Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:7]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24].Cl.Cl[CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[C:12]([C:8]1[CH:9]=[N:10][C:11]2[C:6]([C:7]=1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(=O)c1cnc2c(N)cccc2c1Nc1ccccc1C
Reactant: ClCCCN1CCOCC1
Agent: Cl
Product: CCCC(=O)c1cnc2c(NCCCN3CCOCC3)cccc2c1Nc1ccccc1C
Yield: 5 %

Procedure:
8-Amino-3-butyryl-4-(2-methylphenylamino)quinoline (6.5 g, 0.02 moles) and 3-chloropropylmorpholine hydrochloride (5.0 g, 0.025 moles) were heated together in fusion (150° C) for 20 minutes. The product was partitioned between ethyl acetate and dil. ammonia solution. The organic layer was washed twice with sodium dihydrogen phosphate solution (pH5), dried, filtered and evaporated. Chromatography (silica gel/chloroform/30-0% hexane) and crystallization from hexane gave 3-butyryl-4-(2-methyl phenylamino)-8-(3-morpholinopropylamino)quinoline as orange crystals (0.45 g, 5%), m.p. 110°-11° C.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[N:10]=[N:11][NH:12][N:13]=2)[C:6]2[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:16][C:5]=2[C:4](=[O:23])[N:3]1[CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1.[H-].[Li+].Br[CH2:40][CH3:41]>CN(C=O)C>[CH2:40]([N:13]1[C:9]([CH2:8][N:7]2[C:6]3[CH:14]=[C:15]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[S:16][C:5]=3[C:4](=[O:23])[N:3]([CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)[C:2]2=[O:1])=[N:10][N:11]=[N:12]1)[CH3:41].[CH2:40]([N:11]1[N:12]=[N:13][C:9]([CH2:8][N:7]2[C:6]3[CH:14]=[C:15]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[S:16][C:5]=3[C:4](=[O:23])[N:3]([CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)[C:2]2=[O:1])=[N:10]1)[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)c3sc(-c4ccccc4)cc3n(Cc3nn[nH]n3)c2=O)CC1
Reactant: CCBr
Agent: CC(C)(C)OC(=O)N1CCC(n2c(=O)c3sc(-c4ccccc4)cc3n(Cc3nnn[nH]3)c2=O)CC1
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Product: CCn1nnnc1Cn1c(=O)n(C2CCN(C(=O)OC(C)(C)C)CC2)c(=O)c2sc(-c3ccccc3)cc21
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
To a solution of the tautomeric mixture of tert-butyl 4-[2,4-dioxo-6-phenyl-1-(2H-tetrazol-5-ylmethyl)-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate and tert-butyl 4-[2,4-dioxo-6-phenyl-1-(1H-tetrazol-5-ylmethyl)-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate (255 mg; compound B14b) in DMF (5 ml) under nitrogen atmosphere is added lithium hydride (5.0 mg). After 10 min at RT bromoethane (163 mg) is added. The mixture is stirred for 1.5 h at 40° C. then all volatile materials are removed in vacuo. The residue is purified by flash column chromatography [silica gel, eluation gradient: hexanes/EtOAc/triethylamine, 16/3/1 to 5/4/1 (v/v/v)] to give the two separated isomers tert-butyl 4-{1-[(1-ethyl-1H-tetrazol-5-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (compound B15) and tert-butyl 4-{1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (compound B14) as solids.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][C:3]=1[C:12]1[CH:20]=[C:19]2[C:15]([C:16]3([CH2:25][CH2:24][CH2:23][CH2:22]3)[C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1.[CH3:26]OC(OC)OC.O>C(O)(=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][CH:26]=[N:9][N:8]=2)=[CH:4][C:3]=1[C:12]1[CH:20]=[C:19]2[C:15]([C:16]3([CH2:25][CH2:24][CH2:23][CH2:22]3)[C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(C(=O)NN)cc1-c1ccc2c(c1)NC(=O)C21CCCC1
Reactant: COC(OC)OC
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(-c2nnco2)cc1-c1ccc2c(c1)NC(=O)C21CCCC1
Temperature: 150 °C
Reaction time: 3 h
Yield: 60.3 %

