Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:27][CH3:28])=[C:8]([O:25][CH3:26])[CH:9]=2)[N:4]=1.[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:27][CH3:28])=[C:8]([O:25][CH3:26])[CH:9]=3)[N:4]=[C:3]([CH2:2][N:31]([CH2:32][CH3:33])[CH2:29][CH3:30])[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(F)cc1
Reactant: CCNCC
Product: CCOC(=O)c1c(CN(CC)CC)nc2cc(OC)c(OC)cc2c1-c1ccc(F)cc1

Procedure:
According to the same manner as that described in Example 33, ethyl 2-chloromethyl-4-(4-fluorophenyl)-6,7-dimethoxyquinoline-3-carboxylate was reacted with diethylamine to give ethyl 4-(4-fluorophenyl)-2-(N,N-diethylaminomethyl)-6,7-dimethoxyquinoline-3-carboxylate. This compound was recrystallized from ethyl acetate - hexane. Colorless prisms, mp. 102°-103° C.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][NH2:14])[C:5]=2[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH:22]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23]1>ClCCl>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][NH:14][C:26]([CH:22]3[CH2:25][CH2:24][CH2:23]3)=[O:27])[C:5]=2[CH2:4][CH2:3]1
Reactant: NCCCc1cccc2c1CCO2
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCc1cccc2c1CCO2)C1CCC1
Reaction time: 3 h

Procedure:
3-(2,3-Dihydro-benzofuran-4-yl)-propylamine hydrochloride (100 mg) was suspended in dichloromethane (3 ml) containing triethylamine (0.33 ml) and cooled in ice. A solution of cyclobutanecarbonyl chloride (0.054 ml) in dichloromethane (1 ml) was added and the mixture stirred in ice for 3 h. The mixture was purified by elution through a solid phase extraction cartridge to give the title compound as a white solid (110 mg).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([S:7]([O:10][C:11](=[O:25])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.O.[C:28]1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1.C1(C(C2C=CC=CC=2)=C=O)C=CC=CC=1>C(OCC)C>[C:5]1([CH3:28])[C:4]([S:7]([O:10][C:11](=[O:25])[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=[CH:1][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(=O)C(c2ccccc2)c2ccccc2)cc1
Agent: O=C=C(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1ccccc1S(=O)(=O)OC(=O)C(c1ccccc1)c1ccccc1
Temperature: 22.5 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
The preparation of diphenylacetyl p-toluenesulfonate. A 100-mL, flask equipped with a magnetic stirring bar and Dean-Stark apparatus was charged with p-toluenesulfonic acid monohydrate (9.51 g, 0.05 mol) and toluene (60 mL). The mixture was refluxed for 2 h to remove water and toluene was distilled off to 10 mL volume at normal pressure. This residue was cooled to 20-25° C. and added dropwise to a stirred solution of diphenylketene (9.7 g, 0.05 mol) in anhydrous diethylether (20 mL) at 0-5° C. over 3-5 min. The orange solution of diphenylketene became slightly yellow; the reaction mixture was stirred for 6 h at 0-5° C. The formed precipitate was filtered under a nitrogen atmosphere, washed with anhydrous diethyl ether (15 mL) and dried in a nitrogen flow giving diphenylacetyl toluenesulphonate (12.3 g, 67%), as off white prisms, m.p. 84-87° C. (decomposition). 1H NMR (CDCl3) δ 2.43 (s, 3H), 5.01 (s, 1H), 7.10-7.16 (m, 4H), 7.24-7.32 (m, 8H), 7.82 (d, J=7.9 Hz, 2H); 13C NMR (CDCl3) δ 21.7, 57.0, 127.8, 128.4, 128.8, 129.0, 129.6, 132.6, 136.2, 146.0, 165.5. Anal. Calcd. for C21H18O4S (366.44): C, 68.83; H, 4.95. Found: C, 68.61; H, 4.89.