Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([OH:21])[C@H:12]([NH:15][C:16]([CH:18]([Cl:20])[Cl:19])=[O:17])[CH2:13][F:14])=[CH:9][CH:10]=1)(=[O:4])=[O:3].Cl(O)(=O)(=O)=[O:23]>C(OC(=O)C)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([OH:21])[C@H:12]([NH:15][C:16]([CH:18]([Cl:20])[Cl:19])=[O:17])[CH2:13][F:14])=[CH:9][CH:10]=1)(=[O:4])=[O:3].[C:16]([O-:23])(=[O:17])[CH3:18]
Reactant: [O-][Cl+3]([O-])([O-])O
Agent: CS(=O)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)[O-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
250 g of florfenicol was suspended in 330 ml of acetic anhydride in one liter round bottom flask equipped with a over-head stirrer and a drying tube. To this suspension was added one ml of perchloric acid, while stirring vigorously with a pipette. A clear yellow solution was obtained in a few minutes. Stirring was continued for another 3 hours. After 3 hrs, the reaction mixture was poured into 1000 g of ice and stirring continued to arrive at a suspension of product. Solid present was filtered and resuspended in 500 ml of water, and then stirred for 10 min to remove residual acetic acid. The solid product was filtered using a Buckner finnel under vacuum and then recrystallized in ethanol. The recrystallized product was washed with hexane and dried to obtain around 260 g of solid florfenicol acetate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15](=[O:17])[NH:14][C:13]=3[CH:18]=2)[C:5]([CH3:19])=[CH:4][N:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C(O)(C(F)(F)F)=O>CC(O)C>[O:16]1[C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]3[C:5]([CH3:19])=[CH:4][N:3]=[C:2]([NH:33][C:30]4[CH:29]=[CH:28][C:27]([N:24]5[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]5)=[N:32][CH:31]=4)[N:7]=3)=[CH:18][C:13]=2[NH:14][C:15]1=[O:17]
Reactant: Cc1cnc(Cl)nc1Nc1ccc2oc(=O)[nH]c2c1
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(Nc2ccc(N3CCN(C)CC3)nc2)nc1Nc1ccc2oc(=O)[nH]c2c1
Temperature: 85 °C
Reaction time: 48 h
Yield: 53 %

Procedure:
To a vial with 5-(2-chloro-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one (27.7 mg, 0.5 mmol) and 6-(4-methylpiperazin-1-yl)pyridin-3-amine (38.4 mg, 1.0 mmol), i-PrOH (2 mL) was added, followed by TFA (10 μL, 0.13 mmol). The vial was tightly closed, and the reaction mixture was stirred at 85° C. for 2 days. The solvents were removed in vacuo, and the crude product was purified by RP-HPLC. Purified compound (as a trifluoroacetate salt) was dissolved in MeOH—H2O (1:4, 2 mL) and was passed through a PL-HCO3-MP-SPE column, washing with same solvents (1 mL). The filtrate was collected and the solvent was removed by lyophilization. N4-(benzoxazolin-2-on-5-yl)-N2-[2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine was obtained as a purple solid, 23.1 mg (53% yield); 1H NMR (300 MHz, DMSO) δ 11.57 (s, 1H), 8.73 (s, 1H), 8.30-8.28 (m, 2H), 7.87-7.84 (m, 2H), 7.46-7.28 (m, 2H), 7.22 (d, J=8.5, 1H), 6.71 (d, J=9.1, 1H), 3.40-3.37 (m, 4H, overlapped with H2O), 2.44-2.41 (m, 4H), 2.25 (s, 3H), 2.11 (s, 3H); LCMS (M+) m/z 433.52.
