Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=[CH:7][C:6]=1[CH2:14]O)(=[O:4])=[O:3].C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:17][CH2:14][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][O:11][C:10]=2[C:5]=1[S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: BrC(Br)(Br)Br
Reactant: CS(=O)(=O)c1c(CO)ccc2c1OCO2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1c(CBr)ccc2c1OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
907 mg of [2-(methylsulfonyl)-3,4-methylenedioxyphenyl]methanol, 1.31 g of carbon tetrabromide and 1.03 g of triphenylphosphine were dissolved in 5 ml of dichloromethane, and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3), to give 1.10 g of the title compound as a colorless oil.
Reaction SMILES: [CH:1](=[N:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:2][CH2:3][CH3:4].[Cl:10][CH:11]([Cl:15])[C:12](Cl)=[O:13].C(OCC)C>C(N(CC)CC)C>[C:6]([N:5]([CH:1]=[CH:2][CH2:3][CH3:4])[C:12](=[O:13])[CH:11]([Cl:15])[Cl:10])([CH3:9])([CH3:8])[CH3:7]
Reactant: CCCC=NC(C)(C)C
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCC=CN(C(=O)C(Cl)Cl)C(C)(C)C

Procedure:
In a similar procedure as Example I, 6.6 g. (0.052 mole) N-butylidene-t-butylamine was reacted with 4.8 ml. (0.05 mole) dichloroacetyl chloride in 100 ml. diethyl ether and 7.2 ml. triethylamine. There was obtained 9.3 g. of the title compound, an oil, nD30 = 1.4858.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[NH2:12][C:13]1[CH:19]=[CH:18][C:16]([OH:17])=[CH:15][C:14]=1O.[OH-].[Na+].C1COCC1>CO.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][C:14]3[CH:15]=[C:16]([OH:17])[CH:18]=[CH:19][C:13]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(O)cc1O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Oc1ccc2nc(-c3ccc(Cl)cc3)oc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.2 %

Procedure:
25 g (142.8 mmol) of 4-chlorobenzoyl chloride and 3.0 g (18.6 mmol) of 4-aminoresorcinol hydrochloride were introduced into a three-necked flask provided with a thermometer and a cooling condenser, and the mixture was heated at 170° to 200° C. for 1 hour, then the excessive acid chloride was removed by distillation. To the residue, 8.4 g (210 mmol) of NaOH, 60 ml of THF, 60 ml of water and 30 ml of methanol were added, and the mixture was stirred at room temperature for about 2 hours. The reaction solution was extracted with ethyl acetate, the extract was washed with saturated sodium chloride water solution, and ethyl acetate was distilled off. Recrystallizing the residue with water/methanol/THF and drying the crystal, there was obtained 1.24 g (5.05 mmol) of 2-(4-chlorophenyl)-6-hydroxybenzoxazole. The yield was 27.2%.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[O:3].[Na+].[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]=O)=[CH:14][CH:15]=1>[OH-].[Na+]>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]=[CH:4][C:2](=[O:3])[C:1]([OH:6])=[O:5])=[CH:14][CH:15]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(=O)C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C=CC(=O)C(=O)O)cc1
Temperature: 0 °C

Procedure:
Sodium pyruvate (24.2 g, 0.22 mol) was dissolved in 200 ml 1N aqueous sodium hydroxide at 20° C. To this solution there was added anisaldehyde (27.4 g, 0.20 mol) at 0.2 ml/min. The solution was aged twenty-four hours at 20° C., cooled at 0° C. and acidified with 6N NCl to pH 1.0 while maintaining a temperature of 0° C. The 4-(p-methoxyphenyl)-2-oxo-3-butenoic acid product was then extracted with 500 ml ethyl acetate and isolated as a yellow solid by concentration under vacuum. The yield by HPLC analysis was 88%.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:5][S:6][CH:7]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]([NH:28][CH2:29][C:30]1[N:34]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:33]2[CH:43]=[CH:44][CH:45]=[CH:46][C:32]=2[N:31]=1)[CH3:27].CCN(C(C)C)C(C)C>CC#N>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]([N:28]([CH2:2][C:3]1[C:4]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:5][S:6][CH:7]=1)[CH2:29][C:30]1[N:34]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:41])[CH3:42])[C:33]2[CH:43]=[CH:44][CH:45]=[CH:46][C:32]=2[N:31]=1)[CH3:27]
Reactant: O=C1c2ccccc2C(=O)N1Cc1cscc1CBr
Reactant: CC(NCc1nc2ccccc2n1COCC[Si](C)(C)C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(c1ccccn1)N(Cc1cscc1CN1C(=O)c2ccccc2C1=O)Cc1nc2ccccc2n1COCC[Si](C)(C)C

Procedure:
Using General Procedure A: Reaction of 2-(4-bromomethyl-thiophen-3-ylmethyl)-isoindole-1,3-dione, (1-pyridin-2-yl-ethyl)-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-2-ylmethyl]-amine, DIPEA and KI in CH3CN gave 2-[4-({(1-pyridin-2-yl-ethyl)-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-2-ylmethyl]-amino}-methyl)-thiophen-3-ylmethyl]-isoindole-1,3-dione.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:21]4[CH:22]=[N:23][C:24](Cl)=[CH:25][C:20]=4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:36]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCOC(C)=O>O.O1CCOCC1>[C:36]1([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:41]=[CH:40][C:39]([C:24]2[N:23]=[CH:22][C:21]3[N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])[C:18]([O:17][C@@H:16]4[CH2:15][O:14][C@@H:13]5[C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH2:10][O:11][C@H:12]45)=[N:19][C:20]=3[CH:25]=2)=[CH:38][CH:37]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)ncc2n1COCC[Si](C)(C)C
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(-c3ccc(-c4ccccc4)cc3)ncc2n1COCC[Si](C)(C)C
Temperature: 85 °C
Reaction time: 2 h

Procedure:
Palladium tetrakistriphenylphosphine (42.6 mg, 0.037 mmol) was added to a stirred suspension of 2-(((3R,3aR,6R,6aS)-6-((tert-butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-c]pyridine (Intermediate 46, 100.0 mg, 0.184 mmol), 4-biphenylboronic acid (54.8 mg, 0.277 mmol), and potassium phosphate tribasic (117.0 mg, 0.553 mmol) in degassed 20% water in dioxane (1.44 mL). The reaction mixture stirred under N2 at 85° C. After 2 h, more palladium tetrakistriphenylphosphine (42.6 mg, 0.037 mmol) was added. The reaction mixture heated under N2 at 85° C. for another 7 h, then cooled to room temperature and the lower aqueous layer was drawn off and discarded. The remaining reaction mixture was added to EtOAc (50 mL), filtered, and the resulting solids were washed with EtOAc (2×15 mL). The filtrate was evaporated under reduced pressure. Flash chromatography of the resulting residue utilizing a 24 g silica RediSep Rf® Gold column and employing a 0-100% EtOAc/hexane gradient afforded the title compound. LC-MS: calculated for C36H49N3O5Si2 659.32 observed m/e: 660.13 (M+H)+ (Rt 1.58/2.0 min).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([CH:22]([OH:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[ClH:1].[Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[OH:29])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(C(O)c4ccccc4)cc3c2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: OC(c1ccccc1)c1cc(Cl)c2oc3c(c2c1)CNCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a solution of the product of step A (50.0 mg, 0.12 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (0.4 mL). After stirring for 2 h at ambient temperature the reaction mixture was quenched with 10% sodium bicarbonate solution (15 mL) and extracted with dichloromethane. The organic extract was dried over sodium sulphate and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 9:1 dichloromethane/methanol). The product was converted to hydrochloride salt by dissolving in dichloromethane and treating with 2 M HCl in diethyl ether at 0° C. After stirring for 20 min the reaction mixture was concentrated in vacuo to give (6-chloro-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridin-8-yl)(phenyl)methanol hydrochloride (18 mg, 47%, AUC HPLC 97.1%) as a white solid: mp 260° C. dec.; 1H NMR (CD3OD, 300 MHz) δ 7.46 (s, 1H), 7.41-7.20 (m, 6H), 5.85 (br s, 1H), 4.40 (s, 2H), 3.68 (t, J=6 Hz, 2H), 3.25-3.15 (m, 2H); APCI MS m/z 314 [M+H]+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[NH2:42][CH2:43][CH2:44][CH2:45][OH:46]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:42][CH2:43][CH2:44][CH2:45][OH:46])=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NCCCO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCCCO)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a mixture of 0.08 g (0.18 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-100), 0.16 mL (0.90 mmole) of ethyldiisopropyl amine and 0.016 mL (0.20 mmole) of 3-amino-propan-1-ol in 2.0 mL of dimethylformamide was added 0.085 g (0.20 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.080 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-hydroxy-propyl)-3-methoxy-benzamide (I-41) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:37][CH:38]1[CH2:42][N:41]([CH2:43][CH3:44])[N:40]([CH2:45][CH3:46])[CH2:39]1>C(Cl)(Cl)Cl>[CH2:45]([N:40]1[CH2:39][CH:38]([NH:37][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:2]=2[OH:1])[CH2:42][N:41]1[CH2:43][CH3:44])[CH3:46]
Reactant: CCN1CC(N)CN1CC
Reactant: O=C(O)c1ccc(O)cc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CCN1CC(NC(=O)c2ccc(O)cc2O)CN1CC
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a solution of 2,4- dihydroxybenzoic acid (1.00 g) in tetrahydrofuran anhydride (20 ml) were added 1-hydroxybenzotriazole (1.05 g) and N,N'-dicyclohexyl carbodiimide (1.34 g) while being cooled with ice. After the resulting mixture was stirred for 30 minutes, 4-amino-1,2-diethylpyrazolidine (0.93 g) was added thereto and the mixture was stirred for one night at room temperature. The reaction solution, with chloroform added thereto, was washed with brine and then dried over sodium sulfate anhydride. The resulting organic layer was concentrated under a vacuum and thus formed residue was purified by silica gel column chromatography (chloroform: methanol=20:1) so as to yield 1.17 g (65%) of N-(1,2-diethyl-4-pyrazolidinyl)-2,4- dihydroxybenzamide.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:9]C(=O)OC(C)(C)C)=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:2].Cl.O1CCOCC1.C([O-])([O-])=O.[K+].[K+].C1C(=O)N([Br:37])C(=O)C1>O>[Br:37][C:7]1[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]([NH2:9])=[N:5][CH:6]=1
Reactant: CCc1cccnc1NC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1cc(Br)cnc1N
Temperature: 25 °C
Yield: 76 %

Procedure:
Following a literature procedure (Journal of Molecular Catalysis A: Chemical 2007, 267, 30) tert-butyl 3-ethylpyridin-2-ylcarbamate (820 mg, 3.68 mmol) was treated with 4.0 M HCl in dioxane (4 mL, 4 mmol) and the reaction was maintained at rt for 2 h. Water (2 mL) was added and K2CO3 was added until pH>10. The resulting suspension was filtered and the isolated solid was washed with EtOAc (2 mL). The organic filtrates were concentrated and the resulting residue was dissolved in acetonitrile (4 mL). A portion (2 mL) was treated with NH4OAc (100 mg), followed by NBS (280 mg, 1.57 mmol). The reaction was maintained at rt for 15 min. The reaction was then partitioned between EtOAc and water and the resulting layers separated. The aqueous portion was extract with EtOAc (2×5 mL) and the combined organic layers were concentrated. The resulting residue was purified by reverse phase HPLC. The collected fractions were basified to pH>10 by the addition of saturated aqueous Na2CO3 solution. Extraction with EtOAc (2×20 mL) followed by concentration provided 240 mg of 5-bromo-3-ethylpyridin-2-amine: 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=2.4 Hz, 1H); 7.39 (d, J=2.4 Hz, 1H); 4.41 (br s, 2H); 2.42 (q, J=7.2 Hz, 2H); 1.26 (t, J=7.2 Hz, 3H).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([Br:18])[CH:12]=2.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C(Cl)Cl.CCOC(C)=O>[CH2:28]([O:27][C:25]([NH:7][C:8]1[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([Br:18])[CH:12]=2)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1nc2cc(Br)ccc2cc1N
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc2cc(Br)ccc2cc1NC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Pyridine (727.5 mg, 9.197 mmol) was added to a solution of ethyl 3-amino-7-bromoquinoline-2-carboxylate (Ark Pharm, 1069 mg, 3.622 mmol) in DCM (10.0 mL). The mixture was cooled to −10° C. A solution of benzyl chloroformate (816.5 mg, 4.547 mmol) in DCM (5.0 mL) was added slowly to the solution. The reaction mixture was allowed to warm to room temperature. After stirring at room temperature for 1 h, the reaction mixture was diluted with EtOAc (100 mL), washed with a saturated aqueous solution of NaHCO3 (100 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (0-50% EtOAc in hexanes) to give the sub-title compound as an off-white solid (1.54 g, 99%). LCMS calc. for C20H18BrN2O4(M+H)+: m/z=429.0. found 429.0.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=O.[C:12](#[N:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH2:15].[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([NH2:34])[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([NH:34][C:12]2[C:13]3[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:15]=[C:5]([C:4]3[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=3[OH:2])[N:20]=2)[CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: COc1ccccc1C(=O)Cl
Reactant: N#Cc1ccccc1N
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nc(-c3ccccc3O)nc3ccccc23)C1

Procedure:
The title compound was prepared from 2-methoxybenzoyl chloride, anthranilonitrile, and (R)-3-amino-piperidine-1-carboxylic acid tert-butyl ester using methods analogous to those described in Synthesis 1, steps 1A, 1B, and 1D.
Reaction SMILES: BrC1C=CC2N([CH:16]3[CH2:21]CN[CH2:18][CH2:17]3)C3C(SC=2C=1)=CC=CC=3.[CH:22]12[NH:29][CH:26]([CH2:27][CH2:28]1)[CH2:25][CH:24]([N:30]1[C:43]3[CH:42]=[CH:41][C:40]([Br:44])=[CH:39][C:38]=3[S:37][C:36]3[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:23]2.[C:45](O)(=[O:47])C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CN(C=O)C>[Br:44][C:40]1[CH:41]=[CH:42][C:43]2[N:30]([CH:24]3[CH2:23][CH:22]4[N:29]([CH2:21][C:16]5[CH:17]=[CH:18][O:47][CH:45]=5)[CH:26]([CH2:27][CH2:28]4)[CH2:25]3)[C:31]3[C:36]([S:37][C:38]=2[CH:39]=1)=[CH:35][CH:34]=[CH:33][CH:32]=3
Reactant: CC(=O)O
Reactant: Brc1ccc2c(c1)Sc1ccccc1N2C1CCNCC1
Reactant: Brc1ccc2c(c1)Sc1ccccc1N2C1CC2CCC(C1)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)Sc1ccccc1N2C1CC2CCC(C1)N2Cc1ccoc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-bromo-10-piperidin-4-yl-10H-phenothiazine, 4i (11.2 mg; 0.029 mmol) and 3-furyl carboxaldehyde (8.4 mg; 0.087 mmol) in dichloroethane (120 μL) was added acetic acid (5 μL) and a solution of sodium triacetoxyborohydride (12 mg, 0.057 mmol) in DMF (100 μ). The mixture was stirred at rt for 18 h, quenched with water (50 μL), and lyophilized. The thus obtained crude 3-bromo-10-(8-furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine, 5i as a mixture of endo and exo isomers was used as such for the next reaction.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=3)[O:10][N:9]=2)=[CH:4][CH:3]=1.CO.[Li+].[OH-]>C1COCC1.O>[C:5]1([C:8]2[N:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=3)[O:10][N:9]=2)[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(-c2nc(-c3ccc(F)cc3)no2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(-c2nc(-c3ccccc3)no2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a solution of methyl 4-(3-(4-fluorophenyl) 1,2,4-oxadiazol-5-yl)benzoate (600 mg, 2.14 mmol) in THF (12 mL) was added MeOH (3 mL) and a solution of LiOH (351 mg, 8.57 mmol) in H2O (3 mL). The reaction was stirred at room temperature for 2 h. The reaction was quenched upon the addition of 1N HCl (30 mL) and extracted with EtOAc (2×30 mL). The organic extracts were dried over MgSO4, and concentrated under vacuum to afford 4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzoic acid (550 mg, 87%) as a white solid. 1H-nmr (400 MHz, CDCl3) δ 8.37 (d, J=8 Hz, 2H), 8.30 (d, J=8 Hz, 2H), 8.26-8.19 (m, 2H), 7.62-7.52 (m, 3H); MS (ESI) m/z 266.8
Reaction SMILES: CN(C)C=O.S(Cl)([Cl:8])=O.[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:12]=1[C:13](O)=[O:14]>C1C=CC=CC=1>[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:12]=1[C:13]([Cl:8])=[O:14]
Reactant: O=C(O)c1c(Cl)cccc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1c(Cl)cccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
1 ml of dimethyl formamide and 17.9 gm (0.15 mol) of thionyl chloride were added to a suspension of 20.1 gm (0.1 mol) of 2-chloro-6-nitro-benzoic acid in 150 ml of anhydrous benzene. The reaction mixture was stirred for 30 minutes and heated to reflux temperature. After 3 hours another 17.9 gm (0.15 mol) of thionyl chloride were added. The reaction mixture was further refluxed for 3 hours. After cooling, the reaction mixture filtered, and the filtrate was evaporated in vacuo.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH2:34][NH:35][C:36]2[CH:44]=[CH:43][C:39]([C:40]([OH:42])=O)=[CH:38][CH:37]=2)=[CH:26][CH:25]=1.C(N(CC)CC)C.[NH2:52][CH:53]1[CH2:58][CH2:57][N:56]([CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH2:55][CH2:54]1>CN(C)C=O>[C:60]1([CH2:59][N:56]2[CH2:57][CH2:58][CH:53]([NH:52][C:40](=[O:42])[C:39]3[CH:38]=[CH:37][C:36]([NH:35][CH2:34][C:27]4[C:28]5[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:24]=[CH:25][CH:26]=4)=[CH:44][CH:43]=3)[CH2:54][CH2:55]2)[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1
Reactant: O=C(O)c1ccc(NCc2ccnc3ccccc23)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccc(NCc2ccnc3ccccc23)cc1
Temperature: 100 °C
Yield: 50.6 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.62 g, 18.9 mmol), 1-hydroxybenzotriazole hydrate (2.43 g, 18.0 mmol), and 4-[(4-quinolinylmethyl)amino]benzoic acid (5.00 g, 18.0 mmol) were placed in a flask under nitrogen. N,N-Dimethylformamide (83 mL) was then added followed by triethylamine (4.5 g, 45 mmol, 6.3 mL) and finally 4-amino-1-benzylpiperidine (3.1 g, 3.3 mL, 16 mmol). The mixture was heated at 100° C. for 45 minutes and the N,N-dimethylformamide was then removed under reduced pressure. The resulting viscous orange oil was triturated overnight with a mixture of 75 mL of water and 50 mL of ethyl acetate with vigorous overhead stirring. The resulting solid was filtered, washed with water and dried under reduced pressure at 60° C. for 25 hours. Flash chromatography on silica gel (65 mm column, 5% ammonia saturated methanol in methylene chloride eluent) afforded fractions containing the product which were concentrated to the point where a white powder formed. The powder was filtered and washed with a small amount of methanol and then ether. Drying under reduced pressure at 60° C. for 19.5 hours afforded 3.65 g (8.1 mmol, 50% yield) of the title compound, m.p. 184°-188° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[CH:12][CH:11]=1)[CH2:5][C:6]([O:8][CH3:9])=[O:7].[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>>[CH3:40][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:3][CH:4]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH:18]3[CH2:19][CH2:20][N:21]([C:24]4[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=4)[CH2:22][CH2:23]3)=[CH:14][CH:15]=2)[CH2:5][C:6]([O:8][CH3:9])=[O:7])(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CC(N)c1ccc(OCC2CCN(c3ccncc3)CC2)cc1
Agent: Cl
Product: COC(=O)CC(NS(=O)(=O)c1ccc(C)cc1)c1ccc(OCC2CCN(c3ccncc3)CC2)cc1

Procedure:
Using a procedure similar to that described in Example 19, but starting from the product of Example 61, step (iii) and p-toluenesulphonyl chloride, the title compound was prepared; NMR(CDCl3): 1.34-1.55(m,2H), 1.95(d,2H), 2.0-2.2(m,1H), 2.38(s,3H), 2.62-3.05(m,4H), 3.55(s,3H), 3.78(d,2H), 3.96(d,2H), 4.65(m,1H), 5.65(brs,1H), 6.7(d,2H), 6.72(d,2H), 7.05(d,2H), 7.2(d,2H), 7.65(d,2H), 8.25(d,2H); mass spectrum(+ve FAB,MeOH/NBA): 524(M+H)+.
Reaction SMILES: O.[NH2:2][NH2:3].N1C=CC=CC=1.C[O:11][C:12](=O)[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1>C(O)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][O:14][CH2:13][C:12]([NH:2][NH2:3])=[O:11])=[CH:17][CH:18]=1
Reactant: NN
Reactant: COC(=O)COCc1ccc(OC)cc1
Solvent: CCO
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(COCC(=O)NN)cc1
Yield: 79.7 %

Procedure:
Add hydrazine hydrate (2.1 mL, 42.1 mmol) and pyridine (0.3 mL, 3.8 mmol) to a solution of (4-methoxy-benzyloxy)-acetic acid methyl ester (8.05 g, 38.3 mmol) in ethanol (100 mL, absolute). Heat the reaction to reflux under N2 overnight. Concentrate; add toluene and concentrate (2 times). Purify the residue by flash chromatography on silica gel eluting with 0-40% ACN/CH2Cl2 to afford the title compound (6.42 g, 80%) as clear oil. 1H NMR (400 MHz, DMSO) δ 3.73 (s, 3H); 3.84 (s, 2H); 4.24 (bs, 2H); 4.42 (s, 2H); 6.89 (d, 2H, J=8.3 Hz); 7.27 (d, 2H, J=8.3 Hz); 9.00 (bs, 1H). MS(IS) 209 (M−).