Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:30]([OH:32])=O)=[N:11][C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:33]([O:40][CH2:41][CH2:42][NH:43][CH:44]([CH3:46])[CH3:45])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].[Si](OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2C=CC=CC=2C2C=CC=CC=2)N=1)=O)(C(C)(C)C)(C)C>>[Si:33]([O:40][CH2:41][CH2:42][N:43]([CH:44]([CH3:46])[CH3:45])[C:30]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[N:11]=1)=[O:32])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: O=C(O)c1nc(Cc2ccccc2-c2ccccc2Cl)nc(O)c1OCc1ccccc1
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Agent: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2ccccc2-c2ccccc2Cl)nc(O)c1OCc1ccccc1
Yield: 63.1 %

Procedure:
5-Benzyloxy-2-(2′-chloro-biphenyl-2-ylmethyl)-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (9-04) (2.74 g, 63.03%) was synthesized as a dark liquid from 5-benzyloxy-2-(2′-chloro-biphenyl-2-ylmethyl)-6-hydroxypyrimidine-4-carboxylic acid (7-02) (3 g, 6.72 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropyl amine (8-b) (1.6 g, 7.399 mmol) following the procedure as described for 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (9-01).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: CCCCCCCCCCCBr
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCNc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
p-Aminobenzophenone (75 g.) is heated with undecyl bromide (200 g.) in dry hexamethyl phosphoramide (300 ml.) containing anhydrous potassium carbonate (90 g.) for 16 hours at 100° C. The solution is cooled to room temperature, filtered to remove solids, and the filtrate is diluted with cold water. The solid so obtained is collected and washed with water. Recrystallization from ethanol followed by dichloro methane provides the product of the Example.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[CH:11]=[C:10]([CH3:13])[S:9][C:8]=2[NH:7][C:6]2[CH:14]=[CH:15][C:16]([C:18]#[N:19])=[CH:17][C:5]=2[N:4]=1.[CH3:20][N:21]1[CH2:26][CH2:25]N[CH2:23][CH2:22]1>CS(C)=O.C1(C)C=CC=CC=1>[CH3:13][C:10]1[S:9][C:8]2[NH:7][C:6]3[CH:14]=[CH:15][C:16]([C:18]#[N:19])=[CH:17][C:5]=3[N:4]=[C:3]([N:2]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)[C:12]=2[CH:11]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc2c(s1)Nc1ccc(C#N)cc1N=C2N
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Cc1cc2c(s1)Nc1ccc(C#N)cc1N=C2N1CCN(C)CC1
Temperature: 130 °C

