Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[N+:6]([O-:8])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:9]([CH2:10][C:11]2[C:12]([Cl:18])=[CH:13][CH:14]=[CH:15][C:16]=2[Cl:17])=[O:27])=[N+:6]([O-:8])[CH:7]=1
Reactant: [O-][n+]1cc(Br)ccc1SCc1c(Cl)cccc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=S(Cc1c(Cl)cccc1Cl)c1ccc(Br)c[n+]1[O-]
Reaction time: 0.17 h
Yield: 83.3 %

Procedure:
2.3 g of 5-bromo-2-(2,6-dichlorobenzylthio)pyridine-N-oxide was dissolved in 50 ml of chloroform, and a solution of 1.6 g of metachloroperbenzoic acid (content: 70%) dissolved in 30 ml of chloroform was added dropwise thereto at 5° to 10° C. over 10 minutes. The mixture was stirred at 5° to 10° C. for an additional 2 hours. The resulting mixture was washed twice with potassium carbonate solution and dried over magnesium sulfate. The chloroform was evaporated, and the residue was recrystallized from benzene to obtain 2.0 g of 5-bromo-2-(2,6-dichlorobenzylsulfinyl)pyridine-N-oxide (Compound (2)). Yield, 83%. M.P., 187.5°-188.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[CH3:15][S:16][C:17](SC)=[CH:18][N+:19]([O-:21])=[O:20]>C(O)CC>[CH3:15][S:16][C:17]([NH:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=1)=[CH:18][N+:19]([O-:21])=[O:20]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: COC(=O)C/C=C/c1ccc(N)cc1
Solvent: CCCO
Product: COC(=O)C/C=C/c1ccc(NC(=C[N+](=O)[O-])SC)cc1
Yield: 85.5 %

Procedure:
7.00 g of methyl (E)-4-(4-aminophenyl)-3-butenoate was dissolved in 120 ml of n-propanol, followed by the addition of 30.28 g of 1,1-bis-(methylthio)-2-nitroethylene. The obtained mixture was heated under reflux for 3 hours and distilled to remove the solvent. The residue was purified by silica gel column chromatography (solvent: dichloromethane). The obtained solid was washed with ethyl ether to obtain 9.65 g of the title compound as a yellow powder (yield: 86%).
Reaction SMILES: CS(O[CH:6]([C:8]1[CH:13]=[C:12]([N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:11]2[N:31]=[CH:32][C:33]([C:34]3[CH:35]=[N:36][C:37]4[C:42]([CH:43]=3)=[CH:41][C:40]([F:44])=[CH:39][CH:38]=4)=[C:10]2[N:9]=1)[CH3:7])(=O)=O.C(N(CC)C(C)C)(C)C.[N-:54]=[N+:55]=[N-:56].[Na+]>CS(C)=O>[N:54]([CH:6]([C:8]1[CH:13]=[C:12]([N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:28])[CH3:30])[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:20])([CH3:21])[CH3:22])[N:11]2[N:31]=[CH:32][C:33]([C:34]3[CH:35]=[N:36][C:37]4[C:42]([CH:43]=3)=[CH:41][C:40]([F:44])=[CH:39][CH:38]=4)=[C:10]2[N:9]=1)[CH3:7])=[N+:55]=[N-:56]
Reactant: CC(OS(C)(=O)=O)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(N=[N+]=[N-])c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Reaction time: 4 h
Yield: 98.9 %

