Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:20])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[S:10](=[O:16])(=[O:15])[CH2:9][C:8]([CH3:18])([CH3:17])[C:7]2=[O:19])([OH:3])=O.[CH2:21]([N:23]1[C:27]([OH:28])=[CH:26][CH:25]=[N:24]1)[CH3:22].C1(N=C=NC2CCCCC2)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)(CC)(C)C>[CH2:21]([N:23]1[C:27]([OH:28])=[C:26]([C:1]([C:4]2[C:5]([CH3:20])=[C:6]3[C:11](=[C:12]([CH3:14])[CH:13]=2)[S:10](=[O:15])(=[O:16])[CH2:9][C:8]([CH3:18])([CH3:17])[C:7]3=[O:19])=[O:3])[CH:25]=[N:24]1)[CH3:22]
Reactant: CCn1nccc1O
Reactant: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CC(C)(C)C2=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: CCn1ncc(C(=O)c2cc(C)c3c(c2C)C(=O)C(C)(C)CS3(=O)=O)c1O
Temperature: 25 °C
Yield: 81.9 %

Procedure:
A 50-ml round-bottomed flask was charged with 0.51 g (1.72 mmol) of 6-carboxy-3,3,5,8-tetramethylthiochroman-4-one-1,1-dioxide, 0.21 g (1.88 mmol) of 1-ethyl-5-hydroxypyrazole and 5 ml of t-amyl alcohol, and while the mixture was stirred at room temperature, a solution of 0.42 g (2.04 mmol) of N,N'-dicyclohexylcarbodiimide in 2 ml of t-amyl alcohol was added. The mixture was further stirred at room temperature for 1 hour, and 0.18 g (1.30 mmol) of potassium carbonate was added to the reaction mixture. The mixture was heated at 80~90° C. for 8 hours. The solvent was distilled off under reduced pressure, and ethyl acetate and a 2 wt % sodium carbonate aqueous solution were added to the residue. An insoluble solid was removed by filtration. The mixture was separated into two phases, and an aqueous layer was neutralized and acidified with a 5 wt % hydrochloric acid aqueous solution, and a precipitated solid was extracted with ethyl acetate. An organic layer was washed with diluted hydrochloric acid and with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to give 0.55 g (yield 82%) of 6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonyl-3,3,5,8-tetramethylthiochroman-4-one-1,1-dioxide in the form of a brown solid. This product was recrystallized from mixed solvents of ethyl acetate and n-hexane to give 0.36 g (yield 54%) of a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:32])[C@@H:9]([CH3:31])[C:10]([NH:12][C@@H:13]([CH:28]([CH3:30])[CH3:29])[C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][CH:17]1[C:25](O)=[O:26])=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:7])[N:8]([C@H:9]([C:10](=[O:11])[NH:12][C@H:13]([C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][CH:17]1[CH2:25][OH:26])=[O:15])[CH:28]([CH3:30])[CH3:29])[CH3:31])[CH3:32])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2CC1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2CC1CO
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 73.3 %

Procedure:
To a stirred solution of 1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionyl amino]-3-methyl-butyryl}-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Intermediate 1) (3.8 g, 8.48 mmol) in THF (65 mL) were added N-methylmorpholine (1.11 mL, 10.17 mmol) followed by the addition of isobutyl chloroformate (1.32 mL, 10.17 mmol) at −20° C. The reaction mixture was stirred at −20° C. for 10 min and the white precipitate of N-methylmorpholine hydrochloride salt was removed by filtration. The filtrate was cooled to −20° C., NaBH4 (483 mg, 12.72 mmol) was added followed by cold water (30 mL) at −20° C. After 30 min the reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (80 mL×2). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica gel, 28% EtOAc in hexanes) to give {(S)-1-[(S)-1-(2-hydroxymethyl-2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carbonyl)-2-methyl-propylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (2.7 g), m/z=435 (M+H)
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1C#N.[Cl:13][C:14]1[CH:15]=[CH:16][C:17](=[O:51])[N:18]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]3[N:28]=[CH:29][N:30](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:31]=3)=[CH:22][N:21]=2)[CH:19]=1.C[C:53]#[N:54]>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17](=[O:51])[N:18]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]3[N:28]([CH2:2][C:3]4[CH:4]=[CH:7][C:8]([O:11][CH3:12])=[C:9]([CH:10]=4)[C:53]#[N:54])[CH:29]=[N:30][CH:31]=3)=[CH:22][N:21]=2)[CH:19]=1
Reactant: COc1ccc(CBr)c(C#N)c1
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Reactant: CC#N
Product: COc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1C#N
Temperature: 60 °C

Procedure:
2-Bromomethyl-5-methoxy-benzonitrile from step 4 (70 mg, 0.30 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (200 mg, 0.378 mmol) were dissolved in CH3CN (2 ml) and heated to 60° C. for 16 hours. The solvent was removed in vacuo and redissolved in MeOH (2 ml). The reaction mixture was heated to 60° C. for several hours. Solvent was removed in vacuo and the resulting residue was purified by flash chromatography [4% MeOH(5% NH4OH )/CH2Cl2 ] to yield the final product.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:28][O:29][CH2:30][CH3:31])[N:24]([CH2:25][C:26]#[CH:27])[C:20]=2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1.C(N(CC)CC)C>ClCCl>[Cl:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:28][O:29][CH2:30][CH3:31])[N:24]([CH2:25][C:26]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH:27]=3)[C:20]=2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: ON=C(Cl)c1ccccc1
Reactant: C#CCn1c(COCC)nc2c(Cl)nc3ccccc3c21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(-c2ccccc2)no1
Temperature: 25 °C

Procedure:
N-Hydroxybenzenecarboximidoyl chloride (prepared as described in Part A of Example 2, 1.72 g, 10.5 mmol) was added to a solution of 4-chloro-2-(ethoxymethyl)-1-prop-2-ynyl-1H-imidazo[4,5-c]quinoline (3.00 g, 10.0 mmol) and triethylamine (1.70 mL, 12.0 mmol) in dichloromethane (40 mL). The solution was heated at reflux under a nitrogen atmosphere for 3.5 hours and additional N-hydroxybenzenecarboximidoyl chloride (0.1 g) was added. The solution was heated at reflux for one hour more, then was allowed to cool to room temperature and was diluted with dichloromethane. The solution was transferred to a separatory funnel and was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, gradient elution from 4:1 to 3:2 hexanes/ethyl acetate) to provide pure 4-chloro-2-(ethoxymethyl)-1-[(3-phenylisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline (1.48 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=3)=[CH:13][C:12]([C:23]([F:26])([F:25])[F:24])=[N:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)(Cl)Cl>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]([C:15]3[CH:22]=[CH:21][C:18]([CH2:19][NH:20][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:17][CH:16]=3)=[CH:13][C:12]([C:23]([F:26])([F:24])[F:25])=[N:11]2)=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(CN)cc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(CNS(C)(=O)=O)cc2)cc1

Procedure:
To a solution of 4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzylamine hydrochloride obtained by Example 57 (100 mg) and triethylamine (0.073 ml) in chloroform (10 ml) was added dropwise methanesulfonyl chloride (0.04 ml) at room temperature.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[S:11])=[CH:8][N:7]=1.[ClH:15]>>[CH3:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:15])=[S:11])=[CH:8][N:7]=1
Reactant: Cl
Reactant: Cc1ccc(C(O)=S)cn1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(=S)Cl)cn1

