Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:24][CH2:25][CH:26]2[CH2:28][CH2:27]2)=[CH:13][CH:12]=1)=[O:10].ClC1C=CC=C(C(OO)=[O:38])C=1>C(Cl)(Cl)Cl>[Cl:29][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH+:8]([O-:38])[C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:24][CH2:25][CH:26]2[CH2:27][CH2:28]2)=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Nc1c(Cl)cncc1Cl)c1ccc(OCC2CC2)c2oc3ccccc3c12
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(OCC2CC2)c2oc3ccccc3c12)[NH+]([O-])c1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.2 %

Procedure:
A suspension of N-(3,5-dichloropyrid-4-yl)-4-cyclopropylmethoxy-dibenzo[b,d]furan-1-carboxamide (370 mg, 0.936 mmol) (example 26) and m-chloroperbenzoic acid (50-55%) (1.0 gm, 4.68 mmol) in chloroform (20 ml) was stirred at room temperature for 12 h. The reaction contents were washed with saturated sodium bicarbonate and water. The organic solvent was distilled of in vacuo and the residue was purified by column chromatography using 30% acetone-chloroform as the eluent to give 200 mg of N-(3,5-dichloropyrid-4-yl)-4-cyclopropylmethoxy-dibenzo[b,d]furan-1-carboxamide-N1-oxide as white solid; mp: 263-265° C.
Reaction SMILES: [CH3:1][C@@H:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][CH2:17][C:18]([C:20]2[CH:21]=[CH:22][C:23]3[C:32]4[CH:31]=[C:30]5[CH2:33][CH2:34][CH:35](Br)[C:36](=[O:37])[C:29]5=[CH:28][C:27]=4[O:26][CH2:25][C:24]=3[CH:39]=2)=[O:19])=[O:15])[CH2:4][CH2:3]1.[C:40]([O:44][C:45]([N:47]1[CH2:51][C@@H:50]([CH2:52][O:53][CH3:54])[CH2:49][C@H:48]1[C:55]([OH:57])=[O:56])=[O:46])([CH3:43])([CH3:42])[CH3:41].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O.C(Cl)Cl>[CH3:1][C@@H:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][CH2:17][C:18]([C:20]2[CH:21]=[CH:22][C:23]3[C:32]4[CH:31]=[C:30]5[CH2:33][CH2:34][CH:35]([O:57][C:55]([C@@H:48]6[CH2:49][C@H:50]([CH2:52][O:53][CH3:54])[CH2:51][N:47]6[C:45]([O:44][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:46])=[O:56])[C:36](=[O:37])[C:29]5=[CH:28][C:27]=4[O:26][CH2:25][C:24]=3[CH:39]=2)=[O:19])=[O:15])[CH2:4][CH2:3]1
Reactant: C[C@H]1CC[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCC(Br)C4=O)N1C(=O)OC(C)(C)C
Reactant: COC[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: COC[C@H]1C[C@@H](C(=O)OC2CCc3cc4c(cc3C2=O)OCc2cc(C(=O)COC(=O)[C@@H]3CC[C@H](C)N3C(=O)OC(C)(C)C)ccc2-4)N(C(=O)OC(C)(C)C)C1
Temperature: 40 °C
Yield: 65.3 %

Procedure:
(2S,5S)-2-(2-(9-bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl) 1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (800 mg, 1.34 mmol) was treated with a solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylic acid (485 mg, 1.87 mmol) in acetone (6 mL) and Cs2CO3 (306 mg, 0.94 mmol). The stirred reaction mixture was heated to 40° C. for 16 h, then cooled to RT and diluted with CH2Cl2 and extracted 3×. The organic phase was washed with brine, then dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (40% to 100% EtOAc/hexanes) to afford (2S,5S)-2-(2-(9-((2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carbonyloxy)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl) 1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (680 mg, 65%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)=[O:12])=[CH:5][CH:4]=1.OC1C=C(C(=O)/C=C/C2C=CC=CC=2)C=CC=1>>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[C:11](=[O:12])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C(/C=C/c1ccc(C(F)(F)F)cc1)c1cccc(O)c1
Agent: O=C(/C=C/c1ccccc1)c1cccc(O)c1
Product: O=C1CC(c2ccc(C(F)(F)F)cc2)c2ccc(O)cc21
Reaction time: 120 h
Yield: 38 %

