Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:19][C:20]([C:22]2[C:23](=[O:35])[N:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:25]([CH3:28])[C:26]=2[CH3:27])=[O:21])=[CH:4][C:5]([F:18])=[C:6]([CH:17]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10](C(N)=O)[CH:9]=1.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C.CC#[N:53]>CCOC(C)=O.O>[NH2:53][C:10]1[CH:9]=[C:8]([O:7][C:6]2[C:5]([F:18])=[CH:4][C:3]([NH:19][C:20]([C:22]3[C:23](=[O:35])[N:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:25]([CH3:28])[C:26]=3[CH3:27])=[O:21])=[C:2]([Cl:1])[CH:17]=2)[CH:13]=[CH:12][N:11]=1
Reactant: CC#N
Reactant: Cc1c(C(=O)Nc2cc(F)c(Oc3ccnc(C(N)=O)c3)cc2Cl)c(=O)n(-c2ccccc2)n1C
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2cc(F)c(Oc3ccnc(N)c3)cc2Cl)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a suspension of 4-(5-chloro-4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2-fluorophenoxy)picolinamide (297.6 mg, 0.6 mmol) in EtOAc (4 mL), CH3CN (4 mL) and H2O (2 mL) was added PhI(OAc)2 (97 mg, 0.3 mmol) at 0° C., the mixture was stirred at 0° C. for 30 minutes, then warmed up to rt and stirred for 12 hours. The mixture was concentrated in vacuo and the residue was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=20/1) to give the title compound as a light beige solid (220 mg, 78.3%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:18][C:19]([C:21]2[N:22]=[N:23][NH:24][CH:25]=2)=[O:20])[CH2:10][C@:11]([CH2:16][OH:17])([CH3:15])[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([F:36])=[C:31](B(O)O)[CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].O>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.O1CCOCC1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([F:36])=[C:29]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:18][C:19]([C:21]3[N:22]=[N:23][NH:24][CH:25]=3)=[O:20])[CH2:10][C@:11]([CH2:16][OH:17])([CH3:15])[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=2)[CH:28]=1
Reactant: OB(O)c1cc(Cl)ccc1F
Reactant: C[C@@](CO)(C[C@@H](Cc1ccc(Br)cc1)NC(=O)c1c[nH]nn1)C(=O)O
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1c[nH]nn1)C(=O)O
Temperature: 90 °C
Yield: 4.7 %

Procedure:
(2S,4R)-5-(4-bromophenyl)-2-hydroxymethyl-2-methyl-4-[(1H-[1,2,3]triazole-4-carbonyl)amino]pentanoic acid (38 mg, 92 μmol) was combined with 5-chloro-2-fluorophenylboronic acid (32.2 mg, 185 μmol), sodium carbonate (29.4 mg, 277 μmol), water (0.2 mL) and dioxane (1.5 mL). The reaction vessel was sealed, air was removed by vacuum, and the vessel was purged with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (21.4 mg, 18 μmol) was quickly added and air was removed by vacuum. The mixture was heated at 90° C. for 45 minutes. The mixture was acidified to pH ˜3 and filtered, and the solvate was concentrated. The residue was dissolved in AcOH (0.7 mL) and purified by preparative HPLC to yield the title compound (2 mg). MS m/z [M+H]+ calc'd for C22H22ClFN4O4, 461.13. found 461.2.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH:11]1[C:6]2[S:5][CH2:4][CH2:3][CH2:2][O:12][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: OCCCSc1ccccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc2c(c1)OCCCS2
Temperature: -40 °C
Reaction time: 2.5 h

Procedure:
To 2-(3-hydroxy-propylsulfanyl)-phenol (29.2 g, 158.5 mmol) in THF (450 mL) was added triphenylphosphine (52.0 g, 200.0 mmol). The solution was cooled to −40° C. and diethyl azodicarboxylate (31.5 mL, 164.0 mmol) was added slowly. The solution was warmed to rt and stirred for 2.5 h. The THF was removed by evaporation and the residue was treated with 1 L of Et2O. The formed solids were filtered off, and the filtrate concentrated to an oil which was purified over silica gel (10% Et2O/hexane) to a pink oil (16.2 g, 61%).
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[CH3:13][N:14]1[C:18](=[O:19])[CH2:17][S:16][CH:15]1[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.BrCCCC.[I-].[Na+].P([O-])([O-])([O-])=O>CCCCCC.O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH2:8]([CH:17]1[S:16][CH:15]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:14]([CH3:13])[C:18]1=[O:19])[CH2:9][CH2:10][CH3:11]
Reactant: [Li]CCCC
Reactant: CN1C(=O)CSC1c1cccnc1
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Solvent: CCCCBr
Product: CCCCC1SC(c2cccnc2)N(C)C1=O
Reaction time: 1 h
Yield: 19.2 %

Procedure:
Dry diisopropylamine (1 ml, 5.7 mmol) was added to dry tetrahydrofuran (3 ml), and a butyllithium solution (3.9 ml, 6.2 mmol) in hexane was added dropwise at -40° C., the miXture was kept at -10° C. for 1 hour. A solution of 3-methyl-2-(3-pyridyl)thiazolidin-4-one (1 g, 5.2 mmol) in dry tetrahydrofuran (7 ml) was added dropwise to the mixture at -20° to -10° C. After this reaction mixture had been kept between those temperatures for 1 hour, there were added at -10° C. 1 bromobutane (0.78 g, 5.7 mmol) dissolved in tetrahydrofuran (2 ml), sodium iodide (0.77 g, 5.2 mmol), and hexamethylphosphorotriamide (1 ml). This reaction mixture was kept at room temperature for 2 hours. The resulting mixture, after addition of a phosphate buffer (pH 7.0), was extracted with ethyl acetate. The extract was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated by evaporation under reduced pressure. The residue was chromatographed on silica gel (hexane-ethyl acetate), giving 5-butyl-3-methyl-2-(3-pyridyl)thiazolidin-4-one (250 mg, 20% yield).
Reaction SMILES: CCN(C(C)C)C(C)C.[S:10]([N:20]1[CH2:25][CH2:24][N:23]2[CH:26]=[CH:27][CH:28]=[C:22]2[CH:21]1[CH2:29][C:30]([OH:32])=O)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[F:55][CH:56]1[CH2:61][CH2:60][N:59]([CH2:62][C:63]2[CH:64]=[C:65]3[C:70](=[CH:71][CH:72]=2)[CH:69]([NH2:73])[CH2:68][CH2:67][CH2:66]3)[CH2:58][CH2:57]1>C(Cl)Cl>[F:55][CH:56]1[CH2:61][CH2:60][N:59]([CH2:62][C:63]2[CH:64]=[C:65]3[C:70](=[CH:71][CH:72]=2)[C@H:69]([NH:73][C:30](=[O:32])[CH2:29][CH:21]2[N:20]([S:10]([C:13]4[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=4)(=[O:11])=[O:12])[CH2:25][CH2:24][N:23]4[CH:26]=[CH:27][CH:28]=[C:22]24)[CH2:68][CH2:67][CH2:66]3)[CH2:58][CH2:57]1
Reactant: NC1CCCc2cc(CN3CCC(F)CC3)ccc21
Reactant: Cc1ccc(S(=O)(=O)N2CCn3cccc3C2CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N2CCn3cccc3C2CC(=O)N[C@@H]2CCCc3cc(CN4CCC(F)CC4)ccc32)cc1
Reaction time: 0.5 h
Yield: 38 %

