Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[CH3:11][NH:12][C:13]([C:15]1[C:16]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:17]=2[O:18][C:19]=1[CH3:20])=[O:14].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:11][NH:12][C:13]([C:15]1[C:16]2[CH:24]=[CH:23][C:22]([O:25][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[CH:9][S:10][C:3]=34)=[CH:21][C:17]=2[O:18][C:19]=1[CH3:20])=[O:14]
Reactant: CNC(=O)c1c(C)oc2cc(O)ccc12
Reactant: Clc1ccnc2ccsc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)oc2cc(Oc3ccnc4ccsc34)ccc12

Procedure:
This material was prepared by the reaction of 7-chloro-thieno[3,2-b]pyridine with 6-hydroxy-2-methylbenzofuran-3-carboxylic acid methyl amide 12c and Cs2CO3 in a manner as previously described for example 1. 1H NMR (CD3CN) δ8.48 (1H, d, J=5.3 Hz), 7.91 (1H, d, J=5.6 Hz), 7.84 (1H, d, J=8.6 Hz), 7.53 (1H, d, J=5.6 Hz), 7.41 (1H, d, J=2.0 Hz), 7.20 (1H, dd, J=8.6, 2.0 Hz), 6.62 (1H, d, J=5.3 Hz), 6.60 (1H, bm), 2.91 (3H, d, J=4.6 Hz) 2.66 (3H, s).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=O)[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:19])=O>>[CH2:1]([C:5]1[N:6]=[C:7]([Cl:19])[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCc1[nH]c(=O)ccc1C(=O)OCC
Product: CCCCc1nc(Cl)ccc1C(=O)OCC
Temperature: 120 °C
Yield: 80.9 %

Procedure:
Ethyl 2-butyl-6-oxo-1,6-dihydropyridine-3-carboxylate (450 mg, 2.02 mmol) was stirred in phosphorous oxychloride (10 ml, 30.5 mmol) and heated to 120° C. for 2 hours giving a clear brown solution. The reaction was evaporated and the residue was taken up in EtOAc (25 ml), washed with water (25 ml), saturated brine (25 ml) then dried over MgSO4 filtered and evaporated. Chromatography of the residue (SiO2) eluting with ethyl acetate/isohexane 10-30% gave ethyl 2-butyl-6-chloronicotinate (395 mg, 81%) as a clear oil.
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[H][H].[Br:11][C:12]1[C:13](F)=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O>CS(C)=O>[Br:11][C:12]1[C:13]2[S:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:15][C:14]=2[CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)CS
Reactant: [H][H]
Reactant: O=Cc1cccc(Br)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1cc2cccc(Br)c2s1
Temperature: 0 °C
Yield: 55.3 %

Procedure:
Under an argon atmosphere, 8.2 g (205.7 mmol) of sodium hydride (60% in liquid paraffin) are introduced into 300 ml of absolute DMSO. At room temperature, 16.0 g (150.9 mmol) of methyl mercaptoacetate are slowly added dropwise to the reaction mixture, which is stirred at room temperature until hydrogen evolution ceases (about 15 min). A solution of 27.8 g (137.1 mmol) of 3-bromo-2-fluorobenzaldehyde in 50 ml of absolute DMSO is added at room temperature to the reaction mixture. The latter is stirred until the reaction is complete and then poured into ice-water. The resulting precipitate is filtered off with suction and dried in vacuo at 40° C. overnight. 20.57 g of a mixture of the title compound and of the corresponding acid (approx. 1:1) are obtained.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[CH2:17](B1OC(C)(C)C(C)(C)O1)[CH:18]=[CH2:19].[NH3:29]>CO>[CH2:17]([C:2]1([NH2:29])[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1)[CH:18]=[CH2:19]
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Reactant: O=C1CC[C@@H](C(=O)OCc2ccccc2)C1
Reactant: N
Solvent: CO
Product: C=CCC1(N)CC[C@@H](C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
To a solution of (R)-benzyl 3-oxocyclopentanecarboxylate (WO 2007092681, 1 g, 4.58 mmol) in methanol (5 mL) was added 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.155 g, 6.87 mmol) and ammonia (7N solution in MeOH, 8 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and the residue was subjected to preparative HPLC (Shimadzu VP-ODS 20×100 mm, 8 min. gradient, Solvent A: 10% MeOH, 90% H2O, 0.1% TFA; Solvent B: 90% MeOH, 10% H2O, 0.1% TFA; wavelength: 220 nM). The desired fractions were collected, concentrated and partitioned between ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate solution (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to yield (1R)-benzyl 3-allyl-3-aminocyclopentanecarboxylate (616 mg, 2.38 mmol, 52% yield). MS (ESI+) m/z 260 (M+H)+
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=CC=1OC.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:44]=[CH:45][C:46]=1[O:47][CH3:48])[C:32]([C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=1)=O.C(OP([CH2:57][C:58]#[N:59])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:32]([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)=[CH:57][C:58]#[N:59])[CH:44]=[CH:45][C:46]=1[O:47][CH3:48]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(C(=O)c2ccc3ccccc3c2)cc1OC
Agent: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(C(=CC#N)c2ccc3ccccc3c2)cc1OC

