Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CO.CC(C)=O>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[O:19])[CH2:12][S:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1)[CH3:18]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CO
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)CSc1nc2ccccc2[nH]1
Yield: 92.7 %

Procedure:
A solution of 2-mercaptobenzimidazole (200 mg, 1.33 mmol) and ethyl 3-bromopyruvate (0.20 mL, 1.43 mmol) in methanol (2.5 mL) and acetone (2 mL) was shaken at 20° C. for 4 hours. The solvents were removed under the reduced pressure on a rotary evaporator. The residue was triturated with ethyl acetate. Solvent was decanted and the residue was dissolved in methylene chloride. The solution was washed with diluted aqueous sodium bicarbonate solution and water, and then dried over magnesium sulfate. Removal of the solvent gave the expected product, 3-(1H-Benzoimidazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester (326 mg, 93%). 1H-NMR (CDCl3, 300 MHz) δ (ppm): 7.31 (br. s, 1H), 7.24 (br s, 1H), 7.15-7.05 (m, 2H), 4.32 (q, J=7.1 Hz, 2H), 4.29 (br. s, 1H), 3.90 (br. s, 1H), 1.24 (t, J=7.1 Hz, 3H). MS (ESI): m/z 265 (M+1, 100).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13](N)[C:12]([Cl:16])=[CH:11][C:10]=2[Cl:17])=[C:4]([CH3:18])[N:3]=1.N([O-])=O.[Na+].[ClH:23]>O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([Cl:23])[C:12]([Cl:16])=[CH:11][C:10]=2[Cl:17])=[C:4]([CH3:18])[N:3]=1
Reactant: Cl
Reactant: Cc1nc(N)nc(N)c1-c1cc(N)c(Cl)cc1Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1nc(N)nc(N)c1-c1cc(Cl)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,4-diamino-5-(5-amino-2,4-dichlorophenyl)-6-methylpyrimidine (1.95 g, 7 mmol) was dissolved in a mixture of concentrated hydrochloric acid (3.6 ml) and water (6 ml). The temperature was lowered to 10° C. A chilled aqueous solution (3.6 ml) of sodium nitrite (0.50 g, 7 mmol) was added dropwise, keeping the temperature at 10° C. This mixture was stirred at room temperature for 2 hours, then chilled before adding it dropwise to a cold solution of cuprous chloride (1.7 g, 17 mmol) in concentrated hydrochloric acid (50 ml). A grey solid precipitated which was filtered off and dried. This crude product (2.30 g) was dissolved in ethyl acetate and washed twice with ammonium hydroxide solution and once with brine. After evaporating the ethyl acetate an off-white solid was obtained (2.04 g). After recrystallisation from 10% methanol in chloroform the pure product was obtained (0.55 g, 2 mmol), mp. 262° C. (dec).
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].[OH-:11].[Na+].[CH2:13]=O.Cl>O>[OH:8][C:5]1[C:6](=[O:7])[CH:1]=[C:2]([CH2:9][OH:10])[O:3][C:4]=1[CH2:13][OH:11]
Reactant: [OH-]
Reactant: O=c1cc(CO)occ1O
Reactant: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=c1cc(CO)oc(CO)c1O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
In a 100 mL round bottom flask were added Kojic acid (FLUKA, 5 g), 1N NaOH (39 mL) and H2O (10 mL). The mixture was cooled (ice/water bath) and 37% aqueous formaldehyde (ALDRICH, 2.9 mL) was added dropwise. After 34 h at room temperature additional 37% aqueous formaldehyde (ALDRICH, 0.5 mL) was added dropwise and the solution allowed to stir for 18 h. The mixture was acidified by adding concentrated HCl, and the solvent eliminated to dryness under vacuum to give a crude product which was treated with chilled water to afford a solid precipitated which was filtered and vacuum dried. 3.056 g of the title compound were obtained as a white solid. The filtrate was concentrated under vacuum and a second crop of solid separated. An additional 1.154 g of the title compound were obtained.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH2:8])[CH2:3][CH2:2]1.Cl[C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[CH:17][N:18]=2)[N:15]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>CS(C)=O>[S:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:27])([F:29])[F:28])[CH:20]=4)=[CH:17][N:18]=3)[N:15]=2)[CH2:3][CH2:2]1
Reactant: FC(F)(F)Oc1cccc(-c2cnc3ccc(Cl)nn23)c1
Reactant: NCC1CCSCC1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)Oc1cccc(-c2cnc3ccc(NCC4CCSCC4)nn23)c1
Temperature: 120 °C
Reaction time: 5 h
Yield: 5.6 %