Procedure:
To a solution of 1-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)ethyl methanesulfonate (6.8 g, 10.3 mmol) in DMSO (100 mL) and N,N-diisopropyl-ethylamine (8.95 mL, 51.4 mmol) was added sodium azide (2.0 g, 30.8 mmol). After 4 hours the reaction was complete by HPLC. The contents of the flask were transferred to a separatory funnel, washed twice with water and twice with brine. The organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford 5-(1-azidoethyl)-3-(6-fluoroquinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (6.2 g; 99% yield) as a dark yellow oil. HPLC: 6.67 min (Method D). LCMS: No ion detected.
Reaction SMILES: [OH:1][CH:2]([C@@H:4]1[C@@H:7]([S:8][CH3:9])[N:6]([C:10](=[C:15]([CH3:17])[CH3:16])[C:11]([O:13][CH3:14])=[O:12])[C:5]1=[O:18])[CH3:3].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:21]>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[CH3:16][C:15]([CH3:17])=[C:10]([N:6]1[C@H:7]([S:8][CH3:9])[C@@H:4]([CH:2]([O:1][C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)=[O:21])[CH3:3])[C:5]1=[O:18])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H](C(C)O)[C@H]1SC
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H](C(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)[C@H]1SC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
To a solution of a mixture (1:3) of methyl 2-[(3S,4R)-3-{(1RS)-1-hydroxyethyl}-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (1.84 g) and 4-dimethylaminopyridine (1.23 g) in dichloromethane (20 ml) was added a solution of p-nitrobenzyl chloroformate (1.60 g) in dichloromethane (3 ml) at 0° C. After stirring at 0° C. for 1.5 hours, the mixture was diluted with ethyl acetate (150 ml) and washed with dilute hydrochloric acid, water, a dilute aqueous sodium bicarbonate, and brine. Drying over magnesium sulfate and removal of the solvent left an oil (3.1 g), which was chromatographed on silica gel (90 g) eluting with 10-25% ethyl acetate in hexane to give a mixture (1:3) of methyl 3-methyl-2-[(3S,4R)-4-methylthio-3-{(1RS)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-but-2-enoate (2.90 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1B(O)O.[CH2:19]([O:21][C:22]([C:24]1[S:34][C:27]2[N:28]=[C:29]([NH2:33])[N:30]=[C:31](Cl)[C:26]=2[CH:25]=1)=[O:23])[CH3:20].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:19]([O:21][C:22]([C:24]1[S:34][C:27]2[N:28]=[C:29]([NH2:33])[N:30]=[C:31]([C:3]3[CH:4]=[CH:5][C:6]([O:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:7][C:2]=3[CH3:1])[C:26]=2[CH:25]=1)=[O:23])[CH3:20]
Reactant: CCOC(=O)c1cc2c(Cl)nc(N)nc2s1
Reactant: Cc1cc(OCc2ccccc2)ccc1B(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(-c3ccc(OCc4ccccc4)cc3C)nc(N)nc2s1
Temperature: 80 °C
Yield: 70.7 %

Procedure:
2-methyl-4-benzyloxyphenylboronic acid (225 mg; 0.93 mmol) was added to 2-Amino-4-chloro-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (example 1; step 1) (200 mg; 0.776 mmol) in DMF (10 mL). NaHCO3 (1.0M aq. Solution; 2.33 mL) was added and mixture degassed with N2. Pd(PPh3)2Cl2 was added and reaction mixture heated at 80 degrees C. for 5 hours Reaction mixture was allowed to cool to room temperature and DMF removed in vacuo. The residue was partitioned between ethyl acetate (50 mL) and sat. NaCl (aq) (50 mL) Organic phase was dried over Na2SO4 and filtered, filtrate solvents removed in vacuo to afford a yellow oil which was purified by ion-exchange chromatography (IST SCX-2 column) to afford product as a brown-yellow solid (230 mg; 71%)
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:19]([NH2:20])=[N:18][C:12]2[N:13]=[C:14]([NH2:17])[N:15]=[CH:16][C:11]=2[CH:10]=1.[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[NH2:17][C:14]1[N:15]=[CH:16][C:11]2[CH:10]=[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=3[Cl:1])[C:19]([NH:20][C:26]([NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])=[N:18][C:12]=2[N:13]=1
Reactant: CC(C)(C)N=C=O
Reactant: Nc1ncc2cc(-c3cccc(Cl)c3Cl)c(N)nc2n1
Product: CC(C)(C)NC(=O)Nc1nc2nc(N)ncc2cc1-c1cccc(Cl)c1Cl

