Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-:15].[K+].II.[OH-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O>[Cl:1][C:2]1[C:7]([I:15])=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1
Reactant: [I-]
Reactant: Nc1ccnc(Cl)c1
Agent: II
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Solvent: O
Product: Nc1ccnc(Cl)c1I
Temperature: 100 °C
Reaction time: 12 h
Yield: 19.6 %

Procedure:
Commercially available 2-chloro-4-aminopyridine (15 g, 0.1 mol) and 37.2 g (0.4 mol) of sodium carbonate are suspended in 200 ml of water and warmed to 100° C. 58.3 g (0.4 mol) of potassium iodide and 59.4 g (0.2 mol) of iodine are added to the resultant solution, and the mixture is stirred at the temperature indicated for 12 h. The mixture is subsequently adjusted to pH 13 using sodium hydroxide solution, treated with sodium thiosulfate until completely decolorised and extracted with ethyl acetate. Chromatographic purification gives 5 g (17%) of solid.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[CH3:19])[O:9][C:8]=1[CH3:20])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[O:9][C:8]([CH3:20])=[C:7]([CH:2]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:26][CH:27]=3)[CH2:3][CH:4]([CH3:6])[CH3:5])[CH:11]=2)=[C:13]([CH3:19])[CH:14]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: Cc1cc(F)ccc1-c1cc(C(Cl)CC(C)C)c(C)o1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(F)ccc1-c1cc(C(CC(C)C)Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)c(C)o1
Temperature: 80 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
A mixture of 3-(1-chloro-3-methylbutyl)-5-(4-fluoro-2-methylphenyl)-2-methylfuran (442 mg), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (451 mg), sodium carbonate (191 mg) and sodium iodide (270 mg) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 50% ethyl acetate/hexane). To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.0 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (188 mg, 26%).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>CN(C1C=CN=CC=1)C.C1COCC1>[I:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH:8][C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: NCCc1ccc(I)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)NCCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3.00 g (12.1 mmol) 4-iodophenethylamine and 0.37 g (3.03 mmol) DMAP in 50 mL THF are cooled down to 0° C. 4.95 g (48.5 mmol) acetic anhydride are added and, after removing of the cooling bath, the reaction mixture is stirred for 5 h at r.t. The reaction mixture is quenched in ice cold water and extracted with EtOAc. The organic layer is dried with Na2SO4 and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, DCM/MeOH 98.5/1.5).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][NH:35]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2].[CH:40](=O)[CH:41]([CH3:43])[CH3:42]>>[C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][N:35]4[CH2:40][CH:41]([CH3:43])[CH3:42])=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)C4CCCCN4)ncn3)cccc2s1
Reactant: CC(C)C=O
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)C4CCCCN4CC(C)C)ncn3)cccc2s1

Procedure:
N-(2-(6-(2-Acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)piperidine-2-carboxamide, Example 49(a), (0.50 g, 0.90 mmol) was reacted with isobutyraldehyde (0.16 mL, 1.8 mmol, Aldrich) under the conditions of Example 3(d) to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 613 (M+1). Mp: 153.4-154.9° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:19]Cl)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1.[NH2:21][C:22]1[N:27]=[C:26]([CH:28]2[CH2:32][CH2:31][CH2:30][N:29]2[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:19][NH:21][C:22]3[N:27]=[C:26]([CH:28]4[CH2:32][CH2:31][CH2:30][N:29]4[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:25]=[CH:24][N:23]=3)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccnc(N)n1
