Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[C@@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].[C:14]([O:18][C:19](=[O:35])[NH:20][C@@H:21]([CH:33]=O)[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)([CH3:17])([CH3:16])[CH3:15].C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.O.C(O)(=O)C>[C:14]([O:18][C:19](=[O:35])[NH:20][C@@H:21]([CH2:33][NH:5][C@@H:4]([C:3](=[O:13])[NH:2][CH3:1])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CNC(=O)[C@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](C=O)Cc1ccc2ccccc2c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CNC(=O)[C@@H](Cc1ccccc1)NC[C@@H](Cc1ccc2ccccc2c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.9 %

Procedure:
D-Phenylalanine-N-methyl amide (1.50 g, 8.35 mmol) and (1R)-1-formyl-2-(2-naphthyl)ethylcarbamic acid tert-butyl ester (2.50 g, 8.35 mmol) were dissolved in methanol (40 ml). Molsieves (3 Å, 30 g) and acetic acid (3 ml) were added and the mixture was cooled with ice and sodium cyanoborohydride (0.80 g, 12.5 mmol) was added. The mixture was stirred overnight at room temperature. Water (30 ml) and saturated aqueous sodium hydrogen carbonate (30 ml) were added and the mixture was extracted with methylene chloride (3×40 ml). The combined organic phases were dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was chromatographed on silica (3×30 cm) using ethyl acetate/heptane (1:1) as eluent to afford 1.19 g of ((1R)-1-(((1R)-1-methylcarbamoyl-2-phenylethylamino)methyl)-2-(2-naphthyl)ethyl)carbamic acid tert butyl ester
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1)#[N:10].C([O-])([O-])=O.[K+].[K+].CCOCC>CCO.C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:18][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=2)[CH:3]=1
Reactant: Nc1cccc(S)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Solvent: CCOCC
Product: N#Cc1ccc(CCSc2cccc(N)c2)cc1
Yield: 48.8 %

Procedure:
3-Aminothiophenol (0.87 g; 7.0 mmol), 4-toluenesulfonic acid-2-(4-cyanophenyl)ethyl ester (2.0 g; 6.6 mmol; from step (i) above) and K2CO3 (1 g) were stirred in a mixture of EtOH (10 mL) and CH2Cl2 for 4 hours. Addition of ether, washing with brine and 2M aqueous NaOH, drying (MgSO4), evaporation of the solvent and flash chromatography (SiO2; Et2O:hexane (1:1)) afforded 0.82 g (49%) of the sub-title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[O:36][CH2:35][C:12]3([C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14](C(C4C=CC=CC=4)C4C=CC=CC=4)[C:13]3=[O:34])[C:4]=2[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.C(OCC)(=O)C.[H][H]>CO.[Pd]>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]2([C:4]3[C:5]4[O:10][CH2:9][CH2:8][O:7][C:6]=4[CH:11]=[CH:2][C:3]=3[O:36][CH2:35]2)[C:13]1=[O:34]
Reactant: [H][H]
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1c(Cl)cc3c(c12)OCCO3
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1Nc2ccccc2C12COc1ccc3c(c12)OCCO3
Temperature: 60 °C
Reaction time: 16 h
Yield: 41.7 %

Procedure:
6-chloro-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one (2.1 g, 4.24 mmol) was suspended in methanol (20 mL) and ethyl acetate (80 mL) in a steel bomb and palladium on carbon (20% w/w, 0.45 g) was added. The bomb was pressurized with hydrogen gas (120 psi) and the mixture was stirred at 60° C. for 16 h. The reaction mixture was allowed to cool to ambient temperature and filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo and the residue triturated with ethyl acetate to afford 2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one (0.522 g, 42%) as a colorless solid: mp 259-261° C.; 1H NMR (300 MHz, CD3OD) δ7.27-7.18 (m, 1H), 7.09-6.88 (m, 3H), 6.70 (d, J=8.7 Hz, 1H), 6.39 (d, J=8.7 Hz, 1H), 4.75 (d, J=9.3 Hz, 1H), 4.59 (d, J=9.0 Hz, 1H), 4.12-3.90 (m, 4H); 13C NMR (75 MHz, CD3OD) δ181.0, 157.5, 142.4, 141.3, 139.6, 133.9, 129.8, 124.5, 124.0, 119.0, 117.1, 111.0, 102.9, 82.4, 66.0, 65.2, 59.1; MS (ES+) m/z 296.2 (M+1).
Reaction SMILES: O[CH2:2][C:3]1[C:4]2[N:5]([C:9]([C:12]3[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]([S:20][CH3:21])[N:13]=3)=[CH:10][N:11]=2)[CH:6]=[CH:7][CH:8]=1.COCCN(S(F)(F)[F:32])CCOC.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[F:32][CH2:2][C:3]1[C:4]2[N:5]([C:9]([C:12]3[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]([S:20][CH3:21])[N:13]=3)=[CH:10][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CSc1ncc(C#N)c(-c2cnc3c(CO)cccn23)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CSc1ncc(C#N)c(-c2cnc3c(CF)cccn23)n1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
4.23 g of the 4-[8-(hydroxymethyl)imidazo[1,2-a]pyridin-3-yl]-2-(methylthio)pyrimidine-5-carbonitrile [147-2] was dissolved in 500 mL of chloroform, then 5.2 mL of bis-(2-methoxyethyl)aminosulfur trifluoride was added thereto at −40° C., and stirred at the same temperature for 1 hour. 2.6 mL of bis-(2-methoxyethyl)aminosulfur trifluoride was further added, and stirred at the same temperature for 1 hour. Thereto, a saturated aqueous solution of sodium hydrogen carbonate was slowly added, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine in the subsequent order, and dried over anhydrous magnesium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the thus obtained residue was dissolved in a small amount of chloroform and solidified by adding diethyl ether, to obtain 3.43 g of 4-[8-(fluoromethyl)imidazo[1,2-a]pyridin-3-yl]-2-(methylthio)pyrimidine-5-carbonitrile [147-3] as a light brown solid.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29].C1C=CC=CC=1>C(OCC)(=O)C.[OH-].[Na+]>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:28](=[O:30])[CH3:29])=[CH:18][CH:19]=3)[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of 8.5 g (0.03 mole) of the base of 4-[4-(phenylmethyl)-1-piperazinyl]benzeneamine and 16.0 g (0.16 mole) of triethylamine in 450 ml of ethyl acetate was added, dropwise, a solution of 2.5 g (0.035 mole) of acetyl chloride in 50 ml of ethyl acetate. The mixture was magnetically stirred for 3 hr and then heated at reflux for 1 hr. The excess acetyl chloride was co-distilled with benzene and the resulting oil was shaken in 400 ml of 10% sodium hydroxide solution. The suspended tan solid was collected by filtration, washed thrice with 100 ml portions of water, and dir dried to give 9.7 g (99%) of crude product. A one gram portion was recrystallized from benzene/petroleum ether to give 100 mg of cream colored solid, m.p. 159°-161° C.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([NH2:35])(=[O:34])=[O:33]>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32](=[O:34])(=[O:33])[NH2:35])=[O:15])=[CH:19][CH:20]=1)([O-:3])=[O:2]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: O=C(O)c1cccc(OCc2ccc([N+](=O)[O-])cc2)c1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
A benzene (20 ml) solution containing 1.40 (5.1 mmol) of 3-(4-nitrobenzyloxy)benzoic acid and 2 ml of thionyl chloride was heated under reflux for 2 hours and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in methylene chloride (20 ml), this solution was added dropwise under ice-cooling to a pyridine (30 ml) solution containing 0.97 g (5.6 mmol) of 2-aminobenzenesulfonamide, the mixture was stirred at room temperature for 18 hours and then methylene chloride was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with a 1 N hydrochloric acid aqueous solution, water and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The thus obtained crude crystals were washed with methanol to obtain 1.9 g (yield: 87.0%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][C:12]=1[CH3:13])[NH2:9].Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[C:18]([CH3:26])[CH:17]=1>CCO.Cl>[CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:9][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]([CH3:26])[CH:17]=2)[CH:10]=[CH:11][C:12]=1[CH3:13]
Reactant: Cc1cc(Cl)c2ccccc2n1
Reactant: Cc1ccc(N)cc1OCCN(C)C
Agent: Cl
Solvent: CCO
Product: Cc1cc(Nc2ccc(C)c(OCCN(C)C)c2)c2ccccc2n1
Temperature: 25 °C
Yield: 57.8 %

Procedure:
To a solution of 9 (0.25 g, 1.29 mmol) and 5 (0.29 ml, 1.44 mmol) in EtOH (8 mL) were added 2 drops of conc. HCl. The mixture was heated under reflux overnight. After cooling to room temperature, EtOH was removed under reduced pressure. The residue was partitioned between sat. NaHCO3 (aq.) and EtOAc (100 mL each) and the aquous layer was extracted with EtOAc (2×50 mL). The combined organic layers were dried over MgSO4, the solids were filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on Florisil® (50% EtOAc/Hexanes to 15% MeOH/EtOAc) to yield the title compound as a light yellow solid (0.25 g).
Reaction SMILES: CC[N:3]([CH:7]([CH3:9])C)[CH:4]([CH3:6])C.[CH3:10][O:11][C:12](=[O:22])[C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.N1CCCC1>CN(C=O)C.O>[CH3:10][O:11][C:12](=[O:22])[C:13]1[CH:14]=[CH:15][C:16]([C:17]([N:3]2[CH2:4][CH2:6][CH2:9][CH2:7]2)=[O:19])=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCNC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(C(=O)N2CCCC2)cc1
Reaction time: 0.03 h
Yield: 8.2 %

Procedure:
DIPEA (1.26 g, 9.7 mmol) was added to a stirred solution of terephthalic acid monomethyl ester (500 mg, 2.77 mmol) in DMF (3 mL) followed by HOBt (410 mg, 3.0 mmol) and EDCI (1.32 g, 7.0 mmol). After 2 minutes of stirring, pyrrolidine (215 mg, 3.0 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with cold water, the precipitate was collected to afford 53 mg (81.9% Yield) of 4-(pyrrolidine-1-carbonyl)-benzoic acid methyl ester. LiOH.H2O (285 mg, 6.8 mmol) was added to a solution of 4-(pyrrolidine-1-carbonyl)-benzoic acid methyl ester (530 mg, 2.27 mmol) in a mixture of methanol (2 mL), THF (6 mL) and H2O (2 mL). The reaction mixture was stirred at ambient temperature for 3 hrs. The reaction mixture was concentrated, the residue was diluted with water, and acidified with conc. HCl. The solid was filtered and dried to afford 41 mg (82.32% Yield).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[NH2:47][C@@H:48]([CH3:68])[C:49]([N:51]([CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[C@@H:52]([CH3:60])[CH:53]([O:57][CH2:58][CH3:59])[O:54][CH2:55][CH3:56])=[O:50]>CN(C=O)C.C(Cl)Cl.CN(C1C=CN=CC=1)C.CC(=O)OCC>[CH2:1]([NH:8][C:9](=[O:10])[NH:11][N:12]([CH2:14][C:15]([NH:47][C@@H:48]([CH3:68])[C:49]([N:51]([CH2:61][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1)[C@@H:52]([CH3:60])[CH:53]([O:57][CH2:58][CH3:59])[O:54][CH2:55][CH3:56])=[O:50])=[O:17])[CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1ccccc1)C(=O)[C@H](C)N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(OCC)[C@H](C)N(Cc1ccccc1)C(=O)[C@H](C)NC(=O)CN(C)NC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid VI-3) 115 mg (0.49 mmol) and NMM (N-methylmorpholine) 0.33 ml were added in DMF 1.5 ml. Then, HOBt (hydroxybenzotriazole) 88 mg (0.65 mmol) and EDCI (N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride) 125 mg (0.65 mmol) were added and stirred at room temperature for 10 min. Compound (S)-2-amino-N-benzyl-N—((S)-1,1-diethoxypropan-2-yl)propanamide (IV-10) 100 mg (0.32 mmol) in DCM 1.5 ml and DMAP 4.1 mg (0.03 mmol) were added. The mixture was stirred overnight at room temperature. The mixture was diluted with EA 30 ml and washed with 10% citric acid 15 ml, sat. NaHCO3 15 ml and brine 15 ml. The solvent was removed in vacuum to give crude product, which was used directly in the next step.
Reaction SMILES: [O:1]=[C:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])/[CH:3]=[CH:4]/[CH:5]=[O:6].CC(=CC)C.[O-:24]Cl=O.[Na+]>CC(O)(C)C.O>[O:1]=[C:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])/[CH:3]=[CH:4]/[C:5]([OH:24])=[O:6]
Reactant: CCCCCCCCCCCCC(=O)/C=C/C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCCCCCCCCCCCC(=O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
A solution of (E)-4-oxohexadec-2-enal (400 mg, 1.58 mmol) and 2-methyl-2-butene (1.69 ml, 15.8 mmol) in t-BuOH (20 ml) was treated with NaH2PO4 (2.00 g, 16.7 mmol) and NaClO2 (181 mg, purity 80%, 1.89 mmol), both dissolved in H2O (10 ml), and the resulting mixture was stirred for 2 h at RT. Most of the solvent was removed under reduced pressure, and EtOAc (50 ml) and a saturated NaCl solution (10 ml) were added to the residue. The aqueous phase was acidified to a pH of 1 by dropwise addition of 1 N HCl. The organic phase was then separated off and the aqueous phase was extracted with EtOAC (2×50 ml). The combined organic phases were dried over NaSO4 and concentrated under reduced pressure to give the product as a whitish-yellow solid (350 mg, 1.31 mmol, 83%), melting point 98±0.5° C. 1H NMR (400 MHz, CD3CD2OD) δ 1H ppm: 0.87 (t, 3H, J=7.0 Hz, H-16), 1.08-1.34 (m, 18H), 1.56-1.63 (m, 2H), 2.68 (t, 2H, J=7.0 Hz, H-5), 6.65 (d, 1H, J=16.2 Hz, H-2), 7.01 (d, 1H, J=16.2 Hz, H-3); 13C NMR (100.5 MHz, CD3CD2OD) δ 13C ppm: 15.5 (C-16), 24.6, 25.7, 26.2, 31.0, 31.3, 31.4, 31.5, 31.6, 31.6, 33.9, 43.0 (C-5), 133.7 (C-2), 141.3 (C-3), 169.4 (C-1), 202.8 (C-4); (−)-ESI-CID-MS: m/z 267 [M−H]−, 535 [2M−H]−; (−)-ESI-CID-MS: m/z 269 [M−H]; ESI-FT-ICR-MS: m/z 267.19633 (calculated for C16H27O3−, m/z 267.19633).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:6])[CH3:5].Cl[C:8]1[O:9][C:10]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:12]=1.Cl>O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:12]=[C:8]([O:6][CH:4]([CH3:5])[CH3:3])[O:9][C:10]=2[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:14][CH:15]=1
Reactant: CC(C)O
Reactant: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)Oc1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
Sodium hydride (60% dispersion in oil, 0.60 g) was added to 2-propanol (20 ml), and stirred at room temperature for 10 minutes. To the reaction mixture was added 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (1.43 g), and stirred under reflux for 30 minutes. Next, water was added to the resulting reaction mixture, which was then acidified with 2N hydrochloric acid, and the crystals thus precipitated were collected by filtration to obtain 4-(4-chlorophenyl)-2-isopropoxy-5-oxazolepropionic acid (1.35 g, 87%). This was recrystallized from isopropyl ether to give colorless prisms. mp 116-117° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][C:15]1[O:19][C:18]([CH:20]=O)=[CH:17][CH:16]=1.[BH4-].[Na+]>CCO.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:20][C:18]2[O:19][C:15]([CH3:14])=[CH:16][CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN)cc1OC
Reactant: Cc1ccc(C=O)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: COc1ccc(CCNCc2ccc(C)o2)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4.82 g (26.6 mmol) of 2-(3,4-dimethoxyphenyl)ethylamine and 3.0 g (27.2 mmol) of 5-methylfuran-2-carbaldehyde in 65 ml of EtOH, 18.3 g of molecular sieves (0.3 nm) were added and the mixture was refluxed for 4 hours. After this time the reaction mixture was cooled to room temperature and filtered. The solution obtained was concentrated in vacuo to obtain an oil. This oil was dissolved in 65 ml of MeOH and 1.01 g (26.6 mmol) of NaBH4 were added in small portions, maintaining the temperature of the reaction at room temperature. The mixture was stirred at this temperature for 16 hours more. After this time the solvent was evaporated in vacuo and the residue was treated with 150 ml of water and extracted twice with ether.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][N+:11]#[C-:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:14](I)[CH2:15][CH2:16][CH3:17].ClCCl.[OH-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[N+:11]([CH:10]([S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:13])=[CH:6][CH:5]=1)(=[O:8])=[O:9])[CH2:14][CH2:15][CH2:16][CH3:17])#[C-:12]
Reactant: CCCCI
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: [C-]#[N+]C(CCCC)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86 %

Procedure:
A mixture of p-toluenesulfonylmethyl isocyanide (9.75 g), tetrabutylammonium iodide (3.69 g), 1-butyl iodide (11.3 mL), dichloromethane (100 mL) and 30% aqueous sodium hydroxide solution (100 mL) was stirred at room temperature for 12 hr. The reaction product was diluted with water (200 mL), and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained gum-like residue was extracted 3 times with diethyl ether (100 mL). The extract was concentrated under reduced pressure to give the title compound as a colorless oil (yield 10.8 g, 86%).
Reaction SMILES: C(N(CC)CC)C.[OH:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].[C:20]([O:24][C:25](=[O:46])[NH:26][CH2:27][CH2:28][CH2:29][N:30]1[C:42]2[C:41]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[N:35]=[C:34]([NH2:43])[C:33]=2[N:32]=[C:31]1[CH2:44]Cl)([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C.O>[NH2:43][C:34]1[C:33]2[N:32]=[C:31]([CH2:44][O:8][N:9]3[C:10](=[O:19])[C:11]4[C:12](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:14])[N:30]([CH2:29][CH2:28][CH2:27][NH:26][C:25](=[O:46])[O:24][C:20]([CH3:21])([CH3:23])[CH3:22])[C:42]=2[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[N:35]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)NCCCn1c(CCl)nc2c(N)nc3ccccc3c21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NCCCn1c(CON2C(=O)c3ccccc3C2=O)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 74.8 %

Procedure:
Triethylamine (4.6 mL, 33.1 mmol) was added to a solution of N-hydroxyphthalimide (2.16 g, 13.2 mmol) in DMF (10 mL). A solution of tert-butyl[3-(4-amino-2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]carbamate (4.3 g, 11.0 mmol) in DMF (20 ml) was added. The reaction was stirred at ambient temperature for 3.5 hours and then diluted with water (100 mL). The resulting precipitate was isolated by filtration, washed with water, and then dried in a vacuum oven at 60° C. over the weekend to provide 4.25 g of tert-butyl (3-{4-amino-2-[(1,3-dioxo-1,3-dihydroisoindol-2-yl)oxymethyl]-1H-imidazo[4,5-c]quinolin-1-yl}propyl)carbamate as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][C:11]2([C:15](=[O:16])[N:14]([C:17]3[C:18]([CH3:24])=[N:19][C:20](Br)=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][C@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[C@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][C:11]2([C:15](=[O:16])[N:14]([C:17]3[C:18]([CH3:24])=[N:19][C:20]([N:35]4[CH2:36][CH2:37][C@H:33]([N:29]5[CH2:30][CH2:31][CH2:32][C@@H:28]5[CH3:27])[CH2:34]4)=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(Br)ccc1N1CCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Reactant: C[C@H]1CCCN1[C@H]1CCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N1CCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 90 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
A mixture of 2-(6-bromo-2-methyl-pyridin-3-yl)-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (0.09 g, 0.211 mmol), (2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl (0.065 g, 0.422 mmol), R-(−)-BINAP (0.01 g, 0.016 mmol), and anhydrous toluene (3 mL) was de-gassed and refilled with N2 in three cycles. Pd2(dba)3 (0.005 g, 0.0053 mmol,), and sodium t-butoxide (0.030 g, 0.317 mmol) was then added to the mixture and de-gassed and refilled with N2 in three additional cycles. The reaction mixture was heated and stirred at 90° C. for 16 hours. The reaction mixture was allowed to cool to room temperature and quenched with water (1 mL). The aqueous phase was extracted with dichloromethane (3×10 mL). The combined organics were washed with sodium bicarbonate (5 mL), and brine (10 mL), dried over Na2SO4, concentrated under vacuum. Purification by column chromatography on silica gel (0-10%) methanol in dichloromethane afforded 0.0599 g (57%) of title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([OH:16])=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:16]
Reactant: COc1ccc2[nH]c(C)c(CC(=O)O)c2c1
Reactant: C1COCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(C)c(CC(=O)N3CCOCC3)c2c1
Reaction time: 2 h
Yield: 67 %

Procedure:
To 5-methoxy-2-methyl-3-indoleacetic acid (0.665g; 3.03 mmol) in 6 mL of THF was added DCC (0.661 g; 3.2 mmol). After 2 h of stirring, morpholine (1 mL; 11.4 mmol) was added and stirred for another 1 h. The reaction mixture was filtered and the solvent removed. Chromatography on silica gel (eluted with EtOAc) yielded 0.585 g (64%) of the title compound.