Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[C:16]([NH:19][CH2:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)(=[O:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C.CN(C)C=O>[C:16]([NH:19][CH2:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:4](=[O:6])[CH2:3][CH2:2][C:1]([O:8][CH3:9])=[O:7])[CH:27]=2)[CH2:22]1)(=[O:18])[CH3:17]
Reactant: COC(=O)CCC(=O)O
Reactant: CC(=O)NCC1Cc2ccccc2C1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)c1ccc2c(c1)CC(CNC(C)=O)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.4 %

Procedure:
To 48.3 g of methyl hydrogen succinate dissolved in 840 ml of dichloroethane were added 46.4 g of oxalyl chloride and 2 drops of dimethylformamide. The mixture was stirred at room temperature for 5 hours. Then, under ice cooling, 34.6 g of 2-(acetylaminomethyl)indane dissolved in 280 ml of dichloroethane and 97.6 g of anhydrous aluminum chloride were added to the reaction mixture. After the mixture was stirred for 1 hour, the reaction mixture was poured into ice water. The organic layer was collected by separation, washed with water and dried, and the solvent was removed to obtain 51.8 g of 2-(acetylamino) methyl-5-(3methoxycarbonylpropionyl) indane.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=1B(O)O>>[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1
Reactant: Cc1cccc(C)c1B(O)O
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Product: Cc1cccc(C)c1-n1cnc2ccc(O)nc21

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 2,6-dimethylphenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=239.9 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].[N:13]#[C:14]Br.C(=O)(O)[O-].[Na+].CCCCCC>O1CCOCC1>[NH2:13][C:14]1[O:6][C:5]([C:4]2[CH:9]=[C:10]([OH:12])[CH:11]=[C:2]([Br:1])[CH:3]=2)=[N:7][N:8]=1
Reactant: N#CBr
Reactant: NNC(=O)c1cc(O)cc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1COCCO1
Product: Nc1nnc(-c2cc(O)cc(Br)c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
3-Bromo-5-hydroxybenzohydrazide (400 mg, 1.04 mmol) was suspended in 5 ml dioxane. Cyanogen bromide (110 mg, 1.04 mmol) and sodium bicarbonate (4%, 1 ml, 12 mmol) were added and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and re-dissolved in ethyl acetate. The organic was washed with water, brine and dried over sodium sulphate, filtered and evaporated under reduced pressure. The oil obtained was precipitate with hexane and filtered to give 126 mg (43% yield) of the title compound. Purity 90%.
Reaction SMILES: [CH2:1]([C@H:8]([CH2:25][C@@H:26](CC1C=CC=CC=1)[C:27](O)=O)[C:9]([NH:11][C@H:12]([C:22]([OH:24])=[O:23])[CH2:13]OCC1C=CC=CC=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][C:38]1([CH3:67])[O:42][CH:41]([CH2:43][O:44][C:45]([C@H](CC2C=CC=CC=2)C[C@@H](CC2C=CC=CC=2)C(O)=O)=[O:46])[CH2:40][O:39]1.Cl.CN(C)[CH2:71][CH2:72][CH2:73]N=C=NCC>C(OCC)(=O)C>[CH3:37][C:38]1([CH3:67])[O:42][CH:41]([CH2:43][O:44][C:45]([C@H:26]([CH2:27][C:71]2[CH:72]=[CH:73][CH:25]=[CH:8][CH:9]=2)[CH2:25][C@@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]([NH:11][C@H:12]([C:22]([OH:24])=[O:23])[CH2:13][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[O:46])[CH2:40][O:39]1
Reactant: CC1(C)OCC(COC(=O)[C@H](Cc2ccccc2)C[C@@H](Cc2ccccc2)C(=O)O)O1
Reactant: O=C(O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1(C)OCC(COC(=O)[C@H](Cc2ccccc2)C[C@@H](Cc2ccccc2)C(=O)N[C@@H](CCc2ccccc2)C(=O)O)O1
Reaction time: 8 h

Procedure:
To a solution of 0.5 g of (L)-homophenylalanine 1,2:5,6-di-O-isopropylidene-D-glucofuranos-3-yl ester, 0.51 g of 4-[(2,2-dimethyl-1,3-dioxolan-4-yl)-methoxycarbonyl]-(S,S)-2,4-dibenzylbutyric acid is added 0.23 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The solution is stirred overnight. The solution is diluted with ethyl acetate, washed in sequence with 1N hydrochloric acid, water, saturated sodium bicarbonate, water, dried (Na2SO4), filtered and concentrated. The residue is flash chromatographed on silica gel eluting with ethyl acetate-methylene chloride (1:4) giving N-{4-[(2,2-di-methyl-1,3-dioxolan-4-yl)-methoxycarbonyl]-(S,S)-2,4-di-benzylbutyryl}-(L)-homophenylalanine 1,2:5,6-di-O-iso-propylidene-D-glucofuranos-3-yl ester melting at 48°-50°.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[CH:37]=[CH:36][C:20]3[NH:21][C:22]([CH2:24][O:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)=[N:23][C:19]=3[CH:18]=2)[CH:9]([CH3:10])[O:8]1)(C)(C)C.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1COCC1>[OH:8][CH:9]([CH3:10])[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:37]=[CH:36][C:20]2[NH:21][C:22]([CH2:24][O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:28][CH:27]=3)=[N:23][C:19]=2[CH:18]=1)=[O:6]
Reactant: CC1OC1(O[Si](C)(C)C(C)(C)C)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(O)C(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Temperature: 80 °C
Yield: 88.2 %

Procedure:
A mixture of 5-{2-[2-(tert-butyl-dimethyl-silanyloxy)-3-methyl-oxiranyl]-phenyl}-2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazole (0.040 g, 0.0721 mmol) and toluenesulfonic acid monohydrate (0.016 g, 0.0865 mmol) in THF (2 mL) was heated to 80° C. for 4 hours. The reaction mixture was then concentrated, and the residue was purified by chromatography (silica, hexanes: EtOAc, 1:2) to afford the title compound as a brown oil (0.028 g, 89%). 1H NMR (400 MHz, CD3OD) δ (ppm): 7.66-7.56 (m, 4H), 7.53-7.45 (m, 4H), 7.26-7.22 (m, 3H), 5.43 (s, 2H), 4.12-4.03 (m, 1H), 1.03 (d, 3H, J=7.2 Hz). Mass Spectrum (LCMS, ESI pos.) Calcd. For C26H23F3N3O3: 482.4 (M+MeCN+H), Found 482.3.
Reaction SMILES: O.[NH2:2]N.C[N:5]([CH:7]=[C:8]1[C:13](=O)[CH2:12][CH2:11][CH:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)C>CO>[NH:2]1[C:13]2[CH2:12][CH2:11][CH:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9][C:8]=2[CH:7]=[N:5]1
Reactant: NN
Reactant: CN(C)C=C1CC(NC(=O)OC(C)(C)C)CCC1=O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCc2[nH]ncc2C1
Yield: 55.3 %

Procedure:
Hydrazine monohydrate (0.11 mL, 2.35 mmol) was added to a solution of tert-butyl {3-[(dimethylamino)methylene]-4-oxocyclohexyl}carbamate obtained in Example (242a) (526 mg, 1.96 mmol) in methanol (10 mL), and the mixture was heated under reflux for 18 hours. The reaction solution was concentrated. The resulting residue was azeotropically distilled with toluene and then purified by silica gel column chromatography (elution solvent: dichloromethane/methanol 20/1) to obtain 257 mg of the title compound as an amorphous compound (55%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=[NH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16]1([N:22]=[C:23]=[N:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)(C)(C)C>[CH:25]1([NH:24][C:23]([N:15]=[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]2[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: N=c1ccccn1CCc1ccccc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(C)(C)O
Product: c1ccc(CCn2ccccc2=NC(=NC2CCCCC2)NC2CCCCC2)cc1
Yield: 45.1 %

Procedure:
A solution of 1-(2-phenylethyl)-2-iminopyridine (5.9 g, 0.030 mole) and dicyclohexylcarbodiimide (7.26 g, 0.036 mole) in 100 ml t-butanol is heated at reflux for 24 hours. The solution is cooled and concentrated in vacuo to give a solid. The solid is recrystallized from 200 ml of hexane to give 5.48 g of the title compound which sinters at 132°C and melts at 142.5°-145°C.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]CC.[Na+].Br[CH2:13][CH2:14][Cl:15].O>C(O)C>[C:1]1([S:7][CH2:13][CH2:14][Cl:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCBr
Reactant: Sc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ClCCSc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
Benzenethiol (15.0 g, 0.136 mol) was added to the solution of sodium ethoxide (0.20 mol) in 200 ml of anhydrous ethanol, and the mixture was stirred at room temperature for 15 minutes and then added to the solution of 1-bromo-2-chloroethane in 100 ml of ethanol. The resultant mixture was stirred at room temperature for 3 hours and poured into 300 ml of water. The mixture was extracted three times with ether and the combined organic layer was dried over magnesium sulfate. After removal of the solvent, the compound was purified by flash chromatography using heptane/ethyl acetate (100 to 97/3) as eluent in a yield of 74%.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:33]=[CH:32][C:28](C(O)=O)=[CH:27][CH:26]=2)[CH:20]=1.[NH2:34][CH2:35][CH:36]([OH:47])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1>>[OH:47][CH:36]([CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1)[CH2:35][NH:34][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6](=[O:7])[C:28]1[CH:27]=[CH:26][C:25]([C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)=[CH:33][CH:32]=1)=[O:18]
Reactant: COc1ccc(OCC(O)CN)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Product: CON=C1C[C@@H](C(=O)NCC(O)COc2ccc(OC)cc2)N(C(=O)c2ccc(-c3cccnc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-(3-pyridinyl)benzoic acid, and (2RS)-1-amino-3-(4-methoxyphenoxy)-2-propanol, the title compound was obtained in 63% purity by HPLC. MS(ESI+): m/z=519.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>O1CCCC1>[C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1)(=[O:22])[CH:20]=[CH2:21]
Reactant: Cc1nc2cc(N)ccc2o1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc2oc(C)nc2c1
Temperature: 0 °C

Procedure:
About 150 parts of (2) are dissolved in about 1200 ml of warm tetrahydrofuran in a 3 liter three-necked flask equipped with a mechanical stirrer and dropping funnel. About 113 parts of triethylamine are added to the flask and then cooled to 0° C. using an ice bath. About 100 parts of acryloyl chloride are combined with about 300 ml of tetrahydrofuran in a dropping funnel and added dropwise to the flask while stirring under dry nitrogen. The mixture in the flask is allowed to return to room temperature while being stirred overnight and then filtered. The filter is stirred in about 1 liter of warm tetrahydrofuran for about thirty minutes and filtered again. Both filtrates are combined and about 10 ml of nitrobenzene are added to inhibit polymerization. Solvent is removed using a rotary evaporator and ethyl ether is added to solidify the product. The dark brown solid obtained after filtering is washed with methylene chloride, then ethyl ether to provide 5-acrylamido-2-methyl benzoxazole (3) as a tan solid after drying under vacuum.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[C:8]2[N:10]([CH:13]([CH3:15])[CH3:14])[CH:11]=[N:12][C:7]2=[C:6]([N+:16]([O-])=O)[CH:5]=1)([O-:3])=[O:2].CCN(CC)CC.[CH2:26](N)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCOCC>CN(C=O)C>[CH2:26]([NH:16][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[N:9]=[C:8]2[N:10]([CH:13]([CH3:15])[CH3:14])[CH:11]=[N:12][C:7]=12)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: CC(C)n1cnc2c([N+](=O)[O-])cc([N+](=O)[O-])nc21
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)n1cnc2c(NCc3ccccc3)cc([N+](=O)[O-])nc21
Temperature: 20 °C
Reaction time: 6 h

Procedure:
To a solution of 5,7-dinitro-3-iso-propylimidazo[4,5-b]pyridine, 5, in DMF was added NEt3 and benzylamine. After 6 h stirring at 20° C., 15 mL Et2O was added and the solid which precipited was filtered and washed with Et2O.
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[C:5]([NH:15][S:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:18])=[O:17])[C:4]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].Cl.[C:37](=[O:40])(O)[O-].[Na+].[NH2:42][CH:43](O)C>>[OH:40][CH2:37][CH2:43][NH:42][C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[C:5]([NH:15][S:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:18])=[O:17])[C:4]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35]
Reactant: CC(N)O
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)C=Cc1ccccc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Agent: [Na]
Product: COc1ccccc1Oc1c(NCCO)nc(-c2ncccn2)nc1NS(=O)(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium (693 mg) was added to and dissolved in 18.2 ml of aminoethanol. To this reaction solution was added 3.00 g of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide with stirring at room temperature. The reaction mixture was stirred at 60° C. for one hour and then at 80° C. for two hours followed by pouring into a mixture of 1N hydrochloric acid and ice. This solution was neutralized with a saturated sodium bicarbonate solution and extracted with ethyl acetate and the ethyl acetate layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting residue was purified by a silica gel column chromatography (chloroform-methanol=20:1). The resulting amorphous substance was pulverized in ether and collected by filtration to give 2.40 g of N-[6-(2-hydroxyethylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Reaction SMILES: O1CCOCC1.Cl[C:8]1[CH:13]=[C:12]([CH:14]([S:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[C:11]([Cl:31])=[CH:10][N:9]=1.[NH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38]>CO.C(Cl)Cl>[Cl:31][C:11]1[C:12]([CH:14]([S:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:13][C:8]([NH:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38])=[N:9][CH:10]=1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Reactant: NCCOCCO
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: OCCOCCNc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Temperature: 25 °C
Yield: 35 %

Procedure:
A dioxane (1.5 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine (210 mg, 0.504 mmol) obtained in Example 54 and 2-(2-aminoethoxy)ethanol (400 μl) was heated at 120° C. for 3 days in a sealed tube. The reaction mixture was cooled to room temperature and then, concentrated under reduced pressure. Water was added to the residue thus obtained, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the 30% methanol/methylene chloride eluate was concentrated under reduced pressure to give the title compound (85 mg, 0.175 mmol, 35%) as a colorless oil.
Reaction SMILES: [S:1]([CH2:4][S:5][C:6]1[S:7][C:8](=C)[C:9]([CH2:13][CH3:14])([CH2:11][CH3:12])[N:10]=1)[C:2]#[N:3].ClCl.[Cl:18][CH2:19][Cl:20]>>[S:1]([CH2:4][S:5][C:6]1[S:7][C:8](=[C:19]([Cl:20])[Cl:18])[C:9]([CH2:13][CH3:14])([CH2:11][CH3:12])[N:10]=1)[C:2]#[N:3]
Reactant: ClCCl
Reactant: C=C1SC(SCSC#N)=NC1(CC)CC
Agent: ClCl
Product: CCC1(CC)N=C(SCSC#N)SC1=C(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Thiocyanomethylthio-4,4-diethyl-5-methylenethiazoline, 23. gm, is added to 75 ml of dichloromethane. 0.72 gm of chlorine in 20 ml of dichloromethane is then added to the system. The system is stirred at room temperature for 1 hour. The system is then washed with saturated sodium bicarbonate solution, filtered and the organic solution dried over magnesium sulfate. The dichloromethane is removed by stripping to give the 2-thiocyanomethylthio-4,4-diethyl-5-dichloromethylenethiazoline.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)[CH3:2].[CH3:16][Li].O>CCOCC>[CH2:14]([O:13][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]([OH:10])[CH3:16])=[CH:7][CH:6]=1)[CH3:15]
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Reactant: [Li]C
Solvent: O
Solvent: CCOCC
Product: CCOC(OCC)c1ccc(C(C)O)cc1
Temperature: -75 °C
Reaction time: 2 h

Procedure:
4-(Diethoxymethyl)benzaldehyde (104 g, 0.5 mol) was dissolved in 300 ml of ether and the resulting solution cooled to -75° C. in an acetone-dry ice bath. With vigorous stirring, methyllithium (390 mL of 1.4M in ether, 0.55 mol) was added at a rate which maintained the temperature at less than -60° C. The reaction mixture was allowed to warm to room temperature, stirred for two hours at that temperature, poured into 500 mL of ice and water, stirred 10 minutes and the layers separated. The aqueous layer was extracted with 500 mL ether. The organic layers were combined, washed with 500 mL each of H2O and then brine dried (MgSO4) and stripped in vacuo to yield 110-111.5 (98-100%) of present title product as a viscous, light yellow oil.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH:6]1[C:23]2=[C:24]3[C:13]([C:14]4[C:25]5[C:22]2=[CH:21][CH:20]=[C:19]([C:26]([OH:28])=[O:27])[C:18]=5[C:17]([C:29](O)=[O:30])=[CH:16][CH:15]=4)=[CH:12][CH:11]=[C:10]([C:32](=N)[OH:33])[C:9]3=[C:8]([C:35](=N)[OH:36])[CH:7]=1>>[CH:15]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]4[C:32]([O:2][C:35](=[O:36])[C:8]5[C:9]=4[C:24]=3[C:23](=[CH:6][CH:7]=5)[C:22]3[C:25]=2[C:18]2[C:19]([C:26]([O:28][C:29](=[O:30])[C:17]=2[CH:16]=1)=[O:27])=[CH:20][CH:21]=3)=[O:33]
Reactant: O=S(=O)(O)O
Reactant: N=C(O)c1ccc2c3ccc(C(=O)O)c4c(C(=O)O)ccc(c5ccc(C(=N)O)c1c25)c43
Product: O=C1OC(=O)c2ccc3c4ccc5c6c(ccc(c7ccc1c2c73)c64)C(=O)OC5=O
Temperature: 220 °C

Procedure:
800 g of 95% strength sulfuric acid are initially taken and 200 g of 89.4% strength perylene-3,4,9,10-tetracarboxylic acid diimide are introduced at room temperature. The temperature of the mixture is then raised to 220° C., and this temperature is maintained for two hours. The mixture is then allowed to cool to room temperature and the precipitate which has been formed is filtered off with suction and washed first with 280 g of 80% strength sulfuric acid and then with water until it is neutral. Drying at 80° C. gives 170.9 g of crude perylene-3,4,9,10-tetracarboxylic dianhydride. This is introduced, with exclusion of light, into a solution composed of six liters of water and 140 g of 85% strength potassium hydroxide. While blanketed with nitrogen, the solution is heated to 80°-90° C., and stirring is continued for a further 90 minutes at this temperature. The mixture is then allowed to cool to 25° C., the pH is adjusted to a value of 8-9 and the solid residue is filtered off with suction and washed with 100 ml of water. (The residue is 35.6 g of perylene-3,4,9,10-tetracarboxylic acid diimide which has only been half-saponified, i.e. perylene-3,4,9,10-tetracarboxylic acid monoanhydride-monoimide, and this is expediently added to the next batch.) 60 g of 85% strength potassium hydroxide and 60 g of animal charcoal are introduced into the filtrate, with exclusion of light, and the mixture is then blanketed with nitrogen. After a further hour's stirring at 25° C., a solution of 110 g of nickel(II) sulfate crystals in 600 ml of water is added dropwise, the mixture is stirred for a further hour at 25° C. and is clarified, and the filtrate is then added dropwise to 600 g of concentrated hydrochloric acid, the mixture is kept at 80°-90° C. for one hour and the precipitate is filtered off with suction, washed with water until it is neutral and dried at 80° C. This gives 121.8 g of perylene-3,4,9,10-tetracarboxylic dianhydride having the following extinction values:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>CN(C=O)C.CCOCC>[F:8][C:7]1[C:2](/[N:1]=[CH:12]/[N:13]([CH3:15])[CH3:14])=[N:3][C:4](=[O:9])[NH:5][CH:6]=1
Reactant: COC(OC)N(C)C
Reactant: Nc1nc(O)ncc1F
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)/C=N/c1nc(=O)[nH]cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.6 %

Procedure:
To a magnetically stirred solution of 4-amino-5-fluoropyrimidin-2-ol (4.00 g, 31.0 mmol) in DMF (100 mL) was added N,N-dimethylformamide dimethyl acetal (DMF-DMA; 4.00 g, 34.0 mmol). The mixture was stirred at room temperature for 72 h, diluted with Et2O (200 mL), and filtered. The solid product was washed with heptane to give (E)-N′-(5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)-N,N-dimethylformimidamide (5.23 g, 92%) as a white solid: mp 240-243° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.7 (br s, 1H), 8.59 (s, 1H), 7.7 (d, J=5.6 Hz, 1H), 3.18 (s, 3H), 3.06 (s, 3H); ESIMS m/z 185 ([M+H]+), m/z 183 ([M−H]−).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[Br:32][C:33]1[CH:34]=C2[C:40](=[CH:41][CH:42]=1)[C:39]([CH3:44])([CH3:43])[CH2:38][CH2:37]C2>C1C=CC=CC=1.[O-2].[O-2].[O-2].[Cr+6]>[Br:32][C:33]1[CH:34]=[C:6]2[C:40]([C:39]([CH3:43])([CH3:44])[CH2:38][CH2:37][C:5]2=[O:7])=[CH:41][CH:42]=1
Reactant: CC1(C)CCCc2cc(Br)ccc21
Reactant: CC(=O)OC(C)=O
Agent: [Cr+6]
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [O-2]
Solvent: c1ccccc1
Product: CC1(C)CCC(=O)c2cc(Br)ccc21
Reaction time: 1 h

Procedure:
To a cold mixture (0° C.) of 209 g (200 mmol) of chromium trioxide, 100 ml (1.06 mol) of acetic anhydride and 200 ml (3.5 mol) of acetic a 1 acid was added a solution of 10 g (41.8 mmol) of 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F) in 125 ml of benzene. The reaction mixture was stirred for 1 hour, quenched with ice cold water and extracted with Et2O (3×100 ml). The organic layer was dried over MgSO4, concentrated in vacuo, and purified by column chromatography (silica, 10% EtOAc-hexane) to give the title compound as a white solid.