Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[OH:25][C:26]([C:33]1[S:37][C:36]([CH:38]=[O:39])=[N:35][CH:34]=1)([CH3:32])[CH:27]([O:30][CH3:31])[O:28][CH3:29].C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH2:15][CH2:16][C:38]([C:36]3[S:37][C:33]([C:26]([OH:25])([CH3:32])[CH:27]([O:30][CH3:31])[O:28][CH3:29])=[CH:34][N:35]=3)=[O:39])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: COC(OC)C(C)(O)c1cnc(C=O)s1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(OC)C(C)(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)s1
Yield: 68.5 %

Procedure:
A mixture of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (1.00 g), 5-(1-hydroxy-2,2-dimethoxy-1-methylethyl)-1,3-thiazole-2-carbaldehyde (0.73 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (77 mg), triethylamine (0.16 mL), tetrahydrofuran (8 mL) and ethanol (8 mL) was stirred with heating under reflux for 2 hr. The reaction mixture was concentrated, and the residue was subjected to basic silica gel column chromatography, and the title compound (1.14 g, yield 69%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio). MS: 580 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:18])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[CH2:29][CH:30]=O>>[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[CH2:29][CH2:30][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:13](=[O:18])[CH2:14]1
Reactant: O=CCc1ccc([N+](=O)[O-])cc1F
Reactant: O=C1CNCCN1CCc1ccc([N+](=O)[O-])cc1
Product: O=C1CN(CCc2ccc([N+](=O)[O-])cc2F)CCN1CCc1ccc([N+](=O)[O-])cc1

Procedure:
The title compound was prepared from 1-[2-(4-Nitrophenyl)ethyl]piperazin-2-one and (2-Fluoro-4-nitrophenyl)acetaldehyde following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 417 [M+1]+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:8]=[C:7]([C:14]#[N:15])[C:6]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22]C(=O)C(C)(C)C)[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[Na+]>C(O)C>[CH2:1]([C:5]1[N:9]([C:10]([CH3:11])([CH3:12])[CH3:13])[N:8]=[C:7]2[C:6]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]=[C:14]2[NH2:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(-c2ccccc2NC(=O)C(C)(C)C)c(C#N)nn1C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCc1c2c(nn1C(C)(C)C)c(N)nc1ccccc12
Temperature: 25 °C
Yield: 36.8 %

Procedure:
To a solution of N-[2-(5-butyl-1-tert-butyl-3-cyano-1H-pyrazol4-yl)phenyl]-2,2-dimethylpropanamide (1.63 g, 4.28 mmol) in ethanol was added sodium tert-butoxide (0.494 g, 5.14 mmol). The solution was heated at reflux for 1 day, then was allowed to cool to ambient temperature. A precipitate formed that was isolated by filtration and washed with a small amount of water (24 mL) and ethanol (3 ML) to yield 0.4667 g of 1-butyl-2-tert-butyl-2H-pyrazolo[3,4-c]quinolin-4-amine as off-white crystals, mp 222.0-223.0° C.
Reaction SMILES: [CH:1]1([N:8]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[CH:10]([CH:16]=O)[CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[NH:21][CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>O1CCCC1>[CH:1]1([N:8]2[CH2:9][CH:10]([CH2:16][N:21]([C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[F:18])[CH3:22])[C:11]([CH3:15])([CH3:14])[C:12]2=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)C(=O)N(C2CCCCCC2)CC1C=O
Reactant: CNc1ccccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: C1CCOC1
Product: CN(CC1CN(C2CCCCCC2)C(=O)C1(C)C)c1ccccc1F

