Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[C:13]([Sn](CCCC)(CCCC)CCCC)[N:14]3[S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Br[C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[C:43]([N+:48]([O-:50])=[O:49])[CH:42]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[C:13]([C:41]4[CH:47]=[CH:46][C:44]([NH2:45])=[C:43]([N+:48]([O-:50])=[O:49])[CH:42]=4)[N:14]3[S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:18])=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2ccc(N3CCN(C)CC3)cc2n1S(=O)(=O)c1ccc(C)cc1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(-c3ccc(N)c([N+](=O)[O-])c3)cc3ccc(N4CCN(C)CC4)cc32)cc1
Temperature: 100 °C

Procedure:
6-(4-Methyl-piperazin-1-yl)-1-(toluene-4-sulfonyl)-2-tributylstannanyl-1H-indole (crude) (5.0 g, 7.6 mmol) and 4-bromo-2-nitroaniline (2.05 g, 9.5 mmol) in DMF (50 mL) were placed in a RB flask followed by evacuating and flushing with nitrogen. Pd(PPh3)4 (0.22 g, 0.19 mmol) was added and under nitrogen was heated to 100° C., overnight. Analysis after this period indicated that all starting material had been consumed. Workup was by diluting with EtOAc (200 ml) and repeatedly washing with sat NH4Cl (5×50 ml). Crude NMR spectrum was complex, attributed to the product nitrogen atoms being in various oxidation states. The crude was chromatographically purified (16 cm×6 cm silicagel column, gradient eluting with dichloromethane to 10% methanol in dichloromethane), and all related fractions were pooled together (orange thick oil) 3.0 g, was taken directly to the next step without further purification or attempting to assign the chemical shifts.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1[C:20]2[C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[S:17][C:16]=2[CH:15]=[CH:14][CH:13]=1.C(O)C>C(Cl)(Cl)Cl>[CH:12]1[C:20]2[C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[S:17](=[O:9])[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc2c(c1)sc1ccccc12
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=S1c2ccccc2-c2ccccc21
Temperature: -35 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A solution of mCPBA (8.27 g, 36.9 mmol) in 71 mL chloroform was added dropwise over 30 minutes to a solution of dibenzothiophene in 89 mL chloroform at −35° C. The reaction mixture was stirred at −35° C. for 1 hour and then warmed up to room. The reaction was quenched with saturated sodium bicarbonate aqueous solution. The organic layer was washed with saturated sodium bicarbonate solution twice and dried over MgSO4, concentrated down to give an off-white solid. The solid was dissolved in refluxing ethanol and slowly cooled to room temperature to give a white crystalline solid Dibenzothiophene 5-oxide (5.65 g, 76%). LCMS-ESI−: calc'd for C12H8OS: 200.26. Found: 200.9 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([C:13](=[O:17])[CH:14]=[CH:15][CH3:16])=[CH:5][CH:4]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C>[CH3:1][O:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([C:13](=[O:17])[CH2:14][CH:15]([CH3:16])[N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:5][CH:4]=1
Reactant: C1CCNC1
Reactant: CC=CC(=O)c1ccc(OC)c2c1CCCC2
Solvent: CCO
Product: COc1ccc(C(=O)CC(C)N2CCCC2)c2c1CCCC2
Yield: 58.8 %

Procedure:
A solution of 1-(4-methoxy-5,6,7,8-tetrahydro-1-naphthyl)-2-butene-1-one (3.0 g) and pyrrolidine (1.85 g) in ethanol (100 ml) was stirred for 3 hours at room temperature. The mixture was evaporated in vacuo to give the residue. The residue was partitioned into water and ethyl ether. The ethyl ether was washed with water. The organic layer was extracted with 2N hydrochloric acid. The aqueous layer was neutralized with ammonia water and then extracted with ethyl ether. The ethyl ether was dried over anhydrous magnesium sulfate and then filtered. The filtrate was evaporated in vacuo to give 1-(4-methoxy-5,6,7,8-tetrahydro-1-naphthyl)-3-methyl-3-pyrrolidino-1-propanone (2.31 g, Yield: 53.6%) as an oil. ##STR341##
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[S:14]([NH2:17])(=[O:16])=[O:15])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].II>ClCCl>[F:11][C:10]([F:13])([F:12])[C:7]1[CH:8]=[CH:9][C:4]2[CH2:1][CH:2]3[CH2:3][N:17]3[S:14](=[O:16])(=[O:15])[C:5]=2[CH:6]=1
Reactant: C=CCc1ccc(C(F)(F)F)cc1S(N)(=O)=O
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=S1(=O)c2cc(C(F)(F)F)ccc2CC2CN21
Reaction time: 2 h

