2:10][CH2:11][Si:19]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])[O:18][CH2:16][CH3:17])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCN(CCCC)[Si](C)(C)C(C)(C)C
Agent: [Pt]
Agent: C=C[Si](C)(C)O[Si](C)(C)C=C
Solvent: Cc1ccccc1
Product: CCCCN(CCC[Si](OCC)(OCC)OCC)[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 22.8 g (0.1 mol) of N-t-butyldimethylsilyl-N-butyl-N-allylamine and 0.07 g of a toluene solution of platinum/1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (Pt concentration 3 wt %) and heated at 50° C. Once the internal temperature became steady, 16.4 g (0.1 mol) of triethoxysilane was added dropwise over 1 hour. Stirring was continued at the temperature for a further 1 hour. The reaction solution was distilled, collecting 31.4 g of a fraction having a boiling point of 144-146° C./0.4 kPa.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH2:1][C:2]1[O:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cnc(C)o1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc(CBr)o1
Yield: 65.7 %

Procedure:
111 mg of ethyl 2-methyloxazol-5-carboxylate [see J. Heterocyclic Chem., 17, 721 (1980)] was dissolved in 5 ml of carbon tetrachloride, 133 mg of N-bromosuccinimide and 5 mg of dibenzoyl peroxide was added. The mixture was refluxed for 3 hours under the irradiation of the artificial sun light, and then the solvent was evaporated. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=3/1] to give 110 mg of ethyl 2-bromomethyloxazole-5-carboxylate as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[C:19]1([NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25].C(Cl)(Cl)Cl.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)=[N:26][C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:25]=2)=[CH:4][CH:3]=1
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: Nc1ccccc1N
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2nc3ccccc3nc2-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
In a 500 mL three-necked flask were placed 30 g (82 mmol) of 4,4′-dibromobenzil, 9.3 g (86 mmol) of 1,2-phenylenediamine, and 300 mL of chloroform, which were refluxed under nitrogen stream at 80° C. for 5 hours. After a predetermined time, the solution was cooled to room temperature, and there was added water. The aqueous layer was extracted with chloroform, and the extract and the organic layer were dried together over magnesium sulfate. After drying, the mixture was subjected to suction filtration, and the filtrate was condensed. The obtained solid was dissolved in toluene, and the solution was subjected to suction filtration through Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), and alumina. The filtrate was condensed; thus, 30 g of target white powder of 2,3-bis(4-bromophenyl)quinoxaline was obtained with a yield of 99%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:15])=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=2)[N:7]=1.[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(#N)C>[Br:16][CH2:15][C:8]1[N:6]2[N:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=[N:10][C:9]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(C(F)(F)F)nc2ccc(Cl)nn12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC#N
Product: FC(F)(F)c1nc2ccc(Cl)nn2c1CBr
Temperature: 25 °C
Yield: 35 %

Procedure:
A mixture of 6-chloro-3-methyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazine x35 (3.45 g, 1 eq, 14.64 mmol), N-bromosuccinimide (NBS; 2.87 g, 1.1 eq, 16.11 mmol) and azo-bis-iso-butyronitrile (AIBN; 240 mg, 0.1 eq, 1.5 mmol) in acetonitrile (50 ml) is refluxed for 2 hours. After cooling to room temperature, the solvent is removed under reduced pressure and the crude product is purified by preparative chromatography on silicagel (CH2Cl2) affording 3-(bromomethyl)-6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazine x36.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[NH2:17]>CC(O)C>[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[F:12])[N:5]=[CH:4][N:3]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: Fc1cccc2ncnc(Cl)c12
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Solvent: CC(C)O
Product: Fc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Temperature: 25 °C
Yield: 47.9 %

Procedure:
4-Chloro-5-fluoroquinazoline (6.75 g) was added to a stirred solution of 3-chloro-4-(2-pyridylmethoxy)aniline (9.27 g, obtained as described in Example 15-21 (note u) of WO 96/15118) in IPA (200 ml), and the solution was stirred and heated at reflux for 8 hours. The solution was allowed to cool to ambient temperature overnight and the precipitated solid was filtered off, washed with acetone and dried. The solid was added to 50% aqueous methanol (400 ml) and the mixture was heated on a steam bath until the entire solid had dissolved. The solution was basified by careful addition of aqueous ammonia (0.880), and the mixture was concentrated to remove methanol. Water (300 ml) was added and the mixture was extracted with DCM (600 ml). The extract washed with water, and brine, and dried. The solvent was removed by evaporation to give a solid, which was re-precipitated from a mixture of ethyl acetate, tetrahydrofuran and isohexane to give N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amine as a beige solid (6.75 g, 48%); NMR spectrum (DMSO-d6) 5.3 (s, 2H), 7.2-7.3 (d, 1H), 7.35-7.5 (m, 2H), 7.5-7.65 (m, 3H), 7.8-7.95 (m, 3H), 8.55 (s, 1H), 8.55-8.6 (d, 1H), 9.1-9.2 (bs, 1H); Mass spectrum MH+ 381.
Reaction SMILES: O1CCCC1.[C:6]([C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1)#[CH:7].[O:15]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[N:30][OH:31])=[CH:24][N:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>O>[O:15]([C:22]1[N:23]=[CH:24][C:25]([CH2:28][C:29]2[CH:7]=[C:6]([C:8]3[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=3)[O:31][N:30]=2)=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: ON=C(Cl)Cc1ccc(Oc2ccccc2)nc1
Reactant: C#Cc1ccc(N)nc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(Oc4ccccc4)nc3)no2)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
To a tetrahydrofuran (2 mL) solution of 5-ethynyl-pyridin-2-ylamine (30 mg, 0.25 mmol) described in Manufacturing Example 28-1-3 were added (2-phenoxy-pyridin-5-yl)acetohydroximoyl chloride (100 mg, 0.381 mmol) described in Manufacturing Example 40-1-4 and triethylamine (70.8 μL, 0.508 mmol), which was stirred for 8 hours at 50° C. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (26 mg, 30%).