Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.[OH-].[Na+].[Cl:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:26]=[CH2:27])[CH:25]=1>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][CH2:26][C:24]3[CH:23]=[N:22][CH:21]=[C:20]([Cl:19])[CH:25]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Reactant: C=Cc1cncc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCc2c(n(CCc3cncc(Cl)c3)c3ccc(Cl)cc23)CC1
Temperature: 60 °C
Yield: 3.2 %

Procedure:
The title compound was prepared by following general procedure 4. To a solution of 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.42 mmol) in 50% aq. NaOH solution (5 mL) tetra n-butyl ammonium chloride (9 mg, 0.03 mmol) followed by 3-chloro-5-vinylpyridine (65 mg, 0.47 mmol) was added. The reaction mixture was heated at 60° C. for 8 h. After completion of reaction, the reaction mixture was diluted with water, extracted with ethyl acetate; the organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography to afford 5 mg of 9-chloro-6-(2-(5-chloropyridin-3-yl)ethyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole as the TFA salt.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH:4]([C:9]1[CH:10]=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH:12]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[CH:36](=O)[CH2:37][CH:38]([CH3:40])[CH3:39]>>[CH3:1][O:2][C:3](=[O:35])[CH:4]([C:9]1[CH:10]=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH:12]=[C:13]([N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)[CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)CC=O
Reactant: COC(=O)C(CC(C)C)c1cc(NCc2ccc(C#N)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: COC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N(CCC(C)C)Cc2ccc(C#N)cc2)c1

Procedure:
Following the procedure of Example 39, step (a), reaction of 2-[5-(4-Cyano-benzylamino)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid methyl ester, compound 47a with isovaleraldehyde gave the title compound; Calcd. MW 550.67. Found MH+ 551.4.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([OH:11])=[CH:6][N:5]=1.[CH3:12]I.O>CN(C=O)C>[Cl:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([O:11][CH3:12])=[CH:6][N:5]=1
Reactant: Cc1cc(O)cnc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cnc(Cl)c(C)c1
Yield: 101.5 %

Procedure:
Into a flame dried flask under N2 was placed DMF (150 mL), NaH (50% oil dispersion, 4.0 g, 0.08 mol) and 2-chloro-5-hydroxy-3-methylpyridine (11.7 g, 0.08 mol). The solution was stirred at 0°-5° C. until the evolution of H2 ceased and then a solution of CH3I (5.6 mL, 0.09 mol) in DMF (50 mL) was added dropwise. After the addition, the solution was allowed to stir at room temperature overnight. The resulting slurry was added to H2O and extracted with Et2O (3X). The organic layer was concentrated and the residue distilled at 85° C. (0.6 mm) to yield 12.8 g of 2-chloro-5-methoxy-3-methylpyridine (95%) as an oil; 1H NMR (CDCl3) δ 2.35 (3H, s), 3.8 (3H, s), 7.1 (1H, d, J=3) and 7.9 (1H, d, J=3 ); MS m/e (M+) 157.
Reaction SMILES: CS(O[CH:6]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][CH2:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12](=[O:25])[CH2:11][CH2:10]1)(=O)=O.CN(C)C=O.[Cl-:36].[Li+]>O>[Cl:36][CH:6]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][CH2:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12](=[O:25])[CH2:11][CH2:10]1
Reactant: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)OS(C)(=O)=O
Reactant: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCC(Cl)CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC

Procedure:
A solution of 1.35 g. of ethyl 15-methanesulfonyloxy 9-oxo-prostanoate (Example 90) in 40 ml. of N,N-dimethylformamide containing 650 mg. of lithium chloride is heated on the steam bath for 18 hours. The cooled solution is diluted with water and the resulting mixture is extracted with ether. The ether extract is washed with saline, dried with saline, dried with anhydrous magnesium sulfate and evaporated to dryness to give an oil. Chromatography on silica gel affords an oil; λ max. 5.78 μ (carbonyl groups).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([O:23][CH3:24])=[C:7]([O:21][CH3:22])[CH:8]=2)[N:3]=1.[F-:25].[K+]>CC(N(C)C)=O>[F:25][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([O:23][CH3:24])=[C:7]([O:21][CH3:22])[CH:8]=2)[N:3]=1
Reactant: [F-]
Reactant: COc1cc2nc(Cl)nc(-c3ccc(C(C)C)cc3)c2cc1OC
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2nc(F)nc(-c3ccc(C(C)C)cc3)c2cc1OC
Yield: 33.3 %

Procedure:
A solution of 80 mg (0.23 mmol) 2-chloro-4-(4-isopropyl-phenyl)-6,7-dimethoxy-quinazoline and 100 mg (1.70 mmol) KF in 1 ml dimethylacetamide is stirred at 90° C. for 5 days. After extraction (ethyl acetate/brine) the organic layer is dried and evaporated. Flash-chromatography (hexane/ethyl acetate) yields 25 mg (33%) of the product as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][CH3:27])[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:15]([O:17]C)=[O:16])=[CH:12][C:13]([CH3:14])=[C:8]2[N:7]=[C:6]1[CH3:19].[OH-].[Na+].Cl.O>O1CCOCC1>[Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][CH3:27])[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:15]([OH:17])=[O:16])=[CH:12][C:13]([CH3:14])=[C:8]2[N:7]=[C:6]1[CH3:19]
Reactant: CCCOc1ccc(Cn2c(C)nc3c(C)cc(C(=O)OC)nc32)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCOc1ccc(Cn2c(C)nc3c(C)cc(C(=O)O)nc32)c(Cl)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a suspension of methyl 3-(2-chloro-4-(1-propoxy)benzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (475 mg) in 1,4-dioxane was added 1N aqueous sodium hydroxide solution, and the mixture was heated to 60° C. and stirred for 30 min. It was air cooled and adjusted to pH 4 by dropwise addition of 1N hydrochloric acid. Water (25 ml) was added and the mixture was stirred at room temperature. The precipitated crystals were collected by filtration and dried under reduced pressure at 60° C. Thereto was added acetonitrile (3 ml) and the mixture was heated and stirred at room temperature. The crystals were collected by filtration and dried under reduced pressure at 60° C. to give 3-(2-chloro-4-(1-propoxy)benzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid as thin yellow crystals (426 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:5]2[C:6]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][NH2:14])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:16]([CH2:19][CH3:20])=[C:17]=[O:18]>O1CCCC1>[CH2:19]([NH:16][C:17]([NH:14][CH2:13][C@@H:11]1[CH2:12][C@H:10]1[C:6]1[C:5]2[N:4]([N:3]=[C:2]([CH3:1])[CH:15]=2)[CH:9]=[CH:8][CH:7]=1)=[O:18])[CH3:20]
Reactant: CCN=C=O
Reactant: Cc1cc2c([C@@H]3C[C@H]3CN)cccn2n1
Solvent: C1CCOC1
Product: CCNC(=O)NC[C@@H]1C[C@H]1c1cccn2nc(C)cc12
Yield: 38.4 %

Procedure:
To a solution of trans-1-[2-(2-methylpyrazolo[1,5-a]pyridin-4-yl)cyclopropyl]methanamine (100 mg, 0.497 mmol) in tetrahydrofuran (5 mL) was added isocyanatoethane (43.3 μL, 0.547 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 10 min. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=3/97→15/85) and recrystallization (ethyl acetate/hexane) to give the title compound (52.0 mg, yield 38%).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:16][C@H:17]1[CH2:21][CH2:20][NH:19][C:18]1=[O:22])=[O:15])[N:10]([CH2:23][CH:24]([CH3:26])[CH3:25])[N:9]=[CH:8]2.N[C@H:33]1CCCCN[C:34]1=O>ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:16][C@H:17]1[CH2:34][CH2:33][CH2:21][CH2:20][NH:19][C:18]1=[O:22])=[O:15])[N:10]([CH2:23][CH:24]([CH3:25])[CH3:26])[N:9]=[CH:8]2
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCNC3=O)cc21
Reactant: N[C@H]1CCCCNC1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCCCNC3=O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a solution of 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate (Example 16; 300 mg, 0.677 mmol) in dichloromethane (3 mL) was added (S)-3-aminoazepan-2-one (prepared according to Example 4; 173 mg, 1.35 mmol) and the reaction was allowed to stir overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on a silica gel column, eluting with 80% ethyl acetate/hexanes to yield (S)-5-(2,4-difluorophenoxy)-1-isobutyl-N-(2-oxoazepan-3-yl)-1H-indazole-6-carboxamide (Ic) (290 mg, 94%). Mass spec: 457 (M+1). 1H NMR (CDCl3) δ 9.11 (br, 1H), 8.33 (s, 1H), 7.86 (s, 1H), 7.16 (m, 1H), 7.04 (s, 1H), 7.00 (m, 1H), 6.89 (m, 1H), 6.14 (br, 1H), 4.78 (ddd, 1H), 4.22 (d, 2H), 3.34 (m, 1H), 3.24 (m, 1H), 2.35 (m, 1H), 2.26 (m, 1H), 2.07 (m, 1H), 1.89 (m, 2H), 1.57 (m, 1H), 1.42 (m, 1H), 0.93 (d, 6H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:6]([S:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:4]1=[O:27].C(N(CC)CC)C.[C:35](OC=O)(=[O:37])C>C(Cl)Cl>[CH:35]([O:1][CH2:2][C@H:3]1[C@H:6]([S:7][C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:5][C:4]1=[O:27])=[O:37]
Reactant: O=C1NC(SC(c2ccccc2)(c2ccccc2)c2ccccc2)C1CO
Reactant: CC(=O)OC=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=COC[C@@H]1C(=O)N[C@H]1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 89.6 %

Procedure:
To a cooled (ice-salt) stirred solution of 3-hydroxymethyl-4-triphenylmethylthio-2-azetidinone (1.76 g 4.7 mmol) in CH2Cl2 (10 ml) and triethylamine (2.6 g, 25 mmol) was added dropwise formic-acetic acid anhydride (1.76 g, 20 mmol). The mixture was stirred 20 min at -10° C. and 20 min at room temperature, followed by partition between water and CH2Cl2. Drying and concentration of organic phase gave an oil which crystallized from ether to give 1.7 g (94.4%) of the title compound as white solid, mp 143°-144° C.; 1Hmr (CDCl3) δ: 7.98 (1H, formyl) 7.3 (15H, s), 4.82 (1H, 4-H), 4.25 (2H, d, J=9 Hz) and 3.37 ppm (1H, m); ir (nujol) νmax : 1723, 1763, 1776 cm-1. ##STR832##
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:24])[O:9][C:10]3[CH:11]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:12][CH2:13][CH2:14][C:15]=3[C:16]=2[OH:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:26][CH:27]([CH3:35])[CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[C:1]1([C:7]2[C:8](=[O:24])[O:9][C:10]3[CH:11]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:12][CH2:13][CH2:14][C:15]=3[C:16]=2[O:17][CH2:26][CH:27]([CH3:35])[CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(CCl)CN1CCOCC1
Reactant: O=c1oc2c(c(O)c1-c1ccccc1)CCCC2c1ccccc1
Product: CC(COc1c2c(oc(=O)c1-c1ccccc1)C(c1ccccc1)CCC2)CN1CCOCC1
Yield: 35 %

Procedure:
Prepared according to the method of Example 9 from 3,8-diphenyl-4-hydroxy-5,6,7,8-tetrahydrocoumarin and 1-chloro-2-methyl-3-morpholino-propane. A thick, brown oil is obtained which cannot be crystallised. Yield 35%.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].N1C=CN=C1.[C:13]([Si:17]([CH3:20])([CH3:19])Cl)([CH3:16])([CH3:15])[CH3:14].O>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][Si:17]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCBr
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCCCBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.1 %

Procedure:
A solution of 28 g of the crude 5-bromo-1-pentanol in 144 ml of tetrahydrofuran is treated with 24 g of imidazole. A solution of 30.3 g of tert-butyldimethyl-chlorosilane in 46 ml of tetrahydrofuran is then added dropwise and the mixture is stirred at room temperature for 4 hours. The reaction mixture is poured into water, extracted by shaking with diethyl ether, and the organic phase is washed 4 times with water, dried over sodium sulphate and concentrated. The crude product is chromatographed on silica gel using hexane/diethyl ether. 42 g of the title compound are obtained as a colourless liquid.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][N:18]=1>CN(C=O)C.O>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][O:15][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:11][CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccc(CCO)cc1
Reactant: Clc1ncnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CCOc2ncnc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.4 %

Procedure:
To a solution of 1.1 g of sodium hydride in 50 ml of DMF, 4.0 g of 2-[4-(t-butyl)phenyl]ethanol was added, and the mixture was stirred at room temperature for one hour. Then 3.6 g of 4-chloroquinazoline in 20 ml of DMF were added, and the mixture was stirred at room temperature overnight. The mixture was then poured into a mixture of ice in water. The product was extracted into CH2Cl2, and the resulting solution was concentrated to dryness. TLC showed one major spot and five minor spots. The product was purified by HPLC (silica gel, CH2Cl2). The fractions containing the major product were collected and concentrated, giving 1.9 g of the title product. Yield: 28.4%. M.P. 70°-71° C.
Reaction SMILES: [CH3:1][C:2]1[C:12]2[S:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.CC(O)=O.[N:17]([O-])=[O:18].[Na+]>O>[CH3:1][C:2]1[C:12]2[S:11][CH2:10][CH2:9][CH2:8][N:7]([N:17]=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1SCCCN2
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc2c1SCCCN2N=O
Temperature: 23 °C

Procedure:
To a solution of 9-methyl-2,3,4,5-tetrahydro-1,5-benzothiazepine (500 mg, 2.6 mmol) and AcOH (2 mL) cooled to ˜9° C. was added a solution of NaNO2 (212 mg, 3.1 mmol) and water (1 mL) dropwise over 4 min (internal temperature<12° C.). The cooling bath was removed and the reaction was maintained at 23° C. for 2 h. It was diluted with H2O (50 mL). 9-methyl-5-nitroso-2,3,4,5-tetrahydro-1,5-benzothiazepine was obtained (470 mg, 87%) as a yellow solid after it was collected by vacuum filtration and air-dried at 23° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:46])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:47])[C:3]=1[C:48]([O:50][CH3:51])=[O:49])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:44])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C:35](=[N:39][OH:40])[C@@H:34]([O:41][CH3:42])[C@H:33]([CH3:43])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:45].Cl.O(N)[CH3:54].N1C=CC=CC=1>CO>[CH3:38][O:37][C@H:36]1[C@@H:31]([NH:30][C:14]2[C:13](=[O:44])[C:12]3[CH:11]=[C:10]4[C:19]([C:20](=[O:27])[C@@:21]5([O:25][CH3:26])[C@@:8]([OH:46])([C:9]4=[O:45])[C:7]4[C:2]([OH:1])=[C:3]([C:48]([O:50][CH3:51])=[O:49])[C:4]([CH3:47])=[CH:5][C:6]=4[CH2:23][C@H:22]5[OH:24])=[C:18]([OH:28])[C:17]=3[C:16](=[O:29])[CH:15]=2)[O:32][C@@H:33]([CH3:43])[C@H:34]([O:41][CH3:42])/[C:35]/1=[N:39]/[O:40][CH3:54]
Reactant: CON
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(=NO)[C@H]1OC)C4=O
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CO/N=C1/[C@@H](OC)[C@H](C)O[C@H](NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)OC)c(O)c5[C@]3(O)C4=O)C2=O)[C@@H]1OC
Reaction time: 2 h
Yield: 54 %

Procedure:
To a solution of the ketone from Step A of the preparation of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,5R,6S)-4-(hydroxyimino)-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 [Isomer A] (Example 48) (53 mg, 0.076 mmol) in methanol (1 mL) was added methoxylamine hydrochloride (6.4 mg, 0.076 mmol) and pyridine (0.1 mL) at room temperature. The mixture was stirred under nitrogen for 2 h. The reaction mixture was quenched with 1N HCl and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by preparative TLC (silica gel, 95:5 chloroform/methanol) to afford (6R,6aS,14aR)-methyl 11-((2S,3R,5R,6S,Z)-3,5-dimethoxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-ylamino)-1,6,8,14a-tetrahydroxy-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (30 mg, 54%) as a red solid: 1H NMR (500 MHz, CDCl3) δ 14.15 (s, 1H), 12.09 (s, 1H), 8.20 (s, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.54 (s, 1H), 5.86 (s, 1H), 5.21 (s, 1H), 4.98-4.94 (m, 2H), 4.67-4.64 (m, 2H), 3.97 (s, 3H), 3.84 (s, 3H), 3.71 (d, J=9.5 Hz, 1H), 3.59 (s, 3H), 3.57-3.52 (m, 2H), 3.47 (s, 3H), 3.40 (s, 3H), 3.34 (d, J=19.5 Hz, 1H), 2.40 (s, 3H), 1.38 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 725 (M+H); HPLC 95.9% (AUC), tR 17.05 min.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=1>C1COCC1>[CH3:17][S:16][C:12]1[N:13]=[C:14]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]=[CH:10][N:11]=1
Reactant: CSc1nccc(Cl)n1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CSc1nccc(-c2ccccc2)n1
Reaction time: 0.83 h
Yield: 52.9 %

Procedure:
A solution of phenylmagnesium bromide (1M in THF, 4.2 mL, 4.2 mmol) is added to a solution of 4-chloro-2-methylthio-pyrimidine (296 mg, 1.84 mmol) and Fe(acac)3 (32 mg, 0.09 mmol) in THF (10 mL) at −30° C. After stirring for 50 min at that temperature, the reaction is quenched with brine, the aqueous layer is extracted with Et2O, the combined organic phases are dried over Na2SO4 and evaporated, and the residue is purified by flash chromatography (hexane/ethyl acetate, 10:1). After eluting a first fraction containing biphenyl (90 mg), one obtains 2-methylthio-4-phenyl-pyrimidine as a pale yellow solid (197 mg, 53%). 1H NMR (300 MHz, CD2Cl2) δ 8.53 (d, 1H), 8.09–8.13 (m, 2H), 7.53–7.48 (m, 3H), 7.39 (d, 2H), 2.63 (s, 3H); 13C NMR (75 MHz, CD2Cl2) δ 173.0, 164.0, 158.0, 136.7, 131.1, 131.0, 129.2, 127.5, 127.4, 112.2, 14.3.
Reaction SMILES: [C:1]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3][CH:2]=1.[CH2:8](I)[CH3:9].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:8]([O:6][C:5]([C:1]1[CH2:4][CH2:3][CH:2]=1)=[O:7])[CH3:9]
Reactant: O=C(O)C1=CCC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=CCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 108.4 %

Procedure:
To a solution of 3.2425 g (33.09 mmol) of 1-cyclobutenecarboxylic acid in 60 ml of dimethylformamide were added 12 ml (150 mmol) of ethyl iodide and 5.53 g (40 mmoL) of potassium carbonate, followed by 20 hours of stirring at room temperature. The reaction solution was poured into water and extracted with ether. The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. By evaporating the solvent, 4.5267 g of the title compound was obtained as a mixture with ethyl iodide and ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])=[C:4]([N+:16]([O-])=O)[CH:3]=1>O1CCCC1.[Pd]>[NH2:16][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([NH2:8])[C:5]=1[NH:11][CH2:12][CH2:13][CH2:14][OH:15]
Reactant: O=[N+]([O-])c1cc(F)cc([N+](=O)[O-])c1NCCCO
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc(F)cc(N)c1NCCCO
Yield: 100 %

Procedure:
A solution of 3-[(4-fluoro-2,6-dinitrophenyl)amino]propan-1-ol (3.59 g, 13.8 mmol) in tetrahydrofuran (140 mL) was stirred in the presence of 10% palladium on carbon (50% wet; 720 mg) under'hydrogen atmosphere at room temperature for 1.5 h. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to give the title compound as a pale brown oil (2.75 g, 13.8 mmol, 100%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH3:15])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[C:1]([C:5]1[CH:6]=[C:7]([CH2:15][Br:16])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1
Reaction time: 5 h
Yield: 61.2 %

Procedure:
3,5-Bis(t-butyl)-1-methylbenzene (200 mg, 0.98 mmol) was dissolved in carbon tetrachloride (4 ml), and then N-bromosuccinimide (192 mg, 1.08 mmol) and AIBN (α,α′-azabisisobutyronitrile) (2 mg) were added thereto. The mixture was heated under reflux and stirred for 5 hours. The filtrate obtained from the filtration of the reaction mixture was evaporated under reduced pressure to give 170 mg (yield: 61%) of a pale yellow oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[S:7][CH:8]=[C:9]([CH2:12]O)[C:10]=1[Cl:11]>C(Cl)(Cl)Cl>[Cl:5][C:6]1[S:7][CH:8]=[C:9]([CH2:12][Cl:3])[C:10]=1[Cl:11]
Reactant: OCc1csc(Cl)c1Cl
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCc1csc(Cl)c1Cl
Temperature: 10 °C
Reaction time: 0.58 h

Procedure:
A mixtures of 357 g of thionyl chloride and 150 ml of chloroform is placed in a 1 liter flask and cooled to 10° C. At 10° to 15° C. and over a period of 35 minutes, a solution of 238 g of 2,3-dichloro-4-hydroxymethylthiophene in 350 ml of chloroform is added. After the exothermic reaction has subsided, the solution is stirred for 1 hour at 30° C., concentrated under reduced pressure and, after a small amount of triethylamine has been added, purified by distillation at 66° to 69° C./0.2 mbar. The yield is 192 g, equivalent to 70% of theory.