Reaction SMILES: [F:1][CH2:2][C:3]1[N:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:19])=[CH:11][CH:10]=2)[C:5]([SH:8])=[N:6][N:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](=[O:40])(=[O:39])[NH2:38])=[CH:33][C:32]=1[CH3:41])=[O:29].O>CN(C=O)C>[F:1][CH2:2][C:3]1[N:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:19])=[CH:11][CH:10]=2)[C:5]([S:8][CH2:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([S:37](=[O:40])(=[O:39])[NH2:38])=[CH:33][C:32]=2[CH3:41])=[O:29])=[N:6][N:7]=1
Reactant: Cc1ccc(-n2c(S)nnc2CF)c2ccccc12
Reactant: Cc1cc(S(N)(=O)=O)ccc1NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(S(N)(=O)=O)ccc1NC(=O)CSc1nnc(CF)n1-c1ccc(C)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
In a solution of 5-fluoromethyl-4-(4-methyl-naphthalen-1-yl)-4H-[1,2,4]triazole-3-thiol (89 mg, 0.33 mmol), K2CO3 (50.0 mg, 0.36 mmol) in DMF (2.0 mL) was added 2-chloro-N-(2-methyl-4-sulfamoyl-phenyl)-acetamide (87 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for 16 h. Upon the completion of the reaction, H2O (2.0 mL) was added to the reaction and stirred til precipitation occurred and filtered. Purified by reverse phase HPLC resulted product as a solid in (53.3 mg, 50% yield). 1H NMR (DMSO, 300 MHz) δ 9.84 (broad s, 1H), 8.18 (d,J=8.4 Hz, 1H), 7.71-7.53 (m, 7H), 7.26 (s, 2H), 7.10 (d, J=8.7 Hz, 1H), 5.34 (dd, J=12.0, 27.3 Hz, 1H), 5.18 (dd, J=12.3, 26.4 Hz, 1H), 4.22 (s, 2H), 2.75 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:27]=[CH:26][C:7]([O:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=3)[N:11]([CH2:19][C:20]([O:22]CC)=[O:21])[C:10]=2[CH3:25])=[CH:6][CH:5]=1.O.Cl>C1COCC1>[Cl:3][C:4]1[CH:27]=[CH:26][C:7]([O:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=3)[N:11]([CH2:19][C:20]([OH:22])=[O:21])[C:10]=2[CH3:25])=[CH:6][CH:5]=1
Reactant: CCOC(=O)Cn1c(C)c(Oc2ccc(Cl)cc2)c2cc(F)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Oc2ccc(Cl)cc2)c2cc(F)ccc2n1CC(=O)O

Procedure:
A solution of 2M sodium hydroxide (3 ml) was added to a stirred mixture of the product from step (ii) (0.36 g), water (10 ml) and THF (10 ml). After 2 h the solution was acidified with 2M hydrochloric acid and extracted with diethylether. The organics were washed with water, dried and evaporated under reduced pressure. The residue was recrystallised from diethylether/isohexane. Yield 138 mg
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([CH2:20][N:21]2[CH2:24][CH:23]([C:25]([O:27]C)=[O:26])[CH2:22]2)[CH:14]=[CH:13]3)[CH2:5][CH2:4]1.[OH-].[Na+].Cl>CCO>[F:30][C:2]([F:1])([F:29])[CH:3]1[CH2:4][CH2:5][CH:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([CH2:20][N:21]2[CH2:22][CH:23]([C:25]([OH:27])=[O:26])[CH2:24]2)[CH:14]=[CH:13]3)[CH2:7][CH2:8]1
Reactant: COC(=O)C1CN(Cc2ccc3cc(OC4CCC(C(F)(F)F)CC4)ccc3c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CN(Cc2ccc3cc(OC4CCC(C(F)(F)F)CC4)ccc3c2)C1
Temperature: 0 °C
Yield: 47.2 %

Procedure:
To a solution of methyl 1-((6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylate (100 mg, 0.26 mmol) in EtOH (15 mL) was added aqueous NaOH (3 mL, 20%, 5.0 eq.) and refluxed for 1 h. Then the reaction was cooled to 0° C., the pH of the solution was adjusted to 6 using 1M HCl, concentrated and the residue was dissolved in DCM, washed with water, dried and concentrated to give the title compound as a slight yellow solid (50 mg, yield: 52%). ESI-MS (M+1)+: 408.2 HPLC: 94.97%. 1H NMR (400 MHz, CD3OD) δ: 7.77 (d, 1H), 7.69 (d, 1H), 7.64 (s, 1H), 7.33 (d, 1H), 7.31 (s, 1H), 7.16 (dd, 1H), 4.80-4.71 (m, 1H), 3.57 (s, 2H), 3.25 (t, 2H), 3.09 (t, 2H), 2.79-2.73 (m, 1H), 2.41 (br, 1H), 2.07 (d, 2H), 1.80-1.60 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[C:31]4[CH:32]=[CH:33][C:34]([OH:36])=[CH:35][C:30]=4[S:29][N:28]=3)=[O:26])=[CH:20][C:19]=2[C:37]([F:40])([F:39])[F:38])[CH2:13][CH2:12]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN1C(=O)CCC1>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[C:31]4[CH:32]=[CH:33][C:34]([O:36][C:6]5[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([NH2:1])[N:7]=5)=[CH:35][C:30]=4[S:29][N:28]=3)=[O:26])=[CH:20][C:19]=2[C:37]([F:40])([F:38])[F:39])[CH2:13][CH2:12]1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CN1CCN(Cc2ccc(NC(=O)c3nsc4cc(O)ccc34)cc2C(F)(F)F)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN1CCN(Cc2ccc(NC(=O)c3nsc4cc(Oc5cc(Cl)nc(N)n5)ccc34)cc2C(F)(F)F)CC1

