Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:4]=1.[H-].[Na+].[CH:22](OC)=[O:23]>CN(C=O)C>[OH:23][CH:22]=[C:15]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:4]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC=O
Reactant: COC(=O)CN(C)c1cccc(-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=CO)N(C)c1cccc(-c2ccccc2)c1
Yield: 12.5 %

Procedure:
Methyl (N-methyl-3-phenylanilino)acetate (4.33 g) was formylated as described in Example 1 by treatment with sodium hydride (0.94 g) and methyl formate (21.01 g) in DMF (50 ml) to give methyl 3-hydroxy-2-(N-methyl-3'-phenylanilino)propenoate (0.60 g) as a brown viscous liquid. Methylation with dimethyl sulphate (0.59 g) and potassium carbonate (0.62 g) in DMF (25 ml) for 5 hours afforded on work-up and HpLC (eluent petroleum ether--ether, 70:30) on silica gel a pure sample of the title compound (260 mg) as a yellow liquid.
Reaction SMILES: CCCCCCCCCCCCCC(O[C@H]1[C@@]2(OC(C)=O)C(C)(C)[C@H]2[C@@H]2C=C(CO)C[C@]3(O)C(=O)C(C)=C[C@H]3[C@@]2(O)[C@@H]1C)=O.C[C@H]1[C@@H](CC2[O:73][C:72]3[CH:74]=[CH:75][C:76](NC)=[C:77](C(O)=O)[C:71]=3N=2)O[C@]2(O[C@H]([C@@H](C(C3NC=CC=3)=O)C)[C@H](C)C[C@H]2C)CC1.[NH2:83][C@H:84]([C:87]([OH:89])=[O:88])[CH2:85]S>>[NH2:83][C@H:84]([C:87]([OH:89])=[O:88])[CH2:85][C:76]1[CH:77]=[CH:71][C:72]([OH:73])=[CH:74][CH:75]=1
Reactant: N[C@@H](CS)C(=O)O
Reactant: CNc1ccc2oc(C[C@H]3O[C@@]4(CC[C@H]3C)O[C@H]([C@H](C)C(=O)c3ccc[nH]3)[C@H](C)C[C@H]4C)nc2c1C(=O)O
Agent: CCCCCCCCCCCCCC(=O)O[C@@H]1[C@@H](C)[C@@]2(O)[C@@H](C=C(CO)C[C@]3(O)C(=O)C(C)=C[C@@H]23)[C@@H]2C(C)(C)[C@]12OC(C)=O
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
Reagents Phorbol 12-myristate 13-acetate (PMA) and calcium ionophore A23187 were purchased from Sigma. Bromelain (E.C 3.4.22.4; proteolytic activity, 1,541 nmol/min/mg) was obtained from Solvay Inc. (Germany). E-64 (L-transepoxysuccinylleucylamido-(4-guanidino)butane, a selective cysteine protease inhibitor, was from Sigma.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:28][CH:29]([OH:32])[CH2:30][OH:31]>>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Reactant: OCC(O)CCl
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCC(O)CO)cc12
Yield: 74 %

Procedure:
6-(2,3-Dihydroxy-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime was prepared in 74% yield using the method described in example 85A, starting from 6-Hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (example 81A) and 3-chloro-1,2-propandiol. The title compound was isolated as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([CH3:13])=[CH2:12].O.C1C=C(Cl)C=C(C(OO)=[O:23])C=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1([CH3:13])[CH2:12][O:23]1
Reactant: C=C(C)c1cc([N+](=O)[O-])ccc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: CC1(c2cc([N+](=O)[O-])ccc2F)CO1
Temperature: 10 °C
Reaction time: 48 h

Procedure:
1-fluoro-4-nitro-2-(prop-1-en-2-yl)benzene (1 eq) was dissolved in dichloromethane and cooled to 10° C. using and ice/salt/water bath under nitrogen. MCPBA (1.5 eq) in dichloromethane was then added dropwise and resulting solution allowed to warm to room temperature and allowed to stir 48 h. Solution was quenched with 10% sodium sulfite, neutralized with saturated solution of sodium bicarbonate, extracted with dichloromethane. Organics were washed with brine, dried with sodium sulfate and concentrated. Crude product was purified with flash chromatography (85% Hex:15% EtoAc) to afford 2-(2-fluoro-5-nitrophenyl)-2-methyloxirane.