Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([OH:13])=[O:12])[C:5]=2[N:4]=[N:3]1.[CH2:14](O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:12])[C:5]=2[N:4]=[N:3]1
Reactant: O=C(O)c1cccc2[nH]nnc12
Reactant: CCCCCCCCO
Agent: Cl
Product: CCCCCCCCOC(=O)c1cccc2[nH]nnc12
Temperature: 110 °C
Reaction time: 2 h

Procedure:
n-Octyl alcohol (300 g) was saturated with hydrogen chloride gas passed in subsurface during about 2 hr. while the temperature rose to 55° C. Benzotriazolecarboxylic acid (16.3 g) prepared by the method of Example 1 was added and the reaction mixture was refluxed at 110° C. under reduced pressure for 1.25 hr. during which water was azeotropically distilled and collected in a Dean-Stark trap. Unreacted octyl alcohol was removed by reduced pressure distillation. The residue, which was solid when cooled, was recrystallized from benzene and washed with n-pentane to afford the ester, n-octyl benzotriazolecarboxylate, as a solid mp 64°-65° C. The infrared spectrum was similar to that of the ethyl ester, consistent with the ester structure, and the elemental analysis was as follows:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]=[C:16]=[S:17].C(N(CC)CC)C>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:5](=[O:7])[CH2:4][N:3]([CH2:1][CH3:2])[C:16]1=[S:17]
Reactant: S=C=Nc1ccccc1Cl
Reactant: CCNCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CC(=O)N(c2ccccc2Cl)C1=S
Yield: 30.2 %

Procedure:
The title compound was prepared by the; procedure described in Example 19 using 9.2 g of N-ethyl glycine, 8.48 g of 2-chlorophenyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved through crystallization from ethanol. Title compound (3.85 g) was obtained as an orange solid, m.p. 142°-145° C. Anal. Calcd. for. C11H11Cl N2O S: C, 51.87; H, 4.35; N, 11.00. Found: C, 51.96; H, 4.26; N, 10.97. Mass spectrum (EI, M.+) m/z 254.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH:7]([NH2:28])[CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:21][CH2:20][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:37]1([S:43](Cl)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[C:1]([O:5][C:6](=[O:29])[CH:7]([NH:28][S:43]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:45])=[O:44])[CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:17][CH2:18][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:21]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(N)C(=O)OC(C)(C)C)CCCC2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(NS(=O)(=O)c3ccccc3)C(=O)OC(C)(C)C)CCCC2)CC1

Procedure:
2-Amino-3-{1-[(cis-4-ethoxycarbonyl-cyclohexyl)carbamoyl]cyclopentyl}propanoic acid t-butyl ester (0.605 g, 1.48 mmole) was dissolved in dry dichloromethane (25 ml) and treated at 0° C. with triethylamine (0.45 g, 4.4 mmole) and benzene sulphonyl chloride (0.24 ml, 1.84 mmole). After stirring for 16 hours at room temperature under nitrogen the dichloromethane was removed under vacuum, the residue taken up in diethyl ether (25 ml), washed with dilute hydrochloric acid, dilute sodium hydrogen carbonate and water, dried (Na2SO4) and the solvent evaporated under vacuum to give the crude product. Purification by column chromatography on silica, eluting with diethyl etherdichloromethane mixtures, gave pure title compound as a white foam (0.60 g, 74%). Found: C,61.38; H,7.85; N,5.06. C28H42N2O7S requires C,61.06; H,7.69; N,5.09%.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:20]1[C:28]2[C:23](=[CH:24][C:25]([CH:29]=O)=[CH:26][CH:27]=2)[CH:22]=[CH:21]1>>[NH:20]1[C:28]2[C:23](=[CH:24][C:25]([CH2:29][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)=[CH:26][CH:27]=2)[CH:22]=[CH:21]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccc2[nH]ccc2c1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc5[nH]ccc5c4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1H-indole-5-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1H-indol-5-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[H-].[Na+].I[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].O>CN(C=O)C>[CH3:8][CH:7]([CH3:9])[CH2:6][C@H:2]([O:1][CH2:3][CH2:2][CH2:6][CH2:7][CH3:8])[C:3]([O:5][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:4]
Reactant: CC(C)C[C@H](O)C(=O)O
Reactant: CCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCOC(=O)[C@H](CC(C)C)OCCCCC
Reaction time: 0.33 h

