Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:21])[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]([CH2:18][CH2:19][CH3:20])[CH3:17])[CH:11]=[CH:10]2)([CH3:3])[CH3:2].CN(CCN(C)C)C.[Si:30](OS(C(F)(F)F)(=O)=O)([C:33](C)(C)C)([CH3:32])[CH3:31].[Li]CCCC.Cl[Si](C)(C)C>CCOCC.C1COCC1.CCCCC>[CH:1]([NH:4][C:5](=[O:21])[O:6][C:7]1[C:8]([Si:30]([CH3:33])([CH3:32])[CH3:31])=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]([CH2:18][CH2:19][CH3:20])[CH3:17])[CH:11]=[CH:10]2)([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCCC(C)n1ccc2cc(OC(=O)NC(C)C)ccc21
Agent: CN(C)CCN(C)C
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCC
Product: CCCC(C)n1ccc2c([Si](C)(C)C)c(OC(=O)NC(C)C)ccc21
Temperature: 0 °C

Procedure:
To a stirred solution of 1-(pentan-2-yl)-1H-indol-5-yl isopropylcarbamate (11) (5.752 g, 19.9 mmol, 1.0 equiv.) in Et2O (143 mL) and THF (48 mL) was added TMEDA (4.19 mL, 27.9 mmol, 1.4 equiv.), and the solution was cooled to 0° C. Then, a solution of TBSOTf (5.50 mL, 23.9 mmol, 1.2 equiv.) in n-pentane (16 mL) was added, and the reaction mixture was left to stir for 5 minutes at 0° C., at which point the ice bath was removed and the reaction was stirred for 45 additional minutes. TMEDA (8.97 mL, 59.8 mmol, 3.0 equiv.) was added and the mixture was cooled to −78° C., followed by the slow addition of n-BuLi (2.5 M in hexanes, 23.9 mL, 59.8 mmol, 3.0 equiv.) over 10 minutes. The reaction mixture was stirred at −78° C. for 3 h before chlorotrimethylsilane (TMSCl, 17.4 mL, 140 mmol, 7.0 equiv.) was added slowly over 15 minutes. The reaction mixture was stirred at −78° C. for an additional 1 h. The reaction mixture was quenched with 4 mL of MeOH, followed by 200 mL of 2 M hydrochloric acid, and allowed to warm to room temperature over 1 h with vigorous stirring. Diethylether (100 mL) was added, and the organic phase was separated. The organic phase was washed with 100 mL of water, 100 mL of brine, dried over MgSO4 and concentrated. The crude material was purified via column chromatography (hexane:EtOAc, (gradient of 19:1→15:1→9:1, v/v)) to give 4-(trimethylsilyl)-1-(pentan-2-yl)-1H-indol-5-yl isopropylcarbamate (22) as a very viscous colorless liquid (6.15 g, 86%). 1H NMR (500 MHz, CDCl3) δ7.34 (d, J=8.8 Hz, 1H), 7.21 (d, J=3.3 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 6.66 (d, J=3.2 Hz, 1H), 4.75 (d, J=8.0 Hz, 1H), 4.46 (m, 1H), 3.94 (m, 1H), 1.87 (m, 1H), 1.76 (m, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.30-1.15 (m, 8H), 0.88 (t, J=7.4 Hz, 3H), 0.41 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](O)=[CH:4][C:3]=1[C:13]([OH:15])=[O:14].Cl.[CH2:17]([OH:19])[CH3:18]>>[OH:19][CH:17]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:13]([OH:15])=[O:14])[CH3:18]
Reactant: O=C(O)c1cc(O)c2ccccc2c1O
Reactant: CCO
Agent: Cl
Product: CC(O)Oc1c(C(=O)O)ccc2ccccc12

Procedure:
By refluxing an ethanol solution of 1,4-dihydroxy-2-naphthoic acid under heating and passing hydrogen chloride gas through the solution for 5 hours, 1-hydroxy-ethoxy-2-naphthoic acid having a melting point of 190-195° C was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CI.[C:17]([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCOC(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([CH3:17])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Br)cc2)CCNCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1CCC(O)(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.1 %

