Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1([O:7][CH2:8][C@H:9]([OH:20])[C:10]([NH:12][C:13]2[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4]1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]2[N:28]([C:31]3[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][C:34]([Cl:41])=[CH:33][N:32]=3)[N:29]=[CH:30][C:23]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:41][C:34]1[CH:35]=[C:36]([C:37]([F:40])([F:38])[F:39])[C:31]([N:28]2[C:24]3[N:25]=[CH:26][N:27]=[C:22]([O:20][C@@H:9]([CH2:8][O:7][CH:3]4[CH2:6][CH2:5][CH2:4]4)[C:10]([NH:12][C:13]4[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=4)=[O:11])[C:23]=3[CH:30]=[N:29]2)=[N:32][CH:33]=1
Reactant: Cc1cnc(NC(=O)[C@@H](O)COC2CCC2)cn1
Reactant: FC(F)(F)c1cc(Cl)cnc1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)[C@H](COC2CCC2)Oc2ncnc3c2cnn3-c2ncc(Cl)cc2C(F)(F)F)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.2 %

Procedure:
60% Sodium hydride in mineral oil (60 mg, 1.50 mmol) was added in one portion to (S)-3-cyclobutoxy-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate R1) (251 mg, 1.00 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes and then 4-chloro-1-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate K3) (334 mg, 1.00 mmol) as suspension in dry THF (2.5 mL) added dropwise over 1 minute. The mixture was stirred at 0° C. for 15 mins, allowed to warm to ambient temperature and stirred for 6 hours. 1M Citric acid (10 mL) was added and the mixture extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with water (25 mL) and brine (25 mL), dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, eluting with 50 to 100% ethyl acetate in isohexane to give the product (550 mg, 100%). 1H NMR (400 MHz, CDCl3) δ 1.46-1.54 (1H, m), 1.66-1.74 (1H, m), 1.89-2.01 (2H, m), 2.18-2.25 (2H, m), 2.54 (3H, s), 3.98-4.08 (3H, m), 6.04 (1H, t), 8.12 (1H, d), 8.25 (1H, d), 8.43 (1H, s), 8.62 (1H, s), 8.63-8.65 (1H, m), 8.82 (1H, d), 9.44 (1H, d); m/z (ESI+) (M+H)+=549; HPLC tR=2.56 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH3:17])[O:13][CH:12]([CH2:14][O:15][CH3:16])[CH2:11][O:10]1.[Br:18]Br>BrBr.ClC(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:17][Br:18])[O:13][CH:12]([CH2:14][O:15][CH3:16])[CH2:11][O:10]1
Reactant: BrBr
Reactant: COCC1COC(C)(c2ccc(Cl)cc2Cl)O1
Solvent: ClC(Cl)(Cl)Cl
Product: COCC1COC(CBr)(c2ccc(Cl)cc2Cl)O1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To 100 parts of 2-(2,4-dichlorophenyl)-2-methyl-4-(methoxymethyl)-1,3-dioxolane in 480 parts of tetrachloromethane are added at 45° C. a few drops of bromine till the reaction starts. Subsequently 19.6 parts of bromine are added dropwise and the whole is stirred for 2 hours at 20° C. The pale yellow solution is washed with a sodium hydrogen carbonate solution, dried and evaporated. A high vacuum distillation yields 65 parts of pure 2-(2,4-dichlorophenyl)-2-(bromomethyl)-4-(methoxymethyl)-1,3-dioxolane; bp. 129°-132° C. at 0.01 mm. pressure.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]([CH2:14][C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([Cl:24])[CH:22]=3)[N:17]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:16]=2)=[C:11]([Cl:13])[N:12]=1)(C)(C)C.Cl>ClCCl>[C:28]1([S:25]([N:17]2[C:18]3=[N:19][CH:20]=[C:21]([Cl:24])[CH:22]=[C:23]3[C:15]([CH2:14][C:10]3[S:9][C:8]([NH2:7])=[N:12][C:11]=3[Cl:13])=[CH:16]2)(=[O:27])=[O:26])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(Cl)c(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)s1
Agent: Cl
Solvent: ClCCl
Product: Nc1nc(Cl)c(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.3 %

Procedure:
To [5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-yl]-carbamic acid tert-butyl ester (591, 4.30 g, 7.97 mmol) in dichloromethane (70.0 mL) was added a solution of hydrogen chloride (4.00M in 1,4-dioxane, 42.0 mL). The reaction was stirred at room temperature for 2 days, then concentrated, and triturated with ethyl ether and ethyl acetate to give the desired compound (592, 2.60 g, 74.2%). MS (ESI) [M+H+]+=439.0.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14](OC)=[O:15])=[CH:10][C:9]=2[OH:18])[N:3]=1.[BH4-].[Li+].O>O1CCCC1>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][C:9]=2[OH:18])[N:3]=1
Reactant: COC(=O)c1ccc(-n2nc(C)cc2C)c(O)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)n(-c2ccc(CO)cc2O)n1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 10.6 %

Procedure:
132 mg of methyl 4-(3,5-dimethyl-1H-pyrazol-yl)-3-hydroxybenzene carboxylate was dissolved in 2.6 ml of tetrahydrofuran, and 58 mg of lithium borohydride was added and stirred at 50° C. for 3.5 hours. To the reaction mixture was added 20 ml of water, and extracted with 20 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and purified using preparative thin-layer silica gel column chromatography (hexane:ethyl acetate=1:2) to yield 12.4 mg of the title compound.
Reaction SMILES: [I:1]I.[CH3:3][S:4]([C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)(=[O:6])=[O:5]>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[I:1][C:12]1[CH:13]=[C:7]([S:4]([CH3:3])(=[O:5])=[O:6])[CH:8]=[CH:9][C:10]=1[NH2:11]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(N)c(I)c1
Reaction time: 8 h
Yield: 63.8 %

Procedure:
To a solution of iodine (20.8 g, 81.8 mmol) and silver sulfate (25.5 g, 81.8 mmol) in ethanol (1 L) was added 4-(methylsulfonyl)aniline (14 g, 81.8 mmol). After stirring overnight, the solution was filtered. The precipitate was then suspended in THF and stirred for 48 h, then filtered again and the filtrate was concentrated in vacuo to give 15.5 g (64%) of tan solid. The original filtrate was also concentrated in vacuo and then suspended in ethanol with stirring, then filtered and dried in vacuo to give another 7.92 g (33%) of tan solid.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][S:7]([N:10]1[CH2:15][CH2:14][CH2:13][S:12][C:11]1=[CH:16][N+:17]([O-:19])=[O:18])(=[O:9])=[O:8]>C(Cl)Cl>[CH3:6][S:7]([N:10]1[CH2:15][CH2:14][CH2:13][S:12][C:11]1=[C:16]([Cl:4])[N+:17]([O-:19])=[O:18])(=[O:8])=[O:9]
Reactant: CS(=O)(=O)N1CCCSC1=C[N+](=O)[O-]
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CS(=O)(=O)N1CCCSC1=C(Cl)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.25 g of redistilled sulfuryl chloride in 5 ml of methylene chloride was added drop-by-drop over a 5-minute period to a slurry of (1A) in 50 ml of methylene chloride in a nitrogen atmosphere at 0-5° C. The mixture was stirred for 30 minutes more, then allowed to warm to room temperature. Two drops more of sulfuryl chloride were added and the mixture was stirred for 5 minutes. The resulting mixture was washed with water, then with brine, dried (MgSO4), and stripped of solvent to give a yellow solid. The solid was triturated with ether to give (2), as a yellow solid, m.p. 149°-151° C. (with decomposition).
Reaction SMILES: [C:1](OC)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:22][CH2:23][CH:24]([OH:27])[CH2:25][OH:26]>>[CH2:1]([NH:22][CH2:23][CH:24]([OH:27])[CH2:25][OH:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Reactant: NCC(O)CO
Product: CCCCCCCC/C=C\CCCCCCCCNCC(O)CO
Reaction time: 24 h

Procedure:
5 g of methyl oleat (commercially available under the trade name EDENOR®ME V05 from Cognis GmbH, MW 296) and 1.54 g of 3-amino-1,2-propanediol (MW 91.1, Sigma-Aldrich) were mixed together at 70° C. After addition of 100 mg of Novozym®435 (lipase B from Candida Antarctica, from Novozymes), the reaction was conducted during 24 h at 70° C. under moderate agitation and vacuum (250-300 mbars). The mixture was filtrated to remove the immobilized enzyme. The product of the reaction was analyzed by HPLC-DEDL, to give an area ratio of N-oleyl-(3 amino-1,2-propanediol)/substrates>83%. Thus N-oleyl-(3 amino-1,2-propanediol) is a substance according to formula (I), wherein R1=—(CH2)7—CH═CH—(CH2)7—CH3 and R2=CH2—OH
Reaction SMILES: [OH:1]O.[F:3][C:4]1[C:9]([F:10])=[C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>C(OCC)C>[F:3][C:4]1[C:9]([F:10])=[C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([OH:1])=[CH:22][CH:21]=1
Reactant: CCCCCCCCOc1ccc(-c2ccc(B(O)O)cc2)c(F)c1F
Reactant: OO
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(-c2ccc(O)cc2)c(F)c1F

Procedure:
10% hydrogen peroxide (10.5 ml, 0.023 mol) was added dropwise to a stirred, refluxing solution of 2,3 -difluoro-4 -octoxybiphenyl-4'-yl-boronic acid (10) (2.9g, 8.0 mmol), in diethyl ether (40 ml). The stirred mixture was heated under reflux until tic showed the reaction to be complete. The ether layer was separated and the aqueous layer extracted with ether. The combined ethereal layers were washed with water and dried. The solvent was removed. The crude product was purified by flash chromatography (silica gel/petroleum fraction (bp 40°-60° C.) - ethyl acetate, 2:1) to give a white solid which was recrystallised from pentane/ethyl acetate mixtures.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]2=[O:17].[N-:18]=[N+:19]=[N-:20].[Na+].CN(C=O)C>O>[N:18]([C:2]1[CH:3]=[CH:4][N:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]2=[O:17])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1ccc2cc(Cl)ccn2c1=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc2cc(N=[N+]=[N-])ccn2c1=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
An oven-dried 25 ml round-bottom flask was purged with argon and charged with ethyl 8-chloro-4-oxo-4H-quinolizine-3-carboxylate (2) (250 mg, 1 mmol), NaN3 (300 mg, 4.6 mmol), and 5 ml DMF. The reaction mixture was stirred at 40° C. for 1 h, cooled to room temperature, and poured into 100 ml water. The aqueous layer was extracted three times with 100 ml chloroform, and the combined organic layers were washed three times with 100 ml water. The organic solvent was evaporated and the crude product was purified by flash chromatography (ethyl acetate) to give a deep red crystalline solid (218 mg, 85%). M.p. 145-150° C. 1H NMR (δ, CDCl3): 1.42 (t, J=7 Hz, 3H), 4.41 (q, J=7 Hz, 2H), 6.53 (d, J=8 Hz, 1H), 6.84 (dd, J=2 Hz, J=7 Hz, 1H), 7.08 (d, J=2 Hz, 1H), 8.37 (d, J=8 Hz, 1H), 9.36 (d, J=7 Hz, 1H). MS: m/z 258.0751; required for C12H10N4O3: 258.0753.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:35](OCC)[O:36]CC)=[C:5]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9]>CC(C)=O.Cl>[CH3:1][C:2]1[NH:3][C:4]([CH:35]=[O:36])=[C:5]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9]
Reactant: CCOC(=O)C1=C(C(OCC)OCC)NC(C)=C(C(=O)OCCOCc2ccccc2)C1c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C=O)NC(C)=C(C(=O)OCCOCc2ccccc2)C1c1ccccc1[N+](=O)[O-]
Yield: 94.3 %

