Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]([C:16]2[C:21]3[N:22]([CH:25]([C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[CH3:26])[CH:23]=[N:24][C:20]=3[CH:19]=[C:18]([C:34]#[N:35])[N:17]=2)[CH:13]=[N:14][CH:15]=1>C(Cl)(Cl)Cl.ClCCl>[Br:1][C:23]1[N:22]([CH:25]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]2)[CH3:26])[C:21]2[C:16]([C:12]3[CH:13]=[N:14][CH:15]=[C:10]([Cl:9])[CH:11]=3)=[N:17][C:18]([C:34]#[N:35])=[CH:19][C:20]=2[N:24]=1
Reactant: CC([C@H]1CC[C@H](C)CC1)n1cnc2cc(C#N)nc(-c3cncc(Cl)c3)c21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC([C@H]1CC[C@H](C)CC1)n1c(Br)nc2cc(C#N)nc(-c3cncc(Cl)c3)c21
Temperature: 25 °C

Procedure:
N-bromosuccinimide (4.07 g, 22.9 mmol) was added to a room temperature solution of racemic 4-(5-chloropyridin-3-yl)-3-[1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (4.14 g, 7.63 mmol) stirring in degassed chloroform (38 mL). The reaction was heated to reflux for 1.5 hours. The mixture was cooled to room temperature, diluted with dichloromethane, and washed with saturated aqueous sodium thiosulfate (2×) and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-80% ethyl acetate/hexanes, linear gradient) to afford racemic 2-bromo-4-(5-chloropyridin-3-yl)-3-[1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. The racemic material was then purified by chiral supercritical fluid chromatography (Chiralpak IB, 21×250 mm, 25% methanol in CO2) to afford 2-bromo-4-(5-chloropyridin-3-yl)-3-[(1S)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile and 2-bromo-4-(5-chloropyridin-3-yl)-3-[(1R)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. Faster eluting enantiomer 1: MS ESI calc'd. for C21H21BrClN5 [M+H]+ 458. found 458. Slower eluting enantiomer 2: MS ESI calc'd. for C21H21BrClN5 [M+H]+ 458. found 458.
Reaction SMILES: I[CH2:2][CH3:3].[F:4][CH2:5][CH2:6][O:7][C:8]1[C:16]([O:17][CH2:18][CH2:19][F:20])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)C>[F:4][CH2:5][CH2:6][O:7][C:8]1[C:16]([O:17][CH2:18][CH2:19][F:20])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([O:12][CH2:2][CH3:3])=[O:11]
Reactant: O=C(O)c1cccc(OCCF)c1OCCF
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: CCOC(=O)c1cccc(OCCF)c1OCCF
Temperature: 25 °C
Yield: 89.3 %

