Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[N:12]([CH2:15][C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)=[N+:13]=[N-:14]>>[ClH:1].[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[CH2:15][N:12]1[CH:5]=[C:4]([CH2:3][CH2:2][C:6]2[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=2)[N:14]=[N:13]1
Reactant: [N-]=[N+]=NCc1ccco1
Reactant: C#CCCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(CCc2cn(Cc3ccco3)nn2)c[nH]1
Yield: 72.3 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.068 g, 0.399 mmol) was reacted with 2-azidomethyl furan (0.059 g, 0.478 mmol) following the general procedure for click reactions outlined above to produce 4-[2-(1-Furan-2-ylmethyl-1H-[1,2,3]triazol-4-yl)-ethyl]-1H-imidazol-2-ylamine hydrochloride (0.085 g, 72%) of a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.06 (s, 1H), δ 7.53 (s, 1H), δ 6.59 (t, 1H), δ 6.49 (s, 1H), δ 6.44 (dd, 1H), δ 3.05 (t, 2H), δ 2.89 (t, 2H) ppm; 13C (75 MHz, CD3OD) δ 156.4, 154.9, 147.5, 144.1, 126.0, 125.1, 123.8, 110.7, 109.3, 69.8, 23.8, 17.4 ppm; HRMS (ESI) calcd for C12H14N6O (M+) 259.1301. Found 259.1305.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[C:57]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:56][CH:55]=[CH:54][N:53]=1>CN(C=O)C>[CH3:50][O:51][C:52]1[C:57]([C:58]2[CH:59]=[C:60]([NH:64][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:61]=[CH:62][CH:63]=2)=[CH:56][CH:55]=[CH:54][N:53]=1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: COc1ncccc1-c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ncccc1-c1cccc(NC(=O)c2cc3cccc(OC)c3oc2=O)c1
Temperature: 25 °C
Yield: 91.8 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2-methoxy-pyridin-3-yl)-phenylamine (0.013 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.024 g of product in 92% yield: LCMS (ESI) m/z 403 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[F:8][C:9]([F:19])([F:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][NH2:17].[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:22]=1[C:23](F)=[O:24].[OH-].[Ca+2].[OH-]>O.C(OCC)(=O)C>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:22]=1[C:23]([NH:17][NH:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([F:18])([F:19])[F:8])=[O:24]
Reactant: NNc1ccccc1C(F)(F)F
Reactant: O=C(F)c1c(F)cccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NNc1ccccc1C(F)(F)F)c1c(F)cccc1F
Temperature: 3 °C
Reaction time: 1 h

