Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33].C(N(CC)C(C)C)(C)C>CO.O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:17][CH2:18][N:19]([C:32](=[O:33])[NH:31][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[Cl:24])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Reactant: O=C=Nc1ccccc1Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)Nc3ccccc3Cl)CC2)c1C
Yield: 4.6 %

Procedure:
A solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester (which may be prepared as described above; 153 mg, 0.485 mmol) in methanol (6.0 mL) was added to neat 1-chloro-2-isocyanatobenzene (81.9 mg, 0.534 mmol) at room temperature under nitrogen. The resulting light brown solution was heated at reflux for 15 hours at which time LCMS analysis indicated the presence of significant starting material. Reflux was continued over the weekend. LCMS analysis indicated little change in the reaction progress. To the reaction mixture was added N,N-diisopropylethylamine (93.2 μL, 0.534 mmol) at room temperature and the reaction mixture was then refluxed again for 24 hours. Significant starting material still remained. The reaction mixture was diluted with water (25 mL) and resulting mixture was extracted with ethyl acetate (2×50 mL). The combined extracts were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to give the crude product as a semi-solid (230 mg). Flash chromatography (40 g ISCO column, eluting with 0-100% ethyl acetate/hexanes and finally 25% MeOH/dichloromethane) provided {4-[1-(2-chloro-phenylcarbamoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (10.5 mg, 4.6%) as a viscous oil. MS cald. for C26H27ClFN2O3 [(M+H)+] 469, obsd. 469.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][C:21]=1[C:30]([F:33])([F:32])[F:31]>N1C=CC=CC=1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[S:9][CH2:10][CH2:11][C:12](=[O:13])[N:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)(=[O:27])=[O:28])=[CH:22][C:21]=1[C:30]([F:33])([F:31])[F:32]
Reactant: Nc1cc(Cl)ccc1SCCC(=O)N1CCCC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: c1ccncc1
Product: O=C(CCSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)N1CCCC1
Yield: 17.2 %

Procedure:
Following General Procedure B, the title compound (242 mg, 17%) was prepared from 3-((2-amino-4-chlorophenyl)thio)-1-(pyrrolidin-1-yl)propan-1-one (758 mg, 2.67 mmol) and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (745 mg, 2.67 mmol) in pyridine (10 ml).
Reaction SMILES: [OH:1][CH:2]([CH2:9][NH:10][C:11](=[O:14])[CH2:12][Cl:13])[CH2:3][NH:4][C:5](=[O:8])[CH2:6][Cl:7].[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[O:1][CH:2]([CH2:9][NH:10][C:11](=[O:14])[CH2:12][Cl:13])[CH2:3][NH:4][C:5](=[O:8])[CH2:6][Cl:7]
Reactant: C1=COCCC1
Reactant: O=C(CCl)NCC(O)CNC(=O)CCl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(CCl)NCC(CNC(=O)CCl)OC1CCCCO1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
To a suspension of 2-hydroxy-N,N'-1,3-propanediyl-bis(2-chloroacetamide) (12.16 g; 0.050 mol) and 3,4-dihydro-2H-pyran (6.31 g; 0.075 mol) in 350 ml of CH2Cl2, 1.25 g of pyridinium p-toluenesulfonate (PPTS) (0.005 mol ) are added in portions under stirring at a temperature of 5° C. After 30 minutes, temperature raises up to 20°-25° C. and the stirring is continued during 72 h; the solution is washed with 20% aqueous NaCl (2×100 ml), dried over Na2SO4 and concentrated to dryness under vacuum. The residue solidifies in n-hexane, and then after filtration, is crystallized from EtOH (115 ml) to obtain 14.1 g of 2-[(tetrahydro-2H-pyran-2-yl)oxy]-N,N'-1,3-propanediyl-bis(2-chloroacetamide).
