Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][CH2:12][C:13]1[NH:14][C:15](=[O:23])[C:16]2[CH:22]=[CH:21][CH:20]=[N:19][C:17]=2[N:18]=1>N1C=CC=CC=1>[CH2:1]([NH:8][C:9]([NH:11][CH2:12][C:13]1[NH:14][C:15](=[O:23])[C:16]2[CH:22]=[CH:21][CH:20]=[N:19][C:17]=2[N:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1nc2ncccc2c(=O)[nH]1
Reactant: O=C=NCc1ccccc1
Solvent: c1ccncc1
Product: O=C(NCc1ccccc1)NCc1nc2ncccc2c(=O)[nH]1
Reaction time: 8 h

Procedure:
Benzyl isocyanate was added to a solution of 2-aminomethyl-3H-pyrido[2,3-d]pyrimidin-4-one (example 24.1) in pyridine; the reaction mixture was kept at r.t. overnight. The volatiles were evaporated and the title compound was isolated from the reaction mixture by reversed-phase, preparative HPLC. MS: m/e=308.4 [M−H−].
Reaction SMILES: NS(N)(=O)=O.Cl[CH2:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:33]([NH2:35])=[O:34])[CH:24]=[C:25]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11].[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C([O-])([O-])=O.[K+].[K+]>>[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:7][CH2:8][CH2:9][S:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[C:27]4[C:22](=[C:23]([C:33]([NH2:35])=[O:34])[CH:24]=[C:25]([C:28]5[S:29][CH:30]=[CH:31][CH:32]=5)[CH:26]=4)[NH:21][CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:39][CH2:38]1
Reactant: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: CN1CCNCC1
Agent: NS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN1CCN(CCCS(=O)(=O)N2CCC(c3c[nH]c4c(C(N)=O)cc(-c5cccs5)cc34)CC2)CC1
Yield: 10.2 %

Procedure:
Following the general procedure for aminosulfonamide formation outlined in example 2, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(2-thienyl)-1H-indole-7-carboxamide (40 mg, 0.13 mmol) and 1-methylpiperazine (0.068 mL, 0.65 mmol) were allowed to react in the presence of K2CO3 (74 mg, 0.65 mmol). The resulting residue was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (7.0 mg, 11%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([CH:7]=1)[CH2:8][Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)cc(Br)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(Br)cc(CBr)c1

Procedure:
A mixture of 5-bromo-3-methoxytoluene (20 g, 0.1 m), N-bromosuccinimide (17.8 g, 0.1 m) and dibenzoyl peroxide in carbon tetrachloride (200 ml) is heated to reflux and irradiated with a sunlamp. The mixture is cooled, filtered and concentrated in vacuo to give 5-bromo-3-methoxybenzyl bromide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1.[O:18]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:18]1[CH:22]=[CH:21][C:20]([C:2]2[N:7]=[C:6]([O:8][CH:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=2)=[CH:19]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1OC1CCOCC1
Reactant: OB(O)c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(-c2ccoc2)nc1OC1CCOCC1
Temperature: 80 °C
Yield: 67.9 %

Procedure:
A solution of 6-chloro-3-nitro-2-(tetrahydro-2H-pyran-4-yloxy)pyridine (0.259 g, 1.00 mmol), furan-3-boronic acid (0.123 g, 1.10 mmol), tetrakis(triphenylphosphine)palladium (0) (0.058 g, 0.05 mmol) and potassium carbonate (0.276 g, 2.00 mmol) in 1,4-dioxane/water (5 mL, 4:1) was de-gassed with nitrogen and then heated at 80° C. for 18 hours. The reaction mixture was diluted with EtOAc, washed with water and brine. The organic phase was dried (MgSO4) and the solvent removed in vacuo. The residue was triturated with n-hexane to afford the title compound as an off-white solid (0.197 g, 66%).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH3:4].[CH3:13][S:14][CH2:15]Cl.C(N(CC)CC)C>>[C:1]([O:12][CH2:13][S:14][CH3:15])(=[O:11])[CH2:2][CH:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])[CH3:4]
Reactant: CSCCl
Reactant: CC(C)=CCCC(C)CC(=O)O
Solvent: CCN(CC)CC
Product: CSCOC(=O)CC(C)CCC=C(C)C

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting citronellic acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 110° C./2 mm Hg, nD20 1,4760.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30](B(O)O)=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:30]([C:2]3[CH:3]=[CH:4][C:5]4[N:9]=[CH:8][N:7]([C:10]5[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=5)[C:6]=4[CH:18]=3)=[CH:29][CH:28]=[N:27]2)=[CH:24][CH:25]=1
Reactant: OB(O)c1ccnn1-c1ccc(Cl)cc1
Reactant: COc1ccc(-n2cnc3ccc(Br)cc32)cc1
Product: COc1ccc(-n2cnc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cc32)cc1

Procedure:
The title compound, off-white solid (16 mg, 12%), MS (ISP) m/z=401.5 [(M+H)+], mp 163° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-methoxy-phenyl)-1H-benzo[d]imidazole (intermediate N) (100 mg, 330 μmol) and 1-(4-chloro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate D) (88.1 mg, 396 μmol).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[F:32][C:33]1[CH:34]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1>>[CH:27]1([CH2:26][N:10]2[C:9]3[N:8]=[C:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][S:39]([C:35]5[CH:36]=[CH:37][CH:38]=[C:33]([F:32])[CH:34]=5)(=[O:41])=[O:40])=[CH:31][CH:30]=4)[NH:15][C:14]=3[C:13](=[O:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:11]2=[O:25])[CH2:28][CH2:29]1
Reactant: Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Product: O=c1c2[nH]c(Cc3ccc(NS(=O)(=O)c4cccc(F)c4)cc3)nc2n(CC2CC2)c(=O)n1Cc1ccccc1F

Procedure:
Prepared from 8-(4-amino-benzyl)-3-cyclopropylmethyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 3-fluoro-benzenesulfonyl chloride. Tan solid; EI-HRMS m/e calculated for C29H25F2N5O4S (M+) 577.1595, found 577.1599.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[N:22]([CH3:23])[CH2:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[OH:30])[C:12]3=[O:31])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:38][N:39]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[N:40]1>C1COCC1.C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:30][C@H:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:24]1[N:13]1[C:12](=[O:31])[C:11]2[C:16](=[C:17]3[N:22]([CH3:23])[CH2:21][CH:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([C:42]4[CH:41]=[N:40][N:39]([CH3:38])[CH:43]=4)=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: CN1CC=Cc2c(Cc3ccc(Cl)nc3)cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c21
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CC=Cc2c(Cc3ccc(-c4cnn(C)c4)nc3)cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c21
Temperature: 100 °C

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one (Example 1, 0.040 g, 0.092 mmol) in 2 mL of THF under an atmosphere of nitrogen was added aqueous cesium carbonate (1 M, 0.18 mL, 0.18 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.057 g, 0.28 mmol), and bis(tri-tert-butylphosphine)palladium(0) (4.0 mg, 0.0078 mmol). The reaction was heated at 100° C. for 16 h, cooled to rt, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate and brine. The solution was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 483.1 for [M+H]+: 1H NMR (400 MHz, CD3OD) δ 8.92 (s, 1H), 8.52 (d, J=8.6 Hz, 1H), 8.40 (s, 1H), 8.08 (s, 1H), 7.95 (br s, 2H), 7.61-7.39 (m, 3H), 4.78 (s, 2H), 4.49 (s, 2H), 4.23 (br s, 1H), 3.92 (s, 3H), 3.74 (br s, 1H), 3.20 (s, 3H), 2.11 (br s, 1H), 1.83-1.63 (m, 5H), 1.29-1.23 (m, 2H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1[C:20]2[CH:19]([C:21]([OH:23])=O)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[CH3:24][NH:25][C@@H:26]1[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.C(Cl)(Cl)Cl>[N:28]12[CH2:33][CH2:32][CH:31]([CH2:30][CH2:29]1)[C@@H:26]([N:25]([CH3:24])[C:21]([CH:19]1[C:20]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[O:12][C:13]3[C:18]1=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:23])[CH2:27]2
Reactant: CN[C@H]1CN2CCC1CC2
Reactant: O=C(O)C1c2ccccc2Oc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CN(C(=O)C1c2ccccc2Oc2ccccc21)[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.6 %

Procedure:
Oxalyl chloride (0.540 ml, 0.0062 mol) was added to a solution of 9H-xanthene-9-carboxylic acid (1.16 g, 0.0051 mol) and dimethylformamide (two drops) in 20 ml of CHCl3 (ethanol free) at 0° C. The mixture was allowed to warm to room temperature under stirring and maintained 1 h at this temperature. After this time, the reaction mixture was concentrated to dryness in vacuo and the obtained residue was dissolved in CHCl3 (15 ml) and concentrated again. This procedure was repeated two times. The obtained residue was dissolved in CHCl3 and the solution cooled to 0° C. A solution of 0.865 g (0.0062 mol) of (3R)-N-methylquinuclidin-3-amine (Intermediate I-4) in 10 ml of CHCl3 was added. The mixture was allowed to warm to room temperature under stirring. After 4 hours at this temperature, the reaction mixture was treated with K2CO3 (saturated solution) and the aqueous phase was extracted with CHCl3. The organic solutions were combined and washed with K2CO3 (saturated solution) and water, dried over Na2SO4 filtered and concentrated to dryness. The obtained residue was purified by column chromatography (silica gel, CHCl3: NH4OH 99:1→CHCl3: MeOH:NH4OH 98:2:1 as eluent) to yield 900 mg (50%) of the title product.
Reaction SMILES: [CH2:1]([P:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[Br:14][CH2:15][CH2:16][CH2:17][O:18][C:19](=[O:37])[CH:20]([O:22][N:23]1[C:28]([CH2:30][CH3:31])([CH3:29])[CH2:27][CH:26]([OH:32])[CH:25]([CH3:33])[C:24]1([CH2:35][CH3:36])[CH3:34])[CH3:21]>C(#N)C>[Br-:14].[CH2:10]([P+:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:15][CH2:16][CH2:17][O:18][C:19](=[O:37])[CH:20]([O:22][N:23]1[C:28]([CH2:30][CH3:31])([CH3:29])[CH2:27][CH:26]([OH:32])[CH:25]([CH3:33])[C:24]1([CH2:35][CH3:36])[CH3:34])[CH3:21])[CH2:11][CH2:12][CH3:13]
Reactant: CCC1(C)CC(O)C(C)C(C)(CC)N1OC(C)C(=O)OCCCBr
Reactant: CCCCP(CCCC)CCCC
Solvent: CC#N
Product: CCCC[P+](CCCC)(CCCC)CCCOC(=O)C(C)ON1C(C)(CC)CC(O)C(C)C1(C)CC
Product: [Br-]
Temperature: 60 °C
Reaction time: 23 h
Yield: 105.6 %

Procedure:
Tributylphosphine (3 ml, 0.012 mol) is added to a solution of 2-(2,6-diethyl-4-hydroxy-2,3,6-trimethyl-piperidine-1-yloxy)-propionic acid 3-bromo-propyl ester (4.08 g, 0.01 mol) in acetonitrile (5 ml). The solution is stirred under argon at 60° C. for 23 h. The solvent is evaporated and the residue is triturated with diethyl ether (2×15 ml) to remove the excess of the phosphine. Drying of the oily, in ether insoluble, residue affords 6.45 g of the title compound as a thick resin.
Reaction SMILES: [CH2:1]([O:14][C:15]1[CH:16]=[N:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30]C)=[CH:23][CH:22]=2)=[N:19][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(OC1C=NC(C2C=CC(CCCCCCCCCCC)=CC=2)=NC=1)CCCCCCCCCCCC.C(OC1C=NC(C2C=CC(CCCCCCCCCC)=CC=2)=NC=1)CCCCCCCCCCCC>>[CH2:1]([O:14][C:15]1[CH:20]=[N:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=2)=[N:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCCOc1cnc(-c2ccc(CCCCC)cc2)nc1
Agent: CCCCCCCCCCCCCOc1cnc(-c2ccc(CCCCCCCCCC)cc2)nc1
Agent: CCCCCCCCCCCCCOc1cnc(-c2ccc(CCCCCCCCCCC)cc2)nc1
Product: CCCCCCCCCCCCCOc1cnc(-c2ccc(CCCC)cc2)nc1

Procedure:
5-tridecyloxy-2-(4-pentylphenyl)pyrimidine ##STR11## 5-tridecyloxy-2-(4-heptylphenyl)pyrimidine ##STR12## 5-tridecyloxy-2-(4-decylphenyl)pyrimidine 5-tridecyloxy-2-(4-undecylphenyl)pyrimidine
Reaction SMILES: [OH:1][S:2]([OH:5])(=O)=[O:3].N#N.Cl.[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][N:16]=[CH:17]2)=[CH:12][CH:11]=1>>[Br:9][C:10]1[CH:11]=[C:12]([S:2]([OH:5])(=[O:3])=[O:1])[C:13]2[CH:14]=[CH:15][N:16]=[CH:17][C:18]=2[CH:19]=1
Reactant: O=S(=O)(O)O
Reactant: Brc1ccc2ccncc2c1
Agent: Cl
Agent: N#N
Product: O=S(=O)(O)c1cc(Br)cc2cnccc12
Temperature: 25 °C
Yield: 85.3 %

Procedure:
Add fuming H2SO4 (2,000 mL, 21.33 mol; 26-29.5% free SO3) to a 5-L round bottom flask, equipped with a mechanical stirrer, reflux condenser, N2 line, and thermometer. Cool the fuming H2SO4 to ˜10° C. with an ice/acetone bath, then add 7-bromoisoquinoline HCl (500.00 g, 2.04 mol) portion-wise, keeping the temperature of the reaction mixture below ˜15-20° C. Upon complete addition of 7-bromoisoquinoline HCl, heat the resulting reaction mixture at ˜100° C. overnight. Cool the reaction mixture to room temperature, then slowly pour into a stirring solution of ice H2O. Recover the resulting precipitate by vacuum filtration, washing with H2O, then Et2O, and dry under vacuum filtration, followed by drying in a drying oven under reduced pressure at ˜35° C. to afford the title compound (501.42 g, 85% yield) as an off-white solid: TOF-MS [ES+; m/z] 287.9331/287.9330.
Reaction SMILES: COC([NH:5][C@@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH:8]1[CH2:11][CH2:10][CH2:9]1)=O.Cl.O1C(C)C1>>[CH:8]1([CH2:7][C@H:6]([C:12]([OH:14])=[O:13])[NH2:5])[CH2:11][CH2:10][CH2:9]1
Reactant: COC(=O)N[C@H](CC1CCC1)C(=O)O
Agent: CC1CO1
Agent: Cl
Product: N[C@H](CC1CCC1)C(=O)O

Procedure:
To 1.0 g (5 mmol) of methoxycarbonyl-3-cyclobutyl-D-alanine (Example 2, Step 2) 10 ml of 6M HCl is added and heated to reflux for 3 hours. The solution is evaporated at a pressure of 2.0-2.5 kPa, the residue is dissolved in 5 ml of water and evaporated to dryness and this process is repeated. The traces of water can be removed by azeotropic distillation with ethanol-benzene mixture. The residual oil is dissolved in 10 ml of ethanol and 5 mmol of 1,2-epoxy-propane is added. After cooling the precipitate is filtered off, the solid is washed with diethyl ether and dried.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:24][CH:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:14](=[O:33])[N:13]1[CH:9]([CH2:10][CH:11]([O:34][C:35]3[C:44]4[C:39](=[CH:40][C:41]([O:45][CH3:46])=[CH:42][CH:43]=4)[N:38]=[C:37]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH:36]=3)[CH2:12]1)[C:8](=[O:53])[NH:7]2)=[O:5])C.O.CO.[OH-].[Li+]>O1CCCC1>[C:29]([O:28][C:26]([NH:25][N:15]1[C:14](=[O:33])[N:13]2[CH:9]([CH2:10][CH:11]([O:34][C:35]3[C:44]4[C:39](=[CH:40][C:41]([O:45][CH3:46])=[CH:42][CH:43]=4)[N:38]=[C:37]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH:36]=3)[CH2:12]2)[C:8](=[O:53])[NH:7][C:6]2([C:4]([OH:5])=[O:3])[CH:23]([CH2:24]2)[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)C12CC1C=CCCCCCN(NC(=O)OC(C)(C)C)C(=O)N1CC(Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCN(NC(=O)OC(C)(C)C)C(=O)N4C3)cc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
Compound 17 (39 mg, 0.054 mmol) was dissolved in tetrahydrofuran (3.5 ml), water (1.75 ml) and methanol (1.75 ml). Lithium hydroxide (430 μl, 1 M in water) was then added and the reaction was stirred at room temperature for 24 h. The volume was reduced to half and water (10 ml) was added. Acidification (pH=5) followed by extraction with chloroform gave the pure title compound (34 mg, 90%). MS (M+H+) 700.2
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=2)([CH3:16])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][C:3]=1[C:28]([CH3:31])([CH3:30])[CH3:29].[CH3:32][N:33]1[C:38](C)([CH3:39])[CH2:37]C(O)[CH2:35][C:34]1([CH3:43])[CH3:42].[NH2-].[Li+].C(O)C>C1(C)C=C(C)C=C(C)C=1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=2)([CH3:16])[CH2:9][CH2:10][C:11]([O:13][CH:14]2[CH2:35][C:34]([CH3:43])([CH3:42])[N:33]([CH3:32])[C:38]([CH3:39])([CH3:37])[CH2:15]2)=[O:12])=[CH:4][C:3]=1[C:28]([CH3:30])([CH3:29])[CH3:31]
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Reactant: CCOC(=O)CCC(C)(c1ccc(O)c(C(C)(C)C)c1)c1ccc(O)c(C(C)(C)C)c1
Agent: [Li+]
Agent: [NH2-]
Solvent: Cc1cc(C)cc(C)c1
Solvent: CCO
Product: CN1C(C)(C)CC(OC(=O)CCC(C)(c2ccc(O)c(C(C)(C)C)c2)c2ccc(O)c(C(C)(C)C)c2)CC1(C)C
Temperature: 160 °C

Procedure:
42.7 g of ethyl 4,4-di-(4-hydroxy-3-t-butyl-phenyl)-valerate and 17.1 g of 1,2,2,6,6-pentamethyl-4-hydroxy-piperidine in 120 ml of mesitylene, with the addition of 100 mg of lithium amide as the catalyst, are heated to 160° C. in a nitrogen atmosphere for 5 hours, whilst stirring. During this time, the ethanol formed distils off in the stream of nitrogen and can be measured in a cold trap. After cooling, 100 ml of toluene are added to the batch and the solution is washed with water, dried with calcium chloride and evaporated in vacuo. The crystalline residue is recrystallised from acetonitrile or chlorobenzene. In this way 1,2,2,6,6-pentamethyl-piperidin-4-yl 4,4-di-(4-hydroxy-3-t-butyl-phenyl)-valerate (stabiliser no. 2) is obtained as a white crystalline powder with a melting point of 203° C.
Reaction SMILES: Cl.[NH:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH2:3].C(=O)([O-])O.[Na+].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O[CH:26]=[C:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29])C>O.C(O)C>[CH:15](=[N:3][N:2]([CH:26]=[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)CNN
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CN(C=C(C(=O)OCC)C(=O)OCC)N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.3 %

Procedure:
A mixture of ethyl hydrazinoacetate hydrochloride (15.5 g), sodium hydrogen carbonate (8.40 g), water (15 mL) and ethanol (100 mL) was stirred at room temperature for 30 min. Benzaldehyde (10.61 g) was added to the reaction mixture, and after stirring for 1 hr, diethyl ethoxymethylenemalonate (21.6 g) was added. The mixture was heated under reflux for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1:3, v/v) to give diethyl [(2-benzylidene-1-(ethoxycarbonylmethyl)hydrazino]methylene}malonate as colorless crystals (8.75 g, yield 23%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 105-106° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20](Cl)=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[N:23]2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:30]([NH2:34])[CH:31]([CH3:33])[CH3:32]>ClCCl>[CH2:8]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([NH:34][CH2:30][CH:31]([CH3:33])[CH3:32])=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[N:23]2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Reactant: CC(C)CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.7 %

Procedure:
Triethylamine (38.6 mL, 0.277 mol) was added to a solution of 7-benzyloxy-4-chloro-3-nitroquinoline (72.9 g, 0.232 mol) in dichloromethane (1200 mL). Isobutylamine (25.24 mL, 0.2540 mol) was then added, and the reaction mixture was stirred for 18 hours at ambient temperature. The reaction mixture was diluted with dichloromethane, washed sequentially with water (2×) and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 67.4 g of (7-benzyloxy-3-nitroquinolin-4-yl)-(2-methylpropyl)amine as a brown solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([NH2:10])[CH2:7][CH2:8][CH2:9][C:2]1=2.[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([N:10]3[C:14](=[O:15])[C:13]4=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]4[C:11]3=[O:16])[CH2:7][CH2:8][CH2:9][C:2]1=2
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NC1CCCc2sccc21
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1C1CCCc2sccc21

Procedure:
In 50 ml of toluene, 5 g of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-ylamine, 4.84 g of phthalic anhydride, and 0.5 ml of triethylamine are heated at reflux to azoetropically remove water. After the distillation of water is completed, the mixture is cooled, the crystals are collected and washed with ether to afford N-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)phthalimide, m.p. 166° C. to 167.5° C. Oxidation of this compound by the method of Example 1 affords the title compound, m.p. 163° C. to 166° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:13]2[C:14]3[N:5]([C:6](=[O:16])[CH:7]=[CH:8][C:9]=3[N:10]=[CH:11][C:12]2=[O:15])[CH2:4]1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(CC)CC.CN(C)CCO>C(Cl)Cl.CC(OC)(C)C>[C:17]1([S:23]([O:1][CH2:2][C@H:3]2[N:13]3[C:14]4[N:5]([C:6](=[O:16])[CH:7]=[CH:8][C:9]=4[N:10]=[CH:11][C:12]3=[O:15])[CH2:4]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1ccc2ncc(=O)n3c2n1C[C@H]3CO
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)CCO
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: O=c1ccc2ncc(=O)n3c2n1C[C@H]3COS(=O)(=O)c1ccccc1
Temperature: 42 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
To the suspension of (2S)-2-(hydroxymethyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (26.5 g, 121 mmol) in DCM (320 ml) was added benzenesulfonyl chloride (23.38 ml, 181 mmol) followed by Et3N (39.6 ml, 284 mmol). The reaction mixture was heated at gentle reflux at 42° C. for 2 h. Then, the reaction was cooled to 5° C. and 2-(dimethylamino)ethanol (7.30 ml, 72.5 mmol) was added dropwise. The crude was stirred at room temperature for 30 min and TBME (600 ml) was added. The obtained solid was filtered. The resulting solid was suspended in 100 ml 1N HCl and washed with water and TBME, dried to give [(2S)-3,8-dioxo-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylen-2-yl]methyl benzenesulfonate (37.04 g, 85%) as a cream solid.