Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1)#[N:2].[NH2:13][C:14]1[CH:15]=[C:16]([C:20]([C:22]2[C:30]3[CH:29]=[N:28][CH:27]=[N:26][C:25]=3[N:24]([C:31]3([CH2:34][O:35]C4CCCCO4)[CH2:33][CH2:32]3)[CH:23]=2)=[O:21])[CH:17]=[N:18][CH:19]=1.CCCP(O)(O)=O.C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:20]([C:22]3[C:30]4[CH:29]=[N:28][CH:27]=[N:26][C:25]=4[N:24]([C:31]4([CH2:34][OH:35])[CH2:33][CH2:32]4)[CH:23]=3)=[O:21])[CH:15]=2)=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: Nc1cncc(C(=O)c2cn(C3(COC4CCCCO4)CC3)c3ncncc23)c1
Reactant: N#Cc1ccc(CC(=O)O)cc1
Agent: CCCP(=O)(O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1ccc(CC(=O)Nc2cncc(C(=O)c3cn(C4(CO)CC4)c4ncncc34)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
(4-Cyano-phenyl)-acetic acid (6.1 mg, 0.04 mmol) was added to a solution of (5-Amino-pyridin-3-yl)-{7-[1-(tetrahydro-pyran-2-yloxymethyl)-cyclopropyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-methanone (15 mg, 0.04 mmol) (Preparation 251) in THF (1 mL). Then 1-propylphosphonic acid cyclic anhydride (0.07 mL, 0.11 mmol) and triethylamine (0.02 mL, 0.13 mmol) were added and the mixture was stirred at 25° C. for 4 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (2 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layer was washed with water (5 mL), brine (5 mL), dried over sodium sulphate and evaporated in vacuo. The crude was dissolved in methanol (1 mL), PTSA (5 mg) was added and stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (2 mL) and extracted with dichloromethane (5×5 mL). The combined organic layer was washed with brine (5 mL), dried over sodium sulphate and evaporated in vacuo. The crude material was purified by preparative TLC (dichloromethane:methanol 95:5) to afford the title compound as a white solid in 58% yield, 10 mg.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.Cl[C:15]1[S:16][C:17]([C@@:20]2([O:27][CH3:28])[CH2:25][CH2:24][O:23][C@@H:22]([CH3:26])[CH2:21]2)=[CH:18][N:19]=1>>[CH3:28][O:27][C@:20]1([C:17]2[S:16][C:15]([S:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]4)=[N:19][CH:18]=2)[CH2:25][CH2:24][O:23][C@@H:22]([CH3:26])[CH2:21]1
Reactant: CO[C@]1(c2cnc(Cl)s2)CCO[C@@H](C)C1
Reactant: CN1C(=O)CCc2cc(S)ccc21
Product: CO[C@]1(c2cnc(Sc3ccc4c(c3)CCC(=O)N4C)s2)CCO[C@@H](C)C1

Procedure:
Using an analogous procedure to that described in Example 1, 6-mercapto-1-methyl-1,2,3,4-tetrahydroquinolin-2-one was reacted with (2S,4R)-4-(2-chlorothiazol-5-yl)-4-methoxy-2-methyltetrahydropyran to give (2S,4R)-4-methoxy-2-methyl-4-[2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)thiazol-5-yl]tetrahydropyran in 95Z yield as a foam;
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][OH:8])[CH:4]=[N:3][CH:2]=1.[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[S:17]([NH:20][C:21]1[C:26](Br)=[N:25][C:24]([Br:28])=[CH:23][N:22]=1)(=[O:19])=[O:18]>>[Br:28][C:24]1[N:25]=[C:26]([O:8][CH2:7][C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)[C:21]([NH:20][S:17]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=2[Cl:9])(=[O:19])=[O:18])=[N:22][CH:23]=1
Reactant: O=S(=O)(Nc1ncc(Br)nc1Br)c1cccc(Cl)c1Cl
Reactant: OCc1cncnc1
Product: O=S(=O)(Nc1ncc(Br)nc1OCc1cncnc1)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31 using pyrimidine-5-methanol (0.035 g) and 2,3-dichloro-N-(3,5-dibromo-2-pyrazinyl)benzenesulphonamide (0.16 g). Yield 0.028 g.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[C:13]([C:16](=[O:23])[CH2:17][NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=[CH:11][C:10]=2[OH:24])=[O:6])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CC(C)=O>[CH2:2]([O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[C:13]([C:16](=[O:23])[CH2:17][N:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:19]([CH3:20])([CH3:22])[CH3:21])[CH:12]=[CH:11][C:10]=2[O:24][CH2:16][C:13]1[CH:14]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cc2c(C(=O)CNC(C)(C)C)ccc(O)c2[nH]1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2c(C(=O)CN(Cc3ccccc3)C(C)(C)C)ccc(OCc3ccccc3)c2[nH]1