Procedure:
Following the general procedure of Example 2, 0.502 g of 6-(2,3-dichlorophenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 83 was reacted with 0.206 mL of tert-butyl isocyanate. The product is purified by silica gel chromatography eluting with a gradient of CHCl3 :EtOAc (98:2) to CHCl3 :EtOAc (1:2) to afford the title compound; mp 356°-358° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([Sn](C)(C)C)[N:7]=[C:6]([C:14]#[N:15])[N:5]=1)[CH2:2][CH3:3].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][C:19]=1[C:25]([F:28])([F:27])[F:26]>CN(C)C=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>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:8]2[CH:9]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]=[C:6]([C:14]#[N:15])[N:7]=2)=[CH:20][C:19]=1[C:25]([F:28])([F:27])[F:26]
Reactant: COc1ccc(Br)cc1C(F)(F)F
Reactant: CCCc1cc([Sn](C)(C)C)nc(C#N)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCCc1cc(-c2ccc(OC)c(C(F)(F)F)c2)nc(C#N)n1
Temperature: 80 °C
Yield: 11.7 %

Procedure:
Bis(triphenylphosphine)palladium dichloride (34 mg, 0.05 mmol) was added under a nitrogen atmosphere to a mixture of 4-propyl-6-trimethylstannanyl-pyrimidine-2-carbonitrile (150 mg, 0.48 mmol) and 4-methoxy-3-trifluoromethyl-bromobenzene (148 mg, 0.58 mmol) in dimethylformamide (3 mL). The mixture was heated for 5 hours at 80° C. then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The residue was chromatographed over silica gel (eluent Cyclohexane/DCM 7/3) to afford a solid which was triturated in pentane. After filtration, 4-(4-methoxy-3-trifluoromethyl-phenyl)-6-propyl-pyrimidine-2-carbonitrile (18 mg, 11%) was obtained as an off white solid.
Reaction SMILES: [CH3:1][NH2:2].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]3[C:20]4[C:19]5[CH:21]=[C:22]([NH:25][C:26]([C:28]6[C:33]([Cl:34])=[CH:32][CH:31]=[C:30](Cl)[N:29]=6)=[O:27])[CH:23]=[CH:24][C:18]=5[CH2:17][CH2:16][C:15]=4[C:14]([C:36]([NH2:38])=[O:37])=[N:13]3)=[CH:11][C:6]=2[O:5][CH2:4]1>CC(N(C)C)=O>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]3[C:20]4[C:19]5[CH:21]=[C:22]([NH:25][C:26]([C:28]6[C:33]([Cl:34])=[CH:32][CH:31]=[C:30]([NH:2][CH3:1])[N:29]=6)=[O:27])[CH:23]=[CH:24][C:18]=5[CH2:17][CH2:16][C:15]=4[C:14]([C:36]([NH2:38])=[O:37])=[N:13]3)=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: CN
Reactant: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3nc(Cl)ccc3Cl)cc1-2
Solvent: CC(=O)N(C)C
Product: CNc1ccc(Cl)c(C(=O)Nc2ccc3c(c2)-c2c(c(C(N)=O)nn2-c2ccc4c(c2)OCO4)CC3)n1
Reaction time: 120 h

