Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([O:22]C)=[O:21])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])=[O:10].[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([OH:22])=[O:21])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])=[O:10]
Reactant: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 103.4 %

Procedure:
To a stirred solution of methyl 3-chloro-4-[N′-(2-methylphenyl)ureido]phenylacetate (1.23 g, 3.70 mmol) in THF (30 ml) was added 0.25 N NaOH (30 ml). After stirring at room temperature for 14 h, the solvent was concentrated in vacuo. The residue was triturated by the addition of 1 N HCl and dried over 60° C. for 2 days under a reduced pressure to give 3-chloro-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (1.22 g, 100%) as colorless powder. 1H-NMR (DMSO-d6) 8.26 (s, 3H), 3.40 (s, 2H), 6.95 (t, J=7.3 Hz, 1H), 7.11 (d, J=7.6 Hz, 2H), 7.16 (d, J=7.3 Hz, 1H), 7.32 (s, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.94 (dd, J=9.3, 1.0 Hz, 1H), 8.72 (s, 2H); MS (ESI) m/z 319 (M++1), 321 (M++3), 341 (M++Na).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][C:11]=1[N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.S(Cl)([Cl:26])=O>CN(C=O)C.C(Cl)Cl>[Cl:26][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[C:11]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2N2CCCCC2)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ccc(CCl)cc2N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 35.4 %

Procedure:
To a solution of 67.20D (0.2318 g, 0.73 mmol) in dry DMF (0.03 mL) and dry DCM (3 mL) was added thionyl chloride (0.13 mL, 1.8 mmol) at 0° C. The resulting solution was warmed to room temperature and monitored with TLC and LCMS. After 45 minutes, the reaction was diluted with DCM and then washed once with saturated aqueous sodium bicarbonate and once with brine. After drying over anhydrous magnesium sulfate, filtering, and removing the solvent under reduced pressure, the residue was purified by silica gel flash chromatography (0-5% EtOAc/hexane) to afford 67.20E (86.3 mg, 35% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.16 (1H, m), 7.00 (4H, m), 6.72 (1H, dt, J=9.0, 3.5 Hz), 4.50 (2H, s), 3.71 (3H, s), 2.71 (4H, m), 1.34 (6H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:12][C:11](=[O:21])[C@:10]([CH2:23][CH:24]3[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]3)([CH3:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:31]1([CH3:37])[CH:36]=[CH:35][CH:34]=CC=1.C([Li])CCC.BrC1CCC=C1>CCCCC.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH:31]3[CH2:36][CH2:35][CH:34]=[CH:37]3)[C:11](=[O:21])[C@:10]([CH2:23][CH:24]3[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]3)([CH3:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OCC(C[C@@]2(C)C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)cc3)NC2=O)O1
Reactant: Cc1ccccc1
Agent: BrC1C=CCC1
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC1(C)OCC(C[C@@]2(C)C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)cc3)N(C3C=CCC3)C2=O)O1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To (3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methylpiperidin-2-one (Example 102, Step B) (0.909 g, 2.027 mmol) was added toluene (15 mL) and the mixture was concentrated under reduced pressure. This step was repeated three times. Inhibitor free THF (20 mL) was added and the solution was cooled to −78° C. Butyllithium in pentane (2.0M) (1.014 mL, 2.027 mmol) was added dropwise and the reaction mixture remained colorless. The reaction mixture warmed to 0° C. and the reaction color turned very light yellow. nBuLi in pentane (2.0M) was added dropwise until the reaction mixture remained bright yellow. The reaction mixture was cooled to −78° C. and freshly prepared 3-bromocyclopent-1-ene (0.4 g, 2.72 mmol) in THF (2 mL) was added dropwise. The reaction mixture was wrapped in foil and warmed to 0° C. The reaction mixture was stirred at 0° C. for 1 h and then at rt for 2 days. The reaction was quenched with sat. NH4Cl and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0 to 100% EtOAc in hexanes) to give the title compound as a colorless film.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:12])=[N:4][CH:3]=1.C([O-])(=O)C.[K+].N#N.Cl[C:21]1[N:22]=[C:23]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)[C:24]2[S:29][C:28]([CH2:30][N:31]3[CH2:36][CH2:35][N:34]([C:37]([CH3:42])([CH3:41])[C:38]([NH2:40])=[O:39])[CH2:33][CH2:32]3)=[CH:27][C:25]=2[N:26]=1.C(=O)([O-])[O-].[Na+].[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.C(Cl)Cl.C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:21]2[N:22]=[C:23]([N:43]3[CH2:44][CH2:45][O:46][CH2:47][CH2:48]3)[C:24]3[S:29][C:28]([CH2:30][N:31]4[CH2:32][CH2:33][N:34]([C:37]([CH3:42])([CH3:41])[C:38]([NH2:40])=[O:39])[CH2:35][CH2:36]4)=[CH:27][C:25]=3[N:26]=2)=[CH:3][N:4]=1
Reactant: Nc1ncc(Br)c2ccccc12
Reactant: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(-c4cnc(N)c5ccccc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 80 °C
Yield: 16.2 %

Procedure:
A mixture of 4-bromoisoquinolin-1-amine (126 mg, 0.565 mmol), bispinacol ester boronate (358 mg, 1.41 mmol), and potassium acetate (333 mg, 3.39 mmol) in 1,4-dioxane (4.6 mL) was sparged with N2 for 10 min. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (23.1 mg, 0.0282 mmol) was added. The mixture was sealed under N2 and heated at 80° C. for 20 h, diluted with DCM, the contents were filtered, washed with DCM, and concentrated. The crude product was mixed with 2-(4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide (124 mg, 0.282 mmol), a 1 M solution of sodium carbonate (0.85 mL) and 1,4-dioxane (3.4 mL, 44 mmol). The mixture was sparged with N2 for 10 min. Palladium acetate (6.342 mg, 0.02825 mmol) and a 1.0 M solution of tri-tert-butylphosphine in toluene (0.0565 mL) were added. The mixture was sealed under N2 and heated at 85° C. for 6 h, diluted with DCM, the contents were filtered, and concentrated. The residue was purified with flash chromatography. The fractions containing the desired product were collected, concentrated, and purified with reverse-phase HPLC to give 108 (25 mg, 16%). LCMS: M+H+=467. 1H NMR (400 MHz, CDCl3) δ 8.91 (d, J=8.6, 1H), 8.67 (s, 1H), 7.85 (d, J=8.3, 1H), 7.71-7.64 (m, 1H), 7.53 (t, J=7.3, 1H), 7.34 (s, 1H), 7.10 (s, 1H), 5.29 (s, 2H), 5.20 (s, 1H), 4.10-3.99 (m, 4H), 3.87 (dd, J=9.1, 4.6, 6H), 2.61 (s, 8H), 1.24 (s, 6H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][NH:6][C:7]([C:9]1([CH2:22][CH2:23][CH2:24][CH2:25]Br)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:8].[CH3:31][C@H:32]1[NH:37][C@@H:36]([CH3:38])[CH2:35][N:34]([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=2)[CH2:33]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][NH:6][C:7]([C:9]1([CH2:22][CH2:23][CH2:24][CH2:25][N:37]2[C@H:36]([CH3:38])[CH2:35][N:34]([C:39]3[CH:48]=[CH:47][C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[N:40]=3)[CH2:33][C@@H:32]2[CH3:31])[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:8]
Reactant: C[C@@H]1CN(c2ccc3ccccc3n2)C[C@H](C)N1
Reactant: O=C(NCc1ccc(F)c(F)c1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: C[C@@H]1CN(c2ccc3ccccc3n2)C[C@H](C)N1CCCCC1(C(=O)NCc2ccc(F)c(F)c2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-3,4-difluoro-benzylamide and 2-(cis-3,5-dimethyl-piperazin-1-yl)-quinoline.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(O[C:17]1(O[Si](C)(C)C)[CH2:19][CH2:18]1)C.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH:17]1([NH:1][C@@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC2CC2)C1

Procedure:
To a solution of (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (400 mg, 2.15 mmol), (1-ethoxycyclopropoxy)trimethylsilane (1500 mg, 8.60 mmol) in methanol (30 mL) was added sodium cyanoborohydride (569 mg, 8.60 mmol) and acetic acid (0.2 mL). The mixture was stirred at reflux for 10 h. The volatiles were removed under reduced pressure. The residue was treated with water (20 mL) and extracted with ethyl acetate (3×30 mL). The combined extracts were washed with brine (3×10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound. MS (m/z): 227 (M+H)+.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=O)[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([F:20])[C:13]=1[F:21])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.FC(F)(F)C(O)=O.[NH2:30][CH:31]1[CH2:33][CH:32]1[F:34].C(N(CC)CC)C>C(Cl)Cl>[F:34][CH:32]1[CH2:33][CH:31]1[NH:30][CH:4]=[C:5]([CH2:11][C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([F:20])[C:13]=1[F:21])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Reactant: NC1CC1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(=CNC1CC1F)Cc1cc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 5 ml of methylene chloride were dissolved 850 mg of ethyl 3-ethoxy-2-(2,3,4,5-tetrafluorobenzoyl)acrylate and 700 mg of 1-amino-2-fluorocyclopropane trifluoroacetate. After addition of 1 ml of triethylamine, the mixture was stirred at room temperature for 1 hour. The solvent was removed by distillation, and the residue was purified by column chromatography using 40 g of silica gel. From the chloroform eluate 450 mg of ethyl 3-(2-fluorocyclopropyl)amino-2-(2,3,4,5-tetrafluorobenzyl)acrylate was obtained.
Reaction SMILES: [N+]([O-])([O-])=O.[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[OH2:23].[CH2:24]([O:26][C:27]([C:29]1[O:30][C:31]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)=[C:32]2[C:37]=1[CH:36]=[CH:35][CH:34]=[CH:33]2)=[O:28])[CH3:25]>C(O)(=O)C>[CH2:24]([O:26][C:27](=[O:28])[C:29]([C:37]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:31](=[O:30])[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)=[O:23])[CH3:25]
Reactant: O
Reactant: CCOC(=O)c1oc(-c2ccc(Cl)cc2)c2ccccc12
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)c1ccccc1C(=O)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
11.5 G. of cerium (IV) ammonium nitrate are dissolved in 20 ml. of water and 20 ml. of glacial acetic acid. Thereafter, there are added 3.0 g. of 3-(p-chlorophenyl)-isobenzofuran-1-carboxylic acid ethyl ester and the mixture is boiled for 2-3 minutes until the color of the solution obtained changes from orange to light-yellow. After cooling, there are added 150 ml. of ice-water and the mixture is stirred for 1 hour in an ice-bath. The product which first separates as an oil solidifies. The solid is separated by decantation of the aqueous solution and is dissolved in ether. The ethereal solution is washed with 2-N sodium carbonate and water, dried over sodium sulfate and evaporated. After crystallization of the residue from ethanol, there is obtained [o-(p-chlorobenzoyl)-phenyl]glyoxylic acid ethyl ester in the form of colorless crystals having a melting point of 79°-81° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:11]([C:12]2[S:13][CH:14]=[N:15][N:16]=2)[N:10]=[C:9]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[S:8]1)=[N+:2]=[N-:3].[Br:31]N1C(=O)CCC1=O>C(#N)C>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:11]([C:12]2[S:13][C:14]([Br:31])=[N:15][N:16]=2)[N:10]=[C:9]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[S:8]1)=[N+:2]=[N-:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nncs1
Solvent: CC#N
Product: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nnc(Br)s1
Temperature: 60 °C
Yield: 93.4 %

Procedure:
2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-1,3,4-thiadiazole (0.020 g, 0.0451 mmol) was dissolved in 0.25 mL ACN, followed by addition of N-Bromosuccinimide (0.00883 g, 0.0496 mmol), and the reaction mixture was heated at 60° C. for 14 hours. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was then purified by flash column chromatography, eluting with 5.3:1 (hexanes/ethyl acetate), to afford the desired product as a thick golden oil (22 mg, 93%).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:13]=1[C:14](O)=O.N>>[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:13]=1[C:14]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1c(F)cccc1F
Agent: N
Product: Fc1cccc(F)c1-c1nc(-c2cccnc2)no1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2,6-difluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.29 (t, J=8.6 Hz, 2H), 7.65 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 7.77 (tt, J=8.6, 6.1 Hz, 1H), 8.57 (ddd, J=8.3, 1.9, 1.7 Hz, 1H), 8.75 (dd, J=4.7, 1.7 Hz, 1H), 9.30 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCl/NH3) m/z 260 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:48]1[C:53]([CH3:54])=[CH:52][C:51]([CH3:55])=[CH:50][C:49]=1[CH3:56].[CH3:57][NH:58][CH2:59][CH2:60][NH2:61].CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:57][NH:58][CH2:59][CH2:60][NH:61][C:48]1[C:53]([CH3:54])=[CH:52][C:51]([CH3:55])=[CH:50][C:49]=1[CH3:56]
Reactant: Cc1cc(C)c(Br)c(C)c1
Reactant: CNCCN
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CNCCNc1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a 100 mL round-bottom flask tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (110 mg, 0.120 mmol) and (±)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene ((±)-BINAP) (230 mg, 0.37 mmol) were added to 25 mL toluene and stirred for 20 minutes. Next, 2-bromomesitylene (2.45 g, 12.3 mmol), N-methylethylenediamine (1.01 g, 13.6 mmol) and sodium t-butoxide (NaOtBu) (3.56 g, 37 mmol) were added along with 25 mL toluene. This was stirred for 72 hours at 80° C. The flask was then removed from heat, cooled to room temperature and diluted with 20 mL diethyl ether. The solution was then washed with 5×30 mL water and 3×15 mL brine, and dried over magnesium sulfate. After filtering and vacuum removal of solvent, a dark red oil was recovered and used without further purification.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]2[CH:19]=[CH:18][C:17]3[N:16]([CH3:20])[C:15](=[O:21])[CH2:14][CH2:13][C:12]=3[N:11]=2)[CH:7]=[N:6][CH:5]=1.[BH4-].[Na+]>CO>[OH:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[N:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH2:14][CH2:13]3)[CH:7]=[N:6][CH:5]=1
Reactant: COC(=O)c1cncc(-c2ccc3c(n2)CCC(=O)N3C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1C(=O)CCc2nc(-c3cncc(CO)c3)ccc21
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To a stirred solution of 5-(5-methyl-6-oxo-5,6,7,8-tetrahydro-[1,5]naphthyridin-2-yl)-nicotinic acid methyl ester (270 mg, 0.91 mmol) in MeOH (10 mL) was added sodium borohydride (300 mg, 8.0 mmol) at RT. After stirring overnight, the reaction mixture was quenched by adding water (5.0 mL). It was then concentrated in vacuo to give a light yellow oil. After extraction with EtOAc, the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give 6-(5-hydroxymethyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-[1,5]naphthyridin-2-one (190 mg, 77.6%) as a white solid. MS: 270.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:17])[N:8]2[CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)(C(F)(F)F)=O>CO.CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1.C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:17])[N:8]2[CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([C:22]2[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=2)[N:3]=1
Reactant: OB(O)c1ccncc1
Reactant: Nc1nc(Cl)c2[nH]c(=O)n(C3CCOCC3)c2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: CO
Product: Nc1nc(-c2ccncc2)c2[nH]c(=O)n(C3CCOCC3)c2n1
Temperature: 150 °C
Yield: 51.2 %

Procedure:
Anhydrous ethanol (2 mL) and anhydrous 1,4-dioxane (2 mL) were added to an argon-purged vial containing 2-amino-6-chloro-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one (see preparation Route A, 100 mg, 0.37 mmol), pyridine-4-boronic acid (69 mg, 0.56 mmol, 1.5 equiv.), K3PO4 (157 mg, 0.74 mmol, 2.0 equiv.), Pd(OAc)2 (12.5 mg, 0.018 mmol, 0.05 equiv.) and D-tBPF 1,1′-bis(di-tbutylphosphino)ferrocene (8.8 mg, 0.018 mmol, 0.05 equiv.) and the mixture was heated for 2.5 h in the microwave oven at 150° C. After cooling to ambient temperature, the reaction mixture was diluted with methanol (20 mL), filtered through a Nylon 0.45 μm filter and the filtrate concentrated in vacuo. Preparative HPLC purification of the residue afforded, after evaporation and drying, the desired compound as a yellow solid (59.2 mg, 51% yield) TFA salt. 1H NMR (300 MHz, CD3OD) δ, ppm: 8.92 (d, J=6.4 Hz, 2H), 8.17 (dd, J=5.1, 1.5 Hz, 2H), 4.87-4.55 (m, 1H), 4.10 (dd, J=11.4, 4.3 Hz, 2H), 3.56 (ddd, J=11.3, 6.5, 4.7 Hz, 2H), 2.74 (tdd, J=12.6, 12.5, 4.6 Hz, 2H), 1.77 (dd, J=12.4, 2.4 Hz, 2H); MS (EI) m/z 313.3 (MH)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6]O)[CH2:2]1.C(P(CCCC)CCCC)CCC.[Cl:21][C:22]1[N:23]=[C:24]([Cl:31])[C:25]2[CH:30]=[CH:29][NH:28][C:26]=2[N:27]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C(Cl)Cl>[Cl:21][C:22]1[N:23]=[C:24]([Cl:31])[C:25]2[CH:30]=[CH:29][N:28]([CH2:6][CH:3]3[CH2:4][CH2:5][O:1][CH2:2]3)[C:26]=2[N:27]=1
Reactant: OCC1CCOC1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Product: Clc1nc(Cl)c2ccn(CC3CCOC3)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tetrahydrofuran-3-ylmethanol (8 mL) and tributylphosphine (22 mL) were added to a suspension of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (10 g) in CH2Cl2 (150 mL) at room temperature. 1,1′-(azodicarbonyl)dipiperidine (22 g) was added thereto under ice-cooling, and the mixture was stirred at room temperature overnight. After Hex (300 mL) was added to the reaction mixture, the mixture was stirred, and the insoluble material was separated by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex:EtOAc=9:1 to 6:4), whereby 2,4-dichloro-7-(tetrahydrofuran-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (5.9 g) was obtained as a dark brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6]O.C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][Br:14]
Reactant: COc1ccc(CO)cc1OC
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CBr)cc1OC
Temperature: 60 °C
Yield: 58.5 %

Procedure:
To a solution of 3,4-dimethoxybenzyl alcohol (10 g, 59.5 mmol), carbon tetrabromide (22 g, 65.4 mmol), and THF (250 mL) was added triphenylphosphine (17 g, 65.4 mmol) in THF (75 mL). The reaction was heated at 60° C. for 1 h and concentrated to an oil. To the residue was added 1:1 CH2Cl2:Et2O and the resulting solid was filtered. The filtrate was concentrated and chromatographed on florisil with CH2Cl2 to give the title compound (8.05 g, 59%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13](OCC)=[O:14]>C(Cl)(=O)C>[CH3:11][C:8]1[CH:7]=[C:3]2[C:4]([O:6][C:13](=[O:14])[NH:1][C:2]2=[CH:10][CH:9]=1)=[O:5]
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: CCOC(=O)Cl
Solvent: CC(=O)Cl
Product: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Yield: 80 %

Procedure:
15.1 g (100 mmol) of 2-amino-5-methyl-benzoic acid was refluxed with 60 mL of ethyl chloroformate for 6 h, and then was refluxed for another 3 h after addition of 60 mL of acetyl chloride. The solid was collected, washed with hexane to give 14.2 g (80%) of the 5-methylisatoic anhydride.
Reaction SMILES: Cl.[F:2][CH:3]([F:25])[CH2:4][NH:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:22][CH2:21][CH2:20][NH:19][CH2:18][C:17]=3[CH:23]=2)=[CH:9][CH:8]=1.CCN(C(C)C)C(C)C.[F:35][C:36]1[CH:37]=[C:38]([CH:42]2[CH2:47][C:46](=[O:48])[CH2:45][CH2:44][N:43]2[C:49](Cl)=[O:50])[CH:39]=[CH:40][CH:41]=1>O1CCCC1>[F:25][CH:3]([F:2])[CH2:4][NH:5][C:6](=[O:24])[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:22][CH2:21][CH2:20][N:19]([C:49]([N:43]4[CH2:44][CH2:45][C:46](=[O:48])[CH2:47][CH:42]4[C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([F:35])[CH:37]=4)=[O:50])[CH2:18][C:17]=3[CH:23]=2)=[CH:11][CH:12]=1
Reactant: O=C(NCC(F)F)c1ccc(-c2ccc3c(c2)CNCCO3)cc1
Reactant: O=C1CCN(C(=O)Cl)C(c2cccc(F)c2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C1CCN(C(=O)N2CCOc3ccc(-c4ccc(C(=O)NCC(F)F)cc4)cc3C2)C(c2cccc(F)c2)C1
Temperature: 50 °C
Yield: 13.2 %

Procedure:
To a slurry of N-(2,2-difluoroethyl)-4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzamide hydrochloride (0.19 g, 0.51 mmol), DIPEA (0.45 mL, 2.6 mL) and tetrahydrofuran (3 mL) was added 2-(3-fluorophenyl)-4-oxopiperidine-1-carbonyl chloride (reagent preparation 37) (0.13 g, 0.51 mmol). The reaction mixture was heated (50° C.) for 3 h and then concentrated. Purification by preparative reverse phase HPLC provided N-(2,2-difluoroethyl)-4-(4-{[2-(3-fluorophenyl)-4-oxopiperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzamide (37 mg, 13% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): 7.82 (d, 2H), 7.55 (d, 2H), 7.47 (dd, 1H), 7.20-7.34 (m, 3H), 7.13 (d, 1H), 6.93-7.06 (m, 3H), 6.43 (t, 1H), 5.99 (tt, 1H), 5.34-5.40 (m, 1H), 4.54 (s, 2H), 4.20-4.30 (m, 2H), 3.73-3.93 (m, 5H), 3.20-3.30 (m, 1H), 2.84-3.06 (m, 2H), 2.54-2.64 (m, 1H), 2.32 (d, 1H); MS (EI) for C30H28F3N3O4: 552 (MH+).