Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([CH2:26][C:27](=[O:29])[CH3:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[C:26](/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)\[C:27](=[O:29])[CH3:28])[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Reactant: CC(=O)Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CC(=O)/C(=C\c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1)c1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of 3-benzyloxy-4-nitrobenzaldehyde (83, step A) (1.16 g, 4.5 mmol) and 1-phenylpropane-2-one (0.726 g, 5.4 mmol) in toluene (50 mL) is added a catalytic amount of piperidine/glacial acetic acid and the mixture is refluxed for 3 h using a Dean-Stark apparatus. The mixture is cooled to room temperature and concentrated under reduced pressure. The crude material is purified by flash chromatography using a gradient of 15-50% EtOAc/hexane as eluent to give the title compound as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:29])[CH:7]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>C1COCC1>[C:37]([NH:29][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(N)cc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(NC(C)=O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 84 %

Procedure:
To a solution d 1.4 g (3.44 mmol) of 3-nitro-5-(octadecyloxy)benzenamine and 0.75 ml (5.4 mmol) of triethylamine in 85 ml of THF stirred in an ice bath was added 0.25 ml (3.44 mmol) of acetyl chloride. The ice bath was removed after 15 minutes and the reaction mixture was stirred at room temperature for 17 hours. Triethylamine (0.3 ml) and acetyl chloride (0.15ml ) were added and stirring was continued for 5 hours. The solvent was removed at reduced pressure and the residue was crystallized from ethyl acetate-hexane to give 1.3 g (84% yield, mp 103°-107°) of 3-(acetylamino)-5-(octadecyloxy)nitrobenzene. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.Cl.[C:17]1([CH:23]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[C:24]([OH:26])=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>C1COCC1>[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47]([O:25][C:24](=[O:26])[CH:23]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])[CH2:46]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: Cc1ccccc1NC(C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cc1ccccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 103 %

Procedure:
PS-DCC (1.15 g, 1.44 mmol, loading: 1.25 mmol/g) is suspended in THF (15 mL). Phenyl-o-methylphenylamino-acetic acid hydrochloride (I38) (200 mg, 0.72 mmol) and HOBT (221 mg, 1.44 mmol) are added, followed by (R)-quinuclidin-3-ol (275 mg, 2.16 mmol) and the mixture is shaken for 16 hours at RT. PS-DCC is filtered off and the filtrate is evaporated. The resulting residue is dissolved in EtOAc and washed sequentially with water, sat. NaHCO3, water and brine. The organic layer is dried over Na2SO4, filtered and evaporated to give the title compound as a colorless oil (260 mg, quantitative yield, mixture of diastereoisomers).
Reaction SMILES: C(O)(=O)C(O)=O.[C:7]([O:11][C:12]([N:14]1[CH2:20][C:16]2([CH2:19][NH:18][CH2:17]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[CH2:36][N:37]=[C:38]=[O:39]>ClCCl>[C:7]([O:11][C:12]([N:14]1[CH2:15][C:16]2([CH2:17][N:18]([C:38](=[O:39])[NH:37][CH2:36][C:30]3[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:29]=3[Cl:28])[CH2:19]2)[CH2:20]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC2(CNC2)C1
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2(CN(C(=O)NCc3ccc(Cl)cc3Cl)C2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a stirred solution of 6-(tert-butoxycarbonyl)-2,6-diaza-spiro[3.3]heptane oxalate (200 mg, 1.01 mmol) in dichloromethane (10 mL) was added triethylamine (141 μl, 1.01 mmol) followed by 2,4-dichloro-1-(isocyanatomethyl)benzene (204 mg, 1.01 mmol). The reaction mixture was stirred at ambient temperature for 1 h. The crude reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2; methanol:dichloromethane 0:1 to 1:9) to give the title compound (344 mg, 85%) as a white solid. MS (EI) m/e: 400.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C@@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[N:9]2)[CH2:4][O:3]1.[H][H]>[Pd].C(O)C>[CH3:1][C:2]1([CH3:16])[O:6][C@@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]2)[CH2:4][O:3]1
Reactant: [H][H]
Reactant: CC1(C)OC[C@H](Cn2ccc([N+](=O)[O-])n2)O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)OC[C@H](Cn2ccc(N)n2)O1
Yield: 90.5 %

