Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][CH2:9][C:10](Br)=[O:11]>CN(C=O)C.O1CCOCC1>[Br:8][CH2:9][C:10]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:11]
Reactant: O=C(Br)CBr
Reactant: Nc1ccccc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(CBr)Nc1ccccc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 67.4 %

Procedure:
Aniline (19.4 g, 0.043 mol) was dissolved in the mixture of DMF (25 mL) and dioxane (25 mL). The solution was cooled to +5° C. and bromoacetyl bromide (3.8 mL=8.7 g, 100 mol %) was added dropwise over 30 min. The reaction mixture was warmed to room temperature and stirred for 7 h. The mixture was poured into ice-water, and the white crystalline compound which precipitated was filtered, washed several times with cold water, and then air dried for 24 h, giving 6.2 g (68%) of title compound: 1H NMR (CDCl3) δ8.20 (bs, 1H), 7.54 (dd, J=8.8, J=1.2, 2H), 7.37 (t, J=7.2, 1H), 7.18 (t, J=8, 1H), 4.03 (s, 2H): 13C NMR (CDCl3) δ163.35, 136.88, 129.21, 129.18, 129.11, 125.21, 120.03, 29.47; MS (El, m/z) 213 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[CH:6][N:5]=[C:4]([N:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])=[N:14]2)[N:3]=1.[H-].[Na+].[F:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35]Br>C1COCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([N:8]([CH2:35][C:34]2[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=2[F:32])[C:9](=[O:12])[O:10][CH3:11])=[CH:6][N:5]=[C:4]([N:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])=[N:14]2)[N:3]=1
Reactant: COC(=O)Nc1cnc(-n2nc(Cc3ccccc3F)c3ncccc32)nc1N
Reactant: Fc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)N(Cc1ccccc1F)c1cnc(-n2nc(Cc3ccccc3F)c3ncccc32)nc1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
47 mg (0.12 mmol) of the compound from example 15A were initially charged in 3 ml of THF, and the mixture was cooled to 0° C. Subsequently, 5 mg (0.12 mmol) of sodium hydride (60% in mineral oil) were added and the mixture was stirred at 0° C. for a further 30 min. Thereafter, 14 μl (0.12 mmol) of 2-fluorobenzyl bromide were added dropwise, and the mixture was stirred at RT overnight. The reaction mixture was diluted with ethyl acetate and the organic phase was washed twice with saturated aqueous sodium bicarbonate solution. The organic phase was then dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC (acetonitrile:water (+0.1% formic acid) gradient). The crude product obtained in this manner was purified by means of preparative thin-layer chromatography (mobile phase: dichloromethane-methanol 20:1). This gave 8 mg of the target compound (13% of theory).
Reaction SMILES: [NH2:1][C:2]1[C:12]2[C:11](=[O:13])[NH:10][CH2:9][CH2:8][N:7](C(=O)C(F)(F)F)[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([NH:37][CH3:38])(=[O:36])=[O:35])[C:24]([Cl:39])=[CH:23][N:22]=1.Cl>C(O)(C)C.O1CCOCC1>[Cl:39][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([NH:37][CH3:38])(=[O:36])=[O:35])=[N:26][C:21]([NH:1][C:2]2[C:12]3[C:11](=[O:13])[NH:10][CH2:9][CH2:8][NH:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[N:22][CH:23]=1
Reactant: Nc1cccc2c1C(=O)NCCN2C(=O)C(F)(F)F
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2cccc3c2C(=O)NCCN3)ncc1Cl
Reaction time: 0.17 h
Yield: 15.4 %

