Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[O:5][CH:6]([CH2:21][CH3:22])[C:7]([NH:9][C:10]([CH3:20])([CH3:19])[C:11]#[C:12][CH2:13][CH2:14][CH2:15][S:16]([CH3:18])=[O:17])=[O:8].ClC1C=CC=C(C(OO)=[O:35])C=1.CCCCCC.C(OCC)(=O)C>ClCCl>[Cl:26][C:24]1[CH:23]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:25]=1)[O:5][CH:6]([CH2:21][CH3:22])[C:7]([NH:9][C:10]([CH3:19])([CH3:20])[C:11]#[C:12][CH2:13][CH2:14][CH2:15][S:16]([CH3:18])(=[O:35])=[O:17])=[O:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)NC(C)(C)C#CCCCS(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)NC(C)(C)C#CCCCS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-(3,5-dichlorophenoxy)-N-(6-methyl-1-methylsulphinyl-hept-4-yn-6-yl) butyramide (0.10 g) in dichloromethane (5 ml) at 0° C. was added 3-chloroperbenzoic acid (0.060 g, 70%, stabilised with water). The mixture was stirred for 0.5 hours at 0° C., then for 1 hour at ambient temperature and stored for 18 hours. The solvent was evaporated under reduced pressure and the residue dissolved in diethyl ether, washed with a saturated aqueous solution of sodium hydrogen carbonate (three times) and water (twice), dried over magnesium sulphate and then evaporated under reduced pressure to give a colourless oil. The oil was fractionated by chromatography (silica; hexane/ethyl acetate, 2:1 by volume) to give the required product as a pale yellow oil, 0.040 g, 1H NMR (CDCl3) δ: 0.98-1.02(3H, t); 1.56(3H, s); 1.58(3H, s); 1.92-2.00(4H, m); 2.36-2.40((2H, t); 2.96(3H, s); 3.22-3.26(2H, m); 4.38-4.42(1H, t); 6.26(1H, s); 6.84(2H, s); 7.02(1H, s).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[O:14]1[C:19](=[O:20])[CH2:18][O:17][CH2:16][C:15]1=[O:21].Cl>N1C=CC=CC=1>[O:17]([CH2:18][C:19]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:20])[CH2:16][C:15]([OH:21])=[O:14]
Reactant: CCCCCCCCCCCCO
Reactant: O=C1COCC(=O)O1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCOC(=O)COCC(=O)O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
18.6 g n-dodecanol was dissolved in 25 ml pyridine on a steam bath. When 11.6 g of 1,4-dioxane-2,6-dione was added with stirring, the mixture quickly reached 80° C. After 5 minutes the solution was allowed to cool to room temperature and, after 2 hours, was poured into 200 ml 1 N HCl. The gel which precipitated was extracted with 300 ml ether, washed three times, with 0.1 N HCl and dried over Na2SO4. The ether was evaporated and the resulting clear oil was taken up in petroleum ether. Agitation and cooling under nitrogen precipitated a product which was separated by filtration. The remaining solution was diluted to 250 ml with petroleum ether for precipitation of a second crop. The yield totalled 18.1 g of a white crystalline solid that melted at 57°-59° C. and was soluble in acetone, chloroform, ether and/or methanol. Elemental analysis indicated 56.8% C; 8.5% H (Calc. 56.7% C; 8.5% H).
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10])=[O:5])[CH3:2].S(Cl)([Cl:18])=O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH2:1]([O:3][C:4]([O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([Cl:18])=[O:10])=[O:5])[CH3:2]
Reactant: CCOC(=O)Oc1ccccc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)Oc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
5.9 g (28 mmol) of 2-(ethoxycarbonyloxy)benzoic acid are dissolved in 30 ml of toluene with a few drops of pyridine. 2.15 ml (29 mmol) of thionyl chloride are added dropwise and the mixture is stirred at ambient temperature for 18 h and then concentrated to dryness. The residue is precipitated from pentane. The solid is filtered off and then dried. 5.2 g of 2-(ethoxycarbonyloxy)benzoyl chloride are obtained in the form of a white solid with a yield of 80%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[C:21](=O)[CH:20](Br)[CH2:19][CH2:18][CH2:17][C:7]=2[N:8](C(OC(C)(C)C)=O)[CH:9]=1)=[O:4].[C:24]([NH2:27])(=[S:26])[CH3:25]>CO>[CH3:1][O:2][C:3]([C:5]1[C:6]2[C:21]3[N:27]=[C:24]([CH3:25])[S:26][C:20]=3[CH2:19][CH2:18][CH2:17][C:7]=2[NH:8][CH:9]=1)=[O:4]
Reactant: CC(N)=S
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C(Br)CCC2
Solvent: CO
Product: COC(=O)c1c[nH]c2c1-c1nc(C)sc1CCC2
Yield: 64.1 %

