Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N:14]3[C:26]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:20]4[C:15]3=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[I-:27].[Na+].CNC1CCCCC1NC>[Cu]I.O1CCOCC1>[I:27][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N:14]3[C:26]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:20]4[C:15]3=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(-c2cccc(-n3c4ccccc4c4ccccc43)c2)c1
Reactant: [I-]
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: Ic1cccc(-c2cccc(-n3c4ccccc4c4ccccc43)c2)c1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
9-(3′-bromo-[1,1′-biphenyl]-3-yl)-9H-carbazole (9.50 g, 23.85 mmol), sodium iodide (7.15 g, 47.7 mmol), copper(I) iodide (1.363 g, 7.16 mmol), and dioxane (239 ml) were added into a 500 mL 3-necked flask. N1,N2-dimethylcyclohexane-1,2-diamine (1.881 ml, 11.93 mmol) was added. The reaction mixture was heated and refluxed overnight. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was filtered through a pad of Celite® and washed several times with DCM. The solvent are evaporated in vacuum. The crude material was purified by column chromatography using hexane and DCM (75/25) and gradually increasing DCM to a ratio of hexane/DCM 50/50. The product was further purified by trituration from methanol. 9-(3′-iodo-[1,1′-biphenyl]-3-yl)-9H-carbazole (10.2 g, 22.91 mmol, 96% yield) was obtained as a white solid.
Reaction SMILES: [H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].[C:19]([OH:22])(=[O:21])[CH3:20].[C:23]([OH:26])(=[O:25])[CH3:24].O[C@H:28]1[CH2:33][CH2:32][C@H:31]2[C@H:34]3[C@H:45]([CH2:46][CH2:47][C@:29]12[CH3:30])[C@:42]1([CH2:43]O)[C:37]([CH2:38][C:39](=[O:49])[CH2:40][C@@H:41]1[CH3:48])=[CH:36][C@H:35]3[CH3:50].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O1CCCC1>[C:19]([O:22][C@H:28]1[CH2:33][CH2:32][C@H:31]2[C@H:34]3[C@H:45]([CH2:46][CH2:47][C@:29]12[CH3:30])[C@:42]1([CH2:43][O:25][C:23](=[O:26])[CH3:24])[C:37]([CH2:38][C@@H:39]([OH:49])[CH2:40][C@@H:41]1[CH3:48])=[CH:36][C@H:35]3[CH3:50])(=[O:21])[CH3:20]
Reactant: CC(=O)O
Reactant: C[C@@H]1C=C2CC(=O)C[C@H](C)[C@]2(CO)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(=O)OC[C@]12C(=C[C@@H](C)[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]31)C[C@@H](O)C[C@@H]2C
Temperature: 20 °C
Reaction time: 18 h

Procedure:
To a solution of lithium tri-t-butoxyaluminum hydride in tetrahydrofuran is added a tetrahydrofuran solution of 17β,19-dihydroxy-1α,7α-dimethyl-5-androsten-3-one diacetate. The resulting mixture is stirred at 20° C. for a period of 18 hours after which is added an aqueous solution of sodium potassium tartrate. The mixture is filtered and concentrated to a small volume under reduced pressure. The concentrate is taken up in ether and washed well with water. The combined ether extracts are dried over magnesium sulfate, filtered and the ether removed under vacuum to yield a residue which when crystallized from a mixture of acetone-hexane results in the preparation of the desired 1α,7α-dimethyl-androst-5-ene-3β,17β,19-triol 17,19-diacetate.
