Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1[Cl:33]>C(OCCO)C>[Cl:33][C:27]1[CH:28]=[C:29]([OH:32])[CH:30]=[CH:31][C:26]=1[NH:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: Nc1ccc(O)cc1Cl
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc(O)cc3Cl)c2cc1OC
Yield: 84.1 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 15 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 270.1 mg (1.5 mmol) of 4-amino-3-chlorophenol to give 299.2 mg (84.3%) of the product as a light brown solid, m.p.>250° C., mass (electrospray, m/e): M+H 355.8, 357.8.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[C:14]([O:16][CH3:17])=[O:15])[CH2:2][CH2:3][CH3:4].[Cl:18]N1C(=O)CCC1=O.O>CN(C)C=O>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[Cl:18])=[CH:11][CH:10]=[CH:9][C:8]=2[C:14]([O:16][CH3:17])=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCc1cc2cccc(C(=O)OC)c2[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1[nH]c2c(C(=O)OC)cccc2c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 2-(n-butyl)indole-7-carboxylate (32) (0.3 g) in 6 ml of dimethylformamide at room temperature was added N-chlorosuccinimide (0.17 g). The solution was stirred at room temperature for 16 hours, then water was added, and the mixture extracted with ether. The extract was separated and solvent evaporated under reduced pressure, to give methyl 2-(n-butyl)-3-chloroindole-7-carboxylate, a compound of Formula (33) where X is chloro, as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][NH:17][CH2:18][C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:24][CH2:25][C:26]([NH:28][CH3:29])=[O:27].C(N(C(C)C)CC)(C)C>C(#N)C.Cl.C(OCC)(=O)C>[ClH:24].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][N:17]([CH2:18][C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[CH2:25][C:26]([NH:28][CH3:29])=[O:27])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2cccc(CCNCc3ccco3)c2)cc1
Reactant: CNC(=O)CCl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNC(=O)CN(CCc1cccc(OCc2ccccc2)c1)Cc1ccco1
Yield: 65.4 %

Procedure:
A solution of 3.0 g (9.8 mmol) of [2-(3-benzyloxy-phenyl)-ethyl]-(furan-2-ylmethyl)amine, 15.0 g (10.7 mmol) of 2-chloro-N-methyl-acetamide and 1.87 ml (10.7 mmol) of diisopropylethylamine in 50 ml of acetonitrile was stirred under reflux for 24 hours. The solvent was removed under reduced pressure and the crude reaction mixture was purified by flash chromatography (ethyl acetate/hexane 1:1 v:v). The product isolated was dissolved in anhydrous hydrochloric acid in ethyl acetate. The solvent was removed under vacuum and the residue was triturated with diethyl ether. 2.66 g (65% yield) of the title compound were isolated as a hygroscopic solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21][C:20]2=[O:29])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N:30]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[N:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:42]([O:41][C:39]([N:30]([CH:21]1[CH2:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:20]1=[O:29])[NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: O=C1CCc2ccccc2N1c1ccccc1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)C1Cc2ccccc2N(c2ccccc2)C1=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 69.4 %

Procedure:
To a solution of 0.45 g (0.00448 mole) of diisopropylamine dissolved in 20 ml of tetrahydrofuran was added dropwise 2.6 ml (0.00448 mole) of n-butyl lithium (a 1.6M hexane solution) at 0° C., and the mixture was stirred for 20 minutes. After the mixture was cooled to -78° C., to the mixture was added dropwise a solution of 1.00 g (0.00448 mole) of 1-phenyl-3,4-dihydroquinolin-2 (1H)-one dissolved in 10 ml of tetrahydrofuran, and the mixture was stirred at the same temperature for 30 minutes. Next, to the mixture was added dropwise a solution of 2.06 g of di-t-butyl azodicarboxylate dissolved in 10 ml of tetrahydrofuran, and the mixture was stirred at -78° C. for one hour. After completion of the reaction, the reaction mixture was treated with an ammonium chloride aqueous solution, extracted with chloroform and dried over anhydrous sodium sulfate. Chloroform was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:ethyl acetate:hexane (1:5 v/v)) to obtain 1.41 g of the title compound as a colorless caramel-like product.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[C:15](=[S:27])[O:16][C:17]2[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[F:28][C:29]([F:36])([F:35])[S:30]([O:33]C)(=[O:32])=[O:31]>C(Cl)Cl>[O-:33][S:30]([C:29]([F:36])([F:35])[F:28])(=[O:32])=[O:31].[CH3:29][N+:6]1[C:5]2[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:13]([C:15](=[S:27])[O:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[CH:11]2
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: S=C(Oc1cccc2ccccc12)c1c2ccccc2nc2ccccc12
Solvent: ClCCl
Product: C[n+]1c2ccccc2c(C(=S)Oc2cccc3ccccc23)c2ccccc21
Product: O=S(=O)([O-])C(F)(F)F
Reaction time: 8 h

Procedure:
Naphthyl acridine-9-thiocarboxylate (26.38 g) was suspended in CH2Cl2 (200 mL). Methyl trifluoromethanesulfonate (24.5 ml) was added and the mixture left to stir overnight. The mixture was filtered and the solids washed with CH2Cl2 (300 ml) and hexanes (500 ml). After air drying, the product (28.83 g) was obtained as a yellow solid. 1H NMR (acetone-d6) δ 5.20 (s, 3H), 7.66-7.75 (m, 2H), 7.88-7.92 (m, 1H), 8.03-8.09 (m, 2H), 8.15 (d, 1H), 8.26 (t, 2H), 8.48 (s, 1H), 8.61-8.68 (m, 2H), 8.80 (d, 2H), 9.03 (d, 2H).
Reaction SMILES: [N:1]1[NH:2][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]3[CH2:13][CH2:12][C:11]4=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=[C:10]4[C:9]=1[C:8]=23.[CH:19]1([C:22](O)=[O:23])[CH2:21][CH2:20]1>>[N:1]1[NH:2][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]3[CH2:13][CH2:12][C:11]4[C:14]([NH:18][C:22]([CH:19]5[CH2:21][CH2:20]5)=[O:23])=[CH:15][CH:16]=[CH:17][C:10]=4[C:9]=1[C:8]=23
Reactant: O=C(O)C1CC1
Reactant: Nc1cccc2c1CCc1cccc3[nH]nc-2c13
Product: O=C(Nc1cccc2c1CCc1cccc3[nH]nc-2c13)C1CC1

Procedure:
6,7-Dihydro-2H-benzo[6,7]cyclohepta[cd]indazole-8-amine prepared in Example 8 and cyclopropanecarboxylic acid were subjected to the reaction and purified and separated by LC-MS in the same manner as in Synthesis Process A, to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]1C[O:11]1.Cl[CH2:14]Cl>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([CH3:14])[CH:10]=[O:11]
Reactant: ClCCl
Reactant: Cc1cccc(CC2CO2)c1C
Product: Cc1cccc(C(C)C=O)c1C
Reaction time: 2 h
Yield: 100 %

Procedure:
2-(2,3-Dimethylphenyl)methyloxirane, compound of formula (XXII), prepared according to example 4 (0.84 g, 5.18 mmol), was dissolved in dry dichloromethane (50 mL) and powdered Cu(BF4)2 hydrate (318 mg) was added at room temperature. After 2 h at room temperature, the mixture was washed with water, dried over Na2SO4 and concentrated under reduced pressure to yield 0.84 g (100%) of the title product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C([C:28]1[CH:36]=[C:35]([CH2:37]Br)[CH:34]=[CH:33][C:29]=1[C:30]([OH:32])=[O:31])C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:20])[C@H:5]([CH2:37][C:35]1[CH:36]=[CH:28][C:29]([C:30]([O:32][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:31])=[CH:33][CH:34]=1)[N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc(CBr)cc1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)[C@H](Cc1ccc(C(=O)OCc2ccccc2)cc1)N=C(c1ccccc1)c1ccccc1
Yield: 212.4 %

Procedure:
A mixture of N-(diphenylmethylene)glycine ethyl ester (6.6 g, 24.9 mmol), benzyl 4-(bromomethyl)benzoic acid (7.61 g, 24.9 mmol) and potassium carbonate (50 mmol, 6.9 g) in acetonitrile (300 ml) was refluxed overnight. The solvent was removed in vacuo and the residue partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give the title compound as an oil (13.0 g) δH (CDCl3) 7.90 (2 H, d, J 8.3 Hz), 7.58 (2 H, d, J 7.3 Hz), 7.50-7.25 (11 H, m), 7.14 (2 H, d, J 8.1 Hz), 6.65 (2 H, d, J 6.8 Hz), 5.33 (2 H, m), 4.30-4.15 (3 H, br m), 3.32 (2 H, v br s) and 1.26 (3 H, t, J 7.1 Hz); m/z (ESI, 60 V) 492 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[CH:10](OCC)(OCC)OCC.[CH3:20][C:21]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:22]=1[NH2:23]>C(O)(=O)C>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH:4][CH:10]=[N:23][C:22]1[C:24]([CH3:29])=[CH:25][C:26]([CH3:28])=[CH:27][C:21]=1[CH3:20]
Reactant: CCOC(OCC)OCC
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: Nc1c(F)cccc1F
Solvent: CC(=O)O
Product: Cc1cc(C)c(N=CNc2c(F)cccc2F)c(C)c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
Acetic acid (0.086 mL, 1.5 mmol) was added to a round bottom flask charged with 2,6-difluoroaniline (3 mL, 30 mmol) and triethyl orthoformate (5 mL, 30 mmol). A vigreux column was attached and the solution was heated with stirring to 120° C. for 2 hours. 2,4,6-trimethylaniline (4.22 mL, 30 mmol) was then added to the reaction mixture. The solution was heated to reflux for an additional 2 hours and cooled to room temperature, whereupon crude product precipitated. Trituration with cold hexanes and vacuum filtration provided pure N-(2,6-difluorophenyl)-N′(mesityl)-formamidine (5.35 g, 65%) as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14].[Br:15]Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:15][CH2:11][C:10]([C:5]1[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Br:1])=[C:3]([O:13][CH3:14])[CH:4]=1)=[O:12]
Reactant: COc1cc(C(C)=O)cc(OC)c1Br
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C(=O)CBr)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of 1-(4-bromo-3,5-dimethoxyphenyl)ethanone (0.895 g, 3.45 mmol) in anhydrous CH2Cl2 (5 mL) under a drying tube was added a freshly made solution of Br2 in CH2Cl2 (1.95 M, 1.9 mL, 3.7 mmol) dropwise. The reaction was stirred at room temperature for 30 min then neutralized with a solution of saturated aqueous NaHCO3. The mixture was diluted with CH2Cl2 and the layers were separated. The organics were washed with saturated aqueous NaHCO3 and brine then dried over MgSO4/Na2SO4 and concentrated in vacuo. The crude product was adsorbed onto silica gel (2.9 g) as a CH2Cl2 solution. Purification by chromatography (0-20% EtOAc-hexanes) gave 2-bromo-1-(4-bromo-3,5-dimethoxyphenyl)ethanone as a white solid (0.737 g, 63% yield). Large-scale synthesis of 2-bromo-1-(4-bromo-3,5-dimethoxyphenyl)ethanone was performed without chromatographic purification of the bromide.
Reaction SMILES: [NH:1]([C:32]([O:34][CH2:35][CH:36]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:33])[C@H:2]([C:22](ON1C(=O)CCC1=O)=[O:23])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[C:20]([CH3:21])=[C:18]([CH3:19])[C:15]([O:16][CH3:17])=[CH:14][C:12]=1[CH3:13])(=[O:10])=[O:9].[NH2:49][C@H:50]([C:70]([OH:72])=[O:71])[CH2:51][CH2:52][CH2:53][CH2:54][NH:55][S:56]([C:59]1[C:68]([CH3:69])=[C:66]([CH3:67])[C:63]([O:64][CH3:65])=[CH:62][C:60]=1[CH3:61])(=[O:58])=[O:57].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[NH:1]([C:32]([O:34][CH2:35][CH:36]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:33])[C@H:2]([C:22]([NH:49][C@H:50]([C:70]([OH:72])=[O:71])[CH2:51][CH2:52][CH2:53][CH2:54][NH:55][S:56]([C:59]1[C:68]([CH3:69])=[C:66]([CH3:67])[C:63]([O:64][CH3:65])=[CH:62][C:60]=1[CH3:61])(=[O:58])=[O:57])=[O:23])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[C:20]([CH3:21])=[C:18]([CH3:19])[C:15]([O:16][CH3:17])=[CH:14][C:12]=1[CH3:13])(=[O:10])=[O:9]
Reactant: COc1cc(C)c(S(=O)(=O)NCCCC[C@H](N)C(=O)O)c(C)c1C
Reactant: COc1cc(C)c(S(=O)(=O)NCCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)ON2C(=O)CCC2=O)c(C)c1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)NCCCC[C@H](NC(=O)[C@H](CCCCNS(=O)(=O)c2c(C)cc(OC)c(C)c2C)NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C)c1C

Procedure:
A stirred solution of Fmoc-Lys(Mtr)-OSu 3 (ca 8.672 mmol) and Lys(Mtr) 2 (3.6294 g, 1 equiv) in DMF (70 mL) at rt was treated with DIEA (4.5 mL, 3 equiv). After 4 h the mixture was diluted with ethyl acetate (250 mL). The solution was washed with pH 4 buffer (0.05M biphthalate) (2×), water and brine, dried over sodium sulfate and evaporated the residue was flushed with methylene chloride (400 mL) to give a pale-yellow foam which was carried on without further purification. 1H-NMR (CDCl3/CD3OD) δ 1.10-1.85 (m, 12H), 2.22 (m, 4H), 3.70 (m, 6H), 4.21 (m, 5H), 6.76 (m, 4H), 7.00-7.75 (m, 32H). MS (ESI) 1041. 6 (MH)+.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][CH2:7][C@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5]1)(=[O:3])[NH2:2].[Cl:17][CH2:18][C:19](=O)[CH3:20]>CCO>[ClH:17].[CH3:20][C:19]1[N:2]=[C:1]([C@@H:4]2[CH2:8][CH2:7][C@H:6]([NH2:9])[CH2:5]2)[O:3][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(N)=O)C1
Reactant: CC(=O)CCl
Solvent: CCO
Product: Cc1coc([C@@H]2CC[C@H](N)C2)n1
Product: Cl
Temperature: 25 °C

Procedure:
To a solution of Example 120A (300 mg, 1.3 mmol) in EtOH (2 mL) was added chloroacetone (0.3 mL, 3.9 mmol). The reaction mixture was stirred at reflux for 64 hours, cooled to ambient temperature, and concentrated. Trituration of the residue in diethyl ether afforded the title compound. LC/MS (ESI+) M/Z 167 [M+H]+.
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[C:10]([NH2:18])[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)OC1.[CH3:20][N:21]1[CH2:26][CH:25]=[C:24](OS(C(F)(F)F)(=O)=O)[CH2:23][CH2:22]1.C([O-])([O-])=O.[Na+].[Na+]>CCOCC.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][N:21]1[CH2:22][CH:23]=[C:24]([C:8]2[CH:9]=[C:10]([NH2:18])[CH:11]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:13]=2)[CH2:25][CH2:26]1
Reactant: CN1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: CC1(C)COB(c2cc(N)cc(C(F)(F)F)c2)OC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CN1CC=C(c2cc(N)cc(C(F)(F)F)c2)CC1
Temperature: 80 °C

Procedure:
3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-5-trifluoromethyl-phenylamine (8.8 g, 0.032 mol) was added to trifluoro-methanesulfonic acid 1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl ester (7.91 g, 0.032 mol) and 2N Na2CO3 aqueous solution (25 mL) was bubbled through N2 for 5 min. Pd(PPh3)4 (3.7 g, 3.2 mmol) was added and the reaction was heated to 80° C. for 16 h. The reaction was cooled to RT and diluted with Et2O (100 mL). The mixture was filtered through Celite® and the filtrate was washed with NaHCO3 aqueous solution (25 ml) followed by brine (25 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The desired product was isolated by passing through silica gel column chromatography (EtOAc, then (2M NH3) in MeOH/EtOAc) to provide a yellow oil.
Reaction SMILES: ClC1C=C(C=C(Cl)C=1N)CN.[C:12]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH2:23][C:24]([O:26]C)=[O:25])#[N:13].[Li+].[OH-].CCOC(C)=O>C1COCC1.O>[C:12]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH2:23][C:24]([OH:26])=[O:25])#[N:13]
Reactant: COC(=O)Cc1c[nH]c2ccc(C#N)cc12
Agent: NCc1cc(Cl)c(N)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc2[nH]cc(CC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.7 %

Procedure:
Step H (3): To a solution of methyl 2-(5-cyano-1H-indol-3-yl)acetate (18 mg, 0.08 mmol) in THF (0.8 mL) was added a solution of LiOH (9.6 mg, 0.4 mmol) in water (0.3 mL). The mixture was stirred at rt for 3 h. 50 mL of EtOAc was added, and the resulting solution was washed with 0.1 N HCl and water. The organic layer was dried over Na2SO4, and the solvents was removed to give 11 mg of the title compound 2-(5-cyano-1H-indol-3-yl)acetic acid (yield, 68.7%). MS (ESI) (M−H)+=199.15. 1H NMR (500 MHz, CD3OD) δ ppm 4.86 (s, 2 H) 7.37 (s, 1 H) 7.40 (dd, J=8.24, 1.53 Hz, 1 H) 7.50 (d, J=8.54 Hz, 1 H) 8.01 (s, 1 H).
Reaction SMILES: [OH:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH2:6][CH3:7])[C:3]([OH:5])=O.C(N(C(C)C)CC)(C)C.[F:23][P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.F[C:57]1[CH:58]=[C:59]([CH2:67][NH2:68])[CH:60]=[C:61]([C:63]([F:66])([F:65])[F:64])[CH:62]=1>CN(C)C=O>[F:23][C:58]1[CH:57]=[CH:62][C:61]([C:63]([F:66])([F:65])[F:64])=[CH:60][C:59]=1[CH2:67][NH:68][C:3](=[O:5])[C:2]([OH:1])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][CH3:7]
Reactant: F[P-](F)(F)(F)(F)F
Reactant: CCC(O)(C(=O)O)c1ccccc1
Reactant: NCc1cc(F)cc(C(F)(F)F)c1
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(O)(C(=O)NCc1cc(C(F)(F)F)ccc1F)c1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 2-oxo-2-phenylacetic acid (10 g, 66.6 mmol) (Acros Organics B.V.B.A., Belgium) in tetrahydrofuran (THF, 200 mL) was treated at room temperature with ethylmagnesium bromide (2.5 M, 80 mL, 200 mmol). The reaction mixture was stirred for 5 h, partitioned between ethyl acetate and 1N—HCl. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to afford 2-hydroxy-2-phenylbutanoic acid. A solution of 2-hydroxy-2-phenylbutanoic acid (100 mg, 0.55 mmol) and diisopropylethylamine (188 uL, 1.11 mmol) in N,N-dimethylformamide (2 mL) was treated at room temperature with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 290 mg, 0.55 mmol). After 15 min, (3-fluoro-5-(trifluoromethyl)phenyl)methanamine (107 mg, 0.55 mmol) was added. The reaction mixture was stirred for 3 h, partitioned between dichloromethane and 0.5N—NaOH. The aqueous layer was removed and the organic layer was washed with 0.5N—HCl. The aqueous layer was removed by filtering through a plastic fit. The organic layer was evaporated in vacuo to give the racemic mixture of the amide which was resolved using the chiral column (CiralPak AD) to give the desired product (2-1); HRMS (M+H−H2O)=338.1167; 1H NMR (500 MHz, CDCl3) δ 7.59 (d, 1H, J=7.5 Hz), 7.51 (m, 1H), 7.42 (d, 1H, J=5.0 Hz), 7.37 (t, 1H, J=7.5 Hz), 7.32 (d, 1H, J=7.0 Hz), 7.13 (t, 1H, J=9.0 Hz), 7.01 (bs, 1H), 4.52 (dq, 2H, J=15.6, 6.4 Hz), 2.83 (s, 1H), 2.36 (m, 1H), 2.12 (m, 1H), 0.94 (t, 3H, J=7.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:21]([O:23]CC)=[O:22])[N:15]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:16]=2)=[O:10])=[C:4]([CH3:26])[CH:3]=1.O.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:21]([OH:23])=[O:22])[N:15]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:16]=2)=[O:10])=[C:4]([CH3:26])[CH:3]=1
Reactant: CCOC(=O)c1nc(NC(=O)Nc2ccc(Cl)cc2C)cn1CC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(Cl)ccc1NC(=O)Nc1cn(CC2CC2)c(C(=O)O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.6 g (28.1 mmol) of ethyl 4-({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)-1-(cyclopropylmethyl)-1H-imidazole-2-carboxylate are suspended in 158 ml of ethanol. While cooling in ice, 16.4 ml of water and 6 ml (112 mmol) of 50% strength aqueous sodium hydroxide solution are added. The reaction mixture is stirred at room temperature for 1 h and then concentrated in vacuo. The residue is taken up in 100 ml of isopropanol and, while cooling in ice, 100 ml of 1N hydrochloric acid are added. The crystals are filtered off with suction and dried in vacuo at 40° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])C)=[CH:4][N:3]=1.[CH3:11][C:12]([S@@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>ClC(Cl)C.CCOCC.O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[N:3]=[CH:4][C:5](/[C:8](=[N:17]/[S:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])/[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(Br)nc1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CCOCC
Solvent: O
Solvent: CC(Cl)Cl
Product: C/C(=N\S(=O)C(C)(C)C)c1ccc(Br)nc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a solution of 2-bromo-5-isopropyl-pyridine (2.0 g, 9.99 mmol) in dichloroethane (15 mL) was added (S)-(−)-2-methyl-propane-2-sulfinic acid amide (1.45 g, 11.72 mmol) and titanium(IV) ethoxide (4.15 mL, 19.99 mmol). The mixture was heated at 110° C. in a microwave. After 2 h, the mixture was diluted with ether (20 mL) and water (6 mL). The mixture was stirred for 10 minutes. The layers were separated and the organic layer was dried over magnesium sulfate, filtered and concentrated to afford a residue. The crude residue was purified by normal phase flash chromatography on silica gel using ethyl acetate-dichloromethane (0-40%) to afford 2-methyl-propane-2-sulfinic acid[1-(6-bromo-pyridin-3-yl)-eth-(E)-ylidene]-amide (2.0 g, 66%).
Reaction SMILES: [I-].[Na+].Cl[Si:4]([CH3:7])([CH3:6])[CH3:5].[NH2:8][C:9]1[N:17]=[C:16]2[N:11]([C:12]([O:19][CH3:20])=[N:13][CH:14]=[C:15]2[Cl:18])[N:10]=1.C(N(CC)CC)C>C(#N)C.C(OCC)C>[CH3:5][Si:4]([CH3:7])([CH3:6])[NH:8][C:9]1[N:17]=[C:16]2[N:11]([C:12]([O:19][CH3:20])=[N:13][CH:14]=[C:15]2[Cl:18])[N:10]=1
Reactant: C[Si](C)(C)Cl
Reactant: COc1ncc(Cl)c2nc(N)nn12
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ncc(Cl)c2nc(N[Si](C)(C)C)nn12
Reaction time: 0.17 h

Procedure:
A mixture of 12.7 g (85 mmol) of sodium iodide in 425 mL of dry acetonitrile was prepared under nitrogen in a predried 2 L flask and to this mixture 9.25 g (10.8 mL, 85 mmol) of chlorotrimethylsilane was added by means of a syringe at ambient temperature with stirring. After 10 min, 17.0 g (85 mmol) of 2-amino-8-chloro-5-methoxy[1,2,4]triazolo[1,5-c]pyrimidine and 8.62 g (11.9 mL, 85 mmol) of triethylamine were added with stirring. The mixture was allowed to react for 12 hours at ambient temperature with stirring and was then diluted with 500 mL of dry diethyl ether. The salts that precipitated were removed by filtration on a dry scintered glass filter and the filtrate was concentrated by evaporation under reduced pressure. The residue was diluted with another 500 mL of dry diethyl ether the salt removal procedure was repeated. The title compound was obtained as the solid residue and amounted to 19.5 g (84 percent of theory).