Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[CH3:15][S:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[CH3:15][S:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:6]3[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]=3[S:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc2scc(Br)c2c1
Product: COC(=O)c1ccc2scc(-c3ccc(SC)cc3)c2c1
Yield: 76 %

Procedure:
In the same manner as in Reference Example 19 and using methyl 3-bromo-1-benzothiophene-5-carboxylate instead of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate and [4-(methylthio)phenyl]boronic acid instead of (4-methoxyphenyl)boronic acid, the title compound (yield 76%) was obtained as colorless crystals.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Si:13]([N:20]1[C@@H:23]([CH2:24][C:25]([S:30][CH3:31])([S:28][CH3:29])[S:26][CH3:27])[CH2:22][C:21]1=[O:32])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[C:33](N1C=CN=C1)(=[O:35])[CH3:34]>O1CCCC1>[Si:13]([N:20]1[C@H:23]([CH2:24][C:25]([S:28][CH3:29])([S:26][CH3:27])[S:30][CH3:31])[C@@H:22]([C:33](=[O:35])[CH3:34])[C:21]1=[O:32])([C:16]([CH3:17])([CH3:19])[CH3:18])([CH3:15])[CH3:14]
Reactant: CSC(C[C@H]1CC(=O)N1[Si](C)(C)C(C)(C)C)(SC)SC
Reactant: CC(=O)n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CSC(C[C@@H]1[C@@H](C(C)=O)C(=O)N1[Si](C)(C)C(C)(C)C)(SC)SC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (2.43 ml of 2.4 m solution, 5.84 mmol) is added by syringe to a solution of diisopropylamine (591 mg, 5.84 mmol) in 25 ml of freshly distilled tetrahydrofuran at -78° C. The resulting solution is stirred at -78° C. for 15 minutes prior to the addition of a solution of (4R)-1-(t-butyldimethylsilyl)-4-[2,2,2-tri(methylthio)ethyl]azetidin-2-one (1.00 g, 2,85 mmol) in tetrahydrofuran (5 ml). This solution is stirred at -78° C. for 15 minutes, then added via a Teflon tube to a mixture of N-acetylimidazole (642 mg, 5.84 mmol) in 25 ml of THF at -78° C. The resulting yellow reaction mixture is stirred at -78° C. for 10 minutes, then quenched by addition of saturated aqueous ammonium chloride solution. The mixture is diluted with ether (200 ml) and washed with 2.5N hydrochloric acid solution (50 ml), water (50 ml) and brine (50 ml) and dried over magnesium sulfate. Removal of solvents in vacuo gives a yellow oil which is chromatographed on silica gel (30% ether in petroleum ether) to yield (3S, 4R)-1-(t-butyldimethylsilyl)-3-(1-oxoethyl)-4-[2,2,2-tri(methylthio)ethyl]azetidin-2-one. n.m.r. (CDCl3) δ4.42(m, 1), δ4.32(d, 1) δ2.35(m, 2), δ2.32(s, 3), δ2.2(s, 9), δ0.98(s, 9), δ0.3(2s, 6).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:16][CH2:15][C:9]2([O:13][CH2:12][CH:11]([OH:14])[CH2:10]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].[CH3:19]I>C1COCC1.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9]2([O:13][CH2:12][CH:11]([O:14][CH3:19])[CH2:10]2)[CH2:15][CH2:16]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC2(CC1)CC(O)CO2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC2(CC1)CC(OC)CO2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90.6 %

