Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26](C(OC(C)(C)C)=O)[C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[C:29]([O:34][CH2:35][CH2:36][N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])[CH:28]=3)=[N:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][N:9]=[C:10]2[C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[C:29]([O:34][CH2:35][CH2:36][N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])[CH:28]=2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCN(CC)CCOc1ccc2cc(-c3nn(C(=O)OC(C)(C)C)c4ccc(OCc5ccccc5)cc34)n(C(=O)OC(C)(C)C)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc2cc(-c3n[nH]c4ccc(OCc5ccccc5)cc34)[nH]c2c1

Procedure:
The compound {2-[2-(5-benzyloxy-1H-indazol-3-yl)-1H-indol-6-yloxy]ethyl}diethylamine is prepared in the following way: 390 mg of 5-benzyloxy-3-[1-tert-butoxycarbonyl-6-(2-diethylaminoethoxy)-1H-indol-2-yl]-indazole-1-carboxylic acid tert-butyl ester in solution in 5 ml of dichloromethane and 2 ml of trifluoroacetic acid are stirred at ambient temperature for 20 hours. The solvent is evaporated off under vacuum in a rotary evaporator to obtain 480 mg of {2-[2-(5-benzyloxy-1H-indazol-3-yl)-1-indol-6-yloxy]ethyl}diethylamine in the form of a trifluoroacetate salt.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH:25]([NH2:27])[CH3:26])=[N:23][CH:24]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:17][C:5]1[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)=[N:7][C:2]([NH:27][CH:25]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][N:23]=2)[CH3:26])=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Reactant: CC(N)c1ccc(F)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cn1
Temperature: 185 °C
Yield: 36.2 %

Procedure:
A mixture of 2,5-dichloro-4-(5-cyclopropyl-1H-pyrazole-3-ylamino)pyrimidine (Method 7; 0.14 g, 0.518 mmol), 1-(5-fluoropyridin-2-yl)ethanamine (Method 4; 0.091 g, 0.648 mmol), and DIEA (0.11 ml, 0.648 mmol) in n-BuOH (2 ml) was heated in a sealed tube at 185° C. for 18 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane-EtOAc=1:2) to give the title compound as a white solid (0.070 g, 36%). 1H NMR (400 MHz) 12.51 and 12.09 (s, 1H), 9.65 (s, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 8.02 and 7.93 (b, 1H), 7.64 (m, 1H), 7.41 (m, 1H), 5.93 and 5.80 (b, 1H), 5.06 (m, 1H), 1.83 (m, 1H), 1.45 (d, J=6.8 Hz, 3H), 0.95 (m, 1H), 0.84 (m, 1H), 0.74 (m, 1H), 0.63 (m, 1H). MS: Calcd.: 373. Found: [M+H]+374.
Reaction SMILES: ClCC([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH:9]=[CH:8]2)=O>N1C=CC=CC=1>[NH:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:14][CH:13]=2)[CH:8]=[CH:9][C:10]1=[O:15]
Reactant: O=C(CCl)c1ccc2[nH]c(=O)ccc2c1
Solvent: c1ccncc1
Product: O=c1ccc2ccccc2[nH]1
Reaction time: 2 h

Procedure:
60 Grams of 6-(α-chloroacetyl)carbostyril was suspended in 0.5 kg of pyridine and stirred at 80°-90° C. for 2 hours, then the suspension was stirred under ice-cooling for 1 hour. The crystals thus precipitated were collected by filtration and recrystallized from methanol to obtain 70 g of 6-(α-pyridiniumacetyl)carbostyril chloride 1/2-hydrate in the form of colorless needle-like crystals.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][C:4](O)=[O:5].Cl.[C:10](Cl)(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C>>[CH2:11]([CH:10]1[C:4](=[O:5])[CH2:3][CH2:2][C:1]1=[O:8])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: O=C(O)CCC(=O)O
Reactant: CCCCCCC(=O)Cl
Agent: Cl
Product: CCCCCC1C(=O)CCC1=O
Temperature: 80 °C

