Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.Cl.[CH3:5][O:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:22]=[CH:21][C:20]3[N:19]=[CH:18][C:17]4[CH2:23][N:24]([CH3:34])[C:25](=[O:33])[N:26]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[C:16]=4[C:15]=3[N:14]=2)=[CH:9][CH:8]=1.[C:35](O)(=[O:39])[C@@H:36]([CH3:38])[OH:37].ON1C2C=CC=CC=2N=N1>C(Cl)Cl.CO.C(N(CC)CC)C>[OH:37][C@H:36]([CH3:38])[C:35]([N:30]1[CH2:31][CH2:32][CH:27]([N:26]2[C:16]3[C:15]4[N:14]=[C:13]([C:10]5[CH:11]=[N:12][C:7]([O:6][CH3:5])=[CH:8][CH:9]=5)[CH:22]=[CH:21][C:20]=4[N:19]=[CH:18][C:17]=3[CH2:23][N:24]([CH3:34])[C:25]2=[O:33])[CH2:28][CH2:29]1)=[O:39]
Reactant: C[C@@H](O)C(=O)O
Reactant: COc1ccc(-c2ccc3ncc4c(c3n2)N(C2CCNCC2)C(=O)N(C)C4)cn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(-c2ccc3ncc4c(c3n2)N(C2CCN(C(=O)[C@@H](C)O)CC2)C(=O)N(C)C4)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To DCM (20 mL) were added 9-(6-methoxypyridin-3-yl)-3-methyl-1-(piperidin-4-yl)-3,4-dihydropyrimido[5,4-c][1,5]naphthyridin-2(1H)-one hydrochloride salt (Compound 1) (100 mg, 0.227 mmol) and triethylamine (0.177 mL). The mixture was stirred at ambient temperature for 0.5 h. Then to the mixture were sequentially added (R)-lactic acid (26.7 mg, 0.296 mmol), 1-hydroxybenzotriazole (37.8 mg, 0.280 mmol) and 1-ethyl-(3-dimethyllaminopropyl)carbodiimide hydrochloride (70.8 mg, 0.37 mmol). The reaction mixture was stirred at ambient temperature for 2 h, and the completion of the reaction was indicated by TLC (DCM/methanol=10/1). The reaction mixture was washed sequentially with saturated aqueous sodium carbonate, water and brine. The organic phase was dried over sodium sulfate, concentrated and purified by silica gel column chromatography (DCM/methanol=10/1) to give a white solid (88 mg, 81.4% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8]COC)=[CH:6][CH:5]=[CH:4][N:3]=1.S(O[CH:17]([CH2:21][C:22]#[CH:23])[C:18](=O)[CH3:19])(C)(=O)=O>C(O)C>[OH:8][C:7]1[C:2]2[N:3]([C:17]([CH2:21][C:22]#[CH:23])=[C:18]([CH3:19])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: COCOc1cccnc1N
Reactant: C#CCC(OS(C)(=O)=O)C(C)=O
Solvent: CCO
Product: C#CCc1c(C)nc2c(O)cccn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 21.3 %

Procedure:
A solution of 2-amino-3-methoxymethoxypyridine (7.5 g) and 3-mesyloxy-5-hexyn-2-one (10.18 g) in ethanol (150 ml) was refluxed for 46.5 hours and then evaporated in vacuo. To the residue was added 20% sulfuric acid (75 ml) and the mixture was stirred for 5 hours at room temperature. The mixture was made alkaline with sodium bicarbonate and extracted with chloroform. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (30 g) with chloroform and then a mixture of chloroform and methanol (30:1 to 20:1) as eluents. The eluates were evaporated in vacuo and the residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 8-hydroxy-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (1.93 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([SH:20])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:21])=[CH:4][N:3]=1.[Cl:22][C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1>>[ClH:22].[F:21][C:9]1[CH:10]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20][C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Clc1ncccn1
Reactant: Nc1ncc(-c2ccc(-c3ccccc3S)cc2F)cn1
Product: Cl
Product: Nc1ncc(-c2ccc(-c3ccccc3Sc3ncccn3)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 213 utilizing 4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-thiol and 2-chloropyrimidine. MS (ESI): mass calcd. for C20H14FN5S, 375.10; m/z found, 375.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 2H), 8.56 (d, J=4.9, 2H), 7.79-7.73 (m, 1H), 7.63-7.56 (m, 2H), 7.55-7.48 (m, 2H), 7.33-7.24 (m, 2H), 7.21 (m, 1H), 6.23 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[O:11][C:10](=[O:20])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[CH2:24]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[O:11][C:10](=[O:20])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc2c(-c3cccc(O)c3)cc(=O)oc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(-c3cccc(OCc4ccccc4)c3)cc(=O)oc2c1
