Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[S:8]/[C:9]/1=[N:10]\[C:11](=[O:20])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[OH:19])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:28][C:29]#[N:30]>C1COCC1.CN(C=O)C>[CH2:1]([C:5]1=[CH:6][N:7]([C:21]([CH3:23])([CH3:22])[CH3:24])[S:8]/[C:9]/1=[N:10]\[C:11](=[O:20])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:19][CH2:28][C:29]#[N:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1O
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1OCC#N
Temperature: 80 °C
Reaction time: 8 h
Yield: 4.5 %

Procedure:
To a solution of Example 135 (300 mg, 0.82 mmol) in THF/DMF (1:1, 4 mL) were added sodium hydride (39.2 mg, 0.98 mmol) and 2-bromoacetonitrile (65 μl, 0.98 mmol). The reaction was stirred at 40° C. for 4 hrs and at 80° C. for overnight. The reaction mixture was cooled to room temperature, quenched with saturated NaHCO3 (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in dichloromethane) to afford 15 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.3 Hz, 3 H), 1.20-1.48 (m, 2 H), 1.53-1.77 (m, 2 H), 1.63 (s, 9 H), 2.62-2.82 (m, 2 H), 5.22 (s, 2 H), 7.29 (d, J=9.1 Hz, 1H), 7.58 (dd, J=8.7, 2.8 Hz, 1 H), 7.86 (d, J=2.8 Hz, 1 H), 8.67 (s, 1 H); MS (ESI+) m/z 406 (M+H)+; Anal. Calculated C20H24ClN3O2S: C, 59.17; H, 5.96; N, 10.35. Found: C, 59.18; H, 5.78; N, 10.37.
Reaction SMILES: COP([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])(OC)=O.[H-].[Na+].[Br:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([CH2:25][CH:26]=O)=[C:20]([CH3:28])[CH:19]=1.C([O-])(O)=O.[Na+]>C1COCC1>[Br:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([CH2:25]/[CH:26]=[CH:7]/[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:20]([CH3:28])[CH:19]=1
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Reactant: Cc1cc(Br)cc(C)c1CC=O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1C/C=C/C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
tert-Butyl 2-(dimethoxyphosphoryl)acetate (2.5 mL, 12.7 mmol) was added dropwise to a suspension of NaH (490 mg, 12.7 mmol, 60% dispersion in oil) in THF (60 mL) at 0° C. After stirring for 30 min at ambient temperature a solution of 53A (2.6 g, 11.4 mmol) in THF (10 mL) and stirred for 1 h at ambient temperature. The reaction mixture was poured into 50 mL saturated NaHCO3/400 mL water and extracted with diethyl ether. The combined organics were dried over Na2SO4 and concentrated in vacuo. The crude solid was purified by flash chromatography (0% to 50% EtOAc in hexanes) to yield 53B (2.35 g, 63%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.44 (s, 9 H) 2.22 (s, 6 H) 3.43 (dd, J=5.56, 1.77 Hz, 2 H) 5.43 (dt, J=15.54, 2.02, 1.89 Hz, 1 H) 6.92 (dt, J=15.66, 5.56 Hz, 1 H) 7.17 (s, 2 H).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH:12]=[O:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:14].[Na+]>[N+]([O-])([O-])=O.[Ag+]>[C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [OH-]
Reactant: O=Cc1ccc(-c2ccccc2)o1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Product: O=C(O)c1ccc(-c2ccccc2)o1
Temperature: 60 °C

Procedure:
To 5-phenyl-2-furaldehyde (35) (690 mg, 4.01 mmol) was added solid NaOH (176 mg, 4.40 mmol) then 10% NaOH solution (6.2 mL). Silver nitrate (680 mg, 4.00 mmol) was added and the reaction mixture heated to 60° C. for 4.5 hours then cooled to ambient temperature. The reaction mixture was then filtered and washed with water. The filtrate was acidified to pH 2 using 2N HCl and the precipitated product filtered and dried to give the title compound.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([C:9]#[N:10])=[N:6][C:7]=1[CH3:8].[ClH:11]>CC#N.Cl[Cu]>[Cl:11][C:2]1[CH:3]=[CH:4][C:5]([C:9]#[N:10])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C#N)ccc1N
Reactant: Cl
Agent: Cl[Cu]
Solvent: CC#N
Product: Cc1nc(C#N)ccc1Cl
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of 5-amino-6-methylpicolinonitrile (2) (260 mg, 1.95 mmol), CuCl (290 mg, 2.93 mmol) and t-BuONO (456 mg, 3.9 mmol) in CH3CN (10 mL) was stirred at room temperature under N2 for 2 h, and then warmed to 60° C. After 2 h, 10 mL 6N HCl was added and extracted with EA (3×10 mL). The organic phase was dried with anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep-TLC using PE/EtOAc=1/1 to give title compound as oil.
Reaction SMILES: C(NN)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C[Si](N=C=S)(C)C.[C:18]([OH:21])(=[O:20])C>>[C:18]([OH:21])(=[O:20])[C:3]1[CH:2]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: CC(=O)O
Reactant: NNC(=O)c1ccncc1
Agent: C[Si](C)(C)N=C=S
Product: O=C(O)c1cccnc1
Temperature: 105 °C
Reaction time: 8 h

