Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]([O:16][C:17](=O)[O:18]C(C)(C)C)([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>CN(C=O)C.CN(C)C1C=CN=CC=1>[Br:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Nc1ccc(Br)cc1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccc(Br)cc1C(=O)O
Yield: 86.5 %

Procedure:
2-Amino-5-bromobenzoic acid (4.0 g, 0.018 mol) was dissolved in DMF (90 mL) and treated with carbonic acid di-tert-butyl ester (4.44 g, 0.020 mol), 4-dimethylaminopyridine (0.219 g, 0.0018 mol) and triethylamine (2.8 mL, 0.020 mol) for 16 h at 70° C. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate, washed twice with saturated aqueous sodium bicarbonate, then twice with 1 N hydrochloric acid, dried over sodium sulfate. The organic layers were concentrated to afford 5-bromo-2-tert-butoxycarbonylamino-benzoic acid as a yellow solid (4.92 g, 86.7%). 1H NMR (500 MHz, DMSO-d6) δ 1.46 (s, 9H), 7.72 (dd, J=2.5, J=8.5 Hz, 1H), 8.01 (d, J=2.5 Hz, 1H), 8.22 (d, J=8.5 Hz, 1H), 10.44 (s, 1H). MS: m/z 316 (M+H+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].[NH2:17][C@@H:18]([CH2:36][O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)=[O:20]>>[CH2:38]([O:37][CH2:36][C@H:18]([NH:17][C:14](=[O:16])[CH2:13][C:5]1[CH:6]=[CH:7][C:8]([C:9]([F:10])([F:11])[F:12])=[C:3]([F:2])[CH:4]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)=[O:20])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)c(F)c1
Agent: Cl
Product: O=C(Cc1ccc(C(F)(F)F)c(F)c1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 42.8 %

Procedure:
Proceeding as in Example 1, but substituting 2-(3-fluoro-4-(trifluoromethyl)phenyl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 101, (S)-3-(benzyloxy)-2-(2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (3 mg, 42.8%). MS (EI) for C31H25F5N2O4. found 585.5 (MH+).
Reaction SMILES: [C:1]([CH:4]([C:10](=[O:12])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15]>N12CCCN=C1CCCCC2.C(O)(=O)C>[CH2:8]([O:7][C:5](=[O:6])[C:4]([C:10](=[O:12])[CH3:11])([C:1](=[O:3])[CH3:2])[CH2:15][CH2:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])[CH3:9]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: C=CC(=O)OCC
Solvent: CC(=O)O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CCC(C(C)=O)(C(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.4 %

Procedure:
2.0 g of ethyl 2-acetyl-3-oxo-butyrate was mixed with 5 drops of 1,8-diazabicyclo-[5.4.0]-undec-7-ene. Over 10 minutes, 2.7 g of ethyl acrylate was added dropwise. The mixture was stirred for 30 hours at room temperature, 2 ml of acetic acid was added to neutralize the base, and the mixture was extracted with an aqueous sodium carbonate solution and water. Fractional distillation yields 1.5 g of 2,2-diacetyl-1,5-pentanedioic acid diethyl ester (purity: 70%; colorless).
Reaction SMILES: [N+]([O-])([O-])=O.[Na+].N[C:7]1[C:17]2[O:16][CH2:15][CH2:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[ClH:23].[S:24](=[O:26])=[O:25]>O.[Cu](Cl)Cl.C(O)(=O)C>[Cl:23][S:24]([C:7]1[C:17]2[O:16][CH2:15][CH2:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:26])=[O:25]
Reactant: CCOC(=O)C1=Cc2cccc(N)c2OCC1
Reactant: Cl
Reactant: O=S=O
Agent: Cl[Cu]Cl
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1=Cc2cccc(S(=O)(=O)Cl)c2OCC1
Temperature: -10 °C
Reaction time: 0.83 h

Procedure:
A solution of sodium nitrate (800 mg) in water (3 ml) was added to a suspension of ethyl 9-amino-2,3-dihydro-1-benzoxepin-4-carboxylate (2.56 g) in a mixture of conc. hydrochloric acid (18 ml) and acetic acid (12.5 ml) under sodium chloride—ice bath cooling, and the mixture was stirred at the same temperature for 50 minutes. On the other hand, sulfur dioxide gas was introduced to acetic acid (40 ml) at room temperature, and the solution was cooled to −10° C. under stirring. To this was added copper(II) chloride (545 mg), followed by addition of the diazonium salt solution dropwise. After the addition was completed, the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice-water, and extracted with ethyl acetate (×3). The combined extracts were successively washed with water, saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give ethyl 9-chlorosulfonyl-2,3-dihydro-1-benzoxepin-4-carboxylate (0.72 g) as an oil.
Reaction SMILES: C([O:9][CH2:10][CH:11]([CH2:30][C:31]#[N:32])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=O)C1C=CC=CC=1.[OH-].[Na+]>CO.O1CCCC1>[C:31]([CH2:30][CH:11]([CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:10][OH:9])#[N:32]
Reactant: CCCCCCCCCCCCCCCCOCC(CC#N)COC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOCC(CO)CC#N
Yield: 67.6 %

Procedure:
A mixture of 12.42 g of 2-cyanomethyl-3-hexadecyloxypropyl benzoate n3' and 15.5 ml (31.0 mM) of 2N aqueous sodium hydroxide in 60 ml of methanol and 100 ml of tetrahydrofuran is stirred at room temperature for 1 hour and solvents are evaporated. The product is isolated by ethyl acetate extraction. The ethyl acetate layer is washed with water, dried over anhydrous magnesium sulfate and evaporated. Purification by column silica gel chromatography using n-hexane-ethyl acetate (4:1) affords 6.430 g (67.8% yield) of the titled compound Vn1.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:5])[CH3:2].C1(C)C=CC=CC=1.C(Cl)(=O)C([Cl:24])=O>CN(C)C=O>[CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]([Cl:24])=[O:13])=[O:5])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)COCCCC(=O)O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)COCCCC(=O)Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
36 g (0.19 mol) of 4-ethoxycarbonyhnethoxybutyric acid are charged to 180 ml of toluene and 0.1 ml of dimethyl formamide is added. Then 24.4 ml (0.28 mol) of oxalyl chloride are added dropwise over 30 minutes. When the addition is complete, the reaction mixture is heated to 50° C., stirred for 1 hour and concentrated by evaporation. Distillation of the residue gives 4-ethoxycarbonylmethoxybutyric acid chloride as a clear colourless liquid of b.p. 87°-89° C./2.10-2 torr.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[NH:13][C:12](=[O:14])[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH-:27].[Na+].OO.Cl>CCO>[NH2:2][C:1]([C:3]1[CH:4]=[C:5]([C:9]2[NH:13][C:12](=[O:14])[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1)=[O:27]
Reactant: N#Cc1cccc(C2=NC(c3ccccc3)(c3ccccc3)C(=O)N2)c1
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cccc(C2=NC(c3ccccc3)(c3ccccc3)C(=O)N2)c1
Reaction time: 3 h
Yield: 63 %

Procedure:
To a 50 mL flask was added 0.300 g (0.889 mmol) of the 3-cyano derivative (Example 2) and 6 mL of 95% EtOH. The solution was stirred until homogeneous and then 1 mL of 6M NaOH and 1 mL of 30% hydrogen peroxide were added and the rxn was heated to reflux and allowed to stir for 3 h. Upon completion the reaction was cooled to rt and neutralized with conc. HCl. The solvent was evaporated in vacuo, and the crude residue was purified by column chromatography (Silica gel/Hexanes:Acetone 4:1) producing 0.20 g (63%) of the desired amide as a white solid. LRMS m/z (ESI) 356.2 (M+H)+ ; 1H-NMR (DMSO-d6, 300MHz) δ=8.74 (s, 1H), 8.32 (d, 1H, J=6.0 Hz), 8.10 (d, 1H, J=6.0 Hz), 7.66 (t, 1H, J=6.0 Hz), 7.48 (d, 4H, J=6.0 Hz), 7.33 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[NH:5][CH:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>ClCCl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)c(Cl)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(NC2CCNCC2)cc1Cl

Procedure:
The product of step (i) above (6.5 g) was dissolved in dichloromethane (75 ml) and trifluoroacetic acid (25 ml) added. After 72 hours at room temperature the solution was evaporated and the residue triturated under ether to give the sub-titled product as a solid (6.3 g).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[NH:15]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21]2)[CH2:17][CH2:16]1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:15]3[CH2:20][CH2:19][C:18]4([C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:22][CH2:21]4)[CH2:17][CH2:16]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc2c(c1)CCC21CCNCC1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC2(CCc3ccccc32)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and spiro[indane-1,4'-piperidine]. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 76% overall yield. mp 110°-112°. FDMS m/e=376 (M+ of free base). α[D]589 =-11.60 (c=0.46, methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]2[O:11][CH2:12][O:13][C:8]2=[CH:7][C:4]=1C=O.[C:14]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].N1CCCC[CH2:26]1.C(O)(=O)C>C1C=CC=CC=1>[CH2:12]1[O:11][C:9]2[C:8](=[CH:7][CH2:4][C:3]([O:2][CH3:1])([CH:10]=2)[CH:26]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]([O:22][CH2:23][CH3:24])=[O:21])[O:13]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1cc2c(cc1C=O)OCO2
Reactant: C1CCNCC1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(=CC1(OC)C=C2OCOC2=CC1)C(=O)OCC
Yield: 182.2 %

Procedure:
A solution of the 2-methoxy-4,5-methylenedioxy benzaldehyde (16.00 g, 0.089 mol), diethyl malonate (15.00 mL, 0.090 mol), piperidine (4.40 mL, 0.044 mol) and acetic acid (2.50 mL, 0.045 mol) in benzene (75 mL) stirred at reflux, equipped with a Dean-Stark apparatus, for 24 h. Upon removal of the solvent the crude residue was extracted with ethyl acetate and washed with 10% sodium carbonate solution, water, dried (Na2SO4). After removing the solvent, flash chromatography of the residue (silica gel, 25% ethyl acetate/hexane) provided the title compound as a yellow solid (26.00 g, 91%): 1H NMR (250 MHz, CDCl3) δ 8.50 (s, 1H), 7.45 (d, J=10 Hz, 1H), 7.10 (d, J=15 Hz, 1H), 5.85 (s, 2H), 4.15 (q, 4H), 3.40 (s, 3H), 1.20 (m, 6H); mp: 118° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][NH2:8].[C:14]1([N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][C:22](O)=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OC(=O)C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][NH:8][C:22](=[O:23])[CH2:21][N:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=C(O)CN(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(CCNC(=O)CN(c2ccccc2)c2ccccc2)cc1OC
Yield: 66.9 %

Procedure:
3,4-Dimethoxyphenethylamine (8.05 g) and N,N-diphenylglycine (10 g) were heated for 2 hours at 190° C. After cooling, the reaction mixture was dissolved in ethylacetate. The resulting solution was washed with a 5% sodium bicarbonate aqueous solution and water and then dried. The solvent was distilled off from the solution to give crystals of N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(N,N-diphenylamino)acetamide (11.5 g), mp 88° to 93° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:15][CH2:16][CH3:17])[C:3]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:18](Cl)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].O>C1COCC1>[CH2:21]([O:20][C:18]([NH:1][C@@H:2]([CH2:15][CH2:16][CH3:17])[C:3]([O:9][CH2:10][CH3:11])([O:12][CH2:13][CH3:14])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCC[C@H](N)C(OCC)(OCC)C(=O)OCC
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@H](NC(=O)OCc1ccccc1)C(OCC)(OCC)C(=O)OCC

Procedure:
To (S)-ethyl 3-amino-2,2-diethoxyhexanoate (prepared analogously to examples 1, 10, 11 and 15) (1000 mg, 4 mmol) in THF (20 mL) at ambient temperature was added K2OC3 (829 mg, 6 mmol), followed by CbzCl (628 μL, 4.4 mmol). After 20 h water was added and the aqueous layer was extracted with Et2O. The combined organic layers were dried and the solvent was removed under reduced pressure. Column chromatography (silicagel, cyclohexane:EtOAc 10:1→5:1) gave 1000 mg of the carbamate.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7](O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:19])=O>>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7]([Cl:19])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1ccc(-c2ccccc2)cc1
Product: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Yield: 89.7 %

Procedure:
4-Biphenylsulfonic acid (3.0 g, 12.8 mmol) was heated at 70° C. with phosphorus oxychloride (1.30 ml, 14.0 mol) for 2 h. Excess phosphorus oxychloride was removed under reduced pressure. The residue was decomposed with ice water and extracted with ethyl acetate. The extract was washed with 5% sodium bicarbinate solution, dried over anhydrous magnesium sulfate and concentrated to yield 2.9 g of crude 4-biphenylsulfonyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][N:8]=[C:7](Cl)[CH:6]=1)[CH3:2].[Cl-].[CH:14]1([Zn+])[CH2:18][CH2:17][CH2:16][CH2:15]1.O1CCOC[CH2:21]1>O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[C:9]([CH3:21])[N:8]=[C:7]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:6]=1)[CH3:2]
Reactant: C1COCCO1
Reactant: CCOC(=O)c1ccnc(Cl)c1
Reactant: [Zn+]C1CCCC1
Agent: [Cl-]
Solvent: O
Product: CCOC(=O)c1cc(C)nc(C2CCCC2)c1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
Under argon, Pd(dppf) (200 mg, 0.245 mmol) is added to a solution of 2-chloro-isonicotinic acid ethyl ester (4.80 g, 24.0 mmol) in dioxane (60 mL). A solution of cyclopentyl zinc chloride (50 mL, 24.0 mmol, ˜2 M solution in THF) is added dropwise. The mixture is stirred at 75° C. for 2 h before it is cooled to rt, carefully diluted with water and extracted twice with EA. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 2-cyclopentyl-6-methyl-isonicotinic acid ethyl ester (3.96 g) as an oil; LC-MS: tR=0.72 min, [M+1]+=234.11.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.[CH3:11][NH:12][C@@H:13]([CH2:18][CH:19]=[CH2:20])[C:14]([O:16][CH3:17])=[O:15]>>[F:9][C:2]([F:1])([F:10])[CH2:3][CH2:4][CH2:5][C:6]([N:12]([C@@H:13]([CH2:18][CH:19]=[CH2:20])[C:14]([O:16][CH3:17])=[O:15])[CH3:11])=[O:8]
Reactant: C=CC[C@H](NC)C(=O)OC
Reactant: O=C(O)CCCC(F)(F)F
Product: C=CC[C@@H](C(=O)OC)N(C)C(=O)CCCC(F)(F)F
Yield: 48 %

Procedure:
Step H (1): 5,5,5-Trifluoropentanoic acid and (S)-methyl 2-(methylamino)pent-4-enoate from Step G (1) were coupled according to the conditions described in Step A (1). The crude reaction products were purified by silica-gel column chromatography to give 191 mg (48% yield) of (S)-methyl 2-(5,5,5-trifluoro-N-methylpentanamido)pent-4-enoate as a clear oil. LC-MS (M+H)+=282.1; 1H NMR (500 MHz, CDCl3) δ ppm 1.86-1.95 (m, 2H) 2.12-2.23 (m, 2H) 2.38-2.50 (m, 3H) 2.70-2.80 (m, 1H) 2.91 (s, 3H) 3.67-3.76 (m, 3H) 5.00-5.17 (m, 2H) 5.27 (dd, J=10.83, 5.04 Hz, 1H) 5.61-5.74 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[CH2:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:10](O)(=O)[CH3:11]>CC(C)=O>[C:1]([C:5]1[CH:9]=[C:8]2[C:7](=[C:10]([CH3:11])[CH2:2][C:1]2([CH3:4])[CH3:3])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(C)(C)C1=CC=CC1
Solvent: CC(C)=O
Product: CC1=C2C=C(C(C)(C)C)C=C2C(C)(C)C1
Reaction time: 18 h

Procedure:
In a 1000 ml five neck flask, 24.97 g (204 mmol) of tert-butylcyclopentadiene and 399.04 g of acetone were placed. In an ice water bath, 82.1 g (1.15 mol) of pyrolydine was dropwise added, followed by stirring for 18 hours under reflux. In an ice water bath, 70.91 g (1.18 mol) of acetic acid was dropwise added. From the resulting crude product, the solvent was distilled off under reduced pressure (150 torr, 40° C.), and the resulting product was washed with water, a 5% acetic acid solution, a saturated sodium hydrogen carbonate aqueous solution and a saturated saline solution, followed by drying over magnesium sulfate. After the solvent was distilled off, the remainder was purified by vacuum distillation, whereby 23.4 g of 5-tert-butyl-1,1,3-trimethyl-1,2-dihydropentalene represented by the following formula [1] was obtained. Identification was carried out by a 1H-NMR spectrum and a GC-mass spectrometry spectrum (GC-MS). The results of the measurement are given below.
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][C:7]3([C:11]42[N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]4)[CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[C:20]([CH:22]1[CH2:24][CH2:23]1)#[CH:21].C(N(CC)CC)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:22]1([C:20]#[C:21][C:2]2[CH:19]=[C:18]3[C:5]([CH2:6][C:7]4([C:11]53[N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]5)[CH2:8][CH2:9][CH2:10]4)=[CH:4][CH:3]=2)[CH2:24][CH2:23]1
Reactant: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCC1
Reactant: C#CC1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1=NC2(N=C1N)c1cc(C#CC3CC3)ccc1CC21CCC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a solution of 6′-bromo-5″-methyl-3′H-dispiro[cyclobutane-1,2′-indene-1′,2″-imidazol]-4″-amine (Example 54, 0.10 g, 0.31 mmol) in DMF (10 mL) under argon was added ethynylcyclopropane (0.031 g, 0.47 mmol), tetrakis(triphenylphosphine)palladium(0) (0.036 g, 0.03 mmol) and triethylamine (1.31 mL, 9.43 mmol). The reaction mixture was stirred at r.t. for 5 min before addition of cuprous iodide (8.98 mg, 0.05 mmol). The reaction mixture was stirred overnight at 65° C. The reaction mixture was partitioned between sat aq. NaHCO3 and EtOAc. The organic phase was dried over MgSO4 and concentrated to give a crude product which was purified by preparative chromatography to afford the title compound (0.046 g, 48% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 0.60-0.73 (m, 2H), 0.77-0.89 (m, 2H), 1.46 (tt, 1H), 1.50-1.65 (m, 4H), 1.72-1.85 (m, 1H), 2.08-2.16 (m, 1H), 2.18 (s, 3H), 3.07-3.23 (m, 2H), 6.54 (d, 1H), 6.60 (s, 2H), 7.16 (dd, 1H), 7.20-7.27 (m, 1H); MS (ES+) m/z 304 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1.B.CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([CH2:21][OH:22])[C:9]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CO)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 5 g of 5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid in 130 ml of THF, were added dropwise 40 ml of a 1M solution of borane in THF at room temperature. Then the reaction mixture was heated to reflux for 10 h. The reaction mixture was cooled to room temperature and 20 ml of methanol were carefully added. The solvents were removed under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with 1 M hydrochloric acid, saturated sodium chloride solution and saturated sodium hydrogen carbonate solution. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The product was obtained as a white solid and used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li]C(C)(C)C.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1>C1COCC1>[S:1]1[C:5]([CH:20]([OH:21])[C:19]2[CH:22]=[CH:23][C:16]([Cl:15])=[CH:17][CH:18]=2)=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: O=Cc1ccc(Cl)cc1
Reactant: c1ccc2sccc2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)c1cc2ccccc2s1

Procedure:
α-(2-benzo[b]thienyl)-4-chlorobenzyl alcohol was prepared by the method of Example 40A with benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 m, 9.7 mmoles, 5.7 ml), 4-chlorobenzaldehyde (9.7 mmoles, 1.4 g) and THF (20 ml). The crude material (2.45 g) was taken forward without further purification.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:32](Cl)(=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=3)[C:32](=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCC(=O)Cl
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(C(=O)OC)cc3)cc2)cc1
Product: CCCCCC(=O)N(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)Cc1ccc(C(=O)OC)cc1

Procedure:
The titled compound was prepared following the procedure E using methyl 4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]benzoate and hexanoyl chloride as a colorless oil (69%). 1H NMR (CDCl3, 300 MHz) δ 8.03 (d, 1H), 7.97 (d, 1H), 7.54-7.40 (m, 4H). 7.27-7.09 (m, 6H), 4.62 (m, 2H), 4.46 (m, 2H), 3.92 (m, 3H), 2.62 (t, 2H), 2.40 (m, 2H), 1.77-1.54 (m, 4H), 1.43-1.23 (m, 6H), 0.96-0.83 (m, 6H). M+ (ESI): 510.4. HPLC, Rt: 6.25 min (Purity: 100%).