Procedure:
The procedure of Step 2 of Example 1 was repeated except for using (E)-3-(4-(trifluoromethyl)phenyl)-1-(3-hydroxyphenyl)prop-2-en-1-one obtained in Step 1 as a starting material instead of (E)-1-(3-hydroxyphenyl)-3-phenylprop-2-en-1-one and being stirred for 5 d to obtain the title compound (38%).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[C:5]([NH:24][C:25]1[S:26][CH:27]=[C:28]([C:30](=[N:36][OH:37])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:29]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[C:5]([NH:24][C:25]1[S:26][CH:27]=[C:28]([C:30](=[N:36][O:37][CH2:3][CH:2]=[CH2:1])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:29]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCON=C(C(=O)OCC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 4 h
Yield: 86.4 %

Procedure:
Allyl bromide (2.91 g) was added dropwise to a stirred suspension of ethyl 2-(2-tritylaminothiazol-4-yl)-2-hydroxyiminoacetate (syn isomer, 10 g), N,N-dimethylformamide (100 ml) and potassium carbonate (4.54 g) under ice cooling over 5 minutes, and stirred at the same temperature for 4 hours. After adding water (200 ml) to the resultant solution, the solution was extracted with diethyl ether twice. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solution was concentrated in vacuo, and the residue was triturated with a solution of n-hexane and diethyl ether. The precipitates were collected by filtration to give ethyl 2-(2-tritylaminothiazol-4-yl)-2-allyloxyiminoacetate (syn isomer, 9.4 g), mp. 130° to 132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:17]4[CH:29]=[C:28]([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=5)[S:27][C:18]=4[N:19]=[C:20]([C:22]([O:24]CC)=[O:23])[N:21]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.Cl>CO.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:11][CH2:12][N:13]([C:16]3[C:17]4[CH:29]=[C:28]([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=5)[S:27][C:18]=4[N:19]=[C:20]([C:22]([OH:24])=[O:23])[N:21]=3)[CH2:14][CH2:15]2)=[O:9])=[CH:37][CH:38]=1
Reactant: CCOC(=O)c1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2cc(-c3ccc(F)cc3)sc2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)c1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2cc(-c3ccc(F)cc3)sc2n1
Yield: 43.1 %

Procedure:
A solution of ethyl 4-(4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine-2-carboxylate (0.12 g, 0.22 mmol) in methanol/2M NaOH/CH2Cl2 (5:5:1, 5 ml) was stirred at room temperature for 3 hours after which it was neutralized with a 2N HCl solution in dioxane. The solvents were removed under reduced pressure, and the crude residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH 8:1) to yield the title compound as a pale yellow solid (50 mg, 44%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:32])([CH3:31])[CH2:9]2)=[O:5])[CH3:2].C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:46]2N=CC=[CH:50][C:45]=2[N:44]=N1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(N)(C)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:22]3[CH:23]=[CH:24][C:25]([C:28](=[O:30])[NH:44][CH:45]([CH3:50])[CH3:46])=[CH:26][CH:27]=3)[CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:32])([CH3:31])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-c3ccc(C(=O)O)cc3)c1)N2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-c3ccc(C(=O)NC(C)C)cc3)c1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a stirred solution of 2-(4′-carboxy-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (860 mg, 2 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU) (1.2 g, 3 mmol) and triethyl amine (0.86 mL, 6 mmol) in dichloromethane was added isopropylamine (0.66 mL, 8 mmol) at room temperature and stirred at room temperature for overnight. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(4′-isopropylcarbamoyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (940 mg, quant.) as a light yellow solid which was used for next step without further purification: LC/MS m/e calcd for C30H34N2O3 (M+H)+: 471.62, observed: 471.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([OH:23])[CH:22]=2)[O:19][C:18]([CH3:25])([CH3:24])[CH2:17][C:16]3([CH3:27])[CH3:26])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:36]([CH3:38])[CH3:37]>CC(C)=O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([O:23][CH:36]([CH3:38])[CH3:37])[CH:22]=2)[O:19][C:18]([CH3:24])([CH3:25])[CH2:17][C:16]3([CH3:27])[CH3:26])=[CH:9][CH:10]=1
Reactant: CC(C)I
Reactant: COC(=O)Cc1ccc(C#Cc2cc(O)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Cc1ccc(C#Cc2cc(OC(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Yield: 91 %

Procedure:
A solution of [4-(8-hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl)-phenyl]-acetic acid methyl ester (Intermediate 20, 0.02 g, 0.076 mmol) in acetone (2 mL) was treated with potassium carbonate (0.026 g, 0.19 mmol) and 2-iodopropane (5 mL, large excess) and the resulting reaction mixture was refluxed for 30 h. The volatiles were evaporated in vacuo, the residue was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as an oil (0.02 g, 91%).
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:53]3[O:57][N:56]4[CH2:58][CH2:59][CH2:60][CH:55]4[CH:54]3[C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]>C(O)C.C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:53]3[O:57][N:56]4[CH2:58][CH2:59][CH2:60][CH:55]4[CH:54]3[C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C3ON4CCCC4C3C(=O)OCC)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCCCc1nc2ccc(C3ON4CCCC4C3C(=O)OCC)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 50.4 %

Procedure:
A solution of 0.174 g of ethyl 2-[2-butyl-3,4-dihydro-4-oxo-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-6-quinazolinyl]hexahydro-pyrrolo[1,2-b]isoxazole-3-carboxylate in 2.0 ml of ethanol and 1.0 ml of chloroform containing 2.0 ml of 3M HC1 in ethyl acetate is stirred at room temperature for 1 hour. The volatiles are evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 9:1 chloroform-methanol to give 0.063 g of the desired product as a solid. FAB Mass spec 620 (M+H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:21]([OH:22])=[CH:20][C:7]2[CH2:8][N:9]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1.[CH2:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][N:24]1[C:33]([Cl:35])=[O:34].C(N(CC)CC)C>C(Cl)(Cl)Cl.ClCCl>[ClH:35].[CH3:2][O:3][C:4]1[C:21]([O:22][C:33]([N:24]2[CH2:25][CH2:26][C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23]2)=[O:34])=[CH:20][C:7]2[CH2:8][N:9]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: COc1cc2c(cc1O)CN(Nc1ccncc1)CCC2
Reactant: O=C(Cl)N1CCc2ccccc2C1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1OC(=O)N1CCc3ccccc3C1)CN(Nc1ccncc1)CCC2
Temperature: 25 °C
Yield: 30.8 %

Procedure:
To a solution of [7-methoxy-8-hydroxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-pyridin-4-yl amine hydrochloride (500 mg) in chloroform (10 mL) was added 1,2,3,4-tetrahydroisoquinoline-2-yl carbonyl chloride (362 mg) followed by triethylamine (0.75 mL). The reaction mixture was heated under reflux for 3 hrs, cooled to ambient temperature, diluted with dichloromethane (200 mL), and the mixture was washed with saturated sodium bicarbonate solution. The organic phase was separated, dried under anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was flash chromatographed over silica gel, eluting with chloroform:methanol (9:1). The appropriate fractions were collected and evaporated. The residue was dissolved in methanol and conc hydrochloric acid was added. The precipitate was collected and crystallized from ethyl acetate-petroleum ether to give 230 mg of product, mp >100° C. (dec).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:17])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[N:18]([O-])=O.[Na+]>C(O)(=O)C>[N+:8]([C:6]1[CH:7]=[C:2]2[C:3](=[C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=1)[NH:17][N:18]=[CH:1]2)([O-:10])=[O:9]
Reactant: Cc1cc([N+](=O)[O-])cc(-c2ccccc2)c1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(-c2ccccc2)c2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-Methyl-5-nitro-biphenyl-2-ylamine (91 mg, 0.39 mmole) in pre-heated glacial acetic acid (4 mL) was added 0.44M sodium nitrite solution (1 mL), in a dropwise fashion. The resulting mixture was stirred overnight at room temperature. The crude product was concentrated in-vacuo and the residue re-dissolved in EtOAc (20 mL) and washed with saturated NaHCO3 (2×20 mL) and brine (1×20 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated in-vacuo to yield the desired product (67 mg) as a yellow powder. 1H NMR (400 MHz, CDCl3) δ 7.50(1H, m), 7.58(2H, m), 7.69(2H, m), 8.33 (2H, m), 8.75(1H, s), 10.55(br s). MS (ES+): m/e=240, (ES−): m/e=238.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[ClH:15]>CS(C)=O>[Cl:15][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: COc1ccc(Br)c2c1CCC(=O)N2
Reactant: Cl
Solvent: CS(C)=O
Product: COc1ccc(Cl)c2c1CCC(=O)N2
Temperature: 0 °C