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[N:14][CH:15]=2)[CH2:5][CH2:4]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N1CCN(C2C=C(N[C:54]([C:56]3[C:57]4[N:58]=[CH:59][CH:60]=[N:61][C:62]=4[C:63]([C:66]4[C:75]5[C:70](=[CH:71][CH:72]=[CH:73][CH:74]=5)[CH:69]=[N:68][CH:67]=4)=[CH:64][CH:65]=3)=[O:55])C=CC=2)CC1)C>C(Cl)Cl.CO>[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:54]([C:56]3[C:57]4[N:58]=[CH:59][CH:60]=[N:61][C:62]=4[C:63]([C:66]4[C:75]5[C:70](=[CH:71][CH:72]=[CH:73][CH:74]=5)[CH:69]=[N:68][CH:67]=4)=[CH:64][CH:65]=3)=[O:55])=[N:14][CH:15]=2)[CH2:5][CH2:4]1
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1
Reactant: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4cncc5ccccc45)c4nccnc34)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(NC(=O)c3ccc(-c4cncc5ccccc45)c4nccnc34)nc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture for 17 h at rt, using 2 equiv of 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine hydrochloride (Example 31), TBTU (2 equiv) and 8-isoquinolin-4-yl-quinoxaline-5-carboxylic acid (Example 52). Title compound: ESI-MS: 490.0 [M+H]+; tR=2.21 min (System 1); TLC: Rf=0.17 (DCM/MeOH, 9:1).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.FC(F)(F)C(O)=O.[F:16][C:17]1[C:32]([F:33])=[CH:31][C:20]2[NH:21][C:22]([NH:24][C:25]3[C:29]([CH3:30])=[CH:28][S:27][CH:26]=3)=[N:23][C:19]=2[CH:18]=1>C(O)(=O)C>[Br:1][C:26]1[S:27][CH:28]=[C:29]([CH3:30])[C:25]=1[NH:24][C:22]1[NH:21][C:20]2[CH:31]=[C:32]([F:33])[C:17]([F:16])=[CH:18][C:19]=2[N:23]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cscc1Nc1nc2cc(F)c(F)cc2[nH]1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1csc(Br)c1Nc1nc2cc(F)c(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At room temperature, a solution of N-bromosuccinimide (8 mg) in glacial acetic acid (0.5 ml) was added dropwise to a solution of (5,6-difluoro-1H-benzimidazol-2-yl)-(4-methylthiophen-3-yl)amine trifluoroacetic acid salt (15 mg, example 45) in glacial acetic acid (0.5 ml) in a ReactiVial, and the mixture was stirred at room temperature for 0.5 h. The acetic acid was then removed under reduced pressure and saturated potassium carbonate solution and ethyl acetate were added to the residue. The organic phase was removed and the aqueous phase was then extracted twice with ethyl acetate. The combined organic phases were dried using magnesium sulfate and the drying agent was then filtered off. The residue that remained after removal of the solvent under reduced pressure was purified by preparative chromatography. The product-containing fractions were combined and freed from acetonitrile, saturated sodium bicarbonate solution was added to the residue and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried (MgSO4) and filtered. After removal of the ethyl acetate under reduced pressure, the residue was coevaporated with toluene and then dried under high vacuum. This gave 8.1 mg of the desired compound.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([CH3:34])[C:17]2[O:23][C:22]3[C:24]([Cl:30])=[CH:25][C:26]([CH2:28][NH2:29])=[CH:27][C:21]=3[CH2:20][S:19](=[O:32])(=[O:31])[C:18]=2[CH:33]=1)=[O:13].Cl.ClC1C=CN=CC=1>O1CCOCC1>[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([CH3:34])[C:17]2[O:23][C:22]3[C:24]([Cl:30])=[CH:25][C:26]([CH2:28][N:29]4[CH:3]=[CH:7][CH:6]=[CH:5]4)=[CH:27][C:21]=3[CH2:20][S:19](=[O:31])(=[O:32])[C:18]=2[CH:33]=1)=[O:13]
Reactant: COC1CCC(OC)O1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(CN)cc(Cl)c1O2