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[CH2:13]1[CH:17]2[C@H:18]3[C:23](=[O:24])[O:22][C:20](=[O:21])[C@H:19]3[CH:14]1[CH:15]=[CH:16]2.O>CC(C)=O.CN(C)C1C=CN=CC=1>[OH:6][C:5]1[C@@H:7]([C@@H:9]([OH:10])[CH2:11][O:12][C:23]([CH:18]2[CH:17]3[CH2:13][CH:14]([CH:15]=[CH:16]3)[CH:19]2[C:20]([OH:22])=[O:21])=[O:24])[O:8][C:2](=[O:1])[C:3]=1[OH:4]
Reactant: O=C1OC(=O)[C@H]2C3C=CC(C3)[C@@H]12
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Solvent: O
Product: O=C1O[C@H]([C@@H](O)COC(=O)C2C3C=CC(C3)C2C(=O)O)C(O)=C1O
Temperature: 60 °C
Reaction time: 48 h

Procedure:
In a 50-mL one neck round bottom flask, ascorbic acid, Catalog No. A92902 from Aldrich Co. (4.80 g) was dissolved in acetone (16.42 g). In the same flask, cis-endo-5-norbornene-2,3-dicarboxylic anhydride, Catalog No. 247634 from Aldrich Co. (4.42 g), and 4-dimethylaminopyridine, Catalog No. 522821 from Aldrich Co. (0.06 g), were added. The flask was heated while stirring in a 60° C. oil bath for 48 hours. Water (15 mL) was added and the flask was heated for another 12 hours. The product was extracted in ethyl acetate (100 mL) and dry with magnesium sulfate. The product, a mixture of bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid and 3-({(2S)-2-[(2R)-3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl]-2-hydroxyethoxy}carbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid was isolated by removing ethyl acetate by rotary evaporation.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](I)[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[Cl:25])[CH:10]=2)=[O:5])[CH3:2].[C:27]([Cu])#[N:28]>CN1C(=O)CCC1.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:27]#[N:28])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[Cl:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1nc(I)c2cc(Oc3cc(F)ccc3Cl)ccc2c1O
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1nc(C#N)c2cc(Oc3cc(F)ccc3Cl)ccc2c1O
Temperature: 130 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
A mixture of 7-(2-chloro-5-fluoro-phenoxy)-4-hydroxy-1-iodo-isoquinoline-3-carboxylic acid ethyl ester (180 mg) and CuCN (66 mg) in NMP (2 mL) was stirred at 130° C. for 1 h; then cooled, diluted with DCM, filtered, then washed with water, dil. NaCl solution, dried over sodium sulphate, filtered, concentrated, the residue was column purified to give the desired product (120 mg). LC MS ESI: 387 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]2[C:7]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:8](/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])[O:9][C:5]=2[CH:4]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:13][C:12](=[O:14])/[CH:11]=[CH:10]/[C:8]2[O:9][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:21]=[CH:20][C:6]=3[C:7]=2[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCCc1c(/C=C/C(=O)O)oc2cc(OC)ccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCc1c(/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)oc2cc(OC)ccc12
Yield: 86.2 %

Procedure:
As in Example 113, (E)-3-(6-methoxy-3-pentylbenzofuran-2-yl)-2-propenoic acid (3.35 g) was reacted with 4-nitrophenol (1.8 g) in dichloromethane (35 mL) in the presence of 1,3-dicyclohexylcarbodiimide (2.42 g). The crude product was crystallized from 2-propanol to afford 4.1 g of (E)-3-(6-methoxy-3-pentylbenzofuran-2-yl)-2-propenoic acid 4-nitrophenyl ester, mp 120°-121.5° C. Anal. Calcd for C23H23NO6 : C, 67.47; H, 5.66; N, 3.42 Found: C, 67.29; H, 5.89; N, 3.43
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:32])[N:11]([CH3:31])[C:12]([O:28][CH2:29][CH3:30])=[N:13][C:14]=1[C:15]1[O:19][N:18]=[C:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[N:16]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[CH2:29]([O:28][C:12]1[N:11]([CH3:31])[C:10](=[O:32])[C:9]([OH:8])=[C:14]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[N:16]=2)[N:13]=1)[CH3:30]
Reactant: CCOc1nc(-c2nc(Cc3ccc(F)cc3)no2)c(OCc2ccccc2)c(=O)n1C
Solvent: O=C(O)C(F)(F)F
Product: CCOc1nc(-c2nc(Cc3ccc(F)cc3)no2)c(O)c(=O)n1C
Yield: 92.8 %

Procedure:
A yellow solution of 5-(benzyloxy)-2-ethoxy-6-(3-(4-fluorobenzyl)-1,2,4-oxadiazol-5-yl)-3-methylpyrimidin-4(3H)-one (0.150 g, 0.3421 mmol) in TFA (5 mL) was stirred 6 h at room temperature. Then, the reaction mixture was concentrated and the resulting yellow solid was heated with 1:1 EtOH/H2O and filtered to afford the title compound (0.11 g, 97%) as pale yellow solid. 1HNMR (500 MHz, CDCl3) δ: 9.49 (1H, s), 7.30 (2H, dd, J=8.4, 5.4 Hz), 7.02 (2H, t, J=8.6 Hz), 4.52 (2H, q, J=7.0 Hz), 4.15 (2H, s), 3.49 (3H, s), 1.44 (3H, t, J=7.0 Hz). HRMS (M+H) calcd for C16H16N4O4F: 347.1156. found: 347.3845. Anal calcd for C16H15N4O4F: C, 55.49; H, 4.36; N, 16.17; F, 5.48. found: C, 55.14; H, 4.32; N, 15.66; F, 5.85.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:3].[OH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([C@@H:26]2[CH2:30][C@H:29]([S:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[CH2:28][N:27]2[C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=2)=[O:42])=[O:25])[CH2:20][CH2:19]1>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(OCC)(=O)C>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][O:4][C:2]([O:15][CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][N:21]([C:24]([C@@H:26]3[CH2:30][C@H:29]([S:31][CH2:32][C:33]4[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)[CH2:28][N:27]3[C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=3)=[O:42])=[O:25])[CH2:22][CH2:23]2)=[O:3])=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(CCO)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(CCOC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
5.86 g of 4-dimethylaminopyridine and a solution of 10.35 g of p-nitrobenzyl chloroformate in 40 ml of anhydrous methylene chloride were added to a solution of 22.35 g of (2S,4S)-2-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 7) in 160 ml of anhydrous methylene chloride, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was diluted with 300 ml of ethyl acetate and washed with 100 ml of water, with 100 ml of a saturated aqueous solution of sodium hydrogencarbonate and with 100 ml of a saturated aqueous solution of sodium chloride, in that order. The solvents were removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel. Those fractions eluted with ethyl acetate were collected and concentrated by evaporation under reduced pressure, to give 26.35 g of the title compound as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:19]#[CH:20])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([OH:18])=[O:17])=[CH:7]2.[OH-].[Na+:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:19]#[CH:20])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:14])([F:15])[F:13])[C:8]([C:16]([O-:18])=[O:17])=[CH:7]2.[Na+:22]
