Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C:18](=[O:19])[C:17]2[CH2:16][CH2:15][N:14]3[CH:20]=[C:21]([CH3:23])[N:22]=[C:13]3[C:12]=2[NH:11][C@@H:10]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>>[Si:1]([O:8][C@H:9]1[C:18](=[O:19])[C:17]2[CH:16]=[CH:15][N:14]3[CH:20]=[C:21]([CH3:23])[N:22]=[C:13]3[C:12]=2[NH:11][C@@H:10]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: Cc1cn2c(n1)C1=C(CC2)C(=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](c2ccccc2)N1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Product: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](O[Si](C)(C)C(C)(C)C)C3=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
50.7 g (123.8 mmol) of (8R,9R)-8-(tert-butyldimethylsilanyloxy)-2-methyl-9-phenyl-5,6,7,8,9,10-hexahydroimidazo[1,2-h][1,7]naphthyridin-7-one are treated in portions at 5° C.–10° C. with 35.6 g (153.5 mmol) of 2,3-dichloro-5,6-dicyano-p-benzoquinone. After the end of the addition, the reaction mixture is stirred at room temperature for 2 days. The reaction mixture is extracted with 150 ml of sodium hydroxide solution and the sodium hydroxide solution phase separated off is extracted with 150 ml of toluene and the combined toluene phases are washed with 150 ml of water. The organic phase is concentrated and the residue is dried overnight in a high vacuum. The solid crystallised in this way is stirred in diisopropyl ether, filtered off with suction and dried in vacuo at 50° C. 10.1 g (20% of theory) of the title compound are obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].Cl[C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1>O>[OH:5][CH2:4][CH2:3][O:6][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: OCCO
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cccnc1OCCO

Procedure:
Sodium hydride in oil (60%, 131 mg) is added to ethylene glycol (6.0 ml) and 2-chloro-3-nitropyridine (430 mg) is added. The mixture is stirred for 26 hours during which time additional sodium hydride in oil (60%, 100 mg) is added. Water is added, the pH is adjusted to 9 and the solution is extracted with methylene chloride (3×50 ml). The combined organic layers are dried with saline and sodium sulfate and concentrated. Chromatography on silica gel with a methylene/chloroform gradient affords the title compound, Rf =0.32 (TLC on silica gel, ethyl acetate/hexane [50/50]).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:12][CH:10]([C:4]1[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([NH2:1])[N:3]=1)[CH3:11]
Reactant: Oc1ccccc1Cl
Reactant: CSc1nc(N)nc(C(C)O)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSc1nc(N)nc(C(C)Oc2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
To a solution of 1-(4-amino-6-(methylthio)-1,3,5-triazin-2-yl)ethanol (203 mg) in dry tetrahydrofuran (8 mL) was added 2-chlorophenol (0.122 mL) and triphenylphosphine (314 mg) followed by diisopropyl azodicarboxylate ((0.233 mL) dropwise. The solution was stirred at room temperature for 80 min then was concentrated in vacuo, dissolved in ethyl acetate (40 mL) and washed with 1N sodium hydroxide solution (2×40 mL), dried over sodium sulfate and concentrated to give a yellow oil. Purification by SCX chromatography eluting with a 1:1 mixture of dichloromethane-methanol then 2N ammonia in 1:1 mixture of dichloromethane-methanol followed by flash column chromatography, with 1% acetonirile in dichloromethane to give the title compound (207 mg).