Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[C@H:14]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH2:13][C@H:12]([OH:22])[C@@H:11]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:39](Cl)(=[O:41])[CH3:40].O>ClCCl>[C:39]([O:22][C@@H:12]1[C@H:11]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[C@H:14]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH2:13]1)(=[O:41])[CH3:40]
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](OC2CCCCO2)C[C@@H]1O
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)CCCCCC[C@@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
A solution of methyl 7-[(1R,2S,3R,5S)-2-(t-butyldimethylsilyloxymethyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (26) (109.6 g, 231.8 mmol) in dichloromethane (500 ml) was cooled on ice. Pyridine (28.1 ml, 347 mmol) and acetyl chloride (24.0 ml, 349 mmol) were added drop wise to the solution, and the solution was stirred at room temperature for 1.5 hours. Water (600 ml) was added to the solution and the mixture was stirred, let to stand, separated into two layers, and the aqueous layer was extracted twice with dichloromethane (400 ml). The organic layers were combined and washed with 1N-hydrochloric acid (600 ml), saturated sodium bicarbonate water (800 ml) and saturated aqueous sodium chloride (800 ml). After drying with anhydrous magnesium sulfate, the solution was concentrated under reduced pressure to give methyl 7-[(1R,2S,3R,5S)-5-acetoxy-2-(t-butyldimethylsilyloxymethyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (27) (119.2 g, 231.5 mmol, 99.9%), as slightly yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](Cl)=[N:6][CH:7]=1.[CH:11]1([CH2:14][NH2:15])[CH2:13][CH2:12]1.C([O-])(O)=O.[Na+]>CCCCO.CCOC(C)=O>[Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5]([NH:15][CH2:14][CH:11]2[CH2:13][CH2:12]2)=[N:6][CH:7]=1
Reactant: NCC1CC1
Reactant: Cn1c(Cl)ncc(Br)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Cn1c(NCC2CC2)ncc(Br)c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
A mixture of 5-bromo-2-chloro-3-methylpyrimidin-4(3H)-one (0.100 g, 0.45 mmol), cyclopropylmethanamine (0.051 mL, 0.58 mmol) and NaHCO3 (0.150 g, 1.79 mmol) in n-BuOH (3 mL) was stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature and then diluted with EtOAc. The EtOAc layer washed with H2O and saturated aqueous NaCl. The aqueous phase was re-extracted with EtOAc (1×). The combined EtOAc layers were dried (Na2SO4), filtered and concentrated to yield the desired product (0.114 g, 98%) as a pale yellow solid that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.46 (t, J=5.5 Hz, 1H), 3.33 (s, 3H), 3.19 (t, J=6.2 Hz, 2H), 1.12 (m, 1H), 0.43 (m, 2H), 0.24 (m, 2H). LRMS (ESI pos) m/e 258, 260 (M+1, Br pattern).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:10])[CH:6]=[CH:7][C:8]=1[CH3:9].[F:11][C:12]([F:23])([F:22])[C:13]1[N:18]=[CH:17][C:16]([CH2:19][C:20]#N)=[CH:15][CH:14]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:35])[C:32](O)=[O:33])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:26]=[CH:27][C:28]([C@H:31]([OH:35])[C:32]([N:10]([C:5]2[CH:6]=[CH:7][C:8]([CH3:9])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:20][CH2:19][C:16]2[CH:17]=[N:18][C:13]([C:12]([F:23])([F:22])[F:11])=[CH:14][CH:15]=2)=[O:33])=[CH:29][CH:30]=1
Reactant: O=C(O)C(=O)c1ccc(F)cc1
Reactant: COc1cc(N)ccc1C
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Product: COc1cc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](O)c2ccc(F)cc2)ccc1C

Procedure:
In analogy to example 47 (steps 3 & 4), 3-Methoxy-4-methyl-phenylamine, (6-Trifluoromethyl-pyridin-3-yl)-acetonitrile & (4-Fluoro-phenyl)-oxo-acetic acid were successively coupled then reduced to give after chiral chromatography (+ve rotation) the target compound. MS(m/e): 463.1 [M+H]+.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9](C)=[C:10]([NH:12][C:13]2[O:14][C:15]([C:18]3[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=3)=[CH:16][N:17]=2)[CH:11]=1)(=[O:5])=[O:4])[CH3:2].C[C:27](C)([O-:29])C.[K+].[Cl:32][C:33]1[N:38]=[C:37](Cl)[CH:36]=[CH:35][N:34]=1>C1COCC1.CN(C=O)C.C(OCC)C>[Cl:32][C:33]1[N:38]=[C:37]([O:24][C:20]2[CH:19]=[C:18]([C:15]3[O:14][C:13]([NH:12][C:10]4[CH:11]=[C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH:7]=[CH:8][C:9]=4[O:29][CH3:27])=[N:17][CH:16]=3)[CH:23]=[CH:22][CH:21]=2)[CH:36]=[CH:35][N:34]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)[O-]
