Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=O)[CH:6]=[CH:7][CH:8]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1C=CC=CC=1>[S:29]=[C:10]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:19])([F:18])[F:1])[CH:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(Cc1cccc(C(F)(F)F)c1)N1CCCCC1
Solvent: c1ccccc1
Product: FC(F)(F)c1cccc(CC(=S)N2CCCCC2)c1
Yield: 182.4 %

Procedure:
A mixture of 135.6 g of 1-[[3-(trifluoromethyl)phenyl]acetyl]piperidine, 101.1 g of Lawesson's reagent and 400 ml of benzene was heated at reflux for 6 hours, cooled and concentrated in vacuo. The residue was taken up in dichloromethane, filtered through a bed of neutral alumina with 3 liters of dichloromethane elution. The filtrate was concentrated in vacuo. The resulting oil was vacuum distilled giving 131 g of 1-[1-thioxo-2-[3-(trifluoromethyl) phenyl]ethyl]piperidine, bp 181°-182° C. (3.0 mmHg).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11](I)=[CH:12][CH:13]=2)[C:8](=[O:16])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6]1.[CH:23]([NH:26][C:27](=[O:47])[NH:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[C:31]([C:38]2[S:39][CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[N:42]=2)[CH:30]=1)([CH3:25])[CH3:24].C(=O)(O)[O-].[Na+]>C(COC)OC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:32]3[CH:33]=[N:34][C:29]([NH:28][C:27]([NH:26][CH:23]([CH3:25])[CH3:24])=[O:47])=[CH:30][C:31]=3[C:38]3[S:39][CH:40]=[C:41]([C:43]([F:46])([F:44])[F:45])[N:42]=3)=[CH:12][CH:13]=2)[C:8](=[O:16])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6]1
Reactant: CCOC(=O)c1cn(CCN(C)C)c2ccc(I)cc2c1=O
Reactant: CC(C)NC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1cn(CCN(C)C)c2ccc(-c3cnc(NC(=O)NC(C)C)cc3-c3nc(C(F)(F)F)cs3)cc2c1=O
Temperature: 30 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A suspension of ethyl 1-(2-(dimethylamino)ethyl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (Intermediate 29, 250 mg, 0.60 mmol) in dimethoxyethane (4.8 mL) in a microwave vial was stirred with heating to obtain a solution. The solution was then cooled to 30° C., trans-dichlorobis(triphenylphosphine)palladium (II) (55 mg, 0.08 mmol) was added and the mixture was stirred for 10 min at room temperature. 6-(3-isopropylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 89, 294 mg, 0.79 mmol) was added to the mixture followed by an aqueous solution of sodium bicarbonate (163 mg in 1.2 mL of water) and the vial was sealed. The mixture was stirred at 65° C. for 30 min in a heating block then cooled to room temperature. The crude reaction mixture was placed into fridge for a 2 h. The solid precipitate that formed was collected by filtration, washed with a small amount of dimethoxyethane, methyl tert-butyl ether and dried to give ˜270 mg yellowish solid.
Reaction SMILES: [CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([NH2:14])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[C:20](Cl)(Cl)=[S:21]>ClCCl>[CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([N:14]=[C:20]=[S:21])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(C2CC2)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: S=C=Nc1ccc(C2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 149.7 %

Procedure:
Compound 2 (440 mg, 2.6 mmol) was dissolved in 14 mL of dichloromethane. Sodium bicarbonate (7 mL, sat solution) and thiophosgene (0.2 mL, 2.6 mmol) were added and the mixture stirred at room temperature for 1 h. Then, the organic layer was separated, dried over sodium sulfate and concentrated to afford 877 mg, 99% yield of 1-cyclopropyl-4-isothiocyanatonaphthalene (3) which was used in the next step without further purification
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].[NH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1.C(N(C(C)C)CC)(C)C.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[Br:1][C:2]1[C:3]([CH2:20][N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)=[O:8]
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccc(F)cc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(Nc1cccnc1)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccc(F)cc1
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}-4-(4-morpholinylmethyl)benzoic acid (may be prepared as described in Description 20; 150 mg, 0.35 mmol) in N,N-dimethylformamide (4 ml) was added 3-aminopyridine (39.9 mg, 0.42 mmol), diisopropylethylamine (0.12 ml, 0.71 mmol), 1-hydroxy-7-azabenzotriazole (57.7 mg, 0.42 mmol) and EDC (102 mg, 0.53 mmol). The mixture was stirred for 18 hours, then the solvent removed in vacuo to give a solid. Purification by MDAP yielded the title compound as a solid. 95 mg.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=[N:7][C:6]=2[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].[CH:28]([NH2:32])([CH2:30][CH3:31])[CH3:29]>>[CH:28]([NH:32][C:2]1[C:10]2[NH:9][C:8]([C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=[N:7][C:6]=2[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25])([CH2:30][CH3:31])[CH3:29]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c2[nH]c(C(F)(F)C(F)(F)C(F)(F)F)nc12
Reactant: CCC(C)N
Product: CCC(C)Nc1c(C(F)(F)F)cc([N+](=O)[O-])c2nc(C(F)(F)C(F)(F)C(F)(F)F)[nH]c12

