Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20](=[O:31])[C@H:21]([C:27]([CH3:30])([CH3:29])[CH3:28])[NH:22][C:23]([O:25][CH3:26])=[O:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:9][CH:8]=1.[CH3:40][O:41][C:42]([NH:44][C@@H:45]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:46](O)=[O:47])=[O:43].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:40][O:41][C:42](=[O:43])[NH:44][C@@H:45]([C:49]([CH3:51])([CH3:50])[CH3:52])[C:46](=[O:47])[NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:9][CH:8]=1)[NH:19][C:20](=[O:31])[C@H:21]([C:27]([CH3:30])([CH3:29])[CH3:28])[NH:22][C:23](=[O:24])[O:25][CH3:26]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2cccnc2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2cccnc2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.8 %

Procedure:
To a solution containing the product from Example 148E (0.17 mmol) in tetrahydrofuran (1.7 mL) were added the product from Example 1F (0.036 g, 0.190 mmol), DEPBT (0.077 g, 0.258 mmol), and N,N-diisopropylethylamine (0.15 mL, 0.861 mmol) and the mixture was stirred at room temperature for 18 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic was washed with additional 10% Na2CO3 solution and then brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on reverse phase HPLC on C18 column eluting with a gradient starting with water and ending with methanol to give the product (0.044 g, 37% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80 (s, 9 H), 0.82 (s, 9 H), 1.42-1.59 (m, 2 H), 2.67-2.79 (m, 3 H), 3.47 (s, 3 H), 3.59-3.67 (m, 1 H), 3.81 (d, J=9.6 Hz, 1 H), 3.91 (d, J=9.6 Hz, 1 H), 4.02-4.21 (m, 2 H), 4.87 (d, J=5.2 Hz, 1 H), 6.65 (d, J=9.6 Hz, 1 H), 6.80 (d, J=9.9 Hz, 1 H), 7.12-7.23 (m, 8 H), 7.45-7.55 (m, 4 H), 7.80 (d, J=8.5 Hz, 1 H), 8.01 (d, J=8.1 Hz, 1 H), 8.54 (d, J=4.8 Hz, 1 H), 8.83 (d, J=1.8 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].[CH3:21][NH2:22].CO>>[NH2:1][C:2]1[N:10]=[C:9]([NH:22][CH3:21])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Yield: 83 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) and 40% methylamine/methanol solution (50 ml) were heated at 120° C. for 20 hours in autoclave. The reaction mixture was condensed in vacuo. To the residue was added 5N aqueous sodium hydroxide and the solution was extracted with chloroform. The organic layer was dried on sodium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (163 mg, yield 83%).
Reaction SMILES: [N:1]([C@H:4]([CH3:30])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:18](=[O:19])[C:17]2[NH:16][C:15]([CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:14][C:13]=2[N:12]([CH3:29])[C:10]1=[O:11])=[N+]=[N-].[H][H]>C(O)C.[Pd]>[NH2:1][C@H:4]([CH3:30])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:18](=[O:19])[C:17]2[NH:16][C:15]([CH2:20][NH:21][C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[N:14][C:13]=2[N:12]([CH3:29])[C:10]1=[O:11]
Reactant: C[C@H](CCCCn1c(=O)c2[nH]c(CNC(=O)OC(C)(C)C)nc2n(C)c1=O)N=[N+]=[N-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](N)CCCCn1c(=O)c2[nH]c(CNC(=O)OC(C)(C)C)nc2n(C)c1=O
Yield: 79.2 %

Procedure:
To a solution of (R)-1-(5-azidohexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine (0.7 g, 1.6 mmol) in ethanol (40 ml) was added 10% palladium on carbon catalyst (0.3 g). The mixture was treated with hydrogen gas (50 psi) on a Parr shaker for 18 hours. Removal of the catalyst by filtration and evaporation of the solvent under reduced pressure provided (R)-1-(5-aminohexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine (0.5 g, 77% yield) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH2:4][OH:5].Br[C:12]([CH3:17])([CH3:16])[C:13](=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[OH:5][CH2:4][C:3]1[CH:6]=[C:7]([I:10])[CH:8]=[CH:9][C:2]=1[O:1][C:12]([CH3:17])([CH3:16])[C:13](=[O:15])[CH3:14]
Reactant: CC(=O)C(C)(C)Br
Reactant: OCc1cc(I)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)C(C)(C)Oc1ccc(I)cc1CO
Yield: 104.5 %

Procedure:
A mixture containing 2-hydroxy-5-iodobenzyl alcohol (0.63 g, 0.00252 mol), 3-bromo-3-methyl-2-butanone (0.42 g, 0.00254 mol) and potassium carbonate (0.42 g, 0.00377 mol) in methyl ethyl ketone (7 ml) was heated at reflux for three hours. Then a further equivalent of 3-bromo-3-methyl-2-butanone (0.42 g, 0.00254 mol) was added. After heating at reflux for three hours, the cooled mixture was washed successively with water and aqueous sodium hydroxide solution, then extracted with ethyl acetate. The organic layer was evaporated to afford 0.88 g (100%) of crude 3-(2-hydroxymethyl-4-iodophenoxy)-3-methyl-2-butanone.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1>C1COCC1.O>[CH3:1][S:2][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a solution of sodium thiomethoxide in THF (53 mL) and H2O (20 mL) cooled to 0° C. was added 2-chloro-5-nitropyridine (LXV) (5.09 g, 32.09 mmol). The reaction was warmed to room temperature and stirred for 2 hrs. The reaction was poured into ice water and stirred for 10 minutes, filtered, washed with water, dried under vacuum to yield 2-(methylthio)-5-nitropyridine (CVII) as a yellow solid (5.14 g, 30.20 mmol, 94.1%). 1H NMR (DMSO-d6) δ ppm 2.62 (s, 3H), 7.57 (d, J=8.9 Hz, 1H), 8.38 (d, J=8.9 Hz, 1H), 9.22 (d, J=2.7 Hz, 1H); ESIMS found for C6H6N2O2S m/z 171.1 (M+H).
Reaction SMILES: CS[C:3]1[S:4][CH2:5][CH2:6][CH2:7][N:8]=1.[N+:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])([O-:11])=[O:10].CS>[Cl-].[Zn+2].[Cl-].CCOCC.C(O)(C)C>[N+:9]([C:12](=[C:3]1[NH:8][CH2:7][CH2:6][CH2:5][S:4]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])([O-:11])=[O:10]
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: CSC1=NCCCS1
Agent: CS
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)O
Solvent: CCOCC
Product: CCOC(=O)C(=C1NCCCS1)[N+](=O)[O-]
Reaction time: 1.25 h

Procedure:
To a mixture of 235 g of 5,6-dihydro-2-(methylthio)-4H-1,3-thiazine (A. F. McKay et al., J. Am. Chem. Soc., 80, 3339 (1958)) and 2 g of zinc chloride at approximately 115° in a nitrogen atmosphere, 263 g of ethyl nitroacetate (S. Zen, et al., Kogyo Kagaku Zasshi, 74, 70 (1971)) was added dropwise over a 1.5 hour period. The mixture was held at 110°-120°. When evolution of methyl mercaptan ceased after 45 minutes further stirring of the heated mixture, 1 g of zinc chloride was added and the mixture was stirred at about 115° for 1.25 hours. An additional 1 g of zinc chloride then was added and stirring of the mixture at about 115° was continued for 1.5 hours. The mixture then was poured into a cooled solution of 2/1 (volume) ether/isopropyl alcohol mixture. The crystallized product was collected, washed with ether and dried under reduced pressure to leave a tan solid, m.p. 100° -102°, which on recrystallization from methanol gave ethyl nitro(tetrahydro-2H-1,3-thiazin-2-ylidene)acetate (1A) as a pale yellow solid, m.p. 105° -106°.
Reaction SMILES: Cl.C([N:4]1[CH2:13][CH2:12][C@@:11]2(C3C=CC=C(OC)C=3)[C@@H:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)[CH2:5]1)C.C[N:24](C)[C:25](=O)[C:26](=NNC1C=CC=CC=1)[C:27](=O)C.CC(O[Na])=O>[Zn].C(O)(=O)C>[CH3:27][C:26]1[C:8]2[CH2:7][CH:6]3[CH:11]([CH2:12][CH2:13][NH:4][CH2:5]3)[CH2:10][C:9]=2[NH:24][CH:25]=1
Reactant: CCN1CC[C@]2(c3cccc(OC)c3)CC(=O)CC[C@H]2C1
Reactant: CC(=O)C(=NNc1ccccc1)C(=O)N(C)C
Agent: CC(=O)O[Na]
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1c[nH]c2c1CC1CNCCC1C2
Yield: 84.8 %

Procedure:
1.0 g (3.1 mmol) of (±)-trans-2-ethyl-4a-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline hydrochloride, 2.33 g (10 mmol) of N, N-dimethyl-2-phenylhydrazono-3-oxobutyramide, 0.82 g (1 0 mmol) of CH3COONa, 2.6 g (40 mmol) of zinc dust and 5 ml of glacial acetic acid were treated as described in example 1. The residue was purified by chromatography on silica gel (EtOAc/MeOH 0%→30%) yielding 0.5 g of product which was crystallized from Et2O yielding 0.5 g of the title compound. M.p.=151°-153° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]1>>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])=[CH:6][N:5]=[C:4]([NH:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]2)[N:3]=1
Reactant: CCS(=O)c1ncc(C(=O)c2cc(F)c(C)cc2OC)c(N)n1
Reactant: CC(=O)N1CCC(N)CC1
Product: COc1cc(C)c(F)cc1C(=O)c1cnc(NC2CCN(C(C)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-4-methyl-phenyl)-methanone (Example 341) and 1-(4-amino-piperidin-1-yl)-ethanone to give 1-[4-[4-amino-5-(5-fluoro-2-methoxy-4-methyl-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone as a white solid. MS (M+H)+, 402.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl.[NH:37]1[CH2:42][CH2:41][O:40][CH:39]([C:43]([OH:45])=[O:44])[CH2:38]1>C(Cl)Cl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:37]3[CH2:42][CH2:41][O:40][CH:39]([C:43]([OH:45])=[O:44])[CH2:38]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Reactant: O=C(O)C1CNCCO1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCOC(C(=O)O)C3)ccc2n1CC1CCC(F)(F)CC1
Yield: 75.1 %

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (1.6 g, 4 mmol), N,N-diisopropylethylamine (3.5 mL, 20 mmol) and morpholine-2-carboxylic acid hydrochloride (1.0 g, 6 mmol) in methylene chloride (10 mL). Obtained 1.5 g of crude product which was carried over to step A. 1H NMR (400 MHz, METHANOL-D4) δ 1.53 (d, J=13.67 Hz, 2 H), 1.59 (s, 12 H), 1.63-1.78 (m, 6 H), 1.98-2.12 (m, 3 H), 3.22 (q, J=7.36 Hz, 1 H), 3.72 (m, 1 H), 4.42 (d, J=7.42 Hz, 2 H), 7.69 (d, J=8.40 Hz, 1 H), 7.81 (d, J=8.40 Hz, 1 H), 8.05 (s, 1 H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(C(C)C)C(C)C)C>ClCCl.Cl>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:8])=[CH:5][CH:4]=1
Reactant: C1CCNC1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(CCl)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-chloromethylbenzoyl chloride (5.0 g) and pyrrolidine (2.2 mL) in dichloromethane (30 mL) at 0° C. was treated with ethyldiisopropylamine (5.2 mL). The resulting mixture was warmed to room temperature over 1 hour and then stirred at this temperature for 2 hours. The mixture was diluted with 1.0 M aqueous hydrochloric acid, extracted with dichloromethane and the combined extracts washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound, 6.0 g.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16]C)=[O:15])[CH:12]=2)[NH:7][C:6]=1[CH3:18].C(O)C.[OH-].[Na+].Cl>O>[C:14]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:18])=[C:5]2[CH2:4][C:3]1[CH:19]=[CH:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:22][C:2]=1[Cl:1])([OH:16])=[O:15]
Reactant: COC(=O)c1ccc2[nH]c(C)c(Cc3ccc(-c4ccccc4)cc3Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1[nH]c2ccc(C(=O)O)cc2c1Cc1ccc(-c2ccccc2)cc1Cl
Yield: 76.5 %

Procedure:
To 3-(2-chloro-4-phenylbenzyl)-5-methoxycarbonyl-2-methylindole (0.95 g), added are ethanol (5 ml), water (5 ml) and aqueous sodium hydroxide (0.29 g), and refluxed for 3 hours. The reaction mixture is cooled, and neutralized with HCl. This is extracted with ethyl acetate and water, and the organic layer is dried and concentrated. The resulting residue is crystallized from a small amount of a mixed solution of chloroform and ether. The crystal is taken out through filtration and dried to obtain 5-carboxy-3-(2-chloro-4-phenylbenzyl)-2-methylindole (145) (0.701 g)
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][CH2:10][CH2:9][C:8]12[O:16][CH2:15][CH2:14][O:13]1.[CH2:17]([Li])CCC.CI>O1CCCC1>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]([CH3:17])[CH2:10][CH2:9][C:8]12[O:16][CH2:15][CH2:14][O:13]1
Reactant: [Li]CCCC
Reactant: OCc1cccc2c1NCCC21OCCO1
Solvent: C1CCOC1
Solvent: CI
Product: CN1CCC2(OCCO2)c2cccc(CO)c21
Reaction time: 0.5 h

Procedure:
To a solution of 8-hydroxymethyl-4,4-ethylenedioxy1,2,3,4-tetrahydroquinoline (2.5 g) in tetrahydrofuran (30 ml) was added n-butyllithium (14.5 to 17% solution in n-hexane) (10 ml) at --40° C. and stirred for 30 minutes. Then methyl iodide (1.9 g) was added to the reaction mixture and the mixture was stirred for 3 hours at -30° C. to -10° C. and for 30 minutes at -5° C. After distilling off the solvent, n-hexane-ethyl acetate was added to the resulting residue and the insoluble matter was filtered off. The filtrate was concentrated to give 8-hydroxymethyl-4,4-ethylenedioxy-1-methyl-1,2,3,4-tetrahydroquinoline (1.9 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=4)=[CH:13][C:12]3=[O:27])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][CH2:31][CH2:32][C:3]1=2.CO.C(Cl)[Cl:43].Cl>C(OCC)C>[ClH:43].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][N:18]=4)=[CH:13][C:12]3=[O:27])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:28][NH:29][CH2:30][CH2:31][CH2:32][C:3]1=2
Reactant: ClCCl
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)cc31)CNCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of tert-butyl 6-methyl-8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (80 mg, 0.20 mmol) in 5:1 MeOH/CH2Cl2 (6.0 mL) was treated with anhydrous 1.0 M HCl in diethyl ether (32 mL), and the resulting suspension was stirred at ambient temperature for 1 h. The solids were collected by filtration, washed with Et2O and dried to yield the title compound (58 mg, 85%) as a yellow powder: mp 264-270° C. decomp.; 1H NMR (500 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.89 (s, 2H), 8.39 (dd, J=8.5, 2.0 Hz, 1H), 8.34 (d, J=8.0 Hz, 1H), 7.83 (d, J=7.5 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.28 (d, J=1.5 Hz, 1H), 7.11 (dd, J=8.0, 1.5 Hz, 1H), 7.07 (d, J=7.5, 2.0 Hz, 1H), 4.47 (s, 2H), 3.74 (s, 3H), 3.47-3.45 (m, 2H), 3.11 (t, J=5.0 Hz, 2H), 2.08-2.06 (m, 2H); ESI MS m/z 439 [M+H]+; HPLC (Method A) 95.1% (AUC), tR=14.7 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:10]=1[CH2:11][N:12]([C:15]1[N:20]=[N:19][C:18]([C:21](N)=[O:22])=[CH:17][CH:16]=1)[CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C([OH:34])(C)C.C(O)=O>O>[CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:10]=1[CH2:11][N:12]([C:15]1[N:20]=[N:19][C:18]([C:21]([OH:22])=[O:34])=[CH:17][CH:16]=1)[CH2:13][CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)O
Reactant: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(N)=O)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(=O)O)nn1
Temperature: 70 °C
Yield: 97.2 %

Procedure:
A mixture of 6-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylamino]pyridazine-3-carboxamide (61.7 g), sodium hydroxide (28 g) and isopropanol (400 ml) was heated at reflux for 1 hour. The mixture was cooled to 70° C. and water (800 ml) was added over 30 minutes. The mixture was acidified to pH 3-4 with a solution of formic acid (41.5 ml) in water (200 ml) over 30 minutes, at 25°-30° C. The mixture was cooled to 10° C., the produce filtered off, washed with water and dried to give 6-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylamino]pyridazine-3-carboxylic acid (60.2 g, 97.2% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][CH2:13]O)[CH:6]=[C:7]2[O:11][CH2:10][O:9][C:8]=12.P(Br)(Br)[Br:16].O.C(=O)([O-])O.[Na+]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][CH2:13][Br:16])[CH:6]=[C:7]2[O:11][CH2:10][O:9][C:8]=12
Reactant: BrP(Br)Br
Reactant: COc1cc(CCO)cc2c1OCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COc1cc(CCBr)cc2c1OCO2
Yield: 122.1 %

Procedure:
2.74 g (14 mmol) of 2-(3-methoxy-4,5-methylenedioxyphenyl)ethyl alcohol (3) was dissolved in 10 ml of ethyl ether, to which was added portionwise 1.64 g (6.1 mmol) of phosphorus tribromide in 2 ml of ethyl ether under ice-cooling. The mixture was refluxed under heating for one hour, then cooled and further stirred while adding 10 ml of water and 15 ml of a saturated sodium hydrogencarbonate aqueous solution. The reaction mixture was separated and the ether layer was washed with 10 ml of a saturated saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica column chromatography (eluate: ethyl acetate / n-hexane=1/2) to obtain 1.93 g of 2-(3-methoxy-4,5-methylenedioxyphenyl)ethyl bromide (6) as a crystal with a yield of 53%. Melting point: 78°-79° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][C:17]([Br:20])=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][NH:8][CH:7]=1)=[O:5])[CH3:2].[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][C:17]([Br:20])=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccc(Br)cc21
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccc(Br)cc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using 9-bromo-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester and 4-fluorobenzoyl chloride; 1H-NMR (CDCl3): δ 10.56 (1H, s), 7.98 (1H, s), 7.56 (3H, m), 7.19 (1H, m), 7.09 (2H, m), 4.17 (4H, m), 3.13 (2H, m), 1.13 (3H, t). MS (ESI): 457, 459 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.[NH2:48][C:49]1[C:58]2[C:53](=[CH:54][CH:55]=[C:56]([O:59][Si:60]([C:73]([CH3:76])([CH3:75])[CH3:74])([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[CH:57]=2)[CH:52]=[CH:51][CH:50]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:10])[C:11]([NH:48][C:49]1[C:58]2[C:53](=[CH:54][CH:55]=[C:56]([O:59][Si:60]([C:73]([CH3:76])([CH3:75])[CH3:74])([C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)[C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)[CH:57]=2)[CH:52]=[CH:51][CH:50]=1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)[Si](Oc1ccc2cccc(N)c2c1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccc2ccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reaction time: 3 h

Procedure:
To (R)-N-(tert-butoxycarbonyl)alanine (220 mg, 1.16 mmol) in dry CH2Cl2 (2 mL) under argon were added PYBOP (604 mg, 1.16 mmol), 1-amino-7-(tert-butyldiphenylsilyloxy)naphthalene hydrochloride, as described above in Step C, (250 mg, 0.58 mmol), and N,N-diisopropylethylamine (0.40 mL, 2.3 mmol). The reaction mixture was stirred for 3 hrs, then partitioned between CH2Cl2 (250 mL) and 10% aqueous citric acid (75 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with CH2Cl2-20% ethyl acetate to yield the desired product as a white foam.
Reaction SMILES: [CH3:1][C:2]1[NH:16][CH2:15][CH2:14][C:4]2=[C:5]3[C:10](=[N:11][C:3]=12)[CH:9]=[CH:8][C:7]([O:12][CH3:13])=[CH:6]3.[C:17](OC(=O)C)(=[O:19])[CH3:18].C(OCC)(=O)C>N1C=CC=CC=1>[CH2:1]=[C:2]1[C:3]2[NH:11][C:10]3[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][CH:9]=3)[C:4]=2[CH2:14][CH2:15][N:16]1[C:17](=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)=C1CCNC(C)=C1N=2
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=C1c2[nH]c3ccc(OC)cc3c2CCN1C(C)=O

Procedure:
To a solution of 10-methoxyharmalan (1 mmol) in pyridine (2 ml) is added acetic anhydride (1.1 eq) . After acid hydrolysis and extraction with ethyl acetate, the crude product is flash-chromatographed (eluent: EtOAc/pet. ether; 50/50). The 1-methylene-2-acetyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline elutes off first.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].Cl.[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[O:25][CH:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH:22]3[NH2:35])=[N:16][CH:17]=1)([O-:11])=[O:10].N1C=CC=CC=1>CN(C=O)C>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[O:25][CH:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH:22]3[NH:35][C:1](=[O:3])[CH3:2])=[N:16][CH:17]=1)([O-:11])=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: NC1CC(c2ccccc2)Oc2ccc(Oc3ccc([N+](=O)[O-])cn3)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)NC1CC(c2ccccc2)Oc2ccc(Oc3ccc([N+](=O)[O-])cn3)cc21
Temperature: 0 °C
Reaction time: 20 h

Procedure:
Acetic anhydride (60 μl) was added into a cooled solution of 6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-ylamine hydrochloride (100 mg) and pyridine (41 μl) in dry DMF. Resulting mixture was stirred for a further 20 hours at 0° C. Reaction was quenched with ice water and neutralised. Resulting mixture was extracted with dichloromethane, dried with Na2SO4 and evaporated. Mixture of diastereomers of N-[6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-yl]-acetamide was recrystallised from dichloromethane. (M)+=405 (24%), 301 (14%), 259 (100%), 242 (55%), 224 (96%).