Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:10]([S:11](Cl)(=[O:13])=[O:12])=[C:9]([F:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:16][NH2:17].[ClH:18]>O>[Cl:18][C:7]1[CH:8]=[C:9]([F:15])[C:10]([S:11]([NH:17][CH3:16])(=[O:13])=[O:12])=[CH:2][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cl
Reactant: O=C(O)c1ccc(F)c(S(=O)(=O)Cl)c1Cl
Reactant: CN
Solvent: O
Product: CNS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F
Reaction time: 1 h
Yield: 89 %

Procedure:
20.02 g (73.4 mmol) of 2-chloro-3-chlorosulfonyl-4-fluorobenzoic acid was added as a solid to a cooled solution of 10.5 mL of methylamine (40% aqueous solution, 293.6 mmol) in 400 mL of water. Reaction was monitored by LC/MS and complete after one hour. The reaction was acidified to pH=1 with concentrated HCl, and solid precipitated out. Product was obtained by filtration. 17.54 g obtained as a pale tan solid (89% yield). 1H NMR (300 MHz, DMSO-d6) δ13.83-14.01 (br, 1H), 8.21-8.26 (d, 1H, J=9.11 Hz), 7.98-8.03 (q, 1H, J=4.82), 7.88-7.92 (d, 1H, J=9.11 Hz), 2.55-2.56 (d, 3H, J=4.82 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:23][CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[OH:24]O.N>C(O)(=O)C>[Cl:1][C:2]1[C:3]2[S:23](=[O:24])[CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[CH2:12][CH2:13]2)[N:7]=1
Reactant: OO
Reactant: Clc1ccc(N2CCN(c3nc(Cl)c4c(n3)CCS4)CC2)cc1
Agent: N
Solvent: CC(=O)O
Product: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(Cl)c21
Temperature: 10 °C
Reaction time: 2 h

Procedure:
14.69 g 4-chloro-2-[4-(4-chloro-phenyl)-piperazin-1-yl]-6,7-dihydro-thieno[3,2-d]pyrimidine are placed in 140 ml glacial acetic acid and cooled to 10° C. cooled. 3.79 ml hydrogen peroxide (35%) are added dropwise, then the mixture is stirred for 2 hours. A further 1 eq hydrogen peroxide is added, the mixture is stirred for 8 hours at ambient temperature. Then the reaction mixture is stirred into ice water, made basic with ammonia solution. The precipitate formed is suction filtered, washed with water and dried. 11.90 g of the product are obtained as a powder.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)=[O:13])[CH3:10]>CO.C(Cl)Cl>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:12]([O:11][CH2:9][CH3:10])=[O:13])[CH:15]=2)=[CH:3][CH:4]=1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: Oc1ccc(I)cc1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1cccc(-c2ccc(O)cc2)c1
Reaction time: 8 h
Yield: 71 %

Procedure:
4-Iodophenol and 3-ethoxycarbonylphenylboronic acid were processed as described in Example 136A, except that the reaction was done overnight at room temperature and the chromatography was conducted twice with 50% CH2Cl2/hexanes followed by a gradient of 0 to 1% MeOH/CH2Cl2 to provide the title compound as a white powder (71% yield). 1HNMR (300 MHz, d6-DMSO) δ 1.34 (t, 3H), 4.34 (q, 2H), 6.89 (d, 2H), 7.50-7.59 (m, 3H), 7.83-7.89 (m, 2H), 8.11 (dd, 1H), 9.62 (s, 1H).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=O.[CH3:12][C:13]([CH2:15][C:16](O)=O)=O.[C:19]([O-:22])([O-])=O.[Na+].[Na+]>CO>[CH:13]1[CH:15]=[CH:16][C:2]2[NH:1][C:19]([OH:22])=[C:6]([C:2]3[C:4](=[O:5])[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[N:1]=3)[C:4]=2[CH:12]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CC(=O)CC(=O)O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1C(c2c(O)[nH]c3ccccc23)=Nc2ccccc21
Reaction time: 0.08 h