Procedure:
DIPEA (630 μl, 3.592 mmol, 4.0 eq.) was added to a stirred solution of 2-(2-tosyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid (S11) (300 mg, 0.898 mmol, 1.0 eq.) in DCM (15 ml), followed by EDCl (260 mg, 1.347 mmol, 1.5 eq.) and HOBT (183 mg, 1.347 mmol, 1.5 eq.) which were added at 0° C. The reaction mixture was allowed to stir for 30 min. A solution of R)-6-((4-fluoropiperidin-1-yl)methyl)-1,2,3,4-tetrahydronaphthalen-1-amine (A52) (0.898 mmol, 1.0 eq.) in DCM (5 ml) was added to the reaction mixture and it was stirred at RT for 16 h. The reaction mixture was diluted with DCM (50 ml) and washed with sat. NH4Cl solution (50 ml), sat. NaHCO3 solution (50 ml), water (50 ml) and brine (50 ml), and dried over Na2SO4. The solvent was evaporated under reduced pressure to give crude product which was purified by column chromatography (silica gel; 2% MeOH/DCM) to yield the desired compound as an off white solid. Yield: 38% (197 mg, 0.34 mmol); MS, Rt=3.2 min; m/z=579.1 [M H]+
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>[Rh].C(O)C>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([OH:11])[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [Rh]
Solvent: CCO
Product: CC(C)(C)C1CCC(O)CC1
Yield: 87.5 %

Procedure:
U.S. Pat. No. 2,927,127 discloses that hydrogenation of p-tert-butyl phenol with a Ni catalyst yields p-tert-butyl cyclohexanol having proportions of approximately 30% cis-isomer and approximately 70% trans-isomer. U.S. Pat. No. 2,927,127 further describes the hydrogenation of p-tert-butyl phenol using Rh/C as catalyst in ethanol to yield p-tert-butyl cyclohexanol containing 87.5% of the cis-isomer, which was subsequently converted to the corresponding acetates by reaction with acetic anhydride.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:8]2[CH2:9][CH2:10][C@@H:4]([C@@H:5]3[C@H:7]2[CH2:6]3)[C@H:3]1[C:11]([O:13][CH3:14])=[O:12].C(O)(=O)C.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:1][C@H:2]2[C@@H:8]3[CH2:9][CH2:10][C@@H:4]([C@@H:5]4[C@H:7]3[CH2:6]4)[C@H:3]2[C:11]([O:13][CH3:14])=[O:12])=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)[C@H]1[C@@H](N)[C@@H]2CC[C@H]1[C@H]1C[C@H]12
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1[C@H]2CC[C@H]([C@@H]3C[C@@H]32)[C@@H]1NCc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
The crude rac-Methyl (1R,2R,4S,5S,6R,7S)-7-aminotricyclo[3.2.2.02,4]nonane-6-carboxylate was dissolved in methanol (10 mL). Acetic acid (0.12 mL, 2.14 mmol) was added followed by 4-fluoro-benzaldehyde (0.12 mL, 1.07 mmol). Sodium cyanoborohydride (0.14 g, 2.14 mmol) was added and the mixture was stirred at 60° C. for 16 h. The mixture was cooled to 25° C. and poured into a mixture of saturated aqueous sodium bicarbonate solution (20 mL) and ethyl acetate (30 mL). After shaking, both layers were passed through a plug of Celite. The organic layer was further washed with saturated aqueous sodium bicarbonate solution (10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, rac-Methyl (1R,2R,4S,5S,6R,7S)-7-{[(4-fluorophenyl)methyl]amino}tricyclo[3.2.2.02,4]nonane-6-carboxylate, as a clear oil, which was used in the next step without further purification. LC-MS (ESI) calcd for C17H22FNO2 291.36, found 292.0 [M+H+].
Reaction SMILES: [F:1][CH:2]([F:13])[O:3]C1C=C2C(C=CN2)=CC=1.C(O[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([C:27]([NH2:29])=[O:28])[CH:22]=[C:21]2[N:30]=[C:31]=[O:32])C=C>>[F:1][CH:2]([F:13])[O:3][C:26]1[CH:25]=[C:24]2[C:20]([C:21]([N:30]=[C:31]=[O:32])=[CH:22][N:23]2[C:27]([NH2:29])=[O:28])=[CH:19][CH:18]=1
Reactant: C=CCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Reactant: FC(F)Oc1ccc2cc[nH]c2c1
Product: NC(=O)n1cc(N=C=O)c2ccc(OC(F)F)cc21

