Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]=[CH:6][N:7](C(OCC)C)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=1)[CH3:3].CN(C)CCN(C)C.C([Li])CCC.[F:35][C:36]([F:48])([F:47])[C:37](=[N:42][Si](C)(C)C)[C:38]([F:41])([F:40])[F:39].C(=O)(O)[O-].[Na+]>O1CCCC1.CCCCCC>[CH3:3][CH:2]([C:4]1[N:5]=[C:6]([C:37]([C:38]([F:41])([F:40])[F:39])([C:36]([F:48])([F:47])[F:35])[NH2:42])[NH:7][C:8]=1[C:9]1[CH:10]=[CH:11][C:12]([S:15][CH3:16])=[CH:13][CH:14]=1)[CH3:1]
Reactant: CCOC(C)n1cnc(C(C)C)c1-c1ccc(SC)cc1
Reactant: C[Si](C)(C)N=C(C(F)(F)F)C(F)(F)F
Agent: CN(C)CCN(C)C
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1ccc(-c2[nH]c(C(N)(C(F)(F)F)C(F)(F)F)nc2C(C)C)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 16.8 %

Procedure:
To a stirred solution of 4-(1-methylethyl)-5-(4-methylthiophenyl)-1-(α-ethoxyethyl)imidazole (12.0 g, 0.04 mole) in 150 ml of dry tetrahydrofuran was added 6.85 ml of tetramethylethylenediamine (0.045 moles). The reaction was cooled to -78° C. and 39.47 ml of 1.6M n-butyl lithium in hexane was added dropwise. After stirring the mixture for 20 minutes, 15.45 g of [1,1-di(trifluoromethyl)methyleneamino]-trimethylsilane was added dropwise. The reaction mixture was stirred an additional hour, warmed to 0° C. and 140 ml of saturated aqueous sodium bicarbonate solution was added dropwise. The reaction was warmed to room temperature and the layers were separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and concentrated and the residue was stirred overnight in 260 ml of ethanol and 260 ml of 2N aqueous hydrochloric acid. The ethanol was evaporated and the aqueous was extracted with ether (3×), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (92:8 hexane/ethyl acetate) to afford 2.67 g of a white crystalline solid, m.p. 105°-107° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:8]=[C:7]([NH:17][S:18]([CH2:21][CH2:22][CH3:23])(=[O:20])=[O:19])[C:6]=1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32].[H-].[Na+].Cl[C:36]1[N:41]=[CH:40][C:39]([S:42][CH3:43])=[CH:38][N:37]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:43][S:42][C:39]1[CH:38]=[N:37][C:36]([O:1][CH2:2][CH2:3][O:4][C:5]2[N:10]=[C:9]([C:11]3[N:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[N:8]=[C:7]([NH:17][S:18]([CH2:21][CH2:22][CH3:23])(=[O:20])=[O:19])[C:6]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])=[N:41][CH:40]=1
Reactant: CCCS(=O)(=O)Nc1nc(-c2ncccn2)nc(OCCO)c1Oc1ccccc1OC
Reactant: CSc1cnc(Cl)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1nc(-c2ncccn2)nc(OCCOc2ncc(SC)cn2)c1Oc1ccccc1OC
Temperature: 75 °C
Yield: 52.2 %

