Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][C:3]=1[CH3:21].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][C:24]=1[C:32]([F:35])([F:34])[F:33]>O1CCCC1.ClCCl>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:1][C:2]2[CH:20]=[CH:19][C:5]([O:6][C:7]3[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([CH:16]4[CH2:17][CH2:18]4)=[O:15])[CH:8]=3)=[CH:4][C:3]=2[CH3:21])=[O:31])=[CH:25][C:24]=1[C:32]([F:33])([F:34])[F:35]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1cc(Oc2cc(NC(=O)C3CC3)ncn2)ccc1N
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(Oc2cc(NC(=O)C3CC3)ncn2)ccc1NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Yield: 93.7 %

Procedure:
Dissolve N-[6-(4-amino-3-methyl-phenoxy)pyrimidin-4-yl]cyclopropanecarboxamide (1.8 g, 6.3 mmol) in tetrahydrofuran (50 mL) and dichloromethane (50 mL), add slowly 4-chloro-3-(trifluoromethyl)phenyl isocynate (1.4 g, 6.3 mmol), stir the reaction at room temperature for 15 hrs. Collect the white solid formed by filtration (2.0 g), recover from the mother liquor to give another 1.0 g (total 3.0 g, 93.7% yield). MS: (M+1): 506.2.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:17]=[CH:16][C:10]3[N:11]([CH3:15])[C:12]([OH:14])=[N:13][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[N:1]1([CH2:6][C:7]2[CH:17]=[CH:16][C:10]3[N:11]([CH3:15])[C:12](=[O:14])[N:13]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: ClCc1ccccc1
Reactant: Cn1c(O)nc2cc(Cn3ccnc3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(Cc2ccccc2)c2cc(Cn3ccnc3)ccc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
A mixture of 4.5 parts of 5-(1H-imidazol-1-ylmethyl)-1-methyl-1H-benzimidazol-2-ol, 0.46 parts of a sodium hydride dispersion 50% and 56 parts of N,N-dimethylformamide was stirred for 30 minutes at 50° C. After the addition of 2.53 parts of (chloromethyl)benzene, the solution was stirred for 2 hours at 50° C. The N,N-dimethylformamide layer was evaporated in vacuo. The residue was diluted with water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of 27 parts of ethyl acetate and 44 parts of 2,2'-oxybispropane. The product was filtered off and dried, yielding 5 parts (78.5%) of 1,3-dihydro-5-(1H-imidazol-1-ylmethyl)-1-methyl-3-(phenylmethyl)-2H-benzimidazol-2-one; mp. 129.4° C. (compound 226).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][CH2:12][C@H:13]1[O:17][C@@H:16]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:15][C@@H:14]1[OH:27]>C(OCC)C.[OH-].[Na+]>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][CH2:12][C@H:13]2[O:17][C@@H:16]([N:18]3[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]3=[O:20])[CH2:15][C@@H:14]2[OH:27])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)[nH]c1=O
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)c3ccc(Br)cc3)O2)c(=O)[nH]c1=O
Reaction time: 0.17 h
Yield: 46.1 %

Procedure:
A solution of 219 mg of 4-bromobenzoyl chloride in 5 ml of diethyl ether was added to a solution of 241 mg of 5'-amino-5'-deoxythymidine in 4 ml of 0.25M sodium hydroxide solution and the mixture was shaken vigorously for 10 minutes. The mixture was filtered and the solid was washed with 10 ml of water and 4 ml of diethyl ether, and recrystallized from ethanol to give 195 mg of 5'-(4-bromobenzamido)-5'-deoxythymidine of melting point 250.5°-252° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[OH:19].Br[CH:21]([CH:27](Br)[CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:18])[C:10]3[CH2:17][CH2:16][CH2:15][CH2:14][C:11]=3[C:12]2=[O:13])=[CH:4][C:3]=1[O:19][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][CH3:28]
Reactant: CCOC(=O)C(Br)C(C)Br
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC=C(Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl)C(=O)OCC
Reaction time: 6 h

Procedure:
A mixture of 4.0 g. of N-(4-chloro-3-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide, 4.7 g. of ethyl 2,3-dibromobutyrate, 2.4 g. of potassium carbonate and 35 ml. of acetone was refluxed with stirring for 6 hours and the precipitated salt was separated by a filtration. The filtrate was concentrated under a reduced pressure and 2N-HCl was added to the residue to obtain a crude crystal. The product was washed with water and dried and purified by a chromatography on a column of silica gel (developing solvent: ethyl acetate:n-hexane of 3:7) to obtain 5.2 g. of Compound No. 158 shown in Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([O:15]C)=[C:10]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:32])/[CH:26]=[CH:27]/[CH2:28][N:29]([CH3:31])[CH3:30])[CH2:21][CH2:20]2)=[O:18])[CH:9]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([OH:15])=[C:10]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:32])/[CH:26]=[CH:27]/[CH2:28][N:29]([CH3:30])[CH3:31])[CH2:21][CH2:20]2)=[O:18])[CH:9]=1
Reactant: COc1cc(Cl)c(-c2ccccc2Cl)cc1C(=O)N1CCN(C(=O)/C=C/CN(C)C)CC1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)C/C=C/C(=O)N1CCN(C(=O)c2cc(-c3ccccc3Cl)c(Cl)cc2O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
A solution of (E)-1-(4-(2′,6-dichloro-4-methoxy-[1,1′-biphenyl]-3-carbonyl)piperazin-1-yl)-4-(dimethylamino)but-2-en-1-one (270 mg, 0.57 mmol) in DCM (5 mL) at −78° C., BBr3 (1.43 g, 5.7 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 2 h. The mixture was poured into ice-water, basified with the aqueous NaHCO3 to adjust the pH to 7 and then extracted with DCM (3×20 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (150 mg, 57% yield). 1HNMR (400 MHz, DMSO-d6) δ: 13.12 (s, 1H), 8.02 (s, 1H), 7.81 (s, 1H), 6.81 (m, 1H), 6.13 (dd, J=2.8, 16.8 Hz, 1H), 5.71 (dd, J=2.0, 10.4 Hz, 1H), 4.10 (s, 2H), 3.50-3.60 (m, 8H). ESI-MS m/z: 462.4[M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][OH:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:27][CH:28]1[CH2:30][CH2:29]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23][CH2:27][CH:28]2[CH2:30][CH2:29]2)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CO)nc3N21
Reactant: BrCC1CC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(COCC4CC4)nc3N21
Reaction time: 3 h
Yield: 67.1 %

Procedure:
To a solution of 1.2 g (37.6 mmol) (4R,9aR)-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 30 ml N,N-dimethylformamide was added 0.18 g (41.4 mmol) sodium hydride. After 30 min 0.72 ml (1.01 g, 75.2 mmol) (bromomethyl)cyclopropane was added and the reaction was stirred for 3 h. The reaction mixture was poured into 10% aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel (0.032–0.063 mm) with a gradient of ethyl acetate:n-hexane (1:1 to 100:0) as eluant to afford the compound as a light yellow oil (67.1%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH2:10][CH:9]1[CH2:28][CH:29]([CH3:31])[CH3:30])=O)(C)(C)C.[NH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1>>[CH2:28]([C@@H:9]1[NH:8][CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:32][CH2:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=4)[N:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH2:10]1)[CH:29]([CH3:30])[CH3:31]
Reactant: NCCc1ccc(O)cc1
Reactant: CC(C)CC1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CCN1C(=O)OC(C)(C)C
Product: CC(C)C[C@H]1CN(Cc2cccc(-c3ccnc(NCCc4ccc(O)cc4)n3)c2)CCN1

Procedure:
Intermediate 113 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 447. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.65 (s, 1H), 8.36 (d, 1H), 8.32 (s, 1H), 7.95 (d, 1H), 7.71 (t, 1H), 7.65 (d, 1H), 7.11 (d, 1H), 6.68 (s, 1H), 4.70 (d, 1H), 4.57 (d, 1H), 3.96 (m, 2H), 3.81 (m, 2H), 3.58 (m, 4H), 3.40 (t, 1H), 2.92 (t, 2H), 1.75 (m, 1H), 1.62 (t, 2H), 1.00 (d, 3H), 0.98 (d, 3H).
Reaction SMILES: [F:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]=[CH:7][C:6]=1[N+:15]([O-])=O>C(#N)C.[Pt]>[F:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15]
Reactant: CC(C)(F)CNc1c([N+](=O)[O-])cnc2cccnc12
Agent: [Pt]
Solvent: CC#N
Product: CC(C)(F)CNc1c(N)cnc2cccnc12
Reaction time: 5 h
Yield: 90.5 %

Procedure:
A solution of N-(2-fluoro-2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine (2.64 g, 10.0 mmol) dissolved in 80 mL of acetonitrile was placed in a pressure bottle. Platinum on carbon (5%, 500 mg) was then added and the reaction mixture was shaken under H2 at 50 PSI (3.4×105 Pa). After 5 hours, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with acetonitrile and the combined filtrates were concentrated under reduced pressure to give 2.12 g of N4-(2-fluoro-2-methylpropyl)[1,5]naphthyridine-3,4-diamine as a brown foam.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:18]=[C:17]([Sn](C)(C)C)[CH:16]=[C:15]3[C:11]=2[CH:12]=[N:13][N:14]3S(C2C=CC=CC=2)(=O)=O)=[O:8])[N:6]=1.Br[C:33]1[CH:34]=[C:35]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[C:36]([O:39][CH3:40])=[N:37][CH:38]=1.CN(C=O)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.CO>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:18]=[C:17]([C:33]3[CH:38]=[N:37][C:36]([O:39][CH3:40])=[C:35]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH:34]=3)[CH:16]=[C:15]3[C:11]=2[CH:12]=[N:13][NH:14]3)=[O:8])[N:6]=1
Reactant: COc1ncc(Br)cc1NS(C)(=O)=O
Reactant: Cc1nc(C(=O)Nc2cc([Sn](C)(C)C)cc3c2cnn3S(=O)(=O)c2ccccc2)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ncc(-c2cc(NC(=O)c3csc(C)n3)c3cn[nH]c3c2)cc1NS(C)(=O)=O
Temperature: 120 °C
Reaction time: 0.23 h
Yield: 6.7 %

Procedure:
2-Methyl-N-[1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (200 mg, 0.356 mmol), N-[5-bromo-2-(methyloxy)-3-pyridinyl]methanesulfonamide (120 mg, 0.428 mmol) and Pd(PPh3)4 (41 mg, 0.036 mmol) were weighed to a microwave vial. DMF (3 ml) was added and the reaction was heated in the microwave at 120° C. for 30 mins. The reaction mixture was passed through a 1 g silica cartridge (pre-conditioned with methanol), washing with methanol. The solvent was removed by blow down. The residue was dissolved in DCM and purified on the ISCO companion, using a 40 g Si cartridge, a gradient of 0-6% methanol in DCM containing 1% ammonia, over 14 mins and a 40 ml/min flow rate. LCMS showed still not pure, therefore the material was further purified by MDAP (Method E). The purified material was dissolved in IPA (3 ml) and 2M NaOH (aq, 3 ml) was added. The reaction mixture was left overnight then concentrated and acidified with 2M HCl (aq). The precipitate was filtered, re-dissolved in methanol and dried by blow down to afford the title compound (11 mg).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6]Br)[CH3:2].[Mg].[CH2:9]([N:16]1[C@H:20]2[CH2:21][S:22][C:23](=[O:24])[C@H:19]2[N:18]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:17]1=[O:32])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S(=O)(=O)(O)O>CCOCC.C1C=CC=CC=1.II>[CH2:9]([N:16]1[C@H:20]2[CH2:21][S:22][C:23]([OH:24])([CH2:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C@H:19]2[N:18]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:17]1=[O:32])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Reactant: CCOCCCBr
Agent: II
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCOCCCC1(O)SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Yield: 100.5 %

Procedure:
To a Grignard reagent solution prepared from 3-ethoxypropyl bromide (41.7 g), magnesium metal (shoot, 11.2 g) and iodine (0.2 g) in 110 ml of anhydrous ether and 30 ml of anhydrous benzene, a solution of cis-1,3-dibenzyl-hexahydrothieno[3,4-d]imidazole-2,4-dione ([α]D20 + 91°, 60.0 g) in 700 ml of anhydrous benzene is added with stirring for two and half hours at 25° to 40°C. The mixture is stirred and refluxed at 68° to 73° C for 5 hours. The reaction mixture is decomposed by the addition of 3N sulfuric acid (280 g) below 20°C. The organic layer is washed with water and concentrated in vacuo to give the residual oil of 76 g of cis-1,3-dibenzyl-4-hydroxy-4-(3-ethoxypropyl)-hexahydrothieno[3,4-d]imidazol-2-one. [α]D20 + 17° (C = 1 in CHCl3). IR (Nujol) 3350 cm-1 (OH); 1690 cm-1 (C = O).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1.[CH3:16][N:17]1C(=O)CCC1>[C-]#N.[Zn+2].[C-]#N.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>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]#[N:17])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCOc1ccc(Br)cc1
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCCCCCCOc1ccc(C#N)cc1
Temperature: 100 °C
Yield: 73 %

