Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#N)=[CH:6][N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[O:27]1CCCC1>C(Cl)Cl>[NH2:1][C:2]1[C:7]([CH:8]=[O:27])=[CH:6][N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: N#Cc1cnc(Nc2ccccc2)nc1N
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: Nc1nc(Nc2ccccc2)ncc1C=O
Temperature: 0 °C
Yield: 68 %

Procedure:
To a 0° C. solution of 4-amino-2-phenylamino-pyrimidine-5-carbonitrile (7.00 g, 33.18 mmol) (literature prep: J Org. Chem., 1960:5711) in 170 mL of tetrahydrofuran was added 45 mL of a 1 M solution of diisobutylaluminum hydride in methylene chloride. The ice bath was removed, and an additional 40 mL of a 1 M solution of diisobutylaluminum hydride in methylene chloride was added. The reaction mixture was cooled to 0° C., and 60 mL of methanol was added dropwise. This mixture was then added to a rapidly stirring mixture of 300 mL of ethyl acetate and 250 mL of 1 N HCl. The layers were separated, and the organic layer was extracted with additional 1 N HCl. The acid layers were combined, treated with 330 mL of 1 N NaOH, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated. Purification by flash chromatography eluting with ethyl acetate gave 4.99 g (68%) of 4-amino-2-phenylamino-pyrimidine-5-carboxaldehyde.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)[CH:3]=1.[CH2:18]([NH2:23])[CH:19]([NH2:22])[CH2:20][CH3:21].C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[NH2:22][CH:19]([CH2:20][CH3:21])[CH2:18][NH:23][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)[CH:3]=1
Reactant: Cc1cccc(Nc2cc(Cl)ncc2C#N)n1
Reactant: CCC(N)CN
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(N)CNc1cc(Nc2cccc(C)n2)c(C#N)cn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of 6-chloro-4-[(6-methylpyridin-2-yl)amino]pyridine-3-carbonitrile (PrepEx 1.3) (38 mg, 0.16 mmol) in NMP (1 mL) was added butane-1,2-diamine (107 mg, 1.21 mmol) and N,N-diisopropylethylamine (0.163 mL, 0.932 mmol). The reaction mixture was heated to 100° C. After 16 hours, the reaction mixture was allowed to cool to room temperature, filtered, and purified directly via reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to afford 6-[(2-aminobutyl)amino]-4-[(6-methylpyridin-2-yl)amino]pyridine-3-carbonitrile. MS ESI calc'd. for C16H21N6 [M+H]+ 297. found 297.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:21]([O:28][C:29](=[O:33])[CH2:30][CH2:31][NH2:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C>CN(C)C=O>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([NH:32][CH2:31][CH2:30][C:29]([O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:33])=[O:9])=[CH:3]1
Reactant: Cn1ccc(C(=O)O)c1
Reactant: NCCC(=O)OCc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1ccc(C(=O)NCCC(=O)OCc2ccccc2)c1

Procedure:
Into a solution of 5.01 g (40 mmol) of 1-methyl-3-pyrrolecarboxylic acid and 16.87 g (48 mmol) of β-alanine benzyl ester p-toluenesulfonate in 200 ml of dimethylformamide (hereinafter called “DMF”), a solution of 7.83 g (48 mmol) of diethyl phosphorocyanidate in 50 ml of DMF was added dropwise under ice cooling and stirring. A solution of 9.71 g (96 mmol) of triethylamine in 50 ml of DMF was then added dropwise, and the reaction mixture was stirred at room temperature for 67 hours.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([NH:12][C@@H:13]([C:24]([NH:26][C@H:27]([C:43]([NH:45][C@H:46]([C:50]([NH:52][C@H:53]([C:64]([NH:66][C@H:67]([CH2:71][OH:72])[C@@H:68]([CH3:70])[OH:69])=[O:65])[CH2:54][S:55][CH2:56][C:57]1[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=1)=[O:51])[C@@H:47]([CH3:49])[OH:48])=[O:44])[CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])=[O:25])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:80]>C(O)(C(F)(F)F)=O.O.C(OCC)C>[NH2:1][C@H:2]([C:10]([NH:12][C@@H:13]([C:24]([NH:26][C@H:27]([C:43]([NH:45][C@H:46]([C:50]([NH:52][C@H:53]([C:64]([NH:66][C@H:67]([CH2:71][OH:72])[C@@H:68]([CH3:70])[OH:69])=[O:65])[CH2:54][S:55][CH2:56][C:57]1[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=1)=[O:51])[C@@H:47]([CH3:49])[OH:48])=[O:44])[CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34])=[O:25])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[ClH:80]
Reactant: Cc1ccc(CSC[C@H](NC(=O)[C@@H](NC(=O)[C@H](CCCCNC(=O)OCc2ccccc2)NC(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)[C@@H](C)O)C(=O)N[C@H](CO)[C@@H](C)O)cc1
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Cc1ccc(CSC[C@H](NC(=O)[C@@H](NC(=O)[C@H](CCCCNC(=O)OCc2ccccc2)NC(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)[C@@H](N)Cc2ccccc2)[C@@H](C)O)C(=O)N[C@H](CO)[C@@H](C)O)cc1
Reaction time: 0.5 h

Procedure:
13 g BOC-Phe-(D)Trp-Lys(Z)-Thr-Cys(MBzl)-Thr-ol are dissolved in 60 ml cold TFA/H2O (15:1) and the solution allowed to stand for 30 min. at room temperature. The reaction mixture is stirred into a mixture comprising 3 liters ethyl-ether and 20 ml HCl in ethyl-ether (~5 N) and the precipitated product filtered off, washed with ethyl-ether and dried to yield the title compound:
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][C:25]1[N:29]([C:30]2[S:31][C:32]([CH2:44][CH3:45])=[CH:33][C:34]=2[C:35](=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:28]([CH3:46])=[N:27][N:26]=1.[C:47]1([CH2:53][C:54](Cl)=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:35]([C:34]1[CH:33]=[C:32]([CH2:44][CH3:45])[S:31][C:30]=1[N:29]1[C:28]([CH3:46])=[N:27][N:26]=[C:25]1[CH2:24][NH:23][C:54](=[O:55])[CH2:53][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:43]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)Cc2ccccc2)s1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (4.0 g) was dissolved in dimethylformamide (20 ml). Phenylacetyl chloride (0.9 ml) and triethylamine (3.2 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous citric acid solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethyl acetate to give 1.56 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-2-phenylacetamide.
Reaction SMILES: Br[C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:10].[Cu][C:12]#[N:13].CN1C(=O)CCC1.N>O>[NH2:6][C:5]1[CH:7]=[C:8]([F:9])[C:2]([C:12]#[N:13])=[C:3]([Cl:10])[CH:4]=1
Reactant: N#C[Cu]
Reactant: Nc1cc(F)c(Br)c(Cl)c1
Agent: N
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1c(F)cc(N)cc1Cl
Temperature: 160 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
4-Bromo-3-Chloro-5-fluoroaniline (980 mmol, 220 g), copper(I)cyanide (980 mmol, 88 g) and NMP (1000 ml) were added into the reaction flask, heated up to 160° C. and stirred for 3 h to complete the reaction. The reaction mixture was cooled to RT. Water and 25% ammonia solution was added keeping the mixture at RT. The mixture was stirred overnight and the formed precipitate was separated by filtration and flushed with water. The filtered precipitate was dried under vacuum to give 117.7 g of the title compound. 1H-NMR (400 MHz, DMSO-d6): δ 6.41-6.47 (m, 1H), 6.58-6.62 (m, 1H), 6.86 (bs, 2H).
Reaction SMILES: N1C=CC(C2C=C(C=CC=2)N)=N1.[NH:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[C:20](=[O:28])[C:21](=[O:27])[NH:22]3)=[N:14]1.[CH:29]1[C:34]([NH:35][NH2:36])=[CH:33][CH:32]=[C:31]([S:37]([NH2:40])(=[O:39])=[O:38])[CH:30]=1.Cl>>[NH:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[C:20](=[O:28])[C:21](=[O:27])[NH:22]3)=[N:14]1.[O:27]=[C:21]1[C:20](=[N:36][NH:35][C:34]2[CH:33]=[CH:32][C:31]([S:37]([NH2:40])(=[O:38])=[O:39])=[CH:30][CH:29]=2)[C:19]2[C:23](=[CH:24][CH:25]=[CH:26][C:18]=2[C:15]2[CH:16]=[CH:17][NH:13][N:14]=2)[NH:22]1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: Nc1cccc(-c2cc[nH]n2)c1
Agent: O=C1Nc2cccc(-c3cc[nH]n3)c2C1=O
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3cccc(-c4cc[nH]n4)c32)cc1

Procedure:
4-(1H-Pyrazol-3-yl)-1H-indole-2,3-dione was prepared from 3-(1H-pyrazol-3-yl)aniline according to Procedure A. The title compound was prepared from 4-(1H-pyrazol-3-yl)isatin and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G: 1H NMR (DMSO-d6): δ 6.72 (s, 1H), 7.22 (s, 2H), 7.39 (s, 1H), 7.48–7.60 (m, 4H), 7.76 (d, J=8.7 Hz, 2H), 7.77 (s, 1H), 11.11 (s, 1H), 12.93 (s, 1H); ESI-MS: m/z 381 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1[O:24][CH3:25])[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[OH-].[K+].C(=O)=O.CCOCC.[CH:36]1(CO)[CH2:39][CH2:38][CH2:37]1>>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([O:24][CH2:25][CH:36]3[CH2:39][CH2:38][CH2:37]3)=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22]
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Reactant: OCC1CCC1
Agent: O=C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: COC12C(CO)C3=C(C(=O)C(C)=C(OCC4CCC4)C3=O)N1CC1NC12
Product: NC(=O)O
Yield: 29 %

Procedure:
A solution of mitomycin A (64 mg) in 4 ml of cyclobutane methanol was stirred at room temperature and under nitrogen for 45 minutes with 500 mg of a 1.6% solution of KOH in cyclobutane methanol. The reaction mixture was decomposed with excess dry ice while immersing the flask into a water bath at room temperature. It was then isolated on a silica gel plate using ether, which elutes the cyclobutane methanol to the top of the plate (the plate was developed several times). This procedure gives 21.5 mg (29%) of the title compound, having a melting point of 83°-88° C. (decomposition) and providing the following analysis:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[C:24]([Cl:25])=[C:23]([CH3:26])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>ClCCl>[Cl:15][C:16]1[C:24]([Cl:25])=[C:23]([CH3:26])[CH:22]=[CH:21][C:17]=1[C:18]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:19]
Reactant: Cc1ccc(C(=O)Cl)c(Cl)c1Cl
Reactant: O=C1CNCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)N2CCNC(=O)C2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-piperazinone (1 g, 9.99 mmol, commercially available from e.g. Sigma-Aldrich) and triethylamine (2.78 mL, 19.98 mmol) were dissolved in Dichloromethane (DCM) (25 mL) at 0° C. 2,3-dichloro-4-methylbenzoyl chloride (I71) (2.232 g, 9.99 mmol) dissolved in Dichloromethane (DCM) (25 mL) was added dropwise and the solution stirred to room temperature overnight. Solvents were removed in vacuo and the residue was partitioned between ethyl acetate (50 mL) and saturated sodium bicarbonate solution (25 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water (2×50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated to a crude solid. A 100 mg sample was purified by MDAP to afford product in 69 mg.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:34][NH:35][O:36][CH3:37].C(N(CC)CC)C>CN(C=O)C.O>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:35]([O:36][CH3:37])[CH3:34])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1cccc(I)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C)C(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.7 %

Procedure:
3-Iodobenzoic acid (3.01 g, 12.1 mmol) was dissolved in DMF (30 mL), and HOBt.H2O (2.45 g, 18.1 mmol), WSC.HCl (3.02 g, 15.8 mmol), N,O-dimethylhydroxylamine hydrochloride (1.30 g, 13.3 mmol), and triethylamine (1.86 mL, 14.6 mmol) were added thereto, and then, the mixture was stirred at room temperature for 4 hours. Water (60 mL) was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine, and then, dried over anhydrous sodium sulfate. Then, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel flash column chromatography (ethyl acetate/n-heptane=100/0 to 50/50) to give 3-iodo-N-methoxy-N-methylbenzamide (3.23 g, yield: 82%).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:16])=[O:12])=O)(C)(C)C.[CH3:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][C:33]=1[N+:40]([O-:42])=[O:41].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[NH2:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:36][C:35]2[CH:38]=[CH:39][C:32]([CH3:31])=[C:33]([N+:40]([O-:42])=[O:41])[CH:34]=2)[CH2:23][CH2:24]1)=[O:16])=[O:12]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCNCC1
Reactant: Cc1ccc(C=O)cc1[N+](=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(CN2CCC(CNC(=O)CNC(=O)c3cc(F)c(F)cc3N)CC2)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.050 mmol), 4-methyl-3-nitrobenzaldehyde (0.25 mmol), methanol (1.2 mL), and acetic acid (0.050 mL) was added NaBH3CN (0.50 mmol) in methanol (1.0 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3, in CH3OH (5 mL) and concentrated. The resulting material was dissolved into ethyl acetate/methanol=2/1 (2 mL), loaded onto Varian™ Si column, eluted off using ethyl acetate/methanol=2/1 (6 mL), and concentrated. The residue was dissolved in methanol (1 mL) and 4 N HCl in dioxane (0.50 mL) was added. The solution was stirred at room temperature overnight and concentrated. The residue was dissolved in methanol, loaded onto Varian™ SCX column, washed with CH3OH (5 mL×2), and eluted off using 2 N NH, in CH3OH (5 mL). Concentration afforded 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(4-methyl-3-nitrobenzyl)piperidine.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[C:6]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)#[N:7]>C1C=CC=CC=1>[C:1]([NH:5][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:8]([C:6]#[N:7])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)N
Solvent: c1ccccc1
Product: CC(C)(C)NC(=O)c1ccc(C#N)cc1
Yield: 92 %