Temperature: 45 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
4-[3′-(hydroxy)phenyl]-7-methoxycoumarin (prepared as in Example 1 (ii) (268 g) and 95% sodium methoxide (102 g) were dissolved in methanol (3.00 L) and stirred while heating to 45° C. Benzyl bromide (314 g) was added and the reaction was heated to 60° C. A thick precipitate formed in the pink reaction mixture. After 3 hours, the slurry was cooled in an ice-water bath and filtered to collect the product, which was washed with methanol (500 mL) and water (1.0 L), then dried under vacuum (20 inches of Hg) at 70° C. to give 4-[3-(benzyloxy)phenyl]-7-methoxycoumarin (320 g, 89%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[C:6]([S:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[C:7]2=[O:12].[Br:20]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>CC(OC(C)=O)=O>[Br:20][CH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[C:6]([S:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[C:7]2=[O:12]
Reactant: Cc1cccc2c1C(=O)C=C(SC(C)C(=O)O)C2=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(=O)OC(C)=O
Product: CC(SC1=CC(=O)c2c(CBr)cccc2C1=O)C(=O)O
Reaction time: 0.5 h

Procedure:
The acid 1 (59 mmol), N-bromosuccinimide (59 mmol), and azobis (2-methyl-propionitrile) (0.5 g, 3 mmol) is combined in 200 mL of Ac2O and stirred at 120°-130° C. for about 0.5 hours. When the color lightens, the solution is poured onto ice. The yellow solid is collected and dissolved in CHCl3. The CHCl3 solution is dried using Na2SO4, concentrated to a small volume, and chromatographed on silica gel column (benzene) to yield the brominated acid (5-bromomethyl-1,4-naphthoquinonyl thio)-proprionic acid, designated as compound 1b.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(=O)=O.O.CC(O)C.C([O-])([O-])=O.[K+].[K+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(O)(C(F)(F)F)=O.O>[Br:17][C:15]1[CH:14]=[CH:13][C:12]2[N:8]3[CH2:7][CH2:6][N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][C:9]3=[N:10][C:11]=2[CH:16]=1
Reactant: CC(C)(C)OC(=O)NCc1nc2cc(Br)ccc2n1CCOS(C)(=O)=O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)OC(=O)N1CCn2c(nc3cc(Br)ccc32)C1
Temperature: 105 °C
Reaction time: 48 h
Yield: 88.6 %

Procedure:
2-(5-Bromo-2-((tert-butoxycarbonylamino)methyl)-1H-benzo[d]imidazol-1-yl)ethyl methanesulfonate (883 mg, crude, 1.76 mmol estimated) was stirred in TFA (10 mL) for 1 h and then concentrated. Water/i-PrOH (32 mL/8 mL) and K2CO3 (2.31 g, 16.7 mmol) were added, and the mixture was heated at 105° C. for 2 h and then cooled to room temperature. Di-tert-butyl dicarbonate (812 mg, 3.73 mmol) was added, and the reaction mixture was stirred for 48 h and then diluted with water. The solid was filtered off and dried under vacuum to provide the title compound (549 mg, 89%) as a brown solid: ESI MS m/z 352 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)([OH:25])[CH2:10][N:11]1[CH:15]=[N:14][C:13]([CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[N:12]1.[H-].[Na+].[H][H].[Cl:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Cl)=[CH:39][CH:38]=1.Cl>CN1CCCC1=O>[Cl:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][O:24][C:21]2[CH:22]=[CH:23][C:18]([CH:17]=[CH:16][C:13]3[N:14]=[CH:15][N:11]([CH2:10][C:9]([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])([CH2:26][N:27]4[CH:31]=[N:30][CH:29]=[N:28]4)[OH:25])[N:12]=3)=[CH:19][CH:20]=2)=[CH:39][CH:38]=1
Reactant: Oc1ccc(C=Cc2ncn(CC(O)(Cn3cncn3)c3ccc(F)cc3F)n2)cc1
Reactant: [H][H]
Reactant: ClCc1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: OC(Cn1cncn1)(Cn1cnc(C=Cc2ccc(OCc3ccc(Cl)cc3)cc2)n1)c1ccc(F)cc1F
Reaction time: 3 h

Procedure:
1-(2,4-Difluorophenyl)-2-[3-(4-hydroxystyryl)-1,2,4-triazol-1-yl]-1-(1,2,4-triazol-1-ylmethyl)ethanol (710 mg) was dissolved in N-methylpyrrolidone (10 ml., dried over molecular sieve), and sodium hydride (57% dispersion in oil, 75 mg) was added in portions. When the evolution of hydrogen had ceased, p-chlorobenzyl chloride (300 mg) was added, and the mixture was stirred at 80° for 3 hours and then for 18 hours at room temperature. The reaction mixture was poured into 0.1N hydrochloric acid and extracted with ethyl acetate. The extracts were combined, washed successively with water, 0.5N sodium hydroxide solution (twice), water and brine, and was then filtered through anhydrous sodium sulphate. The filtrate was evaporated, and the crude product was purified by medium pressure liquid chromatography, eluting with chloroform, to give 2-[3-(4-p-chlorobenzyloxystyryl)-1,2,4-triazol-1-yl]-1-(2,4-difluorophenyl)-1-(1,2,4-triazol-1-ylmethyl)ethanol, crystallised from diethylether/ethyl acetate/petroleum ether, m.p. 103°-106°.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.[H-].[Na+].[C:14]1(C)[C:15]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=1.[CH3:25]COC(C)=O>CN(C=O)C>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[N:9]([S:20]([C:15]3[CH:14]=[CH:19][C:18]([CH3:25])=[CH:17][CH:16]=3)(=[O:21])=[O:22])[CH:10]=[CH:11][C:3]=12
Reactant: CCOC(C)=O
Reactant: Clc1cnc2[nH]ccc2c1Br
Reactant: Cc1ccccc1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Br)c(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of 4-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine (D) (1.89 g, 8.16 mmol) in DMF (15 mL) at 0° C. was added NaH (60% in oil, 328 mg) followed by toluenesulfonylchloride (1.72 g, 8.98 mmol). The reaction mixture was warmed to RT and additional NaH (60% in oil, 2×200 mg) was added at 1 h intervals. After a further 1 h, EtOAc was added and the reaction was quenched with sat'd NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (SiO2, 7% EtOAc in hexanes) provided 4-bromo-5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (E) (1.81 g, 58%) as an off white solid. LC/MS Tret=4.8 min, (M+H+) 386.6.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].O[CH:9]1[C:16](=C)C[C@H:14]2[C@@H:10]1[CH2:11][C@@H:12]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[C@H:13]2/[CH:18]=[CH:19]/[C@@H:20]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>N1C=CC=CC=1>[C:5]([O:4][CH:1]1[C:9](=[CH2:16])[CH2:10][C@H:14]2[C@@H:2]1[CH2:11][C@@H:12]([O:34][Si:35]([C:38]([CH3:40])([CH3:39])[CH3:41])([CH3:36])[CH3:37])[C@H:13]2/[CH:18]=[CH:19]/[C@@H:20]([O:26][Si:27]([C:30]([CH3:32])([CH3:31])[CH3:33])([CH3:28])[CH3:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:7])[CH3:6]
Reactant: C=C1C[C@@H]2[C@H](/C=C/[C@H](CCCCC)O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]2C1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C=C1C[C@@H]2[C@H](/C=C/[C@H](CCCCC)O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]2C1OC(C)=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 98 %

Procedure:
Acetic anhydride (0.5 ml) and pyridine (0.5 ml) were added to 95 mg (0.187 mmole) of (1S,2RS,5S,6S,7R)-2-hydroxy-3-methylene-6-[(E,3S)-3-t-butyldimethylsilyloxy-1-octenyl]-7-t-butyldimethylsilyloxybicyclo[3.3.0]octane obtained in Example 3, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure, and then subjected to column chromatography (silica gel 20 g, hexane/ethyl acetate=19/1) to give (1S,2RS,5S,6S,7R)-2-acetoxy-3-methylene-6-[(E,3S)-3-t-butyldimethylsilyloxy-l-octenyl]-7-t-butyldimethylsilyloxybicyclo[3.3.0]octane (101 mg, 0.184 mmole, 98%).
Reaction SMILES: [H-].[Na+].C(COC)OC.P(=O)([O-])O[CH2:11][C:12](=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH:17](C)C.[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]1[C:38]([CH:39]=O)=[C:37]([O:41][CH3:42])[CH:36]=[CH:35][C:34]=1[O:43][CH3:44])([O:25][CH3:26])=[O:24]>C(O)(=O)C>[CH3:44][O:43][C:34]1[CH:35]=[CH:36][C:37]([O:41][CH3:42])=[C:38](/[CH:39]=[CH:11]/[C:12](=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:33]=1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)CCCCCCc1c(OC)ccc(OC)c1C=O
Reactant: CC(C)CCCCC(=O)CO[PH](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CC(=O)O
Product: CCCCCC(=O)/C=C/c1c(OC)ccc(OC)c1CCCCCCC(=O)OC
Temperature: 85 °C

Procedure:
To a slurry of 278 mg. of a dispersion of sodium hydride in mineral oil in 40 ml. of dimethoxyethane is added a solution of 1.33 g. of dimethyl(2-oxoheptyl) phosphonate in 40 ml. of dimethoxyethane and the mixture is stirred for one hour. 1.41 g. of the aldehyde in 40 ml. of dimethoxyethane is added and the mixture heated at 85° C. for eighteen hours. The mixture is then cooled and neutralized with acetic acid and the solvent is removed in vacuo. The residue is then chromatographed on a silica gel column to yield 1,4-dimethoxy-2-(6-carbomethoxyhexyl)-3-(3-oxo-trans-1-octenyl)benzene as a yellow oil.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:36][CH:37]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:38][NH:39][C:40]([CH:42]1[CH2:47][CH:46]([CH3:48])[CH2:45][CH2:44][CH:43]1[CH:49]([CH3:51])[CH3:50])=[O:41]>O.C(OCC)(=O)C.C1COCC1>[C:4]([O:3][C:1](=[O:2])[NH:8][CH:9]([C:11](=[O:13])[NH:36][CH:37]([C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[CH2:38][NH:39][C:40]([CH:42]1[CH2:47][CH:46]([CH3:48])[CH2:45][CH2:44][CH:43]1[CH:49]([CH3:51])[CH3:50])=[O:41])[CH3:10])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC1CCC(C(C)C)C(C(=O)NCC(N)c2ccccc2)C1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC1CCC(C(C)C)C(C(=O)NCC(NC(=O)C(C)NC(=O)OC(C)(C)C)c2ccccc2)C1
Reaction time: 3 h
Yield: 25.5 %

Procedure:
A 15 mL reaction vessel equipped with a stir bar was charged with THF (15 mL), Boc-(R)-alanine (52 mg, 0.273 mmoles), HOBt (37.87 mg, 0.273 mmoles), EDCl (53 mg, 0.273 mmoles) and TEA (37 μl, 0.273 mmoles). The reaction mixture was stirred for 15 min. whereupon 2-isopropyl-5-methyl-cyclohexanecarboxylic acid (2-amino-2-phenyl-ethyl)-amide (75 mg, 0.248 mmol) was added and stirred for an additional 3 h. Ethyl acetate (10 mL) and H2O (10 mL) were added to the reaction mixture. The heterogeneous mixture was transferred to a separatory funnel where the aqueous phase was separated and re-extracted with ethyl acetate (2×10 mL). The organic phases were combined and washed with 1N HCl (2×10 mL), H2O (1×10 mL), sat NaHCO3 (3×10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (20% ethyl acetate/hexane for elution) provided the title compounds as colorless solid (30 mg).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([C:12](O)=[O:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.O>[OH:13][CH2:12][CH:10]1[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(CO)C1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 66.4 %

Procedure:
To a solution of 1-Boc-azetidine-3-carboxylic acid (Astatech, 1.0 g, 4.97 mmol) in tetrahydrofuran (10 mL) at −10° C. was added 4-methylmorpholine (0.55 mL, 5.0 mmol). This mixture was stirred for 1 minute and then ethyl chloroformate (0.47 mL, 4.97 mmol) was added dropwise. The mixture was stirred at −10° C. for 15 min then was filtered through Celite and the filtrate was added dropwise via syringe to a mixture of NaBH4 (0.42 g, 11.2 mmol) in H2O (5 mL) at 5° C. The mixture was allowed to warm to ambient temperature and was stirred vigorously for 3 h. The reaction mixture was quenched with 5 mL saturated, aqueous NH4Cl, the layers were separated and the aqueous layer was extracted with 3×5 mL ethyl acetate. The combined organics were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified by column chromatography (SiO2, 30% hexanes in ethyl acetate) to give the title compound (0.62 g, 3.3 mmol, 66% yield). MS (DCI/NH3) m/z 188 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].C(N(CC)CC)C.[C:17](=[S:19])=[S:18].[CH3:20]I>O1CCCC1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][C:17](=[S:19])[S:18][CH3:20])[CH3:2]
Reactant: CI
Reactant: CCOC(CN)OCC
Reactant: S=C=S
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(CNC(=S)SC)OCC
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a solution of 4 g (0.03 mole) of aminoacetaldehyde diethylacetal in 60 l of tetrahydrofuran was added 3.3 g (0.033 mole) of triethylamine and 2.5 g (0.033 mole) of carbon disulfide. After the reaction mixture was stirred for one hour at 0° to 5° C., 4.7 g (0.033 mole) of methyl iodide was slowly added and stirred at 15°±5° C. for one hour. The solvent was removed from the reactant under reduced pressure, and water was added. The resulting mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure to obtain 6.54 g (yield 98%) of the desired liquid compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][CH:12]([CH3:36])[C:13]([SiH2:16][O:17][C@@H:18]1[C:22]([CH2:25][OH:26])([CH2:23][OH:24])[O:21][C@@H:20]([N:27]2[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:19]1)([CH3:15])[CH3:14].C(N(CC)CC)C>ClCCl>[CH3:11][CH:12]([CH3:36])[C:13]([SiH2:16][O:17][C@@H:18]1[C@@:22]([CH:23]=[O:24])([CH2:25][OH:26])[O:21][C@@H:20]([N:27]2[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:19]1)([CH3:14])[CH3:15]
Reactant: Cc1cn([C@H]2C[C@H](O[SiH2]C(C)(C)C(C)C)C(CO)(CO)O2)c(=O)[nH]c1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cn([C@H]2C[C@H](O[SiH2]C(C)(C)C(C)C)[C@@](C=O)(CO)O2)c(=O)[nH]c1=O
Temperature: -70 °C
Reaction time: 2.5 h
Yield: 78.9 %

Procedure:
To a solution of oxalylchloride (0.575 mL, 6.5 mmole) in dichloromethane (10 mL) at -70° C., was added dimethylsulfoxide (0.47 mL, 6.5 mmole). The mixture was stirred at -70° C. for 30 minutes before a solution of Compound (1) (2.4 g, 6.2 mmole) in dichloromethane (18 mL) was added. Stirring at -70° C. was continued for 150 minutes. Triethylamine (4.3 mL, 31 mmole) was added dropwise and the reaction mixture was allowed to warm to room temperature over a 20 hour period. The reaction was quenched by the addition of methanol (2 mL), followed 10 minutes later by 60 mL of water. The phases were separated. The aqueous phase was extracted three times with dichloromethane (60 mL each). The combined organic extracts were washed with solutions of dilute hydrochloric acid followed by saturated sodium bicarbonate and brine. After drying the organic extracts over magnesium sulfate, the solvent was removed under reduced pressure to provide 3'-O-[(dimethyl-1,1-dimethylethyl) silyl]-4'-formyl-thymidine (1.88 g) in crude form as a white solid.
Reaction SMILES: C(OC)#N.N1C2C(=CC=CC=2)CC1.[C:14]([N:17]1[C:25]2[C:20](=[C:21]([CH3:27])[CH:22]=[C:23]([CH3:26])[CH:24]=2)[CH:19]([CH2:28][CH2:29][O:30][C:31](=[O:33])[CH3:32])[CH2:18]1)(=[O:16])[CH3:15].[Br:34]Br.[N+:36]([O-:39])(O)=[O:37].Cl>CC(O)=O>[C:14]([N:17]1[C:25]2[C:20](=[C:21]([CH3:27])[C:22]([Br:34])=[C:23]([CH3:26])[C:24]=2[N+:36]([O-:39])=[O:37])[CH:19]([CH2:28][CH2:29][O:30][C:31](=[O:33])[CH3:32])[CH2:18]1)(=[O:16])[CH3:15]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)OCCC1CN(C(C)=O)c2cc(C)cc(C)c21
Reactant: BrBr
Agent: COC#N
Agent: Cl
Agent: c1ccc2c(c1)CCN2
Solvent: CC(=O)O
Product: CC(=O)OCCC1CN(C(C)=O)c2c1c(C)c(Br)c(C)c2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.60·2.20 (2H, m, —CH2 CH2O—), 2.04 (3H, s, -OCH3), 2.24 (3H, s, >NCOCH3), 2.24, 2.30 (6H, sx 2, —CH3×2), 3.34 (1H, m, Indoline C3—H), 3.94 (2H, m, Indoline C2—H), 4.12 (2H, t, J=7.1 Hz, —CH2 CH2O—), 6.67 (1H, s, Indoline C5—H), 7.90 (1H, s, Indoline C7—H). (3) 1-Acetyl-3-(2-acetoxyethyl)-4,6-dimethylindoline (2.0 g) was dissolved in AcOH (40 ml) and Br2 (1.9 g) was added, which was followed by stirring at room temperature for 30 min. The reaction mixture was poured into ice water and precipitate was collected by filtration. The precipitate was dissolved in CHCl3, and the mixture was washed with water and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3/MeOH=50/1−10/1) to give 2.7 g of crude crystals of 1-acetyl-3-(2-acetoxyethyl)-5-bromo-4,6-dimethylindoline. The crude crystals were added by portions to a mixture of nitric acid (0.47 ml), AcOH (10 ml) and conc. hydrochloric acid (10 ml) under ice-cooling, and the mixture was stirred at the same temperature for 4 hr. The reaction mixture was poured into ice water and precipitate was collected by filtration. The precipitate was dissolved in CHCl3. After washing with water, the mixture was dried over anhydrous sodium sulfate and CHCl3 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3/MeOH=50/1−10/1) to give 1.4 g of 1-acetyl-3-(2-acetoxyethyl)-5-bromo-4,6-dimethyl-7-nitroindoline.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1)[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[N:6]=1.[CH:23]([CH:25]=[CH2:26])=[O:24].C(N(CC)CC)C.O>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:26]=[CH:25]/[CH:23]=[O:24])=[CH:16][CH:15]=1)[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[N:6]=1
Reactant: C=CC=O
Reactant: CC(C)(C)CN(Cc1ccc(I)cc1)c1ccnc(C#N)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)CN(Cc1ccc(/C=C/C=O)cc1)c1ccnc(C#N)n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 50.6 %

Procedure:
4-[(2,2-Dimethyl-propyl)-(4-iodo-benzyl)-amino]-pyrimidine-2-carbonitrile (1.3 g, 2.5 mmoles), acrolein (0.5 ml, 7.4 mmoles), and triethylamine (0.4 ml, 3.1 mmoles) are dissolved in 25 ml of acetonitrile and Pd(OAc)2 (27 mg, 0.12 mmoles) is added at rt. The mixture is stirred at 80° C. for 18 h. Water is added and the organic layer is extracted with AcOEt, washed with brine, dried over magnesium sulfate and concentrated. The crude product is purified by silica gel column chromatography to give 423 mg of desired 4-{(2,2-dimethyl-propyl)-[4-((E)-3-oxo-propenyl)-benzyl]-amino}-pyrimidine-2-carbonitrile in 39% yield.