Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[NH:8][CH2:7][CH2:6][CH2:5]2.[CH3:17][C:18]1[N:22]=[CH:21][NH:20][N:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.O.[Cu]I>[CH3:14][O:13][CH:12]([O:15][CH3:16])[C:11]1[N:10]=[C:9]2[C:4]([CH2:5][CH2:6][CH2:7][NH:8]2)=[CH:3][C:2]=1[N:20]1[CH:21]=[N:22][C:18]([CH3:17])=[N:19]1
Reactant: Cc1nc[nH]n1
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(OC)c1nc2c(cc1-n1cnc(C)n1)CCCN2
Temperature: 120 °C

Procedure:
A suspension of 6-bromo-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 12) (300 mg, 1.045 mmol), 3-methyl-1H-1,2,4-triazole (104 mg, 1.254 mmol), Cs2CO3 (720 mg, 2.210 mmol) and CuI (40 mg, 0.210 mmol) in DMF (2 ml) was heated to 120° C. for approximately 6 h. The reaction mixture was diluted with ethyl acetate and water, layers were separated and the aqueous layer was extracted with ethyl acetate (3×). Organic layers were combined, washed with water and brine, dried using Na2SO4, filtered, evaporated. The crude product was purified by silica gel column chromatography eluting with a gradient of MeOH (1-10%) in DCM. Product fractions were combined, evaporated and dried to yield the title compound as an orange resin. (UPLC-MS 3) tR 0.57 min; ESI-MS 290.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.21 (s, 1H), 5.35 (s, 1H), 4.95 (s, 1H), 3.51-3.41 (m, 2H), 3.36 (s, 6H), 2.75 (t, 2H), 2.47 (s, 3H), 1.97-1.86 (m, 2H).
Reaction SMILES: BrC1C=CC=C[C:3]=1[C:8]1([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[O:12][CH:11]([CH3:13])[CH2:10][O:9]1.[OH:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:8]1([CH2:3][O:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[O:12][CH:11]([CH3:13])[CH2:10][O:9]1
Reactant: Oc1cccnc1
Reactant: CC1COC(c2ccc(Cl)cc2Cl)(c2ccccc2Br)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC1COC(COc2cccnc2)(c2ccc(Cl)cc2Cl)O1
Reaction time: 18 h

Procedure:
A mixture of 2-(bromophenyl)-2-(2,4-dichlorophenyl)-4-methyl-1,3-dioxolane (10 g.), 3-hydroxypyridine (3.8 g.) and potassium carbonate (5.5 g.) in N,N-dimethylacetamide (90 ml.) was refluxed with stirring for 18 hours. After the mixture was allowed to cool, it was poured into water and extracted with toluene. The toluene fraction, thereby obtained, was washed with 5% aqueous sodium hydroxide and evaporated to yield 3-[[2-(2,4-dichlorophenyl)-4-methyl-1,3-dioxolan-2-yl]methoxy]pyridine as an oil.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:4][CH2:3]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>C(O)C>[NH2:29][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2cc(C(F)(F)F)ccc21
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N)c2cc(C(F)(F)F)ccc21

Procedure:
1.3 g of tert-butyl 4-oxo-6-(trifluoromethyl)-3,4-dihydroquinoline-1(2H)-carboxylate (Example 159A, 4 mmol, 1 equivalent) were initially charged in 12.6 ml of ethanol, and 4.6 g of ammonium acetate (59.5 mmol, 15 equivalents) and 0.3 g of sodium cyanoborohydride (4.8 mmol, 1.2 equivalents) were added. The reaction mixture was divided and each portion was irradiated in a microwave oven at 130° C. for 1 min. The mixture was then concentrated and the residue was taken up in ethyl acetate and washed with water. The organic phase was dried over sodium sulphate, filtered and concentrated. The crude product obtained was purified on silica gel (mobile phase: dichloromethane/ethyl acetate: 5/1, then dichloromethane/methanol:10/1). This gave 0.84 g (78% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])[CH2:11][NH:12]C(=O)OC(C)(C)C)=[O:8])=[CH:4][C:3]=1[C:31]1[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:12][CH2:11][C@@H:10]([NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[C:3]([C:31]2[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=2)[CH:4]=1)=[O:8])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:29])[F:28]
Reactant: Cn1nccc1-c1cc(C(=O)N[C@H](CNC(=O)OC(C)(C)C)Cc2ccccc2C(F)(F)F)sc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1-c1cc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)sc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,1-dimethylethyl {(2S)-2-({[5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate (194 mg, 0.357 mmol) was dissolved in TFA-DCM (3 mL, 1:2) and stirred at 25° C. After 30 min, the solution was concentrated with a toluene azeotrope and the residue neutralized through a silica plug (2-5% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][C@@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][C@@H:11]([CH3:14])[CH2:12][Cl:13]
Reactant: Oc1ccccc1Cl
Reactant: C[C@@H](CCl)CBr
Product: C[C@@H](CCl)COc1ccccc1Cl

