Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH2:22][C:23](=[O:41])[NH:24][C:25]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[C:29]([NH:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[CH:28][C:26]=4[N:27]=3)[CH:16]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:37]([NH:36][C:29]1[C:30]([C:32]([F:33])([F:34])[F:35])=[CH:31][C:25]2[NH:24][C:23](=[O:41])[CH2:22][C:21]([C:17]3[CH:16]=[C:15]([C:12]4[CH:11]=[CH:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:14][CH:13]=4)[CH:20]=[CH:19][CH:18]=3)=[N:27][C:26]=2[CH:28]=1)[CH:38]([CH3:40])[CH3:39]
Reactant: CC(C)CNc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)cc3)c1)=N2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CNc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccc(S(N)(=O)=O)cc3)c1)=N2

Procedure:
) The title compound was prepared from the above described 3′-(8-isobutylamino-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-biphenyl-4-sulfonic acid tert-butylamide (275 mg) and TFA (6 mL) according to the general procedure I step 2. Obtained as a yellow solid (126 mg, 47%). MS (ISN) 529.4 [(M−H)−]; mp 251° C. (dec).
Reaction SMILES: [CH:1]12[N:7]([C:8]3[CH:9]=[CH:10][C:11]([N+:16]([O-])=O)=[C:12]([CH:15]=3)[C:13]#[N:14])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2>[Pd]>[NH2:16][C:11]1[CH:10]=[CH:9][C:8]([N:7]2[CH:1]3[CH2:6][CH2:5][CH:4]2[CH2:3][CH2:2]3)=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: N#Cc1cc(N2C3CCC2CC3)ccc1[N+](=O)[O-]
Agent: [Pd]
Product: N#Cc1cc(N2C3CCC2CC3)ccc1N
Reaction time: 0.25 h
Yield: 94.6 %

Procedure:
A flask charged with 5-(7-azabicyclo[2.2.1]heptan-7-yl)-2-nitrobenzonitrile 22 (205 mg, 0.8427 mmol) and 10% Pd/C (41 mg, 0.39 mmol) was flushed with nitrogen and then evacuated under vacuum. Methanol (4 mL) was added under nitrogen atmosphere and the flask was fitted with a hydrogen balloon. After stirring for 15 min, the Pd/C was removed by filtration and solvent was removed under reduced pressure to provide 2-amino-5-(7-azabicyclo[2.2.1]heptan-7-yl)benzonitrile 23 (170 mg, 95% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.02 (dd, J=2.8, 9.0 Hz, 1H), 6.87 (d, J=2.7 Hz, 1H), 6.68 (d, J=9.0 Hz, 1H), 5.36 (s, 2H), 4.09 (s, 2H), 1.59 (d, J=6.8 Hz, 4H), 1.34 (d, J=6.8 Hz, 4H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1([C:27](Cl)=[O:28])[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2>>[N:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:27]([C:14]2([CH2:13][CH2:12][CH2:11][CH2:10][Br:9])[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:28])=[CH:4][CH:5]=1
Reactant: NCc1ccncc1
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCc1ccncc1)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 4-(aminomethyl)-pyridine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:30])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23]C(C(F)(F)F)=[CH:21][CH:20]=3)=[CH:14][C:13]=2[Cl:29])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].NC1C=CC(C)=C(C(C2C=CC(NC3C=C[C:50]([F:53])=[CH:49]C=3C)=CC=2Cl)=O)C=1>>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:30])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:20]=[CH:21][C:50]([F:53])=[CH:49][C:24]=3[CH3:23])=[CH:14][C:13]=2[Cl:29])=[O:11])[CH:9]=1)=[N+:2]=[N-:3]
Reactant: Cc1cc(F)ccc1Nc1ccc(C(=O)c2cc(N)ccc2C)c(Cl)c1
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Product: Cc1cc(F)ccc1Nc1ccc(C(=O)c2cc(N=[N+]=[N-])ccc2C)c(Cl)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 416, using compound 438 (0.29 mmol). The crude product was used without any further purification.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[CH:12].[CH:13]1([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23](I)[CH:22]=2)(=[O:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>CC#N.C(N(CC)CC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[C:12][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([S:18]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:20])=[O:19])[CH:22]=1
Reactant: O=S(=O)(c1cccc(I)c1)C1CCCC1
Reactant: C#CCCOCCCCCCBr
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccc(C#CCCOCCCCCCBr)c1)C1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-[(6-bromohexyl)oxy]-1-butyne (DE 3513885 A1) (288.9 mg) and 1-(cyclopentylsulfonyl)-3-iodobenzene (500 mg) in MeCN (20 ml) and triethylamine (345 μl) was treated with copper iodide (11.78 mg) and dichlorobis(triphenylphosphine)palladium(II) (43.4 mg) and stirred at room temperature for 3 h. The reaction mixture was partitioned between EtOAc and water, the organic phase was dried (MgSO4) and concentrated in vacuo. The mixture was purified by column chromatography (SPE bond elut, gradient 0 to 40% diethyl ether in cyclohexane) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](Br)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7](C3C=CC=CC=3)[C:6]=2[CH:22]=1.[NH:23]1[CH2:28][CH2:27][S:26][CH2:25][CH2:24]1.C(Cl)Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([N:23]4[CH2:28][CH:27]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:22]=5)[S:26][CH2:25][CH2:24]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[CH:7][C:6]=2[CH:22]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(Br)n1-2
Reactant: C1CSCCN1
Solvent: ClCCl
Solvent: O
Product: Clc1ccc2c(c1)C=NCc1nnc(N3CCSC(c4ccccc4)C3)n1-2
Temperature: 120 °C