Procedure:
Prepared as described in step 6.3 from 401 mg (2.45 mMol) 2-amino-4,6-dichloropyrimidine, 785 mg (1.74 mMol) 6-hydroxy-benzo[d]isothiazole-3-carboxylic acid [4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-amide and 1.5 g (7.1 mMol) K3PO4 in 45 ml NMP: MS: [M+1]+=578/580; HPLC: tRet=14.9.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[OH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]1[C:22](=[O:23])[CH2:21][CH2:20][CH:19]1[C:24]#N.C(O)(=[O:28])C>C1C=CC=CC=1.C(OCC)C>[OH:23][CH:22]1[CH2:21][CH2:20][CH:19]([CH:24]=[O:28])[CH:18]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][OH:11]
Reactant: CC(=O)O
Reactant: N#CC1CCC(=O)C1CCCCCCO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=CC1CCC(O)C1CCCCCCO
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of diisobutylaluminum hydride (19.3 g., 0.125 mole) in benzene (170 ml.) was added, with rapid stirring, to a solution of 2-(6-hydroxyhexyl)-3-oxocyclopentanecarbonitrile (8.8 g., 0.042 mole) in dry diethyl ether (200 ml.) at 10°-15°C. Stirring at ambient temperature was continued for 15 minutes and the mixture was added to 2N aqueous acetic acid (170 ml.) at a temperature lower than 15°C. The organic phase was separated and the aqueous layer was extracted with diethyl ether. The combined organic phases were washed with aqueous sodium bicarbonate, dried over magnesium sulphate and the solvents were removed in vacuo to give crude 3-hydroxy-2-(6-hydroxyhexyl)cyclopentanecarbaldehyde (8.6 g.). It was used without further purification.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[OH:13])(=[O:4])[CH:2]=[CH2:3].[CH:14]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH:14]([N:27]1[CH2:32][CH2:31][N:30]([CH2:3][CH2:2][C:1]([NH:5][C:6]2[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=2[OH:13])=[O:4])[CH2:29][CH2:28]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: C=CC(=O)Nc1cc(C)ccc1O
Solvent: CCO
Product: Cc1ccc(O)c(NC(=O)CCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
A solution of the compound (1) (1.52 g, 8.58 mmol) and 1-benzhydrylpiperazine (4.33 g, 17.2 mmol) in ethanol (14 ml) was heated under reflux for 3 hours. The solvent was distilled off from the reaction mixture, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel to give a colorless glassy substance (2). Yield 3.47 g (94%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][C:10]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20])C1C=CC=CC=1>[C].[Pd].O1CCCC1>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][C:10]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: CCOc1ccc(OCc2ccccc2)c(CC(=O)OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOc1ccc(O)c(CC(=O)OC)c1
Yield: 73.2 %

Procedure:
A mixture of methyl 2-(2-benzyloxy-5-ethoxyphenyl)acetate (1.60 g), 5% palladium carbon (3.0 g) and tetrahydrofuran (50 mL) was subjected to catalytic hydrogenation at room temperature and 1 atm. After filtering off the catalyst, the solvent was evaporated under reduced pressure. Hexane was added to the obtained crystals and the mixture was filtrated to give crystals (0.82 g) of methyl 2-(2-hydroxy-5-ethoxyphenyl)acetate. Recrystallization from diisopropyl ether-hexane gave pale-yellow prism crystals. melting point: 83-84° C.