Procedure:
Thionylchloride (23.8 g) was added to 6-methylthionicotinic acid (15.3 g) (from the above referential example 1a). The reaction mixture was gradually heated with stirring and refluxed until the generation of hydrogen chloride ceased. 6-methylthionicotinoylchloride was stoichiometricly obtained by distilling off excess thionylchloride under reduced pressure. 6-methylthionicotinoylchloride dissolved in ether was added dropwise to 20% aqueous solution of sodium borohydride (6.5 g) at 0°~10° C. After adding, the mixture was stirred for one hour and the ether layer was separated and dried. The ether layer was evaporated under reduced pressure to give 2-methylthiopyridine-5-methanol (9.6 g).
Reaction SMILES: C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC(OC)=CC=1)(O)C(O)=O)(=O)C1C=CC(OC)=CC=1.[C:31]1([C:37]2([CH2:42][CH2:43][OH:44])[CH2:41][CH2:40][NH:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:51][O:52][C:53]1[CH:54]=[C:55]([CH:59]=[C:60]([O:64][CH3:65])[C:61]=1[O:62][CH3:63])[C:56](Cl)=[O:57]>C(OCC)(=O)C.O>[CH3:65][O:64][C:60]1[CH:59]=[C:55]([CH:54]=[C:53]([O:52][CH3:51])[C:61]=1[O:62][CH3:63])[C:56]([N:39]1[CH2:40][CH2:41][C:37]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([CH2:42][CH2:43][OH:44])[CH2:38]1)=[O:57]
Reactant: OCCC1(c2ccccc2)CCNC1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: COc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C(=O)N2CCC(CCO)(c3ccccc3)C2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Combine (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt (56.0 g, 92.1 mmol), sodium carbonate (19.5 g, 184 mmol) in ethyl acetate (2 L) and water (2 L). Cool to about 0° C. in an ice bath. After 30 minutes, slowly add dropwise portionwise 3,4,5-trimethoxybenzoyl chloride (21.2 g, 92.1 mmol). After the addition is complete, warm to ambient temperature. After 1 hour, dilute the reaction mixture ethyl acetate and extract with water, 1 M aqueous hydrochloric acid solution, and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:9]([CH2:10][CH2:11][C:12]3[C:13]4[C@:20]([CH3:28])([CH2:21][CH2:22][C:23]=32)[C@@H:16]([C@@H:17]([OH:19])[CH3:18])[CH2:15][CH:14]=4)[C:8]1([CH3:30])[CH3:29])[CH3:5])[CH3:2].CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.Br[CH2:56][CH:57]=[C:58]([CH3:60])[CH3:59]>O.C1(C)C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:6][C@H:7]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:9]([CH2:10][CH2:11][C:12]3[C:13]4[C@:20]([CH3:28])([CH2:21][CH2:22][C:23]=32)[C@@H:16]([C@H:17]([CH3:18])[O:19][CH2:56][CH:57]=[C:58]([CH3:60])[CH3:59])[CH2:15][CH:14]=4)[C:8]1([CH3:30])[CH3:29])[CH3:5])[CH3:2]
Reactant: CCOC(C)O[C@H]1CC[C@]2(C)C3=C(CC[C@H]2C1(C)C)C1=CC[C@H]([C@H](C)O)[C@@]1(C)CC3
Reactant: CC(C)=CCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(C)O[C@H]1CC[C@]2(C)C3=C(CC[C@H]2C1(C)C)C1=CC[C@H]([C@H](C)OCC=C(C)C)[C@@]1(C)CC3
Temperature: 70 °C

Procedure:
xvii)—A mixture of (3β,5α,20S)-3-[(1-ethoxyethyl)oxy]-4,4-dimethylpregna-8,14-dien-20-ol (17; 1.65 g), dry toluene (115 ml), potassium t-butoxide (5.68 g), 18-crown-6 (0.99 g) and 4-bromo-2-methyl-2-butene (4.44 ml) was heated at 70° C. for 1 h. After cooling, the reaction mixture was poured into water and the product extracted into ethyl acetate. The combined organic phases were washed with water and with brine, dried over sodium sulfate, and concentrated under reduced pressure to give (3β,5α,20S)-3-[(1-ethoxyethyl)oxy]-4,4-dimethyl-22-oxacholesta-8,14,24-triene (compound 18; 2.30 g), which was used in the following step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=O)[CH2:8][CH2:9][NH:10][C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1COCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[S:23])[CH2:8][CH2:9][NH:10][C:4]=2[CH:3]=1
Reactant: O=C1CCNc2cc(Br)ccc2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: S=C1CCNc2cc(Br)ccc2N1
Yield: 74.7 %

Procedure:
A solution of 7-bromo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (3) (1.5 g, 6.25 mmol) and Lawesson's Reagent (2.5 g, 12.5 mmol) in THF (50 mL) was heated at 80° C. overnight. The mixture was evaporated, water (50 mL) was added and the solution was extracted with ethyl acetate (100 mL), washed with water (50 mL), dried and concentrated to give the residue, which was purified by CombiFlash (PE:EA=5:1) to afford 7-bromo-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-thione (1.2 g, yield 75%). LRMS (M+H)+: 256 m/z. 1H NMR (300 MHz, CDCl3) δ 3.13-3.17 (t, J=5.4 Hz, 2H), 3.75-3.79 (t, J=5.4 Hz, 2H), 6.77-6.80 (m, 1H), 6.95-6.98 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][C:14]=1[F:22].CN(C=O)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=2)=[O:18])=[CH:15][C:14]=1[F:22]
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(Br)c(F)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-tert-butyl-phenylamine was added 4-bromo-3-fluoro-benzoic acid, DMF (21 mL) and EDCI and were stirred at room temperature overnight. The reaction was diluted with DCM (8 mL) and was washed with HCl (1 M, 8 mL), NaOH (1 M, 8 mL), and brine (5 mL), dried over Na2SO4, and concentrated by stream of nitrogen. The resulting viscous oil was purified by flash chromatography with increasing concentration ethyl acetate in hexanes to afford the product. LCMS calcd for C17H17FNO (m/e) 349, obsd 350 (M+H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][O:20][CH3:21])[CH2:13]2)[N:3]=1.[O:22]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[C:19]([OH:20])(=[O:22])[CH3:18].[CH3:21][O:20][CH2:19][CH2:18][N:14]1[CH2:15][CH2:16][CH2:17][CH:12]([N:4]2[C:5]3=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]3[C:2]([C:32]3[CH:33]=[CH:34][C:29]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:30][CH:31]=3)=[N:3]2)[CH2:13]1
Reactant: COCCN1CCCC(n2nc(I)c3c(N)ncnc32)C1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
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: COCCOC
Solvent: O
Product: CC(=O)O
Product: COCCN1CCCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Reaction time: 0.08 h
Yield: 116.7 %

Procedure:
A solution of racemic 3-iodo-1-[1-(2-methoxyethyl)-3-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.050 g, 0.00012 mol) in dimethoxyethane (2.5 mL) and water (5 mL) was treated with 4-phenoxyphenylboronic acid (0.029 g, 0.00014 mol), sodium carbonate (0.033 g, 0.00031 mol) and tetrakis(triphenylphosphine)palladium (0) (0.014 g, 0.00001 mol) at 80° C. for 20 hours. The organic solvent was removed in vacuo, and the crude material was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 A, 25 cm; 30% isocratic for five minutes, then 30%-60% acetonitrile-0.1M ammonium acetate over 15 min, 21 ml/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give 1-[1-(2-methoxyethyl)-3-piperidyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate as a white solid (0.038 g, 0.00007 mol).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39](=[O:41])[CH3:40]>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:39](=[O:41])[CH3:40])[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Reactant: CON(C)C(C)=O
Product: CC(=O)c1nc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(Cl)c1F

Procedure:
Starting materials: (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45) and N-methoxy-N-methylacetamide.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:12][C:13]1[CH2:17][CH2:16][C:15](=O)[CH:14]=1)C.Cl>CCOCC>[CH2:1]([C:15]1[CH2:16][CH2:17][C:13](=[O:12])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CCOC1=CC(=O)CC1
Agent: Cl
Solvent: CCOCC
Product: O=C1C=C(Cc2ccccc2)CC1
Temperature: -30 °C
Yield: 75.6 %

Procedure:
To a −78° C. solution of benzyl magnesium chloride (14.3 mL, 28.5 mmol, 1.2 eq, 2 M solution in THF) in ether (50 mL) was slowly added 3-ethoxycyclopent-2-enone (2.84 mL, 23.8 mmol, 1 eq.). The reaction mixture was warmed up to −30° C. over 1 hour. At this point, a 1 M solution of HCl was added to the reaction mixture until the pH was adjusted to 1 as indicated by litmus paper. The solution was warmed up to room temperature and the layers were separated. The aqueous phase was extracted with 40 mL of Et2O (3×) and the combined organic layers were washed with 100 mL of brine (1×), dried over anhydrous MgSO4 and concentrated in vacuo. The residual oil was purified by flash chromatography (25% EtOAc/hexanes) to give (3.1 g, 76% yield) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([Cl:5])(=[O:4])[CH2:2][CH3:3].[CH:6](=[O:10])[CH:7](C)[CH3:8].[C:11]([O-])(O)=O.[Na+]>[Cl-].[Cl-].[Zn+2]>[C:6]([O:4][CH:1]([Cl:5])[CH:2]([CH3:11])[CH3:3])(=[O:10])[CH2:7][CH3:8]
Reactant: CCC(=O)Cl
Reactant: CC(C)C=O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Product: CCC(=O)OC(Cl)C(C)C
Reaction time: 2 h

Procedure:
To a flask containing ZnCl2 (0.57 g) at 0° C. was added dropwise propionyl chloride (32.0 g) followed by isobutyraldehyde (25.0 g) over 30 min. After a period of 2 h at room temperature, saturated NaHCO3 solution was added to the reaction mixture. The mixture was then extracted with EtOAc, dried over NaSO4, filtered and evaporated under reduced pressure. The title compound was distilled using a water pump aspirator
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][C:6]1([CH2:8][CH2:7]1)[C:5]2=O.[CH3:15][C:16]([S:19]([NH2:21])=[O:20])([CH3:18])[CH3:17].O>C1COCC1.C([O-])C.C([O-])C.C([O-])C.C([O-])C.[Ti+4]>[Br:1][C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][C:6]1([CH2:8][CH2:7]1)[C:5]2=[N:21][S:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20]
Reactant: CC(C)(C)S(N)=O
Reactant: O=C1c2cc(Br)ccc2OCC12CC2
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2OCC12CC2
Temperature: 80 °C
Reaction time: 48 h
Yield: 57 %

Procedure:
The mixture of 6-bromo-4H-spiro[chromene-3,1′-cyclopropan]-4-one (8.0 g, 32 mmol), 2-methylpropane-2-sulfinamide (12 g, 99 mmol), and titanium(IV) tetraethanolate (22 g, 95 mmol) in THF (160 ml) was stirred for 48 hours at 80° C. To the mixture was added H2O (20 ml), filtered through Celite and washed by EtOAc (50 ml). The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (hexane:EtOAc=100:0-0:100) to give N-(6-bromo-4H-spiro[chromene-3,1′-cyclopropan]-4-ylidene)-2-methylpropane-2-sulfinamide (6.5 g).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13]([F:18])([F:17])([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[C:19](=[O:21])=[O:20].Cl>CCCCCC.CCOCC>[F:14][S:13]([F:18])([F:17])([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([C:19]([OH:21])=[O:20])=[CH:8][CH:9]=1
Reactant: FS(F)(F)(F)(F)c1ccc(Br)cc1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(O)c1ccc(S(F)(F)(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
A solution of n-butyllithium (9.4 ml of a 1.6 M solution in hexane) was added to a stirred solution of 4-bromophenylsulphur pentafluoride (3.87 g) in ether at -78° C. under an inert atmosphere. After maintaining at -78° C. for 1 hour, solid carbon dioxide (20 g) was added and the mixture allowed to warm to 5° C. during 1.5 hours. Hydrochloric acid (2 M) was added, the mixture stirred for 0.5 hour and the organic phase separated and itself extracted with sodium carbonate solution. The basic extract was washed (ether) and acidified (hydrochloric acid). The precipitated solid was extracted (ether), dried (magnesium sulphate) and evaporated. The residue was triturated (hexane) to give 4-pentafluorosulphanylbenzoic acid as a fawn solid (1.2 g), m.p.188-190° C.
Reaction SMILES: [NH2:1][C:2]([CH2:8][CH3:9])=[CH:3][C:4]([O:6][CH3:7])=[O:5].O[C:11](=[C:14]1C(=O)OC(C)(C)[O:16][C:15]1=O)[CH2:12][CH3:13]>>[CH2:8]([C:2]1[NH:1][C:11]([CH2:12][CH3:13])=[CH:14][C:15](=[O:16])[C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH3:9]
Reactant: CCC(N)=CC(=O)OC
Reactant: CCC(O)=C1C(=O)OC(C)(C)OC1=O
Product: CCc1cc(=O)c(C(=O)OC)c(CC)[nH]1
Temperature: 120 °C
Yield: 44 %

Procedure:
A mixture of methyl 3-aminopentenoate (7.3 g) and 5-(1-hydroxypropylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (23.0 g) (obtained as described in J. Org. Chem., 1978, 43, 2087) was heated at 120° C. for 2 hours. The mixture was cooled to ambient temperature and triturated with ether (50 ml). The product was collected by filtration to give methyl 2,6-diethyl-4-oxo-1,4-dihydropyridine-3-carboxylate (5.2 g) as a solid, m.p. 124°-127° C.; NMR (d6 -DMSO): 1.2(t, 6H), 2.3-2.6(m, 4H), 3.7(s, 3H), 5.9(s, 1H), 11.2(s, 1H); mass spectrum (CI, ammonia): 210 (M+H)+ ; microanalysis, found: C, 63.1; H, 7.5; N, 6.7%; C11H15NO3 requires: C, 63.1; H, 7.2; N, 6.7%.