Procedure:
A mixture of 2.0 gm (5.35 mmol) of 8-chloro-1-bromo-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine and 2.0 ml of thiomorpholine was heated under nitrogen in an oil bath at 120° C. for 18 hr and then allowed to cool. The reaction mixture was treated with methylene chloride and water. The organic layer was separated, washed with dilute brine and concentrated in vacuo. The residue was recrystallized from methanol to yield 1.40 gm (72.7%) with m.p. 241°-243° C. and 0.46 gm (23.9%) with m.p. 239°-241° C. of the title product. Analysis of the title product for carbon, hydrogen, nitrogen, chlorine and sulphur revealed 60.47% C, 4.58% H, 18.03% N, 9.14% Cl, and 8.09% S. Calculated values for such an analysis for the title product are: 60.67% C, 4.58% H, 17.69% N, 8.98% Cl, and 8.10% S.
Reaction SMILES: Cl.CCOCC.CC1(C)[O:12][CH:11]([CH2:13][N:14]2[C:22]([C:23]3[S:24][CH:25]=[C:26]([CH3:28])[N:27]=3)=[C:21]3[C:16]([N:17]([CH3:32])[C:18](=[O:31])[N:19]([CH3:30])[C:20]3=[O:29])=[CH:15]2)[CH2:10][O:9]1.O>C(#N)C>[OH:12][CH:11]([CH2:10][OH:9])[CH2:13][N:14]1[C:22]([C:23]2[S:24][CH:25]=[C:26]([CH3:28])[N:27]=2)=[C:21]2[C:16]([N:17]([CH3:32])[C:18](=[O:31])[N:19]([CH3:30])[C:20]2=[O:29])=[CH:15]1
Reactant: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2CC2COC(C)(C)O2)n1
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2CC(O)CO)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2M HCl in Et2O (5.36 ml, 10.71 mmol) was added dropwise to a solution of 6-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1,3-dimethyl-5-(4-methylthiazol-2-yl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (470 mg, 1.071 mmol) in acetonitrile (10.7 ml) and water (386 mg, 21.43 mmol). The mixture was stirred at room temperature for 1 hour, then evaporated under vacuum to afford the title compound.
Reaction SMILES: [F:1][C:2]([C:18]1[CH:45]=[CH:44][C:21]([C:22]([NH:24][C:25]2[C:29]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:28][N:27]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:26]=2)=[O:23])=[CH:20][CH:19]=1)([F:17])[C:3]([NH:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])=O.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[F:1][C:2]([F:17])([C:3]1[O:16][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])=[N:6][N:5]=1)[C:18]1[CH:45]=[CH:44][C:21]([C:22]([NH:24][C:25]2[C:29]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[CH:28][N:27]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:26]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: COc1ccccc1C(=O)NNC(=O)C(F)(F)c1ccc(C(=O)Nc2nn(-c3ccccc3)cc2NC(=O)OC(C)(C)C)cc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: COc1ccccc1-c1nnc(C(F)(F)c2ccc(C(=O)Nc3nn(-c4ccccc4)cc3NC(=O)OC(C)(C)C)cc2)o1
Temperature: 100 °C

Procedure:
To a solution of tert-butyl {3-[(4-{1,1-difluoro-2-[2-(2-methoxybenzoyl)hydrazino]-2-oxoethyl}benzoyl)amino]-1-phenyl-1H-pyrazol-4-yl}carbamate (0.05 g, 0.08 mmol) in THF (2 mL) was added Burgess reagent (38 mg, 0.16 mmol) and the reaction was sealed and heated to 100° C. for 10 minutes under microwave irradiation. The reaction was evaporated to dryness and purified by reverse phase chromatography (5/95 acetonitrile/water to 95/5 acetonitrile/water) to give tert-butyl {3-[(4-{difluoro[5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}benzoyl)amino]-1-phenyl-1H-pyrazol-4-yl}carbamate as a white solid. ESIMS calcd 603.2 (M++H), found 603.2 (M++H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@@:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH2:7][C:8]#[CH:9])[C:3]1=[O:18].I[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=2)[CH:23]=[CH:22][N:21]=1.N(CC)CC>C1COCC1.[Cu](I)I.[Cu]I>[CH3:1][N:2]1[CH2:6][CH2:5][C@@:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])([CH2:7][C:8]#[C:9][C:20]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:34])([F:35])[F:36])[CH:27]=3)[CH:23]=[CH:22][N:21]=2)[C:3]1=[O:18]
Reactant: C#CC[C@]1(NC(=O)OC(C)(C)C)CCN(C)C1=O
Reactant: FC(F)(F)Oc1cccc(-c2ccnc(I)c2)c1
Agent: I[Cu]I
Agent: [Cu]I
Solvent: CCNCC
Solvent: C1CCOC1
Product: CN1CC[C@](CC#Cc2cc(-c3cccc(OC(F)(F)F)c3)ccn2)(NC(=O)OC(C)(C)C)C1=O
Temperature: 20 °C
Reaction time: 18 h
Yield: 99.7 %

Procedure:
Copper Iodide (104.92 mg, 0.5500 mmol), followed by PdCl2(Ph3P)2 (193.34 mg, 0.2800 mmol) was added portionwise to a solution of the tert-butyl N-[(3S)-1-methyl-2-oxo-3-prop-2-ynyl-pyrrolidin-3-yl]carbamate (2.78 g, 11.02 mmol) (which may be prepared as described in Description 104), 2-iodo-4-[3-(trifluoromethoxy)-phenyl]pyridine (6.03 g, 16.53 mmol) (which may be prepared as described in Description 105) and Et2NH (5.7 mL, 55.09 mmol) in THF (60 mL) under N2 and the reaction was stirred at 20° C. for 18 hrs. Additional PdCI2(Ph3P)2 (1.25 mol %) and CuI (2.5 mol %) catalyst was added. The reaction was left to stir for 3 days. The solvent was evaporated and the residue was suspended in EtOAc and washed with water/sat. aq. NaHCO3. The organics were collected, dried (Na2SO4) and the solvent evaporated to afford a brown oil. This was purified using a Biotage SP4, with 100 g SNAP cartridge, eluting with 0 to 100% EtOAc in i-hexane. Clean fractions were collected and the solvent evaporated to afford a yellow oil. The remaining fractions were collected and re-columned using a SP4, 100 g SNAP cartridge, 0 to 10% MeOH/EtOAc and the product was collected and combined with the clean material from the first column to afford the tert-butyl N-[(3S)-1-methyl-2-oxo-3-[3-[4-[3-(trifluoromethoxy)phenyl]-2-pyridyl]prop-2-ynyl]pyrrolidin-3-yl]carbamate (D106) (5.38 g, 10.991 mmol, 99.8% yield) as a yellow oil containing some Ph3P residues;
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[F:12][C:13]([F:37])([F:36])[C:14]1[CH:15]=[C:16]([CH:29]=[C:30](C(F)(F)F)[CH:31]=1)[CH2:17][O:18][CH2:19][CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:21][NH2:22].C(N(CC)CC)C>C(Cl)Cl>[F:36][C:13]([F:37])([F:12])[C:14]1[CH:15]=[C:16]([CH:29]=[CH:30][C:31]=1[C:13]([F:37])([F:36])[F:12])[CH2:17][O:18][CH2:19][CH:20]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:21][NH:22][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: NCC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC(COCc1ccc(C(F)(F)F)c(C(F)(F)F)c1)c1ccccc1)c1ccc(F)cc1
Yield: 188.2 %