Procedure:
To the solution of compound (tetrahydro-2H-thiopyran-4-yl)methanamine (150 mg, 1.14 mmol) and compound 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (358 mg, 1.14 mmol) in 3 mL DMSO was added DIEA (0.22 mL, 2.28 mmol) and 10 mg CsF, the solvent was stirred for 5 h at 120° C., Then the mixture was purified by HPLC to afford the compound N-((tetrahydro-2H-thiopyran-4-yl)methyl)-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-amine (26 mg, 30%) as yellow oil.
Reaction SMILES: [CH:1]1([CH2:5][N:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:4][CH2:3][CH2:2]1.[Br:12][C:13]1[C:14](Cl)=[C:15]([N+:20]([O-:22])=[O:21])[C:16]([NH2:19])=[N:17][CH:18]=1>CC(O)C.CCN(C(C)C)C(C)C>[Br:12][C:13]1[C:14]([N:9]2[CH2:8][CH2:7][N:6]([CH2:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)[CH2:11][CH2:10]2)=[C:15]([N+:20]([O-:22])=[O:21])[C:16]([NH2:19])=[N:17][CH:18]=1
Reactant: C1CC(CN2CCNCC2)C1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Nc1ncc(Br)c(N2CCN(CC3CCC3)CC2)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 17 h
Yield: 45 %

Procedure:
The resulting 1-(cyclobutylmethyl)piperazine (supposedly 0.086 g, 0.56 mmol, 1 eq) was suspended in iPrOH (0.55 mL) and DIPEA (0.22 mL). To this solution, 5-bromo-4-chloro-3-nitropyridin-2-amine (0.14 g, 0.56 mmol, 1 eq) was added and the reaction mixture was heated and stirred for 17 h at 60° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL), and dried to give the title compound as a bright yellow powder (0.093 g, 45%); 1H-NMR (500 MHz, DMSO-d6): δ 1.73-1.92 (m, 2H), 1.96-2.05 (m, 2H), 2.37 (d, J=7.0 Hz, 2H, piperazine N(CH2)2), 2.41-2.54 (m, 5H), 3.02 (m, 4H), 6.95 (s, 2H, NH2), 8.15 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): Rt=2.02 min—370/372 [(M+H+), Br isotopic pattern, 100%].
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[CH3:15])[CH2:2][CH2:3][CH3:4].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[Br:39]N1C(=O)CCC1=O>O>[CH2:1]([O:5][C:6]1[C:7]([CH2:15][Br:39])=[CH:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCOc1ccc([N+](=O)[O-])cc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCCCOc1ccc([N+](=O)[O-])cc1CBr
Reaction time: 8 h

Procedure:
To a stirred and gently refluxing mixture of 256 parts of butyl (5-nitro-o-tolyl)ether, 1 part of benzoyl peroxide and 4800 parts of anhydrous carbon tetrachloride is added, over a one-day period, a mixture of 213.6 parts of N-bromosuccinimide and 1 part of benzoyl peroxide. Upon completion, stirring at gentle reflux is continued overnight. The reaction mixture is cooled and water is added. The organic layer is separated, washed with water, dried, filtered and evaporated. The oily residue is crystallized on standing overnight in 2-propanol, yielding 189.7 parts of (α-bromo-5-nitro-o-tolyl) butyl ether; mp. 64° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23](C=O)=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C2(C3C=CC=CC=3)CCP(C3C=CC=CC=3)[C:35]2=[CH:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])C=CC=CC=1>C1C=CC=CC=1.CCCCCC.C(OCC)C.C(O)(=O)C1C=CC=CC=1>[Si:1]([O:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23](/[CH:35]=[CH:45]/[C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=C1P(c2ccccc2)CCC1(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](OCc1ccc(C=O)cc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)c1ccccc1
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CCOC(=O)/C=C/c1ccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Reaction time: 2 h
Yield: 347.8 %

