Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[N:3]=[C:4]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15]3[S:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=3)[CH:10]=[CH:9][N:5]2[C:6](=[O:8])[CH:7]=1.C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>C(Cl)Cl>[CH:20]([C:18]1[N:19]=[C:15]([CH2:14][CH2:13][C:11]2[CH:10]=[CH:9][N:5]3[C:6](=[O:8])[CH:7]=[C:2]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[N:3]=[C:4]3[CH:12]=2)[S:16][CH:17]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1csc(CCc2ccn3c(=O)cc(O)nc3c2)n1
Reactant: C1COCCN1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1csc(CCc2ccn3c(=O)cc(N4CCOCC4)nc3c2)n1
Reaction time: 24 h

Procedure:
The 2-hydroxy-8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4 H-pyrido[1,2-a]-pyrimidin-4-one (500 mg) obtained in (A) was dissolved in methylene chloride (20 ml), added with triethylamine (0.26 ml) and p-toluenesulfonyl chloride (360 mg) and stirred for 24 hours under nitrogen atmosphere. The reaction solution was added with morpholine (0.83 ml) and stirred for 12 hours, and the solvent was evaporated. The residue was purified by silica gel column chromatography to obtain the title compound (273 mg).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[NH:10][CH:11]([CH2:31][OH:32])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:15]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]1([CH3:44])[C:35]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:37]=[CH:38][CH:39]=1.O>N1C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:33])[NH:10][CH:11]([CH2:31][O:32][S:40]([C:35]1[C:34]([CH3:44])=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:42])=[O:41])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:15]([C:27]([CH3:30])([CH3:28])[CH3:29])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(CC(CO)NC(=O)OCc2ccccc2)ccc1OCc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccccc1S(=O)(=O)OCC(Cc1ccc(OCc2ccccc2)c(C(C)(C)C)c1)NC(=O)OCc1ccccc1
Reaction time: 6.5 h
Yield: 88.3 %

Procedure:
To a solution of 2-(4-benzyloxy-3-t-butylphenyl)-1-hydroxymethylethylcarbamic acid benzyl ester (2.07 g, 4.63 mmol) in pyridine (46 ml), toluenesulfonyl chloride (6.79 g, 35.6 mmol) was added under cooling with ice. After stirring for 6.5 hours, the mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=2:1), giving the titled compound (2.46 g, 88%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[NH:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH:35]([CH3:37])[CH3:36])[CH2:31][CH2:30]3)=[O:28])=[CH:22][CH:21]=4)=[O:17])[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:38][C:39]1[CH:44]=[C:43](B(O)O)[CH:42]=[CH:41][N:40]=1>>[C:1]1([S:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([C:18]3[N:19]([C:43]4[CH:42]=[CH:41][N:40]=[C:39]([Cl:38])[CH:44]=4)[C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([C:27]([N:29]3[CH2:30][CH2:31][N:32]([CH:35]([CH3:37])[CH3:36])[CH2:33][CH2:34]3)=[O:28])=[CH:22][CH:21]=4)=[O:17])[CH2:14][CH2:15]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)c5ccccc5)CC4)cc3c2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)c4ccccc4)CC2)n3-c2ccnc(Cl)c2)CC1
Yield: 44 %

Procedure:
The title compound was synthesized in analogy to example 5, from (4-benzenesulfonyl-piperazin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 13) and 2-chloropyridine-4-boronic acid to afford the desired product as a light brown solid (44%). MS (ISP): 635.3 (M+H)+.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.Cl.[CH3:13][CH:14]([CH3:34])[CH2:15][C@H:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[NH2:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:17][C@@H:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:15][CH:14]([CH3:34])[CH3:13])=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc(F)nc1
Reactant: CC(C)C[C@@H](N)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N[C@H](CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Temperature: 110 °C
Reaction time: 15 h
Yield: 107.4 %