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11](=[O:24])[CH:12]=[C:13]([C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[CH:22][N:23]=2)[CH:20]=1)[CH3:14]>C(#N)C.C(OCC)(=O)C>[CH3:9][O:10][C:11](=[O:24])[CH:12]=[C:13]([C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([I:1])=[CH:22][N:23]=2)[CH:20]=1)[CH3:14]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)C=C(C)c1ccc2nccn2c1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)C=C(C)c1ccc2ncc(I)n2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
N-iodosuccinimide (252 mg, 1.12 mmol) was added to a mixture of 3-imidazo[1,2-a]pyridin-6-yl-but-2-enoic acid methyl ester (220 mg, 1.02 mmol) in acetonitrile (10 mL) which had been cooled to 0° C. under nitrogen atmosphere. The mixture was stirred for 1 h, then diluted with ethyl acetate (30 mL) and washed with saturated sodium bicarbonate solution (2×10 mL), and brine (1×15 mL). The organic layers were combined, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography (chromatotron, 4μ plate, 50% ethyl acetate in hexanes) to yield 3-(3-iodo-imidazo[1,2-a]pyridin-6-yl)-but-2-enoic acid methyl ester as a pale yellow solid (168.1 mg, 48%). 1H NMR (250 MHz, CDCl3): δ 8.27 (bs, 1H), 7.77 (s, 1H), 7.64 (d, 1H, J=9.4), 7.41 (dd, 1H, J=9.4, J=1.6), 6.27 (d, 1H, J=0.62), 3.84 (s, 3H), 2.68 (d, 3H, J=0.62). MS [EI+] 343 (M+H)+.
Reaction SMILES: [SH:1][C@@H:2]([CH3:13])[C:3]([N:5]1[C@H:9]([C:10]([OH:12])=[O:11])[CH2:8][S:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([C:26](Cl)=[O:27])=[CH:22][CH:21]=1>O>[CH3:29][C:20]1[CH:25]=[CH:24][C:23]([C:26]([S:1][C@@H:2]([CH3:13])[C:3]([N:5]2[C@H:9]([C:10]([OH:12])=[O:11])[CH2:8][S:7][CH2:6]2)=[O:4])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: C[C@H](S)C(=O)N1CSC[C@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(C(=O)S[C@@H](C)C(=O)N2CSC[C@H]2C(=O)O)cc1
Temperature: 25 °C

Procedure:
2.2 g of (4R)-3-[(2S)-2-mercaptopropanoyl]-4-thiazolidinecarboxylic acid and 2.8 g of potassium carbonate are dissolved in 50 ml of water. To this solution, 1.6 g of p-toluoyl chloride is added dropwise with stirring under ice-cooling. After the addition, the mixture is stirred under ice-cooling for 1 hour and at room temperature for additional 1 hour. The reaction solution is washed with ethyl acetate, and acidified with conc. hydrochloric acid to give crystals. The crystals (the titled compound) are collected by filtration, yield 3.3 g (97%), mp. 166°-166.5° C. (ethyl acetate), [α]D25 -148.6° (c=1.1, methanol).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10](Cl)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[N:15]=1.C1N2CCN(CC2)C1>C(#N)C>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:20][C:16]2[N:15]=[N:14][CH:19]=[CH:18][CH:17]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Reactant: Nc1cccnn1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: N#Cc1cc(S(=O)(=O)Nc2cccnn2)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.7 %

Procedure:
To a solution of 3-cyano-4-fluorobenzenesulfonyl chloride (11.55 g, 52.63 mmol) in anhydrous acetonitrile (250 mL) was added pyridazin-3-amine (5 g, 52.63 mmol) followed by DABCO (5.9 g, 52.63 mmol) at 0° C. The reaction was stirred at room temperature for 18 hours, and then filtered. The filtrate was concentrated in vacuo and purified using silica gel column chromatography to afford the title compound (4.5 g, 30%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:18](=[O:19])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:33]([O:35][CH:36]1[CH:41]([CH:42]([CH3:44])[CH3:43])[CH2:40][CH2:39][CH:38]([CH3:45])[CH2:37]1)=[O:34]>C1COCC1>[CH:38]1([CH3:45])[CH2:39][CH2:40][CH:41]([CH:42]([CH3:44])[CH3:43])[CH:36]([O:35][C:33]([CH:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:20])[N:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[F:21])[C:18]2=[O:19])=[O:34])[CH2:37]1
Reactant: O=C1Cc2ccccc2C(=O)N1Cc1ccc(Br)cc1F
Reactant: CC1CCC(C(C)C)C(OC(=O)Cl)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1CCC(C(C)C)C(OC(=O)C2C(=O)N(Cc3ccc(Br)cc3F)C(=O)c3ccccc32)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.4 %

Procedure:
To a cold (-78° C.) solution of 2-[(4-bromo-2-fluorophenyl)methyl]-1,3(2H, 3H)-isoquinolinedione (9.0 g, 25.86 mmol) in anhydrous THF (120 mL) was added lithium bis(trimethylsilyl)amide (1.0M solution in THF, 56.91 mL, 56.91 mmol), dropwise over a 10 minute period. After stirring for 3 hours, (-)menthyl chloroformate (8.48 mL, 38.79 mmol) was added and the reaction was allowed to warm up to room temperature. The mixture during that period turned a dark color. It was stirred an additional 30 minutes and quenched with H2O. The dark solution was poured into H2O, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on acid-washed silica gel (5% H3PO4 in MeOH) gave a clear oil (10.2 g).
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[CH2:13]O>C(Cl)Cl>[Br:2][CH2:13][C:7]1[CH:8]=[C:9]([I:12])[CH:10]=[CH:11][C:6]=1[F:5]
Reactant: BrP(Br)Br
Reactant: OCc1cc(I)ccc1F
Solvent: ClCCl
Product: Fc1ccc(I)cc1CBr

Procedure:
Phosphorus tribromide 1.0 M soln. in DCM (18.9 mL, 18.9 mmol) was added dropwise to a 0° C. solution of (2-fluoro-5-iodo-phenyl)-methanol G-6 (9.52 g, 37.8 mmol) in DCM (215 mL) and the resulting mixture was stirred for 1 h before being quenched with water. The layers were separated and the aqueous phase was re-extracted with DCM (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give the crude product that was purified by flash chromatography (eluting with 5% EtOAc in hexane) to give the title compound as a white solid. LC-MS B: tR=0.92 min; No ionisation; 1H NMR (DMSO) δH: 7.93 (dd, J1=7.1 Hz, J2=2.3 Hz, 1H), 7.74 (ddd, J1=8.6 Hz, J2=4.9 Hz, J3=2.3 Hz, 1H), 7.10 (dd, J1=10.0 Hz, J2=8.7 Hz, 1H), 4.66 (s, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][O:22][CH2:23][C:24]#[N:25])[C:18]3[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.ClCCl.CO.[IH:35]>C(OCC)C>[IH:35].[C:24]([CH2:23][O:22][CH2:21][CH2:20][N:19]1[C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[N:16]=[C:15]1[N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1)#[N:25]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCOCC#N)CC1
Agent: I
