Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:21][C:22]([O:25][C:26](=[O:72])[C@H:27]([CH2:67][CH2:68][CH2:69][CH2:70][NH2:71])[N:28]([CH2:48][CH2:49][N:50]([CH2:59][C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:29][CH2:30][N:31]([CH2:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:24])[CH3:23]>C(Cl)(Cl)Cl>[CH3:24][C:22]([O:25][C:26](=[O:72])[C@H:27]([CH2:67][CH2:68][CH2:69][CH2:70][NH:71][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:28]([CH2:29][CH2:30][N:31]([CH2:40][C:41]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:47])[CH2:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])[CH2:48][CH2:49][N:50]([CH2:51][C:52](=[O:58])[O:53][C:54]([CH3:55])([CH3:56])[CH3:57])[CH2:59][C:60](=[O:61])[O:62][C:63]([CH3:64])([CH3:65])[CH3:66])([CH3:21])[CH3:23]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)CN(CCN(CCN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)[C@@H](CCCCN)C(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCC[C@@H](C(=O)OC(C)(C)C)N(CCN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 62.2 %

Procedure:
Stearoyl chloride (5.45 g; 18 mmol) dissolved in CHCl3 (60 mL) was added dropwise in 1 h to a solution of N2,N2-bis[2-[bis[2-(1,1-dimethylethoxy)-2-oxoethyl]amino]ethyl]-L-lysine 1,1-dimethylethyl ester (13.5 g; 18 mmol) in CHCl3 (300 mL) at 0° C. After 10 min the reaction mixture was allowed to rise to room temperature and TLC analysis showed the complete conversion of the starting materials. The solution was washed with 5% aq. NaHCO3, the organic phase was separated, dried over Na2SO4 and then evaporated under reduced pressure. The crude product was purified by flash chromatography (n-hexane/EtOAc=6/4 (v/v)) to give the desired product (11.3 g; 11.2 mmol). Yield 62%. HPLC: 95% (area %). the 13C-NMR, MS and IR spectra were consistent with the structure.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[CH:28]=[CH:27][C:19]3[O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:18]=3[CH:17]=2)=[O:15])[CH:8]=1)C.CO.C1COCC1.Cl>CC(OC)(C)C>[CH:17]1[C:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]=2[CH:27]=[CH:28][C:16]=1[C:14]([NH:13][C:9]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]([OH:29])=[O:3])[CH:12]=[CH:11][CH:10]=1)=[O:15]
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc3oc4ccccc4c3c2)c1
Agent: Cl
Solvent: CO
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: O=C(O)C=Cc1cccc(NC(=O)c2ccc3oc4ccccc4c3c2)c1
Temperature: 40 °C

Procedure:
The ester (19) (46 mg, 0.12 mmol) was hydrolysed using Method C, except that MeOH (1 mL) and THF (1 mL) were used, and the reaction mixture was heated to 40° C. for 1 hour. After the reaction, TBME was added and the mixture acidified using 6N HCl. The aqueous was extracted with more TBME (×3), EtOAc (×3), dried (MgSO4) and the solvent concentrated in vacuo. The crude solid was triturated with DCM, filtered, washed with heptane and dried to give the title compound. Yield: 34 mg, 81%; LC-MS tr 2.08 min; HPLC Purity: 100%; MS (ES+) m/z 358 (M+H); 1H NMR (400 MHz; DMSO): δ 6.60 (d, 1H), 7.55-7.75 (m, 5H), 7.9 (d, 1H), 7.95-8.05 (m, 2H), 8.25 (s, 1H), 8.30 (d, 1H), 8.40 (d, 1H), 8.95 (s, 1H), 10.65 (s, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].O.[C:23](=[O:26])(O)[O-:24].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([CH:10]1[CH2:11][CH:3]=[CH:4][O:24][C:23]1=[O:26])=[O:7]
Reactant: O=C([O-])O
Reactant: COc1cccc(C(=O)Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C(=O)C2CC=COC2=O)c1
Reaction time: 2 h

