Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][C:3]=1[Cl:13].BrC1C(Cl)=CC(C=O)=CC=1Cl>>[Br:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[Cl:13]
Reactant: COC(=O)c1cc(Cl)c(Br)c(Cl)c1
Agent: O=Cc1cc(Cl)c(Br)c(Cl)c1
Product: OCc1cc(Cl)c(Br)c(Cl)c1

Procedure:
4-Bromo-3,5-dichlorobenzyl alcohol was prepared from methyl 4-bromo-3,5-dichlorobenzoate using stage (iii) of Process B and 4-bromo-3,5-dichlorobenzaldehyde using stage (iv) of Process B.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:23][CH:24]([CH3:26])[CH3:25])=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:22][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:23][CH:24]([CH3:26])[CH3:25])[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1c(OC(C)C)nc2ccc(Cl)cc2c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 6 step B from a mixture of 6-chloro-2-isopropoxy-4-phenyl-quinoline-3-carboxylic acid ethyl ester and 1N NaOH in ethanol. Off white solid (17.2 mg, 47%). LC-MS: 342 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[CH:23][NH:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH:26]([C:28]([CH3:30])=[O:29])=[CH2:27].CN1C=CN=C1.O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[CH:23][N:24]([CH2:27][CH2:26][C:28](=[O:29])[CH3:30])[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1c[nH]cn1
Reactant: C=CC(C)=O
Agent: Cn1ccnc1
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)CCn1cnc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c1
Temperature: 70 °C
Reaction time: 11 h

Procedure:
(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-imidazole-4-carboxamide (600 mg, 1.69 mmol) and methyl vinyl ketone (0.42 ml, 5.18 mmol) were added to a solution of 1-methylimidazole (7 μl, 0.085 mmol) in DMSO (6 ml). The reaction mixture was stirred at 70° C. for 11 h. Then water was added and the product was extracted into ethyl acetate. The combined organic layers were washed with water, dried and concentrated. The crude product was purified by flash chromatography on silica gel by using CH2Cl2-MeOH as a gradient eluent (100:0-98:2) to obtain the title compound. 1H NMR (400 MHz, CDCl3): 1.21 (3H, d), 2.16 (3H, s), 2.92 (2H, t), 4.26 (2H, t), 4.28 (1H, distorted dd), 4.39 (1H, distorted dd), 4.56 (1H, m), 6.60 (1H, d), 7.48 (1H, d), 7.50 (1H, d), 7.52 (1H, d), 7.66 (1H, distorted d), 7.79 (1H, distorted dd), 7.86 (1H, d), 8.17 (1H, d).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([N:14]1[CH:19]2[CH2:20][CH2:21][CH:15]1[CH2:16][C:17](=O)[CH2:18]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S([CH2:33][N+:34]#[C-])(C1C=CC(C)=CC=1)(=O)=O.C(O)C>C(COC)OC>[C:33]([CH:17]1[CH2:16][CH:15]2[N:14]([CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:19]([CH2:20][CH2:21]2)[CH2:18]1)#[N:34]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CC2CCC(C1)N2Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: N#CC1CC2CCC(C1)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
Potassium t-butoxide (2.5 g) was added portionwise to a stirred mixture of 8-benzyl-8-azabicyclo[3.2.1]octan-3-one (2.0 g), tosylmethyl isocyanide (2.36 g) and ethanol (2 ml) in dimethoxyethane (50 ml) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 0.5 hours and then overnight at room temperature. The mixture was then filtered and the solid residue washed with dimethoxyethane. The combined filtrates were evaporated under reduced pressure and chromatographed [SiO2; hexane:ethyl acetate (80:20)] to give 3-cyano-8-benzyl-8-azabicyclo[3.2.1]octane (0.87 g).
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][CH2:10]Br.[F:12][C:13]1[CH:14]=[C:15]([OH:28])[CH:16]=[C:17]([C:19]2([O:26][CH3:27])[CH2:23][CH2:22][CH2:21][CH:20]2[O:24][CH3:25])[CH:18]=1>>[F:12][C:13]1[CH:14]=[C:15]([O:28][CH2:10][C:9]#[C:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[CH:16]=[C:17]([C:19]2([O:26][CH3:27])[CH2:23][CH2:22][CH2:21][CH:20]2[O:24][CH3:25])[CH:18]=1
Reactant: COC1CCCC1(OC)c1cc(O)cc(F)c1
Reactant: BrCC#Cc1ccccn1
Agent: Br
Product: COC1CCCC1(OC)c1cc(F)cc(OCC#Cc2ccccn2)c1
Yield: 83 %

