Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:6]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[C:33](=[O:34])[CH2:32][O:31][C:30]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[N:29]3)=[CH:23][CH:22]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].C(O)C>[CH:1]1([CH:6]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[C:33](=[O:34])[CH2:32][O:31][C:30]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[N:29]3)=[CH:23][CH:22]=2)[C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][CH:15]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)/C=C/c1ccc(NC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C2CCCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCc1ccc(NC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C2CCCC2)cc1
Reaction time: 2 h

Procedure:
50 mg of palladium on carbon (10%) were added to a solution of 46 mg (0.085 mmol) of (2E)-3-{4-[(cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetyl)amino]phenyl}prop-2-enoic acid (Example 96) in 10 ml of ethanol. Under an atmosphere of hydrogen, the mixture was hydrogenated at atmospheric pressure for 2 h. The reaction mixture was then filtered through Tonsil, the filter residue was washed with ethanol and the combined filtrates were concentrated on a rotary evaporator. The crude product was purified by preparative HPLC. This gave 29 mg (63% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([Cl:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.S(Cl)(Cl)(=O)=O>[OH-].[Na+]>[Cl-:12].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:13][CH2:14][CH2:15][CH2:16][NH+:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: NCCCN1CCCC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(=O)(Cl)Cl
Product: COc1ccc(S(=O)(=O)NCCC[NH+]2CCCC2)cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-Methoxybenzenesulphonylchloride (8.26 g, 0.04 mol) was added in portions with stirring to a solution of 1-(3-aminopropyl)-pyrrolidine (5.13 g, 0.04 mol) in 10% NaOH (100 ml), and the resulting mixture was stirred at room temperature for the next 24 hours. Unreacted sulphonylchloride was filtered off, and the filtrate was adjusted to pH 9,8 with dilute HCl.
Reaction SMILES: C(O)C.Br[C:5]1[CH:6]=[CH:7][C:8]2[NH:14][CH2:13][CH2:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]=2[CH:19]=1.B([O-])([O-])O[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH3:34])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:32]([O:31][CH2:30][CH2:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:5]2[CH:6]=[CH:7][C:8]3[NH:14][CH2:13][CH2:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]=3[CH:19]=2)=[CH:27][CH:26]=1)[CH2:33][CH3:34]
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2NCC1
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+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
In toluene (100 ml), ethanol (10 ml) and water (10 ml) were suspended methyl 7-bromo-2,3-dihydro-1-benzazepine-4-carboxylate (3.0 g), 4-propoxyethoxyphenyl borate (3.1 g) and potassium carbonate (3.8 g), and the suspension was stirred for 30 minutes under argon atmosphere. Then, to the suspension was added tetrakistriphenylphosphinepalladium (860 mg), and the mixture was heated at 100° C. for 8 hours under argon atmosphere. After allowing to cool, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) to give the solid, which was washed with hexane to give methyl 7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (2.59 g) as yellow crystals.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[CH2:11][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:14][O:15][C:16]=3[N:17]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(CC)CC.Cl[C:33]([O:35][CH3:36])=[O:34].O>C1COCC1>[CH3:36][O:35][C:33]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:11][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:14][O:15][C:16]=3[N:17]=2)[CH2:2][CH2:3]1)=[O:34]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(N3CCNCC3)ccc2C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N1CCN(c2ccc3c(n2)OCCN(C(=O)OC(C)(C)C)C3)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of the compound (0.26 g) obtained in step 1 and Et3N (0.21 mL) in THF (10 mL) was added methyl chloroformate (0.12 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10→50% ethyl acetate/hexane) to give tert-butyl 8-[4-(methoxycarbonyl)piperazin-1-yl]-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.21 g, 69%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:11]2[CH:18]=[CH:17]C(C#N)=[CH:13][CH:12]=2)[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.[OH-:19].[Na+].[CH2:21]([OH:23])[CH3:22]>O>[CH3:1][C:2]1[N:3]([C:11]2[CH:18]=[CH:17][C:22]([C:21]([OH:19])=[O:23])=[CH:13][CH:12]=2)[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1
Reactant: Cc1nc2cnccc2n1-c1ccc(C#N)cc1
Reactant: CCO
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: Cc1nc2cnccc2n1-c1ccc(C(=O)O)cc1
Yield: 70 %

