Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH:13]2[C:22]3[C:17](=[C:18]([CH3:27])[CH:19]=[C:20]([C:24]([OH:26])=[O:25])[C:21]=3[CH3:23])[S:16](=[O:29])(=[O:28])[CH2:15][CH2:14]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(Cl)(=O)C(Cl)=O.[C:36]1(=O)[CH2:41][CH2:40][CH2:39][CH2:38][C:37]1=[O:42].C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[C:3]([O:12][CH:13]2[C:22]3[C:17](=[C:18]([CH3:27])[CH:19]=[C:20]([C:24]([O:26][C:41]4[CH2:40][CH2:39][CH2:38][C:37](=[O:42])[CH:36]=4)=[O:25])[C:21]=3[CH3:23])[S:16](=[O:28])(=[O:29])[CH2:15][CH2:14]2)=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CCC2Oc1ncc(C(F)(F)F)cc1Cl
Reactant: O=C1CCCCC1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)OC2=CC(=O)CCC2)c(C)c2c1S(=O)(=O)CCC2Oc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.56 g (1.2 mmol) of 4-{[3-chloro-5-(trifluoromethyl)-2-pyridyl]oxy}-5,8-dimethyl-1,1-dioxo-1,2,3,4-tetrahydro-1λ6-thiochromene-6-carboxylic acid in 30 ml of methylene chloride was admixed with 2 drops of N,N-dimethylformamide and 0.48 g (3.8 mmol) of oxalyl chloride, and the mixture was boiled under reflux for 3.5 h. The solvents were subsequently stripped off using a rotary evaporator and the residue was taken up in 100 ml of methylene chloride and, at 0° C., admixed with 0.15 g (1.4 mmol) of cyclohexanedione and 0.22 g (3.7 mmol) of triethylamine. The mixture was stirred at room temperature for 4 h and subsequently concentrated using a rotary evaporator, and the residue was purified by chromatography (silica gel, ethyl acetate: hexane=1:1).
Reaction SMILES: [CH:1]1([N:4]([CH:33]2[CH2:35][CH2:34]2)[C:5]([C:7]2[N:30]([CH2:31][CH3:32])[C:10]3=[N:11][C:12]([NH:19][C:20]([NH:22][C:23]4[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[CH:24]=4)=[S:21])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.C1C(=O)N(I)C(=O)C1>C(Cl)(Cl)Cl>[CH:1]1([N:4]([CH:33]2[CH2:35][CH2:34]2)[C:5]([C:7]2[N:30]([CH2:31][CH3:32])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][C:24]5[C:25]([CH3:29])=[N:26][N:27]([CH3:28])[C:23]=5[N:22]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(=S)Nc3cc(C)nn3C)nc21
Agent: O=C1CCC(=O)N1I
Solvent: ClC(Cl)Cl
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc4c(s3)c(C)nn4C)nc21
Temperature: 0 °C

Procedure:
N,N-Dicyclopropyl-4-(3-(1,3-dimethyl-1H-pyrazol-5-yl)thioureido)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 41B, 41 mg, 0.083 mmol) was dissolved in chloroform (2780 μL) and cooled to 0° C. NIS (18.76 mg, 0.083 mmol) was slowly added and the reaction was warmed to room temperature. The reaction mixture was concentrated. Methanol and ether were added and the mixture was filtered. After standing for a week, product precipitated out of the solution. The product was triturated with methanol. N,N-Dicyclopropyl-4-(1,3-dimethyl-1H-pyrazolo[3,4-d]thiazol-5-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide was isolated as a pale yellow solid (8.1 mg, 20% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH2:9][S:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.[CH3:18][C:19]([CH3:24])([CH2:22]O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:18][C:19]1([CH3:24])[CH2:20][O:21][C:8]([CH2:9][S:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[O:17][CH2:22]1
Reactant: CC(C)(CO)CO
Reactant: CCOC(=O)CSCC(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)CSCC1(c2ccc(C)cc2)OCC(C)(C)CO1
Yield: 61 %