Procedure:
Into a microwave vial was placed 6-amino-1-(2,2,2-trifluoro-acetyl)-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (25 mg, 0.092 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide (27 mg, 0.082 mmol) in isopropyl alcohol (3 mL) with 4 M HCl in dioxane (˜2 drops). The mixture was subjected to microwaves at 120° C. for 10 minutes. Trace starting materials were present so the reaction mixture was resubjected to the same microwave conditions. The resulting solid was collected by filtration and washed with cold methylene chloride and dried in a vacuum oven at 50° C. overnight to give product as an off-white solid 2-[5-Chloro-2-(5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-6-ylamino)pyrimidin-4-ylamino]-N-methylbenzene-sulfonamide (6 mg, 16% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.60 (s, 1H), 9.62 (s, 1H), 9.04 (d, 1H, J=8 Hz), 8.95-8.86 (m, 3H), 8.55 (s, 1H), 7.88-7.25 (m, 4H), 6.71 (d, 1H, J=7.8 Hz), 6.52 (s, 1H), 3.46 (m, 2H), 2.84 (d, 3H), 2.5 (m, 2H); MS (m/e) 474 (M+1)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][C:12]([OH:14])=O>S(=O)(=O)(O)O>[CH3:8][C:5]1[C:4]2[C:12](=[O:14])[CH2:11][CH2:10][S:9][C:3]=2[C:2]([CH3:1])=[CH:7][CH:6]=1
Reactant: Cc1ccc(C)c(SCCC(=O)O)c1
Agent: O=S(=O)(O)O
Product: Cc1ccc(C)c2c1SCCC2=O
Reaction time: 1 h
Yield: 51.4 %

Procedure:
530 mL of concentrated sulfuric acid was added to 24.91 g (0.119 mol) of the title compound of Step A while being cooled with an acetone/ice bath. The ice bath was removed, the mixture stirred for 1 hr and was then poured over crushed ice. The aqueous layer was extracted with a 1:9 mixture of diethyl ether:hexane (6×500 mL), dried (MgSO4), filtered, and evaporated to dryness to yield 11.75 g of the title compound of Step B as an oil. 1H NMR (CDCl3): δ2.3 (s,3H), 2.6 (s,3H), 2.97 (m,2H), 3.2 (m,2H), 6.9-7.1 (m,2H).
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1.[N-:14]=[N+:15]=[N-:16].[Na+].S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[OH-].[Na+]>C(#N)C>[CH3:1][N:2]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=2)=[N:16][N:15]=[N:14]1
Reactant: CNC(=O)c1cccc([N+](=O)[O-])c1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cn1nnnc1-c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 17.7 %

Procedure:
In a dry flask N-methyl-3-nitro-benzamide (30.0 g, 167 mmol) was dissolved in acetonitrile (835 mL) and sodium azide (10.9 g, 167 mmol) was added and the reaction cooled in an ice bath. Triflic anhydride (29 mL, 172 mmol) was added dropwise to maintain the internal temperature below 3° C. The reaction mixture was stirred for 3.5 hours at 0° C. The reaction mixture was poured into IN aqueous sodium hydroxide (100 mL). The organic layer was separated dried with sodium sulfate, filtered, and concentrated in vacuo to 50 mL. The solution was diluted with dichloromethane and added water to precipitate a yellow solid (18.46 g, 54%). A second crop of crystals was obtained by concentrated the filtrate in vacuo and adding it to boiling ethyl acetate. Upon cooling to 0° C., 6.07 g (18%) of additional material was isolated upon filtration. further purification. 1H NMR (300 MHz, CDCl3), δ: 3.67 (m, 1H), 8.49 (dd, J=8, J′=2, 1H), 8.31 (d, J=8, 1H), 7.94 (dd, J=8, J′=8, 1H), 4.22 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([N:16]=[C:17]=[S:18])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[C:19]([NH:22][NH2:23])(=[O:21])[CH3:20].CO>O1CCCC1>[C:19]([NH:22][NH:23][C:17]([NH:16][C:12]1[CH:13]=[CH:14][C:15]2[N:3]([CH2:1][CH3:2])[C:4]3[C:9]([C:10]=2[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[S:18])(=[O:21])[CH3:20]
Reactant: CCn1c2ccccc2c2cc(N=C=S)ccc21
Reactant: CC(=O)NN
Solvent: C1CCOC1
Solvent: CO
Product: CCn1c2ccccc2c2cc(NC(=S)NNC(C)=O)ccc21

Procedure:
3.8 g of 9-ethyl-3-isothiocyanatocarbazole was reacted with 1.1 g of acetylhydrazine in 30 ml of tetrahydrofuran at 60° C. for 2 hours. Then, 10 ml of methanol was added thereto and crystallization was conducted while cooling with ice. Crystals thus precipitated were collected by filtration, and recrystallized from CHCl3 /CH3OH (70 ml/200 ml) to obtain 2.4 g of the desired end compound. m.p. 197°-199° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:20].[Na+].II>CN.C(O)C.O>[OH:19][C:16]1[C:17]([I:20])=[CH:18][C:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:14][CH2:13][C:12]=2[CH:15]=1
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2CC1
Agent: CN
Agent: II
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2cc(O)c(I)cc2CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 7-hydroxy-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylic acid tert-butyl ester (PCT Int. Appl. (2002), WO 02/40471) (5.2 g, 20 mmol) in 33% methylamine in ethanol (30 ml) was stirred at 0° C. A solution of sodium iodide (4.6 g, 30 mmol) and iodine (5.2 g, 20 mmol) in water (30 ml) was added below the surface of the reaction mixture. After stirring at 0° C. for 1 hour the mixture was concentrated in vacuo. The residue was diluted with ethyl acetate and water. The organic layer was separated, washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to afford the title compound (D41); (7.0 g, 90%), 1H NMR (d6-DMSO) 10.0 (1H, br s), 7.41 (1H, s), 6.65 (1H, s), 3.40 (4H, m), 2.70 (4H, m), 1.40 (9H, s).
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[O-:17][Cr](O[Cr]([O-])(=O)=O)(=O)=O.[Na+].[Na+]>C(O)(=O)C>[C:1]([C:4]1[C:5](=[O:17])[C:6]2[C:14](=[CH:15][CH:16]=1)[C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH:7]=2)(=[O:3])[CH3:2]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CC(=O)c1ccc2c(c1)Cc1ccccc1-2
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)C1=CC=C2C(=Cc3ccccc32)C1=O

Procedure:
Known in the present-day practice is a method of producing the bisulfite compound of 2-fluorenonyl-glyoxal, said method consisting in that fluorene is acylated by acetic anhydride in the presence of aluminum chloride to obtain 2-acetylfluorene at a yield of 60 weight percent. Then the thus-obtained 2-acetylfluorene is oxidized by sodium bichromate in an acetic-acid medium at 70°-75° C during 6 hours and 2-acetylfluorenon is isolated at a yield of 50 weight percent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[S:17][C:16]2[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=2[CH:14]=1)=[O:12].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[S:17][C:16]3[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=3[CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: O=C(CBr)c1cc2c(s1)CCCC2
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Cn1cc(Cl)cnc1=O)c1cc2c(s1)CCCC2
Temperature: 25 °C
Yield: 33.1 %

Procedure:
A mixture of 5-chloropyrimidin-2-one (370 mg) and 2-bromoacetyl-4,5,6,7-tetrahydrobenzo[b]thiophene (740 mg) in ethanol (15 ml) was treated with triethylamine (0.6 ml, 4.76 mmol) and then stirred at room temperature. After 1.5 h the mixture was concentrated to ca 5 ml and then diluted with ethyl acetate (50 ml). The resulting solution was washed with water (×3), dried (MgSO4) and evaporated to a pale yellow foam. The foam was subjected to preparative thin-layer chromatography on silica developing with chloroform-ethanol (29:1) (two runs). Elution of the major band with ethyl acetate gave a white solid which was crystallised from ethyl acetate to give the title pyrimidinone (290 mg), m.p. 206°-208° C., λmax (EtOH) 225 nm (ε 10,160), 268.5 nm (ε 9,570), 314 nm (ε 12,260).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[O:8][CH3:9])[CH2:3][OH:4].[N:17]#[C:18]Br>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH:7]([O:8][CH3:9])[CH2:6][CH2:5][C@H:2]2[CH2:3][O:4][C:18]([NH2:17])=[N:1]2)=[CH:11][CH:12]=1
Reactant: COC(CC[C@H](N)CO)c1ccc(Cl)cc1
Reactant: N#CBr
Product: COC(CC[C@H]1COC(N)=N1)c1ccc(Cl)cc1

Procedure:
In analogy to example 1d (S)-2-amino-5-(4-chloro-phenyl)-5-methoxy-pentan-1-ol was reacted with cyanogen bromide to give (S)-4-[3-(4-chloro-phenyl)-3-methoxy-propyl]-4,5-dihydro-oxazol-2-ylamine (mixture of epimers). White solid. MS (ISP): 271.2 ([{37Cl}M+H]+), 269.2 ([{35Cl}M+H]+).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]#[N:26])=[CH:15][CH:14]=2)=[C:5]([C:10](O)=[S:11])[N:6]([CH3:9])[C:7]=1[CH3:8])#[N:2].C(Cl)(=O)C(Cl)=O.C[N:34](C=O)C.[OH-].N>C(Cl)Cl>[C:1]([C:3]1[C:4]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]#[N:26])=[CH:15][CH:14]=2)=[C:5]([C:10]([NH2:34])=[S:11])[N:6]([CH3:9])[C:7]=1[CH3:8])#[N:2]
Reactant: CN(C)C=O
Reactant: Cc1c(C#N)c(-c2ccc(-c3ccccc3C#N)cc2)c(C(O)=S)n1C
Agent: N
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Product: Cc1c(C#N)c(-c2ccc(-c3ccccc3C#N)cc2)c(C(N)=S)n1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirring solution of 4-cyano-3-[4-(2-cyanophenyl)phenyl]-1-methyl-5-methylthiopyrrole-2-carboxylic acid (11.0 mmol, prepared in example A-163) in methylene chloride, add oxalyl chloride (2.0 mmol) and catalytic DMF. Stir this solution for 20 minutes at room temperature and then concentrate in vacuo. Dissolve the residue in methylene chloride and ammonia hydroxide (2.0 mmol). Stir this reaction for one minute. The reaction becomes cloudy. Concentrate in vacuo. Purify the residue via radial chromatography and recrystallize using ether and hexanes to yield the title compound. MS (m/e): 373.1 (M+1) 371.0 (M−1); 1H NMR δ 7.97 (d, 1H), 7.84 (s, 2H), 7.80 (t, 1H), 7.66 (m, 3H), 7.57 (m, 3H), 3.80 (s, 3H), 2.46 (s, 3H).
Reaction SMILES: [N:1]1([CH2:6][C:7]#[C:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)=[CH:19][CH:18]=3)=[O:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Ni].CO>[N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)=[CH:21][CH:22]=3)=[O:16])=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(C#CCN2CCCC2)nc1
Agent: [Ni]
Solvent: CO
Product: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(CCCN2CCCC2)nc1
Reaction time: 1 h
Yield: 76.9 %

Procedure:
Raney nickel (0.3 g, 0.6 mmol, 10 mol %) was added to a solution of (6-(3-(pyrrolidin-1-yl)prop-1-ynyl)pyridin-3-yl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (2.2 g, 5.6 mmol) in 20 mL methanol at room temperature, and the reaction mixture was stirred for 1 h under hydrogen atmosphere. The nickel was filtered off and the filtrate was concentrated in vacuo to afford the desired product as a yellow solid (1.7 g, 77.3% yield).
Reaction SMILES: Cl.[NH2:2][C:3](=[NH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=[CH2:20].C(=O)([O-])O.[Na+]>C(O)C>[C:3]([CH:4]([CH2:20][CH2:19][C:18]([O:22][CH2:23][CH3:24])=[O:21])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[NH:2])[NH2:10]
Reactant: CCOC(=O)CC(=N)N
Reactant: C=CC(=O)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCC(C(=N)N)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-amino-3-iminopropionoate hydrochloride (10 g) and triethylamine (18.4 mL) in ethanol (100 mL) was added ethyl acrylate (7.15 mL), and the mixture was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.5 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:13][C@H:14]1[O:19][C@@H:18]([CH3:20])[CH2:17][N:16]([CH2:21][C:22]2[O:26][C:25]([C:27]3[CH:35]=[C:34]([C:36]4[CH:37]=[C:38]([NH2:44])[C:39]([O:42][CH3:43])=[N:40][CH:41]=4)[CH:33]=[C:32]4[C:28]=3[CH:29]=[N:30][N:31]4[S:45]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)(=[O:47])=[O:46])=[N:24][N:23]=2)[CH2:15]1.O>N1C=CC=CC=1>[CH3:13][C@H:14]1[O:19][C@@H:18]([CH3:20])[CH2:17][N:16]([CH2:21][C:22]2[O:26][C:25]([C:27]3[CH:35]=[C:34]([C:36]4[CH:37]=[C:38]([NH:44][S:9]([C:3]5[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=5[F:1])(=[O:11])=[O:10])[C:39]([O:42][CH3:43])=[N:40][CH:41]=4)[CH:33]=[C:32]4[C:28]=3[CH:29]=[N:30][N:31]4[S:45]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)(=[O:46])=[O:47])=[N:24][N:23]=2)[CH2:15]1
Reactant: COc1ncc(-c2cc(-c3nnc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1N
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Solvent: c1ccncc1
Solvent: O
Product: COc1ncc(-c2cc(-c3nnc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
2,4-Difluorobenzenesulfonyl chloride (0.048 mL, 0.354 mmol) was added dropwise to a solution of 5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinamine (185 mg, 0.321 mmol) in pyridine (1 ml). The mixture was stirred at room temperature for 2 h. 2,4-Difluorobenzenesulfonyl chloride (0.048 mL, 0.354 mmol) was added dropwise and the mixture continued stirring at room temperature for 1 h. Water (10 ml) was added and the resultant brown precipitate collected by filtration and dried in the vacuum oven for 72 h to give the title compound as a brown solid (194 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:20]2[CH:19]=[CH:18][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: Oc1ccc2ccccc2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](Oc2ccc3ccccc3c2)CN1C(=O)OC(C)(C)C

Procedure:
To a stirred mixture of methyl (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarboxylate (4.22 g, 17.2 mmol, 2-naphthol (2.73 g, 18.9 mmol) and PPh3 (4.96 g, 18.9 mmol) in THF (80 ml) was added DIAD (3.72 ml, 18.9 mmol) at room temperature under an atmosphere of nitrogen. After stirring over night, the mixture was concentrated in vacuo. The residue was chromatographed on silica gel [600, CHCl3/EtOAc (10/1)], to give methyl (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylcarboxylate (5.37 g), which was used to the next reaction without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:13]3[C:14]([O:22][CH3:23])=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=3[CH2:11][CH2:10][C@H:9]([NH:24][C:25](=[O:27])[CH3:26])[C:8]=2[CH:28]=1)(O)=[O:2].C1CCC(N=C=NC2CCCCC2)CC1.[NH2:44][CH2:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>CN(C1C=CN=CC=1)C.ClCCl>[C:25]([NH:24][C@@H:9]1[C:8]2[CH:28]=[C:4]([C:1]([NH:44][CH2:45][CH2:46][CH2:47][N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[O:2])[CH:5]=[CH:6][C:7]=2[C:13]2[C:14]([O:22][CH3:23])=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10]1)(=[O:27])[CH3:26]
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(C(=O)O)cc1[C@@H](NC(C)=O)CC2
Reactant: NCCCN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc2c(c(OC)c1OC)-c1ccc(C(=O)NCCCN3CCOCC3)cc1[C@@H](NC(C)=O)CC2
Yield: 30 %

Procedure:
A solution of N-[(5S)-3-carboxy-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide (0.3 g; 0.779 mmol), (Med. Chem. Res. 1991, 142), DCCI (0.322 g; 1.55 mmol), DMAP (0.069 g; 0.389 mmol) and 4-(3-aminopropyl)morpholine (170 μl; 1.17 mmol) in dichloromethane (6 ml) was stirred under argon atmosphere overnight. After removal of the insoluble material by filtration, the residue was purified on reverse phase silica eluting with a gradient of 40–50% methanol/ammonium carbonate buffer (2 g/l, pH7). The appropriate fractions were evaporated to dryness and triturated in ether to give (5S)-5-(acetylamino)-9,10,11-trimethoxy-N-(3-morpholinopropyl)-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-3-carboxamide as a white solid.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH:2]=[CH2:3].C([Li])CCC.CCCCCC.[CH2:33]([Sn:37](Cl)([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH3:36]>C1COCC1>[CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:10][C:11]([Sn:37]([CH2:38][CH2:39][CH2:40][CH3:41])([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH:2]=[CH2:3]
Reactant: C=CCn1ccnc1-c1sccc1-c1ccc(Cl)cc1Cl
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCn1ccnc1-c1sc([Sn](CCCC)(CCCC)CCCC)cc1-c1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
To a stirred solution of 1-allyl-2-[3-(2,4-dichlorophenyl)-2-thienyl]-1H-imidazole (3.40 g, 10.1 mmol) in THF (80 mL) was added dropwise 2.50 M of n-butyllithium in Hexane (4.46 mL, 11.2 mmol) at −78° C. and the resulting solution was stirred for 30 min. A solution of tributyltin chloride (3.44 mL, 12.7 mmol) in THF (40.0 mL) was added dropwise into the cold solution and then the resulting mixture was stirred for 1 hr at −78° C. The reaction mixture was quenched by addition of water (150 ml) and the resulting mixture was extracted with EtOAc (200 ml×3). The combined organic layers were washed with brine, dried using Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, elution with 0-20% EtOAc in hexanes) to provide 3.5 g of product as a yellowish oil (71%). LC/MS (FA) ES+ 625. 1H NMR (400 MHz, d6 DMSO) δ: 7.67 (d, J=2.0 Hz, 1H), 7.34 (dd, J=2.0, 8.3 Hz, 1H), 7.24 (t, J=10.5 Hz, 1H), 7.12 (d, J=1.2 Hz, 1H), 7.07 (d, J=8.3 Hz, 1H), 6.97 (d, J=1.2 Hz, 1H), 5.46-5.57 (m, 1H), 4.98 (dd, J=1.5, 10.2 Hz, 1H), 4.79 (dd, J=1.5, 17.1 Hz, 1H), 4.18-4.22 (m, 2H), 1.44-1.68 (m, 6H), 1.25-1.36 (m, 6H), 1.04-1.23 (m, 6H), 0.82-0.89 (m, 9H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]1([CH3:18])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][SH:17].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.O>[CH3:18][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][S:17][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1CS
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1CSc1ccc(C=O)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
4-fluoro-benzaldehyde (1.16 g, 9.32 mmol) was added dropwise over 2 minutes to a solution of o-tolyl-methanethiol (1.35 g, 9.79 mmol) and Cesium carbonate (3.19 g, 9.79 mmol) in DMF (20 mL). The solution was stirred at 40° C. overnight and then poured into copious water. The pH of the solution was adjusted to 4 with 1N HCl(aq), and the aqueous solution was extracted with ethyl acetate (2×35 mL). The combined organic layers were washed with water, followed by brine. The combined organic layers were then dried (Na2SO4) and the solvent removed under reduced pressure. The resulting residue was purified via radial chromatography (15% ethyl acetate in hexanes) to yield 1.29 g (54%) of 4-(2-Methyl-benzylsulfanyl)-benzaldehyde (28.1). LC/MSD m/e: 243.0 (M+H).