Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17](B(O)O)[CH:16]=1>>[C:9]1([C:6]2[N:5]=[CH:4][C:3]([CH2:2][C:17]3[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=3)=[CH:8][N:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1cccnc1
Reactant: BrCc1cnc(-c2ccccc2)nc1
Product: c1ccc(-c2ncc(Cc3cccnc3)cn2)cc1
Reaction time: 0.5 h

Procedure:
Synthesized using compound 64a (100 mg, 0.41 mmol) and pyridine-3-boronic acid (74 mg, 0.60 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (1:2) as eluent. After flash chromatography the product was solved in ethyl acetate and a few drops of conc. HCl and water were added. After stirring for 30 minutes the phases were separated and water phase was neutralized with aqueous Na2CO3-solution (2M). After extraction with ethyl acetate and drying over MgSO4 the solvent was removed under vacuum. Light orange solid. Yield: 72 mg, 71%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=3.76 (s, 2H), 7.00-7.05 (m, 1H), 7.23-7.29 (m, 4H), 8.16-8.22 (m, 2H), 8.27-8.36 (m, 2H), 8.40-8.43 (m, 2H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=33.5, 123.7, 128.0, 128.6, 130.5, 130.7, 134.2, 136.1, 137.2, 148.4, 150.0, 157.3, 163.3; (ESI): m/z=247.92 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:21]=[CH:20][C:16]3[NH:17][N:18]=[N:19][C:15]=3[CH:14]=2)=[O:12])=[CH:6][CH:5]=1.CO.[OH-].[Na+].Cl>C1COCC1.O>[NH:17]1[C:16]2[CH:20]=[CH:21][C:13]([C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[CH:5][CH:6]=3)=[O:12])=[CH:14][C:15]=2[N:19]=[N:18]1
Reactant: COC(=O)c1ccc(NC(=O)c2ccc3[nH]nnc3c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)c2ccc3[nH]nnc3c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.9 %

Procedure:
4-[(1H-Benzotriazole-5-carbonyl)amino]benzoic acid methyl ester (5.2 g, 17.6 mmol) was dissolved in THF (60 mL) and methanol (10 mL) was added followed by 1N sodium hydroxide (35 mL). The mixture was stirred at room temperature for 16 hours and then 1N hydrochloric acid (45 mL) was added. The mixture was added water (200 mL) and extracted with ethyl acetate (2×500 mL). The combined organic phases were evaporated in vacuo to afford 0.44 g of 4-[(1H-benzotriazole-5-carbonyl)amino]benzoic acid. By filtration of the aqueous phase a further crop of 4-[(1H-benzotriazole-5-carbonyl)amino]benzoic acid was isolated (0.52 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[NH:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[C:3]1=[O:19].[N+:21]([O-])([OH:23])=[O:22].N>S(=O)(=O)(O)O>[CH3:1][C:2]1([CH3:20])[NH:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]([F:18])([F:17])[F:16])=[C:10]([N+:21]([O-:23])=[O:22])[CH:9]=2)[C:3]1=[O:19]
Reactant: CC1(C)NC(=O)N(c2ccc(SC(F)(F)F)cc2)C1=O
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Product: CC1(C)NC(=O)N(c2ccc(SC(F)(F)F)c([N+](=O)[O-])c2)C1=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 3.8 g of 5,5-dimethyl-3-{4-[(trifluoro-methyl)thio]phenyl}imidazolidine-2,4-dione obtained in stage a) below in 7 mL of concentrated sulphuric acid is added dropwise at −5° C. a mixture of nitric acid (0.75 mL) in 3 mL of concentrated sulphuric acid. After stirring for 4 hours at 0° C. (ice bath) the mixture is poured onto 150 g of ice and the pH is raised to 10 by addition of concentrated aqueous ammonia. The aqueous phase is then extracted with twice 150 mL of ethyl acetate and the combined organic phases are dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol (95/5 by volume) to give 1.8 g of 5,5-dimethyl-3-{3-nitro-4-[(trifluoromethyl)thio]phenyl}imidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:20][CH2:19]1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]>>[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:20][CH2:19]2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: O=C(c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN2CCCC2)CC1)C1CC1
Product: O=C(c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN2CCCC2)CC1)C1CC1

Procedure:
Following general procedure M, (6-bromo-4-((trans-4-(pyrrolidin-1-ylmethyl)cyclohexyl)amino)quinolin-3-yl)(cyclopropyl)methanone (46 mg, 0.10 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.16 mmol) to afford the desired product (32 mg, 61%) as a yellow solid. 1H NMR (500 MHz, MeOD) δ 9.10 (s, 1H), 8.28 (s, 1H), 7.94 (dd, J=8.7, 1.9 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.47-7.43 (m, 1H), 7.35 (dd, J=11.9, 2.4 Hz, 1H), 4.15-4.07 (m, 1H), 3.23-3.15 (m, 4H), 2.92 (d, J=6.8 Hz, 2H), 2.87-2.78 (m, 1H), 2.30 (d, J=12.7 Hz, 2H), 2.06-1.97 (m, 6H), 1.87-1.78 (m, 1H), 1.56 (q, J=12.4 Hz, 2H), 1.30-1.14 (m, 4H), 1.13-1.05 (m, 2H). ESI MS m/z 522 [C30H33ClFN3O2+H]+; HPLC>99% (AUC), tR=11.04 min.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].CO>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[F:21])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccccc1F
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4ccccc4F)c3C2=O)C(=O)N1
Yield: 94.9 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and 2-fluorobenzoyl chloride (1.0 mL, 8.4 mmol) in THF (40 mL) was heated to reflux for 15 h. To the mixture was added methanol (10 mL) to give a suspension. The suspension was filtered and washed with methanol (20 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-fluoro-benzamide as a white solid (1.5 g, 93% yield): mp, 300–302° C.; 1H NMR (DMSO-d6) δ 2.05–2.12 (m, 1H, CHH), 2.45–2.65 (m, 2H, CH2), 2.83–2.97 (m, 1H, CHH), 5.18 (dd, J=5.5, 12.9 Hz, 1H, NCH), 7.40–7.49 (m, 2H, Ar), 7.67–7.76 (m, 2H, Ar), 7.88–7.98 (m, 1H, Ar), 8.01–8.05 (m, 1H, Ar), 8.76 (d, J=8.4 Hz, 1H Ar), 10.56 (d, JN-F=10 Hz, 1H, NH), 11.17 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.96, 30.92, 48.97, 116.48, 116.97 (d, JC-F=14 Hz), 118.82, 120.87 (d, JC-F=12 Hz), 125.32 (d, JC-F=1.5 Hz), 125.74, 131.32, 131.39, 134.88 (d, JC-F=9 Hz), 136.22, 136.48, 159.75 (d, JC-F=252 Hz), 161.76 (d, JC-F=7 Hz), 166.58, 168.04, 169.70, 172.71; Anal Calcd for C20H14N3O5F: C, 60.76; H, 3.57; N, 10.63; F, 4.81. Found: C, 60.70; H, 3.64; N, 10.64; F, 4.91.
Reaction SMILES: [C:1]1([NH:7][C@H:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.Cl.C(OCC)(=O)C>[CH3:15][N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C@H:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:9]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)[C@H](C)Nc1ccccc1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CCOC(=O)[C@H](C)N(C)c1ccccc1
Temperature: 70 °C
Yield: 34 %

Procedure:
To a solution of ethyl N-phenylalaninate (2 g, 10.3 mmol) in DMF (103 mL) was added powdered potassium carbonate (2.6 g, 18.5 mmol) followed by iodomethane (1.03 mL, 16.6 mmol) and the resulting mixture was heated at 70° C. over 3 days. The reaction mixture was cooled to room temperature and diluted with 1 M HCl and ethyl acetate. The product was extracted 3 times with ethyl acetate and the combined organics washed with brine, dried (MgSO4), and concentrated in vacuo. Purification by flash chromatography (8:1 hexanes/EtOAc) yielded the title compound as a colorless oil (725 mg, 34%). MS (ES+) m/z 208 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[CH2:3][CH2:2]1.[C:22]([O:26][C:27]([NH:29][CH2:30][C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH:17]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[N:7]([CH:4]3[CH2:5][CH2:6][N:1]([C:31](=[O:32])[CH2:30][NH:29][C:27](=[O:28])[O:26][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:2][CH2:3]3)[C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc2c(c1)CCc1ccccc1N2C1CCNCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC(N2c3ccccc3CCc3ccccc32)CC1
Reaction time: 1 h

Procedure:
60.0 mg (0.216 mmol) of 5-(4-piperidinyl)-10,11-dihydro-5H-dibenzo-[b,f]azepine, 50.0 mg (0.258 mmol) of N-t-butoxycarbonylglycine, 62.1 mg (0.324 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride and 3 mg (0.03 mmol) of 4-dimethylaminopyridine were dissolved in 1 ml of dichloromethane. 43.7 mg (0.432 mmol) of triethylamine was added to the obtained solution, and they were stirred for 1 hour. The product was purified by the silica gel chromatography (hexane:ethyl acetate=89:11 to 65:35) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[N:8]=[C:9]3[N:19]([CH:20]=2)[CH2:18][CH2:17][O:16][C:15]2[C:10]3=[CH:11][CH:12]=[C:13]([C:21]3[CH:22]=[N:23][N:24]([CH3:32])[C:25]=3[CH:26]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]3)[CH:14]=2)[N:4]([CH:33]([CH3:35])[CH3:34])[N:3]=1.[CH3:36][C:37]([CH3:39])=O.[BH3-]C#N.[Na+]>C(O)C>[CH:33]([N:4]1[C:5]([C:7]2[N:8]=[C:9]3[C:10]4[CH:11]=[CH:12][C:13]([C:21]5[CH:22]=[N:23][N:24]([CH3:32])[C:25]=5[CH:26]5[CH2:31][CH2:30][CH2:29][N:28]([CH:37]([CH3:39])[CH3:36])[CH2:27]5)=[CH:14][C:15]=4[O:16][CH2:17][CH2:18][N:19]3[CH:20]=2)=[N:6][C:2]([CH3:1])=[N:3]1)([CH3:35])[CH3:34]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C)c4C4CCCNC4)cc2OCC3)n(C(C)C)n1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C)c4C4CCCN(C(C)C)C4)cc2OCC3)n(C(C)C)n1
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 29.1 %

Procedure:
To a solution of 4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-12-[1-methyl-5-(piperidin-3-yl)-1H-pyrazol-4-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14), 2,4,10,12-pentaene (140 mg, 0.300 mmol) and acetone (174 mg, 3.0 mmol) in ethanol (10 mL) was added Ti(Oi-Pr)4 (171 mg, 0.60 mmol). After being stirred at 20° C. for 20 min, NaBH3CN (37 mg, 0.60 mmol) was added and stirred at 20° C. for 24 h. The solvent was removed and several drops of water were added. The solid was filtered off and the filtrate was evaporated to afford the crude product, which was purified prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/1% formic acid, 17 min) to give racemic 268 (45 mg, 29% yield). LCMS (ESI): RT=5.41 min, m/z: 515.3 [M+H+]. 1H NMR (500 MHz, DMSO-d6) δ 8.40 (d, J=8.0 Hz, 1H), 7.91 (s, 1H), 7.43 (s, 1H), 7.09 (dd, J=8.5, 1.5 Hz, 1H), 6.94 (s, 1H), 5.90-5.82 (m, 1H), 4.53 (s, 4H), 3.90 (s, 3H), 3.11 (m, 1H), 3.10-2.66 (m, 3H), 2.50 (t, J=2.0 Hz, 1H), 2.26 (s, 3H), 2.08 (m, 1H), 1.80-1.20 (m, 10H), 0.95-0.92 (m, 6H)
Reaction SMILES: O1CCCC1.N.[OH:7][C@@H:8]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[CH:10]([CH2:11][C:12](=[O:34])[C@@H:13]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:33])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[C@H:18]([CH3:24])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:9]1.[Li]>O.CO>[CH3:24][C@@H:18]([C@@H:17]1[C@@:25]2([CH3:33])[CH2:26][CH2:27][C@@H:28]3[C@@:29]4([CH3:32])[CH2:30][CH2:31][C@@H:8]([OH:7])[CH2:9][C@H:10]4[CH2:11][C@H:12]([OH:34])[C@H:13]3[C@@H:14]2[CH2:15][CH2:16]1)[CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3C(=O)CC4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: N
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 27 °C
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
A mixture of 9.180 liters of tetrahydrofuran and 0.460 liters of methanol at -10° C. and 7.650 liters of liquid ammonia was stirred for one hour at -35° to -40° C. and then 1.530 kg of 3α-hydroxy-7-keto-cholanic acid were added thereto over 15 minutes. 111 g of lithium were added with stirring at -35° to -38° C. over one hour to the mixture which was then stirred for one hour at -35° to -38° C. 1.530 liters of methanol were added to the mixture over 15 minutes and then 1.530 liters of demineralized water were added to the mixture over 15 minutes and stirring at 20° C. The ammonia was distilled and when the majority of the ammonia was evaporated, 7.650 liters of water were added to the mixture with stirring at 27°±2° C. Then, the tetrahydrofuran-methanol mixture was distilled off under reduced pressure at a bath temperature of 60° C. while progressively adding 1.530 liters of demineralized water to keep the volume constant and after cooling the mixture to about 27° C., 15,300 liters of water were added thereto. 7.650 liters of chloroform were added to the mixture with stirring and then 3,060 liters of 22° Be hydrochloric acid were added thereto over one hour at 27°±2° C. until a pH of 7 was obtained. At this point, acid addition was halted and the mixture was stirred for 30 minutes at 27°±2° C. after which the rest of the acid was added. The mixture was stirred for 2 hours at 27°±2° C. and was vacuum filtered with cotton cloth. The damp product was suspended in 2.300 liters of chloroform at 27°±2° C. and the suspension was stirred at 27°±2° C. for 15 minutes and was vacuum filtered. The product was resuspended in 2300 liters of chloroform at 27°±2° C. for 15 minutes and the suspension was vacuum filtered. The product was washed several times with water and dried at 60° C. to obtain 1.320 g of ursodesoxycholic acid melting at 198° C. and having a specific rotation of [α]D20 =+55.5°±0.5° (c=5% in ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31]OC3CCCCO3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18].ClC1C=C(NC2C=CC(F)=CC=2F)C=CC=1C(C1C=C(C#C)C=CC=1C)=O.N(CC[CH2:72][O:73][CH:74]1[CH2:79][CH2:78][CH2:77][CH2:76][O:75]1)=[N+]=[N-]>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31][CH2:72][O:73][CH:74]3[CH2:79][CH2:78][CH2:77][CH2:76][O:75]3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18]
Reactant: [N-]=[N+]=NCCCOC1CCCCO1
Reactant: Cc1ccc(-c2cn(CCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: C#Cc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Product: Cc1ccc(-c2cn(CCCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 101, using compound 407 (0.44 mmol) and compound 409 (0.44 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 10:90 to 50:50 as the eluent to afford the title compound as colourless foam.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[CH:6]=1.B1([C:14]2[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=2)OCCCO1.C([O-])([O-])=O.[Na+].[Na+]>CCO.C1(C)C=CC=CC=1>[Br:7][C:5]1[CH:6]=[C:2]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[S:3][CH:4]=1
Reactant: Brc1csc(Br)c1
Reactant: c1cncc(B2OCCCO2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1csc(-c2cccnc2)c1
Yield: 72.2 %

