Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=O)[CH3:18])(=[O:9])=[O:8].[CH3:21][O:22][CH:23]([O:26][CH3:27])[CH2:24][NH2:25].C1(C)C(S(O)(=O)=O)=CC=CC=1.O>C1(C)C=CC=CC=1>[CH3:21][O:22][CH:23]([O:26][CH3:27])[CH2:24][N:25]=[C:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][S:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:20])(=[O:9])=[O:8])[CH3:18]
Reactant: COC(CN)OC
Reactant: CC(=O)c1ccccc1NS(=O)(=O)c1ccccc1C
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(CN=C(C)c1ccccc1NS(=O)(=O)c1ccccc1C)OC

Procedure:
33.8 g of o-tolylsulfonylaminoacetophenone, 13.7 g of aminoacetaldehyde dimethylacetal and 0.4 g of toluenesulfonic acid in 400 ml of toluene are boiled for 4 hours in a water separator and concentrated to dryness in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:11](=O)[CH2:10][CH:9]([C:13]([O:15][CH3:16])=[O:14])[C:7](=O)[CH2:6]1)=[O:4].[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.Cl>CO>[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:7]2[CH2:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:11]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([Br:17])=[CH:19][CH:20]=3)[CH2:10][C:9]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:20][CH:19]=1
Reactant: COC(=O)C1CC(=O)C(C(=O)OC)CC1=O
Reactant: Nc1ccc(Br)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)C1=C(Nc2ccc(Br)cc2)CC(C(=O)OC)=C(Nc2ccc(Br)cc2)C1
Yield: 94.9 %

Procedure:
Dimethyl 1,4-cyclohexanedione-2,5-dicarboxylate (4.56 gm; 20 mmol) and methanol (100 ml) were heated to boiling, then 4-bromoaniline (6.88 gm; 40 mmol) was added followed by conc. hydrochloric acid (200 μl). The mixture was refluxed for 5 hours under a nitrogen atmosphere. On cooling a cream solid precipitated out which was collected by filtration, washed with methanol and dried under vacuum to give 10.18 gm (95%) of dimethyl 2,5-bis{(4-bromophenyl)amino}cyclohexa-1,4-diene-1,4-dicaboxylate.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]([C:8]1([C:11]2([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH2:13][O:12]2)[CH2:10][CH2:9]1)#[N:7]>C(#N)C>[C:6]([C:8]1([C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)([OH:12])[CH2:13][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:9][CH2:10]1)#[N:7]
Reactant: c1c[nH]cn1
Reactant: N#CC1(C2(c3ccc(F)cc3)CO2)CC1
Solvent: CC#N
Product: N#CC1(C(O)(Cn2ccnc2)c2ccc(F)cc2)CC1
Yield: 40.5 %

Procedure:
4 g (59 mmol) of imidazole and 2.1 g (10 mmol) of 2-(1-cyanocyclopropyl)-2-(4-fluorophenyl)oxirane (IV-2, Example 33) in 20 ml of abs. acetonitrile are heated under reflux for 8 h under a nitrogen atmosphere. After evaporation of the solvent in vacuo, the residue is taken up in ethyl acetate. The mixture is washed with water and dried over Na2SO4, and the solvent is evaporated in vacuo. Chromatographic purification on silica gel (eluent: dichloromethane containing 2% ethanol) gives 1.1 g (39% of theory) of 1-(1-cyanocyclopropyl)-1-(4-fluorophenyl)-2 -(imidazol-1-yl)ethanol having a melting point of 173° C. (dec.), 1H--NMR (CDCl3):
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([C:13]([OH:15])=[O:14])[C@H:11]([C:16]([OH:18])=[O:17])[N:10]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]1C=CC=C[CH:28]=1.S(=O)(=O)(O)O.[CH2:38](O)[CH3:39]>>[CH2:19]([N:10]1[C@H:11]([C:16]([O:18][CH2:27][CH3:28])=[O:17])[C@H:12]([C:13]([O:15][CH2:38][CH3:39])=[O:14])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCO
Reactant: O=C(O)[C@@H]1[C@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@@H]1[C@H](C(=O)OCC)N(Cc2ccccc2)C(=O)N1Cc1ccccc1

Procedure:
A mixture of cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid (35.4 g), benzene (500 ml), 9.5% ethanol (45 ml) and conc. sulfuric acid (5.0 g) was refluxed for 10 hours, cooled, washed successively with water, 5% aqueous sodium hydroxide and water, and then concentrated under reduced pressure. The residue was recrystallized from 95% ethanol to give diethyl cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylate (32.1 g). M.P., 74°-76° C.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[OH:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14].[OH-:21].[Na+].OO.Cl>CO>[OH:11][C:12]1[C:13](=[O:14])[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:7][C:6]=1[C:5]1[CH:8]=[CH:9][C:2]([C:1]2[O:10][C:16]3[C:15]([C:13](=[O:14])[C:12]=2[OH:21])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:3][CH:4]=1
Reactant: [OH-]
Reactant: O=C(CO)c1ccccc1
Reactant: O=Cc1ccc(C=O)cc1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CO
Product: O=c1c(O)c(-c2ccc(-c3oc4ccccc4c(=O)c3O)cc2)oc2ccccc12
Temperature: 12.5 °C
Reaction time: 24 h

Procedure:
To a three necked round bottomed flask, equipped with reflux condenser, calcium chloride guard tube and nitrogen inlet and magnetic stirrer, was charged methanol (200 ml), Terephthalaldehyde (0.98 g) and 2-hydroxy acetophenone (2.04 g). The reaction mixture was cooled to 10-15° C. and sodium hydroxide (3 g) was added slowly and the reaction was stirred at room temperature (˜25° C.) for 24 hrs. Then methanol (200 ml) was added to the reaction and the reaction mixture was cooled below 15° C. and sodium hydroxide (3 g) and hydrogen peroxide (9 ml) were added to the reaction mixture and the reaction mixture was stirred for 6-8 hrs at room temperature. After this the reaction mixture was cooled to 10° C., neutralized using hydrochloric acid and the solid product that precipitated was filtered. The solid was washed with water till the filtrate is free of acid. The solid product was dried in oven at 70° C.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Cl[Si:20]([CH3:23])([CH3:22])[CH3:21].[NH4+].[Cl-]>O1CCCC1.O>[CH3:21][Si:20]([CH3:23])([CH3:22])[CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: C[Si](C)(C)Cl
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)C1c2ccccc2-c2ccccc21
Reaction time: 1 h

Procedure:
First, 8.3 g (0.05 m) of fluorene was dissolved in 150 ml of tetrahydrofuran. Then 31.8 ml (0.05 m) of butyl lithium (1.6 molar in hexane) was added dropwise to this solution. After a stirring period of one hour, 6.3 ml (0.05 mol) of chlorotrimethylsilane, dissolved in 25 ml of tetrahydrofuran was added to this solution over 3 hours. The reaction mixture was stirred for an additional 3 hours. Then, 50 ml of an aqueous NH4Cl solution was added to the dark yellow solution. The solution was treated with 50 ml of water. The organic phase was dried over Na2SO4. Then the solvent was removed in vacuo. The yellow residue was dissolved in pentane. The product 9-(trimethylsilyl)fluorene was crystallized at 4° C. A yield of 8.33 g was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[O:25][C:26]([CH3:29])=[N:27][N:28]=3)=[CH:20][CH:19]=2)[CH:16]=1)[C:10]([O:12]C)=[O:11])[CH3:5].[OH-].[Na+]>C1COCC1.CO.O>[CH3:1][O:2][CH2:3][CH:4]([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[O:25][C:26]([CH3:29])=[N:27][N:28]=3)=[CH:20][CH:19]=2)[CH:16]=1)[C:10]([OH:12])=[O:11])[CH3:5]
Reactant: COCC(C)Oc1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COCC(C)Oc1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(C(=O)O)c1
Reaction time: 1 h
Yield: 77.7 %

Procedure:
A solution of Methyl 3-(1-methoxypropan-2-yloxy)-5-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)benzoate (Intermediate 2) (6.8 g, 17.08 mmol, 1 equiv.) in a mixture of THF and methanol (70 mL of 1:1 ratio) was treated with a solution of sodium hydroxide (2 g, 51.25 mmol, 3 equiv.) in water (50 mL) and the reaction mixture was stirred for 1 h. The resulting solution was concentrated in vacuo to remove THF and methanol, diluted with water (50 mL), extracted with EtOAc. The aqueous phase was cooled and acidified with 0.1 N HCl and extracted with DCM, combined organic extracts washed with brine, dried over Na2SO4 and concentrated in vacuo to give 3-(1-methoxypropan-2-yloxy)-5-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)benzoic acid (5.1 g) as white solid.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:24][CH3:25])=[C:18]([S:20](Cl)(=[O:22])=[O:21])[CH:19]=1>C(Cl)Cl>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:24][CH3:25])=[C:18]([S:20]([NH:5][CH2:4][CH2:3][Cl:2])(=[O:21])=[O:22])[CH:19]=1
Reactant: NCCCl
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Br)cc1S(=O)(=O)NCCCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 13.4 g (0.115 mol) of 2-chloroethylamine hydrochloride in 150 ml of CH2Cl2 there are added 34 ml (0.241 mol) of triethylamine and then, dropwise, 30 g (0.105 mol) of the product obtained in Step A above dissolved in 200 ml of CH2Cl2. The solution is stirred for 2 hours at ambient temperature and is then washed with 1N HCl solution, water and brine. The organic phase is dried over MgSO4 and evaporated. The solid is re-suspended in ethyl ether and filtered off to yield the title product.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][C:9](=[O:10])[C:5](=[C:6]([CH3:8])[CH3:7])[CH2:4][CH2:3]1.[CH3:12][Al](C)C.C[Si](Cl)(C)C.O>C1COCC1.C1(C)C=CC=CC=1>[C:6]([CH:5]1[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:11][C:9]1=[O:10])([CH3:12])([CH3:7])[CH3:8]
Reactant: CC(C)=C1CC[C@@H](C)CC1=O
Reactant: C[Al](C)C
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1CCC(C(C)(C)C)C(=O)C1
Yield: 86.2 %

Procedure:
1.52 g (10 mmol) of pulegone (2-isopropylidene-5-methylcyclohexanone) and 14.3 mg (0.1 mmol) of CuBr in 10 ml of dry THF are introduced at room temperature. 9.5 ml (11 mmol) of 10% trimethylaluminum in toluene and 1.3 g (12 mmol) of trimethylsilyl chloride are added at 0° C. It is stirred for 5 more hours at room temperature, hydrolyzed with 5 ml of water and extracted twice with 30 ml of ether each, and the organic phases are combined. After the solvent is evaporated, the product is distilled at 10 torr and 120° C. in a bulb tube. 1.45 g (86% of theory) of 2-tert-butyl-5-methylcyclohexanone is obtained.
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH:19]([NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:33][O:34][CH3:35])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=1)=[O:20].[Br:36]N1C(=O)CCC1=O>C1C=CC=CC=1>[CH:19]([NH:21][C:22]1[S:23][C:24]([Br:36])=[C:25]([C:27](=[N:33][O:34][CH3:35])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:26]=1)=[O:20]
Reactant: CCOC(=O)C(=NOC)c1csc(NC=O)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)C(=NOC)c1nc(NC=O)sc1Br
Yield: 94.3 %