Procedure:
Isonicotinic acid hydrazide (1.06 g, 7.73 mmol) and trimethylsilyl isothiocyanate (2.03 g, 15.4 mmol) were dissolved in acetic acid (2.0 ml) in a round bottom flask with a condenser and stirred magnetically at 105° C. overnight. The solution was cooled to room temperature, at which time a solid formed. The acetic acid solution was decanted and any remaining solvent was evaporated with heating on a rotary evaporator. This residue was carried on as such to the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.C([Li])CCC.[F:16][C:17]([F:27])([F:26])[C:18](N1CCCCC1)=[O:19].[Cl-].[NH4+]>C(OCC)C>[F:16][C:17]([C:18]([C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1)=[O:19])([F:27])[F:26]
Reactant: Brc1ccc2c(c1)OCO2
Reactant: O=C(N1CCCCC1)C(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: O=C(c1ccc2c(c1)OCO2)C(F)(F)F
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 50.4 %

Procedure:
4-Bromo-1,2-methylenedioxybenzene (4.02 g, 0.020 mole) was dissolved in dry diethylether (100 ml) and cooled to -30° C. under a dry argon atmosphere. At -30° C. to -40° C. n-butyllithium (12 ml, 0.002 mole; 1.85 molar solution in n-hexane) were added with stirring over 15 minutes. After 50 minutes at -30° C. the mixture was cooled to -50° C. and the solution of N-trifluoroacetyl piperidine (3.62 g, 0.020 mole) in dry ether (20 ml) was added over 5 minutes. After 45 minutes at -50° C. the reaction mixture was warmed up to -40° C. for 30 minutes, and to room temperature over another 30 minutes. Saturated aqueous ammonium chloride (25 ml) was added with vigorous stirring. The layers were separated and the organic top layer washed with 10% aqueous ammonium chloride (3× 50 ml) and dried over anhydrous sodium sulfate. After filtration and removal of the ether under reduced pressure the residual liquid was distilled in vacuo to give trifluoromethyl (3,4-methylenedioxyphenyl)-methanone (2.2 g), (50.4%) b.p. 60° C./0.2 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([NH:21][CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:11]=3[C:12](=[O:14])[CH:13]=2)=[CH:4][C:3]=1[F:28].S(=O)(=O)(O)[OH:30].O>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([NH:21][CH2:22][CH2:23][CH2:24][C:25]([OH:30])([CH3:26])[CH3:27])[C:11]=3[C:12](=[O:14])[CH:13]=2)=[CH:4][C:3]=1[F:28]
Reactant: CC(C)=CCCNc1c(F)cc(F)c2oc(-c3ccc(N)c(F)c3)cc(=O)c12
Reactant: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CC(C)(O)CCCNc1c(F)cc(F)c2oc(-c3ccc(N)c(F)c3)cc(=O)c12
Temperature: 100 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
16 mg (0.041 mmol) of Compound 137 obtained in Example 137 was dissolved in 3 mL of ethanol, 3 mL of 50% sulfuric acid was added and the mixture was stirred at 100° C. for 1 hour. The reaction solution was cooled on ice, water was added and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with an aqueous saturated solution of sodium bicarbonate, once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 14 mg of Compound 138 (yield: 84%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[N+](C1C=C(S(O[CH2:23][C@@H:24]2[O:26][CH2:25]2)(=O)=O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[O:26]1[CH2:25][C@@H:24]1[CH2:23][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=Cc1ccc(OC[C@H]2CO2)cc1
Yield: 89.1 %