Procedure:
The title compound was synthesized from N-methylamine (6 mL of 33 w % solution in EtOH) and the compound of Example 216 (1.04 g) by the same procedure used for Example 207 except that 1 mL of DMA was added. The reaction was carried out at 82° C. for 5 days. The title compound, isolated by preparative HPLC, is a white solid (0.29 g, 52%), M.p. 269-270° C. (decomposition). Its structure was confirmed by 1H NMR and LC/MS: 1H NMR (d6-DMSO): δ 2.76 (d, 3H, J=5.5 Hz), 2.84-3.99 (m, 4H), 6.16 (s, 2H), 6.57 (d, 1H, J=9 Hz), 6.91-7.04 (m, 3H), 7.12 (d, 1H, J=1 Hz), 7.22-7.34 (m, 3H), 7.46-7.54 (m, 3H), 10.19 (s, 1H). ESI mass spectrum for C26H22ClN6O4+: 517 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:13]=1)[C:8]([OH:10])=[O:9])=[O:4].CN(C1C=CC=CN=1)C.[C:28](O)([CH3:31])([CH3:30])[CH3:29].C(Cl)CCl>C(Cl)Cl>[CH3:18][S:15]([O:14][C:12]1[CH:13]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=[C:7]([CH:11]=1)[C:8]([O:10][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:9])(=[O:17])=[O:16]
Reactant: COC(=O)c1cc(OS(C)(=O)=O)cc(C(=O)O)c1
Reactant: CC(C)(C)O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)c1cc(OS(C)(=O)=O)cc(C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 3-(methoxycarbonyl)-5-[(methylsulfonyl)oxy]benzoic acid (0.74 g, 2.7 mmol) in DCM (25 mL) was added dimethylaminopyridine (0.165 g, 1.35 mmol) and tert-butanol (0.226 g, 3.05 mmol). The reaction mixture was cooled to 0° C. To the reaction was added EDC (0.569 g, 2.97 mmol). The reaction stirred at 0° C. for 2 h and then warmed to room temp over 16 h. The reaction mixture was washed with 1N HCl, H2O, dried with MgSO4, filtered, concentrated and purified by flash chromatography (25 g silica, 10-30% EtOAc/hexanes) to give 0.74 g (83%) of tert-butyl methyl 5-[(methylsulfonyl)oxy]isophthalate. 1H NMR (400 MHz, CDCl3) δ 8.58 (m, 1H), 8.09 (m, 1H), 8.05 (m, 1H), 3.96 (s, 3H), 3.23 (s, 3H) 1.61 (s, 9H).
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[C:11]([OH:13])=O.S(Cl)(Cl)=O.[CH2:18]([C@@H:25]1[CH2:30][C@@H:29]([NH2:31])[CH2:28][CH2:27][N:26]1[C:32](=[O:41])[C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([Cl:40])[CH:34]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>>[CH2:18]([C@@H:25]1[CH2:30][C@@H:29]([NH:31][C: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)=[O:13])[CH2:28][CH2:27][N:26]1[C:32](=[O:41])[C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([Cl:40])[CH:34]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1)c1ccc2ccccc2c1
Yield: 95.6 %

Procedure:
142 mg (0.825 mmol) of 2-naphthoic acid are reacted in analogy to Example 2a first with 2 ml (27 mmol) of thionyl chloride and subsequently with 200 mg (0.550 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine and 138 μl (0.991 mmol) of triethylamine to give the title compound (272 mg, 96%). ##STR83## TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.73, FD-MS: (M+H)+ =516, 518, 520, IR: 3420, 1625 cm-1.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.[C:9]12([C:19](Cl)=[O:20])[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2.C(OCC)C>C(N(CC)CC)C>[C:9]12([C:19]([C:5]3[NH:1][N:2]=[C:3]([C:6]([NH2:8])=[O:7])[N:4]=3)=[O:20])[CH2:16][CH:15]3[CH2:14][CH:13]([CH2:12][CH:11]([CH2:17]3)[CH2:10]1)[CH2:18]2
Reactant: NC(=O)c1nc[nH]n1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: NC(=O)c1n[nH]c(C(=O)C23CC4CC(CC(C4)C2)C3)n1

