Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH:22]=O>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:22][N:13]1[CH2:14][CH2:15][C:16]2[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=3[O:9][C:10](=[O:17])[C:11]=2[CH2:12]1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Product: COc1ccc2c3c(c(=O)oc2c1)CN(Cc1ccc(Cl)c(Cl)c1)CC3
Yield: 65 %

Procedure:
Prepared by the procedure of Example 3 from 8-methoxy-1,2,3,4-tetrahydro-chromeno[3,4-c]pyridin-5-one and 3,4-dichlorobenzaldehyde. Yield 65%, mp 144°-146° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[NH:9][C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)(=O)C>CN(C)C(=O)C.O>[CH2:23]([N:12]1[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:9]=[C:8]1[CH3:7])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1nc(C)[nH]c1C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1nc(C)n(Cc2ccccc2)c1C(=O)OCC
Reaction time: 0.5 h

Procedure:
5.21 g of potassium t-butoxide were added to a solution of 10.0 g of diethyl 2-methylimidazole-4,5-dicarboxylate in 100 ml of N,N-dimethylacetamide, whilst ice-cooling and under a nitrogen atmosphere. The mixture was stirred for 30 minutes, until a homogeneous solution was obtained, and then 5.78 ml of benzyl bromide were added dropwise to this solution, whilst ice-cooling. The resulting mixture was stirred at room temperature for 1 hour, after which it was mixed with ethyl acetate and water and shaken. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 12.38 g of the title compound as a syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:26][O:27]S(C)(=O)=O)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:26][O:27][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Oc1cccnc1
Reactant: COC(=O)CCCCCCNC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c1ccc(Cl)cc1
Product: COC(=O)CCCCCCNC(=O)C(COc1cccnc1)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 105 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(6-methoxycarbonylhexyl)propanamide (70.0 mg) was reacted with 3-hydroxypyridine to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(6-methoxycarbonylhexyl)-3-(pyridin-3-yloxy)propanamide (30.3 mg).
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]3[C:48](=[CH:49][CH:50]=2)[C:29]2=[N:30][O:31][C:32]([C:33]4[CH:34]=[N:35][N:36]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:37]=4[C:38]([F:41])([F:40])[F:39])=[C:28]2[CH2:27][CH2:26]3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:51][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC.CN(C=O)C>C1COCC1>[C:1]1([C:7](=[N:14][C:15]([CH3:51])([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]3[C:48](=[CH:49][CH:50]=2)[C:29]2=[N:30][O:31][C:32]([C:33]4[CH:34]=[N:35][N:36]([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[C:37]=4[C:38]([F:40])([F:41])[F:39])=[C:28]2[CH2:27][CH2:26]3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(CCc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F)N=C(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(CCc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F)N=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To a stirred clear solution of ethyl 2-(diphenylmethyleneamino)-4-(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate (Preparation 50B, 150 mg, 0.222 mmol) in anhydrous THF (5 mL) was added a 1 M THF solution of lithium bis(trimethylsilyl)amide (333 μL, 0.333 mmol) dropwise at 0° C. under nitrogen. The reaction mixture was stirred at the same temperature for 30 min before iodomethane (50 μL, 0.800 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min and at room temperature for 1 hr. The reaction was not complete. Anhydrous DMF (2 mL) was added, followed by lithium bis(trimethylsilyl)amide (2 mL, 2 mmol) at 0° C. The reaction mixture was stirred at the same temperature for 30 min before iodomethane (0.2 mL) was added. The mixture was stirred at 0° C. for 1 hr and quenched using saturated aqueous ammonium chloride solution (5 mL), ethyl acetate (10 mL), and water (10 mL). The aqueous solution was separated and re-extracted with ethyl acetate (2×5 mL). The combined ethyl acetate extracts were dried over sodium sulfate and concentrated under reduced pressure. Flash chromatography purification using ISCO (4 g silica gel column, 10→100% ethyl acetate in hexanes) afforded ethyl 2-(diphenylmethyleneamino)-2-methyl-4-(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate (120 mg, 0.174 mmol, 78% yield) as a solid. LC/MS M+1=689.5.
Reaction SMILES: C1N(/C=C2/CC/2CO)C2N=C(N)N=C(O)C=2N=1.[C@@H:18]1([N:27]2[C:36]3[N:35]=[CH:34][N:33]=[C:31]([NH2:32])[C:30]=3[N:29]=[CH:28]2)O[C@H:23]([CH2:24][OH:25])[C@@H:21](O)[C@H:19]1O>ClCCl.CO>[CH2:21]1[C@@H:23]([CH2:24][OH:25])/[C:19]/1=[CH:18]\[N:27]1[C:36]2[N:35]=[CH:34][N:33]=[C:31]([NH2:32])[C:30]=2[N:29]=[CH:28]1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Nc1nc(O)c2ncn(/C=C3/CC3CO)c2n1
Solvent: ClCCl
Solvent: CO
Product: Nc1ncnc2c1ncn2/C=C1/C[C@H]1CO
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of racemic synadenol (1, B=adenin-N9-yl, 200 mg, 0.92 mmol) from Example 5 in 0.05 M Na2HPO4 (pH 7.5, 100 mL) was briefly sonicated. Adenosine deaminase from calf intestine (Type II, Sigma Chemical Co., St. Louis, Mo., 30 mg, 45 units) was added and the mixture was stirred at room temperature. The progress of the reaction was followed by TLC in dichloromethane-methanol (9:1). The deamination stopped after 72 h and the ratio of synadenol (1, B=adenin-N9-yl): synhypoxanthol (1, B=hypoxanthin-N9-yl) was 7:3 as determined by UV spectrophotometry of the eluted spots. Addition of another two portions of enzyme (30 mg every 24 h) did not improve this ratio. The mixture was lyophilized and the resultant product was sonicated with several portions of dichloromethane-methanol (1:1, first 100 mL and then 40 mL) until no UV absorption was detectable in the solvent. The filtrate and washings were combined and evaporated. The residue was adsorbed on silica gel (4 g) and loaded on a column made of the same material. Chromatography using dichloromethane-methanol (9:1) as an eluent afforded (R)-(−)-synadenol (1, B=adenin-N9-yl), 135 mg, 66.5%), [α]25D−59.10 (c 0.04, MeOH) and elution with dichloromethane-methanol (4:1) gave (S)-(+)-synhypoxanthol (1, B=hypoxanthin-N9-yl), 85 mg, [α]25D 91.8° (c 0.1, MeOH).
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44](O)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.[CH3:50][N:51]1[CH:55]=[C:54]([CH2:56][NH2:57])[CH:53]=[N:52]1>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([NH:57][CH2:56][C:54]4[CH:53]=[N:52][N:51]([CH3:50])[CH:55]=4)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:48][CH:49]=1
Reactant: Cn1cc(CN)cn1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cnn(C)c1
Yield: 44 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with (1-methyl-1H-pyrazol-4-yl)methanamine, the title compound was obtained as a colorless solid in 44% yield: mp 173-175° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.29 (t, J=6.0 Hz, 1H), 7.57 (s, 1H), 7.38-7.32 (m, 3H), 7.23-7.17 (m, 2H), 4.42 (s, 2H), 4.18 (d, J=6.0 Hz, 2 H), 3.99 (t, J=9.0 Hz, 2H), 3.78 (s, 3H), 3.45 (t, J=9.0 Hz, 2H), 2.45 (s, 3H); MS (ES+) m/z 429.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH2:14][CH:13]=[CH2:12])[CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(C)ccc1[N+](=O)[O-]
Yield: 94.4 %

Procedure:
A solution of 5-methyl-2-nitrophenol (2.00 g, 13.1 mmol), allyl bromide (1.30 mL, 15.0 mmol), and cesium carbonate (5.5 g, 17 mmol) in DMF (100 mL) was stirred at ambient temperature. After 20 hrs the reaction was filtered, frit washed with methanol, and the filtrate evaporated in vacuo at 50° C. The residue was purified by flash column chromatography (4:1 then 2:1 hexane:ethyl acetate eluant) giving the title compound as a yellow oil (2.39 g, 95%) that crystallized after sitting 3 days at ambient temperature. 1H NMR (300 MHz, CDCl3) δ 7.79 (d, 1H, J=8.2 Hz), 6.86 (s, 1H), 6.82 (m, 1H), 6.05 (ddt, 1H, J=17.3 Hz, 10.6 Hz, 5.0 Hz), 5.50 (ddd, 1H, J=17.3 Hz, 3.3 Hz, 1.7 Hz), 5.33 (ddd, 1H, J=10.6 Hz, 2.9 Hz, 1.5 Hz), 4.67 (dt, 2H, J=4.9 Hz, 1.6 Hz), 2.40 (s, 3H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[CH:13]([CH:16]([CH3:18])[CH3:17])[NH:12]1)[CH2:8]2.[CH3:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[CH3:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([N:12]1[CH:13]([CH:16]([CH3:18])[CH3:17])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2)=[O:23]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CC(C)C1NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: Cc1ccccc1C(=O)N1C(C(C)C)C(=O)N1C1C2CC3CC(C2)CC1C3

Procedure:
2-(Adamantan-2-yl)-4-(propan-2-yl)-1,2-diazetidin-3-one prepared in Process 3 of Example 10 and 2-methylbenzoyl chloride were used for a similar reaction and treatment as Example 96, and the title compound was obtained as a colorless oil.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)C2[CH2:20][CH2:21][N:22]([C:24](=[O:33])[NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=3)[CH2:23][C:12]1=2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CSC.[CH3:37][OH:38]>>[CH2:4]([N:11]1[C:19]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C:37](=[O:38])[CH2:20][CH2:21][N:22]([C:24](=[O:33])[NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=2)[CH2:23][C:12]1=[O:1])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1cccc(NC(=O)N2CCc3c(n(Cc4ccccc4)c4ccccc34)C2)c1
Reactant: CO
Reactant: O=[O+][O-]
Solvent: CSC
Product: Cc1cccc(NC(=O)N2CCC(=O)c3ccccc3N(Cc3ccccc3)C(=O)C2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ozone was bubbled through a solution of 9-benzyl-2-(3-methylphenyl)carbamyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (2.98 g, 7.54 mmol) in methanol (40 ml) at -78° C. until a blue colour persisted. Nitrogen was then bubbled through the solution until clear, followed by the addition of dimethyl sulphide (5.0 ml, 68.1 mmol). The solution was allowed to warm to room temperature and stirring continued for a further 2 hours, followed by evaporation to dryness. The crude product was purified by chromatography on silica gel with ethyl acetate-hexane (3:2) as eluant. (2.0 g, 62%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.Cl.Cl.[CH2:20]([O:22][C:23]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:27]([O:36][CH2:37][CH3:38])=[CH:26][C:24]=1[NH2:25])[CH3:21]>>[CH2:20]([O:22][C:23]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:27]([O:36][CH2:37][CH3:38])=[CH:26][C:24]=1[NH:25][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1)[CH3:21]
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: CCOc1cc(N2CCOCC2)c(OCC)cc1N
Agent: Cl
Product: CCOc1cc(N2CCOCC2)c(OCC)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2,5-diethoxy-4-morpholinoaniline dihydrochloride (98 mg, 0.290 mmol) similar to Example 117 and isolated as a brown oil (3 mg, 3%). 1H NMR (CDCl3): 9.64–9.63 (m, 1H), 8.74–8.69 (m, 2H), 7.42–7.38 (m, 1H), 7.33 (s, 1H), 6.83 (s, 1H), 6.60 (s, 1H), 4.13 (q, J=7.2 Hz, 4H), 3.92–3.89 (m, 4H), 3.14–3.11 (m, 4H), 1.26 (t, J=7.2 Hz, 6H).
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([N+:16]([O-:18])=[O:17])=[CH:10][C:5]=1[O:6][CH2:7][C:8]#[N:9])([CH3:3])[CH3:2].CC(O[CH:24]([N:28]([CH3:30])C)[N:25](C)C)(C)C.Cl.[NH2:32]C1C=CC=CC=1.C(=O)(O)O.NC(N)=N>CCO.CN1C(=O)CCC1>[CH:1]([C:4]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([N+:16]([O-:18])=[O:17])=[CH:10][C:5]=1[O:6][C:7]1[C:24]([NH2:25])=[N:28][C:30]([NH2:32])=[N:9][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COc1cc(C(C)C)c(OCC#N)cc1[N+](=O)[O-]
Reactant: Nc1ccccc1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Agent: Cl
Agent: N=C(N)N
Agent: O=C(O)O
Solvent: CCO
Solvent: CN1CCCC1=O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 71.8 %

Procedure:
A mixture of (2-isopropyl-4-methoxy-5-nitro-phenoxy)-acetonitrile (8.785 g, 35.5 mmol) and Brederick's reagent (14.6 mL, 70.9 mmol) was warmed to 100° C. After 45 min the mixture was evaporated under reduced pressure (50° C., 50 mtorr) to give an orange solid. The solid was added to a solution of aniline hydrochloride (9.19 g, 70.9 mmol) in 150 mL of EtOH. The mixture was warmed to reflux. After 16 hr additional aniline hydrochloride (4.596 g, 35.5 mmol) was added mixture was continued at reflux for 4 h. The solution was concentrated in vacuo and poured into H2O. The mixture was extracted with ethyl acetate, washed with H2O, washed with brine, dried over Na2SO4, and concentrated in vacuo to afford a yellow-green solid. This crude product was added to a mixture of 200 mL NMP and guanidine carbonate (17.70 g, 98 mmol) and warmed to 130° C. After 5 hours the mixture was cooled then poured onto 2 l of an ice/H2O mixture. The resulting precipitate was filtered, washed with H2O and dried under vacuum (50° C.). The crude solid was recrystallized from EtOH to afford 5-(2-isopropyl-4-methoxy-5-nitro-phenoxy)-pyrimidine-2,4-diamine (8.14 g, 63%, 3 steps) as a yellow crystalline solid (solvated 1:1 with EtOH). (M+H)+=320.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH2:20][CH:21](OC)OC)S(C2C=CC(C)=CC=2)(=O)=O)[S:5][C:6]=1[CH3:7].Cl.[OH-].[Na+]>O1CCOCC1>[Br:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]=[CH:20][CH:21]=2)[S:5][C:6]=1[CH3:7]
Reactant: COC(CN(Cc1cc(Br)c(C)s1)S(=O)(=O)c1ccc(C)cc1)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1sc2cnccc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
N-((4-bromo-5-methylthiophen-2-yl)methyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide (20 g, 45 mmol) was dissolved in dioxane (70 ml) and treated with cone HCl (70 ml). The reaction was heated to reflux and stirring continued overnight. The reaction was cooled down to RT, then to 0° C. and rendered neutral with 2N NaOH. The mixture was extracted with ethyl acetate. The organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 20 to 60% EtOAc in hexanes to give 3-bromo-2-methylthieno[2,3-c]pyridine (6.2 g, 61% yield) as an yellow solid. MS (M+H)+ 229
Reaction SMILES: C([N:4]([S:26]([CH3:29])(=[O:28])=[O:27])[N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([C:21]([F:24])([F:23])[F:22])=[C:11]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:12]=2)[NH:7][C:6]1=[O:25])(=O)C>Cl>[CH3:29][S:26]([NH:4][N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([C:21]([F:22])([F:24])[F:23])=[C:11]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:12]=2)[NH:7][C:6]1=[O:25])(=[O:28])=[O:27]
Reactant: CC(=O)NCc1cc2c(=O)n(N(C(C)=O)S(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Agent: Cl
Product: CC(=O)NCc1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Yield: 8 %

Procedure:
A solution of N-[3-(acetyl-methanesulfonyl-amino)-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-ylmethyl]-acetamide (305 mg, 0.70 mmol) in 2M aq HCl (5 mL) was stirred at 80° C. for 1 d. Subsequently, the solvent was evaporated and the crude product was purified by preparative thin-layer chromatography (DCM/MeOH 8/2) to yield N-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-ylmethyl)-acetamide (22 mg, 0.056 mmol, 8%) as a light beige solid. 1H-NMR (DMSO-d6, 400 MHz) 3.13 ppm (s, 3H, SO2—CH3); LC-MS rt=2.35 min; MS: m/z 394.9 [M+H]+ Column: SunFireC18, 4.6*50 nm, 3.5 um; Positive MS Water/Acetonitrile 95:5 to 5:95 in 5 min, Flow: 1.5 mL/min
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:12]1[CH:13]=[C:14]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]#[N:29])=[CH:22][C:21]=2[CH2:30][CH:31]([CH3:33])[CH3:32])[CH:15]=[CH:16][C:17]=1[O:18]C)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>C(Cl)Cl>[CH2:5]([C:12]1[CH:13]=[C:14]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]#[N:29])=[CH:22][C:21]=2[CH2:30][CH:31]([CH3:33])[CH3:32])[CH:15]=[CH:16][C:17]=1[OH:18])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc(-c2ccc(CCC#N)cc2CC(C)C)cc1Cc1ccccc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(C)Cc1cc(CCC#N)ccc1-c1ccc(O)c(Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
2.20 ml (2.20 mmol, 3 eqv) of a 1 M solution of BBr3 in CH2Cl2 was added to a solution of 279 mg (0.73 mmol) 3-(3′-Benzyl-2-isobutyl-4′-methoxy-1,1′-biphenyl-4-yl)propanenitrile (24) in 12 ml dry CH2Cl2 at 0° C. via syringe. After that, the solution was stirred for 2 h at 0° C. and then for 7 h at rt. The reaction mixture was then added to water and extracted with CH2Cl2. The comb. org. fractions were dried over MgSO4 and evaporated. Column chromatography, (Hexanes/EtOAc (2+1)) yielded 258.5 mg (0.70 mmol, 96%) 25 as a pale yellow oil: Rf (Hexanes/EtOAc (2+1)) 0.53; 1H NMR (500 MHz, CDCl3) δ 0.65 (d, 6H, J=6.62 Hz), 1.57 (m, 1H), 2.38 (d, 2H, J=7.25 Hz), 2.57 (t, 2H, J=7.41 Hz), 2.89 (t, 2H, J=7.41 Hz), 3.95 (s, 2H), 4.62 (s, br., 1H), 6.74 (d, 1H, J=8.04 Hz), 6.94-7.24 (m, 10H); LRMS (EI) m/z 369 (8), 335 (10), 293 (15), 161 (13), 160 (66), 91 (35), 86 (63), 84 (100); HRMS (EI) Calcd. for C26H27NO: 369.209264. Found: 369.209026.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:27])[NH2:26].CO[CH:30](OC)[CH:31](Br)[CH3:32].CN(C)C=O>O>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[N:4][N:3]1[C:25]1[S:27][C:31]([CH3:32])=[CH:30][N:26]=1
Reactant: COC(OC)C(C)Br
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(N)=S)OCO3
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc(N2N=C(c3ccc([N+](=O)[O-])cc3)c3cc4c(cc3CC2C)OCO4)s1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 65.6 %

Procedure:
A mixture of 1.50 g (3.90 mmol) of starting material I, 3.57 g (19.50 mmol) of 2-bromopropionaldehyde dimethyl acetal and 15 ml of dimethylformamide was stirred at 90° C. for 1.5 h. Then the reaction mixture was diluted with water and the crude product obtained was purified by column chromatography using silica gel (MN Kieselgel 60; Macherey-Nagel, Düren, Germany) as adsorbent and a mixture of toluene-ethyl acetate (16:1) as eluent to yield 1.08 g (66%) of the title compound; Mp.: 193-195° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[O:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[CH2:7][C:6](=O)[CH2:5]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:3])[C:6]1[CH2:5][O:4][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[CH:7]=1
Reactant: CNC
Reactant: O=C1COc2ccccc2C(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)C1=CC(=O)c2ccccc2OC1

Procedure:
Dimethylamine is introduced while stirring into a boiling solution of 52.8 g (0.3 mole) 2,3,4,5-tetrahydro-1-benzoxepin-3,5-dione and a spatula tip of p-toluene sulfonic acid in 225 ml toluene. The water of reaction is separated by a water separator. After the reaction has ended, the solution is concentrated, the remaining residue is filtered under suction and recrystallized from chloroform/ether. 42 g (69% of the theoretical yield) of 3-dimethylamino-1-benzoxepin-5(2H)-one are obtained. This compound displays a melting point of 136°-136° C.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:24]=[C:25]([O:33][CH3:34])[CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:24]=[C:25]([O:33][CH3:34])[CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: COc1cc(N)c2ncccc2c1
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cc(OC)cc3cccnc23)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
To a stirred solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 73 mg (0.417 mmol) of 8-amino-6-methoxyquinoline was added. The resulting mixture was stirred at room temperature for two hours and the final product was collected by filtration and washed with diethylether to yield the title compound (88 mg, 76.5% yield).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1)[OH:4].[CH3:15][N:16]([CH2:23][CH2:24][C:25](=O)[CH3:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH3-]C#N.[Na+]>C(O)C>[CH3:15][N:16]([CH2:23][CH2:24][CH:25]([NH:1][CH2:2][CH:3]([C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1)[OH:4])[CH3:26])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCC(O)c1ccc(O)c(C(N)=O)c1
Reactant: CC(=O)CCN(C)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(CCN(C)c1ccccc1)NCC(O)c1ccc(O)c(C(N)=O)c1
Reaction time: 16 h

Procedure:
To a solution of 20 mmol 5-(2-amino-1-hydroxyethyl)salicylamide and 3.54 g (20 mmol) 4-(N-methylanilino)-2-butanone [procedure of Craig, et al, J. Org. Chem., 29, 410 (1964)] in 100 ml ethanol add 1.26 g (20 mmol) NaCNBH3. Stir 16 hrs., concentrate, and partition between EtOAc and 1.0 N NaHCO3 solution. Dry and concentrate the organic layer. Recrystallize the residue from methanol to give a white solid, mp 150°-2°.