Procedure:
After charging succinic acid, the mixture was allowed stand to complete generation of HCl gas. Then, thereto was added 60 g (0.4 mol) of heptanoyl chloride, and the resulting mixture was heated at 80° C. for 8 hours. Since heptanoyl chloride is also fuming (HCl gas), measures were taken against corrosion of equipment in the peripheral environment at the time of weighing, but it was with difficulty. The mixture was cooled, poured onto 60 g of ice, and maintained at −10° C. for 10 hours, depositing a product as a solid. The product was subjected to suction filtration, washed with 10% NaCl water and toluene (20 ml×3 times), and dried, yielding 8.4 g (0.05 mol) of 2-pentyl-1,3-cyclopentanedione (a compound in which R1 represents an n-pentyl group in the above formula (3)). Yields were 20.8%, 50.0%, and 12.5% relative to AlCl3, succinic acid, and heptanoyl chloride, respectively. Simultaneously, wastewater containing a large amount of an aluminum-based and a chlorine-based compound was byproduced.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)=[CH:5][C:4]=1[CH3:14].[CH3:15]N(C)C=O.[H-].[Na+].CI>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[CH:12][N:11]([CH3:15])[N:10]=2)=[CH:5][C:4]=1[CH3:14].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:15])[N:11]=[CH:12][CH:13]=2)=[CH:5][C:4]=1[CH3:14]
Reactant: COc1ccc(-c2cc[nH]n2)cc1C
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1ccc(-c2ccn(C)n2)cc1C
Product: COc1ccc(-c2ccnn2C)cc1C

Procedure:
At room temperature, to a mixture of 3-(4-methoxy-3-methyl-phenyl)-1H-pyrazole (described in Reference Preparation example 44) 5.38 g and N,N-dimethylformamide 100 ml was added 55% sodium hydride 1.5 g and the resulting mixture was stirred for a half hour and thereto was added methyl iodide 7.9 g. The resulting mixture was stirred for twelve hours and thereto was added water, and then the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, and was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 3-(4-methoxy-3-methyl-phenyl)-1-methyl-1H-pyrazole 2.9 g and 5-(4-methoxy-3-methyl-phenyl)-1-methyl-1H-pyrazole 1.0 g.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[CH3:25].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=2[CH3:25])=[CH:6][N:7]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1Oc1ccc(Cl)nc1
Temperature: 50 °C

Procedure:
To a suspension of 6-chloropyridin-3-ol (3.37 g, 26.0 mmol) and K2CO3 (7.19 g, 52.0 mmol) in DMF (200 mL) was added 1-fluoro-2-methyl-4-nitrobenzene (4.44 g, 28.6 mmol). After heating to 50° C. for 16 hours, the reaction mixture was cooled to room temperature and poured into water and extracted with ethyl acetate (2×). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the product as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[F:10][B-:11]([F:14])([F:13])[F:12].[C:15]1([C:21]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=[C:23]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O+]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)C.C(OCC)C>ClCCl>[F:10][B-:11]([F:14])([F:13])[F:12].[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N+:5]1[C:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:24][C:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:26][C:21]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1Cl
Reactant: c1ccc(-c2cc(-c3ccccc3)[o+]c(-c3ccccc3)c2)cc1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCO
Solvent: CCOCC
Product: Clc1ccccc1C[n+]1c(-c2ccccc2)cc(-c2ccccc2)cc1-c1ccccc1
Reaction time: 16 h