Procedure:
22.7 Grams of 8-bromo-5-methoxy-3,4-dihydrocarbostyril and 25 g of cuprous chloride are mixed with 100 ml of dimethyl sulfoxide and heated at 135°-140° C. for 4 hours under stirring condition. After the reaction is completed, the reaction mixture is mixed with 200 g of ice and 50 ml of concentrated hydrochloric acid and stirred at room temperature for 1 hour. The crystals thus precipitated are separated by filtration, washed first with diluted hydrochloric acid and then with water and dried. The crude crystals thus obtained are recrystallized from ligroin-benzene to obtain 13 g of 8-chloro-5-methoxy-3,4-dihydrocarbostyril in the form of pale orange needle-like crystals with a melting point of 165° C.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C(C)=CC=CC=1>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:21])(=[O:20])[NH:6][C:5]=1[C:3]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:4])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccccc1)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Reaction time: 8 h
Yield: 55.5 %

Procedure:
A mixture of 9.58 gm (0.03 mol) of 4-hydroxy-2H-naphtho[2,1-e]-1,2thiazine-3-carboxylic acid methyl ester-1,1-dioxide, 3.72 gm (0.04 mol) of aniline and 150 ml of anhydrous xylene was refluxed for 10 hours in a Soxhlet apparatus equipped with a 4-A-molecular sieve. After cooling, the reaction mixture was allowed to stand overnight, whereupon the precipitaed crystals were suction-filtered off and recrystallized from ethylene chloride. 6.10 gm (55% of theory) of 4-hydroxy-N-phenyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide, m.p. 260°-262° C, were obtained.
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@@H:17]([C:29]#[N:30])[C@:18]5([OH:28])[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C([C@@H]1C2[C@](C)(CCC(=[O:51])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[OH:28][C@:18]12[CH2:19][C:20](=[O:51])[CH2:21][CH2:22][C@:23]1([CH3:24])[C@@H:25]1[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]1)([CH3:5])[C:3](=[O:12])[CH2:8][CH2:7]3)[CH2:16][C@H:17]2[C:29]#[N:30]
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[C@]12CC[C@H]3[C@@H](C[C@@H](C#N)[C@@]4(O)CCCC[C@]34C)[C@@H]1CC13OCCOC12OCCO3
Product: C[C@]12CC[C@H]3[C@@H](C[C@@H](C#N)[C@@]4(O)CC(=O)CC[C@]34C)[C@@H]1CCC2=O
Yield: 82 %

Procedure:
The title compound II-ai was prepared in 82% yield from 3,3:17,17-bis(ethylendioxy)-5α-hydroxy-6β-cyanoandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The crude product was purified by flash chromatography (SiO2, n-hexane/CH2Cl2/acetone 60/20/20) to give the title compound II-ae. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 4.27 (s, 1H), 3.21 (d, 1H), 2.92 (m, 1H), 2.62-1.24 (m, 18H), 1.50 (s, 3H), 0.93 (s, 3H).
Reaction SMILES: [OH-].[K+].[CH3:3][P:4]([C:9]1[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])(=[O:8])[O:5][CH2:6][CH3:7].[CH2:19]([OH:21])[CH3:20]>>[CH3:3][P:4]([C:9]1[CH:14]=[C:13]([O:21][CH2:19][CH3:20])[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])(=[O:8])[O:5][CH2:6][CH3:7]
Reactant: CCOP(C)(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: CCOc1ccc([N+](=O)[O-])c(P(C)(=O)OCC)c1
Reaction time: 48 h

Procedure:
To a solution of potassium hydroxide pellets (10.0 mmol) dissolved in ethanol (50 ml) is added ethyl P-methyl-2-nitro-5-chlorophenylphosphinate (20.0 mmol). The mixture is boiled for 48 hours and is then concentrated to a slurry. The residue is diluted with water, acidified with 10% HCl and extracted with ethyl acetate (2X). The combined extracts are washed with brine, dried and evaporated to yield ethyl P-methyl-2-nitro-5-ethoxyphenylphosphinate.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([CH3:16])[O:9][CH:6]1OC)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[C:22]([OH:25])(=[O:24])[CH3:23]>C(OC(=O)C)(=O)C>[C:22]([O:25][CH:6]1[O:9][C@@H:10]([CH3:16])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:5]1[O:4][C:1](=[O:3])[CH3:2])(=[O:24])[CH3:23]
Reactant: COC1O[C@@H](C)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC1O[C@@H](C)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 96 h
Yield: 58 %