Reaction SMILES: C(O[CH:4]=[CH:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([F:13])[C:11]=1[NH2:12])C.Cl>CCO>[F:13][C:10]1[C:11]2[NH:12][CH:4]=[CH:5][C:6]=2[CH:7]=[N:8][CH:9]=1
Reactant: CCOC=Cc1cncc(F)c1N
Agent: Cl
Solvent: CCO
Product: Fc1cncc2cc[nH]c12
Yield: 65 %

Procedure:
A mixture of 3-(2-ethoxy-vinyl)-5-fluoro-pyridin-4-ylamine (Preparation 63, 3.6 g, 19.2 mmol) and concentrated HCl (10 mL) in EtOH (44 mL) was heated to reflux for 4 hours before cooling and concentrating in vacuo. The residue was basified with saturated aqueous NaHCO3 solution, extracted in DCM, the organic layer collected, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 20-100% EtOAc in hexane to afford the title compound (1.7 g)
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[S:14]1[CH:18]=[CH:17][N:16]2[CH:19]=[N:20][CH:21]=[C:15]12.C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(=S)=S.ClCCl>[C:5]([C:21]1[N:20]=[CH:19][N:16]2[CH:17]=[CH:18][S:14][C:15]=12)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1cn2cncc2s1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: S=C=S
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ncn2ccsc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Aluminum chloride (5.33 g) was added to a solution of 4.64 ml of benzoyl chloride in 50 ml of carbon disulfide. A solution of 1.24 g of imidazo[5,1-b]thiazole in 50 ml of dichloromethane was added dropwise thereto. The mixture was stirred at room temperature for 2 hr. The reaction solution was poured into 50 g of ice. Dichloromethane (100 ml) was added thereto. Sodium carbonate (16.7 g) and 16.7 g of sodium sulfate were added in that order to the mixture with stirring. The insolubles were removed by filtration through Celite, and then washed with dichloromethane. Filtrate was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1 to dichloromethane:ethyl acetate=2:1) to give 1.39 g of 7-benzoylimidazo[5,1-b]thiazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@:9]([OH:21])([C@H:15](S(C)(=O)=O)[CH3:16])[CH2:10]S(C)(=O)=O.[NH:22]1[CH:26]=[N:25][CH:24]=[N:23]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@:9]1([CH2:10][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[C@H:15]([CH3:16])[O:21]1
Reactant: C[C@H]([C@](O)(CS(C)(=O)=O)c1cc(F)ccc1F)S(C)(=O)=O
Reactant: c1nc[nH]n1
Product: C[C@@H]1O[C@@]1(Cn1cncn1)c1cc(F)ccc1F
Yield: 56 %

Procedure:
In the same manner as that described in Example 7(iv) above 7.00 g (18.7 mmol) of (2R,3 R)-2-(2,5-difluorophenyl)-1,3-bis(methanesulfonyl)-2-butanol [prepared as described in Step 8(iii) above] were reacted with 1H-1,2,4-triazole and the reaction product was purified by chromatography on a silica gel (100 g) column using a 1:1 to 3:2 mixture of ethyl acetate and hexane as the eluant to afford 2.65 g (yield 56%) of the title compound as an oil.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.[CH3:20][S:21][C:22]1[CH:23]=[CH:24][C:25]2[N:31]3[C:32]([CH2:35]Cl)=[N:33][N:34]=[C:30]3[CH2:29][N:28]=[C:27]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:26]=2[CH:43]=1>CN(C)C=O>[CH3:20][S:21][C:22]1[CH:23]=[CH:24][C:25]2[N:31]3[C:32]([CH2:35][O:1][N:2]4[C:3](=[O:12])[C:4]5=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]5[C:6]4=[O:7])=[N:33][N:34]=[C:30]3[CH2:29][N:28]=[C:27]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:26]=2[CH:43]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CCl)n1-2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CON3C(=O)c4ccccc4C3=O)n1-2

