Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(NC[C@H]1CC[C@H]([C:16]([NH:18][C:19](=[O:29])[C@H:20]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH2:21])=O)CC1)=O)(C)(C)C.[ClH:30].O1CCOCC1>>[ClH:30].[CH3:16][NH:18][C:19](=[O:29])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH2:21]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)NC(=O)[C@@H](N)Cc2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the compound (I) (2.00 g), 4N hydrogen chloride/1,4-dioxane solution (36 ml) was added, and the mixture was stirred under room temperature for one hour. The solvent was evaporated under a reduced pressure and toluene was added to the residue, followed by reevaporation to give L-phenylalanine methylamide hydrochloride quantitatively as a white powder.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[OH:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)C>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[O:20][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C#N)ccc1F
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cc(C#N)ccc1Oc1ccc(Cl)cc1Cl
Reaction time: 22 h

Procedure:
30.8 g of 4-fluoro-3-methoxybenzonitrile, 39.1 g of 2,4-dichlorophenol and 78.2 g of caesium carbonate are dissolved in 180 ml of dimethylformamide and stirred at 120° for 22 h. After cooling, the solution is diluted with diethylether, washed with water, an 1N aqueous solution of sodium hydroxide, an 1N aqueous solution of hydrogen chloride and finally with brine. The organic phase is dried over magnesium sulfate and evaporated to yield 4-(2,4-dichlorophenoxy)-3-methoxybenzonitrile.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][NH:43][C:44]1[N:45]=[N:46][CH:47]=[CH:48][CH:49]=1)[CH2:4][CH2:3]2.O.[OH-].[Li+].C1COCC1.C(O)(C(F)(F)F)=O>O.CO>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][NH:43][C:44]1[N:45]=[N:46][CH:47]=[CH:48][CH:49]=1)[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNc3cccnn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(NCCNc3cccnn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 60 h
Yield: 100 %

Procedure:
A solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyridazin-3-ylamino)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate and lithium hydroxide monohydrate (2.3 mg, 0.055 mmol) in a mixture of water (0.5 mL), THF (0.25 mL) and MeOH (0.25 mL) was stirred at rt for 2.5 days. Purification of the crude mixture by reverse phase preparative HPLC using Prep HPLC Method 10 gave the title compound as a white solid (5.0 mg, 100% yield) bis TFA salt. LCMS: m/e 651.5 (M+H)+, 2.26 min (method 11).
Reaction SMILES: Cl.O1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]([C:19]3[NH:24][CH2:23][CH2:22][NH:21][N:20]=3)[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][C:5]=2OC1.Cl.C1C2C(=CC=CC=2)C=CC=1CC1NCCNN=1.[Cl:43]C1C=CC(CC(C2NCCNN=2)S(C2C=CC(C)=CC=2)(=O)=O)=CC=1>>[ClH:43].[C:9]1([CH:11]([C:19]2[NH:24][CH2:23][CH2:22][NH:21][N:20]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)C(Cc2ccc(Cl)cc2)C2=NNCCN2)cc1
Reactant: c1ccc(CC(C2=NNCCN2)c2ccc3c(c2)OCO3)cc1
Agent: Cl
Agent: c1ccc2cc(CC3=NNCCN3)ccc2c1
Product: c1ccc(CC(C2=NNCCN2)c2ccccc2)cc1

Procedure:
In addition to the compounds listed above, compounds which do not fit the general formula of Table 1 were prepared using the process of the invention. The compounds include: 3-(1-(1,3-benzodioxol-5-yl)-2-phenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine monohydrochloride; 1,4,5,6-tetrahydro-3-(2-naphthalenylmethyl)-1,2,4-triazine monohydrochloride; and 3-(2-(4-chlorophenyl)-1-((4-methylphenyl)sulfonyl)ethyl)-1,4,5,6-tetrahydro-1,2,4-triazine.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[C:28]1[CH:33]=[CH:32][C:31]([O:34][Si](C(C)C)(C(C)C)C(C)C)=[CH:30][C:29]=1[CH2:45][C:46]([CH3:49])([CH3:48])[CH3:47].O>C1COCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:29]=1[CH2:45][C:46]([CH3:49])([CH3:48])[CH3:47]
Reactant: COc1ccc(F)c(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2CC(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)c(-c2ccc(O)cc2CC(C)(C)C)c1
Reaction time: 0.25 h