Procedure:
Prepared using General Procedure 1: A stirred a solution of 1-bromo-4-(heptyloxy)benzene (2.0 g, 7.37 mmol), zinc cyanide (1.73 g, 14.74 mmol) and tetrakis(triphenylphosphine)palladium (76.12 mg, 0.07 mol) in dry NMP (20 mL) was degassed with N2. The reaction was heated to 100° C. for 18 h while stirring under nitrogen. The reaction mixture was cooled and poured into water (100 mL) and DCM (20 mL). The solid material was removed by filtration and the filtrate was extracted with water (3×20 mL). The organic layer was dried over MgSO4 and concentrated. The crude product was purified by chromatography (EA/hexanes) to afford 1.15 g (73%) of 4-(heptyloxy)benzonitrile as a light yellow solid. LCMS-ESI (m/z) calculated for C14H19NO: 217.1; found 218.1 [M+H]+, tR=11.14 min (Method 2). 1H NMR (400 MHz, CDCl3) δ 7.64-7.50 (m, 2H), 7.05-6.83 (m, 2H), 3.99 (t, J=6.5 Hz, 2H), 1.89-1.69 (m, 2H), 1.58-1.12 (m, 8H), 0.90 (dd, J=9.1, 4.5 Hz, 3H). 13C NMR (101 MHz CDCl3) δ 162.47, 133.91, 132.78, 132.12, 129.13, 119.31, 115.18, 103.58, 68.41, 31.73, 28.98, 25.89, 22.58, 14.07.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2>[OH-].[K+].CO>[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH:12]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Brc1ccc2[nH]cc(C3=CCN(Cc4ccccc4)CC3)c2c1
Yield: 90.3 %

Procedure:
Freshly distilled 1-Benzyl-4-piperidone (11.7 g) was added to a stirred solution of 5-bromoindole (11.0 g) in 2M potassium hydroxide in methanol (81ml). The mixture was stirred at reflux for 8 h and then allowed to cool to 25° over 8 h. The solid was collected by filtration, washed with a mixture of methanol:water (2:1, 2×15 ml) and dried in vacuo at 50° for 18 h to give the title compound as a crystalline solid (18.6 g) m.p. 173°-175° (decomp).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[Cl-].[Li+].[CH:12]([Mg]Cl)([CH3:14])[CH3:13].C(Br)C=C>C1COCC1.[Cu]I>[CH2:14]([C:2]1[CH:3]=[C:4]([F:9])[C:5]([Cl:8])=[N:6][CH:7]=1)[CH:12]=[CH2:13]
Reactant: CC(C)[Mg]Cl
Reactant: Fc1cc(Br)cnc1Cl
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCc1cnc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.5 %

Procedure:
In a dry 3-necked flask flushed with argon containing a solution of 5-bromo-2-chloro-3-fluoro pyridine (4.0 g, 19.05 mmol) at 0° C. was added isopropyl magnesium chloride lithium chloride complex (1.3 M THF solution, 24.8 mmol, 19.1 mL) over 10 min. After additional 10 min of stirring at 0° C., CuI (0.73 g, 3.81 mmol) was added, and the mixture was stirred for 10 minutes at 0° C. and then a solution of allyl bromide (38.1 mmol, 3.3 mL) in THF (4.0 mL) was added at 0° C. over 10 min. After further stirring for 1 h at 0° C., the reaction was quenched with 10% citric acid and extracted with ethyl acetate (100 mL×2). The organic layers were washed with brine, dried over Na2SO4, and concentrated. The obtained residue was chromatographed on silica gel eluted with hexane and 10% ethyl acetate in hexanes to afford 2.5 g of 2 (77%) as a colorless oil. 1H NMR (CDCl3) δ 3.40 (2 H, d, J=6.60 Hz), 5.16 (2 H, m), 5.91 (1 H, m), 7.32 (1 H, dd, J=2.20, 9.00 Hz), 8.06 (1 H, d, J=1.76 Hz); LC/MS (M+1) 172.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([CH3:14])[CH:3]=1.[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C)C=O>[N:15]([C:2]1[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([CH3:14])[CH:3]=1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(Cl)c2c(F)ccc(F)c2n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(N=[N+]=[N-])c2c(F)ccc(F)c2n1
Temperature: 0 °C
Yield: 64.6 %

Procedure:
4-Chloro-5,8-difluoro-2-methylquinoline (8.18 g) in dimethylformamide (80 ml) was treated with sodium azide (3.7 g) and the mixture heated for 20 h. The mixture was cooled, poured into ice/water and extracted with dichloromethane (2×200 ml). The organic phase was washed with water, dried (Na2SO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel (5-20% diethyl ether in pentane) to give the title compound (5.45 g) as a colourless solid. (Method C). 1H NMR δ: 2.67 (3H, s), 7.29 (1H, m), 7.54 (1H, s), 7.58(1H, m).
Reaction SMILES: [C:1]1([CH:7]([C:11]([OH:13])=[O:12])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:18]COCC>CN(C)C=O>[C:1]1([CH:7]([C:11]([OH:13])=[O:12])[C:8]([O:10][CH3:18])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOCC
Reactant: O=C(O)C(C(=O)O)c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
Phenylmalonic acid (13.5 g, 0.07 mol) in dry ether (40 mL) was treated with thionyl chloride (8.92 g, 5.4 mL, 0.071 mol) and one drop of N,N-dimethylformamide. The mixture was heated at 40°-50° C. for 3 hours. The clear solution was evaporated under reduced pressure to remove any residual thionyl chloride. The oily residue was redissolved in dry ether (40 mL) and the solution was treated with methyl alcohol (0.075. mol, 3 mL) and refluxed for 2 hours. The reaction mixture was cooled to room temperature and washed with water. The organic layer was extracted with saturated solution of sodium bicarbonate until alkaline. The combined extracts were washed with ether and the aqueous layer acidified with 5N HCl to pH 1. The precipitated oil was extracted with CH2Cl2 (50 ml×3). The combined extracts were washed with water (50 mL×4) and dried over anhydrous MgSO4. The oily product crystallized on standing.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:12][C:13]1[C:18]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[C:20]=2[F:27])=[C:17](Cl)[N:16]2[N:29]=[CH:30][N:31]=[C:15]2[N:14]=1>ClCCl>[Cl:12][C:13]1[C:18]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[C:20]=2[F:27])=[C:17]([NH:4][CH:1]([CH3:3])[CH3:2])[N:16]2[N:29]=[CH:30][N:31]=[C:15]2[N:14]=1
Reactant: Fc1cc(F)c(F)c(-c2c(Cl)nc3ncnn3c2Cl)c1
Reactant: CC(C)N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Nc1c(-c2cc(F)cc(F)c2F)c(Cl)nc2ncnn12
Yield: 81.9 %

Procedure:
A mixture of isopropylamine (1.5 mmol), triethylamine (1.5 mmol) and dichloromethane (10 ml) was added to a mixture of 5,7-dichloro-6-(2,3,5-trifluorophenyl)-[1,2,4]-triazolo[1,5-a]pyrimidine (1.5 mmol, obtained from Ex. 3) and dichloromethane (20 ml) under stirring. The reaction mixture was stirred for 16 h. at 20 to 25° C. and washed with 5% hydrochloric acid. The organic layer was separated, dried and filtered. The filtrate was evaporated and the residue was purified by column chromatography to yield 0.42 g of the title compound of mp. 151° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[C:4]([CH3:12])=[C:3]1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[CH2:19]([O:21][C:22](=[O:27])[C:23](Br)([CH3:25])[CH3:24])[CH3:20]>>[CH2:19]([O:21][C:22](=[O:27])[C:23]([CH3:25])([O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[C:3]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[C:4]2[CH3:12])[CH3:24])[CH3:20]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1c(-c2ccncc2)n(C)c2ccc(O)cc12
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(C)c(-c1ccncc1)n2C

Procedure:
The above compound was prepared from 1,3-dimethyl-2-(4-pyridyl)-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[CH:7]=[CH:6][NH:5]1.[Br:18][CH2:19][CH2:20]Br>CN(C=O)C>[Br:18][CH2:19][CH2:20][N:5]1[CH:6]=[CH:7][C:8]2[C:13](=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[C:4]1=[O:3]
Reactant: BrCCBr
Reactant: COC(=O)c1ccc2cc[nH]c(=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(CCBr)c(=O)c2c1
Reaction time: 0.5 h
Yield: 38.3 %

Procedure:
To a stirred suspension of sodium hydride (60% in mineral oil, 0.81 g, 20.2 mmol) in DMF (30 mL) under an atmosphere of nitrogen was added methyl 1-oxo-1,2-dihydroisoquinoline-7-carboxylate (2.05 g, 10.1 mmol) in DMF (20 mL) dropwise. The mixture was stirred for 30 mins, then 1,2-dibromoethane (8.7 mL, 101 mmol) was added quickly and the resulting solution was stirred for 2 h. The reaction was quenched with water and extracted with EtOAc (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (0% to 40% EtOAc/hexanes) to afford methyl 2-(2-bromoethyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (1.20 g, 38%). LC-MS: (FA) ES+ 311.