Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])=[O:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.I[CH:26]([CH3:28])[CH3:27]>C(OCC)(=O)C>[CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:26]([CH3:28])[CH3:27])[C:6]([O:8][CH3:9])=[O:7])=[O:2]
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC(C)C)c(C=O)c1
Temperature: 60 °C
Yield: 98.9 %

Procedure:
To a mixture of methyl 3-formyl-4-hydroxy-benzoate (10.0 g, 55.5 mmol), potassium carbonate (30.7 g, 222.0 mmol) and N,N-dimethylformamide (62.5 mL) was added 2-iodopropane (18.9 g, 11.1 mL, 111.0 mmol) and the reaction mixture was heated at 60° C. for 18 hours. The reaction mixture was filtered, the filtrate was concentrated in vacuo to give a residue which was dissolved in ethyl acetate (150 mL) and washed sequentially with water (3×75 mL) and brine solution (1×75 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to yield methyl 3-formyl-4-isopropoxy-benzoate (12.2 g, 99%) as a yellow viscous liquid. ESI-MS m/z calc. 222.2. Found 223.3 (M+1)+; Retention time: 1.51 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 10.35 (s, 1H), 8.23 (d, J=2.3 Hz, 1H), 8.17 (dd, J=8.8, 2.3 Hz, 1H), 7.39 (d, J=8.9 Hz, 1H), 4.98-4.83 (m, 1H), 3.85 (s, 3H), 1.38 (d, J=6.0 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:19]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]([OH:20])=[CH:11][CH:10]=1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:34][CH3:35])[N:25]=[CH:24][CH:23]=[C:22]2[O:20][C:12]1[CH:11]=[CH:10][C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1cc(-c2ccc(F)cc2F)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
Ethyl 5-(2,4-difluorophenyl)salicylate (188 mg), 4-chloro-6,7-dimethoxyquinoline (57 mg), and 4-dimethylaminopyridine (93 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure. The residue was purified by column chromatography using acetone-hexane to give the title compound (13 mg, yield 24%).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[CH2:27][NH:28][NH2:29]>C(O)C>[NH2:10][C:6]1[NH:29][N:28]([CH2:27][C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([Br:23])[CH:25]=2)[C:4](=[O:3])[CH:5]=1
Reactant: NNCc1cccc(Br)c1
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2cccc(Br)c2)[nH]1
Reaction time: 2 h

Procedure:
20.5 g of β-amino-β-ethoxyacrylic acid ethyl ester together with 1.5 g of p-toluenesulphonic acid were dissolved in 200 ml of ethanol. 26 g of m-bromobenzylhydrazine were added dropwise to this solution, under nitrogen. After stirring for 2 hours, the mixture was left to stand overnight and the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting Point: 160°, 12 g (35%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]#N)=[CH:13][C:8]=2[N:7]=[N:6]1.C(O)=[O:17]>O>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH:14]=[O:17])=[CH:13][C:8]=2[N:7]=[N:6]1
Reactant: N#Cc1ccc2c(c1)nnn2CCCO
Reactant: O=CO
Solvent: O
Product: O=Cc1ccc2c(c1)nnn2CCCO
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 55 %

Procedure:
A mixture of 500 mg (2.47 mmol) of 1-(3-hydroxypropyl)-1H-1,2,3-benzotriazole-5-carbonitrile (Intermediate 18) and 550 mg of Ni—Al alloy 1:1 in 5.55 ml of 75% formic acid in water is stirred at 90° C. for 2.5 hr. After filtration and evaporation 10 ml of 2N NaOH and 10 ml of EtOH are added to the residue and the system is stirred at rt for 1.5 hr. The pH is made 6-7 by addition of 2N HCl and the system is extracted thoroughly with ethyl acetate. After washing with water, drying and concentrating, 0.35 g of 80% pure title compound (55% yield).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[NH:24][C:23](=O)[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[NH:24][C:23](=[S:35])[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CCCCC(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)N1
Solvent: Cc1ccccc1
Product: S=C1CCCCC(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)N1
Temperature: 100 °C
Yield: 75.3 %

Procedure:
90 mg of 7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one (compound B1) are dissolved in 10 ml of toluene under an atmosphere of dry nitrogen. Subsequently, 144 mg of Lawesson's reagent are added and the solution is heated at 100° C. for 17 hours. Thereafter, the reaction mixture is evaporated to dryness to yield approximately 200 mg of crude material, which is purified by chromatography on basic aluminum oxide (eluent: dichloromethane) to afford 71 mg of the title compound as a light yellow, waxy solid. ESI-MS: 351.2 (MH+). TLC: Rf=0.53 (dichloromethane/ethanol 10:1 parts by volume).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]([F:34])([F:33])[CH2:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>CN(C=O)C>[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:29]([CH2:28][C:27]([F:34])([F:33])[F:26])(=[O:31])=[O:30])[CH2:22][CH2:21]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CC(F)(F)F)CC3)n[nH]c12
Yield: 20.5 %

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (Example 2) (0.030 g, 0.07 mmol) was reacted with 2,2,2-trifluoroethanesulfonyl chloride (0.015 mL, 0.105 mmol) in the presence of triethylamine (0.04 mL, 0.28 mmol) in DMF (2 mL) to give 6.7 mg of white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[CH:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.[CH2:33](O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[CH:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([O:14][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:13])(=[O:7])=[O:6]
Reactant: OCc1ccccc1
Reactant: COc1ccc(COC(C(=O)O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COC(C(=O)OCc2ccccc2)C(C)(C)COS(=O)(=O)CCCCl)cc1
Yield: 38.4 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R/S)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoic acid (14) (0.50 g, 1.2 mmol) dissolved in 5 mL of anhydrous dichloromethane (DCM) was reacted with 0.14 mL (0.2 g, 1.5 mmol) of oxalyl chloride. After completion of the reaction, a solution of 0.34 mL of benzyl alcohol (0.25 mL, 0.26 g, 2.4 mmol) and 0.26 mL of pyridine (0.15 g, 1.9 mmol) in dichloromethane (DCM) was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=1:2) to provide 0.23 g (38% yield) of the title compound (32a) as a colorless oil. The analytical data was consistent with the proposed structure and with the data obtained for the enantiopure compound (31a).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:29]=[CH:28][C:15]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([O:25]CC)=[O:24])[CH:18]=2)=[CH:14][C:13]=1[F:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>C(O)C.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:29]=[CH:28][C:15]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([OH:25])=[O:24])[CH:18]=2)=[CH:14][C:13]=1[F:30])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(Oc2ccc(NC(=O)OCc3ccccc3)c(F)c2)ccn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc(Oc2ccnc(C(=O)O)c2)cc1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
After suspending ethyl 4-(4-benzyloxycarbonylamino-3-fluorophenoxy)pyridine-2-carboxylate (7.51 g) in ethanol (100 ml) and water (20 ml), lithium hydroxide (657 mg) was added at room temperature. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was stirred while cooling in an ice bath and then 1N hydrochloric acid (60 ml) was added thereto. After stirring for 5 minutes, the reaction mixture was concentrated. After concentration, the crystals precipitated in the reaction mixture were filtrated, and the crystals were washed with water. The crystals were then dissolved in ethyl acetate-tetrahydrofuran, the solution was dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure. The obtained precipitate was suspended in hexane and the precipitate was filtered. The solid was dried to provide the title compound (5.04 g, 72.0%) as a pale yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH2:18][C:19]2([C:24]#[N:25])[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:6]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[F:17])=[N:7][CH:8]=1.[CH:26]1([CH:29]([C:36]2[C:41]([F:42])=[CH:40][N:39]=[C:38]([OH:43])[CH:37]=2)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:28][CH2:27]1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[C:24]([C:19]1([CH2:18][C:5]2[CH:4]=[C:3]([CH2:2][O:43][C:38]3[CH:37]=[C:36]([CH:29]([CH:26]4[CH2:28][CH2:27]4)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:41]([F:42])=[CH:40][N:39]=3)[CH:8]=[N:7][C:6]=2[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[F:17])[CH2:20][CH2:21][CH2:22][CH2:23]1)#[N:25]
Reactant: CCOC(=O)CC(c1cc(O)ncc1F)C1CC1
Reactant: COc1ccc(F)c(-c2ncc(CBr)cc2CC2(C#N)CCCC2)c1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1cc(OCc2cnc(-c3cc(OC)ccc3F)c(CC3(C#N)CCCC3)c2)ncc1F)C1CC1
Yield: 16.1 %

Procedure:
Under a nitrogen atmosphere, to a solution of 1-((5-(bromomethyl)-2-(2-fluoro-5-methoxyphenyl)pyridin-3-yl)methyl)cyclopentanecarbonitrile (48 mg) and ethyl 3-cyclopropyl-3-(5-fluoro-2-hydroxypyridin-4-yl)propanoate (40 mg) obtained in Example 42, step E, in toluene (1 mL) was added silver carbonate (48 mg), and the mixture was refluxed for 2 hr. The reaction mixture was filtered, and the solvent in the filtrate was evaporated under reduced pressure and the residue was purified by preparative HPLC (water/acetonitrile, TFA added) to give the title compound (11 mg) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[N+:14]([O-])=O.[Cl:17][CH2:18][C:19](O)=O>CO.[Pd]>[Cl:17][CH2:18][C:19]1[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:3]=2[N:14]=1
Reactant: O=C(O)CCl
Reactant: Nc1cccc(-c2ccccc2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: ClCc1nc2c(-c3ccccc3)cccc2[nH]1
Yield: 92.7 %

Procedure:
A solution of 2-amino-6-phenyl-nitrobenzene (0.600 g, 2.80 mmol) in MeOH (28 mL) was hydrogenated (30 psi) over palladium, 10 wt. % on activated carbon (0.121 g). The resultant crude 3-phenyl-1,2-phenylenediamine was reacted with chloroacetic acid (0.537 g, 5.68 mmol) in refluxing 4 N Hl (6 mL) overnight. After normal workup, 0.63 g (92%) of 2-chloromethyl-4-phenyl-1H-benzimidazole was isolated as a brown solid, which was used without further purification.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)O1>>[N:27]1([C:24]2[N:25]=[CH:26][C:21]([C:2]3[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=3)=[CH:22][CH:23]=2)[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Reactant: NC(=O)c1cc(Br)sc1[N+](=O)[O-]
Product: NC(=O)c1cc(-c2ccc(N3CCOCC3)nc2)sc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 5-bromo-2-nitrothiophene-3-carboxamide (Intermediate 10, Step 4) (2.50 g, 9.96 mmol) and 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]morpholine (2.89 g, 9.96 mmol) according to the general procedure described in Intermediate 10, Step 5.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][NH:33][C:34](=[O:42])[CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:39]5[CH2:38][CH2:37][N:36]([CH2:35][C:34]([NH:33][CH3:32])=[O:42])[CH2:41][CH2:40]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:3]=1
Reactant: CNC(=O)CN1CCNCC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CNC(=O)CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
2-(4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-1-yl)-N-methyl-acetamide was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and N-methyl-2-piperazin-1-yl-acetamide following General Procedure C.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[C:9](=[O:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>C(O)(=O)C.Cl.[Pt]=O>[C:1]1([N:7]2[CH:11]=[C:10]([CH:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[C:9](=[O:18])[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]n(-c2ccccc2)cc1-c1ccncc1
Agent: O=[Pt]
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]n(-c2ccccc2)cc1C1CCNCC1

Procedure:
Platinum oxide (60 mg) was added to a solution of 1-phenyl-4-pyridin-4-yl-1,2-dihydro-3H-pyrazol-3-one (180 mg, 0.758 mmol) in acetic acid (12 mL), concentrated hydrochloric acid (0.100 mL), and water (5 mL). The reaction vessel was evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (50 psi). After 5 h the mixture was filtered and concentrated to give the title compound. MS 244.3 (M+1).
Reaction SMILES: CO[C:3]([C:5]1[C:17](=[O:18])[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:15]2[C:7](=[CH:8][C:9]3[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=1[OH:27])=[O:4].[NH2:28][C@H:29]([C:31]([OH:33])=[O:32])[CH3:30].C[O-].[Na+]>COCCO>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:16]2[N:15]3[C:7](=[CH:8][C:9]4[C:14]3=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:6]([OH:27])=[C:5]([C:3]([NH:28][C@@H:29]([CH3:30])[C:31]([OH:33])=[O:32])=[O:4])[C:17]2=[O:18])=[CH:25][CH:24]=1
Reactant: C[C@H](N)C(=O)O
Reactant: COC(=O)c1c(O)c2cc3ccccc3n2n(Cc2ccc(F)cc2)c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: C[C@H](NC(=O)c1c(O)c2cc3ccccc3n2n(Cc2ccc(F)cc2)c1=O)C(=O)O
Yield: 61.4 %

Procedure:
A mixture of 4-(4-fluoro-benzyl)-1-hydroxy-3-oxo-3,4-dihydro-4,4a-diaza-fluorene-2-carboxylic acid methyl ester (110 mg), L-alanine (268 mg), NaOMe (146 mg) in 2-methoxyethanol (10 mL) was refluxed for 6 h; subsequently, the reaction was cooled and solvent was removed by rotovaping; the residue was dissolved in water and then acidified with 2 M HCl solution; the precipitates were collected via filtration, washed with water, dried, and then purified with column (eluent: DCM/EtOAc, 10/1 (v/v), with 0.5% acetic acid) to give the desired product (78 mg). ESI (m/z): 424 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[C:7]([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12](O)[CH2:11][CH:10]1[CH3:20])=[O:8])[CH3:2].[NH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][CH2:28]1>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[C:7]([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]([N:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][CH2:29][CH2:28]2)[CH2:11][CH:10]1[CH3:20])=[O:8])[CH3:2]
Reactant: CCOc1ccc(C(=O)N2c3ccccc3C(O)CC2C)cc1OCC
Reactant: c1ccc2c(c1)CCCN2
Product: CCOc1ccc(C(=O)N2c3ccccc3C(N3CCCc4ccccc43)CC2C)cc1OCC
Yield: 33.4 %

Procedure:
Starting with 1-(3,4-diethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (600 mg, 1.70 mmol) prepared in Reference Example 20 and 1,2,3,4-tetrahydroquinoline (679 mg, 5.23 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (267 mg, yield: 34%) as a white crystal. (cis:trans=1:1.4)
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:3]=1[C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[C:20]([Cl:23])([Cl:22])=[CH2:21]>C(Cl)Cl>[Cl:22][C:20]([Cl:23])=[CH:21][C:4]([C:3]1[C:2]([Cl:1])=[N:10][C:9]([Cl:11])=[CH:8][C:7]=1[C:12]([F:15])([F:14])[F:13])=[O:5]
Reactant: O=C(Cl)c1c(C(F)(F)F)cc(Cl)nc1Cl
Reactant: C=C(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(C=C(Cl)Cl)c1c(C(F)(F)F)cc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of the 2,6-dichloro-4-(trifluoromethyl)nicotinoyl chloride from the previous reaction in CH2Cl2 (14 mL) was added slowly to a cooled (0° C.) and stirred slurry solution of AlCl3 (4.4 g, 33.0 mmol) in CH2Cl2 (14 mL). After 15 min, vinylidene chloride (2.6 mL, 33.0 mmol) was added to the mixture dropwise. The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was poured over ice and partitioned with CH2Cl2. The organic layer was collected and cooled to 0° C. before TEA (4.6 mL, 33 mmol) was added. After 15 min, the ice bath was removed and the reaction was allowed to warm to room temperature and stirred for an additional 30 min. The solution was washed with 1N HCl, NaHCO3, and water. The organic layer was passed through a pad of silica gel and concentrated in vacuo to afford 3,3-dichloro-1-[2,6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one: (4.3 g, 95%) as a brown oil: LCMS RT: 3.59, MH+: 488.1, Rf=0.44 (EtOAc).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.C(N(CC)CC)C.[CH3:17][NH:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CCO>[Cl:1][C:2]1[N:3]=[C:4]([N:18]([CH3:17])[CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CNC1CCOCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(c1cc(Cl)nc(Cl)n1)C1CCOCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 66.1 %

