Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)=[CH:6][N:5]=[C:4]([N:15]2[CH2:20][C@H:19]([CH3:21])[O:18][C@H:17]([CH3:22])[CH2:16]2)[N:3]=1.[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].CC#N>O1CCOCC1.O.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>[CH3:22][C@H:17]1[O:18][C@@H:19]([CH3:21])[CH2:20][N:15]([C:4]2[N:3]=[C:2]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH3:32])[C:7]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=3)=[CH:6][N:5]=2)[CH2:16]1
Reactant: Cc1ccccc1B(O)O
Reactant: Cc1cc(-c2cnc(N3C[C@@H](C)O[C@@H](C)C3)nc2Cl)ccn1
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: [K+]
Solvent: CC#N
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2cnc(N3C[C@@H](C)O[C@@H](C)C3)nc2-c2ccccc2C)ccn1
Temperature: 20 °C
Yield: 30.3 %

Procedure:
To a suspension of cis-4-(4-chloro-5-(2-methylpyridin-4-yl)pyrimidin-2-yl)-2,6-dimethylmorpholine (0.100 g, 0.314 mmol), o-tolylboronic acid (0.064 g, 0.471 mmol) and potassium carbonate (0.138 g, 1 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) stirred in air at 20° C. was added solid tetrakis(triphenylphosphine)palladium(0) (0.058 g, 0.0500 mmol). The reaction mixture was stirred under nitrogen at 100° C. overnight. The reaction mixture was allowed to cool to room temperature, diluted with water and extracted with ethyl acetate (×3). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The crude product was purified by pre-HPLC, (Gilson GX-281; Shimadzu 15 um 250*19 mm; A:10 mMol NH4HCO3/Water B: CH3CN; 0-7 min 85-95%, 7-14 min 95%; 214 nm; 30 mL/min) to obtain the title compound (35.4 mg, 0.095 mmol, 30.1% yield). LC/MS [M+H]+=375; 1H NMR (400 MHz, CDCl3): δ 8.41 (1H, s), 8.27-8.25 (1H, s), 7.29-7.25 (1H, m), 7.17-7.14 (2H, m), 7.10-7.09 (1H, m), 6.81 (1H, s), 6.69-6.67 (1H, d), 4.69-4.65 (2H, d), 3.72-3.63 (2H, m), 2.69-2.63 (2H, m), 2.43 (3H, s), 2.07 (3H, s), 1.27-1.26 (6H, d).
Reaction SMILES: [CH3:1][NH:2][CH:3]([CH3:5])[CH3:4].C(NC(C)C)(C)C.CN(C)C=O.[Br:18][C:19]1[CH:35]=[CH:34][C:22]2[C:23]3[N:24]=[C:25]([C:31](Cl)=[O:32])[S:26][C:27]=3[CH2:28][CH2:29][O:30][C:21]=2[CH:20]=1>C(OCC)(=O)C>[CH:3]([N:2]([CH3:1])[C:31]([C:25]1[S:26][C:27]2[CH2:28][CH2:29][O:30][C:21]3[CH:20]=[C:19]([Br:18])[CH:35]=[CH:34][C:22]=3[C:23]=2[N:24]=1)=[O:32])([CH3:5])[CH3:4]
Reactant: CNC(C)C
Reactant: O=C(Cl)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)N(C)C(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-methylpropan-2-amine (0.265 g, 3.63 mmol) in N,N-Diisopropylamine (0.758 mL, 4.35 mmol) and N,N-Dimethylformamide (4.49 mL, 58.0 mmol) at room temperature was added 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonyl chloride (0.500 g, 1.45 mmol) portionwise. The reaction mixture was stirred at room temperature for 1 hour, diluted with ethyl acetate, washed with brine, and concentrated in vacuo to give 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid isopropyl-methyl-amide which was not further purified.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])O.[Na+]>C(#N)C>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccccn1
Reactant: O=C(CBr)c1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Oc1ccc(-c2cn3ccccc3n2)cc1
Temperature: 110 °C
Yield: 63.3 %