Procedure:
To a solution of 4-(t-butyldiphenylsilyloxymethyl)benzaldehyde (3.26 g, 8.71 mmol) in benzene (80 mL) were added ethyl (triphenylphospholanylidene)acetate (3.19 g, 9.14 mmol) and benzoic acid (116.0 mg, 0.950 mmol) at room temperature, and the mixture was heated under reflux with stirring for 2 h. The reaction mixture was directly concentrated under reduced pressure, and the residue thus obtained was diluted with hexane (80 mL) and diethyl ether (40 mL) and stirred for 8 h. Precipitated solids were filtered, and the residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (hexane-ethyl acetate 25:1) to give 13.47 g of ethyl (E)-3-{4-[(t-butyldiphenylsilyloxy)methyl]phenyl}acrylate as oil (yield: 90%).
Reaction SMILES: CS(O[CH:6]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([C:24]2([C:27]3[CH:35]=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)[CH2:26][CH2:25]2)=[O:23])=[CH:19][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=O)=O.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.O1C2C=CC(C3(C(NC4C=CC(C(N(C)C)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:31]1[C:30]2[CH:34]=[CH:35][C:27]([C:24]3([C:22]([NH:21][C:18]4[CH:19]=[CH:20][C:15]([CH:6]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=5[O:13][CH3:14])[N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[CH:16][N:17]=4)=[O:23])[CH2:26][CH2:25]3)=[CH:28][C:29]=2[O:33][CH2:32]1
Reactant: C1COCCN1
Reactant: COc1ccccc1C(OS(C)(=O)=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Agent: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N(C)C
Product: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N1CCOCC1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((2-methoxyphenyl)(morpholino)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from (6-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-3-yl)(2-methoxyphenyl)methyl methanesulfonate and morpholine in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((dimethylamino)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH3:16][CH:17]([CH3:23])[CH2:18][S:19](Cl)(=[O:21])=[O:20].[CH3:24][O:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1>>[CH3:24][O:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:19]([CH2:18][CH:17]([CH3:23])[CH3:16])(=[O:21])=[O:20])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:34][CH:35]=1
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: COCCCOc1ccc(N)cc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: COCCCOc1ccc(N2CCC3(CCN(S(=O)(=O)CC(C)C)CC3)C2=O)cc1

Procedure:
Off-white solid. MS (ESI): 439.22 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-methyl-propane-1-sulfonyl chloride, 4-(3-methoxy-propoxy)-phenylamine.
Reaction SMILES: [N:1]#[N:2].[S:3]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:27])[NH2:26])([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:14])[CH3:13])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].[ClH:31].[CH2:32](O)[CH3:33]>>[N:1]#[N:2].[ClH:31].[ClH:31].[CH2:32]([O:29][C:28](=[O:30])[C@H:20]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:26])[NH2:27])[NH:19][S:3]([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:13])[CH3:14])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:5])[CH3:33]
Reactant: CN(C)c1cccc2c(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cccc12
Reactant: CCO
Agent: Cl
Agent: N#N
Product: CCOC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Reaction time: 1 h
Yield: 95 %

Procedure:
A suspension of 1.0 gram of N2 -dansyl-L-arginine in 15 ml of anhydrous ethanol was saturated with dry hydrogen chloride for 1 hour. The reaction mixture was reflexed for an additional one hour. After cooling, the reaction mixture was concentrated in vacuo. The residue was triturated with cold ethyl ether to give a crystalline product. After crystallization from ethanol-ethyl ether, N2 -dansyl-L-arginine ethyl ester dihydrochloride was obtained in 95% yield; mp. 140°-144° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br)=[CH:4][CH:3]=1.[K].[C:25]1([C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][O:27]1)=[O:26].C[N:36](C=O)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:36]2[C:25](=[O:26])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]2=[O:27])=[CH:4][CH:3]=1
Reactant: O=C1OCc2ccccc21
Reactant: Fc1ccc(C(CCCCCCCBr)c2ccc(F)cc2)cc1
Reactant: CN(C)C=O
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1CCCCCCCC(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
9.0 g (23.6 mmol) 8,8-bis-(4-fluorophenyl)-octyl bromide and 4.7 g (25.0 mmol) phthalide potassium salt are stirred in 80 ml DMF for two hours at 70° C. After cooling, the mixture is concentrated and extracted with acetic acid ethyl ester and NaCl solution by shaking. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with petroleum ether/acetic acid ethyl ester (60/1 to 30/1): Yield 8.1 g (77%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[CH:4]=[N:5]O.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:11][C:10]1[C:9]([O:12][CH3:13])=[CH:8][CH:7]=[C:3]([C:4]#[N:5])[C:2]=1[Cl:1])(=[O:16])[CH3:15]
Reactant: COc1ccc(C=NO)c(Cl)c1O
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(C#N)c(Cl)c1OC(C)=O
Reaction time: 1 h

Procedure:
21 g of 2-chloro-3-hydroxy-p-anisaldehyde oxime are heated under reflux for 20 hours together with 400 ml of acetic anhydride. Thereupon, the reaction mixture is evaporated, the residue is treated with 300 ml of ice-water, stirred for 1 hour, decanted, the thus-cooled residue is partitioned between methylene chloride and water, the organic phase is dried over sodium sulfate, evaporated, the residue is dried in a high vacuum, chromatographed on 200 g of silica gel with methylene chloride and recrystallized from methylene chloride/petroleum ether. There is obtained 2-chloro-3-cyano-6-methoxyphenyl acetate of m.p. 97°-99°.
Reaction SMILES: [O:1]1[CH2:3][C:2]1([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>B(F)(F)F.CCOCC.C1C=CC=CC=1>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([CH:2]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:3]=[O:1])=[CH:15][CH:14]=1
Reactant: Clc1ccc(C2(c3ccccc3)CO2)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: O=CC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Borontrifluoride etherate (5 drops) was added to a solution of the crude epoxide (9 0g) in dry benzene (250 ml). After 5 minutes water was added and the benzene layer washed with water until no longer acidic. Evaporation of solvent gave an oil which was chromatographed on silica gel; elution with progressively graded mixtures of light petroleum and ether yielded p-chlorophenyl-phenylacetaldehyde (5 68g 62%9 as an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[N:12]([CH:19]([CH3:21])[CH3:20])[C:11]3=[O:22])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:24]1[NH:32][C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[N:25]=1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[N:25]1[C:26]2[C:27](=[N:28][CH:29]=[CH:30][CH:31]=2)[NH:32][C:24]=1[N:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[N:12]([CH:19]([CH3:20])[CH3:21])[C:11]3=[O:22])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)n1c(=O)n(-c2ccc3c(c2)CCN3)c2ncccc21
Reactant: Clc1nc2cccnc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)n1c(=O)n(-c2ccc3c(c2)CCN3c2nc3cccnc3[nH]2)c2ncccc21
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 5.4 %

Procedure:
A mixture of 3-(2,3-dihydro-1H-indol-5-yl)-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (200 mg) and 2-chloro-3H-imidazo[4,5-b]pyridine (115 mg) in NMP (4 mL) was stirred at 140° C. for 1.5 h, treated with saturated NaHCO3, and extracted with AcOEt. The organic layer was dried over MgSO4, passed through celite pad covered with activated carbon and concentrated in vacuo. The residue was purified by prep. HPLC. The product was crystallized from EtOH/hexane to give the title compound (15.0 mg).
Reaction SMILES: [CH:1]1([N:7]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:17]C#N)=[C:14]([CH3:16])[N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:1]1([N:7]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:17][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[C:14]([CH3:16])[N:15]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1SC#N
Reactant: ClCCN1CCCCC1
Product: Cc1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1SCCN1CCCCC1

