Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li:10]CCCC>CCCCCCC>[CH:1]1([Li:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C1=Cc2ccccc2C1
Reactant: [Li]CCCC
Solvent: CCCCCCC
Product: [Li]C1C=Cc2ccccc21
Reaction time: 8 h
Yield: 99.2 %

Procedure:
To distilled indene (15.0 g, 129 mmol) in heptane (200 mL) was added BuLi (82 mL, 131 mmol, 1.6 M in hexanes) at room temperature. The resulting reaction mixture was stirred overnight. The mixture was filtered and the filter cake washed with heptane (3×30 mL) to give indenyllithium (15.62 g, 99% yield). Indenyllithium (6.387 g, 52.4 mmol) was added as a solid over 5 minutes to a stirred solution of C6F5CH2—Br (13.65 g, 52.3 mmol) in toluene (100 mL) at room temperature. The reaction mixture was heated to 50° C. and stirred for 4 h. The product mixture was filtered and washed with toluene (3×20 mL). The combined filtrates were evaporated to dryness to afford 1-C6F5CH2-indene (13.58 g, 88%). To a stirred slurry of TiCl4.2THF (1.72 g, 5.15 mmol) in toluene (15 mL) was added solid (t-Bu)3P═N—Li (1.12 g, 5 mmol) at room temperature. The resulting reaction mixture was heated at 100° C. for 30 min and then allowed to cool to room temperature. This mixture containing ((t-Bu)3P═N)TiCl3 (1.85 g, 5 mmol) was used in the next reaction. To a THF solution (10 mL) of 1-C6F5CH2-indene (1.48 g, 5 mmol) cooled at −78° C. was added n-butyllithium (3.28 mL, 5 mmol, 1.6 M in hexanes) over 10 minutes. The resulting dark orange solution was stirred for 20 minutes and then transferred via a double-ended needle to a toluene slurry of ((t-Bu)3P═N)TiCl3 (1.85 g, 5 mmol). The cooling was removed from the reaction mixture which was stirred for a further 30 minutes. The solvents were evaporated to afford a yellow pasty residue. The solid was re-dissolved in toluene (70 mL) at 80° C. and filtered hot. The toluene was evaporated to afford pure (1-C6F5CH2-Indenyl)((t-Bu)3P═N)TiCl2 (2.35 g, 74%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>C(O)C.C(Cl)Cl>[F:1][C:2]([F:27])([F:28])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[CH:14]([OH:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)CC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-oxopentanoate (450 mg) in ethanol (5 ml) is added NaBH4 (150 mg) at 0°. The resulting mixture is then stirred at 0° for about 10 minutes. The mixture is diluted with CH2Cl2, washed with saturated NaCl solution, dried and evaporated to dryness to give ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-hydroxypentanoate, in quantitative yield, MS m/e 398 (M+).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:31])[CH:15]([CH2:27][C:28]([OH:30])=O)[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:18])=[CH:9][CH:8]=1.Cl.[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:31])[CH:15]([CH2:27][C:28]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:30])[NH:16][C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[O:18])=[CH:11][CH:12]=1
Reactant: Nc1ccccc1
Reactant: CN1CCN=C1c1ccc(NC(=O)C(CC(=O)O)NC(=O)Nc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CN1CCN=C1c1ccc(NC(=O)C(CC(=O)Nc2ccccc2)NC(=O)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1:1 mixture of the R and S isomers of N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-carboxymethyl-2-(4-chlorophenylaminocarbonylamino)-acetamide (from EXAMPLEs 60 and 62, 45 mg, 0.10 mmol) and aniline hydrochloride (28 mg, 0.22 mmol) in pyridine (2 mL) cooled in an ice-bath, POCl3 (0.040 mL, 0.44 mmol) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by HPLC to the titled compound as a powder (12 mg). MS 519.1 and 521.1 (M+H, Cl pattern).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH:21]([CH3:23])[CH3:22])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1.[C:25](Cl)(=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29]>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH:21]([CH3:22])[CH3:23])[N:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1)[C:25](=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCC(=O)Cl
Reactant: COC(=O)[C@@H](NCc1ccc(-c2ccccc2C#N)cc1)C(C)C
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@H](C(=O)OC)C(C)C