Procedure:
4-Chloro-7-nitro-5-trifluoromethyl-2-heptafluoropropylbenzimidazole is reacted with sec-butylamine to obtain 4-sec-butylamino-7-nitro-5-trifluoromethyl-2-heptafluoropropylbenzimidazole, m.w., 470.3.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[C:5](=O)[C:4]1=[O:14])[CH3:2].O.NN.Cl>CCOC(C)=O>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:14])[CH3:2]
Reactant: CCN1C(=O)C(=O)c2cc(C)ccc21
Agent: Cl
Agent: NN
Solvent: CCOC(C)=O
Solvent: O
Product: CCN1C(=O)Cc2cc(C)ccc21
Temperature: 110 °C
Reaction time: 5 h
Yield: 72.7 %

Procedure:
A mixture of 1-ethyl-5-methyl-1H-indole-2,3-dione (ix-a, 1.53 g, 8.09 mmol) and hydrazine monohydrate (30 mL, 618 mmol) was heated to 110° C. After 5 h, the reaction was cooled to RT and conc. HCl was added to adjust the reaction mixture to approximately pH 3. The mixture was stirred overnight, and poured into a separatory funnel containing EtOAc (150 mL). The mixture was shaken and the layers were separated. The aqueous layer was extracted with EtOAc (2×150 mL) and the combined organic layers were dried, filtered and concentrated to give 1-ethyl-5-methyl-1,3-dihydro-2H-indol-2-one (i-a, 1.03 g, 72.5%). NH4OAc QC conditions. DAD Retention time =1.48 min. M+H=176.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](CC(O)=O)=[CH:2]1.CN1C=CC=[C:12]1[C:16]([OH:18])=[O:17].O1C=CC=C1CC(O)=O>>[S:1]1[CH:2]=[CH:3][CH:4]=[C:5]1[CH2:12][C:16]([OH:18])=[O:17]
Reactant: Cn1cccc1C(=O)O
Reactant: O=C(O)Cc1ccsc1
Agent: O=C(O)Cc1ccco1
Product: O=C(O)Cc1cccs1

Procedure:
3-thienylacetic acid; N-methylpyrrole-2-carboxylic acid; furylacetic acid; 2-, 3- or 4-pyridylacetic acid;
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:46][CH2:47][C:48]1[C:49]([OH:57])=[N:50][C:51]([CH3:56])=[CH:52][C:53]=1[O:54][CH3:55]>ClCCl.O>[OH:57][C:49]1[C:48]([CH2:47][NH:46][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:16][CH:15]=2)=[C:53]([O:54][CH3:55])[CH:52]=[C:51]([CH3:56])[N:50]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: COc1cc(C)nc(O)c1CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1cc(C)nc(O)c1CNC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
To a solution of 4-phenoxybenzoic acid (60 mg, 0.28 mmol) in dichloromethane (15 mL) were added 1-Hydroxybenzotriazole (49 mg, 0.36 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (69 mg, 0.36 mmol) and triethylamine (73 mg, 0.72 mmol). The resulting solution was stirred at room temperature for 30 minutes. Then 3-(aminomethyl)-4-methoxy-6-methylpyridin-2-ol (40 mg, 0.24 mmol) was added to the solution, and it was stirred at room temperature for 16 hours. Water (20 mL) was added to the mixture. It was extracted with dichloromethane (50 mL). The organic layer was concentrated in vacuo to provide crude product which was purified by silica gel column chromatography dichloromethane/methanol=10:1 to afford N-((2-hydroxy-4-methoxy-6-methylpyridin-3-yl)methyl)-4-phenoxy benzamide (32 mg, 37%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[O:10]1CCOCC1.[F:16][CH:17]([F:19])Cl>[OH-].[Na+]>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:10][CH:17]([F:19])[F:16])[N:3]=1
Reactant: FC(F)Cl
Reactant: C1COCCO1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(Cl)cc(OC(F)F)n1
Reaction time: 1 h

Procedure:
A suspension of 16.4 g of 2-amino-4,6-dichloro-pyrimidine in 100 ml of 40% sodium hydroxide solution is stirred at a temperature of 95°-100° C. for 1 hour. 200 ml of dioxane are added, and 20 g of gaseous difluorochloromethane are passed in at a temperature of 70°-75° C. in the course of 1 hour. The organic phase is separated off and concentrated to about 1/5 of its volume, the residue is poured into water and the solid precipitate is separated off to give 6 g of 2-amino-4-chloro-6-difluoromethoxy-pyrimidine of melting point 118°-119° C.
Reaction SMILES: [NH2:1][C:2](=[O:21])[CH2:3][NH:4][C:5]1[C:10]([NH:11][C:12](=O)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:9][CH:8]=[CH:7][N:6]=1>C(O)CO.CO>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:4]([CH2:3][C:2]([NH2:1])=[O:21])[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:10]3[N:11]=2)=[CH:14][CH:15]=1
Reactant: NC(=O)CNc1ncccc1NC(=O)c1ccc(Cl)cc1
Solvent: OCCO
Solvent: CO
Product: NC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 190 °C
Yield: 16.5 %

Procedure:
A mixture of N-[2-[(2-amino-2-oxoethyl)amino]-3-pyridinyl]4-chlorobenzamide (6.0 g, 0.03 mole) in 150 ml of ethylene glycol was heated at 190° C. for 40 minutes. The precipitate, which formed, was filtered off and washed with water. The filtrate was diluted with water to produce a second crop. The first crop was heated to boiling in 300 ml of methanol, filtered through a Celite pad, seeded, and refrigerated overnight. The crystalline precipitate was filtered, washed with cold methanol, and dried under high vacuum at 60° C. overnight to give 1.42 g (25%) of title compound, mp 270°-1° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.[C-:13]#[N:14].[Na+]>CN1CCCC1=O.O.[Ni](Br)Br>[O:12]=[C:6]1[CH2:5][CH2:4][C:3]2[C:2]([C:13]#[N:14])=[CH:11][CH:10]=[CH:9][C:8]=2[NH:7]1
Reactant: O=C1CCc2c(Cl)cccc2N1
Reactant: [C-]#N
Agent: Br[Ni]Br
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1cccc2c1CCC(=O)N2
Temperature: 200 °C

Procedure:
To a stirred solution of 5-chloro-3,4-dihydroquinolin-2(1H)-one (143-4; 1.8 g, 0.0099 mol) and nickel bromide (2.15 g, 0.0099 mol) in N-methyl-2-pyrrolidone (10 mL) was added sodium cyanide (0.97 g, 0.0198 mol) portion wise at room temperature. Reaction mixture was heated at 200° C. for 10 min under microwave irradiation. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to obtain the title compound. MS (M−1): 171.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13])=[O:5])[CH3:2].[O:19]1CCOC[CH2:20]1>C(O)C>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:10]2[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12](=[O:13])[NH:14][C:20]1=[O:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)CCCNc1ccccc1C(N)=O
Reactant: C1COCCO1
Solvent: CCO
Product: CCOC(=O)CCCn1c(=O)[nH]c(=O)c2ccccc21
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-(3-ethoxycarbonylpropylamino)benzamide (1.95 g) and N,N'-carbonyldiimidazole (2.52 g) in dioxane (20 ml) was heated to 150° C. After 30 minutes, the mixture was cooled below 80° C., and diluted with ethanol to give crude crystals. Collected crystals were recrystallized from ethanol to give 1-(3-ethoxycarbonylpropyl)-2,4(1H,3H)-quinazolinedione (1.53 g) as a crystal.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5](=S)[NH:6][NH2:7])[CH3:3].[Cl:9][CH:10]([C:16]([CH3:18])=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>O1CCCC1>[ClH:9].[CH3:18][C:16]1[NH:7][N:6]=[C:5]([NH:4][CH:2]([CH3:3])[CH3:1])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CC(C)NC(=S)NN
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(NC(C)C)n[nH]c1C
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
A stirred slurry of 10.5 g (0.079 mole) of 4-(2-propanyl)-3-thiosemicarbazide in 100 mL of tetrahydrofuran under nitrogen atmosphere was treated with 13 g (0.079 mole) of ethyl 2-chloroacetoacetate. After 30 minutes the reaction mixture became suddenly exothermic, turning green-yellow and amorphous sulfur separated. The reaction mixture was stirred at ambient temperature for 2 hr, diluted with water, made acidic with 3N hydrochloric acid and filtered to remove the insoluble sulfur. The filtrate was adjusted to pH 8 with sodium carbonate and extracted with 3×50 mL of methylene chloride. The extracts were combined, washed with water, dried over magnesium sulfate and the filtrate concentrated in vacuo. The oily residue in acetone was treated with ethereal hydrogen chloride and diluted with an equal volume of isopropyl ether to give the crude product. Recrystallization from acetone gave 6.6 g of large beige crystals, mp 158°-159° C., as the hydrochloride salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:28])[CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([OH:27])=[CH:24][CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH:13]=[N:12]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:40][CH:41]1[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42]1)(=O)=O.O>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:28])[CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH2:40][CH:41]5[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:50])([CH3:52])[CH3:51])=[O:47])[CH2:42]5)=[CH:24][CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH:13]=[N:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cn1cc(Nc2ncnc3cc(O)ccc23)cn1)Nc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc3c(Nc4cnn(CC(=O)Nc5cccc(F)c5)c4)ncnc3c2)C1
Temperature: 80 °C
Yield: 64.5 %

Procedure:
A mixture of N-(3-fluorophenyl)-2-{4-[(7-hydroxyquinazolin-4-yl)amino]-1H-pyrazol-1-yl}acetamide (0.59 g, 1.2 mmol), cesium carbonate (1.95 g, 6.0 mmol) and tert-butyl 3-{[(methylsulphonyl)oxy]methyl}pyrrolidine-1-carboxylate (assumed 1.3 mmol) in dimethyl acetamide (10 ml) was heated at 80° C. for 6 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulphate and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 4 to 7% methanol in dichloromethane to yield tert-butyl 3-[({4-[(1-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-4-yl)amino]quinazolin-7-yl}oxy)methyl]pyrrolidine-1-carboxylate (0.435 g, 65% yield): MS (+ve ESI): 562 (M+H)+.
Reaction SMILES: [C:1](=[O:4])([OH:3])[O-].[Na+].[O:6]=[C:7]1[N:15]([C@@H:16]([CH3:20])[C:17]([OH:19])=[O:18])[CH2:14][CH2:13][C:8]21[NH:12][CH2:11][CH2:10][CH2:9]2.C(=O)([O-])ON1C(=O)CC([CH2:29][CH:30]2[C:42]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:36]3[C:31]2=[CH:32][CH:33]=[CH:34][CH:35]=3)C1=O>O.CC(C)=O>[CH:32]1[C:31]2[CH:30]([CH2:29][O:3][C:1]([N:12]3[C:8]4([CH2:13][CH2:14][N:15]([C@@H:16]([CH3:20])[C:17]([OH:19])=[O:18])[C:7]4=[O:6])[CH2:9][CH2:10][CH2:11]3)=[O:4])[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]=2[CH:35]=[CH:34][CH:33]=1
Reactant: O=C([O-])O
Reactant: O=C([O-])ON1C(=O)CC(CC2c3ccccc3-c3ccccc32)C1=O
Reactant: C[C@@H](C(=O)O)N1CCC2(CCCN2)C1=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C[C@@H](C(=O)O)N1CCC2(CCCN2C(=O)OCC2c3ccccc3-c3ccccc32)C1=O
Reaction time: 18 h

Procedure:
Excess solid sodium bicarbonate was added to (S)-2-(6-oxo-1,7-diazaspiro[4.4]non-7-yl)propionic acid (0.42 g) in water (2 ml) and then 9-fluorenylmethylsuccinimidyl carbonate (0.7 g) in acetone (3 ml) was added. The mixture was stirred for 18 hours. The mixture was then addled to water (10 ml), extracted with ether (10 ml) and the aqueous layer separated. (The ether extracts were discarded). The pH of the aqueous layer was adjusted to 3 with concentrated hydrochloric acid and then it was extracted with dichloromethane (2×10 ml). The combined extracts were separated, dried (MgSO4) and evaporated to give (S)-2-[1-(9-fluorenylmethyloxycarbonyl)-6-oxo-1,7-diazaspiro[4.4]non-7-yl]propionic acid (0.62 g) as a white foam; NMR (d6-DMSO (373K)): some doubling of peaks due to the mixture of diastereoisomers, 1.3 (2d, 3H), 1.6-2.0 (m, 6H), 3.05 (m, 1H), 3.2-3.45 (m, 3H), 4.2-4.4 (m, 1H), 4.5 (m, 1H), 6.2 (s, 2H), 7.35 (m, 4H), 7.8 (m, 4H).
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH:13]1[C:17]([OH:18])=[C:16]([C:19]([CH3:21])=[O:20])[CH2:15][S:14]1.S(Cl)(Cl)(=O)=O>O>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[C:13]1[S:14][CH:15]=[C:16]([C:19]([CH3:21])=[O:20])[C:17]=1[OH:18]
Reactant: CC(=O)C1=C(O)C(c2ccc(Cl)cc2Cl)SC1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)c1csc(-c2ccc(Cl)cc2Cl)c1O
Temperature: -25 °C
Reaction time: 0.67 h
Yield: 101.1 %

