Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)[CH2:4][P:5](C(OCC)OCC)(=[O:9])[O:6]CC>Cl>[NH2:1][CH2:2][CH:3]([C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1)[CH2:4][P:5]([OH:9])[OH:6]
Reactant: CCOC(OCC)P(=O)(CC(CN)c1ccc(C)cc1)OCC
Agent: Cl
Product: Cc1ccc(C(CN)CP(O)O)cc1
Temperature: 25 °C

Procedure:
A solution of 3.7 g of ethyl 3-amino-2-(4-methylphenyl)propyl(diethoxymethyl)phosphinate in 40 ml of 36% aqueous hydrochloric acid is heated to reflux for a period of 1 h. The reaction mixture is then allowed to cool to room temperature, concentrated under reduced pressure and co-evaporated twice with 20 ml of water under reduced pressure. The crude product is dissolved in 20 ml of water, washed twice with 20 ml of diethyl ether and the aqueous layer is then separated and evaporated under reduced pressure. The crude product is dissolved in 50 ml ethanol and 5 ml of propylene oxide is added dropwise. The precipitated solid is collected by filtration and dried to give 3-amino-2-(4-methylphenyl)propylphosphonous acid, m.p. 250°-255° C., 31 p=+24.5 ppm (D2O).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][O:22][CH2:23][C:24]([O:26]C)=[O:25])[C:17]=3[CH:28]=2)[C:3]1=[O:29].Cl>C(O)(=O)C>[CH3:1][N:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][O:22][CH2:23][C:24]([OH:26])=[O:25])[C:17]=3[CH:28]=2)[C:3]1=[O:29]
Reactant: COC(=O)COCc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Agent: Cl
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(COCC(=O)O)c3c2)c1=O
Temperature: 25 °C
Yield: 70.7 %

Procedure:
To a mixture of {{5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazol-3-yl}methoxy}acetic acid, methyl ester (4.19 g, 0.00977 mol) and acetic acid is added 37% hydrochloric acid (5.00 ml). The resultant mixture is stirred overnight at 65° C. and cooled to room temperature. The mixture is concentrated in vacuo. The residue is suspended in water and quenched slowly by the addition of solid sodium bicarbonate to neutral pH. The resultant mixture is partitioned between ether and saturated sodium bicarbonate, and filtered. The filtrate is washed with methylene chloride, acidified with hydrochloric acid, and filtered to give the title product as a white solid (2.87 g, 70.7%, mp 191-192° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:12]([O:14][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[CH:13]=[C:4]([C:3]([O:2][CH3:1])=[O:15])[CH:5]=1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCOc1cc(C(=O)OC)cc(C(=O)OC)c1
Yield: 85.3 %

Procedure:
The product was generated using general protocol D using dimethyl-5-hydroxyisophthalate (3.920 g, 18.7 mmol), 1-bromohexadecane (5.18 g, 17.0 mmol), K2CO3 (9.37 g, 67.8 mmol), CH3CN (100 mL) yielded 6.30 g (86.5%) of a white solid. 1H NMR (CDCl3, 600 MHz) δ: 8.26 (t, 3J=1.4 Hz, 1H, Ar—H), 7.74 (d, 3J=1.5 Hz, 2H, Ar—H), 4.03 (t, 3J=6.5 Hz, 2H, O—CH2), 3.94 (s, 6H, COO—CH3), 1.80 (p, 3J=7.3 Hz, 2H, OCH2CH2), 1.46 (p, 3J=7.6 Hz, 2H, OCH2CH2CH2), 1.26 (m, 24H), 0.88 (t, 3J=6.8, 3H, CH2—CH3.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:5])C.O[Li].O.Cl>C1COCC1.CCO.O>[Cl:15][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Cl)cc(CN3CCOCC3)c2[nH]1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc(Cl)cc(CN3CCOCC3)c2[nH]1
Temperature: 45 °C
Reaction time: 1 h
Yield: 25.4 %