Procedure:
condensation of N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester compound of Formula II or its hydrochloride salt with the valeryl chloride compound of Formula III in the presence of an inorganic base and a suitable solvent to give the (N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester compound of Formula IV;
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[O:14]=[S:15]1(=[O:32])[CH2:20][CH2:19][N:18]2[CH:21]=[CH:22][CH:23]=[C:24]([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[C:17]2=[N:16]1.O>CS(C)=O>[CH:9]1([CH2:8][O:31][C:28]2[CH:27]=[CH:26][C:25]([C:24]3[C:17]4=[N:16][S:15](=[O:32])(=[O:14])[CH2:20][CH2:19][N:18]4[CH:21]=[CH:22][CH:23]=3)=[CH:30][CH:29]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: ICC1CCCC1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(OCC4CCCC4)cc3)C2=N1
Temperature: 130 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
A mixture of potassium carbonate (450 mg), (iodomethyl)cyclopentane (684 mg) and 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (300 mg) in DMSO (5 mL) was stirred at 130° C. for 2 hr. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with 1N NaOH aq. and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was washed with Et2O to give the title compound (311 mg) as a pale yellow solid. The solid was crystallized from CH3CN-IPE to give a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([CH:28]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)ns1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc(C2CCNCC2)ns1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
tert-Butyl 4-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate (38.10 g, 65.95 mmol) was dissolved in CH2Cl2 (500 mL) and cooled to 0° C. TFA (25.40 ml, 329.7 mmol) was added over 5 minutes, keeping the internal temperature below 12° C. The reaction was then warmed to ambient temperature and stirred for 1 hour. More TFA (75 mL, 990 mmol) was added and the reaction was stirred for 2 hours. The reaction was concentrated and redissolved in 10% methanol in dichloromethane (450 mL) and saturated sodium bicarbonate was slowly added. The mixture was stirred for 1 hour and filtered. The solids were washed with water and dried in a vacuum oven to give N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(piperidin-4-yl)-1,2,4-thiadiazol-5-amine (29.7 g, 62.19 mmol, 94.29% yield).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH2:6]([CH:8]1[C:17]2[C:16]3[NH:18][C:19]4[C:24]([C:15]=3[CH2:14][CH2:13][N+:12]=2[CH2:11][CH2:10][CH2:9]1)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:7].ClCCl.[OH-].[Na+]>O>[CH2:6]([C:8]1([CH:10]([CH3:9])[C:11]#[N:12])[C:17]2[N:12]([CH2:13][CH2:14][C:15]3[C:16]=2[N:18]=[C:19]2[C:24]=3[CH:23]=[CH:22][CH:21]=[CH:20]2)[CH2:11][CH2:10][CH2:9]1)[CH3:7]
Reactant: CCC1CCC[N+]2=C1c1[nH]c3ccccc3c1CC2
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCC1(C(C)C#N)CCCN2CCC3=c4ccccc4=NC3=C21
Reaction time: 48 h
Yield: 79.4 %

Procedure:
10.0 g. (28.5 mmoles) of 1-ethyl-2,3,4,6,7,12-hexahydro-indolo(2,3 -a)quinolizinium perchlorate are dissolved in 100 ml. of dichloromethane, and 75 ml. of distilled water and 20 ml. of 2 n sodium hydroxide are added to the solution under constant stirring in argon atmosphere. The reaction mixture is stirred for 10 minutes, thereafter the organic phase is separated and dried over anhydrous potassium carbonate. The drying agent is filtered off, 10 ml. (142 mmoles) of freshly distilled acrylonitrile are added to the filtrate, the mixture is flushed with argon, and allowed to stand at room temperature for 2 days, during which period the solution darkens considerably. Thereafter the solution is evaporated in vacuo under argon atmosphere (bath temperature: maximum 40° to 50° C). The residual dark red oil is triturated with 5 ml. of methanol, and the formed orange-red crystals are filtered off. The thus-obtained crude product, weighing 8.10 g., is recrystallized from 15-fold volume of methanol. 7.30 g. (79.4 %) of crystalline (1-ethyl-1,2,3,4,6,7-hexahydro-indolo[2,3-a]quinolizin-1-yl)-propionitrile are obtained; m.p.: 122-123° C.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:8]([C@@H:13]([C@H:15]([C:17]([O:19]CC)=O)[OH:16])[OH:14])([O:10]CC)=O.CO>O>[CH2:1]([NH:7][C:8](=[O:10])[C@@H:13]([C@H:15]([C:17]([NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:19])[OH:16])[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Solvent: O
Solvent: CO
Product: CCCCCCNC(=O)[C@H](O)[C@@H](O)C(=O)NCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14 %