Procedure:
A solution of Example 4A (30 mg, 0.12 mmoles), 2-fluoro-N-methylaniline (19 mg, 0.15 mmoles) MP-triacetoxyborohydride (137 mg, 0.3 mmoles) in tetrahydrofuran (1.25 mL) was stirred for twelve hours. The reaction was filtered and solvent evaporated in vacuo. The crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 um particle size) using a gradient of 20% to 100% acetonitrile:water (0.1% trifluoroacetic acid) over eighteen minutes at a flow rate of 40 mL/minute to provide the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 6.90-7.10 (m, 4H), 4.01-4.13 (m, 1H), 3.32 (dd, J=9.88, 7.50 Hz, 1H), 3.11-3.21 (m, 2H), 3.09 (t, J=9.36 Hz, 1H), 2.83 (s, 3H), 2.17-2.27 (m, 1H), 1.59-1.70 (m, 6H), 1.45-1.57 (m, 6H), 1.16 (s, 3H), 0.95 (s, 3H). MS (APCI+) m/z 347.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1.COC(=O)C(O)C(C)C.[CH2:35]([O:37][C:38](=[O:43])[C:39](O)([CH3:41])[CH3:40])[CH3:36].CO>C(OCC)(=O)C>[CH2:35]([O:37][C:38](=[O:43])[C:39]([CH3:41])([O:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH2:3][C:2]([F:24])([F:1])[F:25])[N:5]=[CH:6][N:7]=1)[N:18]=3)[CH3:40])[CH3:36]
Reactant: Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Reactant: CCOC(=O)C(C)(C)O
Agent: COC(=O)C(O)C(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2

Procedure:
Following the procedures of Example 426, 2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol, 2-hydroxy-3-methyl-butyric acid methyl ester and 2-hydroxy-2-methyl-propionic acid ethyl ester were reacted and the crude product was subjected to flash chromatography (SiO2, gradient 0-10% methanol in ethyl acetate) to give 2-methyl-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionic acid ethyl ester as a yellow oil contaminated with triphenylphosphine oxide. LCMS: RT=3.68 min, [M+H]+=466
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]2[C:18]3[N:19]=[C:20]([CH3:26])[N:21]([CH2:22][O:23][CH2:24][CH3:25])[C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Br[CH2:40][CH:41]([CH3:44])[CH2:42][Cl:43]>O1CCCC1.C(OCC)C.O>[C:28]1([CH2:27][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]2[C:18]3[N:19]=[C:20]([CH2:26][CH2:40][CH:41]([CH3:44])[CH2:42][Cl:43])[N:21]([CH2:22][O:23][CH2:24][CH3:25])[C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOCn1c(C)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Reactant: CC(CCl)CBr
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCOCn1c(CCC(C)CCl)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29.9 %

Procedure:
A solution of N,N-bis(phenylmethyl)-1-ethoxymethyl-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.8 g, 4.12 mmole, Example 1 Part E) in tetrahydrofuran (40 mL) was cooled to -78° C. Butyllithium (1.7 mL of 2.5M in hexanes, 4.2 mmole) was added and the reaction mixture was stirred for 20 minutes. 1-Bromo-3-chloro-2-methylpropane (4.8 mL, 41 mmole) was added and the reaction mixture was allowed to warm to ambient temperature over a period of 1 hour. The reaction mixture was diluted with diethyl ether and water. The ether layer was separated, dried over magnesium sulfate and then concentrated under vacuum. The resulting residue was purified by flash chromatography (silica gel eluting with 5-20% ethyl acetate in hexanes v/v) to provide 0.65 g of N,N-bis(phenylmethyl)-2-(4-chloro-3-methylbutyl)-1-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=O.[BH4-].[Na+].[N:10]1[CH2:11][CH2:12][N:13]2[C:17]3[CH:18]=[C:19]([NH2:22])[CH:20]=[CH:21][C:16]=3[S:15][C:14]=12>>[F:1][C:2]([F:7])([F:6])[CH2:3][NH:22][C:19]1[CH:20]=[CH:21][C:16]2[S:15][C:14]3=[N:10][CH2:11][CH2:12][N:13]3[C:17]=2[CH:18]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1ccc2c(c1)N1CCN=C1S2
Agent: [BH4-]
Agent: [Na+]
Product: FC(F)(F)CNc1ccc2c(c1)N1CCN=C1S2
Temperature: 0 °C

