Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.[BH3-]C#N.[Na+].Cl>C(O)C>[N:18]1([CH2:17][CH2:16][C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[CH:8]=3)[NH:12][CH:11]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: C1=COC(c2ccc3[nH]cc(CCN4CCCC4)c3c2)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: c1cc2[nH]cc(CCN3CCCC3)c2cc1C1CCCCO1
Reaction time: 3 h
Yield: 58.9 %

Procedure:
To a solution of 5-(2,3-dihydropyran-2-yl)-3-(2-pyrrolidinylethyl)-1H-indole (Example 20b, 0.049 g, 0.165 mmol) in absolute ethanol (5 mL) was added NaBH3CN (0.496 mmol) and methanolic HCl [prepared from acetyl chloride (2 mL) and methanol (10 mL)] alternately. The mixture was allowed to stir for 3 hours at which time the reaction was quenched with sodium bicarbonate (sat.) and the product was extracted three times with CH2Cl2. The organic layer was dried (NaSO4), filtered and concentrated. The crude product was purified by column chromatography (7% NH3 in CH2Cl2) to yield the title compound 0.029 g, 59%) as a clear oil; HRMS-FAB+ for C19H26N2O: calc. MH+ : 99.2123; found MH+ :299.2159.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:31][OH:32]>>[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:31][O:32][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: OCc1ccc(F)c(F)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3ccc(F)c(F)c3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.184 mmol), intermediate 42.1, and 3,4-difluorobenzyl alcohol (108 mg; 0.736 mmol), example 86 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O-:28])=[O:27])=[CH:22][CH:21]=1.[Na+]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=3)[O:6][C:7]=2[CH3:8])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=S([O-])c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Agent: [Na+]
Product: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(Cl)cc3)c(C)o2)cc1
Yield: 67.3 %

Procedure:
Method A. Reaction of chloride 2 (268 mg, 1.0 mmol) and sodium 4-chlorobenzenesulfinate (198 mg, 1.0 mmol) gave benzoate 19 (273 mg, 67%) as a white powder: mp (EtOAc) 186-188° C.; 1H NMR (CDCl3) δ 8.08 (ddd, J=8.7, 1.9, 1.6Hz, 2 H, H-2, H-6), 7.90 (ddd, J=8.7, 1.9, 1.6Hz, 2 H, H-3, H-5), 7.74 (ddd, J=8.7, 2.4, 2.0Hz, 2 H, H-2′, H-6′), 7.49 (ddd, J=8.7, 2.4, 2.0Hz, 2 H, H-3′, H-5′), 4.32 (s, 2 H, CH2SO2), 3.94 (s, 3 H, OCH3), 2.37 (s, 3 H, CH3); MS m/z 407.0 (MH+, 100%), 409.0 (MH+, 35%). Anal. calcd for C19H16ClNO5S: C, 56.23; H, 3.97; N, 3.45. Found: C, 56.11; H, 3.80; N, 3.35%.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[CH:13][CH:14]=2)[C:9]1=[O:19])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[CH:13][CH:14]=2)[C:9]1=[O:19]
Reactant: CC=CCC1Cc2ccc(OC)cc2C1=O
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)C(CC=O)C2
Reaction time: 1.33 h
Yield: 83 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 80 minutes while stirring through a solution, cooled to -70°, of 15.2 g of (RS)-2-(2-buten-1-yl)-6-methoxy-1-indanone in 250 ml of anhydrous dichloromethane and 50 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 7.75 ml of dimethyl sulfide, the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in a vacuum, the residue was treated with 250 ml of dichloromethane and, after the addition of 25 ml of water and 25 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 150 ml of water and neutralized while stirring by the spatula-wise addition of sodium hydrogen carbonate. An additional 100 ml of water were added, the phases were separated and the aqueous phase was extracted twice with 150 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate, concentrated in a vacuum and the crude product obtained was crystallized from diethyl ether/hexane. 12 g (83%) of (RS)-2-(2-oxoethyl)-6-methoxy-1-indanone were obtained as a light yellow solid with m.p. 59°.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.[OH-].[Na+]>O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: OCCCCOc1ccc2ccccc2c1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCCCOc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 4-[(2-naphthalenyl)oxy]butanol (2.4 g), 1.6-dibromohexane (5.3 ml), TAB (1 g) and 50% sodium hydroxide solution (24 ml) was stirred at room temperature for 19 h. The mixture was diluted with water (100 ml) and extracted with ether (2×150 ml). The combined organic fractions were dried and evaporated in vacuo to give an oil. Purification by FCC eluting with hexane followed by hexane-ether (19:1→8:1) gave the title compound as a colourless oil, (2.34 g), t.l.c. (ether-hexane 1:1) Rf 0.85.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([OH:8])[CH2:5][CH:6]=[CH2:7].[C:16]1([N:22]2[CH2:27][CH2:26][CH:25]([CH2:28][NH2:29])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[I-].[K+].CN(C=O)C>CCOC(C)=O>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]([OH:8])([CH2:5][CH:6]=[CH2:7])[CH2:3][CH2:2][NH:29][CH2:28][CH:25]2[CH2:24][CH2:23][N:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:27][CH2:26]2)=[CH:10][CH:11]=1
Reactant: NCC1CCN(c2ccccc2)CC1
Reactant: C=CCC(O)(CCCl)c1ccc(F)cc1
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCC(O)(CCNCC1CCN(c2ccccc2)CC1)c1ccc(F)cc1
Temperature: 80 °C
Yield: 66 %