Procedure:
To a solution of isatin analogs (77 mg, 0.425 mmol) in methanol (5 ml) were added 5-substituted indoxy N, O diacetate (100 mg, 0.425 mmol) and the mixture was stirred for 5 min. Anhydrous Na2CO3 (112.5 mg, 1.06 mmol) was added, and the stirring was continued for 3 h at room temperature. The dark precipitate was filtered and washed with cold water, and dried under reduced pressure to give derivatives of 5,5-substituted indirubin, 7-10. The appropriate indirubin derivative (10 mg, 0.032 mmol) was dissolved in pyridine (0.3 ml) and added hydroxylamine hydrochloride (6.6 mg, 0.095 mmol). The reaction mixture was heated under reflux at 120° C. for 2 h. After cooling, the product was acidified with 1N HCl. The precipitation was filtered and washed with water to afford quantitatively the corresponding 3′-oxime selectively in a (2′Z, 3′E) form. The product was purified by silica gel column chromatography (Chloroform:Methanol=20:1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH:6]([NH2:17])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>C(N(CC)CC)C>[CH3:25][C:24]1[CH:26]=[CH:27][C:21]([S:18]([N:4]([CH2:5][CH:6]([NH:17][S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3][CH2:2][NH:1][S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: NCCNCC(N)Cc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NCCN(CC(Cc2ccc([N+](=O)[O-])cc2)NS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
Intermediate XXII is prepared based on the synthetic approach shown in Scheme 2. N1-(2-aminoethyl)-3-(4-nitrophenyl)propane-1,2-diamine (XX) is protected using tosyl chloride and triethylamine to afford tritosylated compound 4-methyl-N-(2-(4-methylphenylsulfonamido)-3-(4-nitrophenyl)propyl)-N-(2-(4-methylphenylsulfonamido)ethyl)benzenesulfonamide (XXI). Deprotonation of (XXI) with sodium ethoxide in ethanol produces a disodium salt of compound (XXI), compound (XXII). Compound (XX) is produced according to the method of Corson et al. (Corson, D. T.; Meares, C. F. Bioconjugate Chem. 2000, 11, 292-299, the disclosure of which is incorporated herein by reference).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[C:18]([F:22])[C:19]([F:21])=[CH:20][C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[F:21][C:19]1[C:18]([F:22])=[CH:17][C:15]2=[N:16][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[N:13]=[C:14]2[CH:20]=1
Reactant: Brc1ccccn1
Reactant: C#CCCn1nc2cc(F)c(F)cc2n1
Product: Fc1cc2nn(CCC#Cc3ccccn3)nc2cc1F
Yield: 65517.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (50 mg, 0.32 mmol) and 2-(but-3-ynyl)-5,6-difluoro-2H-benzo[d][1,2,3]triazole (60 mg, 0.29 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 54 mg (0.19 mol, 66%) of 5,6-difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow solid (M.P.=131-132° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]([NH2:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:16]([O:19]C(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1>[C:16]([O:19][NH:15][CH:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:18])[CH3:17]
Reactant: Cc1ccsc1C(N)Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)ONC(Cc1ccccc1)c1sccc1C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a stirred solution of 10 g (0.047 mol) of α-(3-methyl-2-thienyl)benzeneethanamine in 50 ml of pyridine at ambient temperature was added dropwise 6.6 ml (0.07 mol) of acetic anhydride. Mixture was allowed to stand overnight, diluted with 500 ml of ETOAC, washed with 1N HCl until acidic, water, brine and dried. The resulting dark oil obtained from concentration of the organics was purified by chromatography on silica gel to give 8.2 g ( 0.032 mol) of N-acetoxy-α-(3-methyl-2-thienyl)benzeneethanamine as a light brown solid. To a stirred suspension of this solid in 45 ml of THF at 0° C. was added dropwise 64 ml (0.064 mol) of a 1.M solution of borane in THF. The resulting mixture was allowed to warm to ambient temperature and stirred overnight. The reaction was quenched by carefully adding 100 ml of 6N HCl and was then warmed at 75° C. for 40 hours. The mixture was cooled, made basic with 50% aqueous NaOH, and extracted with CH2Cl2 (3×200 ml). The organic extracts were combined, washed with water, brine, and dried. The resulting oil obtained from concentration of organics was dissolved in 50 ml isopropanol and made acidic with hydrochlorinated isopropanol. The white solid was collected by filtration and dried giving 5. g of product as a white solid (mp 226°-228° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6](=[O:28])[C:5]2([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:38])[N:29]([CH3:31])[CH3:30].[H-].[Na+].[CH3:41]I.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([N:20]([CH3:41])[C:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[O:22])=[CH:18][CH:19]=1)(=[O:13])=[O:12])[C:6](=[O:28])[C:5]2([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:38])[N:29]([CH3:30])[CH3:31]
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(c3ccccc3Cl)(N(C)C)c3cc(Cl)ccc32)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)N(C)c1ccc(S(=O)(=O)N2C(=O)C(c3ccccc3Cl)(N(C)C)c3cc(Cl)ccc32)cc1
Reaction time: 0.5 h

Procedure:
A solution of 0.420 g of the compound obtained in EXAMPLE 30 in 7 ml of DMF is cooled to 0° C. under an argon atmosphere and 0.027 g of sodium hydride as an 80% dispersion in oil is added. After stirring for 30 minutes, 0.05 ml of methyl iodide is added and the reaction mixture is stirred for 10 minutes. It is poured into water, extracted with AcOEt, washed with water, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica using DCM and then a DCM/AcOEt mixture (95/5; v/v) as the eluent to give the expected product after crystallization from a DCM/iso ether mixture. m=0.211 g. M.p.=145°-148° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=O)C.C1(C2N(C(C)C)N=CC=2C=O)CC1>>[C:15]1([N:9]2[C:10]([C:11]([F:14])([F:12])[F:13])=[C:6]([CH:4]=[O:3])[CH:7]=[N:8]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1C(F)(F)F
Agent: CC(C)n1ncc(C=O)c1C1CC1
Product: O=Cc1cnn(-c2ccccc2)c1C(F)(F)F

Procedure:
1-Phenyl-5-trifluoromethyl-1H-pyrazole-4-carbaldehyde was prepared from 1-phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (Maybridge) in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH2:10][CH2:11][F:12])[CH:3]=1.CO.[OH:15]S(O)(=O)=O>[CH3-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Au+].O>[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH2:9][CH2:10][CH2:11][F:12])[CH:5]=[CH:6][CH:7]=1
Reactant: FCCC#Cc1cccc(Br)c1
Reactant: O=S(=O)(O)O
Agent: [Au+]
Agent: [CH3-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CO
Product: O=C(CCCF)c1cccc(Br)c1
Temperature: 72 °C
Yield: 40 %

Procedure:
A mixture of 0.2 gm (0.89 mmol) of 1-bromo-3-(4-fluorobut-1-ynyl)benzene, 2 mL of MeOH, 1 mg of methyl(triphenylphosphine)gold (I), 25 μL of conc. H2SO4 and 0.44 mL of H2O was placed in a sealed tube, flushed with argon, heated to 72° C. for 2 h and was cooled. The reaction mixture was diluted with EtOAc, washed sequentially with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Chromatography of the concentrate on silica gel with a gradient of 0% to 20% EtOAc-hexanes gave 1-(3-bromophenyl)-4-fluorobutan-1-one as an oil, 0.086 gm (40% yield); 1H NMR (400 MHz, CDCl3) δ: 2.13 (m, 2H), 3.09 (t, 2H, J=7.1 Hz), 4.53 (dt, 2H, J=5.8, 47.1 Hz), 7.33 (t, 1H, J=7.8 Hz), 7.66 (dq, 1H, J=1.0, 7.8 Hz), 7.55 (dq, 1H, J=1.0, 7.8 Hz), 8.07 (t, 1H, J=1.7 Hz).
Reaction SMILES: [NH2:1][C@H:2]([C@@H:6]([OH:10])[CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[C:11]([O-:14])(O)=[O:12].[Na+].[C:16]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]C2C(=O)N(C([O-])=O)C=CC=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.C1COCC1>[OH:10][C@@H:6]([CH:7]([CH3:9])[CH3:8])[C@@H:2]([NH:1][C:11]([O:14][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])[C:3]([OH:5])=[O:4]
Reactant: O=C([O-])n1cccc(CCCCCc2ccccc2)c1=O
Reactant: CC(C)[C@H](O)[C@@H](N)C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@H](O)[C@@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Reaction time: 15 h
Yield: 58.5 %

Procedure:
To a stirred diastereomeric mixture containing (2R*,3R*)- and (2R*,3S*)-2-amino-3-hydroxy-4-methyl-pentanoic acid (0.058 g, 0.4 mmol) and NaHCO3 (0.035 g, 0.4 mmol) in H2O (2.0 mL), at rt, the isomeric mixture containing 5-phenyl-pentyl-2-pyridyl-carbonate and 5-phenyl-pentyl-2-oxopyridine-1-carboxylate (0.38 g, 1.4 mmol) [prepared as for example 32, step 1] in THF (2.0 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×10 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with AcOEt (3×20 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.079 g, 59% over 2 steps), as a diastereoisomeric mixture (anti:syn=8:2), as an off-white solid, which was used in the next step without further purification. MS (ESI) m/z: 338 [M−H]+; (ESI) m/z: 336 [M−H]−. 1H NMR (DMSO-d6) δ 0.81 (d, J=6.69 Hz, 3H), 0.88 (d, J=6.77 Hz, 3H), 1.32 (tt, J=5.81, 9.52 Hz, 2H), 1.57 (td, J=4.08, 8.39 Hz, 4H), 1.70-1.84 (m, 1H), 2.56 (t, J=7.71 Hz, 2H), 3.40 (t, J=6.09 Hz, 1H), 3.93 (t, J=6.61 Hz, 2H), 3.96-4.04 (m, 1H), 4.84 (s, 1H), 7.12-7.21 (m, 4H), 7.27 (t, J=7.49 Hz, 2H), 12.00-12.96 (s, 1H) (reported data refer to the major anti diastereoisomer).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:31])=[C:27](F)[CH:28]=3)[C:23](=[O:32])[N:22]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:21]2=[O:41])=[CH:16][CH:15]=1>>[OH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:31])=[C:27]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:28]=3)[C:23](=[O:32])[N:22]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:21]2=[O:41])=[CH:16][CH:15]=1
Reactant: O=c1c2cc(F)c(F)cc2n(-c2ccc(O)cc2)c(=O)n1OCc1ccccc1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(-c2ccc(O)cc2)c(=O)n1OCc1ccccc1
Yield: 69.8 %

Procedure:
Using General Method 4, the reaction of pyrrolidine (0.04 mL, 0.5 mmol), triethylamine (0.07 mL, 0.5 mmol), and 1-(4-hydroxyphenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example J-1, 0.065 g, 0.16 mmol) provided 0.05 g of the title compound as a solid.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:10][CH2:11][CH2:12][C:3]([C:4]=23)=[C:2]1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH2:20]([N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:10][CH2:11][CH2:12][C:3]([C:4]=23)=[C:2]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1[nH]c2cccc3c2c1CCC3
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2c3c(cccc3n1Cc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 1,3,4,5-tetrahydro-benz[cd]indole-2-carboxylate (0.40 g, 1.74 mmol) was added to a suspension of 60% sodium hydride (0.077 g, 1.92 mmol) in N,N-dimethylformamide (5 ml), followed by stirring at room temperature for 30 minutes. Then, benzyl bromide (0.36 g, 2.09 mmol) was added and the resulting mixture was stirred for 1.5 hours. Thereafter, the same after-treatment as in Reference Example 1 was carried out to obtain an oil of ethyl 1,3,4,5-tetrahydro -1benzyl-benz[cd]indole-2-carboxylate. 1 Hnmr (CDC13) δ:
Reaction SMILES: Cl.[F:2][C@@:3]12[C@:16]3([CH3:17])[C:11](=[CH:12][C:13](=[O:18])[CH:14]=[CH:15]3)[C@@H:10]([F:19])[CH2:9][C@H:8]1[C@@H:7]1[CH2:20][C@@H:21]3[C@:25]([C:26](=[O:32])[CH2:27][O:28][C:29](=[O:31])[CH3:30])([C@@:6]1([CH3:33])[CH2:5][C@@H:4]2[OH:34])[CH2:24][NH:23][CH2:22]3.C(N(CC)CC)C.Cl[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH3:50])[CH:45]=1.CC1C=C(C=CC=1)CBr>C(Cl)Cl>[F:2][C@@:3]12[C@:16]3([CH3:17])[C:11](=[CH:12][C:13](=[O:18])[CH:14]=[CH:15]3)[C@@H:10]([F:19])[CH2:9][C@H:8]1[C@@H:7]1[CH2:20][C@@H:21]3[C@:25]([C:26](=[O:32])[CH2:27][O:28][C:29](=[O:31])[CH3:30])([C@@:6]1([CH3:33])[CH2:5][C@@H:4]2[OH:34])[CH2:24][N:23]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH3:50])[CH:45]=1)[CH2:22]3
Reactant: Cc1cccc(CCl)c1
Reactant: CC(=O)OCC(=O)[C@@]12CNC[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Agent: Cc1cccc(CBr)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)[C@@]12CN(Cc3cccc(C)c3)C[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Temperature: 40 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
In a nitrogen atmosphere, intermediate 6 (200 mg, 0.400 mmol) was dissolved in DCM (5 ml), triethylamine (166 μL, 1.20 mmol) and 1-(chloromethyl)-3-methylbenzene (79 μL, 0.60 mmol) were added, and the mixture was heated at 40° C. for 2 hours and at RT for 16 hours. Then triethylamine (138 μL, 1.00 mmol) and 3-methylbenzyl bromide (54 μL, 0.40 mmol) were added to the mixture, and stirring was continued for 2 hours. The reaction mixture was partitioned between water and DCM, and the aqueous layer was extracted with DCM (3×15 mL), and the organic phase was collected and concentrated. The crude was purified by silica gel flash chromatography (eluent DCM/MeOH 99:1) to yield the title compound (130 mg, 57.2% yield).
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]#[N:13])=[CH:4]1.[F:14][C:15]([F:24])([F:23])[CH2:16][CH2:17][CH:18]([C:21]#[N:22])[C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:12]([C:5]1[C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][N:3]([CH2:2][C:18]([CH2:17][CH2:16][C:15]([F:14])([F:23])[F:24])([C:19]#[N:20])[C:21]#[N:22])[CH:4]=1)#[N:13]
Reactant: N#Cc1cn(CCl)cc1C(F)(F)F
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cn(CC(C#N)(C#N)CCC(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
0.80 g of 1-chloromethyl-3-cyano-4-trifluoromethyl-1H-pyrole and 0.67 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 10 ml of N,N-dimethylformamide. 0.57 g of potassium carbonate was added to the solution under ice cooling, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.33 g of [(3-cyano-4-trifluoromethyl-1H-pyrole-1-yl) methyl](3,3, 3-trifluoropropyl) malononitrile (referred as the compound of the present invention (46), hereinafter) shown by below formula.
Reaction SMILES: [NH2:1][CH:2]([C:4]([OH:6])=[O:5])[CH3:3].C(N(CC)CC)C.C[Si](Cl)(C)C.[CH:19]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1>ClCCl.O>[CH:19]1([C:24]([NH:1][CH:2]([CH3:3])[C:4]([OH:6])=[O:5])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(Cl)C1CCCC1
Reactant: CC(N)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(NC(=O)C1CCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
16.8 g (0.189 mol) of D,L-alanine and 41.98 g (0.415 mol) of triethylamine are initially charged in 200 ml of dichloromethane. At 0° C., 45.07 g (0.415 mol) of trimethylsilyl chloride are added dropwise, and the mixture is then stirred at room temperature for 1 h and then at 40C for 1 h. The solution is cooled to −10° C. and 25 g (0. 89 mol) of cyclopentanecarbonyl chloride are added dropwise. The mixture is stirred at −10° C. for 2 h and at room temperature for 1 h. With ice-cooling, 100 ml of water are added, and the mixture is then stirred for 10 min and the resulting precipitate is filtered off with suction. The precipitate is washed with 300 ml of water and then with 300 ml of diethyl ether and subsequently dried at 60° C.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.Br[C:31]1[CH:32]=[N:33][CH:34]=[C:35]([CH:38]=1)[C:36]#[N:37].[CH2:39]=[CH:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C)C=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH:39](/[C:31]1[CH:32]=[N:33][CH:34]=[C:35]([CH:38]=1)[C:36]#[N:37])=[CH:40]\[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: C=Cc1ccccc1
Reactant: N#Cc1cncc(Br)c1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1cncc(/C=C/c2ccccc2)c1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 33.7 %

Procedure:
Add tris(dibenzylideneacetone)dipalladium (125 mg, 0.136 mmol) and tri-o-tolylphosphine (86 mg, 0.273 mmol) to a solution of triethylamine (0.77 mL, 5.46 mmol), 5-bromonicotinonitrile (500 mg, 2.73 mmol) and styrene (0.48 mL, 4.1 mmol) in anhydrous N,N-dimethylformamide (10 mL) under an inert atmosphere, and stir at 100° C. for 3.5 h. Cool to room temperature, add water and extract three times with diethyl ether. Combine the organic layers, dry (sodium sulfate), filter, and concentrate. Purify the residue by silica gel chromatography, eluting with dichloromethane, to give the title compound as a white solid (190 mg, 34%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH2:12]Br)[CH:3]=1.[OH:14][CH2:15][C:16]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[H-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[CH2:12][O:14][CH2:15][C:16]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: FC(F)(F)c1cc(Br)cc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-Bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (1.0 g, 3.14 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.70 g, 2.4 mmol) were combined in dimethylformamide (8 mL) and cooled to 0° C. The reaction was treated with sodium hydride (115 mg, 4.8 mmol), stirred at 0° C. for 1 h, and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (20% ethyl acetate/hexanes) gave 1.6 g (96%). 1H-NMR (CDCl3, 500 MHz) δ 7.61 (s, 1H), 7.39 (s, 1H), 7.34-7.37 (m, 4H), 7.25-7.28 (m, 2H), 4.35 (s, 2H), 3.75-3.77 (m, 2H), 3.41 (s, 2H), 3.01-3.06 (m, 2H), 2.19-2.22 (m, 2H), 1.83-1.89 (m, 2H), 1.44 (s, 9H). Mass spec.: 530.21 (MH)+.