Procedure:
Ethyl {[2-(4-methylphenyl)-2-oxoethyl]thio}acetate (12.2 g, 48.4 mmol) was dissolved in benzene (350 ml). 2,2-Dimethyl-1,3-propanediol (40.3 g, 0.387 mol) and p-toluene sulfonic acid (1 g) were added. The mixture was stirred at reflux in a Dean-Stark apparatus for two hours, cooled and concentrated under reduced pressure. CH2Cl2 was added and the organic phase was washed twice with brine and dried (MgSO4). Filtration and concentration under reduced pressure afforded a crude oil, which was purified by flash-chromatography (hexane:EtOAc 8:1) to afford 10.0 g (61%) of the title compound as a clear oil.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[O:17][CH2:16]2)=[CH:11][CH:10]=1)([CH3:3])[CH3:2].[NH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=2)=[CH:26][C:25]=1[Cl:37]>>[CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=3)=[CH:26][C:25]=2[Cl:37])=[CH:11][CH:10]=1)([CH3:3])[CH3:2]
Reactant: NCCOc1ccc(C2=NNC(=O)CC2)cc1Cl
Reactant: CC(C)OCCOCc1ccc(OCC2CO2)cc1
Product: CC(C)OCCOCc1ccc(OCC(O)CNCCOc2ccc(C3=NNC(=O)CC3)cc2Cl)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isopropoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=1[S:16][C:17]1[N:18]([CH2:25][C@:26]2([CH3:29])[CH2:28][O:27]2)[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[N:21]=1.[N:30]1([C:36]([O:38][CH2:39][CH:40]=[CH:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=2)=[O:37])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.O>C(OCC)(=O)C>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=1[S:16][C:17]1[N:18]([CH2:25][C@:26]([OH:27])([CH3:29])[CH2:28][N:33]2[CH2:32][CH2:31][N:30]([C:36]([O:38][CH2:39][CH:40]=[CH:41][C:42]3[CH:47]=[CH:46][C:45]([C:48]([F:50])([F:51])[F:49])=[CH:44][CH:43]=3)=[O:37])[CH2:35][CH2:34]2)[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[N:21]=1
Reactant: O=C(OCC=Cc1ccc(C(F)(F)F)cc1)N1CCNCC1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Sc2c(Cl)cccc2[N+](=O)[O-])CO1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@](O)(CN1CCN(C(=O)OCC=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Sc1c(Cl)cccc1[N+](=O)[O-]
Yield: 89.5 %

Procedure:
N,N-Dimethylformamide (0.25 ml) solution of (R)-2-(2-chloro-6-nitrophenylthio)-1-(2-methyl-2-oxiranylmethyl)-4-nitroimidazole (55 mg) and 3-(4-trifluoromethylphenyl)-2-propenyl piperazin-1-carboxylate (51 mg) was stirred at 60° C. for 1 day. To the reaction mixture was added water and ethyl acetate, the organic layer was taken by separation. The ethyl acetate layer was washed with water and an aqueous solution being saturated with sodium chloride, then dried over anhydrous sodium sulfate. The residue obtained by removal of the solvent by distillation was purified by use of a thin layer chromatography (eluent: dichloromethane/methanol=30/1), there was obtained 3-(4-trifluoromethylphenyl)-2-propenyl(S)-4-{3-[2-(2-chloro-6-nitrophenylthio)-4-nitroimidazol-1-yl]-2-hydroxy-2-methylpropyl}piperazin-1-carboxylate (91 mg, yield: 87%) as yellow amorphous product.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[N:8]([CH2:17][CH:18]3[O:23][CH2:22][CH2:21][N:20](CC4C=CC=CC=4)[CH2:19]3)[C:7]=2[CH:31]=1)[CH3:2]>C(O)C.Cl.[Pd]>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[N:8]([CH2:17][CH:18]3[O:23][CH2:22][CH2:21][NH:20][CH2:19]3)[C:7]=2[CH:31]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)N(CC1CN(Cc3ccccc3)CCO1)c1ccccc1CC2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCc1ccc2c(c1)N(CC1CNCCO1)c1ccccc1CC2

