Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C1S(=O)(=[O:17])CCC1.[OH-].[K+].Cl>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([OH:17])[CH:7]=1
Reactant: O=S1(=O)CCCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc(Cl)cc1O
Temperature: 110 °C
Reaction time: 21 h
Yield: 75.8 %

Procedure:
384 g of 2,4-dichloronitrobenzene, 600 g of tetramethylene sulfone (sulfolane) and 1 g of the emulsifier as specified in Example 1 are introduced into the reaction vessel. Within 4 hours 448 g of 50% potassium hydroxide solution are added at 110° C. After stirring for a further 21 hours at 110° C., the reaction product is adjusted to pH 5.5 to 6 with 240 g of 30% hydrochloric acid and worked up as described in Example 1. 263 g of 5-chloro-2-nitrophenol (76% of the theory) are obtained.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][CH2:19][O:20][CH3:21]>CN(C=O)C>[Cl:1][C:2]1[N:7]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:6](=[O:8])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: COCCCBr
Reactant: O=c1cc(Cl)nc(Cl)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCCn1c(Cl)nc(Cl)cc1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.2 %

Procedure:
To a solution of 2,6-dichloro-3H-pyrimidin-4-one (600 mg, 3.65 mmol) in DMF (10 mL) was added K2CO3 (1.0 g, 7.3 mmol) and the mixture was stirred at RT for 10 min. 1-Bromo-3-methoxy-propane (101 mg, 7.3 mmol) was then added dropwise at 0° C., and the mixture was stirred at RT overnight. DMF was concentrated in vacuo, and the residue was purified by silica chromatography to give 400 mg of the title compound (47%). [M+H] Calc'd for; Calc'd for C8H10Cl2N2O2, 237. Found, 237.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)c1ccc(O)c(Cl)c1N
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(COc1ccc(C(C)=O)c(N)c1Cl)OC
Temperature: 65 °C
Yield: 56.6 %

Procedure:
1-(2-Amino-3-chloro-4-hydroxy-phenyl)-ethanone (15.5 g, 83.8 mmol), Cs2CO3 (54.6 g, 167 mmol) and 2-bromo-1,1-dimethoxy-ethane (14.78 mL, 126 mmol) was dissolved in DMF (125 mL) under an atmosphere of nitrogen. The reaction was heated to 65° C. for 6 hours. The reaction was determined to be complete by LC/MS. The reaction was taken up in EtOAc (500 mL) and washed with 5% LiCl(aq) (3×250 mL). Organics were dried over Na2SO4, filtered and solvent removed under reduced pressure. 1-[2-Amino-3-chloro-4-(2,2-dimethoxy-ethoxy)-phenyl]-ethanone (12.99 g, 57%) was isolated by silica gel chromatography as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:10][O:11][C:12]([NH:14][C:15](=NC(OC)=O)SC)=[O:13]>CO.C(O)(=O)C>[CH3:10][O:11][C:12](=[O:13])[NH:14][C:15]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([OH:9])=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1ccc(O)cc1N
Reactant: COC(=O)N=C(NC(=O)OC)SC
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2cc(O)ccc2[nH]1
Yield: 109.7 %

Procedure:
6 g of 3,4-diaminophenol were combined with 9.8 g of 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea in 50 ml methanol and 30 ml acetic acid. The reaction mixture was refluxed for 4 hours. Solvents were then evaporated under reduce pressure yielding 10.8 g crude (5-hydroxy-1H-benzoimidazol-2-yl)-carbamic acid methyl ester. The residue was subjected to flash chromatography eluting with a mixture of dichloromethane-methanol (9:1; v/v) to give 5.6 g of a beige solid. Mass spectrum: 208 [M+H]+, retention time=0.56 minute.
Reaction SMILES: [Br-].[F:2][C:3]([F:31])([F:30])[C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.O=[C:38]1[CH2:43][CH2:42][N:41]([C:44]2[CH:54]=[CH:53][C:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46][CH:45]=2)[CH2:40][CH2:39]1>C1COCC1>[F:31][C:3]([F:2])([F:30])[C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH:6]=[C:38]1[CH2:39][CH2:40][N:41]([C:44]2[CH:54]=[CH:53][C:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46][CH:45]=2)[CH2:42][CH2:43]1
Reactant: CCOC(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: FC(F)(F)c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N2CCC(=Cc3ccccc3C(F)(F)F)CC2)cc1
Temperature: 25 °C

