Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]1[C@H:14]([C:15]([F:18])([F:17])[F:16])[CH2:13][N:12]([C:19]2[C:28]([F:29])=[C:27]3[C:22]([C:23](=[O:36])[C:24]([C:33]([OH:35])=[O:34])=[CH:25][N:26]3[CH:30]3[CH2:32][CH2:31]3)=[CH:21][C:20]=2[F:37])[CH2:11]1)=O)(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].C(OCC)C>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[NH2:8][CH2:9][C@H:10]1[C@H:14]([C:15]([F:17])([F:18])[F:16])[CH2:13][N:12]([C:19]2[C:28]([F:29])=[C:27]3[C:22]([C:23](=[O:36])[C:24]([C:33]([OH:35])=[O:34])=[CH:25][N:26]3[CH:30]3[CH2:31][CH2:32]3)=[CH:21][C:20]=2[F:37])[CH2:11]1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C[C@H]1C(F)(F)F
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC[C@@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C[C@H]1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
In 2 ml of dichloromethane, is suspended 330 mg (0.606 mmol) of 7-(trans-3-(tertbutoxycarbonylaminomethyl)-4-trifluoromethyl-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid obtained in Example 10a. To the suspension, is added 2 ml of trifluoroacetic acid on cooling with ice. The mixture is stirred at 0° C. for 1 hour. Diethyl ether was added to the reaction mixture to give a precipitate. The resulting precipitate was obtained by filtration to give 340 mg of the objective substance as a colorless powder (yield 100%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].Cl.Cl.Cl.[CH3:40][N:41]1[CH:46]2[CH2:47][CH2:48][CH:42]1[CH2:43][CH:44]([N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)[CH2:45]2>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH2:11][C@@H:12]([NH:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[NH:27][C:26]2=[O:36])[CH2:21][CH2:20]1)=[O:18])[C:13]([N:52]1[CH2:53][CH2:54][N:49]([CH:44]2[CH2:45][CH:46]3[N:41]([CH3:40])[CH:42]([CH2:48][CH2:47]3)[CH2:43]2)[CH2:50][CH2:51]1)=[O:14])[CH3:2]
Reactant: CN1C2CCC1CC(N1CCNCC1)C2
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Agent: Cl
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CC4CCC(C3)N4C)CC2)cc1CC

Procedure:
Prepared analogously to Example 9i) from 400 mg (0.81 mmol) (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 320 mg (1.00 mmol) 8-methyl-3-piperazin-1-yl-8-aza-bicyclo[3.2.1]octane trihydrochloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.O1CCOCC1>[N:20]1[CH:21]=[CH:22][N:23]=[CH:24][C:19]=1[NH:18][C:13]1[CH:14]=[CH:15][C:10]([C@@H:8]([NH:7][C:6](=[O:17])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:9])=[CH:11][CH:12]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Reactant: Nc1cnccn1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Nc2cnccn2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
The mixture of 100 mg of the t-butyl[(1S)-1-(4-bromophenyl)ethyl]carbamate [106-1], 38 mg of 2-aminopyrazine, 6.8 mg of tris(dibenzylideneacetone)(chloroform)dipalladium (0), 7.7 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 217 mg of cesium carbonate, and 3 mL of 1,4-dioxane, was stirred overnight at 100° C. After cooling the reaction mixture back to room temperature, the insolubles were filtered through celite, the filtrate was concentrated under reduced pressure, and the thus obtained residue was purified by silica gel chromatography, to obtain 50 mg of t-butyl {(1S)-1-[4-(pyrazin-2-ylamino)phenyl]ethyl}carbamate [106-2] as a pale yellow solid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=[C:10](N(C)C)[O:11][N:12]1[C:16]2N=CC=CC=2N=N1.[Cl:25][C:26]1[C:27]2[N:28]([N:42]=[CH:43][CH:44]=2)[C:29]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)=[C:30]([C:32](O)=[O:33])[CH:31]=1.C(N(CC)C(C)C)(C)C.Cl.CNOC>CN(C)C=O.C(OCC)(=O)C>[Cl:25][C:26]1[C:27]2[N:28]([N:42]=[CH:43][CH:44]=2)[C:29]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)=[C:30]([C:32]([N:12]([O:11][CH3:10])[CH3:16])=[O:33])[CH:31]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc(Cl)c2ccnn2c1-c1cccc(F)c1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc(Cl)c2ccnn2c1-c1cccc(F)c1
Reaction time: 2 h
Yield: 86.9 %