Procedure:
N,N′-Di-n-hexyl L-tartaramide was prepared by the reaction of n-hexyl amine with diethyl L-tartrate. Diethyl L-tartrate (20.007 g, 1.0 eq) and HPLC grade methanol (40 mL) were weighed into a 250 mL round-bottomed flask equipped with a teflon coated magnetic stir bar. n-Hexyl amine (20.614 g, 2.0 eq) was slowly poured into the stirring diethyl L-tartrate solution. Some fuming and a color change from water-white to pale yellow were observed. Additional methanol (10 mL) was used to rinse all of the amine into the reaction flask. The product precipitated after stirring the solution for 30 min at ambient temperature. The white, waxy solid was filtered, washed with methanol (3×30 mL), washed with diethyl ether (2×30 mL), and dried under vacuum. The first crop of product was obtained in 14% yield (4.366 g, 13.80 mmole). A second crop of product was obtained by adding the combined filtrates to 50 mL of water. After filtering, washing with diethyl ether (2×30 mL), and drying under vacuum, 9.382 g of white, waxy solid were obtained. The combined reaction yield was 45%.
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].[C:5]([O:8][CH3:9])(=[O:7])[CH3:6]>>[CH3:1][O:4][CH2:2][CH2:3][CH2:9][O:8][C:5](=[O:7])[CH3:6]
Reactant: COC(C)=O
Reactant: CC1CO1
Product: COCCCOC(C)=O

Procedure:
A process according to claim 1 wherein propylene oxide is reacted with either methyl acetate to produce methoxypropylacetate or with ethyl acetate to produce ethoxypropylacetate.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[CH3:15][C@@H:16]1[NH:21][CH2:20][CH2:19][NH:18][C:17]1=[O:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:15][C@H:16]1[C:17](=[O:22])[NH:18][CH2:19][CH2:20][N:21]1[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1
Reactant: C[C@@H]1NCCNC1=O
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc2oc(N3CCNC(=O)[C@@H]3C)nc12
Yield: 98.8 %

Procedure:
A mixture of methyl 2-chlorobenzoxazole-4-carboxylate (370 mg, 1.75 mmol), (S)-3-methylpiperazin-2-one (200 mg, 1.75 mmol) and K2CO3 (605 mg, 4.38 mmol), in DMF (15 mL), was stirred at ambient temperature for 17 h. The reaction mixture was diluted with H2O (30 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic layers were washed with H2O (3×20 mL), brine (20 mL), dried (Na2SO4). The material was concentrated under reduced pressure to give (S)-methyl 2-(2-methyl-3-oxopiperazine-1-yl)benzoxazole-4-carboxylate (500 mg, 73%) as a yellow oil. 1H NMR consistent.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[C:25]1([Sn](CCCC)(CCCC)CCCC)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(C)C=CC=CC=1>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.COCCOC>[CH3:8][C:7]1[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:5](=[O:19])[C:4]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:3][C:2]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1cc(I)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: CCOC(=O)c1cc(-c2ccccc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 100 °C
Yield: 34.6 %

Procedure:
Ethyl 5-iodo-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylate (2.6 g, 5.76 mmol), phenyltributylstannane (2.24 mg, 6.10 mmol), tetrakis(triphenylphosphine)palladium(0) (17.3 mg, 0.02 mmol), toluene (15 ml) and anhydrous DME (1.5 ml) were placed in a Schlenk vessel equipped with a magnetic stirring bar. The vessel was purged with argon, sealed and heated at 100° C. overnight. After cooling to room temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound as a white solid (0.8 g, 35%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13].OS(O)(=O)=O>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1ccnc2ccccc12
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cccc2c(Cl)ccnc12
Yield: 36 %