Procedure:
A reaction mixture of 4-(4-bromophenyl)piperidin-4-ol (1.5 g, 5.9 mmol), methyl iodide (0.4 mL, 6.4 mmol), and K2CO3 (1.2 g, 8.8 mmol) in acetone was stirred at rt for 90 min. The reaction was diluted with EtOAc and water was added. The resulting mixture was extracted with EtOAc and the combined organic extracts were dried over MgSO4 and concentrated to give the title compound as a yellow solid (1.5 g, used without further purification). 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=8.1 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H), 3.20 (br s, 1H), 2.64-2.61 (m, 2H), 2.39 (t, J=11.8 Hz, 2H), 2.21 (s, 3H), 2.03-1.96 (m, 2H), 1.64-1.61 (m, 2H); MS ESI 270.0 [M+H]+, calcd for [C12H16BrNO+H]+ 270.04.
Reaction SMILES: [C:1]([NH:4][N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:16])(=[O:3])[CH3:2].[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:1]([N:4]([C:17](=[O:19])[CH3:18])[N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)Nn1c(=O)[nH]c2ccccc2c1=O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N(C(C)=O)n1c(=O)[nH]c2ccccc2c1=O

Procedure:
4 g 3-N-acetylamino(1H,3H)quinazoline-2,4-dione are refluxed for 5 hours in 200 cc acetic anhydride. Excess acetic anhydride is then distilled off under reduced pressure. The resulting residue is crystallized from benzene. M.p.=210° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:24])[CH:11]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:12]=C)(=[O:7])=[O:6].O=O.[O:28]=[O+][O-].CSC>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:25])[CH:11]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH:12]=[O:28])(=[O:6])=[O:7]
Reactant: O=[O+][O-]
Reactant: C=CC(OCc1ccc(OC)cc1)C(C)(C)COS(=O)(=O)CCCCl
Agent: O=O
Solvent: ClCCl
Solvent: CSC
Product: COc1ccc(COC(C=O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Yield: 77 %

Procedure:
Following the general procedure for the preparation of aldehydes from alkenes of Description 11, (3R/S)-3-[(4-methoxyphenyl)methoxy]-2,2-dimethylpent-4-enyl (3-chloropropyl)sulfonate (14a) (4.0 g, 10.2 mmol) dissolved in 100 mL of dichloromethane (DCM) was treated with a mixture of oxygen and ozone (O2/O3). Upon completion of the reaction, 2 mL (1.69 g, 27.2 mmol) of dimethyl sulfide (DMS) was added. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 3.1 g (77% yield) of the title compound (14b) as a colorless oil. The analytical data was consistent with the proposed structure and with the data obtained for the enantiopure compound (13b).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C:10]1[C:19]([CH3:20])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:21])[CH:11]=1.[C:22](Cl)(=[O:24])[CH3:23].C(=O)([O-])O.[Na+]>ClCCl>[C:22]([NH:9][C:10]1[C:19]([CH3:20])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:21])[CH:11]=1)(=[O:24])[CH3:23]
Reactant: COC(=O)c1cc(C)c(N)cc1C
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C)c(NC(C)=O)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 111.4 %

Procedure:
Triethylamine (1.16 ml, 8.32 mmol) was added to a suspension of methyl 4-amino-2,5-dimethylbenzoate monohydrochloride (0.600 g, 2.78 mmol) in dichloromethane (8 ml), and the resulting mixture was cooled with ice water, followed by adding dropwise thereto a solution of acetyl chloride (0.263 g, 3.35 mmol) in dichloromethane (2 ml). The resulting mixture was heated to room temperature and stirred for 3 hours, and then acetyl chloride (0.262 g, 3.34 mmol) was further added thereto and stirred for 1.5 hours. The resulting mixture was added to a saturated aqueous sodium hydrogencarbonate solution and extracted three times with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain methyl 4-(acetylamino)-2,5-dimethylbenzoate (0.685 g, 99%).
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH:8]1[C:13](=O)[CH2:12][CH2:11][CH2:10][C:9]1=[O:15])([O:3]CC)=O.[C:16]1([CH2:22][CH2:23][NH2:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C(C)=CC=CC=1>O>[C:16]1([CH2:22][CH2:23][N:24]2[C:13]3[CH2:12][CH2:11][CH2:10][C:9](=[O:15])[C:8]=3[CH2:7][CH2:6][C:1]2=[O:3])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCc1ccccc1
Reactant: CCOC(=O)CCC1C(=O)CCCC1=O
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1CCCC2=C1CCC(=O)N2CCc1ccccc1