Procedure:
To a solution of 53 mg (0.16 mmol) of 5-chloro-7-morpholin-4-ylmethyl-1H-indole-2-carboxylic acid ethyl ester in THF/EtOH/H2O (2.5 ml) at RT was added 21 mg of LiOH.H2O. The reaction mixture was stirred at 45° C. for one hour and then acidified with aqueous HCl 1M. The product was extracted with EtOAc and concentrated under vacuo to afford 12 mg (25%) of 5-chloro-7-morpholin-4-ylmethyl-1H-indole-2-carboxylic acid as a white solid. ES-MS m/e (%): 293.1(M−H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C1CCCCO1)[N:6]=[CH:5]2.C(O)(=O)C.[B-](F)(F)(F)[F:22].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(#N)C>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[F:22]
Reactant: Brc1ccc2c(cnn2C2CCCCO2)c1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Fc1n[nH]c2ccc(Br)cc12
Temperature: 25 °C
Yield: 78.2 %

Procedure:
A mixture of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (10.0 g, 35.7 mmol; Intermediate 1), acetic acid (4 mL), Selectfluor (25.3 g, 71.4 mmol), and acetonitrile (100 mL) was refluxed under N2 for 2 h. The reaction was allowed to cool to rt, diluted with ethyl acetate (420 mL), and then washed with water (270 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified on a silica gel column using EtOAc in petroleum ether (1:20) to afford the title compound as yellow solids (6.0 g, yield 78.1%). 1H NMR (DMSO-d6, 400 MHz): δ 12.77 (s, 1H), 7.96 (s, 1H), 7.54 (d, 1H), 7.48 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH3:23])[CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(N)CCCCC>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([CH3:23])[C:20]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)OC1=O
Solvent: CCCCCCN
Product: CCCCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Yield: 150.5 %

Procedure:
A mixture of 450 mg (1.38 mmole) of (3R, 5S)-5-[(1S)-1-(t-butoxycarbonyl)amino-2-cyclohexylethyl]-3-methyldihydrofuran-2(3H)-one (prepared as described in Preparation 2) and 10 ml of hexylamine was heated under reflux for 2.2 hours, whilst stirring. At the end of this time, the reaction mixture was concentrated by distillation under reduced pressure, after which the residue was purified by column chromatography through silica gel (using a 1:2 by volume mixture of cyclohexane and ethyl acetate as the eluent) to afford 443 mg of the title compound as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:3]=1[O:4][C:5]1[C:6]([N+:36]([O-])=O)=[C:7]([NH:30][CH2:31][C:32](OC)=[O:33])[CH:8]=[CH:9][C:10]=1[C:11]1[C:12]2[CH:21]=[N:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:13]=2[C:14](=[O:18])[N:15]([CH3:17])[CH:16]=1.[Cl-].[NH4+]>C(OCC)(=O)C.CO.ClCCl.[Zn]>[F:1][C:2]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:3]=1[O:4][C:5]1[C:10]([C:11]2[C:12]3[CH:21]=[N:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:13]=3[C:14](=[O:18])[N:15]([CH3:17])[CH:16]=2)=[CH:9][CH:8]=[C:7]2[C:6]=1[NH:36][C:32](=[O:33])[CH2:31][NH:30]2
Reactant: COC(=O)CNc1ccc(-c2cn(C)c(=O)c3c2cnn3COCC[Si](C)(C)C)c(Oc2ccc(F)cc2F)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cn1cc(-c2ccc3c(c2Oc2ccc(F)cc2F)NC(=O)CN3)c2cnn(COCC[Si](C)(C)C)c2c1=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 24.3 %