Procedure:
Using the procedure described in Example 1, 3-(2-pyridyl)prop-2-yn-1-yl bromide hydrobromide was reacted with (1RS,2SR)-1-(5-fluoro-3-hydroxyphenyl)-1,2-dimethoxycyclopentane to give (1RS,2SR)-1-[5-fluoro-3-(3-(2-pyridyl)prop-2-yn-1-yloxy)phenyl]-1,2-dimethoxycyclopentane in 83% yield, as an oil. NMR Spectrum (CDCl3, delta values) 1.6-2.25(m, 6H), 2.94(s, 3H), 2.97(s, 3H), 3.55(m, 1H), 5.21(s, 2H), 6.55-8.0(m, 10H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:18]3[CH2:22][CH2:21][N:20]([C:23](OC(C)(C)C)=[O:24])[CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[C:3]=12.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34]([N:38]=[C:39]=[O:40])[CH:35]=[CH:36][CH:37]=1.C(O)=O.Cl>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:18]3[CH2:22][CH2:21][N:20]([C:23]([NH:38][C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:30])([F:41])[F:42])[CH:33]=4)=[O:24])[CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:39]([NH:38][C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:41])([F:42])[F:30])[CH:33]=4)=[O:40])=[CH:13][CH:12]=3)[C:3]=12
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2nc(-c3ccc(N)cc3)c3c(N)ncnc32)C1
Agent: Cl
Solvent: ClCCl
Solvent: O=CO
Product: Nc1ncnc2c1c(-c1ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc1)nn2[C@@H]1CCN(C(=O)Nc2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of (R)-tert-butyl 3-(4-amino-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate (0.090 g, 0.23 mmol) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this, 3-(trifluoromethyl)phenyl isocyanate (0.032 mL, 0.23 mmol) diluted in CH2Cl2 (5 mL) was added dropwise. The reaction was allowed to warm to room temperature and left stirring for 6 hours. After, formic acid (5 mL) and concentrated HCl (0.5 mL) were added dropwise directly to the reaction mixture. Three major species were observed by LC-MS corresponding to AD73a, AD73b, and AD73c. The reaction mixture was left stirring for 12 hours and then was concentrated in vacuo, resuspended in 50:50 H2O—CH3CN, and purified on a C18 column in CH3CN/H2O/0.1% TFA (1-100% gradient) to afford AD73a (ESI-MS m/z [M+H]+ found 483.5, calculated 483.2), AD73b (ESI-MS m/z [M+H]+ found 483.5, calculated 483.2), and AD73c (ESI-MS m/z [M+H]+ found 670.5, calculated 670.2).
Reaction SMILES: Cl[CH2:2]Cl.C[Li].[Cl:6][C:7]1[CH:8]=[C:9]([C:12]([N+:15]([O-:17])=[O:16])=[CH:13][N:14]=1)[CH:10]=[O:11].O>C(OCC)C.[Ti](Cl)(Cl)(Cl)Cl>[Cl:6][C:7]1[CH:8]=[C:9]([CH:10]([OH:11])[CH3:2])[C:12]([N+:15]([O-:17])=[O:16])=[CH:13][N:14]=1
Reactant: ClCCl
Reactant: O=Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Li]C
Solvent: CCOCC
Solvent: O
Product: CC(O)c1cc(Cl)ncc1[N+](=O)[O-]
Temperature: -50 °C
Yield: 99.7 %

Procedure:
An oven dried 250 mL 3 neck r.b.f. equipped with an internal thermometer was charged with diethyl ether (180 mL) and titanium tetrachloride, 1.0 M in dichloromethane (20.5 mL, 20.5 mmoles) under an Argon atmosphere. The solution was cooled in a CO2(a)/acetone −78° C. bath and methyl lithium, 1.6 M in diethyl ether (12.8 mL, 20.5 mmoles) was added via a syringe at a rate such that the internal temperature was </=−50° C. The resultant anion solution was stirred at −50° C. for 1 hour, at which time 2-chloro-5-nitroisonicotinaldehyde (2.54 g, 13.66 mmoles) in diethyl ether (16+4 mL) was added via syringe with the internal temp </=−50° C. After stirring for an additional hour at −50° C., the reaction was poured into H2O (500 mL), and after mixing two light yellow layers formed. Diethyl ether was added (500 mL), the layers were separated, and the organic was washed with H2O (250 mL), with NaCl(sat.) (250 mL), dried over MgSO4, filtered and concentrated yielding 1-(2-chloro-5-nitropyridin-4-yl)ethanol (2.76 g, 100% yield). LCMS (m/z): 203.0 (MH+); LC Rt=2.42 min. 1H NMR (CDCl3): δ 8.99 (s, 1H), 7.88 (s, 1H), 5.52 (m, 1H), 1.56 (d, J=9.0, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[CH:13]=3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[C:25]([N:26]=[C:27]=[S:28])=[CH:24][CH:23]=[CH:22][N:21]=1>>[N:1]1[C:10]2[C:5](=[C:6]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:27]4[S:28][C:20]5[C:25]([N:26]=4)=[CH:24][CH:23]=[CH:22][N:21]=5)[CH:13]=3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cc(Oc2cccc3ncccc23)ccn1
Reactant: S=C=Nc1cccnc1Cl
Product: c1cnc2sc(Nc3cc(Oc4cccc5ncccc45)ccn3)nc2c1
Yield: 3.83 %

Procedure:
The title compound was prepared according to the method of Example 180 from 4-(quinolin-5-yloxy)pyridin-2-amine and 2-chloro-3-isothiocyanatopyridine; (0.006 g, 3.83% yield) as a light yellow solid. 1H NMR (d6-DMSO) δ 11.47 (s, 1H), 9.00 (dd, 1H), 8.32 (m, 3H), 8.04 (d, 1H), 7.88 (t, 2H), 7.59 (dd, 1H), 7.51 (d, 1H), 7.38 (dd, 1H), 6.77 (dd, 1H), 6.66 (d, 1H).
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[S:10][C:11]([C:29](=[O:31])[CH3:30])=[CH:12][C:13]=1[S:14](=[O:28])(=[O:27])[N:15]([CH2:17][CH:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[OH:19])[CH3:16])C)(C)(C)C.FC(F)(F)C(O)=O>>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH:18]([OH:19])[CH2:17][N:15]([CH3:16])[S:14]([C:13]2[CH:12]=[C:11]([C:29](=[O:31])[CH3:30])[S:10][C:9]=2[NH:7][CH3:6])(=[O:28])=[O:27])=[CH:25][CH:24]=1
Reactant: CC(=O)c1cc(S(=O)(=O)N(C)CC(O)c2ccc(F)cc2)c(N(C)C(=O)OC(C)(C)C)s1
Solvent: O=C(O)C(F)(F)F
Product: CNc1sc(C(C)=O)cc1S(=O)(=O)N(C)CC(O)c1ccc(F)cc1
Yield: 91.9 %

Procedure:
(5-Acetyl-3-{[2-(4-fluorophenyl)-2-hydroxy-ethyl]-methyl-sulfamoyl}-thiophene-2-yl)-methyl-carbamic acid t-butyl ester (600 mg) was treated with trifluoroacetic acid, and the title compound (438 mg) was obtained as a colorless solid, in the same way as Preparation Example 98.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C@@H:14]([NH:16][C:17]2[N:22]=[C:21]([N:23]3[C@@H:27]([C@H:28]([OH:30])[CH3:29])[CH2:26][O:25][C:24]3=[O:31])[C:20]([F:32])=[CH:19][N:18]=2)[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]>CO.[OH-].[OH-].[Pd+2]>[F:32][C:20]1[C:21]([N:23]2[C@@H:27]([C@H:28]([OH:30])[CH3:29])[CH2:26][O:25][C:24]2=[O:31])=[N:22][C:17]([NH:16][C@H:14]([C:4]2[CH:5]=[N:6][C:7]([O:8][CH2:9][C:10]([F:12])([F:13])[F:11])=[CH:2][CH:3]=2)[CH3:15])=[N:18][CH:19]=1
Reactant: C[C@H](Nc1ncc(F)c(N2C(=O)OC[C@@H]2[C@@H](C)O)n1)c1cnc(OCC(F)(F)F)c(Cl)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@H](Nc1ncc(F)c(N2C(=O)OC[C@@H]2[C@@H](C)O)n1)c1ccc(OCC(F)(F)F)nc1
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To (R)-3-(2-(((S)-1-(5-chloro-6-(2,2,2-trifluoroethoxyl)pyridin-3-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (20 mg, 0.042 mmol) in MeOH (10 mL) was added Pd(OH)2 (10 mg, 0.014 mmol). The reaction was purged with N2 and H2 three times each. A hydrogen balloon was applied to the reaction. The reaction mixture was stirred for one hour and concentrated. The residue was applied directly to HPLC separation to give product (15 mg) as a trifluoroacetic acid salt. 1HNMR (CD3OD) δ ppm 8.21 (d, J=3.1 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.12-7.28 (m, 2H), 4.88-5.00 (m, 1H), 4.59 (br. s., 1H), 4.42-4.55 (m, 2H), 3.89 (br. s., 1H), 1.49 (d, J=7.0 Hz, 3H), 0.81 (br. s., 3H). HRMS (B) m/z 446.1448 (M+H)+, RT=1.90 min.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([C:7]2(O)[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8]2)=[CH:3][CH:2]=1.Cl>C1COCC1.O>[C:1]1([CH3:17])[CH:2]=[CH:3][C:4]([C:7]2[CH2:15][C:14]3[C:9]([CH:8]=2)=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:5][CH:6]=1
Reactant: Cc1ccc(C2(O)Cc3ccccc3C2)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C2=Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93 %