Procedure:
Prepared analogously to Example 27 from 2-(2-carbethoxy-ethyl)-cyclohexan-1,3-dione and 2-phenylethylamine in boiling xylene using a water separator.
Reaction SMILES: [Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C@@H:4]1[C@H:6]([C:7](Cl)=[O:8])[C:5]1([CH3:11])[CH3:10].[CH3:16][C:17]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:29][OH:30].N1C=CC=CC=1.ClC(C(F)(F)F)=C[C@@H]1[C@H](C(OC)=O)C1(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C@@H:4]1[C@H:6]([C:7]([O:30][CH2:29][C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:17]=2[CH3:16])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: Cc1c(CO)cccc1-c1ccccn1
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Agent: COC(=O)[C@H]1[C@@H](C=C(Cl)C(F)(F)F)C1(C)C
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1c(COC(=O)[C@H]2[C@@H](C=C(Cl)C(F)(F)F)C2(C)C)cccc1-c1ccccn1

Procedure:
This reaction was conducted in the manner of Example 3, Step 2 using 0.58 g (0.002 mol) of cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride, 0.44 g (0.002 mol) of 2-methyl-3-(2-pyridyl)phenylmethanol, and 0.18 mL (0.002 mol) of pyridine in 30 mL of toluene. The yield of [2-methyl-3-pyridin-2-yl)phenyl]methyl cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate was 0.8 g, b.p. 170° C./0.05 mm.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3](CS([O-])(=O)=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C>[F:1][C:2]([F:16])([F:15])[CH:3]([N:17]=[N+:18]=[N-:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)([O-])CC(c1ccccc1)C(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(c1ccccc1)C(F)(F)F
Temperature: 60 °C
Reaction time: 48 h
Yield: 38.4 %

Procedure:
To a solution of α-(trifluoromethyl)benzylmesylate (2.8 g, 11.0 mmol) in DMF (15 mL), sodium azide (7.38 g, 110 mmol) was added. The reaction mixture was stirred at 60° C. for 48 hours. Then the reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel gave the desired product (849 mg, 37%). EI-MS m/z 202 (M+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][CH:17]=[C:18]([CH2:20][CH2:21][NH:22]C(=O)C(F)(F)F)[N:19]=2)=[CH:11][CH:10]=1)#[N:8]>CO.O>[NH2:22][CH2:21][CH2:20][C:18]1[N:19]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([C:7]#[N:8])=[CH:10][CH:11]=2)[O:16][CH:17]=1
Reactant: N#Cc1ccc(-c2nc(CCNC(=O)C(F)(F)F)co2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(-c2nc(CCN)co2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
K2CO3 (0.20 g, 1.45 mmol) was added portionwise to a solution of N-(2-(2-(4-cyanophenyl)oxazol-4-yl)ethyl)-2,2,2-trifluoroacetamide (0.15 g, 0.49 mmol) in dry methanol:water (10 mL, 7:3 v/v). The reaction mixture was stirred at room temperature for 3 h and then diluted with water. The crude product was extracted with chloroform. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get 4-(4-(2-aminoethyl)oxazol-2-yl)benzonitrile (80 mg), which was used for the next step without further purification. MS (ESI) m/z: Calculated for C12H11N3O: 213.09. found: 214.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([C:13](O)=[O:14])[CH2:9]2)=[CH:4][C:3]=1[C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:18]=2[N:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([C:13]([N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)=[O:14])[CH2:9]2)=[CH:4][C:3]=1[C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:18]=2[N:17]=1
Reactant: Cc1ccc2[nH]c(-c3cc(N4CCC(C(=O)O)C4)ccc3Cl)nc2c1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Product: Cc1ccc2[nH]c(-c3cc(N4CCC(C(=O)N5CCOCC5)C4)ccc3Cl)nc2c1
Temperature: 35 °C
Yield: 47.1 %

