Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:18]([OH:20])=O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:22][O:23][CH2:24][NH2:25].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.ClCCl>[CH3:22][O:23][CH2:24][NH:25][C:18](=[O:20])[C@@H:9]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)O
Reactant: COCN
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCNC(=O)[C@@H](CCc1ccccc1)NC(=O)OC(C)(C)C
Yield: 195.2 %

Procedure:
A mixture of Boc-D-homophenylalanine (3.0 g), methoxymethylamine hydrochloride (1.15 g), PyBrop (5 g); diisopropylethylamine (5.6 mL), and dichloromethane (10 mL) was stirred at 25° C. for 10 h., and the reaction mixture was poured into ethyl acetate and washed successively with water, 1N HCl, sat. sodium bicarbonate and brine. The combined extracts was dried (Na2SO4) and concentrated in vacuo. Further purification by chromatography over silica gel (45% ethyl acetate/hexane) afforded titled compound (6.76 g) as a white solid: 1H NMR (400 MHz, CDCl3) δ 1.46 (s, 9H), 1.85 (m, 1H), 2.04 (m, 1H), 2.72 (m, 2H), 3.17 (s, 3H), 3.63 (s, 3H), 4.69 (m, 1H), 5.25 (bd, 1H, NH), 7.20 (m, 3H), and 7.28 (m, 2H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[CH2:33][CH2:32][N:24]2[C:25]3[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=3[CH:31]=[C:23]2[C:22]1=[O:34])(=[O:3])[CH3:2].Br[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[S:46][C:47]3[CH2:48][N:49]([CH3:54])[CH2:50][CH2:51][C:52]=3[N:53]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1>>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:33][CH2:32][N:24]3[C:25]4[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=4[CH:31]=[C:23]3[C:22]2=[O:34])=[CH:8][CH:9]=[CH:10][C:11]=1[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[S:46][C:47]3[CH2:48][N:49]([CH3:54])[CH2:50][CH2:51][C:52]=3[N:53]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1)(=[O:3])[CH3:2]
Reactant: CN1CCc2nc(Nc3cc(Br)cn(C)c3=O)sc2C1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Product: CC(=O)OCc1c(-c2cc(Nc3nc4c(s3)CN(C)CC4)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 78.4 %

Procedure:
Following Example 147b, 232 mg of 114a and 178 mg of 141b were reacted to give 141c as a yellow solid (240 mg, 80%). LCMS: [M+H]+ 613
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:8][CH:7]=1>C1COCC1.[Cl-].[Cl-].[Zn+2]>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([OH:13])[CH2:1][CH3:2])=[CH:10][CH:11]=1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Reactant: CC[Mg]Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCC(O)(c1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of ethylmagnesium chloride (153.1 mg, 1.723 mmol) in THF (10.0 mL, 123 mmol) was added zinc dichloride (47.0 mg, 0.345 mmol) at rt. The resulting mixture was stirred at rt for 1 h. Then to this mixture, (4-bromophenyl)phenyl methanone (300.00 mg, 1.1489 mmol) in THF (5 mL) was added at 0° C. The mixture was then stirred at 0° C. for 2 h. The solvent was then removed under reduced pressure and the resulting residue was purified by a flash chromatography(2% EtOAc in hexane).
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)[CH2:3]1.C(Cl)C[Cl:22].C1C=CC2N(O)N=NC=2C=1.[CH3:34][C:35]1[C:43]2[C:38]([NH:39][CH:40]=[N:41][C:42]=2[N:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH2:46][CH2:45]2)=[N:37][CH:36]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN1CCCC1=O>[ClH:22].[F:19][C:2]1([F:1])[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([NH:50][CH:47]2[CH2:46][CH2:45][N:44]([C:42]3[N:41]=[CH:40][NH:39][C:38]4=[N:37][CH:36]=[C:35]([CH3:34])[C:43]=34)[CH2:49][CH2:48]2)=[O:15])[CH2:3]1
Reactant: Cc1cnc2[nH]cnc(N3CCC(N)CC3)c1-2
Reactant: O=C(O)c1cccc(OCCN2CCC(F)(F)C2)c1
Reactant: ClCCCl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: Cc1cnc2[nH]cnc(N3CCC(NC(=O)c4cccc(OCCN5CCC(F)(F)C5)c4)CC3)c1-2
Product: Cl