Procedure:
A small amount of benzoyl peroxide was added to a suspension of ethyl 2(2-formamidothiazol-4-yl)-2-methoxyiminoacetate (syn isomer, 7.55 g.) and N-bromosuccinimide (5.75 g.) in dry benzene (150 ml.) and refluxed under heating for an hour. After cooling, the reaction mixture was washed with water three times, dried over magnesium sulfate, treated with activated charcoal and then evaporated in vacuo. The residue was pulverized with n-hexane, and the precipitates were collected by filtration, washed with n-hexane and water successively and dried to give ethyl 2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetate (syn isomer, 9.3 g.).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[NH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1.C(=O)([O-])O.[Na+]>C1COCC1>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([C:16]2[CH:15]=[C:14]3[C:19]([CH2:20][CH2:21][C:12]([C:10]([NH:9][C:6]4[CH:5]=[CH:4][C:3]([CH2:2][NH:29][C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)=[CH:8][CH:7]=4)=[O:11])=[CH:13]3)=[CH:18][CH:17]=2)=[CH:23][CH:24]=1
Reactant: Nc1cccnc1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CNc4cccnc4)cc2)CC3)cc1
Temperature: 25 °C
Yield: 8.1 %

Procedure:
In THF (7 ml) was dissolved N-[4-(chloromethyl)-phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (150 mg), and to the mixture was added 3-aminopyridine (109 mg). The mixture was refluxed for 45 hours. The reaction mixture was cooled to room temperature, and to the mixture was added 5% sodium hydrogen carbonate solution (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=3/1) and recrystallized from ethyl acetate-hexane to give 7-(4-methylphenyl)-N-[4-[N-(3-pyridyl)aminomethyl]phenyl]-3,4-dihydronaphthalene-2-carboxamide (Compound 47) (14 mg) as colorless crystals.
Reaction SMILES: [C:1](=[O:5])([O:3][CH3:4])[NH2:2].O=[C:7]([CH2:11][CH2:12][PH:13]([CH2:15][OH:16])=[O:14])[C:8]([OH:10])=[O:9].C(O)(=O)C>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.ClC1C=CC=CC=1>[CH3:4][O:3][C:1]([NH:2]/[C:7](=[CH:11]\[CH2:12][PH:13]([CH2:15][OH:16])=[O:14])/[C:8]([OH:10])=[O:9])=[O:5]
Reactant: COC(N)=O
Reactant: O=C(O)C(=O)CC[PH](=O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: Clc1ccccc1
Solvent: O
Product: COC(=O)N/C(=C\C[PH](=O)CO)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
5.835 g of methyl carbamate, 0.275 g of p-toluenesulfonic acid monohydrate and 10.000 g of 2-oxo-4-(hydroxymethylphosphinyl)-butanoic acid were added to 16 mL of acetic acid to be suspended. After being dissolved by heating, 80 mL of chlorobenzene was added thereto and then the solution was refluxed with vigorous stirring. A remaining solution was removed appropriately while the internal temperature of the reaction solution was maintained from 106 to 110 deg. C. under a slightly reduced pressure, followed by adding chlorobenzene, the volume of which was equal to the volume of the removed solution. Two hours later, dissipation of almost all the raw materials was confirmed by HPLC measurement. At this point, the