Procedure:
To a solution of (2S)-2-hydroxy-4-methylpentanoic acid 8 (1 g, 7.6 mmol) in 50 mL DMF at 0° C. was added NaH (0.6 g, 15.2 mmol) and stirred for 20 min, followed by the addition of iodopentane (1.5 g, 7.6 mmol). The reaction mixture was stirred at rt for additional 16 h. The solution was poured into water and the layers separated. The aqueous layer was extracted with methylene chloride and the combined extracts were washed with sat'd NaHCO3, dried over magnesium sulfate, and concentrated to a crude product. Upon further purification, compound 9 was obtained as an oil (80 mg, 4%). MS [M+H]+ 273. Step 2: Preparation of (2S)-4-methyl-2-pentyloxypentanoic acid 10. To a solution of (2S)-pentyl 4-methyl-2-pentyloxypentanoate 9 (80 mg, 0.3 mmol) in 20 mL of THF cooled to 0° C. was added dropwise a solution of lithium hydroxide monohydrate (25 mg, 0.6 mmol) in 5 mL of water. The reaction mixture was stirred at rt for 16 h. THF was removed under reduced pressure to give an yellow oil which was diluted with 10 mL of 1 N HCl. The aqueous phase was extracted with CH2Cl2 (8×15 mL), and the extracts were combined, dried over Na2SO4, and concentrated to afford compound 10 (45 mg, 74%). MS [M+H]+ 203. Step 3: Preparation of (7S)-[(2S)-1-oxo-2-pentyloxy-(4-methylpentyl)]amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one, 12. To a solution of (2S)-4-methyl-2-pentyloxypentanoic acid 10 (45 mg, 0.22 mmol) in CH2Cl2/DMF (5:1, 15 mL) at 0° C. was added HOBT (40 mg, 0.26 mmol) and EDC (50 mg, 0.26 mmol). The mixture was stirred for 10 min then the amine 11 (52 mg, 0.22 mmol) was added and stirring was continued for 1 h. The solution was poured into water and the layers separated. The aqueous layer was extracted with methylene chloride and the combined extracts were washed with water, 1 N HCl, sat'd NaHCO3, dried over magnesium sulfate, and concentrated to a glassy solid compound 12 (80 mg, 86%). MS [M+H]+ 423.
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH2:7][CH2:6][CH:5]([O:8][NH2:9])[CH2:4]1.[CH3:10][C@:11]12[CH2:28][CH2:27][C@H:26]3[C@@H:16]([CH2:17][C:18](=[O:30])[CH:19]4[C@:24]3([CH3:25])[CH2:23][CH2:22][C:21](=O)[CH2:20]4)[C@@H:15]1[CH2:14][CH2:13][C:12]2=[O:31].O.[Na+].[Cl-]>C1COCC1>[ClH:1].[NH:3]1[CH2:7][CH2:6][CH:5]([O:8][N:9]=[C:21]2[CH2:22][CH2:23][C@@:24]3([CH3:25])[CH:19]([C:18](=[O:30])[CH2:17][C@@H:16]4[C@@H:26]3[CH2:27][CH2:28][C@@:11]3([CH3:10])[C@H:15]4[CH2:14][CH2:13][C:12]3=[O:31])[CH2:20]2)[CH2:4]1
Reactant: NOC1CCNC1
Reactant: C[C@]12CCC(=O)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@]12CCC(=NOC3CCNC3)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
A solution of 3-(RS)-pyrrolidinyloxyamine dihydrochloride (III-c, Prepn. 3, 227 mg) and androstane-3,6,17-trione (495 mg) in THF: water (2/1, 27 mL) was stirred for 30 min. NaCl was added and stirred till the two phases separated. After extraction of the aqueous layer with THF, the combined organic phases were washed with brine, dried and evaporated. The crude was purified by flash chromatography (SiO2, CH2Cl2:MeOH:NH3 9:1:0.1). To the concentrated fractions 5M HCl in EtOAc was added. After dilution with Et2O, the solid was collected by filtration to give the title compound I-ac (464 mg, 60%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 9.59 (1H, bb), 9.41 (1H, bb), 4.74 (1H, m), 3.80-2.90 (5H, m), 2.60-1.20 (21H, m), 0.78 (6H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C:18]3([CH3:31])[CH3:30])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Cl>ClCCl.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C:18]3([CH3:31])[CH3:30])=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3(C)C)cn2)c1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1cc(Br)cc(Nc2ccc(N3CCNCC3(C)C)cn2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 120.7 %