Procedure:
A solution of 6-valerolactone (2.0 g, 20 mmol) in anhydrous tetrahydrofuran (100 ml) was cooled to −78° C. under a nitrogen atmosphere, and 3-methoxybenzoyl chloride (3.58 g, 21 mmol) and lithium hexamethyldisilazide (40 ml, 1M tetrahydrofuran solution, 40 mmol) were added sequentially. Stirring was carried out for 2 hours, followed by treatment with saturated sodium bicarbonate water. The reaction mixture was extracted with ethyl acetate (100 ml), followed by washing with brine, and subsequently, the solvent was distilled off under reduced pressure, to obtain a brown crude product. Purification by silica gel column chromatography (hexane/ethyl acetate=1/1) afforded the desired compound as a pale yellow liquid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:9]([O-])=O.[Na+].[F:13][B-:14]([F:17])([F:16])[F:15].[Na+]>O>[F:13][B-:14]([F:17])([F:16])[F:15].[C:3]1([N+:2]#[N:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=N[O-]
Reactant: Nc1ccccc1
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O
Product: N#[N+]c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
In a 400 mL beaker containing 30 mL of concentrated hydrochloric acid and 30 mL of water was dissolved 9.2 g (0.1 mole) of aniline. The mixture was cooled to about 0° C. in an ice bath and then diazotized by the addition of a solution containing 7 g (0.1 mole) of sodium nitrite in 12 mL of water. After filtering, the solution was added slowly with stirring to 17 g (0.15 mole) of sodium fluoroborate (NaBF4) dissolved in 30 mL of water at room temperature (although lower temperatures can be used). After stirring another 5 minutes a white precipitate formed which was recovered by filtration, washed with 50 mL of cold water and 50 mL of diethyl ether and dried in vacuum. The yield of benzenediazonium tetrafluoroborate was about 75% of theory. The process (including a final thermal decomposition of the product, which is not employed in this Example), is commonly referred to as the Schiemann method. Kirk-Othmer, Encyclopedia of Chemical Technology, Second Edition, Vol. 9, page 568, Interscience (1966) describes this preparation and shows the equation including the decomposition as follows: ##STR2## A reference to this method is given in U.S. Pat. No. 3,950,444, column 1, lines 29-37, the disclosure of which is hereby incorporated by reference.
Reaction SMILES: [N:1]1([C:6]2[CH:39]=[CH:38][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[OH:23])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:40][O-:41].[Na+]>C1(C)C=CC=CC=1>[N:1]1([C:6]2[CH:39]=[CH:38][C:9]([CH2:10][C:11]3[C:12]([O:41][CH3:40])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[OH:23])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: C[O-]
Reactant: OC(c1cccnc1)(c1cccc(F)c1)c1ccc2nc(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1nc2ccc(C(O)(c3cccnc3)c3cccc(F)c3)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 105 °C

Procedure:
(3-(4-(1H-Pyrazol-1-yl)benzyl)-2,4-dichloroquinolin-6-yl)(3-fluorophenyl)(pyridin-3-yl)methanol (16.2 mg, 0.0292 mmol, Intermediate 36) and sodium methoxide (8.0 mg, 0.15 mmol) were charged to a microwave vial with dry toluene (0.14 mL) and heated to 105° C. for 4 hours. The mixture was allowed to cool to room temperature, then filtered through Celite® and rinsed with dichloromethane. The filtrate was concentrated to dryness and purified by reverse-phase chromatography (acetonitrile/H2O+0.05% TFA). The isolated product fractions were basified with saturated aqueous sodium bicarbonate, extracted with DCM, dried (Na2SO4), filtered, and concentrated to dryness to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 2H), 8.03 (d, J=2.0 Hz, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.70-7.66 (m, 2H), 7.58-7.51 (m, 3H), 7.35 (d, J=8.7 Hz, 2H), 7.33-7.28 (m, 2H), 7.09-7.04 (m, 2H), 7.04-6.99 (m, 1H), 6.45-6.41 (m, 1H), 4.31 (s, 2H), 4.08 (s, 3H); MS m/e 551.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[C:27]([CH3:34])[CH:26]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[C:27]([CH3:34])[CH:26]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1ccc(O)cc1C
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)cc1C

Procedure:
4-[4-(4-Acetyl-3-methyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure B by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 4′-hydroxy-2′-methylacetophenone (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA) in dimethylformamide. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.97-2.06 (m, 4H), 2.33 (s, 3H), 2.67 (s, 3H), 2.94-3.04 (m, 2H), 4.04-4.10 (m, 2H), 4.98-5.04 (m, 1H), 7.29-7.31 (m, 2H), 7.96-7.98 (m, 1H), 8.29 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=452.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]([C:22]([OH:24])=[O:23])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH2:26][CH2:27][CH2:28][CH3:29]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[C:3]([O:7][C:8]([NH:10][C@H:11]([C:22]([OH:24])=[O:23])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:26][CH2:27][CH2:28][CH3:29])[CH:14]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CCCCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCn1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Yield: 52 %

Procedure:
The same procedures as in Example 137 were carried out from sodium hydroxide (4.6 g), methylene chloride (160 mL), N-tert-butoxycarbonyl-L-tryptophan (10.0 g), 1-iodobutane (19 mL), and tetra-n-butylammonium hydrogensulfate (1.1 g), to give the captioned compound (6.2 g, 52%) as an oily product.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.[Cl:7][C:8]1[C:13]2[C:14](=[O:29])[N:15]3[CH2:28][CH2:27][CH2:26][C@H:16]3[C:17]3[N:18]([CH:19]=[N:20][C:21]=3[C:22](=[N:24]O)[NH2:23])[C:12]=2[CH:11]=[CH:10][CH:9]=1>CN(C)C=O>[Cl:7][C:8]1[C:13]2[C:14](=[O:29])[N:15]3[CH2:28][CH2:27][CH2:26][C@H:16]3[C:17]3[N:18]([CH:19]=[N:20][C:21]=3[C:22]3[N:24]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[O:6][N:23]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: O=C(O)C1CC1
Solvent: CN(C)C=O
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(C4CC4)n3)c2[C@@H]2CCCN12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
17.0 g (105 mmol) of N,N'-carbonyldiimidazole are added portionwise to a solution of 8.61 g (100 mmol) of cyclopropanecarboxylic acid in 30 ml of N,N-dimethylformamide. The mixture is stirred at room temperature for 1 hour and then heated rapidly to 50°. The solution obtained is added to a suspension of 33.1 g (100 mmol) of (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamidoxime in 100 ml of N,N-dimethylformamide and the mixture is heated to 90° for 2.5 hours. The solvent is removed on a rotary evaporator and is replaced by 100 ml of acetic acid. After stirring at 120° for 2.5 hours the mixture is again evaporated, the residue is dissolved in methylene chloride and washed with saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulphate and concentrated. By chromatography of the oily residue on silica gel while eluting with ethyl acetate and recrystallization from alcohol and a small amount of methylene chloride there is obtained (S)-8-chloro-1-[5-(cyclopropyl)-1,2,4-oxadiazol-3-yl]-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 236°-237°
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12]CC)=O.[CH3:15][NH2:16]>>[CH3:15][NH:16][C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:12]
Reactant: CN
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: CNC(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C

Procedure:
A suspension of ethyl indole-2-carboxylate (25.30 g, 133.7 mmole) in 40% aqueous CH3NH2 (400 mL) was stirred at RT. The flask was tightly stoppered to keep the material inside the flask. As the reaction proceeded the product began to precipitate. The reaction was stirred at RT for 3 days, then was concentrated to remove approximately 200 mL of the solvent. The remaining residue was diluted with H2O (500 mL), and the solid was collected by suction filtration and washed with H2O. Drying under high vacuum left the title compound (21.50 g, 92%) as a light yellow solid: MS (ES) m/e 175 (M+H)+.
Reaction SMILES: C([Mg]Br)C1C=CC=CC=1.[C:10]([O:14][C:15]([N:17]1[CH2:28][C@H:27](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:26][C@H:18]1[C:19]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11]>O1CCCC1>[C:10]([O:14][C:15]([N:17]1[CH2:28][C@@H:27]2[CH2:26][C@H:18]1[C:19](=[O:20])[N:21]2[C:22]([CH3:25])([CH3:24])[CH3:23])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](C(=O)NC(C)(C)C)N(C(=O)OC(C)(C)C)C2)cc1
Agent: Br[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1C(=O)N2C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.7 %

Procedure:
2.28 ml (4.56 mmol) of a 2M solution of benzylmagnesium bromide in tetrahydrofuran were added dropwise, whilst ice-cooling, to a solution of 1 g (2.27 mmol) of (4R)-1-t-butoxycarbonyl-4-(p-toluenesulfonyloxy)-N-t-butyl-L-prolinamide [prepared as described in Preparation 6(a)] in 15 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic extract was washed with a 10% w/v aqueous solution of citric acid, with a 10% w/v aqueous of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The mixture was dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:3 by volume mixture of ethyl acetate and hexane as the eluent. The resulting crude product was recrystallized from a mixture of methylene chloride, diethyl ether and hexane, to give 260 mg of the title compound as colorless crystals, melting at 167°-168° C.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:35])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[N:21]=[C:20]([CH2:22][NH:23]C(OC(C)(C)C)=O)[O:19][N:18]=3)[CH:15]=2)[N:10]([C:31](=[O:33])[CH3:32])[C@@H:9]([CH3:34])[CH2:8]1)[CH3:3].[ClH:36].CCOCC>O1CCOCC1>[ClH:36].[C:31]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[N:21]=[C:20]([CH2:22][NH2:23])[O:19][N:18]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:35])[O:4][CH:2]([CH3:1])[CH3:3])[CH2:8][C@@H:9]1[CH3:34])(=[O:33])[CH3:32]
Reactant: CC(=O)N1c2ccc(-c3noc(CNC(=O)OC(C)(C)C)n3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(=O)N1c2ccc(-c3noc(CN)n3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 61.9 %

Procedure:
To a solution of 1-methylethyl((2S,4R)-1-acetyl-6-{5-[({[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-1,2,4-oxadiazol-3-yl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation, see Intermediate 60) (132 mg, 0.271 mmol) in 1,4-dioxane (2 mL) at room temperature was added HCl (4N in 1,4-dioxane, 2 mL, 8.00 mmol) and the resulting mixture was stirred at this temperature for 5 h then left standing at 4° C. for 16 h. The mixture was warmed to room temperature and most of the solvent was removed in vacuo. The residue was loaded on a 2 G SCX cartridge and eluted with MeOH then with a 2N NH3 solution in MeOH. The ammonia fractions were collected and concentrated in vacuo, The residue was dissolved in 1,4-dioxane (3 mL) and the solution was treated with 0.5 ml of HCl (4N in 1,4-dioxane) then concentrated in vacuo. Trituration of the residue with Et2O gave 1-methylethyl {(2S,4R)-1-acetyl-6-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate hydrochloride (71 mg, 0.167 mmol, 61.9% yield) as a pale red solid.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[C:17]([Br:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21].CN(C)[CH:24]=[O:25]>C(OCC)C>[Br:19][C:17]1[C:16]([F:20])=[CH:15][C:14]([F:21])=[C:13]([CH:18]=1)[CH:24]=[O:25]
Reactant: Fc1cc(F)c(Br)cc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=Cc1cc(Br)c(F)cc1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 61.1 %

Procedure:
A 1.6 M solution of butyl lithium in hexane (114 mL, 182 mmol) is added to a −78° C. solution of 1,5-dibromo-2,4-difluorobenzene (41.3 g, 152 mmol) in diethyl ether (290 mL). Dimethylformamide (14.4 g, 198 mmol) is added and the reaction is stirred at −78° C. for 15 minutes. The reaction is quenched with 1 N HCl (300 mL), is diluted with water, and extracted three times with ethyl acetate. The organic layer is dried over sodium sulfate and the solvent is removed under reduced pressure to give crude material that is purified by silica gel chromatography with a linear gradient of 0% to 50% CH2Cl2 in hexanes over 30 minutes to give the title compound (20.51 g, 61%). GC-MS m/e (79Br/81Br) 220, 222.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[F:17][C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>O1CCCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[C:7]([C:8]2[N:12]([S:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=3)(=[O:26])=[O:25])[CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: O=Cc1c[nH]c(-c2cccnc2Cl)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(-c2cccnc2Cl)n(S(=O)(=O)c2cccc(F)c2)c1
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
To a solution of 5-(2-chloropyridin-3-yl)-1H-pyrrole-3-carbaldehyde (250 mg) in tetrahydrofuran (25 mL) was added sodium hydride (60% in oil, 73 mg) at room temperature and the mixture was stirred for 15 min. 3-Fluorobenzenesulfonyl chloride (310 mg) was added to the reaction mixture, and the mixture was further stirred for 30 min. The reaction mixture was diluted with saturated brine, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a colorless oil (yield 420 mg, 95%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH3:29][O:30][CH2:31][CH2:32][CH2:33][NH2:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:29][O:30][CH2:31][CH2:32][CH2:33][NH:34][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: COCCCN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 77.5 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (3-methoxy-propyl)-amide (91 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 3-methoxy-propylamine (24 mg), HBTU (111 mg), and DIEA (64 uL). LC/MS: m/z 480.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.37 (bs, 1H), 8.42 (s, 1H), 8.06 (s, 1H), 7.90 (s, 1H), 7.78-7.63 (m, 2H), 7.46 (d, 1H), 7.34 (d, 1H), 3.62 (bs, 3H), 3.38 (t, 2H), 3.34-3.27 (m, 2H), 3.24 (s, 3H), 1.82-1.71 (m, 2H).
Reaction SMILES: Cl.[CH2:2]([S:9][C:10]([CH3:14])([CH3:13])[CH:11]=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:16]/[C:17](=[CH:22]\[C:23]([O:25][CH3:26])=[O:24])/[C:18](OC)=[O:19].[Cl-].[NH4+]>C1COCC1.[Zn]>[CH2:2]([S:9][C:10]([CH:11]1[O:12][C:18](=[O:19])[C:17](=[CH2:16])[CH:22]1[C:23]([O:25][CH3:26])=[O:24])([CH3:14])[CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)/C=C(\CBr)C(=O)OC
Reactant: CC(C)(C=O)SCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C1C(=O)OC(C(C)(C)SCc2ccccc2)C1C(=O)OC
Yield: 38.2 %

Procedure:
To a stirred suspension of zinc dust (0.67 g) activated with hydrochloric acid in THF (15 ml), 2-benzylthio-2-methylpropionaldehyde (1.00 g) dissolved in THF (5 ml) and dimethyl 2-bromomethylfumarate (1.28 g) dissolved in THF (5 ml) were added dropwise in the order named while refluxing under nitrogen atmosphere. The mixture was refluxed for an additional 1.5 hours and saturated aqueous ammonium chloride solution was added to it. After cooling the mixture was filtered by celite. A reaction product was extracted with ethyl acetate from the filtrate. The organic layer was washed with 1N hydrochloric acid, water and then saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was purified by silica gel column chromatography to give 0.63 g (38%) of the titled compound.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.[S:29]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30]1.C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[C:31]1[CH:32]=[CH:33][S:29][CH:30]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: OB(O)c1ccsc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccsc2)c2ncnn12
Reaction time: 16 h
Yield: 85.1 %

Procedure:
To a suspension (15 mL) of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), thiophen-3-ylboronic acid (0.35 g), triethylamine (0.5 mL), pyridine (1 mL) and molecular sieves 4A (1 g) in dichloromethane was added copper(II) acetate (0.49 g), and the mixture was stirred for 16 hr. The reaction mixture was diluted with ethyl acetate, insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.52 g, 85%).