Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:40][CH2:39][C:38]5[CH:41]=[CH:42][C:35]([Cl:34])=[CH:36][CH:37]=5)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccc(Cl)cc1
Reactant: CS(=O)c1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4ccnc(NCc5ccc(Cl)cc5)n4)n[nH]c3n2)CC1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
The mixture of {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 9 supra) (150 mg, 0.32 mmol) and 4-chlorobenzylamine (179 mg, 1.3 mmol) was heated at 130° C. with stirring for 2 hours. The resulting oil was purified by chromatography (silica gel, 6 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) and then further purified by prep-HPLC to afford (4-{3-[2-(4-chloro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester. (Yield 35 mg, 20.1%).
Reaction SMILES: [C:1]([Si:5]([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[O:6][CH2:7][CH:8]([CH3:39])[O:9][C:10]1[CH:11]=[C:12]([O:28][C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25](O)=[O:26])[CH2:22][N:23]=1)=[CH:15]2)([CH3:4])([CH3:3])[CH3:2].Cl.C[N:52](C)CCCN=C=NCC.[NH4+].ON1C2C=CC=CC=2N=N1.CN(C)C=O>CCCCCC.C(OCC)(=O)C.O>[C:1]([Si:5]([C:46]([CH3:48])([CH3:47])[CH3:49])([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[O:6][CH2:7][CH:8]([CH3:39])[O:9][C:10]1[CH:11]=[C:12]([O:28][C:29]2[CH:30]=[CH:31][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][CH:34]=2)[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25]([NH2:52])=[O:26])[CH2:22][N:23]=1)=[CH:15]2)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(CO[Si](c1ccccc1)(C(C)(C)C)C(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: CC(CO[Si](c1ccccc1)(C(C)(C)C)C(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CC(N)=O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
A mixture of (2-{7-(2-{[di-tert-butyl(phenyl)silyl]oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (320 mg), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (165 mg), 1-hydroxybenzotriazole ammonium salt (131 mg) and N,N-dimethylformamide (8 mL) was stirred at room temperature for 18 hr. Water was added to the reaction solution, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtrated, and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=30:70 to 100:0, volume ratio) to give the title compound (262 mg, yield 55%) as an orange oil. MS 742 (MH+).
Reaction SMILES: FC1C(C(O)=O)=C([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)C(C)=CC=1.[F:17][C:18]1[C:19](I)=[C:20]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:21]([OH:23])=[O:22]>>[F:17][C:18]1[C:19]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:20]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:21]([OH:23])=[O:22]
Reactant: Cc1ccc(F)c(C(=O)O)c1-n1nccn1
Reactant: Cc1ccc(C(=O)O)c(I)c1F
Product: Cc1ccc(C(=O)O)c(-n2nccn2)c1F

Procedure:
The title compound was prepared following the same general protocol as described for 6-fluoro-3-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A352 using 3-fluoro-2-iodo-4-methylbenzoic acid. MS (ESI) 222 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[O:10][CH:11]1[CH2:14][O:13][CH2:12]1)([O-])=O>CO.[Pd]>[O:13]1[CH2:12][CH:11]([O:10][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH2:1])[CH2:14]1
Reactant: O=[N+]([O-])c1cnccc1OC1COC1
Agent: [Pd]
Solvent: CO
Product: Nc1cnccc1OC1COC1
Reaction time: 3 h
Yield: 102.2 %

Procedure:
3-Nitro-4-(oxetan-3-yloxy)pyridine (499 mg) was dissolved in methanol (10 mL) and Pd on C, wet, Degussa was added. The reaction mixture was flushed nitrogen twice and then stirred under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through a prewetted (methanol, 5 mL) Celite cartridge (2.5 g) and washed with methanol (25 mL). The filtrate was concentrated in vacuo to afford the desired product as a pale orange oil (432 mg, 97.7%). LC-MS (M+H)+ 196.3; 1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.67 (d, J=5.3 Hz, 1H), 6.45 (d, J=5.3 Hz, 1H), 5.32 (tt, J=6.0, 4.8 Hz, 1H), 4.96 (s, 2H), 4.95 (ddd, J=7.1, 6.0, 1.0 Hz, 2H), 4.59 (ddd, J=7.3, 4.8, 1.0 Hz, 2H).
Reaction SMILES: [S:1]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=1)(=[O:4])(=[O:3])[NH2:2].[N:16]1([C:22]2[C:23]3[CH:30]=[C:29]([CH2:31][C:32]([F:35])([F:34])[F:33])[S:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:15]=[C:13]([N:19]1[CH2:18][CH2:17][N:16]([C:22]2[C:23]3[CH:30]=[C:29]([CH2:31][C:32]([F:34])([F:33])[F:35])[S:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:21][CH2:20]1)[CH2:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][S:1]([NH2:2])(=[O:3])=[O:4])=[CH:11][CH:10]=1
Reactant: NS(=O)(=O)Cc1ccc(CC(=O)O)cc1
Reactant: FC(F)(F)Cc1cc2c(N3CCNCC3)ncnc2s1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: NS(=O)(=O)Cc1ccc(CC(=O)N2CCN(c3ncnc4sc(CC(F)(F)F)cc34)CC2)cc1
Yield: 110.4 %

