Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:17])([Cl:16])[CH2:3][O:4][C:5]([O:7][CH2:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]=O)[N:13]=1)=[O:6].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:25]([CH3:28])[CH:26]=[O:27])C=CC=CC=1>C1C=CC=CC=1>[CH3:28][C:25](=[CH:14][C:12]1[N:13]=[C:9]([CH2:8][O:7][C:5]([O:4][CH2:3][C:2]([Cl:17])([Cl:16])[Cl:1])=[O:6])[S:10][CH:11]=1)[CH:26]=[O:27]
Reactant: O=Cc1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Reactant: CC(C=O)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CC(C=O)=Cc1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
A mixture of 2-(2,2,2-trichloroethoxycarbonyloxymethyl)thiazole-4-carboxaldehyde (21.0 g) and 2-(triphenylphosphoranylidene)propionaldehyde (20.6 g) in 300 mL of benzene is heated at reflux for 3 hours, then cooled to ambient temperature and concentrated. Purification by flash column chromatography on SiO2 (hexanes/ethyl acetate, 4:1) yields the product as a clear oil (21.0 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].[F:13][C:14]([C:17]1[N:21]([CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:20]2[CH:29]=[CH:30][C:31]([S:33](Cl)(=[O:35])=[O:34])=[CH:32][C:19]=2[N:18]=1)([F:16])[CH3:15].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[F:13][C:14]([C:17]1[N:21]([CH2:22][CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[C:20]2[CH:29]=[CH:30][C:31]([S:33]([N:8]3[CH:9]=[CH:10][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:7]3)(=[O:34])=[O:35])=[CH:32][C:19]=2[N:18]=1)([F:16])[CH3:15]
Reactant: CCNC(=O)c1cc[nH]c1
Reactant: CC(F)(F)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNC(=O)c1ccn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(F)F)n3CC2CCOCC2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-Ethyl-1H-pyrrole-3-carboxamide (50 mg, 0.36 mmol) was dissolved in THF (3 mL) and the solution was cooled down to 0° C. NaH (72 mg, 60%, 1.8 mmol) was then added and the reaction mixture was allowed to warm to room temperature and stirred for 1 hour at room temperature. The reaction mixture was cooled down to 0° C. again and 2-(1,1-difluoroethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (114 mg, 0.30 mmol) was added slowly, allowing the reaction to warm to room temperature and stirred for 3 hours. The reaction mixture was slowly added to a stirring mixture of EtOAc and NH4Cl at −20° C., which was extracted with EtOAc, washed with NH4Cl, water then brine. Concentrated under vacuum and purified by LCMS using high pH column 40-70% acetonitrile gradient to afford the title compound as a white solid. Yield: 25 mg (17%). 1H NMR (400 MHz, METHANOL-D4) δ 1.14 (t, J=7.23 Hz, 3 H), 1.32-1.41 (m, 2 H), 1.40-1.43 (m, 3 H), 1.43-1.53 (m, 2 H), 2.25 (t, J=19.53 Hz, 5H), 3.89 (dd, J=11.52, 2.54 Hz, 2 H), 4.37 (d, J=7.62 Hz, 2 H), 6.65 (s, 1 H), 7.31 (t, J=2.34 Hz, 1 H), 7.82 (s, 1 H), 7.88-7.94 (m, 1 H), 7.95-8.01 (m, 1 H), 8.40 (s, 1 H); MS (APPI) (M+H)+=481.2; Anal. Calc. for C22H26F2N4O4S+0.4 TFA: C, 52.05; H, 5.06; N, 10.65. Found: C, 52.41; H, 3.78; N, 10.41.
Reaction SMILES: [CH3:1][C:2]([CH3:59])([CH3:58])[CH2:3][O:4][C:5](=[O:57])[C:6]([CH3:56])([CH3:55])[C:7]([O:9][CH2:10][O:11][C:12]1[N:13]([C:49]2[N:54]=[CH:53][CH:52]=[CH:51][N:50]=2)[N:14]=[C:15]([CH:17]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([NH2:48])=[N:39]C(=O)C3C=CC=CC=3)=[CH:34][CH:33]=2)[C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH2:27][CH2:28][OH:29])[C:19]=2[F:30])[N:16]=1)=[O:8].CO>C(O)(=O)C>[C:5]([OH:57])(=[O:4])[CH3:6].[CH3:1][C:2]([CH3:59])([CH3:58])[CH2:3][O:4][C:5](=[O:57])[C:6]([CH3:56])([CH3:55])[C:7]([O:9][CH2:10][O:11][C:12]1[N:13]([C:49]2[N:50]=[CH:51][CH:52]=[CH:53][N:54]=2)[N:14]=[C:15]([CH:17]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([C:38](=[NH:39])[NH2:48])=[CH:36][CH:37]=2)[C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH2:27][CH2:28][OH:29])[C:19]=2[F:30])[N:16]=1)=[O:8]
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nc(OCOC(=O)C(C)(C)C(=O)OCC(C)(C)C)n(-c3ncccn3)n2)c1
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nc(OCOC(=O)C(C)(C)C(=O)OCC(C)(C)C)n(-c3ncccn3)n2)c1
Temperature: 40 °C
Reaction time: 4 h
Yield: 181.9 %