Procedure:
The N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.46 g, 1.2 mmol) was added to a solution of 4-chloro-7-(3-fluorophenyl)pyrazolo[1,5-a]pyridine-6-carboxylic acid (0.29 g, 1.0 mmol) in N,N-dimethylformamide (3.0 mL) containing N,N-diisopropylethylamine (0.35 mL, 2.0 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.14 g, 1.5 mmol) at room temperature. The reaction was complete after stirring for 2 hours. This was taken up in ethyl acetate, washed with water, brine, dried over magnesium sulfate and concentrated to give the crude amide. The product was purified on silica gel eluting hexane:ethyl acetate gradient to give 4-chloro-7-(3-fluorophenyl)-N-methoxy-N-methylpyrazolo[1,5-a]pyridine-6-carboxamide (0.29 g, 88%) as a glass. LCMS calculated for C16H14ClFN3O2 (M+H)+: m/z=334.1. found: 333.9.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH2:14][OH:15])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].[C:16](OC(=O)C)(=[O:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.C(OCC)(=O)C>[C:16]([O:15][CH2:14][CH2:13][N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1)(=[O:18])[CH3:17]
Reactant: CCN(CCO)c1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCN(CCOC(C)=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
To a flask containing 2-(ethyl-4-nitroanilino)-1-ethanol (4.2 g) and 4-dimethylaminopyridine (0.12 g) in pyridine (20 mL) at 0° C. under a drying tube is added acetic anhydride (5.0 mL) dropwise. The reaction mixture is allowed to warm to room temperature overnight. The reaction mixture is diluted with ethyl acetate and partioned against saturated aqueous sodium carbonate. The layers are separated and the aqueous phase extracted with two additional portions of ethyl acetate. The combined organic phases are washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue is azeotroped three times with toluene to remove residual pyridine. The residue is adsorbed onto silica and chromatographed on silica eluting with 50% ethyl acetate in heptane. The product-containing fractions are evaporated to give 4.9 g of 2-(ethyl-4-nitroanilino)ethyl acetate as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:15]3[CH:16]=[N:17][C:18]([O:21][CH:22]([F:24])[F:23])=[CH:19][CH:20]=3)[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:15]3[CH:16]=[N:17][C:18]([O:21][CH:22]([F:24])[F:23])=[CH:19][CH:20]=3)[NH:13][C:12](=[S:34])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COCC(c2ccc(OC(F)F)nc2)(c2cccc(Br)c2)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: FC(F)Oc1ccc(C2(c3cccc(Br)c3)COCC(=S)N2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (RS)-5-(3-bromo-phenyl)-5-(6-difluoromethoxy-pyridin-3-yl)-morpholin-3-one (1.6 g, 1.0 eq) and Lawesson's reagent (2.0 g, 1.2 eq) in tetrahydrofuran (60 ml) was stirred at room temperature overnight. For the workup, the solvent was removed at reduce pressure. The crude product was purified by chromatography on silica gel using a gradient of hexane/ethyl acetate as the eluent. The (RS)-5-(3-bromo-phenyl)-5-(6-difluoromethoxy-pyridin-3-yl)-morpholin-3-thione was obtained as a yellow foam (1.0 g, 83% of theory). MS (ISP): m/z=415 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:7]([C:18]([O:20]CC)=[O:19])[C:6]=2[CH:23]=1.[Li+].[OH-].Cl>O1CCOCC1.O>[Br:1][C:2]1[C:3]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:7]([C:18]([OH:20])=[O:19])[C:6]=2[CH:23]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2F)oc2cc(NS(C)(=O)=O)c(Br)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cc2oc(-c3ccc(F)cc3F)c(C(=O)O)c2cc1Br
Temperature: 110 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
To a solution of ethyl 5-bromo-2-(2,4-difluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylate (653 mg, 1.38 mmol) in 1,4-Dioxane (10 mL) and H2O (1 mL) was added LiOH (289 mg, 6.88 mmol), then the mixture was stirred at 110° C. After 3 hours, 10% HCl (aq) was added until pH reach 4. The mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to provide 5-bromo-2-(2,4-difluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylic acid (440 mg, yield: 65%). 1H-NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 7.94 (s, 1H), 7.66˜7.94 (m, 1H), 7.08 (d, J=3.0 Hz, 1H), 6.91 (s, 1H), 3.04 (s, 3H). MS (M+H)+: 446/448.
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:6]2[C:7]([C:11](=[O:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].[H-].[Na+].[CH3:21]I.[Cl-].[NH4+]>CN(C)C=O>[CH2:1]([C:3]1[CH:18]=[C:6]2[C:7]([C:11](=[O:17])[CH:12]([CH3:21])[C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1cc2c(C(=O)CC(=O)OC)cccn2n1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCc1cc2c(C(=O)C(C)C(=O)OC)cccn2n1