Procedure:
A stirred mixture of 4-methyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzohydrazide (preparation 53, 0.16 g, 0.24 mmol) and trimethylorthoformate (0.24 mL, 1.44 mmol) in acetic acid (3 mL) were heated to 150° C. in a sealed tube. After 3 hours, the mixture was cooled, poured into water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried (MgSO4) and evaporated in vacuo. Purification of the residue by flash chromatography (1:1 hexanes/ethyl acetate) gave the title compound (0.05 g, 60%) as a white solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH:15]=[CH:16][C:17]#[N:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.C(O)(=[O:24])C.C(O)C>O.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH:15]=[CH:16][C:17]#[N:18])(=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: N#CC=Cc1ccc(Cl)cc1Cc1ccccc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: N#CC=Cc1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 28.8 g (0.14 mol) of 3-[2-benzyl-4-chlorophenyl]-2-propenenitrile, 50 g (0.5 mol) of chromium trioxide, 100 ml of methylene chloride, and 300 ml of acetic acid was stirred at room temperature overnight. The excess chromium trioxide was discharged by the slow addition of 30 ml of ethanol. The mixture was diluted with 800 ml of water and extracted with 500 ml of ether. The ether solution was washed with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The ether solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a yellow oil which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:20]=1[NH2:21].Cl.[OH-].[Na+]>O.C(O)C>[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1
Yield: 18.8 %

Procedure:
A mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (500 mg, 1.93 mmol), 2-methyl,5-nitroaniline (441 mg, 2.90 mmol), and 2N HCl (1.5 ml) in water:ethanol (1:1, 100 ml) was refluxed for 48 h. The mixture was cooled to room temperature and basified with aqueous 2N NaOH to pH 10–12. The resulting precipitate was filtered, washed with water and water:ethanol (2:1). The product was dried under vacuo and then washed with chloroform to give a yellow solid (136 mg, 19%). 1H NMR (DMSO-d6): 9.84 (s, 1H), 9.41 (s, 1H), 8.99 (s, 1H), 8.73 (d, J=4.2 Hz, 1H), 8.57 (d, J=7.8 Hz, 1H), 8.02 (dd, J=1.8, 7.8, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.58–7.54 (m, 1H), 7.39 (s, 1H), 2.45 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([S:21][CH:22]([CH3:24])[CH3:23])=[N:12][C:13]([CH3:20])=[CH:14][C:15]=1[S:16][CH:17]([CH3:19])[CH3:18])=[O:8].[SH:25][C:26]1[O:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[O:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[S:25][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([S:21][CH:22]([CH3:24])[CH3:23])=[N:12][C:13]([CH3:20])=[CH:14][C:15]=1[S:16][CH:17]([CH3:19])[CH3:18])=[O:8]
Reactant: Cc1cc(SC(C)C)c(NC(=O)CCCCCBr)c(SC(C)C)n1
Reactant: Sc1nc2ccccc2o1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC(C)C)c(NC(=O)CCCCCSc2nc3ccccc3o2)c(SC(C)C)n1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 79.4 %

Procedure:
The reaction and the treatment were conducted in the same manner as in Example 35 except that 6-bromohexanoyl chloride was used instead of bromoacetyl bromide to obtain 6-bromo-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]hexanamide. To a DMF (4 ml) solution of this amide (100 mg, 0.23 mmol) and 2-mercaptobenzoxazole (35 mg, 0.23 mmol) were added potassium carbonate (38 mg, 0.28 mmol) and 18-crown-6 (6 mg, 0.02 mmol), and the mixture was stirred at 80° C. for 2.5 hours. The reaction mixture was allowed to cool, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting residue was purified through preparative thin-layer chromatography (eluent—hexane:ethyl acetate=3:1) to obtain 92 mg (yield 79%) of the desired compound as a colorless powdery crystal.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[CH:5]=1.[C-]#N.[K+].[CH3:16][N:17](C=O)C>O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:16]#[N:17])[CH:5]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: COC(=O)c1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-bromomethyl-benzoic acid methyl ester (3.00 g, 13.10 mmol), potassium cyanide (1.02 g, 15.71 mmol) and DMF (25 mL) was heated at 40–45° C. for 45 minutes and was stirred at room temperature for 18 h. The reaction was heated at 40° C. for 24 h, was cooled to room temperature, and additional potassium cyanide (1.02 g, 15.71 mmol) was added. The reaction was heated at 40° C. for 18 h and was cooled to room temperature. Water (25 mL) was added and the product was extracted into EtOAc (3×25 mL). The combined organic layers were washed with 1N LiCl followed by brine, dried over MgSO4, filtered, and concentrated. Flash chromatography (9:1 hexanes:EtOAc to 4:1 hexanes:EtOAc) provided 3-cyanomethyl-benzoic acid methyl ester (1.36 g). MS 193 (M+18).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]([OH:15])[C:11]([F:14])([F:13])[F:12].C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[N:7]=[C:6]([O:15][CH2:10][C:11]([F:14])([F:13])[F:12])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: OCC(F)(F)F
Reactant: Fc1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1cnc(Cl)nc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,4-Dichloro-5-fluoropyrimidine (100 mg, CAS 2927-71-1) was combined with trifluoroethanol (1.09 ml) to give a colourless solution. Potassium carbonate (82.8 mg) was added. The reaction mixture was stirred at room temperature for 30 min. TLC at t=30 min showed the reaction was complete. The reaction mixture was filtered through sintered glass and concentrated in vacuo. The residue was triturated with diethyl ether, then filtered through sintered glass and dried in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[H-].[Na+].[Cl:12][C:13]1[CH:18]=[C:17]([N+]([O-])=O)[CH:16]=[CH:15][N:14]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([O:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:16]=[CH:15][N:14]=1
Reactant: COc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(Oc2ccnc(Cl)c2)cc1
Yield: 99.7 %

Procedure:
Using the method of Example 3, Step A, 4-methoxyphenol (2.35 g, 18.9 mmol), 60% sodium hydride in mineral oil (0.757 g, 18.9 mmol), and 2-chloro-4-nitropyridine (3.00 g, 18.9 mmol) were reacted to provide 2-chloro-4-(4-methoxyphenoxy)pyridine (4.44 g, 99% yield) as an oil. 1H NMR (CDCl3) δ 8.20 (d, 1H), 7.01 (d, 2H), 6.95 (d, 2H), 6.75-6.77 (m, 2H), 3.84 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:10][CH:11]1[CH2:16][C:15](=[O:17])[O:14][C:13](=[O:18])[CH2:12]1.C1(C)C=CC=CC=1.CS(C)=O>O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:15]([CH2:16][CH:11]([CH3:10])[CH2:12][C:13]([OH:18])=[O:14])=[O:17])=[N:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(N)nc1
Reactant: CC1CC(=O)OC(=O)C1
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)cn1
Yield: 14.5 %

Procedure:
A solution of 6-aminonicotinonitrile (100.0 mg, 0.839 mmol) and 4-methyldihydro-2H-pyran-2,6(3H)-dione (118 mg, 0.923 mmol) in a mixed solvent of toluene (3 mL) and DMSO (0.3 mL) was stirred at 120° C. for 24 hr. To the reaction mixture was added cold water, and the mixture was extracted with ethyl acetate (4×30 mL). The organic layer was washed with water, and dried, and the solvent was evaporated under reduced pressure. The obtained solid was washed with 50% dichloromethane/hexane solution to give 4-(5-cyanopyridin-2-ylcarbamoyl)-3-methylbutyric acid (30 mg, 14.49%) as a pale-yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5](OS(C)(=O)=O)[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C(OS(C)(=O)=O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(Nc1ccccc1)c1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Yield: 33.1 %

Procedure:
Methanesulfonyloxy-(4-trifluoromethyl-phenyl)-acetic acid ethyl ester (I102) (594 mg, 1.82 mmol), aniline (0.25 mL, 2.73 mmol), and DIPEA (0.48 mL, 2.73 mmol) are dissolved in acetonitrile (4 mL). The reaction is heated under microwave irradiation at 100° C. for 1 hour and 30 minutes. Aniline (0.17 mL, 1.820 mmol) is added again and the reaction is heated under microwave irradiation at 100° C. for 3 hours. Acetonitrile is removed under vacuum and the residue is purified by flash chromatography (Petroleum ether/DCM=75/25) to afford intermediate I151 as a yellow oil (195 mg, 60% yield).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.S(Cl)(Cl)=O.[CH3:26]O>>[CH3:26][O:10][C:9](=[O:11])[CH2:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][CH:13]=2)=[CH:5][CH:6]=1
Reactant: CO
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CC(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A solution of 2.55 g (8.63 mmol) of the above prepared [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid in 25 ml of methanol was cooled to −10° C.; 1.88 ml (25.9 mmol) of thionyl chloride was added and the reaction mixture was then stirred at ambient temperature for 2 hours. Subsequently, the solution was poured onto ice water, then extracted with three portions of 50 ml of tert.-butyl methyl ether. The combined organic layers were washed with water, aqueous NaHCO3-solution and brine, and dried over sodium sulfate. After evaporation of the solvents, 2.60 g of the title compound was obtained as light brown solid.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C:3]#[C:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[NH:12]C(=O)CCC.CC([O-])(C)C.[K+].O>CN(C=O)C>[C:2]([C:3]1[NH:12][C:6]2[C:5]([CH:4]=1)=[C:10]([F:11])[CH:9]=[CH:8][CH:7]=2)([CH3:19])([CH3:18])[CH3:1]
Reactant: CCCC(=O)Nc1cccc(F)c1C#CC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc2c(F)cccc2[nH]1
Temperature: 90 °C
Yield: 151.6 %

Procedure:
To a solution of N-(2-(3,3-dimethylbut-1-ynyl)-3-fluorophenyl)butyramide (6.0 g, 20 mmol) in DMF (100 mL) was added t-BuOK (5.0 g, 50 mmol) at room temperature. The mixture was heated at 90° C. overnight before it was poured into water and extracted with EtOAc (100 mL×3). The organic layers were washed with sat. NaCl and water, dried over anhydrous Na2SO4, and evaporated under vacuum to give 2-tert-butyl-4-fluoro-1H-indole (5.8 g, 97%). 1H NMR (400 MHz, CDCl3) δ 8.17 (br s, 1H), 7.11 (d, J=7.2 Hz, 1H), 7.05-6.99 (m, 1H), 6.76-6.71 (m, 1H), 6.34 (m, 1H), 1.41 (s, 9H).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9](C(O)=O)[OH:10])[OH:8])[OH:6])[OH:4].O=C(O)[C@H]([C@H]([C@@H]([C@H](CO)O)O)O)O>>[O:1]=[CH:2][C@H:3]([C@@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(=O)O
Agent: O=C(O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Product: O=C[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
FIG. 6 depicts the reaction sequence of FIG. 4 when the D-glucuronic acid (30) compound (30) is a precursor material that is reduced (f2) to a L-gulonic acid (60). The L-gulonic acid (60) undergoes decarboxylation to produce a L-xylose (70) xylitol intermediate, which may be reduced (e2) to xylitol (50).
Reaction SMILES: [F:1][CH:2]([F:36])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:16]2[NH:33][C:19]3[CH:20]=[N:21][N:22](COCC[Si](C)(C)C)[C:23](=[O:24])[C:18]=3[C:17]=2[CH2:34][CH3:35])=[C:8]2[C:13]=1[O:12][C:11]([CH3:15])([CH3:14])[CH:10]=[CH:9]2.[Cl:37]C1C2C(=O)NN=CC=2N(COCC[Si](C)(C)C)C=1C1C=CC(OC(F)F)=C(OC2CC2)C=1>>[ClH:37].[F:36][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:16]2[NH:33][C:19]3[CH:20]=[N:21][NH:22][C:23](=[O:24])[C:18]=3[C:17]=2[CH2:34][CH3:35])=[C:8]2[C:13]=1[O:12][C:11]([CH3:15])([CH3:14])[CH:10]=[CH:9]2
Reactant: CCc1c(-c2ccc(OC(F)F)c3c2C=CC(C)(C)O3)[nH]c2cnn(COCC[Si](C)(C)C)c(=O)c12
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)c(Cl)c2c(=O)[nH]ncc21
Product: CCc1c(-c2ccc(OC(F)F)c3c2C=CC(C)(C)O3)[nH]c2cn[nH]c(=O)c12
Product: Cl
Yield: 93 %

Procedure:
Reaction was carried out in the same manner as in Example 6-(c) except for using 613 mg (1.18 mmol) of 2-(8-difluoromethoxy-2,2-dimethyl-2H-chromen-5-yl)-3-ethyl-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 54-(b) in place of 3-chloro-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one. After completion of the reaction, the solid obtained from the reaction suspension by filtration was washed with hexane and dried under reduced pressure to obtain 467 mg of the title compound as a white solid. (Yield: 93%)
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:28](Cl)(=[O:30])[CH3:29]>>[C:28]([N:20]1[CH2:21][C:16]2[C:15]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[N:14][C:13]([C:10]3[CH:11]=[CH:12][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:8][CH:9]=3)=[N:18][C:17]=2[CH2:19]1)(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(C(C)=O)C3)cc1

Procedure:
Method as example 18 using 1-ethyl-3-(4-(4-morpholino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 14) and acetyl chloride as starting materials.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:27][CH3:28])[C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=O)[N:13]=1.B.C(O)(=O)C.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:27][CH3:28])[C:12]1[N:13]=[C:14]([CH2:19][N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[CH:15]=[C:16]([CH3:18])[N:17]=1
Reactant: CCN(c1nc(C)cc(C(=O)N2CCOCC2)n1)c1ccc(C(C)C)cc1Br
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCN(c1nc(C)cc(CN2CCOCC2)n1)c1ccc(C(C)C)cc1Br
Temperature: 25 °C
Reaction time: 20 h
Yield: 40.2 %

Procedure:
A solution of N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-methyl-6-(4-morpholinylcarbonyl)-2-pyrimidinamine (750 mg, 1.72 mmol) in anhydrous THF (1.4 mL) was stirred at ambient temperature under a nitrogen atmosphere. A solution of borane in THF (1 M, 3.6 mL, 3.6 mmol) was added dropwise. The reaction mixture was then warmed to reflux temperature and stirred for 20 hours. After cooling to room temperature, acetic acid (3.5 mL) was added slowly and the mixture was heated to reflux temperature and stirred for 30 min. After being cooled to ambient temperature, the reaction mixture was poured onto a 3 N NaOH solution, mixed and extracted three times with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. Column chromatography (EtOAc) of the residue afforded the title compound as an oil (300 mg, 39% yield, Rf 0.3): NMR (CDCl3, 300 MHz): d 7.5 (s, 1H), 7.2 (d, 1H, J=7), 7.15 (d, 1H, J=7), 6.5 (s, 1H), 4.3-4.1 (m, 1H), 3.8-3.6 (m, 7H), 3.5-3.3 (m, 2H), 2.9 (septet, 1H, J=7), 2.55-2.35 (br m, 3H), 2.35-2.25 (m, 2H), 1.3 (d, 6H, J=7), 1.2 (t, 3H, J=7); CI-HRMS: calcd: 4.33.1603 (M+H), found: 433.1586.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(N(CC)CC)C.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:10]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=Cc1cccc(Br)c1
Reactant: C#CCCCCCCCCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCCCCC#Cc1cccc(C=O)c1
Temperature: 55 °C
Reaction time: 6 h
Yield: 109.1 %

Procedure:
To a solution of 3-bromobenzaldehyde (30.3 g) and 1-undecyne (29.5 g) in triethylamine (120 ml) was added bis(triphenylphosphine)palladium(II)chloride (1.9 g) followed by copper(I) iodide (0.25 g). The mixture was stirred in the dark at 55° C. for 6 hrs, under nitrogen. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to yield 45.8 g of 3-(1-undecynyl)benzaldehyde, as an oil.
Reaction SMILES: [I:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[C@H:26]2[CH2:31][CH2:30][C@@H:29]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:28][CH2:27]2)(=O)=O)=CC=1>CN(C=O)C>[Si:33]([O:32][C@H:29]1[CH2:28][CH2:27][C@H:26]([N:4]2[C:5]3[CH:10]=[CH:9][N:8]=[C:7]([O:11][CH3:12])[C:6]=3[C:2]([I:1])=[CH:3]2)[CH2:31][CH2:30]1)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CC[C@@H](O[Si](C)(C)C(C)(C)C)CC2)cc1
Reactant: COc1nccc2[nH]cc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nccc2c1c(I)cn2[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-iodo-4-methoxy-1H-pyrrolo[3,2-c]pyridine (0.100 g) in DMF (5 mL) was added sodium hydride (60% dispersion in mineral oil, 36.5 mg), and the mixture was stirred at room temperature for 1 hr. cis-4-((tert-Butyl(dimethyl)silyl)oxy)cyclohexyl 4-methylbenzenesulfonate (351 mg) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (31.1 mg).