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: N#CCOCCn1c(N2CCCNCC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-(2-cyanomethyloxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.36 g, 0.91 mmol), dichloromethane (15 mL), and methanol (5 mL). Cool in an ice bath and add hydriodic acid (0.25 mL, 57%, 1.86 mmol). Warm to ambient temperature. After 5 hours, concentrate the reaction mixture in vacuo to give a residue. Combine the residue and diethyl ether (40 mL) and stir. After 18 hours, decant the solvent, add diethyl ether, and stir to give a solid. Collect the solid by filtration and dry to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]2=[C:15]3[N:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9][CH2:8][CH2:7][C:6]3=[CH:5][C:4]=1[CH:16]=[CH:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1.C([Li])CCC.CN(C)[CH:30]=[O:31].O>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:14]2=[C:15]3[N:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9][CH2:8][CH2:7][C:6]3=[CH:5][C:4]=1[CH:16]=[CH:17][C:18]1[S:19][C:20]([CH:30]=[O:31])=[CH:21][CH:22]=1
Reactant: CN(C)C=O
Reactant: COc1c(C=Cc2cccs2)cc2c3c1CCCN3CCC2
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1c(C=Cc2ccc(C=O)s2)cc2c3c1CCCN3CCC2
Temperature: -70 °C
Reaction time: 1 h
Yield: 35.5 %

Procedure:
In a stream of argon, in 25 ml of tetrahydrofuran was dissolved 1.29 g (4.14 mmol) of 8-methoxy-9-[2-(thiophene-2-yl)vinyl]-2,3,6,7-tetrahydro-1H,5H-benzo[ij]quinolizine, and 3.9 ml of n-butyllithium (1.6 mol solution in hexane) (6.24 mmol) was added dropwise thereto under cooling at −70° C. After the mixture was stirred for 1 hour, 0.43 g (5.88 mmol) of N,N-dimethylformamide was added dropwise thereto. The reaction mixture was stirred for 1 hour and the temperature was allowed to rise. To this mixture, 10 ml of water was added dropwise. After the reaction mixture was added to water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residual liquid was dissolved in 300 ml of ether and 50 mg of iodine pieces were added thereto. After stirred at room temperature, the mixture was washed with a 5% sodium bisulfite solution and then with a saturated saline solution. Drying over anhydrous sodium sulfate and concentration were performed. The residue was purified by silica gel column chromatography to give 496 mg of a dark reddish brown oily matter (yield: 35.5%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:11][C:12]([OH:14])=O)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].S(Cl)([Cl:17])=O>>[Cl:17][C:12](=[O:14])[CH2:11][C:5]1([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: COC(=O)C1(CC(=O)O)CCOCC1
Reactant: O=S(Cl)Cl
Product: COC(=O)C1(CC(=O)Cl)CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
Thionyl chloride (20 mL) was added to [4-(methoxycarbonyl)tetrahydro-2H-pyran-4-yl]acetic acid (970 mg, 4.80 mmol) and the solution was stirred at rt for 3 h. The solvent was then removed and mixture was azeotroped with dichloroethane three times to afford methyl 4-(2-chloro-2-oxoethyl)tetrahydro-2H-pyran-4-carboxylate (1.05 g, 99%), which was used without purification in the next step.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@H:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:35]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:3]([C:1]([NH2:2])=[O:35])=[N:4][CH:5]=1)[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C[C@@H](Nc1cnc(C#N)c(Nc2cnc3ccccc3c2)n1)C(N)=O