Procedure:
A 1.0 L round bottom flask was charged with methyl 6-fluoronicotinate (14.2 g, 91.6 mmol), (R)-3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butan-1-amine hydrochloride (30.0 g, 87.3 mmol), potassium carbonate (36.2 g, 262 mmol) and N,N-dimethylformamide (300 mL). The reaction was heated to 110° C. and stirred for 15 hours. The reaction was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate and saturated ammonium chloride. The layers were separated and the aqueous was extracted with ethyl acetate. The combined organic layers were washed with water (5×) and brine (1×), dried over sodium sulfate, filtered and concentrated to provide (R)-methyl-6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinate (41.5 g) as a light brown solid. 1H NMR (400 MHz, CDCl3, δ): 0.98 (d, J=6.24 Hz, 3H) 1.02 (d, J=6.24 Hz, 3H) 1.67-1.92 (m, 3H) 3.86 (s, 3H) 4.68-4.84 (m, 1H) 6.36 (d, J=8.97 Hz, 1H) 6.65 (br. s., 1H) 7.42-7.47 (m, 2H) 7.55-7.59 (m, 2H) 7.66-7.69 (m, 4H) 8.00 (dd, J=8.97, 2.15 Hz, 1H) 8.66 (d, J=1.95 Hz, 1H). MS (M+1): 443.4.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[C:11]([O:15][C:16]([NH:18][CH2:19][CH2:20][C:21](O)=[O:22])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:11]([O:15][C:16](=[O:17])[NH:18][CH2:19][CH2:20][C:21]([CH:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9])=[O:22])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (3.81 g, 26.4 mmol) in CH2Cl2 (34 mL) at 0° C. was added 3-[(tert-butoxycarbonyl)amino]propanoic acid (5.0 g, 26.4 mmol), DMAP (4.84 g, 39.6 mmol), and EDC (6.08 g, 31.7 mmol). The mixture was stirred at rt for 5 h. The resulting mixture was washed with 10% aq. KHSO4 (4×), dried (Na2SO4) and concentrated to afford the title compound which was used without further purification. LRMS (ESI) m/z 316.1 [(M+H)+; calcd for C14H21NO7: 316].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][C:23]([C:25]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)=[N:22][C:21]=3[C:38](=[O:40])[NH2:39])=[CH:16][CH:15]=2)[CH2:10][C:9]1([CH3:42])[CH3:41])=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:36][C:34]([F:35])([F:37])[C:31]1[CH:32]=[CH:33][C:25]([C:23]2[O:24][C:20]([C:17]3[CH:16]=[CH:15][C:14]([N:11]4[CH2:12][CH2:13][NH:8][C:9]([CH3:41])([CH3:42])[CH2:10]4)=[CH:19][CH:18]=3)=[C:21]([C:38]([NH2:39])=[O:40])[N:22]=2)=[C:26]2[C:30]=1[NH:29][CH:28]=[CH:27]2
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3oc(-c4ccc(C(F)(F)F)c5[nH]ccc45)nc3C(N)=O)cc2)CC1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CN(c2ccc(-c3oc(-c4ccc(C(F)(F)F)c5[nH]ccc45)nc3C(N)=O)cc2)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.2 %

Procedure:
4-{4-[4-Carbamoyl-2-(7-trifluoromethyl-1H-indol-4-yl)-oxazol-5-yl]-phenyl}-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.18 g crude) was dissolved in a mixture of DCM and TFA (30 mL 2:1), and the solution was stirred at RT for 2 hrs, when the solvent was removed in vacuo. The residue was partitioned between water and EtOAc. The organic phase was dried over Na2SO4 and the solvent was removed in vacuo to give the crude product which was purified by prep-HPLC to give the title compound (60 mg, 41% from ethyl 5-(4-(4-(tert-butoxycarbonyl)-3,3-dimethylpiperazin-1-yl)phenyl)-2-iodooxazole-4-carboxylate).
Reaction SMILES: [OH:1]S(O)(=O)=O.[CH2:6]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Br:16])[CH:7]=[CH2:8]>O>[Br:16][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[O:9][CH2:6][CH:7]([OH:1])[CH2:8]2
Reactant: C=CCOc1ccccc1Br
Reactant: O=S(=O)(O)O
Solvent: O
Product: OC1COc2c(Br)cccc2C1
Reaction time: 0.5 h

Procedure:
Tl2O3 (2.38 g, 5.2 mmol) was added at room temperature to a mixture of H2SO4 (6.9 ml) and water (6.1 ml) and this mixture was stirred for 30 min and added to o-allyloxy-bromo-benzene (1.9 g, 8.92 mmol) and water was added (37 ml). The reaction mixture was stirred in 60° C. under Argon. The product was extracted with CH2Cl2 and the organic layer was washed with water, dried (Na2SO4), filtered and the solvent was removed under reduced pressure to give 1.34 g of a raw oil, which was chromatographed (SiO2 and ether as eluant). The fractions containing at least 85% purity of the product were pooled and the solvent was removed, yielding 310 mg of an oil. GC/MS showed M+ /M+2 at m/e=228.00(100%)/230.00(88%).
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[C:13]([NH:15][CH:16]2[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)[CH:12]=[CH:11][C:10]=1[C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])=O)(C)(C)C.[ClH:35]>O1CCOCC1.C(OCC)C>[ClH:35].[NH2:8][C:9]1[C:10]([C:29](=[O:34])[C:30]([F:32])([F:33])[F:31])=[CH:11][CH:12]=[C:13]([NH:15][CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[N:14]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(NC2CCCN(C(=O)OC(C)(C)C)C2)ccc1C(=O)C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Nc1nc(NC2CCCNC2)ccc1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
670 mg (1.37 mmol) of tert-butyl 3-({6-[(tert-butoxycarbonyl)amino]-5-(trifluoroacetyl)pyridin-2-yl}amino)piperidine-1-carboxylate (Example 12A) were dissolved in 25 ml of a hydrochloric acid solution in dioxane (4 M) and stirred at RT for 20 h. On completion of reaction, the reaction mixture was diluted with diethyl ether (100 ml), and the precipitate was filtered off completely and washed with diethyl ether (100 ml) and dried. 286 mg (64% of theory) of the product were obtained in solid form.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:29])[C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([NH:20][CH3:21])=[C:13]([CH3:22])[C:12]=2[N:23]2[CH2:28][CH:27]3[CH:25]([CH2:26]3)[CH2:24]2)[CH2:5][CH2:4]1>[Pd].CO>[F:30][C:2]([F:1])([F:31])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:29])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:20][CH3:21])=[C:13]([CH3:22])[C:12]=2[N:23]2[CH2:24][CH:25]3[CH:27]([CH2:26]3)[CH2:28]2)[CH2:5][CH2:4]1
Reactant: CNc1c([N+](=O)[O-])cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(N2CC3CC3C2)c1C
Agent: [Pd]
Solvent: CO
Product: CNc1c(N)cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(N2CC3CC3C2)c1C

Procedure:
The sub-title compound is prepared in analogy to 6b from N-(trans-4-trifluoromethyl-cyclohexyl)-2-[3-aza-bicyclo[3.1.0]hex-3-yl]-3-methyl-4-methylamino-5-nitro-benzoic acid amide (130 mg, 0.295 mmol), Pd/C (50 mg), MeOH (40 mL) and 3 bar H2-atmosphere. Yield: 85 mg. HPLC Rt=1.31 min (method A). MS m/z: 411 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[N:5]=[C:4]([CH3:18])[N:3]=1.[CH3:19][C:20]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:21]=1[NH2:22]>>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]([CH3:18])[N:3]=[C:2]([NH:22][C:21]3[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:20]=3[CH3:19])[CH:7]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: COc1ccc(-c2cc(Cl)nc(C)n2)cc1OC
Reactant: Cc1cc(C)c(N)c(C)c1
Product: COc1ccc(-c2cc(Nc3c(C)cc(C)cc3C)nc(C)n2)cc1OC
Temperature: 120 °C

Procedure:
The mixture of 4-chloro-6-(3,4-dimethoxyphenyl)-2-methylpyrimidine (2.0 g) and 2,4,6-trimethylaniline (5.3 ml) was stirred at 120° C. for an hour. After cooled, the mixture was triturated with ethyl acetate. The precipitates were collected, and dissolved in chloroform. The solution was washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate, and evaporated to give 6-(3,4-dimethoxyphenyl)-2-methyl-4-(2,4,6-trimethylphenylamino)pyrimidine (2.39 g).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[F:6][C:7]([F:18])([F:17])[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](Cl)=[O:12]>C1C=CC=CC=1.ClCCl>[C:1]([NH:5][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([C:7]([F:6])([F:17])[F:18])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: c1ccccc1
Product: CC(C)(C)NC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To tert-butylamine (2.0 eq) in 75 mL of benzene is added 3-trifluoromethylbenzoyl chloride (1.0 eq). The temperature is maintained below 15° C. during the addition and then the reaction mixture is allowed to warm to ambient temperature and stirred for 3 hours. The solvent is then stripped and the residue is dissolved in 75 mL of dichloromethane. This solution is washed with 5% hydrochloride acid (2×75 mL), water (2×75 mL), dried over MgSO4 and then the solvent is removed in vacuo to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[NH:10][C:11]1[N:16]2[N:17]=[CH:18][C:19]([S:20]([NH2:23])(=[O:22])=[O:21])=[C:15]2[N:14]=[CH:13][C:12]=1[C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25].[C:39](O)(=[O:42])[CH2:40][CH3:41]>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[NH:10][C:11]1[N:16]2[N:17]=[CH:18][C:19]([S:20]([NH:23][C:39](=[O:42])[CH2:40][CH3:41])(=[O:22])=[O:21])=[C:15]2[N:14]=[CH:13][C:12]=1[C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:28][CH2:27]1)=[O:25]
Reactant: CCC(=O)O
Reactant: Cc1cc(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(S(N)(=O)=O)cnn23)c(Cl)cc1F
Product: CCC(=O)NS(=O)(=O)c1cnn2c(Nc3cc(C)c(F)cc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 94.7 %

Procedure:
Using 7-(2-chloro-4-fluoro-5-methylphenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.050 g, 0.089 mmol) obtained in step 5 and propionic acid (0.033 mL, 0.446 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.052 g, 95%) was obtained.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[CH3:8][C:9]([CH3:12])([O-])[CH3:10].[K+].C(O)C(N)(CO)CO>C(Cl)Cl>[CH3:1][CH:2]([CH2:6][CH3:7])[C:3]([O:5][C:9]([CH3:12])([CH3:10])[CH3:8])=[O:4]
Reactant: CC(C)(C)[O-]
Reactant: CCC(C)C(=O)O
Agent: NC(CO)(CO)CO
Agent: [K+]
Solvent: ClCCl
Product: CCC(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2-methylbutanoic acid (1.029 Ml, 8.29 mmol) in DCM (10 Ml) was added potassium tert-butoxide (20 wt % in THF) (4.66 Ml, 8.29 mmol) dropwise at 0° C. The resulting suspension was allowed to warm to room temperature, and stirred for 1.5 hr. The reaction mixture was diluted with DCM (10 Ml), MP-®Trisamine Resin (3.86 g, 3.22 mMol/g; Argonaut Technologies, Inc.) was added, and the resulting suspension was stirred at room temperature for 1.5 hours. The resin was removed by vacuum filtration, and the resulting filtrate was washed with 1 N NaOH (1×20 Ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated to afford tert-butyl 2-methylbutanoate. 1H NMR (500 MHz, CDCl3) δ 2.24 (sextet, 1H), 1.61 (m, 1H), 1.44-1.39 (overlapping s, m, 10H), 1.09 (d, 3H), 0.90 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[CH:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27]>>[CH2:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH:17]1[N:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([CH:26]=[O:27])[CH:33]=2)=[CH:3][CH:4]=1)[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Br)cc1)C1Cc2ccccc2C1
Reactant: O=Cc1cccc(B(O)O)c1
Product: CC(C)(C)OC(=O)N(Cc1ccc(-c2cccc(C=O)c2)cc1)C1Cc2ccccc2C1

Procedure:
The title compound was prepared from 1,1-dimethylethyl [(4-bromophenyl)methyl]2,3-dihydro-1H-inden-2-ylcarbamate (Example V-13) and 3-formylphenylboronic acid according to the procedure described in Example VI-16 Step 1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35 (s, 9 H), 3.00 (d, J=8.56 Hz, 4 H), 4.51 (br. s., 2 H), 7.06-7.19 (m, 4 H), 7.34 (d, J=8.03 Hz, 2 H), 7.69 (t, J=7.67 Hz, 1 H), 7.72-7.77 (m, 2 H), 7.86-7.91 (m, 1 H), 8.01-8.06 (m, 1 H), 8.19-8.24 (m, 1 H), 10.10 (s, 1 H).
Reaction SMILES: [C:1]([CH2:5][C:6](Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:9](=[CH2:11])=[N-:10].C(O)(=O)C>C(OCC)C>[N+:9](=[CH:11][C:6](=[O:7])[CH2:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N-:10]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)(C)CC(=O)C=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl acetyl chloride (1.136 grams) in dry ethyl ether (10 mL) was slowly added to a 0° C. diethyl ether (20 mL) solution of freshly generated diazomethane (from 20 grams Diazald). After stirring for 30 minutes, the reaction was warmed to ambient temperature for another 30 minutes. Acetic acid (2 mL) was added and the reaction partitioned between methyl tert-butyl ether and water. The organic was washed once with water, dried over magnesium sulfate and filtered. Concentration afforded an oil containing the title compound which was immediately used with no further purification.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][O:16][C:17]([C:19]1[CH:20]=[C:21]([CH3:43])[C:22]2[O:28][C:27]3[C:29]([Cl:39])=[CH:30][C:31]([N:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)=[CH:32][C:26]=3[CH2:25][S:24](=[O:41])(=[O:40])[C:23]=2[CH:42]=1)=[O:18]>CN(C=O)C>[CH3:15][O:16][C:17]([C:19]1[CH:20]=[C:21]([CH3:43])[C:22]2[O:28][C:27]3[C:29]([Cl:39])=[CH:30][C:31]([N:33]4[CH2:34][CH2:35][N:36]([CH2:7][C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[CH2:37][CH2:38]4)=[CH:32][C:26]=3[CH2:25][S:24](=[O:40])(=[O:41])[C:23]=2[CH:42]=1)=[O:18]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(Cc4ccccc4)CC3)cc(Cl)c1O2
Temperature: 80 °C

Procedure:
A mixture of cesium carbonate (0.33 g, 0.82 mmol) and benzyl chloride (0.1 mL, 0.82 mmol) was added to a solution of 4-chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester (free base of example 16, 0.3 g, 0.68 mmol) in DMF(10 mL) and heated at 80° C. for 5 h. Reaction mixture was concentrated, water (10 mL) was added and the solid filtered. The crude obtained was purified by column chromatography (silica gel, 1% to 3% methanol in chloroform) to obtain the title compound. Yield: 0.11 g, (30.4%); 1H NMR (DMSO-d6, 300 MHz): δ 2.62 (s, 3H, CH3), 3.18 (s, 4H, 2CH2), 3.31 (s, 4H, 2CH2), 3.50 (s, 2H, CH2), 3.85 (s, 3H, OCH3), 5.14 (s, 2H, CH2), 7.04 (s, 1H, Ar), 7.11 (s, 1H, Ar), 7.3-7.32 (m, 5H, Ar), 8.08 (s, 1H, Ar), 8.14 (s, 1H, Ar); MS: m/e (ES+) 528 (M+1); analysis: C27H27ClN2O5S requires C, 61.53,H, 5.16, N, 5.32, Cl, 6.73, S, 6.08; found: C, 61.22, H, 4.99, N, 4.82, Cl, 6.91, S, 6.15%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33]([O:35][CH2:36][C:37](O)=[O:38])=[O:34].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:37](=[O:38])[CH2:36][O:35][C:33]([C:29]1[S:28][CH:32]=[CH:31][CH:30]=1)=[O:34]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: O=C(O)COC(=O)c1cccs1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(COC(=O)c1cccs1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.9 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (150 mg, 0.357 mmol), 2-(thiophene-2-carbonyloxy)acetic acid (80 mg, 0.428 mmol), EDC (205 mg, 1.071 mmol), and DMAP (43.6 mg, 0.357 mmol) were dissolved in DCM (15 ml), and the solution was stirred at room temperature overnight. The solution was diluted with DCM, washed with 1N HCl and 5% NaHCO3, then with brine. The organic phase was dried over Na2SO4, and the solvent was evaporated. The crude so obtained (233 mg of a pale yellow solid) was triturated with MeOH and sonicated; the fine solid so obtained was filtered and dried in vacuum oven overnight. The desired product was obtained as a white powder (133 mg, 0.226 mmol, 63.3% yield, LC-MS/ESI+ 588.04 [MH]+, [αD]=−24.78, c=0.51, CHCl3).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[C:5](=[O:28])[N:4]([CH3:29])[CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:13][CH:14]=2)[C:5](=[O:28])[N:4]([CH3:29])[CH:3]=1
Reactant: Cn1cc(Br)nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(Br)nc(Nc2ccc(C3CCNCC3)cc2)c1=O
Yield: 99.4 %

Procedure:
Compound 214a was synthesized using the same procedure as for 121c, except using tert-butyl 4-(4-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)phenyl)-piperidine-1-carboxylate (121a) (0.53 g, 1.08 mmol), trifluoroacetic acid (0.9 mL, 10.8 mmol) and methylene chloride (20 mL). Work-up and concentration afforded a quantitative yield of 214a (390 mg) as yellow oil, which was used without purification in the next step.
Reaction SMILES: FC(F)(F)S(O[Si:7]([CH3:18])([CH3:17])[CH:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH3:15])=[C:9]1[CH3:16])(=O)=O.[CH3:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[CH3:31])[C-:27]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:26]=[CH:25]2.[Li+]>CCOCC>[CH3:31][C:30]1[CH:29]=[C:28]2[C:24](=[CH:23][C:22]=1[CH3:21])[CH:25]([Si:7]([CH3:17])([CH3:18])[CH:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH3:15])=[C:9]1[CH3:16])[CH:26]=[C:27]2[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1cc2cc[c-](-c3ccccc3)c2cc1C
Reactant: CC1=C(C)C([Si](C)(C)OS(=O)(=O)C(F)(F)F)C(C)=C1C
Agent: [Li+]
Solvent: CCOCC
Product: CC1=C(C)C([Si](C)(C)C2C=C(c3ccccc3)c3cc(C)c(C)cc32)C(C)=C1C
Reaction time: 24 h

Procedure:
To a solution of dimethyl(2,3,4,5-tetramethylcyclopenta-2,4-dien-1-yl)silyl trifluoromethanesulfonate (Compound C, 7.50 g, 22.8 mmol, 1.00 eq.) in ether (25 mL) at −35° C. was added lithium (5,6-dimethyl-1-phenylindenide) (5.53 g, 24.4 mmol, 1.07 eq.). The reaction was stirred for 24 hours, and was then evaporated under vacuum. The residue was extracted with pentane (40 mL, then 2×25 mL) and the extract was filtered. The resulting solution was evaporated under vacuum to give a sticky solid. Yield 9.34 g (103%). 1H NMR(C6D6): δ 7.71 (d, 2H), 7.62 (s, 1H), 7.36 (s, 1H), 7.31 (t, 2H), 7.20 (m, 1H), 6.57 (s, 1H), 3.70, (s, 1H), 2.98 (br s, 1H), 2.23 (s, 3H), 2.17 (s, 3H), 1.97 (s, 3H), 1.95 (s, 3H), 1.84 (s, 6H), −0.04 (s, 3H), −0.32 (s, 3H).