Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1[CH:3]=[C:4](C=CC=1F)[C:5](O)=[O:6].CC1([C:18]2[CH:31]=[CH:30][C:21]([O:22][C:23]3[N:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=3)=[CH:20][CH:19]=2)OCCO1>>[NH2:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][C:21]2[CH:20]=[CH:19][CH:18]=[C:31]3[C:30]=2[CH2:3][CH2:4][C:5]3=[O:6])=[N:28][CH:27]=1
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: CC1(c2ccc(Oc3ccc(N)cn3)cc2)OCCO1
Product: Nc1ccc(Oc2cccc3c2CCC3=O)nc1

Procedure:
According to the same manner as that described in Example 1 except for using an equimolar amount of 3,4-difluorobenzoic acid in place of 3,4-dichlorobenzoic acid and using an equimolar amount of 6-[4-(2-methyl-1,3-dioxolane-2-yl)phenoxy]-3-pyridinylamine obtained in Reference Example 35 in place of 4-[(5-amino-2-pyridinyl)oxy]-1-indanone, the reaction was carried out to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:17]([I:18])=[CH:16][NH:15][C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1.Cl.Cl[CH2:21][C:22]1[C:27]([CH3:28])=[C:26]([O:29][CH3:30])[C:25]([CH3:31])=[CH:24][N:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:17]([I:18])=[CH:16][N:15]([CH2:21][C:22]3[C:27]([CH3:28])=[C:26]([O:29][CH3:30])[C:25]([CH3:31])=[CH:24][N:23]=3)[C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:12])[CH3:13])[N:7]=1
Reactant: COc1c(C)cnc(CCl)c1C
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)c2c(I)c[nH]c2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
A mixture of N-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethyl-propionamide (37.8 g, 0.1 mol), 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine hydrochloride (23.1 g, 0.104 mol), finely powdered K2CO3, (41.5 g, 0.3 mol, 3.0 eq.), and anhydrous DMF (200 mL) was stirred at rt overnight. The solvent was evaporated, and the residue taken up in CH2Cl2 (500 mL), washed with brine (200 mL×3), evaporated, and recrystallized from MeOH to give the title product as a white powder (42.0 g, 80% yield; HPLC purity 98%). tR: 6.49 min. 1H-NMR (DMSO-d6) δ 10.16 (br. s, 1H), 8.04 (s, 1H), 7.72 (s, 1H), 5.46 (s, 2H), 3.73 (s, 3H), 2.33 (s, 3H), 2.15 (s, 3H), 1.21 (s, 9H).
Reaction SMILES: F[C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]([S@@:13]([NH2:15])=[O:14])([CH3:12])[CH3:11].[Cl-].[O:17]1[CH2:22][CH2:21][CH:20]([C@H:23]([NH3+:25])[CH3:24])[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[CH3:9][C:10]([S@@:13]([NH2:15])=[O:14])([CH3:12])[CH3:11].[I:8][C:7]1[C:2]([NH:25][C@@H:23]([CH:20]2[CH2:21][CH2:22][O:17][CH2:18][CH2:19]2)[CH3:24])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ncccc1I
Reactant: C[C@@H]([NH3+])C1CCOCC1
Agent: CC(C)(C)[S@@](N)=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Product: C[C@@H](Nc1ncccc1I)C1CCOCC1
Temperature: 125 °C
Reaction time: 48 h
Yield: 34.4 %

Procedure:
To a re-sealable vial containing 2-fluoro-3-iodopyridine (2.14 g, 9.60 mmol), (S)- or (R)-1-(tetrahydro-2H-pyran-4-yl)ethanaminium chloride (1.2175 g, 7.35 mmol) and cesium carbonate (7.54 g, 23.14 mmol) was added DMAc (10 mL). The vial was subsequently scaled and placed in a 125° C. bath. After stirring at 125° C. for 48 h, the reaction mixture was cooled to room temperature and partitioned between EtOAc with water. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with a minimal amount of water (2×), dried over Na2SO4, and concentrated to give a heterogeneous brown oil. The oil was diluted with EtOAc/Hexanes (1:3) and filtered. The solids were washed with EtOAc:Hexanes (1:3) and the filtrate was concentrated to give a brown oil. The resultant oil was purified on a Biotage system (40 g, gradient elution 2% EtOAc: 98% Hexanes to 10% EtOAc: 900 Hexanes, then isocratic 10% EtOAc: 90% Hexanes). The product (S)- or (R)-3-iodo-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)pyridin-2-amine (0.84 g, 2.53 mmol, 34.4% yield) was isolated as a clear colorless oil. LRMS (M+H+) m/z: calcd 333.0. found 333.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[NH:26][C:27]1[S:28][C:29]2[CH:35]=[C:34]([NH2:36])[CH:33]=[CH:32][C:30]=2[N:31]=1>O>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[NH:26][C:27]1[S:28][C:29]2[CH:35]=[C:34]([NH:36][C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:11])[CH:33]=[CH:32][C:30]=2[N:31]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Solvent: O
Product: COc1cccc(NC(=O)Nc2ccc3nc(Nc4ncnc5cc(OC)c(OC)cc45)sc3c2)c1

Procedure:
1-[2-(6,7-Dimethoxyquinazolin-4-ylamino)benzothiazol-6-yl]-3-(3-methoxyphenyl)urea was prepared from 3-methoxyphenyl isocyanate (15 μL, 0.113 mmol) and N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 3. The mixture was poured into water (20 mL) and the resulting precipitate was purified by pTLC (dichloromethane:methanol=9:1) to obtain a yellow solid (26 mg, 53 μmol, 46%). LC/ESI-MS: m/z=503 [M+H]+; m/z=501 [M−H]−; Rt=3.12 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH:17]1(Br)[CH2:21][CH2:20][CH2:19][CH2:18]1.Cl>CN(C=O)C.O>[CH:17]1([O:10][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[OH:1])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: BrC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC2CCCC2)c(O)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
A suspension of 3,4-dihydroxybenzaldehyde (5.0 gm, 0.0362 mol), anhydrous potassium carbonate (6.0 gm, 0.0434 mol) and cyclopentyl bromide (6.5 gm, 0.0434 mol) in dry DMF (50 ml) was heated and stirred at 80° C. for 24 hrs. Reaction mixture was then cooled and diluted with water (500 ml), acidified with 1N HCl and extracted with ethyl acetate (3×100 ml). The ethyl acetate extract was washed 5% sodium bicarbonate and brine and dried over anhydrous sodium sulfate. The dried extract on concentration afforded a residue which was purified by silica gel chromatography using 10% ethyl acetate in petroleum ether as the eluent to provide 5.0 gm of the title product as white solid. mp: 87-89° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C:7]2([C:12]([O:14]C(C)(C)C)=[O:13])[CH2:9][C:8]2([F:11])[F:10])=[CH:4][C:3]=1[NH:21][C:22](=[O:37])[C@H:23]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26].C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C:7]2([C:12]([OH:14])=[O:13])[CH2:9][C:8]2([F:11])[F:10])=[CH:4][C:3]=1[NH:21][C:22](=[O:37])[C@H:23]([C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[C@@H:24]([CH3:29])[C:25]([F:26])([F:27])[F:28]
Reactant: C[C@H]([C@H](C(=O)Nc1cc(CC2(C(=O)OC(C)(C)C)CC2(F)F)ccc1Cl)c1ccc(Cl)cc1)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]([C@H](C(=O)Nc1cc(CC2(C(=O)O)CC2(F)F)ccc1Cl)c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.80 g (3.18 mmol) of tert-butyl 1-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}benzyl)-2,2-difluorocyclopropanecarboxylate (as diastereomer mixture) were dissolved in 5 ml of dichloromethane, and 4.9 ml of TFA were added at RT. The reaction mixture was stirred at RT for 1 h and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase first dichloromethane, then dichloromethane/ethyl acetate 10:1→5:1). This gave 1.25 g of the target compound (77.1% of theory).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[F:8][C:9]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[C:15]2[C:10]=1[C:11](=[O:31])[C:12]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[CH:13][NH:14]2.Br[CH2:33][CH2:34][CH2:35][N:36]1[C:40](=[O:41])[C:39]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:38]2[C:37]1=[O:46]>C(OCC)(=O)C.O>[F:8][C:9]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[C:15]2[C:10]=1[C:11](=[O:31])[C:12]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)=[CH:13][N:14]2[CH2:33][CH2:34][CH2:35][N:36]1[C:40](=[O:41])[C:39]2[C:38](=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:37]1=[O:46]
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)c[nH]c12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCCN3C(=O)c4ccccc4C3=O)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
Sodium hydride (60% oil base, 800 mg, 18.3 mmol) was added to a DMF solution (25 ml) of 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (5.0 g, 15.2 mmol). The mixture was stirred for 30 minutes at room temperature. N-Bromopropyl phthalimide (4.48 g, 16.7 mmol) was added to the mixture and stirred at room temperature for 30 minutes and at 50° C. for 5 hours. The reaction mixture was ice-cooled and water (20 ml) and ethyl acetate were added thereto, followed by stirring for 2 hours. The generated insoluble matter was separated, washed with water, and then dried, giving a pale yellow powder of 2-{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1yl]propyl}isoindole-1,3-dione (4.63 g, yield: 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:10]=[C:9]([CH3:11])[C:8]([CH2:12][CH3:13])=[CH:7][C:4]=1[CH:5]=O.[N+:14]([CH3:17])([O-:16])=[O:15].Cl.CN.[OH-].[Na+]>C(O)C.CO>[CH3:1][O:2][C:3]1[C:4]([CH:5]=[CH:17][N+:14]([O-:16])=[O:15])=[CH:7][C:8]([CH2:12][CH3:13])=[C:9]([CH3:11])[N:10]=1
Reactant: C[N+](=O)[O-]
Reactant: CCc1cc(C=O)c(OC)nc1C
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CCc1cc(C=C[N+](=O)[O-])c(OC)nc1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2-methoxy-5-ethyl-6-methylnicotinaldehyde (2.25 g, 12.6 mmol), nitromethane (1.9 g, 31.1 mmol), monomethylamine hydrochloride (69 mg) and sodium hydroxide (20 mg) in absolute ethanol (1.3 mL) was stirred at ambient temperature for three days. This mixture was diluted with methanol and the precipitated yellow crystalline product was collected by filtration to yield 2.39 g (86%), m.p. 105°-107° C.
Reaction SMILES: [CH:1]([Br:4])(Br)[Br:2].[N:5]1([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:9][CH:8]=[CH:7][CH2:6]1>ClCCl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[CH2:13]([O:12][C:10]([N:5]1[CH2:9][CH:8]2[CH:7]([C:1]2([Br:4])[Br:2])[CH2:6]1)=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: BrC(Br)Br
Reactant: O=C(OCc1ccccc1)N1CC=CC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)N1CC2C(C1)C2(Br)Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of bromoform (0.94 mL, 10.8 mmol) in 5 mL of dichloromethane was added over 1.5 hours to a stirred solution of benzyl 3-pyrroline-1-carboxylate (1.77 mL, 9.8 mmol) and benzyltriethylammonium chloride (0.055 g, 0.025 mmol) in 1:1 dichloromethane-50% aqueous NaOH (60 mL). The black solution was stirred for 18 hours at room temperature and then diluted with dichloromethane and H2O. The layers were separated and the organic phase washed with satd NH4Cl, brine, and dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography (0-20% ethyl acetate-hexane) to afford 6,6-dibromo-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[CH3:12][N:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15]>>[O:11]=[C:6]1[C:7]2[C:3](=[C:2]([O:1][C:14](=[O:15])[N:13]([CH3:12])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1
Reactant: O=C1CCc2c(O)cccc21
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1cccc2c1CCC2=O)c1ccccc1