Procedure:
In a similar fashion using route 11 general procedure 57, 4-chloroquinoline 462 (5.0 g, 30.7 mmol), fuming HNO3 (8.3 ml) and concentrated H2SO4 (16.6 ml) to give the title compound (2.3 g, 36%) which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH2:5]([O:12][C:13]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.B(F)(F)F.CCOCC>C(OCC)C.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH2:5]([O:12][C:13]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]1([NH2:16])[CH2:2][CH2:1]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC[Mg]Br
Reactant: N#Cc1cccc(F)c1OCc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: CCOCC
Product: NC1(c2cccc(F)c2OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of ethylmagnesium bromide, 3M in diethyl ether (28.2 mL) was added as a slow stream to a mechanically stirred mixture of tetraisopropyl orthotitanate (13.09 mL), and 2-(benzyloxy)-3-fluorobenzonitrile (Example 283a, 9.6 g) in diethyl ether (400 mL) cooled to −78° C. The resulting solution was stirred at −78° C. for 15 min and then warmed to room temperature over 1 h 30 min. An ice bath was placed around the reaction and boron trifluoride etherate (10.71 mL) was added as a slow stream (caution exothermic) and the mixture was stirred for 30 min. The reaction was cooled (ice bath) and quenched with 1 M aqueous HCl (400 mL added portionwise). The aqueous layer was separated and the diethyl ether layer further extracted into 1M HCl (2×200 mL) (ethyl acetate added to the diethyl ether to aid solubility). The aqueous layer was cooled in an ice bath and basified with stirring with a 10M aqueous NaOH solution. The resulting precipitate was filtered through Celite, washing the pad with water (200 mL) then DCM (4×200 mL) then DCM/MeOH (90:10, 300 mL). The combined filtrates were separated and the aqueous layer further extracted with DCM (2×200 mL). The combined organics were dried (MgSO4) and evaporated, the residue was purified on SCX resin (50 g) eluting with DCM, methanol (discarded) and flushing with 20% ammonia in methanol to give the subtitle compound as an oil (2.54 g).
Reaction SMILES: OS(O)(=O)=O.[CH2:6]([C:8]1([C:11]([C:13]#[N:14])=[O:12])[CH2:10][CH2:9]1)[CH3:7].[OH2:15]>C(O)(C)(C)C.C(Cl)Cl>[C:8]([NH:14][C:13](=[O:15])[C:11]([C:8]1([CH2:6][CH3:7])[CH2:10][CH2:9]1)=[O:12])([CH3:10])([CH3:9])[CH3:6]
Reactant: CCC1(C(=O)C#N)CC1
Reactant: O
Agent: O=S(=O)(O)O
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CCC1(C(=O)C(=O)NC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10 g of H2SO4 (98%) is added dropwise at 0°-5° C., in the course of 10 minutes, to a solution of 12.3 g of 1-ethylcyclopropanecarboxylic acid cyanide in 13 g of tert-butanol and 13 ml of methylene chloride. The solution is subsequently stirred for 4 hours at room temperature; 2 ml of H2O is then added and stirring is continued for a further 30 minutes. The pH value of the solution is brought to 6 with 80 ml of ZnNaOH, and the organic phase is separated. After removal of the solvent, the residue is crysrallised out from 50 ml of petroleum ether (b.p. 40° to 65° C.) at 50° C. to thus yield 13.1 g of white crystals of pure (1-ethylcyclopropyl)-glyoxylic acid tert-butylamide having a melting point of 37.5°-39° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]([C:15]1[CH:34]=[CH:33][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)=O.C(O)(=O)C.C(=O)([O-])O.[Na+]>ClCCCl>[C:1]1([C:7]2[N:8]=[C:9]([NH:12][CH2:13][C:15]3[CH:34]=[CH:33][C:18]([CH2:19][O:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=4)=[CH:17][CH:16]=3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(C=O)cc2)cc1
Reactant: Nc1nc(-c2ccccc2)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)CCc1ccc(OCc2ccc(CNc3nc(-c4ccccc4)cs3)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.3 %

Procedure:
To a solution of 4-phenyl-1,3-thiazol-2-amine (0.25 g, 1.4 mmol), methyl 3-[4-[(4-formylbenzyl)oxy]phenyl]propionate (0.58 g, 2.0 mmol) and acetic acid (0.25 g, 4.2 mmol) in 1,2-dichloroethane (15 mL) was added triacetoxysodium borohydride (0.83 g, 3.9 mmol), and the mixture was stirred at room temperature for 2 days. The reaction mixture was poured into aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4:1) to give the title compound (0.31 g, yield 49%) as an oil.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:23]([OH:25])=[O:24].[OH-].[Na+:27].CCOCC>CN(C)C=O>[O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:22])[C:18]([CH3:20])([CH3:21])[CH3:19])=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:23]([O-:25])=[O:24].[Na+:27]
Reactant: CC(C)(C)C(=O)Nc1ccc2ncn3c(=O)c(C(=O)O)cnc3c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1ccc2ncn3c(=O)c(C(=O)[O-])cnc3c2c1
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
4-Oxo-10-(pivalamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylic acid (3.06 g) was suspended in N,N-dimethylformamide (60 ml). To this suspension was added dropwise sodium hydroxide solution (sodium hydroxide 0.36 g in water 1 ml and ethanol 7 ml) at ambient temperature to give a clear solution. After 30 minutes, ether was added and the precipitated crystals were collected by filtration and washed with ether. The crude crystals were dissolved in water (150 ml) under heating. The solution was filtered to remove insoluble materials, diluted with acetone (800 ml), and allowed to stand at ambient temperature. The crystals were filtered, washed with acetone, and dried to give sodium 4-oxo-10-(pivalamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (1.73 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:17](Cl)(=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].Cl>N1C=CC=CC=1>[S:13]1[CH:14]=[N:15][N:16]=[C:12]1[NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:17](=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: Nc1ccc(S(=O)(=O)Nc2nncs2)cc1
Reactant: CCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Nc2nncs2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Compound 100 (50 mg, 0.20 mmol) was suspended in pyridine (0.3 mL). Decanoyl chloride (39.1 mg, 0.21 mmol) was added gradually over 15 min. The reaction mixture was heated to 95° C. and stirred at this temperature for 1 h, then poured into 10% aqueous HCl solution and extracted with EtOAc (3×0.5 mL). The combined organic extracts were washed with water (3×5 mL), brine (3×5 mL), and dried over anhydrous Na2SO4. Evaporation of the solvent yielded the product (80 mg, 0.20 mmol, 95%). It was recrystallized from hexanes/ethyl acetate to yield an analytical sample, mp 151-152° C.; 1H NMR (250 MHz, CD3OD) δ 0.88 (3, t, J=7.5 Hz), 1.24-1.45 (12, m), 1.68 (2, t, J=7.5 Hz), 2.37 (2, t, J=7.5 Hz), 7.72 (2, d, J=8.5 Hz), 7.79 (2, d, J=8.5 Hz), 8.49 (1, S); 13C NMR (125 MHz, CD3OD) δ 14.4, 23.7, 26.7, 30.3, 30.4, 30.5, 30.6, 33.0, 38.1, 102.4, 128.3, 137.5, 144.0, 145.0, 170.0, 174.9; MS (ESI+) 411.1 (M+H)+; HRMS (IonSpec. HiRES ESL+) calcd. for C18H27N4O3S2 (M+H)+411.1525, obsd. 411.1524.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3](=O)/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[S:16]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1)(=[O:19])(=[O:18])[NH2:17]>>[S:16]([C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH:5]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4][C:3]([C:2]([F:14])([F:13])[F:1])=[N:27]2)=[CH:24][CH:25]=1)(=[O:19])(=[O:18])[NH2:17]
Reactant: O=C(/C=C/c1ccccc1)C(F)(F)F
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: NS(=O)(=O)c1ccc(N2N=C(C(F)(F)F)CC2c2ccccc2)cc1
Yield: 73 %

Procedure:
A solution of trans-1,1,1-trifluoro-4-phenyl-3-buten-2-one (5 mmol) and 4-sulfamylphenyl hydrazine hydrochloride (6 mmol) was subjected to Procedure 3. The title compound was obtained in 73% yield, m.p. 132-135° C.; C, H analysis (C18H15SO2N4F3.H2O):