Procedure:
To a solution of 2-(p-tolyl)-2-indanol (17.27 g, 77.01 mmol) in THF (200 mL) was added a solution of concentrated hydrochloric acid (40 mL) in water (60 mL). The solution was stirred at room temperature overnight (12 h). The solid was collected and washed with pentane (50 mL) and then tetrahydrofuran (50 mL) to give 14.77 g of 2-(p-tolyl)-1H-indene. 1H-N.M.R. (CDCl3) d 2.43(s, 3H), d 3.83 (br s, 2H), d 7.20-7.35(m, 5H), d 7.45(br d, J=7.1 Hz, 2H), d 7.55(br d, J=7.1 Hz, 2H), d 7.60 (br d, J=7.1 Hz, 2H).
Reaction SMILES: [CH3:1][NH2:2].Cl[S:4]([C:7]1[CH:8]=[C:9]([C:17]([OH:19])=[O:18])[C:10]2[O:14][CH:13]([CH3:15])[CH2:12][C:11]=2[CH:16]=1)(=[O:6])=[O:5].[OH-].[Na+]>O>[CH3:1][NH:2][S:4]([C:7]1[CH:8]=[C:9]([C:17]([OH:19])=[O:18])[C:10]2[O:14][CH:13]([CH3:15])[CH2:12][C:11]=2[CH:16]=1)(=[O:6])=[O:5]
Reactant: CC1Cc2cc(S(=O)(=O)Cl)cc(C(=O)O)c2O1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNS(=O)(=O)c1cc2c(c(C(=O)O)c1)OC(C)C2
Temperature: 5 °C

Procedure:
108 g of a 40% aqueous solution of methylamine and 108 ml of water were added into a 2-liter round-bottomed flask. The contents were cooled to 5° C. and 193 g of 5-chlorosulphonyl-2-methyl-2,3-dihydrobenzofuran-7-carboxylic acid were then added in portions of 10 g, while cooling in an ice and salt bath so as to maintain the temperature at 5° C. After each addition of acid, 14.5 ml of a solution containing 140 ml of 30% sodium hydroxide in 140 ml of water were added.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:32])[CH2:26][C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[CH:21]=[CH:22][CH:23]=3)=[N:10][N:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[N:33]1([CH2:38][C:39]2[CH:40]=[C:41]([NH2:45])[CH:42]=[CH:43][CH:44]=2)[CH2:37][CH2:36][CH2:35][CH2:34]1.Cl>O1CCOCC1.CC(O)C>[CH3:17][C:15]1[CH:14]=[CH:13][C:12]2[N:11]([N:10]=[C:9]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:32])[CH2:26][C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[CH:21]=[CH:22][CH:23]=3)[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:45][C:41]3[CH:42]=[CH:43][CH:44]=[C:39]([CH2:38][N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)[CH:40]=3)[N:7]=2)[CH:16]=1
Reactant: Cc1ccc2c(-c3ccnc(Cl)n3)c(-c3cccc(NC(=O)Cc4cccs4)c3)nn2c1
Reactant: Nc1cccc(CN2CCCC2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Cc1ccc2c(-c3ccnc(Nc4cccc(CN5CCCC5)c4)n3)c(-c3cccc(NC(=O)Cc4cccs4)c3)nn2c1
Yield: 53.7 %

Procedure:
N-{3-[3-(2-chloro-4-pyrimidinyl)-6-methylpyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide (100 mg, 0.22 mml), [3-(1-pyrrolidinylmethyl)phenyl]amine (46 mg, 0.26 mmol), and 4N HCl in dioxane (0.10 mL) were combined in i-PrOH (3 mL) in a procedure analogous to Example 67, Step B to afford the title compound as a yellow solid (70 mg, 53%). 1H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.55 (s, 1H), 8.71 (s, 1H), 8.47 (d, J=9.8 Hz, 1H), 8.26 (d, J=5.3 Hz, 1H), 7.91 (s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.72-7.67 (m, 2H), 7.48-7.36 (m, 3H), 7.31-7.19 (m, 2H), 7.00-7.01 (m, 2H), 6.92 (d, J=7.5 Hz, 1H), 6.50 (d, J=5.6 Hz, 1H), 3.91 (s, 2H), 3.57 (s, 2H), 2.52-2.45 (m, 4H), 2.41 (s, 3H), 1.74-1.69 (m, 4H). ES-LC/MS m/z=600 [M+H]+.
Reaction SMILES: [F:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12].[CH3:18][O:19][C:20]1[CH:41]=[CH:40][C:23]([C:24](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:22][CH:21]=1.C(OCC)(=O)C.O>N1C=CC=CC=1>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([O:9][CH2:8][C@H:5]2[O:4][C@@H:3]([N:10]3[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]3=[O:12])[C@H:2]([F:1])[C@@H:6]2[OH:7])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:23]2[CH:40]=[CH:41][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[CH:30][CH:29]=1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](F)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 126.7 %

Procedure:
An operation of dissolving 2′-Deoxy-2′-fluorouridine (3.00 g, 12.2 mmol) in dry pyridine, followed by concentration under reduced pressure was repeated 3 times to perform dehydrative azeotropic distillation. Thereafter, under an argon atmosphere, the reaction mixture was dissolved in dry pyridine (120 ml), 4,4′-dimethoxytrityl chloride (4.55 g, 13.4 mmol) was added, and the mixture was stirred at room temperature for 3 hr. The completion of the reaction was confirmed, and ethyl acetate (150 ml) and water (60 ml) were added to the reaction mixture to allow layer separation. The organic layer was washed 3 times with 5% aqueous sodium hydrogen carbonate solution (20 ml), washed with water (20 ml) and saturated brine (20 ml), and the obtained organic layer was dried over sodium sulfate. The solvent in the filtrate was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50-0/100 (v/v), containing 1% triethylamine). The object fractions were collected and concentrated to give the title compound (8.48 g, quant).
Reaction SMILES: [NH2-].[Na+].[C:3]1([CH2:13][C:14]#[N:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[CH2:16]([CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30]Cl)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CCOCC>[CH2:16]([CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH:13]([C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][CH:4]=2)[C:14]#[N:15])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#CCc1cccc2ccccc12
Reactant: ClCCN1CCC(Cc2ccccc2)CC1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: N#CC(CCN1CCC(Cc2ccccc2)CC1)c1cccc2ccccc12

Procedure:
2 g of sodium amide are added in small portions to a solution of naphth-1-ylacetonitrile in 150 ml of anhydrous ether and the mixture is refluxed for 5 hours. 11.8 g of 2-(4-benzylpiperidino)chloroethane are then added and the mixture is refluxed again for 3.5 hours. 200 ml of water are added and the organic phase is decanted and extracted with 300 ml of 10% hydrochloric acid. The aqueous phase is washed with ether, neutralized with 30% sodium hydroxide and extracted with ether. The organic phase is washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate and the solvent is then evaporated off to give 16.4 g of the expected product.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([CH3:12])[NH:7][C:6]1=[O:13])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24]>CC(C)=O>[CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([CH3:12])[N:7]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:6]1=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)cc(C)[nH]c1=O
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCn1c(=O)cc(C)n(CCC(C)C)c1=O
Temperature: 23 °C
Yield: 91 %

Procedure:
To 5.0 g (27 mmol) of 3-butyl-6-methyluracil in 100 mL of acetone was added 14.9 g (108 mmol) of K2CO3 followed by 4.07 g (27 mmol) of 1-bromo-3-methyl butane. The resulting mixture was refluxed for 48 h. After cooling to 23° C., the reaction mixtyre was filtered and evaporated to give the 8.2 g (24 mmol, a 91% yield) of the title compound as a yellow oil. Yield 91%.; 1H NMR (300 MHz, CDCl3); δ 0.91-0.98 (m, 6H), 1.25 (s, 3H), 1.32-1.40 (m, 2H), 1.48-1.80 (m, 5H), 2.15 (s, 3H), 3.67-3.83 (m, 2H), 3.88-3.96 (m, 2H) 5.57 (s, 1H); IR (KBr, cm31 1): 3476w, 2958w, 2933w, 2872m, 1701s, 1538m, 1432m, 1364m; MS (ES) m/z (relative intensity): 253 (M+ +H).
Reaction SMILES: COB(OC)OC.C1([C@]2(CO)CCCN2C2C=CC=CC=2)C=CC=CC=1.CSC.B.[Cl:31][CH2:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=1)=[O:34]>C1(C)C=CC=CC=1.CO>[Cl:31][CH2:32][C@H:33]([C:35]1[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=1)[OH:34]
Reactant: O=C(CCl)c1ccc(F)c(F)c1
Agent: B
Agent: COB(OC)OC
Agent: OC[C@@]1(c2ccccc2)CCCN1c1ccccc1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CSC
Product: O[C@H](CCl)c1ccc(F)c(F)c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 94.2 %

Procedure:
Trimethoxy borane (2.0 g) was added at room temperature to a stirred solution of (S)-diphenylprolinol (3.5 g) in toluene (100 mL). After stirring this mixture for 90 minutes at about 65-75° C., borane dimethylsulfide (2M THF solution, 105 mL) was added over a period of 50 minutes maintaining the temperature between 65 and 75° C. This mixture was stirred for another 90 minutes at 75° C., then a solution of 2-chloro-1-(3,4-difluorophenyl)ethanone (50.0 g) in toluene (150 mL) was dosed over a period of 25 minutes maintaining the temperature between 65 and 75° C. After the completion of the addition the reaction mixture was stirred for another 100 minutes at 75° C. at which point the completion of reaction was monitored by TLC. Then mixture was cooled to 0-5° C. and methanol (50 mL) was added over a period of 30 minutes controlling the gas formation and the temperature to a maximum of 5° C. After the addition is complete, the obtained solution was subjected to distillation under reduced pressure at below 60° C., followed by sequential addition of 10% aqueous acetic acid solution (250 mL) and toluene (500 mL) to the residue. The layers were separated and obtained water layer was back extracted with toluene (250 mL). Both organic layers were combined and washed with water (500 mL). The resulting organic layer was subjected to complete distillation under vacuum to afford the title compound in 94.2% yield having chiral HPLC purity of 99.62%.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][C:6]=1[C:12]1[C:20]2[C:15](=[C:16]([O:21][CH3:22])[N:17]=[CH:18][CH:19]=2)[N:14]([CH3:23])[CH:13]=1.[CH2:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30].C(N(CC)CC)C.[OH-].[Na+]>ClCCl.O1CCOCC1>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][S:31]([CH2:29][CH3:30])(=[O:33])=[O:32])=[CH:7][C:6]=1[C:12]1[C:20]2[C:15](=[C:16]([O:21][CH3:22])[N:17]=[CH:18][CH:19]=2)[N:14]([CH3:23])[CH:13]=1
Reactant: COc1nccc2c(-c3cc(N)ccc3Oc3ccc(F)cc3F)cn(C)c12
Reactant: CCS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c3c(OC)nccc23)c1
Temperature: 80 °C

Procedure:
A mixture of Example 2D (0.05 g, 0.131 mmol), ethanesulfonyl chloride (0.051 g, 0.393 mmol), and triethylamine (0.080 g, 0.787 mmol) in dichloromethane (3 mL) was stirred at ambient temperature for 2 hours. The solvent was removed, and the residue was treated with sodium hydroxide (0.656 mL, 1.31 mmol) and dioxane (3 mL). The reaction mixture was heated at 80° C. for 3 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to give the title compound.