Procedure:
A mixture of 2,4-dibromothiophene (3 g, 12.4 mmol) and pyridine-3-boronic acid-1,3-propanediol cyclic ester (2.22 g, 13.6 mmol) in EtOH (30 ml) and toluene (30 ml) together with 2N Na2CO3 solution (12.4 ml) was degassed with a stream of N2 for 10 min. Tetrakis-(triphenylphosphine)palladium(0) (0.25 g, 0.22 mmol) was added and the reaction heated at reflux for 4 h. The mixture was concentrated under reduced pressure to remove the organic solvents and H2O (100 ml) was added. The organics were extracted with EtOAc (200 ml) and then washed with brine (75 ml), dried (MgSO4), and concentrated under vacuum. The resulting crude residue was purified by column chromatography on silica using 70% diethyl ether in hexane as the eluent to yield 3-(4-bromothien-2-yl)pyridine (2.15 g, 75%): δH (360 MHz, CDCl3) 7.26 (1H, s), 7.32 (1H, dd, J 8.6 and 4.9), 7.81 (1H, dt, J 8.6 and 1.7), 8.56 (1H, s), 8.86 (1H, s); m/z (ES+) 240, 242 (1:1) (M++H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH:9][C:10](=[O:12])[CH3:11])=O.P(Cl)(Cl)(Cl)=O>>[CH3:11][C:10]1[O:12][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:8][N:9]=1
Reactant: CC(=O)NNC(=O)c1cccs1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nnc(-c2cccs2)o1
Temperature: 90 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
A mixture of N-(2-thienylcarbonylamino)ethanamide (5.37 g) and phosphorus oxychloride (15 ml) was stirred for 8 hours at 90° C. After cooling to ambient temperature, the mixture was concentrated. The residue was partitioned between AcOEt and saturated aqueous NaHCO3 solution. The organic layer was separated and washed with saturated aqueous NaHCO3 solution and brine. The resulting solution was dried over sodium sulfate and concentrated to give 3.65 g of 2-methyl-5-(2-thienyl)-1,3,4-oxadiazole as a solid.
Reaction SMILES: [N:1]1[C:2]([CH2:14][OH:15])=[N:3][N:4]2[C:13]=1[C:12]1[N:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:6]=[CH:5]2>CCO.[O-2].[O-2].[Mn+4]>[N:1]1[C:2]([CH:14]=[O:15])=[N:3][N:4]2[C:13]=1[C:12]1[N:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:6]=[CH:5]2
Reactant: OCc1nc2c3ncccc3ccn2n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCO
Product: O=Cc1nc2c3ncccc3ccn2n1
Yield: 100.9 %

Procedure:
To a solution of [1,2,4]triazolo[1,5-h][1,7]naphthyridin-2-ylmethanol (280 mg, 1.4 mmol) in EtOH (20 mL) was added activated manganese (IV) dioxide (1.21 g, 14.0 mmol). The mixture was stirred at reflux for 2 h. Then the mixture was filtered and the filtrate was concentrated under reduce pressure to give [1,2,4]triazolo[1,5-h][1,7]naphthyridine-2-carbaldehyde as a yellow solid (280 mg, yield 88%). ESI MS: m/z 199.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 10.34 (s, 1H), 9.16 (dd, J=1.6, 4.4 Hz, 1H), 8.55 (d, J=7.2 Hz, 1H), 8.28 (dd, J=1.6, 8.0 Hz, 1H), 7.76 (dd J=4.4, 8.0 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:27]=1[NH2:28].[C:34]([O:38][C:39]([N:41]1[CH2:44][CH:43]([C:45](O)=[O:46])[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].CCN(C(C)C)C(C)C>C(#N)C>[Br:25][C:26]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:27]=1[NH:28][C:45]([CH:43]1[CH2:44][N:41]([C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])[CH2:42]1)=[O:46]
Reactant: Nc1cc(Cl)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(C(=O)Nc2cc(Cl)ccc2Br)C1
Reaction time: 8 h
Yield: 74 %

Procedure:
HATU (980 mg, 2.58 mmol) was added to a mixture of 2-bromo-5-chloroaniline (352 mg, 1.7 mmol) and 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (402 mg, 2 mmol) in Acetonitrile (8 mL) at room temperature followed by DIPEA (0.74 mL, 4.26 mmol). After stifling overnight, reaction mixture was concentrated under reduced pressure and resulting residue was purified via silica gel column chromatography (0-50% ethyl acetate/hexanes) to yield tert-butyl 3-((2-bromo-5-chlorophenyl)carbamoyl)azetidine-1-carboxylate 7.56 (490 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C15H19BrClN2O3: 389.02; found: 389.57.