Procedure:
To the solution of 125c (1.19 g, 1.9 mmol) in dichloromethane (20 mL) was added 3M HCl in diethyl ether (15 mL). The reaction mixture was stirred at room temperature for 4 h. It was then concentrated under reduced pressure to afford 125d (900 mg, 95%). LCMS: [M+H]+ 392.1.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][N:6]([CH2:17][C:18]([O:20]CC)=[O:19])[C:7]1[CH:12]=[C:11]([C:13]([NH2:15])=[S:14])[CH:10]=[CH:9][C:8]=1[CH3:16])C.Cl[CH2:25][C:26](=O)[CH3:27]>C(O)C.CN(C)C=O>[CH3:16][C:8]1[CH:9]=[CH:10][C:11]([C:13]2[S:14][CH:25]=[C:26]([CH3:27])[N:15]=2)=[CH:12][C:7]=1[N:6]([CH2:5][C:4]([OH:3])=[O:23])[CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)CN(CC(=O)OCC)c1cc(C(N)=S)ccc1C
Reactant: CC(=O)CCl
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1csc(-c2ccc(C)c(N(CC(=O)O)CC(=O)O)c2)n1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
The compound (0.70 g, 2.1 mmol) obtained in step A was dissolved in a ethanol (14 ml)-N,N-dimethylformamide (4 ml) mixed solvent. Then, chloroacetone (0.18 ml, 2.3 mmol) was added, and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the obtained oil was diluted with dichloromethane, washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give a crude oil of the title compound containing N,N-dimethylformamide. Using this oil and according to the method of Reference Example 62, step B, the title compound (0.56 g, yield 83%) was obtained as a pale-yellow oil.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=1)=[O:13].[CH3:28][C:29]1[O:33][N:32]=[C:31]([C:34](Cl)=[O:35])[CH:30]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:22][N:21]([CH3:23])[C:17]1[CH:16]=[C:15]([NH:14][C:12](=[O:13])[C:11]2[CH:24]=[CH:25][C:26]([CH3:27])=[C:9]([NH:8][C:34]([C:31]3[CH:30]=[C:29]([CH3:28])[O:33][N:32]=3)=[O:35])[CH:10]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1N
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)Nc2cc(C(=O)Nc3cccc(N(C)C)c3)ccc2C)no1
Yield: 71.2 %

Procedure:
Triethylamine (0.129 ml) was added to a stirred mixture of 3-amino-N-(3-dimethylaminophenyl)-4-methylbenzamide (0.1 g), 4-dimethylaminopyridine (5 mg), 5-methylisoxazol-3-ylcarbonyl chloride (0.081 g) and methylene chloride (3 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with methylene chloride (10 ml), washed with a saturated aqueous sodium bicarbonate solution and dried over magnesium sulphate. The organic solution was evaporated and the residue was triturated under isohexane. The resultant solid was dried at 55° C. under vacuum to give the title compound as a solid (0.1 g); NMR Spectrum: (CDCl3) 2.42 (s, 3H), 2.55 (s, 3H), 2.97 (s, 6H), 6.55 (m, 2H), 6.89 (d, 1H), 7.23 (m, 2H), 7.36 (d, 1H), 7.72 (d, 1H), 7.84 (broad s, 1H), 8.55 (broad s, 2H); Mass Spectrum: M+H+ 379.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.[CH2:12]([O:14][C:15](=[O:27])[C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)=[O:17])[CH3:13].C([O-])([O-])=O.[K+].[K+]>>[CH2:12]([O:14][C:15](=[O:27])[C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]2)[CH:19]=1)=[O:17])[CH3:13]
Reactant: CCOC(=O)C(=O)c1c[nH]c2ccccc12
Reactant: CN1CCN(CCCCl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(=O)c1cn(CCCN2CCN(C)CC2)c2ccccc12
Yield: 53 %

