Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N([C@H]2CC[C@H](CC)CC2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)CCCC1.[CH:28]1([NH:35][CH:36]2[CH2:41][CH2:40][CH:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:38][CH2:37]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:28]1([N:35]([C@H:36]2[CH2:41][CH2:40][C@H:39]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:38][CH2:37]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: c1ccc(C2CCC(NC3CCCCCC3)CC2)cc1
Reactant: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: O=C(O)CSc1cnc(NC(=O)N(C2CCCCCC2)[C@H]2CC[C@H](c3ccccc3)CC2)s1

Procedure:
Prepared in a similar manner to {2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via cycloheptyl-(4-phenyl-cyclohexyl)-amine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester to give the title compound.
Reaction SMILES: [CH2:1]([CH:4]1[C:13]2[N:12]=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][C:8]=2[CH2:7][C:6]2([O:19][CH2:18][CH2:17][O:16]2)[CH2:5]1)[CH:2]=[CH2:3].[H][H]>CCO.[Pd]>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]2[CH2:7][C:6]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[C:13]=2[N:12]=1
Reactant: C=CCC1CC2(Cc3ccc(OC)nc31)OCCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCC1CC2(Cc3ccc(OC)nc31)OCCO2
Yield: 97.8 %

Procedure:
A solution of 4a (1.04 g, 4 mmol) in 100 mL of EtOH was hydrogenated at 60 psi hydrogen pressure (Parr shaker) over 200 mg of 5% Pd/C for 5 h. Filtration, concentration, and flash chromatography of the residue (30% ethyl acetate in hexanes) gave 1.03 g (98%) of 4d: IR (neat) 2955, 1599, 1477, 1084, 1031 cm-1 ; 1H NMR δ7.20 (d, 1H, J=8.3 Hz), 6.50 (d, 1H, J=8.3 Hz), 4.01 (m, 4H), 3.89 (s, 3H), 2.98 (m, 2H), 2.78 (dd, 1H, J=16.0, 2.4 Hz), 2.01 (m, 2H), 1.67 (m, 2H), 1.40 (m, 2H), 0.96 (t, 3H, J=7.2 Hz); 13C NMR δ162.0, 155.7, 139.6, 121.3, 107.9, 107.7, 64.4, 53.0, 39.5, 38.0, 37.2, 35.9, 19.9, 14.3; MS m/z 263 (M+).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=3)=[N:11][N:10]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[C:35]([C:42]([F:45])([F:44])[F:43])[CH:34]=1>C(Cl)Cl>[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([N:2]([CH3:1])[CH:3]2[CH2:4][CH2:5][N:6]([C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=4)=[N:11][N:10]=3)[CH2:7][CH2:8]2)=[O:38])=[C:35]([C:42]([F:45])([F:44])[F:43])[CH:34]=1
Reactant: CNC1CCN(c2nnc(-c3ccnn3C)c3ccccc23)CC1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)c1ccc(F)cc1C(F)(F)F)C1CCN(c2nnc(-c3ccnn3C)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
Treat a solution of N-methyl-1-(4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl)piperidin-4-amine (2.8 g, 8.68 mmol) and triethylamine (3.36 mL, 26.1 mmol) in CH2Cl2 (30 mL) with 4-fluoro-2-(trifluoromethyl)benzoyl chloride (2.14 mL, 10.42 mmol). Stir for 3 h at ambient temperature. Concentrate the reaction mixture under reduced pressure. Purify the resulting residue by flash silica gel chromatography (hexane:ethyl acetate:2 M NH3 in MeOH=20:5:1) to provide the free base as a yellow foam (3.83 g, 86%). ES/MS m/z 513.0 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH2:29][C:30]2[N:31]=[N:32][N:33]([CH3:35])[N:34]=2)=[CH:24][CH:23]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:28]([C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)[CH2:29][C:30]3[N:31]=[N:32][N:33]([CH3:35])[N:34]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: Cn1nnc(CNc2ccc(F)cc2)n1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2nnn(C)n2)c2ccc(F)cc2)[C@H]1O
Yield: 67.6 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using epoxide compound (450 mg, 1.6 mmol) obtained in step 1 of example 2 and N-(4-fluorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (332 mg, 1.6 mmol). The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=1:1), to give desired compound (528 mg, yield: 69%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1.Cl[CH:19]([C:25]([CH3:27])=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:25]([CH3:27])[N:12]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Nc1ncccc1OCc1c(F)cccc1F
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Reaction time: 48 h
Yield: 41 %

Procedure:
170 g of 3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine (Example 1A; 719 mmol, 1 equivalent) were initially charged in 3800 ml of ethanol, and 151 g of powdered molecular sieve 3 Å and 623 g of ethyl 2-chloroacetoacetate (3.6 mol, 5 equivalents) were added. The reaction mixture was heated at reflux for 24 h and then filtered off through silica gel and concentrated under reduced pressure. The mixture was kept at RT for 48 h, and the solid formed was filtered off. The solid was then stirred three times with a little isopropanol and then filtered off and washed with diethyl ether. This gave 60.8 g (23% of theory) of the title compound. The combined filtrates of the filtration steps were concentrated and the residue was chromatographed on silica gel using cyclohexane/diethyl ether as mobile phase. This gave a further 46.5 g (18% of theory; total yield: 41% of theory) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[NH:26]1[C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:29]2[C:28]([CH:35]=O)=[N:27]1>CO.N1CCCCC1>[NH:26]1[C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:29]2[C:28](/[CH:35]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[N:27]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1n[nH]c2ncccc12
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2n[nH]c4ncccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0366 g, 0.105 mmol) synthesized in Example B1, Step 1 in methanol (2 mL) was added with 1H-pyrazolo[3,4-b]pyridine-3-carboxaldehyde (International Patent Publication WO2010/051561, 0.0162 g, 0.110 mmol) and piperidine (5 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-({2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0321 g, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].Cl.[F:31][CH2:32][CH2:33][NH2:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:34][CH2:33][CH2:32][F:31])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: NCCF
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCCF)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 2-fluoroethylamine hydrochloride (20 mg, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[(2-fluoroethyl)aminomethyl]indol-2-yl}isoindolinone.
Reaction SMILES: [C:1]([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]1[C:19]#[N:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:22].[Na+].OO>CC(C)=O>[C:1]([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]1[C:19]([NH2:20])=[O:22])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1C=Cc2ccccc2N1C(=O)c1ccccc1
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Product: NC(=O)C1C=Cc2ccccc2N1C(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 55 %

Procedure:
1-(Benzoyl)-1,2-dihydro-quinoline-2-carbonitrile (26.0 g) was dissolved in acetone (500 mL). Solid sodium bicarbonate (15 g) was added. The mixture was stirred for 30 minutes. 30% Hydrogen peroxide solution (250 mL of a 30% solution) was added drop-wise. After stirring for 4 hours, the acetone was evaporated under vacuum. The residue was acidified with 1N HCl. The precipitate was collected, washed with water and air dried. The solid was slurried in ether then filtered. The title compound (15.3 g) was obtained as an off-white solid, m.p. 169-171° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.BrN1C(=O)CCC1=O>[Br:13][CH2:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(C)cc1O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
Methyl 4-methylsalicylate (98.1 g, 590 mmoles) was dissolved in carbon tetrachloride (600 mL), and N-bromosuccinimide (105.0 g, 590 mmoles) and benzoyl peroxide (0.7 g, 3 mmoles) were added. The mixture was refluxed under nitrogen. After 2 hours, an additional portion (0.7 g) of N-bromosuccinimide was added. Reflux was continued for 16 hours. The reaction mixture was cooled to room temperature and the solid removed by filtration. The yellow filtrate was evaporated to dryness to afford a thick yellow syrup that solidified on standing. Hexanes (500 mL) was added to the solid, and the mixture was boiled until almost all solids dissolved. The hot hexanes solution was filtered and concentrated until a solid just began to precipitate. The mixture was heated to dissolve the solid, and the solution was allowed to cool slowly to room temperature. Pale yellow crystals formed slowly. The mixture was then chilled in ice for 2 hours to complete crystallization. Finally, the solid was filtered, washed with cold hexanes (100 mL), and dried in vacuo to afford 83.5 g (58% yield) of methyl 4-bromomethyl-salicylate (m.p. 73°-75° C., open capillary, uncorrected).
Reaction SMILES: [C:1]1([P:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[C:1]1([P:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][N:10]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccccc1
Reactant: NCCP(c1ccccc1)c1ccccc1
Solvent: CCO
Product: C(=NCCP(c1ccccc1)c1ccccc1)c1ccccc1
Yield: 98 %

Procedure:
Under argon, a solution of 2-diphenylphosphino-ethylamine (590.3 mg, 2.57 mmol) and benzaldehyde (275.0 mg, 2.59 mmol) in ethanol (15 mL) was heated at 65° C. (oil bath) for 4 h. Then, the solvent was removed in-vacuo to give the desired product (>98% by 1H-NMR) as a colourless oil which solidified on standing (733.9 mg, 2.31 mmol, 90%).
Reaction SMILES: I[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][N:16]3[C:20]([CH3:22])([CH3:21])[C:19](=[O:23])[NH:18][C:17]3=[O:24])[N:8]=2)=[CH:4][CH:3]=1.[C:25]1([SH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:21][C:20]1([CH3:22])[N:16]([CH2:15][CH2:14][NH:13][C:9]2[N:8]=[C:7]([C:5]3[S:6][C:2]([S:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:3][CH:4]=3)[CH:12]=[CH:11][N:10]=2)[C:17](=[O:24])[NH:18][C:19]1=[O:23]
Reactant: Sc1ccccc1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2ccc(I)s2)n1
Product: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2ccc(Sc3ccccc3)s2)n1

Procedure:
The title compound was prepared from 1-{2-[4-(5-iodothiophen-2-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethyl-imidazolidine-2,4-dione and thiophenol in a manner analogous to Example 259. MS (M+H)+ 440.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][C:14]([OH:16])=O)=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH:24]=1>>[C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][C:14]([NH:33][CH2:32][CH2:31][CH2:30][CH2:29][C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)=[O:16])=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCC#CC(=O)O)ccc(C(C)=O)c1O
Reactant: NCCCCc1cccnc1
Product: CCCc1c(OCCCC#CC(=O)NCCCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
6-(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hexynoic acid was allowed to react with 3-pyridine butanamine according to procedure B and the product was purified by chromatography on silica gel to give 6-(4-acetyl-3-hydroxy- 2-propylphenoxy)-N-[4-(3-pyridinyl)butyl]-2-hexynamide, the title compound, mp 84°-86° (from hexane) in 42% yield.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1.[CH2:30]([CH:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)[CH2:31][CH3:32]>>[CH2:30]([CH:33]1[CH2:38][CH2:37][CH:36]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]3[C:20]4[CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=[CH:24][C:19]=4[O:18][N:17]=3)[CH2:9]2)[CH2:35][CH2:34]1)[CH2:31][CH3:32]
Reactant: CCCC1CCC(=O)CC1
Reactant: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CNC1
Solvent: O=C(O)C(F)(F)F
Product: CCCC1CCC(N2CC(NC(=O)CNc3noc4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of (N-Azetidin-3-yl-2-(5-trifluoromethyl-benzo[d]isoxazol-3-ylamino)-acetamide TFA salt (as prepared in Example 1, Step D) and 4-n-propyl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: C1(O[C:8](=[O:20])[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([OH:21])=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)=[O:20])[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Product: COc1nc(C)c(C)cc1NC(=O)N1CCN(c2ccc(O)cc2)CC1
Yield: 72 %

Procedure:
Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(4-hydroxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: Br.[NH2:2][C:3]1[CH:8]=[C:7]([CH:9](Br)[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)=O)[CH:6]=[CH:5][N:4]=1.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH2:25])=[S:24].C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]1[S:24][C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([NH2:2])[CH:8]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)[N:25]=1
Reactant: Cc1cccc(C(=O)C(Br)c2ccnc(N)c2)c1
Reactant: NC(=S)c1ccccc1Cl
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nc(-c3ccccc3Cl)sc2-c2ccnc(N)c2)c1
Yield: 70 %

Procedure:
A solution of 2-(2-amino-4-pyridyl)-2-bromo-1-(3-methylphenyl)ethanone hydrobromide (5.00 g, 12.3 mmol) and 2-chlorothiobenzamide (1.06 g, 11.9 mmol) in N,N-dimethylformamide (40 mL) was stirred for 14 hours at room temperature. Aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and extracted with ethyl acetate. The extracts were washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexaneethyl acetate=4:1 to 2:1) to obtain a crystal. This crystal was washed with isopropyl ether, to obtain a title compound (3.15 g, yield 81%).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:17](=[O:27])[NH:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[F:26])=O)(C)(C)C.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[F:31][C:30]([F:33])([F:32])[C:28]([OH:34])=[O:29].[F:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[NH:18][C:17]([CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][NH:8]1)=[O:27]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C1C(=O)Nc1c(F)cccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1c(F)cccc1F)C1NCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2,6-difluoro-phenylcarbamoyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (460 mg, 1.23 mmol, Eq: 1.00) in CH2Cl2 (6 mL) was added TFA (2 mL) dropwise. The reaction was stirred at RT for 1 h. The solvent was evaporated to afford 2,3-dihydro-1H-isoindole-1-carboxylic acid (2,6-difluoro-phenyl)-amide trifluoroacetate which was used without further purification.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH:7]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1>CC(N(C)C)=O>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[N:7]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: Brc1nccs1
Reactant: C1CNCCNC1
Solvent: CC(=O)N(C)C
Product: c1csc(N2CCCNCC2)n1
Yield: 93.9 %

Procedure:
2-Bromothiazole (1.00 g, 6.10 mmol) and homopiperazine (2.44 g, 24.4 mmol) were dissolved in DMA (1 mL) and heated using a microwave (180° C., absorption high) for 30 min. The reaction mixture was dissolved in DCM (50 mL), washed with sat aq Na2CO3 (50 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo to give the crude title compound (1.05 g, 94%) as a yellow solid. LCMS (ES+): 184.2 [MH]+.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([CH3:27])=[C:11]([CH3:26])[C:12]=1[C:13]([C:15]1[CH:20]=[C:19]([CH2:21][CH3:22])[C:18]([O:23]C)=[C:17]([Br:25])[CH:16]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>>[Br:25][C:17]1[CH:16]=[C:15]([C:13]2[C:12]3[C:11]([CH3:26])=[C:10]([CH3:27])[O:9][C:8]=3[CH:1]=[C:2]3[C:7]=2[CH:6]=[CH:5][CH:4]=[CH:3]3)[CH:20]=[C:19]([CH2:21][CH3:22])[C:18]=1[OH:23]
Reactant: CCc1cc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc(Br)c1OC
Agent: BrB(Br)Br
Product: CCc1cc(-c2c3ccccc3cc3oc(C)c(C)c23)cc(Br)c1O
Yield: 11.7 %