Procedure:
A suspension of 2-(trifluoromethyl)benzyl triphenylphosphonium bromide (prepared according to the procedure described in J. Chem. Soc. Perkin Trans. I 1995, 18, 2293-2308) (0.737 g) in THF (10 mL) was treated with n-butyllithium (724 μL, of a 1.6M solution in hexanes) at 0° C., treated with ethyl 4-(4-oxo-1-piperidinyl)benzoate (prepared according to the procedure described in Synthesis 1981, 606-608, 0.32 g), and gradually warmed to room temperature overnight. The reaction mixture was partitioned between ethyl acetate and saturated aqueous NH4Cl and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were dried (MgSO4), filtered, and concentrated. The resulting residue was purified by silica gel chromatography eluting with 10% ethyl acetate in hexanes to give the desired product.
Reaction SMILES: O=S(Cl)Cl.[CH3:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[CH3:19][CH2:20]O>>[CH2:19]([O:17][C:16](=[O:18])[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([S:6]([CH3:5])(=[O:7])=[O:8])=[CH:14][CH:13]=1)[CH3:20]
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1ccc(S(C)(=O)=O)cc1
Temperature: 20 °C

Procedure:
SOCl2 (8.2 mL, 112.0 mmol) was added to a stirred suspension of (4-methanesulfonylphenyl)acetic acid (20.00 g, 93.3 mmol) in EtOH (80 mL) at −10° C. The mixture was allowed to warm up to 20° C. over 16 h, then the solvents were removed under reduced pressure. The remainder was dissolved in EtOAc, then the resulting solution was washed with H2O until the pH of the aqueous phase was neutral. The EtOAc solution was washed further with saturated aqueous Na2CO3, before being dried (MgSO4). Filtration and solvent evaporation furnished the title compound: m/z (ES+)=284.1 [M+MeCN+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][N:11](C(C2C=CC=CC=2)C2C=CC=CC=2)[C@H:10]1[CH2:26][CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][NH:11][C@H:10]1[CH2:26][CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@H]1[C@H](NC(=O)OC(C)(C)C)CN1C(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC[C@@H]1NC[C@H]1NC(=O)OC(C)(C)C
Yield: 70.9 %