Procedure:
A mixture of 5-Bromo-4-oxo-5,6,7,8-tetrahydro-4-H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester(880 mg, 2.27 mmol) and Thioacetamide(426 mg, 4.54 mmol) in MeOH(20 mL) is refluxed for 20 h and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (50% EtOAc/Hex to 10% MeOH/CH2Cl2) to yield 382 mg of 2-Methyl-4,5,6,7-tetrahydro-3-thia-1,7-diaza-cyclopenta[e]azulene-9-carboxylic acid methyl ester as a yellow foam(64%).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[C:14]([CH:21]([CH3:23])[CH3:22])=[CH:13][C:8]=1[C:9]([O:11]C)=[O:10]>CO.O>[CH3:3][O:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[C:14]([CH:21]([CH3:23])[CH3:22])=[CH:13][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCOc1cc(OCOC)c(C(C)C)cc1C(=O)O
Temperature: 25 °C
Yield: 73.3 %

Procedure:
Aqueous potassium hydroxide (50% w/v, 1.0 ml) was added to a mixture of methyl 2,4-bis-(methoxymethyloxy)-5-isopropylbenzoate (560 mg, 1.88 mmol) in methanol (12 ml) and water (4 ml) and the mixture was stirred and held at reflux for 3 hours. Upon cooling to room temperature the organic solvent was removed in vacuo and the residue diluted with water (20 ml) and acidified by the addition of 2M hydrochloric acid (10 ml). The organic material was extracted with dichloromethane (2×20 ml) and the combined organic extracts were evaporated in vacuo. The residue was triturated with a mixture of petroleum ether and diethyl ether to afford 2,4-bis-(methoxymethyloxy)-5-isopropylbenzoic acid (392 mg, 73%) as a colourless solid. 1H NMR (DMSO-d6) 12.38 (1H, br s), 7.59 (1H, s), 6.84 (1H, s), 5.31 (2H, s), 5.20 (2H, s), 3.41 (6H, s), 3.21 (1H, m), 1.18 (6H, d). MS: [M+Na]+ 307.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[Cl:13].[C:14]([S:18][C:19](=[O:24])[CH2:20][C:21](=[O:23])[CH3:22])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([S:18][C:19](=[O:24])[CH:20]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[Cl:13])[C:21](=[O:23])[CH3:22])([CH3:17])([CH3:15])[CH3:16]
Reactant: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Reactant: CC(=O)CC(=O)SC(C)(C)C
Product: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1Cl)C(=O)SC(C)(C)C

Procedure:
The title compound was prepared by the method of Preparation 34a using 1-bromomethyl-2-chloro-4-methanesulfonylbenzene and 3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: [CH2:1]([O:4][P:5]([O:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]CC1C=CC(OC)=CC=1)=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH2:8]([O:7][P:5]([O:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:9]=[CH2:10]
Reactant: C=CCOP(=O)(OCC=C)OCCCC(=O)OCc1ccc(OC)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: C=CCOP(=O)(OCC=C)OCCCC(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 4-methoxybenzyl 4-[[bis(allyloxy)phosphoryl]oxy]butyrate (700 mg, 1.82 mmol) obtained from Example 13-(1) and anisole (0.7 ml) was added trifluoroacetic acid (3 ml) at room temperature. The mixture was stirred at room temperature for 15 minutes, then diluted with toluene, and the solvent was distilled off under reduced pressure. The residue was redissolved in toluene, and the solvent was distilled off under reduced pressure to give crude 4-[[bis(allyloxy)phosphoryl]oxy]butanoic acid as a pale yellow oil.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=O)=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].Cl>N1C=CC=CC=1>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([C:19]2[O:9][C:1](=[O:10])[C:2]3[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=3[N:4]=2)=[CH:22][CH:23]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Nc1ccccc1C(=O)O
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(-c2nc3ccccc3c(=O)o2)cc1
Reaction time: 12 h
Yield: 22 %

Procedure:
To a stirred solution of anthranilic acid (34.3 g, 250 mmol) in pyridine (400 mL) was added 4-tert-butylbenzoyl chloride (94 mL, 500 mL) dropwise via an addition funnel. After stirring for 12 h, the solution was poured onto a slurry of ice and 2 N aqueous hydrochloric acid (100 mL). The mixture was extracted with dichloromethane and the organic extract was concentrated in vacuo. The residue was dissolved in fresh dichloromethane, washed once with 2 N aqueous hydrochloric acid, once with saturated aqueous sodium chloride solution, twice with saturated aqueous sodium bicarbonate solution, three times with water, dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was crystallized from ether/hexanes to give an initial crop of 15.2 g (22%) of the title compound as an off-white solid, followed by additional crops totalling 16.9 g (24%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]([CH3:15])=[CH:13][C:12](O)=[CH:11][C:10]1=[O:17].[F:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22].[Cl:28]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:28][C:11]1[C:10](=[O:17])[N:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])[C:14]([CH3:15])=[CH:13][C:12]=1[NH:22][CH2:21][C:20]1[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:19]=1[F:18]
Reactant: NCc1ccc(F)cc1F
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(O)cc(=O)n1-c1c(F)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(NCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1c(F)cccc1F
Reaction time: 1 h
Yield: 6.4 %

Procedure:
1-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.3 g, 1.26 mmol) and 2,4-difluoro benzylamine (1 mL, 84 mmol) were combined in an nitrogen flushed culture tube. The tube was capped and heated at 180 C for 24 h. The excess amine was distilled in vacuo and the residue was used without further purification. N-Chloro succinimide (168 mg, 1.26 mmol) was added to a solution of the residue in methylene chloride (10 mL). After stirring at 25 C for 1 h, the reaction mixture was poured into saturated aqueous NaHCO3. The aqueous mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica (25:75 hexanes:ethyl acetate) to give the title compound (32 mg, 6%). 1H NMR (400 MHz, CD3OD) δ 7.55 (m, 1H), 7.36 (q, J=9.2 and 15.2 Hz, 1H), 7.18 (t, J=7.6 Hz, 2H), 6.98 (m, 2H), 6.15 (s, 1H), 4.62 (s, 2H), 1.96 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ −113.78 (1F), −116.72 (1F), −121.57 (1F) ppm. ES-HRMS m/z 397.0752 (M+H calcd for C19H14ClF4N2O requires 397.0725).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.OO.S([O-])([O-])=[O:16].[Na+].[Na+]>C1COCC1>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:16]
Reactant: COc1cccc(B(O)O)c1F
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(O)c1F
Temperature: 25 °C

Procedure:
To a solution of 2-fluoro-3-methoxyphenylboronic acid (30.4 g) in THF (300 mL) was added dropwise aqueous hydrogen peroxide (100 mL, 30% wt in water), and the mixture was heated with reflux for 1 hr. The reaction mixture was allowed to be cooled to room temperature, saturated aqueous sodium sulfite was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by combi flash (petroleum ether/ethyl acetate) to give the title compound (24.8 g).
Reaction SMILES: [C:1]12[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=1[S:8][C:7]1[C:6](=[O:14])[NH:5][N:4]=[CH:3][C:2]2=1.[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20](Br)[C:17]=1[CH:18]=[O:19].N(CC(O)=O)C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([N:5]2[C:6](=[O:14])[C:7]3[S:8][C:9]4[CH2:10][CH2:11][CH2:12][CH2:13][C:1]=4[C:2]=3[CH:3]=[N:4]2)[C:17]=1[CH:18]=[O:19]
Reactant: O=Cc1c(Br)cccc1Br
Reactant: O=c1[nH]ncc2c3c(sc12)CCCC3
Agent: CNCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=Cc1c(Br)cccc1-n1ncc2c3c(sc2c1=O)CCCC3
Temperature: 100 °C
Yield: 60.1 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (20 mL), 8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-6-one 117c (618 mg, 3.0 mmol), 2,6-dibromobenzaldehyde (1980 mg, 7.5 mmol), CuBr (215 mg, 1.5 mmol), sarcosine (267 mg, 3.0 mmol), and K2CO3 (828 mg, 6.0 mmol). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 16 h. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 130a (702 mg, 60%) as a yellow solid. MS: [M+H]+ 389.0
Reaction SMILES: Cl.[NH:2]=[C:3]([NH2:5])[CH3:4].[Cl:6][C:7]1[N:12]=[C:11]([C:13](Cl)(Cl)[S:14]Cl)[CH:10]=[CH:9][N:8]=1.[OH-].[Na+].O>C(Cl)Cl>[Cl:6][C:7]1[N:12]=[C:11]([C:13]2[S:14][N:5]=[C:3]([CH3:4])[N:2]=2)[CH:10]=[CH:9][N:8]=1
Reactant: CC(=N)N
Reactant: ClSC(Cl)(Cl)c1ccnc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1nsc(-c2ccnc(Cl)n2)n1
Temperature: 5 °C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
1-Imino-ethanamine hydrochloride (1:1) (0.08 mol) was added at 0° C. to a stirring mixture of intermediate 1 (0.07 mol) in DCM (300 ml). Sodium hydroxide (50%, 20 ml) was added dropwise at 0° C. The mixture was stirred at 5° C. for 1 hour. Water (300 ml) and DCM (300 ml) were added. The mixture was separated into its layers. The aqueous layer was washed twice with DCM. The combined organic layer was dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: DCM). Two pure fractions were collected and their solvents were evaporated, yielding 3.5 g of 2-chloro-4-(3-methyl-1,2,4-thiadiazol-5-yl)pyrimidine (intermediate 2).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]([O:10][CH3:11])=[O:9].[C:12]([O:16][C:17](=[O:30])[C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23](=[O:29])[C@H:24]([CH:26]([CH3:28])[CH3:27])[NH2:25])([CH3:15])([CH3:14])[CH3:13]>O.O1CCCC1.CCOCC>[C:12]([O:16][C:17](=[O:30])[C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23](=[O:29])[C@H:24]([CH:26]([CH3:27])[CH3:28])[NH:25][C:8]([O:10][CH3:11])=[O:9])([CH3:14])([CH3:13])[CH3:15]
Reactant: COC(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(C)C
Temperature: 0 °C

Procedure:
A solution of sodium carbonate (110.5 g) in water (1.5 liters) and L-Valyl-L-Proline tert-butyl ester in tetrahydrofuran (THF; 1 liter) were combined and cooled to 0° C. The mixture was diluted with ether (400 ml) and methyl chloroformate (39.4 g) was added dropwise. The reaction mixture was then allowed to warm ambient temperature over 2 hours. The layers were separated and the organic phase was washed twice with 1M hydrochloric acid, followed by saturated aqueous sodium bicarbonate solution and brine. The aqueous phase was extracted with ether. All organic phases were combined and dried (MgSO4) and the solvent removed to give N-(methoxycarbonyl)-L-valyl-L-proline tert-butyl ester (125.9 g); 1H NMR (300 MHz, DMSO/d4-trifluoroacetic acid): 4.23 (dd, 1H), 4.06 (d, 1H), 3.78 (m, 1H), 3.57 (m, 1H), 3.55 (s, 3H), 2.16 (m, 1H), 1.95 (m, 3H), 1.80 (m, 1H), 1.42 (s, 9H), 0.94 (m, 6H); MS: m/z=329 (M+1).
Reaction SMILES: [CH3:1][C:2](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:3].[Cl:25][C:26]1[N:30]2[N:31]=[C:32]([NH2:35])[CH:33]=[CH:34][C:29]2=[N:28][N:27]=1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[Cl:25][C:26]1[N:30]2[N:31]=[C:32]([NH:35][C:2](=[O:3])[CH3:1])[CH:33]=[CH:34][C:29]2=[N:28][N:27]=1
Reactant: Nc1ccc2nnc(Cl)n2n1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2nnc(Cl)n2n1
Reaction time: 6 h

Procedure:
0.11 cm3 of acetic anhyhdride is added to a mixture of 202 mg of 3-chloro[1,2,4]triazolo[4,3-b]pyridazin-6-amine in 5 cm3 of pyridine at 0° C. The temperature is allowed to rise to 20° C. over 6 h, then 0.05 cm3 of acetic anhydride is again added and stirring is maintained for 24 h. The precipitate formed is spin-filter-dried and then washed with ethyl ether and pentane. This solid is purified by chromatography on Biotage Quad 12/25 (KP-SIL, 60 A; 32-63 μM), elution being carried out with a gradient of dichloromethane/methanol of 100/0 to 90/10. 41 mg of N-(3-chloro[1,2,4]triazolo[4,3-b]pyridazin-6-yl)acetamide are thus obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[O:13])[CH3:12])=[C:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:20]=O.Cl.[CH3:23][NH:24][CH3:25]>C(O)C>[CH3:23][N:24]([CH3:20])[CH2:25][CH2:12][C:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: C=O
Reactant: CC(=O)c1c(-c2ccccc2)n(C)c2ccccc12
Reactant: CNC
Agent: Cl
Solvent: CCO
Product: CN(C)CCC(=O)c1c(-c2ccccc2)n(C)c2ccccc12
Yield: 81.1 %

Procedure:
A mixture of 1-(1-methyl-2-phenyl-1H-indol-3-yl)-1-ethanone (1.0 g), paraformaldehyde (191 mg) and dimethylamine hydrochloride (347 mg) in ethanol (15 ml) was stirred and heated at reflux for 30 h. The mixture was then evaporated and the residue was treated with water (150 ml) and then filtered. The filtrate was brought to pH 10 with 0.88 ammonia solution and the suspension obtained was extracted with ethyl acetate (2×125 ml). The combined organic extracts were washed with water (50 ml), dried and evaporated to leave an oil (997 mg) which was purified by column chromatography eluting with methanol to give an oil (0.50 g). This was dissolved in ether (50 ml) and extracted with 0.5M hydrochloric acid (2×50 ml). The combined acidic extracts were brought to pH 10 with 0.88 ammonia solution and the resulting precipitate was extracted with ethyl acetate (2×70 ml). The combined organic extracts were washed with water (40 ml), dried and evaporated to leave an oil (0.444 g) which was purified by preparative t.l.c. eluting with methanol to give the title compound (0.30 g) as an oil, which was crystallised from light petroleum, m.p. 55°-57°.
Reaction SMILES: [CH2:1]=O.[CH3:3][NH:4][CH3:5].[CH3:6][O:7][C:8]1[CH:25]=[CH:24][CH:23]=[CH:22][C:9]=1[CH2:10][O:11][C:12]1[C:13]2[N:14]([CH:18]=[C:19]([CH3:21])[N:20]=2)[CH:15]=[CH:16][CH:17]=1>C(O)(=O)C>[CH3:3][N:4]([CH2:1][C:18]1[N:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:10][C:9]3[CH:22]=[CH:23][CH:24]=[CH:25][C:8]=3[O:7][CH3:6])[C:13]2=[N:20][C:19]=1[CH3:21])[CH3:5]
Reactant: CNC
Reactant: C=O
Reactant: COc1ccccc1COc1cccn2cc(C)nc12
Solvent: CC(=O)O
Product: COc1ccccc1COc1cccn2c(CN(C)C)c(C)nc12
Reaction time: 0.17 h
Yield: 59 %

Procedure:
To a solution of 37% aqueous formaldehyde (1.57 g) in acetic acid (25 ml) was added dropwise 50% aqueous dimethylamine (1.75 g) with ice-cooling over a period of 10 minutes and the mixture was stirred for an additional 10 minutes. The mixture was heated at 50°-55° C. for 2 hours after an addition of 8-(2-methoxybenzyloxy)-2-methylimidazo[1,2-a]pyridine (4.96 g) thereto and then evaporated in vacuo. The residue was basified with aqueous sodium hydroxide and extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residual solid was recrystallized from diethyl ether to give 3-dimethylaminomethyl-8-(2-methoxybenzyloxy)-2-methylimidazo[1,2-a]pyridine (3.55 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH2:11])=[N:6][CH:5]=1.[C:13]([O:17][C:18](=[O:40])[NH:19][C:20]1([C:24]2[CH:29]=[CH:28][C:27]([C:30](=O)[CH:31](Br)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14]>C(O)(C)C.C(Cl)Cl.O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]2[N:6]([C:31]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[C:30]([C:27]3[CH:26]=[CH:25][C:24]([C:20]4([NH:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:40])[CH2:23][CH2:22][CH2:21]4)=[CH:29][CH:28]=3)[N:11]=2)[CH:5]=1)=[O:12].[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH2:11])=[N:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Agent: COC(=O)c1cnc(N)c(Cl)c1
Solvent: CC(C)O
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1

Procedure:
A mixture of 6-amino-5-chloronicotinic acid methyl ester (0.588 g, 3.15 mmol), {1-[4-(2-bromo-2-phenyl-acetyl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester [Int-1-A] (2.00 g, 70% purity by UPLC-MS, 3.15 mmol) and powdered activated 3 Å molecular sieves in isopropanol (9.7 mL) was heated at reflux for 20 hours. On cooling, the mixture was diluted with DCM and water, filtered through Celite and the organic extract washed with brine, dried and concentrated in vacuo. Purification was achieved by chromatography on silica gel (gradient elution: hexane-hexane/ethyl acetate 1:1) to give the title compound contaminated with 6-amino-5-chloronicotinic acid methyl ester. Further purification was achieved by acid extraction of a solution of the crude product in ethyl acetate with dilute aqueous hydrochloric acid (1 M). The organic extract was washed with brine, dried and concentrated in vacuo to give the title compound;
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:12])[CH3:11])=[N:2]1.C(N(CC)CC)C.[C:20](Cl)(=[O:23])[O:21][CH3:22]>C(Cl)(Cl)Cl>[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([C:20]([O:21][CH3:22])=[O:23])[N:2]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1n[nH]c2ccccc12
Reactant: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)n1nc(C(C)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 1-(1H-indazol-3-yl)ethanone (5.0 g) and triethylamine (6.53 mL) in chloroform (80 mL) was added dropwise a solution of methyl chlorocarbonate (3.24 g) in chloroform (20 mL) under ice-cooling over 1 hour, and the mixture was stirred at room temperature for 14 hours. The reaction solution was washed with aqueous saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated tinder reduced pressure. The resulting residue was triturated with n-hexane to give methyl 3-acetyl-1H-indazole-1-carboxylate) [REx(101-1)] (6.67 g) as a colorless powder.