Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[CH:2]1([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([CH2:15][O:14][CH:2]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OC1CCCCCCCCCCC1
Reactant: ClCc1ccccc1
Agent: [H-]
Product: c1ccc(COC2CCCCCCCCCCC2)cc1
Temperature: 125 °C

Procedure:
The hydride was mixed, under an argon atmosphere and by mechanical stirring, with cyclododecanol (130.0 g. 0.71 mol) and benzyl chloride (650.0 g, 5.14 mol). The reaction mixture was heated to 125° C. The mixture became very viscous when the temperature reached between 60° and 70° C. A mild exotherm was observed at about 100° C. which resulted in a marked viscosity decrease. If an efficient reflux condenser is not used, some external cooling may be necessary during the mild exotherm. The internal flask temperature increased to about 120° C. over ten minutes. The reaction flask was heated at 120° to 125° C. for an additional hour and then it was cooled to 25° C. The excess hydride was carefully destroyed by the addition of 100 mL of 95% ethanol under an argon atmosphere. The mixture was treated with 500 mL of aqueous saturated sodium chloride solution and extracted with three 400 mL portions of hexane. The organic layer was collected, washed with two 100 mL portions of water and two 100 mL portions of aqueous sodium chloride solution. The product mixture was dried over magnesium sulfate, filtered, and concentrated at 50° C. and 15 mm. The product was distilled at 144°-146° C./0.2 mm to give (180.7 g) 93.0% of the theoretical yield. Gas chromatography ("GC") showed that the product was 99% of a single component, IR (neat, cm-1) 2930, 2865, 1475, 1455, 1095 (C-O-C), 1070, 740; 13C NMR (ppm CDC13) 139.31, 128.17, 127.54, 127.21, 76.26 (α-ring carbon), 70.22 (α-chain carbon), 28.91, 24.75, 24.31, 23.30, 23.19, 20.81; MS, m/z (relative intensity) 274 (M+, 1.5), 245(0.1), 230(0.4), 183(8.2), 174(0.9),160(1.0), 145(0.8), 133(2.3), 118(2.7), 104(10.4), 91(100), 81(3.2), 65(12.7), 56(2.1). Anal calcd for C19H30O:C,83.15;H,11.02. Found: C,83.33;H,11.18.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:29])[C:5]([CH3:21])([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Reaction time: 20 h
Yield: 89.3 %

Procedure:
2-Phenoxy-3-(4-benzyloxyphenyl)-2-methyl-propionic acid ethyl ester (830 mg, 2.1 mmol) was dissolved in ethyl acetate (30 mL) and treated with 5% palladium on carbon (300 mg), and then stirred under an atmosphere of hydrogen for 20 h. The suspension was filtered through celite and concentrated in vacuo to produce 3-(4-hydroxyphenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester colorless oil (563 mg, 89%) 1H NMR (300 MHz, CDCl3): δ 7.23 (t, 2H), 7.13 (d, 2H), 6.96 (t, 1H), 6.83 (d, 2H), 6.76 (d, 2H), 4.19 (q, 1H, J=7.1), 3.23 (d, 1H, J=12.4), 3.08 (d, 1H, J=12.4), 1.39 (s, 3H), 1.22 (t, J=7.1). MS [EI+] 318 (M+H)+, [EI−] 359 (M+OAc−).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9](=[O:49])[CH2:10][C:11]1[C:12]([CH2:17][CH2:18][C:19]2[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][N:22]=[C:21]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([CH:36]4[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]4)=[CH:32][CH:31]=3)[N:20]=2)=[N:13][CH:14]=[CH:15][CH:16]=1>C(Cl)Cl.C1CCCCC1>[NH:39]1[CH2:40][CH2:41][CH:36]([C:33]2[CH:34]=[CH:35][C:30]([NH:29][C:21]3[N:20]=[C:19]([CH2:18][CH2:17][C:12]4[C:11]([CH2:10][C:9]([NH2:8])=[O:49])=[CH:16][CH:15]=[CH:14][N:13]=4)[C:24]([C:25]([F:28])([F:26])[F:27])=[CH:23][N:22]=3)=[CH:31][CH:32]=2)[CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncccc4CC(N)=O)n3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Product: NC(=O)Cc1cccnc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 23 h
Yield: 66.6 %