Reactant: C#Cc1cc(Cl)c2c(c1)C=C(C(=O)O)C(C(F)(F)F)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C#Cc1cc(Cl)c2c(c1)C=C(C(=O)[O-])C(C(F)(F)F)O2

Procedure:
A solution of 56.5 mg (0.187 mmole) of 8-chloro-6-ethynyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid in 1.5 mL of ethanol was treated with 1.85 mL of 0.1008N NaOH. The resultant mixture was lyophilized to provide 59 mg (quant.) of an off-white solid: 1H NMR (CD3OD/400 MHz) 5.97 (q, 1H, J=7.0 Hz), 7.31 (d, 1H, J=1.7 Hz), 7.39 (s, 1 H), 7.41 (d, 1H, J=1.9 Hz), the acetylenic proton exchanges under the basic conditions; MS (ES+) 303 (M+l, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH:4]1[CH2:13][C:12](=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5]1.[CH3:20]N(CN(C)C)C.C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH:4]1[C:13](=[CH2:20])[C:12](=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5]1
Reactant: CN(C)CN(C)C
Reactant: O=C1CC(c2ccc(Cl)cc2Cl)Oc2ccccc21
Solvent: CC(=O)OC(C)=O
Product: C=C1C(=O)c2ccccc2OC1c1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 3 g (10 mmol) of the 2',4'-dichloro flavanone and 27 ml of bis-(dimethylamino)methane was stirred at room temperature; 27 ml of acetic anhydride was added dropwise over 15 minutes. A slight temperature rise occurred. One hour later the reaction was partitioned between 200 ml of ether and 200 ml of cold H2O. The aqueous phase was separated, washed with two 250 ml portions of ether, and discarded. The combined ether extracts were washed with saturated aqueous NaHCO3 solution, dried over anhydrous Na2SO4, filtered and evaporated. The residual oil was chromatographed on 200 g of silica gel, eluting with benzene. This gave 2.5 g of 2',4'-dichloro-3-methylene flavanone, isolated as a solid, m.p. 86°-87° C.
Reaction SMILES: [NH:1]([C:3](=[O:9])[C:4](OCC)=[O:5])[NH2:2].[CH3:10][NH:11][CH3:12]>>[NH:1]([C:3](=[O:9])[C:4]([N:11]([CH3:12])[CH3:10])=[O:5])[NH2:2]
Reactant: CNC
Reactant: CCOC(=O)C(=O)NN
Product: CN(C)C(=O)C(=O)NN
Temperature: 70 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a round-bottom flask was added ethyl 2-hydrazinyl-2-oxoacetate (compound 134.1, 2.00 g, 13.6 mmol, 1.00 equiv, 90%). Dimethylamine (10 mL) was added to the reaction, and then the reaction was stirred overnight at 70° C. in an oil bath. The mixture was cooled to room temperature and concentrated in vacuo to yield 1.50 g (76%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH2:23]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[C:19]([CH3:18])[CH:20]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: Cc1cccc(CN)c1
Solvent: COCCOC
Product: Cc1cccc(CNc2nc(N)nc(-c3ccco3)c2C#N)c1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 3-methylbenzylamine in DME. ES-MS m/e (%): 306 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:6]([N+:19]([O-])=O)[CH:5]=1.[Cl-].[NH4+].CO.O1CCCC1>[Fe].O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:6]([NH2:19])[CH:5]=1
Reactant: COC(=O)c1ccc(Sc2ccc(OC)cc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Sc2ccc(OC)cc2)c(N)c1
Yield: 90 %

Procedure:
To a solution of the product from Example 136A, iron powder and ammonium chloride in a methanol, tetrahydrofuran, and water solution was heated to reflux. The resultant mixture was filtered, and the filtrate was concentrated. Then ethyl acetate was added, stirred, filtered and concentrated under vacuum to provide the title compound (7.16 g, 90%).
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH:25]([OH:30])[CH2:26][C:27](O)=[O:28])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:31])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[BH4-].[Na+].II>O1CCCC1.O>[O:32]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH:25]([OH:30])[CH2:26][CH2:27][OH:28])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:31])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(O)CC(=O)O)c2c1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(O)CCO)c2c1
Yield: 41.2 %

Procedure:
A solution of 4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-3-hydroxybutanoic acid (50.0 mg, 0.11 mmol, prepared in analogy to Example 11-3), sodium borohydride (100.0 g, 2.6 mmol) and iodine (300.0 mg, 1.2 mmol) in tetrahydrofuran (10.0 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by preparative HPLC to afford 20.0 mg of the desired product as a light yellow solid (yield was 41.2%). MS obsd. (ESI+) [(M+H)+] 442, 1H NMR (400 MHz, CD3OD) δ ppm 8.04 (d, J=7.58 Hz, 1 H), 7.90 (d, J=7.58 Hz, 1 H), 7.81 (brs, 1 H), 7.75-7.59 (m, 2 H), 7.59-7.41 (m, 2 H), 6.10 (s, 1 H), 5.25 (brs, 2 H), 4.53 (brs, 2 H), 4.12 (brs, 1 H), 3.82 (t, J=5.94 Hz, 2 H), 3.68 (brs, 2 H), 3.55 (dd, J=13.77, 4.17 Hz, 1 H), 3.44 (dd, J=13.64, 7.33 Hz, 1 H), 2.45 (s, 3 H), 1.97-1.73 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:12][NH:11][C:10](=[O:13])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.I[CH3:15].[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[C:7]([CH:8]2[CH2:12][N:11]([CH3:15])[C:10](=[O:13])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C1CC(c2cccnc2F)CN1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CC(c2cccnc2F)CC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
To a solution of 4-(2-fluoropyridin-3-yl)pyrrolidin-2-one (0.254 g, 1.41 mmol) in DMF (5 mL) at 0° C. was added iodomethane (0.090 mL, 1.4 mmol) and sodium hydride (60% weight dispersion in mineral oil, 0.056 g, 1.4 mmol). The reaction mixture was stirred at 0° C. for 30 min, warmed to room temperature, and stirred for 30 min. The reaction mixture was diluted with EtOAc, quenched with water, and diluted with brine and water. The aqueous phase was extracted with EtOAc (6×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (50% to 100% EtOAc (10% MeOH) in hexanes) gave 4-(2-fluoropyridin-3-yl)-1-methylpyrrolidin-2-one (0.226 g, 1.16 mmol, 83% yield) as a pale yellow oil. MS (ESI, pos. ion) m/z: 195.1 (M+1).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:27]3[CH:26]=[C:25]([CH3:28])[C@:24]([CH2:30][CH:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[OH:32])([CH3:29])[CH2:23][C:22]=3[CH:21]=[N:20]2)=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[C:27]3[CH:26]=[C:25]([CH3:28])[C@:24]([CH2:30][CH:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N+:34]=4[O-:6])[OH:32])([CH3:29])[CH2:23][C:22]=3[CH:21]=[N:20]2)=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1=Cc2c(cnn2-c2ccc(F)cc2)C[C@]1(C)CC(O)c1ccccn1
Solvent: ClC(Cl)Cl
Product: CC1=Cc2c(cnn2-c2ccc(F)cc2)C[C@]1(C)CC(O)c1cccc[n+]1[O-]
Reaction time: 3 h

Procedure:
3-chloroperoxybenzoic acid (28 mg, 1.5 eq) was added to a solution of the diastereomer mixture of the alcohols from Examples 75 and 76 in chloroform (3 mL) at room temperature. After 3 h, the mixture was quenched with saturated NaHCO3 (1 mL), diluted with EtOAc (60 mL), washed with water (5 mL), brine (5 mL), dried (MgSO4) and concentrated. Reverse phase HPLC purification (MeOH-water, 50 to 100%) yielded the desired N-oxide as a mixture of two diastereomers (5 mg), which was separated by chiral OD column (isocratic, i-PrOH/heptane, 15%) to give Examples 78 (1.3 mg, 3%, isomer A, faster eluent) and 79 (1.5 mg, 4%, isomer B, slower eluent). MS found: (M+H)+=380.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](=[O:7])[CH2:5]Br.[C:12]([O:16][C:17](=[O:30])[NH:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([N:25]=[CH:26]N(C)C)=[S:24])([CH3:15])([CH3:14])[CH3:13].CCN(CC)CC>C(O)C>[C:12]([O:16][C:17](=[O:30])[NH:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]1[S:24][C:5]([C:4](=[O:7])[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=2[CH3:1])=[CH:26][N:25]=1)([CH3:13])([CH3:15])[CH3:14]
Reactant: Cc1ccccc1C(=O)CBr
Reactant: CN(C)C=NC(=S)NCCCNC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccccc1C(=O)c1cnc(NCCCNC(=O)OC(C)(C)C)s1
Temperature: 100 °C
Yield: 76.9 %

Procedure:
A mixture of 613 mg (2.9 mmol) 2-methyl phenacylbromide (literature: WO9907666), 691 mg (2.4 mmol) [3-(3-Dimethylaminomethylene-thioureido)-propyl]-carbamic acid tert-butyl ester and 1 ml (7.2 mmol) NEt3 in 20 ml ethanol was heated to 100° C. for 16 h. The mixture was concentrated and purified by flash column chromatography on silica eluting with ethyl acetate/n-hexane 1/1. The combined product fractions were evaporated and 693 mg (77%) of the title compound (MS (m/e): 375.9 (MH+, 100%)) were obtained.
Reaction SMILES: [CH:1]1([S:4]([N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14]3[N:19]=[C:18]([C:20]4[N:27]5[C:23]([S:24][CH:25]=[CH:26]5)=[N:22][C:21]=4[C:28]4[CH:33]=[CH:32][C:31]([F:34])=[C:30]([O:35]C)[CH:29]=4)[CH:17]=[CH:16][N:15]=3)[CH2:9][CH2:8]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.B(Br)(Br)Br>C(Cl)Cl>[CH:1]1([S:4]([N:7]2[CH2:8][CH2:9][CH:10]([NH:13][C:14]3[N:19]=[C:18]([C:20]4[N:27]5[C:23]([S:24][CH:25]=[CH:26]5)=[N:22][C:21]=4[C:28]4[CH:33]=[CH:32][C:31]([F:34])=[C:30]([OH:35])[CH:29]=4)[CH:17]=[CH:16][N:15]=3)[CH2:11][CH2:12]2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: COc1cc(-c2nc3sccn3c2-c2ccnc(NC3CCN(S(=O)(=O)C4CC4)CC3)n2)ccc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=S(=O)(C1CC1)N1CCC(Nc2nccc(-c3c(-c4ccc(F)c(O)c4)nc4sccn34)n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
The N-[1-(cyclopropylsulfonyl)piperidin-4-yl]-4-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine (0.226 g, 0.43 mmol) in methylene chloride (8 ml) was cooled to −78° C. and slowly treated with 1 molar solution of boron tribromide in methylene chloride (3.4 ml). The reaction mixture was kept at −78° C. for one hour then was allowed to warm to room temperature for two hours. The mixture was quenched by the addition of methanol (900 μl) at −78° C. and was stirred at room temperature for an additional hour. The mixture was diluted with methylene chloride (100 ml) and washed with three portions of 25 ml of saturated sodium bicarbonate solution, two portions of 25 ml of water and two portions of 25 ml of saturated sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated in vacuo, giving a yellow solid. The crude product was purified by flash chromatography (ethyl acetate), affording 0.19 g (86%) of the title compound as a beige solid. M.p.=224-225° C. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 9.82 (s, 1H), 8.67 (br. s, 1H), 8.12 (d, J=5.5 Hz, 1H), 7.43 (d, J=4.3 Hz, 1H), 7.25-7.14 (m, 3H), 6.99 (ddd, J=8.2, 4.3, 2.0 Hz, 1H), 6.41 (d, J=5.1 Hz, 1H), 3.95-3.84 (m, 1H), 3.68-3.60 (m, 2H), 3.00 (td, J=11.9, 2.7 Hz, 2H), 2.59-2.52 (m, 1H), 2.06-1.98 (m, 2H), 1.66-1.54(m, 2H), 1.04-0.92 (m, 4H). LCMS: 515 [M+H]. Calc. for C23H23N6O3S2F.0.53 diethyl ether.0.17 water: C, 53.46; H, 4.93; N, 14.89. Found C, 53.46; H, 4.60; N, 14.88.