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:26][CH:25]=3)[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[CH3:55][Si:56]1([CH3:74])[CH2:60][C@@H:59]([C:61]([NH:63][C@H:64]2[C:73]3[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=3)[CH2:67][CH2:66][CH2:65]2)=[O:62])[NH:58][CH2:57]1.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:20]([N:58]3[C@H:59]([C:61](=[O:62])[NH:63][C@H:64]4[C:73]5[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=5)[CH2:67][CH2:66][CH2:65]4)[CH2:60][Si:56]([CH3:74])([CH3:55])[CH2:57]3)=[O:21])[CH2:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][CH:29]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: C[Si]1(C)CN[C@H](C(=O)N[C@@H]2CCCc3ccccc32)C1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2C[Si](C)(C)C[C@H]2C(=O)N[C@@H]2CCCc3ccccc32)cc1
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert-butoxycarbonyl)phenyl)propanoic acid (0.14 g, 0.29 mmol) in DMF (1.5 mL) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (86 mg, 0.31 mmol) at rt followed by a solution of (R)-3,3-dimethyl-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,3-azasilolidine-5-carboxamide, TFA (105 mg, 0.261 mmol) and DIEA (115 μL) in DMF (2 mL). After 2 h, the reaction mixture was directly purified by preparative HPLC to afford the title compound (165 mg, 83% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J=8.1 Hz, 2H), 7.75 (d, J=7.5 Hz, 2H), 7.52 (t, J=6.7 Hz, 2H), 7.39-7.06 (m, 10H), 6.51 (d, J=8.4 Hz, 1H), 5.76 (d, J=8.8 Hz, 1H), 5.18-5.00 (m, 3H), 4.38-4.30 (m, 1H), 4.25-4.10 (m, 1H), 3.18 (d, J=13.4 Hz, 1H), 3.08-3.00 (m, 1H), 2.85-2.71 (m, 4H), 2.10-2.02 (m, 1H), 1.91-1.81 (m, 3H), 1.56 (s, 9H), 1.33 (dd, J=14.9, 1.7 Hz, 1H), 1.06 (dd, J=14.7, 10.1 Hz, 1H), 0.46 (s, 3H), 0.29 (s, 3H); MS(ESI+) m/z 758.2 (M+H)+.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH:3]=[C:2]1[C:12]([OH:14])=[O:13].[H][H]>CO.O.[Pd]>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:12]([OH:14])=[O:13]
Reactant: [H][H]
Reactant: O=C(O)c1cc(=O)c2ccccc2o1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: O=C(O)C1CCc2ccccc2O1
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a suspension of commercially available chromone-2-carboxylic acid (50 g, 281 mmol) in methanol (500 mL), slurry of (10% Pd/C wet, 5 g) in water (10 mL) was added under nitrogen atmosphere. The mixture was hydrogenated at 60 psi at room temperature (RT) and further maintained hydrogen reservoir up to 60 psi for 2 h. The progress of reaction was monitored by TLC. Reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to yield chromane-2-carboxylic acid as off-white solid (44.7 g, 95%). m/z-178.02.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].[CH2:12]=[O:13]>C(O)(C)(C)C.CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][CH2:12][OH:13]
Reactant: C=O
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Product: O=[N+]([O-])c1cccc(Br)c1CCO
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A solution of potassium tertiary-butylate (90 mg, 0.8 mmol) in tert-butanol (1 ml, synthesis quality, 99%) was added to 2-bromo-6-nitrotoluene (1.08 g, 5 mmol) and paraformaldehyde (150 mg, 5 mmol in DMSO (2.5 ml, synthesis quality, additionally dried for 2 d over molecular sieve 4 Å). After the addition of the potassium tertiary-butylate solution, a color change from yellow to deep violet occurred. It was stirred for 5 min at room temperature and for 30 min at 70° C. (oil bath temperature). The mixture was then allowed to cool to room temperature and neutralized with a few drops of conc. HCl. The mixture was diluted with EtOAc (30 ml) and washed with H2O (20 ml). The aqueous phase was post-extracted with EtOAc (2×20 ml). Drying of the organic phases over Na2 SO4, filtering and evaporating the solvent under reduced pressure yielded the crude product (1.49 g) which was purified by column chromatography (20 g SiO2, 20×2 cm, solvent: PE 45 ml, PE/EtAOc 10:1 110 ml, 8:1 180 ml, 7.5:1 340 ml, 6:1 140 ml). 2-(2-bromo-6-nitrophenyl)ethanol (867 mg, 70%) was obtained as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH2:10][C:9]([C:13]([OH:15])=O)=[CH:8]2.[CH2:16]([N:18](CC)[CH2:19][CH3:20])[CH3:17].P(C#N)(OCC)(OCC)=[O:24].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH2:10][C:9]([C:13]([N:18]1[CH2:19][CH2:20][O:24][CH2:17][CH2:16]1)=[O:15])=[CH:8]2
Reactant: COc1cccc2c1OCC(C(=O)O)=C2
Reactant: CCOP(=O)(C#N)OCC
Reactant: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1OCC(C(=O)N1CCOCC1)=C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution (200 ml) of 8-methoxy-2H-chromene-3-carboxylic acid (10.0 g) in DMF were added triethylamine (8.6 ml) and diethyl cyanophosphate (10.0 ml) and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/ethyl acetate) to give the title compound (3.5 g) as a brown oil.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[F:9][C:10]([F:15])([F:14])[C:11](=[O:13])[CH3:12].[C:16]1([S:22]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CS(C)=O.O1CCCC1.O>[F:9][C:10]([F:15])([F:14])[C:11]([CH3:2])([OH:13])[CH2:12][O:31][C:28]1[CH:27]=[CH:26][C:25]([S:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:23])=[O:24])=[CH:30][CH:29]=1
Reactant: C[S+](C)(C)=O
Reactant: CC(=O)C(F)(F)F
Reactant: O=S(=O)(c1ccccc1)c1ccc(O)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(O)(COc1ccc(S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Temperature: 10 °C
Reaction time: 0.33 h
Yield: 9.5 %

Procedure:
A suspension of trimethylsulfoxonium iodide (1.6 6 g, 7.56 mmol) and sodium hydride (0.36 g, 7.56 mmol of 50% in oil) was stirred in 25 mL of dimethylsulfoxide for 25 minutes. The mixture was cooled to 10° C. and was treated with a solution of trifluoroacetone (0.72 g, 6.41 mmol) in tetrahydrofuran (3 mL). After stirring for 20 minutes, the solution was allowed to warm to room temperature where it was treated with a solution of 4-(phenylsulfonyl)phenol (1.5 g, 6.40 mmol) and sodium hydride (0.31 g, 6.4 .mmol of 50% in oil) in dimethylsulfoxide (7.5 mL). The mixture was stirred for 1 hour and then heated to 50° C. for 18 hours. The reaction was poured into water, acidified to pH 6, and extracted with diethylether. The combined organic fractions were evaporated to give an oil. Chromatography, eluting with dichloromethane yielded the title compound as a tan solid (0.22 g); mp 94°-96° C.; NMR: 1.39 (s,3, CH3), 4.12 (q,2, CH2), 6.39 (s,1, OH), 7.17 (s,1, Ar), 7.20 (s,1, Ar), 7.63 (m,3, Ar), 7.91 (m,4, Ar); MS: m/z=361(M+1). Analysis for C16H15F3O4S: Calculated: C, 53.33; H, 4.20; Found: C, 53.54: H, 4.25.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Br)=[CH:5][CH:4]=1.[P:11]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])[O:12]CC>>[C:6]1([CH2:9][P:11](=[O:12])([O:15][CH2:16][CH3:17])[O:18][CH2:19][CH3:20])[CH:7]=[CH:8][C:3]([CH2:2][P:11](=[O:12])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])=[CH:4][CH:5]=1
Reactant: CCOP(OCC)OCC
Reactant: BrCc1ccc(CBr)cc1
Product: CCOP(=O)(Cc1ccc(CP(=O)(OCC)OCC)cc1)OCC
Temperature: 130 °C
Yield: 89.1 %

Procedure:
α, α′-Dibromo-p-xylene (5.28 g, 20 mmol, 1 equiv.) and triethyl phosphite (10.3 mL, 60 mmol, 3 equiv.) were placed in a flask with a magnetic stirring bar. A distillation apparatus was attached to collect ethyl bromide formed along with the reaction. The mixture was immersed in an oil bath and heated to 130° C. for 2 h. After cooling down, white crystal crushed out and recrystalized from hexane to give the product (6.74 g, 89% yield). 1H NMR (CDCl3) δ7.24 (s, 4H), 4.00 (m, 8H), 3.12 (d, 4H, J=20.2 Hz), 1.23 (t, 12H, J=7.0 Hz).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]1[C:31]2[CH:30]=[C:29]([CH:32]=O)[N:28]=[CH:27][C:26]=2[O:25][CH2:24][CH2:23]1.C([BH3-])#N.[Na+]>>[O:22]1[C:31]2[CH:30]=[C:29]([CH2:32][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]4[C:15]5[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=5[O:13][CH2:12][C:11]4=[O:21])[CH2:4][CH2:3]3)[N:28]=[CH:27][C:26]=2[O:25][CH2:24][CH2:23]1
Reactant: Cc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: Cc1ccc2c(c1)N(CCN1CCC(NCc3cc4c(cn3)OCCO4)CC1)C(=O)CO2

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-methyl-2H-1,4-benzoxazin-3(4H)-one (Intermediate 91), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described for Example 21 to give the product as an oil, 4.7 mg (2%).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[Cl:16])=[O:5])#[N:2].[CH2:17](OC(OCC)OCC)C.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:30]=1[O:36][CH2:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]1>C(O)(C)C>[C:1]([C:3](=[CH:17][NH:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[C:30]([O:36][CH2:37][CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]2)[CH:31]=1)[C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[Cl:16])=[O:5])#[N:2]
Reactant: CCOC(OCC)OCC
Reactant: COc1cc(NC(=O)CC#N)c(Cl)cc1Cl
Reactant: COc1ccc(N)cc1OCCCN1CCN(C)CC1
Solvent: CC(C)O
Product: COc1cc(NC(=O)C(C#N)=CNc2ccc(OC)c(OCCCN3CCN(C)CC3)c2)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
To a suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide (1.75 g, 6.75 mmol) in 8.2 mL of iso-propanol was added triethylorthoformate (1.5 g, 10.1 mmol). The mixture was heated to reflux. After 20 minutes, 4-methoxy-3-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenylamine in 20 mLs of iso-propanol was added dropwise so as to maintain reflux. After 26 hours, the reaction was cooled to room temperature and the suspended solids were filtered. The solids were rinsed with iso-propanol until effluent was colorless. The yellow solid was dried in vacuo to give 3.45 g (93%) of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-{4-methoxy-3-[3-(4-methylpiperazin-1-yl)-propoxy]-phenylamino}-acrylamide as a mixture of isomers. 1H NMR (300 MHz, CDCl3) δ 11.35 (br d, 1H), 8.17 (m, 2H), 7.76 (d, 1H), 7.41 (s, 1H), 6.88 (m, 1H) 6.69 (m, 2H), 4.10 (t, J=7 Hz, 2H), 3.96 (s, 3H), 3.87 (s, 3), 2.55 (t, J=7 Hz, 2H), 2.48 (m, 8H), 2.29 (s, 3H), 2.06 (m, 2H); MS (ES) m/z548.1 (M+)
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[H-].[Na+].[C:8](Cl)(=[O:12])[CH:9]([CH3:11])[CH3:10]>C1COCC1>[OH:12][C:8](=[C:2]([C:1]#[N:5])[C:3]#[N:4])[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)C(=O)Cl
Reactant: N#CCC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C(O)=C(C#N)C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
A solution of malononitrile (4.0 g, 60 mmol) in THF (30 mL) was added dropwise over 1 h to a suspension of NaH (95%, 3.0 g, 120 mmol) in THF (75 mL) at 0° C. The reaction was then warmed to room temp and stirred for 1 h. The suspension was then cooled to 0° C. and treated dropwise with a solution of isobutyryl chloride (6.3 mL, 60 mmol) in THF (25 mL). The addition was controlled so that the internal temp does not rise above 10° C. Upon completion of the addition the reaction was warmed to room temp and stirred for 24 h. The reaction was then quenched with H2O (10 mL) and evaporated. The residue was then partitioned between EtOAc (100 mL) and 1 N HCl (75 mL). The aqueous layer was extracted again with EtOAc (50 μL) and the combined organic layers were washed with brine (100 mL), dried (c), filtered, and evaporated to yield the desired product (7.95 g, 96%).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.Cl.[CH2:8]([O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl.Cl>[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:20][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[CH:21][CH:22]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(OCc2ccccc2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cyclopropane carbonyl chloride (4.54 ml) was added dropwise over 5 min to a stirred solution of 4-benzyloxyaniline hydrochloride (11.8 g) and triethylamine (15.33 ml) in dichloromethane (60 ml). The reaction mixture was stirred at room temperature under nitrogen for 2 h. The solution was diluted with 2N hydrochloric acid (100 ml) and dichloromethane (200 ml). The organic layer was washed with 2N sodium carbonate (100 ml), water (100 ml), 10% brine (50 ml) and dried over anhydrous sodium sulphate. Concentration in vacuo gave a pale brown solid which was washed with diethyl ether (3×50 ml) to afford the title compound (12 g) as a white solid, m.p. 162°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([N:15]1[C:23]2[N:22]=[C:21]([Cl:24])[NH:20][C:19]=2[C:18](=[O:25])[N:17]([CH2:26][CH2:27][CH2:28][CH2:29]/[C:30](=[N:33]/[H])/[NH:31]O)[C:16]1=[O:35])[CH2:12][CH2:13][CH3:14]>CS(C)=O>[CH2:11]([N:15]1[C:23]2[N:22]=[C:21]([Cl:24])[NH:20][C:19]=2[C:18](=[O:25])[N:17]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[N:31]=[C:4]([C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])[O:6][N:33]=2)[C:16]1=[O:35])[CH2:12][CH2:13][CH3:14]
Reactant: O=C(O)c1ccccc1F
Reactant: [H]/N=C(/CCCCn1c(=O)c2[nH]c(Cl)nc2n(CCCC)c1=O)NO
Solvent: CS(C)=O
Product: CCCCn1c(=O)n(CCCCc2noc(-c3ccccc3F)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 90 °C
Reaction time: 16 h
Yield: 28.6 %

Procedure:
2-Fluorobenzoic acid (36 mg, 0.25 mmol) and CDl (45 mg, 0.28 mmol) were stirred in anhydrous DMSO (0.9 ml) at rt for 1 h. (1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (100 mg, 0.28 mmol) was added and the mixture was stirred at 90° C. for 16 h. The mixture was purified by MDAP. The product fraction was combined and concentrated to give the title compound as a white solid (33 mg, 29%).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH:17]=O)=[CH:16][C:11]=2[CH2:10][CH2:9]1.[OH2:19]>>[O:3]1[C:7]2[CH:13]=[CH:14][C:15](/[CH:16]=[CH:11]/[C:12]([O:8][CH2:9][CH3:10])=[O:19])=[CH:17][C:6]=2[CH2:5][CH2:4]1
Reactant: C1CCOC1
Reactant: O=Cc1ccc2c(c1)CCO2
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)/C=C/c1ccc2c(c1)CCO2
Reaction time: 0.33 h
Yield: 88 %

Procedure:
60% sodium hydride (3.39 g, 84.6 mmols) was added to a tetrahydrofuran (150 ml) solution of triethyl phosphonoacetate (19.0 g, 84.6 mmols) while cooling with ice, and the mixture was stirred for 20 minutes. To this was dropwise added a tetrahydrofuran (15 ml) solution of 2,3-dihydrobenzofuran-5-carbaldehyde (11.4 g, 76.9 mmols) and stirred further for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with a saturated saline solution, then dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified through silica-gel column chromatography (hexane/ethyl acetate=from 95/5 to 9/1) to obtain 14.7 g (yield: 88%) of the target compound. This was oily.
Reaction SMILES: FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)N.C([O:20][C:21](=[O:39])[C@H:22]([CH3:38])[NH:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)C(C)C>>[F:31][C:30]([F:32])([F:33])[C:28]1[CH:29]=[C:24]([NH:23][C@H:22]([C:21]([OH:39])=[O:20])[CH3:38])[CH:25]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:27]=1
Reactant: CC(C)COC(=O)[C@H](C)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: C[C@H](Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)O

Procedure:
Following General Procedure J and using 3,5-di(trifluoromethyl)aniline (Aldrich) and isobutyl R-(+)-lactate (Aldrich), N-[3,5-di(trifluoromethyl)phenyl]-L-alanine isobutyl ester was prepared as an oil. The reaction was monitored by silica gel tic (Rf=0.38 in 10% EtOAc/hexanes). Purification was by preparative plate thin layer chromatography using 10% EtOAc/hexanes as the eluant.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16]CC)=[O:15].[OH-].[Na+]>CCO>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2ncc(C(=O)O)c(N)c2c1
Temperature: 0 °C
Yield: 92.6 %

Procedure:
To a stirred solution of ethyl 4-amino-6-methoxyquinoline-3-carboxylate (Example Aa, 1.23 g, 5.0 mmol) in EtOH (20.0 mL) was added aqueous NaOH (2.0 N, 5.0 mL) at room temperature. The reaction mixture was then refluxed for 3 hr. The solution was then filtered and washed with water. The filtrate was cooled to 0° C. and neutralized carefully with 1 N HCl to pH 7. Most of the EtOH was removed under reduced pressure, and the precipitate was collected by filtration, washed with cold water, and dried under vacuum to give the title compound as an off-white solid (1.01 g, 93%). 1H NMR (400 MHz, DMSO-d6) δ 3.89 (s, 3H), 7.40 (dd, J=2.8, 9.4 Hz, 1H), 7.73 (d, J=9.4 Hz, 1H), 7.77 (d, J=2.8 Hz, 1H), 8.77 (s, 1H). MS 219 (MH+).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:12][C@H:11]([NH:13][C:14]2[C:15]([NH2:21])=[CH:16][CH:17]=[C:18]([F:20])[CH:19]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([NH:29][C@@H:30]([CH3:34])[C:31](O)=O)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:22]([O:26][C:27](=[O:28])[NH:29][C@H:30]([C:31]1[N:13]([C@H:11]2[CH2:12][C@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:10]2)[C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[N:21]=1)[CH3:34])([CH3:25])([CH3:24])[CH3:23]
Reactant: Nc1ccc(F)cc1N[C@H]1C[C@H](OCc2ccccc2)C1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1[C@H]1C[C@H](OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of N2-(trans-3-benzyloxycyclobutyl)-4-fluoro-benzene-1,2-diamine (1.73 g, 2.55 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (0.54 g, 2.81 mmol) and HOAt (0.38 g, 2.81 mmol) in DCM (20 mL) were cooled to 0° C. under nitrogen atmosphere. To this mixture N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.54 g, 2.81 mmol) was added portion wise and the reaction mixture was stirred at RT for 1 h. The reaction mixture allowed to warm to RT then partitioned between DCM (30 mL) and 10% aqueous citric acid (20 mL). The organic layer was washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) to afford the title compound as a off-white gum, which solidified on standing (0.88 g, 75%). NMR: 328289. LCMS (Method B): RT 3.85 min [M+H]+ 458.