Procedure:
13.6 g (98 mmol) of potassium carbonate in 70 ml of water are added at 10° C. while stirring to a suspension of 10.4 g (49 mmol) of α,α,α-trifluoro-o-tolylhydrazine hydrochloride in 50 ml of ethyl acetate. 7.8 g (49 mmol) of 2,6-difluorobenzoyl fluoride are subsequently added dropwise to the clear solution while cooling so that the internal temperature is maintained at 3° C. The mixture is stirred at 5° C. for 60 minutes and thereafter at 25° C. for 4 hours, and the organic phase is separated. The aqueous phase is back-extracted with 50 ml of ethyl acetate and subsequently treated with 1.85 g (25 mmol) of calcium hydroxide in order to precipitate the calcium fluoride. The combined organic phases are washed in each case once with dilute hydrochloric acid and sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. After recrystallization from acetone and n-hexane there is obtained 2,6-difluoro-N' -(α,α,α-trifluoro-o-tolyl)-benzhydrazide as a white crystallizate, m.p. 129°-130° C.; mass spectrum m/e: M+ 316(26), 141(100).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH2:15])[CH:11]=[C:12]([NH2:14])[CH:13]=2)[CH:5]=[CH:4][N:3]=1.[O:16]=[C:17](NC1N=C(C2C=CN=CC=2)SC=1)[C@@H:18]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[NH2:14][C:12]1[CH:11]=[C:10]([NH:15][C:17](=[O:16])[C@@H:18]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[CH:13]=1
Reactant: Cc1cc(-c2cc(N)cc(N)c2)ccn1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1csc(-c2ccncc2)n1
Product: Cc1cc(-c2cc(N)cc(NC(=O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
This title compound was prepared from 51.1C (2.10 g, 10.0 mmol) according the procedure described above for conversion of 4.A to 4.B. The product 51.1D was purified by flash chromatography on silica gel using 0-7% MeOH/CH2Cl2 for elution.
Reaction SMILES: [CH:1]1([C:4]2[N:5]([CH3:29])[C:6]([C:9]3[CH:10]=[C:11]([CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=4)[CH:21]=3)[C:12]([O:14]C(C)(C)C)=[O:13])=[N:7][N:8]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.Cl>CO>[CH:1]1([C:4]2[N:5]([CH3:29])[C:6]([C:9]3[CH:10]=[C:11]([CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=4)[CH:21]=3)[C:12]([OH:14])=[O:13])=[N:7][N:8]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(-c3nnc(C4CC4)n3C)c2)nc1
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2cc(C(=O)O)cc(-c3nnc(C4CC4)n3C)c2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 3-(5-cyclopropyl-4-methyl-4H-1,2,4-triazol-3-yl)-5-(5-methylpyridin-2-yl)benzoate (0.38 g, 0.97 mmol) in methyl alcohol (10 mL) was added trifluoroacetic acid (5.0 mL, 67.3 mmol) and hydrogen chloride (4.0 M in dioxane; 5.0 mL, 20.0 mmol). The reaction mixture was stirred at ambient temperature. After 18 h, the mixture was concentrated and dried under reduced pressure gave the hydrochloride salt of the title compound. MS 335.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][C:6]2=[O:13].[CH3:14][O-:15].[Na+].CO>>[CH3:14][O:15][C:6](=[O:13])[C:5]1[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:8]([OH:7])=[O:12]
Reactant: C[O-]
Reactant: COc1ccc2c(c1)C(=O)OC2=O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(OC)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 5-methoxy-isobenzofuran-1,3-dione (950 mg, 5.33 mmol) is added 0.5 M NaOMe in MeOH (16 mL, 18 mmol). The reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated under reduced pressure and the resulting residue subsequently quenched with 1M HCl aq (100 mL). The quenched reaction mixture is extracted with EtOAc (100 mL×2) and the combined organic layers are dried with Na2SO4 and filtered. The filtrate is concentrated under reduced to afford crude 4-methoxy-phthalic acid 2-methyl ester (850 mg).
Reaction SMILES: [CH:1]([NH:4][C:5]([C@H:7]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([O:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[Sn](Cl)Cl>CO>[NH2:20][C:19]1[C:14]([NH:13][C@@H:10]2[CH2:9][CH2:8][C@H:7]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:12][CH2:11]2)=[CH:15][C:16]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[N:17][CH:18]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OCCN3CCCCC3)ncc2[N+](=O)[O-])CC1
Agent: Cl[Sn]Cl
Solvent: CO
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OCCN3CCCCC3)ncc2N)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of cis-N-isopropyl-4-(5-nitro-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)cyclohexanecarboxamide (10.79 g, 24.89 mmol) in MeOH (124 mL) was added tin (II) chloride (18.88 g, 100 mmol), and the reaction was stirred at 80° C. for 2 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in EtOAc, then diluted with 1N aqueous NaOH. The layers were separated, and the organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to yield cis-4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide (8.06 g, 80% yield). MS m/z=404.2 [M+H], calc 403.56 for C22H37N5O2.
Reaction SMILES: [OH:1][C:2]1([C:8]2[N:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.Cl.CO>C1COCC1>[OH:1][C:2]1([C:8]2[N:13]=[C:12]([CH2:14][NH2:15])[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:4][O:5][CH2:6][CH2:7]1
Reactant: N#Cc1cccc(C2(O)CCOCC2)n1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: NCc1cccc(C2(O)CCOCC2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 63.8 %