Procedure:
To a solution of 2-(2-propenyl)-5-trifluoromethylbenzenesulfonamide (780 mg, 2.94 mmol) in nitrogen-degassed dichloromethane (30 mL) containing potassium carbonate (1.62 g, 11.8 mmol) was added iodine (1.49 g, 5.88 mmol). After stirring for 2 h, the reaction was quenched with 10% aqueous sodium thiosulfate (ca. 14 mL). The dichloromethane was removed in vacuo and the residue was diluted with methanol (10 mL) and 0.25 N potassium carbonate in 70% aqueous methanol. Additional methanol was added to produce a nearly homogeneous solution. After 10 min, the reaction was concentrated in vacuo to remove most of the methanol. The residue was partitioned between dichloromethane (30 mL) and water (10 mL). The aqueous layer was extracted with dichloromethane (5 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated in vacuo to provide 8,8a-dihydro-5-(trifluoromethyl)-1H-azirino[1,2-b][1,2]benzothiazine 3,3-dioxide as a white solid (685 mg (92%): LCMS (net. ion spectrum) m/z 262.
Reaction SMILES: [CH:1]1([C@@H:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][C@H:9]([OH:17])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.N#N>N1C=CC=CC=1>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:17][C@@H:9]2[CH2:8][C@H:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O[C@H]1Cc2ccccc2[C@@H](C2CCCCC2)C1
Agent: N#N
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@H]2Cc3ccccc3[C@@H](C3CCCCC3)C2)cc1
Yield: 62 %

Procedure:
(Wyrick S D, Booth R G, Myers A M, Owens C E, Kula N S, Baldessarini R J, McPhail A T, and Mailman R B (1993) Synthesis and pharmacological evaluation of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes as ligands for a novel receptor with sigma-like neuromodulatory activity. J Med Chem 36:2542-2551) (2R,4R)-4-Cyclohexyl-1,2,3,4-tetrahydronaphthalen-2-ol 2a (0.23 g, 0.1 mol), p-toluenesulfonyl chloride (0.20 g, 0.11 mol), and pyridine (1.5 mL) was stirred in solution for 24 hours at rt, under inert atmosphere (N2). The solvent was removed and the crude material was purified by column chromatography (Si-gel) to give 3a in a 62% yield. HRMS m/z Calcd for C23H28O3S 407.1651 [M+Na]+. Found 407.1631.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:29])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:17][CH:16]=3)[CH:7]=2)[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:39])C=1>ClCCl>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:29])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N+:24]=4[O-:39])=[CH:17][CH:16]=3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccccn2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2cccc[n+]2[O-])cc1
Yield: 57.5 %

Procedure:
N-cyclopropyl-4-methyl-3-{[4-(pyridin-2-ylmethoxy)benzoyl]amino }benzamide (200 mg, 0.5 mmol) was dissolved in dichloromethane (50 mL) and stirred while adding 3-chloroperbenzoic acid (85%, 200 mg). The solution was stirred for one hour at 25° C., then washed twice with sodium bicarbonate solution and dried. The solvent was evaporated to give the title compound as a white solid (120 mg); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.68 (m, 2H), 2.24 (s, 3H), 2.84 (m, 1H), 5.35 (s, 2H), 7.18 (d, 2H), 7.31(d, 1H), 7.42 (m, 2H), 7.60 (m, 2H), 7.78 (m, 1H), 7.99 (d, 2H), 8.36 (m, 2H), 9.84 (s, 1H); Mass Spectrum: M+H+ 418.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:11][C:12]1[C:32]([F:33])=[CH:31][C:15]2[N:16]3[C:20]([CH2:21][C:22](=[O:24])[NH:23][C:14]=2[CH:13]=1)=[N:19][N:18]=[C:17]3[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH2:34]([N:41]([CH:46]([CH3:48])[CH3:47])[C:42](=[O:45])[CH2:43]Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C>[CH2:34]([N:41]([CH:46]([CH3:48])[CH3:47])[C:42](=[O:45])[CH2:43][N:23]1[C:22](=[O:24])[CH2:21][C:20]2[N:16]([C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:18][N:19]=2)[C:15]2[CH:31]=[C:32]([F:33])[C:12]([F:11])=[CH:13][C:14]1=2)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C1Cc2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc2N1
Reactant: CC(C)N(Cc1ccccc1)C(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc21
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
To a solution of KHMDS (0.5 M in THF, 16.6 mL, 8.33 mmol) at 0° C. was added 8,9-difluoro-1-phenyl-4H,6H-2,3,6,10b-tetraaza-benzo[e]azulen-5-one (Preparation 4(C) (2.0 g, 6.4 mmol) in DMF (20 mL). The reaction was stirred at 0° C. for 35 minutes, was cooled to −10° C., and a solution of N-benzyl-2-bromo-N-isopropyl-acetamide (Preparation 1(C) (1.9 g, 7.0 mmol) in DMF (20 mL) was added. The reaction was stirred at −10° C. for 2 hours and at room temperature for 24 hours. The reaction was quenched with a pH 6.8 buffer and the aqueous solution was washed with EtOAc (3×). The combined organic solutions were washed with brine (4×), dried (Na2SO4), filtered and concentrated. Purification by medium pressure chromatography eluting with a solvent gradient (CH2Cl2 to 3% MeOH in CH2Cl2) provided 2.01 g of N-benzyl-2-(8,9-difluoro-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-isopropyl-acetamide. 1H NMR (CD2Cl2) δ 7.60-7.17 (m, 11H), 6.75 (q, 1H), 4.85-4.38 (m, 4H), 4.10 (q, 1H), 3.60 (q, 1H), 3.41 (s, 1H), 1.21 (q, 3H), 1.13 (q, 3H); MS 502.4 (M+1), 500.3 (M−1).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[CH:9]=O)=[CH:3][CH:2]=1.[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(=O)C>[C:11]1([N:17]2[CH:7]([C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)[CH:8]=[CH:9][NH:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C/C=C/c1ccccc1
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Product: C1=CC(c2ccccc2)N(c2ccccc2)N1

Procedure:
13.2 g Zimtaldehyde (cinnamaldehyde) was condensed with 10.8 g Phenylhydrazine in 300 ml boiling acetic acid over 2 hours. At room temperature the sediment was filtered, washed with ethanol and dried.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]#[N:19])=[CH:12][CH:11]=3)#[N:4].[CH2:20](Br)[CH2:21][CH2:22][CH3:23].O>CN(C)C=O>[CH2:20]([N:9]1[C:10]2[CH:11]=[CH:12][C:13]([C:18]#[N:19])=[CH:14][C:15]=2[C:16]2[C:8]1=[CH:7][CH:6]=[C:5]([C:3]#[N:4])[CH:17]=2)[CH2:21][CH2:22][CH3:23]
Reactant: N#Cc1ccc2[nH]c3ccc(C#N)cc3c2c1
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCn1c2ccc(C#N)cc2c2cc(C#N)ccc21
Temperature: 110 °C
Yield: 81.3 %

Procedure:
A slurry of sodium hydride (50% in oil, 480 mg) in 50 ml of anhydrous dimethylformamide is treated with 3,6-dicyanocarbazole (2.17 g) and heated at 110° C for two hours. The reaction mixture is then treated dropwise with butylbromide (1.37 g) and heated for about 16 hours at 110° C. The reaction mixture is poured into water and the resultant precipitate collected by filtration. The solid is dissolved in dichloromethane and filtered through 200 ml of silica gel to yield 2.22 g of the title compound, melting point 215°-217°C.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=5)[CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C@H:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:36][CH3:37])=[O:4].[OH-].[K+].Cl>CO.C1COCC1>[Cl:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[Cl:33])[CH2:26][O:25][C:21]1[CH:20]=[C:19]([C@H:17]2[CH2:16][O:15][C:11]3=[CH:12][C:13]4[CH2:14][C@@H:5]([C:3]([OH:4])=[O:2])[N:6]([C@H:35]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:36][CH3:37])[CH2:7][C:8]=4[CH:9]=[C:10]3[O:18]2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)O3
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)O3
Temperature: 0 °C
Reaction time: 12 h
Yield: 82.7 %

Procedure:
(3S,8S)-3-[3-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (0.14 g, 0.22 mmol) was taken in 1 mL of MeOH:THF (4:1) and cooled to 0° C.; KOH (0.54 mL, 2.5 N) was added and stirred at room temperature for 12 hours. KOH (0.36 mL, 2.5 N) was added and stirred for 24 hours. Then, HCl (2.4 mL, 1 N) was added to the reaction and the product was extracted with EtOAc. The ethyl acetate layer was separated and washed with water and brine, and then dried over Na2SO4, filtered, and evaporated to get (3S,8S)-3-[3-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (0.11 g). LCMS (m/z): 605.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[S:13](Cl)([C:16]1[C:28]2[CH:27]=[CH:26][CH:25]=[C:21]([N:22]([CH3:24])[CH3:23])[C:20]=2[CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14]>>[CH3:23][N:22]([CH3:24])[C:21]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:20]=1[CH:19]=[CH:18][CH:17]=[C:16]2[S:13]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:15])=[O:14]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cccc3c(N(C)C)cccc23)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and dansyl chloride as described in the synthetic METHOD B to give a yellow solid (10.0 mg) with purity >90%. LCMS (pos) m/z 420.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[NH:9]1[CH2:14][CH2:13][CH:12]([C:15](O)=O)[CH2:11][CH2:10]1.[OH-].[K+]>O>[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[O:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH2:11][CH2:10]1
Reactant: O=C(O)C1CCNCC1
Reactant: Nc1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: c1ccc2oc(C3CCNCC3)nc2c1
Temperature: 180 °C
Yield: 84.3 %