Procedure:
A suspension of methyl {[3-(2,4-difluorophenoxy)-4-(6-methyl-7-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)-2-nitrophenyl]amino}acetate (0.048 g, 0.078 mmol) in ethyl acetate (0.452 mL) and methanol (0.452 mL) was cooled to 0° C. and then treated with saturated ammonium chloride solution (0.0679 mL, 1.01 mmol) at that temperature. Zinc (0.0408 g, 0.624 mmol) was added to the reaction mixture in two portions over 5 min and the reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with dichloromethane and filtered through a pad of Celite. The solids were washed with additional dichloromethane and the filtrate was concentrated in vacuo to yield a crude residue. The residue was dissolved in dichloromethane and the organic phase was washed with saturated sodium bicarbonate solution, dried with sodium sulfate, filtered, and concentrated in vacuo to give the crude product. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (10.5 mg, 24%) along with a small amount of the oxidized product, 8-(2,4-difluorophenoxy)-7-(6-methyl-7-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)quinoxalin-2(1H)-one. This mixture was used in the next step without separation. LCMS calculated for C27H30F2N5O4Si (M+H)+: m/z=554.2. found: 554.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:22])=[O:21])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:30][CH:31]([CH3:33])[CH3:32]>C(N)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([O:20][CH2:30][CH:31]([CH3:33])[CH3:32])[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:21])=[O:22])=[CH:4][CH:3]=1
Reactant: CN1C(=O)N(c2ccc(Cl)cc2)S(=O)(=O)c2ccc(O)cc21
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: NC=O
Product: CC(C)COc1ccc2c(c1)N(C)C(=O)N(c1ccc(Cl)cc1)S2(=O)=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
A suspension of 2-(4-chlorophenyl)-6-hydroxy-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (250 mg), potassium carbonate (122 mg) and 1-iodoisobutane (163 mg) in N,Ndimethyl formamide (1 ml) was stirred for 2 hours at 60° C. The mixture was poured into ice water. The separated solid was collected by filtration, dried, and recrystallized from ethanol to yield 2-(4-chlorophenyl)-4-methyl-6-(2-methylpropoxy)-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (169 mg).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[C:9](Cl)(=[O:13])[C:10]([CH3:12])=[CH2:11]>CC(C)=O.N1C=CC=CC=1>[C:9]([OH:13])(=[O:2])[C:10]([CH3:12])=[CH2:11].[C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2]
Reactant: C=C(C)C(=O)Cl
Agent: Oc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: C=C(C)C(=O)O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
350 g of hydroquinone was dissolved in 2.5 kg of acetone and 500 ml of pyridine. After cooling to 0° C., 313.5 g of methacryloyl chloride was added dropwise, with the reaction temperature maintained at 0° to 5° C. Stirring was then carried out for 3 hours at the same temperature. After stirring for one more hour at room temperature, the acetone was evaporated. Water was then added, and hydrochloric acid was used to adjust the solution to an acidic pH (pH 4), with ether extraction then performed. After washing this ether layer with a 5% aqueous solution of sodium hydrogencarbonate, the solution was then washed with water and dried (anhydrous sodium carbonate). The ether was then evaporated out, with a white solid being obtained. This was recrystallized from water, to obtain 420 g of colorless, needle crystals of hydroquinone monomethacrylate having a melting point of 120.5° to 121.5° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)CCC>C1(C)C=CC=CC=1.O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: O=c1[nH]cnc2cc(Br)ccc12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=c1[nH]cnc2cc(-c3ccccn3)ccc12
Temperature: 115 °C
Reaction time: 16 h

Procedure:
To a solution of 7-bromo-3H-quinazolin-4-one (100 mg, 0.444 mmol) in toluene/dioxane (3:1), add 2-tributylstannanyl-pyridine (162 mg, 0.444 mmol) followed by tetrakis-(triphenylphosphine)-palladium(0) (26 mg, 0.022 mmol). Bubble dry nitrogen through the solution for 10 minutes then heat the stirring solution to 115° C. under a nitrogen atmosphere. After several minutes the reaction mixture becomes homogeneous. After 16 hours, cool the reaction vessel and collect the precipitate via filtration. Wash the solid with 25% EtOAc/hexanes followed by hexanes to give 7-pyridin-2-yl-3H-quinazolin-4-one as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@:9]([CH:12]([O:15][CH3:16])[O:13][CH3:14])([CH3:11])[C@H:8]([OH:17])[C@@H:7]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[N:27][C:28]#[N:29])[C:6]=2[CH:30]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:31][S:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@:9]([CH:12]([O:15][CH3:16])[O:13][CH3:14])([CH3:11])[C@H:8]([OH:17])[C@@H:7]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[N:27][C:28]#[N:29])[C:6]=2[CH:30]=1)(=[O:34])=[O:33]
Reactant: COC(OC)[C@@]1(C)Oc2ccc(N)cc2[C@H](n2c(=NC#N)[nH]c3ccccc32)[C@H]1O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(OC)[C@@]1(C)Oc2ccc(NS(C)(=O)=O)cc2[C@H](n2c(=NC#N)[nH]c3ccccc32)[C@H]1O
Temperature: 25 °C
Reaction time: 14 h
Yield: 24.8 %

