Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1.[ClH:19]>C(O)C>[ClH:19].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH:13]=1
Reactant: COc1ccc([N+](=O)[O-])cc1C1=CCN(C)CC1
Agent: Cl
Solvent: CCO
Product: COc1ccc(N)cc1C1=CCN(C)CC1

Procedure:
A solution of 4-(2-methoxy-5-nitrophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (D37) (570 mg, 2 mmol), in ethanol (35 ml), was warmed to 60° C. and treated dropwise with a solution of stannous chloride (2 g) in cone. hydrochloric acid (4 ml). The mixture was heated for a further 2 h after addition, and allowed to cool. The precipitate was filtered off, and washed with ethanol to give the title compound (D39) as a pale yellow powder (580 mg, 99%). MH+=219.
Reaction SMILES: [CH2:1]([CH:18]([CH:39]([OH:57])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]/[CH:47]=[CH:48]\[CH2:49]/[CH:50]=[CH:51]\[CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[C:19](=[O:38])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].O(O)O.[BH4-].[Na+]>CO.C(O)(C)C>[CH2:1]([CH:18]([CH:19]([OH:38])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:39]([OH:57])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]/[CH:47]=[CH:48]\[CH2:49]/[CH:50]=[CH:51]\[CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(=O)C(CCCCCCC/C=C\C/C=C\CCCCC)C(O)CCCCCCC/C=C\C/C=C\CCCCC
Agent: OOO
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(O)C(CCCCCCC/C=C\C/C=C\CCCCC)C(O)CCCCCCC/C=C\C/C=C\CCCCC
Reaction time: 3 h
Yield: 90.4 %

Procedure:
A solution of the keto-alcohol (6Z,9Z,29Z,32Z)-20-((8Z,11Z)-heptadeca-8,11-dien-1-yl)-21-hydroxyoctatriaconta-6,9,29,32-tetraen-19-one (10) (920 mg, 1.16 mmol) in CH3OH (5 mL) and isopropanol (12 mL) was treated with NaBH4 (88 mg, 2.3 mmol). After stirring (1 h) a second portion of NaBH4 (88 mg, 23 mmol) was added and the mixture stirred (3 h). The reaction mixture was carefully quenched by the addition of cold HCl (5% aq.), extracted with CH2Cl2, washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was subjected to chromatography (1%→10% EtOAc-hexanes) to yield (6Z,9Z,29Z,32Z)-19-((8Z,11Z)-heptadeca-8,11-dien-1-yl)octatriaconta-6,9,29,32-tetraene-18,20-diol (11) (832 mg, 90%) as a colorless oil. Rf 0.23 (10% EtOAc-hexanes), FW 793.39, C55H100O2.
Reaction SMILES: C([O:5][C:6](=[O:16])[CH2:7][CH:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9](O)=O)(C)(C)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].CC(C)=CCBr.[Cl-].[NH4+]>C1COCC1.CCOCC.Cl>[CH2:12]([CH:8]1[CH2:9][O:16][C:6](=[O:5])[CH2:7]1)[CH:13]([CH3:14])[CH3:15]
Reactant: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)CC1COC(=O)C1
Temperature: -40 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
Cyanide 3 (0.86 g, 7.1 mmol) in THF (30 mL) was added dropwise over 1 hour to a stirring mixture of lithium hexamethyldisilazide (7.8 mL of a 1 M solution in THF, 7.8 mmol) in THF (40 mL) at −78° C. under argon. The mixture was allowed to warm to −40° C. and stirred for 2 hours. The mixture was cooled to −78° C. and dimethylallyl bromide (1.3 mL, 10.6 mmol) was added. The mixture was stirred for a further 2 hours at −78° C. and then allowed to warm to room temperature overnight. Saturated ammonium chloride solution (20 mL) was added, and the mixture was diluted with ether (50 mL) and dilute hydrochloric acid (30 mL). The aqueous layer was further extracted with ether (2×50 mL), and the combined 15 organic fractions were washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane-ethyl acetate, 98:2) to give the cyanoalkene 4 (0.96 g, 72%) as a colorless oil; Rf(heptane-ethyl acetate, 95:5) 0.38; νmax(film)/cm−1 2230 (CN),1673 (C═C); δH (400 MHz; CDCl3) 5.27 (1H, tt, J 7.6, 1.3, CHCMe2), 2.89 (2H, m), 2.30–2.22 (4H, m), 2.10 (2H, d, J 14.2), 1.94 (2H, m), 1.84–1.62 (2H, m), 1.65 (3 H, s, Me), 1.55 (3H, s, Me); m/z (AP+) 190 (M+H, 100%).
Reaction SMILES: [C:1]([N:5]1[C:9]([CH3:10])=[CH:8][C:7]([C:11](Cl)=[O:12])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[C:18]([C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1)=[O:19]>C1COCC1>[O:29]=[C:25]1[CH2:24][C:23]2[C:27](=[CH:28][C:20]([C:18]([C:17]3[CH:16]=[C:15]([NH:14][C:11]([C:7]4[CH:8]=[C:9]([CH3:10])[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:6]=4)=[O:12])[CH:32]=[CH:31][CH:30]=3)=[O:19])=[CH:21][CH:22]=2)[NH:26]1
Reactant: Cc1cc(C(=O)Cl)nn1C(C)(C)C
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)nn1C(C)(C)C
Temperature: 25 °C
Yield: 47.6 %

Procedure:
A dry flask was charged with 1-tert-Butyl-5-methyl-1H-pyrazole-3-carbonyl chloride (0.207 g, 1.032 mmol) and THF (10 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.260 g, 1.03 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and subsequently vacuum filtered. The solid was washed with 0° C. THF (˜5 mL) and collected to afford the 1-tert-Butyl-5-methyl-1H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.206 g, 0.490 mmol, 48%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]1=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Reactant: O=C(Cl)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccccc2)C1=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a stirred solution of 1-(t-butoxycarbonyl)-2-pyrrolidinone (11.9 g, 64.3 mmol) in dry THF (190 mL) at −78° C. was added a solution of LiHMDS (1.0M in toluene, 135 mL, 135 mmol). After stirring at −78° C. for 2 hours, benzoyl chloride (7.5 mL, 64.3 mmol) was added dropwise over 5 minutes while keeping the temperature below −50° C. The mixture was stirred at −78° C. for 4 hours, and the reaction was then quenched with a saturated aqueous NH4Cl solution (200 mL). The mixture was diluted with EtOAc (300 mL) and the organic layer was washed with saturated NaHCO3 (200 mL×2) and saturated aqueous NaCl (200 mL). The organic layer was dried over MgSO4, filtered and concentrated, and the crude product was purified by flash column chromatography (20-60% EtOAc in hexanes) to afford the title compound (14.5 g) as a yellow oil.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].C([O-])(=O)C.[Na+:15]>C(O)(=O)C>[C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=[O:7].[Na+:15]
Reactant: O=C(O)CCCCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C([O-])CCCCC(=O)O

Procedure:
In reaction ii, sodium bisulfate is reacted with sodium acetate to produce sodium sulfate and solid acetic acid. In reaction iii., malic acid is reacted with sodium acetate to produce sodium hydrogen diglycolate and solid acetic acid. In reaction iv., fumaric acid is reacted with sodium acetate to produce sodium hydrogen fumarate and solid acetic acid. In reaction v., tartaric acid is reacted with sodium acetate to produce sodium hydrogen tartrate and solid acetic acid. In reaction vi., adipic acid is reacted with sodium acetate to produce sodium hydrogen adipate and solid acetic acid. In reaction vii, sulfamic acid is reacted with sodium acetate to produce sodium sulfamate and solid acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[NH:19][C:18]2=[O:28])=[CH:12][C:3]=1[O:4][CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].S(OC)(O[CH3:33])(=O)=O>>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[N:19]([CH3:33])[C:18]2=[O:28])=[CH:12][C:3]=1[O:4][CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)C(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Product: CCOC(=O)C(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
using ethyl 2-[2-chloro-5-(3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl)-4-fluorophenoxy]-propionate and dimethyl sulphate there is obtained ethyl 2-[2-chloro-5-(3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl)-4-fluorophenoxy]-propionate, 1H-NMR (CDCl3, 400 MHz): 7.32 ppm (d,1H), 6.83 ppm (d,0.5H), 6.81 ppm (d,0.5H), 6.34 ppm (2s,1H), 4.53-4.72 ppm (m,1H), 4.13-4.27 ppm (m,2H), 3.50-3.59 ppm (m,3H), 1.67 ppm (d,3H), 1.18-1.28 ppm (m.3H):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11].[CH3:30][N:31]1[CH2:36][CH2:35][CH:34]([NH:37][CH3:38])[CH2:33][CH2:32]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:37]([CH3:38])[CH:34]2[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]2)=[O:26])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11]
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)O)c(F)c2)c2ccccc2Cl)ccc1=O
Reactant: CNC1CCN(C)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CN1CCC(N(C)C(=O)c2ccc(C(CC(=O)c3ccc(=O)n(C)c3)c3ccccc3Cl)cc2F)CC1

Procedure:
In analogy to example 207, step 2, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluorobenzoic acid (example 216, step 4) was coupled with 1-methyl-4-(methylamino)piperidine using BOP reagent in tetrahydrofuran to give the title compound as a colorless foam, MS (ESI+): m/z=524.3 [M+H]+.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][NH:11][CH2:10][C:9](=[O:13])[N:8]2[C:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:16][C:15]=2[C:25]([OH:27])=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:28][C:29]1[N:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.[OH-].[Na+].Cl>CC#N.CCOC(C)=O>[Cl:28][C:29]1[N:34]=[CH:33][C:32]([S:35]([N:11]2[CH2:10][C:9](=[O:13])[N:8]([C:14]3[CH:18]=[C:17]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[S:16][C:15]=3[C:25]([OH:27])=[O:26])[C@H:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:12]2)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: O=C(O)c1sc(-c2ccccc2)cc1N1C(=O)CNCC1C1CCCCC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(O)c1sc(-c2ccccc2)cc1N1C(=O)CN(S(=O)(=O)c2ccc(Cl)nc2)C[C@H]1C1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
To a solution of 3-(2-cyclohexyl-6-oxo-piperazin-1-yl)-5-phenyl-thiophene-2-carboxylic acid (0.80 g, 1.90 mmol, 1.0 equiv) in MeCN (20 mL) at room temperature, was added 6-chloro-pyridine-3-sulfonyl chloride (1.10 g, 5.20 mmol, 2.7 equiv) and followed by NaOH (6.94 mL, 1.5 N solution, 10.4 mmol, 5.5 equiv) dropwise. The mixture was stirred at room temperature for 10 minutes. The mixture was acidified with 3 N HCl (2.5 mL), and then diluted with EtOAc (50 mL). The mixture was washed water (25 mL), brine (25 mL), dried (over Na2SO4), filtered and concentrated to give crude product (1.0 g, 94%) as yellow-green solid. MS: 560 [M−H+].
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][C:8]([CH:10]1[C:16](=[O:17])[C:15]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:14]=2[NH:13][C:12](=[O:23])[CH2:11]1)=[O:9].CI.[Cl-].[NH4+].N>CCCCCC.C(OCC)C>[CH3:6][O:7][C:8]([CH:10]1[C:16](=[O:17])[C:15]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:14]=2[N:13]([CH3:1])[C:12](=[O:23])[CH2:11]1)=[O:9]
Reactant: COC(=O)C1CC(=O)Nc2cc(Cl)ccc2C1=O
Reactant: [Li]CCCC
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CI
Product: COC(=O)C1CC(=O)N(C)c2cc(Cl)ccc2C1=O
Reaction time: 0.67 h

Procedure:
To the mixture, prepared from the dropwise addition of 131 ml of 1.6 molar n-butyl lithium in hexane to 600 ml of liquid amonia while vigorously stirring under an artificial atmosphere of nitrogen for 40 minutes at -76°, 26.7 g of 8-chloro-2,3,4,5-tetrahydro-1-benzazepine-2,5-dione-4-carboxylic acid methyl ester are added all at once and the solution obtained stirred for 1 hour. Thereupon 14.2 g of methyl iodide are added dropwise and the mixture stirred at -35° for 3 hours. It is conbined with 24 g of ammonium chloride and 600 ml of diethyl ether and the ammonia is allowed to evaporate over night at room temperature. 500 ml of water are added to the mixture, its pH adjusted to 6-7 with 6N hydrochloric acid, the organic phase separated and the aqueous layer extracted with diethyl ether. The combined organic solutions are washed with water, dried, filtered, evaporated and the residue recrystallized from diethyl ether, to yield the 8-chloro-1-methyl-2,3,4,5-tetrahydro-1-benzazepine-2,5-dione-4-carboxylic acid methyl ester melting at 134°-136°.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][NH:26][C:27]2[N:28]=[N+:29]([O-:40])[C:30]3[CH:39]=[C:38]4[C:34]([CH2:35][CH2:36][CH2:37]4)=[CH:33][C:31]=3[N:32]=2)[CH2:19]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(Cl)(Cl)Cl.N>[CH3:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][NH:26][C:27]2[N:28]=[N+:29]([O-:40])[C:30]3[CH:39]=[C:38]4[C:34]([CH2:35][CH2:36][CH2:37]4)=[CH:33][C:31]=3[N+:32]=2[O-:4])[CH2:19]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COC1CCCN(CCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)C1
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC1CCCN(CCNc2n[n+]([O-])c3cc4c(cc3[n+]2[O-])CCC4)C1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 8.2 %

Procedure:
H2O2 (70%, 2.5 mL, ca. 51 mmol) was added dropwise to a stirred solution of TFAA (7.1 mL, 51 mmol) in DCM (70 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., added to a solution of 1-oxide 40 (1.75 g, 5.1 mmol) and TFA (0.84 mL, 11 mmol) in CHCl3 (70 mL) at 0° C. The solution was stirred at 20° C. for 5 h, diluted with dilute aqueous NH3 solution until basic and extracted with CHCl3 (3×80 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by column chromatography, eluting with a gradient (4-20%) of MeOH/DCM, to give 1,4-dioxide 41 (0.15 g, 8%) as a red gum: 1H NMR δ 8.91 (br s, 1H, NH), 8.05 (s, 2H, H-5, H-9), 4.09 (t, J=5.8 Hz, 2H, CH2N), 3.84 (td, J=12.8, 1.9 Hz, 1H, CHO), 3.57-3.66 (m, 4H, 2×CH2), 3.57 (s, 3H, OMe), 3.40 (td, J=13.3, 3.5 Hz, 1H, CH2), 3.01-3.12 (m, 5H, H-6, H-8, CH2), 2.19 (p, J=7.4 Hz, 2H, H-7), 2.16-2.23 (m, 1H, CH2), 2.02-2.08 (m, 1H, CH2), 1.62-1.72 (m, 1H, CH2), 1.37-1.48 (m, 1H, CH2); 13C NMR δ 155.6, 149.4, 146.1, 138.1, 129.7, 115.5, 111.7, 73.2, 69.7, 67.6, 61.4, 56.9, 36.5, 33.3, 32.4, 28.5, 25.6, 20.3; HRMS (FAB+) calcd for C18H26N5O3 (MH+) m/z 360.2036, found 360.2039.
Reaction SMILES: O.NN.[CH3:4][NH:5][C:6](=[O:42])[C@H:7]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH:8][C:9](=[O:34])[C@H:10]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:11][S:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]1C(=O)C2=CC=CC=C2C1=O)(=[O:14])=[O:13]>C(O)C.C(Cl)(Cl)Cl.O>[CH3:4][NH:5][C:6](=[O:42])[C@H:7]([CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[NH:8][C:9](=[O:34])[C@H:10]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:11][S:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])(=[O:14])=[O:13]
Reactant: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NS(=O)(=O)CCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NS(=O)(=O)CCCCN
Temperature: 25 °C
Yield: 99.1 %

Procedure:
Hydrazine hydrate (56%, 18.2 ml) was added to a solution of example 17 (7.1 g) in ethanol (120 ml) and the mixture was heated at reflux for 30 min. The mixture was then cooled to RT and diluted with ethanol (300 ml), chloroform (100 ml) and water (200 ml). The layers were separated and the organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was then purified by flash column chromatography, eluting with 0-10% methanol in chloroform containing 2.5% triethylamine, to give the title compound (5.39 g, 99%) as a colourless solid.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N:2]=1.[NH2-:11].[Na+].[OH-].[Na+]>CN(C=O)C>[C:1]1([NH2:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: c1cc2c(cn1)CCCC2
Reactant: [NH2-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1nccc2c1CCCC2
Temperature: 170 °C
Yield: 46.7 %

Procedure:
To a solution of 5,6,7,8-tetrahydroisoquinoline (5.0 g, 37.6 mmol) in DMF (8 mL) was added sodium amide (2.55 g, 63.9 mmol). The resulting mixture was heated to 170° C. for 16 h and cooled to room temperature. To the mixture was added aqueous 2 N NaOH (50 mL). The mixture was extracted with DCM (100 mL×3), and the combined organic phase was dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluting with DCM/MeOH v/v 10:1) to give 5,6,7,8-tetrahydroisoquinolin-1-amine as a yellow solid (2.6 g, yield 46%). ESI MS: m/z 149 [M+H]+. 1H NMR (400 MHz, CDCl1): δ 7.80 (d, J=5.2 Hz, 1H), 6.44 (d, J=5.2 Hz, 1H), 4.34 (br, 2H), 2.67 (t, J=12 Hz, 2H), 2.39 (t, J=12 Hz, 2H), 1.88 (m, 2H), 1.78 (m, 2H).
Reaction SMILES: N([O-])=[O:2].[Na+].N[C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[N:7]=1>O.S(=O)(=O)(O)O>[Cl:13][C:8]1[CH:9]=[C:10]([Cl:12])[CH:11]=[C:6]([OH:2])[N:7]=1
Reactant: O=N[O-]
Reactant: Nc1cc(Cl)cc(Cl)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Oc1cc(Cl)cc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Sodium nitrite (64 mg, 0.93 mmol) dissolved in water (0.6 mL), was added dropwise to a stirred solution of 2-amino-4,6-dichloropyridine (prepared according to the method described in Recl. Trav. Chim. Pays-Bas, 1950, 69, 673) (126 mg, 0.77 mmol) in 5% sulphuric acid (aq) (5 mL) at 0° C., over 5 min. The mixture was stirred at 0° C. for 1 h and then diluted with water (20 mL) and extracted with DCM (3×20 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4 and concentrated in vacuo to afford the 2,4-dichloro-6-hydroxypyridine (116 mg, 0.71 mmol, 92%) M.S. (ESI) (m/z) 164,166 [M+H]+.
Reaction SMILES: CS[C:3]1[N:8]=[CH:7][C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]=1.ClC1C=CC=C(C(OO)=O)C=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+].C(OCC)(=O)C>[C:26]1([NH:25][C:3]2[N:8]=[CH:7][C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cnc(SC)nc1
Reactant: Nc1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(Nc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
Ethyl 2-(methylthio)pyrimidine-5-carboxylate (0.800 g, 4.03 mmol) obtained in Step 1 was dissolved in dichloromethane (40 mL), and m-chloroperbenzoic acid (1.61 g, 6.06 mmol) was added to the solution, followed by stirring at room temperature for 1 hour. After the reaction mixture was diluted with dichloromethane, the dilute solution was washed with a saturated aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dioxane (20 mL), and the solution was added with aniline (0.730 mL, 8.01 mmol) followed by stirring at 90° C. for 6 hours. After the reaction mixture was diluted with an aqueous (+)-potassium sodium tartrate solution and ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3) to obtain ethyl 2-(phenylamino)pyrimidine-5-carboxylate (0.871 g, 89%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH2:12]1[C:17]2[NH:18][C:19]3[C:24]([C:16]=2[CH2:15][CH2:14][NH:13]1)=[CH:23][CH:22]=[CH:21][CH:20]=3.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH2:5]([O:4][C:2]([N:13]1[CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH2:12]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Benzyl chloroformate (1.8 ml, 12.6 mmol) was added to a solution of 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (1.72 g, 10.0 mmol) and sodium bicarbonate (1.85 g, 22.0 mmol) in dioxan (50 ml) at room temperature. The mixture was stirred at room temperature for 16 hours, concentrated in vacuo and the residue dissolved in water (50 ml). The aqueous mixture was extracted with chloroform (3×50 ml), and the combined extracts dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography on silica gel with hexane-ethyl acetate (3:2) as eluant. (3.07 g, 100%).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[C:16](=[O:17])[C:15]3[C:14](C(O)=O)=[CH:13][C:12]([O:21][CH3:22])=[CH:11][C:10]=3[C:9]2=[O:23])[CH2:6][CH2:5][C:4](=[O:24])[NH:3]1.[N-:25]=[N+]=[N-].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>C(N(CC)CC)C>[NH2:25][C:14]1[CH:13]=[C:12]([O:21][CH3:22])[CH:11]=[C:10]2[C:15]=1[C:16](=[O:17])[N:8]([CH:7]1[CH2:6][CH2:5][C:4](=[O:24])[NH:3][C:2]1=[O:1])[C:9]2=[O:23]
Reactant: COc1cc(C(=O)O)c2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: [N-]=[N+]=[N-]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(N)c2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O

Procedure:
reacting 2-(2,6-dioxo-piperidin-3-yl)-6-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindole-4-carboxylic acid with (a) an azide compound, in one embodiment, DPPA; in the presence of (b) a base, in one embodiment, an organic base, in another embodiment, triethylamine; to form 4-amino-2-(2,6-dioxo-piperidin-3-yl)-6-methoxy-isoindole-1,3-dione; and
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-:2].[CH3:8][O:9][C:10]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13]>>[CH3:8][O:9][C:10]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:11]=1[C:12]1[O:13][CH:2]=[N:1][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: [C-]#[N+]CC(=O)OC
Product: COC(=O)c1ncoc1-c1ccc([N+](=O)[O-])cc1OC

Procedure:
The procedures of Example 1-(1) were followed, except for replacing the ethyl isocyanoacetate with 9.9 g (0.1 mol) of methyl isocyanoacetate, to obtain 15.4 g (0.055 mol 61.5% based on the 2-methoxy-4-nitrobenzoic acid) of the title compound.