Reaction SMILES: C([O-])=O.[CH2:4]([N:6]([CH2:30][CH3:31])[C:7](=[O:29])[CH:8]=[CH:9][C:10]1[C:18]2[N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[N:15][C:14]=2[CH:13]=[C:12]([C:25]([F:28])([F:27])[F:26])[CH:11]=1)[CH3:5]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].CS(C)=O>[CH2:30]([N:6]([CH2:4][CH3:5])[C:7](=[O:29])[CH2:8][CH2:9][C:10]1[C:18]2[N:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:16]=[N:15][C:14]=2[CH:13]=[C:12]([C:25]([F:27])([F:28])[F:26])[CH:11]=1)[CH3:31]
Reactant: CCN(CC)C(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Agent: [Rh]
Agent: O=C[O-]
Agent: [Cl-]
Solvent: CS(C)=O
Product: CCN(CC)C(=O)CCc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12

Procedure:
Alumina supported formate was prepared according to the procedure of Danks and Desai (T. N. Danks and B. Desai, Green Chemistry, 2002, 4, 179-180). A Smith Process Vial™ was loaded with alumina supported formate (0.5 g), Wilkinson's catalyst (0.5 mg), N,N-diethyl-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylamide (0.064 mmol, 25 mg) and dimethylsulphoxide (0.5 ml) and was irradiated for 600 s at 180° C. using a Personal Chemistry Smith Creator™ microwave. The mixture was filtered to remove the solid support and the filtrate was purified by LCMS to give, after evaporation, the title compound as a solid (7.8 mg, 31%), m/z 390.0 (M+H)+.
Reaction SMILES: C([NH:8]C1C=C(C=C(S(Cl)(=O)=O)C=1C1C=CC=CC=1)C(O)=O)C1C=CC=CC=1.Cl[S:29]([C:32]1[C:33]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[C:34]([O:41][CH2:42][C:43]#[CH:44])[CH:35]=[C:36]([CH:40]=1)[C:37]([OH:39])=[O:38])(=[O:31])=[O:30]>>[C:45]1([C:33]2[C:32]([S:29](=[O:31])(=[O:30])[NH2:8])=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][C:34]=2[O:41][CH2:42][C:43]#[CH:44])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: C#CCOc1cc(C(=O)O)cc(S(=O)(=O)Cl)c1-c1ccccc1
Reactant: O=C(O)c1cc(NCc2ccccc2)c(-c2ccccc2)c(S(=O)(=O)Cl)c1
Product: C#CCOc1cc(C(=O)O)cc(S(N)(=O)=O)c1-c1ccccc1

Procedure:
By replacing in Example 1, step G, 3-benzylamino-5-chlorosulfonyl-4-phenylbenzoic acid with 5-chlorosulfonyl-4-phenyl-3-propargyloxybenzoic acid, and following the procedure described, 4-phenyl-3-propargyloxy-5-sulfamylbenzoic acid is obtained with a melting point of 154°-155° C.
Reaction SMILES: [C:1](=[S:3])=S.C(N(CC)CC)C.[NH2:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[C:15]([CH2:22][O:23][CH2:24][CH3:25])[N:16]=[CH:17]2.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[CH2:24]([O:23][CH2:22][C:15]1[N:16]=[CH:17][C:18]2[C:13]([CH:14]=1)=[C:12]([N:11]=[C:1]=[S:3])[CH:21]=[CH:20][CH:19]=2)[CH3:25]
Reactant: S=C=S
Reactant: CCOCc1cc2c(N)cccc2cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOCc1cc2c(N=C=S)cccc2cn1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
A solution of carbon disulphide (16 cc) and triethylamine (4.5 cc) in pyridine (20 cc) is cooled to -10° C. A solution of 5-amino-3-ethoxymethylisoquinoline (6.5 g) in pyridine (20 cc) is added dropwise in the course of 5 minutes. The mixture is stirred for 3 hours at -10° C. and a solution of dicyclohexylcarbodiimide (6.6 g) in pyridine (20 cc) is then added. Stirring is continued, whilst leaving the reaction mixture to return to a temperature of about 20° C. The mixture is stirred for 24 hours at this temperature and then concentrated to dryness at 50° C. under reduced pressure (20 mm Hg). The residue is taken up in methylene chloride (25 cc). An insoluble material is filtered off and the filtrate is evaporated to dryness at 40° C. under reduced pressure (20 mm Hg). The residue is taken up in diisopropyl ether (200 cc). The isoluble yellow solid is isolated by filtration, washed with diisopropyl ether (20 cc) and dried. 3-Ethoxymethyl-5-isothiocyanatoisoquinoline (7 g), melting at 66° C., is obtained.
Reaction SMILES: Cl[O-:2].[Li+].[C:4]([C:7]1[S:8][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:10][CH:11]=1)(=[O:6])C.[OH-].[K+]>>[CH2:13]([O:12][C:9]1[S:8][C:7]([C:4]([OH:6])=[O:2])=[CH:11][CH:10]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: [O-]Cl
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(C)=O)s1
Agent: [K+]
Agent: [Li+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
When in Example 3, 1-bromooctadecane is substituted for 1-bromohexadecane, 2-octadecyloxythiophene is obtained. A mixture of 35.3 g (0.1 mole) of 2-octadecyloxythiophene and 12.3 g (0.12 mole) of acetic anhydride is cooled in an ice bath. While rapidly stirring this mixture, 1.4 g of boron trifluoride etherate is added, and the mixture is heated to 100° C with stirring for 1 hour after which it is cooled to room temperature. Ice water is added, and the mixture is extracted with chloroform. The chloroform solution is evaporated to dryness under reduce pressure to give 2-acetyl-5-octadecyloxythiophene. In 500 ml of 10% aqueous potassium hydroxide 2-acetyl-5-octadecyloxythiophene is combined with 35.0 g (0.6 mole) of lithium hypochlorite. The mixture is stirred vigorously on a steam bath overnight, then allowed to cool to room temperature and extracted with ether. The aqueous extract is acidified with hydrochloric acid to precipitate 5-octadecyloxy-2-thiophenecarboxylic acid
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[C:7]([S:14]([NH2:17])(=[O:16])=[O:15])=[C:8]([N+:11]([O-])=O)[S:9][CH:10]=1>C(O)(=O)C.[Fe]>[NH2:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][O:4][CH2:3][O:2][CH3:1])[C:7]=1[S:14]([NH2:17])(=[O:15])=[O:16]
Reactant: COCOCc1csc([N+](=O)[O-])c1S(N)(=O)=O
Agent: [Fe]
Solvent: CC(=O)O
Product: COCOCc1csc(N)c1S(N)(=O)=O
Temperature: 50 °C
Reaction time: 7.5 h
Yield: 61.9 %

Procedure:
A solution of the product of Example 10D (1.8 g, 6.4 mmol) in acetic acid (70 mL) was treated with iron powder (1.43 g, 25.5 mmol), stirred at 50° C. for 7.5 h and concentrated. A mixture of the residue in 5% methanol in dichloromethane (60 mL) and water (6 mL) was filtered through silica gel (20 g), and rinsed with 5% methanol in dichloromethane (300 mL). The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel, eluting with methanol in dichloromethane to give the title compound (1 g, 62%). 1H NMR (300 MHz, DMSO-d6): δ 6.94 (s, 2 H), 6.61 (s, 2 H), 6.28 (s, 1 H), 4.66 (s, 2 H), 4.53 (s, 2 H), 3.30 (s, 3 H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][CH:8]([OH:12])[CH2:9][CH2:10]Cl)[CH3:2].[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K]>>[CH2:1]([O:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][CH:8]([OH:12])[CH2:9][CH2:10][N:21]1[C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]2[C:17]1=[O:27])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOc1ccccc1OCC(O)CCCl
Agent: [K]
Product: CCOc1ccccc1OCC(O)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 30 g. (0.12 mole) of 1-(2-ethoxyphenoxy)-4-chloro-2-butanol and 18.5 g. (0.10 mole) of potassium phthalimide was heated slowly to 130° C. for 10 min. and at 160° C. for one hour with stirring. The reaction mixture was extracted with 250 ml. of hot toluene. A crystalline solid separated from the toluene extract when cooled to room temperature. The solid was recrystallized from toluene and melted at 93°-95° C.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=O)(C)(C)C.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][C:30]([C:33]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[O:34])=[CH:29][C:28]=2[NH:41][C:42]([C:44]2[S:45][CH:46]=[CH:47][C:48]=2[CH3:49])=[O:43])=[N:17]1.O.ON1C2C=CC=CC=2N=N1.C(Cl)CCl>C1COCC1.C(OCC)(=O)C>[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][C:30]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([C:10]([C@@H:9]4[CH2:13][CH2:14][CH2:15][NH:8]4)=[O:12])[CH2:39][CH2:40]3)=[O:34])=[CH:29][C:28]=2[NH:41][C:42]([C:44]2[S:45][CH:46]=[CH:47][C:48]=2[CH3:49])=[O:43])=[N:17]1