Procedure:
A solution of 4-fluorobenzoyl chloride (1.2 mL, 10 mmol) in CH2Cl2 (20 mL) was dropped into a solution of the compound produced in Example 17 (3.31 g, 8.0 mmol) and triethylamine (2.8 mL, 20 mmol) in CH2Cl2 (50 mL) during 30 minutes under cooling with ice. After the solvent was evaporated therefrom in vacuo, water was added to the residue and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water and a saturated saline solution and dried over anhydrous sodium sulfate. The residual oily product produced by evaporation of the solvent therefrom in vacuo was crystallized from petroleum ether to give the Compound 57 (3.76 g, 94%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[CH:6]=1.C([Sn](CCCC)(CCCC)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:7][C:5]1[CH:6]=[C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[S:3][CH:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Brc1csc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Brc1csc(-c2ccccn2)c1
Yield: 73.7 %

Procedure:
2,4-Dibromothiophene (695 mg, 2.87 mmol), 2-(tri-n-butylstannyl)pyridine (830 mg, 1.92 mmol), and tetrakis(triphenylphosphine)palladium (0) (220 mg, 0.19 mmol) were refluxed in 3 mL of toluene at 120° C. overnight. After filtrated out of solid residue, the reaction mixture was purified by flash chromatography using a gradient of ethyl acetate in hexane to give a beige solid as the title compound (340 mg), m/z 240, 242 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:6][C:7]=1[CH:8]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)[CH3:2].[CH3:35][NH:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40]>>[CH2:1]([C:3]1[O:4][C:5]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:27][CH:26]=2)=[CH:6][C:7]=1[CH:8]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:36]([CH3:35])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:15])=[CH:12][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)CCNC
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)O)cc1)c1ccccc1
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)c1ccccc1
Yield: 84.6 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-[{2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}(phenyl)methoxy]benzoic acid (117 mg) as well as ethyl 3-(methylamino)propanoate (39 mg) to give the title compound (117 mg, 98%) as an amorphous compound.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH:27]2[CH2:29][CH2:28]2)[C:12](=[O:26])[C:13]2[CH:18]=[CH:17][C:16]([C@@:19]([OH:25])([CH3:24])[C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH2:7][CH2:6]1)#[N:2].[OH-].[K+].C([OH:36])(C)(C)C>O>[NH2:2][C:1](=[O:36])[CH2:3][CH2:4][CH:5]1[CH2:6][CH2:7][CH:8]([N:11]([CH:27]2[CH2:28][CH2:29]2)[C:12](=[O:26])[C:13]2[CH:14]=[CH:15][C:16]([C@@:19]([OH:25])([CH3:24])[C:20]([F:21])([F:22])[F:23])=[CH:17][CH:18]=2)[CH2:9][CH2:10]1
Reactant: C[C@](O)(c1ccc(C(=O)N(C2CCC(CCC#N)CC2)C2CC2)cc1)C(F)(F)F
Reactant: CC(C)(C)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C[C@](O)(c1ccc(C(=O)N(C2CCC(CCC(N)=O)CC2)C2CC2)cc1)C(F)(F)F
Temperature: 85 °C
Reaction time: 15 h

Procedure:
To (S)—N-(4-(2-cyanoethyl)cyclohexyl)-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide prepared above (0.040 g, 0.098 mmol) and KOH (0.55 g, 0.98 mmol) was added tert-butanol (3.75 mL). The mixture was heated to 85° C. and stirred for 15 h. The solution was diluted with water (10 mL) and extracted with 10% MeOH in CH2Cl2 (2×15 mL). The combined organics were dried over Na2SO4 and removed in vacuo. Silica gel chromatography (gradient of 0-10% MeOH in CH2Cl2) afforded (S)—N-(4-(3-amino-3-oxopropyl)cyclohexyl)-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide. 1H NMR (500 MHz, CD3OD): δ 0.45 (bs, 2H), 0.58 (bs, 2H), 1.05-1.15 (m, 2H), 1.27-1.48 (m, 2H), 1.51-1.59 (m, 2H), 1.77 (s, 3H), 1.90-2.00 (m, 5H), 2.25-2.28 (m, 2H), 2.71 (bs, 1H), 4.00 (bs, 1H), 7.52 (d, J=8 Hz, 2H), 7.70 (d, J=8 Hz, 2H).
Reaction SMILES: [CH:1]1[C:11](=[C:12]([C:15]#[N:16])[C:13]#[N:14])[CH:10]=[CH:9][C:3](=[C:4]([C:7]#[N:8])[C:5]#N)[CH:2]=1.[CH2:17]([N:21]([CH2:30][CH2:31][CH2:32][CH3:33])[C:22]1[CH:27]=[CH:26]C=[C:24]([O:28][CH3:29])[CH:23]=1)[CH2:18][CH2:19][CH3:20]>CN(C)C=O>[C:7]([C:4]([C:5]1[CH:26]=[CH:27][C:22]([N:21]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:23][C:24]=1[O:28][CH3:29])=[C:3]1[CH:2]=[CH:1][C:11](=[C:12]([C:15]#[N:16])[C:13]#[N:14])[CH:10]=[CH:9]1)#[N:8]
Reactant: CCCCN(CCCC)c1cccc(OC)c1
Reactant: N#CC(C#N)=c1ccc(=C(C#N)C#N)cc1
Solvent: CN(C)C=O
Product: CCCCN(CCCC)c1ccc(C(C#N)=c2ccc(=C(C#N)C#N)cc2)c(OC)c1
Yield: 25.8 %

Procedure:
In 8 ml of N,N-dimethylformamide, 460 mg (2.25 mmol) of 7,7,8,8-tetracyanoquinodimethane was dissolved. With stirring under ice cooling, 500 mg (2.12 mmol) of dibutyl(3-methoxyphenyl)amine was dissolved in 2 ml of N,N-dimethylformamide and added dropwise. The mixture was stirred for 1.5 hours. After the ice bath was removed, the mixture was further stirred for 3.5 hours. After the reaction mixture was poured into 100 ml of water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography and washed with chloroform to give 226 mg of an off-white crystal having a mp of 215-238° C. (yield: 25.6%).
Reaction SMILES: BrCC1C=CC=C(C([Cl:11])=O)C=1.C(O)(C)C.[N:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:23]>CCOCC>[ClH:11].[N:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:23]
Reactant: O=C(Cl)c1cccc(CBr)c1
Solvent: Cc1cccc(C)n1
Solvent: CCOCC
Solvent: CC(C)O
Product: Cl
Reaction time: 3 h