Procedure:
The general procedure 1 was then followed using 1-(3-chloropropyl)-4-methylpiperazine (12.5 mmol, 2.2 g), ethyl-2-(1H-indol-3-yl)-2-oxoacetate (10 mmol, 2.17 g) and K2CO3 (10.8 mmol, 1.5 g). The purification was achieved by column chromatography (petro-lether:ethylacetate:diethylamine 5:5:1) to yield ethyl-2-{1-[3-(4-methylpiperazin-1-yl)propyl]-1H-indol-3-yl}-2-oxoacetate (5.3 mmol, 42%). IR [cm−1]=2936; 2790; 1727; 1638. FD-MS m/z (rel. int.)=359.9 (2.05%; M+•.). 1H NMR (300 MHz, CDCl3) 8.40 (m; 2H; indole-H); 7.36 (m; 3H; indole-H); 4.38 (q; 3J=7.1 Hz; 2H; OCH2CH3); 4.25 (t; 3J=6.5 Hz; 2H; indole-CH2CH2CH2N); 2.44 (m; 8H; 4× piperazin-CH2); 2.30 (s; 3H; CH3); 2.26 (t; 3J=6.5 Hz; 2H; indole-CH2CH2CH2N); 2.00 (m; 2H;
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(C(C)C)CC)(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[S:20]([O:9][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])([CH3:19])(=[O:22])=[O:21]
Reactant: CCCCCCC(C)O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCC(C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 100.3 %

Procedure:
To 130 g (0.995 mol) of 2-octanol and 207 ml (1.19 mol, 1.2 equiv) of diisopropylethylamine in 1.5 L dichloromethane at 0° C. under a CaSO4 drying tube was added dropwise 84.4 ml (1.09 mol, 1.1 equiv.) of methanesulfonyl chloride over 1 hour while keeping the internal temperature at less than 5° C. The faintly yellow solution was stirred at 0° C. for an additional 1.5 h. The cold reaction solution was then washed with 2×1 L ice-cold 1M HCl and 1 L of ice-cold H2O and brine and dried over MgSO4. The residue was filtered through Celite and concentrated in vacuo below 35° C. to afford 208 g of a yellow oil. The yellow oil was placed under high-vacuum for 2 h at 25° C. to give 205 g of yellow oil. NMR spectra confirmed the desired title-product having only trace amounts of solvents present.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[Cl-].[Na+].O.O>N1C=CC=CC=1>[O:8]=[C:6]1[NH:5][CH2:4][C@H:3]([CH2:2][O:1][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[O:7]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1NC[C@H](CO)O1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CNC(=O)O2)cc1
Reaction time: 2 h

Procedure:
A solution of (5R)-5-(hydroxymethyl)-1,3-oxazolidin-2-one (10.0 g), prepared as described in Tetrahedron: Asymmetry 1995, 6, 1181-1190, in pyridine (60 mL) at −10° C. was treated with para-toluenesulfonyl chloride (21.2 g), stirred for 2 hours, poured into 1:1 brine/water (100 mL), and extracted with ethyl acetate. The extract was washed with 1:1 saturated sodium bicarbonate/water and 1:1 brine/water, and the washes were back extracted with ethyl acetate. The combined extracts was dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI(+)) m/e 272 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 7.80 (d, 2H), 7.39 (d, 2H), 4.80 (m, 1H), 4.18 (d, 2H), 3.70 (t, 1H), 3.50 (dd, 1H), 2.45 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH2:13]OS(C)(=O)=O)[C@@H:10]([OH:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([SH:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H-].[Na+]>CN(C=O)C.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH2:13][S:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:10]([OH:19])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C[C@H](COS(C)(=O)=O)[C@@H](O)C1
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@H](CSCc2ccccc2)[C@@H](O)C1
Reaction time: 1 h