Procedure:
The compound of Example 180 (830 mg) was dissolved in N,N-dimethylformamide (50 mL) in a stream of argon gas and 60% sodium hydride (135 mg) was added while the solution was stirred in an ice bath. The resulting mixture was stirred at room temperature for 15 min, followed by chilling in an ice bath and addition of methyl iodide (210 μL). The mixture was then stirred at room temperature for 3 hours. Subsequently, a saturated aqueous solution of ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water (×2) and saturated brine and dried over anhydrous sodium sulfate. Evaporation of the solvent and subsequent purification of the residue by silica gel column chromatography (hexane:ethyl acetate=3:1) afforded the title compound as a pale yellow oil (700 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:22])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1)[CH2:5]O.P(Br)(Br)[Br:24]>COCCOC>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:22])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1)[CH2:5][Br:24]
Reactant: BrP(Br)Br
Reactant: COc1ccc(Oc2c(C)cc(CO)cc2C)cc1C(C)C
Solvent: COCCOC
Product: COc1ccc(Oc2c(C)cc(CBr)cc2C)cc1C(C)C
Temperature: 0 °C
Reaction time: 5 h
Yield: 82.6 %

Procedure:
To a stirred solution of 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)benzyl alcohol (1.0 g, 3.4 mmol) in DME (10 mL) at 0° C. was added phosphorous tribromide (1.8 g, 0.5 mL, 6.8 mmol). The reaction mixture was stirred at 0° C. for 5 h, quenched with methanol (2 mL) and stirred for 30 min. The reaction mixture was poured into ice water and extracted with ether (100 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)benzyl bromide as an oil (1.02 g, 82%): 1H NMR (300 MHz, CDCl3): δ 7.15 (s, 2 H), 6.81 (d, J=3.0 Hz, 1 H), 6.67 (d, J=9.0 Hz, 1 H), 6.34 (dd, J=3.0, 8.7 Hz, 1 H), 4.51 (s, 2 H), 3.80 (s, 3H), 3.40-3.25 (m, 1 H), 2.15 (s, 6 H), 1.20 (d, J=7.2 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (2:4); Rf=0.7.
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:13]=2)[CH:8]=[C:7]([C:21]([O:23][CH2:24]C)=[O:22])[CH:6]=1)(=O)C.[OH-].[Na+].Cl.OS(O)(=O)=O>O.C(O)C.CO.C([O-])(O)=O.[Na+]>[OH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:13]=2)[CH:8]=[C:7]([C:21]([O:23][CH3:24])=[O:22])[CH:6]=1
Reactant: CCOC(=O)c1cc(OC(C)=O)c2cc(N3CCOCC3)ccc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(O)c2cc(N3CCOCC3)ccc2c1
Yield: 51.3 %