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: CC(C)C[C@@H](Nc1cnc(C(N)=O)c(Nc2cnc3ccccc3c2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-4-methylpentanamide (70 mg, 0.261 mmol), 3-aminoquinoline (60 mg, 0.416 mmol), K2CO3 (60 mg, 0.434 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 100 C for 20 h. Water and EtOAc were added. Organic phase was separated, dried over Na2SO4, concentrated in vacuo to give (R)-2-(5-cyano-6-(quinolin-3-ylamino)pyrazin-2-ylamino)-4-methylpentanamide as a crude residue (131 mg). The crude (R)-2-(5-cyano-6-(quinolin-3-ylamino)pyrazin-2-ylamino)-4-methylpentanamide (131 mg) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (30 mg). MS 394.4 (M+H); UV 201.1, 247.4, 297.8, 352.3 nm; t 0.476 min.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH:11]([CH2:28][CH2:29][CH3:30])[C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[O:1][CH:11]([CH2:28][CH2:29][CH3:30])[C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5]
Reactant: O=Cc1ccccc1O
Reactant: CCCC(Br)C(=O)OC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCC(Oc1ccccc1C=O)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 103.6 %

Procedure:
A mixture of 2-hydroxybenzaldehyde (2.44 g), diphenylmethyl 2-bromopentanoate (7.26 g), and potassium carbonate (3.45 g) in dimethylsulfoxide (20 ml) was stirred at room temperature for 5 hours. The mixture was diluted with water, neutralized with 1N hydrochloric acid, and was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated to give diphenylmethyl 2-(2-formylphenoxy)-pentanoate (8.04 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=O.[NH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)CC)C.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:7]
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: NCCN1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Nc1ccc(C(=O)NCCN2CCOCC2)cc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.9 %

Procedure:
3,4-Diaminobenzoic acid (5 g, 32.9 mmol), 4-(2-aminoethyl)morpholine (5.2 mL, 39.4 mmol), triethylamine (9.2 mL, 66 mmol), and DMAP (0.40 g, 3.3 mmol) were combined in dry DMF (80 mL) at 0° C. EDC (9.45 g, 49.3 mmol) was added, and the reaction stirred for 24 h at r.t. Concentration in vacuo and purification by silica gel chromatography (10% MeOH/CH2Cl2 with 0.2% NH4OH) gave 2.6 g (31%) of 3,4-diamino-N-(2-morpholin-4-yl-ethyl)-benzamide as a light brown solid. 1H NMR (300 MHz, DMSO-d6) δ 7.72 (t, 1H, J=5.4 Hz), 7.02 (d, 1H, J=1.8 Hz), 6.92 (dd, 1H, J=8.1, 1.8 Hz), 6.46 (d, 1H, J=8.1 Hz), 4.89 (br s, 2H), 4.51 (br s, 2H), 3.55 (t, 4H, J=4.8 Hz), 3.29 (q, 2H, J=7.2 Hz), 2.36-2.43 (m, 6H).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:13])[NH:6][CH2:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])[CH2:2][CH3:3].[S:14](=[O:18])(=[O:17])([OH:16])[OH:15]>CCOCC>[CH2:1]([O:4][C:5](=[O:13])[NH:6][CH2:7][CH2:8][CH2:9][NH+:10]([CH3:11])[CH3:12])[CH2:2][CH3:3].[S:14]([O-:18])([OH:17])(=[O:16])=[O:15]
Reactant: O=S(=O)(O)O
Reactant: CCCOC(=O)NCCCN(C)C
Solvent: CCOCC
Product: CCCOC(=O)NCCC[NH+](C)C
Product: O=S(=O)([O-])O
Reaction time: 2 h

Procedure:
11.0 g (0.0585 mole) of N-(3-dimethylaminopropyl)-carbamic acid propylester are dissolved in 200 ml of ether. While stirring and cooling, 3.2 ml (0.06 mole) of concentrated sulfuric acid are added in drops. Agitation is continued for 2 hours at room temperature, the ether is decanted, the oil is washed with ether and dried in vacuum. One obtains 15.0 g (89.7% of the theory) of the Mp. 44°-50° C.
Reaction SMILES: C(N(CC)C(C)C)(C)C.OC(C(F)(F)F)=O.[NH:17]1[C:21]2=[N:22][CH:23]=[CH:24][C:25]([C:26]3[CH:27]=[N:28][N:29]([C:31]4([CH2:35][C:36]#[N:37])[CH2:34][NH:33][CH2:32]4)[CH:30]=3)=[C:20]2[CH:19]=[CH:18]1.[F:38][C:39]1[CH:40]=[C:41]([CH:46]=[CH:47][C:48]=1F)[C:42]([O:44][CH3:45])=[O:43].C([O-])(O)=O.[Na+]>CN1CCCC1=O>[C:36]([CH2:35][C:31]1([N:29]2[CH:30]=[C:26]([C:25]3[CH:24]=[CH:23][N:22]=[C:21]4[NH:17][CH:18]=[CH:19][C:20]=34)[CH:27]=[N:28]2)[CH2:32][N:33]([C:48]2[CH:47]=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:40][C:39]=2[F:38])[CH2:34]1)#[N:37]
Reactant: N#CCC1(n2cc(-c3ccnc4[nH]ccc34)cn2)CNC1
Reactant: COC(=O)c1ccc(F)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ccnc5[nH]ccc45)cn3)C2)c(F)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
N,N-Diisopropylethylamine (1.6 mL, 9.5 mmol) was added to {3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile TFA salt (2.4 mmol) and methyl 3,4-difluorobenzoate (0.41 g, 2.4 mmol) (Aldrich, Cat. #: 594717) in N-methylpyrrolidinone (NMP) (5.0 mL). The reaction mixture was stirred at 130° C. overnight. The reaction mixture was worked up with saturated aqueous NaHCO3, extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in dichloromethane (0-5%) to afford the desired product (0.34 g, 33%). LCMS (M+H)+: m/z=431.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3[CH:17]=[C:18]4[O:23][CH2:22][O:21][C:19]4=[CH:20][C:15]=3[CH2:14][C:13](=S)[NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:25][CH2:26][C:27]1([CH:32]2[CH2:34][CH2:33]2)OCCO1>COCCO.[Hg]=O>[CH:32]1([C:27]2[N:12]3[N:11]=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)[C:16]4[CH:17]=[C:18]5[O:23][CH2:22][O:21][C:19]5=[CH:20][C:15]=4[CH2:14][C:13]3=[N:25][CH:26]=2)[CH2:34][CH2:33]1
Reactant: O=[N+]([O-])c1ccc(C2=NNC(=S)Cc3cc4c(cc32)OCO4)cc1
Reactant: NCC1(C2CC2)OCCO1
Agent: O=[Hg]
Solvent: COCCO
Product: O=[N+]([O-])c1ccc(C2=Nn3c(C4CC4)cnc3Cc3cc4c(cc32)OCO4)cc1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A suspension of 0.50 g (1.47 mmol) of 5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-8-thione (Example 15D) and 0.42 g (2.94 mmol) of 2-aminomethyl-2-cyclopropyl-1,3-dioxolane in 12 ml of Methyl Cellosolve® with 0.32 g (1.47 mmol) of red mercury oxide is stirred for 12 hours at 110° C. After filtration, the mixture is concentrated by evaporation to a volume of 5 ml and poured into water. The precipitate is suctioned off and dissolved in 10 ml of a 1:1 mixture of concentrated hydrochloric acid and glacial acetic acid and heated to boiling for 1.5 hours. During cooling, the hydrochloride salt of the title compound precipitates.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[C:5]([C:13]([OH:15])=O)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(OC(Cl)=O)C.O.N[N:24]1[N:28]=[N:27][CH:26]=[N:25]1.C[N:30](C)C=O>C(N(CC)CC)C>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[C:5]([C:13](=[O:15])[NH:30][C:26]3[NH:25][N:24]=[N:28][N:27]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(C)c2cccc(C(=O)O)c2n1
Reactant: Nn1ncnn1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C)c2cccc(C(=O)Nc3nnn[nH]3)c2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred ice bath-cooled solution of 4.0 g. (0.020 mole) of 2,4-dimethyl-8-quinoline carboxylic acid in 20 ml. of N,N-dimethyl formamide is added 2.8 ml. of triethyl amine. To this solution is added dropwise 2 ml. of ethylchloroformate. The mixture is stirred for one hour, then 2 g. (0.020 mole) of 2-aminotetrazole monohydrate in 10 ml. of N,N-dimethylformamide is added. The mixture is stirred at 20° C. for about 16 hours then evaporated to provide a residue which is washed with water. The residue is recrystallized twice from acetic acid to provide 2,4-dimethyl-8-(1H-tetrazole-5-ylcarbamoyl)quinoline, m.p. 300°-305° C.