Procedure:
In the manner given in Example 1, N-hydroxyphthalimide and triethylamine in dimethylformamide is treated with 8-methylthio-6-phenyl-1-(chloromethyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 8-methylthio-6-phenyl-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:19](=O)[CH3:20].Cl.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:19][CH:20]1[C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:6](=[O:8])[O:7]1
Reactant: CC=O
Reactant: O=C(O)c1ccsc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CC1OC(=O)c2ccsc21
Temperature: -50 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
A solution of thiophene-3-carboxylic acid (1.00 g, 7.8 mmol) in THF (10 mL) is added dropwise to a cold (−80° C.) solution of lithium bistrimethylsilylamide (8.6 mL of a 2M solution) in THF (15 mL). The resulting pale yellow solution is warmed to −50° C. and is stirred at −50° C. for 1 hr during which time a white precipitate is formed. The reaction mixture is cooled to −80° C. and treated dropwise with acetaldehyde (1.2 mL). The white precipitate gradually disappeared during the addition. The reaction mixture is warmed to −20° C. and stirred for 30 min. The reaction mixture is then poured into aqueous 2M HCl solution (120 mL). The resulting mixture is stirred at room temperature while a stream of air is blown into the reaction vessel to assist in the evaporation of THF. The white precipitate which forms is collected by filtration and dissolved in dichloromethane (5 mL) and Et3N (5 mL). The reaction mixture is treated with p-toluenesulfonyl chloride (0.38 g, 2.0 mmol) and stirred overnight. The reaction mixture is treated with NaHCO3 solution and the organic phase is collected, dried over Na2SO4, filtered and concentrated. The residue is purified by chromatography (silica gel) to give the title compound (0.39 g, 32%).
Reaction SMILES: Br[C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])[C@@H:7]([CH3:17])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][N:42](C(OC(C)(C)C)=O)[CH:43]=2)O1.O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.O>[CH:14]1([C:12]([N:8]2[C:9]3[C:4](=[C:3]([O:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:2]([C:39]4[CH:40]=[N:41][NH:42][CH:43]=4)=[CH:11][CH:10]=3)[CH2:5][CH2:6][C@@H:7]2[CH3:17])=[O:13])[CH2:15][CH2:16]1
Reactant: C[C@H]1CCc2c(ccc(Br)c2Oc2ccccc2)N1C(=O)C1CC1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: C[C@H]1CCc2c(ccc(-c3cn[nH]c3)c2Oc2ccccc2)N1C(=O)C1CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
A 100-mL round-bottom flask was charged with (S)-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.400 g, 1.04 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.083 g, 0.10 mmol), cesium carbonate (0.985 g, 3.02 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (0.343 g, 1.17 mmol), 1,4-dioxane (10 mL) and water (3 mL). The resulting mixture stirred at 100° C. overnight and was cooled to room temperature. The reaction mixture was passed through a short pad of Celite, and the filtrate was concentrated under vacuum. The residue was purified via column chromatography on silica gel (gradient elution with 10-25% ethyl acetate/petroleum ether) to afford (S)-cyclopropyl(2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.200 g, 52%) as a light yellow solid. MS (ESI, pos. ion) m/z 374 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[H-].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]Cl)=[CH:28][N:27]=1.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:32][C:29]2[CH:28]=[N:27][C:26]([Cl:25])=[CH:31][CH:30]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1[nH]c(=O)c2ccc(Br)cc2c1-c1ccccc1
Reactant: ClCc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
To a solution of 6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (290 mg) in DMF (3 ml) was added sodium hydride (60% in oil, 36 mg) under ice-cooling, and the mixture was allowed to warm to room temperature and stirred for 1 hr. To the reaction mixture was added 2-chloro-5-chloromethylpyridine (160 mg) at room temperature, and the mixture was stirred for 2 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethyl acetate to give the title compound (120 mg).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=O)[O:4][C:2]2=[O:3].[CH3:13][NH2:14]>>[CH3:13][N:14]1[C:2](=[O:3])[C:1]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:4]
Reactant: CN
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Product: Cn1c(=O)[nH]c2ccccc2c1=O

Procedure:
6 g isatoic anhydride was stirred in 100 ml dry tetrahydrofurane(THF) and methylamine was passed through the mixture for 5 min. The resulting solution was evaporated and the residue was again dissolved in THF (100 ml) and charged with 15 ml 30% phosgene solution in toluene. The mixture was heated to reflux and additional 15 ml phosgene solution was added After 4 hours reflux the mixture was cooled and evaporated to dryness. The residue was treated with water and the crystals were collected by filtration. The yield was 3.5 g. M.p. 240.4°-240.5° C.
Reaction SMILES: [C:1]1([C:7]2([NH:13][C:14](=[O:16])[CH3:15])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17][C:18]1[CH:43]=[CH:42][C:21]([CH2:22][N:23]([CH3:41])[C:24]([C@@:26]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=3)[CH2:28][C@H:27]2/[CH:29]=[CH:30]/[CH:31]=O)=[O:25])=[CH:20][CH:19]=1.C([BH3-])#N.[Na+]>C(O)C>[F:17][C:18]1[CH:43]=[CH:42][C:21]([CH2:22][N:23]([CH3:41])[C:24]([C@@:26]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=3)[CH2:28][C@H:27]2/[CH:29]=[CH:30]/[CH2:31][N:10]2[CH2:11][CH2:12][C:7]([NH:13][C:14](=[O:16])[CH3:15])([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9]2)=[O:25])=[CH:20][CH:19]=1
Reactant: CN(Cc1ccc(F)cc1)C(=O)[C@@]1(c2ccc(Cl)c(Cl)c2)C[C@H]1/C=C/C=O
Reactant: CC(=O)NC1(c2ccccc2)CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(=O)NC1(c2ccccc2)CCN(C/C=C/[C@@H]2C[C@@]2(C(=O)N(C)Cc2ccc(F)cc2)c2ccc(Cl)c(Cl)c2)CC1
Reaction time: 2 h

Procedure:
N-(4-Phenyl-piperidin-4-yl)-acetamide (140 mg, 0.64 mmol) dissolved in ethanol (3 ml) is added to (1S,2S)-1-(3,4-Dichloro-phenyl)-2-((E)-3-oxo-propenyl)-cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide dissolved in ethanol (5 ml) followed by dropwise addition of sodium cyanoborohydride (1.0M in THF, 1.97 ml, 1.97 mmol) at 0° C. After complete addition the mixture is kept at ambient temperature for 2 hours. The reaction is quenched by addition of sodium bicarbonate (3 ml, sat.) and the ethanol is removed by means of evaporation. Ethyl acetate (30 ml) is added to the remanence. The organic fraction is washed successively with sodium bicarbonate (10 ml, sat.) and brine (10 ml, sat.), dried (MgSO4) and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with ethyl acetate:ethanol:triethylamine (95:0:5)-(90:5:5) to furnish the title compound as an oil. Yield 81 mg (27%). LC/MS (m/z) 610.3 (M+H+).