Procedure:
23 mg of 2-(4-(sulfamoylmethyl)phenyl)acetic acid (0.1 mmol), 20 mg of 4-(piperazin-1-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine (0.067 mmol), 20 mg of EDCI (0.1 mmol) and 4 mg of DMAP (0.033 mmol) was stirred in 2 mL of DCM. After 2 hs reaction mixture was concentrated and residue was loaded on silica gel column. Elution with DCM-MeOH 9:1 and evaporation of fraction produced 38 mg of (4-(2-oxo-2-(4-(6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)ethyl)phenyl)methanesulfonamide (compound 44). 1H NMR (400 MHz, CDCl3): δ 8.44 (s, 1H), 7.36 (d, 2H, J=8 Hz), 7.25 (d, 2H, J=8 Hz), 7.20 (s, 1H), 4.88 (s, 2H), 4.26 (s, 1H), 3.5-4.0 (m, 10H). ESI MS [MH+]: 514.1. Its monohydrochloride salt was obtained by adding 1 equivalent of 1N HCl solution in diethyl ether to a solution of compound in ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:20])([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:20])([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH:9]([OH:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C(C)(Cc1ccc(Cl)cc1)c1cccc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)C(C)(Cc1ccc(Cl)cc1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-(3-bromophenyl)-4-(4-chlorophenyl)-3-methyl-2-butanone (1.6 g, 4.6 mmol) in methanol (50 mL) was added sodium borohydride (0.26 g, 6.8 mmol). After stirring at room temperature for 10 min, the reaction was quenched by addition of saturated aqueous ammonium chloride (25 mL). The precipitate was filtered off and washed with ethyl acetate (25 mL). The organic layer of the filtrate was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography on silica gel eluted with 5% ethyl acetate in hexane to afford the title compound as two separate diastereomers. Faster eluting diastereomer (Diastereomer α) 1H NMR (400 MHz, CD3OD): δ 7.63 (s, 1H), 7.42-7.18 (m, 3H), 7.05 (d, 2H), 6.80 (d, 2H), 3.92 (q, 1H), 3.19 (d, 1H), 2.86 (d, 1H), 1.13 (s, 31), 1.02 (d, 3H). Slower eluting diastereomer (Diastereomer β) 1H NMR (400 MHz, CD3OD): 7.40-7.18 (m, 4H), 7.04 (d, 2H), 6.64 (d, 2H), 4.12 (q, 1H), 3.04 (ABq, 2H), 1.17 (s, 3H), 0.84 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=2[N+:24]([O-])=O)(=[O:15])=[O:14])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl[Sn]Cl>Cl.CCO>[NH2:24][C:17]1[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:16]=1[S:13]([NH:12][C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2)(=[O:14])=[O:15]
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1S(=O)(=O)Nc1ccc(Cl)c2cccnc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cc(F)c(F)cc1S(=O)(=O)Nc1ccc(Cl)c2cccnc12
Yield: 82.9 %

Procedure:
In a similar fashion using route 1 general procedure 4, N-(5-chloro-quinolin-8-yl)-4,5-difluoro-2-nitro-benzenesulfonamide (Intermediate 257) (125 mg, 0.31 mmol), SnCl2 (238 mg, 1.25 mmol), 6N HCl (3 drops) and EtOH (3 ml) for 3.5 h at 85° C. gave the title compound (95 mg, 72%) which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22](I)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:26]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:28]=[CH:29][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:34]1[CH:38]=[CH:37][N:36]=[N:35]1.CNCCNC.CC([O-])(C)C.[K+]>CN(C=O)C.CCOC(C)=O.[Cu]I>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([N:35]4[N:36]=[CH:37][CH:38]=[N:34]4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:26]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:28]=[CH:29][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1c[nH]nn1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(I)cc32)cc1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: CNCCNC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(-n4nccn4)cc32)cc1
Temperature: 180 °C

