Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([N+:16]([O-])=O)[C:12]([O:14][CH3:15])=[CH:13][C:8]=2[CH2:7][N:6]([CH2:19][CH3:20])[CH2:5][C:4]1=[O:21])[CH3:2].C(O)C.C(OCC)(=O)C>[Pd]>[NH2:16][C:11]1[C:12]([O:14][CH3:15])=[CH:13][C:8]2[CH2:7][N:6]([CH2:19][CH3:20])[CH2:5][C:4](=[O:21])[N:3]([CH2:1][CH3:2])[C:9]=2[CH:10]=1
Reactant: CCN1CC(=O)N(CC)c2cc([N+](=O)[O-])c(OC)cc2C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCN1CC(=O)N(CC)c2cc(N)c(OC)cc2C1
Yield: 73.7 %

Procedure:
1,4-Diethyl-7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.50 g, 0.0017 mol) was hydrogenated in a solution of Ethanol (40 mL, 0.7 mol), Ethyl acetate (40 mL, 0.4 mol) and 10% Pd/C (10:90, Palladium:carbon black, 0.05 g) for 12 hrs. The reaction was filtered and the filtrate evaporated to give an oil. This was chromatographed on Alumina (12 g) and eluded with DCM/EtOH (20-1) to give 8-Amino-1,4-diethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one as an oil (0.33 g, 74%). LCMS (m/e) 264 (M+1); 1H-NMR (DMSO, 400 MHz) δ 6.76 (s, 1H), 6.61 (s, 1H), 5.75 (s, 1H), 4.86 (s, 2H), 3.77 (s, 3H), 3.72-70 (q, 2H, J=6.06 Hz), 3.38 (s, 2H), 2.89 (s, 2H), 1.05-01 (t, 3H, J=7.07 Hz).
Reaction SMILES: [Cl:1][CH:2]([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+:16]>O>[Cl:1][CH:2]([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O-:5])=[O:4].[Na+:16]
Reactant: O=C(O)C(Cl)COCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])C(Cl)COCc1ccccc1
Reaction time: 0.25 h

Procedure:
85 g of 2-chloro-3-benzyloxypropionic acid (0.396 mol) were suspended in 550 ml of water and neutralized to pH 7 with 10% sodium hydroxide. After stirring for 15 min, the resulting aqueous solution was washed with ethyl ether and evaporated to dryness under vacuum to give the desired compound.
Reaction SMILES: [C:1]([O:20][C@@H:21]1[C@@H:25]([CH2:26][O:27][C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:24][C@@H:23]([N:47]2[C:56]3[N:55]=[CH:54][N:53]([CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[C:51](=[O:52])[C:50]=3[N:49]=[CH:48]2)[C@@H:22]1[OH:64])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:72](Cl)([C:75]([F:78])([F:77])[F:76])(=[O:74])=[O:73]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([O:20][C@@H:21]1[C@@H:25]([CH2:26][O:27][C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:24][C@@H:23]([N:47]2[C:56]3[N:55]=[CH:54][N:53]([CH2:57][C:58]4[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=4)[C:51](=[O:52])[C:50]=3[N:49]=[CH:48]2)[C@@H:22]1[O:64][S:72]([C:75]([F:78])([F:77])[F:76])(=[O:74])=[O:73])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: O=c1c2ncn([C@@H]3O[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@@H](OC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]3O)c2ncn1Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1c2ncn([C@@H]3O[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@@H](OC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]3OS(=O)(=O)C(F)(F)F)c2ncn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a solution of 3',5'-di-O-trityl-1-benzylinosine (2.0 g, 2.4 mmol), 4-dimethylaminopyridine (290 mg, 2.4 mmol) and triethylamine (480 mg, 4.8 mmol) in methylene chloride (40 mL) is added triflyl chloride (800 mg, 4.8 mmol), and the mixture is stirred at room temperature for 1 hour, and then concentrated in vacuo. The residue is chromatographed on a silica gel column using a mixture of tetrachloromethane and ethyl acetate (5:1 v/v) as the eluent to give 3',5'-di-O-trityl-2'-O-triflyl-1-benzylinosine as a foam (1.82 g, 78% yield), 1H NMR (Me2SO-d6) δ 2.92-2.96 (2H, m, H-5',5"), 3.62-3.69 (1H, m, H-4'), 4.41-4.43 (1H, m, H-3'), 5.23 (2H, s, CH2Ph), 5.89-5.95 (1H, m, H-2'), 6.66 (1 H, d, H-1', J1',2' =6.3 Hz), 7.18-7.34 (35H, m, 2 x Tr and CH2Ph), 8.29, 8.32 (1H each, s, H-2, H-8). Analyses calculated for C56H45F3N4O5S: C, 68.98, H, 4.65, N, 5.63. Found: C, 68.94, H, 4.76, N, 5.63.
Reaction SMILES: C([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[C:13]2[CH:17]=[C:16]([CH3:18])[N:15]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:14]=12)C1C=CC=CC=1.C(N(CC)CC)C.[H][H]>CO.[Pd]>[CH2:19]([N:15]1[C:14]2[C:9](=[O:8])[NH:10][N:11]=[CH:12][C:13]=2[CH:17]=[C:16]1[CH3:18])[CH:20]([CH3:22])[CH3:21]
Reactant: Cc1cc2c(Cl)nnc(OCc3ccccc3)c2n1CC(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cc2cn[nH]c(=O)c2n1CC(C)C
Yield: 52 %