Procedure:
8-Ethoxycarbonyl-3-hydroxy-1-oxa-8-azaspiro[4.5]decane (1 g, 0.0044 mol) was dissolved in anhydrous THF (40 ml) under nitrogen and cooled with an ice-bath. Sodium hydride (0.22 g, 5.5 mmol as a 60% oil dispersion) was added and the reaction was stirred at 0° C. for 20 minutes. Methyl iodide (2.0 g, 0.9 ml) in THF (10 ml) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 3 hours. An additional 0.9 ml of methyl iodide was added at 0° C. and stirring was continued overnight. The cooled reaction was diluted with water (10 ml). The aqueous THF was washed with saturated brine and dried over Na2SO4. The solvents were evaporated and the residue was purified by flash chromatography on silica gel by elution with ammoniated 2% methanol/chloroform. Evaporation of the solvents gave 0.97 g of a pale orange oil.
Reaction SMILES: B(F)(F)F.CCOCC.[CH3:10][O:11][C:12](=[O:34])[C:13]1[CH:25]=[C:24]([C:26](=O)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[C:15]([C:16]([N:18]([CH3:22])[CH2:19][CH2:20][CH3:21])=[O:17])[CH:14]=1.[CH2:35]([SH:39])[CH2:36][CH2:37][SH:38]>ClCCl>[CH3:10][O:11][C:12](=[O:34])[C:13]1[CH:25]=[C:24]([C:26]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[S:39][CH2:35][CH2:36][CH2:37][S:38]2)[CH:23]=[C:15]([C:16]([N:18]([CH3:22])[CH2:19][CH2:20][CH3:21])=[O:17])[CH:14]=1
Reactant: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C(=O)c2ccccc2)c1
Reactant: SCCCS
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C2(c3ccccc3)SCCCS2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
Add boron trifluoride diethyl etherate (0.358 mL, 2.83 mmol) to a solution of 5-benzoyl-N-methyl-N-propyl-isophthalamic acid methyl ester (0.192 g, 0.566 mmol) in dichloromethane (3 mL) at 0° C. Add 1,3-propanedithiol (0.114 mL, 1.12 mmol). Stir at room temperature overnight. Partition between water (20 mL) and dichloromethane (20 mL) and extract the aqueous layer with dichloromethane (20 mL). Dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 30:70 ethyl acetate:hexanes) to give the title compound (51%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C@H:6]([NH2:8])[CH3:7])=[CH:4][CH:3]=1.C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C@H:6]([NH:8][C:40]([C:36]2[CH:35]=[C:34]3[C:39](=[CH:38][CH:37]=2)[N:31]([CH2:30][C:27]2[CH:26]=[CH:25][C:24]([C:19]4[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:29][CH:28]=2)[C:32]([CH3:44])=[C:33]3[CH3:43])=[O:41])[CH3:7])=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccc(F)cc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H](C)c3ccc(F)cc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 4-fluoro-α-(R)-methylbenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 521 (M+H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.Cl[C:15]1[C:16]2[CH:23]=[CH:22][NH:21][C:17]=2[N:18]=[CH:19][N:20]=1.CCN(C(C)C)C(C)C>CCO>[N:18]1[C:17]2[NH:21][CH:22]=[CH:23][C:16]=2[C:15]([N:1]2[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Yield: 88.6 %

Procedure:
A mixture of (R)-tert-butyl pyrrolidin-3-ylcarbamate (250 mg, 1.34 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (206 mg, 1.34 mmol) and DIPEA (0.35 mL, 2.01 mmol) in EtOH (3 mL) was stirred at reflux temperature for 16 hours. The volatiles were removed under reduced pressure. The residue was dissolved in EtOAc (15 mL), and filtered. The filtrate was washed with brine (3×5 mL), dried over anhydrous Na2SO4, and concentrated to give the title compound (360 mg, 88% yield). MS (m/z): 304 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([Br:25])[C:22]([OH:26])=[C:21]([Br:27])[CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][CH2:33][CH2:34][CH2:35][CH:36](O)[C:37]([O:39]CC)=[O:38]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]([Br:27])[C:22]([O:26][CH:36]([CH2:35][CH2:34][CH2:33][CH3:32])[C:37]([OH:39])=[O:38])=[C:23]([Br:25])[CH:24]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1Br
Reactant: CCCCC(O)C(=O)OCC
Product: CCCCC(Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1Br)C(=O)O

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-3,5-dibromo-biphenyl-4-ol, and ethyl DL-2-hydroxycaproate, in substantially the same manner, as described in Example 1, steps g-h , and was obtained as a white solid, mp 75-76° C.; MS m/e 645 (M−H)+;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[Na+].[I-:16].Cl.N>O.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11]([I:16])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: Clc1ccc(-c2ccc(Cl)nn2)cc1
Agent: Cl
Agent: N
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Clc1ccc(-c2ccc(I)nn2)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
20 ml ACN are added to 0.50 g (1.11 mmol) 3-(4-chlorophenyl)-6-chloropyridazine and 3.33 g (22.2 mmol) NaI before 189 μl fuming conc. HCl are added and the mixture is stirred at 80° C. for 4 h. The mixture is alkalised with aq. Ammonia solution (32%) diluted with water and extracted with EtOAc. The org. phases are combined, dried with Na2SO4 and the solvent is removed in vacuo. The resulting crude product is triturated with TBME.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[N:12]([C:13]([CH3:15])=[CH2:14])[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[N:9]=1.N1C=CC=CC=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl>[S:32]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[N:12]([C:13]([CH3:15])=[CH2:14])[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[N:9]=1)([C:29]1[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=1)(=[O:34])=[O:33]
Reactant: C=C(C)n1c(OCCCCCO)nc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C(C)n1c(OCCCCCOS(=O)(=O)c2ccc(C)cc2)nc2ccccc21
Reaction time: 5 h
Yield: 69.1 %

