Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([N:10]1[CH2:15][CH2:14][C:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([OH:16])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:24]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=[C:29]([CH3:37])[CH:28]=1)=[C:25]=[O:26]>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:17]([C:13]1([OH:16])[CH2:14][CH2:15][N:10]([CH:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:2][NH:1][C:25]([NH:24][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=[C:29]([CH3:37])[CH:28]=2)=[O:26])[CH2:11][CH2:12]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cc(N=C=O)c2ccccc2n1
Reactant: NCC(c1ccccc1)N1CCC(O)(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cc(NC(=O)NCC(c2ccccc2)N2CCC(O)(Cc3ccccc3)CC2)c2ccccc2n1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of 1-(2-amino-1-phenyl-ethyl)4-benzyl-piperidin-4-ol (54.3 mg, 0.18 mmol) in CH2Cl2 is added a freshly prepared solution of 4-isocyanato-2-methyl-quinoline (33.8 mg, 0.16 mmol) in toluene (2 mL). The mixture is stirred for 15 h at 20° C. Evaporation of the solvent and purification by HPLC provides the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]2)=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.CCN(C(C)C)C(C)C.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:36]([C:33]3[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:35][CH:34]=3)(=[O:38])=[O:37])[C@H:10]([CH3:14])[CH2:9]2)=[C:4]([C:15]([F:17])([F:16])[F:18])[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1CN(c2ccc(F)cc2C(F)(F)F)CCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)N2CCN(c3ccc(F)cc3C(F)(F)F)C[C@H]2C)cc1
Reaction time: 14 h

Procedure:
To solution of 1-(4-Fluoro-2-trifluoromethyl-phenyl)-3-methyl-piperazine (200 mg, 0.76 mmol) and DIPEA (0.33 mL, 1.90 mmol) in DCM (8.0 mL) was added 4-Methoxybenzenesulfonyl chloride. The reaction was allowed to stir over a 12-16 hr period, after which it was judged complete by TLC. The reaction mixture was concentrated in-vacuo, and the resultant crude oil was purified via normal phase SiO2 column chromatography using a 2%-10% EtOAc/Hex solvent gradient. The desired product, was isolated in >95% purity. HRMS: calcd for C19H20F4N2O3S+H+, 433.12035. found ([M+H]1+), 433.12037.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8](Cl)[CH:7]=[C:6]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20].O.[NH2:24][NH2:25]>>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:24][NH2:25])[CH:7]=[C:6]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20]
Reactant: NN
Reactant: FC(F)(F)c1ccc2nc(Cl)cc(-c3ccccc3Cl)c2c1
Solvent: O
Product: NNc1cc(-c2ccccc2Cl)c2cc(C(F)(F)F)ccc2n1

Procedure:
In the manner given in Example 1, 6-(trifluoromethyl)-2-chloro-4-(o-chlorophenyl)quinoline is reacted at reflux with hydrazine hydrate to give 6-(trifluoromethyl)-4-(o-chlorophenyl)-2-hydrazinoquinoline.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:12]2[S:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[N:9][S:10][CH:11]=1)(=O)=O.[F:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[CH:22]=[C:23]([F:26])[C:24]=1O>>[Cl:17][C:14]1[S:13][C:12]([C:8]2[C:7]([CH2:6][O:5][C:24]3[C:23]([F:26])=[CH:22][C:21]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:20][C:19]=3[F:18])=[CH:11][S:10][N:9]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: CS(=O)(=O)OCc1csnc1-c1ccc(Cl)s1
Product: O=C(O)CCc1cc(F)c(OCc2csnc2-c2ccc(Cl)s2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 91 following Step 5 and 6 by coupling (3-(5-chlorothiophen-2-yl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 7.45 (d, J=2.5 Hz, 1H), 6.97 (d, J=2.5 Hz, 1H), 6.76 (d, J=7.0 Hz, 2H), 5.25 (s, 2H), 2.90 (d, J=6.3 Hz, 2H), 2.68 (d, J=6.3 Hz, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH3:12])[CH2:8][CH:7]([NH2:9])[CH2:6][C:5]([CH3:11])([CH3:10])[CH2:4]1.[C:13]([NH:16][NH:17][C:18](N)=[O:19])(N)=[O:14]>CN1CCCC1=O>[O:14]=[C:13]1[N:1]([CH2:2][C:3]2([CH3:12])[CH2:8][CH:7]([N:9]3[C:18](=[O:19])[NH:17][NH:16][C:13]3=[O:14])[CH2:6][C:5]([CH3:11])([CH3:10])[CH2:4]2)[C:18](=[O:19])[NH:17][NH:16]1
Reactant: NC(=O)NNC(N)=O
Reactant: CC1(C)CC(N)CC(C)(CN)C1
Solvent: CN1CCCC1=O
Product: CC1(C)CC(n2c(=O)[nH][nH]c2=O)CC(C)(Cn2c(=O)[nH][nH]c2=O)C1

Procedure:
765 g of 1-aminomethyl-5-amino-1,3,3-trimethyl cyclohexane and 708 g of hydrazodicarbonamide are stirred in 1 liter of N-methyl pyrrolidone for 4 hours at 175° C., for 5 hours at 200° C. and for 15 hours at 220° C. The solvent is then distilled off in vacuo and the residue is dried in vacuo, giving 1473 g (97% of the theoretical) of 1-(3,5-dioxo-1,2,4-triazolidin-4-yl-methyl)-1,3,3-trimethyl-5-(3,5-dioxo-1,2,4-triazolidin-4-yl)-cyclohexane in the form of colourless crystals melting at 213 C. (decomposition).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[CH:9][N:8]([C@@H:11]3[O:23][C@H:22]([CH3:24])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[C:7]=2[CH:25]=1.[Br:28]C1N([C@@H]2O[C@H](C)[C@@H](OC(=O)C)[C@H]2OC(=O)C)C2C=CC(C(F)(F)F)=CC=2N=1>CCOC(C)=O.CCCCCC>[Br:28][C:9]1[N:8]([C@@H:11]2[O:23][C@H:22]([CH3:24])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]2[O:13][C:14](=[O:16])[CH3:15])[C:7]2[CH:25]=[C:3]([C:2]([F:1])([F:26])[F:27])[CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2cc(C(F)(F)F)ccc21
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cnc2ccc(C(F)(F)F)cc21
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2ccc(C(F)(F)F)cc21
Yield: 52 %

Procedure:
Starting with 6-trifluoromethyl-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole, this compound was prepared in a manner analogous to that described for 2-bromo-5-trifluoromethyl-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole. Following flash column chromatography on silica with EtOAc/hexane (2:3), a 52% yield of the title compound was obtained as an oil. 1H NMR (DMSO-d6) δ1.48 (d, 3H, CH3), 2 (s, 3H, COCH3), 2.1 (s, 3H, COCH3), 4.2-4.3 (m, 1H, CH), 5.2 (t, 1H, CH), 5.63 (t, 1H, CH), 6.22 (d, 1H, CH), 7.6 (d, 1H, aromatic), 7.8 (d, 1H, aromatic), 8.1 (s, 1H, aromatic).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[C:14](OCC)(=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].[O-]CC.[Na+]>C(O)C>[CH:8]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[O:1][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][C:11]2=[O:13])([CH3:10])[CH3:9]
Reactant: CC(=O)c1cccc(C(C)C)c1O
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2cccc(C(C)C)c2o1
Temperature: 25 °C

Procedure:
To a solution of Example 13A (2.048 g, 11.5 mmol) in ethanol (60 mL) was added diethyl oxalate (3.43 mL, 25.3 mmol) and sodium ethoxide (21% in EtOH, 12.9 mL, 34.5 mmol) and the mixture was refluxed for 30 minutes. The mixture was cooled to ambient temperature, partitioned between diethyl ether (150 mL) and water (150 mL). Hydrochloric acid (12N, 3 mL) was added and the separated organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford ethyl 8-isopropyl-4-oxo-4H-chromene-2-carboxylate. After dissolving the intermediate in acetic acid (45 mL) and 12N hydrochloric acid (7.5 mL), the mixture was heated to reflux for 5.5 hours then cooled to ambient temperature. Water (400 mL) was added and the mixture was extracted with ethyl acetate (400 mL). The combined organic layers were washed with water (400 mL) and brine, dried over anhydrous sodium sulfate and filtered. The solution was concentrated under reduced pressure and vacuum dried overnight to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.32 (d, 6H), 3.56 (m, 1H), 6.91 (s, 1H), 7.48 (t, 1H), 7.78 (dd, 1H), 7.89 (dd, 1H). MS (ESI) m/z 232.94 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(N3CCCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and piperidine according to conditions described in general procedure C. 1H NMR (400 MHz, DMSO-d6) δ 1.34-1.58 (m, 12 H), 3.21-3.35 (m, 8 H), 6.18 (d, J=5.5 Hz, 1 H), 6.95 (d, J=12.4 Hz, 1 H), 7.15 (d, J=10.6 Hz, 1 H), 7.40 (d, J=8.0 Hz, 1 H), 7.46 (s, 1 H), 7.55-7.60 (m, 3 H), 7.81-7.83 (m, 1 H), 7.97 (d, J=7.3 Hz, 1 H), 8.24 (d, J=5.5 Hz, 1 H), 10.43 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1B(O)O.Br[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:15]1[CH:21]=[CH:20][CH:19]=[C:17]([NH2:18])[CH:16]=1
Reactant: Nc1cccc(Br)c1
Reactant: COc1ccc(OC)c(B(O)O)c1
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: COCCOC
Product: COc1ccc(OC)c(-c2cccc(N)c2)c1
Temperature: 25 °C
Yield: 91 %

Procedure:
2,5-dimethoxyphenyl boronic acid (0.126 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H20 and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (0-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.091 g in 91% yield.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:12][C:13]([S:16]([NH2:18])=[O:17])([CH3:15])[CH3:14]>C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[C:13]([S:16]([N:18]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:17])([CH3:15])([CH3:14])[CH3:12]
Reactant: CCOC(=O)CCCCC=O
Reactant: CC(C)(C)S(N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CCOC(=O)CCCCC=NS(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A yellow solution of ethyl 6-oxohexanoate (44.80 mmol) in DCM (92 ml) was treated with 2-methylpropane-2-sulfinamide (5.431 g; 44.80 mmol) and with anh. CuSO4 (14.302 g; 89.61 mmol). The resulting beige heterogeneous mixture was further stirred at rt, under nitrogen, for 24 h. The resulting heterogeneous mixture was then filtered over a short pad of celite, and the separated solids were further washed with DCM. The obtained orange filtrate was concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded ethyl 6-((tert-butylsulfinyl)imino)hexanoate as a yellow/orange oil. LC-MS (conditions B): tR=0.81 min.; [M+H]+: 262.07 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:17][CH2:18][C:19](Cl)=[O:20]>O1CCCC1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:19](=[O:20])[CH2:18][Cl:17])=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.1 %

Procedure:
To a stirred mixture of 4-fluorobenzylamine (685 uL, 6.0 mmol) and dry tetrahydrofuran (20 mL) was added triethylamine (1.25 mL, 9.0 mmol) under nitrogen. The resulting mixture was stirred for 10 minutes at ambient temperature. Next, chloroacetyl chloride (477 uL, 6.0 mmol) was added and the resulting mixture was stirred for 1 h. at ambient temperature. The resulting mixture was partitioned between ethyl acetate and water. The organic layer was washed with water (2×20 mL) and brine (1×20 mL), dried over magnesium sulfate, and filtered. Evaporation of the filtrate in vacuo followed by chromatography on silica gel eluting with ethyl acetate-hexane gave 1.09 g (91%) of the pure title compound.
Reaction SMILES: CC(=CC)C.[C:6]([O:10][C:11]([C@@:13]1([CH2:36][CH:37]=[O:38])[C@@H:17]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16](=[O:27])[N:15]([C@@H:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:29])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].Cl([O-])=[O:40].[Na+].O.O.P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[C:6]([O:10][C:11]([C@@:13]1([CH2:36][C:37]([OH:40])=[O:38])[C@@H:17]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16](=[O:27])[N:15]([C@@H:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:29])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: C[C@H](c1ccccc1)N1C[C@@](CC=O)(C(=O)OC(C)(C)C)[C@@H](COCc2ccccc2)C1=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: C[C@H](c1ccccc1)N1C[C@@](CC(=O)O)(C(=O)OC(C)(C)C)[C@@H](COCc2ccccc2)C1=O
Yield: 83.2 %

Procedure:
2-Methyl-2-butene was added to a solution of (3S,4S)-4-benzyloxymethyl-5-oxo-3-(2-oxoethyl)-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (4.58 g, 10.1 mmol) in tert-butyl alcohol (25.2 mL) under ice-cooling, and the mixture was stirred. Sodium chlorite (2.29 g, 25.3 mmol) was added to a solution of sodium dihydrogenphosphate dihydrate (4.10 g, 26.3 mmol) in water (20.2 mL) to separately prepare a solution. This solution was added to the above solution under ice-cooling, and the mixture was stirred at room temperature for one hour. The precipitated solid was collected by filtration, washed with water and hexane, and then dried under reduced pressure at 40° C. to give 3.93 g of the title compound as white powder crystals.
Reaction SMILES: [H-].[Na+].C[O:4][CH2:5][C:6]([O:8][CH3:9])=O.[CH3:10][CH:11]([CH3:15])[C:12](=[O:14])[CH3:13]>CCOCC>[CH3:9][O:8][CH2:6][C:5](=[O:4])[CH2:13][C:12](=[O:14])[CH:11]([CH3:15])[CH3:10]
Reactant: COCC(=O)OC
Reactant: CC(=O)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: COCC(=O)CC(=O)C(C)C
Reaction time: 15 h
Yield: 79.7 %

Procedure:
To a stirred slurry of NaH (1.02 g, 26 mmol, washed with anhydrous hexanes) in ether (10 mL) was added methyl methoxyacetate (2.3 mL, 23 mmol) followed by 3-methyl-2-butanone (2.4 mL, 23 mmol) in ether (5 mL). The resulting mixture was stirred for 15 h and became a clear yellow solution. The reaction was quenched with saturated aqueous NH4Cl. The resulting mixture was extracted with EtOAc (2×20 mL). The combined organic layer was washed with H2O, brine, dried with Na2SO4 and concentrated under reduced pressure to provide 1-methoxy-5-methylhexane-2,4-dione (2.90 g, 80%) as a mixture of keto and enol form.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][C:5]1([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[O:9][CH2:8][CH2:7][O:6]1.O>C1COCC1>[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][C:5]1([C:10]2[CH:11]=[CH:12][C:13]([CH2:14][NH2:15])=[CH:16][CH:17]=2)[O:9][CH2:8][CH2:7][O:6]1
Reactant: CC(C)(C)CCC1(c2ccc(C#N)cc2)OCCO1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)CCC1(c2ccc(CN)cc2)OCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
Dissolve 4-[2-(3,3-dimethyl-butyl)-[1,3]dioxolan-2-yl]-benzonitrile (271 mg, 1.046 mmol) in anhydrous THF (10 mL). Add under nitrogen 1M lithium aluminum hydride in THF (2.1 mL, 2.1 mmol) at 0° C. and stir the mixture at room temperature for 2 h. Cool to 0° C., add water and extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo to obtain the desired intermediate as an oil (0.263 mg) that was used without any further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([O:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[NH:20][C:21]1[C:22]2[C:29]([CH3:30])=[C:28]([C:31](O)=[O:32])[S:27][C:23]=2[N:24]=[CH:25][N:26]=1)[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:35](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.N>CN(C=O)C>[C:31]([C:28]1[S:27][C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][CH:10]([CH3:11])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[C:22]=2[C:29]=1[CH3:30])(=[O:32])[NH2:35]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC(C)CNC(=O)OC(C)(C)C)c12
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC(C)CNC(=O)OC(C)(C)C)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(2-(1-(tert-Butoxycarbonylamino)propan-2-yloxy)-4-fluorophenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (250 mg) and TBTU (170 mg) was dissolved in DMF (3 ml) and triethylamine (1900) was added. The mixture was stirred at room temperature for 10 min, then 0.5 ml conc. ammonia was added. The reaction was stirred for 2 h. Then the reaction mixture was concentrated in vacuo and purified by RP-chromatography (water with 0.2% trifluoroacetic acid/methanol 72-100%) to give the title compound.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH:11]=[O:12])=[CH:9][C:8]([I:13])=[C:7]2[C:3]=1[CH:4]([O:24][CH3:25])[N:5]([C:15]([CH3:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[C:6]2=[O:14].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH3:33][S:34]([O:1][C:2]1[C:10]([CH:11]=[O:12])=[CH:9][C:8]([I:13])=[C:7]2[C:3]=1[CH:4]([O:24][CH3:25])[N:5]([C:15]([CH3:16])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:23])[C:6]2=[O:14])(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: COC1c2c(O)c(C=O)cc(I)c2C(=O)N1C(C)(C)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1c2c(OS(C)(=O)=O)c(C=O)cc(I)c2C(=O)N1C(C)(C)c1ccccc1
Yield: 100 %

Procedure:
In a similar manner to Step 1 of Example 289, 4-hydroxy-5-formyl-3-methoxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (325 mg, 0.720 mmol) was dissolved in dichloromethane (10 mL), and the solution was treated with triethylamine (0.401 mL, 2.88 mmol) and methanesulfonyl chloride (0.111 mL, 1.43 mmol), followed by purification by flash column chromatography (hexane/ethyl acetate=95/5 to 80/20) to obtain 4-methanesulfonyloxy-5-formyl-3-methoxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (381 mg, yield 58%).
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C@H:9]([OH:12])[CH2:10][OH:11])=[CH:5][CH:4]=1)#[N:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>N1C=CC=CC=1>[C:1]([C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C@H:9]([OH:12])[CH2:10][O:11][S:16]([CH3:15])(=[O:18])=[O:17])=[CH:5][CH:4]=1)#[N:2]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(OC[C@H](O)CO)cc1
Solvent: c1ccncc1
Product: CS(=O)(=O)OC[C@@H](O)COc1ccc(C#N)cc1
Reaction time: 8 h

Procedure:
57.2 g of (2R)-3-(4 cyanophenoxy)propane-1,2-diol was dissolved in dry pyridine, (300 ml) and treated dropwise with methanesulfonyl chloride, (20.7 ml), at -10° C. The reaction mixture was kept at 5° C. overnight, evaporated at reduced pressure and poured on ice and 2 M hydrochloric acid. The solid precipitate was recrystallized three times from methanol to yield 12.3 g of the title compound, m.p. 119°-121° C., [α]D20 +9.7° (c 1.0, CH3OH).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH2:21]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH2:21][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=C1CCCc2ccc(O)cc21
Reactant: Clc1ccc(Br)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CCCc2ccc(OCc3cc(Cl)ccc3Br)cc21
Reaction time: 18 h
Yield: 88.7 %

Procedure:
To a stirred solution of 7-hydroxy-1-tetralone (13.9 g, 85.7 mmol) and 1-bromo-2-(bromomethyl)-4-chlorobenzene (25.6 g, 90.0 mmol) in dimethylformamide (850 mL) was added potassium carbonate (24 g, 172 mmol). The reaction was stirred under argon for 18 hours then diluted with ethyl acetate (1 L). The organics were washed three times with water and once with brine. The organic layer was then dried with magnesium sulfate, filtered and concentrated. To the resulting oil was added methanol (500 mL) and the suspension was agitated for thirty minutes. 7-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1 (2H)-one (27.8 g, 89% yield) was isolated by filtration.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]([C:58]1[CH:63]=[CH:62][C:61]([CH3:64])=[CH:60][CH:59]=1)=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:56]([NH:55][C:58]2[CH:63]=[CH:62][C:61]([CH3:64])=[CH:60][CH:59]=2)=[O:57])[CH2:49][CH2:48]1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)cc1
Yield: 30 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1-isocyanato-4-methylbenzene as starting materials in 30% yield. LCMS for C32H34ClN8O2 (M+H)+: m/z=597.2.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH2:30][S:31][CH3:32])[C:23]4=[O:33])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.CO.[OH:36]OS([O-])=O.[K+]>O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH2:30][S:31]([CH3:32])=[O:36])[C:23]4=[O:33])=[CH:20][CH:21]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=S([O-])OO
Reactant: CSCCOc1cccn(-c2ccc(-n3cc(CNC(=O)c4ccc(Cl)s4)nn3)cc2)c1=O
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)CCOc1cccn(-c2ccc(-n3cc(CNC(=O)c4ccc(Cl)s4)nn3)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of Example 48 in a 2:1 mixture of methanol and water was added 1.0 equivalent of oxone. The mixture was stirred at room temperature for 10 min and directly subjected to reverse phase HPLC to isolate the title compound as a white powder after lyophilization. MS found for C22H20ClN5O4S2 (M+H)+ 518.1, 520.1 (Cl pattern).