Procedure:
4.5 g (13.6 mmol) of 7-benzyloxy-4-chloro-1-isobutyl-2-methylpyrrolo[2,3-d]pyridazine (contaminated with about 40% of the isomeric 4-benzyloxy compound), 4 ml of triethylamine and 0.5 g of palladium (5%)/carbon catalyst are hydrogenated with hydrogen for 5 h in 500 ml of methanol. Purification: chromatography on silica gel (eluent: toluene/dioxane 4:1). Yield: 52%, m.p.: 188°-191° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:38])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][CH2:33]Br)[C:22]=1[CH2:35][CH2:36][CH3:37])[CH3:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.CN(C)C=O>[CH2:15]([O:17][C:18](=[O:38])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][CH2:33][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:22]=1[CH2:35][CH2:36][CH3:37])[CH3:16]
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCCBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2c(C(C)=O)ccc(OCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 68 %

Procedure:
A mixture of 1.17 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.41 g of 4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy acetic acid ethyl ester, 1.66 g of anhydrous potassium carbonate and 0.1 g of potassium iodide in 15 ml of anhydrous acetone and 15 ml of anhydrous dimethylformamide was stirred at reflux for 18 hours. The solvent was removed in vacuo, 50 ml of 0.1N hydrochloric acid was added to the residue and the product was extracted with methylene chloride. The dried, over sodium sulfate, extract was concentrated in vacuo and the crude product was crystallized from methanol to yield 2.1 g, mp 45°-46°, (68% yield) of [4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]acetic acid ethyl ester.
Reaction SMILES: Br[C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.C([Li])(C)(C)C.[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C>C1COCC1>[CH3:17][C:13]1[N:12]=[C:11]([C:3]2[C:2]([B:23]([OH:28])[OH:24])=[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][N:5]3[N:4]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cccc(-c2nn3ccccc3c2Br)n1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1cccc(-c2nn3ccccc3c2B(O)O)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-bromo-2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine (PREP. 17, 0.2 g, 0.69 mmol) in THF (10 mL) is cooled to −78° C. and treated with tert-butyllithium (1.7 M in pentane, 1.6 mL, 2.8 mmol). This solution is stirred for 30 minutes at −78° C., treated with triisopropyl borate (0.39 g, 2.08 mmol), and stirred for 2 hr at −78° C. The reaction is then quenched with 1N HCl and stirred for 30 minutes at room temp. Evaporation leads to the solid crude product that is used without further purification. MS ES+ m/e 253.9 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].CN(C=O)C.[OH-].[Na+].Cl>O>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(Cc1ccc(N)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 2-ethoxy-3-(4-nitrophenyl)acrylate containing 3.6 wt % DMF (26.07 g corrected, 98.3 mmol) was dissolved in IMS (500 ml) and a solution of NaOH (1.44 g, 36.1 mmol) in water (260 ml) was added. The resulting mixture was stirred at ambient temperature for 18 hr then acidified with 1M HCl (120 ml) and the resulting solid collected by filtration, washed with water (2×100 ml) and suction dried on the filter for 30 mins, followed by
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:14](O)=O)[C@H:10]([CH3:13])[O:11][CH3:12])=O)(C)(C)C.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([NH2:28])[CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:26]=[CH:25][C:24]2[NH:27][C:14]([C@H:9]([NH2:8])[C@@H:10]([O:11][CH3:12])[CH3:13])=[N:28][C:23]=2[CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CO[C@@H](C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Product: CO[C@@H](C)[C@@H](N)c1nc2cc(C(C)(C)C)ccc2[nH]1

Procedure:
The title compound was prepared according to Method 1 using N-(tert-butoxycarbonyl)-O-methyl-D-threonine and 4-tert-butyl-1,2-diaminobenzene. The residue was purified by elution through an SCX cartridge with MeOH followed by 2M NH3 in MeOH followed by silica gel column chromatography eluting with 90:10:1 DCM:MeOH:NH3.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:20]3[CH2:26][CH:25]4[NH:27][CH:22]([CH2:23][CH2:24]4)[CH2:21]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:44]1[CH:48]=[CH:47][C:46]([CH:49]=O)=[CH:45]1>C(Cl)Cl>[CH2:28]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:20]3[CH2:26][CH:25]4[N:27]([CH2:49][C:46]5[CH:47]=[CH:48][O:44][CH:45]=5)[CH:22]([CH2:23][CH2:24]4)[CH2:21]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:29]
Reactant: O=Cc1ccoc1
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2Cc1ccoc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.2 %

Procedure:
To a sample of compound 10a (0.65 g, 1.7 mmol) dissolved in 20 mL CH2Cl2 was added sodium triacetoxyborohydride (0.53 g, 2.5 mmol) and 3-furaldehyde (0.17 mL, 2.0 mmol). The reaction was stirred at room temperature for 24 h. The reaction was diluted with 10 mL CH2Cl2 and washed with 1 N NaOH. The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography, eluting with 5% 0.5 M NH3 in methanol/CH2Cl2 to give Compound 12a (0.25 g, 0.53 mmol). MS m/z=469.0 (M+1); 1H NMR 300 MHz (DMSO-d6) δ 1.1 (br s, 6H), 1.35 (m, 2H), 2.1 (m, 2H), 2.5 (m, 2H), 3.0 (m, 2H), 3.2 (m, 2H), 3.5 (m, 2H), 3.85 (br s, 2H), 4.05 (d, 2H), 6.8 (s, 1H), 7.1-7.5 (m, 7H), 7.8 (s, 1H), 7.9 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:17]([O:19]C)=[O:18])[N:8](C(OCC)=O)[CH2:9]2)=[CH:4][CH:3]=1>Cl>[ClH:1].[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:17]([OH:19])=[O:18])[NH:8][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1Cc2cc(Cl)ccc2CC1C(=O)OC
Agent: Cl
Product: O=C(O)C1Cc2ccc(Cl)cc2CN1
Temperature: 102.5 °C
Yield: 187.3 %

Procedure:
A mixture of 2-ethyl 3-methyl 7-chloro-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (2.19 g, 7.36 mmol) in 6 M aqueous HCl (30 mL) was heated to 100-105° C. for 2 days. The resulting mixture was concentrated under reduced pressure and triturated with toluene (2×100 mL). Once the supernatant was removed, the solid residue was dried under high vacuum to give 7-chloro-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride (1.71 g, 94%) as a faint yellow solid which was used in the next step without further purification. 1H NMR (DMSO-d6, 400 MHz) δ 14.2 (bs, ˜1 H), 10.0 (bs, ˜2 H), 7.41 (s, 1 H), 7.32 (m, 2 H), 4.40 (m, 1H), 4.32 (m, 2 H), 3.32 (dd, J=17, 4.9 Hz, 1 H), 3.10 (dd, J=17, 11 Hz). LC-MS gives ESI+MS found for C10H10ClNO2 m/z 212.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=1)[CH3:2].[I-].[NH2:16][N+:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=2)=[N:16][N:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=12)=[O:14])[CH3:2]
Reactant: CCOC(=O)C#Cc1cccc(C)n1
Reactant: N[n+]1ccccc1
Agent: [I-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1c(-c2cccc(C)n2)nn2ccccc12
Yield: 24.1 %

Procedure:
A solution of (6-methyl-pyridin-2-yl)-propynoic acid ethyl ester (0.62 g, 3.3 mmol) and 1-aminopyridinium iodide (0.8 g, 3.6 mmol) in acetonitrile (15 mL) is treated with DBU (0.5 mL, 3.3 mmol) and heated to reflux for 0.5 hours. The reaction is concentrated to a dark solid and purified by silica gel column chromatography (1:1 hexane/ethyl acetate) to afford 0.224 g (24%) of desired product as a yellow solid. MS ES+ m/e 282.2 (M+1). UV (95% EtOH) λmax 275 nm (ε 13005), 234 nm (ε 26550), 225 nm (ε 26057). TOF MS ES+ exact mass calculated for C11H11NO2 (p+1): m/z=282.1243. Found: 282.1244. Anal. Calcd for C16H15N3O2: C, 68.31; H, 5.37; N, 14.94. Found: C, 68.04; H, 5.28; N, 14.65.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl.[CH3:26][C:27]1[N:28]=[C:29]([CH3:56])[N:30]2[C:35]=1[C:34]([O:36][C:37]1[CH:42]=[C:41]([O:43][CH3:44])[C:40]([O:45][CH3:46])=[C:39]([O:47][CH3:48])[CH:38]=1)=[N:33][C:32]([C:49]1[CH:50]=[C:51]([CH:53]=[CH:54][CH:55]=1)[NH2:52])=[N:31]2>>[CH3:26][C:27]1[N:28]=[C:29]([CH3:56])[N:30]2[C:35]=1[C:34]([O:36][C:37]1[CH:38]=[C:39]([O:47][CH3:48])[C:40]([O:45][CH3:46])=[C:41]([O:43][CH3:44])[CH:42]=1)=[N:33][C:32]([C:49]1[CH:50]=[C:51]([NH:52][C:1](=[O:4])[CH3:2])[CH:53]=[CH:54][CH:55]=1)=[N:31]2
Reactant: CC(=O)O
Reactant: COc1cc(Oc2nc(-c3cccc(N)c3)nn3c(C)nc(C)c23)cc(OC)c1OC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: COc1cc(Oc2nc(-c3cccc(NC(C)=O)c3)nn3c(C)nc(C)c23)cc(OC)c1OC

Procedure:
14.25 mg (0.24 mmol) of acetic acid, 32.06 mg (0.24 mmol) of HOBt, 72.00 mg (0.71 mmol) of 4-methylmorpholine, 50.03 mg (0.26 mmol) of EDC and 100 mg (0.24 mmol) of 3-[5,7-dimethyl-4-(3,4,5-trimethoxyphenoxy)imidazo[5,1-f][1,2,4]-triazin-2-yl]aniline from example 6 are reacted analogously to example 2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].C1C=C(Cl)C=C(C(OO)=[O:17])C=1>ClCCl>[CH3:1][C:2]1[CH:3]=[N+:4]([O-:17])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccncc1C
Solvent: ClCCl
Product: Cc1cc[n+]([O-])cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
To a solution of 3,4-dimethylpyridine (100.0 g, 0.93 mol) in dichloromethane was added m-CPBA (320.0 g, 1.87 mol) at the room temperature. The reaction mixture was stirred at room temperature overnight, and then quenched with saturated solution of Na2S2O3 (100 mL). The organic layer was separated and the aqueous phase was extracted with CH2Cl2 (300 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated under vacuum to yield a residue that was purified by column chromatography on silica gel (10-100% MeOH in EtOAc) to give 3,4-dimethylpyridine 1-oxide (70.0 g, 61%).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][C:12](=[O:14])[CH:11]=[CH:10][N:9]1C(OCC1C=CC=CC=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd].[Ni]>[CH2:1]([C@@H:8]1[CH2:13][C@H:12]([OH:14])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=CN(C(=O)OCc2ccccc2)C(Cc2ccccc2)C1
Agent: [Ni]
Agent: [Pd]
Solvent: CO
Product: O[C@@H]1CCN[C@H](Cc2ccccc2)C1

Procedure:
150 g (0.467 mol) of 2-benzyl-N-benzyloxycarbonyl-2,3-dihydro-4-(1H)-pyridone in 1.5 l of methanol are hydrogenated with 7.5 g of Pd/C (10% ) as catalyst, then 50 g of Raney nickel and a further 200 ml of methanol are added, and hydrogenation is left to go to completion. Filtration is followed by evaporation in a rotary evaporator, and the brownish oil is chromatographed on silica gel with methylene chloride/methanol/conc. ammonia (60:10:1). The title compound is obtained as a semi-crystalline mass which is used further without additional purification. Crystallisation of a sample from ether/hexane yielded white crystals of melting point 111°-112°. TLC: methylene chloride/methanol/conc. ammonia (40:10:1) Rf =0.55, FD-MS: M+ =191.
Reaction SMILES: Cl.[F:2][C:3]([F:10])([F:9])[CH2:4][C:5]([NH2:8])([CH3:7])[CH3:6].[N-:11]([C:14]#[N:15])[C:12]#[N:13].[Na+]>C(O)CCC>[C:12]([NH:11][C:14]([NH:8][C:5]([CH3:7])([CH3:6])[CH2:4][C:3]([F:10])([F:9])[F:2])=[NH:15])#[N:13]
Reactant: CC(C)(N)CC(F)(F)F
Reactant: N#C[N-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CC(C)(CC(F)(F)F)NC(=N)NC#N
Yield: 82.3 %

Procedure:
A mixture of 3,3,3-trifluoro-1,1-dimethylpropylamine hydrochloride (2.67 g, 15 mol), sodium dicyanamide (1.34 g, 15 mmol), and n-butanol (7.5 ml) was sealed in vacuo in a Pyrex ampoule and was heated at 105° for 119 h to give, after solvent removal, a residue (2.87 g) which was crushed and stirred with water (7 ml), then filtered and washed with water, then dried to give a solid (2.57 g) with m.p. 153° (shrinks 145°). The solid was dissolved in methanol (25 ml) then filtered to remove what is presumed to be polymeric dicyanamide (0.06 g). Removal of solvent and drying gave the guanidine (2.35 g) m.p. 153°-4°.
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:13][C:12]1=[O:23])C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[OH:8][CH2:9][CH2:10][N:11]1[CH2:16][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][CH2:13][C:12]1=[O:23]
Reactant: O=c1ccc(-c2ccccc2)cn1CCOCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C1CCC(c2ccccc2)CN1CCO

Procedure:
A solution of 1-(2-(benzyloxy)ethyl)-5-phenylpyridin-2(1 H)-one (100 mg, 327 μmol) in MeOH (10 mL) was sparged with argon for 10 min. A portion of palladium hydroxide (46 mg, 327 μmol) was added and the reaction was subjected to 55 psi hydrogen in a Parr shaker for 1 hr. The mixture was filtered through a pad of Celite, and concentrated to a white solid under reduced pressure. MS (ESI pos. ion) m/z (MH+): 220. Calc'd exact mass for C13H17NO2: 219. 1H NMR (400 MHz, Chloroform-d) δ ppm 2.00-2.14 (m, 2 H) 2.46-2.67 (m, 2 H) 3.07-3.18 (m, 1H) 3.33 (br. s., 1 H) 3.42-3.56 (m, 3 H) 3.60-3.68 (m, 1 H) 3.83 (t, J=4.89 Hz, 2H) 7.21-7.30 (m, 3 H) 7.35 (t, J=7.24 Hz, 2 H). 13C NMR (101 MHz, Chloroform-d) δ ppm 27.75, 31.9, 40.37, 51.24, 55.88, 61.79, 126.99, 127.30, 128.85, 141.51, 171.78.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][OH:7])=[O:5])[CH3:3].CO.[CH3:10][C:11]([CH:13]=O)=O.[OH-].[Na+]>O>[CH3:3][C:2]1[N:1]=[C:11]([CH3:13])[CH:10]=[N+:6]([O-:7])[C:4]=1[OH:5]
Reactant: CC(=O)C=O
Reactant: C[C@H](N)C(=O)NO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c[n+]([O-])c(O)c(C)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 3.6 %

Procedure:
407 mmol (42.4 g) alanine hydroxamic acid were cooled to −10° C. in 200 ml water and methanol each, 400 mmol (57 ml 40% solution) methylglyoxal were added dropwise and subsequently the pH was adjusted to approximately pH 11 with 19 ml 30% NaOH. Heating up to 0° C. was carried out within 2 h and then pH 3 was adjusted with 20% NaOH. The solution was concentrated until dryness under vacuum distillation, the residue was heated to reflux with 50 ml ethanol, after cooling filtering was carried out and the filtrate again concentrated until dryness. 44 g of the solid residue were dissolved in 50 ml water and 15 mmol (4.06 g) FeCl3*6H2O were added, heated up to 50° C. for 30 minutes, concentrated and stored at 5° C. for 4 h. The precipitated solid was filtered off and dried. 3.7 g solid in 50 ml water and 10 ml ethanol were adjusted to pH 11 with 6 ml 1 M NaOH, stirred over night and centrifugalized. The supernatant was decanted, pH 3 was adjusted with 3 ml 1 M HCl and concentrated until dryness. 4.2 g solid were refluxed in 20 ml ethanol, cooled and filtered off. The filtrate was again concentrated until dryness and the obtained 2.8 g solid were suspended with 10 ml water, heated up to 50° C. and left for cooling over night. The suspension was centrifugalized, the supernatant decanted and concentrated until dryness. 2.0 g (3.5% yield) of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH:34]=O)=[CH:4][N:3]=1.[CH3:36][NH:37][NH2:38]>O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([CH:32]2[N:37]([CH3:36])[N:38]=[CH:34][CH2:33]2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(/C=C/C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CNN
Solvent: O
Product: COc1cc(-c2csc3c(C4CC=NN4C)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
N-(4-{4-amino-7-[(1E)-3-oxoprop-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (0.10 g, 0.207 mmol) was stirred with methyl hydrazine (0.5 mL) at ambient temperature for 3 hours then water (8 mL) was added and the white precipitate was collected by filtration and dried to give the title compound. Rt=3.62 min (Conditions a) MS m/e: 511 (M+H)+, 509 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].[C:51](=O)([O-])[O-].[K+].[K+].IC>>[OH:24][C@H:22]1[C@:21]2([O:25][CH3:26])[C@@:8]([OH:45])([C:9](=[O:44])[C:10]3[C:19]([C:20]2=[O:27])=[C:18]([OH:28])[C:17]2[C:16](=[O:29])[CH:15]=[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)[C:13](=[O:43])[C:12]=2[CH:11]=3)[C:7]2[C:2]([O:1][CH3:51])=[C:3]([C:47]([O:49][CH3:50])=[O:48])[C:4]([CH3:46])=[CH:5][C:6]=2[CH2:23]1
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COC(=O)c1c(C)cc2c(c1OC)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Yield: 48.2 %

Procedure:
Following General Procedure: Method A using (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (25 mg, 0.035 mmol), potassium carbonate (15 mg, 0.11 mmol) and iodomethane (7 μL, 0.11 mmol), the product was purified by preparative TLC (silica gel, 95:5 dichloromethane/methanol) to afford (6R,6aS,14aR)-methyl 6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-1,6a-dimethoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (12 mg, 48%) as a brown solid: 1H NMR (500 MHz, CDCl3) δ 14.15 (s, 1H), 8.11 (s, 1H), 6.84 (d, J=9.0 Hz, 1H), 6.81 (s, 1H), 5.88 (s, 1H), 5.04 (br s, 1H), 4.96 (dd, J=10.3, 6.6 Hz, 1H), 4.69 (d, J=8.9 Hz, 1H), 4.54 (d, J=10.6 Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.74-3.71 (m, 1H), 3.69 (dd, J=3.1, 1.2 Hz, 1H), 3.60 (s, 3H), 3.59 (s, 3H), 3.61-3.56 (m, 1H), 3.40 (s, 3H), 3.39-3.33 (m, 2H), 3.12 (t, J=9.2 Hz, 1H), 2.47 (d, J=4.6 Hz, 1H), 2.18 (s, 3H), 1.36 (d, J=6.2 Hz, 3H); MS (ESI+) m/z 712 (M+H); HPLC 95.9% (AUC), tR 12.66 min.