Procedure:
A solution of 2 g of the compound obtained in Example 14a in 20 ml of dichloromethane was added with 5 ml of pyridine and 1.8 g of p-toluenesulfonyl chloride and stirred for 5 hours. The organic layer was washed with 10% aqueous citric acid and then with water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain 2.2 g of the title compound (yield: 69%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[C:9]([NH:12][CH2:13][C:14]([OH:16])=[O:15])(=O)[CH3:10].CC([O-])=O.[Na+]>CC(OC(C)=O)=O.[OH-].[Na+].C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([CH:7]=[C:13]2[C:14](=[O:15])[O:16][C:9]([CH3:10])=[N:12]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)s1
Reactant: CC(=O)NCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC1=NC(=Cc2ccc(Cl)s2)C(=O)O1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
A mixture consisting of 5-chlorothiophene-2-carboxaldehyde (1.00 g, 6.82 mmol), N-acetylglycine (0.96 g, 8.18 mmol), NaOAc (0.67 g, 8.18 mmol) in Ac2O (5 mL) is warmed at reflux for 16 hours. The reaction mixture is cooled to ambient temperature and diluted with dilute aqueous NaOH (0.5 M, 100 mL) and CH2Cl2 (100 mL). The layers are separated and the organic phase is washed with aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated to provide 1.5 g (100%) of the title compound as a colorless oil which is used without further purification in the next reaction. 1H NMR (300 MHz, CDCl3) δ2.39 (s, 3H), 6.94 (d, J=4.0 Hz, 1H), 7.21 (s, 1H), 7.26 (d, J=4.0 Hz, 1H) ppm.
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[CH2:24](C([SnH3])=C(CCCC)CCCC)[CH2:25]CC>C1(C)C=CC=CC=1.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>[CH:15]1([N:7]2[C:8]3[C:3](=[C:2]([CH:24]=[CH2:25])[C:11]([F:12])=[C:10]([F:13])[C:9]=3[F:14])[C:4](=[O:23])[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6]2)[CH2:17][CH2:16]1
Reactant: CCCCC([SnH3])=C(CCCC)CCCC
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(Br)c2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)OCC)cn2C1CC1
Temperature: -18 °C

Procedure:
5.9 g of ethyl 5-bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 6.7 g of tributylvinylstannane and 0.69 g of tetrakis(triphenylphosphine)palladium(0) are refluxed for 10 hours in 60 ml of absolute toluene under a nitrogen atmosphere. The reaction mixture is cooled to -18° C., and the solid which has precipitated is filtered off with suction, washed with toluene and dried. 4.46 of the title compound are obtained (88% of theory).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:19][C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:23]([NH:25][O:26][CH3:27])=[O:24])=[N:5][C:6](S(C)=O)=[N:7][C:8]=1[N:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10])#[N:2].C([N:39]1[CH2:43][CH2:42][C@@H:41]([NH2:44])[CH2:40]1)(OC(C)(C)C)=O.CCN(C(C)C)C(C)C>O1CCOCC1>[C:1]([C:3]1[C:4]([NH:19][C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:23]([NH:25][O:26][CH3:27])=[O:24])=[N:5][C:6]([NH:44][CH:41]2[CH2:42][CH2:43][NH:39][CH2:40]2)=[N:7][C:8]=1[N:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10])#[N:2]
Reactant: CONC(=O)c1ccc(C)c(Nc2nc(S(C)=O)nc(N(C)CC(C)(C)C)c2C#N)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CONC(=O)c1ccc(C)c(Nc2nc(NC3CCNC3)nc(N(C)CC(C)(C)C)c2C#N)c1

Procedure:
3-{5-Cyano-6-[(2,2-dimethyl-propyl)-methyl-amino]-2-methanesulfinyl-pyrimidin-4-ylamino}-N-methoxy-4-methyl-benzamide (33 mg) and 1-N-Boc-3-(R)-aminopyrrolidine (30 mg), DIEA (0.2 mL) and p-dioxane (2 mL) were heated in a sealed tube at 75° C. for overnight. After the removal of the solvent in vacuo, the product was purified by silica gel column chromatography and treated with TFA/DCM (1:1) in order to remove the Boc-group. The product was then converted to hydrochloride salt by treating it with hydrochloric acid (1 M in ether) (Yield: 20 mg). MS (m/z): 567 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][CH:10]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[N:12]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]1[O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][CH:10]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1csc(-c2cccc(O)c2)n1
Reactant: BrCCCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1csc(-c2cccc(OCCCCCOC3CCCCO3)c2)n1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 2-(3-hydroxyphenyl)thiazole-4-carboxylate (24), (223 mg, 0.95 mmol, 1 eq.) and 2-(5-bromopentyloxy)tetrahydro-2H-pyran (357 mg, 1.42 mmol, 1.5 eq) in DMF (3 mL) was added powdered potassium carbonate (392 mg, 2.84 mmol, 3.0 eq.) The mixture was stirred vigorously for 4 h at 70° C., then concentrated in vacuo. The residue was diluted with ethyl acetate, washed with NaH2PO4 buffer (pH 5, 1M) and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (ethyl acetate:hexanes gradient). Yield 250 mg (65%). TLC Rf=0.44 (ethyl acetate:hexanes 3:7), MS m/z 322 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][S:10][C:11]#[N:12])=[C:4]([F:14])[CH:3]=1.[OH-].[Na+].O.[BrH:18]>C(O)(=O)C>[Br:18][C:11]1[S:10][CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:14])[N:12]=1
Reactant: N#CSCC(=O)c1ccc(Br)cc1F
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Fc1cc(Br)ccc1-c1csc(Br)n1
Reaction time: 8 h
Yield: 98 %

Procedure:
2-(4-Bromo-2-fluorophenyl)-2-oxoethyl thiocyanate (2.1 g, 7.6 mmol), prepared in the previous step, in 15 mL of 33% hydrogen bromide in acetic acid was stirred overnight. The reaction was neutralized with 60 mL of 2N NaOH and 60 mL of water. The resulting residue was collected by suction filtration and placed under high vacuum to give 2.6 g of a brown paste. The crude product was purified on silica gel using a stepwise gradient of 5-20% ethyl acetate:hexane to give 2-bromo-4-(4-bromo-2-fluorophenyl)-1,3-thiazole (2.5 g, 98%), MS (ES) m/z 338 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH2:22])[C:16]=3[C:15]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)=[CH:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[F:37].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC#N>[NH2:22][C:21]1[C:16]2[C:15]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:27][CH:28]=3)=[C:14]([F:37])[N:13]([C@@H:10]3[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]3)[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@@H](n2c(F)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
A suspension of (R)-tert-butyl 3-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (2) (1.0 g, 2.1 mmol) in MeCN (30.0 mL) was cooled to 0° C. with ice bath. Selectfluor (1.5 g, 4.2 mmol) was added to the reaction mixture in one portion. After addition, the ice-water bath was removed, and the stifling was continued for 1 hr at r. t. The reaction mixture was susequently partitioned between water (30 mL) and DCM (50 mL). The layers were separated and the aqueous phase was extracted with DCM (10 mL×3). Combined organic phases were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product which was purified by column chromatographic (silica gel, 0 to 50% ethyl acetate in DCM) to afford (R)-tert-butyl 3-(4-amino-6-fluoro-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (3) (175 mg, 17% yield) as a yellow solid. LC-MS (ESI): (M+1) 490.1.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][NH:4][N:3]=1.S(Cl)(Cl)=O.[CH3:14]O>>[CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:14])=[O:8])=[CH:5][NH:4][N:3]=1
Reactant: Cc1n[nH]cc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1c[nH]nc1C
Reaction time: 12 h
Yield: 57 %

Procedure:
To a solution of 3-methyl-1H-pyrazole-4-carboxylic acid (1.26 g, 10 mmol) in methanol (100 mL) was added thionyl chloride (5.73 g, 45 mmol) at 0° C. The mixture was stirred for 12 hours. The solvent was evaporated in vacuo. To the residue, saturated sodium bicarbonate aqueous solution was added and the mixture was extracted with ethyl acetate (100 mL×3), the organic phase was dried by sodium sulfate. The mixture was filtered and the filtrate was concentrated in vacuo to give methyl 3-methyl-1H-pyrazole-4-carboxylate (0.8 g, 57%). 1H NMR (300 MHz, CDCl1): δ 7.87 (s, 1H), 3.84 (s, 3H), 2.53 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]([C:14](OC3C=CC([N+]([O-])=O)=CC=3)=[O:15])[C:12]([O:26][CH3:27])=[N:11][C:10]([CH3:28])=[C:9]2[C:29]([O:31][CH3:32])=[O:30])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>CO.C(Cl)Cl>[C:46]([O:45][C:43](=[O:44])[CH2:42][CH2:41][CH2:40][NH:39][C:14]([N:13]1[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([C:29]([O:31][CH3:32])=[O:30])=[C:10]([CH3:28])[N:11]=[C:12]1[O:26][CH3:27])=[O:15])([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)CCCN
Reactant: COC(=O)C1=C(C)N=C(OC)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1=C(C)N=C(OC)N(C(=O)NCCCC(=O)OC(C)(C)C)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99460.8 %