Procedure:
A solution of ethyl 4-acetoxy-6-morpholino-2-naphthoate (12.0 g, 34.9 mmol) and sodium hydroxide (8.4 g, 210 mmol) in water (200 cm3) and ethanol (40 cm3) was maintained at 80-90° C. for 3 hours. The cooled solution was poured into water (750 cm3) and cautiously neutralised with HCl (2M). The resulting suspension was extracted with EtOAc.(5×100 cm3). The combined extracts were dried (Na2SO4) and evaporated to give a brown solid. This solid was dissolved in methanol (200 cm3) containing c. H2SO4 (˜3 cm3) and was refluxed for 5 hours. The cooled mixture was diluted with water (900 cm3) and aq. sat. NaHCO3 solution (100 cm 3) then extracted with EtOAc (6×50 cm3). The combined extracts were washed with aq. sat. NaHCO3 (4×100 cm3) and water (100 cm3). Removal of the dried (Na2SO4) EtOAc gave a pale brown solid which was recrystallised from EtOAc/hexane to afford methyl 4-hydroxy-6-morpholino-2-naphthoate (yield=5.14 g, theoretical yield=10.0 g, 51.2%, m.p.=231-233.5° C. (uncorrected)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[O:10]1[CH2:15][CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH2:12][CH2:11]1.C1(P(C2CCCCC2)C2(OC)CC=CC(OC)=C2C2C=CC=CC=2)CCCCC1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:5]1[C:4]([NH2:9])=[CH:3][C:2]([C:13]2[CH2:14][CH2:15][O:10][CH2:11][CH:12]=2)=[CH:7][N:6]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COC1=C(c2ccccc2)C(OC)(P(C2CCCCC2)C2CCCCC2)CC=C1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(C2=CCOCC2)cnc1Cl
Temperature: 90 °C
Reaction time: 4.5 h

Procedure:
A stirred mixture of 5-bromo-2-chloropyridin-3-amine (0.39 g, 1.9 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.48 g, 2.3 mmol), ground 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl, (S-Phos) (0.15 g, 0.37 mmol), palladium (II) acetate (42.9 mg, 0.19 mmol), and potassium phosphate tribasic (1.20 g, 5.7 mmol) in DMF (9 mL) and water (0.4 mL) was purged 3 times with argon and placed under vacuum 3 times. The reaction mixture was carefully heated to 90° C. After 4.5 h, the reaction was cooled to rt, then diluted with water and extracted 3 times with EtOAc. The organic extractions were combined and washed twice with brine. After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The residue was purified using silica gel chromatography (0-100% EtOAc in hexanes) to afford a light yellow solid as 2-chloro-5-(3,6-dihydro-2H-pyran-4-yl)pyridin-3-amine. 1H NMR (400 MHz, CDCl3) δ ppm 7.87 (1H, d, J=1.8 Hz), 7.05 (1H, m), 6.16 (1H, m), 4.32 (2H, q, J=2.9 Hz), 3.93 (2H, t, J=5.5 Hz), 2.51 (2H, m). 2,5-bis(3,6-dihydro-2H-pyran-4-yl)pyridin-3-amine was also isolated. 1H NMR (400 MHz, CDCl3) δ ppm 8.13 (1H, d, J=2.0 Hz), 7.11 (1H, br. s.), 6.34 (2H, m), 4.46 (4H, m), 4.20 (6H, m), 2.67 (2H, m), 2.55 (2H, m). Mass Spectrum (pos.) m/e: 259.1 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7](F)=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[CH3:14][NH2:15]>CCO>[F:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH:15][CH3:14]
Reactant: CN
Reactant: COc1ccc([N+](=O)[O-])c(F)c1F
Solvent: CCO
Product: CNc1c([N+](=O)[O-])ccc(OC)c1F
Reaction time: 1 h