Agent: Cl
Agent: Clc1ccncc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(Cn3cccc3)cc(Cl)c1O2
Temperature: 110 °C
Reaction time: 2 h

Procedure:
2,5-Dimethoxytetrahydrofuran (0.090 mL, 0.655 mmol) was added with stirring to a solution of Example 198k (0.2 g, 0.52 mmol) in dry dioxane (10 mL) followed by the addition of 4-chloropyridine hydrochloride (0.008 g, 0.05 mmol). The reaction mixture was allowed to stir at 110° C. for 2 h under nitrogen atmosphere. It was concentrated, treated with cold water and the solid that precipitated was filtered, washed with water, dried and purified using flash chromatography (silica gel, chloroform/pet ether) to obtain the title compound as a white solid. Yield: 0.086 g, (41.54%); 1H NMR (DMSO-d6): δ 2.69 (s, 3H, CH3), 3.92 (s, 3H, OCH3), 4.67 (s, 2H, CH2), 5.02 (s, 2H, CH2), 6.22 (s, 2H, Ar), 6.68 (s, 2H, Ar), 7.04 (s, 1H, Ar), 7.38 (s, 1H, Ar), 8.09 (s, 1H, Ar), 8.46 (s, 1H, Ar); MS: m/e (ES+) 432 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[N:11]=[C:12]=[S:13].[N-:14]=[N+:15]=[N-:16].[Na+].O.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[N:11]1[C:12]([SH:13])=[N:16][N:15]=[N:14]1
Reactant: COc1ccc(OC)c(N=C=S)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(OC)c(-n2nnnc2S)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.1 %

Procedure:
2,5-Dimethoxyphenylisothiocyanate (39 g, 0.22 mol) and sodium azide (14.3 g, 0.22 mol) were added to a mixture of water (150 ml) and ethanol (60 ml) and the mixture was heated on a steam bath to about 80° C. to 90° C. with stirring for 3 hours. The reaction mixture was cooled to room temperature and a 2N HCl solution (100 ml) was added. The raw crystals formed were collected by filtration and recrystallized from isopropanol to obtain 1-(2,5-dimethoxyphenyl)-5-mercaptotetrazole (35.7 g, yield 75%). The melting point was 151° to 152° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[Li]CCCC.C1CCCCC1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>C1COCC1>[CH2:10]([O:9][C:3](=[O:8])[CH2:4][C:5](=[O:6])[CH2:7][CH2:28][C:27]1[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=1)[CH3:11]
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCOC(=O)CC(=O)CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred suspension of NaH (60% suspension in mineral oil, 1.42 g, 36 mmol) in dry THF (50 mL) was added ethyl acetoacetate (4.3 g, 33 mmol) dropwise at 0° C. After 10 min stirring at this temperature, a 2.0 M solution of n-BuLi in cyclohexane (17.7 mL, 35 mmol) was added dropwise under N2. The stirring was continued at 0° C. for 10 min., 4-fluorobenzyl bromide (9.45 g, 50 mmol) was then added dropwise at 0° C. The resultant solution was allowed to warm to rt. After 20 min, the reaction as quenched with 2 N HCl/Et2O (20 mL/40 mL). Layers were separated, the aqueous layer was extracted with ether (3×50 mL). Combined ether solution was washed with H2O (50 mL), brine (50 mL), and dried with Na2SO4. After removal of the solvent under reduced pressure, the resultant oily material was purified by flush column chromatography on silica gel (hexane to 4:1 hexane/EtOAc). The corresponding intermediate 5-(4-Fluoro-phenyl)-3-oxo-pentanoic acid ethyl ester was obtained as a colorless liquid (7.16 g, 92%). 1H NMR (300 MHz, CDCl3) δ1.25 (t, 3H, J=7), 2.80-2.95 (m, 4H), 3.40 (s, 2H), 4.10-4.25 (m, 2H), 6.9-7.0 (m, 2H), 7.1-7.2 (m, 2H). ESMS calcd (C13H15FO3): 238.1; found: 239.1 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6](=[O:26])[CH:7]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([O:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)[CH:13]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:2]1>CC(O)=O.O.[Zn]>[CH:1]1([CH2:4][O:5][C:6](=[O:26])[CH:7]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([O:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)[CH:13]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:2]1
Reactant: CC(C)CC(C(=O)OCC1CC1)c1ccc([N+](=O)[O-])c(OCC2CC2)c1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)CC(C(=O)OCC1CC1)c1ccc(N)c(OCC2CC2)c1
Yield: 73.7 %

Procedure:
2-(3-Cyclopropylmethoxy-4-nitro-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (34.0 g, 94.2 mmol) was dissolved in AcOH (300 mL) and water (20 mL). Then, Zn powder (60.0 g, 923 mmol) was added in portions. The reaction mixture was refluxed for 1 h and after cooling the precipitate was filtered. The solvent was evaporated and water (150 mL) was added. The reaction mixture was extracted with EtOAc (3×100 mL) and the combined organic phases were washed with water (3×100 mL) and brine (100 mL). Drying of the organic phase was performed with magnesium sulfate. The evaporation of the solvent gave crude product as a brown oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc to give 2-(4-amino-3-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester as a yellow oil (23 g, 75%). 1H NMR (300 MHz, CDCl3/TMS): δ 6.73-6.61 (m, 3H), 3.94-3.78 (m, 6H), 3.53 (t, J=7.7 Hz, 1H), 1.94-1.85 (m, 1H), 1.65-1.56 (m, 1H), 1.52-1.43 (m, 1H), 1.28-1.18 (m, 1H), 1.11-1.03 (m, 1H), 0.90 (d, J=6.6 Hz, 6H), 0.64-0.58 (m, 2H), 0.53-0.47 (m, 2H), 0.36-0.33 (m, 2H), 0.24-0.21 (m, 2H); 13C NMR (75 MHz, CDCl3/TMS): δ 174.6, 146.4, 135.3, 129.3, 120.5, 114.6, 111.2, 73.1, 69.0, 49.2, 42.7, 25.8, 22.6, 22.4, 10.4, 9.8, 3.2.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]3[N:18]=[C:17]([NH2:19])[CH:16]=[CH:15][N:14]3[CH:20]=2)[CH:8]=[CH:9][CH:10]=1.[CH2:21]([O:23][C:24]([C:26]1[CH:27]=[N:28][N:29]([CH3:34])[C:30]=1[C:31](O)=[O:32])=[O:25])[CH3:22].CCN(C(C)C)C(C)C>CCOC(C)=O>[CH2:21]([O:23][C:24]([C:26]1[CH:27]=[N:28][N:29]([CH3:34])[C:30]=1[C:31](=[O:32])[NH:19][C:17]1[CH:16]=[CH:15][N:14]2[CH:20]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][CH2:2][F:1])[CH:6]=3)[N:12]=[C:13]2[N:18]=1)=[O:25])[CH3:22]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Reactant: Nc1ccn2cc(-c3cccc(OCCF)c3)nc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2cc(-c3cccc(OCCF)c3)nc2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(3-(2-Fluoroethoxy)phenyl)imidazo[1,2-a]pyrimidin-7-amine (1 eq.) was combined with EtOAc (7.50 ml) to give a light yellow suspension. 4-(Ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (1 eq.) and DIPEA (6 eq.) were added. The reaction mixture was cooled down to 0° C. and n-propylphosphonic acid anhydride, cyclic trimer (1.17 g, 1.1 ml, 1.84 mmol, 2.50 eq.) was added dropwise. After stirring at 0° C. during 30 min, the reaction mixture was stirred and allowed to warm-up to RT overnight. The reaction mixture (yellow solution) was poured into 50 ml EtOAc and extracted with H2O (1×30 ml). The aqueous layer was back-extracted with DCM (3×20 ml). The organic layers were combined and washed with sat. NaCl-solution (1×30 ml), dried over MgSO4, filtrated and concentrated under vacuum to give a yellow solid (207 mg). The crude material was purified by flash chromatography (silica gel, 20 g, CH2Cl2 to 50% CH2Cl2/MeOH/NH3 aq. 140:10:1). Yellow solid (332 mg, 31%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([C:32]1[N:33]=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CCC[C@H]1CN>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH2:24][C@H:23]2[CH2:32][NH2:33])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: NC[C@@H]1CCCN1