Procedure:
Starting from a mixture of an oil (2.5 g) of 2-benzyloxyethyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate in acetone (25 ml) and 6 N hydrochloric acid (2 ml) was obtained a reddish oil (2.05 g) of 2-benzyloxyethyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate, in a substantially similar manner to that of Example 2-6).
Reaction SMILES: CN(OC)[C:3](=[O:10])[C@@H:4]([CH:6]1[CH2:9][CH2:8][CH2:7]1)[CH3:5].[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH:6]1([C@@H:4]([CH3:5])[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:9][CH2:8][CH2:7]1
Reactant: [Li]c1ccccc1
Reactant: CON(C)C(=O)[C@H](C)C1CCC1
Product: C[C@@H](C(=O)c1ccccc1)C1CCC1
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A dry flask was charged with N-Methyl-N-methoxy-(R)-2-cyclobutylpropionamide (2.62 grams, 15.4 mmol, from Step D). The vessel was purged with nitrogen and 40 mL THF was added. The mixture was cooled to −10 C and a solution of phenyllithium (30 mL, 1.8M, 53.9 mmol) was added. The solution was stirred for 1 h at −10 C then the reaction was quenched with sat'd ammonium chloride. The mixture was extracted with ethyl acetate and the organic portion was dried over sodium sulfate and concentrated. Flash chromatography (99/1 hexane/ethyl acetate) afforded 2.06 grams (70%) of the title compound. 1H NMR (400 MHz, CDCl3). δ1.13 (d, 3H), 1.59-1.7 (m, 1H), 1.73-2.0 (m, 5H), 2.05-2.15 (m, 1H), 2.6-2.7 (m, 1H), 3.43-3.53 (m, 1H), 7.44-7.5 (t, 2H), 7.55-7.6 (m, 1H), 7.97-8.0 (d, 2H).
Reaction SMILES: [N:1]1([C:8]#[N:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][O-:11].[Na+]>CO>[N:1]1([C:8](=[NH:9])[O:11][CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CN1CCCCCC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)N1CCCCCC1

Procedure:
In the manner given in Example 2, 1-hexahydroazepinecarbonitrile is treated with sodium methoxide in methanol to give methyl 1-hexahydrazepinecarboximidate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]2.Br[C:20]1[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=[C:24]([Br:26])[N:25]=1.C(N(CC)CC)C>CC(O)C>[Br:26][C:24]1[N:25]=[C:20]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]3)[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Reactant: Cn1cc(Br)nc(Br)c1=O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cn1cc(Br)nc(Nc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)C3)c1=O
Temperature: 70 °C
Yield: 65 %

Procedure:
A mixture of tert-butyl 6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (3 g, 12 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (2.68 g, 10 mmol), and triethylamine (1.5 g, 15 mmol) in IPA (50 mL) was heated at 70° C. for 15 h. The mixture was cooled to room temperature. The resulting yellow solids were collected by filtration and dried in vacuum to afford 120a as a yellow solid (2.83 g, 65%).MS: [M+H]+ 435.
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[CH2:5][NH:4][C:3]1=[O:16]>C(O)C.[H][H].[Ni]>[NH2:13][C:10]1[CH:9]=[CH:8][C:7]([CH:6]2[CH2:5][NH:4][C:3](=[O:16])[CH:2]2[CH3:1])=[CH:12][CH:11]=1
Reactant: [H][H]
Reactant: CC1C(=O)NCC1c1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CCO
Product: CC1C(=O)NCC1c1ccc(N)cc1

Procedure:
45 g. of the 3-methyl-4-p-nitrophenyl-2-pyrrolidinone prepared in Example 5 are dissolved in 3 liters of absolute ethanol and hydrogenated at 100°C. with hydrogen at a pressure of 90 kg./cm.2, in the presence of 5 g. of Raney nickel as catalyst. When the hydrogen absorption has finished, the catalyst is filtered off and the filtrate is evaporated to dryness. The residue is recrystallized twice from ethanol. 30 g. of 4-p-aminophenyl-3-methyl-2-pyrrolidinone are obtained. M.P. : 190°-194°C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:13][C:14](=[O:25])[NH:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[C:8](Br)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]>S1(CCCC1)(=O)=O.C(=O)([O-])[O-].[Ag+2]>[CH2:1]([O:3][C:4]([C:6]1[N:7]2[CH2:13][C:14](=[O:25])[N:15]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=3[CH3:24])[C:8]2=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc(Br)n1CC(=O)Nc1c(C)cc(C)cc1C
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: O=S1(=O)CCCC1
Product: CCOC(=O)c1c(C)nc2n1CC(=O)N2c1c(C)cc(C)cc1C
Temperature: 150 °C

Procedure:
A suspension of 2-bromo-5-methyl-3-[(2,4,6-trimethyl-phenylcarbamoyl)-methyl]-3H-imidazole-4-carboxylic acid ethyl ester (17.4 mg, 0.038 mmol) and silver carbonate (11.6 mg, 0.042 mmol) in sulfolane (0.5 mL) was heated at 150° C. for 4 h. The resulting reaction mixture was cooled to room temperature and filtered through a short pad of celite. The final purification was achieved by a reverse-phase preparative HPLC to give the desired product as white solid. Yield—12.2 mg (73%). 1H NMR (DMSO d-6, 500 MHz) δ 7.04 (s, 2H), 4.99 (s, 2H), 4.26 (q, J=7.2 Hz, 2H), 2.34 (s, 3H), 2.30 (s, 3H), 2.06 (s, 6H), 1.31 (t, J=7.2 Hz, 3H); LC/MS: tR=1.75 min., MS: [M+H]=328.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23]([OH:25])=O)[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.CN.C[CH2:37][N:38]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](=[O:25])[NH:38][CH3:37])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C(=O)O
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C(=O)NC
Yield: 82 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained by the method described in Example (50a) (100 mg, 0.21 mmol), methylamine hydrochloride (35 mg, 0.52 mmol), WSC hydrochloride (120 mg, 0.63 mmol) and HOBT (28 mg, 0.21 mmol), to obtain 84.2 mg of the title compound as a white solid (82%).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C:3]=1[C:15]([O:17]C)=O.[CH3:19][N:20]=[C:21]=[S:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:8]([N:5]1[CH2:6][CH2:7][C:2]2[NH:1][C:21](=[S:22])[N:20]([CH3:19])[C:15](=[O:17])[C:3]=2[CH2:4]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)C1=C(N)CCN(Cc2ccccc2)C1
Reactant: CN=C=S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cn1c(=S)[nH]c2c(c1=O)CN(Cc1ccccc1)CC2
Temperature: 20 °C

Procedure:
788 g of methyl 4-amino-1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylate from a) were dissolved in 2.5 l of toluene, and 447 g of methyl isothiocyanate and 625 ml of triethylamine were added, with stirring. After stirring for 24 h at an internal temperature of 100° C., the mixture was allowed to cool to 20° C. and the precipitate was filtered off with suction and washed with toluene. After drying, this gave 420 g of crude 6 benzyl-3-methyl-2-thioxo-2,3,5,6,7,8-hexahydro-1H-pyrido[4,3-d]pyrimidin-4-one, which was reacted further in c).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-].CCO>[Fe].O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([OH:16])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(N2CCC(O)CC2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(N2CCC(O)CC2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
1-(4-nitrophenyl)piperidin-4-ol (4.725 g, 21.26 mmol), Fe (11.87 g, 212.6 mmol), NH4Cl (11.41 g, 212.6 mmol), EtOH (100 mL) and water (50 mL) were mixed. The mixture was stirred at 100° C. overnight. Then Fe (5.9 g, 106.3 mmol) was added and reacted at 100° C. for 7 hours. Filtrated and the liquid was concentrated, purified by flash chromatography to give 1.8 g yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[N+:17]([O-])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl-].[NH4+]>CO.C(OCC)(=O)C.[Zn]>[NH2:17][C:11]1[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=1[C:9]([NH:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)=[O:20]
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)Nc2cccnc2Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(N)c(C(=O)Nc2cccnc2Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
A solution of N-(2-chloropyridin-3-yl)-5-methyl-2-nitrobenzamide (5.07 g, 17.38 mmol), ammonium chloride (5.30 g, 99.1 mmol) in methanol (170 mL) was treated with zinc dust (8.1 g, 123.9 mmol) and stirred for 1 hour at room temperature. The mixture was diluted with ethyl acetate (300 mL) then filtered and concentrated under reduced pressure. The crude product was dissolved in refluxing methanol (350 mL) then cooled to room temperature and treated with water (300 mL) to give a white precipitate which was filtered, washed with water (50 mL) and dried under high vacuum at 60° C. to give 2-amino-N-(2-chloropyridin-3-yl)-5-methylbenzamide (3.3 g). M.p.=187-190° C.; 400 MHz 1H NMR (DMSO-d6) δ: 9.87 (s, 1H), 8.25 (dd, J=2.0, 4.8 Hz, 1H), 8.02 (dd, J=2.0, 8.0 Hz, 1H), 7.52 (s, 1H), 7.45 (dd, J=4.8, 8.0 Hz, 1H), 7.04 (dd, J=2.0, 8.8 Hz, 2H), 6.67 (d, J=8.4 Hz, 1H), 6.21 (s, 2H), 2.19 (s, 3H); LCMS [M+H]: 262.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:11][OH:12])[CH:7]=[CH:8][C:9]=1[F:10].Cl[C:14]1[CH:15]=[C:16]2[N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21][N:17]2[C:18](=[O:20])[N:19]=1>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:11][O:12][C:14]1[CH:15]=[C:16]2[NH:23][CH2:22][CH2:21][N:17]2[C:18](=[O:20])[N:19]=1
Reactant: OCc1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1nc(OCc2ccc(F)c(F)c2)cc2n1CCN2

Procedure:
Prepared in a manner similar to that described for E65 using sodium hydride (44.2 mg, 1.104 mmol) in THF (5 mL), (3,4-difluorophenyl)methanol (106 mg, 0.736 mmol) and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate (100 mg, 0.368 mmol).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][C:8](SC)=[N:9][CH:10]=2)[N:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[N:17]=1)[CH:2]=[CH2:3].[CH3:27][O:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=2)[CH2:33][CH2:32]1>>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C:18]1[N:17]=[C:16]([N:5]2[C:6]3=[N:7][C:8]([NH:41][C:40]4[CH:39]=[CH:38][C:37]([N:34]5[CH2:33][CH2:32][N:31]([CH2:30][CH2:29][O:28][CH3:27])[CH2:36][CH2:35]5)=[CH:43][CH:42]=4)=[N:9][CH:10]=[C:11]3[C:12](=[O:13])[N:4]2[CH2:1][C:2]#[CH:3])[CH:21]=[CH:20][CH:19]=1
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1cccc(CC(C)(C)O)n1
Reactant: COCCN1CCN(c2ccc(N)cc2)CC1
Product: C#CCn1c(=O)c2cnc(Nc3ccc(N4CCN(CCOC)CC4)cc3)nc2n1-c1cccc(CC(C)(C)O)n1

Procedure:
31 mg of the entitled compound was obtained as a yellow solid in the same manner as in Example 113-1 to 113-2, for which, however, 2-allyl-1-[6-(2-hydroxy-2-methylpropyl)pyridin-2-yl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one obtained in Example 81-2 was used in place of 2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one used in Example 113-1, and 4-[4-(2-methoxyethyl)piperazin-1-yl]aniline was used in place of 4-(4-methylpiperazin-1-yl)aniline used in Example 113-2.