Procedure:
2-Chlorobenzylamine (2.0 g, 14 mmol) was added dropwise to a suspension of 2,4,6-triphenylpyrylium tetrafluoroborate (5.1 g, 13 mmol) in dichloromethane (40 mL). The reaction mixture was stirred for 16 h. Ethanol (4 mL) and excess diethyl ether were added to precipitate the product. The precipitate was filtered and dried. This provided 6.14 g (92%) of N-(2-chlorobenzyl)-2,4,6-triphenylpyridinium tetrafluoroborate.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([C:8]([O:10]C1C=CC([N+]([O-])=O)=CC=1)=O)[CH2:5][CH2:6][Cl:7].C([N:22](CC)CC)C.NCC[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>CN(C)C=O>[Cl:1][CH2:2][CH2:3][N:4]([C:8]([NH:22][C:30]1[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=1)=[O:10])[CH2:5][CH2:6][Cl:7]
Reactant: NCCc1ccc(O)cc1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N(CCCl)CCCl
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(O)cc1)N(CCCl)CCCl
Yield: 73.6 %

Procedure:
27 (860 mg, 2.8 mmol) was dissolved in dimethylformamide (20 mL) and triethylamine (0.9 mL, 5.6 mmol) was added. The mixture was stirred at reflux for 30 minutes and tyramine (0.76 mg, 5.6 mmol) was added. The mixture was heated under reflux for a further 6 hours and then concentrated in vacuo. Purification by column chromatography (silica gel, dichloromethane then methanol) gave prodrug 28 as an orange/brown oil (571 mg, 67%). νmax 3400, 1660, 1444, 1380, 1145/cm−1; δ 1H (400 MHz, CDCl3) 2.61 (2H, t, J 3.72 Hz, 4,CH2Ar), 3.17–3.22 (10H, m, ArCH2CH2, 2×CH2CH2Cl), 6.67 (2H, d, J 5.7 Hz, 2×ArH), 6.9 (2H, d, J 5.7 Hz, 2×ArH), 7.82 (1H, brs, NH); 13C (100 MHz, CDCl3), 30.1 (CH2), 43.1 (CH2), 43.4 (CH2), 44.2 (CH2), 46.2 (CH2), 46.7 (CH2), 115.9 (2×CH), 130 (2×CH), 130.1 (C), 155.6 (C), 161.5 (C). m/z (Cl) 269 (87%), 224 (50), 138 (100), 121 (45), 108 (35).
Reaction SMILES: [F:1][C:2]1([CH2:9][OH:10])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[H-].[Na+].F[C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][C:15]=1[S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25].O>O1CCCC1.ClCCl>[F:1][C:2]1([CH2:9][O:10][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][C:15]=2[S:24]([C:27]([F:28])([F:30])[F:29])(=[O:26])=[O:25])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1
Reactant: CN1CCC(F)(CO)CC1
Reactant: NS(=O)(=O)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC(F)(COc2ccc(S(N)(=O)=O)cc2S(=O)(=O)C(F)(F)F)CC1
Reaction time: 0.25 h

