Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[Si:9]([O:16][CH2:17][C@@H:18]([N:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][N:36]=[C:35](S(C)(=O)=O)[N:34]=2)=[CH:29][C:28]1=[O:43])[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([F:26])[CH:20]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].O>C(O)(CC)C>[Si:9]([O:16][CH2:17][C@@H:18]([N:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[N:7]=3)[N:34]=2)=[CH:29][C:28]1=[O:43])[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([F:26])[CH:20]=1)([C:12]([CH3:15])([CH3:13])[CH3:14])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1=O
Reactant: Cc1nccc(N)n1
Solvent: CCC(C)O
Solvent: O
Product: Cc1nccc(Nc2nccc(-c3ccn([C@H](CO[Si](C)(C)C(C)(C)C)c4ccc(Cl)c(F)c4)c(=O)c3)n2)n1
Temperature: 110 °C
Yield: 31.6 %

Procedure:
2-Methylpyrimidin-4-amine (0.41 g, 3.7 mmol) and (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (0.10 g, 0.19 mmol) were placed in sec-BuOH (1 mL), heated to 110° C. in a sealed tube for 18 hours, then poured into water, and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by column chromatography (500:5 DCM/MeOH to remove impurity, then 500:15 for product) to give (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((2-methylpyrimidin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.034 g, 32% yield).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:19](=[O:21])[CH3:20].[CH3:22]OC(OC)N(C)C.C1(C)C(C)=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.CCOCC.C(O)C.CO>[C:13]1([CH2:12][O:11][C:6]2[CH:5]=[CH:4][C:3]3[C:19](=[O:21])[CH:20]=[CH:22][O:1][C:2]=3[C:7]=2[CH2:8][CH2:9][CH3:10])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(OC)N(C)C
Reactant: CCCc1c(OCc2ccccc2)ccc(C(C)=O)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CO
Product: CCCc1c(OCc2ccccc2)ccc2c(=O)ccoc12
Reaction time: 2 h
Yield: 87.4 %

Procedure:
A mixture of 3.09 g (10.88 mmol) of 1-[2-hydroxy-4-(phenylmethoxy)-3-propylphenyl]ethanone, 1.55 g (13 mmol) of dimethylformamide dimethyl acetal, and 2.7 mL of xylene was stirred and heated in a 120°-130° C. oil-bath as methanol was distilled out using a 3 in. Vigreux column, over a 2 hr period. The bath temperature was then raised to 150°-160° C. and the reaction mixture was stirred at this temperature for an additional 30 min. The mixture was cooled and concentrated at 60° C./high vacuum. To the viscous, red-brown, oily residue was added 2.48 g (13 mmol) of p-toluenesulfonic acid monohydrate and 25 mL of ethanol. The resulting solution was stirred and refluxed for 1.5 hr, then cooled and diluted with 100 mL of water. Work-up with ether in the usual manner gave a crude product which was purified by flash chromatography on silica gel, eluting with 1:1 hexane-ether. There was obtained 2.8 g (87.5%) of 7-(phenylmethoxy)-8-propyl-4H-1-benzopyran-4-one as a beige solid. An analytical specimen was obtained from another experiment by recrystallization from ethyl acetate-hexane, as a colorless solid, mp 87.5°-89° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([F:25])[C:23]=1[F:24])[CH2:19]Br.C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([F:25])[C:23]=1[F:24])[CH2:19][N:11]1[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Fc1cc(CBr)cc(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(Cc2cc(F)c(F)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.1 %

Procedure:
A mixture of piperidin-4-ylcarbamic acid tert-butyl ester (2.5 g, 12.4 mmol), 3,4,5-trifluorobenzyl bromide (2.5 g, 11.3 mmol) and diisoproylethylamine (2.9 ml, 16.9 mmol) in dichloromethane (25 ml) was stirred at room temperature for 2 h. After this period, trifluoroacetic acid (15.6 ml) was added and the reaction was stirred for a further 2 h. The solvent was evaporated in vacuo and a saturated solution of sodium carbonate was added. The mixture was extracted with dichloromethane and the separated organic layers were dried (Na2SO4), filtered, and the solvent evaporated in vacuo to yield D8 (2.9 g, 96%) as a solid. C12H15F3N2 requires 244. Found 245 (MH+)
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[N:16]2[CH2:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[OH-].[Na+]>>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[C:10]2/[CH:11]([N:16]3[CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:13][CH2:14][CH2:15]/2)=[CH:7][CH:8]=1
Reactant: OC(c1ccc(C(F)(F)F)cc1)C1CCCCC1N1CCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)c1ccc(/C=C2\CCCCC2N2CCC2)cc1
Reaction time: 0.33 h

Procedure:
A 0.4 g (1.3 mmole) portion of 1-[2-[[4-(trifluoromethyl)phenyl](hydroxy)methyl]cyclohexyl]azetidine, from step A above was added during 5 min to 4 ml of ice cooled sulfuric acid. The mixture was stirred in ice for 20 min. The resulting mixture was poured into ice, basified with sodium hydroxide, and extracted with six 30 ml portions of chloroform. The chloroform extracts were combined and dried with magnesium sulfate and evaporated to give 0.173 g of (±)-(E)-1-[2-[[4-(trifluoromethyl)phenyl]methylene]cyclohexyl]azetidine. The crystalline p-toluenesulfonic acid salt of this azetidine derivative was prepared, mp 135°-136° C. UV λmax(ε)219sh(17,350) 222(17,400) 227sh(15,250) 246(11,750)IR,NH Rf 3000b, 2600, 1660 C=C, 1615, 1575, 1495, 1325 SO3 /CF3, 1230, 1215, 1175, 1125, 1065, 1035, 1010, 814 aromatic, 805, 680. NMR (d6DMSO)δ7.75,7.1(2d,4H,aromatic of TSA), 7.6-7.4 (m,4H,aromatic), 4.1-3.8(m,5H,--CH--N(CH2)--CH2 move upfield with addition of NaOH, 2.6-211 (m,4H,CH2 --C=C+C--CH2 -- of azetidine), 2.3 (s,3H,CH3), 1.9-1.45(m,6H,CH2 's).
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[C-:18]#[N:19].[K+]>C(#N)C.C(OCC)(=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.[Cu](I)I>[CH3:12][C:8]1[CH:7]=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([C:18]#[N:19])=[CH:3][CH:4]=2)[N:9]=1
Reactant: Cc1cc(N2CCCC2)c2ccc(I)cc2n1
Reactant: [C-]#N
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCCC2)c2ccc(C#N)cc2n1
Yield: 75.2 %

Procedure:
A suspension of 7-iodo-2-methyl-4-pyrrolidin-1-yl-quinoline (1.50 g, 4.43 mmol), potassium cyanide (578 mg, 8.87 mmol), tetrakis(triphenylphosphine)palladium(0) (256 mg, 0.22 mmol), and copper iodide (85 mg, 0.44 mmol) in acetonitrile (10 mL) was refluxed for 90 min. After cooling the mixture was diluted with ethyl acetate, filtered, and the filtrate was washed with brine, dried (Na2SO4), and evaporated. Chromatography (SiO2, dichloromethane/methanol 19:1) yielded the title compound (791 mg, 75%). Light brown solid, ISP-MS: m/e=238.3 ([M+H]+).
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]([O:7][C:8]([NH:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[C:16]([C:20]([O:22]C)=[O:21])[NH:17]2)=[CH:13][CH:12]=1)=[O:9])([CH3:6])[CH3:5].C1COCC1.CO>O>[CH3:6][C:4]([O:7][C:8]([NH:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[C:16]([C:20]([OH:22])=[O:21])[NH:17]2)=[CH:13][CH:12]=1)=[O:9])([CH3:3])[CH3:5]
Reactant: COC(=O)c1cc2ccc(NC(=O)OC(C)(C)C)cc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc2cc(C(=O)O)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.1 %

Procedure:
Lithium hydroxide (0.095 g, 3.96 mmol) was added to a solution of methyl 6-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-indole-2-carboxylate (0.115 g, 0.396 mmol) in a 3:1:1 mixture of THF:methanol:water (2 ml). The reaction mixture was stirred at RT overnight. The solvent was evaporated. The residue was dissolved in water and acidified with 1N aqueous HCl. The resulting suspension was extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and the solvent was evaporated to give the title compound (0.115 g, >99%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.18 (s, 1H), 9.21 (s, 1H), 7.70 (s, 1H), 7.37 (d, 1H), 6.93 (dd, 1H), 6.74 (s, 1H), 1.46 (s, 9H). MS: m/z 275 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH:9]2OC(C)(C)C(C)(C)O2)[CH:3]=1.[F:18][C:19]([F:38])([F:37])[C:20]1[CH:21]=[C:22]([CH:34]=[CH:35][CH:36]=1)[CH2:23][NH:24][C:25](=[O:33])[C:26]1[CH:31]=C[N:29]=[C:28](Br)[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[F:18][C:19]([F:37])([F:38])[C:20]1[CH:21]=[C:22]([CH:34]=[CH:35][CH:36]=1)[CH2:23][NH:24][C:25](=[O:33])[C:26]1[CH:27]=[CH:28][N:29]=[C:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[NH2:8])[CH:31]=1
Reactant: CC1(C)OC(c2cc(Cl)ccc2N)OC1(C)C
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ccc(Cl)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Temperature: 85 °C
Reaction time: 2 h
Yield: 54.8 %

Procedure:
Into a 50-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-chloro-2-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)benzenamine (300 mg, 1.17 mmol, 1.00 equiv) in ethylene glycol dimethyl ether (15 mL), N-(3-(trifluoromethyl)benzyl)-2-bromoisonicotinamide (432 mg, 1.20 mmol, 1.00 equiv), a solution of sodium carbonate (636 mg, 6.00 mmol, 5.00 equiv) in water (3.0 mL), and Pd(PPh3)4 (138 mg, 0.12 mmol, 0.10 equiv). The resulting solution was stirred for 2 h at 85° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined, and washed with brine. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (10:1-5:1). The product was obtained as 260 mg (55%) of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:21])[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:5]=[CH:6][CH:7]=1.C[O:23][C:24](=[O:47])[C@H:25]([C@@H:44]([CH3:46])O)[NH:26]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([O:21][C@H:44]([CH3:46])[C@@H:25]([C:24]([OH:47])=[O:23])[NH2:26])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]3[C:20]2=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2cccc(Cl)c2)c2ccccc2-c2ccccc21
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Product: C[C@@H](OC1(c2cccc(Cl)c2)c2ccccc2-c2ccccc21)[C@H](N)C(=O)O

Procedure:
from 9-(3-chlorophenyl)-9H-fluoren-9-ol (Example 3e) and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester;
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[CH:6]=[C:5]([CH3:11])[C:4]=1[C:12](C1C=CC=CC=1)(O)[CH:13]([CH3:15])[CH3:14]>Br>[CH3:15][C:13]1([CH3:14])[CH:12]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:4]2[C:5]([CH3:11])=[CH:6][C:7]([CH3:10])=[C:8]([CH3:9])[C:3]=2[O:2]1
Reactant: COc1c(C)c(C)cc(C)c1C(O)(c1ccccc1)C(C)C
Agent: Br
Product: Cc1cc(C)c2c(c1C)OC(C)(C)C2c1ccccc1
Yield: 175.4 %

Procedure:
1-(2-Methoxy-3,4,6-trimethylphenyl)-l-phenyl-2-methylpropanol (3.1 g, 10.4 mmol) was suspended in 48% hydrobromic acid (20 ml). The suspension was heated under reflux for 18 hours. The product was extracted with isopropyl ether, washed with water, dried and then concentrated. The residue was crystallized from ethanol to obtain the desired compound (2.43 g, yield: 87.8%), m.p. 86°-87 C.
Reaction SMILES: [O:1]=[C:2]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=O.[NH:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20]>>[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([C:2]([CH2:3][CH2:4][C:5]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19]([OH:21])=[O:20])=[O:7])=[O:1])=[CH:9]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(O)CCC(=O)c1c[nH]c2ccccc12
Product: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)c1c[nH]c2ccccc12

Procedure:
As for Example 1, 4-oxo-4-(3-indolyl)butyric acid (0.1 mole) is coupled to L-proline to give 1-[3-(3-indolylcarbonyl)propionyl]-L-proline. The preceding compound is reacted with bromine in acetic acid and the brominated derivative is reacted with sodium thioacetate in acetonitrile to give the product of the Example as a glass.
Reaction SMILES: C([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][C@@H:22]([OH:24])[CH3:23])[C:13](=[O:25])[N:12]([CH3:26])[C:11]=2[N:10]=[CH:9]1)C1C=CC=CC=1.C(O)(=O)C.[H][H]>[Pd].CO>[OH:24][C@@H:22]([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][N:14]1[C:15](=[O:17])[C:16]2[NH:8][CH:9]=[N:10][C:11]=2[N:12]([CH3:26])[C:13]1=[O:25]
Reactant: C[C@H](O)CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@H](O)CCCCn1c(=O)c2[nH]cnc2n(C)c1=O
Yield: 62.6 %

Procedure:
(S)-7-benzyl-1(5-(4-nitrobenzoyloxy)hexyl)-3-methylxanthine (25 g, 49.5 mmol) was added to a solution for sodium hydroxide (3.36 g, 84 mmol) in methanol (200 ml). After stirring for 2 hours, the pH was adjusted to 4 by addition of 1 N hydrochloric acid solution. After concentrating under reduced pressure, the residue was partitioned between water (150 ml) and ethyl acetate (300 ml). The organic layer was washed with saturated aqueous sodium chloride solution (150 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 20% hexane-ethyl acetate to provide (S)-7-benzyl-1-(5-hydroxyhexyl)-3-methylxanthine (14 g). c) A mixture of (S)-7-benzyl-1-(5-hydroxyhexyl)-3-methylxanthine (14 g, 39 mmol), acetic acid (100 ml), methanol (50 ml), and 10% palladium on carbon (5 g) was treated with hydrogen gels (40 psi) for 14 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 10% methanol-ethyl acetate to give (S)-1-(5-hydroxyhexyl)-3-methylxanthine (6.5 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[NH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH:20]([N:24]2[CH:28]=[C:27]([C:29]3[C:30]4[CH:37]=[CH:36][N:35](COCC[Si](C)(C)C)[C:31]=4[N:32]=[CH:33][N:34]=3)[CH:26]=[N:25]2)[CH2:21][C:22]#[N:23])[CH2:15][CH2:14]1.C(N(CC)CC)C.C(Cl)Cl.FC(F)(F)C(O)=O.C(N)CN>C(#N)C.CO>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH:20]([N:24]2[CH:28]=[C:27]([C:29]3[C:30]4[CH:37]=[CH:36][NH:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH:26]=[N:25]2)[CH2:21][C:22]#[N:23])[CH2:15][CH2:14]1)=[O:5]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CC4CCNCC4)c3)ncnc21
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CC#N
Product: N#CCC(CC1CCN(C(=O)c2ccc(F)cc2F)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,4-Difluorobenzoyl chloride (110 mg, 0.621 mmol), 4-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (from example 5, step 4; 0.26 g, 0.52 mmol), and triethylamine (216 μL, 0.00155 mol) were dissolved in acetonitrile (2.5 mL). The mixture was stirred at RT for 1 h. Solvents were evaporated. The crude product was treated with DCM (3 mL, 0.05 mol) and trifluoroacetic acid (3 mL, 0.04 mol) for 30 min, and evaporated to dryness under reduced pressure. To the resultant residue was added methanol (5 mL) and ethylenediamine (0.5 mL, 0.007 mol). The reaction mixture was stirred at RT for 30 min, and concentrated under reduced pressure. The residue was purified on RP-HPLC (XBridge C-18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH, at flow rate 60 mL/min) to give the desired product. LCMS calculated for C25H24F2N7O(M+H)+: m/z=476.2; Found: 476.0. 1H NMR (400 MHz, CD3OD): δ 8.96 (1H, d, J=10.0 Hz), 8.87 (1H, s), 8.51 (1H, s), 7.84 (1H, m), 7.38 (1H, m), 7.26 (1H, m), 7.06 (2H, m), 4.96 (1H, m), 4.59 (1H, m), 3.49 (2H, m), 3.15 (2H, m), 2.74 (1H, m), 2.23 (2H, m), 2.03 (1H, m), 1.86 (2H, m), 1.39 (1H, m), 1.28 (1H, m) ppm.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([N:20]([CH3:22])[CH3:21])([C:18]#[N:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:23]S(O)(=O)=O>C(Cl)Cl>[CH:1]([N:14]1[CH2:17][C:16]([N:20]([CH3:22])[CH3:21])([C:18]([NH2:19])=[O:23])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: CN(C)C1(C#N)CN(C(c2ccccc2)c2ccccc2)C1
Solvent: ClCCl
Product: CN(C)C1(C(N)=O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A vigorously stirred solution of 1-benzhydryl-3-dimethylaminoazetidine-3-carbonitrile (I-3A-3a; 1.55 g, 5.32 mmol) in methylene chloride (30 ml) cooled in an ice bath was treated with H2SO4 (3.0 ml, 54 mmol), dropwise. After warming to room temperature and stirring overnight, the reaction was cooled in an ice bath and then carefully quenched with concentrated aqueous NH4OH to pH 11. The mixture was extracted with methylene chloride. The combined organic layers were dried (Na2SO4) and then concentrated. The crude product (4:1 product to starting material) was then purified on a Biotage™ Flash 40M column using 3% methanol in methylene chloride as eluant. The residue (1.04 g) was then triturated from ether to afford I-3A-3b (0.75 g, 45%): +ESI MS (M+1) 310.3; 1H NMR (400 MHz, CD3OD) δ 7.40 (d, J=7.5 Hz, 4H), 7.24 (t, J=7.5 Hz, 4H), 7.17 (t, J=7.3 Hz, 2H), 4.42 (s, 1H), 3.41 (d, J=8.7 Hz, 2H), 3.12 (d, J=8.7 Hz, 2H), 2.26 (s, 6H).
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH2:21])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7].Cl[C:24]([O:26][CH3:27])=[O:25]>>[CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH:21][C:24]([O:26][CH3:27])=[O:25])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1ccccc1-c1ccccc1CN
Reactant: COC(=O)Cl
Product: COC(=O)NCc1ccccc1-c1ccccc1C(=O)NCCC(C)C

Procedure:
From 0.34 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid (3-methylbutyl)amide (precursor 5 c) and methyl chloroformate, according to the general working procedure followed by extraction with EA and purification by flash chromatography 29 mg of 2′-(methoxycarbonylaminomethyl)biphenyl-2-carboxylic acid (3-methylbutyl)amide were obtained as a resin.
Reaction SMILES: CN(C1C=CC=CN=1)C.[OH:10][CH:11]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[C:31](OC(=O)C)(=[O:33])[CH3:32].Cl>N1C=CC=CC=1>[C:31]([O:10][CH:11]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CCC(C(=O)OCC)C(O)c1ccccc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)CCC(C(=O)OCC)C(OC(C)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5 mg of dimethylaminopyridine was added to a mixed solution comprising 500 mg of diethyl 4-hydroxy-4-phenyl-1,3-butanedicarboxylate, 5 ml of pyridine and 1 ml of acetic anhydride, followed by stirring at room temperature overnight. 2N hydrochloric acid was added to the reaction solution, and then the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with 2N hydrochloric acid, a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to obtain 497 mg of the above-identified compound as colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[CH:15][CH:14]=2)[CH:3]=1.B1C2CCCC1CCC2.[OH-:30].[Na+].OO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:30])=[CH:15][CH:14]=2)[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: [OH-]
Reactant: C=Cc1ccc(Oc2cc(Cl)cc(C(F)(F)F)c2)cc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1ccc(Oc2cc(Cl)cc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
To the solution of 1-chloro-3-[(4-ethenylphenyl)oxy]-5-(trifluoromethyl)benzene (2.63 g, 8.81 mmol) in dry THF (25 mL), was added 9-BBN (30 mL, 15.00 mmol) at 0° C. The mixture was stirred at room temperature overnight, and quenched with water (2 mL), followed by aq. NaOH (11 mL, 33.0 mmol), and 30% H2O2 (10 mL). The reaction mixture was heated at 50° C. for 3 h. Then THF was removed under reduced pressure, and the residue was diluted with EA. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, concentrated and purified by flash chromatography to afford the title compound (2.8 g, 8.84 mmol, 100% yield) as a colorless oil. LCMS: rt=3.70 min, [M+H+]=299
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:20])([CH3:19])[CH2:17][NH2:18])=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C>C(#N)C>[Br:8][C:4]1[N:3]=[C:2]([NH:18][CH2:17][C:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)([CH3:20])[CH3:19])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC(C)(CN)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(CNc1cccc(Br)n1)c1ccc(F)cc1
Temperature: 137 °C
Yield: 13.6 %

Procedure:
To a 5 mL microwave reaction vial was added 2,6-dibromopyridine (1.25 g, 5.0 mmol, 1.0 equiv), 2-(4-fluorophenyl)-2-methylpropan-1-amine (1.06 g, 6 mmol, 1.2 equiv), DIPEA (1.9 mL, 11.0 mmol, 2.2 equiv), and acetonitrile (5 mL). The vial was sealed and heated in an oil bath at 137° C. for 48 h, concentrated, and purified by silica gel column chromatography to give 220 mg (14%) of 6-bromo-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridin-2-amine as a white solid (m/z [M+H]=323).