Procedure:
3-Ethyl-5-(4-benzyl-2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine (0.6 g) in ethanol and conc. hydrochloric acid (1 ml) was hydrogenated over 10% palladium-on-charcoal (0.4 g) . The reaction mixture was filtered, and the filtrate was concentrated to dryness. The residue was dissolved in benzene, washed with 10% aqueous sodium hydroxide and water, dried over anhydrous sodium sulfate and evaporated to afford 3-ethyl-5-(2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine. M.P. 146°-150° C (oxalate).
Reaction SMILES: [CH3:1][S:2]([NH:5][C@H:6]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[CH3:7])(=[O:4])=[O:3].[CH3:17][C:18]1[C:19]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=1>>[CH3:17][C:18]1[C:19]([N:25]2[CH2:26][CH2:27][N:28]([C:12]([C:11]3[CH:10]=[CH:9][C:8]([C@@H:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH3:7])=[CH:16][CH:15]=3)=[O:14])[CH2:29][CH2:30]2)=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=1
Reactant: C[C@H](NS(C)(=O)=O)c1ccc(C(=O)O)cc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc([C@H](C)NS(C)(=O)=O)cc3)CC2)c(C)c1
Yield: 104.4 %

Procedure:
Using (S)-4-(1-methanesulfonylaminoethyl)benzoic acid (146 mg) described in Preparation Example 73 and 1-(3,5-dimethylpyridin-2-yl)piperazine (126 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 87, the title compound (261 mg) was obtained.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[Cl:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([Cl:33])[C:24]=1[N:34]1[N:38]=[C:37]([CH2:39][OH:40])[C:36]([CH3:41])=[N:35]1.CCOCC>ClCCl>[Cl:33][C:25]1[CH:26]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:28]=[C:23]([Cl:22])[C:24]=1[N:34]1[N:38]=[C:37]([CH:39]=[O:40])[C:36]([CH3:41])=[N:35]1
Reactant: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1CO
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C=O
Reaction time: 8 h

Procedure:
Pyridinium dichromate (7.5 g) was added, with stirring, to a solution of crude [2-(2,6-dichloro-4-trifluoromethylphenyl)-5-methyl-2H-1,2,3-triazol-4-yl]methanol (4.3 g) in dichloromethane (50 ml) at room temperature. The mixture was stirred overnight and then ether (100 ml) and silica (4 g) was added. After 10 minutes, the mixture was filtered through a pad of magnesium sulphate and the solvent was evaporated to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-5-methyl-2H-1,2,3-triazole-4-carboxaldehyde, as a crude brown solid. This product was then treated in similar manner to Example 1 with diaminomaleonitrile to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-[(2-amino-1,2-dicyanoethenylimino)methyl]-5-methyl-2H-1,2,3-triazole, m.p. 238°-239°.
Reaction SMILES: N1C=CC=CC=1.[CH:7]([N:10]([CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[S:11]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)(=[O:13])=[O:12])([CH3:9])[CH3:8]>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[CH:7]([N:10]([CH2:22][CH2:23][CH2:24][CH:25]=[O:26])[S:11]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)(=[O:12])=[O:13])([CH3:9])[CH3:8]
Reactant: CC(C)N(CCCCO)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)N(CCCC=O)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
Pyridine-chromic acid complex was prepared by adding chromium trioxide (26.4 g, 94 m. moles) to pyridine (41.76 g) in methylene chloride (660 ml). The reaction mixture was stirred at room temperature for 3/4 hours. Then N-isopropyl-N-(4-hydroxybutyl)-3,4-dichlorobenzenesulfonamide prepared in the preceding paragraph (15.01 g) in methylene chloride (150 ml) was added all at once. After 1/2 hour the liquid was decanted and washed with 5% aqueous NaOH, 5% aqueous HCl, 5% aqueous NaHCO3 and finally brine. After removal of solvent there was obtained N-isopropyl-N-(4-oxobutyl)-3,4-dichlorobenzenesulfonamide as a dark oil (9.01 g) which started to nicely crystallize but was used below without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[C:11]([CH2:13]C(O)=O)#[N:12]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])/[CH:5]=[CH:13]\[C:11]#[N:12]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: N#CCC(=O)O
Solvent: c1ccncc1
Product: N#C/C=C\c1ccc(Cl)c(Cl)c1