Procedure:
649 mg (corresponding to 3.0 mmol) of 2-bromo-4′-hydroxyacetophenone and 285 mg (corresponding to 3.0 mmol) of 2-aminopyridine were dissolved in 20 mL of acetonitrile. The resulting solution was refluxed in an oil bath at 110° C. for one hour. After the reaction solution was cooled down to room temperature, 254 mg (corresponding to 5.4 mmol) of sodium hydrogencarbonate was added thereto. The resulting mixture was refluxed in an oil bath at 100° C. for one hour. After the completion of the reaction, the reaction solution was cooled to room temperature, and precipitates were filtered and recovered therefrom. The precipitates were washed with acetonitrile and water, and then dried under reduced pressure to obtain 405 mg (corresponding to 1.9 mmol) of 2-(4′-hydroxyphenyl)imidazo[1,2-a]pyridine (FIG. 4, Step 2).
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O)[CH:3]([F:5])[F:4].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[CH3:54][O:55][NH:56][CH3:57]>CN(C=O)C>[CH3:54][O:55][N:56]([CH3:57])[C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([O:6][C:2]([F:1])([F:16])[CH:3]([F:4])[F:5])[CH:8]=1
Reactant: CNOC
Reactant: O=C(O)c1cccc(OC(F)(F)C(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cccc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(1,1,2,2-tetrafluoroethoxy)benzoic acid (10 g, 42.0 mmol) was dissolved in DMF (200 mL) and Hunig's Base (20.54 mL, 118 mmol). Benzotriazol-1-yl-oxy-tris-(dimethylamino)phosphonium hexafluorophosphate (BOP, 27.9 g, 63.0 mmol) and N-methoxy-N-methylamine hydrochloride (4.51 g, 46.2 mmol) were added to the reaction flask, and the resulting reaction mixture was stirred at 25° C. overnight. Crude reaction mixture was concentrated and purified on a silica gel column (340 g cartridge 0-10% EtOAc/Hexanes gradient) to afford N-methoxy-N-methyl-3-(1,1,2,2-tetrafluoroethoxy)benzamide. 1H NMR (400 MHz, CDCl3) δ 3.38 (s, 3H), 3.57 (s, 3H), 5.95 (t, J=52.9, 2.9 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.58 (s, 1H), 7.63 (d, J=7.7 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6](=O)[C@H:5](OS(C)(=O)=O)[CH2:4][C@H:3]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.[C-:21]#[N:22].[Na+]>CN(C=O)C.O>[C:21]([C@@H:5]1[CH2:6][N:2]([CH3:1])[C@H:3]([CH2:13][O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:4]1)#[N:22]
Reactant: [C-]#N
Reactant: CN1C(=O)[C@H](OS(C)(=O)=O)C[C@H]1COc1cccnc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C[C@@H](C#N)C[C@H]1COc1cccnc1
Temperature: 100 °C
Yield: 35.1 %

Procedure:
To a solution of 300 mg (1.05 mmol) of 3-((trans-1-methyl-4-methanesulfonyloxy-5-oxo-2(S)-pyrrolidinyl)-methoxy)pyridine, prepared as in Example 88a above, dissolved in 7 mL of 6:1 DMF:H2O was added 0.51 g (10.5 mmol) of NaCN, and the reaction mixture was heated at 100° C. for 5 hours. The reaction mixture was cooled, diluted with water, and extracted with chloroform. The extract was dried over MgSO4 and concentrated. The residue was purified on a silica gel column, eluting with 100:2 chloroform:methanol, to give 80 mg of the title compound.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[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.[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:29][CH2:30][C:31]#[C:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)=[C:25]([CH:28]=1)[CH2:26][Br:27]>ClCCl>[Br-:27].[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:29][CH2:30][C:31]#[C:32][C:33]2[CH:34]=[CH:35][C:36]([C:39]([F:40])([F:41])[F:42])=[CH:37][CH:38]=2)=[C:25]([CH:28]=1)[CH2:26][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Fc1ccc(OCC#Cc2ccc(C(F)(F)F)cc2)c(CBr)c1
Solvent: ClCCl
Product: Fc1ccc(OCC#Cc2ccc(C(F)(F)F)cc2)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
63.7 mg (0.24 mmol) of triphenylphosphine are dissolved in 2 ml of dichloromethane, 94 mg (0.24 mmol) of 5-fluoro-2-[3-(4-trifluoromethylphenyl)prop-2-ynyloxy]benzyl bromide, dissolved in 2 ml of dichloromethane, are added dropwise, and the mixture is stirred at room temperature overnight. The solvent is distilled out in vacuo, and the crystalline residue is stirred with petroleum ether. The resulting colorless crystals are filtered off with suction and dried on a clay dish. 109 mg (0.17 mmol, 69% of theory) of the title compound are obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][C:11]#[N:12].[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O>CCCCCCC.CCOC(C)=O>[C:14]1([CH3:13])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][C:11]#[N:12]
Reactant: N#CCCNc1cnccc1I
Reactant: Cc1ccccc1B(O)O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccncc1NCCC#N

Procedure:
The title compound was prepared in analogy to example 72, from 3-(4-iodo-pyridin-3-ylamino)-propionitrile and 2-methylphenylboronic acid (CAS RN 16419-60-6) and using a gradient of heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light brown solid (81%). MS (ESI): m/z=238.13 [M+H]+.
Reaction SMILES: [CH2:1]=O.[NH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1>>[CH3:1][N:3]1[CH2:4][CH2:5][CH:6]([O:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: C=O
Reactant: COC(=O)c1ccc(OC2CCNCC2)cc1
Product: COC(=O)c1ccc(OC2CCN(C)CC2)cc1

Procedure:
Prepared using essentially the same procedure used in reference example 114a except using formaldehyde and Methyl 4-(piperidin-4-yloxy)-benzoate (reference example 123) as substrates. 1H NMR (CDCl3): d 8.01 (d, 2H), 6.91 (d, 2H), 4.80 (s, 1H), 3.89 (s, 3H), 3.35 (brd, 2H), 3.13 (q, 2H), 2.80 (d, 3H), 2.65 (t, 2H), 2.18 (d, 2H). MS (ion spray) m/z 250 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[C:12]3[C:13]([O:16][CH2:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:14][O:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:24][C:25]([CH3:32])([CH:30]=O)[C:26]([O:28][CH3:29])=[O:27].C(C1(C(OC)=O)CCC1)=O>>[CH:1]1([CH2:5][O:6][C:7]2[C:12]3[C:13]([O:16][CH2:17][CH:18]4[CH2:19][CH2:20][N:21]([CH2:24][C:25]([CH3:32])([CH3:30])[C:26]([O:28][CH3:29])=[O:27])[CH2:22][CH2:23]4)=[N:14][O:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)C(C)(C)C=O
Reactant: c1cc(OCC2CCC2)c2c(OCC3CCNCC3)noc2c1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C(C)(C)CN1CCC(COc2noc3cccc(OCC4CCC4)c23)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using 4-(cyclobutylmethoxy)-3-(piperidin-4-ylmethoxy)-1,2-benzisoxazole (EXAMPLE 17, Step 4) and methyl 2,2-dimethyl-3-oxopropanoate (Tetrahedron Asymmetry 2003, 14, 3371-3378) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutan-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.N1C=CC=CC=1.[S:52](Cl)(=[O:55])(=[O:54])[NH2:53]>O1CCCC1>[F:8][C:6]1[CH:7]=[C:2]([NH:1][S:52]([NH2:53])(=[O:55])=[O:54])[CH:3]=[C:4]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:45])[CH3:44])[CH:10]=2)[CH:5]=1
Reactant: NS(=O)(=O)Cl
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(N)cc(F)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(F)cc(NS(N)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
(S)-2-(1-((5-(3-Amino-5-fluorophenyl)-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 (40 mg, 0.06 mmol) was treated with pyridine (20 μL, 0.25 mmol) and sulfamoyl chloride (24 mg, 0.21 mmol) in tetrahydrofuran (0.5 ml) according to the method described in Preparation 175 but stirring at room temperature overnight. The title compound was obtained (46 mg, 93% yield) without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.Cl.CO>O>[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[C:8]2=[O:12])=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1C(=Cc2ccc(Br)cc2)CCc2cc(O)ccc21
Temperature: 25 °C
Yield: 35.5 %

Procedure:
After 6-hydroxy-1-tetralone 1.0 g and 4-bromobenzaldehyde 1.37 g were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the mixture was refluxed for one hour and cooled to room temperature, and water 250 ml was added. The precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for four hours under reduced pressure to obtain the desired compound 0.72 g.
Reaction SMILES: [OH-:1].[Na+].Cl.O[NH2:5].Br[CH2:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=O)=[O:9].Cl>C(O)C>[CH:19]1([C:17]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:8](=[O:9])[CH2:7][N+:5]=2[O-:1])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(CBr)Nc1ccccc1C(=O)C1CCCCC1
Reactant: NO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1C[N+]([O-])=C(C2CCCCC2)c2ccccc2N1
Temperature: 40 °C
Reaction time: 20 h

Procedure:
To a stirred 2.63N aqueous sodium hydroxide (40 ml) was added hydroxyamine hydrochloride (8.70 g) and ethanol (40 ml), and the mixture was heated at 40° C. To the heated mixture was added dropwise a solution of N-bromomethylcarbonyl-2-cyclohexylcarbonylaniline (5.25 g) in ethanol (30 ml) at the same temperature, and stirred for 20 hours under the same condition. To the mixture was dropwise conc. HCl (7.3 ml) at the same temperature and stirred for 1 hour. After cooling to the room temperature, the mixture was concentrated in vacuo. The residue was taken up with ethyl acetate and water. The organic layer was separated and dried over sodium sulfate. The organic layer was concentrated to give a crude product. The crude product was purified by column chromatography on silica gel with a mixture of ethyl acetate and chloroform. The desired fractions were combined and concentrated in vacuo to give 5-cyclohexy-2,3-dihydro-1H-1,4-benzodiazepin-2-one-4-oxide.
Reaction SMILES: [Se](=O)=O.[O:4]1CCOCC1.[S:10]([NH:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=1)([CH3:13])(=[O:12])=[O:11].C>O>[S:10]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[O:4])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=1)([CH3:13])(=[O:11])=[O:12]
Reactant: C1COCCO1
Reactant: CCOC(=O)Cc1csc(NS(C)(=O)=O)n1
Agent: CCOC(=O)Cc1csc(=NS(C)(=O)=O)[nH]1
Agent: O=[Se]=O
Solvent: O
Product: CCOC(=O)C(=O)c1csc(NS(C)(=O)=O)n1

Procedure:
To a solution prepared by stirring a mixture of selenium dioxide (0.22 g.), dioxane (10 ml.) and water (0.2 ml.) for 10 minutes at 110° C. was added ethyl 2-(2-mesylamino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (0.53 g.), and the mixture was refluxed for 1 hour. After the reaction, the reaction mixture was treated with activated charcoal. The precipitated crystals in the filtrate were collected by filtration and dried to give white crystals of ethyl 2-(2-mesylamino-1,3-thiazol-4-yl)glyoxylate, which can be represented as ethyl 2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, (0.22 g.), mp. 222° to 225° C. On the other hand, the remaining filtrate was concentrated and the residue was washed with water and diethyl ether in turn and then dried to give the same object compound (0.12 g.)
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:22]=[C:21]([N:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][C:4]=1[C:5]([C:7]1[CH:15]=[C:14]([N:16]([CH3:18])[CH3:17])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=O.C(OC(=O)C)(=O)C.[CH3:34][N:35]([CH3:45])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([N:42]([CH3:44])[CH3:43])[CH:37]=1>Cl>[CH3:43][N:42]([CH3:44])[C:38]1[CH:37]=[C:36]([N:35]([CH3:45])[CH3:34])[CH:41]=[CH:40][C:39]=1[C:5]1([C:4]2[CH:19]=[CH:20][C:21]([N:23]([CH3:24])[CH3:25])=[CH:22][C:3]=2[N:2]([CH3:26])[CH3:1])[C:7]2[C:8](=[CH:12][CH:13]=[C:14]([N:16]([CH3:17])[CH3:18])[CH:15]=2)[C:9](=[O:10])[O:11]1
Reactant: CN(C)c1ccc(C(=O)O)c(C(=O)c2ccc(N(C)C)cc2N(C)C)c1
Reactant: CN(C)c1cccc(N(C)C)c1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3ccc(N(C)C)cc32)c(N(C)C)c1

Procedure:
A mixture of 2-(2,4-bis(dimethylamino)benzoyl)-4-(dimethylamino)benzoic acid or the 5-(dimethylamino) isomer thereof (10 g.), N,N,N'-tetramethyl-m-phenylenediamine (2.30 g.) and acetic anhydride (50 ml.) was warmed (at 30°-35° C.) during one hour. More N,N,N',N'-tetramethyl-m-phenylenediamine (1.15 g.) was added and warming was continued. The mixture was diluted with dilute hydrochloric acid (10%) and ice and filtered. The filtrate was made alkaline. Crystallization of the product from toluene afforded 3,3-bis(2,4-bis(dimethylamino)phenyl)-5-(dimethylamino)phthalide (I: X=Y2 =Y4 =Z5 =(CH3)2N, Z4 =Z6 =Z7 =H) (m.p. 188°-192° C.) or the 6-(dimethylamino) isomer thereof.
Reaction SMILES: [CH:1]12[O:7][CH:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2]2.[C:13]1([CH2:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[OH:7][C@H:1]1[C@H:6]([NH:20][CH2:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2]1.[OH:7][C@@H:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][C@H:1]1[NH:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)N1CCC2OC2C1
Solvent: CCO
Product: CCOC(=O)N1CC[C@@H](NCc2ccccc2)[C@H](O)C1
Product: CCOC(=O)N1CC[C@@H](O)[C@H](NCc2ccccc2)C1
Reaction time: 4 h

Procedure:
A mixture of 3.4 parts of ethyl 7-oxa-3-azabicyclo[4,1,0]heptane-3-carboxylate, 2.1 parts of benzenemethanamine and 40 parts of ethanol was stirred and refluxed for 17 hours. Another 0.3 parts of ethyl 7oxa-3-azabicyclo[4,1,0]heptane-3-carboxylate were added and stirring at reflux was continued for 4 hours. The reaction mixture was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 3.4 parts (61.8%) of a mixture of ethyl trans-3-hydroxy-4-[(phenylmethyl)amino]-1-piperidinecarboxylate and ethyl trans-4-hydroxy-3-[(phenylmethyl)amino]-1- piperidinecarboxylate as an oily residue (intermediates 35 and 36).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:54]=[CH:53][C:8]([C:9]([O:24][CH2:25][C@H:26]2[O:30][C@@H:29]([N:31]3[CH:39]=[C:37]([CH3:38])[C:35](=[O:36])[NH:34][C:32]3=[O:33])[CH2:28][C@:27]2([CH2:41][O:42]S(C2C=CC(C)=CC=2)(=O)=O)O)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][C:13](OC)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1.C1C[O:58][CH2:57]C1>>[CH3:57][O:58][C:5]1([O:4][CH3:3])[CH:6]=[CH:7][C:8]([C:9]([O:24][CH2:25][C@H:26]2[O:30][C@@H:29]([N:31]3[CH:39]=[C:37]([CH3:38])[C:35](=[O:36])[NH:34][C:32]3=[O:33])[CH2:28][C@:27]32[CH2:41][O:42]3)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:53][CH2:54]1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@]2(O)COS(=O)(=O)c2ccc(C)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COC1(OC)C=CC(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@]23CO3)(c2ccccc2)c2ccccc2)=CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.5 %

Procedure:
To a suspension of NaH (60% in mineral oil, 0.18 g; 7.5 mmol) in anhydrous THF (18 ml) at 0° C. under argon was added dropwise a solution of 5′-O-(4,4′-dimethoxytrityl)-3′-p-toluensulfonyloxymethylthymidine (1.5 g; 2.06 mmol) in THF (10 ml). The resulting reaction mixture was stirred at room temperature for 2 h, cooled to 0° C., and quenched by addition of water. The mixture was diluted with EtOAc (250 ml), washed with water (2×200 ml), then with 10% NaHCO3 (2×200 ml), dried over Na2SO4, and concentrated. The residue was purified by chromatography on silica (5% CH3OH in CH2Cl2) to yield 0.97 g (8.5%) of 5′-O-(4,4-dimethoxytrityl)-3′-C,O-methylene thymidine as a foam.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Br:16][C:17]1[CH:22]=[CH:21][C:20](O)=[C:19]([CH:24]([CH3:26])[CH3:25])[CH:18]=1.N1C=CC=CC=1.Cl>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:20]1[CH:21]=[CH:22][C:17]([Br:16])=[CH:18][C:19]=1[CH:24]([CH3:26])[CH3:25])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)c1cc(Br)ccc1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)c1cc(Br)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Trifluoromethanesulfonic anhydride (0.469 mL) was added to an ice-cooled mixture of 4-bromo-2-isopropylphenol (0.5 g) and pyridine (0.28 mL) in methylene chloride (5 mL). The mixture was stirred for 10 minutes, and poured into a mixture of ethyl acetate and 1 mol/L hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: diethyl ether/n-hexane=1/10) to afford 4-bromo-2-isopropylphenyl trifluoromethanesulfonate (0.705 g).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.O.O.[Sn](Cl)Cl.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][C:16]([CH2:20][OH:21])=[CH:15][N:14]=1>C(Cl)(Cl)Cl>[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][C:16]([CH2:20][O:21][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)=[CH:15][N:14]=1
Reactant: C1=COCCC1
Reactant: OCc1cnc(Cl)c(Cl)c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: Clc1cc(COC2CCCCO2)cnc1Cl
Temperature: 25 °C
Reaction time: 63 h

Procedure:
3,4-Dihydro-2H-pyran (1.1 mL) and tin (II) chloride dihydrate (0.38 g) were added to a chloroform solution of 2,3-dichloro-5-hydroxymethylpyridine (1.5 g), and the reaction mixture was stirred at room temperature for 63 hours. The reaction mixture was filtered, and the solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0 to 90:10). The title compound (1.7 g) was obtained as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[CH:5]=[C:6]([N:11]=[N+]=[N-])[C:7]([O:9][CH3:10])=[O:8]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][C:16]=1[F:17])[NH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5]2
Reactant: COC(=O)C(=Cc1ccc(F)c(Cl)c1)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: COC(=O)c1cc2cc(Cl)c(F)cc2[nH]1

Procedure:
A mixture of methyl 3-chloro-4-fluoro-α-azidocinnamate (Japanese Patent Application Laid-Open No. 149723/1995) (1.85 g) and xylene (140 ml) was heated under reflux for 1 hour, and the solvent was then distilled off. The residue was purified by column chromatography on silica gel (methylene chloride) to obtain the title compound (491 mg).