Procedure:
To a mixture of 2,2-dimethylmalonic acid 5-{(4-{amino[benzoylimino]methyl}phenylamino)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}-2-pyrimidin-2-yl-2H-[1,2,4]triazol-3-yloxymethyl ester 2,2-dimethylpropyl ester (500 mg) and methanol (4 mL), acetic acid (1 mL) was added, and the resulting mixture was stirred at 40° C. for 4 hours. The mixture was concentrated under reduced pressure, and the residue obtained was purified by reverse phase silica gel column chromatography (mixed solvent of acetonitrile-water, containing 0.1% of acetic acid) to obtain the captioned compound (430 mg).
Reaction SMILES: [C@H]12O[C@H:6]1[CH2:5][CH2:4][C@@H:3]([NH:8][C:9](=O)OC(C)(C)C)C2.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)S)C=CC=CC=1.[C:36](#[N:38])[CH3:37]>>[CH2:4]1[CH2:3][N:8]2[C:6](=[N:38][CH2:36][CH2:37][CH2:9]2)[CH2:5]1
Reactant: CC#N
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H]2O[C@@H]2C1
Agent: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: C1CN=C2CCCN2C1

Procedure:
1 g of tert-butyl (1R,3R,6S)-(7-oxa-bicyclo[4.1.0]hept-3-yl)-carbamate (Example 1 Step E), 1.56 g of triphenylmethanethiol, and 16.4 mL of acetonitrile were charged to a flask. To the mixture obtained 560 μL of DBN was added, and the mixture obtained was heated to 40° C. and stirred for 22.5 h. Upon completion of the reaction (TLC), the mixture obtained was cooled to rt, diluted with EtOAc, and washed with H2O and brine. The organic layer obtained was dried over MgSO4, concentrated in vacuo and the crude product obtained was subjected to column chromatography (eluent: cyclohexane/EtOAc 5:1). The required fractions were identified, combined and concentrated in vacuo.
Reaction SMILES: O1CCCC1.[S:6]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=O)[S:7]1.Cl.[CH3:17][O:18][C:19](=[O:23])[CH2:20][CH2:21][NH2:22].P(C#N)(OCC)(OCC)=O>C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C>[S:6]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([NH:22][CH2:21][CH2:20][C:19]([O:18][CH3:17])=[O:23])=[O:15])[S:7]1
Reactant: O=C(O)CCC1CCSS1
Reactant: COC(=O)CCN
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)CCNC(=O)CCC1CCSS1
Yield: 3.5 %

Procedure:
5 ml of anhydrous tetrahydrofuran were added to 6 ml of a mixture of 2.5 mmol of 3-(1,2-dithiolan-3-yl)propionic acid in a mixture of ethyl acetate and dimethylformamide. 0.6 ml of triethylamine, 349 mg of β-alanine methyl ester hydrochloride and 0.38 ml of diethyl cyanophosphate were added to the reaction solution, whilst ice-cooling, and the resulting mixture was stirred, whilst ice-cooling for 1 hour. At the end of this time, the reaction mixture was stirred at room temperature for 30 minutes, and then the solvent was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 2:1, 3:1 and 1:0 by volume mixtures of ethyl acetate and hexane as the eluent. The residue was then subjected to reverse phase preparative silica gel column chromatography, using a 2:3 by volume mixture of acetonitrile and water as eluent, and the acetonitrile was removed from the solution by evaporation under reduced pressure, after which the residue was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilised, to obtain 22.9 mg of the title compound as a yellow oil having an Rf value of 0.24 (silica gel thin layer chromatography; using a 3:1 by volume mixture of ethyl acetate and hexane as developing solvent).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH3:9][C:10]([CH3:12])=O.[O-]S([O-])(=O)=O.[Mg+2]>[Pd]>[CH:10]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])([CH3:12])[CH3:9]
Reactant: CC(C)=O
Reactant: Nc1ccccc1O
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: CC(C)Nc1ccccc1O
Temperature: 100 °C

Procedure:
Into a 300 mL autoclave were charged 12 g (109.92 mmol) of o-aminophenol, 100 mL (79 g; 1.4 mol) of acetone, 0.6 g of Pd/C (Pd content: 5% by mass) and 30 g of MgSO4, and the contents of the autoclave were heated at 100° C. while stirring under a hydrogen pressure of 1.0 MPa. After the elapse of 1 h, the hydrogen absorption was ceased, and the reaction was terminated. The resultant reaction solution was subjected to suction filtration to remove Pd/C and MgSO4 therefrom, and the filtrate thus separated was concentrated and then mixed with water to crystallize a reaction product. The thus obtained reaction product was dried to obtain 2-(isopropylamino)phenol. As a result, it was confirmed that the yield of 2-(isopropylamino)phenol was 93%, and the oxygen absorption initiation time as an index of determining an oxidation-inhibiting property thereof was 370 min.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[S:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[NH2:32]>>[S:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[NH:32][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([S:11]([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)(=[O:12])=[O:13])=[CH:15][CH:16]=1
Reactant: Nc1nc2ccccc2s1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Product: O=C(Nc1nc2ccccc2s1)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with benzo[d]thiazol-2-amine (39 mg, 0.26 mmol) using method B. The residue was purified using flash chromatography eluting with 0-20% EtOAc in hexanes to give N-(benzo[d]thiazol-2-yl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamide as an off-white solid. Yield: 29 mg (25%). 1H-NMR: 8.22 (d, J=8.5 Hz, 2H), 8.02 (d, J=8.0 Hz, 1H), 7.73 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.0 Hz, 1H), 7.50-7.45 (m, 1H), 7.37-7.32 (m, 1H), 7.24-7.19 (m, 1H), 7.14-7.08 (m, 2H), 3.84-3.80 (m, 2H), 2.44 (t, J=7.0 Hz, 2H), 1.66-1.58 (m, 2H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.Cl.[CH3:8][C:9]1[N:22]=[C:21]([NH2:23])[C:12]2[N:13]=[C:14]3[CH2:20][NH:19][CH2:18][CH2:17][CH2:16][N:15]3[C:11]=2[C:10]=1[CH3:24].C(N(CC)CC)C>CN(C=O)C>[CH3:8][C:9]1[N:22]=[C:21]([NH2:23])[C:12]2[N:13]=[C:14]3[CH2:20][N:19]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:18][CH2:17][CH2:16][N:15]3[C:11]=2[C:10]=1[CH3:24]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(N)c2nc3n(c2c1C)CCCNC3
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(N)c2nc3n(c2c1C)CCCN(S(C)(=O)=O)C3
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
Methanesulfonyl chloride (198 mg, 1.73 mmol) was added to a solution of 3,4-dimethyl-7,8,9,10-tetrahydro-6H-pyrido[3′,4′:4,5]imidazo[1,2-a][1,4]diazepin-1-amine dihydrochloride (400 mg, 1.31 mmol) and triethylamine (350 mg, 3.46 mmol) in DMF (250 mL) and stirred overnight at ambient temperature. The reaction mixture was concentrated under reduced pressure and adsorbed onto silica gel. The material was purified by column chromatography on silica gel, concentrated under reduced pressure, dissolved in dimethyl sulfoxide (DMSO), and purified by reverse phase prep HPLC (eluting with 0.5% formic acid in water/0.5% formic acid in acetonitrile in a 10-minute gradient from 5:95 to 95:5) using a HPLC purification system obtained from Shimadzu corporation (based in Kyoto, Japan) to afford 135 mg of 3,4-dimethyl-9-(methylsulfonyl)-7,8,9,10-tetrahydro-6H-pyrido[3′,4′:4,5]imidazo[1,2-a][1,4]diazepin-1-amine. HRMS (EI) calcd for C13H19N5O2S 310.1338, found 310.1346.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.CN1CCOCC1.[CH2:25]([O:27][C:28](=[O:32])[C:29](Cl)=[O:30])[CH3:26]>C(Cl)Cl>[CH2:25]([O:27][C:28](=[O:32])[C:29]([NH:17][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[N:4]=1)=[O:30])[CH3:26]
Reactant: Nc1nc(OCc2ccc(F)cc2)ncc1F
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)C(=O)Nc1nc(OCc2ccc(F)cc2)ncc1F
Reaction time: 16 h
Yield: 49.4 %

Procedure:
To a mixture of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.235 g, 0.99 mmol), N-methyl morpholine on polystyrene (0.538 g, 1.24 mmol), and CH2Cl2 (5 mL) was added chloro-oxo-acetic acid ethyl ester (0.135 g, 0.99 mmol) and the resulting mixture was agitated on an orbital shaker for 16 h. The reaction contents were filtered onto an acidic SPE cartridge and eluted with CH2Cl2. The CH2Cl2 filtrate was evaporated to give 0.165 g (50%) of N-[5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]oxalamic acid ethyl ester as a clear oil: 1H NMR (300 MHz, CDCl3) δ 9.21 (bs, 1H), 8.38 (d, J=2.3 Hz, 1H), 7.48 (m, 2H), 7.03 (t, J=8.5 Hz, 2H), 5.40 (s, 2H), 4.48 (q, J=7.1 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H); HPLC-MS (ESI) m/z 338 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9].[CH:12]1([CH2:15]Br)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:15][CH:12]2[CH2:14][CH2:13]2)[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9]
Reactant: BrCC1CC1
Reactant: OCc1c(F)cc(O)cc1Cl
Product: OCc1c(F)cc(OCC2CC2)cc1Cl
Yield: 77 %

Procedure:
This compound was prepared from 3-Chloro-5-fluoro-4-hydroxymethyl-phenol and cyclopropylmethylbromide according to the procedure described in Example 179 to give the product as a yellowish oil (305 mg, 77%); MS (EI): 230.1 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4](Br)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[CH3:1][O:2][C:3](=[O:13])[CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C(Br)c1ccccc1F
Reactant: Nc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(Nc1ccccc1)c1ccccc1F
Yield: 99.8 %

Procedure:
A solution of bromo-(2-fluoro-phenyl)-acetic acid methyl ester (I259) (1.47 g, 5.95 mmol), aniline (814 ul, 8.93 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.53 mL, 8.93 mmol) in acetonitrile (10 mL) is heated under microwave irradiation at 100° C. for 1 hour. The solvent is evaporated, the residue is taken up with DCM and washed with water and brine, dried over Na2SO4 and evaporated to afford intermediate I262 as a dark brown oil (1.54 g, quantitative yield).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=CC=1)(=O)C.[CH3:22]O>Cl>[CH2:5]([OH:4])[C:6]#[C:7][CH2:12][CH2:11][CH2:10][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:22]
Reactant: CO
Reactant: CCCCCCCC(=O)c1ccc(CCOC(C)=O)cc1
Agent: Cl
Product: CCCCCCCCCCCCC#CCO
Temperature: 65 °C

Procedure:
The compound (12.374 g) of (1) above was dissolved in a 1N solution (230 ml) of hydrochloric acid in methanol and the mixture was heated at 65° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 8.465 g of 2-pentadecynyl alcohol.
Reaction SMILES: [C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]([CH:30]=[O:31])[CH2:26][C:27]([OH:29])=[O:28])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:32])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][C:34](OC(C)=O)=[O:35].OS([O-])(=O)=O.[Na+]>N1C=CC=CC=1>[C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]3[CH2:26][C:27](=[O:29])[O:28][CH:30]3[O:31][C:34](=[O:35])[CH3:33])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:32])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=CC(CC(=O)O)NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)OC1OC(=O)CC1NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12
Reaction time: 6 h
Yield: 37.6 %

Procedure:
A solution of 214e (287 mg, 0.65 mmol) in pyridine (5 mL) was treated with Ac2O (0.4 mL, 3.62 mmol). After 6 hours, the reaction mixture was poured into 5% NaHSO4 and extracted 3 times with EtOAc. The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. Chromatography (SiO2, EtOAc) afforded 119 mg of 2100h, 1HNMR (CDCl3, mixture of four diastereoisomers) δ1.80-2.05(m), 2.12(s), 2.13(s), 2.19(s), 2.22(d), 2.67-2.75(m), 2.80-2.95(m), 3.00-3.20(m), 3.21-3.33(m), 3.50-3.95(four discrete multiplets), 4.19(m), 4.55(m), 4.57-4.65(m), 4.69(m), 4.85-4.95(m), 5.04(m), 5.10(s), 5.10-5.22(m), 6.46(d), 6.03(s), 6.50(d), 6.58(d), 6.75(d), 6.95-7.05(m), 7.22(m), 7.30(m), 7.71(d), 7.75-7.83(m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([N:17]([CH3:39])[C:18]3[CH:19]=[CH:20][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[C@@H:27]([CH3:38])[CH2:26]4)=[N:22][CH:23]=3)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]([N:17]([CH3:39])[C:18]3[CH:23]=[N:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][C@@H:27]([CH3:38])[CH2:26]4)=[CH:20][CH:19]=3)=[O:16])[CH2:13][CH2:14]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)N3CCC(Nc4cccc(F)c4)CC3)cn2)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)N3CCC(Nc4cccc(F)c4)CC3)cn2)CCN1
Yield: 91.9 %

Procedure:
A solution of 1,1-dimethylethyl (2S)-4-({5-[({4-[(3-fluorophenyl)amino]-1-piperidinyl}carbonyl)(methyl)amino]-2-pyridinyl}methyl)-2-methyl-1-piperazinecarboxylate (D62) (320 mg, 0.593 mmol) in DCM (16 ml) and TFA (4 ml) was stirred at room temp for 2 h. The solvent was removed in vacuo and the residue was taken up in MeOH, and loaded onto an Isolute SCX cartridge which was eluted with MeOH then 2M NH3 in MeOH. The ammoniacal fraction was concentrated to give the crude product as a yellow oil. Column chromatography eluting with 0-10% (2M NH3 in MeOH)/DCM gave the title compound as a pale yellow oil (240 mg). MS (ES) MH+ 441.3.
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])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[N+:18]([C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br)([O-:20])=[O:19]>>[CH3:16][C:13]1([CH3:17])[N:12]([CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[N+:18]([O-:20])=[O:19])[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: O=[N+]([O-])c1ccccc1CBr
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccccc1[N+](=O)[O-]

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-nitrobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=O)[CH2:24][C:25]([CH:27]1[CH2:29][CH2:28]1)=[O:26])=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=[S:40])[CH2:24][C:25]([CH:27]1[CH2:29][CH2:28]1)=[O:26])=[O:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)CC(=O)C1CC1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(=O)C1CC1

Procedure:
In analogy to the procedure described in example 192f, (2S,4R)-1-(3-cyclopropyl-3-oxo-propionyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 363a) was reacted with Lawesson's reagent to give the title compound as brown oil. MS (ESI): m/z=364.1 [M+H]
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=2)=[CH:5][CH:4]=1.C(Cl)CCl.[CH:21]1[CH:22]=CC2N(O)N=[N:27][C:25]=2[CH:26]=1.N1CCCC1>CN(C=O)C>[N:27]1([C:14]([C:12]2[N:13]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[CH:8][CH:7]=3)[O:10][CH:11]=2)=[O:16])[CH2:22][CH2:21][CH2:26][CH2:25]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1coc(-c2ccc(CO)cc2)n1
Solvent: C1CCNC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(c1coc(-c2ccc(CO)cc2)n1)N1CCCC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A stirred solution of 2-[4-(hydroxymethyl)phenyl]-1,3-oxazole-4-carboxylic acid (0.99 g, 4.5 mmol) in DMF was treated sequentially with EDC (1.04 g, 5.4 mmol), HOBt (0.67 g, 5.0 mmol and pyrrolidine (0.35 g, 5.0 mmol), stirred at 80° C. for 4 hours and evaporated to dryness. The resultant residue was dissolved in EtOAc and water. The layers were separated and the organic layer was washed successively with 1M HCl, water, saturated NaHCO3 and brine, dried over Na2SO4 and concentrated under reduced pressure The resultant residue was purified by flash chromatography (silica, EtOAc:hexanes 25%) to give the title product in 84% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 273 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[H-].[Na+].F[C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH2:18])=[O:17]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH2:18])=[O:17])[CH2:6][CH2:5]2
Reactant: Brc1ccc2c(c1)CCN2
Reactant: NC(=O)c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: NC(=O)c1ccccc1N1CCc2cc(Br)ccc21
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
A slurry was prepared from 5-bromoindoline (9.85 g, 50 mmoles) dimethylsulfoxide (DMSO) (35 ml), sodium hydride (2.6 g, 50% in oil, washed with hexane, 1.1 eq). The slurry was stirred for 30 minutes. To this a solution of o-fluorobenzamide (7.9 g, 1.1 eq) in DMSO (15 ml) was added dropwise with temperature between 12°-13° C. At the end of addition the reaction mixture was stirred at ambient temperature for 4 hours, then heated up to 55° C. for 24 hours. The reaction mixture was partitioned between dichloromethane (300 ml) and water (250 ml). The aqueous phase was separated and extracted twice with dichloromethane (DCM) (150 ml). The combined DCM solution was washed twice with water (100 ml), twice with 2N HCl (100 ml), twice with brine (50 ml), dried over Na2SO4 and concentrated to a solid. Purification was on a flash chromatographic column (150 gm of silica gel) eluted with dichloromethane (DCM) (3 l). This gave 6.4 g of product (40%). Recrystallization from a small amount of ether yielded the 2-(5-bromo-indolin-1-yl)benzamide, m.p. 120°-122° C.
Reaction SMILES: [CH3:1][C:2](=[C:4]1[C:15](=[O:16])[C:7]2=[C:8]3[CH2:14][CH2:13][O:12][C:9]3=[N:10][CH:11]=[C:6]2[CH2:5]1)[CH3:3]>CO.[C].[Pd]>[CH:2]([CH:4]1[C:15](=[O:16])[C:7]2=[C:8]3[CH2:14][CH2:13][O:12][C:9]3=[N:10][CH:11]=[C:6]2[CH2:5]1)([CH3:3])[CH3:1]
Reactant: CC(C)=C1Cc2cnc3c(c2C1=O)CCO3
Agent: [Pd]
Solvent: CO
Product: CC(C)C1Cc2cnc3c(c2C1=O)CCO3
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
To a solution of 7-(1-methylethylidene)-1,2,6,7-tetrahydro-8H-cyclopenta[d]furo[2,3-b]pyridin-8-one (539 mg, 2.51 mmol) in methanol (20 mL) was added palladium-carbon powder (50 mg), and the mixture was stirred at room temperature for 3 hr under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→40/60) to give the title compound (465 mg, yield 85%).