Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:19]=[CH:18][C:8]([CH2:9][O:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[N:14]2)=[C:7]([CH3:20])[CH:6]=1)C=C.CN1C(=O)CC(=O)N(C)C1=O>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:20][C:7]1[CH:6]=[C:5]([OH:4])[CH:19]=[CH:18][C:8]=1[CH2:9][O:10][CH2:11][CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[N:14]1
Reactant: C=CCOc1ccc(COCCn2ccnn2)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Product: Cc1cc(O)ccc1COCCn1ccnn1
Temperature: 40 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
A solution of 7.30 g (26.7. mmol) 1-[2-(4-Allyloxy-2-methyl-benzyloxy)-ethyl]-1H-[1,2,3]-triazole in 100 ml dichloromethane was added to a solution of 13.02 g (83.4 mmol) 1,3-dimethylbarbituric acid an 959 mg (0.8 mmol) Pd(PPh3)4 in 30 ml dichloromethane and stirred overnight at 40° C. The mixture was extracted with 3× sat. NaHCO3-solution. The combined aqueous phases were extracted with dichloromethane. The combined organic extracts were dried over Na2SO4. Solvents were distilled off and the residue was purified by chromatography on silica gel (heptane/ethyl acetate 1/1 to 0/1) to yield 3.30 g (53%) 3-Methyl-4-(2-[1,2,3]triazol-1-yl-ethoxymethyl)-phenol as a yellow solid melting at 92-93° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:25])[C:7]3[C:8](=[CH:11][S:12][C:13]=3[N:14]3C(=O)C4C(=CC=CC=4)C3=O)[C:9]=2[CH:10]=1.CC1C2C(=O)C3C(=CSC=3N3C(=O)C4C(=CC=CC=4)C3=O)C=2C=CC=1.O.NN>C(O)C>[NH2:14][C:13]1[S:12][CH:11]=[C:8]2[C:9]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[C:6](=[O:25])[C:7]=12
Reactant: Cc1ccc2c(c1)-c1csc(N3C(=O)c4ccccc4C3=O)c1C2=O
Agent: Cc1cccc2c1C(=O)c1c-2csc1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)-c1csc(N)c1C2=O
Temperature: 25 °C

Procedure:
To a mixture of 2-(5-methyl-8-oxo-8H-2-thia-cyclopenta[a]inden-1-yl)-isoindole-1,3-dione and 2-(7-methyl-8-oxo-8H-2-thia-cyclopenta[a]inden-1-yl)-isoindole-1,3-dione (0.45 mmol, Example & 3, Part E) in absolute ethanol (5 mL) was added hydrazine hydrate (0.5 mmol). The suspension was heated to reflux for one hour, cooled to room temperature, concentrated in vacuo, and the residue dissolved in methylene chloride. The solution was chilled to 5° C. for one hour, during which time the phthaloyl hydrazide precipitated. The precipitate was removed by filtration, the filtrate concentrated in vacuo, and the residue purified by column chromatography on silica gel, eluting with a 4:1 mixture of petroleum ether:ethyl acetate. Fractions containing the individual products were pooled, evaporated, and each product was isolated after recrystallization from petroleum ether.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[N:33]1[CH:38]=[CH:37][C:36]([CH2:39][NH2:40])=[CH:35][CH:34]=1>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:40][CH2:39][C:36]3[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=3)=[O:18])=[CH:20][CH:21]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1)(=[O:25])=[O:24]
Reactant: NCc1ccncc1
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4ccncc4)cc3)oc2C)cc1
Yield: 72.8 %