Procedure:
To a solution of 10-amino-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene-7-carbonitrile hydrochloride, prepared as described in the previous step, (0.6 g) in DMSO (6 mL) and toluene (6 mL), was added 1-methylpiperazine (4 mL). The mixture was heated in a 130° C. oil bath for 17 hours. The solution was concentrated, diluted with ethyl acetate (50 mL), washed with water (20 mL) and brine (20 mL), and then concentrated. The solid was dissolved in dichloromethane (10 mL) and treated with saturated sodium bicarbonate solution. The title compound was collected as a light yellow precipitate, washed with water and dichloromethane, dried, and used in the next step without additional purification. LC-MS: m/z 338 (M+1). 1H NMR (CD3OD, 400 MHz): δ (ppm) 7.19-7.15 (m, 2H), 6.74 (d, 1H), 6.37 (s, 1H), 3.51 (m, 4H), 2.53 (m, 4H), 2.34 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17](=[O:25])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO>[C:19]1([CH2:18][C:17]([O:16][CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOC(=O)Cc2ccccc2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=C(Cc1ccccc1)OCCC1CCNCC1
Reaction time: 8 h
Yield: 87.4 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-[2-(phenylacetoxy)ethyl]piperidine (431 mg, 1.24 mmol) in MeOH (0.2 mL) was added 2N anhydrous HCl/ether (1.5 mL, 3.0 mmol). The reaction mixture was stirred overnight. After evaporation, the residue was dissolved in deionized water. EtOAc was used to wash the aqueous layer before the pH was altered to approx. 9-10. The aqueous layer was extracted three times with CH2Cl2, and the combined organic phases were dried over Na2SO4. After evaporation, 4-[2-(phenylacetoxy)ethyl]piperidine (268 mg, 87%) was obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:17]([O-])=O.O.C([O-])=O.[NH4+]>CN(C)C=O.[Zn]>[NH2:17][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=[O:15])[CH2:9]2)=[N:7][C:2]=1[NH2:1]
Reactant: Nc1nc(N2CCC[C@@H](C(=O)O)C2)ccc1[N+](=O)[O-]
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(N2CCC[C@@H](C(=O)O)C2)nc1N
Temperature: 45 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-1-(6-amino-5-nitropyridin-2-yl)piperidine-3-carboxylic acid in N,N-dimethylformamide (91 mL) was added water (9.8 mL), ammonium formate (3.85 g, 61.25 mmol), and active zinc dust (2.1 g, 30.6 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 45° C. for 16 h. The mixture was filtered and concentrated under reduced pressure to afford (R)-1-(5,6-diaminopyridin-2-yl)piperidine-3-carboxylic acid which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]2[S:16][CH:15]=[CH:14][C:4]=2[NH:5][C:6](=[O:13])[C:7]=1[C:8]([O:10]CC)=O.[NH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.C1(C)C(C)=CC=CC=1>CN(C)C=O>[OH:1][C:2]1[C:3]2[S:16][CH:15]=[CH:14][C:4]=2[NH:5][C:6](=[O:13])[C:7]=1[C:8]([NH:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[O:10]
Reactant: Nc1ccncc1
Reactant: CCOC(=O)c1c(O)c2sccc2[nH]c1=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccncc1)c1c(O)c2sccc2[nH]c1=O
Temperature: 140 °C
Yield: 66.6 %

Procedure:
A mixture of 2.48 g (10.4 mmols) of ethyl 4,5-dihydro-7-hydroxy-5-oxothieno[3,2-b]pyridine-6-carboxylate [J. Chem. Res. (S), 6 (1980); J. Chem. Res. (M), 113 (1980)], 1.01 g (10.7 mmols) of 4-aminopyridine, 50 ml of xylene and 10 ml of dimethylformamide was heated at 140° C. for an hour. After completion of the reaction, insoluble matters were filtered and tritylated with dimethylformamide with heating to give 1.99 g (yield: 67%) of Compound 2.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[OH:11][C:12]1([NH3+:15])[CH2:14][CH2:13]1.C(N(CC)CC)C>O1CCCC1>[OH:11][C:12]1([NH:15][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: O=C(Cl)c1ccccc1
Reactant: [NH3+]C1(O)CC1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1(O)CC1)c1ccccc1