Procedure:
To a solution of (4-fluoro-1-methylpiperidin-4-yl)methanol (0.315 g) in tetrahydrofuran (5 mL) was added sodium hydride (0.342 g). After stirring for 15 minutes, 4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (0.658 g) was added as a solution in tetrahydrofuran (2 mL) followed by additional tetrahydrofuran (5 mL). After stirring for 1 hour, the reaction was poured in dichloromethane (50 mL) and water (25 mL) and the pH of the water layer was adjusted to 8. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The resulting oil was chromatographed over silica gel (Reveleris 40 g) eluting with a gradient of 1.0% to 10% 7N NH3 in methanol/dichloromethane over 20 minutes then maintaining 10% 7N NH3 in methanol/dichloromethane for 5 minutes (flow=30 mL/min) to provide the title compound.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([CH2:10][C@@H:11]([NH:15][C:16]([CH2:18][CH2:19][C@@H:20]([NH2:24])[C:21](O)=[O:22])=[O:17])[C:12]([OH:14])=[O:13])=[CH:8][NH:9][C:4]2=[CH:3][CH:2]=1.[NH2:25][C@@H](C(N[C@@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1)=O)CCC(=O)O>>[NH2:24][C@@H:20]([C:21](=[O:22])[NH2:25])[CH2:19][CH2:18][C:16]([NH:15][C@@H:11]([C:12]([OH:14])=[O:13])[CH2:10][C:7]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[NH:9][CH:8]=1)=[O:17]
Reactant: N[C@H](CCC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O)C(=O)O
Reactant: N[C@H](CCC(=O)O)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: NC(=O)[C@H](N)CCC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
A method for the preparation of thymodepressin was disclosed in example 1 of U.S. Pat. Nos. 5,736,519, 6,103,699 and 6,410,515. However, the manufacture of thymodepressin on a large scale cannot be conducted using the experimental details of this method since a mixture of D-glutamyl-D-tryptophan and D-isoglutamyl-D-tryptophan is produced which must be separated and purified by ion exchange chromatography resulting in a very low yield (12.25%) of thymodepressin.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[C:3](=[O:21])[CH:4](OC1C=CC(C=NOC)=CC=1)[N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.CC(C)(C)C(=O)CN1C=NC=N1.[Br:36]Br>>[Br:36][CH:4]([N:5]1[CH:9]=[N:8][CH:7]=[N:6]1)[C:3](=[O:21])[C:2]([CH3:23])([CH3:22])[CH3:1]
Reactant: BrBr
Reactant: CON=Cc1ccc(OC(C(=O)C(C)(C)C)n2cncn2)cc1
Agent: CC(C)(C)C(=O)Cn1cncn1
Product: CC(C)(C)C(=O)C(Br)n1cncn1

Procedure:
Thus, for example, it is possible to prepare 3,3-dimethyl-1-(4-methoxyiminomethyl-phenoxy)-1-(1,2,4-triazol-1-yl)-2-butanone of the formula ##STR11## by first reacting 3,3-dimethyl-1-(1,2,4-triazol-1-yl)-2-butanone with bromine to give 1-bromo-1-(1,2,4-triazol-1-yl)-3,3-dimethyl-2-butanone, and then reacting the latter with 4-hydroxybenzaldoxime O-methyl ether in the presence of a base. This synthesis can be illustrated by formulae as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:15]O)[CH:5]=[CH:6][C:7]=1[O:8][C@@H:9]([CH3:14])[C:10]([F:13])([F:12])[F:11].O=S(Cl)[Cl:19].O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][Cl:19])[CH:5]=[CH:6][C:7]=1[O:8][C@@H:9]([CH3:14])[C:10]([F:13])([F:12])[F:11]
Reactant: C[C@H](Oc1ccc(CO)cc1Cl)C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: C[C@H](Oc1ccc(CCl)cc1Cl)C(F)(F)F

Procedure:
A solution of {3-chloro-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}methanol (284 mg) and SOCl2 (179 μL) in DCM (7 mL) was stirred at room temperature for 2 hours. The reaction liquid was poured into water, followed by extraction with chloroform. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure to obtain 2-chloro-4-(chloromethyl)-1-[(1S)-2,2,2-trifluoro-1-methylethoxy]benzene (285 mg) as a colorless liquid.
Reaction SMILES: CS(NCCN[C@@:9]1(CCN)[CH2:18][C@@H:17]2[N:12]([CH2:13][CH2:14][C:15]3[CH:22]=[C:21]([O:23]C)[CH:20]=[CH:19][C:16]=32)[CH2:11][CH2:10]1)(=O)=O.C(Cl)Cl.N1C=CC=[CH:33][CH:32]=1.C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH:18]1[CH2:9][CH:10]=[CH:11][N:12]2[C:17]=1[C:16]1[O:23][C:21]3[CH:20]=[CH:19][CH:33]=[CH:32][C:22]=3[C:15]=1[CH:14]=[CH:13]2
Reactant: COc1ccc2c(c1)CCN1CC[C@@](CCN)(NCCNS(C)(=O)=O)C[C@@H]21
Reactant: c1ccncc1
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C1=CN2C=Cc3c(oc4ccccc34)C2=CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.50 grams (11.35 mmol) of (2R,11bS) 2-(2-methanesulfonamidoethylamino)-2-(2-aminoethyl)-9-methoxy-1,3,4,6,7,11b-hexahydrobenzo[a]quinolizine and 600 milliliters of methylene chloride containing 6.02 milliliters (25.01 mmol) of dry pyridine was cooled to 0° C. and 6.02 milliliters (11.91 mmol) of a 1.98M solution of phosgene in toluene was added dropwise over two hours. The mixture was stirred overnight at room temperature, washed with saturated aqueous NaHCO3 and brine, dried, filtered and concentraed in vacuo. The residue was chromatographed on 80 grams of silica gel using 1:4 methanolethyl acetate as eluant to obtain 1 gram of (2R,11bS) 9-methoxy-1,3,4,5',6,6',7,11b-octahydro-3'-(2-methanesulfonamidoethyl)-spiro-benzo[a]quinolizine-2,4'-(1'H-pyrimidin-2'-(3'H)-one as the free base. The HCl salt was prepared from 2-propanol and concentrated HCl. The HCl salt has a melting point 170°-174° C. with decomposition. The specific rotation for the HCl salt was -32.2°, c=0.012 g/ml, methanol.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)O.N1C=CC=CC=1.S(Cl)(Cl)=[O:28]>ClC1C=CC=CC=1>[C:1]([NH:9][NH:10][C:12]1[CH:13]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:8])[C:2]1[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:28]
Reactant: NNC(=O)c1ccccc1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1O
Solvent: Clc1ccccc1
Solvent: c1ccncc1
Product: O=C(NNc1ccccc1)c1ccccc1O
Yield: 67 %

Procedure:
13.6 g (0.1 mol) of benzhydrazide and 13.8 g (0.1 mol) of salicylic acid are initially introduced into 200 ml of chlorobenzene and the mixture is heated to the boil. After adding 3.0 g (0.038 mol) of pyridine, 13.1 g (0.11 mol) of thionyl chloride are added dropwise over the course of 1 hour. The reaction starts immediately whilst the product separates out as a white precipitate. After cooling, the mixture is filtered and the product is washed with methanol and dried. N-Salicyloyl-N'-phenyl-hydrazine of melting point 259° C is thus obtained in 67% yield.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].[C:29]([OH:38])(=[O:37])[CH:30]([CH:32]([C:34]([OH:36])=[O:35])[OH:33])[OH:31]>CS(C)=O>[CH3:1][CH2:2][O:3][C:4]([C:6]1[C@H:11]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].[C:29]([O-:38])(=[O:37])[C@@H:30]([C@H:32]([C:34]([O-:36])=[O:35])[OH:33])[OH:31]
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: CS(C)=O
Product: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)[C@H]1c1ccccc1Cl
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Reaction time: 3 h

Procedure:
To a stirred solution of 100 gm (0.245 moles) of RS amlodipine in 150 ml DMSO was added a solution of 9.2 gm (0.06 moles, 0.25 eq) of L (+) tartaric acid in 100 ml DMSO. The solid starts separating from clear solution within 5-10 mins. This was stirred for 3 hrs and solid was filtered off, washed with acetone and dried to give 58.6 gm (40.5%) R (+) amlodipine hemi L(+) tartarate mono DMSO solvate. mp. 160-162° C., 96.8% d.e. by chiral HPLC.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].[I:12]I>S([O-])([O-])(=O)=O.[Ag+2]>[I:12][C:6]1[CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]([CH3:1])=[CH:3][C:4]=1[NH2:5]
Reactant: II
Reactant: Cc1cc(N)ccc1[N+](=O)[O-]
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Product: Cc1cc(N)c(I)cc1[N+](=O)[O-]