Procedure:
A chloroform (3 mL) solution of 2-(2,4-dichlorophenyl)-3-hydroxy-4-methylcarbonyl-2,5-dihydrothiophene (0.3 g, 0.93 mmol, purity: 90%) was cooled to −36° C., and to this solution, a chloroform (5 mL) solution of sulfuryl chloride (0.082 mL, 1.2 equivalent amounts) was dropwise added over a period of 10 minutes, followed by stirring at −25° C. for 40 minutes. The temperature of the solution was raised to 5° C., and water (0.6 mL) was dropwise added, followed by liquid separation. The obtained chloroform solution was sequentially washed with water, a saturated salt solution, a sodium hydroxide aqueous solution, a saturated sodium thiosulfate aqueous solution and a saturated salt solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to give the desired product as a yellow solid (0.27 g, yield: 91%).
Reaction SMILES: [Br:1][CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:17]1([P:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCOCC>[Br-:1].[CH2:2]([P+:23]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCCCCCCCCC#CCBr
Solvent: CCOCC
Product: CCCCCCCCCCCCC#CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
1-Bromo-2-pentadecyne (0.01 mole) and triphenylphosphine (0.01 mole) are mixed in ether to give pentadec-2-ynyl-triphenylphosphonium bromide. The salt (0.01 mole) is dissolved in absolute ethanol containing one equivalent of sodium ethoxide. Ethyl 5-oxopentanoate (0.01 mole) is added and the mixture is refluxed for 24 hours to give a mixture of cis-and-trans ethyl 5-eicosen-7-ynoate. The isomers are separated by chromatography and the trans isomer is converted to 5-hydroxy-6-(1,4-dimethyl-5-carboxy-2-imidazolylthio)-7-eicosynoic acid as described in Example 14(c).
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:13][C:14]#[N:15].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([CH2:13][C:14]#[N:15])[CH2:3][CH2:2]1)=[O:8])[CH3:11]
Reactant: N#CCCl
Reactant: CCOC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N1CCN(CC#N)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3 g (19.0 mmol) of ethyl N-piperazinecarboxylate in 25 mL of CH3CN was added 1.57 g (1.32 mL 20.1 mmol) of 2-chloroacetonitrile and 15.6 g (95 mmol) K2CO3.1½H2O. The suspension was stirred at room temperature for 16 hours. The reaction was analyzed using TLC (35% Ethyl acetate/Hexanes, product r.f. 0.38 vs. sm r.f. of 0.02). The analysis indicated the reaction was complete. The golden yellow solution was evaporated to dryness. The residue was extracted with CH2Cl2/H2O, dried with MgSO4, and concentrated.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[N:10]=1.CN([CH:25]=[O:26])C>>[N:16]1([CH2:15][C:11]2[N:10]=[C:9]([O:5][CH2:4][CH2:3][CH2:2][NH:1][CH:25]=[O:26])[CH:14]=[CH:13][CH:12]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN(C)C=O
Reactant: NCCCO
Reactant: Clc1cccc(CN2CCCCC2)n1
Agent: [H-]
Agent: [Na+]
Product: O=CNCCCOc1cccc(CN2CCCCC2)n1
Reaction time: 17 h

Procedure:
3-Aminopropanol (12.84 g, 0.171 mole) was added to a suspension of 50% sodium hydride in mineral oil (7.96 g, 0.166 mole) in 180 mL of dry DMF and the mixture was warmed to 80°-83°. A solution of 2-chloro-6-piperidinomethylpyridine (34.0 g, 0.161 mole) [prepared in Step A] in 180 mL of dry DMF was then added dropwise and when complete, the temperature was raised to 125°-128° for 3 hours followed by 17 hours at ambient temperature. The precipitated salts were removed by filtration and the solvent stripped under vacuum. The oily residue was dissolved in methylene chloride, washed with water, dried and the solvent evaporated. This residue was redissolved in acetonitrile and extracted with skelly B. After removing the solvent the crude oil was purified by flash chromatography on 270 g of silica gel (230-400 mesh) using a gradient elution of methanol-methylene chloride and evaporated to give the title product as a yellow oil, 21.63 g (48.4%).