Procedure:
The title compound was prepared according to the procedure in Example 1, step 5, using (2-benzyl-4,5-dimethyl-furan-3-yl)-(3-bromo-5-ethyl-4-methoxy-phenyl)-methanone (7.85 g, 18.4 mmol) and boron tribromide (13.2 mL, 0.139 mol). Purification on silica gel eluting with 2% EtOAc/hexane, followed by trituration with hexane gave 0.85 g (12%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 1.15 (t, 3 H), 1.59 (s, 3 H), 2.37 (s, 3 H), 2.64-2.77 (m, 2 H), 7.09 (d, 1 H), 7.31 -7.35 (m, 2 H), 7.42 (d of t, 1 H), 7.52 (d, 1 H), 7.95 (s, 1 H), 7.99 (d, 1 H), 9.17 (s, 1 H). mass spectrum (EI) m/z 394 (M+). Anal. Calcd. for C22H19Br1O2 : C, 66.85; H, 4.84; N, 0.00. Found: C, 67.07; H, 4.85, N, 0.05.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[H][H]>[Pt].[Pt]=O.C(OC(=O)C)C.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1
Reactant: [H][H]
Reactant: Brc1ccc2[nH]cc(C3=CCNCC3)c2c1
Agent: O=[Pt]
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Brc1ccc2[nH]cc(C3CCNCC3)c2c1
Reaction time: 18 h
Yield: 75.5 %

Procedure:
To a solution of 13.61 gm (49 mmol) 5-bromo 3-[1,2,3,6-tetrahydro-4-pyridinyl]-1H-indole in 75 ml 2:1 tetrahydro-furan ethyl acetate were added 8.0 gm 3% sulfided platinum on carbon and 4.0 gm platinum oxide. The reaction mixture was hydrogenated with an initial hydrogen pressure of 60 p.s.i. at 40° C. for 18 hours and then at ambient temperature for 30 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give 10.33 gm (75.6%) of the title compound as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]=[C:7](SC)[S:8][C:4]=2[CH:3]=1.[Br-].[CH2:14]([Zn+])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>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.CCOC(C)=O>[CH2:14]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([Br:1])[CH:12]=[CH:11][C:5]=2[N:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: CSc1nc2ccc(Br)cc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCOC(C)=O
Product: Brc1ccc2nc(Cc3ccccc3)sc2c1
Temperature: 60 °C
Yield: 28 %

Procedure:
A degassed mixture of 6-bromo-2-(methylthio)-1,3-benzothiazole (4.20 g, 16.14 mmol), tetrakis(triphenylphosphine)palladium(0) (186 mg, 0.161 mmol) and benzylzinc bromide (0.5 M in THF, 61.34 mL) was heated at 60° C. for 4 hrs. EtOAc (200 mL) was added and the organic layer was washed with saturated, aqueous NaHCO3 (3×150 mL), then water (3×150 mL). The organic layer was dried over MgSO4 and concentrated. The crude material was purified by ISCO® chromatography using 4% EtOAc in hexane to obtain the desired product (1.50 g, 28%). 1H NMR (400 MHz, acetone-d6) δ 8.20 (s, 1H), 7.88 (d, 1H), 7.62 (d, 1H), 7.44-7.30 (m, 5H), 4.44 (s, 2H); LC-MS m/z [M+H]+ 304.2 & 306.1, RT 4.02 min.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>>[CH2:6]([NH:13][CH2:3][CH:2]([F:5])[F:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: FC(F)CCl
Reactant: NCc1ccccc1
Agent: Cl
Product: FC(F)CNCc1ccccc1
Yield: 41.1 %

Procedure:
An amount of 5 g (49.7 mmol) of 2,2-difluoro-1-chloroethane and 11.3 g (105 mmol) of benzylamine are heated in an autoclave at an internal temperature of 120° C. for 16 hours. Subsequently, 100 g of 1N hydrochloric acid are added and the solvent is removed under vacuum. The residue is taken up in 50 ml of water and 50 ml of dichloromethane and adjusted to pH 8 with solid sodium hydrogencarbonate. The phases are subsequently separated and the aqueous phase is again extracted with 20 ml of dichloromethane. The organic phase is distilled. An amount of 3.5 g of N-benzyl-2,2-difluoroethanamine is obtained, which corresponds to a yield of 41%, based on 2,2-difluoro-1-chloroethane used.