Procedure:
Trifluoroacetic acid (0.337 mL, 4.40 mmol) was added to a solution tert-butyl 4-(4-((4-(2-(3-(2-amino-2-oxoethyl)pyridin-2-yl)ethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I124) (64.3 mg, 0.110 mmol) in dry DCM (15 mL) under an atmosphere of nitrogen and the reaction was stirred at room temperature for 23 hours. The volatiles were removed in vacuo and the residue partitioned between EtOAc (40 mL) and 2 M NaOH (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were washed with water (40 mL), brine (40 mL) and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give a yellow solid which was suspended in DCM (5 mL) and cyclohexane (15 mL). The precipitate was filtered to afford the title compound (32) (35.5 mg, 53%) as yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.05 (s, 1H), 8.64 (s, 1H), 8.36 (dd, J=4.8, 1.7 Hz, 1H), 7.62-7.55 (m, 3H), 7.53 (s, 1H), 7.18 (dd, J=7.6, 4.8 Hz, 1H), 7.15 (d, J=8.6 Hz, 2H), 7.00 (s, 1H), 3.53 (s, 2H), 3.24 (s, 4H), 3.02 (d, J=11.9 Hz, 2H), 2.61-2.52 (m, peaks obscured by solvent), 1.67 (d, J=11.3 Hz, 2H), 1.49 (qd, J=12.2, 3.8 Hz, 2H). LCMS Method C: rt 1.50, 1.59 min; m/z 485 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[C:6]2[NH:14][C@H:13]([C:15]([F:18])([F:17])[F:16])[CH2:12][CH2:11][N:7]2[C:8](=[O:10])[CH:9]=1.Br.Br[CH2:21][C:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:23]>CN(C=O)C>[Cl:3][C:4]1[N:5]=[C:6]2[N:14]([CH2:21][C:22](=[O:23])[C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[C@H:13]([C:15]([F:16])([F:17])[F:18])[CH2:12][CH2:11][N:7]2[C:8](=[O:10])[CH:9]=1
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: O=C(CBr)c1cccnc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F)c1cccnc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A suspension of 750 mg (15.77 mmol) of sodium hydride in 50 mL of DMF is cooled to 0° C. under argon. A solution of 2 g (7.89 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 50 mL of DMF is added dropwise. The mixture is stirred for 10 minutes at room temperature. After cooling the reaction medium to 0° C., 2.92 g (9.86 mmol) of 3-(bromoacetyl)pyridine hydrobromide are added portionwise. The reaction mixture is allowed to warm to room temperature and is stirred overnight. The reaction medium is evaporated to dryness and the residue is taken up in water and extracted with EtOAc. The organic phase is dried over magnesium sulfate and evaporated to dryness. The crude product obtained is purified by chromatography on silica gel (eluent: 100% EtOAc). After evaporating the fractions under reduced pressure, 1.90 g of (8S)-2-chloro-9-(2-oxo-2-pyrid-3-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1([C:12]#[N:13])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[NH2:14][OH:15]>>[Cl:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1([C:12](=[NH:13])[NH:14][OH:15])[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1
Reactant: NO
Reactant: N#CC1(COCCCl)CCOCC1
Product: N=C(NO)C1(COCCCl)CCOCC1
Yield: 84 %

Procedure:
Reaction of 4-((2-chloroethoxy)methyl)tetrahydro-2H-pyran-4-carbonitrile (10.78 g, 52.9 mmol) with hydroxylamine gave 10.59 g (84% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.60 (2H, m, CH2), 2.04 (2H, m, CH2), 3.52 (2H, s, CH2), 3.55-3.85 (8H, m, 4×CH2), 5.01 (2H, broad s). MS (ESI+) m/e 237 [M+H+].
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19]C(=O)C)=[CH:15][CH:14]=2)=[C:7]([NH2:23])[CH:6]=1)(=O)C.Cl.[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[C:29](Cl)=O>>[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[CH2:29][NH:23][C:7]1[CH:6]=[C:5]([OH:4])[CH:10]=[CH:9][C:8]=1[CH:11]=[CH:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)c(F)c1
Reactant: CC(=O)Oc1ccc(C=Cc2ccc(OC(C)=O)cc2N)cc1
Agent: Cl
Product: Oc1ccc(C=Cc2ccc(O)cc2NCc2ccc(OCCN3CCCCC3)c(F)c2)cc1
Yield: 20 %

