Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[C:14](S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[NH:37]([C:14]1[C:15]2[C:16](=[O:26])[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23](=[O:25])[C:24]=2[C:11]([S:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=2)(=[O:3])=[O:2])=[CH:12][CH:13]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cc1ccc(S(=O)(=O)c2ccc(S(=O)(=O)c3ccc(C)cc3)c3c2C(=O)c2ccccc2C3=O)cc1
Reactant: Nc1ccccc1
Product: Cc1ccc(S(=O)(=O)c2ccc(Nc3ccccc3)c3c2C(=O)c2ccccc2C3=O)cc1
Yield: 79 %

Procedure:
1-(anilino)-4-tosylanthraquinone was prepared by reaction of 1,4-ditosylanthraquinone with aniline. The isolated and purified reaction product has the structure illustrated below (where "Ts" is ##STR12## The yield was 79% and the m.p. 185°-186° C. Mass spec m/e 469 (M+), 314 (M-C7H7SO2), 155 (C7H7SO2), 91 (C7H7); H-NMR (CD2Cl2)δ11.50 (br s, 1H), 8.26-8.12 (m, 2H), 8.02-7.84 (m, 2H), 7.79-7.62 (m, 4H), 7.54-7.13 (m, 7H), 2.31 (s, 3H); IR (Nujol) 1355 cm-1 (asymmetric SO2 stretch), 1184 cm-1 (symmetrical SO2 stretch), 945 cm-1, 872, 840, 822, 810, 800, 788, 755 (S--O--C stretch); UV/VIS max (Xylenes) 500 nm (ε7000).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=3)[NH:8][C:4]=2[C:3]=1[CH2:23][C:24]([OH:26])=O.Cl.CN(C)CCCN=C=NCC.[CH2:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CC(N(C)C)=O>[F:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([O:19][CH3:20])[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=3)[NH:8][C:4]=2[C:3]=1[CH2:23][C:24]([NH:46][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:26]
Reactant: NCc1ccccc1
Reactant: COc1cc(-c2nc3ccc(F)c(CC(=O)O)c3[nH]2)cc(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Product: COc1cc(-c2nc3ccc(F)c(CC(=O)NCc4ccccc4)c3[nH]2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 2-[5-fluoro-2-(3,4,5-trimethoxyphenyl)benzimidazolyl]acetic acid (1.8 mmole, 650 mg) in DMA (5 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (2.7 mmole, 0.52 g) and benzylamine (2.52 mmole, 0.28 ml) is stirred at room temperature for 22 hours. The reaction mixture is added dropwise onto ice (50 g), and the precipitate is filtered off and dried in vacuo (R1=(CH2)x—C(O)—NH—(CH2)y—R5, x=1, R5=phenyl, R2=3,4,5-trimethoxy-phenyl, R3=F, n=1, y=1).
Reaction SMILES: Br[C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:10][N:11]1[C:19]2[C:14](=[N:15][C:16]([Sn](CCCC)(CCCC)CCCC)=[CH:17][CH:18]=2)[CH:13]=[N:12]1.[Li+].[Cl-]>O1CCOCC1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([C:16]2[N:15]=[C:14]3[CH:13]=[N:12][N:11]([CH3:10])[C:19]3=[CH:18][CH:17]=2)[C:3]([CH3:9])=[N:4][CH:5]=1
Reactant: Cc1ncc(Br)cc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(cnn2C)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: Cc1ncc(Br)cc1-c1ccc2c(cnn2C)n1
Temperature: 100 °C

Procedure:
To a solution of 3,5-dibromo-2-methylpyridine (320 mg, 1.28 mmol) in dioxane (10 mL), was added 1-methyl-5-(tributylstannyl)-1H-pyrazolo[4,3-b]pyridine (540 mg, 1.28 mmol), CuI (73 mg, 0.38 mmol), LiCl (271 mg, 6.4 mmol) and Pd(PPh3)4 (147 mg, 0.12 mmol). The reaction mixture was heated at 100° C. for 2 h. The reaction was cooled down, washed by sat. NaHCO3, extracted by EtOAc, dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in hexanes give the product. LCMS-ESI+: calc'd for C13H11BrN4: 303.0 (M+H+); Found: 303.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:14](#[N:18])/[CH:15]=[CH:16]/[CH3:17]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH:16]([CH3:17])[CH2:15][C:14]#[N:18])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C/C=C/C#N
Reactant: COc1ccc(CCN)cc1OC
Product: COc1ccc(CCNC(C)CC#N)cc1OC
Temperature: 100 °C
Reaction time: 30 h

Procedure:
A mixture of 10.0 g of 2-(3,4-dimethoxyphenyl)ethylamine with 14 ml of crotononitrile was stirred at 100° C. for 30 h.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=O)=[CH:4][CH:3]=1.[NH2:13][C:14]1[S:15][CH2:16][CH2:17][N:18]=1.[BH4-].[Na+].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[NH:13][C:14]2[S:15][CH2:16][CH2:17][N:18]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCCc2ccc(Cl)cc21
Reactant: NC1=NCCS1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Solvent: CO
Product: Clc1ccc2c(c1)C(NC1=NCCS1)CCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Titanium isopropoxide (710 mg, 0.74 mls, 2.5 mmol) is added to a mixture of 7-chloro-1-tetralone (360 mg, 2 mmol) and 2-aminothiazoline (224 mg, 2.2 mmol). The reaction mixture is stirred for 16 hours at room temperature, then diluted with dry methanol (5 ml). Excess sodium borohydride is added carefully portionwise over a period of 45 minutes. The reaction mixture is stirred for a further 2 hours, then added to a saturated aqueous solution of Rochelle's salt and extracted with dichloromethane (2×25 mls). The organic phases are combined, washed sequentially with water and saturated brine, then filtered through a pad of magnesium sulphate. The filtrate is concentrated under reduced pressure to give the crude product as a pale yellow gum. The crude product is purified by column chromatography on silica, eluting with ethyl acetate to give the title compound as a white solid Mp 164-6° C. Nmr data: (CDCl3): 7.39 (1H, s, CH), 7.13 (1H, dd, CH), 7.01 (1H, s, CH), 4.90 (1H, m, CH), 4.06 (2H, m), 3.37 (2H, m), 2.72 (2H, m), 2.08 (1H, m), 1.85 (3H, m)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15](=O)[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([SH:14]([CH2:15][CH:16]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[C:6]([O:5][CH3:1])=[O:7])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CO
Product: COC(=O)[SH](CC1CCCCC1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -10 °C
Reaction time: 18 h
Yield: 87.5 %

Procedure:
Intermediate 6 (0.50 g) and Intermediate 12 (0.46 g) were combined in anhydrous methanol, degassed, cooled to −10° C., and treated with sodium bis(trimethylsilyl)amide (1.78 ml, as a 1.0 M solution in tetrahydrofuran), and the mixture stirred for 18 h, slowly warming to room temperature. The reaction was then reduced in vacuo, diluted with water (20 ml) and extracted with ethyl acetate (2×20 ml). The combined organic extracts were washed with aqueous 2% citric acid (20 ml), water (20 ml), saturated sodium bicarbonate (20 ml), saturated brine (20 ml), dried (Na2SO4) and solvents removed in vacuo to leave a straw coloured oil. This crude product was the purified by silica gel column chromatography, eluting with a gradient of 2% diethyl ether in dichloromethane rising to 4% diethyl ether in dichloromethane, to furnish the title compound as a colourless oil (0.29 g, 44%).
Reaction SMILES: C([O:4][C:5]1[C:15]([O:16][C:17](=[O:19])[CH3:18])=[CH:14][C:8]2[C:9](=[O:13])[N:10]([CH3:12])[S:11][C:7]=2[CH:6]=1)(=O)C>N1CCOCC1.CN(C)C=O>[OH:4][C:5]1[C:15]([O:16][C:17](=[O:19])[CH3:18])=[CH:14][C:8]2[C:9](=[O:13])[N:10]([CH3:12])[S:11][C:7]=2[CH:6]=1
Reactant: CC(=O)Oc1cc2sn(C)c(=O)c2cc1OC(C)=O
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc2c(=O)n(C)sc2cc1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of acetic acid 6-acetoxy-2-methyl-3-oxo-2,3-dihydro-benzo[d]isothiazol-5-yl ester (0.21 g) in dimethylformamide morpholine (0.070 g) was added at 0° C. The mixture was stirred at 0° C. for one hour and then poured to ice water. The precipitated product was filtered.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:34](=[O:35])[N:6]2[C:7]([C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])=[C:8](OP(OC3C=CC=CC=3)(OC3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@@H:5]12)[CH3:3].[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([SH:47])[CH2:44][C@H:43]1[CH2:48][CH:49]1[CH2:53][N:52]([C:54]([O:56][CH2:57][CH:58]=[CH2:59])=[O:55])[C@H:51]([C:60](=[O:62])[NH2:61])[CH2:50]1)=[O:41])[CH:37]=[CH2:38].C(N(CC)C(C)C)(C)C>>[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([S:47][C:8]2[C@H:9]([CH3:10])[C@@H:5]3[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:34](=[O:35])[N:6]3[C:7]=2[C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])[CH2:44][C@H:43]1[CH2:48][CH:49]1[CH2:53][N:52]([C:54]([O:56][CH2:57][CH:58]=[CH2:59])=[O:55])[C@H:51]([C:60](=[O:62])[NH2:61])[CH2:50]1)=[O:41])[CH:37]=[CH2:38]
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CC1C[C@@H](C(N)=O)N(C(=O)OCC=C)C1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC3C[C@@H](C(N)=O)N(C(=O)OCC=C)C3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 78.9 %

Procedure:
The same procedure as in Example 8-1 was carried out by using allyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-diphenoxyphosphoryloxy-1-carbapen-2-em-3-carboxylate (264 mg, 0.49 mmol), (2R,4S)-N-allyloxycarbonyl-2-[(2S)-N-allyloxycarbonyl-2-carbamoylpyrrolidin-4-ylmethyl]-4-mercaptopyrrolidine (210 mg, 0.49 mmol) and N,N-diisopropylethylamine (92 μl, 0.49 mmol) to obtain allyl (1R,5S,6S)-2-[(2R,4S)-N-allyloxycarbonyl-2-[(2S)-N-allyloxycarbonyl-2-carbamoylpyrrolidin-4-ylmethyl]pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (250 mg, yield: 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ClC1C=C(C=CC=1)C(OO)=[O:27].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:16]1([S:15]([C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[O:27])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Sc3ccccc3)c2cc1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2nccc(S(=O)c3ccccc3)c2cc1OC
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 6,7-dimethoxy-4-phenylsulfanyl-quinoline (Step a, 1.0 g, 3.4 mmol) in CH2Cl2 (30 mL) at −78° C., 3-chloroperoxybenzoic acid (0.64 g, 3.7 mmol) was added in CH2Cl2 dropwise slowly. The reaction was stirred at −78° C. for 2 h. The solution was poured into saturated NaHCO3 and extracted with CH2Cl2 3×. The combined organic layer was washed with saturated NaHCO3, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography with (70-100% EtOAc/Hexane) to give the titled compound as a white solid. MS (ESI, pos. ion) m/z: 314.4 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:45]([C:46]#[CH:47])=[CH:44][C:5]([CH2:6][C@@H:7]([NH:23][C:24]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:38][CH2:37][C:36]4[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=4[NH:34][C:33]3=[O:43])[CH2:28][CH2:27]2)=[O:25])[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[Cl:48].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[NH2:1][C:2]1[C:45]([CH2:46][CH3:47])=[CH:44][C:5]([CH2:6][C@@H:7]([NH:23][C:24]([N:26]2[CH2:27][CH2:28][CH:29]([N:32]3[CH2:38][CH2:37][C:36]4[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=4[NH:34][C:33]3=[O:43])[CH2:30][CH2:31]2)=[O:25])[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[Cl:48]
Reactant: C#Cc1cc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc(Cl)c1N
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: [Cl-]
Solvent: C1=CCCC=CCC1
Product: CCc1cc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc(Cl)c1N
Reaction time: 2 h

Procedure:
54 mg (73.0 mmol) 4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidine-1-carboxylic acid-{(R)-1-(4-amino-3-chloro-5-ethynyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide, 10 mg (0.02 mmol) of bis(1,5-cyclooctadiene)-di-rhodium(I)-dichloride, 16.5 mg (0.04 mmol) 1,3-bis(diphenylphosphino)-propane were dissolved in 10 ml degassed methanol and 0.1 ml degassed triethylamine and then hydrogenated for 2 hours at ambient temperature and 3 bar hydrogen pressure. The reaction mixture was evaporated down under reduced pressure and taken up in ethyl acetate. The insoluble precipitate was removed by suction filtering and the filtrate was evaporated down under reduced pressure. The residue was purified by column chromatography.
Reaction SMILES: [CH2:1]1[O:26][C:4]2=[CH:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([O:22][CH3:23])[CH:14]=4)=[N:11][NH:10][C:9](=[O:24])[CH2:8][C:7]=3[CH:25]=[C:3]2[O:2]1.C(O)C.O>CC(C)=O.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[C:6]3[CH:5]=[C:4]4[O:26][CH2:1][O:2][C:3]4=[CH:25][C:7]=3[CH2:8][C:9](=[O:24])[NH:10][N:11]=2)=[CH:14][C:15]=1[O:22][CH3:23]
Reactant: COc1cc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(C)=O
Solvent: O
Solvent: CCO
Product: COc1cc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)ccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
To a solution of 7,8-methylenedioxy-1-(3-methoxy-4-nitrophenyl)-3,5-dihydro-2,3-benzodiazepin-4(4H)-one (136 mg, 0.387 mmol) in acetone (6 mL) was added ethanol (3 mL), water (4 mL), 5% Pd/C (33 mg) and HCO2NH4 (240 mg, 3.81 mmol). The mixture was stirred at room temperature for 3 h. The catalyst was filtered out. The filtrate was concentrated in vacuo and the resulting residue was collected by filtration, washed with water, and dried in vacuo to afford the title compound as a light yellow solid (98 mg, 0.31 mmol, 80%), mp: 147°-150° C. 1H NMR (CDCl3) 8.32 (s, 1H), 7.24 (d, J=1.9, 1H), 6.87 (dd, J=1.9, 8.0, 1H), 6.82 (s, 1H), 6.73 (s, 1H), 6.02 (s, 2H), 4.08 (s, 2H), 3.90 (s, 3H), 3.43 (s, 211). Anal. calcd. for C17H15N3O4.(3/8)H2O: C, 61.49; H, 4.78; N, 12.65. Found: C, 61.33; H, 4.39; N, 12.54.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:17][OH:18])(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:34][CH:35]=[CH:36][N:37]=2)=[C:29]([F:38])[C:28]=1[F:39].O1C=NC(C2C=CC(CN([C@@H]3CCCC[C@H]3CO)S(C3C=CC(Cl)=CC=3)(=O)=O)=CC=2)=N1>>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[O:34][CH:35]=[CH:36][N:37]=3)=[C:29]([F:38])[C:28]=2[F:39])[C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:17][OH:18])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: Fc1c(CBr)ccc(-c2ncco2)c1F
Reactant: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(Cl)s1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncon2)cc1)[C@@H]1CCCC[C@H]1CO
Agent: [Cs+]
Product: O=S(=O)(c1ccc(Cl)s1)N(Cc1ccc(-c2ncco2)c(F)c1F)[C@@H]1CCCC[C@H]1CO
Yield: 17.4 %

Procedure:
The title compound was synthesized from 5-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)thiophene-2-sulfonamide (100 mg, 0.32 mmol), cesium carbonate (126 mmol, 0.39 mg), and 2-(4-(bromomethyl)-2,3-difluorophenyl)oxazole (93 mg, 0.39 mmol) according to the procedure described for N-(4-(1,2,4-oxadiazol-3-yl)benzyl)-4-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (Example 11) to give 5-chloro-N-(2,3-difluoro-4-(oxazol-2-yl)benzyl)-N-(trans-2-(hydroxymethyl)cyclohexyl)thiophene-2-sulfonamide (28 mg, 17%). 1H NMR (400 MHz, CDCl3) δ ppm 7.78-7.84 (m, 1H), 7.79 (s, 1H), 7.50-7.57 (m, 1H), 7.37 (d, J=4.03 Hz, 1H), 7.32 (s, 1H), 6.95 (d, J=3.78 Hz, 1H), 4.58 (d, J=14.00 Hz, 1H), 4.42 (d, J=14.00 Hz, 1H), 3.53-3.73 (m, 2H), 2.98-3.19 (m, 1H), 2.38 (br. s., 1 H), 1.59-1.84 (m, 3H), 1.40-1.57 (m, 2H), 1.29-1.39 (m, 1H), 1.01-1.26 (m, 3H). Analytical HPLC R.T.=22.41 min. MS [M+H]+=503. HRMS [M+H]+ calc'd 503.0678, found 503.0654.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][NH2:17])=[N:14][N:15]=3)[N:12]=2)[O:4][N:3]=1.Cl[C:19]1[CH:20]=[CH:21][N:22]=[C:23]2[C:28]=1[N:27]=[CH:26][C:25]([O:29][CH3:30])=[CH:24]2>CC(O)CC>[CH3:30][O:29][C:25]1[CH:24]=[C:23]2[C:28]([C:19]([NH:17][CH2:16][C:13]3[N:11]4[N:12]=[C:7]([C:5]5[O:4][N:3]=[C:2]([CH3:1])[CH:6]=5)[CH:8]=[CH:9][C:10]4=[N:15][N:14]=3)=[CH:20][CH:21]=[N:22]2)=[N:27][CH:26]=1
Reactant: Cc1cc(-c2ccc3nnc(CN)n3n2)on1
Reactant: COc1cnc2c(Cl)ccnc2c1
Solvent: CCC(C)O
Product: COc1cnc2c(NCc3nnc4ccc(-c5cc(C)no5)nn34)ccnc2c1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To a microwave vial (10-20 mL) was added (6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine (1.00 g, 4.34 mmol) and 8-chloro-3-methoxy-1,5-naphthyridine (1.10 g, 5.65 mmol) in 2-butanol (12 mL). The suspension was stirred at 120° C. under microwave irradiation for four hours. The mixture was concentrated and taken up in ammonia in methanol (2.0 M) then purified by MPLC chromatography (eluted with 0-10% methanol in dichloromethane) to yield the product as a tan solid. MS m/z=389.0 [M+1]+. Calc'd for C19H16N8O2: 388.1
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][N:15]2[C:20]([C:22]2[N:23]=[C:24]([CH3:34])[S:25][C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[O:21])[O:11][CH:12]=1.[CH3:35][N:36]1C(=O)CCC1>C(OCC)(=O)C>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:26]2[S:25][C:24]([CH3:34])=[N:23][C:22]=2[C:20]([N:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]2[CH2:13][C:10]2[O:11][CH:12]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[C:35]#[N:36])[N:9]=2)=[O:21])=[CH:28][CH:29]=1
Reactant: CN1CCCC1=O
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2nc(-c3ccccc3Br)co2)c(-c2ccc(F)cc2)s1
Solvent: CCOC(C)=O
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc(-c3ccccc3C#N)co2)c(-c2ccc(F)cc2)s1
Temperature: 180 °C

Procedure:
A mixture of the bromide (0.240 g) of example 176, Cu(I)CN (0.060 g) and N-Methyl pyrrolidinone (5 ml) was heated at 180° C. for 16 h. The cooled reaction mixture was diluted with ethyl acetate and passed through kiesselguhr, washing with ethyl acetate. The filtrate was washed with water, dried (sodium sulfate) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 20-50% ethyl acetate-pentane) to give the title compound as a pale yellow gum (0.101 g
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[O:18]1[CH2:22][CH2:21][NH:20][C:19]1=[O:23].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([N:20]2[CH2:21][CH2:22][O:18][C:19]2=[O:23])[CH:3]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: O=C1NCCO1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cccc(N2CCOC2=O)c1
Yield: 21.9 %

Procedure:
Methyl 3-bromobenzoate (500 mg, 2.33 mmol), caesium carbonate (1.06 g, 3.26 mmol), oxazolidin-2-one (243 mg, 2.80 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (107 mg, 0.186 mmol) and tris(dibenzylideneacetone)dipalladium (0) (43 mg, 0.047 mmol) were refluxed under argon in dioxane (6 ml) for 18 h. After cooling, the mixture was filtered and evaporated in vacuo. Column chromatography on silica gel eluting with a gradient of 10–50% ethyl acetate in hexane gave the title compound (113 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C([O:19]C(N(C)C)N(C)C)(C)(C)C>CN(C=O)C>[N+:12]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[CH:1]=[O:19])[N:9]=[CH:8][CH:7]=[CH:6]2)([O-:14])=[O:13]
Reactant: Cc1cc2ncccc2cc1[N+](=O)[O-]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Product: O=Cc1cc2ncccc2cc1[N+](=O)[O-]
Reaction time: 1.5 h
Yield: 70 %

Procedure:
7-Methyl-6-nitroquinolin (1.22 g; 6.5 mmol) and tert.butoxy-bis(dimethylamino)methan (5.2 ml; 27.3 mmol) in DMF (13 ml) were heated for 15 min. in an oil bath, which was preheated to 160° C. The reaction mixture was evaporated to dryness, taken up in THF (26 ml). NalO4 (8.3 g; 39 mmol) in water (520 ml) was added at room. temperature within 1.5 h and after stirring for another 1 h the reaction mixture was extracted with EtOAc twice. The combined organic phases were dried over Na2SO4, evaporated and purified via chromatography (SiO2; TBME) to yield the title compound as a yellow foam (920 mg; 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].[CH:13]1(Br)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+].C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[CH:13]1([O:12][C:4]2[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
2-Methyloxy-5-nitrophenol (14.27 g, 84.4 mmol) was dissolved in dry dimethylformamide (80 ml). Cyclopentylbromide (176 g, 127 ml, 118.2 mmol) and cesium carbonate (38.5 g, 118.2 mmol) were added and the suspension stirred overnight at room temperature. The mixture was poured into saturated Na2CO3 (200 ml) and extracted with ethyl acetate (700 ml). The organic layer was washed with saturated Na2CO3 until no yellow colour was detected. The organic layer was then dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow solid (15.0 g).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][S:15](=[O:18])[CH2:14][CH2:13]2)[C:9]2[C:4](=[N:5][C:6]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[C:7]([Cl:19])[N:8]=2)[N:3]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:19][C:7]1[N:8]=[C:9]2[C:4](=[N:5][C:6]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[N:3]=[C:2]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[N:11]=[C:10]2[N:12]1[CH2:17][CH2:16][S:15](=[O:18])[CH2:14][CH2:13]1
Reactant: O=S1CCN(c2nc(Cl)nc3nc(N4CCOCC4)c(Cl)nc23)CC1
Reactant: C1CNCCN1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3nc(N4CCOCC4)c(Cl)nc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 2,6-dichloro-7-morpholino-4-(1-oxido-thiomorpholino)pteridine and piperazine.
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:19])[N:17]2[C:18]3[C:9]([S:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=42)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4]1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[O:30].Cl>CN(C=O)C>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[NH:28][C:29]([CH:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[S:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[N:17]([C:18]=23)[C:3]1=[O:19])=[O:30]
Reactant: O=C1Cc2cccc3c2N1c1ccccc1S3
Reactant: O=C=Nc1ccc(F)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1F)C1C(=O)N2c3ccccc3Sc3cccc1c32
Reaction time: 12 h
Yield: 360.3 %

Procedure:
To a suspension of sodium hydride (0.14 g) in DMF (10 ml) was added pyrrolo[3,2,-1kl]phenothiazine-1-one (0.48 g) and to the resulting solution was slowly added 2,4-difluorophenyl isocyanate (0.31 g) . The reaction mixture was stirred for 12 hours and then poured onto ice water (50 ml). The resulting mixture was acidified to pH 2.0 with 6N HCl and the precipitated solid was collected and then air dried-to yield the title compound (2.84 g). A sample recrystallized from methylene chloride had a m.p. of 208°-209° C.