Procedure:
2-Aminophenol (200 mg) and 4-piperidinecarboxylic acid (236 mg) were mixed with polyphosphoric acid (1 g) and stirred with heating at 180° C. for 2 hours. After cooling to room temperature, the reaction was stopped by adding water. The filtrate was adjusted to pH 12 with 50% potassium hydroxide aqueous solution and then extracted with methylene chloride. The organic layer was washed with saturated brine and dried with magnesium sulfate, and then the solvent was evaporated under a reduced pressure to obtain the title compound 2-(4-piperidyl)benzoxazole (311.5 mg).
Reaction SMILES: I.[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]1=[NH:13])[CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27](Cl)=[O:28]>C(Cl)Cl>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[N:13]\[C:27](=[O:28])[C:26]1[CH:30]=[C:22]([Cl:21])[CH:23]=[CH:24][C:25]=1[O:31][CH3:32])[CH2:3][CH2:4][CH3:5]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CCCCn1c(C)c(C)sc1=N
Agent: I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCn1c(C)c(C)s/c1=N\C(=O)c1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of Example 1A (312 mg, 1 mmol) and triethylamine (0.42 mL, 3 mmol) in CH2Cl2 (15 mL) at 0° C. was added 5-chloro-2-methoxybenzoyl chloride (Waterstone, 205 mg, 1 mmol), the mixture was allowed to warm to room temperature and was stirred for 14 hours. The solution was washed sequentially with water, brine, dried with anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ: 0.93 (t, J=7 Hz, 3H), 1.35 (sextet, J=7 Hz, 2H), 1.68 (quintet, J=7 Hz, 2H), 2.21 (s, 3H), 2.26 (s, 3H), 3.78 (s, 3H), 4.26 (t, J=7 Hz, 2H), 7.10 (d, J=9 Hz, 1H), 7.44 (d-d, J=9 Hz, 3 Hz, 1H), 7.70 (d, J=3 Hz, 1H); MS (ESI+) m/z 353 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.C([Li])CCC.CCCCCC.CN(C)[CH:29]=[O:30]>CCOCC>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([S:7][C:3]2[S:4][CH:5]=[CH:6][C:2]=2[CH:29]=[O:30])=[CH:9][CH:10]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(Sc2sccc2Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1ccc(Sc2sccc2C=O)cc1
Temperature: -78 °C

Procedure:
To a stirred solution of 3-bromo-2-(4-methoxyphenylthio)thiophene (12.77 g, 0.042 mol) in anhydrous ether (100 ml) cooled to -78° C. was added dropwise over 1 hour. 1.55M n-butyl lithium in hexane (28.7 ml, 0.045 mol) under nitrogen atmosphere. The solution was stirred at -78° C. for another hour and then the temperature was allowed to rise to -30° C. over 1/4 hour. The temperature was lowered to -60° C. and dry dimethylformamide (6.2 g, 0.085 mol) was added over 5 minutes. The cooling bath was removed and the temperature was allowed to rise to 15° C. over 3/4 hour. The mixture was cooled to -20° C. and acidified by slowly adding 3NHCl (40 ml). The ether layer was separated and washed with saturated NaCl, saturated NaHCO3 and again with saturated NaCl. The solution was dried, filtered and concentrated in vacuo. A quantitative recovery of an amber oil which solidified to a waxy yellow solid was obtained. The product recrystallized from n-butyl chloride-hexane, mp 58°-60° C. The structure and purity were confirmed by NMR, mass spectral analysis and elemental analyses.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[C:16](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:16])[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cc2cc(Br)ccc2n1C
Temperature: 50 °C
Yield: 30.1 %

Procedure:
In dimethylformamide (5 mL), combine ethyl 5-bromo-1H-indole-2-carboxylate (1.00 g, 13.7 mmole), potassium carbonate (1.4 g, 10 mmole), and methyl iodide (280 μL, 4.50 mmole). Heat the mixture to 50° C. for 18 hours. Cool to room temperature and partition between EtOAc and water. Extract with EtOAc (3×), wash with brine (3×), dry (MgSO4) and concentrate to provide crude material. The crude material is purified on 120 g silica gel with 0 to 50% EtOAc in heptane to give 850 mg (81%) of the title compound. ES/MS m/e (81Br) 284.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:10])[N:3]=1.[CH3:11][C@H:12]1[CH2:17][NH:16][CH2:15][C@@H:14]([CH3:18])[NH:13]1>CS(C)=O>[CH3:11][C@H:12]1[NH:13][C@@H:14]([CH3:18])[CH2:15][N:16]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:10])[N:3]=2)[CH2:17]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: O=Cc1ccc(Cl)nc1O
Solvent: CS(C)=O
Product: C[C@@H]1CN(c2ccc(C=O)c(O)n2)C[C@H](C)N1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
6-Chloro-2-hydroxynicotinaldehyde (1.06 g, 6.76 mmol) was dissolved in DMSO (20 mL) at room temperature. The solution was treated with cis-2,6-dimethylpiperazine (1.16 g, 10.18 mmol) at room temperature. The reaction mixture was stirred at 100° C. for 3 hours and cooled to room temperature to yield crude 6-(cis-3,5-dimethylpiperazin-1-yl)-2-hydroxynicotinaldehyde. MS m/z 236 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH:13]=[C:14]([C:16]([OH:18])=O)[CH:15]=[C:5]2[C:4]1=[O:19])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:32][C:33]1[NH:37][N:36]=[N:35][N:34]=1>CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH:13]=[C:14]([C:16]([NH:32][C:33]3[NH:37][N:36]=[N:35][N:34]=3)=[O:18])[CH:15]=[C:5]2[C:4]1=[O:19])[CH3:2]
Reactant: CCn1c(=O)c2cc(C(=O)O)cn2c2ccccc21
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCn1c(=O)c2cc(C(=O)Nc3nnn[nH]3)cn2c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
A mixture of 1.2 g (4.7 mmole) of 4,5-dihydro-5-ethyl-4-oxo-pyrrolo-[1,2-a]-quinoxaline-2-carboxylic acid (prepared by the process of French application No. 2,387,230), 0.81 g (5.0 mmole) of carbonyldiimidazole and 25 ml of anhydrous dimethylformamide was stirred until a clear solution was obtained and 0.425 g (5.0 mmole) of anhydrous 5-amino-tetrazole were added thereto. The mixture was stirred at room temperature for 30 minutes and was then filtered. The recovered product was washed with ethyl acetate and dried over P2O5 under vacuum to obtain 1.4 g of 4,5-dihydro-5-ethyl-4-oxo-N-(1H-tetrazol-5-yl)-pyrrolo-[1,2-a]-quinoxaline-2-carboxamide in the form of white crystals melting at 315°-318° C.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[C:9](Cl)(=[O:13])[C:10]([CH3:12])=[CH2:11]>[OH-].[Na+].CC(C)=O>[C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C(O)[C@H]1CCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C=C(C)C(=O)N1CCC[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
D-Proline, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath; the resulting alkaline solution was diluted with acetone (71 mL). An acetone solution (71 mL) of methacryloyl chloride (13.56 g, 0.13 mol) and 2N NaOH solution (71 mL) were simultaneously added over 40 min to the aqueous solution of D-proline in an ice bath. The pH of the mixture was kept at 10-11° C. during the addition of the methacryloyl chloride. After stirring (3 h, room temperature), the mixture was evaporated in vacuo at a temperature at 35-45° C. to remove acetone. The resulting solution was washed with ethyl ether and was acidified to pH 2 with concentrated HCl. The acidic mixture was saturated with NaCl and was extracted with EtOAc (100 mL×3). The combined extracts were dried over Na2SO4, filtered through Celite, and evaporated in vacuo to give the crude product as a colorless oil. Recrystallization of the oil from ethyl ether and hexanes afforded 16.2 g (68%) of the desired compound as colorless crystals: mp 102-103° C. (lit. [214] mp 102.5-103.5° C.); the NMR spectrum of this compound demonstrated the existence of two rotamers of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers, vinyl CH2), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for the second rotamer (totally 1H for both rotamers, CH at the chiral canter), 3.57-3.38 (m, 2H, CH2), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH2, CH, Me); 13C NMR (75 MHz, DMSO-d6) δ for major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737 (C═O), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm−1; [α]D26+80.8° (c=1, MeOH); Anal. Calcd. for C9H13NO3: C, 59.00; H, 7.15; N, 7.65.