Procedure:
Benzoyl chloride (4.2 g, 30 mmol) is added to a suspension of 1-hydroxycyclopropylammonium chloride (2.67 g, 24.5 mmol) in dry tetrahydrofuran. Triethylamine (6.5 g, 65 mmol) is added dropwise with stirring and ice-cooling (1 hr). The precipitate is filtered off and washed with tetrahydrofuran. The filtrate obtained is evaporated in vacuo. The crystalline residue is recrystallised from chloroform yielding N-(1-hydroxycyclopropyl)-benzamide, mp 153°-155° (3.0 g, 69%); NMR=δCDCl 3=0.87-1.38 (m, 4H), 4.7 (br. s, 1H), 7.3-7.9 (m, 6H, incl. NH).
Reaction SMILES: Br[C:2]1[C:3](=[O:23])[O:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8].[C:24]([O:33][CH3:34])(=[O:32])[C:25]1[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=1)[SH:27].N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:4][C:3](=[O:23])[C:2]=1[S:27][C:26]1[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=1[C:24]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)c1ccccc1S
Reactant: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Br
Solvent: C1CCNCC1
Solvent: ClCCl
Product: COC(=O)c1ccccc1SC1=C(O)CC(CCc2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 1.9 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (prepared in example BBB), 2.2 mmol of methyl thiosalicylate and 2.1 mmol of piperidine in 30 mL of dichloromethane. The crude product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound (m.p. 91°-92° C.). 1H NMR (DMSO-d6) δ2.25 (m, 2H), 2.38 (m, 1H), 2.62 (m, 1H), 3.44 (q, 2H), 3.82 (s, 3H), 6.06 (bd, 1H), 6.90 (t, 1H), 7.05-7.52 (m, 11H), 7.81 (dd, 1H).
Reaction SMILES: [CH3:1][C:2]([CH2:4][O:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH3:11])=[CH2:3].[CH3:12][O:13][SiH:14]([O:17][CH3:18])[O:15][CH3:16]>O.Cl.Cl.Cl[Pt](Cl)(Cl)Cl.O1CCCC1>[CH3:11][O:10][CH2:9][CH2:8][O:7][CH2:6][O:5][CH2:4][CH:2]([CH3:1])[CH2:3][Si:14]([O:17][CH3:18])([O:15][CH3:16])[O:13][CH3:12]
Reactant: C=C(C)COCOCCOC
Reactant: CO[SiH](OC)OC
Agent: Cl[Pt](Cl)(Cl)Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COCCOCOCC(C)C[Si](OC)(OC)OC
Yield: 60 %

Procedure:
Into a 200-ml flask, 8.01 g (50% by mol) of 2-methyl-4,9,6-trioxa-1-decene, 0.026 g (0.05% by mol) of hexachloroplatinic(IV) acid hydrate, and 100 g of tetrahydrofuran were charged. Into the mixed solution, 7.94 g (65% by mol) of trimethoxysilane was added dropwise under a nitrogen stream with stirring with a magnetic stirrer. After the addition, the mixture was reacted at ambient temperature for 24 hours. Then, the reaction mixture was distilled to afford 8.47 g of (3-((2-methoxyethoxy)methoxy)-2-methylpropyl)trimethoxysilane (corresponding to the compound of Formula (A-29)).
Reaction SMILES: [Na].[K].[CH2:3]([S:5][CH2:6][C@H:7]([CH3:16])[C@@H:8]([OH:15])[C@H:9]([NH:13][CH3:14])[C:10]([OH:12])=[O:11])C.Cl.CN.[Cl-].[NH4+].N[CH:23](C(O)C(C)CSC)C(O)=O.Cl.C(N)C>>[CH2:14]([NH:13][CH:9]([CH:8]([OH:15])[CH:7]([CH3:16])[CH2:6][S:5][CH3:3])[C:10]([OH:12])=[O:11])[CH3:23]
Reactant: CCSC[C@H](C)[C@@H](O)[C@H](NC)C(=O)O
Reactant: CSCC(C)C(O)C(N)C(=O)O
Agent: CCN
Agent: CN
Agent: Cl
Product: CCNC(C(=O)O)C(O)C(C)CSC

Procedure:
For example, when sodium (or potassium) ethylmercaptide was used in place of the sodium methylmercaptide in Step A, one obtained (2S, 3R, 4R)-5-(ethylthio)-3-hydroxy-4-methyl-2-(methylamino)pentanoic acid. Likewise, when the methylamine hydrochloride of Step H was replaced by ammonium chloride, (2S, 3R, [4R]4S)-2-amino-3-hydroxy-4-methyl-5-(methylthio)-pentanoic acid was obtained, and when ethylamine hydrochloride was used, (2A, 3R, [4R]4S)-2-(ethylamino)-3-hydroxy-4-methyl-5-(methyl-thio)pentanoic acid was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=O)[N:8](O)[C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([F:16])=[C:11]([F:17])[CH:10]=2)=[O:5])[CH3:2].C(OC(C1C(=O)NC2C(C=1)=CC(F)=C(F)C=2)=O)C.P(Cl)(Cl)[Cl:39].P(Cl)(Cl)(Cl)=O>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:39])=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([F:16])=[C:11]([F:17])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(F)c(F)cc2n(O)c1=O
Reactant: ClP(Cl)Cl
Agent: CCOC(=O)c1cc2cc(F)c(F)cc2[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)c1cc2cc(F)c(F)cc2nc1Cl
Temperature: 0 °C
Yield: 88 %