Procedure:
3,4-Dichlorobenzaldehyde (175 gms; 1 m), cyanoacetic acid (100 g; 1.15 m), and pyridine were refluxed for one day. Evaporation produced an oil which was fractionally distilled using a column (1 ft. long, 1/2 inch diameter) filled with glass helices. Overall yield 88.9 g (45%; 30% cis/70% trans).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:11]=[CH:12][N:13]2[C:18]=1[C:17](=[O:19])[NH:16][C:15]([CH3:20])=[N:14]2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[CH2:1]([N:16]1[C:17](=[O:19])[C:18]2=[C:10]([Cl:9])[CH:11]=[CH:12][N:13]2[N:14]=[C:15]1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nn2ccc(Cl)c2c(=O)[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1
Temperature: 95 °C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
Benzyl bromide (9.97 ml, 83.9 mmol) was added to a solution of 5-chloro-2-methyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (14 g, 76.3 mmol) and Cs2CO3 (29.7 g, 91.5 mmol) in dioxane (300 mL). The reaction mixture was stirred at 95° C. for 3 h, cooled to room temperature, filtered through Celite® and the filtrate concentrated in vacuo. The residue was dissolved in CHCl3 (100 mL), treated with saturated NaCl solution (200 mL), and extracted with CHCl3 (3×100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was triturated with Et2O, the solid filtered, washed with petroleum ether and dried in vacuo to afford the title compound (19.5 g, 94%) as a white solid: 1H NMR (DMF-d7) δ 7.57 (m, 1H), 7.32–7.41 (m, 5H), 6.65 (m, 1H), 5.31 (s, 2H), 2.38 (s, 3H); MS (ESI+) 274 (M++H), HRMS (ESI+): calculated: 274.0747 (M++H). found: 274.0757 (M++H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=4)[CH:22]=[C:21]([C:33]([F:36])([F:35])[F:34])[N:20]=3)[CH:18]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:32][C:27]1[CH:26]=[C:25]([C:23]2[CH:22]=[C:21]([C:33]([F:35])([F:34])[F:36])[N:20]=[C:19]([N:17]3[CH:18]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[N:15]=[CH:16]3)[N:24]=2)[CH:30]=[CH:29][C:28]=1[F:31]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)cn2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 35.8 %

Procedure:
To a cooled and stirred solution of 5-{1-[4-(3,4-difluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.24 g) in dichloromethane (4 ml) was added TFA (4 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N NaHCO3 solution (25 ml) and extracted ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash cromatography on silica gel (MeOH/dichloromethane) and crystallization (dichloromethane/heptane) yielded the title compound as a light yellow solid (0.077 g, 46%). MS (ISP) 487.9 [(M+H)+]; mp 228° C.
Reaction SMILES: [N+](C(OC(C)C)=O)(C(OC(C)C)=O)=[N-].[O:15]=[C:16]1[NH:21][N:20]=[C:19]([C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]#[N:26])[CH:18]=[CH:17]1.[CH3:30][C:31]1[CH:32]=[N:33][C:34]([C:37]2[CH:38]=[C:39]([CH2:43]O)[CH:40]=[CH:41][CH:42]=2)=[N:35][CH:36]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:30][C:31]1[CH:36]=[N:35][C:34]([C:37]2[CH:38]=[C:39]([CH:40]=[CH:41][CH:42]=2)[CH2:43][N:21]2[C:16](=[O:15])[CH:17]=[CH:18][C:19]([C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[C:25]#[N:26])=[N:20]2)=[N:33][CH:32]=1
Reactant: Cc1cnc(-c2cccc(CO)c2)nc1
Reactant: N#Cc1cccc(-c2ccc(=O)[nH]n2)c1
Agent: CC(C)OC(=O)[N+](=[N-])C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cnc(-c2cccc(Cn3nc(-c4cccc(C#N)c4)ccc3=O)c2)nc1

Procedure:
8.3 147 μl (0.75 mmol) of diisopropyl diazodicarboxylate are added dropwise to a suspension of 98.6 mg (0.50 mmol) of 3-(6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, 100 mg (0.50 mmol) of [3-(5-methylpyrimidin-2-yl)phenyl]methanol and 197 mg (0.75 mmol) of triphenylphosphine in 3 ml of THF, and the resultant solution is stirred at room temperature for 18 hours. The reaction mixture is evaporated in vacuo, and 2-propanol is added to the residue. The resultant precipitate is filtered off with suction and chromatographed on a silica gel column with dichloromethane/methanol as eluent: 3-{1-[3-(5-methylpyrimidin-2-yl)benzyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile (“A15”) as yellowish solid; ESI 380;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([C:7]([NH:9][C:10]2[C:11]([CH3:30])=[C:12]([CH3:29])[C:13]3[O:17][C:16]([CH3:19])([CH3:18])[CH:15]([C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)[C:14]=3[C:27]=2[CH3:28])=O)=[CH:5][CH:4]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:9][C:10]2[C:11]([CH3:30])=[C:12]([CH3:29])[C:13]3[O:17][C:16]([CH3:19])([CH3:18])[CH:15]([C:20]4[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=4)[C:14]=3[C:27]=2[CH3:28])=[CH:31][CH:32]=1
Reactant: COc1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C)cc2)C(C)(C)O3)cc1
Solvent: CCO
Product: COc1ccc(CNc2c(C)c(C)c3c(c2C)C(c2ccc(C)cc2)C(C)(C)O3)cc1
Yield: 58 %

Procedure:
By using 4-methoxy-N-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]benzamide, the title compound was synthesized according to Example 2b. Yield: 58%. Melting point: 97-98° C. (Ethanol)
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[OH:11])([CH3:3])[CH3:2].[NH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17](F)[C:14]=1[C:15]#[N:16]>>[NH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:11][C@@H:5]2[CH2:6][C@H:7]([CH3:10])[CH2:8][CH2:9][C@H:4]2[CH:1]([CH3:3])[CH3:2])[C:14]=1[C:15]#[N:16]
Reactant: N#Cc1c(N)cccc1F
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1Oc1cccc(N)c1C#N

Procedure:
Prepared as in Example 22b from (1R,2S,5R)-2-isopropyl-5-methylcyclohexanol and 2-amino-6-fluorobenzonitrile as a white solid (51%). MS 273 (MH+).
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH3:13][C:14]1[O:18][C:17]([CH2:19][CH2:20]O)=[CH:16][CH:15]=1.CC1C=CC(S([O-])(=O)=O)=CC=1>CC(C)=O>[CH3:13][C:14]1[O:18][C:17]([CH2:19][CH2:20][NH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:16][CH:15]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: Cc1ccc(CCO)o1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1ccc(CCNS(=O)(=O)c2ccccc2)o1
Temperature: 90 °C
Yield: 23 %