Procedure:
Prepared by Procedure U and Scheme AK using 2-chlorophenol and (2S)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[N:27]1([CH2:33][C:34]2[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=2)[NH2:37])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.[OH-].[Na+]>CN(C=O)C.CO>[N:27]1([CH2:33][C:34]2[CH:35]=[C:36]([NH:37]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:38]=[CH:39][CH:40]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Nc1cccc(CN2CCCCC2)c1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1cccc(CN2CCCCC2)c1)c1ccccc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 3-piperidinomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: CC1CCCCC1=[O:8].Cl[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18]O)=[O:17])[CH:11]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[OH:8][CH:14]([CH3:13])[CH2:15][CH2:10][CH2:11][CH2:12][C:16]([OH:18])=[O:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1CCCCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(O)CCCCC(=O)O
Reaction time: 3 h
Yield: 66.2 %

Procedure:
A solution of 2-methylcyclohexanone (11.1 g, 0.099 mol) in chloroform (15 ml) was added during 20 minutes, under nitrogen, to a stirred suspension of m-chloroperbenzoic acid (24.6 g, 0.143 mol) in chloroform (250 ml). After 3 hours, 40 minutes, the mixture was poured into aqueous sodium bicarbonate and extracted with methylene chloride. The extract was washed with brine, dried (MgSO4) and concentrated. The residue was distilled from a small amount of K2CO3 to give 9.58 g, bp 78°-79° C. (2.5-3 mm Hg) of 6-hydroxyheptanoic acid, ε-lactone.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(F)=NC(F)=NC=1[F:21]>ClCCl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH:12]([C:16]([F:21])=[O:18])[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: ClCCl
Product: CC(C)C(NC(=O)OCc1ccccc1)C(=O)F
Reaction time: 8 h
Yield: 120.1 %

Procedure:
Formula 502 where R6 is Isopropyl and R6′ is H: To a solution of dichloromethane (100 mL) and N-benzyloxycarbonyl D-valine (9 g, 35.8 mmol) was added cyanuric fluoride (2.4 mL, 26.1 mmol). The reaction mixture was stirred overnight and then filtered through Celite. The remaining solution was washed with ice-water and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the substantially pure acid fluoride product of Formula 502, (1-fluorocarbonyl-2-methyl-propyl)-carbamic acid benzyl ester (7.94 g, 87.6%).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([C@H:12]1[N:15](C(CC2C=CC(OC)=CC=2)CC2C=CC(OC)=CC=2)[C:14](=[O:35])[C@@H:13]1[C@H:36]([O:38][C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[CH3:37])[CH3:11])(C(C)(C)C)(C)C.COC1C=CC=C(OC)C=1.B(F)(F)F.CCOCC>ClCCl>[OH:8][CH2:9][C@@H:10]([C@@H:12]1[NH:15][C:14](=[O:35])[C@@H:13]1[C@H:36]([O:38][C:39]([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])[CH3:37])[CH3:11]
Reactant: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)[C@H]([C@@H](C)OC(=O)OCc3ccccc3)[C@H]2[C@@H](C)CO[Si](C)(C)C(C)(C)C)cc1
Agent: COc1cccc(OC)c1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@H](CO)[C@@H]1NC(=O)[C@@H]1[C@@H](C)OC(=O)OCc1ccccc1

Procedure:
To a solution of (3S,4R)-4-(1-(R)-t-butyldimethylsilyloxymethylethyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (20 g) in dry dichloromethane (200 ml), there were added 1,3-dimethoxybenzene (7.8 g) and boron trifluoride etherate (23 g) at 10°-20° C., and the resultant mixture was stirred at room temperature for 3 hours, followed by heating under reflux for 3-5 hours. The reaction mixture was cooled down to 10°-15° C., washed successively with brine (200 ml×2), 2.5% aqueous sodium bicarbonate solution (200 ml) and brine (200 ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo to give an oily residue, which was purified by silica gel chromatography to yield (3S,4S)-4-(1-(R)-hydroxymethylethyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-2-azetidinone.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)/[CH:4]=[C:5](/[CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])\[CH3:6].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>>[CH2:3]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)/[CH:4]=[C:5](/[CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])\[CH3:6]
Reactant: CC(C)=CCC/C(C)=C/COCCCCBr
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Product: CC(C)=CCC/C(C)=C/COCCCCn1ccnc1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
Sodium hydride (1.1 g 60% dispersion in oil, 0.66 g, 27.5 mmol) was weighed out in a 100 mL round bottom flask. The sodium hydride was washed with hexane (3×5 mL) to remove the mineral oils. DMF (anhydrous, 20 mL) was added, followed by geranyloxybutyl bromide (1.51 g, 5.47 mmol). The reaction mixture was stirred at room temperature under N2 for a couple of minutes. Imidazole (1.84 g, 103 mmol, 27.1 equiv) was added slowly in small portions while cooling in an ice bath. The addition of imidazole was exothermic and the reaction mixture bubbled vigorously becoming initially a milky off-white and then clear brown in colour. This was left stirring at room temperature overnight. The reaction mixture was diluted with chloroform (50 mL) and then it was washed with brine (3×50 mL), and dried (Na2SO4). The solvent was removed under reduced pressure followed by high vacuum to give the product as a brown oil (1.37 g, 90%).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:32])[CH:10]([N:14]1[C:18]2[CH:19]=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:17]=2[N:16]=[C:15]1[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[CH:11]1[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(OC(=O)C)(=O)C.[N:44]([O-])=[O:45].[Na+]>>[CH2:1]([N:8]([N:44]=[O:45])[C:9](=[O:32])[CH:10]([N:14]1[C:18]2[CH:19]=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:17]=2[N:16]=[C:15]1[C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)[CH:11]1[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: O=C(NCc1ccccc1)C(C1CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=NN(Cc1ccccc1)C(=O)C(C1CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a ice-cold solution of 13.15 g (29.1 mmol) N-benzyl-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclopropyl-acetamide in 95 ml (1.659 mol) acetic acid and 199.7 ml (3.52 Mol) acetic anhydride were added in portions over 60 min. 10.04 g (145 mmol) sodium nitrite. The reaction mixture was stirred for 1 h at 0° C., then at room temperature overnight. The mixture was evaporated and the residue was taken up in saturated aqueous sodium bicarbonate solution and ethyl acetate and the pH was adjusted to 7 with solid sodium bicarbonate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 50:50) to give the desired compound as a light yellow solid (53%). MS (Turbo Spray): m/z=481.1 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[C:5]([O:28][CH3:29])[C:4]=1B(O)O.[CH2:33]([O:35][C:36](=[O:57])[C@H:37]([CH2:49][C:50]1[CH:55]=[CH:54][C:53](Br)=[CH:52][CH:51]=1)[NH:38][C:39](=[O:48])[C:40]1[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][C:41]=1[Cl:47])[CH3:34].C([O-])([O-])=O.[K+].[K+]>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>[CH2:33]([O:35][C:36](=[O:57])[C@H:37]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][C:7]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:25])[CH3:26])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:6][C:5]=2[O:28][CH3:29])=[CH:52][CH:51]=1)[NH:38][C:39](=[O:48])[C:40]1[C:41]([Cl:47])=[CH:42][CH:43]=[CH:44][C:45]=1[Cl:46])[CH3:34]
Reactant: COc1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc(OC)c1B(O)O
Reactant: CCOC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1c(Cl)cccc1Cl
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: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(OC)cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 80 °C
Yield: 97.9 %

