Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[N:4][N:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=2)[CH:6]=1.[CH2:21]([O:28]/[N:29]=[C:30]1\[CH2:31][CH2:32][C:33]2[C:38]\1=[CH:37][CH:36]=[C:35](B(O)O)[CH:34]=2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH2:21]([O:28]/[N:29]=[C:30]1\[CH2:31][CH2:32][C:33]2[C:38]\1=[CH:37][CH:36]=[C:35]([C:2]1[C:3]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[N:4][N:5]([C:7]3[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=3)[CH:6]=1)[CH:34]=2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: N#Cc1ccc(-n2cc(Br)c(-c3ccncc3)n2)nc1
Reactant: OB(O)c1ccc2c(c1)CC/C2=N\OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(-n2cc(-c3ccc4c(c3)CC/C4=N\OCc3ccccc3)c(-c3ccncc3)n2)nc1
Temperature: 80 °C
Yield: 39 %

Procedure:
To 6-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)nicotinonitrile (0.26 g; Example 6, step 1) in 16 mL acetonitrile and 4 mL water was added (E)-1-(benzyloxyimino)-2,3-dihydro-1H-inden-5-ylboronic acid (0.34 g; Example 2, Step 4) and 0.33 g potassium carbonate. The reaction mixture was purged with nitrogen and 46 mg tetrakis(triphenyphosphine)palladium(0) catalyst was added. The reaction mixture was heated to 80° C. for 1.5 hours, filtered through celite, the filter cake was washed with acetonitrile. The filtrate was evaporated to yield crude product, which was purified by chromatography, eluting with a 10:1 mixture of dichloromethane-methanol to afford 0.15 g (36% yield) product as a pale yellow solid. 1H NMR (CDCl3) was consistent with the desired structure. LC/MS showed one peak with a M+1 molecular ion of m/z 483.2 by positive ESI.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:28][NH2:29])[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[F:39][C:40]1[N:45]=[C:44]([F:46])[C:43]([F:47])=[C:42](F)[C:41]=1[F:49]>C(#N)C.CO>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([NH:13][C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:28][NH:29][C:42]3[C:41]([F:49])=[C:40]([F:39])[N:45]=[C:44]([F:46])[C:43]=3[F:47])[CH2:20][CH2:21]2)=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:8]=1
Reactant: NCc1ccccc1N1CCN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reactant: Fc1nc(F)c(F)c(F)c1F
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2ccccc2CNc2c(F)c(F)nc(F)c2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
4-(2-Aminomethyl-phenyl)piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)amide (50 mg, 0.11 mmol) was dissolved in 500 mL of acetonitrile. Then, triethylamine (20 L, 0.14 mmol) was added, followed by pentafluoropyridine (16 μL, 0.15 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was diluted to 2 mL in volume with methanol and the mixture was purified by reverse phase HPLC to give 44 mg of the product as a white solid. 1H NMR (CDCl3) δ 7.87 (s, 2H), 7.51 (s, 1H), 7.29-7.36 (m, 2H), 7.16-7.21 (m, 2H), 6.78 (s, 1H), 5.90 (br s, 1H), 4.79 (d, 2H), 3.71 (m, 4H), 3.02 (t, 4H) ppm.
Reaction SMILES: [Cl:1][CH:2]([Cl:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10].[NH2:16][C:17]1[N:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([CH3:25])[N:18]=1>C(#N)C>[Cl:15][CH:2]([Cl:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:12][C:13]([NH:16][C:17]1[N:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([CH3:25])[N:18]=1)=[O:14])(=[O:11])=[O:10]
Reactant: COc1nc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1C(Cl)Cl
Solvent: CC#N
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(Cl)Cl)n1
Reaction time: 18 h

Procedure:
2-(Dichloromethyl)benzenesulfonyl isocyanate prepared from 10 mmol of sulfonamide as described in the synthesis of Example 1, was treated with acetonitrile (15 ml) and 2-amino-4-methoxy-6-methyl-1,3,5-triazine (1.40 g). The mixture was stirred for 18 hrs. and filtered. The filtrate was evaporated and recrystallized from acetone to give 0.78 g of white solid, mp 168°-169° (dec).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([NH2:19])=O)=[C:4]2[CH2:3]1.O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]#[N:19])=[C:4]2[CH2:3]1
Reactant: CN1Cc2c(C(N)=O)ncn2-c2ccccc2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CN1Cc2c(C#N)ncn2-c2ccccc2C1=O

Procedure:
0.5 g of 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide is heated to reflux while stirring for 40 hours together with 0.5 g of Sicapent in 150 ml of toluene. The mixture is treated with a 0.5 g portion of Sicapent after 16 hours, 19 hours and 24 hours. The mixture is subsequently cooled and treated with water. The mixture is adjusted to pH 9 with 28 percent sodium hydroxide. After separation of the organic phase, the alkaline-aqueous phase is extracted twice with 250 ml of ethyl acetate each time. The organic extracts are washed twice with saturated sodium chloride solution, dried and evaporated. After crystallisation of the residue from methylene chloride/hexane, there is recovered a portion of unreacted starting material. The mother liquor is evaporated and chromatographed on 100 g of silica gel while eluting with ethyl acetate and alcohol. After recrystallisation of the thus-obtained substance from acetone, there is obtained 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[ 1,5-a][1,4]benzodiazepine-3-carbonitrile of melting point 184°-185° C.
Reaction SMILES: C1(CCO)CC1.[C:7]12([CH2:17][OH:18])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.FC1C=C(F)C(F)=CC=1C(NS(C)(=O)=O)=O.[Cl:35][C:36]1[C:37](F)=[CH:38][C:39]([F:49])=[C:40]([CH:48]=1)[C:41]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])=[O:42]>>[C:7]12([CH2:17][O:18][C:37]3[C:36]([Cl:35])=[CH:48][C:40]([C:41]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])=[O:42])=[C:39]([F:49])[CH:38]=3)[CH2:14][CH:13]3[CH2:12][CH:11]([CH2:10][CH:9]([CH2:15]3)[CH2:8]1)[CH2:16]2
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: CS(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Agent: OCCC1CC1
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 1 and making variations as required to replace 2-cyclopropylethanol with adamantan-1-ylmethanol and 2,4,5-trifluoro-N-(methylsulfonyl)benzamide with 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (WO 2012007883 A1), the title compound was obtained as a colorless solid (0.20 g, 8%): 1H NMR (300 MHz, DMSO-d6) δ 12.10 (s, 1H), 7.77 (d, J=7.5 Hz 1H), 7.23 (d, J=12.5 Hz, 1H), 3.72 (s, 2H), 3.35 (s, 3H), 1.99 (br s, 3H), 1.75-1.64 (m, 12H); 13C NMR (75 MHz, DMSO-d6) δ 162.3 (d, J=2.0 Hz), 159.8 (d, JC-F=255 Hz), 158.3 (d, JC-F=11 Hz), 130.6 (d, JC-F=4 Hz), 116.8 (d, JC-F=3 Hz), 113.6 (d, JC-F=14 Hz), 102.7 (d, JC-F=28 Hz), 79.1, 41.2, 38.5, 36.4, 33.4, 27.3; MS (ES+) m/z 415.6, 417.6 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[CH:4]=1.BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:20]1=[O:40]>>[O:40]=[C:20]1[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]1[CH2:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9]#[N:10]
Reactant: N#Cc1cccc(CBr)c1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Product: N#Cc1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)c1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using α-bromo-m-tolunitrile to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1H)-one, 3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzonitrile was obtained (66%) as a colorless solid: mp 173-178° C. (ethyl acetate/diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.60-7.63 (m, 3H), 7.44-7.47 (m, 1H), 7.21-7.24 (m, 2H), 7.05 (t, J=7.5 Hz, 1H), 6.72 (d, J=7.5 Hz, 1H), 6.50 (s, 1H), 6.18 (s, 1H), 4.93-4.97 (m, 3H), 4.66-4.69 (m, 1H), 4.13-4.17 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.7, 155.3, 144.8, 141.5, 138.4, 137.4, 132.1, 131.8, 131.7, 130.9, 129.9, 129.0, 124.3, 123.9, 120.7, 118.4, 113.1, 111.4, 108.8, 99.5, 80.1, 64.5, 63.9, 58.0, 43.4; MS (ES+) m/z 410.8 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1>>[ClH:1].[CH3:12][C:8]1[N:7]=[C:6]2[C:11]([C:2]([NH:29][C:28]3[CH:27]=[CH:26][C:25]([O:24][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=4)=[CH:31][CH:30]=3)=[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Nc1ccc(Oc2ccccn2)cc1
Reactant: CCOC(=O)c1cnc2nc(C)ccc2c1Cl
Product: CCOC(=O)c1cnc2nc(C)ccc2c1Nc1ccc(Oc2ccccn2)cc1
Product: Cl
Reaction time: 8 h

Procedure:
A mixture of ethyl 4-chloro-7-methyl-1,8-naphthyridine-3-carboxylate (2.49 g) and 4-(2-pyridyloxy)aniline (1.85 g) in IMS (50 ml) was boiled under reflux for 1 hour. The mixture was allowed to stand at ambient temperature overnight and then evaporated under reduced pressure. The residue was triturated with ethyl acetate and filtered to give a solid which was recrystallised from ethanol/ethyl acetate. This solid was dissolved in IMS and hydrogen chloride gas was bubbled through the solution with cooling. The solvent was then evaporated under reduced pressure and the residue was recrystallised from ethanol/ethyl acetate to give ethyl 7-methyl-4-[4-(2-pyridyloxy)anilino]-1,8-naphthyridine-3-carboxylate hydrochloride, m.p. 207°-208° C. Active (2/2) at 30 mg/kg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C>CS(C)=O.C(OCC)(=O)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][N:27]2[CH2:28][CH2:29][N:30]([C:6]3[CH:5]=[CH:4][C:3]([S:9]([NH2:12])(=[O:11])=[O:10])=[C:2]([F:1])[CH:7]=3)[CH2:31][CH2:32]2)=[CH:16][CH:15]=1
Reactant: Clc1ccc(-c2ccccc2CN2CCNCC2)cc1
Reactant: NS(=O)(=O)c1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: NS(=O)(=O)c1ccc(N2CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC2)cc1F
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of 2,4-difluorobenzenesulfonamide (1.56 g) and 1-((4′-chlorobiphenyl-2-yl)methyl)piperazine (2.32 g) in dimethylsulfoxide (20 mL) was added N,N-diisopropylethylamine (5 mL). The mixture was stirred at 120° C. overnight. The mixture was diluted with ethyl acetate (300 mL) and washed with water (3×) brine and dried over Na2SO4. After filtration and evaporation of the solvent, the residue was loaded on a column and eluted with 40% ethyl acetate in hexane to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[CH3:29][OH:30]>C1(C)C=CC=CC=1>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:13](=[O:16])[CH2:14][C:29](=[O:30])[CH2:24][CH2:25][CH2:8][CH2:7][CH2:6][CH2:15][CH2:2][CH2:3][CH3:4])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CO
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCCCCCCC(=O)CC(=O)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Temperature: 20 °C
Yield: 63 %

Procedure:
To a solution of 100 mg (0.30 mmole) of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) in 8 mL of toluene, magnetically stirred at 20° C., 103 mg of the compound of example 19 were added. The mixture was refluxed during 2.5 hours, and then allowed to cool to 20° C. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 97:3 volume ratio) to provide 79 mg (yield: 63%) of the desired product (formula below) as a red powder.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[OH:5][C@H:6]1[CH2:10][CH2:9][O:8][CH2:7]1>C1(C)C=CC=CC=1>[O:8]1[CH2:9][CH2:10][C@H:6]([O:5][C:1]([Cl:4])=[O:2])[CH2:7]1
Reactant: O[C@H]1CCOC1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)O[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
14.1 ml (27.24 mmol) of a 20% solution of phosgene in toluene are added dropwise to 14 ml of toluene. After the mixture has been cooled in an ice-bath, a solution of 2 g (22.7 mmol) of (S)-(+)3-hydroxy-tetrahydrofuran (JPS CHIMIE, Bevaix, Switzerland) in a small amount of toluene is added, the mixture is then stirred for 1 h at RT, and the excess phosgene is expelled with argon. After concentration in a rotary evaporator at reduced pressure, distillation is carried out for the purpose of purification. Boiling point at 12 torr: 130° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:22]3[O:21][C:20]([C:23]#[N:24])=[C:19]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:18]=3[CH:17]=[C:16]([CH3:32])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B1([O-])O[O:34]1.O.O.O.O.[Na+].C(O)C>[Cl-].[Na+].O.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:22]3[O:21][C:20]([C:23](=[O:34])[NH2:24])=[C:19]([CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:18]=3[CH:17]=[C:16]([CH3:32])[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2oc(C#N)c(Cc3ccccc3)c2c1
Reactant: [O-]B1OO1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2oc(C(N)=O)c(Cc3ccccc3)c2c1
Temperature: 130 °C
Yield: 79.4 %

Procedure:
4-(3-Benzyl-2-cyano-5-methyl-benzofuran-7-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.302 gm, 0.7 mmol), sodium perborate tetrahydrate (0.43 gm, 2.8 mmol), ethanol (8 ml) and water (8 ml) were combined in a vial and heated in a microwave reactor to 130° C. for 10 minutes. The reaction mixture was cooled to room temperature, diluted with brine and water and extracted three times with ethyl acetate. The solution was dried over magnesium sulfate and purified by column chromatography (methanol/dichloromethane gradient) to give 4-(3-benzyl-2-carbamoyl-5-methyl-benzofuran-7-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.25 gm, 80% yield).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=O)C(F)(F)F)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21].O>CN(C)C=O>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH3:11])[CH:5]=1)=[O:3]
Reactant: CC(=O)c1cccc(NC(=O)C(F)(F)F)c1
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CNc1cccc(C(=O)C=CN(C)C)c1
Temperature: 150 °C
Yield: 55 %

Procedure:
8.37 g (36.21 mmol) de N-(3-acetylphenyl)-2,2,2-trifluoro-acetamide were dissolved in 80 ml of N,N-dimethyl formamide. To the resultant solution 24.23 ml (181.02 mmol) of N,N-dimethylformamide dimethyl acetal were added and heated at 150° C. for 2 h. The solvent was removed by reduced pressure distillation to yield an oil which was treated with 50 ml of water and extract with 3×100 ml of dichloromethane. The organic layers were washed with 2×200 ml of a saturated solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness by reduced pressure distillation. A solid was obtained, which precipitated from a mixture of ethanol-ethyl ether to give 4.1 g (yield=55%) of 3-(dimethylamino)-1-[3-(methylamino)phenyl]prop-2-en-1-one.
Reaction SMILES: C=O.[Cl:3][C:4]1[CH:29]=[CH:28][C:7]2[N:8]3[C:12]([CH2:13][NH:14][CH2:15][C:6]=2[CH:5]=1)=[N:11][N:10]=[C:9]3[CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:18][CH2:17]1.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[ClH:3].[ClH:3].[ClH:3].[Cl:3][C:4]1[CH:29]=[CH:28][C:7]2[N:8]3[C:12]([CH2:13][N:14]([CH3:30])[CH2:15][C:6]=2[CH:5]=1)=[N:11][N:10]=[C:9]3[CH:16]1[CH2:17][CH2:18][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:20][CH2:21]1
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ccccn3)CC2)C1
Product: Cl
Reaction time: 18 h
Yield: 143.7 %

Procedure:
Formaldehyde (37% w/v aqueous, 0.1 ml, 1.2 mmol) was added to a solution of the amine of example 4 (200 mg, 0.53 mmol) in dichloromethane (5 ml). The mixture was stirred at room temperature for 0.25 hours before sodium triacetoxyborohydride (500 mg, 2.4 mmol) was added, and the reaction mixture was stirred for a further 18 hours. The reaction mixture was partitioned between 2N aqueous sodium hydroxide solution (10 ml) and dichloromethane (10 ml). The organic layer was evaporated under reduced pressure and purified by chromatography on silica gel using methanol in dichloromethane (5:95) as eluant. The residue was dissolved in dichloromethane (2 ml) and hydrochloric acid (1M in diethyl ether, 2 ml) was added. The solvent was evaporated under reduced pressure to give the title compound as a brown foam (96 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][O:5][C:4](=[O:7])[C:3]1=O.[ClH:10].[NH2:11][NH:12][C:13]([NH:15][NH2:16])=[NH:14].O>C(O)C>[ClH:10].[NH2:14][C:13]1[N:15]([NH2:16])[C:4](=[O:7])[C:3]([C:2]([CH3:9])([CH3:1])[CH2:6][OH:5])=[N:11][N:12]=1
Reactant: CC1(C)COC(=O)C1=O
Reactant: N=C(NN)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(CO)c1nnc(N)n(N)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
Dihydro-4,4-dimethyl-2,3-furandione (2 g, 15.6 mmole) and 1,3-diaminoguanidine monohydrochloride (12.96 g, 15.61 immole) were dissolved in ethanol and the resulting solution heated to reflux temperatures. To the refluxing reaction mixture, was added water until a clear solution was obtained. The mixture was then refluxed overnight, cooled to room temperature and stored at -20° C. overnight. The product which separated was filtered and dried. It was crystallized from a mixture of ethanol and water to give 3,4-diamino-6-(1',1'-dimethyl-2'-hydroxyethyl)-1,2,4,-triazin-5(4H)-one hydrochloride (2.24 g, 61%), m.p. 221-222° C. (dec).
Reaction SMILES: CNN.[Si:4]([O:11][CH2:12][CH:13]([O:24][N:25]1C(=O)C2=CC=CC=C2C1=O)[CH2:14][CH2:15][P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]>ClCCl>[Si:4]([O:11][CH2:12][CH:13]([O:24][NH2:25])[CH2:14][CH2:15][P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])([C:7]([CH3:9])([CH3:8])[CH3:10])([CH3:6])[CH3:5]
Reactant: CCOP(=O)(CCC(CO[Si](C)(C)C(C)(C)C)ON1C(=O)c2ccccc2C1=O)OCC
Agent: CNN
Solvent: ClCCl
Product: CCOP(=O)(CCC(CO[Si](C)(C)C(C)(C)C)ON)OCC
Reaction time: 8 h

Procedure:
Methylhydrazine (0.97 ml, 18 mmol) was added to a solution of diethyl [4-(t-butyldimethylsilyloxy)-3-(phthalimidooxy)butyl]phosphonate (5.9 g, 12 mmol) in dichloromethane (40 ml). A white solid separated after a few minutes. The mixture was stirred overnight, filtered, the solvent evaporated and the residue chromatographed on silica gel using dichloromethane-methanol (98:2) as eluant. The title compound was obtained as a colorless oil (3.05 g, 70%). IR: υmax (film). 3320, 2970, 2940, 2860, 1595, 1470, 1390, 1250, 1160, 1060, 1030, 960, 840, 780, cm-1. 1H NMR: δH (CDCl3) 0.08 (6H, s, SiMe2), 0.9 (9H, s, SiBut), 1.3 (6H, t, J=7Hz, (OCH2CH3)2), 1.5-2.2 (4-H, m, CH2CH2P), 3.4-3.9 (3H, m, OCH2CH), 4.15 (4H, m, (OCH2CH3)2), 5.3 (2H, broad, D2O exchangeable NH2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=[O:15])[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].[CH3:16][N:17]([CH3:25])[C:18]1[CH:19]=[C:20](O)[CH:21]=[CH:22][CH:23]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:22](=[CH:23][C:18]([N:17]([CH3:25])[CH3:16])=[CH:19][CH:20]=3)[O:15][CH:14]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH2:13]2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: C1COCCN1
Reactant: CN(C)c1cccc(O)c1
Reactant: COc1cc(C=CC=O)cc(Br)c1OC
Solvent: CO
Product: COc1cc(C2CC(N3CCOCC3)Oc3cc(N(C)C)ccc32)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of the 3-(3-bromo-4,5-dimethoxy-phenyl)-propenal (200 mg; 0.74 mmol), 3-(dimethylamino)phenol (101 mg, 0.74 mmol) and morpholine (65 μl; 0.75 mmol) in dry methanol (5 ml) was refluxed for 2 h and stirred at room temperature for 16 h. The solvent was removed and the intermediate [4-(3-bromo-4,5-dimethoxy-phenyl)-2-morpholin-4-yl-chroman-7-yl]-dimethyl-amine was obtained (350 mg).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[Cl:6][C:7]1[CH:8]=[C:9]([N:13]=[C:14]=[S:15])[CH:10]=[CH:11][CH:12]=1.[CH3:16]I>CN(C=O)C>[Cl:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[C:2]([C:1]#[N:5])[C:3]#[N:4])[S:15][CH3:16])[CH:10]=[CH:11][CH:12]=1
Reactant: N#CCC#N
Reactant: S=C=Nc1cccc(Cl)c1
Reactant: CI
Solvent: CN(C)C=O
Product: CSC(Nc1cccc(Cl)c1)=C(C#N)C#N
Reaction time: 0.08 h

Procedure:
Dissolved malononitrile (3.328 g) in DMF (35 mL), added TEA (1 eq., 6.983 mL), and stirred for 5 minutes before adding 3-chlorophenylisothiocyante (1 eq., 8.54 mL) dropwise, then stirred until complete by TLC (absence of 3-chlorophenylisothiocyanate, 3 hrs). Added methyl iodide (1 eq., 3.136 mL) dropwise, then stirred until intermediate was fully consumed (absent on TLC, 18 hrs); poured into 500 mL ice water, then filtered resulting solution to 2-(((3-chlorophenyl)amino)(methylthio)methylene)malononitrile as a white powder.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[C:12]([C:15]([F:18])([F:17])[F:16])[NH:11][C:10]=2[C:9](=[O:19])[NH:8]/[C:7]/1=[N:20]\[NH2:21])[CH2:2][CH2:3][CH2:4][CH3:5].[CH:22](OCC)(OCC)OCC>>[CH2:1]([N:6]1[C:14]2[N:13]=[C:12]([C:15]([F:16])([F:18])[F:17])[NH:11][C:10]=2[C:9](=[O:19])[N:8]2[CH:22]=[N:21][N:20]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCOC(OCC)OCC
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]c(C(F)(F)F)nc21
Product: CCCCCn1c2nc(C(F)(F)F)[nH]c2c(=O)n2cnnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 227.3 %

Procedure:
A mixture of (2E)-3-pentyl-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-dione-2-hydrazone (0.020 g, 0.14 mmol) and triethyl orthoformate (2 mL, 0.01 mol) was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum and the residue was purified by preparative LCMS. The product fractions were collected and lyophilized to yield pure product as white powder (0.1 g, 48%). LCMS calculated for C12H13F3N6O: (M+H) 315.1. Found: 315.1.