Product: CC(C)(C)c1nc(N2CCC[C@H]2CN)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (S)-pyrrolidin-2-ylmethanamine. MS(m/e): 400.4 (MH+).
Reaction SMILES: [Br:1][C:2]([OH:12])([CH3:11])[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C.CN(C1C=CN=CC=1)C>[Br:1][C:2]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])([CH3:11])[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1
Reactant: CC(O)(Br)CCC1CCC(=O)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(Br)(CCC1CCC(=O)N1)O[Si](C)(C)C(C)(C)C
Reaction time: 24 h
Yield: 98.4 %

Procedure:
To a solution of 5-(3-bromo-3-hydroxy-butyl)-pyrrolidin-2-one (6.76 g, 21.6 mmol) in DMF (86 mL) was added tert-butyldimethylsilyl chloride (3.59 g, 23.8 mmol) followed by imidazole (2.95 g, 43.3 mmol) and DMAP (264 mg, 2.16 mmol). The reaction was stirred for 24 h and was quenched with saturated aqueous ammonium chloride. The aqueous solution was washed with EtOAc (3×) and the combined organic extracts were dried (MgSO4), filtered, and concentrated. Purification by medium pressure chromatography using a solvent gradient (CH2Cl2 to 1% MeOH in CH2Cl2 to 3% MeOH in CH2Cl2 to 5% MeOH in CH2Cl2 to 8% MeOH in CH2Cl2) provided 5-[3-bromo-3-(tert-butyl-dimethyl-silanyloxy)-butyl]-pyrrolidin-2-one (7.45 g). 1H NMR (CDCl3) δ7.30 (m, 2H), 7.12 (m, 1H), 7.04 (m, 1H), 5.71 (m, 1H), 3.81 (m, 1H), 3.56 (m, 1H), 2.66 (m, 2H), 2.32-2.17 (m, 3H), 1.70-1.35 (m, 5H), 0.82 (s, 9H), −0.06 (d, 3H), −0.24 (d, 3H); MS 426.2, 428.2 (M+).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.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.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:25]4[CH:32]=[CH:31][CH:30]=[C:27]([C:28]#[N:29])[CH:26]=4)[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N#Cc1cccc(I)c1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCCC(=O)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3cccc(C#N)c3)CCCC(=O)C2)cc1OC1CCCC1
Temperature: 80 °C
Yield: 72.5 %

Procedure:
To a solution of the compound from Example 3 (E1) (0.125 g, 0.4 mmol) and 3-iodobenzonitrile (Transworld, 0.09 g, 0.4 mmol) in triethylamine (3 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C. for 0.2 h, was cooled to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, was dried (MgSO4) and was evaporated. The residue was purified by flash chromatography, eluting with 2:1 hexanes/ethyl acetate, to provide the title compound as a clear yellow glass (0.12 g, 73%). MS(EI) m/e 414 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([NH2:15])[N:3]=1.[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=2)[CH2:19][CH2:18][NH:17]1>>[NH2:15][C:4]1[N:3]=[C:2]([N:17]2[CH2:18][CH2:19][C:20]3[C:25](=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[CH2:16]2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=1
Reactant: N#Cc1ccc2c(c1)CNCC2
Reactant: CN1CCN(c2cc(Cl)nc(N)n2)CC1
Product: CN1CCN(c2cc(N3CCc4ccc(C#N)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 1 starting from 4-chloro-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and 1,2,3,4-tetrahydroisoquinoline-7-carbonitrile (Asta Tech, Cat. No. 48330). LCMS (M+H)+: m/z=350.2.
Reaction SMILES: Cl.[C:2]1([S:8]([C:11]2[C:19]3[C:14](=[C:15]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]=O>C(O)C.[Pd]>[C:2]1([S:8]([C:11]2[C:19]3[C:14](=[C:15]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)(=[O:9])=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: O=S(=O)(c1ccccc1)c1c[nH]c2c(N3CCNCC3)cccc12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN1CCN(c2cccc3c(S(=O)(=O)c4ccccc4)c[nH]c23)CC1

Procedure:
A solution of 3-benzenesulfonyl-7-piperazin-1-yl-1H-indole (101) (500 mg, 1.46 mmol) and 1 mL of 37% aqueous formaldehyde in 25 mL of ethanol was hydrogenated at atmospheric pressure in the presence of 250 mg of 10% Pd-C for 30 min. The mixture was filtered, diluted with water and extracted with ethyl acetate. The ethyl acetate was washed with water and brine, dried, and evaporated to yield the crude free base of 3-benzenesulfonyl-7-(4-methyl-piperazin-1-yl)-1H-indole. The hydrochloride salt was crystallized from ethanol-ether to afford 290 mg of (501), m.p. 160-162° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[CH3:18][N:19](C=O)C.N.C1(C)C=CC=CC=1>O>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:18]#[N:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: CN(C)C=O
Reactant: COCCc1ccc(-c2ccc(I)cc2)cc1
Agent: N
Solvent: O
Solvent: Cc1ccccc1
Product: COCCc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 149 °C
Reaction time: 6 h

Procedure:
Into a 200 ml three-neck flask were added 4'-(β-methyloxyethyl)-4-iodobiphenyl obtained in Step C (20 g, 0.59 mol), cuprous cyanide (6.2 g, 0.688 mol) and DMF (67 ml), and the mixture was reacted together under reflux with stirring at 149° C. for 6 hours. After completion of the reaction, the reaction liquid was cooled down to room temperature and 29% aqueous ammonia (20 ml) was added, followed by agitation. Toluene (50 ml) and water (100 ml) were then added and the reaction liquid was subjected to suction-filtration. The toluene layer of the filtrate was washed with 6 N-hydrochloric acid and then with sodium hydroxide aqueous solution and further with water till the layer became neutral. The resulting toluene layer was dried with anhydrous sodium sulfate (10 g), and passed through an active alumina layer, followed by distilling off toluene, recrystallizing the residual crystals from methanol (30 ml), filtering and drying to obtain objective 4'-(β-methyloxyethyl)-4-cyanobiphenyl (3 g) having a melting point (C-I point) of 50.7° C. When this product was mixed with 4'-octyloxy-4-cyanobiphenyl and the mixture was subjected to measurement for N→I point, its N→I point through extrapolation was -5° C. (With the above product alone, measurement of N→I point was impossible.) The values of the elemental analysis of the product accorded well with the calculated values thereof as follows: