Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH2:4]Cl)=[CH2:3].[OH:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(=O)([O-])[O-].[K+].[K+].O>C1COCC1.CN(C=O)C>[CH2:13]([O:12][C:10](=[O:11])[C:9]1[CH:15]=[CH:16][CH:17]=[C:7]([O:6][CH:1]=[C:2]([CH3:4])[CH3:3])[CH:8]=1)[CH3:14]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(OC=C(C)C)c1

Procedure:
A mixture of 2-methyl-3-chloropropene (64.2 g, 710 mmol), ethyl 3-hydroxybenzoate (48.21 g, 590 mmol), and potassium carbonate (122.3 g, 890 mmol) in THF (600 ml) and DMF (600 ml) was heated to reflux for 6 hr. The mixure was poured into water (3 L) and extracted with ethyl acetate three times. The ethyl acetate extracts were combined and washed with water and dried with brine. The ethyl acetate extracts were concentrated in vacuo to a yellow oil that was vacuum distilled to a clear oil (112.9 g, 87%).
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([C:18]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)=[O:19])[C:8]1=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:31](O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCN=C=NCCCN(C)C.CN(C1C=CC=CN=1)C>C1COCC1>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([C:18]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([O:27][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:26])=[CH:23][CH:22]=2)=[O:19])[C:8]1=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: OCc1ccccc1
Reactant: CCCCCCn1c(=O)c(C(=O)Nc2ccc(C(=O)O)cc2)c(O)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CCCCCCn1c(=O)c(C(=O)Nc2ccc(C(=O)OCc3ccccc3)cc2)c(O)c2ccccc21
Reaction time: 8 h

Procedure:
A solution of 4-(1-hexyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido)benzoic acid (41 mg, 0.1 mmol) in THF is cooled to 0° C., and benzyl alcohol (21 mg, 20 μl, 0.2 mmol) is added, along with EDCI (19 mg, 0.1 mmol) and dimethylaminopyridine (3 mg, 0.02 mmol). The reaction mixture is left to stir overnight. The organic phase is washed with water and evaporated under reduced pressure. The crude product is purified by column chromatography, using 4:1 petroleum ether: ethyl acetate, with a yield of 30 mg (60%). 1H NMR (DMSO): δ 8.16 (d, J=8 Hz, 1H), 8.04 (d, J=8 Hz, 2H), 7.83 (d, J=8 Hz, 3H), 7.68 (d, J=8 Hz, 1H), 7.46-7.25 (m, 6H), 7.38 (m, 1H), 5.30 (s, 2H), 4.28 (bs, 2H), 1.59 (bs, 2H), 1.41-1.15 (m, 6H), 0.84 (bs, 3H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][SH:15])=[CH:10][CH:9]=1.I[C:17]1[CH:22]=[N:21][NH:20][C:19](=[O:23])[CH:18]=1>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][S:15][C:17]2[CH:22]=[N:21][NH:20][C:19](=[O:23])[CH:18]=2)=[CH:10][CH:9]=1
Reactant: SCc1ccc(Cl)cc1
Reactant: O=c1cc(I)cn[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=c1cc(SCc2ccc(Cl)cc2)cn[nH]1
Temperature: 100 °C
Reaction time: 18 h
Yield: 51.9 %

Procedure:
A mixture of K2CO3 (65.4 mg, 0.47 mmol), (4-chlorophenyl)methanethiol (250 mg, 1.58 mmol), and 5-iodopyridazin-3(2H)-one (35 mg, 0.16 mmol) was stirred at 100° C. for 18 hours. After removal of the precipitate by filtration and concentration of the filtrate, the crude product was purified by prep-HPLC (C18 column/H2O:MeOH:TFA 90:10:0.1 to 10:90:0.1 gradient) to yield 5-(4-chlorobenzylthio)pyridazin-3(2H)-one 9A (21 mg, 51.6% yield). 1H NMR (400 MHz, Chloroform-D) δ ppm 11.08 (1H, br. s.), 7.57 (1H, d, J=2.01 Hz), 7.33 (4H, s), 6.57 (1H, d, J=2.01 Hz), 4.12 (2H, s).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[S:14][CH:15]=[C:16]([C:18]([OH:20])=O)[N:17]=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:42][O:43][CH2:44][CH2:45][CH2:46][NH2:47].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:42][O:43][CH2:44][CH2:45][CH2:46][NH:47][C:18]([C:16]1[N:17]=[C:13]([C:10]2[CH:11]=[N:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][CH:9]=2)[S:14][CH:15]=1)=[O:20]
Reactant: O=C(O)c1csc(-c2cnc(-c3ccccc3)nc2)n1
Reactant: COCCCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCCNC(=O)c1csc(-c2cnc(-c3ccccc3)nc2)n1
Reaction time: 18 h

Procedure:
To a solution consisting of 2-(2-phenylpyrimidin-5-yl)thiazole-4-carboxylic acid (Example 63, 80 mg, 0.28 mmol) in dichloromethane (10 mL) was added EDAC (75 mg, 0.39 mmol) and HOBt (53 mg, 0.39 mmol) at 0° C. To this mixture was added 3-methoxypropylamine (25 mg, 0.28 mmol) dissolved in dichloromethane (2 mL) and diisopropylethylamine (0.52 mL, 390 mg, 3.0 mmol). The solution was allowed to reach room temperature and stirred for 18 hours. The solvent was evaporated away under reduced pressure and the residue was purified by silica gel flash chromatography (1:1 v/v hexane-ethyl acetate to 100% ethyl acetate gradient) through a 25-g Silicycle® flash silica cartridge. The title compound was obtained as an off-white solid (21 mg, 21% yield); Rf 0.70 with 4:1 v/v ethyl acetate-hexane; melting point 134-136° C.; 1H-NMR (300 MHz; CDCl3) δ 9.31 (s, 2H), 8.52 (dd, 2H), 8.20 (s, 1H), 7.88 (br t, 1H), 7.53 (m, 3H), 3.62 (t, 2H); 3.59 (t, 2H); 3.41 (s, 3H), 1.96 (m, 2H); MS (ESI+) m/z 355 (M+1); H-PGDS FPBA IC50: 3.4 μM.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14]C)=[O:13])[C:6]([CH3:16])=[C:5]2[S:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]([CH3:16])=[C:5]2[S:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=[O:18])=[O:19]
Reactant: COC(=O)Cn1c(C)c(S(=O)(=O)c2ccc(Cl)cc2)c2cc(Cl)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(S(=O)(=O)c2ccc(Cl)cc2)c2cc(Cl)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from step (c) (0.09 g) in THF (5 ml) was added a 1.25 M solution of NaOH(aq) (0.25 ml). The reaction was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and the residue dissolved/suspended in water. The pH was adjusted to 2 using dilute HCl (aq) and the solid which precipitated was isolated by filtration, dried under vacuum at 40° C. to give the title compound.
Reaction SMILES: [C:1]1([C:17](O)=[O:18])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[NH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][N:51]1[CH2:65][CH2:64][CH2:63][N:62]([S:66]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=2[N+:75]([O-:77])=[O:76])(=[O:68])=[O:67])[CH2:61][C:60]2[N:78]=[C:56]([CH:57]=[CH:58][CH:59]=2)[CH2:55][N:54]([S:79]([C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][C:83]=2[N+:88]([O-:90])=[O:89])(=[O:81])=[O:80])[CH2:53][CH2:52]1>C1COCC1>[C:1]1([C:17]([NH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][N:51]2[CH2:65][CH2:64][CH2:63][N:62]([S:66]([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=3[N+:75]([O-:77])=[O:76])(=[O:67])=[O:68])[CH2:61][C:60]3[N:78]=[C:56]([CH:57]=[CH:58][CH:59]=3)[CH2:55][N:54]([S:79]([C:82]3[CH:87]=[CH:86][CH:85]=[CH:84][C:83]=3[N+:88]([O-:90])=[O:89])(=[O:81])=[O:80])[CH2:53][CH2:52]2)=[O:18])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1
Reactant: NCCCCCN1CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])Cc2cccc(n2)CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Reactant: O=C(O)c1ccc2ccc3cccc4ccc1c2c34
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(NCCCCCN1CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])Cc2cccc(n2)CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC1)c1ccc2ccc3cccc4ccc1c2c34
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
A solution of 1-pyrenecarboxylic acid (0.22 g, 0.89 mmol) and 4-methymoroholine (0.12 g, 1.14 mmol) in 5 mL of anhydrous THF was stirred for 30 min. After addition of DCC (0.16 g, 0.76 mmol) and HOBT (0.11 g, 0.76 mmol), the solution was stirred another 30 min. A solution of 6-(5-amino-1-pentanyl)-3,10-bis(2-nitrobenzenesulfonyl)-3,6,10,16-tetraazabicyclo[10.3.1]hexadeca-1(16),12,14-triene (0.51 g, 0.76 mmol) was added into the above solution and stirred at rt overnight. The solvent was evaporated and the residue was dissolved in CH2Cl2. The resulting solution was washed with 5% NaHCO3 solution and brine, dried and concentrated. The residue was purified by flash chromatography on a silica gel column using 100:1 CH2Cl2—MeOH as an eluent to give 0.45 g (65%) of the title compound as a yellow foam.
Reaction SMILES: C(N(C(C)C)C(C)C)C.Cl.Cl.[C:12](=[NH:20])([O:18][CH3:19])[CH2:13][C:14](=[NH:17])[O:15][CH3:16].[N+:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31](O)=O)([O-:23])=[O:22].C(C1NC=CN=1)(C1NC=CN=1)=O>ClCCl.CC(O)C>[CH3:16][O:15][C:14]1[CH:13]=[C:12]([O:18][CH3:19])[N:20]=[C:31]([CH2:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N+:21]([O-:23])=[O:22])[N:17]=1
Reactant: COC(=N)CC(=N)OC
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(OC)nc(Cc2ccccc2[N+](=O)[O-])n1
Temperature: -40 °C
Reaction time: 0.42 h
Yield: 32.9 %

Procedure:
Ethyl diisopropylamine (240 ml) was added dropwise to a stirred suspension of dimethyl malonimidate dihydrochloride (73.2 g) in dichloromethane (400 ml) at -40° C. under nitrogen, and the mixture was stirred at -40° C. for 25 minutes to give suspension A. 2-Nitrophenylacetic acid (65.16 g) was added portionwise to a stirred suspension of carbonyl diimidazole (53.3 g) in dichloromethane (400 ml) at room temperature. The resulting solution was stirred for 10 minutes and was added dropwise over 30 minutes to the suspension A at -40° C. The mixture was stirred at -40° C. for a further 45 minutes and then at room temperature overnight, after which the solution was washed with water (400 ml), 2N HCl (400 ml) and saturated sodium bicarbonate solution (400 ml), dried and evaporated to give an orange solid. It was then stirred with propan-2-ol (50 ml) for 10 minutes and filtered. The solid was washed with a further 50 ml of propan-2 -ol and then dried to give 32.6 g of the desired product as a yellow solid, mp 92°-93° C.
Reaction SMILES: C([O:4][C:5]1[C:6]([O:24][CH3:25])=[CH:7][C:8]2[NH:9][C:10]3[C:15]([S:16](=[O:21])(=[O:20])[C:17]=2[C:18]=1[Br:19])=[CH:14][C:13]([O:22][CH3:23])=[CH:12][CH:11]=3)(=O)C.[OH-].[Na+].C(O)(=O)C>CO.O>[Br:19][C:18]1[C:17]2[S:16](=[O:20])(=[O:21])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:22][CH3:23])[CH:14]=3)[NH:9][C:8]=2[CH:7]=[C:6]([O:24][CH3:25])[C:5]=1[OH:4]
Reactant: COc1ccc2c(c1)S(=O)(=O)c1c(cc(OC)c(OC(C)=O)c1Br)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)S(=O)(=O)c1c(cc(OC)c(O)c1Br)N2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 106.4 %

Procedure:
To a suspension of 3-acetoxy-4-bromo-2,7-dimethoxy-10H-phenothiazine-5,5-dioxide (10.0 g) in methanol (105 ml) there was added 2N aqueous sodium hydroxide solution (74 ml) and the resulting mixture was stirred at room temperature for 20 minutes. There was then added 10% aqueous acetic acid solution (250 ml) and a thick precipitate was formed. The mixture was diluted with water (105 ml) and filtered, the solid washed with water and ether, and dried in a desiccator, affording the title compound (9.6 g). Further purification of a small sample was achieved through chromatography on a short column of silica gel, eluting with acetone. m.p.: 252°-260° (dec).
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21](OCC)(=[O:24])[CH:22]=[CH2:23].CCCCCCC>C(O)C.C(Cl)Cl>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH:13]3[O:17][C:16]4=[N:18][C:21](=[O:24])[CH2:22][CH2:23][N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=CC(=O)OCC
Reactant: NC1=NCC(COc2ccc(C3CCCCC3)cc2)O1
Solvent: CCO
Solvent: ClCCl
Solvent: CCCCCCC
Product: O=C1CCN2CC(COc3ccc(C4CCCCC4)cc3)OC2=N1
Temperature: 150 °C
Yield: 26.2 %

Procedure:
To a solution of 5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (350 mg, 1.28 mmol) in ethanol (6 mL) was added ethyl acrylate (255.8 mg, 2.56 mmol). The reaction mixture was heated in a microwave oven at 150° C. for 40 min. The solvent was removed under vacuum, and the residue purified via flash column chromatography (silica gel, 0.5-12% EtOH/CH2Cl2) to afford an oil, which was dissolved in a small amount of methylene chloride and to which was then added heptane. A white solid precipitated to afford 110 mg of 2-(4-cyclohexyl-phenoxymethyl)-2,3,5,6-tetrahydro-oxazolo[3,2-a]pyrimidin-7-one.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C@H:7]([CH2:9][C:10]([NH:12][C@H:13]([C:18]([NH:20][C@H:21]([C:28]([NH:30][C@H:31]([C:44]([O:46][CH3:47])=[O:45])[CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:29])[CH2:22][C:23]1[N:27]=[CH:26][NH:25][CH:24]=1)=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(=O)=O>CO>[NH2:1][C@H:2]([C@H:7]([CH2:9][C:10]([NH:12][C@H:13]([C:18]([NH:20][C@H:21]([C:28]([NH:30][C@H:31]([C:44]([O:46][CH3:47])=[O:45])[CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:29])[CH2:22][C:23]1[N:27]=[CH:26][NH:25][CH:24]=1)=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC
Agent: O=C=O
Solvent: CO
Product: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@@H](N)CC(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC

Procedure:
1 g of Z-Sta-Ile-His-Lys(Boc)-OMe is dissolved in 10 ml of 95% strength MeOH and hydrogenated with 100 mg of Pd-on-carbon (10% pd) with CO2 -absorption until saturation. After filtering off the catalyst and concentrating to dryness there is obtained H-Sta-Ile-His-Lys(Boc)-OMe in the form of amorphous powder, which is directly further processed; Rf (B)=0.32; Rf (I)=0.17.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH2:17][NH:16][CH2:15][CH2:14]3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[O:21]1[CH2:24][C:23](=O)[CH2:22]1.[BH3-]C#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH2:17][N:16]([CH:23]2[CH2:24][O:21][CH2:22]2)[CH2:15][CH2:14]3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: O=C1COC1
Reactant: Cn1cc(Br)nc(Nc2ccc3c(c2)CCNC3)c1=O
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(Br)nc(Nc2ccc3c(c2)CCN(C2COC2)C3)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-bromo-1-methyl-3-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyrazin-2(1H)-one 221a (2.75 g, 7.5 mmol), oxetan-3-one (2.5 g, 37.5 mmol), NaBH3CN (4.75 g, 22.5 mmol) and zinc chloride (5 g, 37.5 mmol) in methanol (125 ml) was stirred for 4 hours at room temperature. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with 20:1 DCM/methanol to 222a (0.76 g, 25.9%). LC/MS: m/z 392 (M+H)+
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]([C:20]([NH2:22])=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(Cl)Cl.CO>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]([CH2:20][NH2:22])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)C1CN(c2ccccc2)CCN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: NCC1CN(c2ccccc2)CCN1Cc1ccccc1

Procedure:
To 4-phenyl-1-(phenylmethyl)-2-piperazinecarboxamide (28.5 g, 96 mmol) dissolved in tetrahydrofuran (220 mL) add lithium aluminum hydride (9.0 g,0.24 mol) portionwise. Stir and heat the reaction to reflux. Monitor the progress of the reaction by thin-layer chromatography. Upon completion, slowly add water (9 mL), 2N NaOH (9 ml), and H2O (27 mL). Suction filter the slurry through celite and wash the pad with ethyl acetate (500 mL). Remove the solvent in vacuo to give a brown oil. Flash chromatograph the oil on silica (400 g) with 19/1 CH2Cl2 /MeOH to give the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].[CH:10](O)=[O:11].C(OC(=O)C)(=O)C>O>[CH:10]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8])=[O:11]
Reactant: O=C(O)C1COCCN1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=CN1CCOCC1C(=O)O
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
To a mixture of morpholine-3-carboxylic acid (5 g, 38.1 mmol) and formic acid (46.6 g, 1.01 mol) cooled at 0-5° C. was added acetic anhydride (26.7 g, 262 mmol) dropwise. The resulting mixture was stirred at room temperature for 2 h. An excess of water was added while cooling the mixture. The resulting mixture was then concentrated under reduced pressure. The crude product 4-formyl-morpholine-3-carboxylic acid (6 g) was used in the next step without further purification. LC/MS (method 7): Rt=0.13 min; m/z=160.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16](Br)=[N:15][CH:14]=[CH:13][N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][CH:14]=[CH:13][N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccccc1
Reactant: Cc1cc(NC(=O)c2nccnc2Br)ccn1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1cc(NC(=O)c2nccnc2Nc2ccccc2)ccn1
Temperature: 150 °C
Reaction time: 0.83 h

Procedure:
3-Bromo-pyrazine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide (130 mg, 0.44 mmol) and aniline (54 mg, 0.58 mmol) were dissolved in 4 mL dry dioxane. 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (51 mg, 0.09 mmol), cesium carbonate (290 mg, 0.89 mmol) and tri(dibenzylideneacetone)dipalladium chloroform complex (46 mg, 0.044 mmol) were added and the reaction mixture was stirred under microwave irradiation for 50 minutes at 150° C. The reaction mixture was then evaporated and purified by flash chromatography on silica gel (heptane/ethyl acetate 1:1->100% ethyl acetate). The desired product was obtained as a yellow solid (47 mg, 35%), MS: m/e=306.2 (M+H+).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH:26]=[O:27])[CH2:24][CH2:23][CH2:22][C:21]([C:28](O)=[O:29])=[CH:20][C:19]=3[CH:31]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH2:43]([N:46]1[C:50]([CH2:51][S:52]([C:54]2[CH:60]=[CH:59][C:57]([NH2:58])=[CH:56][CH:55]=2)=[O:53])=[CH:49][N:48]=[CH:47]1)[CH2:44][CH3:45]>O1CCCC1.O.N1C=CC=CC=1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH:26]=[O:27])[CH2:24][CH2:23][CH2:22][C:21]([C:28]([NH:58][C:57]4[CH:56]=[CH:55][C:54]([S:52]([CH2:51][C:50]5[N:46]([CH2:43][CH2:44][CH3:45])[CH:47]=[N:48][CH:49]=5)=[O:53])=[CH:60][CH:59]=4)=[O:29])=[CH:20][C:19]=3[CH:31]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCn1cncc1CS(=O)c1ccc(N)cc1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCCN3C=O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)cc2)CCCN3C=O)cc1
Reaction time: 1 h

Procedure:
(−)-4-(((1-Propylimidazol-5-yl)methyl)sulfinyl)aniline di-p-toluoyl-D-tartarate monohydrate (6.58 g) was dissolved in ethyl acetate (50 ml) and 1N hydrochloric acid (33.5 ml), followed by separation. To the aqueous layer was added an aqueous 25% potassium carbonate solution (33.5 ml), followed by extraction with 2-propanol-ethyl acetate (1:4) twice. The organic layers were combined and washed with saturated brine, dried with magnesium sulfate, and the solvent was distilled off under reduced pressure. To the resulting residue tetrahydrofuran was added, after which the solvent was distilled off again under reduced pressure to give (−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. Then, to a solution of 8-(4-(2-butoxyethoxy)phenyl)-1-formyl-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylic acid (3.0 g) in tetrahydrofuran (30 ml) was added a drop of DMF, and then oxalyl chloride (0.86 ml) was added, and the mixture was stirred under nitrogen atmosphere for 1 hour. The resulting solution was added dropwise to a solution of (−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline and pyridine (16 ml) in tetrahydrofuran (70 ml) at 0° C. under nitrogen atmosphere. The mixture was returned to room temperature and stirred for 3 hours, after which water was added and extracted with ethyl acetate. The organic layer was washed with 10% aqueous acetic acid solution twice, with aqueous saturated sodium bicarbonate solution twice, and with saturated brine once, after which the resultant was dried with magnesium sulfate. After distilling off the solvent under reduced pressure, the resultant was separated and purified with a basic silica gel column chromatography (methanol:ethyl acetate=1:25) to give (−)-8-[4-(2-butoxyethoxy) phenyl]-1-formyl-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (3.34 g) (Compound 29) as a yellow amorphous material.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[C:6]1([CH:12]2[CH2:17][NH:16][CH2:15][C:14]3[CH:18]=[CH:19][S:20][C:13]2=3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH2:1]([N:16]1[CH2:17][CH:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:13]2[S:20][CH:19]=[CH:18][C:14]=2[CH2:15]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCBr
Reactant: c1ccc(C2CNCc3ccsc32)cc1
Product: CCCCN1Cc2ccsc2C(c2ccccc2)C1

Procedure:
Butyl bromide is condensed with 7-phenyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (Example 4) according to the procedure of Example 8.
Reaction SMILES: [S:1]=[C:2]1[CH2:6][O:5][C:4](=[O:7])[NH:3]1.[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:6]2[O:5][C:4](=[O:7])[NH:3][C:2]2=[S:1])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: O=C1NC(=S)CO1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C1NC(=S)C(=Cc2cc(O)c(O)c([N+](=O)[O-])c2)O1
Temperature: 100 °C

Procedure:
A solution containing 0.25 g of 4-thioxo-2-oxazolone 0.38 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.1 ml of piperidine in 5 ml of acetic acid was heated overnight at 100° C. The product was filtered and washed with attic acid. Yield 0.05 g, mp 245° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[N:18]=[C:17](O)[C:16]([S:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:15][N:14]=1)(=[O:11])=[O:10].O=P(Cl)(Cl)[Cl:38]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[N:18]=[C:17]([Cl:38])[C:16]([S:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:15][N:14]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Nc1ncc(Sc2ccc(S(=O)(=O)N3CCCCC3)cc2)c(O)n1)c1ccc(Cl)cc1Cl
Reactant: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Nc1ncc(Sc2ccc(S(=O)(=O)N3CCCCC3)cc2)c(Cl)n1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 92.6 %

Procedure:
A solution of 10 (150 mg, 0.26 mmol) in POCl3 (0.24 mL, 2.6 mmol) was heated to 90° C. for 3.5 hours. The mixture was cooled to room temperature and poured onto ice. The precipitate was collected by filtration, washed with water and dried under vacuum to afford 11 as a pale yellow solid (143 mg), which was used without further purification. Mass Spectrum m/e=594.8 (M+1)