Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.C(N(CC)CC)C.[Cl:34][C:35]1[CH:36]=[C:37]([S:42](Cl)(=[O:44])=[O:43])[CH:38]=[C:39]([Cl:41])[CH:40]=1>C(Cl)Cl>[Cl:41][C:39]1[CH:38]=[C:37]([S:42]([N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)(=[O:43])=[O:44])[CH:36]=[C:35]([Cl:34])[CH:40]=1
Reactant: Fc1ccc(CNCc2ccccc2CNCc2ccc(F)cc2)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cc(Cl)cc(Cl)c1)N(Cc1ccc(F)cc1)Cc1ccccc1CNCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
To a mixture of N,N′-(1,2-phenylenebis(methylene))bis(1-(4-fluorophenyl)methanamine) (1 g, 2.8 mmol, 1 eq) in DCM (HPLC grade 50 mL) at 0° C. was added triethylamine (0.87 g, 8.6 mmol, 3 eq) followed by 3,5-dichlorobenzenesulfonyl chloride (0.52 g, 2.1 mmol, 0.75 eq). The mixture was stirred at 0° C. for 1 h, before being concentrated to dryness. Water was added to the residue and the aqueous mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 before being evaporated under reduced pressure. The resulting residue was purified by silica gel (230-400) column chromatography eluting with 6% ethyl acetate in hexane to afford the desired product (0.8 g, 53%). 1H NMR (400 MHz, CD3OD) δ 7.76-7.72 (m, 1H), 7.33-7.23 (m, 2H), 7.20-7.17 (m, 2H), 7.13-7.10 (m, 4H), 7.03-6.95 (m, 4H), 6.80-6.77 (m, 2H), 4.80 (s, 2H), 4.30 (s, 2H), 3.70 (s, 2H), 3.60 (s, 2H). MS (ESI): 562.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][OH:15].N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C)C=O>[Si:24]([O:15][CH2:14][C:13]1[CH:12]=[C:11]([C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[F:1])[CH:18]=[CH:17][CH:16]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1ccc(F)c(-c2cccc(CO)c2)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(-c2cc([N+](=O)[O-])ccc2F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A mixture of 4.04 g 3-(2-fluoro-5-nitrophenyl)-benzyl alcohol, 2.23 g imidazole and 2.46 g t-butyldimethylsilylchloride in 100 ml N,N-dimethylformamide was stirred at room temperature for 30 minutes. The reaction mixture was then partitioned between water and ether. The combined organic extracts were washed three times with water, dried and evaporated yielding the product as a yellow oil (5.9 g, 99% yield) which was purified on silica gel to give a yellow solid of m.p. 44°-45° C. NMR (CDCl3, 250 MHz): 8.4 (dd, 1H), 8.34 (eight line multiplet, 1H), 7.5 (m, 4H), 7.3 (m, 1H), 4.83 (s, 2H), 0.95 (s, 9H), 0.15 (s, 6H).
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[N:18]([C:21]1[CH:22]=[C:23]([CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])[CH2:30]2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28])=[C:19]=[O:20]>C(Cl)Cl>[C:3]1([CH2:2][O:9][NH:10][C:19]([NH:18][C:21]2[CH:22]=[C:23]([CH:29]3[CH2:34][CH2:33][CH2:32][N:31]([C:35](=[O:40])[C:36]([F:38])([F:39])[F:37])[CH2:30]3)[CH:24]=[CH:25][C:26]=2[O:27][CH3:28])=[O:20])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NOCc1ccccc1
Reactant: COc1ccc(C2CCCN(C(=O)C(F)(F)F)C2)cc1N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2CCCN(C(=O)C(F)(F)F)C2)cc1NC(=O)NOCc1ccccc1
Reaction time: 2 h
Yield: 85.2 %

Procedure:
1.68 g of O-benzyl-hydroxylamine hydrochloride suspended in 30 ml of methylene chloride were added to 1.52 ml of triethylamine and then 3.2 g of the product of Step A in 10 ml of methylene chloride were added dropwise with stirring for 2 hours, followed by evaporating to dryness under reduced pressure. The residue was chromatographed on silica, (eluent: methylene chloride-ethyl acetate 96-4) to obtain 3.75 g of the expected product melting at 134° C. after crystallization from a 1-1 mixture of methylene chloride and isopropyl ether.
Reaction SMILES: [NH2:1][C:2]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.O[CH2:11][C:12]1(N)[CH2:16][CH2:15][CH2:14][CH2:13]1.OCCN.C1(=O)CCCCC1>>[CH2:3]1[C:2]2([CH2:7][O:9][C:11]3([CH2:12][CH2:16][CH2:15][CH2:14][CH2:13]3)[NH:1]2)[CH2:6][CH2:5][CH2:4]1
Reactant: NC1(C(=O)O)CCCC1
Reactant: NC1(CO)CCCC1
Solvent: NCCO
Solvent: O=C1CCCCC1
Product: C1CCC2(CC1)NC1(CCCC1)CO2

Procedure:
1-Aminocyclopentanecarboxylic acid was converted to the methyl ester according to Method B1c, Step 1. The ester reduced to 1-hydroxymethylcyclopentanamine according to Method B1c, Step 2. The hydroxyethylamine was reacted with cyclohexanone according to Method B4a, Step 1 to give 6-aza-13-oxadispiro[4.1.5.2]tetradecane. The oxazolidine was reduced according to Method B4a, Step 2 to give 1-(cyclohexylamino)-1-(hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was reacted with SOCl2 according to Method B7b to 1-(cyclohexylamino)-1-(chloromethyl)cyclopentane. The 2-chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford 1-cyclohexyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-1-azaspiro[4.4]nonane.
Reaction SMILES: [CH2:1]([C:8]1[CH:12]=[C:11](N2CCCCC2)[N:10]([CH2:19][CH3:20])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:21].[C:22]([Cl:25])(=O)[CH3:23]>CO>[ClH:25].[ClH:21].[CH2:1]([C:8]1[CH:12]=[C:11]([CH:23]2[CH2:22][CH2:19][NH:10][CH2:11][CH2:12]2)[N:10]([CH2:19][CH3:20])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: CCn1nc(Cc2ccccc2)cc1N1CCCCC1
Agent: Cl
Solvent: CO
Product: CCn1nc(Cc2ccccc2)cc1C1CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 199.8 %

Procedure:
1-(t-Butoxycarbonyl)4-(3-benzyl-1-ethyl-(1H)-pyrazol-5-ylpiperidine 5 from Step D (18.5 g, 50 mmol) was added to a solution of HCl (530 mmol) in methanol (300 mL) prepared by the slow addition of acetyl chloride (38 mL, 530 mmol) and aged for 90 min. The reaction was stirred at rt for 16 h and then evaporated to dryness to afford 17.1 g (100%) of the title compound as a hygroscopic white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[S:10](Cl)([CH3:13])(=[O:12])=[O:11]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccnc(F)c1
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccnc(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
(2-Fluoropyridin-4-yl)methanol (1 g) was dissolved in DCM (40 ml), added with TEA (3.3 ml) and mesyl chloride (0.67 ml), and the mixture was stirred at 0° C. for 1 hr. The mixture was concentrated and then purified by silica gel column (n-hexane/ethyl acetate=4/1) to obtain the title compound (1.18 g, 77%).
Reaction SMILES: [Br:1][C:2]1[C:6]([CH3:7])=[C:5]([I:8])[S:4][C:3]=1[CH:9]=[O:10].[CH2:11](O)[CH2:12][OH:13]>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[C:6]([CH3:7])=[C:5]([I:8])[S:4][C:3]=1[CH:9]1[O:13][CH2:12][CH2:11][O:10]1
Reactant: OCCO
Reactant: Cc1c(I)sc(C=O)c1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Cc1c(I)sc(C2OCCO2)c1Br
Yield: 94.3 %

Procedure:
3-Bromo-5-iodo-4-methylthiophene-2-carbaldehyde (27 g, 82 mmol), ethylene glycol (5.9 mL, 110 mmol) and p-toluenesulfonic acid monohydrate (0.50 g, 2.6 mmol) were combined in benzene (200 mL) and the mixture was heated at reflux under Dean-Stark conditions for 8 h. At this time, the cooled solution was washed with 2.5 N aqueous NaOH (200 mL), water (4×200 mL) and brine (200 mL), dried (K2CO3) and concentrated in vacuo to give the title compound (29 g, 94%) as an orange oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[N+:17]([O-])([OH:19])=[O:18].C([O-])(O)=O.[Na+]>CC(O)=O.O>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: O=[N+]([O-])O
Reactant: CNc1nccc(Oc2ccc(O)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CNc1nccc(Oc2ccc(O)c([N+](=O)[O-])c2)n1
Reaction time: 18 h

Procedure:
4-(2-Methylamino-pyrimidin-4-yloxy)-phenol (Step C, 0.20 g, 0.92 mmol) was dissolved in 5 mL AcOH at RT. Fuming HNO3 (0.064 g, 0.92 mmol) was diluted with about 0.012 mL water, then added dropwise over 1 min to the reaction. The reaction was stirred for 18 h, after which it was added slowly to 40 mL saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic layer was washed with NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography using hexanes/EtOAc gradient to yield the title compound. MS (MH+)=263.1; Calc'd 262.23 for C11H10N4O4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][NH:17][CH2:16][CH2:15]4)=[CH:4][CH:3]=1.ClCCl.[F:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1.C(N(C(C)C)CC)(C)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:39]([C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)(=[O:41])=[O:40])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1
Reactant: O=C(c1ccccn1)[C@@]12CNCCC1=Cc1c(cnn1-c1ccc(F)cc1)C2
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccccn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(F)cc1)C2
Reaction time: 1.25 h

Procedure:
A solution of (R)-(1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone in dichloromethane (2.5 ml) (2.7 mL, ˜0.2 mmol) containing disiopropylethylamine (174 μL, 1 mmol) was added to 4-fluoro-phenyl sulfonyl chloride (48 mg, 0.25 mmol) and diisopropylethylamine (100 μL, 0.57 mmol) and the mixture stirred for 1.25 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (gradient: 20-30% ethyl acetate in cyclohexane) to afford (R)-(1-(4-fluorophenyl)-6-((4-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone as a white solid (72 mg). LCMS (Method D, ESI): RT 5.32 min, m+H=533.0; 1H NMR (400 MHz, CDCl3): δ 8.62-8.63 (m, 1 H); 7.85-7.86 (m, 2 H); 7.69-7.70 (m, 2 H); 7.44-7.45 (m, 3 H); 7.28 (s, 1 H); 7.14 (dt, J=12.9, 8.5 Hz, 4 H); 6.48 (d, J=2.2 Hz, 1 H); 5.51 (dd, J=12.2, 2.1 Hz, 1 H); 4.29 (d, J=16.9 Hz, 1 H); 3.82-3.86 (m, 1 H); 2.84-2.86 (m, 2 H); 2.72 (d, J=12.2 Hz, 1 H); 2.46-2.51 (m, 2 H).
Reaction SMILES: [NH:1]1[C:6](=[O:7])[CH2:5][S:4][C:3]2[CH:8]=[CH:9][C:10]3[C:15]([C:2]1=2)=[CH:14][CH:13]=[CH:12][CH:11]=3.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.C[O-].[Na+].CN(C)C=O>O>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[C:5]2[S:4][C:3]3[CH:8]=[CH:9][C:10]4[C:15]([C:2]=3[NH:1][C:6]2=[O:7])=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:19][CH:18]=1
Reactant: O=C1CSc2ccc3ccccc3c2N1
Reactant: O=Cc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2c(ccc3ccccc23)SC1=Cc1ccc(Cl)cc1
Yield: 52.8 %

Procedure:
A mixture of 1H-naphtho[2,1-b][1,4]thiazin-2(3H)-one (5.17 g), 4-chlorobenzaldehyde (5.62 g), sodium methoxide (1.73 g) and dimethylformamide (80 ml) is refluxed for 4.5 hours. After cooling, the reaction mixture is poured into water and the resulting precipitate is separated by filtration, washed and dried and then is recrystallized from tetrahydrofuran-n-hexane to give 3-(4-chlorobenzylidene)-1H-naphtho[2,1-b][1,4]thiazin-2(3H)-one (4.28 g). M.p. 277°-279° C.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl[C:11]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[O:12].O>[OH-].[Na+]>[CH3:17][O:16][CH2:15][CH2:14][O:13][C:11]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:12]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: COCCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCOC(=O)N[C@@H](CC(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.5 %

Procedure:
To a solution of L-leucine (25 g, 0.19 mol) was dissolved in 2M NaOH (0.12 L) was slowly added 2-methoxyethyl chloroformate (30 g, 0.22 mol) and 1M NaOH at the same time under the ice-cooled condition. The mixture was stirred at room temperature for 18 hours, diluted into water (600 mL) and washed with ethyl ether (2×200 mL). The aqueous phase was cooled in an ice bath and acidified to pH 3 with 6M HCl. This mixture was extracted with ethyl acetate (EtOAc) (5×150 mL). The organic phase was dried over anhydrous MgSO4 and filtered, and the filtrate was concentrated in vacuo to yield N-((2-methoxyethoxy)carbonyl)-L-leucine (41 g, 92%) as a colorless oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:21]3[C:25](/[CH:26]=[CH:27]/[S:28]([CH3:30])=[O:29])=[CH:24][N:23]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:22]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1.ClC1C=CC=C(C(OO)=[O:48])C=1.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:21]3[C:25](/[CH:26]=[CH:27]/[S:28]([CH3:30])(=[O:48])=[O:29])=[CH:24][N:23]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:22]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/S(C)=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/S(C)(=O)=O)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a mixture of 2-(2-furyl)-4-({2-methoxy-4-[({4-[(E)-2-(methylsulfinyl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazole (0.47 g) and tetrahydrofuran (30 mL) was added m-chloroperbenzoic acid (0.18 g) at room temperature, and the mixture was stirred at the same temperature for 1 hr. Saturated aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was stirred at room temperature for 10 min, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to give 2-(2-furyl)-4-({2-methoxy-4-[({4-[(E)-2-(methylsulfonyl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazole as colorless crystals (0.41 g, yield 85%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 152-153° C.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[O:24][CH:25]=[CH:26][C:27]=4[CH3:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:29].[N:30]1([CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1>C1COCC1>[O:29]=[C:4]1[C:3](=[CH:2][NH:43][C:40]2[CH:41]=[CH:42][C:37]([CH2:36][CH2:35][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:38][CH:39]=2)[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[O:24][CH:25]=[CH:26][C:27]=4[CH3:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5]1
Reactant: Nc1ccc(CCN2CCCC2)cc1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: C1CCOC1
Product: Cc1ccoc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(CCN3CCCC3)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 17 %

Procedure:
A small screw cap test tube was charged with 3-Methyl-furan-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 200 mg, 0.515 mmol) and THF (5.0 mL). To the resulting solution was added 4-(2-Pyrrolidin-1-yl-ethyl)-phenylamine (98 mg, 0.515 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified by flash silica gel chromatography (EtOAc:MeOH mix eluant with gradient of 1% MeOH to 10% MeOH) to afford the title compound in 17% yield (0.049 g, 0.087 mmol).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[C:19]([OH:21])[N:18]=[C:17]([NH:22][NH2:23])[N:16]=2)=[CH:11][CH:10]=1>C1COCC1>[C:5]([NH:23][NH:22][C:17]1[N:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=2)[N:20]=[C:19]([OH:21])[N:18]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: NNc1nc(O)nc(-c2ccc(Cl)cc2)n1
Solvent: C1CCOC1
Product: CC(=O)NNc1nc(O)nc(-c2ccc(Cl)cc2)n1
Temperature: 25 °C

Procedure:
Acetic anhydride (6 ml) is added to a suspension of 6-(4-chlorophenyl)-4-hydrazino-2-hydroxy-1,3,5-triazine in THF (500 ml) and the mixture stirred under reflux for 21/2 hours. The mixture is cooled to RT overnight and the solid filtered, washed with ether and air dried, yielding 13.95 g of the solid. The solid is washed in 500 ml of boiling dioxane, filtered, washed with ether and air dried, leaving 13.8 g of the acetyl hydrazine triazine, m.p. 250° C.
Reaction SMILES: [O:1]=[C:2]1[N:13]2[C:14]3[C:10]([CH:11]=[CH:12]2)=[CH:9][C:8]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[CH:18]=O)=[CH:7][C:6]=3[CH2:5][NH:4][CH2:3]1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>O>[N:23]1([CH2:18][C:17]2[CH:16]=[C:15]([C:8]3[CH:9]=[C:10]4[C:14]5=[C:6]([CH2:5][NH:4][CH2:3][C:2](=[O:1])[N:13]5[CH:12]=[CH:11]4)[CH:7]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCNC1
Reactant: O=Cc1cccc(-c2cc3c4c(ccn4C(=O)CNC3)c2)c1
Solvent: O
Product: O=C1CNCc2cc(-c3cccc(CN4CCCC4)c3)cc3ccn1c23
Yield: 92 %

Procedure:
Using the reductive amination procedure described in Example 82, the title compound was synthesized from 3-(1-oxo-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-6-yl)-benzaldehyde and pyrrolidine in 92% yield as a pale-yellow solid: mp 158-160° C.; 1H NMR (DMSO-d6) δ 1.71 (br s, 4H), 2.49 (br s, 4H), 3.49 (br s, 2H), 3.68 (br s, 2H), 4.30-4.33 (m, 2H), 6.70 (s, 1H), 7.17 (t, 1H, J=9.0 Hz), 7.38-7.52 (m, 4H), 7.79 (d, 1H, J=9.0 Hz), 7.82 (d, 1H, J=9.0 Hz), 8.38 (t, 1H, J=6.0 Hz). HRMS calcd. for C22H23N3O 345.1841 (M+), found 345.1848. Anal. (C22H23N3O.0.4 H2O) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[CH3:16])=[CH:8][CH2:9][OH:10].C(P(CCCC)CCCC)CCC.[CH2:30]([O:32][C:33](=[O:46])[CH:34]([O:43][CH2:44][CH3:45])[CH2:35][C:36]1[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=1)[CH3:31]>>[CH2:30]([O:32][C:33](=[O:46])[CH:34]([O:43][CH2:44][CH3:45])[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:10][CH2:9][CH:8]=[C:7]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[CH3:16])[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[CH3:1])=[CH:38][CH:37]=1)[CH3:31]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: Cc1ccsc1C(=CCO)c1sccc1C
Agent: CCCCP(CCCC)CCCC
Product: CCOC(=O)C(Cc1ccc(OCC=C(c2sccc2C)c2sccc2C)cc1)OCC
Yield: 36.2 %

Procedure:
Reaction of 3,3-bis-(3-methylthiophen-2-yl)-prop-2-en-1-ol (1.0 mg, 3.99 mmol), tributylphosphine (0.91 g, 4.5 mmol), 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (1.07 g, 4.5 mmol) and azodicarboxylic dipiperidide (1.14 g, 4.5 mmol) in an identical manner to example 3 gave the title compound (680 mg, 36%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:19][C:18]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]=2[CH:12]=1)=[O:10].[N+](C1C=CC([O:29][C:30](=O)[O:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=2)=CC=1)([O-])=O.CCN(CC)CC>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:19][C:18]2[CH2:17][CH2:16][N:15]([C:30]([O:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=3)=[O:29])[CH2:14][C:13]=2[CH:12]=1)=[O:10]
Reactant: Nc1ccccc1NC(=O)c1cc2c(s1)CCNC2
Reactant: COc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1OC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(OC(=O)N2CCc3sc(C(=O)Nc4ccccc4N)cc3C2)cc1OC
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2-aminophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (1.0 eq) obtained in step VIII of example 203 in DMF was treated with Carbonic acid 3,4-dimethoxy-phenyl ester 4-nitro-phenyl ester (1.0 eq) in presence of base like Et3N and stirred at 50° C. for 8 h Reaction was then quenched with water and extracted with ethyl acetate and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.Cl.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: ClCCN1CCOCC1
Reactant: Oc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: Brc1ccc(OCCN2CCOCC2)cc1

Procedure:
The first step is a Williamson ether synthesis between 4-bromophenol (131 g) and N-chloroethylmorpholine (1 as the HCl salt; 141 g) using K2CO3 powder (3 to 3.5 equivalents) as the base and having acetonitrile as the solvent. The ingredients were mixed and stirred at reflux overnight with high conversion (96.3-99.1%). After dilution with dichloromethane and heptane, the reaction mixture was filtered and evaporated to give the desired product 2 in essentially a quantitative yield (216 g). Note that with similar substrates (e.g., 4-bromo-3-fluorophenol), conversions (even with extensive heating) were not always so high (e.g., 59.9-98.3%). Both the alkyl chloride and the K2CO3 are preferably purchased from Aldrich. If continued heating does not drive reaction to completion, unreacted bromophenol can readily be removed by dissolving the crude reaction mixture in 4 parts toluene and washing out the phenol with 4 parts 15% aqueous NaOH.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33]>>[Cl:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1
Reactant: COc1ccccc1Br
Product: COc1ccccc1C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1

Procedure:
This compound is prepared by method C using compound 12l and 2-bromoanisole
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:9])[CH2:10][C:11]2[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=2)[O:17][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(Cc1cccc(O)c1)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc(CC(=O)c2cccc(O)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,3'-dihydroxydeoxybenzoin (0.05 mol), ethyl bromoacetate (0.05 mol) ad K2CO3 (0.05 mol) in 50 mL of DMF is stirred at room temperature overnight. The reaction mixture is poured into water and extracted with EtOAc. The organic solution is dried and evaporated to dryness. The crude products are separtated by flash chromatography to give the ethyl 2-(3-(2-(3-hydroxyphenyl)-2-oxoethyl)phenoxy)acetate and the ethyl 2-(3-(2-(3-hydroxyphenyl)-1-oxoethyl)phenoxy)acetate.