Procedure:
Methyl 5-deoxy-2,3-di-O-acetyl-L-ribofuranoside (33 g, 15.2 mmol) was dissolved in acetic acid (20 mL) and acetic anhydride (5 mL). The solution was cooled to ice bath temperatures and concentrated sulfuric acid was added dropwise (1 mL). The solution was kept at 5° C. for 4 days, then it was poured into ice water (50 mL) and extracted with 3:1 ethyl acetate hexanes (200 mL and 75 mL). The combined organics were washed with 10% sodium biarbonate (2×50 mL) and water (50 mL). The organic layers were dried, and concentrated and the residue purified on a silica gel column (5×15 cm, 230-400 mesh) with ethyl acetate:hexanes (1:3). Both anomers were observed but were isolated together as a clear oil (2.2 g, 8.8 mmol, 58%); 1H NMR (DMSO-d6) δ5.96 (d, 1H J=1 Hz), 5.23 (d, 1H, H-2, J=5 Hz), 4.96 (t, 1H, H-3, J=5.7 Hz), 4.24-4.16 (m, 1H, H-4), 2.07 (s, 3H, OAc), 2.05 (s, 3H, OAc), 2.02 (s, 3H, OAc), 1.27 (d, 3H, H-5, J=6.3 Hz).
Reaction SMILES: C(OP([CH:9]([F:11])[F:10])(=O)OCC)C.C([N-]C(C)C)(C)C.[Li+].[CH3:20][O:21][C:22]1[CH:39]=[CH:38][C:37]2[C@@H:36]3[C@H:27]([C@H:28]4[C@@:32]([CH2:34][CH2:35]3)([CH3:33])[C:31](=O)[CH:30]=[CH:29]4)[CH2:26][CH2:25][C:24]=2[CH:23]=1>O1CCCC1>[F:11][C:9]([F:10])=[C:31]1[CH:30]=[CH:29][C@H:28]2[C@H:27]3[C@H:36]([CH2:35][CH2:34][C@:32]12[CH3:33])[C:37]1[CH:38]=[CH:39][C:22]([O:21][CH3:20])=[CH:23][C:24]=1[CH2:25][CH2:26]3
Reactant: CCOP(=O)(OCC)C(F)F
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)C=C[C@@H]12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=C(F)F)C=C[C@@H]12
Reaction time: 1 h
Yield: 47.8 %

Procedure:
A solution of 9.4 g of diethyl-(difluoromethyl)-phosphonate in 150 ml of tetrahydrofuran is slowly mixed with 25 ml of 2 M lithium diisopropylamide solution at a bath temperature of -50° C., and it is stirred for 1 hour. Then, a solution of 5.6 g of 3-methoxy-estra-1,3,5(10),15-tetraen-17-one in 173 ml of tetrahydrofuran is slowly added, stirred for 15 minutes, slowly heated at a bath temperature of from -50° C. to 100° C. and refluxed for 6 hours. For working-up, half the volume is concentrated by evaporation in a vacuum, diluted with ethyl acetate, washed with water as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate/triethylamine. 3.0 g of 17-difluoromethylene-3-methoxy-estra -1,3,5(10),15-tetraene is obtained as colorless crystals with a melting point of 122-123° C., [α]D22 -120.9° (c=0.515% in pyridine).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[CH2:26]([O:28]C(C1C=CNC=1C)=O)C.COC1C=C(C=CC=1)CCl>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:28][CH3:26])[CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc[nH]c1C
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccc(F)cc1
Agent: COc1cccc(CCl)c1
Product: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1cccc(OC)c1

Procedure:
Prepared similarly according to a reaction sequence in Example 117 steps (a), (b), (c) and (d) for the synthesis of 2,3-dibromo-1-(4-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester starting from 2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester, 3-methoxybenzyl chloride. The title compound, ESI MS (m/z): 483 (M+H)+.