Procedure:
A 1.0M solution of tetrabutylammonium fluoride in THF (73.6 mL) was added to a solution of ((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)oxy)triisopropylsilane (total amount) obtained in Example 2, step F, in THF (30 mL) at room temperature, and the mixture was stirred for 15 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (8.68 g) as a pale-yellow amorphous solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([O:18][CH2:19][CH3:20])[CH:9]=2)[CH:5]=[C:4]([C:21]([F:24])([F:23])[F:22])[N:3]=1.[Br:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[Br:25][C:26]1[CH:31]=[C:30]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([O:18][CH2:19][CH3:20])[CH:9]=3)[CH:5]=[C:4]([C:21]([F:24])([F:23])[F:22])[N:3]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F
Reactant: OB(O)c1cccc(Br)c1
Product: CCOc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chloro-4-(3-ethoxy-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example A.10) (0.25 g, 0.67 mmol) and commercially available 3-bromo-benzene-boronic acid (0.17 g, 0.85 mmol) according to the general procedure IVb. Obtained as a light yellow solid (0.32 g, 97%). MS (EI) 492.0 [(M)+]; mp 108° C.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[NH:39]1[CH2:42][CH:41]([C:43]#[N:44])[CH2:40]1.CS(C)(=O)=O>O1CCOCC1>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14]([N:39]3[CH2:42][CH:41]([C:43]#[N:44])[CH2:40]3)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Reactant: N#CC1CNC1
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CCC[C@H](Nc2nc(N3CC(C#N)C3)ncc2-c2cnc3[nH]ccc3n2)C1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, azetidine-3-carbonitrile was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give 1-[4-((S)-1-methanesulfonyl-piperidin-3-ylamino)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-2-yl]-azetidine-3-carbonitrile. MS: (ES+): 454
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-])=O)=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][N:10]=2)[CH:7]=1>CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][N:10]=2)[C:5]([NH2:16])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1Nc1ccc(F)cn1
Solvent: CCOC(C)=O
Product: Nc1ccc(F)cc1Nc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
A mixture of (5-fluoro-2-nitrophenyl)-(5-fluoropyridin-2-yl)amine (34 mg, 0.14 mmol) in EtOAc (5 mL) was degassed with a stream of nitrogen prior to addition of 10% Pd/C (10 mg) and was stirred at RT under a hydrogen atmosphere for 3 h. The mixture was filtered through a phase separator and the filtrate concentrated in vacuo to afford the title compound as a dark oil (30 mg, quantitative). LCMS (Method C): RT 1.95 min [M+H]+ 222.2.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[C:7]1([S:13]([C:16]2[C:17]([S:27][CH3:28])=[N:18][N:19]3[C:24](Cl)=[CH:23][C:22]([CH3:26])=[N:21][C:20]=23)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[C:7]1([S:13]([C:16]2[C:17]([S:27][CH3:28])=[N:18][N:19]3[C:24]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[CH:23][C:22]([CH3:26])=[N:21][C:20]=23)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)CCN
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Product: CSc1nn2c(NCCN(C)C)cc(C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 113.4 %

Procedure:
0.088 g (1 mmol) of 2-dimethylaminoethylamine was added to a solution of 0.17 g (0.5 mmol) of 3-benzenesulphonyl-7-chloro-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 3 ml of DMF and stirred at 60° for 2 hrs. The reaction solution was cooled to RT and evaporated in a high vacuum. The residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH 19:1) and crystallization from EtOH yielded 0.23 g (73%) of N-(3-benzenesulphonyl-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-yl)-N′,N′-dimethyl-ethane-1,2-diamine as colorless crystals, m.p. 190-191°.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][CH2:12][NH2:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1.C(N(CC)CC)C.N>CN(C)C=O.C(Cl)Cl>[C:1]([NH:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:15][CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: NCCCNC(=O)c1ccccc1
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCCCNCCc1c[nH]c2ccccc12)c1ccccc1

Procedure:
A solution of 8 g N-benzoyl-1,3-diaminopropane, 6,7 g 3-(2-bromoethyl)indole and 5 ml anhydrous triethylamine in 15 ml anhydrous dimethylformamide is maintained for 72 hours in nitrogen atmosphere. A dilute ammonia solution and methylene chloride are then added to the reaction mixture and the organic phase is dried and evaporated. The residue is chromatographied on silicagel using as eluant methylene chloride+5% methanol+0.3% ammonia, to yield the title compound (M.pt. of the naphthalene-2-sulfonate 203°-204° with decomposition after crystallization from ethanol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[N:5]2[CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=[C:4]2[CH:3]=1.[CH2:21]([N:23]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)[S:24]([CH3:27])(=[O:26])=[O:25])[CH3:22].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Pd]>[CH2:21]([N:23]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=3)[N:5]3[CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=[C:4]3[CH:3]=2)[CH:33]=1)[S:24]([CH3:27])(=[O:25])=[O:26])[CH3:22]
Reactant: Cc1cc(Nc2nc(Cl)cc3nc(C(C)C)cn23)n[nH]1
Reactant: CCN(c1cccc(B(O)O)c1)S(C)(=O)=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCN(c1cccc(-c2cc3nc(C(C)C)cn3c(Nc3cc(C)[nH]n3)n2)c1)S(C)(=O)=O
Temperature: 150 °C

Procedure:
7-chloro-2-isopropyl-N-(5-methyl-1H-pyrazol-3-yl)imidazo[1,2-c]pyrimidin-5-amine (0.17 mmol, 0.05 g), 3-(N-ethylmethylsulfonamido)phenylboronic acid (0.35 mmol) and (Ph3)4 Pd (O) (0.086 mmol, 0.1 g) were stirred in dioxane (3 mL) and sat. K2CO3 (1.5 mL). The reaction mixture was heated to 150° C. using a microwave reactor for 20 minutes. The mixture was then concentrated and purified by LC-MS to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.06 (t, J=7.07 Hz, 3H) 1.35 (d, J=6.82 Hz, 6H) 2.29 (s, 3H) 3.04 (s, 3H) 3.76 (q, J=7.07 Hz, 2H) 6.70 (s, 1H) 7.57 (s, 1H) 7.59-7.67 (m, 2H) 8.11 (d, J=7.58 Hz, 1H) 8.17 (s, 1H) 8.45 (s, 1H) 10.80 (s, 1H) 12.35 (s, 1H); ESI-MS: m/z calc'd for C22H27N7O2S 453.56; found 454.4 (M+H)+.
Reaction SMILES: CC[O-].[Na+].[NH:5]([CH2:12][CH2:13][C:14]#[N:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:16]([O:18][C:19](=[O:38])[NH:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH:29](O)CS(C)(=O)=O)=[CH:23][C:22]=1[O:36][CH3:37])[CH3:17].CS(C)=O>O>[CH2:16]([O:18][C:19](=[O:38])[NH:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH2:29][C:13]([C:14]#[N:15])=[CH:12][NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:23][C:22]=1[O:36][CH3:37])[CH3:17]
Reactant: N#CCCNc1ccccc1
Reactant: CCOC(=O)Nc1c(OC)cc(C(O)CS(C)(=O)=O)cc1OC
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Nc1c(OC)cc(CC(C#N)=CNc2ccccc2)cc1OC

Procedure:
A mixture of 4.42 g. of sodium ethylate, 5.1 g. of β-anilino-propionitrile and 10.0 g. of 4-[1-hydroxy-2-(methylsulfonyl)-ethyl]-2,6-dimethoxy-carbanilic acid ethyl ester in 150 ml. of dimethylsulfoxide was stirred at 50° C. for 2 hours with the exclusion of moisture. The solution was poured into 1.5 liters of water and the resulting emulsion extracted with two 1 liter portions of ethyl acetate. The ethyl acetate extracts were washed with two 500 ml. portions of water, combined, dried over magnesium sulfate and evaporated under vacuum. The residue was chromatographed on 800 g. of silica gel using methylene chloride/ethyl acetate (3:1) and there was obtained 4-(3-anilino-2-cyano-allyl)-2,6-dimethoxy-carbanilic acid ethyl ester having a melting point of 150°-151° C. (recrystallization from alcohol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]([CH3:17])[C:12](OCC)=[O:13])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C([NH2:20])=O.C[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:11]([CH3:17])[C:12]([NH2:20])=[O:13])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: NC=O
Reactant: CCOC(=O)C(C)c1cc(F)cc2ccoc12
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C(N)=O)c1cc(F)cc2ccoc12
Temperature: 100 °C
Yield: 25 %

Procedure:
To a solution of 0.27 gm (1.15 mMol) ethyl 2-(5-fluorobenzofur-7-yl)propionate in 4 mL dimethylformamide were added sequentially 0.16 mL (3.91 mMol) freshly distilled formamide and 0.81 mL (0.80 mMol) sodium methoxide (1 M in methanol) dropwise and the resulting mixture was heated at 100° C. for 45 minutes. The reaction mixture was cooled to room temperature and was then diluted with 25 volumes of ethyl acetate. The mixture was then washed sequentially with water and saturated aqueous sodium chloride, and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with 2:1 ethyl acetate:hexane. Fractions containing product were combined and concentrated under reduced pressure to provide 0.060 gm (25%) of the desired compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH3:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[C:12]([C:14]([C:20]#[N:21])=[C:15](C#N)[C:16]#[N:17])#[N:13].CCCCCC>CN(C=O)C.C(=O)([O-])O.[Na+]>[CH2:10]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([C:15]([C:16]#[N:17])=[C:14]([C:20]#[N:21])[C:12]#[N:13])=[CH:6][CH:5]=1)[CH3:11]
Reactant: N#CC(C#N)=C(C#N)C#N
Reactant: CCN(CC)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(C(C#N)=C(C#N)C#N)cc1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 73.8 %

Procedure:
In an atmosphere of argon, 42.3 g (0.28 mol) of N,N-diethylaniline was dissolved in 570 ml of anhydrous DMF, and the solution obtained was cooled to 0° C., and then 46.3 g (1.25-fold equivalent weight) of tetracyanoethylene was added thereto. Then, the solution obtained was restored to room temperature, and stirred for 4.5 hours, which was thereafter poured in 1 liter of a saturated aqueous sodium hydrogencarbonate solution. The solid thus deposited was filtered to obtain a residue, and the residue was subjected to azeotropic distillation twice with 300 ml of toluene to remove the water content. Thereafter, 300 ml of ethyl acetate was added, and the atmosphere was replaced with argon, followed by heating at 80° C. for 1 hour to effect dissolution. To the mixture obtained, 800 ml of hexane was added with stirring, and the solution obtained was cooled to room temperature. The solid thus deposited was collected by filtration, and the residue obtained was vacuum-dried to obtain 51.7 g of N,N-diethyl-4-tricyanovinylaniline (yield: 74%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[C:8]([CH:16](Br)[CH:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CN(C)C=O.CCCCCC>[C:8]([CH:16]=[C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: c1nc[nH]n1
Reactant: O=C(c1ccccc1)C(Br)C(Br)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(C=C(c1ccccc1Cl)n1cncn1)c1ccccc1
Temperature: 100 °C

Procedure:
This Example illustrates the preparation of compound no. 3 of Table I. 1,2,4-Triazole (4.64 g) in dry dimethylformamide (10 ml) was added slowly to a suspension of sodium hydride (2.88 g of 50% dispersion in mineral oil, washed free of oil with dry petrol) in dry dimethylformamide (10 ml) with cooling and stirring. A solution of 1-benzoyl-1,2-dibromo-2-(o-chlorophenyl) ethane (8.45 g) in dry dimethylformamide (10 ml) was then added and the mixture heated at 100° C. for 1 hour. The mixture was poured into cold water (1 liter) and extracted with ether. The ether extracts were dried and evaporated to give a yellow oil. This was dissolved in hexane and the solution cooled to -15° C. The light yellow fibrous crystals were filtered off to give 1-benzoyl-2-o-chlorophenyl-2-(1,2,4-triazol-1-yl)-ethylene (compound no. 3 of Table I) having a melting point of 79°-81° C.
Reaction SMILES: [CH3:1][C:2](=O)[C:3](=[N:7]O)[C:4](=[O:6])[CH3:5].[Cl:10][C:11]1[N:16]=[CH:15][C:14]([CH2:17][NH2:18])=[CH:13][CH:12]=1>C(#N)C>[Cl:10][C:11]1[N:16]=[CH:15][C:14]([C:17]2[NH:18][C:2]([CH3:1])=[C:3]([C:4](=[O:6])[CH3:5])[N:7]=2)=[CH:13][CH:12]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: CC(=O)C(=NO)C(C)=O
Solvent: CC#N
Product: CC(=O)c1nc(-c2ccc(Cl)nc2)[nH]c1C
Temperature: -10 °C
Reaction time: 18 h
Yield: 31.5 %

Procedure:
A mixture of 4.5 g (0.035 mole) of 2,3,4-pentanetrione 3-oxime and 5.3 g (0.037 mole) of 6-chloro-3-pyridylmethylamine in 100 ml of acetonitrile was stirred at the reflux temperature for 18 hours. The reacted mixture was cooled at -10° C. with formation of a precipitate. The precipitate was washed, dried and recrystallized as for Example 24 to give 2.6 g of the desired product as a pale yellow solid, mp 239°-240° C.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]=[C:5]1[S:9][C:8]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[N:7][C:6]1=[O:19].[OH-].[Na+].Cl>C1COCC1>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[NH:10][C:8]1[S:9][C:5](=[CH:4][C:3]([OH:20])=[O:2])[C:6](=[O:19])[N:7]=1
Reactant: COC(=O)C=C1SC(Nc2c(Cl)cccc2Cl)=NC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C=C1SC(Nc2c(Cl)cccc2Cl)=NC1=O
Temperature: 40 °C
Reaction time: 48 h

Procedure:
A reaction mixture of [2-(2,6-dichloro-phenylamino)-4-oxo-4H-thiazol-5-ylidene]-acetic acid methyl ester (3 g, Example 1), NaOH (1N in H2O, 30 mL), THF (20 mL) was heated to 40° C. and stirred for 48 hours. The mixture was acidified to PH=1 by adding 10% aqueous HCl. Then the mixture was extracted with ethyl acetate (25 mL×3). The organic extracts were dried over MgSO4, filtered, concentrated, and dried under vacuum to yield the desired product as a white solid.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[N:22]3[CH:23]=[CH:24][N:25]=[C:26]([NH2:27])[C:21]3=[C:20]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[C:30]([O:41][CH3:42])[CH:29]=3)[N:19]=2)[CH2:14][CH2:13]1)C1C=CC=CC=1.O>Cl>[NH2:10][CH2:11][C@H:12]1[CH2:13][CH2:14][C@H:15]([C:18]2[N:22]3[CH:23]=[CH:24][N:25]=[C:26]([NH2:27])[C:21]3=[C:20]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[C:30]([O:41][CH3:42])[CH:29]=3)[N:19]=2)[CH2:16][CH2:17]1
Reactant: COc1cc(-c2nc([C@H]3CC[C@H](CNC(=O)OCc4ccccc4)CC3)n3ccnc(N)c23)ccc1Oc1ccccc1
Agent: Cl
Solvent: O
Product: COc1cc(-c2nc([C@H]3CC[C@H](CN)CC3)n3ccnc(N)c23)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
trans-{4-[8-Amino-1-(3-methoxy-4-phenoxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexylmethyl}-carbamic acid benzyl ester (80 mg, 0.0001 mol) was dissolved in conc. HCl (3 mL) at 0° C. The resulting mixture was allowed to stir at rt overnight. LCMS indicates the reaction is over. Water was added to the reaction mixture and the mixture was extracted with EtOAc. The aq. phase was concentrated in vacuo to give a residue which was purified by flash chromatography (eluted by 10% MeOH in DCM). 1H NMR (400 MHz, CDCl3) δ 1.08 (dd, J=12.13, 3.28 Hz, 2H) 1.74-1.89 (m, 2H) 1.90-1.98 (m, 2H) 2.00-2.09 (m, 2H) 2.57 (d, J=6.57 Hz, 2H) 2.78-2.90 (m, 1H) 3.83 (s, 3H) 6.89-6.95 (m, 2H) 6.95-7.04 (m, 3H) 7.09 (dd, J=8.21, 1.89 Hz, 1H) 7.16 (d, J=5.05 Hz, 1H) 7.21-7.28 (m, 3H). MS (ES+): m/z: 444.17 [MH+]. HPLC: tR=1.88 min (OpenLynx: polar—5 min).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[C:25]1([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37][O:38]S(C3C=CC(C)=CC=3)(=O)=O)[N:35]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:38][CH2:37][CH2:36][C:34]2[N:35]=[C:31]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:32][C:33]=2[CH3:49])=[CH:11][CH:12]=1)[C:4]([OH:24])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(OC)c1
Product: COc1cccc(OC(C)(Cc2ccc(OCCc3nc(-c4ccccc4)oc3C)cc2)C(=O)O)c1

Procedure:
Standard Procedure (B) was utilized to prepare the title compound from 3-(4-hydroxy-phenyl)-2-(3-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester.