Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[C@@H:17]2[CH2:22][C@H:21]([CH3:23])[CH2:20][C@H:19]([NH:24]C(=O)OC(C)(C)C)[CH2:18]2)=[O:9])[CH:5]=[CH:4][C:3]=1[F:32].[F:33][C:34]1[C:39]([OH:40])=[CH:38][CH:37]=[C:36]([F:41])[C:35]=1B(O)O.[F-].[K+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>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].O.C1COCC1>[NH2:24][C@H:19]1[CH2:20][C@@H:21]([CH3:23])[CH2:22][C@@H:17]([C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[NH:10][C:8](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([F:32])=[C:2]([C:35]3[C:36]([F:41])=[CH:37][CH:38]=[C:39]([OH:40])[C:34]=3[F:33])[N:7]=2)[CH2:18]1
Reactant: OB(O)c1c(F)ccc(O)c1F
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)C[C@H](c2ccncc2NC(=O)c2ccc(F)c(Br)n2)C1
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: C1CCOC1
Solvent: O
Product: C[C@@H]1C[C@H](N)C[C@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)ccc(O)c3F)n2)C1
Temperature: 100 °C

Procedure:
To a solution of tert-butyl (1S,3R,5S)-3-(3-(6-bromo-5-fluoropicolinamido)pyridin-4-yl)-5-methylcyclohexylcarbamate (1.0 equiv.) in a microwave vial was added 2,6-difluoro-3-hydroxyphenylboronic acid (5.0 equiv.), KF (5.5 equiv.) and Pd2(dba)3 (0.2 equiv.) followed by THF and water (10:1, 0.03 M). To this mixture was added P(t-Bu)3 (0.4 equiv.) and the reaction was heated in the microwave at 100° C. for 30 min. The organic phase was then separated, the aqueous layer was washed with ethyl acetate, and the organics were combined and concentrated in vacuo. The crude mixture was purified via prep-HPLC, the product fractions were lyophilized and the resulting BOC group was deprotected as described in Method 9 yielding, after RP HPLC purification and lyophilization, N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluoro-3-hydroxyphenyl)-5-fluoropicolinamide as the TFA salt. LCMS (m/z): 457.2 (MH+); LC Rt=2.17 min.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]#[N:16])[CH2:9][CH2:8]2)[CH2:3]1.C(N(CC)C(C)C)(C)C.[N+](C1C=CC([O:39][C:40]([N:42]2[C@@H:46]([C:47]3[CH:52]=[CH:51][C:50]([F:53])=[C:49]([F:54])[CH:48]=3)[C@H:45]([CH2:55][O:56][CH:57]3[CH2:62][CH2:61][CH2:60][CH2:59][O:58]3)[O:44][C:43]2=[O:63])=O)=CC=1)([O-])=O.C(OCC)(=O)C>CCCCCC>[C:15]([C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[N:10]1[CH2:11][CH2:12][CH:7]([N:4]2[CH2:5][CH2:6][C@@H:2]([NH:1][C:40]([N:42]3[C@@H:46]([C:47]4[CH:52]=[CH:51][C:50]([F:53])=[C:49]([F:54])[CH:48]=4)[C@H:45]([CH2:55][O:56][CH:57]4[CH2:62][CH2:61][CH2:60][CH2:59][O:58]4)[O:44][C:43]3=[O:63])=[O:39])[CH2:3]2)[CH2:8][CH2:9]1)#[N:16]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1C(=O)O[C@@H](COC2CCCCO2)[C@@H]1c1ccc(F)c(F)c1
Reactant: N#Cc1ccccc1N1CCC(N2CC[C@@H](N)C2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1N1CCC(N2CC[C@@H](NC(=O)N3C(=O)O[C@@H](COC4CCCCO4)[C@@H]3c3ccc(F)c(F)c3)C2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.1 %

Procedure:
To a solution of 2-[4-(3-amino-(3R)-pyrrolidin-1-yl)piperidin-1-yl]benzonitrile (166 mg, 0.44 mmol) in dry, degassed N,N-dimethylformamide (4 mL) was added N,N-diisopropylethylamine (230 μL, 1.3 mmol) followed by (4S,5R)-4-(3,4-difluorophenyl)-2-oxo-5-(tetrahydropyran-2-yloxymethyl)-oxazolidine-3-carboxylic acid 4-nitrophenyl ester (210 mg, 0.44 mmol). The reaction mixture was stirred at room temperature for 4 h when the volatiles were removed under reduced pressure, the residue dissolved in ethyl acetate (100 mL), washed with 10% aqueous sodium carbonate solution (8×100 mL), brine (1×100 mL), dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure and the resulting oil was purified by pressurized silica gel chromatography (1:1 then 2:1 ethyl acetate:hexane) to afford (4S,5R)-4-(3,4-difluorophenyl)-2-oxo-5-(tetrahydropyran-2-yloxymethyl)oxazolidine-3-carboxylic acid {1-[1-(2-cyanophenyl)piperidin-4-yl]-(3R)-pyrrolidin-3-yl}amide as a white foam (156 mg, 0.26 mmol, 59%).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH2:11][CH3:12])[N:8]([CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:7](=[O:20])[C:6]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[NH:38][C:37](=[O:39])[O:36][N:35]=2)=[CH:24][CH:23]=1)[CH2:2][CH2:3][CH3:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([C:5]1[N:10]=[C:9]([CH2:11][CH3:12])[N:8]([CH2:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:18])[CH3:17])[C:7](=[O:20])[C:6]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[NH:38][C:37](=[O:39])[O:36][N:35]=2)=[CH:24][CH:23]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CC)n(CC(O)C(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CCCCc1nc(CC)n(CC(=O)C(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 1 h
Yield: 100.4 %

Procedure:
6-Butyl-2-ethyl-3-(2-hydroxy-3,3-dimethylbutyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one (2.9 g) was dissolved in dichloromethane (60 mL), 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (2.8 g) was added, and the mixture was stirred for 1 hr. A saturated aqueous sodium hydrogen carbonate solution and sodium thiosulfate 5 hydrate were added, and the mixture was further stirred for 1 hr. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (2.9 g, 100%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].[NH2:18][C:19](=[N:30]O)[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[O:10][N:30]=[C:19]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=3)[N:18]=2)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C
Reactant: COC(=O)c1ccc(C(N)=NO)cc1
Product: COC(=O)c1ccc(-c2noc(-c3ccc(-c4ccccc4C)c(C)c3)n2)cc1

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 3 (113.14 mg; 0.50 mmol) and methyl 4-[amino(hydroxyimino)methyl]benzoate (Maybridge; 97.10 mg; 0.50 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/EtOAc: 9.5/0.5), affording the title compound as a colorless oil. LC/MS (Method A): 385.0 (M+H)+. HPLC (Method A) Rt 6.16 min (Purity: 98.5%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH2:6]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:13][CH2:12]2)[CH3:7]>ClCCl>[CH2:6]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[S:2]([Cl:1])(=[O:5])=[O:3])[CH2:15][N:14]([C:19](=[O:24])[C:20]([F:21])([F:22])[F:23])[CH2:13][CH2:12]2)[CH3:7]
Reactant: CCOc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CCOc1cc2c(cc1S(=O)(=O)Cl)CN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of chlorosulfonic acid (0.48 mL) in dichloromethane (5 mL) at 0° C. was added dropwise a solution of 1-(6-ethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoro-ethanone (0.39 g, 1.43 mmol). The mixture was stirred at room temperature overnight before partitioning between water and dichloromethane. The organic layer was removed, dried over sodium sulfate, filtered and evaporated to dryness yielding the subtitled compound as a clear oil (0.34 g). 1H NMR δ (CDCl3) 1.46-1.63 (3H, t), 2.95-3.06 (2H, m), 3.80-3.95 (2H, m), 4.18-4.32 (2H, m), 4.69-4.80 (2H, d), 6.84-6.93 (1H, d), 7.70-7.79 (1H, d).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][O:30][CH2:29][CH2:28][NH:27]2)=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.C([O-])([O-])=O.[Na+].[Na+]>CN1C(=O)CCC1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]2[N:27]([C:2]3[C:11]4[C:6](=[CH:7][C:8]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=5[CH3:18])=[CH:9][CH:10]=4)[CH:5]=[N:4][N:3]=3)[CH2:28][CH2:29][O:30][CH2:31]2)=[CH:24][CH:25]=1
Reactant: Clc1ccc(C2COCCN2)cc1
Reactant: Cc1ccccc1-c1ccc2c(Cl)nncc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1ccccc1-c1ccc2c(N3CCOCC3c3ccc(Cl)cc3)nncc2c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A solution of 1-chloro-6-o-tolylphthalazine (0.100 g, 0.393 mmol) in NMP (2 mL) was treated with 3-(4-chlorophenyl)morpholine (0.155 g, 0.785 mmol) and diisopropylethylamine (0.219 mL, 1.26 mmol). The reaction solution was stirred at 120° C. in a sealed tube for 16 hours. After cooling to RT, the reaction solution was treated with saturated aqueous Na2CO3 (50 mL). The mixture was extracted with ethyl acetate (3×60 mL) and the combined organic phases were washed with brine. The organic solution was dried over magnesium sulfate and concentrated under reduced pressure. Flash chromatography on silica gel (ethyl acetate) gave 1-(3-(4-chlorophenyl)morpholino)-6-o-tolylphthalazine as a yellow solid. MS (ESI, pos.ion) m/z: 416.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:26].[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[N:35]=[C:36]=[O:37]>C1(C)C=CC=CC=1>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:24]=[CH:25][C:2]([NH:1][C:36]([NH:35][C:29]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:28]=2[F:27])=[O:37])=[C:3]([F:26])[CH:4]=1)#[N:18]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COCCOc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1C#N
Solvent: Cc1ccccc1
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(F)c3)c2cc1C#N

Procedure:
4-(4-Amino-3-fluorophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (352 mg) was suspended in toluene (20 ml) and the suspension was heated to reflux for dissolution, after which 2,4-difluorophenyl isocyanate (236 μl) was added dropwise and the mixture was heated to reflux for 30 minutes. After cooling, the precipitated solid was filtered out, washed with ether and ethyl acetate and dried to obtain 380 mg of the title compound.
Reaction SMILES: [Na+].[I-].[Si](Cl)(C)(C)C.[CH3:8][N:9]([CH3:75])[C:10]([S:12][C:13]1[C:24]2[O:23][C:22]([CH3:26])([CH3:25])[O:21][C:20]=2[C:19]([C:27]([C:51]2[C:61]3[O:62][C:63]([CH3:66])([CH3:65])[O:64][C:60]=3[C:59]([S:67][C:68]([N:70]([CH3:72])[CH3:71])=[O:69])=[C:53]3[O:54][C:55]([CH3:58])([CH3:57])[O:56][C:52]=23)([C:29]2[C:39]3[O:40][C:41]([CH3:44])([CH3:43])[O:42][C:38]=3[C:37]([S:45][C:46]([N:48]([CH3:50])[CH3:49])=[O:47])=[C:31]3[O:32][C:33]([CH3:36])([CH3:35])[O:34][C:30]=23)O)=[C:18]2[C:14]=1[O:15][C:16]([CH3:74])([CH3:73])[O:17]2)=[O:11].[O-]S([O-])(=S)=O.[Na+].[Na+]>CC#N.C(Cl)Cl>[CH3:50][N:48]([CH3:49])[C:46]([S:45][C:37]1[C:38]2[O:42][C:41]([CH3:43])([CH3:44])[O:40][C:39]=2[C:29]([CH:27]([C:19]2[C:20]3[O:21][C:22]([CH3:26])([CH3:25])[O:23][C:24]=3[C:13]([S:12][C:10]([N:9]([CH3:8])[CH3:75])=[O:11])=[C:14]3[O:15][C:16]([CH3:73])([CH3:74])[O:17][C:18]=23)[C:51]2[C:61]3[O:62][C:63]([CH3:66])([CH3:65])[O:64][C:60]=3[C:59]([S:67][C:68]([N:70]([CH3:71])[CH3:72])=[O:69])=[C:53]3[O:54][C:55]([CH3:58])([CH3:57])[O:56][C:52]=23)=[C:30]2[C:31]=1[O:32][C:33]([CH3:36])([CH3:35])[O:34]2)=[O:47]
Reactant: CN(C)C(=O)Sc1c2c(c(C(O)(c3c4c(c(SC(=O)N(C)C)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(SC(=O)N(C)C)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c1OC(C)(C)O3)OC(C)(C)O2
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])([O-])=S
Agent: [I-]
Solvent: ClCCl
Solvent: CC#N
Product: CN(C)C(=O)Sc1c2c(c(C(c3c4c(c(SC(=O)N(C)C)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(SC(=O)N(C)C)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c1OC(C)(C)O3)OC(C)(C)O2
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
NaI (1.135 g, 8.00 mmol) and Me3SiCl (1 mL, 8.0 mmol) were stirred in CH3CN (70 mL) at 0° C. Tris(8-dimethylaminocarbonylthio-2,2,6,6-tetramethylbenzo-[1,2-d:4,5-d']bis(1,3)-dioxole-4-yl)methanol (1.00 g, 0.9979 mmol (Example 43)) dissolved in CH3CN 10 mL) was added and the resulting solution stirred for 30 minutes when 1H NMR analysis of a small sample showed conversion to be complete. Na2S2O3 (sat., 30 mL) was added and the two phase system was stirred 30 minutes when more Na2S2O3 (sat. 30 mL) was added and the stirring was continued for 5 more minutes. The phases were separated and the organic layer was dried (MgSO4), filtered, the filter washed with diethyl ether (30 mL) and the solution was evaporated, yielding 1.16 g yellow to brown crystals. The crystals were dissolved in CH2Cl2, the solution was washed with NaHCO3 (30 mL, sat.) and H2O (30 mL), dried (MgSO4) and evaporated yielding 0.92 g of the pure title compound.
Reaction SMILES: [Mg].[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1.BrC(Br)C.[CH2:22]1[O:24][CH2:23]1.O1CCCC1>O1CCCC1.O>[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:22][CH2:23][OH:24])=[CH:13][CH:12]=1
Reactant: C1CO1
Reactant: Brc1ccc(CCOC2CCCCO2)cc1
Agent: CC(Br)Br
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1ccc(CCOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
Magnesium (1.31 g, 53.90 mmol) was added to a solution of 4-(2-(tetrahydropyran-2-yloxy)ethyl)bromobenzene (14.00 g, 49.09 mmol) in tetrahydrofuran (20 ml). Then dibromoethane (0.1 ml) was added under an atmosphere of nitrogen gas, and the mixture was stirred under room temperature for 1 hour. After cooling to ice-cooling temperature, 2M-ethylene oxide/tetrahydrofuran solution (49.09 ml, 98.18 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Then, water (40 ml) was added to the reaction mixture. The mixture was extracted with ethyl ether and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2) to give the desired 4-(2-(tetrahydropyran-2-yloxy)ethyl)phenethyl alcohol (6.00 g, 42%) .
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([F:12])([F:11])[F:10].[Li]CCCC.[I:18]I>C1COCC1>[Cl:1][C:2]1[C:3]([O:8][C:9]([F:11])([F:10])[F:12])=[CH:4][CH:5]=[CH:6][C:7]=1[I:18]
Reactant: FC(F)(F)Oc1ccccc1Cl
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: FC(F)(F)Oc1cccc(I)c1Cl
Reaction time: 0.67 h

Procedure:
To a solution of 1-chloro-2-(trifluoromethoxy)benzene (2.54 mmol) in 10 mL THF were added 1.42 mL n-BuLi (2.5 M solution in hexane) at −78° C. After 40 min, a solution of iodine (2.8 mmol) in 2.5 mL THF was added and stirring was continued at RT overnight.
Reaction SMILES: [N:1]1([C:7]([NH:9]C(=O)C2C=CC=CC=2)=[S:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[N:1]1([C:7](=[S:8])[NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(NC(=S)N1CCOCC1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(=S)N1CCOCC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a round-bottom flask was added a solution of N-(morpholine-4-carbonothioyl)benzamide (compound 211.9, 3.00 g, 12.0 mmol, 1.00 equiv) in methanol (20 mL). A solution of sodium hydroxide (1.44 g, 36.0 mmol, 3.00 equiv) in water (20 mL) was added to the reaction. The resulting solution was stirred overnight at 60° C. After cooling to ambient temperature, the organic solvent was removed under reduced pressure. The residue was extracted with 2×20 mL of ethyl acetate/petroleum ether(1:1). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 430 mg (25%) of morpholine-4-carbothioamide as a yellow solid.
Reaction SMILES: C([O:5]O)(C)(C)C.C(CC(C)(C)C)(C)C.[CH2:15]([OH:29])/[CH:16]=[CH:17]/[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.O.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH2:18]([C@@H:17]1[O:5][C@H:16]1[CH2:15][OH:29])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCC/C=C/CO
Reactant: CC(C)(C)OO
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CC(C)CC(C)(C)C
Solvent: O
Product: CCCCCCCCCCC[C@@H]1O[C@H]1CO
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of 1.00 g of 4A powdered molecular sieves in 50 ml of dry CH2Cl2 was cooled to 0° C. under argon. To the cooled suspension was added 403 mg (1.42 mmole) of Ti(OiPr)4 and 463 mg (1.98 mmole) of L(+)diisopropyl tartrate via syringe. The mixture was stirred for 15 min and cooled to -20° C. A solution of tert-butylhydroperoxide in isooctane (3.8M, 5.58 ml, 21.2 mmole) was added slowly to the mixture and the catalyst was allowed to "age" for 30 min at -20° C. A solution of 3.00 g (14.2 mmole) of E-2-tetradecen-1-ol in 10 ml of CH2Cl2 was dried over 3A molecular sieves for 15 min before being added to the mixture slowly, with stirring, at -20° C. The solution was then placed in the freezer (-30° C.) and allowed to stand of 24 H. The mixture was warmed to 0° C. and poured into a solution of 1.00 g of citric acid and 5.00 g of FeSO4 in 15 ml H2O. The organic layer was separated and the aqueous layer washed twice with 20 ml of CH2Cl2. The CH2Cl2 layers are combined, dried over MgSO4, filtered and evaporated to yield a sticky white solid. Recrystallization from Et2O: petroleum ether afforded 2.34 g of white solid, mp 68°-70° C. 1H NMR δ3.92 (ddd, 1, J=2.5, 6, 12 Hz), 3.63 (ddd, 1, J=4, 7, 12 Hz), 2.95 (m, 2), 1.64 (dd, 1, J=7, 5 Hz), 1.6-1.2 (m, 20), 0.88 (t, 3, J=5 Hz). Mass Spectra: M-31(-CH2O H)(1.0)197.2, M(100)55.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:24][CH2:25][C:26](Cl)=[O:27].C(OCC)C.O>O1CCOCC1>[Cl:24][CH2:25][C:26]([C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[NH:14][CH:13]=1)=[O:27]
Reactant: O=C(Cl)CCl
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(CCl)c1c[nH]c2ccc(OCc3ccccc3)cc12
Reaction time: 1 h

Procedure:
5-(Benzyloxy)indole in dioxane containing pyridine was stirred for 1 hr. at 65° C. under nitrogen while chloroacetyl chloride in dioxane was added dropwise. The reaction mixture was stirred for another 1 hr., then poured into diethyl ether-water. The precipitate was collected by filtration and washed thoroughly with cold Et2O to yield 19, an orange solid.
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[CH3:15][C:16]1[NH:17][C:18](=[O:32])[CH2:19][S:20][C:21]=1[CH:22]1[N:26](C(OCC)=O)[CH2:25][CH2:24][S:23]1>ClCCl>[CH3:15][C:16]1[NH:17][C:18](=[O:32])[CH2:19][S:20][C:21]=1[C:22]1[S:23][CH:24]=[CH:25][N:26]=1
Reactant: CCOC(=O)N1CCSC1C1=C(C)NC(=O)CS1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: CC1=C(c2nccs2)SCC(=O)N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.3 %

Procedure:
DDQ (0.16 g) was added to 5-methyl-6-(3-ethoxycarbonyl-dihydro-2-thiazolyl)-2H-1,4-thiazin-3(4H)-one (0.2 g) in dichloromethane (5 ml) and the reaction mixture was stirred at ambient temperature for 1.5 hours. The resulting crystals were filtrated, were washed with saturated aqueous calcium bicarbonate and successively with water, was recrystallized from methanol to give the titled compound (0.08 g, yield 54.0%) as white needles.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH2:8].[CH:9]1([C:12]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])[CH2:11][CH2:10]1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][C:19]([C:21]([F:22])([F:23])[F:24])=[CH:20][C:12]=1[CH:9]1[CH2:10][CH2:11]1
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C1CC1
Product: N[C@H]1CCCC[C@H]1NC(=O)c1ccc(C(F)(F)F)cc1C1CC1

Procedure:
The title compound, yellow solid, MS: m/e=327.2 [(M+H)+], was prepared in accordance with the general method of intermediate G from cis-1,2-diaminocyclohexane and 2-cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate K).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.CC[N:16]([CH:20]([CH3:22])C)[CH:17]([CH3:19])C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.N1CCCC1>CN(C=O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:5]([N:16]2[CH2:17][CH2:19][CH2:22][CH2:20]2)=[O:7])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cc(C(=O)N2CCCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.9 %

Procedure:
To a solution of 3-methyl-4-nitrobenzoic acid (0.5 g, 2.76 mmol) in DMF (4 mL) was added DIPEA (0.9 mL, 5.79 mmol), followed by HOBT (0.39 g, 2.89 mmol), EDC (0.44 g, 2.89 mmol) and pyrrolidine (0.196 g, 2.76 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with water and extracted with EtOAc. The organic layer was washed with brine, then concentrated to provide crude material which was further purified by column chromatography (silica:100-200 mesh, MeOH:DCM 8-10%), to afford the title compound (0.31 g, 48.1%). LCMS (ES+) 235.05 (M+H)+, RT 2.04 minutes (method 1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[Mg].[CH:8]12[O:13][CH:9]1[CH2:10][CH2:11][CH2:12]2>CCOCC.C1COCC1.[Cu]I>[CH2:2]([C@@H:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[OH:13])[CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C1CC2OC2C1
Reactant: C=CCCCBr
Agent: [Cu]I
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCCC[C@@H]1CCC[C@H]1O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
A solution of 5-bromopent-1-ene (11.81 mL, 100 mmol) in Et2O (100 mL) was added to magnesium (2.43 g, 100 mmol) over 20 minutes. The resulting suspension was heated under reflux for 40 minutes, then cooled to 20° C., taken up in a syringe, and added dropwise at −5° C. to a stirred suspension of CuI (3.17 g, 16.6 mmol) in THF (160 mL). The resulting solution was stirred for 30 minutes at −5° C., then cooled to −20° C. Cyclopentene oxide (7.21 mL, 83 mmol) was added dropwise, and the resulting mixture was warmed to 20° C. over 2 hours, then stirred for 48 hours. The reaction was quenched by addition of NH4Cl(aq.); then the layers were separated, and the aqueous layer was extracted with Et2O. The combined organic phases were washed with H2O and brine, then dried over Na2SO4. Filtration and removal of the volatiles gave a residue that was purified by column chromatography on SiO2 (gradient elution, 1-100% EtOAc/petroleum ether) to afford the title compound (7.92 g, 62%) as a liquid. 1H NMR (400 MHz, CDCl3) δ 5.88-5.76 (m, 1H), 5.01 (d, J=17.2 Hz, 1H), 4.95 (d, J=10.6 Hz, 1H), 3.83 (br s, 1H), 2.12-2.00 (m, 2H), 1.99-1.84 (m, 2H), 1.76-1.30 (m, 7H), 1.24-1.11 (m, 2H).