Reactant: CCS(=O)(=O)c1ccc(C)c(Nc2ncc(-c3cccc(O)c3)o2)c1
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(-c3cccc(Oc4ccnc(Cl)n4)c3)o2)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a mixture of the title compound of Example 158 (100 mg, 0.27 μmol) in THF (3 mL) was added a solution of 1M potassium t-butoxide in THF (320 mL, 0.32 μmol 1.2 eq.), followed by a solution of 2,4-dichloropyrimidine (40 mg, 0.27 μmol) in DMF (1 mL). The mixture was stirred at 50° C. for 30 min. After cooling to RT, the mixture was diluted with diethyl ether and washed with 6N HCl. The aqueous layer was made basic with 5N NaOH and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. Purification by silica gel chromatography yielded the title compound (55 mg, 42%) as an off-white solid. 1H NMR (300 MHz, d6-DMSO): 9.81 (s, 1H), 8.79 (d, J=2.2, 1H), 7.69 (d, J=5.7, 1H), 7.66 (s, 1H), 7.60 (d, J=4.9, 2H), 7.54–7.51 (m, 2H), 7.28–7.22 (m, 3H), 4.00 (s, 3H), 3.22 (q, J=7.3, 2H), 1.13 (t, J=7.3, 3H). MS (ES+, m/z)=487,489 (m+H)+.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:38][C:39]1[CH:40]=[C:41]([C:45]2[C:50]3[N:51]([CH2:63][C@H:64]4[CH2:69][CH2:68][C@H:67]([CH3:70])[CH2:66][CH2:65]4)[C:52]([N:54]4[CH2:59][CH2:58][NH:57][C@@H:56]5[CH2:60][CH2:61][CH2:62][C@@H:55]45)=[N:53][C:49]=3[CH:48]=[C:47]([C:71]#[N:72])[N:46]=2)[CH:42]=[N:43][CH:44]=1>CS(C)=O.CCOC(C)=O>[C:1]([N:57]1[CH2:58][CH2:59][N:54]([C:52]2[N:51]([CH2:63][C@H:64]3[CH2:69][CH2:68][C@H:67]([CH3:70])[CH2:66][CH2:65]3)[C:50]3[C:45]([C:41]4[CH:42]=[N:43][CH:44]=[C:39]([Cl:38])[CH:40]=4)=[N:46][C:47]([C:71]#[N:72])=[CH:48][C:49]=3[N:53]=2)[C@@H:55]2[CH2:62][CH2:61][CH2:60][C@@H:56]12)(=[O:4])[CH3:2]
Reactant: CC(=O)O
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCN[C@@H]4CCC[C@H]43)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
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: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(=O)N1CCN(c2nc3cc(C#N)nc(-c4cncc(Cl)c4)c3n2C[C@H]2CC[C@H](C)CC2)[C@@H]2CCC[C@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic acid (60.7 mg, 1.01 mmol), N,N-diisopropylethylamine (174 mg, 1.348 mmol) and HATU (513 mg, 1.348 mmol) were added to 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(4aR,7aR)-octahydro-1H-cyclopenta[b]pyrazin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (177 mg, 0.33 mmol) in DMSO (1.5 ml), and the mixture was stirred at room temperature overnight. The reaction was then diluted with EtOAc, washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane to give 2-[(4aR,7aR)-4-acetyloctahydro-1H-cyclopenta[b]pyrazin-1-yl]-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C29H34ClN7O [M+H]+ 532. found 532.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]([CH2:25][O:26][C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[CH3:34])=[C:23]3[C:18]([NH:19][C:20]([CH3:38])([CH3:37])[C:21](=[O:36])[N:22]3[CH3:35])=[CH:17][CH:16]=2)=[C:11]([O:39][CH3:40])[CH:10]=1)(=[O:7])=[O:6].[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.[I-].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:41]([NH:48][CH2:2][CH2:3][CH2:4][S:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]([CH2:25][O:26][C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[CH3:34])=[C:23]3[C:18]([NH:19][C:20]([CH3:38])([CH3:37])[C:21](=[O:36])[N:22]3[CH3:35])=[CH:17][CH:16]=2)=[C:11]([O:39][CH3:40])[CH:10]=1)(=[O:7])=[O:6])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: NCc1ccccc1
Reactant: COc1cc(OS(=O)(=O)CCCCl)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(OS(=O)(=O)CCCNCc2ccccc2)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 50 °C
Reaction time: 5 h
Yield: 38.2 %

Procedure:
A mixture of 7-[4-(3-chloropropylsulfonyloxy)-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 1-40, 50.0 mg, 0.0846 mmol), benzylamine (92.4 μL, 0.846 mmol), and potassium iodide (16.9 mg, 0.102 mmol) was suspended in anhydrous N,N-dimethylformamide (0.4 mL) and stirred at 50° C. for 5 hours. After cooling down, ethyl acetate (50 mL) was added thereto. The organic layer was washed with water (50 mL) and saturated brine (30 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (21.4 mg) as a colorless amorphous product. (Yield 38%)
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Li]CCCC.[Br:16][CH2:17][C:18]1C=CC=C2C=1CC(C)=C2.CC1C(CC2C=CC=C3C=2CC(C)=C3)C2C(C=1)=CC=CC=2>CCOCC.C1COCC1.O>[Br:16][CH2:17][CH2:18][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH2:3][C:2]([CH3:1])=[CH:10]2
Reactant: CC1=Cc2ccccc2C1
Reactant: CC1=Cc2cccc(CBr)c2C1
Agent: CC1=Cc2cccc(CC3C(C)=Cc4ccccc43)c2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC1=Cc2cccc(CCBr)c2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.30 g (10 mmol) of 2-methyl-1H-indene in 90 ml of ether 4.0 ml of 2.5 M (10 mmol) n-BuLi in hexanes was added at 0° C. This mixture was stirred for 2 h at room temperature, and then a solution of 2.23 g (10 mmol) of 7-(bromomethyl)-2-methyl-1H-indene in 15 ml of THF was added dropwise at vigorous stirring for 10 min at −80° C. The resulting mixture was stirred for 12 h at room temperature, and then 1 ml of water was added. This mixture was evaporated to dryness, and 100 ml of water was added. The crude product was extracted with 3×50 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and evaporated to dryness. The product was isolated by flash chromatography using a short column with Silica Gel 60 (40-63 um, d 60 mm, l 70 mm; eluent: hexanes. Yield 2.50 g (92%) of 2-methyl-1-[(2-methyl-1H-inden-7-yl)methyl]-1H-indene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][CH2:14][CH2:15][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.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH:38]=O)=[N:30]1>CO.N1CCCCC1>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](/[CH:38]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][CH2:14][CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:30]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1CCCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1CCCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
A solution of tert-butyl 4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)propyl]piperidine-1-carboxylate (0.0330 g, 0.0847 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0124 g, 0.0847 mmol) and piperidine (5 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was subjected to silica gel column chromatography (chloroform/methanol). The resulting crude product was further purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (Z)-4-(3-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}propyl)piperidine-1-carboxylate (0.0313 g, 71%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]3[CH2:14][CH2:13]3)[CH:11]=1)[O:8][C:7]([CH3:16])([CH3:15])[CH2:6][C:5]2([CH3:18])[CH3:17].[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21].C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH:12]1([C:10]2[CH:11]=[C:2]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])[CH:3]=[C:4]3[C:9]=2[O:8][C:7]([CH3:16])([CH3:15])[CH2:6][C:5]3([CH3:18])[CH3:17])[CH2:14][CH2:13]1
Reactant: CC1(C)CC(C)(C)c2cc(Br)cc(C3CC3)c2O1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)CC(C)(C)c2cc(C#C[Si](C)(C)C)cc(C3CC3)c2O1

Procedure:
Following general procedure D and using 6-bromo-8-cyclopropyl-2,2,4,4-tetramethyl chroman (Intermediate 32, 0.376 g, 1.22 mmol), (trimethylsilyl)acetylene (4 mL, 28 mmol), triethyl amine (3 mL), anhydrous tetrahydrofuran (5 mL), copper(I)iodide (0.025 g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.11 mmol), the title compound was obtained as an oil (0.173 g, 43%).