Procedure:
Benzenesulfonamide (157 mg, 1.00 mmol) was added to a 10% aqueous solution of sodium hydroxide (0.40 mL, 4.0 mmol). A solution of compound 24A (280 mg, 1.00 mmol) in acetone (1 mL) was then added. The reaction mixture was heated at 90° C. for 8 h then cooled to room temperature. Ice was added and the mixture was extracted with CH2Cl2. The combined organic layers were washed with water, dried and concentrated under reduced pressure. Purification by flash chromatography on silica gel, eluting with CH2Cl2 gave 60 mg (0.23 mmol, 23%) of compound 24B as yellow oil.
Reaction SMILES: C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC(OC)=CC=1)(O)C(O)=O)(=O)C1C=CC(OC)=CC=1.[C:31]1([C:37]2([CH2:42][CH2:43][OH:44])[CH2:41][CH2:40][NH:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:51][O:52][C:53]1[CH:54]=[C:55]([CH:59]=[C:60]([O:64][CH3:65])[C:61]=1[O:62][CH3:63])[C:56](Cl)=[O:57]>C(OCC)(=O)C.O>[CH3:65][O:64][C:60]1[CH:59]=[C:55]([CH:54]=[C:53]([O:52][CH3:51])[C:61]=1[O:62][CH3:63])[C:56]([N:39]1[CH2:40][CH2:41][C:37]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([CH2:42][CH2:43][OH:44])[CH2:38]1)=[O:57]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: OCCC1(c2ccccc2)CCNC1
Agent: COc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C(=O)N2CCC(CCO)(c3ccccc3)C2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Combine (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt (56.0 g, 92.1 mmol), sodium carbonate (19.5 g, 184 mmol) in ethyl acetate (2 L) and water (2 L). Cool to about 0° C. in an ice bath. After 30 minutes, slowly add dropwise portionwise 3,4,5-trimethoxybenzoyl chloride (21.2 g, 92.1 mmol). After the addition is complete, warm to ambient temperature. After 1 hour, dilute the reaction mixture ethyl acetate and extract with water, 1 M aqueous hydrochloric acid solution, and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][OH:5].CS(O[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][N:29]=3)[N:26]=2)[CH2:17][CH2:16]1)(=O)=O>>[F:33][C:30]([F:31])([F:32])[C:27]1[N:25]2[N:26]=[C:21]([N:18]3[CH2:17][CH2:16][CH:15]([CH2:14][O:5][CH2:4][C:3]([O:7][CH3:8])=[O:6])[CH2:20][CH2:19]3)[CH:22]=[CH:23][C:24]2=[N:29][N:28]=1
Reactant: COC(=O)CO
Reactant: CS(=O)(=O)OCC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)COCC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 100 °C
Yield: 17.4 %

Procedure:
Sodium hydride (60% dispersion in oil, 0.120 g, 3.0 mmol) was added to neat methyl glycolate (1.544 mL, 20.0 mmol). When the effervescence had subsided 6-[4-(methanesulfonyloxymethyl)piperidin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (0.759 g, 2.0 mmol) was added and the mixture was heated at 100° C. for 40 minutes. The reaction mixture was partitioned between DCM and water. The organic phase was washed with water and brine, dried over MgSO4 and evaporated. The product was isolated by MPLC silica chromatography, eluting with ethyl acetate. The product containing fractions were evaporated to an oil which crystallised from ether, giving methyl 2-[[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]methoxy]acetate (0.130 g, 17%).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[C:11]=2[N:10]([CH3:33])[C:9]1=[O:34])(=O)C.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:15]2[C:12]3[C:13](=[O:14])[N:8]([CH2:7][CH2:6][CH2:5][OH:4])[C:9](=[O:34])[N:10]([CH3:33])[C:11]=3[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)=[CH:16]2)=[CH:31][CH:30]=1
Reactant: CC(=O)OCCCn1c(=O)c2c(c(-c3cccc(Cl)c3)cn2Cc2ccc(Cl)cc2)n(C)c1=O
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCO)c(=O)c2c1c(-c1cccc(Cl)c1)cn2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-7-(3-chlorophenyl)-1-methyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (50 mg, 0.1 mmol) in THF (0.5 mL) and water (0.5 mL) was added LiOH.H2O (8.4 mg, 0.2 mmol). The reaction was stirred at RT for 30 min then diluted with EA (5 mL). The organic layer was washed with brine (5 mL), dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-7-(3-chlorophenyl)-3-(3-hydroxypropyl)-1-methyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione (20 mg, 41% yield). 1H NMR (CDCl3) δ: 7.39-7.29 (m, 5H), 7.25-7.17 (m, 3H), 6.91 (s, 1H), 5.56 (s, 2H), 4.28-4.15 (m, 2H), 3.62 (s, 1H), 3.52 (d, J=4.8 Hz, 2H), 3.21 (s, 3H), 1.96-1.82 (m, 2H). LCMS: MH+ 458 and TR=2.953 min.