Procedure:
To a cooled, stirred mixture of 2 g. of 1,2,4-triazole-3-carboxamide and 5.4 g. of adamantylcarbonyl chloride in 125 ml. of anhydrous diethyl ether is added rapidly 2.75 g. of triethylamine. The cooling bath is removed and the mixture is stirred at room temperature for 23.5 hours. The mixture is filtered and the solid is washed successively with diethyl ether, cold water, diethyl ether and dried in vacuo for 3 hours yielding 4.5 g. of colorless solid. This solid is extracted with hot dry acetonitrile, cooled and washed with acetonitrile yielding 0.4 g. of colorless crystals. The remaining 3.5 g. of acetonitrile insoluble solid is further extracted with acetonitrile, yielding an additional 0.6 g. of product, m.p. 213°-216° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][C:8](=[O:19])[CH2:9][N:10]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[CH:12]=[C:11]3[C:4]=2[CH:3]=1.[CH2:22]1COCC1>>[Br:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][C:8]([CH3:22])([OH:19])[CH2:9][N:10]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[CH:12]=[C:11]3[C:4]=2[CH:3]=1
Reactant: O=C1COc2ccc(Br)cc2-c2cc3ccccc3n2C1
Reactant: C1CCOC1
Product: CC1(O)COc2ccc(Br)cc2-c2cc3ccccc3n2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
MgBrCH3 (0.12 mL, 0.352 mmol) was added to the solution of 2-bromo-6H-benzo[2,3][1,5]oxazocino[5,4-a]indol-7(8H)-one (60 mg, 0.176 mmol) in THF (1 mL) at 0° C. under N2. The mixture was stirred at room temperature for 30 minutes. The mixture was then quenched with saturated NH4Cl (10 mL) and extracted with ethyl acetate (10 mL×3). The organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using p-TLC (petroleum ether:EA=3:1) to provide 2-bromo-7-methyl-7,8-dihydro-6H-benzo[2,3][1,5]oxazocino[5,4-a]indol-7-ol (30 mg, yield: 47.6%). 1H-NMR(CDCl3, 400 MHz) δ 7.56˜7.59 (m, 2H), 7.36˜7.40 (m, 2H), 7.18˜7.22 (m, 1H), 7.08 (t, J=7.2 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 6.61 (s, 1H), 3.81˜4.15 (m, 4H), 2.34 (s, 1H), 1.24 (s, 3H). MS (M+H)+: 358/360.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]([CH2:11][C:12]1[CH:13]=[C:14]([CH:48]=[CH:49][CH:50]=1)[C:15]([NH:17][C:18]1[S:19][C:20]2[CH2:47][CH2:46][CH2:45][CH2:44][C:21]=2[C:22]=1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)=[O:24])=[O:16])[CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8].C(N(C(C)C)C(C)C)C.[CH3:60][C:61]1([CH3:68])[CH2:65][C:64](=[O:66])[O:63][C:62]1=[O:67]>O1CCOCC1>[CH3:41][O:40][C:38]([C:37]1[CH:42]=[CH:43][C:34]([CH2:33][CH2:32][C:29]2[CH:28]=[CH:27][C:26]([NH:25][C:23]([C:22]3[C:21]4[CH2:44][CH2:45][CH2:46][CH2:47][C:20]=4[S:19][C:18]=3[NH:17][C:15]([C:14]3[CH:13]=[C:12]([CH:50]=[CH:49][CH:48]=3)[CH2:11][N:5]([CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8])[CH2:4][CH2:3][N:2]([CH3:1])[C:64](=[O:66])[CH2:65][C:61]([CH3:68])([CH3:60])[C:62]([OH:63])=[O:67])=[O:16])=[O:24])=[CH:31][CH:30]=2)=[CH:35][CH:36]=1)=[O:39]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: CCC(CC)N(CCNC)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)N(CCN(C)C(=O)CC(C)(C)C(=O)O)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a mixture of 200 mg of methyl 4-[2-(4-{[(2-{[3-({[2-(methylamino)ethyl](pentan-3-yl)amino}methyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 48 mg of N-ethyl-N-isopropylpropan-2-amine and 4 mL of dioxane was added 44 mg of 3,3-dimethyldihydrofuran-2,5-dione, followed by stirring overnight at 65° C. The reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography, thereby obtaining 200 mg of 4-[(2-{[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)benzyl](pentan-3-yl)amino}ethyl)(methyl)amino]-2,2-dimethyl-4-oxobutanoic acid.
Reaction SMILES: C(O[CH:6]=[CH:7][C:8](=O)[C:9]([F:12])([F:11])[F:10])CCC.C[CH2:15][O:16][C:17]([CH2:19][C:20]([NH2:22])=[O:21])=[O:18].C[O-].[Na+].Cl>CO.O>[O:21]=[C:20]1[C:19]([C:17]([O:16][CH3:15])=[O:18])=[CH:6][CH:7]=[C:8]([C:9]([F:10])([F:11])[F:12])[NH:22]1
Reactant: CCOC(=O)CC(N)=O
Reactant: CCCCOC=CC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(C(F)(F)F)[nH]c1=O
Temperature: 25 °C
Yield: 75.4 %

Procedure:
To a stirred solution of 2.0 g (0.0102 mol) of 4-butoxy-1,1,1-trifluoro-3-buten-2-one (VIIIa) and 1.3 g (0.0102 mol) of ethyl malonate monoamide in 10 mL methyl alcohol was added 2.2 mL (0.0102 mol) of a 25% solution of sodium methoxide in methanol. The solution turned into a thick yellow suspension which was refluxed overnight. The suspension was cooled to room temperature, poured into water, acidified with one normal hydrochloric acid and extracted with methylene chloride. The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated to afford 1.7 g (74%) of a yellow solid. m.p. 63°-64° C.; 1H NMR (CDCl3) δ4.0 (3H, s), 7.33 (1H, d, J=8 Hz), 8.4 (1H, d, J=8 Hz); IR (mineral oil) 3080, 1675 (br), 1605, 1450, 1375 cm-1.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.I[CH3:14]>O1CCCC1>[CH3:14][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: CI
Reactant: c1ccc2c(c1)CCCN2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCCc2ccccc21
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
NaH (12 g, 60%, 300.00 mmol) was added in several batches, to a solution of 1,2,3,4-tetrahydroquinoline (26.6 g, 199.70 mmol) in tetrahydrofuran (150 mL) at 0-5° C. The resulting solution was maintained at 0-5° C. for 30 minutes, then iodomethane (50 g, 352.11 mmol) was added dropwise (at 0-5° C.). The resulting solution was then stirred at room temperature overnight. The mixture was filtered, and the filtrate was purified by column chromatography using a 1:100 ethyl acetate/petroleum ether solvent system to afford 19 g (61%) of 1-methyl-1,2,3,4-tetrahydroquinoline as a yellow liquid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[NH:12][C:11]([CH:13]=[O:14])=[C:10](C(O)=O)[C:9]=1[CH2:18][CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[I:25]I>C(Cl)Cl.O>[CH2:18]([C:9]1[C:10]([I:25])=[C:11]([CH:13]=[O:14])[NH:12][C:8]=1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:19]
Reactant: II
Reactant: CCc1c(C(=O)OC(C)(C)C)[nH]c(C=O)c1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCc1c(C(=O)OC(C)(C)C)[nH]c(C=O)c1I
Temperature: 25 °C

Procedure:
To a solution of 5-(tert-butoxycarbonyl)-4-ethyl-2-formyl-1H-pyrrole-3-carboxylic acid (0.548 g, 2.05 mmol) in CH2Cl2 (8.30 mL) was added a solution of NaHCO3 (0.691 g, 8.21 mmol) water (8.2 mL). The mixture was stirred vigorously during the addition of a solution of KI (1.021 g, 6.15 mmol) and I2 (0.570 g, 2.23 mmol) in water (11.15 mL). The resultant mixture was heated to 45° C. for 60 min until the initial red/brown color faded. The reaction was cooled to ambient temperature and quenched with saturated aqueous Na2SO3 (25 ml) prior to separation of the phases. The aqueous layer was extracted with CH2Cl2 (1×30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The resultant residue was purified by normal phase chromatography (10-30% ethyl acetate/hexanes). Proton NMR for the product was consistent with the title compound. 1H NMR (500 MHz, CD3OD) δ 9.59 (s, 1H); 2.77 (q, J=7.6 Hz, 2H); 1.60 (s, 9H); 1.10 (t, J=7.6 Hz, 3H). HRMS (ES) exact mass calculated for C12H16INNaO3 (M+Na+): 372.0072. Found 372.0067.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([CH3:12])[CH:11]=[C:4]2[N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]2[N:9]=[C:10]([CH3:12])[CH:11]=[C:4]2[N:3]=1
Reactant: Cc1cc2nc(Cl)cc(Cl)n2n1
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: Cc1cc2nc(Cl)cc(N3CCOCC3)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
There was dissolved, in 1,4-dioxane (20 mL), 5,7-dichloro-2-methyl-pyrazolo-[1,5-a]pyrimidine (1.00 g, 4.95 mM), then morpholine (863 μL, 9.90 mM) was added to the solution and the mixture was stirred at room temperature for one hour. The solvent was then distilled off from this reaction mixture, the resulting residue was diluted with water and the mixture was extracted with methylene chloride. The resulting extracts were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with methanol to thus give the title compound (927 mg, yield: 74%).