Procedure:
Under a dry nitrogen atmosphere 0.91 gram (0.0058 mole) of iodoethane was added dropwise to a stirred mixture of 1.2 gram (0.0049 mole) of 2,3-di(2-fluoroethoxy)benzoic acid (Compound 105) and 1.4 grams (0.0097 mole) of potassium carbonate in 40 ml of acetone. The reaction mixture was heated at reflux for 24 hours and then was allowed to cool to room temperature. The solvent was evaporated under reduced pressure leaving a residue. This residue was dissolved in diethyl ether, and the solution was washed with water followed by an aqueous, saturated sodium chloride solution. The washed organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 1.2 gram of ethyl 2,3-di(2-fluoroethoxy)benzoate as an oil, Compound 107 of Table 1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl-].[CH2:16]([N:18]([CH2:22][CH3:23])[C:19](=[O:21])C)[CH3:17]>CN(C=O)C>[CH2:16]([N:18]([CH2:22][CH3:23])[C:19]([N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)=[O:21])[CH3:17]
Reactant: CCN(CC)C(C)=O
Reactant: O=C1CCNCC1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)N1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of piperidin-4-one in DMF was added triethylamine (1.5 eq.) and N,N-diethylacetamide chloride (1.5 eq.). The resulting solution was stirred at room temperature for 5 hours or until completion observed by TLC. The solvent was evaporated and the residue was partitioned in H2O and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by a CombiFlash chromatography system using silica gel cartridge and CH2Cl2/MeOH gradient eluent to afford 4-oxo-piperidine-1-carboxylic acid diethylamide, which was subsequently reacted with 3-hydroxybenzaldehyde (2.5 eq.) in acetic acid (99.7%) and purged with HCl gas (0.5-1 h). After stirring at room temperature for 3 hours, the solvent was evaporated and the crude was purified by a Combiflash chromatography system with hexanes/EtOAc as eluent, followed by crystallization from MeOH, to afford Compound 12 as a yellow crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([O:11][C:12](=[O:27])[NH:13][C:14]1[C:15]([CH3:26])=[N:16][O:17][C:18]=1[C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)[CH3:10].[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:22]2[CH:23]=[CH:24][C:19]([C:18]3[O:17][N:16]=[C:15]([CH3:26])[C:14]=3[NH:13][C:12]([O:11][CH:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH3:10])=[O:27])=[CH:20][CH:21]=2)=[CH:35][CH:34]=1)[CH3:29]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)c1ccc(F)cc1F
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccc(F)cc3F)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-(2,4-difluoro-phenyl)-ethyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide (4′-{4-[1-(2,4-Difluoro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 34, Step 2.
Reaction SMILES: [C:1]1([CH2:6]Br)[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:8][C:9]1[O:14][CH2:13][N:12]([C:15]([CH3:19])([CH3:18])[CH:16]=[O:17])[C:11](=[O:20])[C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C.Cl>O1CCCC1.[Zn]>[CH3:8][C:9]1[O:14][CH2:13][N:12]([C:15]([CH3:18])([CH3:19])[CH:16]([CH:2]2[CH2:3][CH2:4][CH2:5][C:1]2=[CH2:6])[OH:17])[C:11](=[O:20])[C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCC1=CCCC1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C=O)CO1
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C1CCCC1C(O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Temperature: 53 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A solution of (cyclopent-1-enyl)methylbromide (3.8 g) in tetrahydrofuran was added to a stirred mixture of 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropionaldehyde (3.5 g) and zinc powder(1.6 g) in tetrahydrofuran at 20° C. under an inert atmosphere. The temperature increased to 53° C. slowly and after 2 hours, ethyl acetate and hydrochloric acid (1N) were added and the organic phase washed with brine, dried (magnesium sulphate), evaporated and purified by silica gel column chromatography, eluting with n-hexane/ethyl acetate (2:1) to give 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methyl-1-(2-methylenecyclopentyl)propan-1-ol (3.66 g), NMR: 1.46(s,3H), 1.61(s,3H), 1.88(s,3H), 1.5-1.9(4H), 2.24(2H), 2.50(1H), 3.24(d,1H), 3.80(s,1H), 4.93(s,1H), 5.06(s,1H), 5.19(d,1H), 5.26(d,1H), 7.22-7.38(5H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](=[S:5])[NH2:4].CC(O)(C)C.Cl[CH:14]([C:20](=O)[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>CCOC(C)=O>[CH3:21][C:20]1[N:4]=[C:3]([C:2]([F:7])([F:6])[F:1])[S:5][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: NC(=S)C(F)(F)F
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(C(F)(F)F)nc1C

Procedure:
To a mixture of 2,2,2-trifluoroethanethioamide (200 mg) and t-BuOH (10 mL) was added ethyl 2-chloro-3-oxobutanoate (0.217 mL) at room temperature. The mixture was refluxed for 2 days. After cooling, EtOAc was poured into the mixture, and the mixture was washed successively with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane) to give the title compound (133 mg).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([N:12]2[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[NH:14][C:13]2=[O:20])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].[CH3:25]I>CN(C)C=O>[N+:9]([C:8]1[CH:7]=[CH:6][C:5]([N:12]2[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[N:14]([CH3:25])[C:13]2=[O:20])=[CH:4][C:3]=1[C:2]([F:1])([F:21])[F:22])([O-:11])=[O:10]
Reactant: CI
Reactant: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)C1(C)C
Reaction time: 0.25 h

Procedure:
A solution of 3.17 g of 1-(3-trifluoromethyl-4-nitrophenyl)-4,4-dimethyl-imidazoline-2,5-dione (French Patent No. 2,329,276) and 32 ml of dimethylformamide were added at 23° C. to 26° C. to a 50% suspension of 492 mg of sodium hydride in oil and 3 ml of dimethylformamide and after stirring for 15 minutes, a solution of 0.7 ml of methyl iodide in 2 ml of dimethylformamide was added. The mixture was stirred for 25 minutes at 24° C. to 28° C. and was then poured into 200 g of a 1--1 water-ice mixture. The mixture was extracted with ether and the organic phase was washed with saturated aqueous sodium chloride, dried, filtered and evaporated to dryness under reduced pressure to obtain 3.6 g of the desired product melting at 116° C. An analytical sample was crystallized from isopropyl alcohol to obtain 2.73 g of the product melting at 116° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH:12]([CH3:16])[C:13](O)=[O:14])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.Cl.C([N:20]=C=NCCCN(C)C)C.CN(C=O)C>O>[NH2:20][C:13](=[O:14])[CH:12]([CH3:16])[O:11][C:3]1[C:2]([Br:1])=[CH:6][S:5][C:4]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCN=C=NCCCN(C)C
Reactant: COC(=O)c1scc(Br)c1OC(C)C(=O)O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1scc(Br)c1OC(C)C(N)=O
Yield: 88.9 %

Procedure:
A solution of 2-{[4-bromo-2-(methoxycarbonyl)thiophen-3-yl]oxy}propanoic acid (220 mg), 1H-benzotriazol-1-ol 1 ammonium salt (162 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (205 mg) and DMF (4 mL) was stirred at room temperature for 1.5 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of Et2O and hexane to give the title compound (195 mg, 89%) as colorless crystals.
Reaction SMILES: CS(Cl)(=O)=O.O[C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH3:21])[C:12]3[C:17]([S:18][C:19]=2[CH:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3.C(N(CC)CC)C.[Cl:29][CH2:30]Cl>O>[Cl:29][CH2:30][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH3:21])[C:12]3[C:17]([S:18][C:19]=2[CH:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: CN1c2ccccc2Sc2cc(O)ccc21
Reactant: ClCCl
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CN1c2ccccc2Sc2cc(CCl)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
With ice-cooling, methanesulfonyl chloride (3.9 ml, 50 mmol) was added dropwise to a mixture of 3-hydroxy-10-methylphenothiazine (10.9 g, 45 mmol), triethylamine (8.2 ml, 59 mmol) and dichloromethane (80 ml), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and the reaction product was extracted with chloroform. The extract was washed with a saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in that order, dried over anhydrous magnesium sulfate, and concentrated under a reduced pressure to give the title compound (8.09 g, 30.9 mmol, 69%) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[CH2:17]([O:19][C:20](=[O:32])[CH2:21][CH2:22][CH2:23][C:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=O)[CH3:18].C1([SiH3])C=CC=CC=1.C([Sn](Cl)(Cl)CCCC)CCC>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][CH:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:23][CH2:22][CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:32])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Reactant: CCOC(=O)CCCC(=O)C1CCCCC1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)CCCC(Nc1cc(-c2ccccc2)sc1C(=O)OC)C1CCCCC1
Temperature: 120 °C
Yield: 15.4 %

Procedure:
A flask was charged with 3-amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (515 mg, 2.2 mmol, 1.0 equiv), 5-cyclohexyl-5-oxo-pentanoic acid ethyl ester (500 mg, 2.2 mmol, 1.0 equiv), phenyl silane (240 mg, 2.2 mmol, 1.0 equiv), dibutyltin dichloride (67 mg, 0.22 mmol, 0.1 equiv) and dioxane (2.0 mL). The resulting solution was heated at 120° C. with microwave for 2 hours. The solution was then concentrated and the residue was purified by silica gel column chromatography, EtOAc/heptane 5% to 40%, to give oil that contained starting material. The material was further purified with silica gel column chromotography, EtOH/DCM 2% to 10% to give product 150 mg (yield 15%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)COB([C:35]2[CH:36]=[CH:37][C:38]([NH:42]C(=O)OC(C)(C)C)=[N:39][C:40]=2[CH3:41])OC1>>[CH3:41][C:40]1[N:39]=[C:38]([NH2:42])[CH:37]=[CH:36][C:35]=1[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)ccc1B1OCC(C)(C)CO1
Product: Cc1nc(N)ccc1-c1nc(N2CCOCC2)c2sc(CN3CCN(S(C)(=O)=O)CC3)cc2n1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with tert-butyl 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-methylpyridin-2-ylcarbamate via General Procedure A. Purification on silica yielded 258. NMR (CDCl3): 2.60-2.63 (m, 4H, 2×CH2), 2.65 (s, 3H, CH3), 2.74 (s, 3H, CH3), 3.22-3.24 (m, 4H, 2×CH2), 3.78-3.81 (m, 6H, 3×CH2), 3.91-3.94 (m, 4H, 2×CH2), 4.43 (s, 2H, NH2), 6.36 (d, H, ArH, J=8.38 Hz), 7.22 (s, H, ArH), 7.98 (d, H, ArH, J=8.41 Hz). MS: (ESI+): MH+ 504.22
Reaction SMILES: [CH:1]1([C:6]2[CH:18]=[CH:17][C:9]([C:10]([CH2:12][CH2:13][C:14](O)=[O:15])=O)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:20][NH2:21]>C(O)C>[CH:1]1([C:6]2[CH:18]=[CH:17][C:9]([C:10]3[CH2:12][CH2:13][C:14](=[O:15])[NH:20][N:21]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCC(=O)c1ccc(C2CCCC2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C1CCC(c2ccc(C3CCCC3)cc2)=NN1

Procedure:
A solution of 3-(p-cyclopentylbenzoyl)propionic acid (4.9 g.) in warm ethanol (50 ml.) was treated with hydrazine hydrate (1.1 g.) and the mixture heated on the steam bath for 1 hour. The colourless crystalline material which separated, was collected and recrystallised from ethanol to yield the product (4.2 g.) in large, colourless needles, m.p. 191°-192° C.
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].[ClH:10].[CH3:11][CH:12]1OC(C)OC(C)O1>C(O)C(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[ClH:10].[NH2:8][C:7]1[NH:6][C:4]([N:2]([CH3:3])[CH3:1])=[N:5][CH:11]([CH3:12])[N:9]=1
Reactant: CC1OC(C)OC(C)O1
Reactant: CN(C)C(=N)N=C(N)N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CC(C)CO
Product: CC1N=C(N)NC(N(C)C)=N1
Temperature: 12 °C
Yield: 183.1 %

Procedure:
Synthesis according to the invention: A mixture of 1002.6 g of metformin hydrochloride, 359.1 g of paraldehyde and 51.6 g of toluene-4-sulfonic acid monohydrate in 2405.9 g of isobutanol was heated under reflux for 6 hours. Some of the solvent was removed by distillation. The mixture was cooled to 12° C., and the white precipitate was separated off, giving 953.8 g (81.4%) of 4-amino-3,6-dihydro-2-dimethylamino-6-methyl-1,3,5-triazine hydrochloride.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[C:20](Cl)=[O:21]>>[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[C:20]([O:9][CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:21]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: OCCN1CCOCC1
Product: O=C(OCCN1CCOCC1)c1ccc2ccccc2c1
Yield: 95 %

Procedure:
The procedure of Synthesis Example 1 was repeated except that 2-morpholinoethanol was used instead of the triethanolamine, and 2-naphthoyl chloride was used instead of the benzoyl chloride, to give 2-morpholinoethyl 2-naphthalenecarboxylate in a yield of 95%.
Reaction SMILES: CN(C=O)C.[OH:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[H-].[Na+].Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][N:18]=1>O>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:18][CH:19]=1
Reactant: OCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(OCCN2CCCC2)nc1
Reaction time: 1 h

Procedure:
To a stirred DMF solution (25 mL) containing N-(2-hydroxyethyl)pyrrolidine (2.18 g, 18.9 mmol) under N2 was added 60% NaH in mineral oil (0.76 g, 18.9 mmol). The mixture was stirred for 1 hr while gas evolution ceased. Subsequently 2-chloro-5-nitropyridine (2.0 g, 12.6 mmol) was added. After stirring overnight, the dark solution was poured into H2O (100 mL) and extracted 3× with EtOAc. The combined organic layers were washed 2× with H2O prior to drying over Na2SO4. Concentration under vacuum yielded an orange oil which was chromatographed on silica gel employing ˜10% MeOH/CH2Cl2 to elute 1.62 g of 5-nitro-2-(pyrrolidin-1-yl)-ethoxy)pyridine (54%). The above product reduced to the corresponding substituted aminopyridine by hydrogenation in an EtOH solution (20 mL) containing 10% Pd/C (0.1 g) under 60 psi of H2 for 4 hr. Upon completion the reaction was filtered prior to concentration under vacuum. The resulting dark oil was chromatographed on silica. Gradient elution (CH2CL2 to 20% MeOH/CH2Cl2) eluted 1.03 g of the title compound as a broad peak.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH:8]=[N:9][NH:10][C:5]2=[C:4]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)[CH:3]=1.Cl.CS(C)=O.[CH2:26](O)[CH3:27]>>[C:16]([C:15]1[CH:19]=[CH:20][C:12]([NH:11][C:4]2[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]3[CH:8]=[N:9][NH:10][C:5]=23)=[CH:13][CH:14]=1)([O:18][CH2:26][CH3:27])=[O:17]
Reactant: CCO
Reactant: Cc1cc(Nc2ccc(C(=O)O)cc2)c2[nH]ncc2n1
Agent: Cl
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(Nc2cc(C)nc3cn[nH]c23)cc1

Procedure:
The carboxylic acid (E2) of Example 2 (0.5 g, 0.0019 mole) was heated at reflux in ethanol (25 ml) to which several drops of a saturated ethanol solution of hydrogen chloride had been added. Dimethyl sulphoxide (5.5 ml) was added after 11/2 h to aid solution and heating continued for a further 71/4 h. The solution was filtered and solvent removed under reduced pressure. Ether and a small amount of ethyl acetate were added and the resulting yellow solid (518 mg, 94%) collected, m.p. 247°-250° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:16]([OH:18])=O)=[N:7][N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:9]=1)=[O:4].[C:19](N1C=CN=C1)([N:21]1C=CN=[CH:22]1)=O.CNC>CN(C=O)C>[CH3:19][N:21]([CH3:22])[C:16]([C:6]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:9][N:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:7]=1)=[O:18]
Reactant: COC(=O)c1nn(-c2ccccc2)nc1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: CN(C)C=O
Product: COC(=O)c1nn(-c2ccccc2)nc1C(=O)N(C)C
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
A solution of 5-methoxycarbonyl-2-phenyl-2H-1,2,3-triazole-4-carboxylic acid (0.203 g, 0.82 mmol) in dry DMF (3 mL) at 23° C. was treated with carbonyldiimidazole (0.146 g, 0.90 mmol). The resulting mixture was stirred for 1.5 h at 23° C., cooled to 0° C. and treated with dimethylamine (2.0 M, in THF, 2.05 mL, 4.10 mmol). The resulting mixture was allowed to warm to 23° C. over 16 h and concentrated in vacuo. The residue was partitioned between water and EtOAc. The aqueous layer was extracted with an additional portion of EtOAc. The combined organic extracts were washed with HCl (1 M), brine, NaHCO3 (sat. aq. sol.) and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by filtering it through a silica gel plug (EtOAc-hexanes 50:50) to afford 0.201 g (89%) of methyl 5-(N,N-dimethylcarbamoyl)-2-phenyl-2H-1,2,3-triazole-4-carboxylate.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:31]=[C:30]([F:32])[C:7]([O:8][C:9]([C:12]2[N:13]([CH:27]([CH3:29])[CH3:28])[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[NH:21][CH2:20]4)=[N:15][N:16]=2)([CH3:11])[CH3:10])=[C:6]([F:33])[CH:5]=1.I[CH3:35]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([F:33])[C:7]([O:8][C:9]([C:12]2[N:13]([CH:27]([CH3:29])[CH3:28])[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([CH3:35])[CH2:20]4)=[N:15][N:16]=2)([CH3:10])[CH3:11])=[C:30]([F:32])[CH:31]=1
Reactant: CI
Reactant: CC(C)n1c(-c2ccc3c(c2)CNC3=O)nnc1C(C)(C)Oc1c(F)cc(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c(-c2ccc3c(c2)CN(C)C3=O)nnc1C(C)(C)Oc1c(F)cc(Cl)cc1F
Reaction time: 1 h

Procedure:
Sodium hydride (55% mineral oil, 30 mg) was added to a mixture of 5-{5-[1-(4-chloro-2,6-difluorophenoxy)-1-methylethyl]-4-isopropyl-4H-1,2,4-triazol-3-yl}isoindolin-1-one (200 mg) and DMF (5 ml) under ice cooling, followed by stirring for one hour, iodomethane (0.084 ml) was added thereto, followed by stirring for one hour, while slowly elevating to room temperature. The reaction solution was concentrated, water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate and the solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 90:10) and then was solidified from ethyl acetate-diisopropylether, and the solid was collected by filtration, washed with diisopropylether and then dried under reduced pressure to obtain 5-{5-[1-(4-chloro-2,6-difluorophenoxy)-1-methylethyl]-4-isopropyl-4H-1,2,4-triazol-3-yl}-2-methylisoindolin-1-one (111 mg) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1)=O.C(O)=O.C([NH2:16])=O>>[Br:10][C:6]1[CH:5]=[C:4]([CH:2]([NH2:16])[CH3:1])[CH:9]=[CH:8][CH:7]=1
Reactant: NC=O
Reactant: CC(=O)c1cccc(Br)c1
Solvent: O=CO
Product: CC(N)c1cccc(Br)c1
Temperature: 172.5 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
A mixture of 3-bromoacetophenone (10.0 g, 50 mmol), formic acid (12.0 g, 250 mmol) and formamide (50 mL) was heated at 165-180° C. with stirring for 24 h. The reaction mixture was cooled to room temperature and extracted with toluene; the extract was concentrated in vacuo. The residue was mixed with 3N hydrochloric acid (20 mL) and heated at reflux for 48 h, cooled to room temperature, washed with ether and neutralized with 20% aqueous NaOH solution. The neutralized solution was extracted with ether; the extract was dried over solid KOH and concentrated in vacuo to provide the title compounds as a light brown oil (5.7 g, 57%). 1H NMR (400 MHz, CDCl3): δ 7.53 (s, 1H), 7.37 (d, 1H), 7.29 (d, 1H), 7.21 (t, 1H), 4.14 (br d, 3H), 1.39 (d, 3H). MS (ESI) m/z: Calculated: 199; Observed: 200 (M+H+).