Procedure:
To a solution of 3-{[2-(3,3-difluoro-1-pyrrolidinyl)ethyl]oxy}benzoic acid D53 (127 mg), EDC (149 mg, 0.778 mmol) and HOBT (119 mg, 0.778 mmol) in DCM (15 mL) stirred at 25° C. was added a solution of 1-(5-methyl-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine D11a (90 mg) and DIEA (201 mg, 1.556 mmol) in N-Methyl-2-pyrrolidone (NMP) (5 mL).
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[OH:12])[CH3:3].[H-].[Na+].[CH3:15][N:16]=[C:17]=[O:18]>O1CCCC1>[CH3:15][NH:16][C:17]([O:12][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:6]=1[N:5]=[CH:4][N:2]([CH3:1])[CH3:3])=[O:18]
Reactant: CN=C=O
Reactant: CN(C)C=Nc1ccncc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1cnccc1N=CN(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a hot suspension of 4-[[(dimethylamino)methylene]amino]-3-pyridinol (7.0 g) in dry tetrahydrofuran (THF) were added sodium hydride (168 mg) and methyl isocyanate (2.6 ml). The reaction mixture was stirred at room temperature overnight, cooled in an ice-methanol bath and filtered. The solid was washed with diethyl ether and distributed between methylene chloride (250 ml) and saturated ammonium chloride (30 ml) and, extracted twice more with methylene chloride (200 ml). The solution was dried (MgSO4) and concentrated and the solid was recrystallized from ethyl acetate and dried under high vacuum and refluxing ethanol to yield 6.18 g of crystals, m.p. 137°-139° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]2[CH:17]=[C:16]([OH:18])[N:15]([CH3:19])[N:14]=2)[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].[OH-].[Na+].[CH2:22]=O.[C:24]1([CH3:33])[CH:29]=[CH:28][C:27]([S:30]([O-:32])=[O:31])=[CH:26][CH:25]=1.[Na+].Cl>C(O)C.O>[N+:1]([C:4]1[CH:5]=[C:6]([C:13]2[C:17]([CH2:22][S:30]([C:27]3[CH:28]=[CH:29][C:24]([CH3:33])=[CH:25][CH:26]=3)(=[O:32])=[O:31])=[C:16]([OH:18])[N:15]([CH3:19])[N:14]=2)[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2]
Reactant: C=O
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: Cn1nc(-c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)Cc2c(-c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)nn(C)c2O)cc1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
3-(3,5-Dinitrophenyl)-5-hydroxy-1-methylpyrazole (0.65 g (2.5 mmol)) synthesized in Reference Example 4 and 0.15 g (3.8 mmol) of sodium hydroxide were dissolved in 5 mL of ethanol. While stirring the resulting solution at room temperature, 0.5 g (5.5 mmol) of a 35% formalin solution was added dropwise thereto, followed by stirring at the same temperature for 1 hour. Subsequently, 0.45 g (2.5 mmol) of sodium p-toluenesulfinate was charged thereto at room temperature, and the obtained mixture was stirred for 2 hours. After the reaction, 2.5 g (25 mmol) of 35% hydrochloric acid was added dropwise thereto, 15 mL of water was further added, and the precipitated crystal was collected by filtration, washed twice with 10 mL of water and dried by a hot air drier to obtain 0.9 g (yield: 89.3%) of the title compound as a brown crystal.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:14]=[O:15]>[OH-].[Na+]>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:14][OH:15]
Reactant: C=O
Reactant: COc1ccc2c(O)ccnc2c1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2c(O)c(CO)cnc2c1
Reaction time: 18 h

Procedure:
4-Hydroxy-7-methoxyquinoline was reacted with formaldehyde in aqueous sodium hydroxide (initially at 40°-50°, then kept at 60° for 18 hours) to give the novel compound 4-hydroxy-3-hydroxymethyl-7-methoxyquinoline, m.p. 291°-297°.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[N:32][CH:33]=1>C(#N)C.O>[CH3:18][O:17][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:2]=1[O:1][CH2:27][C:28]1[CH:33]=[N:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: COc1ccc(CCl)cn1
Reactant: COc1cc(CNC(=O)OC(C)(C)C)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(COc2ccc(CNC(=O)OC(C)(C)C)cc2OC)cn1
Temperature: 25 °C
Reaction time: 23 h
Yield: 96.2 %

