Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CI.[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[CH:12]1[C:21]2[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:16]=2[N:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:14](=[O:33])[NH:13]1)[C:7]#[N:8].[C:34](=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[CH:12]1[C:21]2[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:16]=2[N:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=2)[C:14](=[O:33])[N:13]1[CH3:34])[C:7]#[N:8]
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyliodide (3.55 mL, 57.1 mmol) is added to a mixture of 3-bromo-4-[2,5-dioxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4,5,6,7,8-octahydro-quinazolin-4-yl]-benzonitrile (INTERMEDIATE 22, 14.0 g, 28.6 mmol) and cesium carbonate (18.6 g, 57.1 mmol) in DMF (140 mL). The mixture is stirred at room temperature for 90 min. Ethyl acetate is added and the organic phase is washed with water three times, dried over MgSO4 and concentrated. The crude product is purified by flash chromatography on silica (cyclohexane/ethyl acetate 30:70). Yield: 13.4 g. ESI mass spectrum: [M+H]+=504 (bromine isotope pattern); Retention time HPLC: 0.70 min (X012_S02).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([N:24]1[CH2:28][C@@H:27]2[C@@H:29]([NH2:32])[CH2:30][CH2:31][C@@H:26]2[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:17]([N:24]1[CH2:28][C@@H:27]2[C@@H:29]([NH:32][C:14]([C@@H:9]3[CH2:10][C@@H:11]([F:13])[CH2:12][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[CH2:30][CH2:31][C@@H:26]2[CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (2.87 g, 12.31 mmol) and (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Example 33 Step A (2.93 g, 13.54 mmol) in dichloromethane (16.97 mL) was added 1-hydroxybenzotriazole hydrate (2.073 g, 13.54 mmol). After 2 minutes, N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (2.388 mL, 13.54 mmol) was added and the reaction was stirred at ambient temperature overnight. The reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The solvent was removed in vacuo. The crude material was purified using an 80 g silica gel cartridge eluted with a gradient of 0-5% methanol (2 N ammonia)/dichloromethane over 20 minutes to give (2S,4R)-tert-butyl 2-((3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-ylcarbamoyl)-4-fluoropyrrolidine-1-carboxylate: 1H NMR (400 MHz, pyridine-d5) δ ppm 7.70 (s, 1H), 7.38-7.36 (m, 2H), 7.33-7.26 (m, 2H), 7.24-7.17 (m, 1H), 5.19 (dd, J=53.5, 3.3, 1H), 4.59 (t, J=7.8, 1H), 4.31-4.22 (m, 1H), 4.04-3.92 (m, 1H), 3.68 (dd, J=12.9, 3.7, 1H), 3.62-3.57 (m, 1H), 3.60-3.45 (m, 2H), 2.83-2.76 (m, 1H), 2.56-2.58 (m, 1H), 2.52-2.43 (m, 3H), 2.35 (m, 3H), 2.10 (dq, J=12.5, 6.3, 1H), 1.92-1.82 (m, 1H), 1.67-1.57 (m, 1H), 1.49 (s, 9H), 1.46-1.36 (m, 1H); MS (ESI+) m/z 432 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16](=[S:18])[NH2:17])[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[CH:3]=1.Br[CH2:24][C:25]([C:27]1[CH2:31][C@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][N:28]=1)=O>C(O)C.O>[C:32]1([C@@H:30]2[O:29][N:28]=[C:27]([C:25]3[N:17]=[C:16]([CH:13]4[CH2:14][CH2:15][N:10]([C:8](=[O:9])[CH2:7][N:6]5[C:2]([CH3:1])=[CH:3][C:4]([C:19]([F:22])([F:20])[F:21])=[N:5]5)[CH2:11][CH2:12]4)[S:18][CH:24]=3)[CH2:31]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(CBr)C1=NO[C@@H](c2ccccc2)C1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(C(N)=S)CC1
Solvent: CCO
Solvent: O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C3=NO[C@@H](c4ccccc4)C3)cs2)CC1
Temperature: 50 °C

Procedure:
A mixture of 1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidine-carbothioamide (i.e. the product of Example 8, Step C) (1.7 g, 5.0 mmol) and 2-bromo-1-[(5R)-4,5-dihydro-5-phenyl-3-isoxazolyl]ethanone (i.e. the product of Example 12, Step E or E1) (1.35 g, 5 mmol) in ethanol (15 mL) was heated at 50° C. for 30 minutes. The reaction mixture was diluted with water and extracted with dichloromethane. The extract was washed with brine, dried (MgSO4), and concentrated under reduced pressure to give the title product, a compound of the present invention, as a pale-yellow gum. High performance liquid chromatography (HPLC) analysis showed that the title product was about 95% pure and contained the (R)-enantiomer in about 98% enantiomeric excess.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19](Br)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([Sn](CCCC)(CCCC)[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1)CCC>C1(C)C=CC=CC=1>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19]([C:31]2[CH:30]=[N:29][CH:28]=[N:33][CH:32]=2)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(Br)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(-c2cncnc2)c1
Yield: 116.3 %

Procedure:
To the solution of 3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-5-bromo-6-chloropyridine (400 mg, 1.1 mmol) in toluene (10 mL) was added tetrekis(triphenylphosphine)palladium (40 mg, 1%) and tributyl(pyrimidinyl)tin (0.51 g, 1.38 mmol). The mixture was stirred and heated under reflux for 16 h. Solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtOAc, 10:1 to 2:1) to afford an oil (500 mg, 100%): 1H NMR (CDCl3, 300 MHz) δ 1.40 (s, 9H), 1.85-2.00 (m, 2H), 2.00-2.10 (m, 2H), 3.34-3.44 (m, 1H), 4.00 (m 1H), 4.14 (m, 1H), 4.24 (m, H), 7.40 (s, 1H), 8.20 (d, 1H, J=3.0 Hz), 8.88 (s, 2H), 9.28 (s, 1H); MS (CI/NH3) m/z 391 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[AlH4-].[Li+]>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1cccnc1Cl
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccnc1Cl
Temperature: 25 °C

Procedure:
To a stirred solution of 2-chloronicotinic acid (8.00 g, 51.0 mmol) in THF (120 mL) at 0° C. under nitrogen was slowly added lithium tetrahydroaluminate (51 mL, 51 mmol) over five minutes. The reaction was allowed to warm to RT over 2 h and was monitored by TLC. The reaction was quenched by addition of small amounts of ice followed by water. Extracted product into EtOAc, washed 2×H2O , 1×NaCl, dried with Mg2SO4, filtered through fritted funnel, and concentrated the solution to yield (2-chloropyridin-3-yl)methanol as an orange oil. Used without further purification.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].CO[CH:12]([N:15]([CH3:17])[CH3:16])OC>>[CH2:8]([O:7][C:1](=[O:6])[C:2](=[CH:12][N:15]([CH3:17])[CH3:16])[C:3](=[O:4])[CH3:5])[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: COC(OC)N(C)C
Product: CCOC(=O)C(=CN(C)C)C(C)=O
Yield: 99.3 %

Procedure:
Add ethyl acetoacetate (15 mL, 0.118 mol) to dimethoxymethyl-dimethyl-amine (19 mL, 0.142 mol) and reflux the mixture for one hr. Evaporate the mixture to give 2-dimethylaminomethylene-3-oxo-butyric acid ethyl ester (21.7 g, 99%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:8](=[O:20])[C:7]([C:21]([O:23]CC)=[O:22])=[CH:6][C:5]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.CO.O>[CH3:3][C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[C:8](=[O:20])[C:7]([C:21]([OH:23])=[O:22])=[CH:6][C:5]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(-c2ccccc2)cc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
Aqueous 2M sodium hydroxide solution (2.5 ml, 5.0 mmol) was added to a solution of ethyl 6-methyl-2-oxo-5-phenyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylate (0.85 g, 2.12 mmol) in THF (5 ml), methanol (3 ml) and water (1 ml). The reaction mixture was stirred at room temperature for 2 h and then concentrated in vacuo. Acetonitrile (3 ml) was added to the residue and the solution was acidified using TFA. The resulting solid was collected by filtration, washed with water and acetone and air dried to give the title compound as white solid (0.62 g, 78%).
Reaction SMILES: Cl.[Cl:2]C1C=C(C(C2(O)CCN(C)CC2)CN2CCNCC2)C=CC=1Cl.[CH2:26]([NH:33][C:34](=O)[CH:35]([C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([Cl:50])[CH:44]=1)[C:36]1([OH:42])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[ClH:2].[CH2:26]([NH:33][CH2:34][CH:35]([C:36]1([OH:42])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1)[C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([Cl:50])[CH:44]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CN1CCC(O)(C(CN2CCNCC2)c2ccc(Cl)c(Cl)c2)CC1
Reactant: O=C(NCc1ccccc1)C(c1ccc(Cl)c(Cl)c1)C1(O)CCCCC1
Agent: Cl
Product: OC1(C(CNCc2ccccc2)c2ccc(Cl)c(Cl)c2)CCCCC1

Procedure:
In an analogous manner to Example 1, step 2 4-[1-(3,4-dichlorophenyl)-2-piperazin-1-ylethyl]-1-methylpiperidin-4-ol hydrochloride was prepared from N-benzyl-2-(3,4-dichlorophenyl)-2-(1-hydroxycyclohexyl)acetamide. HRMS: calcd for C21H25Cl2NO.HCl, 413.1080; found (ESI_FT), 378.13864.
Reaction SMILES: [OH:1][CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1[N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18].[H-].[Na+].[CH3:21]I>CN(C)C=O>[CH3:21][O:1][CH:2]1[C:7]([CH3:8])([CH3:9])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1[N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18]
Reactant: CI
Reactant: CC1(C)Oc2ccsc2C(N2CCCC2=O)C1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1C(N2CCCC2=O)c2sccc2OC1(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 71.3 %

Procedure:
5,6-Dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl) -7H-thieno[3,2-b]pyran (1.1 g, 4.11 mmol) was added to a mixture of sodium hydride (60% in mineral oil, 0.172 g, 4.32 mmol) in N,N-dimethylformamide (20 ml) at 0° C. and stirred for 1.5h. Methyl iodide (0.28 ml, 4.52 mmol) was added to the resultant mixture and the mixture stirred at rt for 1h. The mixture was poured into ice water (100 ml) and extracted with dichloromethane. The dichloromethane solution was washed with water (5x) and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was crystallized from dichloromethane and hexanes to give the product 0.825 g (71%) as a colorless solid; mp 117°-118° C.; IR(KBr): 2979, 1677, 1572 and 1420 cm-1 ; MS: m/z 282 (MH+); 1H NMR (CDCl3) δ 1.27 (s,3H), 1.48(s,3H), 2.05(m,2H), 2.50(m,2H), 3.33(m,2H), 3.41(d,J=8.8Hz, 1H), 3.51(s,3H), 5.33(d,J=8.8Hz, 1H), 6.55(d,J=5.4Hz, 1H) and 7.09 (d,J=5.4Hz, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)=[O:8].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>>[CH3:19][N:20]([CH3:22])/[CH:21]=[C:6](\[C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)/[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)=[O:8]
Reactant: N#Cc1ccc(C(=O)Cc2ncc[nH]2)cc1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C(/C(=O)c1ccc(C#N)cc1)c1ncc[nH]1
Temperature: 75 °C
Reaction time: 12 h

Procedure:
A mixture of 4-(2-imidazolylacetyl)benzenecarbonitrile (0.30 M) and N,N-dimethylformamide dimethyl acetal (DMFDMA) (80 ml) was stirred for 12 h at 75° C. The DMFDMA was then removed under reduced pressure and dried under high vacuum for several hours giving an orange-yellow solid 4-[(2E)-3-(dimethylamino)-2-imidazolylprop-2-enoyl]benzenecarbonitrile in quantitative yield. The enaminone product was typically used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:30][C:31]1[S:35][C:34]([CH2:36][CH3:37])=[N:33][C:32]=1[CH3:38]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:30][C:31]1[S:35][C:34]([CH2:36][CH3:37])=[N:33][C:32]=1[CH3:38])[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1nc(C)c(CCl)s1
Reactant: Cc1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)nc1
Product: CCc1nc(C)c(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C)cn2)s1
Yield: 46.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 132 using 5-benzyloxy-N-(5-methylpyridin-2-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.43 g) and 5-chloromethyl-2-ethyl-4-methylthiazole (0.68 g) as starting materials, 5-benzyloxy-N-[(2-ethyl-4-methylthiazol-5-yl)methyl]-N-(5-methylpyridin-2-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.92 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:5][N:6]([CH3:32])[C:7](=[O:31])[C@@H:8]([N:20]([CH2:28][CH:29]=C)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1.C[N+]1([O-])CC[O:41]CC1.S(=O)(O)[O-].[Na+].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.[Os](=O)(=O)(=O)=O.O.O1CCCC1.CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:5][N:6]([CH3:32])[C:7](=[O:31])[C@@H:8]([N:20]([CH2:28][CH:29]=[O:41])[C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: C=CCN(C(=O)OC(C)(C)C)[C@@H](Cc1ccc2ccccc2c1)C(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)[C@H](Cc1ccc2ccccc2c1)N(CC=O)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Combine (S)-N-(3,4-dichlorobenzyl)-N-methyl-2-[N'-(t-butoxycarbonyl)-allylamino]-3-(naphth-2-yl)-propionamide (0.26 g, 0.50 mmol), N-methylmorpholine-N-oxide (0.065 g, 0.55 mmol), acetone (10 mL), tetrahydrofuran (5 mL), and water (5 mL). Add osmium tetraoxide (0.26 mL, 0.04M in THF, 0.042 mmol) and stir under an inert atmosphere for 18 hours. Pour the reaction mixture into a saturated solution of sodium bisulfite and extract the intermediate diol into ethyl acetate. Dry the separated organic layer over MgSO4, filter, and evaporate in vacuo to give the crude diol which is taken on to the next step without further purification. Dissolve the crude diol in chloroform (10 mL). Add a solution of lead tetraacetate (0.24 g, 0.55 mmol) in chloroform (10 mL). Stir for 30 minutes and then pour the reaction mixture into a saturated solution of sodium bicarbonate. Extract with dichloromethane and separate the organic layer. Dry the separated organic layer over MgSO4, filter and evaporate in vacuo to give the title compound which may be used without further purification.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li]CCCC.CCCCCC.[CH2:21]([O:23][C:24](=[O:31])[CH2:25]/[N:26]=[CH:27]/[N:28]([CH3:30])[CH3:29])[CH3:22].ClC1[CH2:34][N:35]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=2[O:55][CH3:56])[C:36](=[O:45])[C:37]2[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40]C=2N=1>C1COCC1.O.C(O)(=O)C>[CH2:21]([O:23][C:24]([C:25]1[N:26]=[CH:27][N:28]2[C:30]=1[CH2:34][N:35]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=1[O:55][CH3:56])[C:36](=[O:45])[C:37]1[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:29]2=1)=[O:31])[CH3:22]
Reactant: CCOC(=O)C/N=C/N(C)C
Reactant: COc1ccc(CN2CC(Cl)=Nc3ccc(C)cc3C2=O)c(OC)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)c1ncn2c1CN(Cc1ccc(OC)cc1OC)C(=O)c1cc(C)ccc1-2
Temperature: -70 °C
Reaction time: 1 h

Procedure:
Hexamethyldisilazane (68.7 mL, 330 mmol) was dissolved in THF (350 mL), cooled under Argon to −70° C., and treated slowly with a 1.6 M solution of n-BuLi in hexane (206 mL, 330 mmol). After stirring for 1 h at −70° C., a solution of (E)-(dimethylamino-methyleneamino)-acetic acid ethyl ester (31.6 g, 200 mmol) in THF (30 mL) was added, and stirring continued for 1 h at −70° C. Then a solution of 2-chloro-4-(2,4-dimethoxy-benzyl)-7-methyl-3,4-dihydro-benzo[e][1,4]diazepin-5-one (35.9 g, 100 mmol) (prepared as described above) was added at −70° C., and subsequently allowed to warm up to at 10° C. over 1 h, then cooled again to −30° C. After 30 min, acetic acid (57 mL) was added at −30° C. and the suspension was allowed to warm up to room temperature and water (57 mL) added and the resulting mixture heated under reflux for 14 h. After cooling, the mixture was evaporated and then dissolved in DCM (300 mL). This solution was then washed with HCl (1 M, 2×100 mL) and 10% sodium hydrogen carbonate (100 ml), dried (Na2SO4) and evaporated. Chromatography on silica gel eluting with EtOAc. Yield: 17.6 g (41%). m/z 436 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][NH:5][C:6](=[O:23])[N:7]([CH:20]([CH3:22])[CH3:21])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1>[Pd]>[CH3:24][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6](=[O:23])[N:7]([CH:20]([CH3:21])[CH3:22])[CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1
Reactant: CC(C)N(CCOc1ccc([N+](=O)[O-])cc1)C(=O)NCCN(C)C
Agent: [Pd]
Product: CC(C)N(CCOc1ccc(N)cc1)C(=O)NCCN(C)C

Procedure:
N'-[2-(dimethylamino)ethyl]-N-(1-methylethyl)-N-[2-(4-nitrophenoxy)ethyl]urea, free base in Example 62, is hydrogenated over palladium-on-charcoal catalyst to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1Cl)=[O:5])[CH3:2].[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: NCc1ccccn1
Product: CCOC(=O)c1cnc(Cl)cc1NCc1ccccn1

Procedure:
From 4,6-dichloropyridine-3-carboxylic acid ethyl ester synthesized according to the method described in US2006/0217417 and 2-(aminomethyl)pyridine in a manner similar to Example 339, the title compound was obtained as a colorless crystalline powder (yield 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][N:11]=[C:10]([Cl:13])[C:9]=2[C:14]#[N:15])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[N:24]=[C:25]=[O:26]>C1COCC1>[Cl:13][C:10]1[C:9]([C:14]#[N:15])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:25]([NH:24][C:18]3[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=3[F:16])=[O:26])=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: N#Cc1c(Cl)nsc1-c1ccc(N)cc1
Reactant: Cc1ccc(F)c(N=C=O)c1
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3snc(Cl)c3C#N)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.3 %

Procedure:
A solution of 5-(4-Aminophenyl)-3-chloroisothiazole-4-carbonitrile (4.565 g, 19.4 mmol) and 2-fluoro-5-methylphenyl isocyanate (5.85 g, 38.7 mmol) in 100 mL of dry THF was heated to reflux overnight. TLC indicated presence of considerable amount of starting material. Additional 2 g of 2-fluoro-5-methylphenyl isocyanate was added and the reaction was continued for another 24 h. The reaction was cooled to RT. THF was removed in vacuo and the resulting solid was stirred in 200 mL of Et2O for 1 h. Product was collected by filtration and washed with Et2O/hexanes to afford a light yellow solid (6.78 g, 90%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[C@H:8]([NH:10][C:11]([C:13]1([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14]1)=[O:12])[CH3:9].C(=O)([O-])[O-].[Cs+].[Cs+].[F:32][C:33]([F:54])([F:53])[S:34]([O:37][C:38]1[C:43]([O:44][S:45]([C:48]([F:51])([F:50])[F:49])(=[O:47])=[O:46])=[CH:42][CH:41]=[CH:40][C:39]=1Cl)(=[O:36])=[O:35].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.CO.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]>[F:50][C:48]([F:49])([F:51])[S:45]([O:44][C:43]1[C:38]([O:37][S:34]([C:33]([F:32])([F:53])[F:54])(=[O:35])=[O:36])=[C:39]([C:4]2[CH:5]=[CH:6][C:7]([C@H:8]([NH:10][C:11]([C:13]3([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14]3)=[O:12])[CH3:9])=[C:2]([F:1])[CH:3]=2)[CH:40]=[CH:41][CH:42]=1)(=[O:47])=[O:46]
Reactant: C[C@@H](NC(=O)C1(NC(=O)C(F)(F)F)CC1)c1ccc(B(O)O)cc1F
Reactant: O=S(=O)(Oc1cccc(Cl)c1OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)C1(NC(=O)C(F)(F)F)CC1)c1ccc(-c2cccc(OS(=O)(=O)C(F)(F)F)c2OS(=O)(=O)C(F)(F)F)cc1F
Temperature: 85 °C

Procedure:
3-Fluoro-4-{-(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)amino]ethyl}-phenylboronic acid (0.050 g, 0.138 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.013 g, 0.014 mmol), and cesium carbonate (0.054 g, 0.166 mmol) were added to a flame-dried flask under argon. 2-chloro-6-{[(trifluoromethyl)sulfonyl]oxy}phenyl trifluoromethanesulfonate (0.068 g, 1.66 mmol) as a solution in dioxane (0.33M) and tri-tert-butyl phosphine (0.007 g, 0.035 mmol) as a solution in dioxane (1.65M) were added to the solids and heated at 85° C. After 1.5 hours the reaction was diluted with methanol, filtered and purified by reverse phase chromatography using a gradient from 95/5H2O/CH3CN to 5/95H2O/CH3CN. The product was lyophilized to yield the title compound as a solid. High resolution mass spectrometry: C22H16F10N2O8S2 requires: 691.0261, found: 691.0275. 1H NMR (400 MHz, (CD3)2SO) δ 9.80 (s, 1H), 8.32 (d, J=7.4 Hz, 1H), 7.86-7.92 (m, 1H), 7.76-7.81 (m, 2H), 7.53 (t, J=7.9 Hz, 1H), 7.37 (dd, J=11 Hz, J=1.7 Hz, 1H), 7.33 (dd, J=7.9 Hz, J=1.7 Hz, 1H), 5.24 (qn, J=7.4 Hz, 1H), 1.41 (d, J=7.4 Hz, 3H), 1.30-1.37 (m, 2H), 0.92-1.08 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][O:13][CH3:14])=[CH:7][C:6]=1[C:15]1[CH2:16][C:17]([Br:23])([CH:21]=[O:22])[CH:18]=[CH:19][CH:20]=1)C.[OH-].[K+].CCOC(C)=O>CO.O.Cl>[Br:23][C:17]1([CH:21]=[O:22])[CH:18]=[CH:19][CH:20]=[C:15]([C:6]2[CH:7]=[C:8]([O:11][CH2:12][O:13][CH3:14])[CH:9]=[CH:10][C:5]=2[C:4]([OH:24])=[O:3])[CH2:16]1
Reactant: CCOC(=O)c1ccc(OCOC)cc1C1=CC=CC(Br)(C=O)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COCOc1ccc(C(=O)O)c(C2=CC=CC(Br)(C=O)C2)c1
Reaction time: 8 h

Procedure:
To a suspension of 3-bromo-3-formylphenyl-4-methoxymethoxybenzoic acid ethyl ester (1.4 g, 3.56 mmol) in 10 mL MeOH/20 mL H2O was added solid KOH (220 mg, 3.91 mmol). The reaction mixture was refluxed for 3 hours then additional solid KOH (23 mg, 0.42 mmol) was added and the temperature of the reaction was lowered to ca 50° C. after which point the reaction was stirred overnight. The workup of the reaction consisted of diluting with water and acidifying with 2N HCl to pH 1 then extracting with EtOAc (3×). The combined organic layers were dried over Na2SO4 then the solvent was removed in vacuo to give a beige solid. This solid was subjected to flash chromatography (50% EtOAc:50% Hexanes to 100% EtOAc) to give the desired acid as a beige solid plus a fraction that contained starting ester and desired acid. This fraction was rechromatographed to give more acid for a total yield of 920 mg, 70.7%. 1H NMR (CDCl3+DMSO-d6) δ 2.91 (s, 3H); 4.67 (s, 2H); 5.2-6.6 (bs, 1H); 7.26 (t, J=8.18 Hz, 1H); 7.67 (d, J=8.18 Hz, 1H); 7.73 (d, J=8.18 Hz, 1H); 7.83-7.90 (m, 2H); 8.11 (d, J=1.64 Hz, 1H); 9.90 (s, 1H).