Procedure:
53.6 g of 4-(N-tert-butylaminoacetyl)-7-hydroxyindole-2-carboxylic acid ethyl ester hydrochloride is combined with 59.3 g of potassium carbonate, 63.6 ml of benzyl bromide, and 1000 ml of acetone and heated under reflux for 6 hours. The mixture is then concentrated under vacuum and the residue combined with ethyl acetate and saturated sodium bicarbonate solution. The organic phase is washed three times with sodium bicarbonate solution and once with water, dried over calcium sulfate, and concentrated. The residue is recrystallized twice from ethyl acetate/hexane, thus obtaining 47 g of 7-benzyloxy-4-(N-benzyl-N-tert-butylaminoacetyl)indole-2-carboxylic acid ethyl ester, mp 155°-157° C.
Reaction SMILES: CI.[CH2:3]([O:10][C:11]1[C:16](=[O:17])[C:15]([CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:14][NH:13][C:12]=1[CH3:23])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:24](=O)([O-])[O-].[K+].[K+]>C(#N)C.ClCCl>[CH2:3]([O:10][C:11]1[C:16](=[O:17])[C:15]([CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]([CH3:24])[C:12]=1[CH3:23])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1[nH]cc(CC(F)(F)F)c(=O)c1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Solvent: CC#N
Product: Cc1c(OCc2ccccc2)c(=O)c(CC(F)(F)F)cn1C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 95 %

Procedure:
Methyl iodide (11 mL, 176 mmol) was added to a suspension of 3-benzyloxy-2-methyl-5-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one (1.18 g, 4.0 mmol) and potassium carbonate (1.06 g, 7.7 mmol) in acetonitrile (25 mL). The resulting mixture was heated to reflux, and the reaction was completed within 40 min. The mixture was cooled to RT, and the solid particulates was filtered off. The filtrate was concentrated in vacuo to give a solid. The solid was taken up in dichloromethane, and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 3-benzyloxy-1,2-dimethyl-5-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one as a colorless oil (1.3 g, 95% yield, HPLC Method 1 (Example 24), RT=15.9 min, HPLC purity (peak percent area): 98% at λ=280 nm).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C-:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)=[CH:5][CH:4]=1.[CH-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[Fe+2:19].[C:20]([O-:23])(=[S:22])[CH3:21].[K+]>CN(C=O)C>[C:20]([S:22][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C-:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)=[CH:5][CH:4]=1)(=[O:23])[CH3:21].[CH-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[Fe+2:19]
Reactant: BrCc1ccc(-[c-]2cccc2)cc1
Reactant: CC([O-])=S
Agent: [Fe+2]
Agent: [K+]
Agent: c1cc[cH-]c1
Solvent: CN(C)C=O
Product: CC(=O)SCc1ccc(-[c-]2cccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
Following a general procedure (Zhang et al. (1999) Tetrahedron Lett., 40: 603-606), a solution of 19 (1.5 g, 4.2 mmol) in DMF (10 mL) was added to a solution of potassium thioacetate (0.60 g, 5.0 mmol) in DMF (10 mL) and the mixture was stirred overnight at rt. The mixture was filtered and water was added to the filtrate. The filtrate was extracted with ethyl ether (3×50 mL), and the combined organic layers were dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography (silica, petroleum ether/diethyl ether, 10:1) affording a yellow solid (1.3 g, 90%): mp 79-81° C.; 1H NMR δ 2.38 (s, 3H), 4.05 (s, 5H), 4.12 (s, 2H), 4.31 (A2B2, J=1.5 Hz, 2H), 4.62 (A2B2, J=1.5 Hz, 2H), 7.21, 7.41 (AA′BB′, J=8.5 Hz, 2×2H); 13C NMR δ 31.1, 34.0, 67.2, 69.6, 70.3, 85.7, 127.0, 129.5, 135.7, 139.1, 196.1; FAB-MS obsd 350.0431, calcd exact mass 350.0428; Anal. Calcd for C19H18FeOS: C, 65.15; H, 5.18. Found: C, 64.91; H, 5.15.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22]2[N:23]=[N:24][N:25]([CH2:27][C:28](OC)=[O:29])[N:26]=2)=[C:9]1[C:32]([O:34][CH2:35][CH3:36])=[O:33].[OH-].[NH4+:38]>O1CCOCC1>[C:28]([CH2:27][N:25]1[N:24]=[N:23][C:22]([CH2:21][O:20][CH2:19][C:10]2[NH:11][C:12]([CH3:18])=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:26]1)(=[O:29])[NH2:38]
Reactant: [NH4+]
Reactant: CCOC(=O)C1=C(COCc2nnn(CC(=O)OC)n2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(COCc2nnn(CC(N)=O)n2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 5-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}-2-methoxycarbonylmethyl-(2H)-tetrazole (0.52 g), dioxane (15 ml) and 0.880 aqueous ammonium hydroxide solution (10 ml) was stirred at room temperature for 2.5 hours and then evaporated. The residual oil was partitioned between water and ethyl acetate and the organic layer washed with water, dried (Na2SO4) and evaporated. The residual oil was triturated with diethyl ether and the resulting solid collected, washed with diethyl ether and dried to give the title compound (0.31 g), m.p. 101°-103° decomp.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[CH3:32][C:33]1[CH:38]=[C:37]([CH:39]=[O:40])[CH:36]=[CH:35][N:34]=1>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([CH:39]([OH:40])[C:37]3[CH:36]=[CH:35][N:34]=[C:33]([CH3:32])[CH:38]=3)=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: Cc1cc(C=O)ccn1
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(O)c1ccnc(C)c1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (494 mg, 1.0 mmol) in anhydrous THF (10 mL) was added 2 M isopropylmagnesiumchloride in THF (1.20 mL, 2.4 mmol) at −40° C. After 5 minutes dry ice-acetone bath was replaced with a ice water bath and stirred at 0° C. for 1 h. Solid 2-methyl-pyridine-4-carbaldehyde (327 mg, 2.7 mmol) was added in one portion and the progress of the reaction was followed by LCMS. The reaction mixture was warmed to room temperature and stirred overnight. It was then quenched with saturated aqueous NH4Cl (2 mL), and extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to provide the desired product which was utilized in the following step without further purification. MS m/z: 536.0 (M+H).
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[Cl:8][C:9]1[CH:10]=[C:11]([CH2:16][C:17]([OH:19])=[O:18])[CH:12]=[C:13]([F:15])[CH:14]=1.[C:20](O)(=O)C>CO.C1(C)C=CC=CC=1>[CH3:20][O:18][C:17](=[O:19])[CH2:16][C:11]1[CH:12]=[C:13]([F:15])[CH:14]=[C:9]([Cl:8])[CH:10]=1
Reactant: CC(=O)O
Reactant: O=C(O)Cc1cc(F)cc(Cl)c1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)Cc1cc(F)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
Trimethylsilyldiazomethane (2 M solution in diethyl ether, 0.199 mL, 0.398 mmol) was added to a solution of (3-chloro-5-fluoro-phenyl)acetic acid (50 mg, 0.265 mmol) in methanol (0.5 mL) and toluene (2 mL), and the mixture was stirred at room temperature for 10 minutes. Acetic acid was added to the reaction mixture to terminate the reaction, and then the mixture was concentrated under reduced pressure to give the target compound as a colorless oil (53 mg, 99%).
Reaction SMILES: CN(C)C=[O:4].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[OH:18])[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2.C(=O)([O-])[O-].[K+].[K+].[CH2:37]([C@@H:39]1[O:41][CH2:40]1)Cl>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:37][C@H:39]([OH:41])[CH2:40][OH:4])[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Reactant: CN(C)C=O
Reactant: ClC[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OC[C@H](O)CO
Temperature: 70 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
N,N-Dimethylformamide (3 ml) was added to 6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (100 mg), potassium carbonate (125 mg), and (R)-epichlorohydrin (124 mg), and the mixture was stirred at 70° C. overnight. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was dissolved in dichloromethane (3 ml), trifluoroacetic acid (3 ml) was added dropwise to the solution at 0° C., and the mixture was then stirred at room temperature for 3 hr. The reaction solution was made alkaline by the addition of a 1 N aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (24 mg, yield 76%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[S:30](=[O:32])(=[O:31])[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]4)[C:20]4[C:15](=[N:16][CH:17]=[CH:18][N:19]=4)[CH:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1>Cl.C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[S:30](=[O:32])(=[O:31])[CH2:29][CH2:28][NH:27][CH2:26]4)[C:20]4[C:15](=[N:16][CH:17]=[CH:18][N:19]=4)[CH:14]=3)=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCS(=O)(=O)C(CNc2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=S1(=O)CCNCC1CNc1nc(-c2ccc(N3CCOCC3)cc2)cc2nccnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
The tert-butyl 2-((7-(4-morpholinophenyl)pyrido[4,3-b]pyrazin-5-ylamino)methyl)-1,1-dioxo-thiomorpholine-4-carboxylate (52 mg, 0.094 mmol) was dissolved in the solution of HCl in ethyl acetate (3 mL), and the mixture was stirred at room temperature for 2 hours until TLC indicated Boc group was removed. The volatile materials was removed, the residue was neutralized with ammonium hydroxide (25%, 1 mL) and purified by C18 column to afford yellow solid 33 mg. MS (m/z): 455 (M+H)+
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:9]1([CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH:33]=[CH:34][CH:35]=2)[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](=[O:32])(=[O:31])[NH2:30])=[O:21])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>CN(C)C1C=CN=CC=1.O1CCCC1>[CH:9]1([CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH:33]=[CH:34][CH:35]=2)[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([NH:30][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])(=[O:32])=[O:31])=[O:21])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCC2CCCCC2)c1
Reactant: CCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
In a stream of nitrogen and at 0° C., 0.16 ml (1.10 mmol) of hexanoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 400 mg (1.00 mmol) of 3-cyclohexylmethoxy-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 7 and 237 mg (1.90 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 490 mg (yield: 97.8%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:50]C(Cl)C>>[ClH:50].[ClH:50].[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:33]2[CH2:34][CH2:35][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)[CH2:31][CH2:32]2)=[CH:11][C:10]=1[O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CCOC(=O)COc1cc(C=O)ccc1OCc1ccccc1
Reactant: CC(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCOC(=O)COc1cc(CN2CCN(c3ccccn3)CC2)ccc1OCc1ccccc1
Product: Cl
Yield: 42.1 %

Procedure:
To a solution of 4-benzyloxy-3-(ethoxycarbonylmethoxy)benzaldehyde (0.2 g) in dichloroethane (4 ml) was added (pyridin-2-yl)piperazine (0.12 ml) and sodiumtriacetoxy borohydride (0.25 g), with stirring. The reaction mixture was stirred at ambient temperature for 1.5 hrs, poured into ice/saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash chromatographed (silica gel), eluting with dichloromethane, 1% and 2% methanol/dichloromethane. The appropriate fractions were collected and concentrated. The residue was dissolved in ether and ethereal hydrochloric acid was added. The suspension was filtered and the filter cake dried for 2 hrs at ambient temperature. Recrystallization from ethanol provided 0.143 g (42.1%) of product, mp 151-191° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][C:19]#[CH:20])[C:10]([O:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1.C(NCC)C>C(OCC)C.[Cu](I)I.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>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]#[C:19][CH2:18][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]([O:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)=[O:11])=[CH:23][CH:24]=1
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC1CCCC1
Reactant: Brc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H](CC#Cc1ccc(Br)cc1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a mixture of cyclopentyl(2S)-2-[(tert-butoxycarbonyl)amino]pent-4-ynoate (2.45 g, 8.72 mmol) and 4-iodo-bromobenzene (2.96 g, 10.46 mmol) in diethyl ether (4 ml) was added copper iodide (0.166 g, 0.872 mmol) and PdCl2(PPh3)2 (0.306 g, 0.436 mmol). Diethylamine (5.43 ml, 52.3 mmol) was then added and the mixture stirred at RT. After 2 hrs, LCMS showed complete reaction. The mixture was poured onto water and extracted with diethyl ether. The combined organic layers were washed with water and brine, dried over magnesium sulphate, filtered and evaporated in vacuo. The crude residue was subjected to column chromatography eluting with 5 to 10% EtOAc in hexanes. Yield=2.9 g, 6.51 mmol, 75% yield. LCMS purity 98%: m/z 437 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([F:14])=[C:6]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=2)[NH2:7])[CH2:3][CH2:2]1.C[Si]([N:19]=[N+:20]=[N-:21])(C)C.[CH3:22]OC(OC)OC.[OH-].[Na+]>CC(O)=O.CCOC(C)=O>[CH:1]1([C:4]2[C:5]([F:14])=[C:6]([N:7]3[CH:22]=[N:19][N:20]=[N:21]3)[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=2)[CH2:3][CH2:2]1
Reactant: Nc1cc([N+](=O)[O-])cc(C2CC2)c1F
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COC(OC)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(C2CC2)c(F)c(-n2cnnn2)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 92.4 %

Procedure:
A mixture of 3-cyclopropyl-2-fluoro-5-nitroaniline (1.27 g, 6.47 mmol, 1 equiv), trimethylsilyl azide (4.26 mL, 32.37 mmol, 5 equiv), trimethylorthoformate (7.09 mL, 67.74 mmol, 10 equiv) in AcOH (15 mL) was heated to 70° C. and stirred for 7 hours behind a blast shield. After allowing to cool to room temperature, the mixture was further cooled in ice-water and basified to ca. pH 12-14 with 1N NaOH and diluted with EtOAc. The aqueous and organic layers were partitioned and the aqueous extracted with EtOAc (2×200 mL). The combined organic extracts were washed with 1N NaOH (1×200 mL), dried (Na2SO4), filtered, and the solvent removed under vacuum—silica gel was added at this stage so that the crude product was absorbed directly on to silica gel. The crude product was purified by column chromatography on silica gel using EtOAc/hexanes (30-50% EtOAc in increments of 10% EtOAc) to give the product 1-(3-cyclopropyl-2-fluoro-5-nitrophenyl)-1H-tetrazole (1.49 g, 92%) as a light-yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:4][CH:3]=1.[C:16](Cl)(=[O:20])[C:17](Cl)=O.[CH3:22][N:23]([CH3:26])C=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([N:23]([CH2:22][CH:9]([O:20][CH2:16][CH3:17])[O:10][CH2:11][CH3:12])[CH2:26][CH2:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[O:15])=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCOCCc1ccc(Br)cc1
Reactant: CN(C)C=O
Solvent: ClCCl
Product: CCOC(CN(CCc1ccccc1)C(=O)CCOCCc1ccc(Br)cc1)OCC
Reaction time: 2 h

Procedure:
3-[2-(4-Bromophenyl)ethoxy]propanoic acid (Example 10b), 0.46 g) was dissolved in dichloromethane (10 mL) and treated with oxalyl chloride (0.28 g) and a drop of dimethylformamide. The resultant solution was stirred at room temperature for 1.5 hours. The solution was then concentrated and azeotroped with dichloromethane (2×10 mL). The residue was dissolved in dichloromethane (10 mL) and added, portionwise, to a stirred solution of 2,2-diethoxy-N-phenethyl-ethanamine (0.40 g) and diisopropylamine (0.5 mL), dissolved in dichloromethane (5 mL). The resultant solution was stirred for 2 hours, concentrated and taken up in ethyl acetate (30 mL). Washing with water (2×30 mL), and brine (30 mL) followed by drying over anhydrous magnesium sulphate, filtering and concentration gave the sub-titled compound (0.72 g) as an oil.