Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].[C:14](O)(=[O:23])[C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:16].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>O.Cl.CN(C)CCCN=C=NCC.CN(C)C=O.C(N(CC)CC)C>[OH:16][C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([NH:13][CH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=1)=[O:23]
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)[C@H](O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCCc1ccc([N+](=O)[O-])cc1)[C@H](O)c1ccccc1
Temperature: 87 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a mixture of 5.90 kg of 4-nitrophenylethylamine monohydrochloride, 4.43 kg of (R)-mandelic acid, 2.94 kg of triethylamine and 22 liters of N,N-dimethylformamide were added 3.93 kg of hydroxybenztriazole and 5.58 kg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (EDC) followed by stirring at about room temperature for 2 hours. EDC (0.28 kg) was further added thereto and the mixture was stirred at about room temperature throughout one night. The reaction solution was diluted with 110 liters of water and extracted with ethyl acetate (60 liters, 30 liters). The organic layer was successively washed with 60 liters of 1 M aqueous hydrochloric acid, 60 liters of 20% aqueous solution of potassium carbonate and water (60 liters, 60 liters) and concentrated in vacuo at 10 to 19° C. The residue was dissolved in 35 liters of toluene with heating at 87° C., cooled and stirred at 20° C. throughout one night. The resulting crystals were filtered and washed with 10 liters of toluene. This was dried in vacuo to give 7.66 kg of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide as light yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]([O:15]C)=[O:14].O[Li].O>C1COCC1.CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14]
Reactant: COC(=O)Cc1cc(OC)c(C#N)cc1Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(CC(=O)O)c(Cl)cc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of methyl (2-chloro-4-cyano-5-methoxyphenyl)acetate (30 mg, 0.125 mmol) in 15 mL of THF/MeOH/H2O (V/V/V=2:2:1) was added LiOH H2O (11 mg, 0.250 mmol). The mixture was stirred at rt. For 1 hr, and then most of the solvent was concentrated. The residue was diluted with water, adjusted pH=3 with 3 N HCl, and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to give (2-chloro-4-cyano-5-methoxyphenyl)acetic acid. 1H-NMR (400 MHz, CDCl3) δ ppm 7.56 (s, 1H), 6.91 (s, 1H), 3.92 (s, 3H), 3.83 (s, 2H).
Reaction SMILES: CC[O:3]C(/N=N/C(OCC)=O)=O.C(OC(=O)CCCCCCCCCCCO)C1C=CC=CC=1.[C:35]1([P:41]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.ON1C(=O)C2=CC=CC=C2C1=O>C1COCC1.CCCCCC.C(OC(=O)C)C>[C:48]1([P:41](=[O:3])([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C(CCCCCCCCCCCO)OCc1ccccc1
Agent: O=C1c2ccccc2C(=O)N1O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Diethylazodicarboxylate (DEAD, 16.96 ml, 107.7 mmol) was added dropwise to the mixture of 12-Hydroxydodecanoic acid benzyl ester (21 g, 71.8 mmol), triphenylphosphine (28.29 g, 107.7 mmol) and N-hydroxyphthalimide (12.88 g, 78.98 mmol) in absolute THF (250 ml) at −20°-−30° C. under stirring. The reaction mixture was stirred at this temperature for additional 2-3 h, after which time TLC (hexane-ethylacetate 3:1) indicated reaction completion. The solvent was removed in vacuo and the residue was treated ether (250 ml). Formed precipitate of triphenylphosphine oxide was filtered off, mother liquor was evaporated to dryness and the residue was dissolved in methylene chloride and purified by flash chromatography on silica gel in hexane-ethyl acetate (7:3). Appropriate fractions were pooled and evaporated to dryness to afford 26.5 g (84.4%) of compound 15.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@@H:5]([CH3:18])[NH:6][CH2:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:17])[CH3:2].[H][H]>C(O)C.[Ni]>[CH2:1]([O:3][C:4](=[O:19])[C@@H:5]([CH3:18])[NH:6][CH2:7][C:8]1[C:9]([Cl:17])=[CH:10][CH:11]=[CH:12][C:13]=1[NH2:14])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)[C@@H](C)NCc1c(Cl)cccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)[C@@H](C)NCc1c(N)cccc1Cl
Yield: 98.4 %

Procedure:
A solution of 14.3 g of N-(2-chloro-6-nitrobenzyl)-D-alanine ethyl ester in 50 ml of ethanol was hydrogenated in the presence of 1 g of Raney nickel. 3.35 liters of hydrogen were taken up in 2 hours. The catalyst was then filtered off and the filtrate was evaporated to dryness. There were obtained 12.6 g (99% of theory) of N-(2-amino-6-chlorobenzyl)-D-alanine ethyl ester; nD23 =1.5405; [α]D =+55.8° (c=1% in ethanol).
Reaction SMILES: [CH:1]1([C@@H:4]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[S:28][C:27]5[C:22](=[N:23][CH:24]=[CH:25][C:26]=5[O:29][CH3:30])[CH:21]=4)[N:18]=3)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:12]=2)=[O:10])[C:5]([OH:7])=O)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[NH:47]1[CH2:50][CH:49]([C:51]#[N:52])[CH2:48]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:51]([CH:49]1[CH2:50][N:47]([C:5](=[O:7])[C@H:4]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[S:28][C:27]5[C:22](=[N:23][CH:24]=[CH:25][C:26]=5[O:29][CH3:30])[CH:21]=4)[N:18]=3)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:36])[CH3:37])[CH:12]=2)=[O:10])[CH:1]2[CH2:2][CH2:3]2)[CH2:48]1)#[N:52]
Reactant: COc1ccnc2cc(-c3cnc4c(n3)c(C(=O)N[C@@H](C(=O)O)C3CC3)cn4COCC[Si](C)(C)C)sc12
Reactant: N#CC1CNC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccnc2cc(-c3cnc4c(n3)c(C(=O)N[C@@H](C(=O)N3CC(C#N)C3)C3CC3)cn4COCC[Si](C)(C)C)sc12
Reaction time: 16 h
Yield: 64 %

Procedure:
To a solution of (R)-cyclopropyl-{[2-(7-methoxy-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-acetic acid (27 mg, 0.049 mmol) in DMF (2 mL) at room temperature was added triethylamine (34.0 μL, 0.24 mmol), azetidine-3-carbonitrile hydrochloride (6 mg, 0.049 mmol and PyBOP (31 mg, 0.059 mmol). The reaction mixture was stirred for 16 h at the same temperature then poured into EtOAc (25 mL) and washed with water (4×30 mL). The organic phase was dried over Na2SO4 and evaporated under vacuum. The crude residue was purified by column chromatography (SiO2, 23 g, hex:EtOAc, 9:1 to 100% in 30 min) to give 26 mg (64%) of 2-(7-methoxy-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide.
Reaction SMILES: [Br-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].[Li]CCCC.[CH3:29][O:30][C:31](=[O:38])[CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=O.O>C1COCC1>[CH3:29][O:30][C:31](=[O:38])[CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[C:2]([CH3:4])[CH3:3]
Reactant: COC(=O)CCCCC=O
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCCCC=C(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 101.1 %

Procedure:
To a stirred suspension of isopropyltriphenylphosphonium bromide (10.9 g, 28.3 mmol) in THF (60 mL) was added dropwise n-BuLi (12.0 mL, 2.5 M solution in hexanes, 30.0 mmol) at 0° C. under N2. The resulting solution was stirred at this temperature for 30 min and cooled to −78° C. A solution of 6-oxo-hexanoic acid methyl ester (3.95 g, 19.7 mmol) in THF (10 mL) was added quickly. The resulting mixture was then allowed to warm to room temperature and stirred overnight. Water (30 mL) was added. The aqueous phase was extracted with hexane. The combined organic phases were washed with saturated aqueous NH4Cl and brine and dried. Concentration and purification of the residue by flash chromatography on silicagel (hexane:ethyl acetate, 10:1) afforded 7-methyl-oct-6-enoic acid methyl ester (3.39 g, 72%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.08 (1H, m), 3.64 (3H, s), 2.29 (2H, t, J=7.2 Hz), 1.97 (2H, m), 1.66 (3H, s), 1.62 (2H, m), 1.58 (3H, s), 1.36 (2H, m); 13C NMR (75 MHz, CDCl3) δ 174.26, 140.05, 131.80, 124.27, 51.67, 34.29, 29.60, 27.89, 25.97, 24.87, 17.94.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:22]3[CH2:24][CH2:23]3)=[N:9][C:10]=2[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH2:21])[CH:15]=2)=[O:12])[CH:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C.O>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:22]3[CH2:24][CH2:23]3)=[N:9][C:10]=2[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][S:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:40])=[O:39])[CH:15]=2)=[O:12])[CH:5]=[CH:6][N:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCc1cccc(NC(=O)c2nc(C3CC3)n3ccnc(N)c23)c1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1nccn2c(C3CC3)nc(C(=O)Nc3cccc(CNS(=O)(=O)c4ccccc4)c3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 68A (0.102 g) in DMF 3 mL was treated with triethylamine (0.112 ml, 0.800 mmol) and benzenesulfonyl chloride (0.026 ml, 0.200 mmol), stirred at room temperature overnight then diluted with water and extracted with ethyl acetate. The extract was washed (brine), dried (MgSO4), concentrated to dryness and purified by preparative HPLC. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.01-1.29 (m, 4H) 2.34-2.58 (m, 1H) 3.98 (d, J=5.95 Hz, 2H) 7.04 (d, J=7.54 Hz, 1H) 7.19-7.36 (m, 2H) 7.48-7.69 (m, 4H) 7.72 (s, 1H) 7.77-7.91 (m, 2H) 7.98 (d, J=5.55 Hz, 1H) 8.18 (t, J=6.35 Hz, 1H) 9.08 (s, 1H) 10.32 (s, 1H) 10.69 (s, 1H). MS (ESI(+)) m/e 463 (M+H)+.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:16]([N:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)=[C:11]3[C:10](/[CH:36]=[CH:37]\[C:38]3[CH:39]=[N:40][N:41](CC4C=CC(OC)=CC=4)[CH:42]=3)=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:62]>>[ClH:62].[NH:41]1[CH:42]=[C:38](/[CH:37]=[CH:36]\[C:10]2[C:11]3[C:12](=[N:13][CH:14]=[C:15]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:16]=3[N:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)[NH:8][N:9]=2)[CH:39]=[N:40]1
Reactant: ClCCl
Reactant: COc1ccc(Cn2cc(/C=C\c3nn(Cc4ccc(OC)cc4)c4ncc(-c5ccccc5)c(N5CCN(C(=O)OC(C)(C)C)CC5)c34)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: C(=C\c1n[nH]c2ncc(-c3ccccc3)c(N3CCNCC3)c12)\c1cn[nH]c1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