Procedure:
In a Parr shaker bottle was placed 1-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-3-nitro-1H-pyrazole (700 mg, 3.08 mmol), 10% palladium on carbon (500 mg) and ethanol (25 mL). The bottle was then placed on the Parr shaker at 50 psi of hydrogen pressure for 4 h. The reaction was then filtered through a pad of celite and washed with ethanol and concentrated in vacuo to afford 1-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (550 mg, 91%) as a yellow oil: LR-ES-MS m/z calculated for C9H15N3O2 [M]+ 197, observed 198 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])([O-])=[O:14].[Na+].[Na+]>OS(O)(=O)=O>[NH2:1][C:2]1[CH:10]=[C:9]([C:11](=[O:14])[NH2:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(C(=O)O)c(N)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)c1ccc(C(=O)O)c(N)c1
Temperature: 45 °C
Yield: 89 %

Procedure:
2-amino-4Cyanobenzoic acid (3.01 g, 18.3 mmol), prepared by the method of Chan and Bruice, J. Am. Chem. Soc., 99: 6721 (1977), was dissolved in 60 mL of 97% H2SO4 and heated to 45° C. for 12 h. The mixture was added to ice, and saturated Na2CO3 solution was added to adjust the pH=3. The mixture was then filtered, and the yellow solid lyophilized to yield the title compound (2.94 g, 89%): mp 276°-278° C. 1H NMR (300 MHz, DMSO-d6) δ 8.72 (br s, 3H), 7.90 (br s, 1H), 7.71 (d, 1H), 7.37 (br s, 1H), 7.21 (d, 1H), 6.92 (dd, 1H), 6.75 (br s, 2H); MS (DCI/NH3) m/z 181 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([N+:11]([O-])=O)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]>CO.O=[Pt]=O>[NH2:11][C:5]1[CH:4]=[C:3]([O:14][CH3:15])[C:2]([OH:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COc1cc([N+](=O)[O-])c(C(=O)O)cc1O
Agent: O=[Pt]=O
Solvent: CO
Product: COc1cc(N)c(C(=O)O)cc1O
Reaction time: 4 h
Yield: 97.4 %

Procedure:
5-Hydroxy-4-methoxy-2-nitro-benzoic acid (18 g, 84.51 mmol, J. Indian Chem. Soc. 1970, 70, 925) is suspended in MeOH (1 L) and treated PtO2 (100 mg). The flask is flushed with hydrogen gas and the reaction mixture is stirred under hydrogen atmosphere (45 psi) for 4 hours. The reaction mixture is filtered through a celite plug and the solvent is removed under reduced pressure. The crude product is redissolved in DCM, dried (MgSO4) and concentrated to yield 15.06 g (82.3 mmol, 97%) of the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]([NH:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2)=[O:15].C([Sn]([CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)(CCCC)CCCC)CCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN1CCCC1=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH:22]1[C:23]2[C:19](=[CH:18][C:17]([NH:16][C:14](=[O:15])/[CH:13]=[CH:12]/[C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=3[CH2:39][C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)=[CH:25][CH:24]=2)[CH:20]=[CH:21]1
Reactant: CCCC[Sn](CCCC)(CCCC)Cc1cccnc1
Reactant: O=C(/C=C/c1ccc(C(F)(F)F)cc1Br)Nc1ccc2[nH]ccc2c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: O=C(/C=C/c1ccc(C(F)(F)F)cc1Cc1cccnc1)Nc1ccc2[nH]ccc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of (2E)-3-[2-bromo-4-(trifluoromethyl)phenyl]-N-indol-5-ylprop-2-enamide, Example 97, (110 mg, 0.27 mmol), 3-(tributylstannanylmethyl)pyridine, Example 90(a), (160 mg, 0.43 mmol), tris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.027 mmol, Aldrich) and triphenylphosphine (28 mg, 0.11 mmol, Aldrich) in 1-methyl-2-pyrrolidinone (1.5 mL) was stirred at 100° C. overnight. The reaction mixture was filtered through a pad of Celite and diluted with water (50 mL). The aqueous phase was extracted with EtOAc (3×60 mL). The combined organic extracts were washed with satd NaCl (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (gradient: 0-70% EtOAc in hexane) provided the title compound as an orange solid. MP 202-203° C. MS (ESI, neg. ion) m/z: 420 (M−1).
Reaction SMILES: [NH2:1][CH:2]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[OH:4].[F:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([C:40](O)=[O:41])=[CH:32][CH:31]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[OH:4][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:10]=1)[CH:2]([NH:1][C:40]([C:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:30]([F:29])=[CH:31][CH:32]=1)=[O:41])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Oc2ccccc2)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-phenoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.03 mmol) in acetonitrile (30 ml) were added 4-fluoronaphthalenecarboxylic acid (196 mg, 1.03 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (297 mg, 1.55 mmol) and 1-hydroxy-1H-benzotriazole (158 mg, 1.03 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (520 mg, 90%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@:13]32[C@H:8]([C@H:9]([C:21](=[O:23])[CH3:22])[CH2:10][CH2:11][C@@H:12]3[CH3:20])[CH:7]=[C:6]1[CH3:24])(=[O:3])[CH3:2].C(N(CC)CC)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[Br:44]N1C(=O)CCC1=O>C(OCC)C>[C:1]([O:4][C@H:5]1[C@@H:14]2[O:15][C:16]([CH3:18])([CH3:19])[O:17][C@@:13]32[C@H:8]([C@H:9]([C:21](=[O:23])[CH2:22][Br:44])[CH2:10][CH2:11][C@H:12]3[CH3:20])[CH:7]=[C:6]1[CH3:24])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)O[C@@H]1C(C)=C[C@H]2[C@H](C(C)=O)CC[C@H](C)[C@]23OC(C)(C)O[C@@H]13
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)O[C@@H]1C(C)=C[C@H]2[C@H](C(=O)CBr)CC[C@@H](C)[C@@]23OC(C)(C)O[C@@H]13
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
To a stirred, cooled (0° C.) solution of the product of (3aS,4R,6aS,7R,10S,10aS)-7-acetyl-2,2,5,10-tetramethyl-4,6a,7,8,9,10-hexahydro-3aH-naphtho[1,8a-d][1,3]dioxol-4-yl acetate (Preparation 148, 1.8 g) in diethyl ether (30 ml) was added triethylamine (1.8 ml) and trimethylsilyltrifluoromethanesulfonate (2.3 ml). After 30 minutes, N-bromosuccinimide (1.2 g) was added and the reaction mixture was allowed to warm to room temperature over three hours. The reaction mixture was partitioned between saturated aqueous sodium chloride and ethyl acetate. The organic phase was dried (MgSO4), evaporated and purified by flash column chromatography on silica gel using a gradient elution ethyl acetate:hexane (1:9 to 2:8) to give the product as a gum (1.81 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1.Br[C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=1>>[CH3:31][C:29]1[CH:28]=[CH:27][N:26]=[C:25]([NH:2][C:3]2[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=2)[CH2:6][NH:7][C:8]2[C:17]3[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)[CH:30]=1
Reactant: Cc1ccnc(Br)c1
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Agent: Cl
Product: Cc1ccnc(Nc2cccc(CNc3ncnc4c(C(N)=O)cccc34)c2)c1

Procedure:
The title compound was prepared according to Example 549 starting 4-(3-Amino-benzylamino)-quinazoline-8-carboxylic acid amide hydrochloride and 2-Bromo-4-methyl-pyridine:
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].COC(OC)OC.[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][C:2]1([CH3:7])[CH2:5][O:6][CH:20]([C:19]2[CH:22]=[CH:23][C:16]([Br:15])=[CH:17][CH:18]=2)[O:4][CH2:3]1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: ClCCl
Product: CC1(C)COC(c2ccc(Br)cc2)OC1
Yield: 101.3 %

Procedure:
After successive addition of 37.5 g of 2,2-dimethyl-propane-1,3-diol, 18,75 ml of ortho-formic acid trimethylester and 20 mg of p-toluene sulfonic acid, a solution of 25 g of 4-bromobenzaldehyde in 250 ml of dichloromethane is stirred for 24 hours at room temperature. To finish the compound it is poured into saturated, aqueous NaHCO3 solution and extracted with diethylether. Crystallization of the crude product from hexane yields 37.1 g of 4-(5,5-dimethyl-1-,3-dioxan-2-yl)-bromobenzene with a melting point of 62°-64° C.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][C:26]([O:28]C)=[O:27])[CH:13]=[CH:14][C:15]=1[CH2:16][NH:17]C(OC(C)(C)C)=O)=O)(C)(C)C.[OH-].[Na+]>CO.C1COCC1.Cl>[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][C:26]([OH:28])=[O:27])[CH:13]=[CH:14][C:15]=1[CH2:16][NH2:17]
Reactant: COC(=O)Cc1ccc(CNC(=O)OC(C)(C)C)c(CNC(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NCc1ccc(CC(=O)O)cc1CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
The methyl 2-(3,4-bis((tert-butoxycarbonylamino)methyl)phenyl)acetate (1.1 g,) was dissolved in a mixture of MeOH/THF (50 mL, 2:1). 1N NaOH (10 mmol, 10 mL) was added and the reaction mixture was stirred at room temperature overnight. IN HCl was added to adjust the pH of the reaction to ˜3. The aqueous was extracted with EtOAc. The organic phase was washed with IN HCl, brine, dried and concentrated in vacuo to afford the product (0.38 g) as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1F.[OH-].[NH4+:13]>>[NH2:13][C:7]1[C:6]([F:9])=[C:5]([F:10])[N:4]=[C:3]([F:11])[C:2]=1[Cl:1]
Reactant: [NH4+]
Reactant: Fc1nc(F)c(Cl)c(F)c1F
Agent: [OH-]
Product: Nc1c(F)c(F)nc(F)c1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
This compound was prepared by a modification of the procedure of Chambers et al., J. Chem. Soc. 1964, 5634-5640. A mixture of 3-chloro-2,4,5,6-tetrafluoropyridine (1, 37.4 g, 201 mmol) and 150 mL of 28% ammonium hydroxide was stirred at room temperature for 5 h. The resulting white crystals were collected and carefully washed with ice water to give 2 as a white solid (35 g). The combined filtrate and washings were extracted with ether. The ether extract was dried (MgSO4), filtered and evaporated in vacuo to give additional 2 (1.3 g); total yield: 26.3 g (99%). The product was used directly for the next step in the reaction. A small sample was purified by silica gel column chromatography: mp 118-120° C. (Lit., Chambers et al., J. Chem. Soc. 1964, 5634-5640, mp 117-118° C.).
Reaction SMILES: [CH2:1]([O:6][C:7](=[O:31])[C:8]1[C:13]([S:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:12][N:11]=[C:10]([NH2:30])[CH:9]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[S:40](Cl)(=[O:42])=[O:41]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH2:1]([O:6][C:7](=[O:31])[C:8]1[C:13]([S:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)(=[O:23])=[O:22])=[CH:19][CH:20]=2)=[CH:12][N:11]=[C:10]([NH:30][S:40]([C:34]2[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:33]=2[Cl:32])(=[O:42])=[O:41])[CH:9]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOC(=O)c1cc(N)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCCCOC(=O)c1cc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Yield: 29.3 %

Procedure:
A solution of the 2-amino-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-isonicotinic acid pentyl ester (500 mg, 1.1 mmol), 2,4-dichlorobenzenesulfonylchloride (327 mg, 1.33 mmol) and 4-dimethylaminopyridine (134 mg, 1.1 mmol) in pyridine (10 ml) was stirred at 40° C. overnight. The pyridine was removed under reduced pressure and the residue purified by flash column chromatography using ethyl acetate 1/2 hexane as eluent to afford 2-(2,4-dichloro-benzenesulfonylamino)-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-isonicotinic acid pentyl ester as a yellow foam (217 mg, 29%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:9]([CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1)#[N:10]
Reactant: N#CCc1ccccc1N
Reactant: O=C(Cl)c1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#CCc1ccccc1NC(=O)c1cccnc1
Reaction time: 8 h

Procedure:
2-aminophenylacetonitrile (5.0 g, 37.1 mmol) and nicotinoyl chloride (7.5 g, 40.8 mmol) are taken up in dry dichloromethane (200 mL) and diisopropylethylamine (12.1 g, 92.7 mmol) is added while cooling the mixture with a cold water bath. The mixture is stirred overnight, whereupon it is washed twice with saturated aqueous sodium bicarbonate. The combined aqueous layer is back-extracted with ethyl acetate. The combined organic phase is dried over MgSO4 and concentrated in vacuo to give a residue, which is purified by silica gel flash chromatography (dichloromethane-methanol, 1:0 to 19:1) to give N-(2-cyanomethyl-phenyl)-nicotinamide as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.02 (s, 2H), 7.32-7.37 (m, 1H), 7.39-7.44 (m, 2H), 7.50 (d, J=7.1 Hz, 1H), 7.59 (dd, J=8.1, 4.8 Hz, 1H), 8.30-8.33 (m, 1H), 8.78 (dd, J=4.8, 1.5 Hz, 1H), 9.14 (d, J=1.8 Hz, 1H), 10.36 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[O:21])=[CH:9][CH:8]=[C:7]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:6]=2.[CH3:28][O:29][CH2:30][CH2:31][C:32](Cl)=O>>[CH3:28][O:29][CH2:30][CH2:31][C:32]1[N:12]([CH2:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[C:11]2[C:10]3[CH:9]=[CH:8][C:7]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: COCCC(=O)Cl
Reactant: Nc1cnc2cc(-c3ccccc3)ccc2c1NCCCN1CCCC1=O
Product: COCCc1nc2cnc3cc(-c4ccccc4)ccc3c2n1CCCN1CCCC1=O

Procedure:
The methods described in Parts A of Example 204 were used to treat 1-[3-(3-amino-7-phenylquinolin-4-ylamino)propyl]pyrrolidin-2-one (1.19 g, 3.30 mmol) with 3-methoxypropionyl chloride (0.45 mL, 4.1 mmol) to afford 1-{3-[2-(2-methoxyethyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one, which was oxidized and then aminated according to the methods described in Parts H and I of Example 1. The product from amination was recrystallized twice from acetonitrile and dried in a vacuum oven at 60° C. to provide 1-{3-[4-amino-2-(2-methoxyethyl)-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one as a light brown solid, mp 187–191° C.
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[CH2:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C1C=CC=CC=1>[CH2:8]([O:4][C:3](=[O:5])[C:2](=[O:1])[CH2:6][CH3:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCC(=O)C(=O)O
Reactant: OCc1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: CCC(=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
A mixture of 2-oxobutyric acid (11.5 g, 113 mmol), and benzyl alcohol (14.0 mL, 135 mmol) in benzene (100 mL) was heated to reflux under a Dean-Stark water separator. After refluxing for 16 hrs˜2 mL of water had collected in the trap (˜100% of theoretical). The reaction mixture was allowed to cool to ambient temperature, and then concentrated under reduced pressure to afford a pale yellow oil. The crude material was purified by flash chromatography eluting with a gradient from 0% to 15% ethyl acetate/hexane to afford 2-oxo-butyric acid benzyl ester (13.0 g, 60% yield) as a clear colorless oil. 1H-NMR (400 MHz, CDCl3): δ 7.42-7.35 (5H, m), 5.28 (5H, s), 2.87 (2H, q, J=7.2 Hz), 1.12 (3H, t, J=7.2 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([CH2:16][C@@H:17]2[C@H:20]([N:21](CC3C=CC(OC)=CC=3)C(=O)OCC3C=CC=CC=3)[C:19](=[O:41])[NH:18]2)[N:13]=[N:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)=O>CO.[Pd]>[NH2:21][C@@H:20]1[C:19](=[O:41])[NH:18][C@@H:17]1[CH2:16][C:14]1[N:13]=[N:12][N:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH:15]=1
Reactant: COc1ccc(CN(C(=O)OCc2ccccc2)[C@@H]2C(=O)N[C@@H]2Cc2cn(CCNC(=O)OC(C)(C)C)nn2)cc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CC(C)(C)OC(=O)NCCn1cc(C[C@H]2NC(=O)[C@H]2N)nn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a slurry of benzyl ((2R,3S)-2-((1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-4-oxoazetidin-3-yl)(4-methoxybenzyl)carbamate (20.2 mg, 0.036 mmol) in MeOH (0.68 mL) was added Pd black (19 mg, 0.018 mmol) and formic acid (31 μl, 0.711 mmol). After stirring at rt for 3 h, more Pd black (9.7 mg) was added. After stirring at rt for additional 5.5 h, the reaction mixture was filtered through cellulose with MeOH eluent, and the filtrate was concentrated in vacuo. It was used in step 6 without further purification. LCMS: Rt=0.396 min, m/z=311.1 (M+1). Method 2m_acidic.