Procedure:
In 800 ml of anhydrous methyl ethyl ketone was dissolved 23.54 g of 4-hydroxybenzaldehyde and 50 g of (R)-(-)-glycidyl m-nitrobenzenesulfonate. To the solution was added 34.6 g of anhydrous potassium carbonate, and the mixture was refluxed with heating for 2.5 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was extracted with ethyl acetate. The extract was washed with water, dried with magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and purified with chloroform to give 30.6 g of the title compound (yield 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[CH:24]([C:26]1[S:27][CH:28]=[CH:29][N:30]=1)[OH:25]>CO.C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[C:24]([C:26]1[S:27][CH:28]=[CH:29][N:30]=1)=[O:25]
Reactant: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C(O)c2nccs2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C(=O)c2nccs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-methoxy-phenyl]-thiazol-2-yl-methanol (90 mg) was dissolved in methanol/methylene chloride (3 ml/9 ml) to prepare a solution, manganese dioxide (90 mg) was added to the solution, and the mixture was stirred at room temperature overnight. The reaction solution was filtered through Celite, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (65 mg, yield 74%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].N1CC[O:22]CC1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][O:22][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3]
Reactant: C1COCCN1
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)O)c1
Yield: 80 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-(methane-2-sulfonyl)-benzoic acid and morpholine and obtained in 80% yield. MS (m/e): 284.1 (MH−, 100%).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:9][N:10]=[C:4]2[C:3]=1[C:16]#[N:17].O(Cl)[Cl:19].[P+5].C([O-])(O)=O.[Na+]>>[Cl:19][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:9][N:10]=[C:4]2[C:3]=1[C:16]#[N:17]
Reactant: ClOCl
Reactant: N#Cc1c(O)ccn2c(CC(F)(F)F)cnc12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [P+5]
Product: N#Cc1c(Cl)ccn2c(CC(F)(F)F)cnc12
Temperature: 130 °C

Procedure:
A mixture of compound D9 (1 g, 4.148 mmol) and phosphorus(V) oxychloride (2 ml) was subjected to microwave heating at 130° C. for 15 min. After cooling to room temperature, the solvent was evaporated in vacuo. The residue thus obtained was then treated with NaHCO3 (aqueous sat. solution) and extracted with DCM. The organic layer was separated, dried (MgSO4) and evaporated in vacuo. The crude product was purified by column chromatography (silica gel; Et2O as eluent). The desired fractions were collected and evaporated in vacuo to yield compound D10 (0.6 g, 56%) as yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[BH4-].[Na+].II.Cl.[OH-].[Na+]>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(c2ccc(C#N)cc2)CC1
Agent: Cl
Agent: II
Agent: [BH4-]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(c2ccc(CN)cc2)CC1
Reaction time: 1 h
Yield: 51.2 %

Procedure:
To a mixture of ethyl-4-(4-cyanophenyl)-1-piperazine carboxylate (10 g), sodium borohydride (3.4 g), and tetrahydrofuran (50 mL) was added a mixture of iodine (9.8 g) and tetrahydrofuran (50 mL) under a nitrogen gas flow while ice-cooling, followed by stirring at the same temperature for 1 hour, and then further heating and refluxing for 3 hours. The reaction solution was ice-cooled and a 6 M hydrochloric acid solution was added thereto to adjust the pH to 1. The reaction solution was stirred at 70° C. for 30 minutes. After leaving to be cooled, sodium hydroxide was added thereto to adjust the pH to 10, followed by extraction with ethyl acetate. The extracts were washed with saturated brine, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was made into powder using tetrahydrofuran, ethyl acetate, and diisopropyl ether, to obtain ethyl-4-[4-(aminomethyl)phenyl]-1-piperazine carboxylate (5.2 g).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[N+:21]([O-])=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)C>[C:4]([C:17]1[C:16]([NH2:21])=[C:15]([N:11]2[CH2:12][CH2:13][CH2:14][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10]2)[CH:20]=[CH:19][N:18]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)OC1CCCN(c2ccncc2[N+](=O)[O-])C1
Solvent: CCO
Product: CC(C)(C)c1nccc(N2CCCC(O[Si](C)(C)C(C)(C)C)C2)c1N