Procedure:
A mixture of 2,6-dimethoxy-4-[(t-butyldiphenylsilyloxy)methyl]benzeneboronic acid (5.2 g), N-(2,6-dichlorobenzoyl)-4-bromo-L-phenylalanine ethyl ester (1.71 g), Pd(PPh3)4 (0.44 g) and K2CO3 (1.59 g) in DME/H2O (20 mL/0.5 mL) was heated at 80° C. for 24 h under N2. The mixture was worked up and purified in a similar procedure as described in Example 8-3) to yield 2.9 g of N-(2,6-dichlorobenzoyl)-4-[2,6-dimethoxy-4-[(t-butyldiphenylsilyloxy)methyl]phenyl]-L-phenylalanine ethyl ester. ESMS: m/z 770 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:26][C:25]1[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=1)[CH2:7][CH2:6][CH2:5]2
Reactant: COc1ccc(CCl)cc1
Reactant: Brc1ccc2c(c1)CCCN2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCCc3cc(Br)ccc32)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 62.2 %

Procedure:
To a stirred solution of 6-bromo-1,2,3,4-tetrahydro-quinoline (3.00 g, 12.1 mmol) in dimethylformamide (25 mL) was added potassium carbonate (3.3 g, 24.1 mmol), sodium iodide (0.905 g, 6.0 mmol) and 4-methoxybenzyl chloride (2.5 mL, 18.1 mmol) and heated at 50° C. After 18 h, reaction mixture was cooled to room temperature and quenched by the addition of water and extracted with ethyl acetate (2×20 mL). The organic layer was washed with water (2×20 mL), brine (20 mL), dried over sodium sulfate, concentrated and purified by the silica gel column chromatography to furnish 6-bromo-1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinoline (2.5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:46]C)=[C:6]([C:8]([CH3:45])([CH3:44])[CH2:9][C@:10]([OH:43])([C:39]([F:42])([F:41])[F:40])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([C:29]([N:31]3[CH2:38][CH2:37][CH2:36][C@@H:32]3[C:33]([NH2:35])=[O:34])=[O:30])[CH:26]=[CH:27][CH:28]=2)[CH:7]=1.C(=O)=O.CC(C)=O.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:46])=[C:6]([C:8]([CH3:44])([CH3:45])[CH2:9][C@:10]([OH:43])([C:39]([F:40])([F:42])[F:41])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([C:29]([N:31]3[CH2:38][CH2:37][CH2:36][C@@H:32]3[C:33]([NH2:35])=[O:34])=[O:30])[CH:26]=[CH:27][CH:28]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)C[C@@](O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N2CCC[C@@H]2C(N)=O)c1)C(F)(F)F
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1cc(NC[C@](O)(CC(C)(C)c2cc(F)ccc2O)C(F)(F)F)c2cnn(-c3cccc(C(=O)N4CCC[C@@H]4C(N)=O)c3)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.5 %

Procedure:
1-{[3-(4-{[(2R)-4-[5-Fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)phenyl]carbonyl}-D-prolinamide (340 mg, 0.5185 mmol) was dissolved in anhydrous dichloromethane (12 mL) and cooled to −78° C. (cardice/acetone bath) under nitrogen. Boron tribromide (1.0M in dichloromethane, 2.57 mL, 2.57 mmol) was then added portionwise and after 5 minutes the stirred mixture was allowed to warm slowly to room temperature under nitrogen. After 4 hours, LCMS suggested little reaction had occurred and the mixture was re-cooled to −78° C. and additional boron tribromide (1.0M in dichloromethane, 2 mL, 2 mmol) was added and the mixture was then stirred at room temperature overnight. LCMS still indicated the reaction was incomplete and the mixture was re-cooled to −78° C. once more and more boron tribromide (1.0M in dichloromethane, 2 mL, 2 mmol) was added and the mixture stirred at room temperature for 3 hours before being re-cooled to −78° C. and quenched by the gradual addition of methanol (5 mL). The reaction was warmed to room temperature when more dichloromethane (30 mL) and aqueous saturated sodium hydrogen carbonate solution (75 mL) were added and the mixture stirred vigorously for 5 minutes. The organic phase was separated by passing through a hydrophobic frit and evaporated in vacuo. This crude product was purified by mass-directed autopreparation. Product containing fractions were combined and partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was washed successively water and brine, dried through a hydrophobic frit and evaporated in vacuo to give the title compound (98 mg).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][N:12]([C@H:22]3[CH2:27][CH2:26][C@H:25]([O:28][Si](C(C)(C)C)(C)C)[CH2:24][CH2:23]3)[C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4]>CO.Cl>[CH2:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][N:12]([C@H:22]3[CH2:23][CH2:24][C@H:25]([OH:28])[CH2:26][CH2:27]3)[C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ncc2c(-c3ccc(F)cc3)cn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2n1
Agent: Cl
Solvent: CO
Product: CCCCNc1ncc2c(-c3ccc(F)cc3)cn([C@H]3CC[C@H](O)CC3)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of crude N-butyl-7-(trans-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-5-(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine in MeOH (2.0 mL) was added a concentrated HCl solution (3 drops, 37% in water). The resulting solution was stirred at room temperature overnight, then concentrated. The residue was purified by pre-HPLC to provide the desired product (UNC1671A) (0.025 g, 36% over 3 steps). 1H NMR (400 MHz, CD3OD) δ 8.73 (s, 1H), 7.80 (s, 1H), 7.69-7.62 (m, 2H), 7.24-7.16 (m, 2H), 4.64-4.52 (m, 1H), 3.79-3.67 (m, 1H), 3.55 (t, J=7.1 Hz, 2H), 2.18-2.11 (m, 2H), 2.11-2.01 (m, 4H), 1.77-1.66 (m, 2H), 1.59-1.44 (m, 4H), 1.03 (t, J=7.4 Hz, 3H); MS m/z 383.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH:18][C:19](=[O:25])[CH2:20][CH2:21][C:22](O)=[O:23])=[O:5].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.O>CN(C)C=O>[Cl:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][N:18]1[C:22](=[O:23])[CH2:21][CH2:20][C:19]1=[O:25])=[O:5]
Reactant: O=C(O)CCC(=O)NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccc2c(NN3C(=O)CCC3=O)ccnc12)c1c(Cl)cccc1Cl
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To a solution of 8-(2,6-dichlorobenzoylamino)-4-[2-(3-carboxypropanoyl)hydrazino]quinoline (138 mg) in dimethylformamide (3 ml) were added 1-hydroxybenzotriazole (45.9 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (65.1 mg) at ambient temperature, and the mixture was stirred at the same temperature overnight. To the mixture was added water, and the resulting precipitates were collected by filtration to give 8-(2,6-dichlorobenzoylamino)-4-(2,5-dioxopyrrolidin-1-ylamino)quinoline (72 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:17][CH2:18][C:19]([OH:21])=O)[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:23]1CCOCC1.ClC(OCC(C)C)=O.N>O1CCCC1.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH2:17][CH2:18][C:19]([NH2:23])=[O:21])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N(CCC(=O)O)CCC1CCCCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(CCC(N)=O)CCC1CCCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
Next, anhydrous tetrahydrofuran (7 ml) was added to 3-[N-(t-butoxycarbonyl)-N-(2-cyclohexylethyl)amino]propionic acid (0.59 g, 2.0 mmol), and the mixture was stirred at −78° C. N-Methylmorpholine (0.22 ml, 2.0 mmol) and a solution of isobutyl chloroformate (0.38 ml, 2.9 mmol) in tetrahydrofuran (3 ml) were added successively to the mixture. After one hour, a 28% aqueous ammonia solution (6.0 ml, 9.8 mmol) was added to the reaction mixture, and the whole was stirred for 1.5 hours. Chloroform (50 ml) was added thereto, the temperature was raised to room temperature, and the whole was washed with a saturated aqueous sodium hydrogencarbonate solution (20 ml) and saturated brine (20 ml) successively. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 3-[N-(t-butoxycarbonyl)-N-(2-cyclohexylethyl)amino]propionamide (0.34 g, 58%) as colorless crystals.