Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH:10]12[O:16][CH:15]1[CH2:14][CH2:13][CH2:12][CH2:11]2>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:14]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:15]2[OH:16])=[CH:4][CH:3]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: C1CCC2OC2C1
Solvent: C1CCOC1
Product: OC1CCCCC1c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
To a cooled solution of 4-Fluorophenylmagnesium bromide (1.0M in THF, 4.94 mL, 4.94 mmol) in dry THF (10 mL) at −78° C. is added Copper (I) Bromide Dimethylsulfide complex (51 mg, 0.25 mmol) and the resulting mixture is stirred at −78° C. for 10 min, followed by the slow addition of a solution of 7-Oxa-bicyclo[4.1.0]heptane (500 μL, 4.94 mmol) in THF (2 mL). The reaction is warmed to 0° C. and is stirred for 2 hour. Then the reaction is quenched with saturated NH4Cl solution (20 mL). The resulting mixture is extracted with EtOAc (10 mL×3). The organic layers are combined, washed with brine (10 mL×1), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude is purified by silica flash column chromatography using EtOAc in Heptane (gradient from 0% to 35%) to give 700 mg of desired product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:15]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20]([CH3:24])=[C:19]([Br:25])[C:18]=3[O:26][CH3:27])[CH3:16])[N:9]=[C:10]([CH:11]([OH:14])CO)[C:3]=12.C(O)(=O)C.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:15]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20]([CH3:24])=[C:19]([Br:25])[C:18]=3[O:26][CH3:27])[CH3:16])[N:9]=[C:10]([CH:11]=[O:14])[C:3]=12
Reactant: COc1c(C(C)n2nc(C(O)CO)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COc1c(C(C)n2nc(C=O)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Reaction time: 2 h

Procedure:
To a solution of 1-{4-amino-1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}ethane-1,2-diol (0.10 g, 0.22 mmol) in tetrahydrofuran (1.6 mL)/water (1.0 mL) was added acetic acid (0.0032 mL, 0.057 mmol) and sodium periodate (0.140 g, 0.657 mmol) at 0° C. After stirring for 2 h, the reaction mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to give the desired crude product which was used directly in the next step. LCMS calculated for C16H16BrClN5O2 (M+H)+: m/z=424.0; Found: 423.9
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][C:16](NC)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33].N[CH2:35][C@H](O)C.CN1CCOCC1>>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][C@H:16]([OH:17])[CH3:35])=[O:13])[CH:5]=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33]
Reactant: C[C@@H](O)CN
Reactant: CNC(=O)CNC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Solvent: CN1CCOCC1
Product: Cc1ccc(C(=O)NC[C@@H](C)O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Yield: 55 %

Procedure:
The title compound was prepared by a procedure similar to the one described for 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methyl-N-{1-[(methylamino)carbonyl]methyl}benzamide using (R)-(−)-1-amino-2-propanol (0.16 mL 2.5 mmol) as the amine and without the addition of a second equivalent of N-methylmorpholine. After reverse phase HPLC purification, the organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (377.8 mg, 55%) as beige solid. 1H-NMR (CD3OD, 400 MHz) δ 8.32 (s, 1H), 7.93 (dd, 1H, J=1.6 Hz), 7.77 (d, 1H, J=1.6 Hz), 7.62 (m, 1H), 7.53 (d, 1H, J=8 Hz), 7.01 (m, 2H), 5.60 (q, 2H, J=12.4 Hz), 3.93 (m, 1H), 3.32 (m, 2H), 2.19 (s, 3H), 1.18 (d, 3H, J=6.4 Hz); ES-HRMS m/z 508.0687 (M+H C22H21BrF2N3O4 requires 508.0678).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:4]=2[N:3]1C(OCC1C=CC=CC=1)=O.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]1[CH:42]=[C:41]2[C:36]([CH:37]=[CH:38][C:39]([C:43]#[N:44])=[CH:40]2)=[CH:35][CH:34]=1>CN(C=O)C.C(OCC)(=O)C>[C:43]([C:39]1[CH:40]=[C:41]2[C:36]([CH:35]=[CH:34][C:33]([CH2:32][N:6]3[C:5]4[CH:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:4]=4[NH:3][C:2]3=[O:1])=[CH:42]2)=[CH:37][CH:38]=1)#[N:44]
Reactant: COC(=O)c1ccc2[nH]c(=O)n(C(=O)OCc3ccccc3)c2c1
Reactant: N#Cc1ccc2ccc(CBr)cc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)[nH]c(=O)n2Cc1ccc2ccc(C#N)cc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.7 %

Procedure:
To a chilled solution of methyl 2-oxo-3-(benzyloxycarbonyl)—(3H)—benzimidazole-5-carboxylate (110 mg, 0.337 mmol) in DMF (3 mL) was added cesium carbonate (0.275 g, 0.84 mmol) followed by 7-(bromomethyl)naphthalene-2-carbonitrile (108 mg, 0.44 mmol). The reaction was stirred at room temperature for 1.5 hours, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated in vacuo. This residue was redissolved in methanol (4 mL), CH3CN (3 mL) and IN LiOH (0.7 mL). The reaction mixture was stirred for 1 hour, acidified with 1N HCl (0.7 mL), filtered and dried to yield methyl 1-[(7-cyano(2-naphthyl))methyl]-2-oxo-(3H)—benzimidazole-5-carboxylate (84 mg, 70%) as awhite solid. ES-MS (M+H)+=358.1.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][C:12]2[S:13][C:14]([CH2:17][S:18][C:19]3[CH:20]=[CH:21][C:22]([CH3:28])=[C:23]([CH:27]=3)[C:24](O)=[O:25])=[CH:15][N:16]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[N:31]1[CH:36]=[CH:35][CH:34]=[N:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][C:12]2[S:13][C:14]([CH2:17][S:18][C:19]3[CH:20]=[CH:21][C:22]([CH3:28])=[C:23]([C:24]([N:40]4[CH2:41][CH2:42][N:37]([C:32]5[N:31]=[CH:36][CH:35]=[CH:34][N:33]=5)[CH2:38][CH2:39]4)=[O:25])[CH:27]=3)=[CH:15][N:16]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: Cc1ccc(SCc2cnc(NC(=O)c3ccc(C(C)(C)C)cc3)s2)cc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(SCc2cnc(NC(=O)c3ccc(C(C)(C)C)cc3)s2)cc1C(=O)N1CCN(c2ncccn2)CC1
Temperature: 65 °C
Yield: 63 %

Procedure:
A mixture of the product of Example 32, part B (0.250 g, 0.567 mmol), 1-(2-pyrimidyl) piperazine (0.121 g, 0.737 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (0.476 g, 1.08 mmol), 4-methylmorpholine (0.31 mL, 2.82 mmol) in DMF (6 mL) was heated at 65° C. for 5 h. The mixture was then diluted with ethyl acetate, washed with water, 1N NaOH solution, water, and brine. The solution was dried over anhydrous MgSO4 and concentrated under vacuum. The residue was purified using flash column chromatography (ethyl acetate) to provide the desired product (0.210 g, 63%) as a white solid: LC/MS RT=3.94 min; mass spectrum (M+H)+=587.42.
Reaction SMILES: [CH3:1][CH2:2][O-].[Na+].[CH:5]([O:7][CH2:8][CH3:9])=[O:6].C(OC(=O)CCl)C.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22]([C:25](=[S:27])[NH2:26])=[CH:21][CH:20]=1>CCOCC>[CH2:8]([O:7][C:5]([C:1]1[S:27][C:25]([C:22]2[CH:23]=[CH:24][C:19]([C:18]([F:28])([F:17])[F:29])=[CH:20][CH:21]=2)=[N:26][CH:2]=1)=[O:6])[CH3:9]
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Reactant: CCOC=O
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(=O)CCl
Product: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.6 %

Procedure:
To a solution of NaOEt (21% in EtOH, 215 ml, 584 mmol) were added ethyl formate (46.97 ml, 584 mmol) and then, with cooling (max. 28° C.), chloro acetic acid ethyl ester in Et2O (200 ml). The mixture was stirred at RT for 20 h and filtered after adding Et2O (200 ml). The resulting solid was dissolved in EtOH (400 ml) and after addition of 4-(trifluoromethyl)benzene-1-carbothioamide (11.98 g, 58.4 mmol) stirring to reflux was accomplished for 20 h. After filtration, the EtOH was removed under reduced pressure and extracted with CH2Cl2 (3×)/H2O. The organic phases were washed with H2O, dried (Na2SO4) and evaporated to give crude compound which was crystallized (Et2O/n-pentane) to give 12.43 g (71%) of 2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester as off-white crystals, MS: 301 (M+), MP: 98-110° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[CH:3]=1.[O:31]=[C:32]1[NH:36][C@H:35]([CH2:37][O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:34][O:33]1>>[C:39]([O:38][CH2:37][C@@H:35]1[CH2:34][O:33][C:32](=[O:31])[N:36]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[CH:3]=1)(=[O:46])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4COC(=O)c4ccccc4)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 66.2 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 91 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (986 mg) described in Preparation Example 118 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (487 mg), the title compound (838 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Li]CCCC.CN([CH:17]=[O:18])C>C1COCC1>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:17]=[O:18])[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cccc(Br)n1
Reaction time: 0.75 h
Yield: 28.7 %

Procedure:
To a solution of 5.0 g (21.2 mmol) of 2,6-dibromopyridine in THF at −78° C. was added 9.2 mL (21 mmol) of 2.3 M solution of n-BuLi in hexanes, followed by 2.3 mL (30 mmol) of DMF. The mixture was stirred for 45 min in the cold, quenched with saturated NaHCO3, extracted with ethyl acetate and the product purified by column chromatography (3% ethyl acetate in hexanes) to furnish 1.13 g of 2-bromo-6-formylpyridine.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[O:3]1.[CH3:19]I.Br[C:22]1[CH:23]=[C:24]([NH:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:25]=[C:26]([O:28]CC2C=CC(OC)=CC=2)[CH:27]=1>>[CH3:22][N:13]1[C:14]2[C:10](=[C:9]([B:4]3[O:3][C:2]([CH3:18])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)[CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12]1.[CH3:19][N:13]1[C:14]2[C:10](=[C:9]([C:22]3[CH:27]=[C:26]([OH:28])[CH:25]=[C:24]([NH:38][C:39]4[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=4)[CH:23]=3)[CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12]1
Reactant: CI
Reactant: COc1ccc(COc2cc(Br)cc(Nc3cccnc3)c2)cc1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Product: Cn1ccc2c(-c3cc(O)cc(Nc4cccnc4)c3)cccc21
Product: Cn1ccc2c(B3OC(C)(C)C(C)(C)O3)cccc21

Procedure:
1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole was prepared from 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole and methyl iodide, and was coupled with [3-bromo-5-(4-methoxy-benzyloxy)-phenyl]-pyridin-3-yl-amine in the same manner as described for Example 25. Deprotection was carried out as described for Example 34 to give 3-(1-methyl-1H-indol-4-yl)-5-(pyridin-3-ylamino)-phenol. 1H NMR (400 MHz, CD3OD): δ 8.32 (br s, 1H), 7.98 (br s, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.42-7.36 (m, 1H), 7.34 (d, J=8.2 Hz, 1H), 7.21 (d, J=7.2 Hz, 1H), 7.19-7.17 (m, 1H), 7.08 (dd, J=7.2, 0.8 Hz, 1H), 6.91 (t, J=1.7 Hz, 1H), 6.79-6.77 (m, 1H), 6.62 (t, J=2.0 Hz, 1H), 6.59 (d, J=3.1 Hz, 1H), 3.81 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])O[C:3]1=[O:4].[NH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.C1(C)C(C)=CC=CC=1>O>[CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[N:9]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:3]1=[O:4]
Reactant: CC1CC(=O)OC1=O
Reactant: Nc1ccncc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CC1CC(=O)N(c2ccncc2)C1=O
Reaction time: 3.5 h

Procedure:
The starting material is prepared as follows: The mixture of 28.5 g of 2-methylsuccinic anhydride, 23.5 g of 4-aminopyridine and 350 ml of xylene is refluxed on a water separator while stirring for 3.5 hours. The hot solution is decanted from some gummy residue, cooled, filtered, the residue suspended in 100 ml of boiling isopropanol and filtered off again, to yield the 3-methyl-1-(4-pyridyl)-pyrrolidin-2,5-dione melting at 119°-120°.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[F:12][CH:13]1[CH2:16][NH:15][CH2:14]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[C:3]([C:9]([N:15]2[CH2:16][CH:13]([F:12])[CH2:14]2)=[O:11])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1ncc(F)cc1F
Reactant: FC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ncc(F)cc1F)N1CC(F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.6 %

Procedure:
To a solution of 3,5-difluoropicolinic acid (16.40 g, 103.1 mmol), 3-fluoroazetidine (8.59 g, 114 mmol) and triethylamine (27.70 ml, 199.0 mmol) in 100 mL of DMF was added HATU (45.40 g, 119.0 mmol). The mixture was stirred at room temperature for 3 hr, quenched with water, extracted with 3× EtOAc. The combined organic layer was washed with 2×H2O, dried with Na2SO4, and concentrated to provide an oil that was purified by Biotage eluting with 25-40% EtOAc in hexanes to give a yellow solid (11.49 g, 46.3% yield). 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J=2.53 Hz, 1 H) 7.31-7.46 (m, 1 H) 5.27-5.52 (m, 1 H) 4.62-4.79 (m, 1 H) 4.42-4.59 (m, 2 H) 4.22-4.38 (m, 1 H); MS for C9H7F3N2O m/z 217.00 (M+H)+
Reaction SMILES: [Na].[CH2:2]([OH:4])[CH3:3].[C:5](OCC)(=O)[CH2:6]C(OCC)=O.Cl[C:17]1[CH:30]=[CH:29][C:20]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])=[CH:19][C:18]=1[N+:31]([O-])=O>C(Cl)Cl>[CH2:5]([N:31]1[C:18]2[C:17](=[CH:30][CH:29]=[C:20]([C:21](=[O:22])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=2)[CH2:3][C:2]1=[O:4])[CH3:6]
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCO
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: ClCCl
Product: CCN1C(=O)Cc2ccc(C(=O)c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of sodium ethoxide, formed by reacting 4.6 g. (0.2 mole) of sodium metal with 200 ml. of ethanol, at 0° C. was added 32 g. (0.2 mole) of diethyl malonate followed by 26.1 g. (0.1 mole) of 4-chloro-3-nitrobenzophenone. The mixture was allowed to stir at room temperature for 2 hours and was then poured into 400 ml. of ice cold 2N hydrochloric acid and 300 ml. of methylene chloride. The organic layer was separated, dried over magnesium sulfate and concentrated to an oil. The residual oil was induced to crystallize by trituration with hexane containing trace amounts of diisopropyl ether, 34.75 g., m.p. 68°-70° C. The sample was further purified by trituration with hot hexane-diisopropyl ether, 30.84 g. (80% yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:6][N:7]([CH3:25])[C:8]([N:10]1[C@@H:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH3:24])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:9].C=O.[C:32](OC(OC(=O)C)(OC(=O)C)C(O[BH3-])=O)(=O)C.[Na+]>ClCCCl>[Cl:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:6][N:7]([CH3:25])[C:8]([N:10]1[C@@H:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH3:24])[CH2:15][CH2:14][N:13]([CH3:32])[CH2:12][CH2:11]1)=[O:9]
Reactant: Cc1cc(F)ccc1[C@H]1CCNCCN1C(=O)N(C)Cc1cc(Cl)cc(Cl)c1
Reactant: [BH3-]OC(=O)C(OC(C)=O)(OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1cc(F)ccc1[C@H]1CCN(C)CCN1C(=O)N(C)Cc1cc(Cl)cc(Cl)c1
Yield: 20.6 %

Procedure:
A mixture of example 6 (51 mg), aqueous formaldehyde (33 μL) and sodium triacetoxyacetoxyborohydride (50 mg) in anhydrous 1,2-dichloroethane (2 mL) was stirred at r.t. overnight. The mixture was washed with water (2 mL) and brine (2 mL) and concentrated in vacuo. The residue was purified by flash chromatography (AcOEt 100%) to give 7-(R)-(4-fluoro-2-methyl-phenyl)-4-methyl-[1,4]-diazepane-1-carboxylic acid, (3,5-dichloro-benzyl)-methylamide (10 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=1.N1C=CC=CC=1.[Cl:26][C:27]([Cl:32])([Cl:31])[C:28](Cl)=[O:29].Cl>C1COCC1>[Cl:26][C:27]([Cl:32])([Cl:31])[C:28]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[C:3]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=3)[CH:4]=2)[NH:8][CH:7]=1)=[O:29]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CCOc1ccc(-c2cc3cc[nH]c3cc2Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOc1ccc(-c2cc3c(C(=O)C(Cl)(Cl)Cl)c[nH]c3cc2Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 9 %

Procedure:
To a solution of 6-chloro-5-(4-ethoxyphenyl)-1H-indole (500.0 mg, 1.84 mmol) in anhydrous THF (5 mL) was added pyridine (436.0 mg, 5.52 mmol) and trichloroacetyl chloride (10 mL) at 0° C. under N2. The reaction mixture was stirred at room temperature under N2 for 12 hours. The mixture was poured into 0.5 N HCl (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (9-25% EtOAc/petroleum ether:EtOAc) to give the title compound (70.0 mg, 9%) as a green solid. 1H NMR (400 MHz, CDCl3) δ 8.80 (br, 1 H), 8.40 (s, 1 H), 8.36 (d, J=3.2 Hz, 1 H), 7.59 (s, 1 H), 7.42 (d, 2H), 6.97 (d, 2 H), 4.12 (q, J=7.00 Hz, 2 H), 1.45 (t, J=7.00 Hz, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:10][O:9]1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:9])[CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Fc1ccccc1C1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=Cc1ccc(OCC(O)c2ccccc2F)cc1
Temperature: 78 °C
Yield: 11 %

Procedure:
To a stirring solution of 2-(2-fluorophenyl)oxirane (5.30 g, 38.4 mmol) in toluene (65 ml) was added 4-hydroxybenzaldehyde (7.0 g, 58.0 mmol), 1M NaOH (65 ml) and PEG4000 (polyethylene glycol, 0.85 g) and the stirring mixture was heated at 78° C. overnight. The reaction was allowed to cool to RT and then extracted with EtOAc (2×150 ml). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting light brown oil was adsorbed onto silica gel and chromatographed, eluting with 30-40% EtOAc/hexanes. There are 2 major spots. Fractions containing the higher Rf spot were combined and evaporated in vacuo to give 1.10 g (11%) of the title compound as a colorless oil. Fractions containing the lower Rf spot were combined and evaporated in vacuo to give 0.67 g (7%) of the regioisomer as a colorless oil.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9]C(O)=O)[S:2]1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:20])C=CC=CC=1.C([N:32]([CH2:35]C)CC)C>C1C=CC=CC=1>[S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][N:32]=[C:35]=[O:20])[S:2]1
Reactant: O=C(O)CCCCC1CCSS1
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: O=C=NCCCCC1CCSS1

Procedure:
The reaction of 5-(1,2-dithiolan-3-yl)pentanoic acid and diphenylphosphoryl azide in a solution of triethyl amine and benzene provided a solution comprising 4-(1,2-dithiolan-3-yl)butyl isocyanate (I.R.: 2270 cm-1), which was reacted with 5-fluorouracil to provide 1-[N-[4-(1,2-dithiolan-3-yl)butyl]carbamoyl]-5-fluorouracil substantially in the similar method to that of Example 13.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[O:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](OC)=O.N(CCO)CCO.C1CCCCCCCOC(=O)CCCCCCC1>>[OH:2][CH2:1][CH2:3][NH:4][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][O:5]1
Reactant: COC(=O)CCCCCCCCCCCCCCCOC1CCCCO1
Reactant: NCCO
Agent: O=C1CCCCCCCCCCCCCCCO1
Solvent: OCCNCCO
Product: OCCNCCCCCCCCCCCCCCCCOC1CCCCO1

Procedure:
A reaction was conducted in the same manner as in Preparation Example 37 except that ethanolamine and methyl 16-(2-tetrahydropyranyloxy)hexadecanate were used in place of diethanolamine and cyclohexadecanolide, respectively, in Preparation Example 37, thereby obtaining the title compound (IId-4).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[N:11]([O-])=[O:12].[Na+].CCOC(C)=O>CC(O)=O.O>[N:11]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:12]
Reactant: O=N[O-]
Reactant: c1ccc2c(c1)CCCN2
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=NN1CCCc2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
1,2,3,4-Tetrahydroquinoline (2.12 g, 15.9 mmol) was dissolved in AcOH (30 mL) and water (10 mL). The solution was cooled to 0° C. An aqueous solution of NaNO2 (1.20 g, 17.5 mmol in 3 mL water) was added dropwise. The reaction was warmed to RT and stirred 2 hrs. Water (20 mL) and EtOAc (20 mL) were added. The layers were separated and the aqueous phase was extracted (2×20 mL) with EtOAc. The combined organic layers were washed with brine, dried, and concentrated to afford a crude orange oil (2.62 g). The product was purified by column chromatography (20-40% EtOAc/hexane) to afford 1-nitroso-1,2,3,4-tetrahydroquinoline (2.48 g, 96%) as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ8.07 (d, 1H, J=8.1 Hz), 7.21-7.34 (m, 3H), 3.91 (t, 2H, J=6.2 Hz), 3.81 (t, 2H, J=6.2 Hz), 1.97-2.05 (m, 2H) ppm.