Reaction SMILES: O[CH2:2][NH:3][C:4](=[O:9])[C:5]([F:8])([F:7])[F:6].[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>OS(O)(=O)=O>[Cl:10][C:11]1[CH:19]=[CH:18][C:17]([CH2:2][NH:3][C:4]([C:5]([F:8])([F:7])[F:6])=[O:9])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1ccccc1Cl
Reactant: O=C(NCO)C(F)(F)F
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(Hydroxymethyl)trifluoroacetamide (70 mmol; 10.0 g) was added to a mixture of 2-chlorobenzoic acid (70 mmol; 10.9 g) and conc. H2SO4 (120 mL). The mixture was stirred at rt overnight, poured into ice water and stirred for 2 h. The precipitate was collected by filtration, dried and recrystallised from toluene/butan-2-one (7:1) to give the subtitle compound. Yield: 9.6 g (49%). MS [M−H]−=280 (Cl isotope pattern), TLC: Rf=0.57 (RP-8, MeOH:5%-aq NaCl-solution 6:4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@:19]([CH2:32][OH:33])([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17]2)=[CH:12][C:11]=1[O:34][CH3:35].[CH3:36]I.[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[C@:19]([CH2:32][O:33][CH3:36])([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17]2)=[CH:12][C:11]=1[O:34][CH3:35]
Reactant: COC(=O)[C@]1(CO)CC[C@H](c2ccc(OCc3ccccc3F)c(OC)c2)N1C(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@@]1(C(=O)OC)CC[C@H](c2ccc(OCc3ccccc3F)c(OC)c2)N1C(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 85.1 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2R,5R)-5-[4-{[(2-fluorophenyl)methyl]oxy}-3-(methyloxy)phenyl]-2-(hydroxymethyl)-1,2-pyrrolidinedicarboxylate (D62, 170 mg, 0.35 mmol) and methyl iodide (44 μl, 0.70 mmol) in dry DMF (2 ml) at 0° C. was added NaH (60% dispersion in mineral oil) (21 mg, 0.52 mmol) and the mixture was stirred for 1.5 h from 0° C. to r.t. The reaction was quenched with brine and extracted with ethyl acetate. The organic layer was washed three times with ice cold brine, dried (Na2SO4) and evaporated and the residue was purified by chromatography on silica gel using cyclohexane/ethyl acetate (1:0 to 85:15) to afford the title compound as a colourless oil (150 mg, 86%); Rt (HPLC): 6.62 min; MS: (ES/+) m/z: 526 [M+Na] C27H34FNO7 requires 503.
Reaction SMILES: [CH2:1](Cl)[C:2](=[CH2:4])[CH3:3].[CH3:6]C(C)([O-])C.[K+].[CH2:12]([OH:18])[C:13]1[O:17][CH:16]=[CH:15][CH:14]=1.O>CS(C)=O>[CH3:6][C:13]1([O:17][CH:16]=[CH:15][CH2:14]1)[CH2:12][O:18][CH2:1][C:2](=[CH2:4])[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: OCc1ccco1
Reactant: C=C(C)CCl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C=C(C)COCC1(C)CC=CO1
Temperature: 25 °C

Procedure:
Methallyl chloride (0.85 M) was added to a solution of potassium t-butoxide (0.89 M) and furfuryl alcohol (0.89 M) in dimethyl sulfoxide (0.5 L). The exothermic reaction (~95° C.) was allowed to cool to room temperature over 2 hr and then added to 1.5 L water and extracted with 0.5 L ether. Crude product (125 g) was isolated from the ether phase and distilled at ~20 mm at 127° C. to yield 110 g (0.72 M) of methallyl 2-methylfurfuryl ether. Hydrosilylation of the methallyl group was accomplished by mixing with 0.93 M of dichloromethylsilane, 0.2 g of SIP6831.0 in xylene and heating to a gentle reflux. The reaction proceeded to completion with a brief vigorous reflux.