Procedure:
To a stirred solution of 6-[(4-tert-butylphenyl)sulfonyl]-8-iodo-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (intermediate 52, 109 mg, 0.19 mmol) in DMF (4 mL) was added 1,2,3-triazole (39 mg, 0.56 mmol), CuI (71 mg, 0.37 mmol), N,N′-dimethylethylenediamine (0.08 mL, 0.74 mmol), and KOtBu (1.0M/THF, 1.5 mL, 1.5 mmol). The resulting solution was heated to 180° C. in a microwave reactor for 1 h. The solution was diluted with EtOAc and washed with sat aqueous NaHCO3. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated, and the oily residue was purified by silica gel chromatography to give the title compound. 1H NMR (500 MHz, (CD3)2CO): δ 8.60 (s, 1H), 8.20 (s, 1H), 8.00 (m, 2H), 7.78 (d, 1H), 7.50 (d, 1H), 7.22 (d, 2H), 7.18 (d, 1H), 7.05 (d, 2H), 4.90 (br s, 2H), 1.20 (s, 9H). LCMS: m/e 529.0 (M+H)+.
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.C(N(CC)C(C)C)(C)C.[OH:38][CH2:39][C:40]1([C:43](O)=[O:44])[CH2:42][CH2:41]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O.O>[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][N:26]([C:39]([C:40]6([CH2:43][OH:44])[CH2:42][CH2:41]6)=[O:38])[CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1
Reactant: O=C(O)C1(CO)CC1
Reactant: C1=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CC1)C1(CO)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of benzothiazol-6-yl-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine tris-hydrochloride (230 mg, 0.50 mmol) in N,N-dimethylformamide (4 mL) were added N,N-diisopropylethylamine (0.7 mL, 4.0 mmol), 1-hydroxymethyl-cyclopropanecarboxylic acid (70 mg, 0.6 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (190 mg, 0.6 mmol). The resulting mixture was stirred at rt overnight. The mixture was diluted with water (30 mL), and the precipitate was collected by filtration and dried in vacuum, giving the title compound as brown solid. LC-MS (ES, Pos.): 447 [MH+]. 1H NMR (DMSO-d6, 400 MHz): δ=0.74 (s, 2H), 0.77 (s, 2H), 2.51 (m, 2H), 3.50 (d, J=5.9 Hz, 2H), 3.85 (m, 2H), 4.20 (m, 2H), 4.90 (br s, 1H), 6.44 (s, 1H), 6.84 (s, 1H), 7.88 (dd, J=8.9 Hz, 2.1 Hz, 1H), 8.04 (d, J=8.9 Hz, 1H), 8.34 (s, 1H), 8.92 (d, J=2.1 Hz, 1H), 9.24 (s, 1H), 9.62 (s, 1H), 12.02 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]2=[O:23])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1.C[N+]1([O-])CCOCC1.CO.C(Cl)(Cl)Cl.O1CCNC1=O>C(#N)C.ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]2=[O:23])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:11][C:10](=[O:12])[CH2:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CC(O)C3)c(F)c2)C(=O)O1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CC(=O)C3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of (S)-N-[[3-[3-fluoro-4-(3-hydroxy-1-azetidinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (EXAMPLE 2, 0.440 g, 1.36 mmol) in 10% acetonitrile/dichloromethane (100 mL) was treated with powdered 4 angstrom molecular sieves (0.682 g), 4-methylmorpholine N-oxide (0.319 g, 2.72 mmol) and then tetra-n-propylammonium perruthenate (0.024 g, 0.068 mmol) at ambient temperature. After stirring 1.5 hours at ambient temperature, TLC analysis (10% methanol/chloroform) revealed a small amount of starting alcohol still remained. The addition of more 4-methylmorpholine N-oxide did not consume the starting material. The reaction mixture was concentrated under reduced pressure to a dark purple solid which was then chromatographed over silica gel (20 g), eluting with a gradient of 1-3.5% methanol/chloroform, to afford, after concentration of appropriate fractions, 0.204 g (47%) of the title oxazolidinone antibacterial agent as a white solid with mp 192°-193° C. and MS(EI) 321 (M+).
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[C:9]([O:13][C:14]([C@@:16]1([CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:20][C:19](=[O:21])[N:18]([C@@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OCC)(=O)C>[C:9]([O:13][C:14]([C@@:16]1([CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:38])([CH3:37])[CH3:39])([CH3:35])[CH3:34])[CH:20]([CH3:1])[C:19](=[O:21])[N:18]([C@@H:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH3:23])[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)[N-]C(C)C
Reactant: C[C@H](c1ccccc1)N1C[C@@](CCO[Si](C)(C)C(C)(C)C)(C(=O)OC(C)(C)C)CC1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CCOC(C)=O
Product: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
A 1.8 M solution of lithium diisopropylamide in tetrahydrofuran (3.10 mL) was added dropwise to a solution of (3S)-3-[2-(tert-butyldimethylsilyloxy)ethyl]-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (2.24 g, 5.00 mmol) in tetrahydrofuran (20 mL) in a nitrogen atmosphere at −72° C. over five minutes. After stirring at the same temperature for 10 minutes, methyl iodide (0.34 mL, 5.50 mmol) was added. The mixture was stirred at the same temperature for 15 minutes and then heated to −10° C. over 10 minutes. Thereafter, a 10% citric acid aqueous solution (5 mL) was added. The reaction solution was poured into a mixture of ethyl acetate (100 mL) and 10% citric acid solution (50 mL), followed by extraction with ethyl acetate (200 mL). The organic layer was washed with brine (50 mL×2), dried over anhydrous sodium sulfate, and filtered. The filtrate was then concentrated under reduced pressure. The resulting dark brown residue was used for the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][C:12](=O)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:20][CH3:21])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:22]N(C=NC=[N+](C)C)C.[Cl-].C([O-])(=O)C.[Na+].C(O)(=O)C>O1CCOCC1>[CH2:12]([O:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:6][CH:22]=[N:1]2)=[CH:7][C:8]=1[O:20][CH3:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cc(C(N)=O)c(N)cc1OC(=O)c1ccccc1
Reactant: CN(C)C=NC=[N+](C)C
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Yield: 77 %

Procedure:
A mixture of 2-amino-4-benzoyloxy-5-methoxybenzamide (10 g, 0.04 mol), (prepared according to J. Med. Chem. 1977, 20, 146–149), and Gold's reagent (7.4 g, 0.05 mol) in dioxane (100 ml) was stirred and heated at reflux for 24 hours. Sodium acetate (3.02 g, 0.037 mol) and acetic acid (1.65 ml, 0.029 mol) were added to the reaction mixture and it was heated for a further 3 hours. The volatiles were removed by evaporation, water was added to the residue, the solid was collected by filtration, washed with water and dried. Recrystallisation from acetic acid yielded 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.7 g, 84% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]([N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH:24]1([NH:27][C:28](=[O:45])[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:30]=2)[CH2:26][CH2:25]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:24]1([NH:27][C:28]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([C:2]3[CH:23]=[CH:22][C:5]4[C:6]([N:9]5[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]5)=[N:7][O:8][C:4]=4[CH:3]=3)[CH:30]=2)=[O:45])[CH2:25][CH2:26]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCN(c2noc3cc(Br)ccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCN(C(=O)OC(C)(C)C)CC3)noc2c1
Yield: 60.2 %

Procedure:
A mixture of 1,1-dimethylethyl 4-(6-bromo-1,2-benzisoxazol-3-yl)-1-piperazinecarboxylate (Intermediate 25) (0.04 g), N-Cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 5) (0.035 g), 2N aqueous sodium carbonate (2 ml) and tetrakis(triphenylphosphine)palladium(0) (1 mg) in isopropanol (6 ml) was stirred at reflux under nitrogen for 16 h. The residue was absorbed onto silica Merck 7734) and applied to a Varian Bond-Elut SPE cartridge (silica, 5 g). Elution with dichloromethane:methanol (98:2) gave the title compound as a cream solid (0.03 g).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[C:12]2[O:11][CH2:10][CH2:9][C:8]=2[CH:7]=[C:6]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH:5]=1.Cl>O1CCCC1>[Br:3][C:4]1[C:12]2[O:11][CH2:10][CH2:9][C:8]=2[CH:7]=[C:6]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:5]=1
Reactant: CCOC(=O)CCc1cc(Br)c2c(c1)CCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCc1cc(Br)c2c(c1)CCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
An aqueous solution (100 ml) of sodium hydroxide (15 g) was added to a tetrahydrofuran (20 ml) solution of ethyl 3-(7-bromo-2,3-dihydrobenzofuran-5-yl)propionate (19.1 g, 63.8 mmols), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was made acidic with hydrochloric acid added thereto, and this was then extracted with ethyl acetate. The extract was washed with a saturated saline solution, then dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to obtain 12.8 g (yield: 73%) of the target compound.
Reaction SMILES: [F:1]/[C:2](=[C:5](/[C:7]1[CH:16]=[C:15]2[C:10]([C:11]([CH3:21])([CH3:20])[CH2:12][CH:13]=[C:14]2[CH:17]([CH3:19])[CH3:18])=[CH:9][C:8]=1[O:22][CH2:23][CH2:24][CH3:25])\[CH3:6])/[CH2:3][OH:4].C[N+]1([O-])CCOCC1.ClCCl>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1]/[C:2](=[C:5](/[C:7]1[CH:16]=[C:15]2[C:10]([C:11]([CH3:21])([CH3:20])[CH2:12][CH:13]=[C:14]2[CH:17]([CH3:19])[CH3:18])=[CH:9][C:8]=1[O:22][CH2:23][CH2:24][CH3:25])\[CH3:6])/[CH:3]=[O:4]
Reactant: CCCOc1cc2c(cc1/C(C)=C(/F)CO)C(C(C)C)=CCC2(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CCCOc1cc2c(cc1/C(C)=C(/F)C=O)C(C(C)C)=CCC2(C)C

Procedure:
As described in General Procedure H-1, (2E)-2-fluoro-3-(4,4-dimethyl-6-n-propoxy-1-isopropyl-3,4-dihydronaphthalen-7-yl)-2-butenol (Compound A-53, 0.024 g, 0.069 mmol), tetrapropylammonium perruthenate (0.012 g, 0.038 mmol) and 4-methylmorpholine N-oxide (0.022 g, 0.19 mmol) were reacted in acetonitrile (0.2 mL) and dichloromethane (1 mL) to produce the title compound as an oil.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Cl:11][C:12]1[CH:17]=[C:16](F)[CH:15]=[CH:14][N:13]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[Cl:11][C:12]1[CH:17]=[C:16]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH:15]=[CH:14][N:13]=1
Reactant: Fc1ccnc(Cl)c1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Clc1cc(N2CCC3(CC2)OCCO3)ccn1
Temperature: 120 °C
Yield: 73.1 %

Procedure:
To a solution of 1,4-dioxa-8-azaspiro[4.5]decane (895 μL, 6.98 mmol) and 2-chloro-4-fluoropyridine (1.01 g, 7.68 mmol) in dioxane (15 mL) was added N,N-diisopropylethylamine (1.83 mL, 10.5 mmol). Argon was bubbled through the reaction mixture for 5 minutes before it was heated to 120° C. in microwave for 3 hours. After evaporation, purification by chromatography (silica gel, 20 g, 30 to 10% ethyl acetate in heptane) afforded the title compound (1.3 g, 73%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[C:11]([C:13]#[C:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Li+].CO>O>[CH3:16][C:15]([CH3:18])([CH3:17])[C:14]#[C:13][C:11]1[CH:10]=[CH:9][C:3]([C:4]([OH:6])=[O:5])=[C:2]([CH3:1])[CH:12]=1
Reactant: CCOC(=O)c1ccc(C#CC(C)(C)C)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C#CC(C)(C)C)ccc1C(=O)O
Yield: 94.8 %

Procedure:
Ethyl 2-methyl-4-(3,3-dimethylbut-1-ynyl)benzoate (4.8 g, 0.020 mol) and lithium hydroxide (2.8 g, 0.058 mol) were placed in 3:1 mixture of methanol:water (80 mL) and heated at 60° C. for 3.5 h. TLC and LCMS indicated product formation. The reaction was cooled and concentrated in vacuo to a volume of 20 mL. The mixture was placed in an ice-water bath and acidified to pH 5 with conc. HCl. A white solid crashed out which was filtered and washed thoroughly with water. The solid was dried in a vacuum oven to give the product (4.1 g, 97%) as a solid. m/z=215.1 (M−1).