Procedure:
To a stirred mixture of 60 parts of trifluoroacetic acid and 4 parts of sodium borohydride are added portionwise, during a 5 hours-period, 4 parts of 2,3-dihydroimidazo[2,1-b]benzothiazol-6-amine at 30°-40° C. The reaction mixture is poured onto 300 parts of ice-water. The precipitated product is filtered off, washed with water and taken up in trichloromethane. The mixture is washed with ammonium hydroxide. The organic phase is dried, filtered and evaporated. The residue is crystallized from acetonitrile, yielding 3.3 parts of 2,3-dihydro-N-(2,2,2-trifluoroethyl)imidazo[2,1-b]benzothiazol-6-amine; mp. 211.7° C.
Reaction SMILES: [Br:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][C:7]2[S:8][C:9]([CH3:40])=[C:10]([CH3:39])[C:11]=2[C:12]([C:14]2[CH:33]=[CH:32][C:17]([O:18][S:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([OH:31])[CH:23]=3)(=[O:21])=[O:20])=[C:16]([CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1.[I-].[Mg+2].[I-].[C:46](OC(=O)C)(=[O:48])[CH3:47]>CCOCC>[C:46]([O:31][C:24]1[CH:23]=[C:22]([S:19]([O:18][C:17]2[CH:32]=[CH:33][C:14]([C:12]([C:11]3[C:10]([CH3:39])=[C:9]([CH3:40])[S:8][C:7]=3[CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:42][CH:41]=3)=[O:13])=[CH:15][C:16]=2[CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38]2)(=[O:21])=[O:20])[CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=[O:27])(=[O:48])[CH3:47]
Reactant: Cc1sc(Cc2ccc(Br)cc2)c(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C3CCCC3)c2)c1C
Reactant: CC(=O)OC(C)=O
Agent: [I-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(=O)Oc1cc(S(=O)(=O)Oc2ccc(C(=O)c3c(Cc4ccc(Br)cc4)sc(C)c3C)cc2C2CCCC2)ccc1C(=O)O

