Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:7][C:8]1[N:9]=[C:10]([OH:39])[C:11]2[CH2:17][CH:16]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([C:35]([O:37]C)=[O:36])[N:23]([Si](C(C)C)(C(C)C)C(C)C)[CH:24]=3)[CH2:15][NH:14][C:12]=2[N:13]=1)(=O)C(C)(C)C>[OH-].[Na+]>[NH2:7][C:8]1[N:9]=[C:10]([OH:39])[C:11]2[CH2:17][CH:16]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([C:35]([OH:37])=[O:36])[NH:23][CH:24]=3)[CH2:15][NH:14][C:12]=2[N:13]=1
Reactant: COC(=O)c1cc(CCC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)cn1[Si](C(C)C)(C(C)C)C(C)C
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(O)c2c(n1)NCC(CCc1c[nH]c(C(=O)O)c1)C2
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A suspension of methyl 4-[2-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]-1-triisopropylsilylpyrrole-2-carboxylate (390.4 mg, 0.7 mmol) in 1N sodium hydroxide (1 mL) was heated under reflux until clear (about 4 hours). The mixture was cooled to room temperature, extracted with ethyl acetate, and then acidified with glacial acetic acid. The solid which formed was collected by filtration, washed with water, and dried in vacuo to give 4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]pyrrole-2-carboxylic acid (199 mg, 94%), mp >260° C.: 1H NMR (DMSO-d6) δ 11.39 (s, 1H), 9.72 (br s, 1H), 6.73 (s, 1H), 6.55 (s, 1H), 6.25 (s, 1H), 5.93 (s, 2H), 3.16 (br d, 1H, J=9.5 Hz), 2.72 (m, 1H), 2.43 (m, 3H), 1.75 (m, 1H), 1.42-1.53 (m, 3H); 1H NMR (CD3OD) δ 6.69 (s, 1H), 6.63 (s, 1H), 3.31 (brd, 1H, J=12.1 Hz), 2.91 (dd, 1H, J=12.1, 9.2 Hz), 2.67 (dd, 1H, J=15.3, 4.4 Hz), 2.55 (m, 2H), 1.99 (dd, 1H, J=15.3, 9.4 Hz), 1.76 (m, 1H), 1.60 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH:13]=O)=[CH:11][C:10]2[N:9]([CH3:15])[C:8](=[O:16])[CH2:7][CH2:6][C:5]=2[N:4]=1.[C:17]1([C@H:23]2[C@@H:28]([NH2:29])[CH2:27][CH2:26][CH2:25][NH:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][NH:29][C@H:28]1[CH2:27][CH2:26][CH2:25][NH:24][C@H:23]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:9]([CH3:15])[C:8](=[O:16])[CH2:7][CH2:6]2
Reactant: COc1nc2c(cc1C=O)N(C)C(=O)CC2
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1nc2c(cc1CN[C@H]1CCCN[C@H]1c1ccccc1)N(C)C(=O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
The 2-methoxy-5-methyl-6-oxo-5,6,7,8-tetrahydro-[1,5]naphthyridine-3-carbaldehyde prepared in step 5 (0.35 g; 1.4 mmol) was dissolved in 20 ml of dichloroethane. To this was added 250 mg (1.1 mmol) of 2-(S)-phenyl-piperidin-3(S)-ylamine and 0.4 ml (2.8 mmol) of triethylamine, and the mixture was stirred for 60 minutes at room temperature. To this mixture was added 0.7 g (3.3 mmol) of sodium triacetoxyborohydride, and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water and stirred at room temperature for 30 minutes. The pH of the mixture was adjusted to 8.5 with Na2CO3. The organic layer was separated from the water layer. An additional 20 ml of water was added to the organic layer. The pH of the mixture was adjusted to 2 with 1N HCl and extracted with ethyl acetate. The pH of the water layer was adjusted to 7.5 with sodium bicarbonate and extracted with ethyl acetate. The pH=7.5 ethyl acetate extracts were combined, dried (Na2SO4), and evaporated to yield 300 mg of 6-methoxy-1-methyl-7-[(2(S)-phenyl-piperidin-3(S)-ylamino)-methyl]-3,4-dihydro-1H-[1,5]naphthyridin-2-one. 1H NMR (CDCl3) δ 7.2–7.4 (m, 5H), 6.85 (s, 1H), 3.90 (s, 1H), 3.85 (s, 3H), 3.60,3.38 (d,d 2H), 3.30 (d, 1H), 3.10 (s, 3H), 3.0 (s, 1H), 2.90 (m, 2H), 2.80 (m, 2H), 2.66 (m, 2H), 2.0–2.2 (m, 3H), 1.9 (m, 1H), 1.6 (m, 1H), 1.45 (m, 1H). Mass spectrum: m/e=381.1 (p+1). TLC: Rf=0.5; (5:1 chloroform/methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)=[O:5].[OH:20][CH2:21][CH2:22][O:23][C:24]1[C:31]([CH3:32])=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=1[CH3:33]>C(O)C.[Cu](Cl)Cl>[Br:13][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:17][CH:16]=[C:15]([O:18][CH3:19])[CH:14]=3)[N:1]=[C:28]2[C:27]2[CH:30]=[C:31]([CH3:32])[C:24]([O:23][CH2:22][CH2:21][OH:20])=[C:25]([CH3:33])[CH:26]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(N)c(C(=O)Nc2ccc(Br)cc2)c1
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Agent: Cl[Cu]Cl
Solvent: CCO
Product: COc1ccc2nc(-c3cc(C)c(OCCO)c(C)c3)n(-c3ccc(Br)cc3)c(=O)c2c1

Procedure:
To a solution of 2-amino-N-(4-bromo-phenyl)-5-methoxy-benzamide (0.240 g, 0.740 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (0.145 g, 0.740 mmol) in anhydrous ethanol (20 mL) was added anhydrous copper (II) chloride (0.298 g, 2.22 mmol). The reaction mixture was stirred at reflux for 4 hours under nitrogen. The solvent was removed and the residue was diluted with ethyl acetate (100 mL) and water (100 mL). After separation the organic phase was further backwashed with water (100 mL), brine (100 mL), dried over sodium sulfate, and concentrated. The crude was purified by column chromatography (SiO2, hexane/ethyl acetate=1:1) to give the title compound as white solid. Yield: 120 mg (33%). MP 160-162° C. 1H-NMR (400 Hz, CDCl3): δ 7.74 (d, 1H), 7.69 (s, 1H), 7.46 (d, 2H), 7.40 (m, 1H), 7.03 (d, 2H), 6.96 (s, 2H), 3.94 (s, 3H), 3.91 (m, 2H), 3.82 (t, 2H), 2.17 (s, 6H), 2.05 (t, 1H). MS (ES+) m/z: 497.41 (M+1).
Reaction SMILES: [NH2:1][C:2](=[N:19][N+:20]([O-:22])=[O:21])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:16]([OH:18])=O)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[NH2:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=1)=[O:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:16](=[O:18])[C@@H:7]([CH2:6][CH2:5][CH2:4][NH:3][C:2]([NH2:1])=[N:19][N+:20]([O-:22])=[O:21])[NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[CH:30][CH:29]=1)=[O:25]
Reactant: NCc1ccc(CNC(N)=O)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: CC(C)(C)OC(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)NCc1ccc(CNC(N)=O)cc1
Yield: 35 %

Procedure:
Prepared analogously to Example 69a) from (R)-N5 -[amino(nitroimino)methyl]-N2 -[(1,1-dimethylethoxy)carbonyl]-ornithine, 4-(amino-carbonylaminomethyl)benzenemethanamine and TBTU in a yield of 35% of theory.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[CH3:29][NH:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1>>[C:35]([C:34]1[CH:37]=[CH:38][C:31]([N:30]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)[CH3:29])=[CH:32][CH:33]=1)#[N:36]
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Reactant: CNc1ccc(C#N)cc1
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2C(F)(F)F)cc1)c1ccc(C#N)cc1
Yield: 71 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzene sulfonamide (Intermediate 9), and 4-(N-methylamino)benzonitrile, the title compound was isolated as a yellow solid in 71% yield (94% purity by HPLC).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]([C:19]([NH:22]C(=O)OCC3C=CC=CC=3)([CH3:21])[CH3:20])[N:13]([CH3:18])[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1>[Pd]>[NH2:22][C:19]([C:12]1[N:13]([CH3:18])[C:14](=[O:17])[C:15]([OH:16])=[C:10]([C:8]([NH:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:34][CH:33]=2)=[O:9])[N:11]=1)([CH3:21])[CH3:20]
Reactant: Cn1c(C(C)(C)NC(=O)OCc2ccccc2)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Agent: [Pd]
Product: Cn1c(C(C)(C)N)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O