Procedure:
A mixture of 4-(2-methylimidazo[4,5-c]pyrid-1-yl)benzonitrile (see EP-0310386) (12.0 g, 51.3 mmol) and sodium hydroxide (22.0 g, 0.55 mmol) in a mixture of ethanol (55 ml) and water (55 ml) was heated under nitrogen at reflux for 1.5 hours, cooled and concentrated under reduced pressure. The brown residue was dissolved in ice-water and glacial acetic acid (33 ml) was added. The resulting precipitate was collected, washed with water and dried under vacuum at 70° C. to give the title compound (9.1 g, 70%) as a buff coloured solid which as characterised by its 1H-NMR spectrum. 1H NMR (DMSO-d6), 2.50(3H,s), 7.25(1H,d,J=5 Hz), 7.72(2H,d,J=8 Hz), 8.16(2H,d,J=8 Hz), 8.30(1H,d,J=5 Hz), 8.92(1H,s).
Reaction SMILES: Br[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:17][CH:18]=[CH:19][C:20]=1[O:21][CH3:22])/[C:5](=[O:14])[NH:6]2.[NH:23]1[C:31]2[C:26](=[CH:27][C:28](B(O)O)=[CH:29][CH:30]=2)[CH:25]=[CH:24]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[NH:23]1[C:31]2[C:26](=[CH:27][C:28]([C:2]3[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]4[C:3]=3/[C:4](=[CH:15]/[C:16]3[NH:17][CH:18]=[CH:19][C:20]=3[O:21][CH3:22])/[C:5](=[O:14])[NH:6]4)=[CH:29][CH:30]=2)[CH:25]=[CH:24]1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(Br)c21
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(-c3ccc4[nH]ccc4c3)c21
Temperature: 90 °C

Procedure:
A solution of (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (112 mg, 0.31 mmol) (Starting Material 6), 5-indoleboronic acid (71 mg, 0.44 mmol) (from Example 40, Step A, supra) and sodium carbonate (110 mg, 1.03 mmol) were dissolved in 10 mL DMF and 5 mL water. The solution was degassed for 30 minutes by bubbling argon through the solution. At this time, dichlorobis(triphenylphosphine) palladium(II) (11 mg) (Aldrich) was added, and the reaction was heated, under argon, at 90° C. for 2 days. Water (20 mL) was then added and the precipitate was filtered off and dried. The product was purified via flash column chromatography (SiO2, 230-400 mesh) with 5% MeOH/CHCl3 to give (Z)-1,3-dihydro-4-(5-indolyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one as a red powder. (Yield 38 mg, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([OH:13])[CH2:11][OH:12])[CH:5]=[N:6][C:7]=1Cl.CCO.CC1(C)C(C)(C)OB([C:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH:26]=2)O1>C1COCC1.O.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>[C:34]([O:33][C:31]([N:28]1[CH2:29][CH2:30][C:25]([C:7]2[C:2]([Cl:1])=[CH:3][C:4]([CH2:9][CH:10]([OH:13])[CH2:11][OH:12])=[CH:5][N:6]=2)=[CH:26][CH2:27]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: OCC(O)Cc1cnc(Cl)c(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC=C(c2ncc(CC(O)CO)cc2Cl)CC1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 95.4 %

Procedure:
To a solution of 3-(5,6-dichloropyridin-3-yl)propane-1,2-diol 59 (255 mg, 1.148 mmol) in THF (1.8 ml)-EtOH (0.7 ml)-3M K2CO3 aq. (0.842 ml, 2.53 mmol) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2 H)-carboxylate 33 (391 mg, 1.263 mmol) and PdCl2(PPh3)2 (24.18 mg, 0.034 mmol) at room temperature under N2. The mixture was stirred at 85° C. for 1.5 hr. The reaction mixture was diluted with H2O, then extracted with EtOAc (3×10 mL). The organic layers were combined and washed with brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude product was added to a silica gel chromatography column and was eluted with CHCl3/MeOH (10:1) Collected fractions were evaporated to afford 60 (404 mg 1.095 mmol 95%) as a yellow oil.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=3Br)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:22]1(=[O:26])[CH2:25][CH2:24][CH2:23]1>O1CCCC1>[C:1]12([CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=3[C:22]3([OH:26])[CH2:25][CH2:24][CH2:23]3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C1CCC1
Reactant: N#Cc1ccc(OCC23CC4CC(CC(C4)C2)C3)c(Br)c1
Solvent: C1CCOC1
Product: N#Cc1ccc(OCC23CC4CC(CC(C4)C2)C3)c(C2(O)CCC2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a cooled (0° C.) stirred solution of 4-(adamantan-1-ylmethoxy)-3-bromobenzonitrile (3.20 g, 9.24 mmol) in tetrahydrofuran (40 mL) was added a solution of isopropylmagnesium chloride lithium chloride complex in tetrahydrofuran (1.3 M, 15.0 mL, 19.5 mmol) dropwise. The reaction mixture was stirred at 0° C. for 2 h and cyclobutanone (1.52 mL, 20.33 mmol) was added. Stirring was continued at 0° C. for 2 h and quenched with saturated ammonium chloride solution (30 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 10% to 25% gradient of ethyl acetate in hexanes to afford 4-(adamantan-1-ylmethoxy)-3-(1-hydroxycyclobutyl)benzonitrile as colorless solid (2.34 g, 69%): 1H NMR (300 MHz, CDCl3) δ 7.62-7.53 (m, 2H), 7.00-6.93 (m, 1H), 3.64 (s, 2H), 3.43 (s, 1H), 2.59-2.36 (m, 4H), 2.17-2.00 (m, 4H), 1.84-1.61 (m, 13H).
Reaction SMILES: [CH2:1]([C:3]([OH:18])([CH2:16][CH3:17])[C:4]#[C:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=1)=O)[CH3:2].C(NCC)C.C[OH:25]>>[CH2:16]([C:3]1([CH2:1][CH3:2])[C:4](=[O:25])[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([S:14][CH3:15])=[CH:12][CH:13]=2)[O:18]1)[CH3:17]
Reactant: CO
Reactant: CCC(O)(C#CC(=O)c1ccc(SC)cc1)CC
Solvent: CCNCC
Product: CCC1(CC)OC(c2ccc(SC)cc2)=CC1=O

Procedure:
A solution 10 g of 4-ethyl-4-hydroxy-1-{4-(methylthio)phenyl}-2-hexyn-1-one in 300 ml methanol was stirred in the presence of 4 ml diethylamine at room temperature for 12 hours. Then the solvent was removed in vacuo and the resulting residue was extracted with dilute aqueous HCl and dichloromethane (50 ml×3). The organic layer was washed with brine and then concentrated under reduced pressure to yield 5.6 g of 2,2-diethyl-5-{4-(methylthio)phenyl}-3(2H)-furanone. The crude product was used for the next step without further purification. NMR: δ0.85 (t, J=7.5 Hz, 6H), 1.88 (q, J=7.5 Hz, 4H), 2.54 (s, 3H), 5.96 (s, 1H), 7.31 (d, J=9.0 Hz, 2H), 7.75 (d, J=9.0 Hz, 2H). IR (cm−1): 2971, 1690, 1597, 1487, 1408, 1364, 1162, 1095.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[OH:24].C[O:26][C:27](=[O:36])[CH:28](Br)[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([CH2:29][CH:28]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:24][C:18]3[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=3[F:16])[CH:6]=[N:5]2)[C:27]([OH:26])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: Cc1ccc(F)c(O)c1
Product: Cc1ccc(F)c(Oc2cnn(C(CC3CCCC3)C(=O)O)c(=O)c2)c1

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2-fluoro-5-methyl-phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[4-(2-fluoro-5-methyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid as a white solid (14.5 g, 74% for the final step); LC-MS: 361 [M+1]+, tR=5.20 min. Purity on HPLC: 98.2% (214 nm), 98.9% (254 nm), tR=8.93 min. 1H NMR (300 MHz, CDCl3): δ9.54 (s, 1H broad), 7.89 (d, 1H, J=2.1), 7.14˜7.08 (m, 2H), 6.99 (d, 1H, J=9.0), 5.98 (s, 1H), 5.53 (dd, 1H J1=10.5 Hz, J2=4.5 Hz), 2.35 (s, 3H), 2.39˜2.20 (m, 1H), 2.15˜2.06 (m, 1H), 1.79˜1.49 (m, 7H), 1.20˜1.11 (m, 3H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@@H:12]([CH3:22])[O:11][C@H:10]1[N:23]1[CH:30]=[C:29]([I:31])[C:27]([NH2:28])=[N:26][C:24]1=[O:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)Cl.Cl[C:36]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:37]>>[Si:1]([O:8][C@@H:9]1[C@H:13]([O:14][Si:15]([C:18]([CH3:20])([CH3:21])[CH3:19])([CH3:17])[CH3:16])[C@@H:12]([CH3:22])[O:11][C@H:10]1[N:23]1[CH:30]=[C:29]([I:31])[C:27]([NH:28][C:36]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:37])=[N:26][C:24]1=[O:25])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H]1O[C@@H](n2cc(I)c(N)nc2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CCCCCOC(=O)Cl
Solvent: ClCCl
Product: CCCCCOC(=O)Nc1nc(=O)n([C@@H]2O[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]2O[Si](C)(C)C(C)(C)C)cc1I
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a stirred solution of 5′-deoxy-2′,3′-bis-O-(tert-butyldimethylsilyl)-5-iodocytidine (116 mg, 0.200 mmol) in CH2Cl2 (2 ml) pyridine (84 μl, 1.00 mmol), N,N-dimethylamino-pyridine (6 mg, 0.05 mmol), and n-pentyl chloroformate (95 μl, 0.600 mmol) was added at room temperature under Ar. After stirring for 30 minutes, the reaction mixture was partitioned with dichloromethane and water and the organic phase was separated and the water phase was extracted with CH2Cl2 (15 ml×4). The combined organic phase was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was evaporated under reduced pressure. The crude product was purified by flash chromatography on SiO2 (eluent: 20% EtOAc/n-hexane) to give 2′,3′-bis-O-(tert-butyldimethylsilyl)-5′-deoxy-5-iodo-N4-(n-pentyloxycarbonyl)cytidine as a colorless amorphous solid. (132.4 mg, 91% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([S:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH:3]=1.P(=O)(O)(O)O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][C:9](=[O:11])[C:14]3[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=3[S:12][C:4]=2[CH:3]=1
Reactant: O=C(O)Cc1ccc(F)cc1Sc1ccc([N+](=O)[O-])cc1
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: O=C1Cc2ccc(F)cc2Sc2ccc([N+](=O)[O-])cc21
Reaction time: 2 h
Yield: 43.8 %

Procedure:
[4-Fluoro-2-(4-nitrophenylthio)phenyl]acetic acid (17.6 g) was added at 150° C. to polyphosphoric acid, prepared from 60 ml 85% phosphoric acid and 100 g phosphorus pentoxide, and the mixture stirred at 150°-155° C. for two hours. After cooling, it was decomposed by pouring into a mixture of ice and water. The precipitated crude product was filtered and boiled for a short time under stirring with a mixture of a 10% sodium carbonate solution and benzene. It was filtered again, the benzene layer separated and benzene evaporated. The residue was dissolved in a small volume of benzene and the solution chromatographed on a column of 420 g alumina (act. II) Benzene eluted first a small amount of a less polar and high-melting by-product. The elution was continued with benzene and finally with a mixture of benzene and chloroform; 7.25 g of the desired crystalline 3-fluoro-8-nitrodibenzo(b,f)thiepin-10(11H)-one were obtained, m.p. 161°-163° C. (benzene-petroleum ether).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C.O>[C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:35][CH:34]=2)=[CH:11][C:10]=1[CH2:16][O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1COC(=O)NC1CCCCC1
Reactant: BrCCCOc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)cc1COC(=O)NC1CCCCC1
Yield: 65 %

Procedure:
A mixture of 3-(2-cyclohexylcarbamoyloxymethyl-4-hydroxy-phenyl)-propionic acid tert-butyl ester (50 mg, 0.13 mmol; Example 652 Step D), 4-(3-bromo-propoxy)-biphenyl (58 mg, 0.2 mmol; Tetrahedron 1994, 50, 3427, and potassium carbonate (53 mg, 0.39 mmol) in acetonitrile (6 mL) was heated at 80° C. overnight. Ethyl acetate (20 mL) and H2O (20 mL) were added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude mixture was purified by silica gel column chromatography (hexane/ethyl acetate 4/1) to give the title compound (50 mg, 65%). 1H-NMR (300 MHz, CDCl3): δ 7.54 (m, 4H), 7.42 (t, 2H, J=7.6), 7.32 (d, 1H, J=8.4), 7.12 (d, 1H, J=8.3), 6.99 (d, 2H, J=8.7), 6.93 (d, 1H, J=2.2), 6.82 (dd, 1H, J=8.4, 2.7), 5.09 (s, 2H), 4.74 (d, 1H, J=7.5), 4.18 (m, 4H), 3.56-3.42 (m, 1H), 2.90 (t, 2H, J=7.8), 2.48 (t, 2H, J=7.8), 2.28 (qn, 2H, J=6.0), 1.95-1.88 (m, 2H), 1.75-1.08 (m, 8H), 1.44 (s, 9H).
Reaction SMILES: CC1(C)[C@@H]2CC[C@@]1(CS(O)(=O)=O)C(=O)C2.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C@@H:21]([NH2:26])[CH2:20]2.C1CCN2C(=NCCC2)CC1.[CH3:38][CH:39]([S:41](Cl)(=[O:43])=[O:42])[CH3:40]>C(Cl)Cl.Cl>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C@@H:21]([NH:26][S:41]([CH:39]([CH3:40])[CH3:38])(=[O:43])=[O:42])[CH2:20]2
Reactant: CC(C)S(=O)(=O)Cl
Reactant: N[C@@H]1Cc2ccc(Br)cc2C1
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(Br)cc2C1
Reaction time: 1 h
Yield: 86.9 %

Procedure:
(R)-5-bromo-2,3-dihydro-1H-inden-2-amine((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (7.88 mmol, 3.5 g) was suspended in DCM (40 mL) and DBU (23.63 mmol, 3.53 mL, 3.60 g) was added. The mixture was purged with nitrogen and cooled in an ice bath before dropwise addition of propane-2-sulfonyl chloride (15.75 mmol, 1.760 mL, 2.246 g). Stirring was continued at 0° C. for 1 h before allowing to come to room temperature. The mixture was diluted with DCM (100 mL) and 1N HCl (100 mL) and the phases mixed and separated. The aqueous phase was further extracted with DCM (2×100 mL) before combined organics were washed with brine. Concentration gave a light yellow oil which was purified on silica eluting with 75% DCM/heptane then neat DCM. Desired fractions were collected and concentrated to give (R)—N-(5-bromo-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide as a colourless oil (2.18 g, 87%). 1H NMR (400 MHz, CDCl3) δ 1.39 (d, 6H) 2.88 (m, 2H) 3.17 (sept, 1H) 3.28 (m, 2H) 4.27 (m, 2H) 7.08 (d, 1H) 7.30 (d, 1H) 7.35 (s, 1H)
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][C@H:8]1[CH2:20][CH2:21][N:22]1[C:26]([CH:27]=[O:28])=[CH:25][N:24]=[CH:23]1)=[O:6])[CH:2]=[CH2:3].[BH4-].[Na+].Cl>O1CCCC1.CO>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:15])[CH3:14])[CH2:9][C@H:8]1[CH2:20][CH2:21][N:22]1[C:26]([CH2:27][OH:28])=[CH:25][N:24]=[CH:23]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCn1cncc1C=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCn1cncc1CO
Yield: 80.5 %

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-{2-(5-formylimidazol-1-yl)ethyl}pyrrolidine (12.65 g) in a mixture of tetrahydrofuran (60 ml) and methanol (60 ml) was portionwise added sodium borohydride (1.17 g) with stirring under ice-cooling. The mixture was stirred at the same temperature for 1 hour. The reaction mixture was adjusted to pH 8 with 6N hydrochloric acid at the same condition. The resulting precipitates were filtered off and the filtrate was evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (250 g) eluting with a mixture of chloroform and methanol (9:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2R,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-{2-(5-hydroxymethylimidazol-1-yl)ethyl}pyrrolidine (10.23 g).
Reaction SMILES: [CH3:1][S:2]/[C:3](=[N:18]\[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)/[N:4]1[CH2:9][CH2:8][C:7]2[N:10]=[C:11]([C:13]([O:15]CC)=[O:14])[S:12][C:6]=2[CH2:5]1.C([O-])([O-])=O.[K+].[K+].O>CO>[CH3:1][S:2]/[C:3](=[N:18]\[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)/[N:4]1[CH2:9][CH2:8][C:7]2[N:10]=[C:11]([C:13]([OH:15])=[O:14])[S:12][C:6]=2[CH2:5]1
Reactant: CCOC(=O)c1nc2c(s1)CN(/C(=N/c1ccccc1)SC)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS/C(=N\c1ccccc1)N1CCc2nc(C(=O)O)sc2C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of ethyl 5-[(Z)-(methylthio)(phenylimino)methyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylate (1 eq) obtained in step II in methanol, K2CO3 (2 eq) and few drops of water were added and the reaction mixture was stirred at room temperature for 15 h. Solvent was evaporated and the residue was treated with etheral HCl. The solvent was then evaporated and the residue was as such used for further reaction without purification.