Procedure:
The preparation of Example 1 was repeated with the changes that the starting reactants were tert-butyl amine (4.38 g, 0.060 mole) and 4-cyanobenzoyl chloride (5.08 g, 0.030 mole) and the reaction was carried out in benzene to produce 5.58 g of crystals of the desired product (92% yield), mp 146°-148° C. Proton nuclear magnetic resonance (89.55 MHz) showed absorptions at 7.829 ppm (d, 8.4 Hz, 2H; 3,5-aryl H); 7.690 ppm (d, 8.4 Hz, 2H; 2,6-aryl H); 5.996 ppm (bs, 1H; N-H); 1.477 ppm (s, 9H; tert-butyl H) .
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]([NH2:28])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[CH3:31][NH:28][C:18]1[CH:17]=[CH:16][C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH2:10][CH2:11]2)=[CH:20][C:19]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1Nc1ccccc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CNc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 10.1 %

Procedure:
A suspension of 5-(4-benzoylpiperazin-1-yl)-N1-phenylbenzene-1,2-diamine (0.2 g, 0.54 mmol), paraformaldehyde (0.025 g, 1.01 mmol), and 6 drops of acetic acid in 10 ml 1,2-dichloroethane was stirred at room temperature for 5 hours. Sodium triacetoxyborohydride (0.45 g, 2.2 mmol) was added and stirred overnight before quenching with 10 ml water. The mixture was extracted with ethyl acetate (3×20 ml) and dried over anhydrous sodium sulfate. ((4-(4-(Methylamino)-3-(phenylamino)phenyl)piperazin-1-yl)(phenyl)methanone (0.021 g, 10%) was obtained by flash column chromatograph (50% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) 8 (ppm) 2.86 (s, 3H), 2.97 (s, br, 4H), 3.58 (s, br, 2H), 3.94 (s, br, 3H), 5.18 (s, 1H), 6.88 (m, 6H), 7.25 (m, 2H), 7.47 (m, 6H).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:45][NH2:46].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:46][CH2:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=1)=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCc1ccccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCc1ccccn1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 41.3 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.031 mL, 0.278 mmol), pyridin-2-ylmethanamine (9.03 mg, 0.083 mmol), and BOP (36.9 mg, 0.083 mmol). This was stirred overnight and was then purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(pyridin-2-ylmethyl)acetamide (9.9 mg, 0.019 mmol, 40.5% yield): LCMS=522.0 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.47 (1H, dd, J=5.40, 1.88 Hz), 8.11-8.23 (2 H, m), 7.62-7.77 (5 H, m), 7.48-7.61 (3 H, m), 7.21-7.32 (2 H, m), 5.20 (1 H, s), 4.44-4.62 (2 H, m); Analytical LCMS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 90:10 acetonitrile:water with 0.05% TFA; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.1 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:12][C:11]=1[C:26](O)([C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:27].C(N(CC)CC)C.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:29][C:28]([CH3:31])([CH3:30])[C:26]([C:11]1[CH:12]=[C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1])=[CH2:27]
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(C)(O)C(C)(C)C)c2)cc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: C=C(c1cc(OCc2ccc(OC)cc2)ccc1-c1cc(OC)ccc1F)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a solution of 2-(2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)biphenyl-2-yl)-3,3-dimethylbutan-2-ol (182 mg) and triethylamine (0.12 mL) in toluene (5 mL) was added thionyl chloride (60 μL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (153 mg) as a colorless oil.