Procedure:
(3R,4R)-1-tert-Butoxycarbonyl-3-hydroxy-4-(mesyloxymethyl)pyrrolidine (see Example 34, 1.10 g, 3.7 mmol) was dissolved in DMF (2 mL) and added dropwise to a solution of benzyl mercaptan (870 μL, 7.4 mmol) and NaH (270 mg, 60% oil dispersion, 6.8 mmol) In DMF (10 mL) and stirred at room temp. for 1 h. The reaction was diluted with toluene, washed with water then brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography to afford (3R,4S)-1-tert-butoxycarbonyl-3-hydroxy-4-(benzylthiomethyl)pyrrolidine as a syrup. Without further characterisation, the product was dissolved in MeOH (5.0 mL) and cHCl (1.0 mL) and concentrated in vacuo to afford (3R,4S)-3-hydroxy-4-(benzylthiomethyl)pyrrolidine hydrochloride (53) as a syrup (730 mg, 76% overall yield for two steps). 1H NMR (D2O) δ 7.40-7.27 (m, 5H), 4.26-4.22 (m, 1H), 3.74 (s, 2H), 3.56 (dd, J=12.4, 7.2 Hz, 1H), 3.37 (dd, J=12.8, 5.2 Hz, 1H), 3.21 (dd, J=12.8, 3.0 Hz, 1H), 3.07 (dd, J=12.4, 5.5 Hz, 1H), 2.61-2.52 (m, 1H), 2.47-2.34 (m, 2H). 13C NMR (D2O) δ 138.7, 129.5, 129.3, 127.9, 73.5, 51.5, 48.5, 45.4, 35.9, 31.8. (MH+) calc for C12H18NOS: 224.1109. Found 224.1102.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH2:6]([O:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]2[NH:22][CH2:21][CH2:20][C:19]([C:23]([O:25][CH3:26])=[O:24])=[CH:18][C:17]=2[CH:27]=1)[CH2:7][CH3:8].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([N:22]1[C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][O:9][CH2:6][CH2:7][CH3:8])=[CH:27][C:17]=2[CH:18]=[C:19]([C:23]([O:25][CH3:26])=[O:24])[CH2:20][CH2:21]1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: CCCOCCOc1ccc2c(c1)C=C(C(=O)OC)CCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOCCOc1ccc2c(c1)C=C(C(=O)OC)CCN2C(=O)CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Propionyl chloride (1.0 ml) was added dropwise to a suspension of methyl 7-(2-propoxyethoxy)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.2 g) and potassium carbonate (2.2 g) in DMF (10 ml) under ice-cooling. The mixture was stirred at room temperature overnight under nitrogen atmosphere, and poured into water, which was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-propionyl-7-(2-propoxyethoxy)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.2 g) as pale yellow oil.
Reaction SMILES: N1C=CN=C1[C:6]([C:8]1[CH:9]=[CH:10][C:11]2[O:22][C:15]3[NH:16][C:17](=[S:21])[NH:18][C:19](=[O:20])[C:14]=3[CH2:13][C:12]=2[CH:23]=1)=[O:7].[NH2:24][C:25]1[NH:29][N:28]=[N:27][N:26]=1.O.Cl>CN(C)C=O>[NH:26]1[C:25]([NH:24][C:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:22][C:15]4[NH:16][C:17](=[S:21])[NH:18][C:19](=[O:20])[C:14]=4[CH2:13][C:12]=3[CH:23]=2)=[O:7])=[N:29][N:28]=[N:27]1
Reactant: O=C(c1ccc2c(c1)Cc1c([nH]c(=S)[nH]c1=O)O2)c1ncc[nH]1
Reactant: Nc1nnn[nH]1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nnn[nH]1)c1ccc2c(c1)Cc1c([nH]c(=S)[nH]c1=O)O2

Procedure:
Suspend 7-(imidazolylcarbonyl)-(1H,3H,5H)-(1)-benzopyrano-(2,3-d)-pyrimidine-4-one-2-thione (0.6 g.) in dry dimethylformamide (20 ml.). With stirring, add 5-aminotetrazole (0.61 g.) and warm the mixture to 65°-75° C. and keep at that temperature for about 3/4 hour. Allow the mixture to cool, pour into water and acidify with hydrochloric acid. Filter and wash with isopropanol and ether to yield 7-(5-tetrazolylaminocarbonyl)-(1H,3H,5H)-(1)-benzopyrano-(2,3-d)-pyrimidine-4-one-2-thione.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([C:13]2[C:21]([Cl:22])=[C:20]([Cl:23])[C:19]([Cl:24])=[C:18]([Cl:25])[C:14]=2[C:15]([OH:17])=O)=[O:12])=[C:3]1[CH3:26].[CH3:27][N:28]([CH3:38])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH3:37])[CH3:36])[CH:30]=1.C(OC(=O)C)(=O)C.[OH-].[NH4+]>Cl>[CH3:36][N:35]([CH3:37])[C:31]1[CH:30]=[C:29]([N:28]([CH3:38])[CH3:27])[CH:34]=[CH:33][C:32]=1[C:11]1([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[C:3]=2[CH3:26])[C:13]2[C:14](=[C:18]([Cl:25])[C:19]([Cl:24])=[C:20]([Cl:23])[C:21]=2[Cl:22])[C:15](=[O:17])[O:12]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: Cc1c(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c2ccccc2n1C
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: Cc1c(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c2ccccc2n1C
Temperature: 25 °C

Procedure:
A mixture of 1.55 g (0.0036 mole) of 2-[(1,2-dimethyl-3-indolyl)carbonyl]-3,4,5,6-tetrachlorobenzoic acid prepared in a manner similar to part A of Example 2, 0.58 g (0.0035 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine and ten ml of acetic anhydride was heated to reflux for approximately one hour. After cooling to room temperature, the reaction mixture was poured into 20 ml of 10 percent hydrochloric acid and the mixture then rendered alkaline by the addition of concentrated ammonium hydroxide. The purple solid which separated was collected by filtration, dried, and recrystallized twice from isopropyl acetate to obtain 3-[2,4-bis(dimethylamino)phenyl]-3-(1,2-dimethyl-3-indolyl)-4,5,6,7-tetrachlorophthalide (Formula III: R°=R1 =R2 =R3 =Cl; R=R5 =R6 =CH3 ; R4 =N(CH3)2 ; Y1 =H) which decomposed at 228°-229° C. The mass spectrum showed an m/e at 575 (M+, 4 Cl). A toluene solution of the product spotted on silica gel developed an intense purple-colored image.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:25])=[C:11]([NH:13][C:14](=[O:24])[C:15]3[CH:20]=[C:19]([F:21])[C:18](F)=[C:17]([F:23])[CH:16]=3)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][OH:33].CC(C)([O-])C.[K+]>CN1C(=O)CCC1.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:25])=[C:11]([NH:13][C:14](=[O:24])[C:15]3[CH:20]=[C:19]([F:21])[C:18]([O:33][CH2:32][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=4)=[C:17]([F:23])[CH:16]=3)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)c(F)c(F)c1
Reactant: OCc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)c(OCc2ccccn2)c(F)c1
Temperature: 180 °C
Yield: 23 %

Procedure:
A mixture of N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-3,4,5-trifluorobenzamide (100 mg, 0.29 mmol), 2-pyridinylmethanol (400 μl) and potassium t-butoxide (32 mg, 0.29 mmol) in NMP (600 μl) was heated in the microwave at 180° C. for 1.5 hrs. The reaction mixture was cooled and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic phase was washed with dilute aqueous citric acid. Evaporation of the ethyl acetate gave impure product which was purified on silica column chromatography eluting with 0 to 100% ethyl acetate in isohexane. The solvents were evaporated to give a residue which was dissolved in ethyl acetate, then extracted with dilute hydrochloric acid. The aqueous extracts were basified with saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate to give the title compound as a solid (29 mg, 23%); NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.69 (m, 2H), 2.25 (s, 3H), 2.85 (m, 1H), 5.36 (s, 2H), 7.37 (m, 2H), 7.64 (m, 2H), 7.84 (m, 4H), 8.40 (m, 1H), 8.56 (m, 1H), 10.14 (s, 1H); Mass Spectrum: M−H− 436.