Procedure:
n-Propanesulfonic acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (92 mg) was dissolved in THF (6 ml). Sodium hydride (40 mg) and 2-chloro-5-methylsulfanyl-pyrimidine (71 mg) were added and the mixture was heated to 75° C. for 6 h, then poured onto water, acidified with solid citric acid and the precipitate was filtered off. The crude material was purified by crystallization from methanol to give n-propanesulfonic acid [6-[2-(5-methylsulfanyl-pyrimidin-2-yloxy)-ethoxy]-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (61 mg) as a white powder. LC-MS: tR: 4.37, [M+H]+: 586.19.
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].[N:5]([C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:28])[C:13]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[C:14]([CH:18]([CH3:20])[CH3:19])[O:15]2)=[CH:10][CH:9]=1)=[N+]=[N-]>O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:13]2[C:12](=[O:28])[C:11]3[CH:10]=[CH:9][C:8]4[N:5]=[C:1]([CH3:2])[O:3][C:17]=4[C:16]=3[O:15][C:14]=2[CH:18]([CH3:20])[CH3:19])=[CH:22][CH:23]=1
Reactant: CC(=O)O
Reactant: CC(C)c1oc2cc(N=[N+]=[N-])ccc2c(=O)c1-c1ccc(Cl)cc1
Solvent: O
Product: Cc1nc2ccc3c(=O)c(-c4ccc(Cl)cc4)c(C(C)C)oc3c2o1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
Acetic acid (20 ml) is added to polyphosphoric acid (˜25 g) heated to 80° C. The viscous solution is stirred vigorously for 5 min. 7-azido-3-(4-chlorophenyl)-2-isopropyl-chromen-4-one (1.0 g, 2.95 mmol) is added portionwise over a period of 10 min. The reaction mixture is heated at 120° C. for 3 h, cooled to room temperature and poured into water (200 ml), and the product is extracted with CH2Cl2. The organic phase is washed with water and brine, dried (MgSO4) and filtered. Methanol (30 ml) is added, followed by partial evaporation in vacuo to give a precipitate, which is isolated by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C@@H:16]([CH2:17][CH3:18])[C:15](=O)[C:14]3[NH:20][N:21]=[CH:22][C:13]=3[C@H:12]2[CH2:23][CH3:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC([O-])=O.[Na+].Cl.[NH2:31][OH:32]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C@@H:16]([CH2:17][CH3:18])/[C:15](=[N:31]/[OH:32])/[C:14]3[NH:20][N:21]=[CH:22][C:13]=3[C@H:12]2[CH2:23][CH3:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC[C@@H]1c2cn[nH]c2C(=O)[C@H](CC)N1S(=O)(=O)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC[C@@H]1c2cn[nH]c2/C(=N\O)[C@H](CC)N1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of compound 62 (67 mg, 0.17 mmol) in a mixture of MeOH/H2O (5:1, 9 mL) was added NaOAc (141 mg, 1.7 mmol) followed by hydroxylamine hydrochloride (131.6 mg, 1.9 mmol). The resulting solution was stirred at room temperature for a weekend. The solvent was removed by rotary evaporation and the residue was taken up in EtOAc. The organic phase was washed with water, brine and dried (MgSO4). After removal of the solvent under reduced pressure, the crude product was purified by flash chromatography to give a white solid as the product 63 1H NMR (CDCl3) δ 10.28 (bs, 1H), 7.56 (d, J=9.0 Hz, 2H), 7.45 (s, 1H), 7.20 (d, J=9.0 Hz, 2H), 5.48 (dd, J=4.5, 10.5 Hz, 1H), 4.97 (t, J=7.5 Hz, 1H), 2.06-1.96 (m, 1H), 1.91-1.77 (m, 2H), 1.68-1.57 (m, 1H), 1.22 (t, J=6.9 Hz, 3H), 114 (t, J=7.2 Hz, 3H); MS (m/z) 383.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][CH:14]=2)=[CH:6][C:7]=1[CH3:8].[C:19]([NH:22][NH2:23])(=O)[CH3:20]>C(O)CCC>[CH3:20][C:19]1[N:3]2[N:4]=[C:5]([C:9]3[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][CH:14]=3)[CH:6]=[C:7]([CH3:8])[C:2]2=[N:23][N:22]=1
Reactant: CC(=O)NN
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)nnc1Cl
Solvent: CCCCO
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)nn2c(C)nnc12

Procedure:
As in Example 36, a mixture of 8.0 g. of 3-chloro-4-methyl-6-(α,α,α-trifluoro-m-tolyl)pyridazine, 4.34 g. of acetylhydrazine in 125 ml. of n-butanol is refluxed for 48 hrs. to give 3.9 g. of product as crystals, m.p. 196°-198° C.
Reaction SMILES: C(S[C:9]1[C:10]([O:23][CH3:24])=[C:11]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])[CH:12]=[C:13]([F:15])[CH:14]=1)C1C=CC=CC=1.[S:25]([Cl:29])(Cl)(=[O:27])=[O:26]>>[F:15][C:13]1[CH:12]=[C:11]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])[C:10]([O:23][CH3:24])=[C:9]([S:25]([Cl:29])(=[O:27])=[O:26])[CH:14]=1
Reactant: COc1c(SCc2ccccc2)cc(F)cc1N1CCCCC1=O
Reactant: O=S(=O)(Cl)Cl
Product: COc1c(N2CCCCC2=O)cc(F)cc1S(=O)(=O)Cl

