Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([C:16]2[C:17]([CH:32]3[CH2:34][CH2:33]3)=[N:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[N:20][CH:21]=2)[CH3:15])=[CH:9][C:8]=1[CH3:35])C.[Li+].[OH-]>C1COCC1.CCOCC>[CH:32]1([C:17]2[C:16]([CH:14]([O:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:36])=[O:3])=[C:8]([CH3:35])[CH:9]=3)[CH3:15])=[CH:21][N:20]=[C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=3)[N:18]=2)[CH2:33][CH2:34]1
Reactant: CCOC(=O)COc1ccc(OC(C)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(OC(C)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)ccc1OCC(=O)O
Yield: 86.2 %

Procedure:
154 mg (0.307 mmol) of [rac]-(4-{1-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethoxy}-2-methyl-phenoxy)-acetic acid ethyl ester and 0.62 ml 1N LiOH in 1.6 ml THF were stirred for 2 h at RT. The reaction mixture was taken up in ether and washed with 1N HCl and water. The crude product was suspended in AcOEt/heptane 1:19 and the resulting crystals were filtered off to give 125 mg of pure [rac]-(4-{1-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethoxy}-2-methyl-phenoxy)-acetic acid.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[CH:19]=2)=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][O:11]2.C(O)(C(F)(F)F)=O.[K+].[Br-]>C(#N)C.O>[F:35][C:32]([F:33])([F:34])[C:29]1[CH:28]=[CH:27][C:26]([CH2:25][O:24][C:20]2[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=2)[CH2:17][S:16][C:13]2[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:36])=[O:2])=[C:7]3[C:12]=2[O:11][CH2:10][CH2:9][CH2:8]3)=[CH:31][CH:30]=1
Reactant: COC(=O)COc1ccc(SCc2cccc(OCc3ccc(C(F)(F)F)cc3)c2)c2c1CCCO2
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(SCc2cccc(OCc3ccc(C(F)(F)F)cc3)c2)c2c1CCCO2

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 84A. mp 113-115° C.; HPLC: area %=97.30, r.t.=3.140 min, γ=214 nm, mobile phase=acetonitrile/water w/0.10% TFA; IR (KBr) cm−1: 2952, 2577, 1742, 1582, 1323, 1120; 400 MHz 1H NMR (DMSO-d6): δ 87.67-7.74 (m, 2H), 7.56-7.63 (m, 2H); 7.13 (t, 1H, J=7.8 Hz), 6.76-6.93 (m, 4H), 6.22 (d, 1H, J=8.7 Hz), 5.08 (s, 2H), 4.45 (s, 2H), 4.08 (t, 2H, J=4.8 Hz), 3.91 (s, 2H), 2.54 (t, 2H, J=6.6 Hz), 1.82 (pentet, 2H); MS m/z 505 (M+1). Anal. Calc'd for C26H23F3O5S: C, 61.90; H, 4.60. found: C, 61.49; H, 4.44.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[Si:14]([O:21][C@@H:22]1[C@@H:26]([CH2:27][OH:28])[O:25][C@@H:24]([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C(Cl)Cl.N1C=CC=CC=1>[Si:14]([O:21][C@@H:22]1[C@@H:26]([CH2:27][O:28][C:2]([O:4][C:5]2[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)=[O:3])[O:25][C@@H:24]([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:23]1)([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:15])[CH3:16]
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](COC(=O)Oc3ccc([N+](=O)[O-])cc3)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
p-Nitrophenyl chloroformate (252 mg, 1.25 mmol) in anhydrous methylene chloride was added to a stirred solution of 3'-O-(t-butyldimethylsilyl)thymidine (356 mg, 10 mmol, Wang et al. Nucleosides Nucleotides 1998, 17, 1033-1051) in anhydrous methylene chloride (4 mL) and pyridine (0.5 mL). The resulting solution was stirred at room temperature overnight, then cooled with ice, quenched with water (2 mL), stirred at 0° C. for 30 min, diluted with methylene chloride, washed with dilute acetic acid, water, then 5% sodium bicarbonate, dried over sodium sulfate, and concentrated to dryness. Chromatography on silica with ethyl acetate-hexanes (1:1 to 3:2) gave 505 mg of the titled compound as a colorless foam.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9](O)[CH2:10][C:4]=2[CH:3]=1.[Cl-:18].[Ca+2].[Cl-].Cl>C1C=CC=CC=1>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]([Cl:18])[CH2:10][C:4]=2[CH:3]=1
Reactant: [Cl-]
Reactant: OC1Cc2cc(Br)ccc2Sc2ccccc21
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccccc1
Product: ClC1Cc2cc(Br)ccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
50 g of 2-bromo-10,11-dihydro-dibenzo[b,f]thiepin-10-one are dispersed in 250 ml of ethanol, treated with 9.9 g of sodium borohydride and stirred for 1 hour. After the addition of water, the mixture is extracted with ether. The organic phase is washed with water, dried over magnesium sulphate and evaporated. There is obtained 2-bromo-10,11-dihydro-dibenzo[b,f]thiepin-10-ol of melting point 108°-110° C. 49.9 g of 2-bromo-10,11-dihydro-dibenzo[b,f]thiepin-10-ol, 250 ml of benzene and 18 g of finely powdered calcium chloride are saturated with hydrochloric acid gas at 15° C and then stirred for a further 3 hours at room temperature. The precipitate is filtered off and washed with benzene. The filtrate is concentrated under reduced pressure. There is obtained 2-bromo-10-chloro-10,11-dihydro-dibenzo[b,f]thiepin of melting point 122.5°-124° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH3:13])[CH2:11][O:10]1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Product: C[C@@H](n1cncn1)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 56.5 %

Procedure:
Using (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (1.17 g) and 1H-1,2,4-triazole (404 mg), (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(1H-1,2,4-triazol-1-yl)ethyl]oxirane (830 mg) was obtained by the same way as in Reference Example 2.
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=2)[C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[C:36]([C:38]1[CH:43]=[CH:42][C:41](OB(O)O)=[CH:40][CH:39]=1)#[N:37].[ClH:48].C(OCC)(=O)C>C(OCC)C>[ClH:48].[C:36]([C:38]1[CH:43]=[CH:42][C:41]([C:31]2[CH:30]=[CH:29][C:28]([CH2:27][N:18]([C:19]3[N:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][N:24]=3)[CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:35])[S:12][CH:13]=3)=[CH:33][CH:32]=2)=[CH:40][CH:39]=1)#[N:37]
Reactant: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(Br)cc2)nc1
Reactant: N#Cc1ccc(OB(O)O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)O)n2)Cc2ccc(-c3ccc(C#N)cc3)cc2)nc1

Procedure:
A compound obtained using 2-[(4-{2-[(4-bromobenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 402-1 and 4-cyanophenylboric acid as starting materials and by an operation similar to that of Example 407 was dissolved in diethyl ether, and reacted with 4 mol/L hydrochloric acid-ethyl acetate to give the title compound.
Reaction SMILES: COC([CH2:5][NH:6][N:7]1[C:16]2[CH:15]=[C:14]3[O:17][CH2:18][O:19][C:13]3=[CH:12][C:11]=2[C:10](=[O:20])[C:9]([C:21]([O:23]CC)=[O:22])=[CH:8]1)=O.[OH-].[Na+].O>C(O)(=O)C>[CH3:5][NH:6][N:7]1[C:16]2[CH:15]=[C:14]3[O:17][CH2:18][O:19][C:13]3=[CH:12][C:11]=2[C:10](=[O:20])[C:9]([C:21]([OH:23])=[O:22])=[CH:8]1
Reactant: CCOC(=O)c1cn(NCC(=O)OC)c2cc3c(cc2c1=O)OCO3
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CNn1cc(C(=O)O)c(=O)c2cc3c(cc21)OCO3
Temperature: 95 °C
Reaction time: 4.5 h
Yield: 86.7 %

Procedure:
A mixture of 4.6 g (0.0132 mole) of ethyl 5,8-dihydro-5-[(methoxycarbonyl)methylamino]-8-oxo-1,3-dioxolo[4,5-g]-quinoline-7-carboxylate (Example 5), 1.6 g (0.0396 mole) of sodium hydroxide and about 100 ml of water was stirred at 95° C. for 4.5 hours. The reaction mixture was cooled, acidified with 5 ml of acetic acid with stirring, and kept in a refrigerator overnight. The solid product was collected by filtration, washed with water and recrystallized from 70 ml of boiling dimethylformamide. There was obtained 3 g of 5,8-dihydro-5-(methylamino)-8-oxo-1,3-dioxolo[4,5-g]quinoline-7-carboxylic acid, colorless crystals, m.p. above 300° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)[CH:3]=1.B(Br)(Br)Br.C(=O)([O-])[O-].[K+].[K+].Cl>ClCCl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1
Reactant: COc1ccc(Cc2cc(I)ccc2C)cc1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Cc1ccc(I)cc1Cc1ccc(O)cc1
Temperature: 0 °C

Procedure:
To an ice-cold solution of 4-iodo-2-(4-methoxy-benzyl)-1-methyl-benzene (12.5 g) in dichloromethane (70 mL) is added a solution of boron tribromide in dichloromethane (1 mol/L, 40 mL). The resulting solution is stirred in the ice-bath for 1 h and at ambient temperature overnight. The solution is then cooled in an ice bath and saturated aqueous potassium carbonate solution is added dropwise. At ambient temperature the mixture is adjusted with aqueous hydrochloric acid (1 mol/L) to a pH of 1, the organic phase is separated, and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried (sodium sulphate) and concentrated in vacuo to give the crude product.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:19])[N:3]=1)=[C:11]([F:16])[CH:10]=[C:9]([O:17][CH3:18])[CH:8]=3.[Cl:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>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>[Cl:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:19])[N:3]=1)=[C:11]([F:16])[CH:10]=[C:9]([O:17][CH3:18])[CH:8]=3
Reactant: COc1cc(F)c2nc(C)c3c(C)nc(Br)n3c2c1
Reactant: OB(O)c1ccc(F)cc1Cl
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+]
Product: COc1cc(F)c2nc(C)c3c(C)nc(-c4ccc(F)cc4Cl)n3c2c1
Yield: 20.1 %

Procedure:
Following the general Suzuki coupling procedure, reaction of bromide 6A (65 mg, 0.2 mmol), 2-chloro-4-fluorophenylboronic acid (52 mg, 0.3 mmol), K2CO3 (82 mg, 0.6 mmol) and Pd(PPh3)4 (5 mg, 0.004 mmol) provided the coupling product as an off-white powder (15 mg, 20% yield). EIMS 374.1 [M+H]+.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[OH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH2:29][CH:30]([CH3:35])[C:31]([O:33][CH3:34])=[O:32])=[CH:23]2.O[CH2:37][CH2:38][CH2:39][NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1.C(P(CCCC)CCCC)CCC>O1CCCC1>[CH3:35][CH:30]([CH2:29][C:24]1[NH:25][C:26]2[C:22]([CH:23]=1)=[CH:21][C:20]([O:19][CH2:37][CH2:38][CH2:39][NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1)=[CH:28][CH:27]=2)[C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)C(C)Cc1cc2cc(O)ccc2[nH]1
Reactant: OCCCNc1ccccn1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)C(C)Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.1 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (0.13 g, 0.57 mmol) was added to the solution of methyl 3-(5-hydroxyindolyl)-2-methylpropanoate (0.062 g, 0.27 mmol), as prepared in the preceding step, 2-(3-hydroxypropyl)aminopyridine (0.06 g, 0.40 mmol), as prepared in step b of Example 1, and tri-n-butylphosphine (0.11 g, 0.53 mmol) in tetrahydrofuran (6.0 mL). After stirring at ambient temperature overnight (16 h), the reaction was concentrated and the residue was purified by flash chromatography on silica gel (10%–50% ethyl acetate in hexane) to give the title compound as a yellow oil (0.015 g, 15%). 1H-NMR (400 MHz, CDCl3) δ 8.07 (m, 1H), 7.40 (m, 1H), 7.21 (d, J=8.9 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 7.04 (d, J=3.1 Hz, 1H), 6.88 (dd, J=8.9, 2.4 Hz, 1H), 6.54 (m, 1H), 6.41 (m, 1H), 4.89 (br s, 1H), 4.45 (dd, J=14.2, 7.3 Hz, 1H), 4.10 (m, 4H), 3.63 (s, 3H), 5.52 (q, J=6.5 Hz, 2H), 2.13 (m, 2H), 1.66 (m, 1H), 1.52 (m, 1H), 1.16 (d, J=7.1 Hz, 3H), 0.93 (m, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][C:12]([C:14]3[C:19]([OH:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[O:22][C@@H:23]3[O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]3[OH:25])=[O:13])[CH:8]=[CH:9][C:2]1=2.Cl[C:35]([O:37][CH3:38])=[O:36]>N1C(C)=CC(C)=CC=1C>[O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][C:12]([C:14]3[C:19]([OH:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[O:22][C@@H:23]3[O:31][C@H:30]([CH2:32][O:33][C:35]([O:37][CH3:38])=[O:36])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]3[OH:25])=[O:13])[CH:8]=[CH:9][C:2]1=2
Reactant: Cc1cc(O)c(C(=O)CCc2ccc3occc3c2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1
Reactant: COC(=O)Cl
Solvent: Cc1cc(C)nc(C)c1
Product: COC(=O)OC[C@H]1O[C@@H](Oc2cc(C)cc(O)c2C(=O)CCc2ccc3occc3c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 23 h
Yield: 81.1 %

Procedure:
To a solution of 3-(5-benzo[b]furanyl)-2'-(β-D-glucopyranosyloxy)-6'-hydroxy-4'-methylpropiophenone (10 g) in 2,4,6-collidine (100 ml) is added dropwise methyl chloroformate (10.31 g) at 0° C., and the mixture is stirred at 0° C. for 23 hours. The reaction mixture is poured into ice-10% hydrochloric acid (300 ml--300 ml), and the mixture is extracted with ethyl acetate (350 ml). The organic layer is washed with water, a saturated aqueous sodium hydrogen carbonate solution, and a saturated sodium chloride solution, dried, and concentrated under reduced pressure. The residue (11.96 g) is dissolved in tetrahydrofuran (200 ml), and thereto is added t-butyl amine (20 ml), and the mixture is stirred at room temperature for four hours. The reaction mixture is poured into ice-10% hydrochloric acid (150 ml--150 ml), and extracted with ethyl acetate (250 ml). The organic layer is washed with water, a saturated aqueous sodium hydrogen carbonate solution, and a saturated sodium chloride solution, dried, and concentrated under reduced pressure. The reside is recrystallized twice from water-diethyl ether-diisopropyl ether to give 3-(5-benzo[b]furanyl)-2'-(6-O-methoxycarbonyl-β-D-glucopyranosyloxy)-6'-hydroxy-4'-methylpropiophenone (9.14 g).
Reaction SMILES: I[C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C[Si]([C:22]#[CH:23])(C)C.C[O-].[Na+]>CC#N.CCN(CC)CC.CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:22]([C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1)#[CH:23]
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CO
Product: C#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
5-Iodo-2′-deoxyuridine (5, 1.0 g, 2.82 mmol) was dissolved in MeCN/Et3N (66 mL of 1:1, v/v) under argon atmosphere. Trimethylsilylacetylene (1.6 mL, 11.3 mmol), bis-(triphenylphosphine)-palladium(II) chloride (42.2 mg, 0.60 mmol), and CuI (28 mg, 0.15 mmol) were added, and the mixture was heated for 3.5 h in the flask immersed into a preheated oil bath (50° C.). The solvents were removed in vacuo to give a residue that was purified by silica gel flash column chromatography. Elution with CHCl3/MeOH (9:1, v/v) afforded trimethylsilyl intermediate as a solid (0.75 g, 82%). To the solution of this intermediate (0.7 g, 2.16 mmol) in anhydrous MeOH (16 mL) under argon atmosphere, a solution of NaOMe in MeOH (145 mL of 0.05 N) was added, and the reaction was stirred at 25° C. for 2 h. The pH of the solution was adjusted to 5-6 using Dowex 50 WX8-200 (H+), the mixture was filtered, and concentrated in vacuo to give a residue that was purified by silica gel column flash chromatography using CHCl3/MeOH (8:2, v/v) as eluent to yield 5-ethynyl-2′-deoxyuridine (EdU) as a white solid (395 mg, 73%); 1H NMR (DMSO-d6) δ 11.62 (s, 1H, NH), 8.29 (s, 1H, H-6), 6.10 (dd, J=6.56, 6.56 Hz, 1H, H-1′), 5.24 (d, J=4.31 Hz, 1H, C-3′ OH), 5.12 (t, J=4.91 Hz, 1H, C-5′ OH), 4.23 (m, 1H, H-3′), 4.10 (s, 1H, C≡CH), 3.79 (q, J=3.25, 3.25, 3.26 Hz, 1H, H-4′), 3.59 (m, 2H, H-5′, H-5″), 2.16 (m, 2H, H-2′, H-2″). HRMS calcd for C11H11N2O14 251.0673 (M−H)−. found 251.0683.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[C:5]([F:23])[CH:4]=1)#[N:2].[ClH:24].CCOC(C)=O>>[F:23][C:5]1[CH:4]=[C:3]([CH:22]=[CH:21][C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:1]#[N:2].[ClH:24]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)cc2F)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(OC2CCNCC2)c(F)c1
Reaction time: 5 h

Procedure:
A solution of tert-butyl 4-(4-cyano-2-fluorophenoxy)piperidine-1-carboxylate (42 g, 131 mmol) dissolved in 4:1 HCl/EtOAc (100 mL) was stirred for 5 h. The mixture was concentrated to give the title compound as its HCl salt (12 g, 36%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.89 (m, 2H), 2.14 (m, 2H); 3.08 (m, 2H), 3.21 (m, 2H), 4.86 (m, 1H), 7.48 (t, J=8.4 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.89 (m, 1H); ESI-MS m/z [M+H]+220.7.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][C:13]2[S:14][C:15]3[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:9]1)(C)(C)C.[ClH:24].O1CCOCC1>>[ClH:24].[F:22][C:20]1[CH:19]=[CH:18][C:16]2[N:17]=[C:13]([NH:12][C@H:10]3[CH2:9][C@H:8]([NH2:7])[CH2:11]3)[S:14][C:15]=2[CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2nc3ccc(F)cc3s2)C1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1C[C@H](Nc2nc3ccc(F)cc3s2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl(trans-3-aminocyclobutyl)carbamate (0.099 g, 0.533 mmol), 2-chloro-6-fluoro-1,3-benzothiazole (0.100 g, 0.533 mmol) and diisopropylethylamine (0.185 ml, 1.066 mmol) in DMSO (0.5 mL) contained in a microwave vial was capped and heated to 120° C. for 2 hrs. The mixture was diluted with water and extracted with EtOAc. EtOAc extract was concentrated to give crude tert-butyl(trans-3-((6-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)carbamate. To the crude tert-butyl(trans-3-((6-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)carbamate was added hydrogen chloride, 4N in 1,4-dioxane (10 ml, 40.0 mmol) and the resulting solution stirred at room temperature for 2 h and concentrated to afford crude trans-N1-(6-fluorobenzo[d]thiazol-2-yl)cyclobutane-1,3-diamine hydrochloride. The crude trans-N1-(6-fluorobenzo[d]thiazol-2-yl)cyclobutane-1,3-diamine hydrochloride was added to mixture of methyl (2-chloropyridin-3-yl)(methyl)carbamate, INTERMEDIATE 40, (0.107 g, 0.533 mmol), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2′-4′-6′-triisopropyl-1,1′-biphenyl)]2-(2-aminoethyl)Ph)Pd(II) (0.021 g, 0.027 mmol), and sodium tert-butoxide (0.261 ml, 2.132 mmol) in dioxane (10 mL). The mixture was stirred at 100° C. for 2 h and concentrated. The residue was diluted with water and extracted with EtOAc. EtOAc extract was concentrated and residue purified with ISCO on silica gel column eluting with 0-80% EtOAc/hexanes to give the title compound 3-(trans-3-((6-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (0.092 g, 0.249 mmol, 46.7% yield). m/z: 370.1 (M+1); 1H NMR (400 MHz, CHLOROFORM-d) δ: ppm 8.07 (dd, J=5.18, 1.27 Hz, 1 H), 7.49 (dd, J=8.90, 4.79 Hz, 1 H), 7.32 (dd, J=8.12, 2.64 Hz, 1 H), 7.17 (dd, J=7.73, 1.27 Hz, 1 H), 6.97-7.07 (m, 2 H), 5.90 (br. s., 1 H), 5.33-5.50 (m, 1 H), 4.48-4.74 (m, 1 H), 3.48-3.67 (m, 2 H), 3.43 (s, 3 H), 2.34-2.63 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:37])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:31][C@@H:32]([OH:36])[C:33]([OH:35])=[O:34])[NH:16][C:17]([C:19]3[NH:23][C:22](=[O:24])[N:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:20]=3)=[O:18])=[CH:10][CH:9]=2)[CH:7]=1.[F:38][C:39]([F:46])([C:42]([F:45])([F:44])[F:43])[CH2:40]O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:38][C:39]([F:46])([C:42]([F:45])([F:44])[F:43])[CH2:40][O:34][C:33](=[O:35])[C@H:32]([OH:36])[CH2:31][N:15]([CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:37])=[CH:13][CH:12]=1)[NH:16][C:17]([C:19]1[NH:23][C:22](=[O:24])[N:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:20]=1)=[O:18]
Reactant: OCC(F)(F)C(F)(F)F
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1nn(-c2ccccc2)c(=O)[nH]1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)OCC(F)(F)C(F)(F)F)c1nn(-c2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
A mixture of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(5-oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl)hydrazino]-2-hydroxypropionic acid (200 mg, 380 μmol), 2,2,3,3,3-pentafluoropropan-1-ol (114 mg, 760 μmol), HOBT (103 mg, 760 μmol), EDC (145 mg, 760 μmol) and DIPEA (200 mg, 1.5 mmol) in DMF (5.0 mL) was stirred at room temperature overnight. The mixture was then poured into water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with saturated aqueous NaCl (30 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (PE:EtOAc=2:1) to yield the title compound as a white solid (20 mg). LC-MS: 658 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 3.44-3.40 (m, 2H), 4.25 (br, 2H), 4.58-4.61 (m, 3H), 7.14-7.08 (m, 1H), 7.41-7.55 (m, 8H), 7.84-7.92 (m, 3H).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10](Br)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[Br:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:27])=[C:23]([CH:26]=1)[CH:24]=[O:25].[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:27])=[C:23]([CH:24]([C:10]2[CH:9]=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:11]=2)[OH:25])[CH:26]=1
Reactant: Brc1cnn(-c2ccccc2)c1
Reactant: O=Cc1cc(Br)ccc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1cnn(-c2ccccc2)c1)c1cc(Br)ccc1Cl
Reaction time: 5 h

Procedure:
A solution of 1-phenyl-4-bromopyrazole (see M. A. Khan, et al., Can. J. Chem., (1963) 41 1540) (2.23 g) in diethyl ether (30 ml) wad cooled to −78° C. under argon atmosphere, and added dropwise thereto was n-butyl lithium (1.59 M hexane solution, 6.9 ml). The mixture was stirred at −20° C. to −10° C. for 5 hours, and added dropwise thereto at the same temperature was a solution of 5-bromo-2-chlorobenzaldehyde (2.19 g) obtained in Reference Example 16-(1) in diethyl ether (30 ml). The mixture was stirred at the same temperature for 30 minutes, and added thereto was tetrahydrofuran (30 ml), and the mixture was stirred at 0° C. for further 30 minutes. A saturated aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=83:17-80:20) to give 5-bromo-2-chlorophenyl-1-phenyl-4-pyrazolylmethanol (831 mg) as yellow oil. APCI-Mass m/Z 363/365 (M+H). (2) The above 5-bromo-2-chlorophenyl-1-phenyl-4-pyrazolylmethanol was treated in a manner similar to Reference Example 120-(2) to give the desired 5-bromo-2-chloro-1-(1-phenyl-4-pyrazolylmethyl)benzene as colorless powder. APCI-Mass m/Z 347/349 (M+H).