Procedure:
10% Pd/C (100 mg) was added to a solution of trans(±)-3-(tert-butoxycarbonyl)amino-1-(diphenylmethyl)-2-ethylazetidine obtained in Example (234d) (530 mg, 1.45 mmol) in methanol (7 mL), and the mixture was stirred in a hydrogen stream at 40° C. for 13 hours. The reaction solution was filtered, and then the filtrate was concentrated under reduced pressure. A 1 N aqueous hydrochloric acid solution was added to the resulting residue. The aqueous layer was washed with ethyl acetate, and then saturated aqueous sodium bicarbonate solution was added, followed by extraction with ethyl acetate and a chloroform/methanol mixed solvent. The combined organic layers were dried over anhydrous magnesium sulfate and filtered. Thereafter, the filtrate was concentrated under reduced pressure to obtain 206 mg of the title compound as a white solid (71%).
Reaction SMILES: Cl.Cl.[C:3]([N:7]1[C:11]([NH:12][C:13]2[N:18]=[C:17]([CH2:19][C:20]3([C:26]4[O:30][C:29](=[O:31])[NH:28][N:27]=4)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=[N:8]1)([CH3:6])([CH3:5])[CH3:4].[Cl:32][C:33]1[C:34]([F:42])=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](O)=[O:37].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1>[C:3]([N:7]1[C:11]([NH:12][C:13]2[N:18]=[C:17]([CH2:19][C:20]3([C:26]4[O:30][C:29](=[O:31])[NH:28][N:27]=4)[CH2:21][CH2:22][N:23]([C:36](=[O:37])[C:35]4[CH:39]=[CH:40][CH:41]=[C:33]([Cl:32])[C:34]=4[F:42])[CH2:24][CH2:25]3)[CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=[N:8]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(O)c1cccc(Cl)c1F
Reactant: CC(C)(C)n1nccc1Nc1cccc(CC2(c3n[nH]c(=O)o3)CCNCC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)n1nccc1Nc1cccc(CC2(c3n[nH]c(=O)o3)CCN(C(=O)c3cccc(Cl)c3F)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 40 mg of 5-(4-((6-((1-tert-butyl-1H-pyrazol-5-yl)amino)pyridin-2-yl)methyl)piperidin-4-yl)-1,3,4-oxadiazol-2(3H)-one dihydrochloride in 2 ml of pyridine were added 17.8 mg of 3-chloro-2-fluorobenzoic acid and 24.4 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at room temperature. The reaction mixture was stirred at room temperature overnight, followed by concentrating in vacuo. The reaction mixture was dissolved in ethyl acetate, and washed with water. The resulting ethyl acetate layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane to ethyl acetate) to give the title compound as a pale yellow oil.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O.[C:16]([O:21]C)(=[O:20])/[CH:17]=[CH:18]/[CH3:19]>C(O)(C)(C)C>[CH3:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:19][CH:18]=[CH:17][C:16]([OH:21])=[O:20])[CH:13]=[CH:14][CH:15]=1
Reactant: C/C=C/C(=O)OC
Reactant: Cc1cccc(C=O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1cccc(C=CC=CC(=O)O)c1
Temperature: 25 °C

Procedure:
A mixture of potassium tert-butoxide (68 g) and tert-butanol (130 ml) was treated dropwise with a mixture of 3-methylbenzaldehyde (33.8 g) and methyl crotonate (45 ml). The temperature of the reaction mixture rose to 65° C. during the addition and this was maintained for a further 3 hours. The reaction mixture was cooled to room temperature, poured into ice/water and washed with diethyl ether. The aqueous phase was acidified with concentrated HCl and extracted with diethyl ether. The organic phase was washed with water, dried (MgSO4) and evaporated under reduced pressure. Purification was by trituration with isohexane and filtration.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH:12]([C:17]#[N:18])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH:12]([C:17]#[N:18])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#CC1CN(Cc2ccccc2)CCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#CC1CN(Cc2ccccc2)CCC1O
Reaction time: 2 h

Procedure:
Sodium borohydride (0.89 g, 23.37 mmole) was added to the stirred solution of 1-benzyl-3-cyanopiperidin-4-one (2.5 g, 11.68 mmole) in ethanol (125 ml) at 0° C. over a period of 30 min, and stirring was continued for 2 hr at 5° C. The reaction mixture was concentrated to dryness, triturated with water (20 ml) and extracted with ethyl acetate. The extract was concentrated to dryness to furnish 1-benzyl-3-cyano-4-hydroxypiperidine product as oil. Yield 1.85 g (73%) C13H16N2O, m/z 217 (M+1), PMR (CDCl3): 1.78 (2H, m, H5), 2.22 (1H, m, H3), 2.6-3.12 (4H, m, H2 & H6), 3.58 (1H, m, H4), 3.65 (2H, s, CH2—Ar), 7.32 (5H, s, ArH).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([C:16]([O-:18])=[O:17])C(C)=CC=CC=1O.[K+].C(=O)=O>>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:16]([OH:18])=[O:17])=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: Cc1cccc(O)c1C(=O)[O-]
Agent: O=C=O
Agent: [K+]
Product: O=C(O)c1ccc(O)cc1
Yield: 73.2 %