Procedure:
Intermediate 14 (1.6 g, 4.63 mmol) was converted to the title compound sulfonyl chloride using the procedure described in example 1; 1.6). The crude material was used without further purification in the next step.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:31]([C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccccn3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(Cc5ccccn5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-(pyridin-2-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.043 g, 0.11 mmol), and ethanol (2.5 ml) was added 4-methoxybenzaldehyde (0.024 g, 0.18 mmol) with the aid of ethanol (1 ml) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was heated at 70° C. for 4 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with ethyl acetate/dichloromethane (v/v; 1:1), and then 4% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a yellow solid after trituration with diethyl ether (0.010 g, 19%); 1H-NMR (500 MHz, DMSO-d6) 2.67 (br s, 4H, piperazine N(CH2)2), 3.68 (br s, 4H, piperazine N(CH2)2), 3.70 (s, 2H, NCH2), 3.84 (s, 3H, OMe), 7.10 (d, J=8.86 Hz, 2H) and 8.13 (d, J=8.75 Hz, 2H) (3,5-C6H4OMe and 2,6-C6H4—OMe), 7.28 (dd, J=5.00, 6.45 Hz, 1H), 7.52 (d, J=7.80 Hz, 1H), 7.79 (td, J=1.75, 7.65 Hz, 1H) and 8.52 (d, J=4.80 Hz, 1H) (pyrid-2-yl protons), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.35 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.CO[CH:11](OC)[N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15]>C1(C)C(C)=CC=CC=1>[CH3:15][CH2:14][CH2:13][N:12]([CH:11]=[N:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][CH:3]=1)[CH2:16][CH2:17][CH3:18]
Reactant: Nc1cccc(O)n1
Reactant: CCCN(CCC)C(OC)OC
Solvent: Cc1ccccc1C
Product: CCCN(C=Nc1cccc(=O)[nH]1)CCC

Procedure:
8.3 g (76 mmol) of 6-amino-2-hydroxypyridine and 20 g (114 mmol) of N,N-di-n-propylformamide dimethyl acetal are placed in 70 ml of xylene under argon. .The whole is heated at 100° for 1/2 hour while stirring It is then allowed to cool, is concentrated by evaporation under a water-jet vacuum and the residue is filtered over 10 times the amount of Florisil using methylene chloride. The fractions containing the product are concentrated by evaporation and then crystallised from n-hexane. N-(2-hydroxy-6-pyridyl)-N',N'-di-n-propylformamidine and N-(2-pyridon-6-yl)-N',N'-di-n-propylformamidine having a melting point of 102°-104° are obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:6]=1)=[O:4].S(Cl)([Cl:19])(=O)=O.CCOCC>CC#N>[NH2:11][C:9]1[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:6]=[C:5]([C:3]([OH:2])=[O:4])[C:10]=1[Cl:19]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)c1cc(N)cc(C(F)(F)F)n1
Solvent: CC#N
Solvent: CCOCC
Product: Nc1cc(C(F)(F)F)nc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.5 %

Procedure:
To a solution containing 4-amino-6-trifluoromethylpyridine-2-carboxylic acid methyl ester (0.75 g, 3.4 mmol) in 5 mL of CH3CN was added dropwise a solution of sulfuryl chloride (0.27 mL, 3.4 mmol) in 1 mL of CH3CN. After stirring at RT for 1 hr, reaction mixture was added to 50 mL of Et2O and washed with aqueous NaHCO3, dried over MgSO4, filtered and concentrated to give a solid. The crude product was purified by chromatography, eluting with 10% ethyl acetate-hexane to give 200 mg of product as a white solid; mp 131-3° C.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].CC(C)([O-])C.[Na+].[Br:13][C:14]1[CH:19]=[N:18][C:17](Br)=[CH:16][N:15]=1>C1COCC1.C(OCC)(=O)C>[Br:13][C:14]1[N:15]=[CH:16][C:17]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[N:18][CH:19]=1
Reactant: Brc1cnc(Br)cn1
Reactant: CN(C)CCO
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)CCOc1cnc(Br)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87.5 %

Procedure:
To a solution of 2-(dimethylamino)ethanol (28-1, 8.00 g, 78.9 mmol) in THF (100 mL) was added sodium tert-butoxide (10.0 g, 102.0 mmol) at room temperature. The reaction was stirred for 15 min. The reaction mixture was cooled to 0° C. and added with a solution of 2,5-dibromopyrazine (28-2, 20.0 g, 82.4 mmol) in THF (100 ml) slowly in a period of 5.0 min. The reaction mixture was warmed to room temperature and stirred for 16 h. The mixture was diluted with ethyl acetate and washed with saturated NH4Cl. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give 2-((5-bromopyrazin-2-yl)oxy)-N,N-dimethylethanamine (28-3, 17.0 g) as yellow oils in 88% yield: 1H NMR (500 MHz, CDCl3) δ 8.46 (s, 1 H), 8.16 (d, J=1.1 Hz, 1 H), 8.06 (d, J=1.1 Hz, 1 H), 4.68 (t, J=4.8 Hz, 2 H), 3.20 (s, 2 H), 2.70 (s, 6 H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([C@H:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20](O)([OH:23])[CH2:21][CH3:22]>>[C:1]([C:9]1[CH:10]=[C:11]([C@H:15]([CH3:19])[C:16]([O:18][CH2:22][CH2:21][CH2:20][OH:23])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Reactant: CCC(O)O
Product: C[C@H](C(=O)OCCCO)c1cccc(C(=O)c2ccccc2)c1
Yield: 56.1 %

Procedure:
Compound 18 was synthesized as described above for compound 10 from (S)-(+)-3-benzoyl-α-methylbenzeneacetic acid (ketoprofen, 17) (3.8 g, 15 mmol) and propanediol (9) (5.7 g, 75 mmol). The compound was purified by flash chromatography on a silica gel column using 200:1 CH2Cl2—MeOH as the eluent to give 2.63 g (56%) of the compound 18 as a colorless oil; 1H NMR (CDCl3) δ1.54 (d, 3H), 1.82 (m, 2H), 1.82-1.82 (b, 1H, ex D2O), 3.58 (m, 2H), 3.79-3.83 (q, 1H), 4.25 (m, 2H), 7.42-7.80 (m, 9H); MS (ES) m/z 313.1 (M+H)+ (C19H21O4 requires 313.3).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]([C:18]2[CH:23]=[C:22]([O:24]C(C)C)[C:21]([Cl:28])=[CH:20][C:19]=2[F:29])[C:6](=[O:17])[CH:7]=[C:8]([C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[N:9]=1)[CH3:2].S(=O)(=O)(O)O>>[CH2:1]([O:3][C:4]1[N:5]([C:18]2[CH:23]=[C:22]([OH:24])[C:21]([Cl:28])=[CH:20][C:19]=2[F:29])[C:6](=[O:17])[CH:7]=[C:8]([C:10]([F:16])([F:15])[C:11]([F:12])([F:13])[F:14])[N:9]=1)[CH3:2]
Reactant: CCOc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(OC(C)C)c(Cl)cc1F
Agent: O=S(=O)(O)O
Product: CCOc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F

Procedure:
using 2-ethoxy-1-(4-chloro-2-fluoro-5-isopropoxyphenyl)-4-pentafluoroethyl-6(1H)-pyrimidinone with concentrated sulphuric acid at 0° C. during 1.5 minutes there is obtained 2-ethoxy-1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-pentafluoroethyl-6(1H)-pyrimidinone, m.p. 117°-120° C.;
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:20]1[C:21](O)=[CH:22][C:23]3[O:27][CH2:26][CH2:25][C:24]=3[CH:28]=1)([CH2:18][OH:19])[C:5](=[O:17])[N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].ClC1C=CC(Cl)=C2C=1C(C1C(O)=CC3OCOC=3C=1)(CO)C(=O)N2CCCCC>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:18][O:19][C:21]3[CH:22]=[C:23]4[C:24](=[CH:28][C:20]1=3)[CH2:25][CH2:26][O:27]4)[C:5](=[O:17])[N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)OCC3)c2c(Br)cccc21
Agent: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2c(Cl)ccc(Cl)c21
Product: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2c(Br)cccc21

Procedure:
Following the procedure as described in EXAMPLE 1.22, and making non-critical variations using ethyl [4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate to replace 4,7-dichloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (41%) as a colorless solid: MS (ES+) m/z 445.5 (M+1).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[S:22][CH:21]=[CH:20][C:16]=3[N:17]([CH3:19])[N:18]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)=O)C>C(Cl)Cl>[CH3:19][N:17]1[C:16]2[CH:20]=[CH:21][S:22][C:15]=2[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:18]1
Reactant: Cn1nc(N2CCN(Cc3ccccc3)CC2)c2sccc21
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: Cn1nc(N2CCNCC2)c2sccc21
Yield: 80 %

Procedure:
To a solution of a mixture of 3-(4-Benzyl-piperazin-1-yl)-1-methyl-1H-thieno[3,2-c]pyrazole and the 2-methyl analog (189.0 g, 0.60 mol) is dissolved in DCM (1.25 L) is added 1-chloroethylchloroformate (78.6 mL, 0.72 mol). The solution is heated at reflux for 1 hour when the mixture is cooled and the solvent is removed by evaporation. The residue is taken up in methanol (1 L) and heated at reflux for 30 minutes. After cooling, the solution is treated with 1 N HCl in ether (200 mL) and an additional 1 L of ether to afford the precipitation of the product. The solid is collected via filtration and washed with cold ether. The solid is recrystallized from methanol (1 L) and the HCl salt is collected by filtration, washed with ether and dried under vacuum yielding 123.04 g (80%) of the desired product as an 80:1 mixture of regioisomers in favor of the desired regioisomer as seen by NMR.
Reaction SMILES: C(O)C.[OH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1.Cl[C:26]1[N:31]([CH3:32])[C:30](=[O:33])[N:29]([CH3:34])[C:28](=[O:35])[CH:27]=1>C(N(CC)CC)C>[CH3:32][N:31]1[C:26]([N:7]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[CH2:14][CH2:15]2)[CH2:6][CH2:5][OH:4])=[CH:27][C:28](=[O:35])[N:29]([CH3:34])[C:30]1=[O:33]
Reactant: O=[N+]([O-])c1ccc(N2CCN(CCNCCO)CC2)cc1
Reactant: Cn1c(Cl)cc(=O)n(C)c1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cn1c(N(CCO)CCN2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc(=O)n(C)c1=O

Procedure:
To 10 ml of ethanol were added 1.0 g of the thus obtained compound 75, 0.52 g of 6-chloro-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione and 2 ml of triethylamine as starting materials, and the resulting mixture was treated in the same procedure as in Example 39-(2) to obtain 0.73 g of 1,3-dimethyl-6-{N-(2-hydroxyethyl)-2-[4-(4-nitrophenyl)piperazin-1-yl]ethylamino}-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: Cl[CH2:2][Si:3]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Na].[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1>CN(C)C=O>[CH3:13][C:12]([CH3:15])([O:11][Si:3]([CH3:10])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:2][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH3:14]
Reactant: CC(C)(C)O[Si](C)(CCl)c1ccccc1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)(C)O[Si](C)(Cn1cncn1)c1ccccc1
Reaction time: 2 h
Yield: 65.4 %

Procedure:
A mixture of 3.6 g (0.015 mol) of chloromethyl(1,1-dimethylethoxy)methyl(phenyl)silane and 1.3 g (0.015 mol) of 1,2,4-triazole sodium salt in 8 ml of dimethylformamide was stirred at 80° for 2 hours, cooled, and poured onto water. The resulting mixture was extracted with ether, and the ether extracts were washed with water and brine, dried over magnesium sulfate, and evaporated to leave 2.7 g of a yellow oil. Chromatography on silica gel, eluting with 50:50 ethyl acetate-hexanes, provided 1.5 g (36%) of the title compound as a pale yellow oil: nD21 1.5134; ir (neat) 3120, 3070, 3045, 2975, 2925, 1500, 1425, 1380, 1365, 1270, 1255, 1240, 1190, 1140, 1115, 1050, 1020, 1010, 830, 810, 790, 740, 700, 680 cm-1 ; nmr (CDCl3): 0.6 (3H, s), 1.3 (9H, s), 3.9 (2H, s), 7.3-7.7 (5H, m), 7.9 (1H, s) and 8.0 (1 H, s).
Reaction SMILES: COS([O-])(=O)=O.[N:7]1([C:12]2[CH:13]=[C:14]3[C:20]([CH2:21][N+](C)(C)C)=[CH:19][NH:18][C:15]3=[CH:16][N:17]=2)[CH:11]=[N:10][CH:9]=[N:8]1.[C-:26]#[N:27].[K+]>O>[N:7]1([C:12]2[CH:13]=[C:14]3[C:20]([CH2:21][C:26]#[N:27])=[CH:19][NH:18][C:15]3=[CH:16][N:17]=2)[CH:11]=[N:10][CH:9]=[N:8]1
Reactant: [C-]#N
Reactant: C[N+](C)(C)Cc1c[nH]c2cnc(-n3cncn3)cc12
Agent: COS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: N#CCc1c[nH]c2cnc(-n3cncn3)cc12
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 63.9 %

Procedure:
To a solution of N-([5-(1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]methyl-N,N,N-trimethylammonium methylsulphate (0.56 g, 1.5 mmol) in water (4ml) was added a solution of potassium cyanide (0.239 g, 3.7 mmol) in water (2ml). This mixture was heated at 70° C. for 1 h. Further potassium cyanide (80mg, 1.2 mmol) was added and the mixture heated for another hour at 70° C. Further potassium cyanide (80mg, 1.2 mmol) was added and the mixture heated at 70° C. for 1 hour and then at 100° C. for 20 min. The mixture was then cooled in ice for 30 min. The precipitate was collected by filtration and washed with water. The solid was chromatographed on silica eluting with 5% MeOH in DCM to afford the title compound (0.215 g, 63%) as a colourless solid; mp 218°-220° C. 1H NMR (250 MHz, d6 -DMSO) δ 4.19 (2H, s), 7.78 (1H, s), 8.12 (1H, s), 8.26 (1H, s), 8.71 (1H, s), 9.29 (1H, s), 11.93 (1H, br s).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[C:3]([OH:5])=[O:4].CI.[C:13](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:1][CH:2]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[C:3]([O:5][CH3:13])=[O:4]
Reactant: O=C(O)C(O)c1ccsc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)C(O)c1ccsc1
Yield: 65.3 %

Procedure:
A mixture of (RS) 2-hydroxy-2-(thien-3-yl)acetic acid (prepared as described in Akiv. Kemi., 58, 519, 1957) (6.32 g), methyl iodide (17 g) and potassium carbonate (6 g) in acetone was refluxed for 2 hours, evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The organic extracts, after drying over magnesium sulphate, were evaported to leave the title compound as a yellow oil (4.49 g, 67%).
Reaction SMILES: CS(O[CH:6]([C:8]1[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([Cl:17])[CH:11]=2)[CH3:7])(=O)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O>[N:25]([CH:6]([C:8]1[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([Cl:17])[CH:11]=2)[CH3:7])=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(OS(C)(=O)=O)c1cc2ccc(Cl)cc2n1-c1cccc(F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])c1cc2ccc(Cl)cc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the crude 1-[6-chloro-1-(3-fluorophenyl)-1H-indol-2-yl]ethyl methanesulfonate in N,N-dimethylformamide (1 mL) was added sodium azide (57 mg, 0.88 mmol). The reaction was stirred at room temperature for 2 hours, quenched with water, and then extracted with EtOAc. The extracts were combined, washed with brine, dried over MgSO4 and concentrated to give the desired azide (55 mg), which was used directly in the next step. LCMS calculated for C16H12ClFN (M-N3)+: m/z=272.1. Found: 271.9.
Reaction SMILES: C(N(CC)CC)C.[NH:8]=[C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]=[CH:10]1.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23].O>C(Cl)Cl>[C:21]([N:8]=[C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:11]=[CH:10]1)(=[O:25])[C:22]([CH3:24])=[CH2:23]
Reactant: N=c1ccn(-c2ccccc2)nc1
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C=C(C)C(=O)N=c1ccn(-c2ccccc2)nc1
Reaction time: 2 h
Yield: 21 %

Procedure:
24.0 g (237 millimoles) of triethylamine were added dropwise to 15.0 g (72.2 millimoles) of 1,4-dihydro-4-imino-1-phenylpyridazine hydrochloricde and 12.8 g (~98 millimols) of ~80% strength methacryloyl chloride in 200 ml of methylene chloride at room temperature, while stirring. After the addition was complete, stirring was continued for a further 2 hours at room temperature, after which water was added to the reaction mixture. The organic phase was separated off, washed with water and evaporated down. The residue was recrystallized three times from toluene. 3.6 g (21% of theory) of 1,4-dihydro-4-methacryloylimino-1-phenylpyridazine were isolated as yellow crystals of melting point 136° C.