Procedure:
Synthesized from acetic acid 4-[2-(4-acetoxy-2-aminophenyl)vinyl]phenyl ester (300 mg) and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoyl chloride hydrochloride (370 mg) according to an analogous synthetic method to Example 152, the title compound (89 mg) was obtained.
Reaction SMILES: [OH:1][C@H:2]([C@@H:8]([OH:35])[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=3)=[CH:20][CH:19]=2)[CH:10]=1)[C:3]([O:5]CC)=O.[NH3:36]>>[OH:1][C@H:2]([C@@H:8]([OH:35])[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:27][N:26]=3)=[CH:20][CH:19]=2)[CH:10]=1)[C:3]([NH2:36])=[O:5]
Reactant: N
Reactant: CCOC(=O)[C@H](O)[C@@H](O)c1cn(-c2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)c2ccccc12
Product: NC(=O)[C@H](O)[C@@H](O)c1cn(-c2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)c2ccccc12

Procedure:
(2R,3S)-2,3-Dihydroxy-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propanamide (5) was prepared as follows: A solution of compound 4 (100 mg) and NH3 (in MeOH ˜7N, 6 mL) was shaken at room temperature for 72 hours. The solvent was evaporated, and the residue was purified by column (EtOAc/MeOH 8/1.5) to afford compound 5 as a white solid (70 mg): 1H-NMR (400 MHz, CD3OD) δ: 8.49 (s, 1H), 8.06 (1H, dd, 2.6 & 8.7 Hz), 7.82 (1H, d, 7.8 Hz), 7.56-7.65 (m, 4H), 7.38-7.41 (m, 2H), 7.15-7.25 (m, 3H), 5.51 (dd, 1H, 0.8 & 2.6 Hz), 4.37 (1H, d, 2.6 Hz); LC/MS: m/z=480.2 [M+Na+] (Calc: 457.4).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH2:27][CH:28]=O)=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH2:33]([NH2:35])[CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl.O1CCCC1.C(O)(=O)C>[CH2:33]([NH:35][CH2:28][CH2:27][C:24]1[CH:23]=[CH:22][C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]2)=[CH:26][CH:25]=1)[CH3:34]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CC=O)cc4)cc23)CC1
Reactant: CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CCNCCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.3 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(2-oxoethyl)phenyl]-1H-indole-7-carboxamide (50 mg, 0.11 mmol) in methanol (5 mL) and methylene chloride (5 mL) at room temperature was added 2 M ethylamine in tetrahydrofuran (0.4 mL), followed by 1 drop of acetic acid. The reaction was stirred at room temperature for 2 h followed by an addition of sodium triacetoxyborohydride (200 mg, 0.94 mmol). This reaction was stirred overnight. It was then purified by flash chromatography to give 15 mg of the title compound (28.3%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1([C:38]2[C:39]([O:44][CH2:45][CH3:46])=[N:40][CH:41]=[CH:42][CH:43]=2)[C:20]2[C:15](=[CH:16][C:17]([F:23])=[C:18]([C:21]#[N:22])[CH:19]=2)[N:14]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=2[O:35][CH3:36])(=[O:26])=[O:25])[C:13]1=[O:37]>N1C=CC=CC=1>[C:21]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[F:23])[N:14]([S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[O:35][CH3:36])(=[O:25])=[O:26])[C:13](=[O:37])[C:12]2([NH:11][C:2](=[O:3])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:38]1[C:39]([O:44][CH2:45][CH3:46])=[N:40][CH:41]=[CH:42][CH:43]=1)#[N:22]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOc1ncccc1C1(N)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2cc(F)c(C#N)cc21
Solvent: c1ccncc1
Product: CCOc1ncccc1C1(NC(=O)Oc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2cc(F)c(C#N)cc21
Reaction time: 0.08 h
Yield: 71.9 %

Procedure:
61 μl (0.49 mmol) of phenyl chloroformate were slowly added dropwise to a solution, cooled to 0° C., of 226 mg (0.44 mmol) of 3-amino-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile in 4 ml of pyridine. After 5 minutes, the solvent was evaporated. The residue was mixed with 20 ml of water and extracted with diethyl ether (2×). The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (Redisep cartridge, mobile phase gradient from 0 to 5% methanol in ethyl acetate). 200 mg of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Na+].Br[CH2:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18]>C(COC)OC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: [Na+]
Solvent: COCCOC
Product: N#Cc1cccc(CS(=O)(=O)c2ccc(Cl)cc2)c1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
A dimethoxyethane (15 ml) suspension of sodium 4-chlorobenzenesulfinate (270 mg, 1.36 mmol) and 3-bromomethylbenzonitrile (222 mg, 1.13 mmol) was stirred at 70° C. for 3 days. After cooling the reaction mixture to room temperature, the solvent was concentrated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed successively with water and brine and then, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column and the fraction obtained from the hexane:ethyl acetate (=3:1) eluate was concentrated under reduced pressure, whereby the title compound (318 mg, 96%) was obtained as a white solid.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[CH2:15][N:14]([S:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][N:11]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:36])([CH3:35])[C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1)C1C=CC=CC=1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[CH3:44][S:45]([O:8][CH2:9][CH:10]1[CH2:15][N:14]([S:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:18])[CH2:13][CH2:12][N:11]1[C:24]1[CH:25]=[CH:26][C:27]([C:30]([OH:36])([CH3:35])[C:31]([F:34])([F:32])[F:33])=[CH:28][CH:29]=1)(=[O:47])=[O:46]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2COCc2ccccc2)cc1)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2COS(C)(=O)=O)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
A 25-mL round bottomed flask was charged with 1,1,1-trifluoro-2-(4-(2-(hydroxymethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (400 mg, 0.888 mmol, Example 44), triethylamine (136 μL, 0.977 mmol) and CH2Cl2 (5 mL). After cooling to 0° C., methanesulfonyl chloride (69.2 μL, 0.888 mmol) was slowly added via syringe. The reaction was then warmed to room temperature and stirred for 3 h. After this time, the mixture was concentrated and the crude material was purified by column chromatography (12 g silica gel, 5%-80% (10% MeOH—CH2Cl2) in CH2Cl2) to give (4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (403 mg) as a colorless foam.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[S:4][CH:5]=[C:6]([CH:8]2[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)[N:7]=1.[C:16]([CH:20]=[C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](=O)[CH3:31])=[CH:25][CH:24]=1)[CH3:22])([O:18][CH3:19])=[O:17]>>[C:16]([CH:20]=[C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([N:10]2[CH2:11][CH2:12][O:13][CH:8]([C:6]3[N:7]=[C:3]([C:2]([F:14])([F:1])[F:15])[S:4][CH:5]=3)[CH2:9]2)[CH3:31])=[CH:25][CH:24]=1)[CH3:22])([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C=C(C)c1ccc(CC(C)=O)cc1
Reactant: FC(F)(F)c1nc(C2CNCCO2)cs1
Product: COC(=O)C=C(C)c1ccc(CC(C)N2CCOC(c3csc(C(F)(F)F)n3)C2)cc1

Procedure:
Prepared analogously to Example 13 by reaction of 2-(2-trifluoromethyl-thiazol-4-yl)morpholine with 1-[4-(2-carbomethoxy-1-methylethenyl)phenyl]propan-2-one followed by purification of the base on a silica gel column using chloroform/ethyl acetate=19:1 as eluant.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>N1C=CC=CC=1>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:6]2[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]2=[O:8])=[O:19])=[CH:13][CH:12]=1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)cc1)n1cc(F)c(=O)[nH]c1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 58.2 %

Procedure:
A solution of 5-fluorouracil (2.6 g.) in pyridine (25 ml.) was added to 4-chlorophenyl isocyanate (3.07 g.) and the solution was stirred at 80° C. for 4 hours. The resultant solution was allowed to stand overnight in a refrigerator. The crystalline precipitates were collected by filtration, washed successively with ethyl acetate, diethyl ether, and then dried to give 1-[N-(4-chlorophenyl)carbamoyl]-5-fluorouracil (3.30 g.); colorless crystalline powder.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=1)[OH:11].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:12]1[CH:13]=[C:14]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[CH:15]=[CH:16][CH:17]=1)[OH:11]
Reactant: COc1ccc(B(O)O)cc1
Reactant: OC(c1cccc(Br)c1)c1nc2ccccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cccc(C(O)c3nc4ccccc4s3)c2)cc1
Temperature: 25 °C

Procedure:
A mixture of benzothiazol-2-yl(3-bromophenyl)methanol (200 mg), 4-methoxy-phenylboronic acid (142 mg), tetrakis(triphenylphosphine)palladium (50 mg), potassium carbonate (259 mg), water (4 mL), ethanol (1 mL) and toluene (9 mL) is purged with argon and refluxed for one night. After cooling at room temperature, the mixture is diluted with water and diethylether. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography (heptane/ethyl acetate 2/1) to afford benzothiazol-2-yl(4′-methoxybiphenyl-3-yl)methanol as a beige solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]1[C@@H:10]([CH2:11][O:12][C:13](=[O:16])[CH2:14][CH3:15])[O:9][C@@H:8]([N:17]2[CH:24]=[C:23]([F:25])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:7]1)(=[O:4])[CH2:2][CH3:3].C(N(CC)CC)C.[CH3:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37]>O1CCOCC1>[CH3:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36]([N:20]1[C:21](=[O:22])[C:23]([F:25])=[CH:24][N:17]([C@@H:8]2[O:9][C@H:10]([CH2:11][O:12][C:13](=[O:16])[CH2:14][CH3:15])[C@@H:6]([O:5][C:1](=[O:4])[CH2:2][CH3:3])[CH2:7]2)[C:18]1=[O:19])=[O:37]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(=O)CC
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3ccccc3C)c2=O)C[C@@H]1OC(=O)CC
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
2.0 Grams of 2'-deoxy-3',5'-di-O-propionyl-5-fluorouridine are dissolved in 25 ml of dry dioxane and the solution is ice cooled. 2 Milliliters of triethylamine and 1.7 g of 2-methylbenzoyl chloride are added to the solution and the mixture is subjected to reaction at room temperature for 15 minutes and then at 70° C. for 30 minutes. The reaction liquid is cooled and triethylamine hydrochloride is filtered off. The filtrate is concentrated under reduced pressure and the oily residue is purified by column chromatography on silica gel (elution solvent: chloroform). The The purified oily substance is dissolved in about 15 ml of dimethyl sulfoxide and the solution is added dropwise to about 400 ml of ice water under vigorous agitation whereupon a precipitate is formed. The resultant precipitate is collected by filtration, washed with water and dried at room temperature under reduced pressure whereby 1.5 g (yield: 56.4%) of powdery 3-(2-methylbenzoyl)-2'-deoxy-3',5'-di-O-propionyl-5-fluorouridine are obtained.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH2:13]([C@@H:15]1[O:17][CH2:16]1)Cl>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.CO>[CH2:13]([C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6])[C@H:15]1[O:17][CH2:16]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClC[C@H]1CO1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [K]
Solvent: CO
Product: O=C1NC(=O)c2c(C[C@@H]3CO3)cccc21
Temperature: 20 °C
Reaction time: 15 h
Yield: 68.2 %

Procedure:
Into a reaction vessel were put potassium phthalimide (5.00 g, 27.0 mmol), benzyltrimethylammonium chloride (0.50 g, 2.70 mmol) and methanol (50 ml) and then thereto was added (R)-epichlorohydrin (9.99 g, 81.0 mmol). The mixture was stirred at 20° C. for 15 hours and the solvent was removed. To the residue was added ethyl acetate (30 ml), the mixture was washed with water (20 ml) and ethyl acetate was removed to give crude (R)-glycidylphthalimide (3.74 g, yield: 68%, optical purity: 99% e.e.) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:25][CH2:26][CH2:27][C:28]#[N:29])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24])=[CH:10][CH:9]=2)=O)C.[BH4-].[Li+]>C1COCC1>[Cl:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([Cl:23])[C:17]=1[CH2:16][O:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:25][CH2:26][CH2:27][C:28]#[N:29])[C:6]([CH2:4][OH:3])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(OCc3c(Cl)cccc3Cl)ccc2n1CCCC#N
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CCCCn1c(CO)cc2cc(OCc3c(Cl)cccc3Cl)ccc21
Yield: 95.8 %

Procedure:
To a solution of 1-(3-cyanopropyl)-5-(2,6-dichlorobenzyloxy)-1H-indole-2-carboxylic acid ethyl ester (2.0 g, 4.64 mmol), from Example 1(c), in THF (20 mL) at room temperature was added lithium borohydride (0.25g, 11.6 mmol). The reaction was refluxed for 20 h and then quenched slowly by adding methanol until the evolution of gas ceased. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over Na2SO4. Filtration and evaporation of the solvent yielded the desired alcohol as a white solid (1.73 g, 96%). MS(ES) m/e 389.0 [M+H]+.