Procedure:
To a stirred solution of tert-butyl 4-hydroxy-3-methoxybenzylcarbamate (22.44 g, 88.59 mmol) in acetonitrile (250 mL) was added potassium carbonate (30.61 g, 221.5 mmol) and 5-(chloromethyl)-2-methoxypyridine hydrochloride (18.33 g, 94.46 mmol). The resulting mixture was heated to reflux and stirred. After 23 h, the light green suspension was allowed to cool to room temperature and was diluted with water (600 mL), resulting in the formation of a precipitate. The solids were isolated by filtration and washed with water. The moist solids were dissolved in dichloromethane (300 mL), and a small amount of water separated and was removed. The organic phase was dried over magnesium sulfate, filtered, and concentrated to provide 31.92 g (96%) of tert-butyl 3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzylcarbamate as an off-white solid.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[C:17]([CH2:24]I)[C:16]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:15]2[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=1.O>CN(C)C=O>[O:3]=[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]1[CH2:24][C:17]1[C:16]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:15]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=2)[C:14]2[C:19](=[CH:20][C:21]([O:22][CH3:23])=[C:12]([O:11][CH3:10])[CH:13]=2)[N:18]=1
Reactant: Oc1ccccn1
Reactant: CCOC(=O)c1c(CI)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Cn2ccccc2=O)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.8 %

Procedure:
Oily sodium hydride (60%, 0.117 g) was added to a solution of 2-hydroxypyridine (0.277 g) in N,N-dimethylformamide (DMF)(10 ml), and the mixture was stirred at room temperature for 15 minutes. To this solution was added ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-iodomethylquinoline-3-carboxylate(1.2 g) . The mixture was stirred at room temperature for 8 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residual oil was subjected to column chromatography on silica gel. The fractions eluted with chloroform/ethyl acetate (10/1, v/v) gave ethyl 2-(1,2-dihydro-2-oxopyridine-1-ylmethyl)-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (0.64 g, 57%) which was then recrystallized from ethanol. Colorless prisms. mp. 154°-156° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][S:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.[CH:15]1([N:21]=[C:22]=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[N-]=C=O>C1C=CC=CC=1.C(N(CC)CC)C>[CH:15]1([NH:21][C:22](=[O:23])[O:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:5][CH2:4][CH:3]([O:2][CH3:1])[O:13][CH3:14])[CH:7]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(CSc1cccc(O)c1)OC
Reactant: O=C=NC1CCCCC1
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COC(CSc1cccc(OC(=O)NC2CCCCC2)c1)OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3-(2,2-Dimethoxyethylthio)phenol (0.05 mole) dissolved in benzene (10 ml) is charged into a glass reaction flask equipped with a mechanical stirrer. Cyclohexyl isocyanate (0.06 mole) and triethylamine (3 drops) are then added, and the resulting mixture is stirred at room temperature for a period of about 6 hours. The mixture is then stripped of solvent and unreacted isocyanate to yield the desired product O-[3-(2,2-dimethoxyethylthio) phenyl] N-cyclohexylcarbamate as the residue.
Reaction SMILES: FC(F)(F)[C:3](OC1C(OC(=O)C(F)(F)F)=C(I)C=CC=1)=[O:4].[F:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[C:30]1[O:31][C:32]2[C:38](N)=[CH:37][C:36]([O:40]C)=[CH:35][C:33]=2[N:34]=1.[OH2:42]>C(#N)C.O>[F:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[C:30]1[O:42][C:35]2[C:36](=[O:40])[CH:37]=[C:38]([O:4][CH3:3])[C:32](=[O:31])[C:33]=2[N:34]=1
Reactant: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O
Reactant: COc1cc(N)c2oc(-c3cc(F)ccc3F)nc2c1
Solvent: CC#N
Product: COC1=CC(=O)c2oc(-c3cc(F)ccc3F)nc2C1=O
Temperature: -5 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
7 g (16.2 mmol; 2.2 equivalents) of bis(trifluoroacetoxy)iodobenzene dissolved in 130 ml of an acetonitrile/water mixture 4/1 is added dropwise to a solution of 2.04 g (7.38 mmol) of 2-(2,5-difluorophenyl)-5-methoxy-1,3-benzoxazol-7-amine in 75 ml of an acetonitrile/water mixture 4:1 at −5° C. After stirring for 1 hour at −5° C., 150 ml of water is added to the reaction medium and the product formed is extracted with twice 300 ml of dichloromethane. The organic phases are combined and dried over sodium sulphate, then the solvents are evaporated off under reduced pressure. The residue is then purified by chromatography on a silica column (eluent: dichloromethane/methanol mixture 98:2) and 200 mg (10% yield) of 2-(2,5-difluorophenyl)-5-methoxy-1,3-benzoxazole-4,7-dione is obtained in the form of a yellow powder.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH:16]=1)[C@@H:8]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:9]1)#[CH:2].Cl[Si](C)(C)C.C(N([CH2:29][CH3:30])CC)C.[C:31]1(C)[C:32]([C:37](Cl)=[O:38])=[CH:33][CH:34]=C[CH:36]=1>C(#N)C>[C:1]([C:3]1[C:4](=[O:18])[N:5]([C:37]([C:32]2[CH:33]=[CH:34][C:29]([CH3:30])=[CH:36][CH:31]=2)=[O:38])[C:6](=[O:17])[N:7]([CH:16]=1)[C@@H:8]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:9]1)#[CH:2]
Reactant: CCN(CC)CC
Reactant: Cc1ccccc1C(=O)Cl
Reactant: C#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: C[Si](C)(C)Cl
Solvent: CC#N
Product: C#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n(C(=O)c2ccc(C)cc2)c1=O
Temperature: 25 °C
Yield: 5.1 %

Procedure:
To a stirred suspension of 2'-deoxy-5-ethynyluridine (J. Med. Chem., 26(5), 661-6, (1983)) (0.4 g, 1.6 mmol) in dry acetonitrile (15 ml) and chlorotrimethyl silane (0.7 ml, 5.6 mmol) was added, with ice cooling, triethylamine (1.13 ml, 8.1 mmol) and stirring was maintained at room temperature for 2.5 hr. Toluoylchloride (0.3 ml, 2.1 mmol) was then added and after stirring for a further 7 hr the mixture was filtered, the filtrate evaporated to dryness and the residue dissolved in ethanol (20 ml). Glacial acetic acid was then added and after stirring for 0.5 hr at room temperature the solvent was evaporated and residual acetic acid coevaporated with ethanol. Purification of the product by thick layer silica chromatography eluting with methanol/methylenechloride (1:24) followed by recrystallisation from methanol afforded title compound (0.03 g) melting at 176-9° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[N:18]#[C:19]Cl.[CH2:21]([N:23](CC)CC)C>CC(C)=O>[O:1]([C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:19]#[N:18])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1)[C:21]#[N:23]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CCN(CC)CC
Reactant: N#CCl
Solvent: CC(C)=O
Product: CC(C)(c1ccc(OC#N)cc1)c1ccc(OC#N)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
According to Example 7 of U.S. Pat. No. 3,553,244, 228 parts by weight of 2,2-bis-(4-hydroxyphenyl)-propane are dissolved in 400 parts by weight of acetone and cooled to 0° C. 135 parts by weight of cyanogen chloride are added dropwise at that temperature. 120 parts by weight of triethylamine are then added with external cooling, the temperature being kept below 10° C. On completion of the dropwise addition, the mixture is stirred for 30 minutes, after which the triethylamine hydrochloride which has crystallized out is filtered off. After the acetone has been distilled off, 2,2-bis-(4-cyanatophenyl)-propane is obtained from the filtrate in the form of colorless crystals melting at 77° to 80° C in a quantity of 212 parts by weight (corresponding to a yield of 76%, based on the theoretical amount). The purity amounts to approximately 95% (as determined by IR-spectroscopy).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7](O)=[O:8])=[C:5]([CH3:10])[S:4][N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:8][CH2:7][C:6]1[C:2]([CH3:1])=[N:3][S:4][C:5]=1[CH3:10]
Reactant: Cc1nsc(C)c1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nsc(C)c1CO

Procedure:
3,5-Dimethyl-4-isothiazolecarboxylic acid is converted to the methyl ester and the ester is reduced with lithium aluminium hydride in tetrahydrofuran to give 4-hydroxymethyl-3,5-dimethylisothiazole. Treating this hydroxymethyl compound with thionyl bromide gives 4-bromomethyl-3,5-dimethylisothiazole which is used as the starting material in the procedure of Example 121 to give N-cyano-N'-methyl-N"-[2-((3,5-dimethyl-4-isothiazolyl)-methylthio)ethyl]guanidine.
Reaction SMILES: C([O:8][C:9]1[C:10]([O:42]CC2C=CC=CC=2)=[CH:11][C:12]2[CH2:18][CH2:17][CH2:16][C:15]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:40])[C:28]4[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=4)[CH2:23][CH2:22]3)=[O:20])=[CH:14][C:13]=2[CH:41]=1)C1C=CC=CC=1.Br.O.C(OCC)(=O)C>C(O)(=O)C>[OH:8][C:9]1[C:10]([OH:42])=[CH:11][C:12]2[CH2:18][CH2:17][CH2:16][C:15]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:40])[C:28]4[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=4)[CH2:23][CH2:22]3)=[O:20])=[CH:14][C:13]=2[CH:41]=1
Reactant: COc1cc(C(=O)N2CCN(C(=O)C3=Cc4cc(OCc5ccccc5)c(OCc5ccccc5)cc4CCC3)CC2)cc(OC)c1OC
Agent: Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C(=O)N2CCN(C(=O)C3=Cc4cc(O)c(O)cc4CCC3)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
In acetic acid (40 ml) is dissolved 1-(2,3-dibenzyloxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)-4-(3,4,5-trimethoxybenzoyl)piperazine (4.0 g). To the solution is added an acetic acid solution of 30% hydrobromic acid (40 ml). The mixture is stirred at room temperature for one hour. To the reaction mixture is added water and ethyl acetate, and the mixture is shaken. The organic layer is washed with water and an aqueous solution of sodium hydrogencarbonate, dried and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent, acetone:ethyl acetate:hexane:methylene chloride=2:1:1:1) to give 1-(2,3-dihydroxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)-4-(3,4,5-trimethoxybenzoyl)piperazine (1.25 g). This product is recrystallized from ethyl acetate to give colorless crystals, m.p. 206°-207° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[NH2:6].[C:16]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C:25]1=O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(OC)C=CC=CC=1>[Pd].C(N(CC)CC)C>[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[NH:6][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16](=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C1CCCCC1C(=O)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: COc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccccc1

Procedure:
A mixture of tyrosine methyl ester hydrochloride (4.8 g), 2-benzoylcyclohexanone (5.0 g), palladium on carbon (1.0 g, 10%), triethylamine (2.9 ml) and anisole (70 ml) was heated at reflux for 20 hours. The reaction mixture was filtered and the filtrate was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using hexane: ethyl acetate=3:1 as the eluant to afford the title compound (1.83 g, Rf=0.39: thin layer chromatography on a silica gel plate using hexane: ethyl acetate=3:1 as the eluant).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4][N:3]1[CH2:23][C:24](=[S:26])[NH2:25].[CH2:27](OC(OCC)CBr)[CH3:28]>CO.C(Cl)(Cl)Cl>[O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4][N:3]1[CH2:23][C:24]1[S:26][CH:27]=[CH:28][N:25]=1
Reactant: CCOC(CBr)OCC
Reactant: NC(=S)Cn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1Cc1nccs1

Procedure:
A mixture of 3-(3-oxo-2-thiocarbamoylmethyl-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.50 g) and bromoacetaldehyde diethyl acetal (0.54 ml) in a mixture of methanol (2.5 ml) and chloroform (5 ml) was refluxed for 54 hours. After evaporating the solvent, the residue was chromatographed on silica gel (40 ml) using a mixture of chloroform and ethyl acetate (20:1). The desired fractions were collected and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 3-[3-oxo-2-(2-thiazolylmethyl)-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.23 g) as yellow needles.
Reaction SMILES: O.[NH2:2][NH2:3].O=[C:5]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)[CH2:6][C:7]#[N:8]>C(O)C>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:12]1[CH2:11][CH2:10][CH:9]([C:5]2[CH:6]=[C:7]([NH2:8])[NH:3][N:2]=2)[CH2:14][CH2:13]1
Reactant: N#CCC(=O)C1CCN(c2ccccn2)CC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1cc(C2CCN(c3ccccn3)CC2)n[nH]1
Reaction time: 5 h
Yield: 89.1 %

Procedure:
Hydrazine monohydrate (0.20 mL, 4.12 mmol) was added to a solution of 3-oxo-3-[1-(pyridin-2-yl)piperidin-4-yl]propanenitrile (138 mg, 0.60 mmol) produced in Reference Example 1 in ethanol (20 mL), and the mixture was stirred for 5 hours under heating to reflux. The reaction solution was left until reaching room temperature, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elute: ethyl acetate/methanol=100/0-94/6 (gradient)] to obtain the title compound (130 mg, yield: 89%).