Procedure:
Prepared as described in general procedure (H) using 1,1-dicyclohexyl-3-(4-methyl-5-thiocyanato-thiazol-2-yl)-urea and N-(2-chloroethyl)piperidine.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3]/[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[O:21]=[O+][O-].CSC>ClCCl.N1C=CC=CC=1>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][O:5][CH2:4]/[CH:3]=[C:2](/[CH3:1])\[CH2:15][CH2:16][CH:17]=[O:21])=[CH:12][CH:11]=1.[CH3:1]/[C:2](/[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3]/[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1
Reactant: O=[O+][O-]
Agent: COc1ccc(COC/C=C(/C)CCC=C(C)C)cc1
Solvent: ClCCl
Solvent: CSC
Solvent: c1ccncc1
Product: COc1ccc(COC/C=C(/C)CCC=O)cc1
Temperature: 25 °C

Procedure:
1-({[(2Z)-3,7-dimethylocta-2,6-dien-1-yl]oxy}methyl)-4-methoxybenzene (75.0 g, 273 mmol) was dissolved in dichloromethane (1.13 l) and pyridine (11.3 ml). This reaction solution was cooled to −78° C., to which ozone was bubbled (flow rate 2 l/min, electric voltage 90 V) for 170 minutes with stirring. After addition of dimethylsulfide (80.3 ml, 1.09 mol), the reaction solution was allowed to warm to room temperature and was stirred overnight. The reaction solution was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (Kanto Chemical, commercial name Silica gel 60N, granular, neutral, 0.040 mm-0.100 mm; n-heptane:ethyl acetate=4:1) and the title compound (36.9 g) was obtained as a colorless oil while 1-({[(2Z)-3,7-dimethylocta-2,6-dien-1-yl]oxy}methyl)-4-methoxybenzene (14.1 g) was recovered.
Reaction SMILES: [N:1]1[C:5]2[CH2:6][CH2:7][CH:8]([C:10]([OH:12])=O)[CH2:9][C:4]=2[NH:3][CH:2]=1.[Cl:13][C:14]1[CH:25]=[CH:24][C:17]([O:18][CH2:19][CH2:20][CH2:21][NH:22][CH3:23])=[CH:16][CH:15]=1>>[ClH:13].[Cl:13][C:14]1[CH:25]=[CH:24][C:17]([O:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:23])[C:10]([CH:8]2[CH2:7][CH2:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH2:9]2)=[O:12])=[CH:16][CH:15]=1
Reactant: O=C(O)C1CCc2nc[nH]c2C1
Reactant: CNCCCOc1ccc(Cl)cc1
Product: CN(CCCOc1ccc(Cl)cc1)C(=O)C1CCc2[nH]cnc2C1
Product: Cl

Procedure:
By a similar procedure as described in Example 65, the title compound was prepared from 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid and 3-(4-chlorophenoxy)propylmethylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1C#N.Cl.[NH2:12][OH:13].[C:14](=[O:17])(O)[O-].[Na+]>C(O)C.O>[NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:14]([NH:12][OH:13])=[O:17]
Reactant: N#Cc1ccc(Cl)cc1N
Reactant: NO
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)ccc1C(=O)NO
Yield: 85.7 %