Procedure:
Method E—Step a To a vial with 1-[4-Chloro-3-(5-methyl-1H-benzoimidazol-2-yl)-phenyl]-pyrrolidine-3-carboxylic acid (obtained as described in general method 5, step b) (0.09 g, 0.25 mmol), HATU (0.10 g, 0.26 mmol), TEA (0.07 mL, 0.53 mmol) and morpholine (0.03 mL, 0.33 mmol) dichloromethane (2 mL) was added and the reaction mixture was heated at 35° C. overnight. Reaction was cooled to room temperature, saturated NaHCO3 solution (2 mL) was added with stirring, the organic layer recovered by filtration through phase separator, and the solvent removed under reduced pressure. The crude was purified by NH2 column (eluent: dichloromethane:MeOH from 10:0 to 5:5), and SCX to obtain 0.05 g of the title compound (46%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19]CC)=[O:18])=[CH:12][CH:11]=1)=[O:5])C.[OH-].[K+]>>[C:4]([C:6]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:7]=1[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:14][CH:15]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)Cc1ccc(OCc2cc(OC)ccc2C(=O)OCC)cc1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(C(=O)O)c(COc2ccc(CC(=O)O)cc2)c1

Procedure:
Reaction of ethyl 4-(2-ethoxycarbonyl-5-methoxybenzyloxy)phenylacetate with potassium hydroxide as described in Example 1c provides 4-(2-carboxy-5-methoxybenzyloxy)phenylacetic acid as colorless crystals, mp 200°-208° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.[CH3:18][S:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[N:26][CH:27]=1)(=[O:21])=[O:20].C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:18][S:19]([C:22]1[CH:23]=[C:24]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[C:5]3[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:25]=[N:26][CH:27]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1cncc(B(O)O)c1
Reactant: Brc1ccc2nccc(-c3ccncc3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cncc(-c2ccc3nccc(-c4ccncc4)c3c2)c1
Temperature: 25 °C

Procedure:
A mixture of (6-bromo-4-(4-pyridinyl)quinoline (250 mg, 0.88 mmol), 5-methylsulfonyl pyridine-3-boronic acid (201 mg, 1.0 mmol), tetrakistriphenylphosphine palladium (0) (104 mg, 0.09 mmol), and sat. aqueous NaHCO3 (1.75 mL), in dioxane (5 mL) was heated at 110° C. for 1 h then cooled to room temperature. The r×n was filtered through Celite and Na2SO4 onto silica and the crude product was purified by column chromatography (5% EtOAc/Hex—10% Ethanol/EtOAc; 30 min gradient). Evaporation and precipitation from MeOH/water (2/98) provided the title compound as a yellow solid. (160 mg, 50%). ESMS [M+H]+=362.1
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N:16]1[CH2:21][CH2:20][CH2:19][CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1.[NH2:30][C:31]1[C:32]([C:38](O)=[O:39])=[N:33][C:34]([Br:37])=[CH:35][N:36]=1>C(#N)C>[NH2:30][C:31]1[C:32]([C:38]([NH:1][C:2]2[CH:7]=[C:6]([C:8](=[O:15])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:5]=[CH:4][C:3]=2[N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:17]2)=[O:39])=[N:33][C:34]([Br:37])=[CH:35][N:36]=1
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ccc(C(=O)c3ccccc3)cc2N)C1
Reactant: Nc1ncc(Br)nc1C(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCCN(c2ccc(C(=O)c3ccccc3)cc2NC(=O)c2nc(Br)cnc2N)C1
Yield: 30 %

Procedure:
Following method 11, tert-butyl 1-(2-amino-4-benzoylphenyl)piperidin-3-ylcarbamate was coupled to 3-amino-6-bromopyrazine-2-carboxylic acid with TEA (1.5 eq) in ACN at 55° C. for 48 hours. Concentrated, triturated in cold ACN, filtered, and dried in vacuo yielding tert-butyl 1-(2-(3-amino-6-bromopyrazine-2-carboxamido)-4-benzoylphenyl)piperidin-3-ylcarbamate (30%). LCMS (m/z): 595.1 (MH+); LC Rt=3.87 min.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:9]([CH2:22][CH3:23])[C:10]([C:12]([CH2:20][CH3:21])([CH2:18][CH3:19])[C:13](OCC)=[O:14])=O)[CH3:8].CC(OC(C)=O)=O.O>C1COCC1.C(Cl)(Cl)Cl>[CH2:22]([N:9]([CH2:7][CH3:8])[CH2:10][C:12]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:13][OH:14])[CH3:23]
Reactant: CCOC(=O)C(CC)(CC)C(=O)N(CC)CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)CC(CC)(CC)CO
Reaction time: 0.2 h
Yield: 48.9 %

Procedure:
To THF (300 ml.) is added LiAlH4 (1.2 g), the mixture is refluxed for 20 min, and an additional quantity of LiAlH4 (15.8 g., 0.42 mole) is added in two portions at 5°-21° over 1 min with mechanical stirring. The mixture is cooled to 5° and a solution of ethyl 2-(N,N-diethylcarbamoyl)-2-ethylbutyrate (29 g., 0.12 mole) in THF (80 ml.) is added at 5°-11° in 5 min. The temperature (exothermic) is allowed to rise to 60° over 12 min, is maintained at 49°-53° for 7 min, is heated gradually to reflux over 10 min, and then is refluxed for 6 hours. After it stands at room temperature for 18 hours, the reaction mixture is treated with Ac2O (55 ml.) at 10°-20°, is stirred in an ice bath for 0.5 hour, is treated with H2O (150 ml.) at 10°-18°, and finally is treated with CHCl3 (250 ml.) at 10°-22° with slow stirring. The CHCl3 -layer is washed with H2O (50 ml.), is dried over MgSO4, is filtered, and is concentrated to dryness under reduced pressure. The resultant oil (30 ml.) is treated with 10% HCl (280 ml.) and is subjected to steam distillation for 1.3 hours, collecting 1 liter of distillate. The distillate is concentrated to 50 ml. by distillation under reduced pressure, is made basic with solid NaC2O3 to pH 8-9 in the cold, is extracted with ether, is dried over MgSO4 and activated charcoal, is filtered, and concentrated to dryness. The residual oil (12 g. plus 5.0 g. from previous run) is distilled at 60°-68°/1 mm to yield 11 g (35%) of 3-diethylamino-2,2-diethylpropanol.
Reaction SMILES: [C:1]12([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7][C:4]([C:9]([O:11]C)=[O:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[OH-].[Na+]>CO>[C:1]12([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:2][CH2:3][C:4]([C:9]([OH:11])=[O:10])([CH2:5][CH2:6]1)[CH2:7][CH2:8]2
Reactant: COC(=O)C12CCC(C(=O)OC(C)(C)C)(CC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)C12CCC(C(=O)O)(CC1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
1,1-Dimethylethyl methyl bicyclo[2.2.2]octane-1,4-dicarboxylate (495 mg) was dissolved in methanol (5 mL). To this solution, a 2 mol/L aqueous sodium hydroxide solution (0.92 mL) was added and the mixture was stirred at room temperature for 8 hours and then at 50° C. for 2 hours. Methanol in the mixture was evaporated under reduced pressure. Water was added to the resulting residue and the mixture was washed with diethyl ether and was neutralized with 3 mol/L hydrochloric acid. The resulting crystals were filtered, washed with water, and dried under reduced pressure to give 1,1-dimethylethyl hydrogen bicyclo[2.2.2]octane-1,4-dicarboxylate (344 mg).
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:17]=[N:16][C:15]3[C:10](=[CH:11][C:12]([C:18]4[CH:19]=[N:20][CH:21]=[C:22]([NH:24][S:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)(=[O:27])=[O:26])[CH:23]=4)=[CH:13][CH:14]=3)[N:9]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.FC(F)(F)C(O)=O>C(#N)C.C(OCC)(=O)C>[O:1]=[C:2]1[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:8]1[CH:17]=[N:16][C:15]2[C:10]([N:9]=1)=[CH:11][C:12]([C:18]1[CH:23]=[C:22]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:21]=[N:20][CH:19]=1)=[CH:13][CH:14]=2
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc3ccc(-c4cncc(NS(=O)(=O)c5ccccc5)c4)cc3n2)C(=O)C1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1CNCCN1c1cnc2ccc(-c3cncc(NS(=O)(=O)c4ccccc4)c3)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a solution of 1,1-dimethylethyl 3-oxo-4-(7-{5-[(phenylsulfonyl)amino]-3-pyridinyl}-2-quinoxalinyl)-1-piperazinecarboxylate (0.21 mmol) in acetonitrile (4 ml) was added concentrated trifluoroacetic acid (4 ml). The reaction stirred at ambient temperature for 1 hour and was then concentrated to an orange oil. The residue was neutralized with saturated sodium bicarbonate solution upon which a precipitate formed. The precipitate was dissolved in ethyl acetate and crashed out of solution with hexanes, which was filtered and dried to afford the title compound (66 mg, 67%) as an off-white solid. MS(ES)+ m/e 461.2 [M+H]+.
Reaction SMILES: [C:1]1([NH:7][C@@H:8]([CH3:12])[CH2:9][C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:20])C(=O)C1>CN(C)C=O>[Br:20][C:4]1[CH:5]=[CH:6][C:1]([NH:7][C@@H:8]([CH3:12])[CH2:9][C:10]#[N:11])=[CH:2][CH:3]=1
Reactant: C[C@@H](CC#N)Nc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: C[C@@H](CC#N)Nc1ccc(Br)cc1
Reaction time: 0.33 h

Procedure:
(3S)-3-(phenylamino)butanenitrile (for a preparation see Intermediate 31) (11.3526 g, 70.9 mmol) was taken up in N,N-dimethylformamide (DMF) (200 mL) under nitrogen and cooled in an ice-bath. NBS (12.61 g, 70.9 mmol) was added and the reaction stirred. After 20 mins, the reaction was partitioned between EtOAc (1000 ml) and water (500 ml). The organic layer was washed with 2M NaOH ×2, water and brine (500 ml each) and then dried with Na2SO4, filtered and concentrated to yield the product as a cream solid (17.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[NH:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:14]([N:16]([CH2:19][CH2:20]Cl)[CH2:17][CH3:18])[CH3:15].O>CN(C)C=O>[OH2:9].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[N:10][CH2:15][CH2:14][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:9])=[CH:4][CH:3]=1
Reactant: CS(=N)(=O)c1ccc(Br)cc1
Reactant: CCN(CC)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCN=S(C)(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 121.3 %

Procedure:
A solution of 4-bromophenyl-methylsulfoximine (10.0 g, 42.7 mmol) in dimethylformamide (50 mL) was added dropwise to a stirring slurry of sodium hydride (2.04 g, 51.2 mmol, 60% oil dispersion washed (3×20 mL) with hexane) which was maintained at 0° C. After stirring for 30 minutes, a solution of diethylaminoethyl chloride (6.58 g, 48.3 mmol) in dimethylformamide (20 mL) was added dropwise. The reaction mixture was warmed at 60° C. for 18 h. The reaction mixture was then cooled to ambient temperature, and 5 mL of water was added. The resulting solution was concentrated in vacuo. The residue was partitioned between 0.1N aqueous HCl (100 mL) and methylene chloride (100 mL). The layers were separated, and the aqueous layer was extracted with methylene chloride (2×50 mL). The aqueous layer was then made basic with 50% aqueous sodium hydroxide, and the resulting slurry was extracted with methylene chloride. These combined organic extracts were washed with saturated sodium chloride, dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed (flash, SiO2, 9:1 methylene chloride:methanol) to give 9.1 g (62%) of clear oil.