Procedure:
120 mg (0.29 mmol) of the compound obtained in example 5 was dissolved in 2 ml of methylenechloride, then 23 μl (0.29 mmol) of methanesulfonyl chloride and 76 μl (0.44 mmol) of diisopropylethylamine were added thereto. The reaction was stirred at room temperature for 14 hours, saturated NaHCO3 solution was added, and aqueous layer was extracted with 30 ml of methylenechloride. Organic layer was dried over anhydrous MgSO4, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), to give 35 mg (yield: 26%) of the target compound.
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[C@H:23]2[C@@H:27]3[O:28][C:29]([CH3:32])([CH3:31])[O:30][C@@H:26]3[C@@H:25]([C:33]([OH:35])=O)[O:24]2)=[C:16]([NH:36][CH2:37][CH:38]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:15]=1.[CH3:51][NH:52][O:53][CH3:54].Cl.[OH-].[Na+]>ClCCl>[CH3:54][O:53][N:52]([CH3:51])[C:33]([C@@H:25]1[C@@H:26]2[C@@H:27]([O:28][C:29]([CH3:31])([CH3:32])[O:30]2)[C@H:23]([N:20]2[CH:19]=[N:18][C:17]3[C:21]2=[N:22][C:14]([Cl:13])=[N:15][C:16]=3[NH:36][CH2:37][CH:38]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[O:24]1)=[O:35]
Reactant: CNOC
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](C(=O)O)O[C@H]2n1cnc2c(NCC(c3ccccc3)c3ccccc3)nc(Cl)nc21
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: [Na+]
Solvent: ClCCl
Product: CON(C)C(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Reaction time: 1 h

Procedure:
Carbonyl di-imidazole (2.37 g, 14.6 mmol) was added to a stirring solution of (3aS,4S,6R,6aR)-6-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid (prepared by following the method of Preparation 4 in International Patent Application No. WO94/17090) (6.015 g, 11.23 mmol) in dry dichloromethane (30 ml) under nitrogen. Mixture was stirred for 1 h. A dichloromethane solution of N,O-dimethylhydroxylamine (25.8 mmol; generated by basification of a 10 ml aqueous solution of 2.57 g of the corresponding hydrochloride at 0° C. with aqueous sodium hydroxide, followed by extraction with 3×5 ml dichloromethane and dried over sodium sulphate) was added. Mixture was stirred at room temperature for 60 h, quenched with aqueous citric acid (10% w/v, 40 ml). Organic solution was separated, washed with aqueous sodium bicarbonate (8% w/v, 40 ml), dried (sodium sulphate) and filtered. Removal of solvent in vacuo gave the title compound as a creamy white foam (6.66 g). TLC (100% ethyl acetate, visualised under an UV lamp) rf=0.51.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][CH3:16])[N:13]=[C:12]([CH3:17])[C:11]=2[CH:18]=[O:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][CH3:16])[N:13]=[C:12]([CH3:17])[C:11]=2[CH2:18][OH:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCn1nc(C)c(C=O)c1Sc1cc(Cl)cc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCn1nc(C)c(CO)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.5 %

Procedure:
A mixture of 1.1 g of 5-(3,5-dichloro-phenylsulphanyl)-1-ethyl-3-methyl-1H-pyrazole-4-carbaldehyde and 0.53 g of sodium borohydride in 25 ml of anhydrous methanol was stirred under nitrogen at room temperature for 15 minutes. Water (25 ml) was added and the mixture was extracted three times with 20 ml of diethyl ether. The combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum ether (bp 40–60° C.) (1:3) for the elution to give 902 mg of 5-(3,5-dichloro-phenylsulphanyl)-1-ethyl-3-methyl-1H-pyrazol-4-yl-methanol as a yellow oil. Mass spectrum (ES) m/z 317 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][OH:15])=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[N:10]1.CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][S:27]([CH3:26])(=[O:29])=[O:28])=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[N:10]1
Reactant: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-yl]-methanol (0.100 g) in dichloromethane (2 mL) is added Et3N (0.25 mL) followed by methanesulfonyl chloride (0.075 mL). The reaction mixture is stirred at room temperature for 2 h. The reaction is diluted with ethyl acetate (20 mL) and washed with water (2×20 mL). The organic layer is dried (Na2SO4) and concentrated under reduced pressure to give the title compound (101 mg). 1H NMR (400 MHz, CDCl3): δ 7.40-7.60 (m, 3H), 5.10 (s, 2H), 3.20-3.30 (m, 1H), 2.85 (s, 3H), and 1.40-1.50 (d, 6H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([C:17]#[N:18])[C:14]([CH2:19]O[Si](C)(C)C)=[C:13]([O:25][CH3:26])[CH:12]=1)[CH3:2].C(Br)(Br)(Br)[Br:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)=O>CC#N.CCOCC.O>[Br:28][CH2:19][C:14]1[C:15]([C:17]#[N:18])=[N:16][C:11]([C:4]2[C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:9][CH3:10])=[CH:12][C:13]=1[O:25][CH3:26]
Reactant: BrC(Br)(Br)Br
Reactant: CCc1cccc(CC)c1-c1cc(OC)c(CO[Si](C)(C)C)c(C#N)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Solvent: CC(C)=O
Product: CCc1cccc(CC)c1-c1cc(OC)c(CBr)c(C#N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of 6-(2,6-diethyl-phenyl)-4-methoxy-3-trimethylsilanyloxy methyl-pyridine-2-carbonitrile (200 mg, 0.54 mmol) in CH3CN (5 mL) is treated with CBr4 (270 mg, 0.81 mmol) and triphenylphosphine (215 mg, 0.81 mmol) at 0° C. under nitrogen. After one hour, acetone (50 mg) is added and the resulting mixture is stirred at room temperature overnight. Water (5 mL) and ether (10 mL) are then added to the mixture, and the organic layer is separated. The organic layer is washed with water, dried, and concentrated to give 3-bromomethyl-6-(2,6-diethyl-phenyl)-4-methoxy-pyridine-2-carbonitrile.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:23][O:24][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]3=[O:22]>CO.C(OCC)(=O)C.[Pd]>[CH2:17]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2([C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=3[O:24][CH2:23]2)[C:9]1=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCN1C(=O)C2(COc3cc(Br)ccc32)c2ccccc21
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCN1C(=O)C2(COc3ccccc32)c2ccccc21
Reaction time: 16 h
Yield: 96.4 %

Procedure:
A mixture of 6-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.10 g, 0.27 mmol) and palladium/carbon (0.09 g, 0.01 mmol) in methanol/ethyl acetate (1/1, 4.00 mL) was stirred under hydrogen at atmospheric pressure for 16 h. The solvent was evaporated and the black residue was subjected to column chromatography (ethyl acetate/hexane, 1/6) to give the title compound (0.08 g, 97%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.30 (dd, 1H), 7.18 (dd, 1H), 7.20 (d, 1H), 7.02 (dd, 1H), 6.96-6.90 (m, 2H), 6.79 (dd, 1H), 6.69 (d, 1H), 4.93 (d, 1H), 4.67 (d, 1H), 3.89-3.64 (m, 2H), 1.81-1.66 (m, 2H), 1.44-1.31 (m, 4H), 0.92 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 177.2, 160.7, 142.5, 132.8, 129.7, 129.0, 128.8, 123.9, 123.3, 123.1, 121.3, 110.4, 108.6, 58.1, 40.4, 29.0, 27.2, 22.3, 14.0; MS (ES+) m/z 308.5 (M+1).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:11]1([NH:10][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1ccccc1Br
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: N#Cc1ccccc1Nc1ccccc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a suspension of 2-bromobenzonitrile (1.5 g, 8.2 mmol), aniline (1.1 g, 12.4 mmol), Xantphos (0.7 g, 1.2 mmol) and cesium carbonate (5.4 g, 16.5 mmol) in dioxane (50 mL) was added Pd2dba3 (375 mg, 0.4 mmol) at rt under N2. The reaction was stirred at 90° C. for 8 h. The reaction mixture was filtered and concentrated. Purification by silica gel chromatography (PE:EtOAc=200:1) gave 1.3 g (81%) of the title compound as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 6.36 (1H, br s), 6.86 (1H, td, J=0.9, 7.8 Hz), 7.13-7.18 (4H, m), 7.36-7.41 (3H, m), 7.51 (1H, dd, J=1.8, 7.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][OH:6]
Reactant: COc1ccc(C=O)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CO)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a solution of 3-fluoro-4-methoxybenzaldehyde (1 g, 6.5 mmol) in methanol (15 mL) was added under ice-cooling sodium borohydride (378 mg, 10 mmol) and the mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give an almost pure title compound (1 g, 100%).