Procedure:
The title product was prepared from 4-hydroxyindanone and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (77%, light yellow oil). HPLC-MS: m/z=282.1 (M+1); Rt: 3.54 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=[O:19])[CH2:6][C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2].[F:21][C:22]([Si](C)(C)C)([F:24])[F:23].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4](=[O:20])[C:5]([OH:19])([C:22]([F:24])([F:23])[F:21])[CH2:6][C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(=O)C(=O)CC1(c2ccccc2)CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(CC1(c2ccccc2)CCCCC1)C(F)(F)F
Yield: 82.9 %

Procedure:
12.6 g (45.9 mmol) of ethyl-2-oxo-3-(1-phenylcyclohexyl)-propionate (WO9854159) and 19.9 ml (138 mmol) of (trifluoromethyl)-trimethylsilane in 215 ml of THF are cooled to −70° C. and mixed with 8.6 ml of a 1 molar tetrabutylammonium fluoride solution in THF. The reaction mixture is allowed to heat over 18 hours to room temperature and then poured onto saturated sodium chloride solution. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 20%), 13.1 g of ethyl-2-hydroxy-3-(1-phenylcyclohexyl)-2-(trifluoromethyl)-propionate is obtained as a yellow oil. At 0° C., a solution of 3.33 g (87.7 mmol) of lithium aluminum hydride in 173 ml of THF is added in drops to 13.1 g (38.1 mmol) of ester in 174 ml of THF, and it is stirred for 16 hours at room temperature. 20 ml of saturated ammonium chloride solution is carefully added to the batch at 0° C., and it is stirred vigorously for 15 more minutes. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried with sodium sulfate, and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 0%-33%), 6.1 g of 3-(1-phenyl)-cyclohexyl)-2-(trifluoromethyl)-propane-1,2-diol is obtained. 15.7 ml (113 mmol) of triethylamine and, in portions over 10 minutes, 13.8 g (87 mmol) of pyridine SO3 complex are added to 6.1 g (20.2 mmol) of diol in 245 ml of dichloromethane and 79 ml of DMSO. It is stirred over 3 hours, and saturated ammonium chloride solution is added. The mixture is stirred for another 15 minutes, the phases are separated, and it is extracted with dichloromethane. It is washed with water and dried on sodium sulfate. The solvent is removed in a vacuum, and after chromatographic purification on silica gel (hexane/ethyl acetate, 0-33%), the desired product is obtained quantitatively.
Reaction SMILES: ClC1C=CC(C(C2C=CC(Cl)=CC=2)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].[N+]([C:26]1[CH:27]=[C:28]([C:34]#[N:35])[C:29](=[CH:32][CH:33]=1)[C:30]#[N:31])([O-])=O.Cl>C1(C)C=CC=CC=1.CS(C)=O>[C:34](#[N:35])[C:28]1[C:29](=[CH:32][CH:33]=[CH:26][CH:27]=1)[C:30]#[N:31]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1C#N
Temperature: 140 °C
Yield: 407.3 %

Procedure:
To a 250 mL, three-necked flask fitted with a thermometer, a Dean-Stark trap with condenser, and a nitrogen inlet were added bisphenol A6F (15.0 g, 44.6 mmol), 4,4′-dichlorobenzophenone (5.60 g, 22.3 mmol), powdered anhydrous K2CO3 (9.24 g, 67.0 mmol), (PPh3)3CuBr (100 mg), toluene (15 mL), and dimethylsulfoxide (DMSO) (100 mL). Toluene was used to control the refluxing azeotropic removal of water and to control the temperature of the reaction content. The resulting mixture was degassed with nitrogen at ambient temperature and the Dean-Stark trap was filled with toluene. The mixture was refluxed at 135-145° C. under a nitrogen atmosphere for 6-16 hr or until no more water was observed being collected in the Dean-Stark trap. The toluene was then slowly distilled and the mixture was cooled to 50° C. At this time, 4-nitrophthalonitrile (7.90 g, 45.6 mmol) was added in one portion and the reaction mixture was heated at 80° C. for 6-8 hr. The mixture was allowed to cool to ambient temperature and poured into a 5% aqueous HCl solution resulting in the formation of a solid. The material was broken up and collected using a Büchner funnel. The white solid was washed with 200 mL of a 5% aqueous KOH solution, with 200 mL portions of distilled water until neutral, with 200 mL of a 5% aqueous HCl solution, and finally with 200 mL portions of water until neutral. The isolated solid was vacuum dried to yield the 2:1 oligomeric phthalonitrile (23.8 g, 97% yield). IR [cm−1]: ν3075 (C═CH), 2232 (CN), 1650 (C═O), 1587 (C═C), 1477 (aromatic), 1306 (aromatic), 1308 (C—O), 1245 (CH3), 1160 (C—O), 929 (C—O), 845 (aromatic).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:10][CH:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([N+:12]([O-:14])=[O:13])=[C:2]([NH:15][CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]2)[CH:7]=1)[CH3:11]
Reactant: CC(C)Oc1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc([N+](=O)[O-])c(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 80 °C
Reaction time: 17 h
Yield: 97.5 %

Procedure:
A solution of 2-fluoro-4-[(1-methylethyl)oxy]-1-nitrobenzene (D46, 276 mg, 1.39 mmol) in dimethylformamide (10 ml) was treated with 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (278 mg, 1.39 mmol) and diisopropylethylamine (0.241 ml, 1.39 mmol) and stirred at approx. 80° C. for 17 hrs. The mixture was concentrated under vacuum and the residue treated with water and extracted with a mixture of ethyl acetate/diethyl ether (×2). The combined extract was dried and concentrated under vacuum to afford the title compound as a yellow oil/solid (514 mg, 97%).
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[CH3:8][C:9]1([CH3:16])[CH2:14][CH2:13][C:12](=[CH2:15])[CH2:11][CH2:10]1.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+].[OH-].[K+]>C(OCC)C>[CH3:8][C:9]1([CH3:16])[CH2:14][CH2:13][C:12]2([NH:5][C:6](=[O:7])[CH2:15]2)[CH2:11][CH2:10]1
Reactant: C=C1CCC(C)(C)CC1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC1(C)CCC2(CC1)CC(=O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
Chlorosulfonyl isocyanic acid (0.67 mL, 7.7 mmol) was dropped into the dehydrated diethyl ether (11 mL) solution of 1,1-dimethyl-4-methylene-cyclohexane (0.91 g, 7.4 mmol), which had been obtained in 1), in an ice bath. The reaction mixture was stirred at room temperature for 1 hour, and chlorosulfonyl isocyanic acid (0.67 mL, 7.7 mmol) was added in the reaction required in the ice bath and further stirred at room temperature for 1 hour. After chlorosulfonyl isocyanic acid (0.32 mL, 3.7 mmol) had been added in the reaction mixture in the ice bath and further stirred at room temperature for 2 hours, the aqueous solution (4.5 mL) containing sodium thiosulfate pentahydrate (4.56 g, 18.4 mmol) and 10% potassium hydroxide solution was added alternately in the reaction mixture in the ice bath and the pH was adjusted to be about 10, and then the reaction mixture was stirred for 2 hours. The insoluble matter was removed by filtration, and the filtrate was extracted with chloroform. Then the organic layer was washed with water and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and a colorless solid (0.75 g) was obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[Cu][C:14]#[N:15]>CN(C=O)C.CCCCCC.CCOC(C)=O.O>[C:14]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1)#[N:15]
Reactant: N#C[Cu]
Reactant: COC(=O)c1ccc(Br)cc1F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(=O)c1ccc(C#N)cc1F
Temperature: 25 °C
Yield: 75.3 %

Procedure:
Slurry methyl 4-bromo-2-fluoro-benzoate (5 g, 21.5 mmol) and copper(I) cyanide (3.8 g, 42.9 mmol) in anhydrous DMF (90 mL). Heat the mixture to reflux for 20 h under a nitrogen atmosphere. Cool the mixture to room temperature, dilute with hexane/EtOAc (1:1, 300 mL) and water (150 mL). Filter the mixture through Celite® washing with hexane/EtOAc (1:1) to reduce the emulsion layer. Separate the organic layer and extract the aqueous layer with hexane/EtOAc (1:1, 2×200 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1 gradient) to obtain the desired intermediate (2.9 g, 76%). GC-MS m/z: 179 (M).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([O:12][CH:13]([F:15])[F:14])[CH:6]=1)=[O:4].[C:16]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([OH:27])=[O:26])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(N(CC)CC)C>CC#N.CCOC(C)=O>[N:23]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([O:27][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([O:12][CH:13]([F:15])[F:14])[CH:6]=1)=[O:4])=[O:26]
Reactant: O=C(CBr)c1ccc(Br)c(OC(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OCC(=O)c1ccc(Br)c(OC(F)F)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 78 %

Procedure:
2-Bromo-1-(4-bromo-3-(difluoromethoxy)phenyl)ethanone (6.65 mmol) and Boc-proline (1.72 g, 7.98 mmol) were suspended in MeCN (13 mL) and triethylamine (1.00 mL, 7.32 mmol) was added. The reaction mixture was stirred at RT for 14 h, then diluted with EtOAc. The organic solution was washed with water saturated aqueous NaHCO3 and brine, then dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (19% to 40% EtOAc/Hex) to afford (S)-2-(2-(4-bromo-3-(difluoromethoxy)phenyl)-2-oxoethyl) 1-tert-butyl pyrrolidine-1,2-dicarboxylate (2.48 g, 78% over 4 steps).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]#[N:14])[CH:3]=1.[F:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>CCOC(C)=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>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([C:17]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=3[F:15])=[CH:3][C:4]([C:13]#[N:14])=[N:5]2)=[CH:10][CH:9]=1
Reactant: N#Cc1cc(Cl)c2ccc(Cl)cc2n1
Reactant: COc1ccc(B(O)O)c(F)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: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc(C#N)nc3cc(Cl)ccc23)c(F)c1
Temperature: 75 °C
Reaction time: 18 h
Yield: 52.3 %

Procedure:
To a stirred solution of 4,7-dichloroquinoline-2-carbonitrile (6 g, 26.9 mmol), (2-fluoro-4-methoxyphenyl)boronic acid (5.03 g, 29.6 mmol), 2M sodium carbonate (29.6 ml, 59.2 mmol) in 10:1 toluene (48.9 ml) ethanol (4.89 ml) was added tetrakis(triphenylphosphine)palladium(0) (0.777 g, 0.672 mmol). The mixture was stirred at 75° C. under N2 for 18 hours. The reaction was allowed to cool to ambient temperature. The cooled reaction mixture was diluted with EtOAc and then washed with H2O, brine, dried (MgSO4) and concentrated. The residue was mostly dissolved in warm EtOAc (100 ml), added 100 ml of Et2O, allowed to stand at ambient temperature for 1 hour. The solid was collected and washed with cold Et2O (50 ml) to give 7-chloro-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carbonitrile (4.4 g, 14.07 mmol, 52.3% yield) as a yellow solid.