Procedure:
To a solution of 5-methyl 1-(4-nitrophenyl) 6-(4-fluorophenyl)-2-methoxy-4-methyl-1,5(6H)-pyrimidinedicarboxylate (88.7 mg, 0.200 mmol) and K2CO3 (41.5 mg, 0.300 mmol) in CH3OH/CH2Cl2 (0.1/2.0 mL) was added tert-butyl 4-aminobutanoate (31.8 mg, 0.200 mmol). After stirring at rt for 1 h, the mixture was washed with saturated Na2CO3 and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (5%-10% 2 M NH3/MeOH in 50% EtOAc/Hexanes) to afford the product (92.2 g, 99%). mp 135-138° C.; 1H NMR (CD3OD) δ 7.29-7.23 (m, 2H), 6.97-6.88 (m, 2H), 6.65 (s, 1H), 3.98 (s, 3H), 3.66 (s, 3H), 3.38-3.30 (m, 2H), 2.43 (s, 3H), 2.28 (t, 2H, J=7.2 Hz), 1.89-1.78 (m, 2H), 1.43 (s, 9H); ESMS m/e: 464.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5]#[N:6].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:5]#[N:6])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1ccc(-c2ccccc2)c(O)c1
Reactant: BrCc1ccccc1
Product: N#Cc1ccc(-c2ccccc2)c(OCc2ccccc2)c1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 20 using 3-hydroxy-4-phenylbenzonitrile instead of tert-butyl N-(3′-hydroxybiphenyl-4-ylmethyl)carbamate and benzyl bromide instead of 1-bromopropane.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([OH:8])[CH:3]=1.[H-].[Na+].CI.[C:13]([O-])(O)=O.[Na+]>CN(C)C=O>[I:1][C:2]1[CH:7]=[CH:6][N:5]([CH3:13])[C:4](=[O:8])[CH:3]=1
Reactant: O=C([O-])O
Reactant: Oc1cc(I)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ccc(I)cc1=O
Reaction time: 0.08 h

Procedure:
To a solution of 4-iodopyridin-2-ol (450 mg, 2.0 mmol, Maybridge, Cat. No. MO07919) in N,N-dimethylformamide (7 mL) was added sodium hydride (120 mg, 3.0 mmol, 60% dispersion in mineral oil) at 0° C., the solution was stirred 5 min., then methyl iodide (250 uL, 4.1 mmol) was added. The reaction mixture was stirred at r.t. for 2 h., and then poured into aqueous NaHCO3 solution, extracted with AcOEt. The organic layer was washed by water and brine, dried over MgSO4, filtered, and concentrated to afford the desired compound which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=235.9.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C>CO>[CH2:9]([NH:16][CH:3]([CH3:5])[CH2:2][C:1]([O:7][CH3:8])=[O:6])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)CC(C)=O
Reactant: NCc1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CC(C)NCc1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 15.8 %

Procedure:
Ru(OCOCH3)2((R)-dm-binap)(20.5 mg, 0.0215 mmol), methyl acetoacetate (500 mg, 4.305 mmol), benzylamine (461 mg, 4.305 mmol) and methanol (2.5 mL) were placed in a 2.5 mL-stainless autoclave under atmosphere of nitrogen, and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was cooled down to room temperature, and acetic acid (259 mg, 4.305 mmol) was added thereto. The mixture was further stirred under a hydrogen pressure of 3 MPa at 80° C. for 15 hours. After completion of the reaction, the solvent was removed by evaporation in vacuo, and the residue was purified by column chromatography on silica gel (eluent:hexane ethyl acetate/triethylamine=75/25/5) to give the objective methyl (−)-3-(benzylamino)butanoate (141 mg) as a colorless oil in 15.8% yield. The enantiomeric excess of the resulting methyl (−)-3-(benzylamino)butanoate was determined to be 44.5% ee by HPLC analysis using a CHIRALCEL OD-H column.