Procedure:
3-Methyl-4-nitroaniline was treated with iodine and silver sulfate to give 2-iodo-5-methyl-4-nitroaniline. Treatment of the nitroaniline with 2-(trimethylsilyl)acetylene under the typical Sonogashira conditions gave 5-methyl-4-nitro-2-[(trimethylsilyl)ethynyl]aniline, which was treated with a base in an aqueous methanolic solution to give 2-ethynyl-5-methyl-4-nitroaniline. A subsequent base-induced cyclization at an elevated temperature gave 5-nitro-6-methylindole, which was treated under a high pressure hydrogenation condition to provide 5-amino-6-methylindole.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([N:13]2[C:12]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3ccc(Cl)cc3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: Clc1ccc(-n2nc3c(c2-c2ccccc2)CCNCC3)cc1
Yield: 38.4 %

Procedure:
The title compound (50.4 mg) was prepared from 201.1 mg of 2-(4-chloro-phenyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (made from (4-chloro-phenyl)-hydrazine as in Example 176, Steps A and B), and 65.1 mg of phenylboronic acid as described in Example 204. MS (ESI): exact mass calculated for C19H18ClN3, 323.12. found, m/z 324.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.39-7.34 (m, 3H), 7.22-7.19 (m, 2H), 7.15-7.11 (m, 4H), 3.11-3.07 (m, 2H), 3.04-3.00 (m, 2H), 2.99-2.96 (m, 2H), 2.67-2.64 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[O:34]=[C:35]1[CH2:39][CH2:38][CH2:37][N:36]1[CH2:40][CH2:41][CH2:42][NH2:43]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([NH:43][CH2:42][CH2:41][CH2:40][N:36]1[CH2:37][CH2:38][CH2:39][C:35]1=[O:34])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCN1CCCC1=O
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCCN1CCCC1=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 29.7 %

Procedure:
In 100 ml of THF was dissolved 9.97 g of compound (29) and after adding slowly thereto 4.45 g of triethylamine and then 6.01 g of isobutyl chloroformate under ice-cooling, the reaction was performed under ice-cooling. To the reaction mixture was slowly added 11.37 g of 3-(2-oxo-1-pyrrolidinyl)-propylamine and then the reaction was performed for one hour under ice-cooling. Precipitates were filtered off, the filtrate was concentrated, and the residue thus formed was subjected to silica gel column chromatography. By eluting the product with ethyl acetatemethanol (4:1), 4.43 g of (S)-1-benzyloxycarbonyl-N-[3-(2-oxo-pyrrolidinyl)propyl]-2-pyrrolidine carboxamide (99) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:18]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[N:19]3)[O:11][C:12]=2[CH2:13][CH2:14][C:15](O)=[O:16])=[CH:4][CH:3]=1.ON1C2N=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[CH3:46][N:47]1[CH2:52][CH2:51][CH:50]([CH2:53][N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:49][CH2:48]1>O.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:18]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[N:19]3)[O:11][C:12]=2[CH2:13][CH2:14][C:15]([N:57]2[CH2:56][CH2:55][N:54]([CH2:53][CH:50]3[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]3)[CH2:59][CH2:58]2)=[O:16])=[CH:4][CH:3]=1
Reactant: Cc1cc(C)n(-c2nc(-c3ccc(Cl)cc3)c(CCC(=O)O)o2)n1
Reactant: CN1CCC(CN2CCNCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)n(-c2nc(-c3ccc(Cl)cc3)c(CCC(=O)N3CCN(CC4CCN(C)CC4)CC3)o2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
A mixture of 3-[4-(4-chlorophenyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-oxazolyl]propionic acid (51.5 mg), 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (41 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (46 mg), 4-[(1-methyl-4-piperidinyl)methyl]piperazine (60 mg) and N,N-dimethylformamide (0.5 ml) was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was concentrated, introduced into preparative HPLC and purified. Ethyl acetate was added to the obtained oil and the mixture was washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated to give 1-{3-[4-(4-chlorophenyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-oxazolyl]propanoyl}-4-[(1-methyl-4-piperidinyl)methyl]piperazine (54.5 mg, yield 72%). Recrystallization from ethanol-isopropyl ether gave colorless prism crystals. melting point: 126–127° c.