Procedure:
To a solution of 2,4,6-trichloro-pyrimidine (9.2 g, 50 mmol) and triethylamine (10.1 g, 100 mmol) in EtOH (100 mL) was added N-methyltetrahydro-2H-pyran-4-amine (5.17 g, 45 mmol) dropwise at −40° C. The mixture was warmed up to room temperature then stirred for 14 h., quenched with H2O (25 mL), concentrated and the residue was extracted with EtOAc (100 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by chromatographic column on silica gel (petroleum ether/EtOAc=30/1 to 2/1) to give (2,6-dichloro-pyrimidin-4-yl)-methyl-(tetrahydro-pyran-4-yl)amine as white solid (7.8 g, 60% yield). ESI-LCMS (m/z): 263.14 [M+1]+;
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[NH:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[F:28][C:25]1[CH:24]=[CH:23][C:22]([CH:10]([NH:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH3:13])[C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)=[CH:27][CH:26]=1
Reactant: CC(NC(c1ccc(F)cc1)c1cccc([N+](=O)[O-])c1)c1ccc(F)c(F)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(NC(c1ccc(F)cc1)c1cccc(N)c1)c1ccc(F)c(F)c1
Yield: 21 %

Procedure:
In a similar manner to that described in Example (15b), a solution of N-[(3-nitrophenyl)-(4-fluorophenyl)methyl]-N-[1-(3,4-difluorophenyl)ethyl]amine (3.0 g) [prepared as described in step (a) above] in methanol (10 ml), nickel chloride hexahydrate (3.69 g) and sodium borohydride (1.24 g) were reacted, and the reaction mixture was purified to afford isomer A of the title compound (630 mg) as a pale yellow oil and isomer B of the title compound (580 mg) as a pale yellow oil.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH:19][N:18]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:16][C:17]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:19]([C:4]2[CH:5]=[CH:6][C:1]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:2][CH:3]=2)[N:18]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)c1cc(C)n[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(C)nn1-c1ccc(-c2ccccc2)cc1
Yield: 26 %

Procedure:
To a solution of 4-biphenylboronic acid (1.0 g, 5.1 mmol) and ethyl 3-methylpyrazole-5-carboxylate (0.78 g, 5.1 mmol) in 25 mL dry DCM were added pyridine (1.2 mL, 15 mmol) and anhydrous powder of copper(II) acetate (1.84 g, 10 mmol). Some activated molecular sieve powder was added afterwards. The resulting slurry was refluxed for 2 days under argon. The mixture was diluted with DCM, filtered through celite. The blue filtrate was washed with water (×2), dried, concentrated, purified with flush column to yield ethyl 3-methyl-1-(4-phenylphenyl)-1H-pyrazole-5-carboxylate (26%), Rf 0.67 (1:2 EtOAc: hexane), ES-MS: (M+H)+ 307; and its regioisomer, ethyl 5-methyl-1-(4-phenylphenyl)-1H-pyrazole-3-carboxylate (31%), Rf 0.50 (1:2 EtOAc: hexane), ES-MS: (M+H)+ 307.