Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]([OH:12])[O:5][C:6]2=[O:7].[C:13](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[C:3]([CH:4]=[O:12])=[C:8]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:5][CH3:13])=[O:7]
Reactant: O=C([O-])[O-]
Reactant: O=C1OC(O)c2c(F)cccc21
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cccc(F)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
A stirred mixture containing 7.36 g 4-fluoro-3-hydroxyphthalide, 18.15 g potassium carbonate and 11 mL methyl iodide in 125 mL acetone is heated at reflux for two hours. After stirring overnight at room temperature, the mixture is filtered and concentrated. The residue is dispersed in 200 mL ether, filtered and the filtrate concentrated to give 7.6 g residue which is used directly without further purification. The nmr spectrum of this material is consistent with that expected for the desired product.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][CH:15]([CH2:18][OH:19])[O:14][C:13]=2[CH:20]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][CH:15]([CH2:18][OH:19])[O:14][C:13]=2[CH:20]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)OC(CO)CO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2c(c1)OC(CO)CO2
Temperature: 25 °C
Reaction time: 15 h
Yield: 46 %

Procedure:
Acetic anhydride (0.24 g, 2.4 mmol) was added to a stirred mixture of the title compound from Step 1 above (0.30 g, 1.66 mmol) and Et3N (0.70 g, 6.9 mmol) in CH2Cl2(30 mL). The reaction was stirred at room temperature for 15 h. More acetic anhydride (0.10 g, 1.0 mmol) was added and the mixture was stirred for a further 5 h at room temperature. The mixture was concentrated and the residue purified by chromatography on silica gel using EtOAc/isohexane (1:3 to 2:3) as eluent to give 170 mg (46%) of the title product as an oil.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:14][C:15]1([CH3:27])[C:19]([CH3:21])([CH3:20])[O:18][B:17]([C:22]2[CH:23]=[N:24][NH:25][CH:26]=2)[O:16]1>C1(C)C=CC=CC=1>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[N:25]1[CH:26]=[C:22]([B:17]2[O:16][C:15]([CH3:27])([CH3:14])[C:19]([CH3:21])([CH3:20])[O:18]2)[CH:23]=[N:24]1
Reactant: C1=COCCC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OB(c2cnn(C3CCCCO3)c2)OC1(C)C
Temperature: 90 °C

Procedure:
3,4-Dihydro-2H-pyran (5.6 g, 67 mmol) and trifluoroacetic acid (1.17 g, 10.3 mmol) were added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10.0 g, 51.5 mmol) in toluene (200 mL), and the reaction mixture was heated to 90° C. for 2 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate solution (100 mL), and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 10% to 50% ethyl acetate in petroleum ether) provided the product as a white solid. Yield: 13.4 g, 48.2 mmol, 94%. 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.83 (s, 1H), 5.41 (dd, J=9.5, 2.5 Hz, 1H), 4.01-4.08 (m, 1H), 3.65-3.74 (m, 1H), 1.98-2.18 (m, 3H), 1.6-1.76 (m, 3H), 1.32 (s, 12H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:31](=[O:32])[N:30]([CH2:33][CH3:34])[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[C:4]([Cl:35])[CH:3]=1.[CH3:36][C:37]1[S:41][C:40]([Sn](CCCC)(CCCC)CCCC)=[N:39][CH:38]=1>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.C1(C)C=CC=CC=1>[Cl:35][C:4]1[CH:3]=[C:2]([C:40]2[S:41][C:37]([CH3:36])=[CH:38][N:39]=2)[CH:7]=[CH:6][C:5]=1[C:8]1[C:31](=[O:32])[N:30]([CH2:33][CH3:34])[C:11]2[N:12]=[C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:14]=[CH:15][C:10]=2[CH:9]=1
Reactant: CCn1c(=O)c(-c2ccc(Br)cc2Cl)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncc(C)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCn1c(=O)c(-c2ccc(-c3ncc(C)s3)cc2Cl)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Temperature: 140 °C

Procedure:
6-(4-Bromo-2-chlorophenyl)-8-ethyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (12, 194 mg, 0.35 mmol), 5-methyl-2-(tributylstannyl)-thiazole (171 mg, 0.44 mmol), Pd(PPh3)4 (50 mg) and toluene (15 mL) were placed in a microwave tube and oxygen was removed by a stream of argon. The reaction was heated by microwave at 140° C. for 1.5 h and was monitored by LC/MS. The reaction mixture was evaporated and the solid was extracted with chloroform (100 mL). The solids were removed and the filtrate was evaporated and purified by silica gel chromatography (CHCl3+5% MeOH). Yield 17 mg, 0.03 mmol, 8% as yellow solid. LCMS m/z 572 (M+H)+Rt 1.74 min; 1H NMR (400 MHz, CDCl3) δ ppm 8.56 (s, 1H), 8.04 (s, 1H), 7.81-7.83 (d, 1H), 7.54-7.61 (m, 4H), 7.46-7.48 (d, 1H), 7.32-7.37 (s, 1H), 6.97-7.00 (d, 2H), 4.48-4.54 (q, 2H), 3.24-3.26 (m, 4H), 2.63-2.65 (m, 4H), 2.54 (s, 3H), 2.40 (s, 3H), 1.38-1.42 (t, 3H).
Reaction SMILES: Br[C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:7][N:6]1[CH3:26].[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[O:33][CH2:34][C:35]#[CH:36]>>[CH3:26][N:6]1[C@H:5]2[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:17]=3[C:3]([CH2:4]2)=[C:2]([C:36]#[C:35][CH2:34][O:33][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][O:27]2)[NH:16]4)=[CH:9][C@H:8]([NH:18][C:19](=[O:25])[N:20]([CH2:21][CH3:22])[CH2:23][CH3:24])[CH2:7]1.[OH:27][C:17]([CH3:15])([CH3:11])[C:3]#[CH:2]
Reactant: C#CCOC1CCCCO1
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(Br)c(c34)C[C@H]2N(C)C1
Product: C#CC(C)(C)O
Product: CCN(CC)C(=O)N[C@H]1C=C2c3cccc4[nH]c(C#CCOC5CCCCO5)c(c34)C[C@H]2N(C)C1
Yield: 25 %

Procedure:
Starting with 3-(2-bromo-6-methyl-8α-ergolinyl)-1,1-diethylurea, 3-(tetrahydropyran-2-yloxy)-1-propyne yields 3-[9,10-didehydro-6-methyl-2-[3-(tetrahydropyran-2-yloxy)-1-propynyl]-8α-ergolinyl]-1,1-diethylurea (25%) and 3-hydroxy-3-methyl-1-butyne yields 3-[9,10-didehydro-2-(3-hydroxy-3-methyl-1-butynyl)-6-methyl-8α-ergolinyl]-1,1-diethylurea (31%).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[F:22][C:23]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C(Cl)Cl>[C:1]([NH:5][C:6]1[C:11]([NH:12][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:23]=2[F:22])=[CH:10][CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Nc1ncccc1N
Reactant: O=C(Cl)c1cccc(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)Nc1ncccc1NC(=O)c1cccc(F)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of N2-tert-butylpyridine-2,3-diamine in dry DCM (150 mL) was added DIEA (17 mL, 95.5 mmol). The solution was cooled to 0° C. and carefully added 2,3-difluorobenzoyl chloride (8.35 g, 47.30 mmol). The reaction was allowed to warm up to RT and stirred for 1 hr. The mixture was then washed with water, saturated NaHCO3, and dried over MgSO4. Removal of the solvent by evaporation, the residue was purified by silica gel chromatography (5%-60% EtOAc/hexane) to yield N-(2-(tert-butylamino)pyridin-3-yl)-2,3-difluorobenzamide (4.0 g, 13.10 mmol); LC-MS m/e=306.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=[C:4]([O:15][CH3:16])[N:3]=1.[CH2:17](Br)[CH:18]=[CH2:19].C(=O)([O-])[O-].[Na+].[Na+]>CC#N>[CH2:19]([N:8]([C:7]1[C:2]([Br:1])=[N:3][C:4]([O:15][CH3:16])=[CH:5][CH:6]=1)[C:9](=[O:14])[C:10]([F:13])([F:11])[F:12])[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: COc1ccc(NC(=O)C(F)(F)F)c(Br)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C=CCN(C(=O)C(F)(F)F)c1ccc(OC)nc1Br
Temperature: 80 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
A mixture of N-(2-bromo-6-methoxy-pyridin-3-yl)-2,2,2-trifluoro-acetamide (5.52 g, 18.5 mmol), allyl bromide (3.57 g, 27.7 mmol) and sodium carbonate (5.1 g, 11 mmol) in CH3CN (60 mL) is stirred at 80° C. for 3 h. The mixture is filtered and the filtrate is concentrated in vacuo. The residue is purified by silica gel column chromatography eluting with 0-60% DCM in heptane to afford N-allyl-N-(2-bromo-6-methoxy-pyridin-3-yl)-2,2,2-trifluoro-acetamide (5.55 g) as an oil. 1H NMR (300 MHz, CDCl3): δ 3.66 (q, H), 4.00 (s, H), 5.95 (q, H), 5.08-5.30 (q, 2H), 5.75-5.94 (m, H), 6.74 (d, H), 7.38 (d, H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:9]2[C:10](=[O:32])[N:11]([CH2:17][C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)[CH2:12][CH2:13][O:14][C:15]=2[N:16]=1)(=O)C.[OH-].[Na+]>C(O)C>[F:31][C:28]([F:29])([F:30])[C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=1)[CH2:17][N:11]1[C:10](=[O:32])[C:9]2[C:8]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:7][C:6]([CH2:5][OH:4])=[N:16][C:15]=2[O:14][CH2:13][CH2:12]1
Reactant: CC(=O)OCc1cc(-c2ccccc2)c2c(n1)OCCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1c2c(-c3ccccc3)cc(CO)nc2OCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
A mixture of 8-acetoxymethyl-4-[3,5-bis(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido[3,2-f][1,4]oxazepine (Example 37) (4,51 g), ethanol (50 ml), and 4N-NaOH (50 ml) was stirred for 1.5 hours at room temperature. After evaporation of the solvent, water was added to the residue. The pH of the mixture was adjusted to ca.8 using dilute hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried and evaporated to give the entitled compound as colorless crystals (4.10 g).
Reaction SMILES: C([O:8][CH2:9][N:10]1[C:25](=[O:26])[C:24]2[C:23]3[C:22]4[C:17](=[C:18]([O:27]CC5C=CC=CC=5)[CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]=3[C:14]3[N:35]([C@:50]4([C:70](=[O:72])[CH3:71])[O:58][C@H:57]([CH2:59][OH:60])[C@@:55]([C:61](=[O:63])[CH3:62])([OH:56])[C@:53]([C:64](=[O:66])[CH3:65])([OH:54])[C@@:51]4([C:67](=[O:69])[CH3:68])[OH:52])[C:36]4[C:37]([O:42]CC5C=CC=CC=5)=[CH:38][CH:39]=[CH:40][C:41]=4[C:13]=3[C:12]=2[C:11]1=[O:73])C1C=CC=CC=1.C(OCC)(=O)C>[C].[Pd].C(O)C>[OH:42][C:37]1[C:36]2[N:35]([C@:50]3([C:70](=[O:72])[CH3:71])[O:58][C@H:57]([CH2:59][OH:60])[C@@:55]([C:61](=[O:63])[CH3:62])([OH:56])[C@:53]([C:64](=[O:66])[CH3:65])([OH:54])[C@@:51]3([C:67](=[O:69])[CH3:68])[OH:52])[C:14]3[C:15]4[NH:16][C:17]5[C:22](=[CH:21][CH:20]=[CH:19][C:18]=5[OH:27])[C:23]=4[C:24]4[C:25](=[O:26])[N:10]([CH2:9][OH:8])[C:11](=[O:73])[C:12]=4[C:13]=3[C:41]=2[CH:40]=[CH:39][CH:38]=1
Reactant: CC(=O)[C@@]1(O)[C@](O)(C(C)=O)[C@](C(C)=O)(n2c3c(OCc4ccccc4)cccc3c3c4c(c5c6cccc(OCc7ccccc7)c6[nH]c5c32)C(=O)N(COCc2ccccc2)C4=O)O[C@H](CO)[C@]1(O)C(C)=O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)[C@@]1(O)[C@](O)(C(C)=O)[C@](C(C)=O)(n2c3c(O)cccc3c3c4c(c5c6cccc(O)c6[nH]c5c32)C(=O)N(CO)C4=O)O[C@H](CO)[C@]1(O)C(C)=O
Yield: 57.7 %

Procedure:
To 4.5 mg of 6-benzyloxymethyl-1,11-dibenzyloxy-12,13-dihydro-13-(tetraacetyl-β-D-glucopyranosyl)-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H )-dione were added 1.5 ml of ethyl acetate and 9 ml of ethanol to make a solution, and the solution was subjected to hydrogenation reaction in the presence of palladium-carbon catalyst (two medical spoonsful) for 3 hours. After the reaction, the palladium-carbon was removed by filtration and washed with methanol and tetrahydrofuran. The filtrate and the washings were concentrated under reduced pressure, the residue was subjected to thin layer chromatography (Kiesel gel 60; developed with chloroform-methanol =19:1), and the desired product was scraped and extracted with methanol to give 12,13-dihydro-1,11-dihydroxy-6-hydroxymethyl-13-(tetraacetyl-β-D-glucopyranosyl)-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (yield: 57.7%).
Reaction SMILES: CO.[NH:3]1[CH2:6][CH:5]([N:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]4[N:16]([C:18]([CH2:21][C:22]5[CH:23]=[C:24]6[C:29](=[CH:30][C:31]=5[F:32])[N:28]=[CH:27][CH:26]=[CH:25]6)=[CH:19][N:20]=4)[N:17]=3)[CH:9]=[N:8]2)[CH2:4]1.C=O.[BH3-][C:36]#N.[Na+]>C(Cl)Cl.C(O)(=O)C>[F:32][C:31]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[CH2:21][C:18]1[N:16]2[N:17]=[C:12]([C:10]3[CH:9]=[N:8][N:7]([CH:5]4[CH2:4][N:3]([CH3:36])[CH2:6]4)[CH:11]=3)[CH:13]=[CH:14][C:15]2=[N:20][CH:19]=1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(C4CNC4)c3)nn12
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CC(n2cc(-c3ccc4ncc(Cc5cc6cccnc6cc5F)n4n3)cn2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A flask was charged with MeOH (1 mL). 6-[6-(1-Azetidin-3-yl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-7-fluoro-quinoline (Stage 146.1, 26 mg, 0.065 mmol), formaldehyde (9.7 μL, 0.130 mmol) and NaBH3CN (20 mg, 0.325 mmol) were then added. The pH was adjusted to 5-6 with a drop of acetic acid and the RM was stirred at rt for 2 h. The mixture was then diluted with DCM, washed with NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with a 4 g RediSep® silica gel column, DCM/(DCM/MeOH 19:1)=100:0→0:100)). The residue crystallized in DCM. The solid was filtered off, and dissolved in EtOAc. The solution was washed again with NaHCO3, dried over Na2SO4, filtered and concentrated to afford the title compound as a foam (tR 2.93 min (conditions 3), MH+=414.1, 1H-NMR in DMSO-d6: 8.85 (m, 1H); 8.60 (s, 1H); 8.35 (m, 1H); 8.09 (m, 3H); 7.77 (m, 1H); 7.58 (m, 2H); 7.47 (m, 1H); 5.01 (m, 1H); 4.55 (s, 2H); 3.71 (m, 2H); 3.40 (m, 2H); 2.34 (s, 3H))
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=O)[CH2:11][CH2:10]4)[C@H:7]([CH2:22][CH2:23][CH3:24])[CH2:6][C:5]=2[CH:4]=1.C[NH:26][NH:27][CH3:28].F[C:30](F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH3:30][N:27]([CH3:28])[N:26]=[C:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C:18]1[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:6][C@H:7]3[CH2:22][CH2:23][CH3:24]
Reactant: O=C(O)C(F)(F)F
Reactant: CNNC
Reactant: CCC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)C(=NN(C)C)CC[C@H]3[C@H]12
Temperature: 25 °C

Procedure:
To a solution of 11.2 g. of 7a-propyl-3-O-methylestrone 5 in 60 ml of toluene were added 6 ml of dimethylhydrazine and 0.5 ml. of trifluoroacetic acid. The mixture was refluxed for 1.5 hr. After cooling to r.t. the reaction mixture was neutralized with 5% NaHCO3 and the organic layer was washed several times with water and dried over sodium sulfate. After concentration and chromatography 11.4 g of the hydrazone 6 remained as an oil; Rf 030 (hept/ethylac. 7/3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][CH3:14])[C:7]([CH2:15]O)=[CH:6]2.O=S(Cl)[Cl:19]>C(Cl)Cl>[ClH:19].[Cl:19][CH2:15][C:7]1[C:8]([NH:13][CH3:14])=[N:9][C:10]2[C:5]([CH:6]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2
Reactant: O=S(Cl)Cl
Reactant: CNc1nc2ccc(OC)cc2cc1CO
Solvent: ClCCl
Product: CNc1nc2ccc(OC)cc2cc1CCl
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of (6-methoxy-2-(methylamino)quinolin-3-yl)methanol SLA 28152 (0.906 g, 4.15 mmol) in dry CH2Cl2 (100 mL) in a 250 mL round-bottomed flask equipped with a magnetic stirrer was added dropwise SOCl2 (6.03 mL, 83.1 mmol). The mixture was stirred for 1 h at RT then concentrated to dryness at 40° C. under vacuum. The residue was then taken up in CH2Cl2 (20 mL) before concentration back to dryness at 40° C. under vacuum (done 3 times) to give 3-(chloromethyl)-6-methoxy-N-methylquinolin-2-amine hydrochloride SLA 28154 (1.20 g, >100%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:4][CH:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(N(C(C)C)C(C)C)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][CH2:10][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(O)COCc1cccc(Br)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COCc1cccc(Br)n1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [(6-bromopyridin-2-yl)methoxy]acetic acid (1.6 g, 7.5 mmol) and morpholine (0.65 g, 7.5 mmol) in dichloromethane at 0° C. was added N-ethyl-N-isopropylpropan-2-amine (3.9 mL, 22.5 mmol), 1-hydroxybenzotriazole hydrate (1.5 g, 11.25 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.1 g, 11.25 mmol). The reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography, eluting with ethyl acetate:hexanes (3:7) to afford the title compound.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[CH2:5]=O.S([O-])([O-])(=O)=O.[Na+].[Na+].N[CH:15]1[CH:32]2[C:19]([OH:38])([C:20]([OH:37])=[C:21]3[CH:30]([CH2:31]2)[S:29][C:28]2[C:23](=[C:24]([OH:35])[CH:25]=[CH:26][C:27]=2[O:33][CH3:34])[C:22]3=[O:36])[C:18](=[O:39])[C:17]([C:40]([NH2:42])=[O:41])=[C:16]1[OH:43]>CO.C(Cl)(Cl)Cl>[CH3:5][N:2]([CH3:1])[CH:15]1[CH:32]2[C:19]([OH:38])([C:20]([OH:37])=[C:21]3[CH:30]([CH2:31]2)[S:29][C:28]2[C:23](=[C:24]([OH:35])[CH:25]=[CH:26][C:27]=2[O:33][CH3:34])[C:22]3=[O:36])[C:18](=[O:39])[C:17]([C:40]([NH2:42])=[O:41])=[C:16]1[OH:43]
Reactant: C=O
Reactant: [BH3-]C#N
Reactant: COc1ccc(O)c2c1SC1CC3C(N)C(O)=C(C(N)=O)C(=O)C3(O)C(O)=C1C2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(O)c2c1SC1CC3C(N(C)C)C(O)=C(C(N)=O)C(=O)C3(O)C(O)=C1C2=O
Reaction time: 0.5 h

Procedure:
400 mg of sodium cyanoborohydride, 0.5 ml of 35% aqueous formaldehyde solution and a little sodium sulphate are added to a solution of 434 mg of 4-de-dimethylamino-4-amino-7-methoxy-6-thiatetracycline (obtained in accordance with Example 1) in 80 ml of methanol and the mixture is stirred for 30 minutes at 20°. Chloroform is then added, followed by washing with dilute hydrochloric acid, drying and evaporation to give 7-methoxy-6-thiatetracycline, m.p. 225°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])([CH3:14])[C:9](F)=[CH:10][C:11]#N)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C([O:28]CC)C>CCCCCC.O.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])([CH3:14])[CH:9]=[CH:10][CH:11]=[O:28])=[CH:4][CH:3]=1
Reactant: CC(C)(C(F)=CC#N)c1ccc(Cl)cc1
Reactant: CCOCC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C=CC=O)c1ccc(Cl)cc1
Temperature: -40 °C
Reaction time: 0.58 h
Yield: 97 %

Procedure:
A solution of 4-(p-chlorophenyl)-3-fluoro-4-methyl-2-pentenenitrile, (Z)- (15.6 g, 69.7 mmol) in diethyl ether is treated dropwise with diisobutylaluminum hydride (83.6 mmol, 83.6 mL of a 1M solution in hexane) over 90 minutes at -45° C. under nitrogen, stirred at -40° C. for 35 minutes, and diluted sequentially with water and 2N hydrochloric acid at -10° C. The resultant aqueous mixture is stirred at room temperature for one hour and extracted with diethyl ether. The organic extracts are combined, washed sequentially with water, 2N hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a brown oil (15.34 g, 97% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([NH2:17])=[O:16])=[C:6]2[C:11]=1[O:10][CH2:9][CH:8]([N+:12]([O-])=O)[CH2:7]2.C(O)C>O1CCCC1.[Ni]>[NH2:12][CH:8]1[CH2:7][C:6]2=[C:5]([C:15]([NH2:17])=[O:16])[CH:4]=[CH:3][C:2]([F:1])=[C:11]2[O:10][CH2:9]1
Reactant: NC(=O)c1ccc(F)c2c1CC([N+](=O)[O-])CO2
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: NC(=O)c1ccc(F)c2c1CC(N)CO2
Reaction time: 48 h
Yield: 99 %

Procedure:
8-Fluoro-3-nitro-3,4-dihydro-2H-1-benzopyran-5-carboxamide (9.0 g, 37.5 mmol), dissolved in tetrahydrofuran (100 mL) and absolute ethanol (400 mL), was subjected to atmospheric hydrogenation conditions using Raney nickel (W-2, 9 g) at room temperature. The reaction was complete after 48 hours, at which time the catalyst was filtered off, washed with hot ethanol and the combined solvents were removed in vacuo to give 7.8 g (99% yield) of an off-white solid. A portion was recrystallized from ethyl acetate to give white crystals as the title compound (mp 187-188° C). EIMS (70 eV) m/z (relative intensity) 210 (6, M+), 194 (30), 193 (100), 192 (20), 178 (12).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10](Br)[CH:11]=3)[C:5]=2[N:6]=1.C([Sn](CCCC)(CCCC)C([O:23][CH2:24][CH3:25])=C)CCC.[F-].[K+].[O:36]1CCO[CH2:38][CH2:37]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:6]1[C:5]2[C:7]3[C:12]([CH2:13][CH2:14][C:4]=2[S:3][C:2]=1[C:24](=[O:23])[CH3:25])=[CH:11][C:10]([C:37](=[O:36])[CH3:38])=[CH:9][CH:8]=3
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: C1COCCO1
Reactant: Brc1ccc2c(c1)CCc1sc(Br)nc1-2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Product: CC(=O)c1ccc2c(c1)CCc1sc(C(C)=O)nc1-2
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
A solution of 2,7-dibromo-4,5-dihydronaphtho[1,2-d]thiazole (4b) (1.7 g, 5.07 mmol) in 30 ml of anhydrous dioxane was degassed by passing nitrogen gas for 15 min. Tributyl(1-ethoxyvinyl)stannane (4.58 g, 12.68 mmol) was added to it followed by PdCl2(PPh3)2 (0.36 g, 0.51 mmol) and the solution was heated at 90° C. overnight. After cooling, the volume of dioxane was reduced and a saturated solution of KF was added to it and stirred for 15 min., after which the mixture was passed through a pad of celite and washed with ethyl acetate. The combined filtrate was stirred with 4 N HCl solution for 1 h and the organic layer was dried and concentrated and the residue was purified by column chromatography to obtain the diacetyl compound (4c) (1.37 g, 73%). m/z 271.0 (M+).