Procedure:
Following Method 2 of Example 49, (+/−)-4-(3-(tert-butyl dimethylsilyloxy)piperidin-1-yl)-3-nitropyridine in ethanol was reduced yielding tert-butyl (+/−)-4-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)pyridin-3-amine. LCMS (m/z): 308.2 (MH+); LC Rt=3.47 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[CH:6]=1)[CH3:2].[CH2:13]([O:20][CH2:21][N:22]1[N:26]=[N:25][C:24]([Sn](CCCC)(CCCC)CCCC)=[N:23]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.[Cu]I.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>[CH2:13]([O:20][CH2:21][N:22]1[N:26]=[N:25][C:24]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:4]([O:3][CH2:1][CH3:2])=[O:12])=[N:23]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1cccc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nnn(COCc2ccccc2)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(-c2nnn(COCc3ccccc3)n2)c1
Temperature: 25 °C

Procedure:
A solution of ethyl-3-bromobenzoate (0.47 g, 2.05 mmol) and 2-(benzyloxymethyl)-5-(tributylstannyl)-2H-tetrazole in toluene (20 mL) was degassed under vacuum and argon. To this solution was added copper (I) iodide (20 mg, 0.20 mmol) and tetrakis(triphenylphosphine)palladium(0) (115 mg, 0.10 mmol), and the mixture was again degassed under vacuum and argon. The flask and condenser were covered in foil to exclude light, and the reaction was heated at reflux temperature for 3 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated in-vacuo. The residue was purified over a 3.5×12 cm silica gel column, eluting with 5% then 10% then 15% ethyl acetate/hexanes to yield the title compound as a colorless oil which contained 5% of a tributyltin impurity. MS (ESI+)=339.22, (M+H)+. The oil was used as-is in the next step.
Reaction SMILES: Cl.C([N:4]=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH3:24][C:25]1[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:28]([CH3:35])[O:27][C:26]=1[C:36]([OH:38])=O.N>O.N1C=CC=CC=1>[CH3:24][C:25]1[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:28]([CH3:35])[O:27][C:26]=1[C:36]([NH2:4])=[O:38]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOC(=O)c1c(C)oc(C(=O)O)c1C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)oc(C(N)=O)c1C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (248 mg, 1.30 mmol) and 1-hydroxybenzotriazole monohydrate (199 mg, 1.30 mmol) were added to a pyridine (4 ml) solution of the 3,5-dimethyl-4-ethoxycarbonylfuran-2-carboxylic acid (250 mg, 1.18 mmol) obtained in Example 2 (1). After a 28% aqueous ammonia solution (0.19 ml, 11.8 mmol) was added, heated to 80° C. and stirred for 4 hours. The mixture was cooled to room temperature with stirring, and after addition of water to reaction mixture, precipitate was collected by filtration, thereby giving 3,5-dimethyl-4-ethoxycarbonylfuran-2-carboxamide (176 mg, 71%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][CH:8]=[N:9]2)=[C:4]([O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:3]=1.P(Cl)(Cl)([Cl:22])=O.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:22][C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[CH:3][C:4]=2[O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:9]=[CH:8][N:7]=1
Reactant: O=c1[nH]cnc2cc(F)cc(OC3CCOCC3)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Fc1cc(OC2CCOCC2)c2c(Cl)ncnc2c1
Temperature: 80 °C

Procedure:
A first portion (0.25 g) of 7-fluoro-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one was added to a stirred mixture of phosphoryl chloride (1.76 ml), diisopropylethylamine (3.95 ml) and acetonitrile (10 ml) that had been heated to 80° C. The resultant mixture was heated to 80° C. for 3 hours. A second portion (0.25 g) of 7-fluoro-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one was added and the mixture was heated to reflux for a further 90 minutes. There was thus obtained a solution of 4-chloro-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline which was used without being isolated. A solution of 6-chloro-2,3-methylenedioxyaniline (0.32 g) in acetonitrile (3 ml) was added and the reaction mixture was heated to 80° C. for 2.5 hours. As the required conversion was incomplete, the reaction mixture was evaporated and toluene (15 ml) was added as reaction solvent. A second portion of 6-chloro-2,3-methylenedioxyaniline (0.32 g) was added and the reaction mixture was heated to reflux for 3 hours. The reaction mixture was cooled to ambient temperature and partitioned between methylene chloride and an aqueous sodium chloride solution. The organic phase was washed with water, dried over magnesium sulphate and evaporated. There was thus obtained 4-(6-chloro-2,3-methylenedioxyanilino)-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline as a foam (0.73 g); NMR Spectrum: (DMSOd6) 1.9-2.05 (m, 2H), 2.1-2.2 (m, 2H), 3.5-3.6 (m, 2H), 3.8-3.95 (m, 2H), 5.1 (m, 1H), 6.1 (s, 2H), 7.0 (d, 1H), 7.1 (d, 1H), 7.3 (d, 1H), 7.4 (m, 1H), 8.6 (s, 1H), 9.3 (s, 1H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([OH:10])=[CH:4][C:3]=2[O:2]1.Cl[CH:12]([S:22][CH3:23])[C:13]([NH:15][C:16]([CH3:21])([C:18]#[C:19][CH3:20])[CH3:17])=[O:14]>>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([O:10][CH:12]([S:22][CH3:23])[C:13]([NH:15][C:16]([CH3:17])([C:18]#[C:19][CH3:20])[CH3:21])=[O:14])=[CH:4][C:3]=2[O:2]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CC#CC(C)(C)NC(=O)C(Cl)SC
Product: CC#CC(C)(C)NC(=O)C(Oc1ccc2c(c1)OCO2)SC