Procedure:
A methanolic solution of Benzyl 1-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-methylethylcarbamate was stirred over night under a hydrogen atmosphere in the presence of catalytic 10% Pd/C. Catalyst was then filtered off through celite, and the filtrate was concentrated. Product was obtained after trituration with ethyl ether.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:39])[CH2:10][N:11]1[C:16]([CH3:17])=[C:15]([Cl:18])[N:14]=[C:13]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29](C(OC(C)(C)C)=O)[CH3:30])[CH:23]=2)[C:12]1=[O:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:15]1[N:14]=[C:13]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:29][CH3:30])[CH:23]=2)[C:12](=[O:38])[N:11]([CH2:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:39])[C:16]=1[CH3:17]
Reactant: Cc1c(Cl)nc(NCCc2cccc(CN(C)C(=O)OC(C)(C)C)c2)c(=O)n1CC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cccc(CCNc2nc(Cl)c(C)n(CC(=O)OCc3ccccc3)c2=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.3 %

Procedure:
Benzyl-2-[3-[(3-[(tert-butoxycarbonyl)(methyl)amino]methylphenethyl)amino]-5-chloro-6-methyl-2-oxo-1(2H)-pyrazinyl]acetate (preparation 18) (0.7 g, 1.26 mmol) was dissolved in CH2Cl2 (10 ml) and treated with TFA (1.0 ml). After stirring at room temperature for 3 hr, the reaction mixture was evaporated to dryness then dissolved in ethyl acetate (200 ml) washed with sat. aq NaHCO3, sat aq brine, dried over MgSO4. Removal of the drying agent by filtration followed by evaporation of the solvent gave a dark brown oil which was purified by chromatography (SiO2, gradient elution with 100% CH2Cl2; 98:2 CH2Cl2:MeOH; 95:5 CH2Cl2:MeOH; 95:5:1 CH2Cl2:MeOH:NH3) to give the desired product (0.38 g, 65%). 1H NMR (CDCl3) δ 2.00 (s, br, 1H), 2.20 (s, 3H), 2.45 (s, 3H), 2.90 (t, 2H), 3.70 (m, 2H), 3.75 (s, 2H), 4.80 (s, 2H), 5.20 (s, 2H), 6.10 (m, br, 1H), 7.10 (m, 1H), 7.15 (m, 2H), 7.25 (m, 1H), 7.35 (m, 5H). LRMS m/z=455.0, 457.2 (M+1)+.
Reaction SMILES: C(O[C:4]([C:6]1[N:14]([CH2:15][C:16]#[C:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:26][C:27]1[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=1[F:34])=[O:5])C.[OH-].[Na+].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:58]([O:60][CH2:61][CH2:62][O:63][NH2:64])=[CH2:59].CCN(C(C)C)C(C)C>C1COCC1.CO[2H]>[CH:58]([O:60][CH2:61][CH2:62][O:63][NH:64][C:4]([C:6]1[N:14]([CH2:15][C:16]#[C:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:26][C:27]1[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=1[F:34])=[O:5])=[CH2:59]
Reactant: CCOC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1CC#CCOC1CCCCO1
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [2H]OC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=COCCONC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1CC#CCOC1CCCCO1
Temperature: 65 °C
Reaction time: 1 h
Yield: 29.8 %

Procedure:
To a stirred solution of 3-(2-fluoro-4-iodo-phenylamino)-1-[4-(tetrahydro-pyran-2-yloxy)-but-2-ynyl]-1-H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (147.0 mg, 0.25 mmol) in anhydrous THF (1.0 mL) and MeOD (3.0 mL) under N2 was added freshly prepared 1N aqueous sodium hydroxide (0.51 ml, 2.0 eq). The reaction mixture was stirred at 65° C. for 1 h. The resultant reaction mixture was evaporated in vacuo and azeotroped with toluene (3×5 ml) to give a yellow foam. The yellow foam was redissolved in anhydrous THF (7.9 ml). EDCI (103.3 mg, 0.54 mmol, 2.2 eq) and HOBT (72.8 mg, 0.54 mmol, 2.2 eq) were added. The reaction mixture was stirred at room temperature. After 5 minutes O-(2-vinyloxy-ethyl)-hydroxylamine (50.5 mg, 0.49 mmol, 2.0 eq) and DIPEA (0.19 mL, 1.10 mmol, 4.5 eq) were added, and the reaction mixture was stirred at ambient temperature under N2 for 17 h. The reaction mixture was absorbed onto silica and purified by flash column chromatography (silica, ISCO, 45 mL/min, Hexane:EtOAc, gradient 100:1 to 1:100) to give the desired product as a yellow solid (47.2 mg, 30.3%). 1H-NMR (400 MHz, CDCl3) δ ppm 8.60 (s, 1H), 8.40 (d, J=5.95 Hz, 1H), 7.54-7.36 (m, 2H), 7.21 (d, J=8.48 Hz, 1H), 6.43-6.34 (m, 2H), 6.20 (broad s, 1H), 5.49 (s, 2H), 4.71 (m, 1H), 4.26-4.11 (m, 4H), 4.03 (dd, J=6.80, 2.4 Hz, 1H), 3.93-3.86 (m, 2H), 3.80-3.72 (m, 1H), 3.48 (m, 3H), 1.82-1.64 (m, 2H), 1.62-1.44 (m, 4H); LC-MS (method C): [M+H]+=635.1, RT=0.839 min.
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([CH:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:23]([O:25]C)=[O:24])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)=[O:8].[ClH:39]>>[ClH:39].[C:27]1([CH:22]([N:19]2[CH2:20][CH2:21][N:16]([C:13]3[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=4[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:8])=[CH:11][CH:12]=3)[CH2:17][CH2:18]2)[C:23]([OH:25])=[O:24])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)CC1
Agent: Cl
Product: O=C(Nc1ccc(N2CCN(C(C(=O)O)c3ccccc3)CC2)cc1)c1ccccc1-c1ccccc1

Procedure:
A mixture of intermediate (37) (0.053 mol) in HCl (36%; 300 ml) was stirred and refluxed for 2 days, cooled, filtered and dried. The residue was triturated in 2-propanone. The precipitate was filtered off and dried, yielding 21.5 g of α-phenyl-4-[4-[([1,1′-biphenyl]-2-ylcarbonyl)amino]phenyl]-1-piperazineacetic acid hydrochloride (1:2) 2-propanolate (1:1) (intermediate 38).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:30])[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH2:16][CH2:15]1)([O-])=O.Cl>[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:30])[CH2:12][CH2:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH2:18][CH2:19]1
Reactant: O=C(CCN1CCN(c2cccc(C(F)(F)F)c2)CC1)Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Product: Nc1ccccc1NC(=O)CCN1CCN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
The compound was prepared according to the method described in J. Med. Chem. 30, 13 (1987) by catalytic reduction of N-(2-nitrophenyl)-4-(3-trifluoromethylphenyl)-1-piperazin propionamide in the presence of 10% Pd/C. Monohydrochloride salt. M.p. 194°-196° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.[SH:13][C:14]1[CH:15]=[C:16]([C:20]2([C:26]#[N:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.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]>[O:12]=[C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([C:26]#[N:27])[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[CH:17]=[CH:18][CH:19]=3)[CH:3]=2)[NH:8]1
Reactant: O=c1ccc2cc(I)ccc2[nH]1
Reactant: N#CC1(c2cccc(S)c2)CCOCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(c2cccc(Sc3ccc4[nH]c(=O)ccc4c3)c2)CCOCC1
Temperature: 80 °C

Procedure:
6-Iodo-1H-quinolin-2-one (5.13 g, 18.9 mmol) and 4-(3-Mercapto-phenyl)-tetrahydro-pyran-4-carbonitrile (5f, 4.57 g, 20.8 mmol) were dissolved in 1,4-dioxane (160 mL) and degassed for 10 minutes with N2. iPr2NEt (6.6 mL, 37.9 mmol) was added, followed by Pd2dba3 (434 mg, 0.47 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (548 mg, 0.95 mmol), and the reaction was degassed for another 10 minutes with N2. The reaction was then sealed and heated to 80° C. overnight. After cooling to room temperature, the reaction was filtered and concentrated, and the residue was purified by silica gel chromatography (0-100% MeOH in EtOAc) to give the desired product, 5g.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[C:3]#[C:4][C:5]1[CH:6]=[N:7][N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)[CH:9]=1.O1CCCC1>[Fe].C(O)(=O)C>[CH3:1][C:2]([CH3:20])([CH3:19])[C:3]#[C:4][C:5]1[CH:6]=[N:7][N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])[CH:9]=1
Reactant: CC(C)(C)C#Cc1cnn(-c2ccccc2[N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)C#Cc1cnn(-c2ccccc2N)c1
Temperature: 80 °C

Procedure:
A mixture of 4-(3,3-dimethyl-but-1-ynyl)-1-(2-nitro-phenyl)-1H-pyrazole (20 g, 74 mmol), tetrahydrofurane (100 ml) and acetic acid (425 ml of a 5% aqueous solution) was heated to 80° C. Iron powder (66 g, 1.2 mol) was added in small portions at this temperature. The reaction mixture was heated for 5 hours to reflux. After cooling, it was poured onto ice and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated, delivering Compound No. 5.030.r (20 g).
Reaction SMILES: C([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([F:20])[N:15]=1)[CH3:7])(C)(C)C.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[F:20][C:16]1[N:15]=[C:14]([N:9]2[C@@H:8]([C@H:6]([OH:5])[CH3:7])[CH2:12][O:11][C:10]2=[O:13])[CH:19]=[CH:18][N:17]=1
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1c1ccnc(F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C[C@@H](O)[C@H]1COC(=O)N1c1ccnc(F)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.6 %

Procedure:
A solution of (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (1.0 g, 3.35 mmol) in 20 ml of DCM was cooled in an ice bath, and treated with 8.16 mL of TFA. The mixture was stirred at same temperature for 4 hours, and allowed to warm to room temp and stir 16 h. The reaction was poured into 10 mL water. The DCM was removed in vacuo. The aqueous was basified by slow addition of saturated NaHCO3 solution, then extracted with (2×mL) EtOAc. The organics were washed with 30 mL brine, and dried over Na2SO4. Filtered and concentrated to give the desired alcohol, (R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (0.56 g, 70% yield) as a white solid. HRMS(B) tR=0.80 min; MS m/z 228.4 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C@@H:11]2[C@@H:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[N:5](C(OCC2C=CC=CC=2)=O)[CH2:4][CH2:3]1>CO>[CH3:1][N:2]1[C@@H:11]2[C@@H:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[NH:5][CH2:4][CH2:3]1
Reactant: CN1CCN(C(=O)OCc2ccccc2)[C@@H]2CCCC[C@@H]21
Solvent: CO
Product: CN1CCN[C@@H]2CCCC[C@@H]21
Yield: 144.8 %

Procedure:
Phenylmethyl (4aS,8aR)-4-methyloctahydro-1(2H)-quinoxalinecarboxylate (2.7 g, 9.4 mmol) was dissolved in 140 mL of MeOH, degassed and placed under argon. 10% Pd/C (400 mg) was added, and the contents were thoroughly degassed and placed under a hydrogen balloon for approximately 2 hrs. The contents were then degassed and filtered through Celite, and the Celite pad was washed with DCM and MeOH. After 19.6 mL 1N HCl was added, the resulting filtrate was concentrated in vacuo to provide the hydrochloride salt of (4aR,8aS)-1-methyldecahydroquinoxaline (2.1 g, 100%). LCMS: (M+H)+: 155.1.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)[CH:8]=1)([O-:3])=[O:2].NN>C(O)C>[N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH:8]=1)([O-:3])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1CCCCn1cnc([N+](=O)[O-])c1
Agent: NN
Solvent: CCO
Product: NCCCCn1cnc([N+](=O)[O-])c1
Yield: 169.2 %

Procedure:
A mixture of 33.31 g of the product of Stage A, 555 ml of ethanol and 11.33 ml of hydrazine are taken to reflux for 20 hours. After filtering, the reaction medium is left to return to ambient temperature and brought to dryness. 33.04 g of product is obtained.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[C:9]([C:12]([O:14]CC)=[O:13])[CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH:17]=[CH:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[N:3]12.[OH-].[Na+].Cl>O>[O:1]=[C:2]1[C:11]2[CH:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH:17]=[CH:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[N:3]12
Reactant: CCOC(=O)c1ccc2nc3ccc4ccccc4n3c(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc2nc3ccc4ccccc4n3c(=O)c2c1

Procedure:
2.8 gm of ethyl 12-oxo-12-H-quino[2,1-b]quinazoline-10-carboxylate (see Example 3) were refluxed in 20 ml of an aqueous 10% sodium hydroxide solution for 30 minutes. The solution was then heated with 5 times its quantity of semiconcentrated hydrochloric acid for half an hour on a boiling water bath. After diluting with water, the precipitated yellow crystals were collected by suction filtration and washed with water and acetonitrile, yielding the compound of the formula ##STR26##
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10].[K].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH:26]=[CH:25][C:24]([OH:27])=[N:23]2)=[CH:18][CH:17]=1>CS(C)=O>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH:26]=[CH:25][C:24]([O:27][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10])=[N:23]2)=[CH:20][CH:21]=1
Reactant: Oc1ccn(-c2ccc(Cl)cc2)n1
Reactant: COC(=O)C(=O)c1ccccc1F
Agent: [K]
Solvent: CS(C)=O
Product: COC(=O)C(=O)c1ccccc1Oc1ccn(-c2ccc(Cl)cc2)n1
Temperature: 60 °C

Procedure:
A solution of 4.2 g of methyl 2-fluorophenylglyoxalate in 30 ml of anhydrous dimethyl sulfoxide was added dropwise to a solution of 5.0 g of the potassium salt of 1-(4-chlorophenyl)-3-hydroxy-pyrazole in 30 ml of anhydrous dimethyl sulfoxide. The batch was heated at 60° C. for 3.5 more hours, cooled and divided into two halves. One half was poured into ice-water/methyl tert-butyl ether for working-up. After the organic phase had been separated off, the aqueous phase was extracted three more times with methyl tert-butyl ether. The combined organic phases were dried over sodium sulfate and concentrated. The crude product was purified by chromatography over silica gel (eluent heptane/ethyl acetate 80/20→70/30). This gave 1.0 g of the title compound as a pale oil.
Reaction SMILES: CC1(C)N([O])C(C)(C)CCC1.[C:12]([O:16][C:17]([N:19]1[C@H:23]([CH2:24][OH:25])[CH2:22][C@@H:21]([CH:26]([CH3:28])[CH3:27])[C@@H:20]1[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42])[CH:30]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])O.[Na+].[Br-].[K+].Cl[O-].[Na+].S([O-])([O-])=O.[Na+].[Na+]>ClCCl.O>[C:12]([O:16][C:17]([N:19]1[C@H:23]([CH:24]=[O:25])[CH2:22][C@@H:21]([CH:26]([CH3:28])[CH3:27])[C@@H:20]1[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42])[CH:30]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: COCCCOc1cc([C@H]2[C@H](C(C)C)C[C@@H](CO)N2C(=O)OC(C)(C)C)ccc1OC
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: COCCCOc1cc([C@H]2[C@H](C(C)C)C[C@@H](C=O)N2C(=O)OC(C)(C)C)ccc1OC
Temperature: 5 °C
Yield: 52.3 %

Procedure:
Using TEMPO: A mixture of 0.96 g of the alcohol 6, 0.044 g of sodium hydrogencarbonate, 0.026 g of potassium bromide and 0.051 g of TEMPO in 3 mL of dichloromethane and 1.2 mL of water is cooled to 5° C. To the mixture is added dropwise 0.13 g of 10-13% sodium hypochlorite solution, and the mixture stirred for 5 h between 5° C. and 20° C., before addition of 0.57 g of sodium sulfite. The phases are then separated and the organic phase washed twice with 5 mL of water. Evaporation of the solvent in vacuum affords e.g. 0.50 g of the aldehyde 7 as an oil.