Procedure:
A mixture of 3-ethoxycarbonyl-6,7-difluoro-1-hydroxy-2-oxoquinoline (25 g at a concentration of 75 mol %, equivalent to 69.65 mmol), 3-ethoxycarbonyl6,7-difluoro-2-oxoquinoline (25 g at a concentration of 5 mol %, equivalent to 4.9 mmol), phosphorus trichloride (59.6 g, equivalent to 433.5 mmol) and phosphoryl chloride (15.05 g, equivalent to 98.05 mmol) in 1,2-dichloroethane (170 cm3) is heated at reflux for 3 hours. After cooling to 0° C., the reaction mixture is poured onto slushed ice (250 g of ice +250 g of water at 0° C.) and left to separate overnight. The organic phase is washed with saturated NaHCO3 solution (100 cm3), followed by water (100 cm3), and then concentrated to dryness in order to obtain 19.8 g of 3-ethoxycarbonyl-6,7-difluoro-2-chloroquinoline of 90% assay (HPLC), equivalent to a yield of 88%.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:38])[C:19]([C:25]3[CH:26]=[CH:27][C:28]4[O:33][CH2:32][C:31](=[O:34])[N:30]([CH2:35][CH3:36])[C:29]=4[CH:37]=3)([OH:24])[C:20]([F:23])([F:22])[F:21])=[C:14]([Cl:39])[CH:13]=2)[CH:8]=[CH:9][C:10]=1[Cl:11])=[O:4]>CCCCCCC>[Cl:11][C:10]1[CH:9]=[CH:8][C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:38])[C:19]([C:25]3[CH:26]=[CH:27][C:28]4[O:33][CH2:32][C:31](=[O:34])[N:30]([CH2:35][CH3:36])[C:29]=4[CH:37]=3)([OH:24])[C:20]([F:22])([F:21])[F:23])=[C:14]([Cl:39])[CH:13]=2)=[CH:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(-c4ccc(Cl)c(C(=O)OC)c4)cc3Cl)C(F)(F)F)cc21
Solvent: CCCCCCC
Product: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(-c4ccc(Cl)c(C(=O)O)c4)cc3Cl)C(F)(F)F)cc21

Procedure:
In analogy to Example 56, step 6, 4,3′-Dichloro-4′-[2-(4-ethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-biphenyl-3-carboxylic acid methyl ester was hydrolyzed (3 h, 65° C.). The product was treated with heptane for 17 h, filtered and dried to give the title compound as a white solid. MS (m/e, ISP neg. ion)=566.2 [M−H+].
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11](Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[F:18][CH2:19][C:20]#[N:21].Cl>O1CCCC1>[F:18][CH:19]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[C:20]#[N:21]
Reactant: N#CCF
Reactant: CC(C)(C)C(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)C(F)C#N
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A solution of lithium hexamethyldisilazide (LHMDS) in tetrahydrofuran (THF) (1M, 33.9 mL, 2 equiv) was added dropwise to a chilled (−78° C.) solution of pivaloyl chloride (2.04 g, 1 equiv) and FCH2CN (1.00 g, 1 equiv) in THF (50 mL). The mixture was allowed to warm to room temperature and 1 N HCl was added dropwise until the solution was pH=2. The mixture was concentrated in vacuo to provide the title compound (2.40 g, 99% yield).
Reaction SMILES: C([O:8][CH2:9][CH:10]1[O:24][C:14]2=[C:15]3[C:20](=[CH:21][CH:22]=[C:13]2[O:12][CH2:11]1)[N:19]=[C:18]([CH3:23])[CH:17]=[CH:16]3)C1C=CC=CC=1.C1CCCCC=1>CCO.[Pd]>[CH3:23][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]3[O:12][CH2:11][C@@H:10]([CH2:9][OH:8])[O:24][C:14]3=2)[N:19]=1
Reactant: Cc1ccc2c3c(ccc2n1)OCC(COCc1ccccc1)O3
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: Cc1ccc2c3c(ccc2n1)OC[C@@H](CO)O3
Yield: 97.7 %

Procedure:
To a solution of (2S)-2[(benzyloxy)methyl-8-methyl-2,3-dihydro[1,4]dioxino [2,3-f]quinoline (0.16 g, 0.5 mmol) in EtOH (1 mL) was added cyclohexene (0.5 mL) then 10% Pd/C (0.016 g, 10 mol %). The mixture was heated to reflux under N2 for 18 h then cooled and filtered. The catalyst was rinsed with methanol and the filtrate was concentrated in vacuo to afford 0.113 g (98%) of the title alcohol as an off-white solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCOCC1>[C:31]([N:18]1[C:19](=[O:20])[C:21]([F:23])=[CH:22][N:15]([C@@H:7]2[O:8][C@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6]2)[C:16]1=[O:17])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3ccccc3)c2=O)C[C@@H]1OC(C)=O
Reaction time: 1 h
Yield: 79.1 %

Procedure:
1.0 g of 2'-deoxy-3',5'-di-O-acetyl-5-fluorouridine and 0.76 ml of triethylamine were dissolved in 10 ml of dry dioxane, and the resulting solution was cooled with ice. To the solution was added 0.65 g of benzoyl chloride, and the resulting mixture was allowed to stand at room temperature for 60 minutes and then at 45° C. for 30 minutes. The crystals formed were filtered off, and the filtrate was concentrated under reduced pressure. The oily residue was purified by column chromatography on silica gel [column, diameter 3.5 cm; length, 21 cm; solvent, chloroform-methanol (99/1)]. The purified oily substance was dissolved in 10 ml of dimethylsulfoxide and added dropwise to 300 ml of water with vigorous agitation to be deposited as a solid. This solid was collected by filtration, washed sufficiently with water and dried at room temperature under reduced pressure. There was obtained 1.04 g (yield: 79.1%) of 3-benzoyl-2'-deoxy-3',5'-di-O-acetyl-5-fluorouridine as powder. The structure was supported by the absorption spectra and elemental analysis.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[CH2:22][S:23][CH2:24][C:25]([F:28])([F:27])[F:26].Cl.[CH3:30]CO>>[CH3:30][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=2[CH2:22][S:23][CH2:24][C:25]([F:28])([F:26])[F:27])[CH:4]=1
Reactant: O=C(O)Cc1ccc(O)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1
Reactant: CCO
Agent: Cl
Product: COC(=O)Cc1ccc(O)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
{4-Hydroxy-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid (3.6 mmol) and hydrogen chloride (4N in 1,4-dioxane) were combined in EtOH and stirred at 80° C. for 3 hours. After concentrating to dryness, the residue was purified by silica gel chromatography to give {4-hydroxy-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([Cl:12])[CH:3]=1.[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:15]3[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=3[CH3:13])[CH2:22][CH2:23]2)=[O:8])=[C:4]([Cl:12])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(Br)cc1Cl
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3cc(F)c(Br)cc3Cl)CC2)c(C)c1
Yield: 101.2 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 1 and using 4-bromo-2-chloro-5-fluorobenzoic acid (5 g) and 1-(2,4-dimethylphenyl)piperazine (3.8 g), the title compound (8.5 g) was obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[C:15](=[O:16])[N:14]3[C:17]4([NH:23][C:24](=[O:25])[C:13]3=[C:12]([CH3:26])[CH:11]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:4]=1[Cl:27].[CH:28]([N:31](CC)C(C)C)(C)[CH3:29].BrCC#N>CN(C)C=O.[Cl-].[NH4+]>[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[C:15](=[O:16])[N:14]3[C:17]4([NH:23][C:24](=[O:25])[C:13]3=[C:12]([CH3:26])[CH:11]=2)[CH2:22][CH2:21][N:20]([CH2:29][C:28]#[N:31])[CH2:19][CH2:18]4)[C:4]=1[Cl:27]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(Nc2ncnc(N)c2Cl)c(=O)n2c1C(=O)NC21CCNCC1
Agent: Cl
Agent: N#CCBr
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1cc(Nc2ncnc(N)c2Cl)c(=O)n2c1C(=O)NC21CCN(CC#N)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-((6-Amino-5-chloropyrimidin-4-yl)amino)-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione hydrochloride (5, 75 mg, 0.20 mmol) was dissolved in dimethylformamide (5 mL). To this mixture N,N-diisopropylethylamine (77 mg, 0.60 mmol) and bromoacetonitrile (36 mg, 0.30 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. After completion reaction mixture was diluted with saturated ammonium chloride solution (50 mL). The yellow precipitate out was filtered and dried under reduced pressure. The crude was purified by prep purification to afford 2-(6-((6-amino-5-chloropyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-1′-yl)acetonitrile (Cpd. No. 238) as white solid. Yield: 14 mg, 17%; MS (ESI) m/z 414.85 [M+1]+; 1H NMR (400 MHz, DMSO-d6 with d1-TFA) δ 8.49 (s, 1H), 8.33 (s, 1H), 4.49 (s, 2H), 3.76-3.71 (m, 2H), 3.58-3.41 (m, 4H), 2.42 (s, 3H), 1.90-1.87 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[Br:16]N1C(=O)CCC1=O.C(OCC)(=O)C>N(C(C)(C)C#N)=NC(C)(C)C#N.CCCCCC>[Br:16][CH2:15][C:14]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(C)c(OCC)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(CBr)c(OCC)c1
Reaction time: 14 h
Yield: 87 %

Procedure:
To a mixture of ethyl 3-ethoxy-4-methylbenzoate (2.0 g), N-bromosuccinimide (1.9 g) and ethyl acetate (40 mL) was added 2,2′-azobis(2-methylpropionitrile) (15 mg), followed by stirring for 14 hours under heating with reflux. The mixture was left to be cooled, hexane was added thereto, the precipitated solid was separated by filtration, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane:5/95) to obtain ethyl 4-(bromomethyl)-3-ethoxybenzoate (2.4 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[Si:32]([O:39][C@@H:40]1[CH2:44][CH2:43][C@@H:42]([OH:45])[CH2:41]1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].[C:46]1([C:52]2[CH:57]=[CH:56][C:55](O)=[CH:54][CH:53]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C1COCC1>[C:46]1([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:51]=[CH:50][C:49]([O:45][C@H:42]2[CH2:43][CH2:44][C@@H:40]([O:39][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:41]2)=[CH:48][CH:47]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@@H](O)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](Oc2ccc(-c3ccccc3)cc2)C1
Reaction time: 0.33 h

Procedure:
A solution of triphenylphosphine (0.195 g, 0.742 mmol) in 5 mL of dry THF was treated at 0° C. with diethylazodicarboxylate (0.117 mL, 0.742 mmol) and stirred for 20 min. A solution of (1R*,3R*)-3-(tert-butyldimethylsilanyloxy)cyclopentanol (0.146 g, 0.675 mmol) and 4-phenyl phenol (0.126 g, 0.0.724 mmol) in 5 mL of dry THF was added to the solution, and the mixture was stirred at room temperature overnight. The solution was concentrated under vacuum and purified by silica gel chromatography (silica gel, hexanes/ethyl acetate 6:1, Rf0.66). 1H-NMR (200.15 MHz, CDCl3): δ 7.58–7.29 (m, 7H); 6.93 (d, 2H, J=8.92), 4.76–4.65 (m, 1H), 4.32–4.21 (m, 1H), 2.38 (qn, 1H, J=7.0), 2.04–1.94 (m, 2H), 1.87–1.78 (m, 3H), 0.90 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H).