Procedure:
was prepared from 6-difluoromethoxy-1H-indole [200207-21-2] using the protocol described for steps B-E in Scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=1)([CH3:3])[CH3:2].Cl.[O:13]1[C:18]2([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:16]2[CH2:17][C:18]3([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[O:13][CH2:14][CH2:15]2)=[O:11])[N:8]=1)([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Reactant: CC(C)c1nc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cs1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 2-isopropylthiazole-4-carboxylic acid (1 g) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (1.71 g) in DMF (30 mL) was cooled in an ice bath and treated with triethylamine (2.442 mL) followed by HATU (2.89 g). The ice bath was removed and the mixture was stirred at 20° C. for 1 hour. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 70% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 2 g.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[N:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20][CH3:21].[Br:35][C:36]1[CH:37]=[N:38][C:39](Cl)=[N:40][CH:41]=1.C(NC(C(C)C)(C(C)C)C)C.C(OCC)(=O)C>C1(C)C=CC=CC=1.O>[F:1][C:2]([F:33])([F:34])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([C:39]1[N:40]=[CH:41][C:36]([Br:35])=[CH:37][N:38]=1)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:17])([F:16])[F:18])[CH:12]=[CH:11][C:10]=1[N:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20][CH3:21]
Reactant: CCCCN(CC)c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Clc1ncc(Br)cn1
Agent: CCNC(C)(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
{2-[(3,5-Bis-trifluoromethyl-benzylamino)-methyl]-4-trifluoromethyl-phenyl}-butyl-ethyl-amine (4.6 g), 5-bromo-2-chloropyrimidine (3.56 g) and N-ethyldiisopropylethylamine (4.8 ml) are dissolved in toluene (100 ml) and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, and the mixture is separated and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→9:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amine (5.24 g). MS (m/z): 657/659 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:15][CH3:16])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2C(OC)=O)[CH:7]=1.BrC1C2N(N=CC=2C(OC)=O)C=C(OC)C=1.Br.[OH-].[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:15][CH3:16])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1
Reactant: COC(=O)c1cnn2cc(Br)cc(OC)c12
Agent: Br
Agent: COC(=O)c1cnn2cc(OC)cc(Br)c12
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc(Br)cn2nccc12
Temperature: 100 °C

Procedure:
A mixture of methyl 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (4.33 g, 15.2 mmol) and methyl 4-bromo-6-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (1.44 g, 5.05 mmol) was suspended in hydrobromic acid (100 ml, 884 mmol) and heated to 100° C. for 60 minutes. The mixture was cooled to 0° C. and carefully quenched via the addition of 1N aqueous sodium hydroxide (152 ml, 909 mmol). The reaction mixture was diluted in ethyl acetate, washed with 1N aqueous sodium hydroxide and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (Ethyl acetate/isohexane gradient) to give 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (faster eluting isomer) and 4-bromo-6-methoxypyrazolo[1,5-a]pyridine (slower eluting isomer).
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[CH2:7]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:23]=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>O1CCOCC1.O>[CH2:29]([O:28][C:27]1[CH:26]=[CH:25][C:22]([CH:23]=[CH2:1])=[CH:21][C:20]=1[O:19][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCCCCCCOc1ccc(C=O)cc1OCCCCCCCCCCCC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1ccc(OCCCCCCCCCCCC)c(OCCCCCCCCCCCC)c1
Temperature: 95 °C
Yield: 65.5 %