Procedure:
A pressure vessel was charged with 4.70 g of phenol, 25.57 g of potassium meta cresolate being in a dry powder form and 56 g of NeoSK 1400. With stirring, reaction was carried out at a carbon dioxide pressure of 9 kg/cm2 (G) and at 320° C. for one hour. An analysis of the reaction mixture after conversion to acid form showed a para-hydroxybenzoic acid yield of 73.2% on the basis of phenol.
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=O)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[C:34]1([NH:44]N)[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1>>[CH3:1][CH:2]([CH3:32])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[C:35]4[C:34](=[C:43]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]5=[CH:37][CH:36]=4)[NH:44][C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCC(=O)c3ccccc3)CC2)c1
Reactant: NNc1cccc2ccccc12
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCc3c(-c4ccccc4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(7-oxo-7-phenylheptyl)-4-piperidinyl]phenyl)propanamide and 1-(1-naphthyl)hydrazine hydrochloride: ESMS m/e: 558.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8]O.S(Cl)([Cl:12])=O>C(Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][Cl:12]
Reactant: CN1CCCCC1CO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CN1CCCCC1CCl
Yield: 34 %

Procedure:
Treatment of 1-methyl-2-piperidinemethanol (12.9 g, 0.1 mol) with thionyl chloride (7.6 ml) in chloroform (40 ml), as described in example 3, gave 1-methyl-2-(chloromethyl) piperidine (5.0 g, 34%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[CH2:7][CH2:8]O)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>CN(C)C=O>[C:1]([O:4][CH2:5][CH:6]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[CH2:7][CH2:8][Br:35])(=[O:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(=O)OCC(CCO)COC(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)OCC(CCBr)COC(C)=O
Yield: 993.2 %

Procedure:
A mixture of 2-acetoxymethyl-4-hydroxy-but-1-yl acetate 10 g, 49 mmol), triphenylphosphine (19.25 g, 73 mmol) and carbon tetrabromide (24.4 g, 73 mmol) was stirred for 18 hours at 4° C. in dimethylformamide (150 ml). The solvent was then evaporated, and the residue purified by column chromatography on silica gel, eluting with ether-light petroleum 2:3 to afford 2-acetoxymethyl-4-bromobut-1-yl acetate as a pale oil (130 g, 99%). δH (CDCl3) 1.73-2.56 (3H, m, CHCH2CH2), 2.04 (6H, s, 2×OCOCH3), 3.44 (2H, t, CH2Br), 4.04 (4H, d, 2×CH2OCOCH3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)=[CH:4][CH:3]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:40])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:40])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2cccc3[nH]ccc23)cc1
Reactant: CC(=O)O
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To the suspension of 4-(4-fluoro-phenyl)-1H-indole (2.28 g, 10.79 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (147 mL) was added pyridinium tribromide (90% purity from Aldrich, 11.51 g, 32.38 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (108 mL). Zinc dust (10.52 g, 162 mmol) was added to the reaction mixture portionwise, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated and the syrupy residue was suspended in water for 4 hour. The solid product was precipitated out, filtered, and washed repeatedly with water to remove the zinc salt and pyridine salt. After high vacuum dry, a pure product (2.40 g, 98%) was obtained.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[O:13][C:14]([CH2:17][NH:18][CH3:19])=[CH:15][CH:16]=1)SC)#[N:2].[CH2:20]([NH2:23])[C:21]#[CH:22]>CO>[C:1]([NH:3][C:4]([NH:23][CH2:20][C:21]#[CH:22])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[O:13][C:14]([CH2:17][NH:18][CH3:19])=[CH:15][CH:16]=1)#[N:2]
Reactant: C#CCN
Reactant: CNCc1ccc(CSCCN=C(NC#N)SC)o1
Solvent: CO
Product: C#CCNC(=NCCSCc1ccc(CNC)o1)NC#N

Procedure:
A mixture of N-cyano-N'-{2-[(5-methylaminomethyl-2-furyl)methylthio]ethyl}-S-methylisothiourea [prepared according to the procedure described in Belgian Pat. No. 857,388] and propargylamine in methanol is stirred and heated under a positive pressure of nitrogen to give, after workup and chromatography, the title compound.
Reaction SMILES: O1CCOCC1.Cl[C:8]1[CH:13]=[C:12]([CH:14]([S:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[C:11]([Cl:31])=[CH:10][N:9]=1.[NH2:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1>CCCCCC>[Cl:31][C:11]1[C:12]([CH:14]([S:23][C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:13][C:8]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)=[N:9][CH:10]=1
Reactant: NCc1ccncc1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Solvent: CCCCCC
Solvent: C1COCCO1
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(NCc3ccncc3)ncc2Cl)c1
Temperature: 25 °C
Yield: 14 %

Procedure:
A dioxane (1.5 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine (229 mg, 0.550 mmol) obtained in Example 54 and 4-aminomethylpyridine (200 μl) was heated at 120° C. for 3 days in a sealed tube. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=1:3 eluate was concentrated under reduced pressure to give the title compound (37 mg, 0.076 mmol, 14%) as an amorphous substance.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[C:11]([Cl:13])[N:10]=[CH:9]2)[N:5]=[CH:4][N:3]=1.[NH3:14]>C(O)(C)C>[Cl:13][C:11]1[N:10]=[CH:9][N:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH2:14])[CH:7]=2)[CH:12]=1
Reactant: N
Reactant: Clc1cc(-n2cnc(Cl)c2)ncn1
Solvent: CC(C)O
Product: Nc1cc(-n2cnc(Cl)c2)ncn1
Yield: 98.2 %

Procedure:
A solution of 4-chloro-6-(4-chloro-1H-imidazol-1-yl)pyrimidine (0.99 g, 4.60 mmol) in 2 M ammonia (20 mL, 40.0 mmol)/isopropanol was heated at 80° C. in a sealed vial for 18 h. After cooling the solid precipitate was filtered and dried to give 6-(4-chloro-1H-imidazol-1-yl)pyrimidin-4-amine (884 mg, 98% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (1H, d, J=1.51 Hz), 8.32 (1H, d, J=0.76 Hz), 7.96 (1H, d, J=1.51 Hz), 7.30 (2H, br. s.), 6.58 (1H, d, J=1.01 Hz). LCMS: RT=0.57 min, MH+=196.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17]C)=O)=[C:10]3[CH2:9][C:8](=[O:19])[N:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]=2[CH:26]=1.[CH3:27][N-:28][CH3:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([N:28]([CH3:29])[CH3:27])=[O:17])=[C:10]3[CH2:9][C:8](=[O:19])[N:7]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:6]=2[CH:26]=1
Reactant: COC(=O)c1ncn2c1CC(=O)N(c1ccccc1)c1cc(Cl)ccc1-2
Reactant: C[N-]C
Product: CN(C)C(=O)c1ncn2c1CC(=O)N(c1ccccc1)c1cc(Cl)ccc1-2

Procedure:
As described in previous example, 8-chloro-4,6-dihydro-6-phenyl-5-oxo-5H-imidazo[1,5-a][1,5]benzodiazepine-3-carboxylic acid, methyl ester was converted to the dimethylamide, mp. 255°-257°.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C1COCC1>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CN2CCNCC2)cc1