Procedure:
The title compound was prepared according to the procedure in Example 22 using 4-{4-[2-(4-bromo-benzyl)-4,5-dimethyl-thiophene-3-carbonyl]-2-cyclopentyl-phenoxysulfonyl}-2-hydroxy-benzoic acid (0.211 g, 0.315 mmol), magnesium iodide (0.0876 g, 0.315 mmol) and acetic anhydride (2.5 mL) in ether. Purification on 2% H3PO4/MeOH treated silica gel, eluting with a 10 & 20% EtOAc/pet ether step gradient followed by crystallization from acetone/hexane gave 0.185 g (57%) of the tide compound as a white solid, mp 113-114° C. 1H NMR (DMSO-d6) δ1.27-1.34 (m, 2 H), 1.51-1.58 (m, 2 H), 1.63-1.78 (m, 4 H), 1.80 (s, 3 H), 2.25 (s, 3 H), 2.28 (s,3 H), 2.95 (quintet, 1 H), 3.86 (s, 2 H), 6.97 (d, 2 H), 7.24 (d, 1 H), 7.38 (d, 2 H) 7.52 (dd, 1 H), 7.57 (d, 1 H), 7.86 (d, 1 H), 7.92 (dd, 1 H), 8.16 (d, 1 H) 13.8 (br,s 1 H). mass spectrum (−ESI) m/z 709 (M−H). Anal. Calcd. for C34H31BrO8S2: C, 57.38; H, 4.39; N, 0.00. Found: C, 56.99; H, 4.38; N, 0.02.
Reaction SMILES: [C:1]1(/[CH:10]=[CH:11]\[C:12]2[C:13]([C:18]([OH:20])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:2]([C:7]([OH:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:21][O:22][C@H:23]1[O:28][C@H:27]([CH2:29][O:30][S:31]([O-:34])(=[O:33])=[O:32])[C@@H:26]([O:35][C@@H:36]2[O:41][C@@H:40]([C:42]([OH:44])=[O:43])[C@@H:39]([O:45][C@H:46]3[O:51][C@H:50]([CH2:52][O:53][S:54]([O-:57])(=[O:56])=[O:55])[C@@H:49]([O:58][C@@H:59]4[O:64][C@H:63]([C:65]([OH:67])=[O:66])[C@@H:62]([O:68][C@H:69]5[O:74][C@H:73]([CH2:75][O:76][S:77]([O-:80])(=[O:79])=[O:78])[C@@H:72]([OH:81])[C@H:71]([OH:82])[C@H:70]5[NH:83][S:84]([O-:87])(=[O:86])=[O:85])[C@H:61]([OH:88])[C@H:60]4[OH:89])[C@H:48]([O:90][S:91]([O-:94])(=[O:93])=[O:92])[C@H:47]3[NH:95][S:96]([O-:99])(=[O:98])=[O:97])[C@H:38]([OH:100])[C@H:37]2[O:101][S:102]([O-:105])(=[O:104])=[O:103])[C@H:25]([OH:106])[C@H:24]1[NH:107][S:108]([O-:111])(=[O:110])=[O:109].[Na+:112].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+]>O>[CH2:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([OH:20])=[O:19])[CH2:10][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].[CH3:21][O:22][C@H:23]1[O:28][C@H:27]([CH2:29][O:30][S:31]([O-:34])(=[O:32])=[O:33])[C@@H:26]([O:35][C@@H:36]2[O:41][C@@H:40]([C:42]([OH:44])=[O:43])[C@@H:39]([O:45][C@H:46]3[O:51][C@H:50]([CH2:52][O:53][S:54]([O-:57])(=[O:56])=[O:55])[C@@H:49]([O:58][C@@H:59]4[O:64][C@H:63]([C:65]([OH:67])=[O:66])[C@@H:62]([O:68][C@H:69]5[O:74][C@H:73]([CH2:75][O:76][S:77]([O-:80])(=[O:78])=[O:79])[C@@H:72]([OH:81])[C@H:71]([OH:82])[C@H:70]5[NH:83][S:84]([O-:87])(=[O:85])=[O:86])[C@H:61]([OH:88])[C@H:60]4[OH:89])[C@H:48]([O:90][S:91]([O-:94])(=[O:93])=[O:92])[C@H:47]3[NH:95][S:96]([O-:99])(=[O:98])=[O:97])[C@H:38]([OH:100])[C@H:37]2[O:101][S:102]([O-:105])(=[O:104])=[O:103])[C@H:25]([OH:106])[C@H:24]1[NH:107][S:108]([O-:111])(=[O:110])=[O:109].[Na+:112].[Na+:112].[Na+:112].[Na+:112].[Na+:112].[Na+:112].[Na+:112].[Na+:112].[Na+:112].[Na+:112]
Reactant: O=C(O)c1ccccc1/C=C\c1ccccc1C(=O)O
Agent: CO[C@H]1O[C@H](COS(=O)(=O)[O-])[C@@H](O[C@@H]2O[C@@H](C(=O)O)[C@@H](O[C@H]3O[C@H](COS(=O)(=O)[O-])[C@@H](O[C@@H]4O[C@H](C(=O)O)[C@@H](O[C@H]5O[C@H](COS(=O)(=O)[O-])[C@@H](O)[C@H](O)[C@H]5NS(=O)(=O)[O-])[C@H](O)[C@H]4O)[C@H](OS(=O)(=O)[O-])[C@H]3NS(=O)(=O)[O-])[C@H](O)[C@H]2OS(=O)(=O)[O-])[C@H](O)[C@H]1NS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccccc1CCc1ccccc1C(=O)O

Procedure:
Hydrogenation of (Z)-stilbene-2,2'-dicarboxylic acid bis-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylamide) decasodium salt (see Example 76) as described under Example 10 gave 2,2'-ethylenedibenzoic acid bis-(2,3,4,5,6-penta-O-sulfo-D-glucit-1-ylamide) decasodium salt, [α]D20 -11.0° (c 0.5; water), MS: m/z 1617.2 (reconstructed M).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[O:21][CH2:20]3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[C:29]1([CH2:35][CH2:36][NH2:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH:19]([OH:21])[CH2:20][NH:37][CH2:36][CH2:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: NCCc1ccccc1
Reactant: Fc1ccc(C(CCCN2CCN(CC3CO3)CC2)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(CNCCc1ccccc1)CN1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 9.8 %

Procedure:
3.86 g (0.01 mol) of 1-[4,4-bis(4-fluorophenyl)butyl]-4-(2,3-epoxypropyl)piperazine and 1.2 g (0.01 mol) of 2-phenylethylamine were refluxed with heating together with 200 ml of DMF for 24 hours in the presence of a catalytic amount of an alkali such as potassium carbonate. DMF was distilled off under reduced pressure, and a residue was extracted with ethyl acetate. After washing with water and drying, the ethyl acetate was distilled off under reduced pressure to obtain 5 g of a crude subject compound of a viscous liquid. The obtained compound was refined by flush chromatography and fractional thin-layer chromatography with solvent mixtures of ethyl acetate--methanol and methylene chloride--methanol respectively to obtain 0.5 g of the subject compound in a viscous liquid state.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:13][N:12]([CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])[C:11](=[O:20])[C:10]=1[OH:21])=[O:8].[CH3:27][S:28]([NH2:31])(=[O:30])=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:13][N:12]([CH2:14][CH2:15][CH2:16][C:17]([NH:31][S:28]([CH3:27])(=[O:30])=[O:29])=[O:18])[C:11](=[O:20])[C:10]=1[OH:21])=[O:8]
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCCC(=O)O)C1
Reactant: CS(N)(=O)=O
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCCC(=O)NS(C)(=O)=O)C1

Procedure:
Compound 755 was prepared from 4-{4-[(3,4-dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-butyric acid and methane sulfonamide using the method described for compound 751. The title compound was purified by preparative HPLC (C18, ODS-A, S-75 μm, 30%–40% acetonitrile/water/0.5% TFA) and isolated as a white powder (0.0158 g, 13% yield). HRMS (M−H) calcd for C18H20N3Cl2O6S: 476.04499; found: 476.0431.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[H-].[Na+].[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([Cl:17])=[CH:12][N:11]=1>CN(C=O)C>[Cl:9][C:10]1[N:15]=[C:14]([O:1][CH:2]2[CH2:6][CH2:5][O:4][CH2:3]2)[C:13]([Cl:17])=[CH:12][N:11]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: OC1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ncc(Cl)c(OC2CCOC2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-hydroxy-tetrahydrofurane (115 mg, 1.31 mmol) in DMF (4 ml) at 0° C. was treated with NaH (60% dispersion in mineral oil, 45.8 mg, 1.145 mmol), the resulting suspension was allowed to warm to room temperature, stirred for 15 min and then added to a solution of 2,4,5-trichloropyrimidine (200 mg, 1.09 mmol) in DMF (4 ml) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h. The reaction mixture was quenched by addition of sat. aq. NH4Cl and extracted with EtOAc. The org. layer was washed with water and brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a colorless liquid. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 5.67-5.62 (m, 1H), 3.91-3.84 (m, 3H), 3.81-3.74 (m, 1H), 2.36-2.25 (m, 1H), 2.14-2.06 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5]1.[CH2:15]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31](O)=[O:32])[CH2:27][CH2:26]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(OCC)(=O)C.C(OC(C)C)(C)C>CN(C=O)C.O>[CH2:15]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]([NH:1][CH2:2][CH2:3][CH:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=3)[CH2:6][CH2:5]2)=[O:32])[CH2:27][CH2:26]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COc1ccc2c(c1)C(CCN)CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: COc1ccc2c(c1)C(CCNC(=O)C1CCN(C(=O)OCc3ccccc3)CC1)CC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
To a solution of 1-(2-aminoethyl)-6-methoxyindan (1.00 g, 5.23 mmol), 1-benzyloxycarbonyl-4-piperidinecarboxylic acid (1.38 g, 5.23 mmol) and 1-hydroxy-1H-benzotriazole (0.78 g, 5.75 mmol) in DMF (20 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC; 1.10 g, 5.75 mmol). The mixture was stirred for 6 hours at room temperature. To the reaction mixture was added water, and the mixture was subjected to extraction with ethyl acetate. The extract solution was washed with brine, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (chloroform/methanol, 95:5) to give 2.10 g (yield 92%) of the above-titled compound, m.p.132-133° C. (recrystallized from ethyl acetate/isopropyl ether).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][C:17]1[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=1)[O:20][C:21]1[N:26]=[CH:25][C:24]([CH:27]([NH2:29])[CH3:28])=[CH:23][C:22]=1[CH3:30]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:29]([CH:27]([C:24]3[CH:25]=[N:26][C:21]([O:20][C:19]4[CH:31]=[CH:32][CH:33]=[C:17]([F:16])[CH:18]=4)=[C:22]([CH3:30])[CH:23]=3)[CH3:28])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)cnc1Oc1cccc(F)c1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1Oc1cccc(F)c1
Yield: 50 %

Procedure:
The title compound is prepared in 50% yield (140 mg, colorless amorphous solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (200 mg, 0.73 mmol, Step-1 of Intermediate-1) and 1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (240 mg, 0.86 mmol, Amine-40, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].CS(C1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[C:13]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[CH:12][N:11]=1)(=O)=O.CNC>CCOCC>[CH3:1][N:2]([C:4]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[C:13]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)=[CH:12][N:11]=1)[CH3:3]
Reactant: CS(=O)(=O)c1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: CN(C)C=O
Agent: CNC
Solvent: CCOCC
Product: CN(C)c1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 100 °C

Procedure:
To a 25 mL thick glass wall pressure tube was added a stirrer bar, 4 mL DMF and 2-methylsulfonyl-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (42 mg 0.1 mmol). Then excess dimethylamine in ether (2M) was added, the tube sealed and heated at 100° C. for 18 h. The solvents were removed under high vacuum, and product was obtained. HPLC/MS: m/e=379 (M+1); Rt=3.79 min; 1H-NMR 500 MHz (CDCl3): δ 3.18 (s, 6H), 7.40 (d, J=9 Hz, 1H), 7.5-7.6 (m, 3H), 7.8 (m, 2H), 8.20 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1F.[CH3:18][O-:19].[Na+]>>[Cl:1][C:2]1[C:3]([O:19][CH3:18])=[C:4]([N+:14]([O-:16])=[O:15])[C:5]2[C:10]([CH:11]=1)=[N:9][C:8](=[O:12])[C:7](=[O:13])[N:6]=2
Reactant: C[O-]
Reactant: O=c1[nH]c2cc(Cl)c(F)c([N+](=O)[O-])c2[nH]c1=O
Agent: [Na+]
Product: COc1c(Cl)cc2c(c1[N+](=O)[O-])=NC(=O)C(=O)N=2

Procedure:
Similarly, the reaction of 7-chloro-6-fluoro-5-nitro-1,4-dihydroquinoxaline-2,3-dione with sodium methoxide gave 7-chloro-6-methoxy-5-nitroquinoxaline-2,3-dione, and with ethanethiol gave 7-chloro-6-ethylthio-5-nitroquinoxaline-2,3-dione.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:17][CH3:18])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]([NH:15][OH:16])=[NH:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2].CO[C:21](OC)(N(C)C)[CH3:22]>>[CH2:1]([C:3]1[C:4]([O:17][CH3:18])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]3[N:14]=[C:21]([CH3:22])[O:16][N:15]=3)[N:12]=2)[C:8]=1[CH3:9])[CH3:2]
Reactant: CCc1c(OC)nc2nc(C(=N)NO)cn2c1C
Reactant: COC(C)(OC)N(C)C
Product: CCc1c(OC)nc2nc(-c3noc(C)n3)cn2c1C
Temperature: 100 °C
Yield: 95 %

Procedure:
A mixture of 1.70 g of 6-ethyl-N-hydroxy-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-carboxamidine and 3.5 ml of dimethylacetamide dimethyl acetal was heated at 100° C. for 15 minutes and the resulting mixture was evaporated to dryness and purified by flash chromatography. The resulting solid was crystallized from aqueous methanol to give 1.76 g of 6-ethyl-7-methoxy-5-methyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)imidazol[1,2-a]pyrimidine (95% yield) as a white crystalline solid melting at 176°-177° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[O:5][C:4](=[O:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27]Cl)[CH2:21][CH2:20]1>>[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][O:1][C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[O:5][C:4](=[O:12])[C:3]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:21][CH2:20]1
Reactant: O=c1oc2c(c(O)c1-c1ccccc1)CCCC2
Reactant: ClCCCN1CCOCC1
Product: O=c1oc2c(c(OCCCN3CCOCC3)c1-c1ccccc1)CCCC2
Yield: 45.7 %

Procedure:
Obtained by causing the reaction, as indicated in Example 14, Stage B, of 14.5 g. (0.06 mol) of 4-hydroxy-3-phenyl-5,6,7,8-tetrahydrocoumarin with 15.6 g. (0.078 mol) of 3-morpholino-1-chloropropane. 10.1 g. of a paste which cannot be crystallised are isolated. Yield 45.7% (theoretical yield 22.1 g.).