Procedure:
3-(3,4-Dimethoxyphenyl)-3-naphth-2-ylacrylonitrile was prepared analogously to methyl 3,3-bis-(3′,4′-dimethoxyphenyl)acrylate using 2-(3,4-dimethoxybenzoyl)naphthalene (2.9 g, 10 mmol), diethylcyanomethylphosphonate (1.8 mL, 11 mmol) and lithium hexamethyldisilazide (8.5 mL, 11 mmol, 1.3M) with a reaction time of 1 hour at reflux. The crude product was purified by chromatography (silica gel, methylene chloride) to afford 2.93 g (93%) of a mixture of the E and Z isomers as a white solid: mp 121-123° C.; 1HNMR (CDCl3) δ8.11-6.78 (m, 20 H), 5.76 (s, 1 H), 5.75 (s, 1 H), 3.96 (s, 3 H), 3.92 (s, 3 H), 3.85 (s, 3 H), 3.80 (s, 3 H); 13C NMR (CDCl3) δ162.7, 162.7, 151.2, 150.6, 148.9, 148.7, 136.6, 134.5, 134.0, 133.8, 132.8, 131.5, 129.7, 129.4, 129.0, 128.6, 128.6, 128.3, 128.1, 127.7, 127.7, 127.4, 127.2, 126.8, 126.6, 125.4, 123.2, 122.2, 118.4, 118.2, 112.7, 111.1, 110.8, 93.9, 93.4, 56.0, 56.0, 55.9; Anal. Calcd for C21H17NO2. Theoretical: C, 79.98; H, 5.43; N, 4.44. Found: C, 79.90; H, 5.65; N, 4.46.
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10]Br)=[CH:5][CH:4]=1.[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C:14](=[O:20])[CH2:13]2>O1CCCC1>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:14]2([OH:20])[CH:15]3[CH2:18][CH2:19][N:12]([CH2:17][CH2:16]3)[CH2:13]2)=[CH:5][CH:4]=1
Reactant: O=C1CN2CCC1CC2
Reactant: Clc1ccc(CCBr)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cl
Product: OC1(CCc2ccc(Cl)cc2)CN2CCC1CC2

Procedure:
To 2.43 g (0.10 mole) of magnesium in 30 ml of anhydrous tetrahydrofuran under an N2 atmosphere is added slowly 21.95 g (0.10 mole) of 2-(4-chlorophenyl)ethyl bromide. The addition rate is such that a gentle reflux of the solvent is maintained. After the addition is complete the mixture is refluxed until the magnesium metal is thoroughly reacted. Cool the reaction mixture to 40°-45° C. and add a solution of 12.52 g (0.1 mole) of 3-quinuclidinone in 100 ml of anhydrous tetrahydrofuran at a sufficient rate to bring the mixture to a gentle reflux. When the addition is complete reflux the mixture for 1 hour. Follow the progress of the reaction by thin-layer chromatography on silica gel (acetonitrile: ammonium hydroxide, 95:5). At the completion of the reaction cool the mixture to 0°-5° C. in an ice/water bath. Quench the reaction mixture by the slow addition of 20 ml of 10% hydrochloric acid solution. Remove the tetrahydrofuran in vacuo. Add 100 ml of water to the residue then add sufficient 10% sodium hydroxide with cooling to bring the pH of the mixture to 11-12. Remove any magnesium hydroxide which may have precipitated by filtration, then wash the filtered solids with methylene chloride. Extract the aqueous base mixture with three 150 ml portions of methylene chloride. Combine all methylene chloride extracts and wash them with 75 ml of water followed by 75 ml of saturated sodium chloride solution. Dry the methylene chloride solution over anhydrous sodium sulfate. Remove the drying agent by filtration and strip the solvent in vacuo to provide the title compound as the free base.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH3:13])([O-:3])=[O:2].[CH2:14]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1CCCC1>CN(C)C=O.C(O)(C)C>[CH2:14]([O:21][C:22]1[CH:23]=[CH:24][C:25](/[CH:26]=[CH:13]/[C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:28][CH:29]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: C1CCNC1
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(/C=C/c2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
18.21 g (0.1 mol) of 2,4-dinitrotoluene, 21.23 g (0.1 mol) of 4-benzyloxy-benzaldehyde and 1.8 mL of pyrrolidine in 140 mL of dimethylformamide were heated for 2 hours at 100° C. which caused the reaction mixture to assume a dark-brown color. The reaction mixture was then allowed to cool to room temperature after which it was diluted with 210 mL of isopropanol and allowed to agitate for an additional hour with ice cooling. The product was suction-filtered off, washed with a small amount of cold isopropanol and then dried at 40° C. under vacuum.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[Na+].[Br-:11].[OH2:12]>ClCCl>[Br-:11].[Br-:11].[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:1]1[O:12][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:2](=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: O=Cc1ccccc1
Product: c1ccc(C2CO2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.6 %
Yield: 0.01 %

Procedure:
To 1.818 g (17.456 mmol) of styrene dissolved in 5 ml of dichloromethane in 250 ml round bottom flask, 5 ml of 12 N hydrochloric acid and 10 ml of water were added. A mixture of (3.035 g, 29.47 mmol) NaBr and 0.879 g (5.819 mmol) of NaBrO3 dissolved in 20 ml water was added under stirring at room temperature over a period of 90 min. The organic layer was evaporated to get 39.3% of styrene dibromide, 60.6% styrene epoxide and 0.01% benzaldehyde.
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:5]=[C:6]([NH:31][C:32]([NH:34][C:35](=[O:44])[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)=S)[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[C:16]2=[C:17]([CH3:30])[C:18]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:19][N:15]2[N:14]=[CH:13][N:12]=1.FC1C=CC(CC(N=C=O)=[O:54])=CC=1>C1COCC1.Cl.FC1C=C(C(C(NC2C=CC(F)=CC=2)=O)C(N)=O)C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1>[ClH:1].[ClH:1].[F:3][C:4]1[CH:5]=[C:6]([NH:31][C:32]([NH:34][C:35](=[O:44])[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)=[O:54])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[C:16]2=[C:17]([CH3:30])[C:18]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:19][N:15]2[N:14]=[CH:13][N:12]=1
Reactant: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Agent: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(C(C(N)=O)C(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of 3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (20 mg, 0.05 mmol, Compound B of Example 45) in 1 mL of THF at room temperature was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (0.36 M, 0.18 mL, Compound C of Example 4) and the solution was allowed to stir overnight. HPLC analysis and LC-MS analysis indicated the completion of the reaction and the organic solvent was thus removed under reduced pressure. The residue was purified on preparative HPLC. The title compound (15 mg, 46%) was finally obtained as a 2.HCl salt after a work-up similar to that described for Compound D of Example 36. 1H NMR (DMSO-d6) δ 11.02 (s, 1H), 10.58 (s, 1 if), 8.04 (s, 11H), 7.99 (s, 1H), 7.70(d, 1H), 7.35 (m, 4H), 7.16 (m, 2H), 4.44 (br.s, 2H), 3.40–3.70 (m, 12H), 2.81 (s, 3H), 2.39 (s, 3H); MS(ESI+) m/z 580.1 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.ClCCCOC1C=C(C2C3SC=CC=3ON=2)C=CC=1.[F:39][C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42][NH2:43].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[F:39][C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42][NH:43][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:7]=1
Reactant: NCc1ccccc1F
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Agent: ClCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Fc1ccccc1CNCCCOc1cccc(-c2noc3ccsc23)c1
Temperature: 80 °C
Yield: 94.1 %

Procedure:
Combine a mixture (1 mmol total) of 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 3-[3-(3-chloro-propoxy)-phenyl]-thieno[2,3-d]isoxazole with 2-fluorobenzylamine (0.63 g, 5.0 mmol), potassium carbonate (0.41 g, 3.0 mmol) and a mixture of acetonitrile:water (80:20) and heat (80° C.) for 30 hours. Cool the reaction mixture and concentrate to give a residue. Purify the residue by column (silica) chromatography (ethyl acetate). Combine the appropriate fractions and concentrate to give the title compound (0.36 g, 94% Yield) as an oil. Purity by LC/MS (APCI)=100% area, [M+H]+=383 g/mol.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:26]=[CH:25][C:9]([O:10][CH2:11][CH2:12][CH:13]2[CH2:16][N:15]([CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[CH2:14]2)=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH:13]2[CH2:14][N:15]([CH:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH3:18])[CH2:16]2)=[CH:25][CH:26]=1)=[O:4]
Reactant: CC(c1ccccc1)N1CC(CCOc2ccc(N)cc2)C1
Reactant: CN=C=O
Solvent: ClC(Cl)Cl
Product: CNC(=O)Nc1ccc(OCCC2CN(C(C)c3ccccc3)C2)cc1
Reaction time: 3 h

Procedure:
Under anhydous conditions, methyl isocyanate (10 mmol) is added dropwise to a stirred solution of 3-[2-(4-aminophenoxy)ethyl]-1-(1-phenylethyl)azetidine (10 mmol) in chloroform (100 ml). After stirring for 3 hr the solvent is removed and the residue purified by standard laboratory procedures.
Reaction SMILES: [CH3:1][C:2]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])([CH3:26])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[N+:23]([O-])=O>[Pt].C(#N)C>[NH2:23][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:5]=1[NH:4][CH2:3][C:2]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])([CH3:26])[CH3:1])=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:10]=2
Reactant: CC(C)(CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12)NS(C)(=O)=O
Agent: [Pt]
Solvent: CC#N
Product: CC(C)(CNc1c(N)cnc2cc(OCc3ccccc3)ccc12)NS(C)(=O)=O
Reaction time: 2 h
Yield: 91.3 %

Procedure:
N-[1,1-Dimethyl-2-(3-nitro-7-benzyloxyquinolin-4-ylamino)ethyl]methanesulfonamide (14.8 g, 33.3 mmol) was mixed with acetonitrile (300 mL) and added to a Parr flask; 5% platinum on carbon (2 g) was added. The reaction was flushed with nitrogen and placed under hydrogen pressure (40 psi, 2.8×105 Pa) for 5.5 hours with the hydrogen replaced after two hours. An analysis by TLC indicated the presence of starting material. Additional acetonitrile (200 mL) and 5% platinum on carbon (2 g) were added, and the reaction was placed under hydrogen pressure overnight. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. Toluene and dichloromethane were added and removed under reduced pressure twice to yield 12.6 g of N-[2-(3-amino-7-benzyloxyquinolin-4-ylamino)-1,1-dimethylethyl]methanesulfonamide as a foam.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+].[H][H]>C1COCC1.O>[C:24]([O:23][C:21](=[O:22])[NH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH2:13][OH:14])([CH3:27])([CH3:25])[CH3:26]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCCCC(NC(=O)OCc1ccccc1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCC(CO)NC(=O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
To a stirred solution of 2-benzyloxycarbonylamino-6-tert-butoxycarbonylamino-hexanoic acid (Cbz-Lys(Boc)-OH) (Chem-Impex International, 3.8 g, 10 mmol) in THF (25 mL) in a 100 mL round flask was added 1,1′-carbonyldiimidazole (CDI) (1.7 g, 10.5 mmol) at room temperature. After 20 minutes, the THF solution was transferred via a Teflon canula (φ=2 mm) to a stirred solution of sodium borohydride (0.75 g, 20 mmol) in water (10 mL) in a 1 L round flask immersed in a water bath at 5-10° C. The addition caused a strong evolution of hydrogen gas and the mixture was stirred for a couple of hours. The volatiles were then removed on a rotovap, and the residue was dissolved in ethyl acetate (150 mL). The ethyl acetate solution was extracted successively with cold 1 N HCl (2×50 mL), saturated sodium bicarbonate solution (2×50 mL), brine (100 mL), and was dried with anhydrous sodium sulfate. The dried ethyl acetate solution was then pass through a one inch flash pad of silica gel, and concentrated to provide a colorless solid (3.3 g, 91%), TLC Rf=0.24 (95:5:2 EtOAc:MeOH:H2O).
Reaction SMILES: [C:1](O)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(OC(Cl)=O)C.C(N(CC)CC)C.[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1.Cl>C(#N)C>[C:25]([C:24]1[CH:28]=[CH:29][C:21]([NH:20][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[CH:22][CH:23]=1)([OH:27])=[O:26]
Reactant: C=C(C)C(=O)O
Reactant: Nc1ccc(C(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C(C)C(=O)Nc1ccc(C(=O)O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
Into a 1 liter flask 600 ml of acetonitrile, 95.2 g (1.1 mol) of methacrylic acid and 120.1 g (1.1 mol) of chloroformic acid ethyl ester were added. To this mixture 111.8 g (1.1 mol) of triethylamine was added over a period of 1 hour in a cold bath. Stirring was continued for 1 hour at room temperature. 137.1 g (1 mol) of 4-aminobezoic acid was added to the mixture. The mixture was heated for 2 hours at 50° C. The mixture was poured into 5 liter of 1% HCl solution. The deposit was filtered, washed and dried to produce 170.9 g of N-(4-carboxyphenyl)-methacrylamide.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][N:7]=1.[C:8]1(=[O:17])[O:16][C:13]([CH3:15])([CH3:14])[O:12][C:10](=[O:11])[CH2:9]1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:14][C:13]1([CH3:15])[O:16][C:8](=[O:17])[C:9](=[C:3]2[CH2:4][CH2:5][CH2:6][NH:7]2)[C:10](=[O:11])[O:12]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COC1=NCCC1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)OC(=O)C(=C2CCCN2)C(=O)O1
Temperature: 25 °C
Yield: 71.3 %

Procedure:
A solution of 5-Methoxy-3,4-dihydro-2H-pyrrole (5.35 g, 54.0 mmol), isopropylidene malonate (7.78 g, 54.0 mmol), triethylamine (1.35 mL, 9.7 mmol) and benzene (55 mL) is refluxed under nitrogen overnight. The reaction is cooled to RT and concentrated and the crude product is recrystalized from EtOH (95 mL) to give the title compound as a white solid (8.13 g, 38.5 mmol). 1H NMR (CDCl3, 300 MHz) 3.73(t, 2H), 3.35(t, 2H), 2.20-2.08(m, 2H), 1.66(s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:47]([O:49][C:50]1[CH:51]=[C:52]([C@@H:58]2[C@H:63]([NH2:64])[CH2:62][CH2:61][O:60][CH2:59]2)[CH:53]=[CH:54][C:55]=1[O:56][CH3:57])[CH3:48]>ClCCl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:64][C@@H:63]2[CH2:62][CH2:61][O:60][CH2:59][C@@H:58]2[C:52]2[CH:53]=[CH:54][C:55]([O:56][CH3:57])=[C:50]([O:49][CH2:47][CH3:48])[CH:51]=2)=[O:10])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CCOc1cc([C@H]2COCC[C@H]2N)ccc1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc([C@H]2COCC[C@H]2NC(=O)c2ccc(C(=O)OC)cc2)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1 mmol of terephthalic acid monomethyl ester, 5 mmol of ethyl di-isopropylamine and 1.1 mmol of O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate (HBTU) in 20 ml of dichloromethane is stirred for 30 min at RT. After addition of 1.1 mmol of (3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-tetrahydro-pyran-4-ylamine the suspension is stirred over night at RT. The mixture is concentrated under reduced pressure and the solid residue is purified by column chromatography on SiO2 (dichloromethane/ethyl acetate 85/15 vol/vol), the main product fraction is separated and concentrated yielding the title compound as grayish solid residue. M.p. 166-167.5° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([NH:12][C:13]2[N:17]=[C:16]([NH2:18])[NH:15][N:14]=2)=[CH:4][C:3]=1[Cl:19].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][C:5]([NH:12][C:13]2[N:17]=[C:16]([NH:18][CH2:26][C:25]3[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:30])[F:31])=[CH:29][CH:28]=3)[NH:15][N:14]=2)=[CH:4][C:3]=1[Cl:19]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: Nc1nc(Nc2cc(Cl)c(Br)c(C(F)(F)F)c2)n[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: FC(F)(F)c1ccc(CNc2nc(Nc3cc(Cl)c(Br)c(C(F)(F)F)c3)n[nH]2)cc1
Reaction time: 1 h
Yield: 73 %

Procedure:
A solution of N3-(4-bromo-3-chloro-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 1 (50 mg, 140 μmol) and 4-(trifluoromethyl)benzaldehyde (48.8 mg, 280 μmol) in MeOH (3 ml) was stirred at room temperature for 2 days, NaBH4 (31.8 mg, 841 μmol) was added and the reaction was stirred for 1 hour. The solvent was removed, and the reaction mixture was re-dissolved in DCM and was washed with water (2×4 ml), dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 24 g, 3% to 5% MeOH in DCM) and recrystallized from DCM to give a light yellow powder as desired product (53 mg, 73% yield). MS +m/z: 514 (M+H)+
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:15])=[N-].[ClH:16]>C(OCC)C>[Cl:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)CCCc1ccccc1
Reactant: Cl
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: O=C(CCl)CCCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Phenylbutanoyl chloride (14.7 g.) was added dropwise to a stirred solution of diazomethane (7.5 g.) in diethyl ether (340 ml.) at 0° C. The solution was stirred in an ice bath for 1 hour further and then it was saturated with anhydrous hydrogen chloride gas. After 1 hour at 0° C., dry nitrogen was passed through this solution, which was then poured onto crushed ice (about 300 ml.). The ethereal layer was separated and the aqueous phase was diluted with water (150 ml.), saturated with sodium chloride, and extracted with diethyl ether. The combined ethereal solutions were washed with water, aqueous sodium carbonate solution (2 N), and then again with water, and dried over anhydrous magnesium sulphate. The solution was evaporated and the residue was distilled, to give 1-chloro-2-oxo-5-phenylpentane (11.5 g.), b.p. 150°-151° C./10 mm.Hg (Elemental analysis: C, 67.4; H, 7.1; Cl, 18.0%; C11H13ClO requires C, 67.2; H, 6.7; Cl, 18.0%. νmax 1455 cm-1, 1500 cm-1, 1725 cm-1).