Procedure:
Synthesized according to General Procedure A: 4-tert-butylbenzyl bromide (4 {20}, 4.05 mL, 22.0 mmol, 1 equiv.), piperazine (11.4 g, 132.1 mmol, 6 equiv.), THF (48.1 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{20} (3.75 g, 73%) as a beige solid. 1H-NMR (500 MHz, CDCl3): δ 7.30 (d, 2H, J=8.5 Hz), 7.22 (d, 2H, J=8.5 Hz), 3.44 (s, 2H), 2.85 (t, 4H, J=5.0 Hz), 2.38 (br s, 4H), 1.54 (br s, 1H), 1.29 (s, 9H). 13C-NMR (125 MHz, CDCl3): δ 149.6, 134.7, 128.7, 124.8, 63.1, 54.3, 45.9, 34.2, 31.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][CH:12]=[CH2:13])=[CH:7][C:8]=1[O:9][CH3:10].CO[CH:16]([O:21][CH3:22])[C:17](=[CH2:20])[C:18]#[N:19].C(Cl)Cl>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:17]([C:18]#[N:19])=[CH:16][O:21][CH3:22])[C:6]([CH2:11][CH:12]=[CH2:13])=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C=CCc1ccc(OC)c(OC)c1
Reactant: C=C(C#N)C(OC)OC
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCc1cc(OC)c(OC)cc1CC(C#N)=COC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 10 g. of methyl eugenol and 8.1 g. of 2-dimethoxymethylacrylonitrile in 200 ml. of dry methylene chloride was added 1.97 ml. of stannic chloride. After stirring for 5 hours at room temperature, 300 ml. of ether was added and the mixture washed with a 5% sodium bicarbonate solution (until basic). The organic layer was dried (MgSO4) and the solvent removed under reduced pressure. The residue was triturated with ether to give 1,2-dimethoxy-4-(2-propenyl)-5-(2-cyano-3-methoxy-2-propenyl)benzene, m.p. 77°-79°.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Li+].O>C1COCC1>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]#[C:8][C:5]2([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]2)=[CH:15][CH:14]=1
Reactant: COC(=O)C1(C#Cc2ccc(OC)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C#CC2(C(=O)O)CC2)cc1
Reaction time: 6 h
Yield: 0.1 %

Procedure:
A mixture of 1-(4-methoxy-phenylethynyl)-cyclopropanecarboxylic acid methyl ester (2.2 g, 9.4 mmol), lithium hydroxide (0.6 g, 14 mmol) in THF (30 mL), and water (30 mL) was stirred for 6 hours. The solution was washed with ether and the aqueous layer was acidified to pH=4 and then extracted with ether. The organic layer was dried over sodium sulfate, and evaporated to dryness to yield 1-(4-methoxy-phenylethynyl)-cyclopropanecarboxylic acid as a white solid (2.0 g, 0.0092 mmol, 98%). ESI-MS m/z calc. 216.1. found; 217.16 (M+1)+ 1H NMR (CDCl3): δ 7.35 (d, J=8.8 Hz, 2H), 6.80 (d, J=8.8 Hz. 2H), 3.79 (s, 3H), 1.69 (m, 2H), 1.47 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([OH:8])=[N:6][CH:7]=1.[CH:10](Br)([CH3:12])[CH3:11]>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5](=[O:8])[N:6]([CH:10]([CH3:12])[CH3:11])[CH:7]=1
Reactant: Cc1cc(Br)cnc1O
Reactant: CC(C)Br
Product: Cc1cc(Br)cn(C(C)C)c1=O

Procedure:
Examples 508-511 as described in Table 22 were prepared in three steps. Using conditions similar to those described in WO2005/40151 (Preparation 6), 5-bromo-3-methylpyridin-2-ol was N-alkylated with isopropyl bromide to give 5-bromo-3-methyl-1-propan-2-ylpyridin-2-one which was then reacted with 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane using conditions similar to those described in Example 248, step 2 to give the pinacol ester, 3-methyl-1-propan-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one. This pinacol ester was then substituted for the pinacol ester of the example shown under Synthetic Method in Table 22 and reacted in the same way as the example to obtain the title compounds.