Procedure:
2-Amino-4-chloro-benzonitrile (5.3 g, 35 mmol) was dissolved in ethanol (180 ml) aided by heating. An aqueous solution of hydroxylamine hydrochloride (4.9 g, 70 mmol) and sodium bicarbonate (11.1 g, 105 mmol) was added and the mixture was refluxed for 8 hours. The solvent was then reduced and the product suspended in water (100 ml) and filtered off to yield 5.6 g (86%) of a white powder (m.p. 131-133° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH:5]([N:16]([CH:30]1[CH2:32][CH2:31]1)[C:17](=O)[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)[C:6]([C:8]1[CH:9]=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1)=O)[CH3:2].FC(F)(F)C([O-])=O.[NH4+:41]>>[CH2:1]([O:3][C:4]([C:5]1[N:16]([CH:30]2[CH2:31][CH2:32]2)[C:17]([C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]([F:26])([F:28])[F:27])=[CH:22][CH:23]=2)=[N:41][C:6]=1[C:8]1[CH:9]=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1)=[O:33])[CH3:2]
Reactant: CCOC(=O)C(C(=O)c1cnc(SC)nc1)N(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Reactant: [NH4+]
Agent: O=C([O-])C(F)(F)F
Product: CCOC(=O)c1c(-c2cnc(SC)nc2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1

Procedure:
The title compound was prepared from 2-[cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-3-(2-methylsulfanyl-pyrimidin-5-yl)-3-oxo-propionic acid ethyl ester in direct analogy to intermediate 8B, by reaction with ammonium trifluoroacetate. MS: 465.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:4]3[C:5](=[C:29]([CH3:32])[O:30][N:31]=3)[C:6](=[O:28])[N:7]([CH:12]3[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18][NH:19][C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:13]3)[C:8]=2[CH:9]=[CH:10][CH:11]=1.[CH3:33][C:34](O)=[O:35].CCN=C=NCCCN(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:34]([NH:1][C:2]1[C:3]2[C:4]3[C:5](=[C:29]([CH3:32])[O:30][N:31]=3)[C:6](=[O:28])[N:7]([CH:12]3[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18][NH:19][C:20](=[O:27])[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:13]3)[C:8]=2[CH:9]=[CH:10][CH:11]=1)(=[O:35])[CH3:33]
Reactant: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)c3ccccc3)C1)c1cccc(N)c21
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc2c1c1noc(C)c1c(=O)n2C1CCCC(CNC(=O)c2ccccc2)C1
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a solution of a compound from Example 667 (0.025 g, 0.06 mmol) and AcOH (0.02 mL, 0.36 mmol) in DMF (1 mL) under N2 was added EDCI (0.023 g, 0.12 mmol) and DMAP (0.002 g, 0.01 mmol). The solution was stirred overnight, diluted with EtOAc, washed (H2O then brine), dried (MgSO4), filtered, and concentrated. Flash chromatography (silica gel, acetone/CH2Cl2 gradient) gave the title compound (0.023 g, 82%). Mass Spectrum (ES+) (m/z) 473.3 [M+1]
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6](CN2CCCC2)[O:5][CH:4]=[C:3]1[O:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[CH3:23][O:24][C:25]([CH:27]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:26].[C:47]1(C)C=CC=CC=1>>[CH3:23][O:24][C:25](/[CH:27]=[CH:47]/[C:4]1[O:5][CH:6]=[CH:7][C:2](=[O:1])[C:3]=1[O:14][CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[O:26]
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OC(=O)COc1coc(CN2CCCC2)cc1=O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)/C=C/c1occc(=O)c1OCC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a solution of tert-butyl [[4-oxo-6-[(1-pyrrolidinyl)methyl]-4H-pyran-3-yl]oxy]acetate (compound obtained in Reference Example 249(2), 12 g) in toluene is added (1-methoxycarbonylmethylidene)triphenylphosphoran (17.36 g) and the mixture is stirred at 60° C. for 3 hours. The reaction mixture is concentrated and the residue is purified by flash column chromatography on silica gel (Solvent; n-hexane:ethyl acetate=1:1) to give tert-butyl [2-[(1E)-2-(methoxycarbonyl)vinyl]-4-oxo-4H-pyran-3-yl]-oxyacetate (10.99 g, yield; 75%) as colorless crystals. MS (ESI) m/z; 311 [M+H]+, M.p. 115-116° C.