Procedure:
A solution of 2,3-Difluoro-4-nitroanisole (7-1, 1.0 g, 5.29 mmol) in EtOH (20 ml) was treated with Methylamine (2M in THF, 3.17 ml, 6.35 mmol, 1.2 eq) and the resulting yellow solution was stirred at 23 deg C. for 1 h. The reaction was complete by LC/MS, but allowed to stir at 23 deg C. for an additional 17 h. The residual bright orange-yellow solution was concentrated in vacuo, then partitioned between EtOAc (2×80 ml) and water (90 ml). The combined organic layers were dried over Na2SO4 and concentrated, leaving the title compound, 2-fluoro-3-methoxy-N-methyl-6-nitroaniline (7-2), as an orange solid with >90% purity. 1H NMR (500 MHz, CDCl3) δ 8.01 (d, 1H, J=1.9 Hz), 7.84 (bs, 1H), 6.81-6.83 (m, 1H), 3.95 (s, 3H), 3.24 (m, 3H). LRMS m/z: Calc'd for C8H9FN2O3 (M+H) 201.2, found 200.9.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:14][CH2:15][Cl:16])[P:5]1(=[O:13])[NH:10][CH:9](OC)[CH2:8][CH2:7][O:6]1.[CH:17]1([NH3+:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[SH:24][CH2:25][CH2:26][S:27]([O-:30])(=[O:29])=[O:28].ClC(Cl)(Cl)C(O)=O.CCOCC>CN(C)C=O>[CH:17]1([NH3+:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[Cl:1][CH2:2][CH2:3][N:4]([CH2:14][CH2:15][Cl:16])[P:5]1(=[O:13])[NH:10][CH:9]([S:24][CH2:25][CH2:26][S:27]([O-:30])(=[O:29])=[O:28])[CH2:8][CH2:7][O:6]1
Reactant: COC1CCOP(=O)(N(CCCl)CCCl)N1
Reactant: O=S(=O)([O-])CCS
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [NH3+]C1CCCCC1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=P1(N(CCCl)CCCl)NC(SCCS(=O)(=O)[O-])CCO1
Reaction time: 20 h

Procedure:
2.9 g (10 mmol) of 2-(bis-(2-chloroethyl)-amino)-4-methoxy-tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide and 2.4 g (10 mmol) of cyclohexylammonium-2-mercaptoethanesulphonate were dissolved with some trichloroacetic acid in 10 ml of dimethylformamide and were stored at -25° C. for 20 hours. After leaving the mixture to stand for another three hours at 0° C., it was mixed with ether until clouding commenced, triturated, the crystallised material was filtered with suction after standing for 20 hours at 0° C., and was washed and dried.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:47][C@H:48]4[CH2:53][CH2:52][CH2:51][NH:50][CH2:49]4)=[C:42]([O:45][CH3:46])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1.C(N(C(C)C)CC)(C)C.[CH3:64][O:65][CH2:66][C:67](O)=[O:68]>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:47][C@H:48]4[CH2:53][CH2:52][CH2:51][N:50]([C:67](=[O:68])[CH2:66][O:65][CH3:64])[CH2:49]4)=[C:42]([O:45][CH3:46])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1O[C@H]1CCCNC1
Reactant: COCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)N1CCC[C@H](Oc2cc3ncnc(Nc4cccc(Cl)c4F)c3cc2OC)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 80.9 %

Procedure:
HATU (0.24 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-6-methoxy-7-[(3S)-piperidin-3-yloxy]quinazolin-4-amine dihydrochloride (250 mg), diisopropylethylamine (0.37 ml) and methoxyacetic acid (0.054 g) in methylene chloride (9 ml) and the mixture was stirred at room temperature for 2.5 hours. Methylene chloride (20 ml) was added and the organic layer was washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The resulting product was purified by flash column chromatography eluting with methanol (3%) and methylene chloride (97%) gave a foam. This was re-precipitated by stirring in diethyl ether (20 ml) to give the title product as a white solid (0.202 g); 1H NMR Spectrum: (DMSO d6 373K) 1.60 (m, 1H), 1.88 (m, 2H), 2.10 (m, 1H), 3.32 (s, 3H), 3.51 (m, 2H), 3.62 (m, 1H), 3.87 (m, 1H), 3.98 (s, 3H), 4.02 (d, J=14 Hz, 1H), 4.12 (d, J=14 Hz, 1H), 4.66 (m, 1H), 7.26 (m, 1H), 7.33 (s, 1H), 7.43 (m, 1H), 7.62 (m, 1H), 7.83 (s, 1H), 8.40 (s, 1H), 9.34 (br s, 1H); Mass Spectrum: (M+H)+ 475.
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.CC([O-])(C)C.[K+].C1COCC1.[N:30]1[N:31]=[C:32]([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[C:42](F)[CH:43]=[CH:44][CH:45]=3)[N:40]=2)[N:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=12>CN(C=O)C>[N:30]1[N:31]=[C:32]([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[C:42]([O:8][C@@H:7]4[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)=[O:10])[CH2:3][C@H:2]4[F:1])[CH:43]=[CH:44][CH:45]=3)[N:40]=2)[N:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=12
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](O)[C@H](F)C1
Reactant: Fc1cccc2ccc(-c3nnc4ccccn34)nc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CC[C@@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)[C@H](F)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Non-racemic (trans)-benzyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (0.192 g, 0.757 mmol) was treated with 1.0 M KOtBu in THF (0.757 mL, 0.757 mmol) and stirred at ambient temperature for 15 minutes. 2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-8-fluoroquinoline (0.200 g, 0.757 mmol) was added along with DMF (2.25 mL) and the mixture was stirred at 50° C. for 15 hours. The reaction was cooled and chromatographed on SiO2, eluting with a gradient of 2% NH4OH in isopropanol/methylene chloride. After concentration in vacuo, the desired product was isolated as a beige solid (0.306 g). MS APCI (+) m/z 498.1 (M+1) detected.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:22]([C:23]#[N:24])=[CH:21][N:20]=[C:19]3[S:25][C:26]4[CH2:27][NH:28][CH2:29][CH2:30][C:31]=4[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Cl.[CH3:33][N:34]([CH3:41])[CH2:35]/[CH:36]=[CH:37]/[C:38](O)=[O:39]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:22]([C:23]#[N:24])=[CH:21][N:20]=[C:19]3[S:25][C:26]4[CH2:27][N:28]([C:38](=[O:39])/[CH:37]=[CH:36]/[CH2:35][N:34]([CH3:41])[CH3:33])[CH2:29][CH2:30][C:31]=4[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CN(C)C/C=C/C(=O)O
Reactant: N#Cc1cnc2sc3c(c2c1Nc1ccc(OCc2ccccn2)c(Cl)c1)CCNC3
Agent: Cl
Product: CN(C)C/C=C/C(=O)N1CCc2c(sc3ncc(C#N)c(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1

Procedure:
In analogy to Example 89, the title compound was prepared from 4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c′]dipyridine-3-carbonitrile from Example 57A (100 mg, 0.22 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (52 mg, 0.31 mmol) to yield 71 mg (53%).
Reaction SMILES: C(N[CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:8]([CH3:21])([CH3:20])[CH2:7]1)CCC.[N:22]1[C:29]([Cl:30])=[N:28][C:26]([Cl:27])=[N:25][C:23]=1Cl.C(=O)(O)[O-].[Na+]>>[OH:19][C:16]([CH3:17])([CH3:18])[CH2:15][O:14][N:9]1[C:8]([CH3:20])([CH3:21])[CH2:7][CH:6]([CH2:11][CH2:6][CH2:7][CH2:8][NH:9][C:23]2[N:22]=[C:29]([Cl:30])[N:28]=[C:26]([Cl:27])[N:25]=2)[CH2:11][C:10]1([CH3:12])[CH3:13]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCCCNC1CC(C)(C)N(OCC(C)(C)O)C(C)(C)C1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(O)CON1C(C)(C)CC(CCCCNc2nc(Cl)nc(Cl)n2)CC1(C)C

Procedure:
The compound prepared in Example 23B is reacted with an equimolar amount of cyanuric chloride and sodium bicarbonate at 0° C. to give the title compound.