Procedure:
In a similar procedure, 3,4-methylenedioxyphenol was reacted with 2-(chloro)-2-(methylthio)-N-(2-methylpent-3-yn-2-yl)acetamide to give 2-(3,4-methylenedioxy-phenoxy)-2-methylthio-N-(2-methylpent-3-yn-2-yl)acetamide (Compound No. 4 of Table 3).
Reaction SMILES: [ClH:1].C([CH2:9][NH:10][CH2:11][CH2:12][N:13]1[C:22]2[C:17](=[C:18]([CH3:24])[CH:19]=[C:20]([CH3:23])[N:21]=2)[CH:16]=[CH:15][C:14]1=[O:25])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[ClH:1].[CH3:9][NH:10][CH2:11][CH2:12][N:13]1[C:22]2[C:17](=[C:18]([CH3:24])[CH:19]=[C:20]([CH3:23])[N:21]=2)[CH:16]=[CH:15][C:14]1=[O:25]
Reactant: Cc1cc(C)c2ccc(=O)n(CCNCCc3ccccc3)c2n1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CNCCn1c(=O)ccc2c(C)cc(C)nc21

Procedure:
1(2-Benzylmethylaminoethyl)-5,7-dimethyl-1,8-naphthyridin-2(1H)-one hydrochloride (8.56 g., 0.024 mole) is dissolved in 80 ml. of ethanol, 5% palladium on carbon (0.8 g.) catalyst is added and the mixture is hydrogenated at a pressure of 45 lbs. per sq. inch until hydrogen is no longer taken up. The mixture is filtered concentrated under reduced pressure and the residue is crystallized from isopropanol. 1-(2-Methylaminoethyl)-5,7-dimethyl-1,8-naphthyridin-2(1H)-one hydrochloride having a melting point of 106°-109° C. is obtained.
Reaction SMILES: Cl.[OH:2]/[N:3]=[C:4](/[C:10]1[N:11]=[C:12]([NH:15]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:13][CH:14]=1)\[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:35]1([CH2:41]Br)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>C(O)=O>[NH2:15][C:12]1[S:13][CH:14]=[C:10](/[C:4](=[N:3]/[O:2][CH2:41][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:11]=1
Reactant: BrCC1CCCCC1
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Solvent: O=CO
Product: CCOC(=O)/C(=N\OCC1CCCCC1)c1csc(N)n1
Yield: 62 %

Procedure:
Ethyl (Z)-2-(hydroxyimino)-2-(2-tritylaminothiazol-4-yl)acetate hydrochloride (3.08 g) was reacted with cyclohexylmethyl bromide as described in Example 5a. The product was deprotected with formic acid as described in Example 1a. Crystallisation from cyclohexane/hexane gave the title compound as a white solid (1.2 g, 62%), m.p. 107.0°-107.5° C. [Found: C: 54.21; H: 6.58; N: 13.31. C14H21N3O3S requires C: 54.00; H: 6.80; N: 13.49%]. νmax (CHCl3) 3400, 2920, 1730, 1600 cm-1 ; δH (CDCl3) 1.0 (2H, m), 1.2 (3H, m), 1.33 (3H, t), 1.7 (6H, m), 3.97 (2H, d), 4.35 (2H, q), 5.60 (2H, br s, exch. D2O), 6.63 (1H, s).