Procedure:
A round bottom flask was charged with Ph3PMeBr (8.79 g, 24.6 mmol), K2CO3 (3.4 g, 24.6 mmol), and 3,4-bis-dodecyloxy-benzaldehyde (10.0 g, 21.1 mmol) in a mixture of 25 mL of 1,4-dioxane and 0.3 mL of H2O. The reaction mixture was refluxed at 95° C. for 24 h. The reaction mixture was allowed to cool down to room temperature and extracted with CH2Cl2. The organic layer was washed with H2O and dried over anhydrous MgSO4. The solvent was removed under reduced pressure to give an off-white solid. The crude product was purified by column chromatography (silica gel, hexanes:dichloromethane=2:1 (v/v)) to give a white solid (6.53 g, 65.6%). 1H NMR (300 MHz, CDCl3, δ): 6.96 (d, J=1.9 Hz, 1H), 6.90 (dd, J=8.0 Hz, 1.9 Hz, 1H), 6.80 (d, J=8.2 Hz, 1H), 6.62 (dd, J=17.3 Hz, 10.7 Hz, 1H), 5.57 (dd, J=17.6 Hz, 0.5 Hz, 1H), 5.11 (d, J=11.5 Hz, 1H), 3.98 (q, J=6.6 Hz, 4H), 1.74-1.85 (m, 4H), 1.19-1.50 (m, 36H), 0.87 (t, J=6.6 Hz, 6H). 13C{1H} NMR (75 MHz, CDCl3, δ): 149.01, 148.98, 136.44, 130.63, 119.46, 113.44, 111.50, 111.18, 69.24, 32.00, 29.78, 29.72, 29.51, 29.45, 29.38, 29.34, 26.12, 22.78, 14.22. HRMS-EI (m/z): [M]+ calcd for C32H56O2, 472.4280; found, 472.4267. Anal. Calcd C32H56O2: C, 81.29; H, 11.94. Found: C, 81.36; H, 11.99.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](F)[CH:10]=2)[C:5]([OH:13])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:20]1(CBr)C[CH2:21]1>C(#N)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:13][CH2:20][CH3:21])=[CH:4][N:3]=1
Reactant: Oc1cnc(Cl)c2cc(F)ccc12
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1cnc(Cl)c2ccccc12
Temperature: 50 °C
Yield: 66.6 %

Procedure:
To a solution of 1-chloro-7-fluoro-4-hydroxyisoquinoline (1.0 g, 5.06 mmol) in acetonitrile (10 ml) was added K2CO3 (2 g, 15.18 mmol) followed by cyclopropylmethylbromide (1.36 g, 10.12 mmol) at room temperature. The reaction mixture was heated to 50° C. for 2 hr. Solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get 1-chloro-4-ethoxyisoquinoline (0.7 g, 55%) as pale yellow solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.38-8.34 (q, J=8 Hz, 1H), 7.89-7.86 (d, J=12 Hz, 1H), 7.81 (s, 1H), 7.65 (t, J=10 Hz, 1H), 4.11-4.09 (d, J=8 Hz, 2H), 1.43-1.37 (m, 1H), 0.72-0.67 (m, 2H), 0.46-0.39 (m, 2H); MS: MS m/z 252.0 (M++1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[SH:15][CH2:16][CH2:17][OH:18]>>[OH:18][CH2:17][CH2:16][S:15][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: OCCS
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])c(Cl)c1
Product: CC(=O)Nc1ccc([N+](=O)[O-])c(SCCO)c1

Procedure:
Starting with 42.9 g (0.2 mol) of 2-chloro-4-acetylaminonitrobenzene and 23.4 g (0.3 mol) of 2-mercaptoethanol, pale yellow crystals (46.6 g) of the expected compound are obtained, the melting point of which is 174° C. (recrystallized from 96° ethanol) and the elemental analysis of which, calculated for C10H12N2O4S.1/2CH3CH2OH, is:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([CH:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:23][CH:24]=[CH2:25])[N:16]=3)=[C:9]([F:32])[CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1C[CH2:46][CH2:45][CH2:44]1.C(I)C=C>CN(C=O)C>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([CH2:46][CH:45]=[CH2:44])[CH2:23][CH:24]=[CH2:25])[N:16]=3)=[C:9]([F:32])[CH:8]=1
Reactant: C1CCOC1
Reactant: C=CCC(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Agent: C=CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC(CC=C)(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Reaction time: 0.03 h

Procedure:
To a slurry of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylbut-3-enyl)-thiazolo[5,4-b]pyridine (1.17 g, 2.62 mmol) in 20 mL DMF under argon was added sodium bis(trimethylsilyl)amide, 1.0M solution in tetrahydrofuran (3.28 mL, 3.28 mmol). The reaction mixture became deep blue/purple. After 2 min, allyl iodide (0.362 mL, 3.93 mmol) was added and the reaction became light orange after 1 min. After 5 min total, the reaction mixture was quenched with sat'd aq. NH4Cl, EtOAc, and water. The organic layer was washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography, ISCO, 80 g, 0-40% EA/hexanes to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(4-phenylhepta-1,6-dien-4-yl)thiazolo[5,4-b]pyridine as a white foam. MS (ESI) m/z: Calculated: 486.2; Observed: 487.1 (M++1).
Reaction SMILES: [Br:1][C:2]1[C:11]2[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18]CC)=[O:17])=[CH:7][C:6]=2[CH:5]=[C:4]([Cl:21])[CH:3]=1.C(O)C.[OH-].[Na+].Cl>O.O1CCCC1>[Br:1][C:2]1[C:11]2[O:10][CH:9]([C:12]([F:14])([F:13])[F:15])[C:8]([C:16]([OH:18])=[O:17])=[CH:7][C:6]=2[CH:5]=[C:4]([Cl:21])[CH:3]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(Br)c2OC1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1=Cc2cc(Cl)cc(Br)c2OC1C(F)(F)F
Yield: 71.9 %

Procedure:
Ethyl 8-bromo-6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-caboxylate (0.3 g), ethanol (15 mL), tetrahydrofuran (10 mL), and sodium hydroxide solution (10 mL, 2.5 N) were stirred at room temperature for 16 h. Hydrochloric acid (1 N) was added until the mixture was acidic to pH paper. The addition of water (50 mL) caused the formation of a precipitate which was collected by filtration yielding the title compound as a white solid (0.2 g, 72%): mp 227.8–228.9° C. 1H NMR (acetone-d6/300 MHz) 7.90 (s, 1H), 7.65 (dd, 2H, J=2.4 and J=28.8 Hz), 6.00 (qH-F, 1H, J=7.2 Hz). FABHRMS m/z 356.9134 (M+H, Calc'd 356.9141). Anal. Calc'd for C11H5BrClF3O3: C, 36.96; H, 1.41. Found: C, 37.05; H, 1.33.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[Si](Cl)(Cl)(Cl)Cl>C(O)(=O)C>[C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Agent: Cl[Si](Cl)(Cl)Cl
Solvent: CC(=O)O
Product: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Reaction time: 0.33 h
Yield: 55 %

Procedure:
5 G of cytidine are dissolved in 50 ml of acetic acid. 4.75 ml of silicon tetrachloride are added to the solution. The mixture is stirred at 60° to 70°C for 20 minutes. Then, the mixture is refluxed for 3 hours under heating. The reaction mixture is concentrated under reduced pressure. The residue is dissolved in ice-water, and the aqueous solution is adjusted to pH 12.5 with an aqueous 2 N-sodium hydroxide solution. After the aqueous solution is stirred at room temperature for 30 minutes, said solution is passed through a column of 200 ml of a strong acidic ion exchange resin (H+ -form) (Diaion SK-IB). The column is washed with water and eluted with 1300 ml of aqueous 1N-ammonia. The eluate is concentrated under reduced pressure. The residue thus obtained is crystallized with ethanol and then recrystallized from 50 % ethanol. 2.7 G of 1-β-D-arabinofuranosyl cytosine are thereby obtained. Yield: 55 % M.p. 213°-214°C (decomp.)