Reactant: Cc1ccsc1C(=O)Nc1cc(C(=O)N2CCNCC2)ccc1/C=C/c1n[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccsc1C(=O)Nc1cc(C(=O)N2CCN(C(=O)[C@@H]3CCCN3)CC2)ccc1/C=C/c1n[nH]c2ccccc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 58.6 %

Procedure:
N-(tert-butoxycarbonyl)-L-proline (0.20 g, 0.42 mmol) was dissolved in THF (10 mL) and the solution was added with Compound 99 (0.14 g, 0.42 mmol), 1-hydroxybenzotriazole monohydrate (75 mg, 0.54 mmol) and EDC (0.11 g, 0.59 mmol), followed by stirring at 60° C. for 2 hours. After the reaction, the reaction mixture was added with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution and the organic layer was concentrated under reduced pressure. The obtained (S)-(E)-N-2-(4-{4-[2-(1H-indazol-3-yl)vinyl]-3-[(3-methylthiophene-2-carbonyl)amino]benzoyl}piperazine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in methanol (5.0 mL) and 4 mol/L hydrogen chloride-methanol solution (1.0 mL) was added thereto, followed by heating under reflux at 60° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was added with saturated aqueous sodium hydrogencarbonate solution and ethyl acetate and then extracted. The obtained crude product was crystallized from ethanol to obtain Compound 231 (0.14 g, 56%).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[N:17]2[CH2:22][CH2:21][N:20]([CH:23]3[CH2:26][O:25][CH2:24]3)[CH2:19][CH2:18]2)[N:4]=[N:3]1>CCO.CO.[Pd]>[NH2:14][C:12]1[CH:11]=[CH:10][C:9]([N:17]2[CH2:22][CH2:21][N:20]([CH:23]3[CH2:26][O:25][CH2:24]3)[CH2:19][CH2:18]2)=[C:8]([N:5]2[C:6](=[O:7])[N:2]([CH3:1])[N:3]=[N:4]2)[CH:13]=1
Reactant: Cn1nnn(-c2cc([N+](=O)[O-])ccc2N2CCN(C3COC3)CC2)c1=O
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: Cn1nnn(-c2cc(N)ccc2N2CCN(C3COC3)CC2)c1=O
Yield: 78 %

Procedure:
1-methyl-4-(5-nitro-2-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1,4-dihydro-5H-tetrazol-5-one (0.75 g, 1.0 eq, 2.1 mmol) was suspended in a mixture of EtOH/MeOH (1:1, 100 mL) in a 250 mL round bottom flask and the reaction flask was charged with Pd—C (10% loading, 0.25 g). The reaction flask was evacuated under house vacuum and subsequently filled with hydrogen while stirring. This procedure was repeated three times and the reaction mixture was stirred for 3 hours under an H2 balloon. The mixture was filtered through celite and the filter cake was washed with MeOH (2×10 mL). The filtrate was concentrated on a rotovap to leave a white solid which upon high vacuum drying gave the product in 78% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10](=[O:15])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:16]=1.[I:17][Si](C)(C)C.II>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10](=[O:15])[CH:9]([I:17])[CH2:8][CH2:7][C:6]=2[CH:16]=1
Reactant: CC(C)N1C(=O)CCCc2cc(F)ccc21
Reactant: C[Si](C)(C)I
Agent: II
Solvent: ClCCl
Product: CC(C)N1C(=O)C(I)CCc2cc(F)ccc21
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
An oven-dried round-bottom flask containing the product of Step 4 (1.92 g, 8.68 mmol) was fitted with a stirbar and septa and flushed with nitrogen. Dichloromethane (50 mL) and N,N′,N′-tetramethylethylenediamine (5.80 mL, 38.4 mmol) were added, giving a solution that was cooled to −10° C. Iodotrimethylsilane (4.80 mL, 35.3 mmol) was added, and stirring was continued at −10° C. for 30 minutes. Iodine (4.71 g, 18.6 mmol) was then added, and the reaction was warmed to 0° C. After stirring 2 hours at 0° C., the reaction was diluted with dichloromethane (100 mL) and washed with 10% aqueous sodium sulfite solution (2×50 mL). The organic layer was then dried over MgSO4, filtered and concentrated in vacuo to give an oil that was purified via flash chromatography on silica gel (0% to 30% ethyl acetate/hexanes linear gradient) to give the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[CH2:12][CH2:11][C:10]([F:14])([F:13])[CH2:9][C@@H:8]([NH:15][S:16]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)(=[O:18])=[O:17])[C:7]1=[O:25].[CH3:32][O:33][C:34]1[N:39]=[CH:38][C:37]([CH2:40]O)=[CH:36][CH:35]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[CH2:12][CH2:11][C:10]([F:13])([F:14])[CH2:9][C@@H:8]([N:15]([CH2:40][C:37]2[CH:38]=[N:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)[S:16]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)(=[O:17])=[O:18])[C:7]1=[O:25]
Reactant: COc1ccc(CN2CCC(F)(F)C[C@@H](NS(=O)(=O)c3ccc(Cl)s3)C2=O)c(OC)c1
Reactant: COc1ccc(CO)cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2CCC(F)(F)C[C@@H](N(Cc3ccc(OC)nc3)S(=O)(=O)c3ccc(Cl)s3)C2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Chloro-thiophene-2-sulfonic acid [(R)-1-(2,4-dimethoxy-benzyl)-5,5-difluoro-2-oxo-azepan-3-yl]-amide (0.20 g, 0.40 mmol), (6-methoxy-pyridin-3-yl)-methanol (0.07 g, 0.48 mmol), triphenyl phosphine (0.22 g, 0.80 mmol) were dissolved in dry THF (15 ml) at 0-5° C. (ice-water bath) under an argon atmosphere followed by the dropwise addition of diisopropyl azodicarboxylate (0.16 ml, 0.80 mmol) in dry THF (1.5 ml). The reaction mixture was further stirred for 1 h at r.t. and then concentrated under reduced pressure. The crude oil was purified over silica gel (first: heptane-ethylacetate, 97:3-0:100; second: dichloromethane-methanol, 98:2-90:10): white solid 0.19 g (53%);
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].[CH3:50][N:51]([CH:55]1[CH2:59][CH2:58][NH:57][CH2:56]1)[C:52](=[O:54])[CH3:53]>>[C:28]([C:32]1[N:33]=[C:34]([N:57]2[CH2:58][CH2:59][CH:55]([N:51]([CH3:50])[C:52](=[O:54])[CH3:53])[CH2:56]2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(=O)N(C)C1CCNC1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(=O)N(C)C1CCN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and N-methyl-N-(pyrrolidin-3-yl)acetamide. MS(m/e): 442.4 (MH+).
Reaction SMILES: C(OC(NOS(C1C(C)=CC(C)=CC=1C)(=O)=O)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][C:37]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)=[N:38]O)=[N:34][CH:35]=1>C(Cl)(Cl)Cl>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([N:38]=[C:37]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)[CH:36]=2)[CH:35]=1
Reactant: ON=C(Cc1ccc(Cl)cn1)c1ccc(F)cc1
Agent: Cc1cc(C)c(S(=O)(=O)ONC(=O)OC(C)(C)C)c(C)c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(-c2cc3ccc(Cl)cn3n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
Solid t-butoxycarbonyl-O-mesitylenesulfonylhydroxylamine (8.45 g 26.8 mmol) was added portionwise with stirring to TFA (100 ml) over 10 min then stirred for a further 30 minutes. The solution was poured onto ice (˜250 ml) and left until the ice melted. The resulting white solid was filtered off, washed with water, and dissolved in chloroform (200 ml). The solution was dried over 4 Å mol. sieves for 1.5 hours, filtered and 2-(5-chloropyridin-2-yl)-1-(4-fluorophenyl)ethanone oxime (3.56 g 13.4 mmol) in chloroform (100 ml) was added. The reaction was stirred at room temperature for 18 hours, washed with water (2×50 ml) and dried. Removal of solvent gave a brown solid which was purified by Biotage chromatography. Elution with cyclohexanelethyl acetate (35/1) gave the title compound as a yellow solid (2.476 g 75%). NMR (CDCl3) δ 6.76 (1H, s, H-3); 7.08 (1H, dd, J 9 & 2 Hz, H-5); 7.13 (2H, t, J 9 Hz, H-3′); 7.45 (1H, d, J 9 Hz, H-4); 7.9 (2H, dd, J 9 & 5 Hz, H-2′); 8.5 (1H, d, J 2 Hz, H-7);
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:17])[C:12]1[S:13][CH:14]=[CH:15][N:16]=1)([CH3:4])[CH3:3].O[C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[C:22]#[N:23]>>[CH3:4][C:2]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][CH2:10][CH:11]([O:17][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[C:22]#[N:23])[C:12]1[S:13][CH:14]=[CH:15][N:16]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCC(O)c1nccs1
Reactant: N#Cc1ccc(Cl)cc1O
Product: CC(C)(C)OC(=O)NCCCC(Oc1cc(Cl)ccc1C#N)c1nccs1

Procedure:
The subtitle compound was prepared according to the method of Example 19 step (b) using the product of step (c) above and 2-hydroxy-4-chlorobenzonitrile.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][N:8]([C@@H:23]([C:25]1[N:26]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]([F:47])([F:46])[F:45])=[CH:38][CH:37]=2)[C:27](=[O:35])[C:28]2[CH:34]=[CH:33][CH:32]=[N:31][C:29]=2[N:30]=1)[CH3:24])[C:9](=[O:22])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1)(=[O:5])=[O:4])[CH3:2]>[Pd].CO>[CH2:1]([S:3]([CH2:6][CH2:7][N:8]([C@@H:23]([C:25]1[N:26]([C:36]2[CH:37]=[CH:38][C:39]([O:42][CH2:43][C:44]([F:47])([F:45])[F:46])=[CH:40][CH:41]=2)[C:27](=[O:35])[C:28]2[CH2:34][CH2:33][CH2:32][NH:31][C:29]=2[N:30]=1)[CH3:24])[C:9](=[O:22])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:19])([F:21])[F:20])[CH:12]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)CCN(C(=O)Cc1ccc(F)c(C(F)(F)F)c1)[C@H](C)c1nc2ncccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: [Pd]
Solvent: CO
Product: CCS(=O)(=O)CCN(C(=O)Cc1ccc(F)c(C(F)(F)F)c1)[C@H](C)c1nc2c(c(=O)n1-c1ccc(OCC(F)(F)F)cc1)CCCN2
Temperature: 25 °C
Reaction time: 20 h
Yield: 104.8 %

Procedure:
A mixture of A3 (58 mg, 0.084 mmol) and 10% palladium on carbon (18 mg, 0.017 mmol) in 2 mL of methanol was allowed to stir at room temperature under hydrogen balloon for 20 h. Upon completion, the mixture was filtered through a short column of celite, and the filtrate was concentrated in vacuo and dried to give 61 mg of 1. 1H NMR: a mixture of cis/trans amide rotamers in ca. 3:1 ratio (400 MHz, CDCl3; T=25° C.) δmajor 7.00-7.47 (m, 7H), 5.31 (br s, 1H), 4.71 (q, J=6.62 Hz, 1H), 4.36 (m, 2H), 3.89-4.02 (m, 1H), 3.69-3.76 (m, 1H), 3.36-3.44 (m, 3H), 2.91-3.04 (m, 3H), 2.51-2.66 (m, 2H), 1.87-1.92 (m, 2H), 1.37-1.43 (m, 4H), 1.33 (d, J=6.7 Hz, 3H) and δminor 5.15 (q, J=7.04 Hz, 1H), 4.77 (br s, 1H), 1.28 (d, J=7.08 Hz, 3H). MS (ESI+) 693 [M+H]+.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7](OCC)(=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[H-].[Na+]>O1CCCC1>[O:13]=[C:7]([CH:2]1[CH2:3][CH2:4][CH2:5][C:1]1=[O:6])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=C1CCCC1
Reactant: CCOC(=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C1CCCC1=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 15.5 mL (0.175 mol) of cyclopentanone and 23.8 mL (0.175 mol) of diethyl oxalate in 90 mL of tetrahydrofuran are added dropwise at 0° C. to a suspension of 7.0 g (0.175 mol) of sodium hydride (50% in oil) in 60 mL of tetrahydrofuran. The mixture is stirred for another 10 minutes at 0° C. and then heated to ambient temperature. After 5 hours, an exothermic reaction sets in and the mixture heats up to 50° C. After 16 hours, it is combined with ice water and extracted with ether. The aqueous phase is adjusted to pH 4 with glacial acetic acid and extracted with ethyl acetate, dried and concentrated by evaporation. The residue is distilled in vacuo. BP(23 mbar)=135° C.-141° C. Yield: 19.6 g (61%).