Reactant: Fc1ccc(-c2nc3ccc(Cl)cn3c2CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCC1c1ccnc(NCc2c(-c3ccc(F)cc3)nc3ccc(Cl)cn23)n1
Temperature: 60 °C
Yield: 54 %

Procedure:
To a solution of 6-chloro-3-(chloromethyl)-2-(4-fluorophenyl)imidazo[1,2-a]pyridine hydrochloride (100 mg, 0.35 mmol) in acetonitrile (25 mL) was added tert-butyl 2-(2-aminopyrimidin-4-yl)pyrrolidine-1-carboxylate (prepared according to the procedures described in WO 2007/09117 A1)(190 mg, 0.71 mmol) and freshly ground potassium carbonate (150 mg, 1.1 mmol) and the reaction mixture was heated to 60° C. for 16 h. After this time the reaction mixture was cooled to room temperature, diluted with ethyl acetate (20 mL) and washed with brine (2×20 mL). The organic layer was separated, dried over Na2SO4, concentrated and purified by column chromatography (methanol/methylene chloride) to afford the desired product. (0.10 g, 54% yield). M/e+ 523.1 for C27H28ClFN6O2 (M+H)+, 1H-NMR (500 MHz, CDCl3, δ) 8.45 (d, J=1.0 Hz, 1H), 8.28 (s, 1H), 7.77-7.74 (m, 2H), 7.58 (d, J=9.5 Hz, 1H), 7.20-7.15 (m, 3H), 6.55 (d, J=5.0 Hz, 1H), 5.18 (s, 1H), 5.07-5.01 (m, 2H), 4.62 (s, 1H), 3.61-3.52 (m, 2H), 2.34 (m, 1H), 1.98-1.94 (m, 1H), 1.91-1.86 (m, 2H), 1.26 (s, 9H) and signals due to a minor tautomer (ca. 44%): 4.77 (d, J=5.0 Hz), 1.46 (s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]2[C:38]([CH3:40])([CH3:39])[CH2:37][C:36]3[C:31](=[C:32]([C:42]([OH:44])=[O:43])[CH:33]=[C:34]([Cl:41])[CH:35]=3)[NH:30]2)[CH:26]=[CH:27][CH:28]=1>CN(C)C=O>[Cl:41][C:34]1[CH:35]=[C:36]2[C:31](=[C:32]([C:42]([OH:44])=[O:43])[CH:33]=1)[NH:30][CH:29]([C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([NH:22][C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[O:9])[CH:24]=1)[C:38]([CH3:40])([CH3:39])[CH2:37]2
Reactant: CC1(C)Cc2cc(Cl)cc(C(=O)O)c2NC1c1cccc(N)c1
Reactant: O=C(O)c1cnccn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(Cl)cc(C(=O)O)c2NC1c1cccc(NC(=O)c2cnccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.7 %

Procedure:
A solution of pyrazine-2-carboxylic acid (0.412 g, 3.3 mmol) and 1,1′-carbonyldiimidazole (0.7 g, 4.3 mmol) in N,N-dimethylformamide (10 mL) was stirred at 70° C. for 1 h. A solution of 2-(3-amino-phenyl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (0.75 g, 2.3 mmol) in N,N-dimethylformamide (5 mL) was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 6-chloro-3,3-dimethyl-2-{3-[(pyrazine-2-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (228 mg, 15%) as a light yellow solid: LC/MS m/e calcd for C23H21ClN4O3 (M+H)+: 437.90, observed: 437.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:15][NH:16][C:17]3[C:18]([CH3:32])=[C:19]([CH:28]=[CH:29][C:30]=3[CH3:31])[O:20][CH2:21][C:22]([O:24]C(C)C)=[O:23])[CH:11]=[C:12]([CH3:14])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[Li+].[OH-]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:15][NH:16][C:17]3[C:18]([CH3:32])=[C:19]([CH:28]=[CH:29][C:30]=3[CH3:31])[O:20][CH2:21][C:22]([OH:24])=[O:23])[CH:11]=[C:12]([CH3:14])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(CNc2c(C)ccc(OCC(=O)OC(C)C)c2C)cc(-c2cccc(F)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(CNc2c(C)ccc(OCC(=O)O)c2C)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
To a solution of isopropyl 2-[3-[[3-(3-fluorophenyl)-5-methyl-phenyl]methylamino]-2,4-dimethyl-phenoxy]acetate (114 mg, 0.26 mmol, 1.0 eq) in THF (10 mL) at 0° C. was added LiOH (2M aqueous solution, 4 mL, 8 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The THF was removed under reduced pressure and the aqueous solution that remained was diluted with water and adjusted to pH 4-6 by the addition of dilute HCl. The solid precipitate that formed was collected by filtration, washed with water and dried in vacuo to give title compound as a yellow solid (70 mg, 68%).