Reaction SMILES: CO[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)=[CH:6][C:5]=1[F:19].[CH3:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:27][C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1>>[F:19][C:5]1[CH:6]=[C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[CH:8]=[CH:9][C:4]=1[C:3]([N:29]1[CH2:30][CH2:31][CH2:32][C@H:28]1[CH2:27][N:23]1[CH2:24][CH2:25][CH2:26][C@H:22]1[CH3:21])=[O:20]
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Reactant: COC(=O)c1ccc(OCc2cccc(C)n2)cc1F
Product: Cc1cccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCC[C@H]3C)c(F)c2)n1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure F from 2-Fluoro-4-(6-methyl-pyridin-2-ylmethoxy)-benzoic acid methyl ester and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) 412.3
Reaction SMILES: [C:1]([O:4][C@H:5]([CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=O)[NH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:19][CH3:20])(=[O:3])[CH3:2].S(Cl)([Cl:29])=O>CN(C=O)C>[C:1]([O:4][C@H:5]([CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([Cl:29])=[N:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:19][CH3:20])(=[O:3])[CH3:2]
Reactant: COc1cc2c(=O)[nH]cnc2cc1OC[C@@H](CN1CCCC1)OC(C)=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OC[C@@H](CN1CCCC1)OC(C)=O
Temperature: 80 °C
Yield: 90 %

Procedure:
A solution of (2R)-7-(2-acetoxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (556 mg, 1.54 mmol) in thionyl chloride (6 ml) containing DMF (3 drops) was heated at 80° C. for 4 hours. The volatiles were removed under vacuum. The residue was dissolved in methylene chloride and the organic layer was washed with aqueous sodium hydrogen carbonate, brine, dried (MgSO4) and evaporated to give (2R)-7-(2-acetoxy-3-(pyrrolidin-1-yl)propoxy)-4-chloro-6-methoxyquinazoline (530 mg, 90%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[N:41]1([O:50]C(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.NO>CN(C)C=O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=2)[CH2:11][C:12]([NH:41][OH:50])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1coc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1coc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 14.6 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-[4-(ethoxycarbonyl)-1,3-oxazol-2-yl]hexanoic acid (Preparation 63) (130 mg, 0.39 mmol) and N,N-diisopropylethylamine (67 μl, 0.39 mmol) in N,N-dimethylformamide (6 ml) was treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (220 mg, 0.58 mmol) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 45 minutes. Further N,N-diisopropylethylamine (270 μl, 1.54 mmol) was then added, followed by hydroxylamine hydrochloride (80 mg, 1.16 mmol) and the mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and pH 7 aqueous buffer. The organic layer was separated, washed sequentially with water and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (99:1) gradually changing to dichloromethane:methanol (98:2) to afford the title compound (20 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3]([OH:5])=[O:4].[CH3:7][C:8]1[CH:22]=[CH:21][C:11]([S:12][C:13]([O:15][CH:16](Cl)[CH:17]([CH3:19])[CH3:18])=[O:14])=[CH:10][CH:9]=1>[Ag-]=O.COC(C)(C)C>[CH3:1][CH:2]([CH3:6])[C:3]([O:5][CH:16]([O:15][C:13]([S:12][C:11]1[CH:21]=[CH:22][C:8]([CH3:7])=[CH:9][CH:10]=1)=[O:14])[CH:17]([CH3:19])[CH3:18])=[O:4]
Reactant: Cc1ccc(SC(=O)OC(Cl)C(C)C)cc1
Reactant: CC(C)C(=O)O
Agent: O=[Ag-]
Solvent: COC(C)(C)C
Product: Cc1ccc(SC(=O)OC(OC(=O)C(C)C)C(C)C)cc1
Temperature: 95 °C

Procedure:
2-Methylpropanoic acid (5 mL) and silver (I) oxide (2.3 g) were charged to a vessel at room temperature. 1-Chloro-2-methylpropyl (4-methylthiophenoxy)formate (2.46 g) D4 was added to the reaction vessel. The reaction was heated to 95° C. and the mixture was maintained at approximately 90° C. for 1 hour. The reaction was then cooled to room temperature and tert-butyl methyl ether (20 mL) was added. The solid was filtered and the filter was washed with tert-butyl methyl ether (2×15 mL). The organic phase was washed with water (4×25 mL), bicarbonate (2×25 mL), and dried over sodium sulfate. The organic volatiles were removed under vacuum to provide 3.2 g of the title compound D5 as a pale-yellow oil.
Reaction SMILES: C([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][C@@H:22]([OH:24])[CH3:23])[C:13](=[O:25])[N:12]([CH3:26])[C:11]=2[N:10]=[CH:9]1)C1C=CC=CC=1.C(O)(=O)C.[H][H]>[Pd].CO>[OH:24][C@@H:22]([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][N:14]1[C:15](=[O:17])[C:16]2[NH:8][CH:9]=[N:10][C:11]=2[N:12]([CH3:26])[C:13]1=[O:25]
Reactant: C[C@H](O)CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@H](O)CCCCn1c(=O)c2[nH]cnc2n(C)c1=O
Yield: 62.6 %

Procedure:
(S)-7-benzyl-1(5-(4-nitrobenzoyloxy)hexyl)-3-methylxanthine (25 g, 49.5 mmol) was added to a solution for sodium hydroxide (3.36 g, 84 mmol) in methanol (200 ml). After stirring for 2 hours, the pH was adjusted to 4 by addition of 1 N hydrochloric acid solution. After concentrating under reduced pressure, the residue was partitioned between water (150 ml) and ethyl acetate (300 ml). The organic layer was washed with saturated aqueous sodium chloride solution (150 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 20% hexane-ethyl acetate to provide (S)-7-benzyl-1-(5-hydroxyhexyl)-3-methylxanthine (14 g). c) A mixture of (S)-7-benzyl-1-(5-hydroxyhexyl)-3-methylxanthine (14 g, 39 mmol), acetic acid (100 ml), methanol (50 ml), and 10% palladium on carbon (5 g) was treated with hydrogen gels (40 psi) for 14 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 10% methanol-ethyl acetate to give (S)-1-(5-hydroxyhexyl)-3-methylxanthine (6.5 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:25]=[CH:24][C:11]([O:12][C:13]2[N:23]=[CH:22][CH:21]=[CH:20][C:14]=2[C:15]([O:17]CC)=[O:16])=[CH:10][CH:9]=1.[OH-].[Li+].CO.O>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[N:23]=[CH:22][CH:21]=[CH:20][C:14]=2[C:15]([OH:17])=[O:16])=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1cccnc1Oc1ccc(Nc2ccccn2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cccnc1Oc1ccc(Nc2ccccn2)cc1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 2-(4-(pyridin-2-ylamino)phenoxy)nicotinate (6.23 g, 18.6 mmol) in THF (0.28 M) was added lithium hydroxide (1.33 g, 55.7 mmol). The reaction was stirred for 16 h before adding an addition equivalent of lithium hydroxide and a volume of methanol and water relative to THF to make a 3:2:1 solution of THF:methanol:water. The resulting suspension was heated to 40° C. for 1.5 h. The solid was filtered away from the filtrate to afford the product as a pale orange solid. MS (ESI, pos. ion) m/z: 308.0 (M+1). IC50 (uM) 8.955.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[N:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]=1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[CH:30]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[CH2:30][N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[N:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]=3)[CH2:3][CH:4]2[CH2:8]1
Reactant: CCOC(=O)c1cnc(N2CC3CNCC3C2)nc1
Reactant: O=Cc1ccc2ccccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)c1cnc(N2CC3CN(Cc4ccc5ccccc5c4)CC3C2)nc1
Reaction time: 3 h
Yield: 93.1 %

Procedure:
To a solution of ethyl 2-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-ylpyrimidine-5-carboxylate (0.187 g, 0.71 mmol) in DCE (2 ml) was added 2-naphthaldehyde (0.205 g, 1.31 mmol) and sodium triacetoxyborohydride (0.274 g, 1.25 mmol). The mixture was stirred for 3 h, then poured into DCM (100 ml). Sat. NaHCO3 (100 ml) was added, and extracted with further DCM (100 ml). The combined organic extracts were dried (MgSO4), concentrated and purified by flash column chromatography to yield the title compound (0.266 g, 99%). 1H NMR (300 MHz, CDCl3) δ: 1.39 (3H, t, J=6.9 Hz), 2.59 (2H, d, J=6.9 Hz), 2.73-2.90 (2H, m), 2.94-3.10 (2H, m), 3.67 (2H, d, J=11.7 Hz), 3.82 (2H, s), 3.90 (2H, dd, J=8.1, 12 Hz), 4.37 (2H, q, J=7.2 Hz), 7.41-7.43 (3H, m), 7.74 (1H, s), 7.76-7.89 (3H, m), 8.88 (2H, s).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[C:13](Cl)=[O:14].[NH2:16][C:17]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].C(N(CC)CC)C>O1CCCC1>[C:19]([C:18]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:17]=1[NH:16][C:13](=[O:14])/[CH:12]=[CH:11]/[C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)([OH:21])=[O:20]
Reactant: O=C(Cl)/C=C/c1ccc2ccccc2c1
Reactant: Nc1ccc(F)cc1C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc2ccccc2c1)Nc1ccc(F)cc1C(=O)O

Procedure:
Prepared analogously to Example 31 from trans-3-(naphth-2-yl)-acrylic acid chloride and 2-amino-5-fluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine.