Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14]2)C1C=CC=CC=1>O1CCCC1.C(O)C.[C].[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OCc3ccccc3)c2[nH]1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O)c2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.1 %

Procedure:
Ethyl 7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (0.40 g) was dissolved in a tetrahydrofuran (5 mL)-ethanol (5 mL) mixed solvent, 10% palladium-carbon (containing water (50%), 0.80 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized from diethyl ether and the obtained solid was washed with a diethyl ether-hexane mixed solvent to give the title compound (0.31 g, yield 96%) as a pale-yellow solid. The pale-yellow solid was recrystallized from ethanol-hexane to give pale-yellow crystals.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1[CH3:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:15][O-:16].[Na+]>O1CCCC1>[CH3:15][O:16][C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1[CH3:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CC1=C(Cl)C(=O)c2ccccc2C1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1=C(C)C(=O)c2ccccc2C1=O
Reaction time: 8 h

Procedure:
A solution of 2-chloro-3-methyl-1,4-naphthoquinone (10.3 g) in tetrahydrofuran (100 mL) was treated dropwise with a solution of sodium methoxide (320 g) in tetrahydrofuran (25 mL) at room temperature. After stirring overnight, the mixture was evaporated, and the residue was taken up in ether. The organic layer was washed with brine, dried, filtered and evaporated. Chromatography over silica gel gave 2-methoxy-3methyl-1,4-naphthoquinone, m.p. 93°-94° C.
Reaction SMILES: [C:1](#[N:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[ClH:7].[CH2:8]([OH:10])[CH3:9]>>[ClH:7].[C:1](=[NH:6])([O:10][CH2:8][CH3:9])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C#N
Reactant: CCO
Agent: Cl
Product: CCOC(=N)C(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
Pivalonitrile (1.3 mL, 12.0 mmol) was dissolved in anhydrous ethanol (28 mL) under an atmosphere of Ar. The solution was cooled to 0° C., saturated with HCl gas, stirred for 6 h, allowed to warm to RT, and stirred for 54 h. The solvent was removed in vacuo to afford ethyl pivalimidate hydrochloride (2.0 g, 100%) as an off white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.19 (br s, 1H), 4.42 (q, J=6.9 Hz, 2H), 1.33 (t, J=6.8 Hz, 3H), 1.24 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([N+:24]([O-])=O)[CH:20]=4)[N:15]=3)[CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-])=O>C(O)C.[H][H].[Pd]>[NH2:1][C:4]1[CH:28]=[CH:27][C:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([NH2:24])[CH:20]=4)[N:15]=3)[CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN(Cc1ccc3cc([N+](=O)[O-])ccc3n1)CC2
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)CCN(Cc1ccc3cc(N)ccc3n1)CC2

Procedure:
The title compound was prepared similarly to the procedure of Preparation 5 by the hydrogenation of 7-nitro-3-(6-nitroquinol-2-ylmethyl)-1,2,4,5-tetrahydro-3H-3-benzazepine using H2 /Pd/C in ethanol.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:25])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15]CC3C=CC=CC=3)[C:11]=2[C:23]#[N:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([OH:32])C=CC=CC=1>S(=O)(=O)(O)O>[C:1]1([O:7][C:8](=[O:25])[NH:9][C:10]2[S:14][N:13]=[C:12]([OH:15])[C:11]=2[C:23](=[O:32])[NH2:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1c(OCc2ccccc2)nsc1NC(=O)Oc1ccccc1
Reactant: Oc1ccccc1
Agent: O=S(=O)(O)O
Product: NC(=O)c1c(O)nsc1NC(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The wet solid, (3-Benzyloxy-4-cyano-isothiazol-5-yl)-carbamic acid phenyl ester, (320 g) was added slowly to concentrated sulfuric acid (650 mL) over 1.5 hours. Additional concentrated sulfuric acid (100 mL) was added and the mixture stirred a further 3 hours. The viscous solution was diluted by slow addition of ice (2000 g) followed by vigorous stirring for an additional 2 hours. The acid was partially removed by dividing the suspension into eight containers that were placed in a centrifuge, spun at 3000 rpm for 45 minutes at 21° C. The aqueous layer was discarded, additional pure water was added, the pellet resuspended, and the process repeated. After seven dilution/centrifugation/redilution cycles, the pH of the aqueous layer had increased to ˜4 and the solid was collected and dried by drawing air through a cake in a funnel for 2 days. The less-wet solid was crushed, placed again in the filter, and air was again drawn through the solid for another day. This process was repeated until the solid was dry to afford a tan solid (234 g, 105% over two steps, minor impurities present—did not interfere appreciably with the subsequent steps). 1H NMR (400 MHz, DMSO) δ 7.00 (broad s, 1H), 7.27-7.31 (m, 3H), 7.40-7.45 (m, 2H), 7.89 (s, 1H), 8.08 (s, 1H), 11.92 (s, 1H); MS (APCl, m/z): 184 [M-(H and PhOH)]−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([OH:19])=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.O.ON1C2C=CC=CC=2N=N1.Cl.Cl.[N:55]1[CH:60]=[CH:59][C:58]([N:61]2[CH2:66][CH2:65][C:64]3([CH2:71][CH2:70][NH:69][CH2:68][CH2:67]3)[CH2:63][CH2:62]2)=[CH:57][CH:56]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[N:55]1[CH:56]=[CH:57][C:58]([N:61]2[CH2:66][CH2:65][C:64]3([CH2:67][CH2:68][N:69]([C:17]([C:13]4[CH:14]=[C:15]5[C:10](=[CH:11][CH:12]=4)[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:16]5)=[O:19])[CH2:70][CH2:71]3)[CH2:63][CH2:62]2)=[CH:59][CH:60]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C(=O)O)cc2C1
Reactant: c1cc(N2CCC3(CCNCC3)CC2)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2ccc(C(=O)N3CCC4(CC3)CCN(c3ccncc3)CC4)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(tert-Butoxycarbonyl)isoindoline-5-carboxylic acid (0.5 g, 0.0019 mol) ([CAS: 149353-71-9] available commercially from Milestone, for example), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.6 g, 0.0019 mol) and 1-hydroxybenzotriazole hydrate (0.26 g, 0.0019 mol) were dissolved in tetrahydrofuran, under protecting gas, and stirred for 30 min at RT. A solution of 3-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane dihydrochloride (F-09) (0.5 g, 0.0019 mol) and diisopropylethylamine (DIPEA) (0.86 g, 0.066 mol) in tetrahydrofuran was added, and the reaction mixture was stirred for 15 h at RT. Tetrahydrofuran was then removed in vacuo, the residue was taken up in ethyl acetate and sat. sodium hydrogen carbonate solution, and the phases were separated. The aqueous phase was extracted with ethyl acetate and the combined organic phases were in turn washed with sat. sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (ethyl acetate/methanol 10:1+1% ammonia solution (25% aq.)). Yield: 0.85 g (94%)
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][CH3:11])[N:5]=1)([O-])=O.CO.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:9]([N:6]1[CH:7]=[CH:8][C:4]([NH2:1])=[N:5]1)[CH2:10][CH3:11]
Reactant: [H][H]
Reactant: CCCn1ccc([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCn1ccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
3-Nitro-1-propyl-1H-pyrazole (92 mg, 0.59 mmol) was dissolved in ethyl acetate (3 mL) and methanol (3 mL) was added. Palladium, 10 wt. % on carbon, wet (˜50 mg) was added to the mixture. The vial was charged with hydrogen gas (via balloon) and the mixture stirred for 16 h at 25° C. The mixture was passed through a plug of celite and concentrated in vacuo followed by purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 25% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) afforded 1-propyl-1H-pyrazol-3-ylamine (54 mg, 73%) as a golden oil: LC-MS (ESI) m/e calcd for C6H11N3 [M+] 125.10, found 126.3 [M+H+], 251.3 [2M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH3:9])[N:3]=1.[N+:10]([O-])([OH:12])=[O:11].[OH-].[Na+]>OS(O)(=O)=O>[NH2:1][C:2]1[C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]([Cl:8])=[C:4]([CH3:9])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1nc(N)ccc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(N)c([N+](=O)[O-])cc1Cl
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 67.3 %

Procedure:
To stirred conc H2SO4 (70 mL) at 0° C. was added 45 (6.0 g, 41.8 mmol) in portions. To the resulting dark brown solution was added dropwise 70% HNO3 (3.5 mL, 54 mmol) at 0° C. After the addition, the reaction mixture was stirred at 50° C. under N2 for 2.5 h, cooled to room temperature and poured into crushed ice (about 700 g). The mixture was basified to pH 9 by the addition of 40% aq. NaOH dropwise with stirring and cooling (ice-water bath). The precipitate was filtered, washed with water (4×100 mL) and MeOH (3×25 mL), and dried to give 5.28 g (67%) of 46 as a yellow powder, mp 214°-5° C. (lit. 214°-6° C., Cress et al., J. Org. Chem. 93-6 (1976)). 1H NMR (DMSO-d6) δ 2.445 (s, 3H), 8.011 (bs, 2H), 8.340 (s, 1H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C@@H:14]2[C@@H:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C:7]1=[O:15])C.N.O=C1[N:23](CC(N)=O)[C@H]2CCC[C@H]2C1>CO>[O:15]=[C:7]1[N:6]([CH2:5][C:4]([NH2:23])=[O:3])[C@H:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:8]1
Reactant: CCOC(=O)CN1C(=O)C[C@@H]2CCCC[C@@H]21
Reactant: NC(=O)CN1C(=O)C[C@@H]2CCC[C@@H]21
Agent: N
Solvent: CO
Product: NC(=O)CN1C(=O)C[C@@H]2CCCC[C@@H]21
Reaction time: 24 h

Procedure:
A solution of cis-octahydro-2-oxo-1H-indole-1acetic acid ethyl ester (15.43 g, 0.068 mole) in methanol (200 ml) is saturated with ammonia and stirred at ambient temperatures 24 hours. The solution is concentrated at reduced pressure to yield a solid. cis-Hexahydro-2-oxo-cyclopenta[b]pyrrole-1(2H)-acetamide with a mp 145°-145.5° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Br:5][C:6]1[CH:15]=[C:14]2[C:9]([N:10]=[C:11]([O:18][CH3:19])[C:12]([O:16][CH3:17])=[N:13]2)=[C:8]([CH2:20]Br)[CH:7]=1.O>CN(C)C=O>[N:1]([CH2:20][C:8]1[CH:7]=[C:6]([Br:5])[CH:15]=[C:14]2[C:9]=1[N:10]=[C:11]([O:18][CH3:19])[C:12]([O:16][CH3:17])=[N:13]2)=[N+:2]=[N-:3]
Reactant: COc1nc2cc(Br)cc(CBr)c2nc1OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc2cc(Br)cc(CN=[N+]=[N-])c2nc1OC
Reaction time: 3 h

Procedure:
743 mg (2 eq.) of sodium azide are added at 20° to 2.07 g (5.72 mmol) of 7-bromo-5-bromomethyl-2,3-dimethoxyquinoxaline in 25 ml of dimethylformamide. After 3 hours, the mixture is poured into water, extracted with diethyl ether, and the extract is washed with water and brine and dried using magnesium sulfate. The solvent is evaporated.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]([CH2:21][C:22](=O)[CH2:23][CH3:24])[C:11]([NH:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[CH3:20])=[O:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.CO>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH:21]=[C:22]([CH2:23][CH3:24])[N:13]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][C:19]=4[CH3:20])[C:11]3=[O:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCC(=O)CN(C(=O)Nc1cnccc1C)c1ccc2ncsc2c1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: CCc1cn(-c2ccc3ncsc3c2)c(=O)n1-c1cnccc1C
Yield: 28.5 %

Procedure:
1-Benzothiazol-6-yl-3-(4-methyl-pyridin-3-yl)-1-(2-oxo-butyl)-urea (I-168b: 185 mg, 0.522 mmol) in toluene (15 mL) was refluxed at 120° C. for 20 hours. The reaction was monitored by TLC (5% MeOH in chloroform). The reaction mixture was concentrated under reduced pressure and the crude residue was purified by column chromatography on silica gel (2.5% methanol in chloroform) to afford 50 mg of the product (28.57% yield).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH:24]4[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]4)[CH2:20]3)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32]>N1C=CC=CC=1>[ClH:27].[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([C@@H:19]3[CH:24]4[CH2:23][CH2:22][N:21]([CH2:26][CH2:25]4)[CH2:20]3)=[O:18])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)=[O:32]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1)c1cccc(Cl)c1

Procedure:
A solution of 50 mg (0.13 mmol) of ((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) and 44.4 mg (0.25 mmol) of 3-chlorobenzoyl chloride in 1.0 ml of pyridine is stirred at room temperature for 3 h. The reaction mixture is concentrated in vacuo, and the residue is purified by preparative HPLC. The product fractions are concentrated, mixed with 3 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 62 mg (98.5% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>CN(C)C(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: C1COCCN1
Reactant: Clc1ccc(Br)cn1
Solvent: CC(=O)N(C)C
Product: Brc1ccc(N2CCOCC2)nc1
Temperature: 130 °C
Reaction time: 48 h

Procedure:
5-Bromo-2-chloropyridine (5.0 g) was mixed with N,N-dimethylacetamide (25 ml), and morpholine (23 ml) was added thereto, followed by stirring at 130° C. for 2 days. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with EtOAc, and the organic layer was washed with saturated brine and dried over Na2SO4. The organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 4-(5-bromopyridin-2-yl)morpholine (6.07 g).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:18][CH2:19][CH:20]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:42][C:39]1[CH:38]=[CH:37][C:36]([CH:29]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[N:30]2[CH2:31][CH2:32][N:33]([CH2:20][CH2:19][CH2:18][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:34][CH2:35]2)=[CH:41][CH:40]=1
Reactant: O=CCCc1cc(-c2ccccc2)n(-c2ccccc2)n1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(C(c2ccc(F)cc2)N2CCN(CCCc3cc(-c4ccccc4)n(-c4ccccc4)n3)CC2)cc1

Procedure:
126 mg (75%) of target compound was obtained by using a method same as in Example 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.289 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (83 mg, 0.289 mmol), DIPEA (0.076 mL, 0.434 mmol) and NaBH(OAc)3 (184 mg, 0.868 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22]>>[C:17]1([CH3:22])[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1
Reactant: Cc1ccccc1I
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Product: COC(=O)CCc1ccc(C#Cc2ccccc2C)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (90 mg, 0.48 mmol) and iodo-2-methylbenzene (0.07 mL, 0.55 mmol) according to the general procedure IB to give 36 mg (31%) of an orange oil after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:30→1:10). Rf: 0.27 (EtOAc:hexanes, 1:5); 1HNMR (CDCl3) δ 7.49-7.44 (m, 3H), 7.23-7.17 (m, 5H), 3.67 (s, 3H), 2.99-2.94 (t, 2H, J=7.8 Hz), 2.66-2.61 (t, 2H, J=7.8 Hz), 2.50 (s, 3H); 13CNMR (CDCl3) δ 173.1, 140.8, 140.1, 131.8, 131.6, 129.4, 128.3, 128.2, 125.5, 123.1, 121.5, 93.2, 88.1, 51.6, 35.4, 30.8, 20.7; ESI-MS m/z 301.1 (MNa+).
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:36])[C@@H:15]([O:33][CH2:34][CH3:35])[C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][C:19]=1[F:32])[OH:17])C1C=CC=CC=1.[CH3:37][O-:38].[Na+]>CO>[CH3:37][O:38][C:14](=[O:36])[C@@H:15]([O:33][CH2:34][CH3:35])[C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:20][C:19]=1[F:32])[OH:17]
Reactant: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCc2ccccc2)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(OCc2ccccc2)cc1F

Procedure:
In analogy to the procedure described in example 1 b], (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-fluoro-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one was treated with sodium methoxide in methanol to give (2S,3R)-3-(4-benzyloxy-2-fluoro-phenyl)-2-ethoxy-3-hydroxy-propionic acid methyl ester as colorless liquid. According to 1H-NMR spectroscopy, one single diastereomer was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9](Cl)[O:8][N:7]=1)=[O:5])[CH3:2].[C:12]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([F:23])[CH:15]=1)#[N:13].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:17]2[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][C:16]=2[F:23])[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)on1
Reactant: N#Cc1ccc(B(O)O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(-c2ccc(C#N)cc2F)on1
Temperature: 140 °C

Procedure:
A mixture of 5-chloro-isoxazole-3-carboxylic acid ethyl ester (600 mg), 4-cyano-2-fluorophenylboronic acid (665 mg), and aqueous Na2CO3 solution (2 M; 4.41 mL) in 1,4-dioxane (15 mL) is purged with argon for 15 min prior to the addition of Pd(PPh3)4 (276 mg). The reaction mixture is heated under an argon atmosphere to 140° C. for 20 min in a microwave oven. The solvent is evaporated in vacuo and the residue is mixed with water and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product is purified by silica gel chromatography (cyclohexane/ethyl acetate 80:20→50:50). LC (method 3): tR=1.50 min; Mass spectrum (ESI+): m/z=261 [M+H]+.
Reaction SMILES: [CH3:1][NH2:2].O1CCCC1.C[Al](C)C.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:17][C:16]=1[OH:27]>C1(C)C=CC=CC=1>[OH:27][C:16]1[CH:17]=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:19]=[CH:20][C:15]=1[C:14]([NH:2][CH3:1])=[O:13]
Reactant: CN
Reactant: COC(=O)c1ccc(N2CCOCC2)cc1O
Agent: C[Al](C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CNC(=O)c1ccc(N2CCOCC2)cc1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a cooled (0° C.), stirred solution of methylamine in dry tetrahydrofuran (1.27 mL of 2.0 M solution; 2.52 mmol) was slowly added a solution of trimethylaluminum in dry toluene (1.27 mL of 2.0 M solution; 2.52 mmol) via syringe under a nitrogen atmosphere. The resulting solution was allowed to warm to room temperature and stir for 2 hours. To the resulting solution, a solution of the 2-hydroxy-4-morpholin-4-yl-benzoic acid methyl ester (100 mg; 0.42 mmol) in dry toluene (4.0 mL) was added via cannula and the resulting solution was heated to reflux for 2 hours. After cooling to room temperature, the reaction was quenched with the careful addition of 1 N aqueous hydrochloric acid to pH 4. The mixture then was extracted with EtOAc (3×10 mL), and the combined organic layers washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was recrystallized from CH2Cl2— hexanes to provide the amide (93 mg; 93%).
Reaction SMILES: [NH2:1][C:2]1[N:11]([CH2:12][CH2:13][C:14]([N:16]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH3:17])=[O:15])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:24](O)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:8]=2)[N:3]=1.O=[Si]=O>CO.Cl.CC(O)C.[Pd]>[NH2:1][C:2]1[N:11]([CH2:12][CH2:13][C:14]([N:16]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH3:17])=[O:15])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:8]=2)[N:3]=1
Reactant: CN(C(=O)CCN1Cc2cc(C(O)c3ccccc3)ccc2N=C1N)C1CCCCC1
Agent: [Pd]
Agent: Cl
Agent: O=[Si]=O
Solvent: CO
Solvent: CC(C)O
Product: CN(C(=O)CCN1Cc2cc(Cc3ccccc3)ccc2N=C1N)C1CCCCC1

Procedure:
A mixture of 3-[2-amino-6-(hydroxy-phenyl-methyl)-4H-quinazolin-3-yl]-N-cyclohexyl-N-methyl-propionamide (0.0012 mol) in methanol (40 mL) and HCl/2-propanol (0.5 mL) was hydrogenated at 50° C. with 10% Pd/C (0.4 g) as a catalyst. After uptake of H2 (1 equiv.), the reaction mixture was filtered over Dicalite and the solvent was evaporated. The residue was triturated under diisopropyl ether, then the resulting solids were filtered off and dried to yield the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[F:19][C:20]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>C1(C)C=CC=CC=1>[F:19][C:20]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH:26]=[CH:25][C:21]=1[C:22]([NH:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:23]
Reactant: COC(=O)c1cccc(N)c1O
Reactant: O=C(Cl)c1ccc(-c2ccccn2)cc1F
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NC(=O)c2ccc(-c3ccccn3)cc2F)c1O
Temperature: 70 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
To a solution of methyl 3-amino-2-hydroxybenzoate (1.42 g, 8.50 mmol) and pyridine (1.0 mL, 8.5 mmol) in toluene (20 ml) was added 2-fluoro-4-(pyridine-2-yl)benzoyl chloride (2.0 g, 8.50 mmol) portion wise at 0° C. and then stirred at 70° C. for 4 h. The resulting mixture was extracted with ethyl acetate (4×100 mL). The organic phase was washed with water and saturated sodium bicarbonate, dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain methyl 3-(2-fluoro-4-(pyridin-2-yl)benzamido)-2-hydroxybenzoate as a yellow solid (1.40 g, yield 45%). LC-MS (ESI) m/z: 367 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[O:19]1[CH2:24][CH2:23][CH:22]([CH2:25][NH2:26])[CH2:21][CH2:20]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][CH2:25][CH:22]1[CH2:23][CH2:24][O:19][CH2:20][CH2:21]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: NCC1CCOCC1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NCC1CCOCC1
Yield: 94.1 %

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (265 mg, 1.0 mmol) was treated with C-(tetrahydro-pyran-4-yl)-methylamine (1.5 mmol) following general procedure B to afford 8-methoxy-4-[(tetrahydro-pyran-4-ylmethyl)-amino]-quinoline-3-carboxylic acid ethyl ester (324 mg). 3-Ethyl-7-methoxy-1-(tetrahydro-pyran-4-ylmethyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (19 mg) was prepared from 8-methoxy-4-[(tetrahydro-pyran-4-ylmethyl)-amino]-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) and ethyl isocyanate (0.4 mmol) following general procedure C. LCMS: m/z 370 [M+1]+.