area ratio of Z form to E form was 93:7. After removing about 50 mL of the solvent under a reduced pressure, followed by adding 20 mL of acetic acid, and then the resultant was stirred for 1 hour at 80 deg. C. The precipitate which was obtained by cooling the solution gradually to room temperature and stirring over-night, was filtered and then the filtrate was washed with acetic acid. After being washed with acetone, dried for 6 hours from 40 to 50 deg. C. under a reduced pressure, 9.505 g of the objective compound was obtained (72.2% yield, Z:E=99.5:0.5).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[N:5]=[CH:4][N:3]=1.[CH2:16]([OH:20])[C:17]#[C:18][CH3:19].[H-].[Na+].O>CN(C)C=O>[F:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=1[C:6]1[CH:7]=[C:2]([O:20][CH2:16][C:17]#[C:18][CH3:19])[N:3]=[CH:4][N:5]=1
Reactant: Fc1cccc(F)c1-c1cc(Cl)ncn1
Reactant: CC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1cc(-c2c(F)cccc2F)ncn1
Temperature: 25 °C
Reaction time: 9 h
Yield: 43.9 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 226 mg of 4-chloro-6-(2,6-difluorophenyl)pyrimidine and 84 mg of 2-butyn-1-ol, to which 48 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 9 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 114 mg of 4-(2,6-difluorophenyl)-6-(2-butynyloxy)pyrimidine (the present compound (87)).
Reaction SMILES: FC1C=C(CN)C=NC=1.[O:10]1[CH:14]=[C:13]([CH2:15][NH2:16])[N:12]=[CH:11]1.[CH2:17]([N:21]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][C:28]([C:32](O)=[O:33])=[C:29]([CH3:31])[N:30]=2)[C:22]1=[O:35])[CH:18]([CH3:20])[CH3:19]>>[CH2:17]([N:21]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][C:28]([C:32]([NH:16][CH2:15][C:13]3[N:12]=[CH:11][O:10][CH:14]=3)=[O:33])=[C:29]([CH3:31])[N:30]=2)[C:22]1=[O:35])[CH:18]([CH3:20])[CH3:19]
Reactant: NCc1cocn1
Reactant: Cc1nc(N2CCN(CC(C)C)C2=O)sc1C(=O)O
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CC(C)C)C2=O)sc1C(=O)NCc1cocn1
Yield: 17 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with oxazol-4-ylmethanamine to react with 2-(3-isobutyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid in place of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 17% yield: mp 115-118° C.; 1H NMR (300 MHz, CDCl3) δ7.85 (s, 1H), 7.64 (s, 1H), 6.36-6.32 (m, 1H), 4.47 (d, J=5.5 Hz, 2H), 4.11-4.06 (m, 2H), 3.59-3.54 (m, 2H), 3.09 (d, J=7.4 Hz, 2H), 2.56 (s, 3H), 1.97-1.83 (m, 1H), 0.91 (d, J=7.4 Hz, 6H); MS (ES+) m/z 377.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][C:5]([NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[C:4]([F:20])[CH:3]=1.[OH:21]C(C(C)=C)C(OCC)=O.Cl.[C:32]1([CH3:38])C=CC=C[CH:33]=1>>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][C:5]([N:14]2[C:18](=[O:21])[C:17](=[C:32]([CH3:38])[CH3:33])[O:16][C:15]2=[O:19])=[C:4]([F:20])[CH:3]=1
Reactant: C=C(C)C(O)C(=O)OCC
Reactant: Cc1ccccc1
Reactant: CCOC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Agent: Cl
Product: CC(C)=C1OC(=O)N(c2cc(OC3CCCC3)c(Cl)cc2F)C1=O
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 50.9 %

Procedure:
Ethyl N-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)carbamate (3.01 g, 10 mmol) and ethyl 2-hydroxy-3-methyl-3-butenoate (4.32 g, 30.0 mmol) were introduced into a flask (25 cc) equipped with a distillation unit, and the reaction was conducted at 215° C. for 16.5 hours. After the reaction solution was cooled to room temperature, toluene (20 mL) was added, and then the reaction solution was washed with water (20 mL), then 1N sodium hydroxide (20 mL) and 1N hydrochloric acid (20 mL). The organic layer was dried over magnesium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure. To the resulting oily crude product, methanol (3.5 mL) acidified with hydrochloric acid was added to form a homogeneous solution. Then, 6N hydrochloric acid (0.4 mL) was further added, and the solution was left to stand at room temperature. The precipitated crystals were collected by filtration, then washed with a 10:1 mixed solvent consisting of methanol and 6N hydrochloric acid and dried to obtain 3-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (1.80 g, yield 50.9%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:25][C:26]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[NH:38][N:37]=2)=[CH:31][C:27]=1[C:28]([OH:30])=O.C(N(CC)CC)C.[CH3:54][O:55][C:56]1([CH3:62])[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>CN(C)C=O>[F:25][C:26]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[NH:38][N:37]=2)=[CH:31][C:27]=1[C:28]([N:59]1[CH2:60][CH2:61][C:56]([O:55][CH3:54])([CH3:62])[CH2:57][CH2:58]1)=[O:30]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: COC1(C)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC1(C)CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.597 g, 1.57 mmol) was added in one portion to 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.188 g, 0.63 mmol) and triethylamine (0.193 mL, 1.39 mmol) in N,N-dimethylformamide (2 mL) at ambient temperature under an air atmosphere. The resulting solution was stirred at 25° C. for 15 minutes. A solution of 4-methoxy-4-methylpiperidine (23) (89.5 mg, 0.69 mmol) in N,N-dimethylformamide (1 mL) was added dropwise and the resulting solution was stirred at 25° C. for 4 hours. The crude mixture was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to the desired compound as a solid (0.110 g, 42.7%); 1H NMR (400.132 MHz, DMSO) δ 1.11 (3H, s), 1.25-1.34 (1H, m), 1.42 (1H, td), 1.56 (1H, d), 1.75 (1H, dd), 3.10-3.18 (4H, m), 4.09 (3H, q), 4.32 (2H, s), 7.21 (1H, t), 7.31 (1H, dd), 7.39-7.43 (1H, m), 7.83 (1H, td), 7.88 (1H, td), 7.96 (1H, dd), 8.27 (1H, dd), 12.57 (1H, s); m/z (LC-MS, ESI+), RT=1.79 (M+H 409).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8][CH3:9])=[C:6](Cl)[N:5]=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]([CH3:18])[CH3:17])[N:3]=1.[NH3:19]>CO>[NH2:19][C:6]1[C:7]([S:8][CH3:9])=[C:2]([Cl:1])[N:3]=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]([CH3:18])[CH3:17])[N:5]=1
Reactant: N
Reactant: CSc1c(Cl)nc(NCCCOC(C)C)nc1Cl
Solvent: CO
Product: CSc1c(N)nc(NCCCOC(C)C)nc1Cl
Yield: 87 %

Procedure:
100 g (0.322 mole) of 4,6-dichloro-2-(3-isopropoxypropylamino)-5-methylthio-pyrimidine are dissolved in 400 ml of methanol and the solution is heated at 100° C. with 500 ml of ammonia in an autoclave for 3 hours. The undissolved residue is filtered off. After the methanol phase has been concentrated, the residue which remains is taken up in methylene chloride, the mixture is washed with water and the resulting organic phase is dried. After removal of the solvent, the resulting oil is stirred with petroleum ether. The crystals thereby obtained are filtered off with suction. 81 g (87% of theory) of the desired pyrimidine, melting point: 76° C., are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Br[CH2:13][C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+].N12CCCN=C1CCCCC2>CN(C)C=O.CC(C)=O>[CH3:11][O:10][C:8]1[CH:7]=[CH:6][C:3]2[CH:4]=[C:13]([C:14]#[N:15])[O:1][C:2]=2[CH:9]=1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2cc(C#N)oc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
To a mixture of 2-hydroxy-4-methoxybenzaldehyde (10.0 g), bromoacetonitrile (5.04 mL) and acetone (100 mL) was added potassium carbonate (18.1 g), and the mixture was stirred at room temperature for 3 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give a pale-brown solid. To a solution (100 mL) of the obtained solid in N,N-dimethylformamide was added 1,8-diazabicyclo[5.4.0]undec-7-ene (9.83 mL), and the mixture was stirred at 140° C. for 1.5 hr. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the residue, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:17, volume ratio) to give the title object compound (5.32 g, 47%) as a yellow solid.