Procedure:
Reaction of oxalyl chloride (178 λL, 2.0 mmol) and benzoic acid 4 (379 mg, 1.0 mmol) with subsequent coupling to 4-pyridinylmethylamine (114 λL, 1.1 mmol) gave benzamide 10 (336 mg, 71%) as a white powder: mp (EtOAc) 169-172° C.; 1H NMR δ 9.24 (t, J=5.9 Hz, 1H, CONH), 8.50 (dd, J=4.4, 1.6 Hz, 2H, H-2′, H-6′), 8.03 (dd, J=8.6, 1.8 Hz, 2H, H-2, H-6), 7.92 (dd, J=8.6, 1.8 Hz, 2H, H-3, H-5), 7.67 (d, J=8.3 Hz, 2H, H-2″, H-6″), 7.42 (d, J=8.3 Hz, 2H, H-3″, H-5″), 7.32 (dd, J=4.4, 1.6 Hz, 2H, H-3′, H-5′), 4.63 (s, 2H, CH2SO2), 4.51 (d, J=5.9 Hz, 2H, CH2N), 2.41 (s, 3H, CH3), 2.14 (s, 3H, CH3); 13C NMR δ 165.7, 158.0, 150.0, 148.9 (2), 148.4, 144.5, 135.6, 135.3, 129.7 (2), 128.9, 128.3 (2), 128.1 (2), 126.0, 125.5 (2), 122.2 (2), 53.0, 41.8, 21.1, 9.7; MS m/z 462.8 (MH+, 100%). Anal. calcd for C25H23N3O4S: C, 65.06; H, 5.02; N, 9.10. Found: C, 65.10; H, 4.96; N, 9.10%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.C([O:14][CH:15]1[CH2:23][CH2:22][CH:21]2[CH:17]([CH2:18][N:19]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20]2)[C:16]1=[O:31])(=O)C.[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[CH2:24]([N:19]1[CH2:18][CH:17]2[CH:21]([CH2:22][CH2:23][CH:15]([OH:14])[C:16]2([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[OH:31])[CH2:20]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1ccccc1[Mg]Br
Reactant: CC(=O)OC1CCC2CN(Cc3ccccc3)CC2C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccccc1C1(O)C(O)CCC2CN(Cc3ccccc3)CC21
Temperature: 0 °C
Yield: 26.8 %

Procedure:
To a suspension of 27.6 g of 2-methoxyphenylmagnesium bromide in 60 cm' of tetrahydrofuran are added dropwise, at room temperature and with stirring, a solution of 4.7 g of (3aRS,5RS,7aSR)-5-acetoxy-2-benzyl-4-perhydroisoindolone in 90 cm3 of tetrahydrofuran. The reaction mixture is stirred at room temperature for 3 hours, treated with 200 cm3 of saturated aqueous ammonium chloride solution and taken up in 200 cm3 of ethyl ether and 100 g of ice. The organic phase is separated out after settling has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 80 cm3 of petroleum ether and then chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 1 cm, height 20 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and methanol (95/5 by volume) and collecting 25 cm3 fractions. Fractions 14 to 21 are combined and then concentrated to dryness under reduced pressure (2.5 kPa). 1.55 g of (3aRS,4RS,5RS,7aSR)-2-benzyl-4-(2-methoxyphenyl)-4,5-perhydroisoindolediol are obtained, melting at 140° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100.2 %

Procedure:
To a stirred solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (16 g, 85.4 mmol) and triethylamine (19 mL, 129 mmol) in 130 mL CH2Cl2 was added methanesulfonyl chloride (10 mL, 129 mmol) in 20 mL CH2Cl2 dropwise at 0° C. After addition, the reaction was stirred for 2.5 h at rt, then quenched with sat. NaHCO3 (aq.), and extracted with CH2Cl2. The extract was dried and concentrated to give the desired product (22.7 g, 100% yield) as a yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[O:29]([C:31]#[N:32])[K]>CC#N.O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:31](=[O:29])[NH2:32])[CH2:21]3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: N#CO[K]
Reactant: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCNC3)n2)c1
Solvent: O
Solvent: CC#N
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCN(C(N)=O)C3)n2)c1
Reaction time: 4 h
Yield: 6.8 %

Procedure:
To a mixture of 2-(3-acetamidophenylamino)-4-(piperidin-3-ylmethylamino)pyrimidine-5-carboxamide (40 mg, 0.104 mmol) in CH3CN (2 mL), a solution of KOCN (50 mg, 0.617 mmol) in H2O (1 mL) was added. The mixture was stirred at 70 C for 4 h. It was then purified by HPLC to give the titled compound (3 mg). MS 427.4 (M+H); UV 202.2, 248.6 nm.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:13])[C:4]1[C:5](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:6](N)=[O:7].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1>CN(C=O)C.O>[F:29][C:28]([F:30])([F:31])[C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:1][N:2]2[C:6](=[O:7])[C:5]3[C:4](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:3]2=[O:13])=[CH:23][CH:24]=1
Reactant: NC(=O)c1ccccc1C(=O)NO
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1OCc1ccc(C(F)(F)F)cc1
Reaction time: 3 h
Yield: 87 %

Procedure:
To a stirring solution of N-hydroxy phthalamide (5.25 g, 32.3 mmol) in DMF (30 mL) was added cesium carbonate (15.80 g, 48.5 mmol) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (5 ml, 32.3 mmol) at RT. Reaction mixture was stirred for 3 h. and then diluted with water. Precipitated product was filtered and dried to get titled compound in 87% yield.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:30]=[CH:29][C:9]([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:19]3=[O:20])[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32]>CO>[CH2:31]([N:33]([CH2:34][CH3:35])[CH2:3][CH:2]([OH:4])[CH2:1][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:19]3=[O:20])[CH2:14][CH2:13]2)=[O:11])=[CH:29][CH:30]=1)[CH3:32]
Reactant: O=C(c1ccc(OCC2CO2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Reactant: CCNCC
Solvent: CO
Product: CCN(CC)CC(O)COc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[1-(4-Glycidoxybenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (200 mg) is dissolved in methanol (4 ml) and thereto is added diethylamine (0.26 ml) and the mixture is stirred at room temperature overnight, and then refluxed with heating for 3 hours. The solvent is concentrated and the residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1→dichloromethane:methanol=10:1) to give 1-{1-[4-(3-diethylamino-2-hydroxypropoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (0.18 g)
Reaction SMILES: [NH2:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][CH:3]=1.C1N=CN([C:13](N2C=NC=C2)=[S:14])C=1>O1CCCC1>[CH3:7][C:6]1[C:2]([N:1]=[C:13]=[S:14])=[CH:3][S:4][CH:5]=1
Reactant: Cc1cscc1N
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1cscc1N=C=S
Temperature: 25 °C
Reaction time: 5 h

Procedure:
is obtained by reacting equimolar amounts of 3-amino-4-methylthiophene and N,N′-thiocarbonyldiimidazole in anhydrous tetrahydrofuran (THF) by stirring the reaction mixture at room temperature for 5 hours and then allowing the mixture to stand at room temperature overnight. 4-Methyl-3-thienyl isothiocyanate is isolated by distillative removal of the solvent under reduced pressure using a rotary evaporator, dissolving the residue in ethyl acetate and washing the organic phase repeatedly with water. The organic phase is dried over sodium sulfate and the organic solvent is then distilled off under reduced pressure using a rotary evaporator, giving 4-methyl-3-thienyl isothiocyanate as a brown oily residue. 4-Methyl-3-thienyl isothiocyanate can be used without further purification.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[N:24]=[C:23]([N:25]([CH3:27])[CH3:26])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.[F:36][C:37]1(C(O)=O)[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:39][CH2:38]1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:27][N:25]([CH3:26])[C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([NH:14][C@H:11]2[CH2:12][CH2:13][C@H:8]([NH:7][C:6]([C:46]3[CH:45]=[CH:44][C:43]([C:40]4[CH:39]=[CH:38][C:37]([F:36])=[CH:42][CH:41]=4)=[CH:48][CH:47]=3)=[O:5])[CH2:9][CH2:10]2)[N:24]=1
Reactant: O=C(O)C1(F)C=CC(c2ccccc2)=CC1
Reactant: CN(C)c1nc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)nc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1nc(N[C@H]2CC[C@H](NC(=O)c3ccc(-c4ccc(F)cc4)cc3)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of trans-[4-(4-dimethlyamino-quinazolin-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (0.76 g, 0.20 mmol) in CH2Cl2 (20 mL) was added TFA (304 μL, 0.39 mmol). The solution was stirred at ambient temperature for 4 hr. The resulting mixture was concentrated and the residue was dissolved in CH2Cl2. The organic layer was washed with a dilute aqueous NaOH and aqueous NaHCO3 solution. The aqueous layer was extracted with CH2Cl2 (twice) and the organic layers combined, dried over MgSO4, and concentrated. To a solution of the residue (0.1 g) and 4-fluoro-biphenyl-4-carboxylic acid (76 mg, 0.35 mmol) in CH2Cl2 were added HOAt (62 mg, 0.46 mmol), WSC—HCl (87 mg, 0.46 mmol), and diisopropylethylamine (31 uL, 0.18 mmol). The mixture was stirred for 1 hr at ambient temperature and the reaction was quenched with water. The aqueous layer was extracted with CH2Cl2 (twice). The organic layers were combined, dried over MgSO4, concentrated and the residue purified by column chromatography (silica gel, 2% to 4% 2 M NH3/MeOH in CH2Cl2) to give trans-4′-fluoro-biphenyl-4-carboxylic acid [4-(4-dimethlyamino-quinazolin-2-ylamino)-cyclohexyl]-amide (35 mg, 0.072, 21%) as a white solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10](O)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[O:41]=[C:42]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)[CH2:43][NH:44][C:45](=[O:59])[C:46]1[CH:51]=[CH:50][C:49]([O:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:48][CH:47]=1>CN(C=O)C.O>[C:10]([N:63]1[CH2:62][CH2:61][N:60]([C:42](=[O:41])[CH2:43][NH:44][C:45](=[O:59])[C:46]2[CH:47]=[CH:48][C:49]([O:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[CH:50][CH:51]=2)[CH2:65][CH2:64]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2)CC1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
DIPEA (0.138 mL, 0.80 mmol) was added drop wise to benzoic acid (39 mg, 0.32 mmol) in DMF (5 mL). EDCI (127 mg, 0.67 mmol) and HOBT (43 mg, 0.32 mmol) were added consecutively. After 10 mins, N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenoxy-benzamide hydrochloride (100 mg, 0.27 mmol) was added and the resulting mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification using column chromatography (silica gel of mesh size of 60-120 using 70:30 EtOAc:hexane as eluent) afforded N-[2-(4-benzoyl-piperazin-1-yl)-2-oxo-ethyl]-4-phenoxy-benzamide in 57% yield. LC-MS purity: 99%, 1H NMR (DMSO-D6): δ 8.6 (t, 1H), 7.9 (d, 2H), 7.5 (m, 7H), 7.2 (t, 1H), 7.1 (m, 4H), 4.2 (d, 2H), 3.6 (m, 8H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.N1CCCC1.O.C1(C)C=CC([S:20](O)(=O)=O)=CC=1.[S].[N:26]#[C:27][NH2:28]>>[N:26]1[C:4]2[CH2:3][CH2:2][O:1][CH2:6][C:5]=2[S:20][C:27]=1[NH2:28]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: N#CN
Reactant: O=C1CCOCC1
Agent: [S]
Solvent: C1CCNC1
Solvent: O
Product: Nc1nc2c(s1)COCC2

Procedure:
Commercially available dihydro-2H-pyran-4(3H)-one (Aldrich), pyrrolidine (Aldrich), p-toluenesulfonic acid monohydrate (Aldrich) sulfur (Aldrich) and cyanamide (Aldrich) were processed using the method described in Example 240A to afford the title compound. MS (ESI+) m/z 157 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[N:11]/[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:22]=[C:23]([CH3:25])[CH3:24].B(F)(F)F.CCOCC>C(#N)C>[CH3:22][C:23]1([CH3:25])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:19])([F:20])[F:21])[CH:16]=2)[NH:11][CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:24]1
Reactant: O=[N+]([O-])c1cccc(/C=N/c2ccc(C(F)(F)F)cc2)c1
Reactant: C=C(C)C
Agent: FB(F)F
Solvent: CC#N
Solvent: CCOCC
Product: CC1(C)CC(c2cccc([N+](=O)[O-])c2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 27.1 %

Procedure:
A mixture of [1-(3-nitro-phenyl)-meth-(E)-ylidene]-(4-trifluoromethyl-phenyl)-amine (18.2 g of crude, 62.1 mmol), isobutene (52 mL, 620.6 mmol) and boron trifluoride etherate (1.6 mL, 12.4 mmol) in acetonitrile in a hydrogenated kettle was stirred for two days at room temperature. The solution was evaporated in vacuo and the residue was crystallized by treating with ethyl acetate to give 5.9 g of 4,4-Dimethyl-2-(3-nitro-phenyl)-6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (yield: 27.1%).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:30])[C:11](=[O:29])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[C:14]([F:28])[CH:13]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:38][C:39]([CH3:44])([CH3:43])[CH2:40][CH:41]=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:30])[C:11](=[O:29])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][N:25]([CH2:41][CH2:40][C:39]([CH3:44])([CH3:43])[CH3:38])[CH2:26][CH2:27]3)=[C:14]([F:28])[CH:13]=2)=[CH:6][CH:5]=1
Reactant: CN(C(=O)c1ccc(OCCCN2CCNCC2)c(F)c1)c1ccc(Cl)cc1
Reactant: CC(C)(C)CC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CN(C(=O)c1ccc(OCCCN2CCN(CCC(C)(C)C)CC2)c(F)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
N-(4-Chloro-phenyl)-3-fluoro-N-methyl-4-(3-piperazin-1-yl-propoxy)-benzamide dihydrochloride from Example E71.2 (184 mg, 0.4 mmol) was dissolved in methanol (4.95 ml) and triethylamine (0.167 ml, 1.2 mmol). Acetic acid (0.05 ml) then 3,3-dimethylbutyraldehyde (46 mg, 0.44 mmol) were added and the mixture was stirred for 1 h at room temperature. Sodium cyanoborohydride (31 mg, 0.5 mmol) was added and the mixture was stirred for 20 h at room temperature then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 10% methanol:90% dichloromethane) to give a white foam identified as the title compound (77 mg, 37%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([CH2:15][CH3:16])[C:13]2[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[C:18]([F:21])[CH:19]=[CH:20][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([N:14]1[C:13]2[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[C:18]([F:21])[CH:19]=[CH:20][C:12]=2[N:11]=[C:10]1[C@@H:8]([NH2:7])[CH3:9])[CH3:16]
Reactant: CCn1c([C@H](C)NC(=O)OC(C)(C)C)nc2ccc(F)c(-c3ccccn3)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1c([C@H](C)N)nc2ccc(F)c(-c3ccccn3)c21
Yield: 86.9 %

Procedure:
[(S)-1-(1-Ethyl-6-fluoro-7-pyridin-2-yl-1H-benzoimidazol-2-yl)ethyl]-carbamic acid tert-butyl ester (0.65 g, 1.7 mmol) was added to 20% TFA in DCM (10 mL) and the resultant solution stirred at 20° C. for 1 hour. The reaction mixture was concentrated in vacuo and the residue loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH then concentrated in vacuo to give title compound as a light yellow gum (0.42 g, 88%). LCMS (Method B): RT 1.65 min [M+H]+ 285.1
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Mg].[C:10]1([CH3:18])[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][CH:11]=1.[NH4+].[Cl-]>CCOCC>[CH3:18][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([OH:17])[C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(Br)cc1
Reactant: Cc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1ccc(C(O)c2ccc(C)cc2)cc1

Procedure:
To the Grignard reagent prepared from 47.2 g of p-bromotoluene and 7.2 g of magnesium in 200 ml of ether was added dropwise 30 g of p-tolualdehyde in 50 ml of ether with cooling. When the addition was complete the reaction was refluxed for 15 minutes, cooled in ice, and 40 ml of saturated NH4Cl solution was added dropwise. The reaction was filtered and the ether was removed under reduced pressure to give a yellow oil which crystallized on standing. Recrystallization from petroleum ether gave 26.1 g of nearly colorless 4,4'-dimethylbenzhydrol, m.p. 70°-71°.
Reaction SMILES: CC(O[C:6](=O)[N:7]([CH2:9][CH2:10][NH:11][C:12]1[N:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1)C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Br:18][C:15]1[CH:16]=[N:17][C:12]([NH:11][CH2:10][CH2:9][NH:7][CH3:6])=[N:13][CH:14]=1
Reactant: CN(CCNc1ncc(Br)cn1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCNc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
An ice-cooled solution of [2-(5-bromo-pyrimidin-2-ylamino)-ethyl]-methyl-carbamic acid dimethyl-ethyl ester, D10 (2.32 g, 7.0 mol) in dichloromethane (90 ml) was treated with trifluoroacetic acid (10 ml). The reaction mixture was stirred for 2 h at room temperature, under argon then poured onto K2CO3 (excess)/ice. The aqueous layer was separated, washed with dichloromethane (3×) and the combined organics dried (MgSO4) and the solvent removed in vacuo to afford the title compound (1.00 g, 61%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=S)[S:10]CC(O)=O)=[CH:5][CH:4]=1.[OH-].[K+].O.[NH2:21][NH2:22].C(O)(=O)C>CO.O>[CH:5]1[C:6]([C:9]([NH:21][NH2:22])=[S:10])=[CH:7][CH:8]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:4]=1
Reactant: O=C(O)CSC(=S)c1ccc(C(F)(F)F)cc1
Reactant: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: NNC(=S)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
[((4-(Trifluoromethyl)phenyl)thioxomethyl)thio]acetic acid (6.7 g) was dissolved in methanol (50 ml). Potassium hydroxide (1.34 g) in water (15 ml) was added followed by hydrazine hydrate (1.28 ml). The mixture was stirred for 4 hours at room temperature. Glacial acetic acid was added until the pH was 5 and the solvent was removed under reduced pressure. The product was extracted with diethyl ether (250 ml) and the solvent was evaporated under reduced pressure. The resulting solid was crystallised from cyclohexane as pale pink crystals (4.0 g) mp 114°-115.5°.