Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:4]([O:6][CH2:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)=[O:5].C(N(CC)CC)C.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[C:33]1([S:39]([NH:2][CH:3]([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[C:4]([O:6][CH2:7][C:8]2[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=2)=[O:5])(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(C)cc(COC(=O)C(N)Cc2c[nH]c3ccccc23)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(COC(=O)C(Cc2c[nH]c3ccccc23)NS(=O)(=O)c2ccccc2)c1
Reaction time: 0.25 h

Procedure:
3,5-Dimethylbenzyl 2-amino-3-(3-indolyl)propionate hydrochloride (1.0 g) was suspended in tetrahydrofuran (10 ml). Triethylamine (0.38 ml) was added and the solution was stirred for 15 mins. Benzenesulphonyl chloride (0.35 ml) was added and the solution was stirred at room temperature for 1 hour. Work-up as for Example 14 gave a solid which was recrystallised from ethanol to yield the title compound, 0.85 g, m.p. 114°-116° C. 1H NMR (360 MHz, CDCl3) δ7.98 (1H, s), 7.72 (2H, d, J=7 Hz), 7.54-7.30 (5H, m), 7.17 (1H, t, J=7 Hz), 7.06 (1H, t. J=7 Hz), 6.94 (1H, s), 6.89 (1H, s), 6.62 (2H, s), 5.17 (1H, d, J=9.2 Hz), 4.68 (2H, ABq, J=11.9 Hz), 4.33 (1H, m), 3.27 (2H, m), 2.27 (6H, s).
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C:12]1[C:19](=[O:20])[N:15]2[CH2:16][CH2:17][CH2:18][N:14]2[C:13]=1[NH2:21].[NH2:22][C:23]1[CH:24]=[C:25]([OH:31])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].N.OO>O.C(O)C>[NH2:21][C:13]1[N:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:20])[C:12]=1/[N:11]=[C:26]1/[C:25]([OH:31])=[CH:24][C:23](=[NH:22])[C:28]([O:29][CH3:30])=[CH:27]/1
Reactant: Nc1c(N)n2n(c1=O)CCC2
Reactant: COc1ccc(O)cc1N
Agent: CS(=O)(=O)O
Agent: N
Agent: OO
Solvent: CCO
Solvent: O
Product: COC1=C/C(=N\c2c(N)n3n(c2=O)CCC3)C(O)=CC1=N

Procedure:
0.05 mmol of 2,3-diamino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one dimethane sulfonate was dissolved in a mixture of water and ethanol (7.5 ml/1.5 ml). This solution was admixed with 0.05 mmol of 3-amino-4-methoxyphenol, then with 1.8 ml of concentrated aqueous ammonia, then with 9 ml of hydrogen peroxide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[NH:4][C@@H:5]([CH2:23][CH2:24]SC)[C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10]1)=[O:7].C(Cl)Cl.CI>CO>[CH3:1][O:2][C:3](=[O:27])[NH:4][C@H:5]1[CH2:23][CH2:24][N:8]([C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10]2)[C:6]1=[O:7]
Reactant: COC(=O)N[C@@H](CCSC)C(=O)N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Solvent: CI
Solvent: ClCCl
Solvent: CO
Product: COC(=O)N[C@H]1CCN([C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl[(2S)-1-({trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}amino)-4-(methylsulfanyl)-1-oxobutan-2-yl]carbamate (2.0 g), methylene chloride (20 mL) and methanol (20 mL) was added methyl iodide (15.5 mL), followed by stirring at room temperature overnight. The solvent was evaporated under reduced pressure, and to a mixture of the residue and dimethylformamide (10 mL) was added cesium carbonate (4.8 g), followed by stirring overnight. To the reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and then the solvent was evaporated under reduced pressure. To the residue was added ethanol, and the resulting solid was collected by filtration and dried under reduced pressure to obtain methyl[(3S)-1-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-2-oxopyrrolidin-3-yl]carbamate (0.65 g).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)C.[OH-].[Na+].C(O)C.O.Cl>O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:7]2[N:6]([CH2:5][C:4]([OH:22])=[O:3])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 111.2 %

Procedure:
A mixture of 14.6 g (0.04 mole) of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester, 2.9 g (0.073 mole) of sodium hydroxide pellets, and 150 ml of ethanol/water (1:1) was refluxed for 45 min. The reaction mixture was poured into a 250-ml of water, acidified with concentrated hydrochloric acid; and filtered, giving 12.8 g (97%) of a white solid. A 2-g portion was recrystallized from methanol-water to give 1.2 g of white needles, mp 271°-273° C. with decomposition.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH:20]([NH:23][CH3:24])([CH3:22])[CH3:21]>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:23]([CH:20]([CH3:22])[CH3:21])[CH3:24])[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: CNC(C)C
Solvent: CS(C)=O
Product: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl

Procedure:
The title compound was prepared from (4,5-dichloro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A20) (5.0 g, 16.3 mmol) and N-isopropyl-methylamine (5.95 g, 81.4 mmol) in DMSO (50 mL) at 75° C. according to the general procedure C. Obtained as a yellow solid (4.07 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:14])=[N:7]2.[Se](=O)=[O:16]>O1CCOCC1>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:14]=[O:16])=[N:7]2
Reactant: O=[Se]=O
Reactant: Cc1ccc2c(Cl)cc(Cl)c(O)c2n1
Solvent: C1COCCO1
Product: O=Cc1ccc2c(Cl)cc(Cl)c(O)c2n1
Temperature: 80 °C

Procedure:
A solution of 5,7-dichloro-2-methyl-quinolin-8-ol 16 (1.5 g, 6.58 mmol) in 1,4-dioxane (20 mL) was added dropwise over 3 h to a stirred suspension of selenium dioxide (1.3 g, 11.72 mmol) in 1,4-dioxane (60 mL) at 50-55° C. The resulting mixture was then heated at 80° C. overnight, cooled, and the solids filtered off (celite). The filtrate was concentrated and the residue, after washing with diethyl ether (10 mL×3), gave 17 as a yellow solid (quantitative yield). This material was used in the subsequent step without further purification. 1H NMR (CDCl3, 400 MHz): δ 10.26 (s, 1H), 8.69 (d, J=8.8, 1H), 8.37 (br, 1H), 8.17 (d, J=8.8, 1H), 7.76 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[C:9]([O:12][CH:13]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[CH2:14][NH:15][C:16]([C:18]1[C:23]([I:24])=[C:22]([NH2:25])[C:21]([I:26])=[C:20]([C:27]([NH:29][CH2:30][CH:31]([O:37][C:38](=[O:40])[CH3:39])[CH2:32][O:33][C:34](=[O:36])[CH3:35])=[O:28])[C:19]=1[I:41])=[O:17])(=[O:11])[CH3:10]>>[C:9]([O:12][CH:13]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[CH2:14][NH:15][C:16]([C:18]1[C:23]([I:24])=[C:22]([NH:25][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[C:21]([I:26])=[C:20]([C:27]([NH:29][CH2:30][CH:31]([O:37][C:38](=[O:40])[CH3:39])[CH2:32][O:33][C:34](=[O:36])[CH3:35])=[O:28])[C:19]=1[I:41])=[O:17])(=[O:11])[CH3:10]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Reactant: O=C(Cl)CCCCCl
Product: CC(=O)OCC(CNC(=O)c1c(I)c(NC(=O)CCCCCl)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Reaction time: 1 h
Yield: 97 %

Procedure:
5-Chloropentanoyl chloride (5.1 g, 33 mmol) was added dropwise to a stirred solution of N,N'-bis[2,3-bis(acetyloxy)propyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide (20.5 g, 23 mmol) in N,N'-dimethylacetamide (75 ml) at 0°-5°. The reaction mixture was stirred at 5° for 1 hour, and then at room temperature for 30 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (250 ml). The solution was washed with water (2×50 ml), followed by saturated aqueous NaCl (50 ml), and then dried over anhydrous sodium sulfate. Removal of the solvent in vacuo gave N,N'-bis[2,3-bis(acetyloxy)propyl]-5-[(5-chloro-1oxopentyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide as an off-white fluffy solid (22.1 g, yield 97%, purity 98.5%).
Reaction SMILES: [N:1]([C@H:4]1[C@:14]2([CH3:16])[O:15][C@@:6]3([C@H:17]4[C@H:10]([N:11]([C:19]5[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=5)[C:12](=[O:18])[C@@H:13]24)[O:9][CH2:8][CH2:7]3)[CH2:5]1)=[N+]=[N-].P(C)(C)C>C1COCC1>[NH2:1][C@H:4]1[C@:14]2([CH3:16])[O:15][C@@:6]3([C@H:17]4[C@H:10]([N:11]([C:19]5[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:28])([F:29])[F:30])[CH:20]=5)[C:12](=[O:18])[C@@H:13]24)[O:9][CH2:8][CH2:7]3)[CH2:5]1
Reactant: C[C@@]12O[C@]3(CCO[C@@H]4[C@H]3[C@H]1C(=O)N4c1ccc(C#N)c(C(F)(F)F)c1)C[C@H]2N=[N+]=[N-]
Agent: CP(C)C
Solvent: C1CCOC1
Product: C[C@@]12O[C@]3(CCO[C@@H]4[C@H]3[C@H]1C(=O)N4c1ccc(C#N)c(C(F)(F)F)c1)C[C@H]2N
Reaction time: 0.17 h
Yield: 90.9 %

Procedure:
To Example 12 (10.3 g, 0.0246 mol) in THF (50 mL) cooled in a water bath was added PMe3 (49 mL, 1M in THF). The mixture was stirred for 10 min then the solvent was removed in vacuo. The residue was dissolved in MeOH (30 mL) and 50% NaOH (0.7 mL, aq) was added. The mixture was stirred for 30 min and then concentrated in vacuo. To the residue was added water and brine and then extracted twice with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting solid was triturated with EtOAc/hexane (100 mL, 1:1) and filtered with EtOAc/hexane rinse, then dried to afford 8.8 g of Example 13.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)=[N:4][CH:3]=[N:2]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[O:1]1[C:5]([C:6]2[CH:13]=[CH:12][C:9](/[CH:10]=[CH:22]/[CH:23]=[O:24])=[CH:8][CH:7]=2)=[N:4][CH:3]=[N:2]1
Reactant: O=Cc1ccc(-c2ncno2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1ccc(-c2ncno2)cc1

Procedure:
The title compound is prepared by a procedure analogous to Reference Example 30 by substituting 4-(1,2,4-oxadiazol-5-yl)benzaldehyde (prepared as described in Reference Example 76) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 201 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[CH:8]=[C:7]2[NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[CH:21]1[C:26]([CH:27]=O)=[CH:25][C:24]2[O:29][CH2:30][O:31][C:23]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+]>>[Br:1][C:2]1[CH:3]=[C:4]([Cl:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[CH:8]=[C:7]2[NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:27][C:26]2[CH:21]=[CH:22][C:23]3[O:31][CH2:30][O:29][C:24]=3[CH:25]=2)[CH2:18][CH2:19]1
Reactant: O=c1cc(NC2CCNCC2)c2cc(Cl)cc(Br)c2o1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=c1cc(NC2CCN(Cc3ccc4c(c3)OCO4)CC2)c2cc(Cl)cc(Br)c2o1

Procedure:
8-bromo-6-chloro-4-(piperidin-4-ylamino)-chromen-2-one and piperonal were allowed to react under reductive alkylation conditions for 44 hours at room temperature, then treated with 1 M K2CO3, extracted with CH2Cl2, filtered through silica gel (5 g SepPak), rinsed with 95:5 CH2Cl2:MeOH, and concentrated. Purification by silica gel preparatory plate (0.25 mm×20 cm×20 cm) developed with 95:5 CH2Cl2:MeOH to give the title compound as a white solid (6 mg). 1H NMR (300 MHz, ppm, DMSO-d6) δ 1.6 (m, 2H), 1.9 (m, 2H), 2.1 (m, 2H), 2.8 (m, 2H), 3.4-3.5 (m, 3H), 5.33 (s, 1H), 5.99 (s, 2H), 6.77 (m, 1H), 6.85 (m, 2H), 7.38 (m, 1H), 8.05 (d, J=2 Hz, 1H), 8.36 (d, J=2 Hz, 1H). MS(ESI) 493 (M+H), 491 (M−H).
Reaction SMILES: C(O[C:6]1[C:7](=[O:18])[C:8](=[O:17])[C:9]=1[NH:10][CH:11]([CH3:16])[C:12]([CH3:15])([CH3:14])[CH3:13])CCC.[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23]>O1CCCC1>[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH2:22][NH:23][C:6]1[C:7](=[O:18])[C:8](=[O:17])[C:9]=1[NH:10][CH:11]([CH3:16])[C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: CCCCOc1c(NC(C)C(C)(C)C)c(=O)c1=O
Reactant: NCc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: CC(Nc1c(NCc2ccc(Cl)cc2Cl)c(=O)c1=O)C(C)(C)C
Yield: 28.8 %

Procedure:
Tetrahydrofuran (10 mL), 3-butoxy-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione (1.01 g, 3.99 mmol, Example 1) and 2,4-dichlorobenzylamine (0.70 g, 4.0 mmol) were stirred together at room temperature for 14 hours. Following removal of solvent, the residue was triturated with diethyl ether and dried. The off-white solid product was recrystallized twice from nitromethane to yield 0.408 g (29%) of the title compound as a white solid: mp 234°-235° C.; 1H NMR: (DMSO-d6): δ 7.67 (m, br, 1H), 7.65 (m, br, 1H), 7.48 (m, 2H), 7.32 (m, br, 1H), 4.80 (m, 2H), 3.90 (m, 1H), 1.10 (d, 3H), 0.86 (s, 9H) ppm. IR (KBr): 3140, 1790, 1640 cm-1 ; MS (m/z): 354/356/358. HPLC indicates a major component (99%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:12][C:11]([CH:13]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:10][CH:9]=2)=[N:5][CH:4]=1.Cl.C(N=C=N[CH2:36][CH2:37][CH2:38][N:39](C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.C1(N)CC1>CN(C)C=O.C(OCC)(=O)C>[CH:38]1([NH:39][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([CH:13]([C:11]3[NH:12][C:8]([C:6]4[S:7][C:3]([CH2:2][OH:1])=[CH:4][N:5]=4)=[CH:9][CH:10]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:29][CH:28]=2)[CH2:36][CH2:37]1
Reactant: O=C(O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ncc(CO)s3)[nH]2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NC1CC1)c1ccc(C(CC2CCOCC2)c2ccc(-c3ncc(CO)s3)[nH]2)cc1
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of 4-[1-{5-[5-(hydroxymethyl)-1,3-thiazol-2-yl]-1H-pyrrol-2-yl}-2-(tetrahydro-2H-pyran-4-yl)ethyl]benzoic acid (270 mg) in N,N-dimethylformamide (5 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140 mg), 1-hydroxybenzotriazole (100 mg) and N-methylmorpholine (215 μL), and the mixture was stirred for 1 hr. To the reaction mixture was added cyclopropylamine (50 μL), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid. The obtained aqueous layer was neutralized with 1M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (210 mg, yield 71%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate. MS: 452 (MH+).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.[CH2:14]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[OH:4][CH2:3][C:2]([NH:1][C:22](=[O:23])[O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:6])[CH3:5]
Reactant: CC(C)(N)CO
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(CO)NC(=O)OCc1ccccc1
Yield: 100 %

Procedure:
A solution of 2-amino-2-methylpropan-1-ol (1.0 g, 11.2 mmol), triethylamine (1.7 mL, 12.2 mmol) and N-(benzyloxycarbonyloxy)-succinimide (3.1 g, 12.4 mmol) in THF (100 mL) at 0° C. were reacted for 0.5 hours then at room temperature for an additional hour. The reaction was concentrated and extracted with ethyl acetate (100 mL). The organic extract was washed sequentially with water, brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with a gradient of ethyl acetate in dichloromethane (0-20%) to give the title compound as a colorless oil (2.5 g, quantitative).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([N:9]=[CH:10]N(C)C)=[C:4]([Cl:14])[N:3]=1.P([O-])([O-])([O-])=[O:16].[K+].[K+].[K+].OP([O-])(O)=O.[K+].P(=O)(O)(O)O>P(=O)(O)(O)O>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:10]=[O:16])=[C:4]([Cl:14])[N:3]=1
Reactant: CN(C)C=Nc1c(Cl)nc(N)nc1Cl
Reactant: O=P([O-])([O-])[O-]
Agent: O=P(O)(O)O
Agent: O=P([O-])(O)O
Agent: [K+]
Product: Nc1nc(Cl)c(NC=O)c(Cl)n1
Temperature: 125 °C
Yield: 68 %

Procedure:
A slurry of 2-amino-4,6-dichloro-5-{[(dimethylamino)methylene]amino}pyrimidine (Example 2, 1.50 g, 6.41 mmol) and 1.5 M aqueous potassium phosphate buffer (35 mL, prepared by adjusting the pH of a 1.5 M solution of KH2PO4 to 3.2 by addition of 85% phosphoric acid) was gently refluxed (in an oil bath at 125° C.). After 4 hours of reflux, the pH of the mixture was adjusted from 4 to 3 by addition of 4 drops of 85% phosphoric acid. After a total of 6 hours of reflux, TLC(silica gel plates developed in 5% methanolchloroform) showed that the starting material bad been largely converted to a lower-Rf product. The solid was filtered and washed with water (5 mL), methanol (5 mL), and dried to give the title compound as a white solid (0.900 g, 68%), m.p. >250° C. dec.; mass spectrum (CI/CH4): 209, 207 (M+1); 1H-NMR (DMSO-d6)δ: 9.81 and 9.46 (s and d, J=11 Hz, total 1, NH), 8.25 and 8.00 (s and d, J=11 Hz, total 1, CHO), 7.69 and 7.63 (both s, total 2, NH2).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2I)=[O:4].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C.Cl>Cl[Cu].O.C(OCC)(=O)C.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=1)=[O:4]
Reactant: COC(=O)c1ncc2c(I)cccc2c1O
Reactant: COc1ccc(O)cc1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ncc2c(Oc3ccc(OC)cc3)cccc2c1O
Reaction time: 0.25 h
Yield: 10.3 %

Procedure:
A mixture of 4-Hydroxy-8-iodo-isoquinoline-3-carboxylic acid methyl ester (7 mmol, 2.3 g), 4-methoxy-phenol (35 mmol, 4.39 g), Cs2CO3 (35 mmol, 11.42 g), 2,2,6,6-tetramethyl-heptane-3,5-dione (2.8 mmol, 0.59 mL), CuCl (7 mmol, 0.70 g), and anhydrous DMF (42 mL) was refluxed under nitrogen with stirring for 15 min. before it was poured into ethyl acetate (700 mL). Water (700 mL) and 5 N hydrochloric acid (5 mL) were added and the mixture was stirred for 15 min. The organic phase was then separated and washed with water (2×700 mL) before it was dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel using hexanes:EtOAc=75:25 as the eluent gave the title compound as a tan solid (234 mg); MS-(+)-ion: M+1=326.4.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C@H:7]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C@H:23]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[OH:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])[CH3:14])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(=O)=O>CO.[Pd]>[NH2:1][C@H:2]([C@H:7]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C@H:23]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[OH:24])[CH2:19][CH:20]([CH3:21])[CH3:22])=[O:16])[CH3:14])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: COC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C=O
Solvent: CO
Product: COC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@@H](N)CC(C)C

Procedure:
259 mg of Z-Sta-Ala-Sta-OMe (from stage 13.5) dissolved in 10 ml of 90% strength methanol are hydrogenated in the presence of 30 mg of palladium-on-carbon catalyst (10% Pd) at 25° under normal pressure with CO2 -absorption (CO2 from the removal of the Z-protecting group) until saturation. The catalyst is filtered off, the filtrate is concentrated by evaporation and the residue is dried in a high vacuum. H-Sta-Ala-Sta-OMe is obtained in the form of a colourless foam; Rf (chloroform/methanol/ammonia [40:10:1])=0.41; Rf (C)=0.29.
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[C:18]1[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][CH2:26][C:27](OCC)=O)[CH2:22][CH:23]=1>>[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[C:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][C:27]2[O:9][N:8]=[C:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=23)[CH2:20][CH:19]=1
Reactant: ON=C1CCCCCC1
Reactant: CCOC(=O)CCCN1CC=C(c2cccc(Cl)c2Cl)CC1
Product: Clc1cccc(C2=CCN(CCCc3onc4c3CCCCC4)CC2)c1Cl

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(2,3-dichlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate, 3-(3-(4-(2,3-dichlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [CH2:1]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4][NH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1)([O-:23])=[O:22]>CN(C=O)C>[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:3]2[CH2:2][CH2:1][C@@H:10]3[C@H:5]([CH2:6][CH2:7][C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=43)[CH2:4]2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: c1ccc2c(c1)CC[C@@H]1CNCC[C@@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CN2CC[C@H]3c4ccccc4CC[C@@H]3C2)cc1
Yield: 19.8 %

Procedure:
Following the procedure of Example 3, step 4, 0.153 g (0.815 mmol) of crude trans-1,2,3,4,4a, 5,6,10b-octahydrobenz[f]isoquinoline in 10 ml of anhydrous DMF was reacted with 0.124 g (0.897 mmol) of anhydrous potassium carbonate and 0.184 g (0.852 mmol) of 4-nitrobenzyl bromide. Chromatography on flash silica, eluting with 30-40% ethyl acetate/petroleum ether, gave 0.052 g (20%) of the title product as a white solid. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent and recrystallisation from ethanol/ethyl acetate/methanol, the title product hydrochloride was obtained as a white solid, m.p. 198°-201° C. NMR δ(D2O/CD3CN) 1.45-1.57 (1H, m), 1.61-1.74 (1H, m), 1.79-1.83 (2H, m), 2.60-2.69 (2H, m), 2.88-2.94 (3H, m), 3.20 (1H, t, of d), 3.44 (1H, m), 3.64 (1H, m), 4.44 (2H, d, J=2.9 Hz), 7.17-7.22 (3H, m), 7.26-7.28 (1H, m), 7.77 (2H, d, J=8.8 Hz), 8.34 (2H, d, J=8.8 Hz). m/z (CI+, NH3) 323 (M+H)+, 308 (M-O+H)+, 248, 211, 174, 133, 106. Analysis calcd. for C22H28ClN: C, 66.94; H, 6.46; N, 7.81%. Found: C, 66.83; H, 6.49; N, 7.81%.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:15]=[C:14](S(C)(=O)=O)[N:13]=2)=[CH:4][CH:3]=1.[CH2:25]([NH2:27])[CH3:26]>C(O)C>[CH2:25]([NH:27][C:14]1[N:13]=[C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([F:1])=[CH:3][CH:4]=2)[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:15]=1)[CH3:26]
Reactant: CCN
Reactant: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(S(C)(=O)=O)n1
Solvent: CCO
Product: CCNc1nc(-c2ccc(F)c3ccccc23)cc(C(C)C)n1
Reaction time: 6 h
Yield: 49 %

Procedure:
4-(4-fluoronaphth-1-yl)-6-isopropyl-2-methanesulfonylpyrimidine (0.100 g, 0.29 mmol) was added to a solution of ethylamine (0.33 mL, 5.8 mmol) in ethanol (1 mL). The reaction vessel was placed in a sonication bath for 6 hours at a bath temperature of 45° C. The ethanol was removed in vacuo leaving a viscous oil. The oil was crystallized from ethanol and water to give 2-ethylamino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine (49%), m.p. 77-78° C.