Procedure:
1-Chloro-3-(4-fluorophenyl)hex-5-en-3-ol (223 mg, 0.97 mmol), (1-phenylpiperidin-4-yl)methanamine (295 mg, 1.6 equiv.), potassium iodide (178 mg, 1.1 equiv.) and DIEPA (186 μL, 1.1 equiv.) were mixed with DMF (5 mL) and heated at 80° C. for overnight. The mixture was diluted with EtOAc (50 mL), washed by water (2×15 mL), brine (2×10 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography on a 12-g silica gel cartridge eluted with a 0˜20% methanol in CH2Cl2 gradient to afford 3-(4-fluorophenyl)-1-((1-phenylpiperidin-4-yl)methylamino)hex-5-en-3-ol (245 mg. 66%).
Reaction SMILES: [C:1]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:2][C:3]([CH2:10][C:11]([O:13]CC)=[O:12])([C:5]([O:7][CH2:8][CH3:9])=[O:6])[OH:4].[OH-].[Na+]>C(O)C.O>[OH:4][C:3]([C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH2:2][C:1]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)CC(O)(CC(=O)OCC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(O)(CC(=O)O)C(=O)OCC
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 28.6 %

Procedure:
A solution of triethyl citrate (34.1 g, 123 mmol) in ethanol and water (30 ml) is treated with sodium hydroxide (3.70 g, 92.6 mmol) and stirred at room temperature under argon for 4.5 hours. The reaction mixture is concentrated on a rotary evaporator then diluted with water (50 ml). The pH is adjusted to ca. 1 using 2N HCl. The aqueous solution is then extracted with a large excess of chloroform (4×150 ml). The combined organic layers are dried (MgSO4), filtered and concentrated to give crude oil. Purification by flash chromatography (5% MeOH/CH2Cl2 to 1% AcOH/5%MeOH/CH2Cl2) gives 8.72 g of product (38% as a racemate.
Reaction SMILES: [C:1]([C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:34]=[CH:33][C:23]([O:24][CH:25]([CH2:31][CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][O:38][NH2:39]>>[CH3:37][O:38][N:39]=[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][CH:25]([CH2:31][CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:33][CH:34]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1
Reactant: CON
Reactant: CCOC(=O)C(CC)Oc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Product: CCOC(=O)C(CC)Oc1ccc(OCCn2c(=O)sc3cc(C(=NOC)c4ccccc4)ccc32)cc1

Procedure:
Starting from the compound obtained in Step A, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-methylhydroxylamine.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH2:24]([O:23][C:21](=[O:22])[C:20]1[CH:26]=[CH:27][CH:28]=[C:18]([O:16][CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[CH:19]=1)[CH3:25]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(OCCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
N-Boc-4-piperidine ethanol (15 g, 65 mmol) and ethyl 3-hydroxybenzoate (11 g, 65 mmol) were dissolved in dry THF (750 ml) under N2. To this was added tri-n-butylphosphin (24 ml, 98 mmol) and ADDP (25 g, 98 mmol) resulting in a suspension, which was stirred overnight at 20° C. The mixture was concentrated in vacuo to 100 ml, filtered, and the filtrate was evaporated with silica gel. Flash chromatography (EtOAc/heptane 1:4) afforded 24 g of the title compound. LC-MS (m/z): 401 (M+23).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[CH2:16]([O:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1ncccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ncccc1OCc1ccccc1
Yield: 82.8 %

Procedure:
A suspension of 3-hydroxypicolinonitrile (3.00 g, 25.0 mmol), which was prepared according to “Synthesis” 316 (1983) and “J. Org. Chem.” 48 1375 (1983), potassium carbonate (5.40 g, 39.1 mmol) and benzyl bromide (5.10 g, 29.8 mmol) in acetone (150 mL) was stirred at room temperature for 20 hrs. The reaction mixture was filtrated and the filtrate was evaporated. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane=1/3 to 1/2) followed by recrystallization from ethyl acetate/n-hexane=1/4 to give 3-benzyloxypicolinonitrile as a colorless solid (4.354 g, yield; 83%).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@@H:2]1[C:7]([OH:9])=[O:8].[CH3:10][CH2:11]O>S(=O)(=O)(O)O>[O:6]=[C:5]1[NH:1][C@@H:2]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:4]1
Reactant: O=C1CC[C@H](C(=O)O)N1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@H]1CCC(=O)N1

Procedure:
To a solution of D-pyroglutamic acid (compound I-A, 20.4 g, 0.16 mol) in 100 mL of EtOH, 1.2 mL of conc. sulfuric acid was added. The mixture was heated under reflux overnight. Solvent was removed under reduced pressure to give (R)-ethyl 5-oxopyrrolidine-2-carboxylate (compound II-AA).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:11][CH2:10][CH:9]2[CH:7]([CH2:8]2)[C:6]1([C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]([F:20])[CH:14]=1)[OH:12])[CH3:3].[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=[O:24].C(N(CC)CC)C>C(Cl)Cl>[CH3:3][N:2]([CH2:4][CH:5]1[CH2:11][CH2:10][CH:9]2[CH:7]([CH2:8]2)[C:6]1([C:13]1[CH:18]=[C:17]([O:19][C:23](=[O:24])[C:22]([CH3:27])([CH3:26])[CH3:21])[CH:16]=[C:15]([F:20])[CH:14]=1)[OH:12])[CH3:1]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CN(C)CC1CCC2CC2C1(O)c1cc(O)cc(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CC1CCC2CC2C1(O)c1cc(F)cc(OC(=O)C(C)(C)C)c1
Yield: 59.2 %

Procedure:
Stir a mixture of 3-dimethylaminomethyl-2-(3-fluoro-5-hydroxy-phenyl)-bicyclo[4.1.0]heptan-2-ol (295 mg, 1.06 mmol), 2,2-dimethyl-propionyl chloride (153 mg, 1.27 mmol) and triethyl-amine (321 mg, 3.18 mmol) in CH2Cl2 (40 mL) at ambient temperature for 5 hours. Quench the mixture with 10 mL of H2O, Separate the aqueous layer off, and concentrate the organic layer under reduced pressure. Purify the residue by preparative TLC to give 2,2-dimethyl-propionic acid 3-(3-dimethylaminomethyl-2-hydroxy-bicyclo[4.1.0]hept-2-yl)-5-fluoro-phenyl ester as white solid (228 mg, Yield: 59.2%). MS (m/z): 364 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.25-7.28 (d, J1=10.4, J2=1.6, 1H), 7.14 (s, 1H), 6.76-6.78 (d, J1=9.2, J2=2.4, 1H), 2.37-2.46 (m, 1H), 2.15-2.19 (m, 7H), 1.99-2.03 (d, J=13.2, 1H), 1.82 (m, 2H), 1.53-1.68 (m, 2H), 1.37 (s, 9H), 1.17 (m, 1H), 1.01-1.06 (m, 1H), 0.75-0.81 (m, 1H), 0.48-0.50 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]([Mg]Br)([CH3:13])=[CH2:12].[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:8][C:11]([CH3:13])=[CH:12]2
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: C=C(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc2cccc(Br)c2[nH]1
Temperature: -55 °C
Reaction time: 1 h

Procedure:
27.0 g of 2-bromonitrobenzene are placed in 400 ml of THF. The mixture is placed under nitrogen and cooled to −55° C. and then 800 ml of isopropenylmagnesium bromide at 0.5 M in THF are added dropwise. The mixture is left with stirring for 1 hour and then poured into saturated NH4Cl solution. It is extracted with ether, the extract is evaporated and then the residue is taken up in DCM. It is washed with saturated NaCl solution. It is dried and evaporated and then the residue is chromatographed on silica, eluting with an AcOEt/cyclohexane (1/9; v/v) mixture. This gives 10.7 g of the expected compound.
Reaction SMILES: Cl.[S:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[C:3]1[CH:11]=[O:12].[C:13](Cl)(=[O:15])[CH3:14]>C(Cl)Cl>[C:13]([N:7]1[CH2:8][CH2:9][C:10]2[S:2][C:3]([CH:11]=[O:12])=[CH:4][C:5]=2[CH2:6]1)(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: O=Cc1cc2c(s1)CCNC2
Agent: Cl
Solvent: ClCCl
Product: CC(=O)N1CCc2sc(C=O)cc2C1
Yield: 71.4 %

Procedure:
To a cold (0° C.) suspension of 1.5 g.(7.4 mmol) of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carbaldehyde hydrochloride in 50 mL methylene chloride, under N2 atm., dry conditions, was added dropwise under stirring 2.6 mL (2.5 eqs) of triethylamine. RM stirred for 30 min at 0°C. and a solution of 0.7 g.(8.1 mmol,1.1 eqs) of acetyl chloride in 15 mL methylene chloride was dropwise added, RM allowed to reach RT and stirred for 3 hours. Filtered trough a celite pad, filtrate washed with 3×50 mL water, dried, evaporated, gave 1.1 g.(71.4%) of the title compound, viscous oil, (M+H)+210.3.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[C:8](OC)=[O:9].CO.O>COCCOC>[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[CH2:8][OH:9]
Reactant: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: COCCOC
Product: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reaction time: 1 h

Procedure:
At room temperature, sodium borohydride (35.7 mg) was suspended in 1,2-dimethoxyethane (0.2 ml). Then a solution (0.8 ml) of methyl (2S)-2-(2,3,4-trifluoroanilino)propionate (200 mg, 99.8% ee) in DME was added to the solution. After adding methanol (137.4 mg), the liquid reaction mixture was stirred for 1 hour. Then water was added to the liquid reaction mixture followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography to thereby give 176 mg (99.8% ee) of the title compound as an oily substance. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 51.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([CH2:48][CH2:49][C:50]([N:52]2[CH2:57][CH2:56][N:55]([CH2:58][CH2:59][OH:60])[CH2:54][CH2:53]2)=[O:51])[CH:45]=[CH:46][CH:47]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[C:44]([CH2:48][CH2:49][C:50]([N:52]6[CH2:53][CH2:54][N:55]([CH2:58][CH2:59][OH:60])[CH2:56][CH2:57]6)=[O:51])[CH:45]=[CH:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: O=C(CCc1cccc(Br)c1)N1CCN(CCO)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(CCC(=O)N4CCN(CCO)CC4)c3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (200 mg) and 3-(3-bromo-phenyl)-1-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propan-1-one (180 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 3-[3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-1-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propan-1-one was obtained, and further PMB group was removed according to the above Deprotection method 2, to obtain the desired compound (D-192) as a pale yellow powder (95 mg, 48%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.CN.[CH3:14][N:15](C1C=CC=CN=1)C.Cl.CN(C)CCCN=C=NCC>ClCCl.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:15][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CN(C)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)Cc1cccc(Br)c1
Yield: 81.6 %

Procedure:
A solution of 3-bromophenyl acetic acid (2.15 g), a tetrahydrofuran solution of methyl amine (6 ml, 2M), dimethylaminopyridine (1.32 g), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.06 g) in dichloromethane was stirred at room temperature for 16 hrs. The organic solution was washed thrice with 2M hydrochloric acid solution, dried over magnesium sulphate, filtered and evaporated to afford a solid (1.86 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]2[CH:16]=[C:17]3[O:25][CH2:24][O:23][C:18]3=[CH:19][C:20]=2[C:21]=1[SH:22])=[O:11].C(N(CC)CC)C.II>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[C:10](=[O:11])[C:12]2[CH:13]=[N:14][C:15]3[CH:16]=[C:17]4[O:25][CH2:24][O:23][C:18]4=[CH:19][C:20]=3[C:21]=2[S:22]1
Reactant: O=C(NCCc1ccccn1)c1cnc2cc3c(cc2c1S)OCO3
Agent: II
Solvent: CCN(CC)CC
Solvent: CO
Product: O=c1c2cnc3cc4c(cc3c2sn1CCc1ccccn1)OCO4
Yield: 83 %

Procedure:
To 4.1 g (0.012 mol) of 8-mercapto-[1,3]dioxolo [4,5-g]quinoline-7-carboxylic acid (2-pyridin-2-yl-ethyl)-amide (from Preparation 34) and 5 mL (0.035 mol) of triethylamine in 750 mL of methanol was added 2.95 g (0.012 mol) of iodine in 100 mL of methanol. The mixture was heated at reflux for 2 hours, cooled, and then concentrated to an oil. The residue was slurried in water, and the solid was collected and recrystallized in ethanol to give 3.5 g of the title compound, mp 200°-201° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][O:9]1
Reactant: Oc1cccc(F)c1
Reactant: C1=COCCC1
Product: Fc1cccc(OC2CCCCO2)c1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
To 75 g (669 mmol) of 3-fluorophenol at -35 ° C. was added 79 g (928 mmol) of 3,4-dihydro-2H-pyran. The ice bath was removed and added 1.0 mL of concentrated HCl. The temperature was allowed to warm to room temperature and the reaction progress was monitored by HPLC. 500 ml of diethyl ether and 500 mL of 1 M NaHCO3 were added to the reaction. The organic layers were washed with NaHCO3 (2×) and brine. The organic layers were dried over Na2SO4, filtered, and concd to afford a yellow oil which was purified by silica gel chromatography with EtOAc/hexane (1:9). Concentration of the desired fractions afforded 102.1 g (78%) of a white solid: 1H NMR (CDCl3/400 MHz) 1.56-2.03 (m, 6H), 3.58-3.63 (m, 1H), 3.85-3.91 (m, 1H), 5.39 (t, 1H, J=3.2 Hz), 6.65-6.70 (m, 1H), 6.78-6.84 (m, 2H), 7.21 (dd, 1H, J=8.2, 15.0 Hz); HRMS (EI+) m/z calcd for (C11H13FO2) 196.0900, found 196.0890.
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:15][CH3:16])[C:8](=[O:14])[CH2:9][CH2:10][C:11](=O)[CH3:12])=[CH:5][N:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.C([O-])(=O)C.[Na+].[NH2:28][OH:29].Cl>C1COCC1.O.CCOC(C)=O>[Cl:1][C:2]1[C:6]([N:7]([CH2:15][CH3:16])[C:8](=[O:14])[CH2:9][CH2:10]/[C:11](=[N:28]/[OH:29])/[CH3:12])=[CH:5][N:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1
Reactant: CCN(C(=O)CCC(C)=O)c1cn(-c2cccnc2)nc1Cl
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(C(=O)CC/C(C)=N/O)c1cn(-c2cccnc2)nc1Cl

Procedure:
To a solution of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-4-oxo pentanamide (0.10 g, 0.31 mmol) in THF (3.0 mL) was added a solution of sodium acetate (0.064 g, 0.78 mmol) and hydroxylamine.HCl salt (0.033 g, 0.47 mmol) in water (0.5 mL), and the mixture stirred for one hour. The mixture was diluted with EtOAc and water. The organic phase was separated, and the aqueous extracted with EtOAc. The combined organic phase was washed with brine, dried over MgSO4, and filtered. Removal of the volatiles under reduced pressure gave colorless gum, which was purified on silica gel eluting with MeOH/CH2Cl2 to give the title compound F105 as a colorless gum (0.088 g, 80%).