(Z)-tert-Butyl 4-(1-(4-methoxybenzyl)-3-(2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)vinyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.084 g, 0.12 mmol) in DCM (1 mL) was added TFA (0.5 mL) and stirred at room temperature for 1 hour. The solvent was removed. The residue was dissolved in TFA (4 ml) and heated at 78° C. (bath) in a sealed tube overnight. The solvent was removed. The residue was dissolved in DCM (0.5 mL) and 2N HCl in ether (1 mL) was added. The solid formed was collected by filtration to give (Z)-3-(2-(1H-pyrazol-4-yl)vinyl)-5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine hydrochloride (0.051 g, 97%) as a solid.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1)[CH3:2].[C:16]([Li])(C)(C)C.CI>C(OCC)C.O>[CH2:1]([C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]([CH3:16])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1cccc(NC(=O)C(C)(C)C)n1
Reactant: [Li]C(C)(C)C
Solvent: O
Solvent: CI
Solvent: CCOCC
Product: CCc1ccc(C)c(NC(=O)C(C)(C)C)n1
Temperature: -20 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
A solution of N-(6-ethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (24.0 g, 0.116 mol) in diethyl ether (600 mL, 0.2 M) is cooled to −78° C. and treated with tert-butyllithium (144 mL 1.7 M in pentane). After the addition is complete the solution is warmed to −20° C. for 2 h, treated with a solution of methyliodide (23 mL, 0.372 mol) in diethylether (10 mL) and warmed to room temperature. After stirring overnight the reaction is diluted with water, extracted with diethyl ether and dried over MgSO4. The resulting solution is filtered through a short pad of silica gel, concentrated and recrystallized from heptane to give N-(6-ethyl-3-methyl-pyridin-2-yl)-2,2-dimethyl-propionamide (17.6 g, 69%) as an off-white crystalline solid. mp 72-75° C.; Rf 0.43 (50% ethyl acetate in hexanes); 1H NMR (DMSO-d6, 300 MHz) δ 9.48 (s, 1H), 7.53 (d, J=7.8 Hz, 1 H), 7.48 (d, J=7.5 Hz, 1 H), 2.65 (q, J=7.5 Hz, 2 H), 2.02 (s, 3 H), 1.20 (s, 9 H), 1.18 (t, J=7.5 Hz, 3 H); LRMS calcd for C13H20N2O: 220.3; found 220.0 (M)+. Anal. Calcd for C13H20N2O : C, 70.87; H, 9.15; N, 12.72. Found C, 70.70; H, 9.18; N, 12.74.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[C:7]([NH:9][N:10]([CH3:20])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[S:12])=[O:8])(OC)=[O:2].C(N)(C)(C)C.[CH:30]([OH:33])([CH3:32])[CH3:31]>>[C:1]([C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[C:7]([NH:9][N:10]([CH3:20])[C:11]([NH:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[S:12])=[O:8])([O:33][CH:30]([CH3:32])[CH3:31])=[O:2]
Reactant: COC(=O)c1ccccc1C(=O)NN(C)C(=S)Nc1ccccc1
Reactant: CC(C)O
Solvent: CC(C)(C)N
Product: CC(C)OC(=O)c1ccccc1C(=O)NN(C)C(=S)Nc1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 5.0 g (0.014 mole) of 1-(2-carbomethoxybenzoyl)-2-methyl-4-phenyl-3-thiosemicarbazide in 75 ml of isopropyl alcohol was added 1.0 g (0.014 mole) of tert-butylamine and the solution was stirred at room temperature for 16-18 hours. Most of the isopropyl alcohol was removed at reduced pressure, and water was added and the resulting precipitate was collected. The title compound thus produced had a melting point of 115°-117°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:19]=[C:18](F)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Br:8].[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:19]=[C:18]([NH:28][CH2:27][C:26]4[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Br:8]
Reactant: COc1ccc(CN)cc1
Reactant: Fc1cc2c(Nc3ccc(Br)c(Br)c3)ncnc2cn1
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CNc2cc3c(Nc4ccc(Br)c(Br)c4)ncnc3cn2)cc1
Temperature: 70 °C
Reaction time: 138 h
Yield: 94.5 %

Procedure:
A mixture of compound 207 (3.40 g, 8.54 mmol) and 4-methoxybenzylamine (11.2 mL, 85.4 mmol) in dry DMSO (22 mL) was stirred under a nitrogen atmosphere at 70° C. (bath temperature) for 138 h. The mixture was then cooled and poured into water (400 mL). Petroleum ether (400 mL) was added and stirred at room temperature for 30 min. The layers were allowed to separate and the petroleum ether layer was decanted. This procedure was repeated with more petroleum ether (400 mL). It was filtered and washed solid with water (3×30 mL). The sticky yellow/orange solid was stirred with acetone (100 mL) at room temperature for ca. 30 min. to give a fine orange precipitate. Water (200 mL) was added and stirred further at room temperature for 2 h. The solid was collected by suction-filtration, washed with water/acetone (2:1) (5×30 mL), and dried in vacuum over silica-gel/KOH to give pure N4-(3,4-dibromophenyl)-N6-(4-methoxybenzyl)pyrido[3,4-d]pyrimidine-4,6-diamine (216) (4.16 g, 95%) as a greenish yellow solid, mp 166-169° C.; 1H NMR δ [(CD3)2SO] 9.72 (s, 1H), 8.77 (s, 1H, 8.42 (s, 1H), 8.40 (br s, 1H), 7.89 (br d, J=7.7 Hz, 1H), 7.76 (d, J=8.7, Hz, 1H), 7.40-7.25 (m, 3H), 7.17 (s, 1H), 6.88 (br d, J=8.3 Hz, 2H), 4.49 (d, J=5.9 Hz, 2H), 3.71 (s, 3H). Anal. Calcd for C21H17Br2N5O.0.25hexane: C, 50.35; H, 3.85; N, 13.05%. Found C, 50.56; H, 3.54; N, 12.87%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[CH3:17][CH:18]1[NH:23][CH:22]([CH3:24])[CH2:21][N:20]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:19]1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:31][C:28]1[CH:27]=[CH:26][C:25]([N:20]2[CH2:19][CH:18]([CH3:17])[NH:23][CH:22]([CH3:24])[CH2:21]2)=[CH:30][CH:29]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: CC1CN(c2ccc(N)cc2)CC(C)N1
Solvent: CN(C)C=O
Product: CC1CN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC(C)N1
Temperature: 100 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
An amount of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.5 g, 1.77 mmol) in 5 mL of N,N′-dimethylformamide is added [4-(3,5-dimethylpiperazin-1-yl)phenyl]amine (0.44 g, 2.13 mmol). The mixture reaction is stirred at 100° C. for 3 h. Mass spectroscopy suggested the completion of reaction. Solvent is subsequently evaporated under high-pressure vacuum to brown solid. The solid is stirred in ether, filtered and washed with a small amount of methanol, excess amount of ether and hexane, and dried in oven overnight to give 0.65 g (80.0% yield) of yellow solid:
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([SH:11])[CH:7]=[CH:8]2)=[CH:3][CH:2]=1.[C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:17]=1[OH:26])([CH3:15])([CH3:14])[CH3:13].C=O.[CH2:29](NCCCC)CCC>C(O)C>[C:22]([C:18]1[CH:19]=[C:20]([CH:21]=[C:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:17]=1[OH:26])[CH2:29][C:5]1[C:4]2[C:9](=[CH:10][CH:1]=[CH:2][CH:3]=2)[CH:8]=[CH:7][C:6]=1[SH:11])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: Sc1ccc2ccccc2c1
Reactant: CCCCNCCCC
Agent: C=O
Solvent: CCO
Product: CC(C)(C)c1cc(Cc2c(S)ccc3ccccc23)cc(C(C)(C)C)c1O

Procedure:
Thio-2-naphthol (16.0 g, 0.1 mol), 2,6-di-tertbutylphenol (20.6 g, 0.1 mol), paraformaldehyde (3.0 g, 0.1 mol) and di-n-butylamine (1 ml) in ethanol (100 ml) are heated, under reflux for thirteen hours, after which time thin layer chromatography shows the reaction to be complete. A small amount of solid impurity is filtered off and the solvent removed by rotary evaporation. A yellow oil is left which solidifies below 30° C. Petroleum (40°-60°) is added and a white solid (20.9 g, 55% of theory) of m.p. 30° C. is collected.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[C@@H:14]([OH:37])[C@H:15]([N:23]=[C:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:38](N1C=CN=C1)(=[O:40])[CH3:39].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:38](=[O:40])[CH3:39])[CH2:10][C@@H:9]1[C@@H:14]([OH:37])[C@H:15]([N:23]=[C:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1[C@@H](O)[C@@H](Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Reactant: CC(=O)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](Cc2ccccc2)N=C(c2ccccc2)c2ccccc2)C1

Procedure:
Dissolve 2-(R)-[2-(R)-(benzhydrylidene-amino)-1-(S)-hydroxy-3-phenylpropyl]-piperazine-1-carboxylic acid tert-butyl ester (144 mg, 0.29 mmol)) in dry dichloromethane (3 mL). Add 1-acetylimidazole (48 mg, 0.43 mmol) and triethylamine (0.081 mL, 0.58 mmol) and stir for 2 h. Dilute with ethyl acetate and wash with 1 N HCl and saturated aqueous sodium bicarbonate, dry (magnesium sulfate), and concentrate to give the title compound which is used in the next step without further purification.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22]OS(C)(=O)=O)[O:19][C:18]4=[O:28])=[CH:13][C:12]=3[F:29])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C)C=O.O>[O:4]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][N:30]=[N+:31]=[N-:32])[O:19][C:18]4=[O:28])=[CH:13][C:12]=3[F:29])[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(N3CCC4(CC3)OCCO4)c(F)c2)C(=O)O1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(N3CCC4(CC3)OCCO4)c(F)c2)C(=O)O1
Reaction time: 4 h
Yield: 91.9 %

Procedure:
(5R)-3-(4-(1,4-Dioxa-8-azaspiro[4,5]dec-8-yl)-3-fluorophenyl)-5-methanesulfonyloxymethyl-oxazolidin-2-one (3.03 g, 7.04 mM) was dissolved in N,N-dimethylformamide (50 ml), treated with sodium azide (732 mg, 11.3 mM), and heated with stirring at 50° for 4 hours. After cooling the mixture was diluted with water (250 ml), and extracted into ethyl acetate (3×100 ml). The combined organics were dried (magnesium sulfate), and evaporated to give product (2.44 g), of sufficient quality for use without purification.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]([CH3:35])[C:27]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1.[C:36](Cl)(=[O:39])[CH:37]=[CH2:38]>C(Cl)Cl>[C:36]([NH:10][CH:11]1[CH2:12][CH2:13][N:14]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([N:26]([CH3:35])[C:27]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])=[CH:24][CH:25]=2)(=[O:18])=[O:19])[CH2:15][CH2:16]1)(=[O:39])[CH:37]=[CH2:38]
Reactant: CN(C(=O)C1CCOCC1)c1ccc(S(=O)(=O)N2CCC(N)CC2)cc1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)NC1CCN(S(=O)(=O)c2ccc(N(C)C(=O)C3CCOCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.4 %

Procedure:
Diisopropylethylamine (0.34 ml, 2.1 mmol) was added in one portion to a stirred solution of tetrahydro-pyran-4-carboxylic acid [4-(4-amino-piperidine-1-sulfonyl)-phenyl]-methyl-amide (0.17 g, 0.4 mmol) in DCM (10 ml), followed by the drop wise addition of acryloyl chloride (0.04 ml, 0.42 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the mixture was diluted with DCM (20 ml) and washed sequentially with HCl (1M solution, 10 ml), NaOH (1M solution, 10 ml) and brine (10 ml). The organic layer was separated, dried (MgSO4), filtered, concentrated and the resulting residue was purified by flash column chromatography (elution: 97% EtOAc, 3% Methanol) to give the title compound (0.032 g, 18% yield) as a white solid.