Procedure:
To a vessel containing 20 g (about 0.093 mol) of crude α-bromo-m-toluoyl chloride and 6 g (0.10 mol) of isopropyl alcohol in 50 ml of ether is added, with cooling, about 10 g (0.093 mol) of 2,6-lutidine. After about 3 hours, 4.3 g of solid 2,6-lutidine hydrochloride is filtered off. After an additional 21 hours, 100 ml of ether is added and the mixture is filtered to give an additional 5.4 g of 2,6 -lutidine hydrochloride. The filtrate is washed with 2 × 100 ml of ice water, two 100 ml portions of cold dilute hydrogen bromide, 100 ml of ice water and two 100 ml portions of ice cold sodium bicarbonate solution and the ether layer is dried over calcium sulfate and concentrated under vacuum to yield 17.6 g oil. To this oil is added 16.0 g (0.079 mol) of tributylphosphine in 100 ml of acetonitrile and is heated at reflux under N2 for about 70 minutes then concentrated under vacuum to a black oil. The oil is triturated twice with 200 ml of ether and chromatographed on 150 g acid Woelm Act. I alumina with benzene. The first liter of eluate provides 15.3 g of solid which is crystallized twice from ethylacetate containing a small portion of acetonitrile to yield 6.4 g of m-isopropoxycarbonylbenzyltributylphosphonium bromide, a white solid having a melting point of 151°-153°.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[O:8][CH2:9][C:10](=O)[NH:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].B.C1COCC1.CO.Cl>C1COCC1>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[O:8][CH2:9][CH2:10][NH:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])c1ccc2c(c1)NCCO2
Temperature: 75 °C
Reaction time: 3.5 h

Procedure:
To a suspension of 6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (1.45 g, 7.47 mmol) in THF (11 mL) was added BH3.THF (1 M solution in THF, 60 mL) at rt and the mixture was stirred at 75° C. After 3.5 h, the mixture was cooled to rt. To the cooled mixture was added MeOH (30 mL) and mixture was stirred at rt. After 30 minutes, the mixture was treated with concentrated HCl (6 mL, 72 mmol) and concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL×4), washed with brine (100 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column using 0 to 100% gradient of EtOAc in hexane as eluent to give 6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine as a reddish-orange solid: Mass Spectrum (ESI) m/e=181.0 (M+1).
Reaction SMILES: [Na].ClC1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7](=[O:46])[N:6]([CH2:47][CH2:48][CH3:49])C(=O)C=1.[CH2:51]([OH:54])[CH2:52][CH3:53]>>[CH2:47]([N:6]1[C:51](=[O:54])[CH:52]=[C:53]([O:54][CH2:51][CH2:52][CH3:53])[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]1=[O:46])[CH2:48][CH3:49]
Reactant: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Reactant: CCCO
Agent: [Na]
Product: CCCOc1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 69 %

Procedure:
To a solution of sodium (0.09 g) in propanol was added 6-chloro-3-propyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.8 g) was added and the mixture was heated under reflux for 14 hours. The reaction mixture was concentrated to dryness. The resulting residue was dissolved in methylene chloride-water. The aqueous layer was acidified with 1N hydrochloric acid and extracted with methylene chloride. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless amorphous powders (0.38 g, 69%).
Reaction SMILES: C[Al](C)C.[CH:5]([NH2:8])([CH3:7])[CH3:6].C[O:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:21]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:22][O:23][C:24]=2[C:25]([F:28])([F:27])[F:26])=[N:14][CH:13]=1.O>O1CCOCC1>[CH:5]([NH:8][C:11](=[O:10])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:21]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:22][O:23][C:24]=2[C:25]([F:28])([F:27])[F:26])=[N:14][CH:13]=1)([CH3:7])[CH3:6]
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Reactant: CC(C)N
Agent: C[Al](C)C
Solvent: O
Solvent: C1COCCO1
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 529 μL, 1.1 mmol) was added dropwise (exothermic) to a solution of isopropylamine (63 mg, 91 μL, 1.1 mmol) in dioxane (7 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (100 mg, 0.26 mmol) in dioxane (4 mL) was added. The resulting mixture was then heated at 85-95° C. for 5 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (102 mg, 95%) which was obtained as a white solid. MS: m/e=406.4 [M+H]+.