Reaction SMILES: [CH3:1][C:2]1([CH2:16][CH2:17][CH2:18][OH:19])[C:7]2=[C:8]([CH3:15])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4][O:3]1.CS(C)=O.C1C=CC=CC=1.FC(F)(F)C(O)=O.C(O)(=O)C(O)=O>O.CO.CCOCC.N1C=CC=CC=1>[CH3:1][C:2]1([CH2:16][CH2:17][CH:18]=[O:19])[C:7]2=[C:8]([CH3:15])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4][O:3]1
Reactant: Cc1c2n(c3ccccc13)CCOC2(C)CCCO
Agent: O=C(O)C(=O)O
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: Cc1c2n(c3ccccc13)CCOC2(C)CCC=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
N,N-Dicyclohexylcarbodiimide (2.87 g.) is added to a cooled, stirred solution of the primary alcohol, 1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-propanol (1.0 g.), described in Example 462, in 10 ml. of dimethyl sulfoxide-benzene (2:1) containing trifluoroacetic acid (0.18 ml.) and pyridine (0.38 ml.). The reaction is stirred at room temperature under nitrogen for 5 hr. The reaction mixture is now diluted with 100 ml. of ether, followed by the dropwise addition of a solution of oxalic acid (1.26 g.) in 6 ml. of methanol. After thirty minutes, water (100 ml.) is added and the insoluble material is collected. The organic phase is washed with water (2X), 5% aqueous sodium bicarbonate (2X) and water (2X). After drying (MgSO4) the organic phase is evaporated to yield an oil. The oil is purified by chromatography on silica gel. Elution with 10% ether in benzene affords the title compound as an oil, γCHCl3Max 1720 cm-1.
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:13])[C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.C[O:15][C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[N:3]=[N+:4]([O-:13])[C:5]3[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:20][CH:19]=1)([OH:17])=[O:15]
Reactant: [O-][n+]1nc(Cl)nc2ccc(O)cc21
Reactant: COC(=O)c1ccc(B(O)O)cc1
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: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2nc3ccc(O)cc3[n+]([O-])n2)cc1

Procedure:
3-chloro-7-hydroxybenzo[e][1,2,4]triazine 1-oxide (2 mmol) was mixed with 1.0 equivalent of 4-(methoxycarbonyl)phenylboronic acid and 2 equivalents of K2CO3 in 20 ml of 50% dioxane/water. A catalytic amount of Pd(PPh3)4 was added and the mixture was heated to reflux for 2 hours. The reaction was concentrated and re-dissolved in 20 ml water and 5 ml 1N NaOH was added to hydrolyze the ester. The mixture was extracted with DCM (3×10 ml). The aqueous layer was filtered and the filtrate was neutralized with 1N HCl to pH=5. The precipitate was filtered and washed with water and dried. 500 mg of product was obtained. 1H NMR (DMSO-d6 400 MHz): δ 11.38 (s, 1H), 8.44 (d, 2H), 8.15 (m, 3H), 7.67 (d, 1H), 7.60 (s, 1H). MS (ESI): m/z 284.5 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:15][CH:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)[C:4]=2[C:5]([N:8]=CN(C)C)=[N:6][CH:7]=1.[C:37]1([S:43](Cl)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[NH2:8][C:5]1[C:4]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)=[CH:14][S:15][C:3]=2[C:2]([NH:1][S:43]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:45])=[O:44])=[CH:7][N:6]=1
Reactant: COc1cc(-c2csc3c(N)cnc(N=CN(C)C)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: O=S(=O)(Cl)c1ccccc1
Product: COc1cc(-c2csc3c(NS(=O)(=O)c4ccccc4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using N-[4-(7-amino-4-{[(dimethylamino)methylene]amino}thieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide and phenylsulfonyl chloride using General Procedure G followed by General Procedure M. 1H NMR (DMSO-d6, 400 MHz) δ 9.80 (br, 1H), 9.49 (s, 1H), 7.97 (d, 1H), 7.75 (d, 2H), 7.70 (d, 1H), 7.64 (d, 1H), 7.58 (m, 3H), 7.51 (s, 1H), 7.34 (m, 2H), 7.17 (m, 2H), 7.15 (s, 1H), 7.05 (d, 1H), 5.50 (br, 2H), 4.03 (s, 3H), 3.90 (s, 3H); MS: (MH)+ 584.
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.CS(C)=O.[CH2:17]([N:19]1[C:25](=[O:26])[C:24]([CH3:28])([CH3:27])[C:23](=[O:29])[N:22]([CH3:30])[C:21]2[CH:31]=[C:32]([CH2:35][N:36]([CH2:50][C:51]3[C:52]([CH2:57][OH:58])=[N:53][CH:54]=[CH:55][CH:56]=3)[CH2:37][CH2:38][N:39]3[CH:44]=[CH:43][C:42]4[O:45][C:46]([CH3:48])=[CH:47][C:41]=4[C:40]3=[O:49])[CH:33]=[CH:34][C:20]1=2)[CH3:18]>O>[CH2:17]([N:19]1[C:25](=[O:26])[C:24]([CH3:28])([CH3:27])[C:23](=[O:29])[N:22]([CH3:30])[C:21]2[CH:31]=[C:32]([CH2:35][N:36]([CH2:50][C:51]3[C:52]([CH:57]=[O:58])=[N:53][CH:54]=[CH:55][CH:56]=3)[CH2:37][CH2:38][N:39]3[CH:44]=[CH:43][C:42]4[O:45][C:46]([CH3:48])=[CH:47][C:41]=4[C:40]3=[O:49])[CH:33]=[CH:34][C:20]1=2)[CH3:18]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3cccnc3CO)ccc21
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: O
Solvent: CS(C)=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3cccnc3C=O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
2-iodoxybenzoic acid (IBX, 0.235 g) was added to the dimethyl sulfoxide suspension (10 mL) of 1-ethyl-7-((N-((2-(hydroxymethyl)pyridin-3-yl)methyl)-N-(2-(2-methyl-4-oxofuro[3,2-c]pyridin-5(4H)-yl)ethyl)amino)methyl)-3,3,5-trimethyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione (0.48 g) and the mixture was stirred overnight at room temperature. Water was added to the resulting mixture and then the mixture was extracted with ethyl acetate twice. The combined organic layer was concentrated under reduced pressure, and then the residue was purified by column-chromatography (ethyl acetate: hexanes=50:50→100:0). The purified product was recrystallized from ether to afford the titled compound as ivory powder (0.29 g).
Reaction SMILES: [C:1]([N:8]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3Cl)[C@H:11]([OH:25])[C@@H:10]1[OH:26])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClC1N=C2C(N=CN2[C@@H]2C[C@H](N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)C=C2)=C([NH:64][CH2:65][CH:66]([C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)N=1>>[Cl:24][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@@H:12]2[CH2:13][C@H:9]([N:8]([C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C@@H:10]([OH:26])[C@H:11]2[OH:25])=[C:19]([NH:64][CH2:65][CH:66]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[N:18]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)C1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to (1S,2R,3S,5R)-3-(di-Boc-amino)-5-(2,6-dichloro-purin-9-yl)-cyclopentane-1,2-diol by replacing di-Boc-[(1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl]-amine with {2-chloro-9-[(1R,4S)-4-(di-Boc-amino)-cyclopent-2-enyl]-9H-purin-6-yl}-(2,2-diphenyl-ethyl)-amine.
Reaction SMILES: [CH3:1][N:2]([CH2:36][C:37]([O:39]C)=[O:38])[C:3]([CH:5]1[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])([OH:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:22])[CH:11]=2)[N:6]1[S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1)(=[O:25])=[O:24])=[O:4].O.[OH-].[Na+].S([O-])(O)(=O)=O.[K+]>CO.[OH-].[Na+]>[CH3:1][N:2]([CH2:36][C:37]([OH:39])=[O:38])[C:3]([CH:5]1[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])([OH:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:22])[CH:11]=2)[N:6]1[S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1)(=[O:24])=[O:25])=[O:4]
Reactant: COC(=O)CN(C)C(=O)C1N(S(=O)(=O)c2ccc(OC)c(OC)c2)c2ccc(Br)cc2C1(O)c1ccccc1F
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(S(=O)(=O)N2c3ccc(Br)cc3C(O)(c3ccccc3F)C2C(=O)N(C)CC(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
200 mg of the compound prepared in Example 1a are dissolved in 3 ml of MeOH and 1 ml of water containing 13 mg of sodium hydroxide. After stirring for 24 hours at RT, one drop of concentrated sodium hydroxide solution is added to bring the reaction to an end and then, after 15 minutes, the mixture is acidified to pH 3 by addition of a potassium hydrogensulfate solution. Water is added, the mixture is extracted with AcOEt and the extract is washed with water and dried over magnesium sulfate and the solvent is evaporated under vacuum. The product obtained is recrystallized from DCM/isopropyl ether.
Reaction SMILES: [CH3:1][CH:2]1[CH:27]2[O:28][C:26]2([CH3:29])[CH:25]([O:30]C(CC(C)C)=O)[CH2:24][C:22](=[O:23])[N:21]([CH3:37])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:38])=[CH:9][CH:8]=[CH:7][CH:6]([O:39][CH3:40])[C:5]2([OH:45])[NH:41][C:42]([O:44][CH:3]1[CH2:4]2)=[O:43].Cl.[Al]>C(OCC)(=O)C.O.O1CCCC1>[CH3:1][CH:2]1[CH:27]2[O:28][C:26]2([CH3:29])[CH:25]([OH:30])[CH2:24][C:22](=[O:23])[N:21]([CH3:37])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:38])=[CH:9][CH:8]=[CH:7][CH:6]([O:39][CH3:40])[C:5]2([OH:45])[NH:41][C:42]([O:44][CH:3]1[CH2:4]2)=[O:43]
Reactant: COc1cc2cc(c1Cl)N(C)C(=O)CC(OC(=O)CC(C)C)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)C=CC=C(C)C2
Agent: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)/C=C/C=C(\C)C2
Agent: Cl
Agent: [Al]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)C=CC=C(C)C2
Temperature: -42 °C
Reaction time: 0.17 h

Procedure:
This example describes reduction of ansamitocins with LiAl(OMe)3H using water followed by aqueous HCl. Ansamitocins (200 mg, 0.32 mmol) were weighed into a 25 mL round bottomed flask. Tetrahydrofuran (1.0 mL) was added to the flask with stirring, and the flask was cooled in a −42° C. cooling bath. After 10 min, a solution of 0.67 M LiAl(OMe)3H in tetrahydrofuran (3.8 mL, 2.52 mmol) was added dropwise by syringe. The bath temperature was maintained between −34° C. and −42° C. throughout the addition. After addition was complete, the reaction was stirred for 2 hours at between −32° C. and −37° C. 1 mL of deionized water was added dropwise to the reaction. After a 30 min holding period, 2 mL of 3 M HCl and 10 mL of ethyl acetate were quickly added to the flask. The cooling unit was turned off, and most of the aluminum byproducts went into solution. The contents were transferred to a separatory funnel and mixed well. The organic layer was retained and washed with 2 mL of saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, and solvent was removed by rotary evaporation. The residue was purified by silica chromatography using a mobile phase of dichloromethane:methanol 95:5 (v:v) to give 117 mg of maytansinol (66% yield by weight).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[C:15]([CH:20]=O)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[N+:22]([CH3:25])([O-:24])=[O:23].Cl.CN.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[C:15]([CH:20]=[CH:25][N+:22]([O-:24])=[O:23])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(C=O)c3c2c1C
Agent: CN
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)c1ncc2[nH]c3cccc(C=C[N+](=O)[O-])c3c2c1C
Reaction time: 120 h

Procedure:
A solution of 5-formyl-4-methyl-beta-carboline-3-carboxylic acid ethyl ester (10 g), nitromethane (2 ml) and methylamine hydrochloride (0.2 g) in ethanol (50 ml) is mixed with sodium carbonate (0.3 g) and left for 5 days at 20° C. with occasional shaking. Then it is evaporated to beginning crystallization. 5 g of the title compound crystallizers from the solution cooled with ice water.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:11][CH:10]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:11][CH:10]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1CC1c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)C1CC1c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.4 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer was charged with 20 mL of dichloromethane. To the stirred solvent was added ethyl 2-(4-methoxyphenyl)cyclopropanecarboxylate (0.9 g, 4 mmol). The reaction mixture was cooled to 0° C. and boron tribromide (0.9 mL) was added drop wise, stirred for 30 minutes at the same temperature. The reaction mixture was quenched by the addition of ethanol drop wise at 0° C. The reaction mixture was concentrated to distill off the solvent; water was added to the crude and extracted with ethyl acetate. The organic layer was washed with saturated solution of NaHCO3 (25 mL), followed by brine solution (25 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as pale yellow liquid (0.3 g, yield: 35.6%). 1H NMR (300 MHz, DMSO-d6): δ 9.27 (s, 1H), 6.94-6.97 (d, 2H), 6.64-6.67 (d, 2H), 4.05-4.12 (q, 2H), 2.28-2.36 (m, 1H), 1.75-1.80 (m, 1H), 1.35-1.41 (m, 2H), 1.15-1.28 (t, 3H).