Procedure:
6-(4-Hydroxytetrahydropyran-4-yl)pyridine-2-carbonitrile (ca. 18.9 mmol) was dissolved in anhydrous THF (80 mL) and a 1 M solution of BH3 in THF (95 mL, 95 mmol) added. The solution was stirred at ambient temperature for 2.5 hours, then quenched with methanol. The solution was adjusted to pH 1 by addition of 2 N hydrochloric acid solution and then neutralised to pH 5 with a 5 N solution of sodium hydroxide. Extraction with dichloromethane was followed by addition of further 2 N sodium hydroxide to the aqueous phase until the pH reached 14. This phase was twice extracted with dichloromethane and these combined extracts were evaporated to give a yellow gum. The aqueous extracts were acidified with 2 N hydrochloric acid and concentrated to dryness to yield a white residue. Three triturations of this residue with methanol and concentration of the methanolic liquors yielded a second crop of yellow gum. Drying in vacuo gave the title compound (2.51 g, 64%) as a foamy yellow solid; NMR δH (400 MHz, DMSO) 8.53 (1H, br s), 7.85 (1H, t, J 7.8 Hz), 7.62 (1H, d, J 7.8 Hz), 7.34 (1H, d, J 7.5 Hz), 5.75 (1H, s), 3.72 (4H, m), 3.16 (2H, s), 2.29 (2H, m), 1.42 (1H, d, J 12.3 Hz); LC-MS Retention time 0.43 min, (M+H)+ 209.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]C(=O)N(C)C)=[CH:8][C:7]=1[CH3:18].C[O-].[Na+].Cl>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][C:7]=1[CH3:18]
Reactant: COC(=O)CCc1ccc(SC(=O)N(C)C)cc1C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CCc1ccc(S)cc1C
Temperature: 25 °C
Yield: 118.3 %

Procedure:
3-(4-Dimethylcarbamoylsulfanyl-2-methyl-phenyl)-propionic acid methyl ester (5.01 g, 17.8 mmol) is diluted with methanol (30 mL) and to this is added sodium methoxide (1.7 mL of 4M in methanol, 7.23 mmol). The reaction is heated to reflux under nitrogen and monitored by TLC. After complete conversion, 20 h., the reaction is allowed to cool to room temperature. The reaction is nuetralized with 1N HCl (7.23 mL) and diluted with ethyl acetate (150 mL). The two phases are seperated and the organic layer is washed with water (75 mL), then brine (75 mL). The organic layer is then dried over anhydrous sodium sulfate, then concentrated to yield 4.43 g crude product that is used without further purification.
Reaction SMILES: N(CCO)CCO.CCOCC.[CH3:13][CH:14]([C:18]([CH3:20])=[O:19])[C:15]([OH:17])=[O:16].[N+]([O-])([O-])=O.[Ag+:25]>O>[CH3:13][CH:14]([C:18]([CH3:20])=[O:19])[C:15]([O-:17])=[O:16].[Ag+:25]
Reactant: CC(=O)C(C)C(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: OCCNCCO
Solvent: CCOCC
Product: CC(=O)C(C)C(=O)[O-]

Procedure:
Diethanolamine (4.4 g) was dissolved in water (5 mL), and this solution was added to the ether solution of α-methylacetoacetic acid while cooling with ice. A solution of silver nitrate (6.8 g) dissolved in water (8 mL) was then added dropwise. The white precipitate that precipitated was filtered off, washed with ice water and then isopropanol, and then dried, yielding silver α-methylacetoacetate as a white precipitate (yield 4.78 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][CH2:16][C:17]([CH3:22])([N+:19]([O-])=O)[CH3:18])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[C].[Pd]>[CH3:13][O:12][C:10](=[O:11])[C@H:9]([CH2:14][CH2:15][CH2:16][C:17]([CH3:22])([CH3:18])[NH2:19])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: [H][H]
Reactant: COC(=O)[C@H](CCCC(C)(C)[N+](=O)[O-])NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](CCCC(C)(C)N)NC(=O)OC(C)(C)C
Yield: 80.8 %

Procedure:
Methyl (S)-2-t-butoxycarbonylamino-6-methyl-6-nitroheptanoate (300 mg, 0.94 mmol) was dissolved in methanol (10 ml) and 5% palladium-carbon (0.15 g, 50% wet) was added. The mixture was stirred at a hydrogen pressure of 20 atm and 80° C. for 24 h. Palladium-carbon was removed by filtration and methanol was evaporated by concentration under reduced pressure to give the objective compound (219 mg, yield 80.8%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.C(N(CC)CC)C.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CS(C)=O>[OH:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[NH:3][C:2](=[O:1])[C:7]=1[C:25]([NH:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:26]
Reactant: COc1nc(O)cc(O)n1
Reactant: O=C=Nc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1nc(O)c(C(=O)Nc2ccccc2)c(=O)[nH]1

Procedure:
To a solution of 4,6-dihydroxy-2-methoxypyrimidine (6 g) in dry dimethyl sulfoxide was added triethylamine (5.9 ml). The solution was brought to 60° and phenyl isocyanate (5 g) was added; the solution was maintained at 80°-90° for two hours, cooled and water added slowly to cause precipitation.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:31])[C@@H:6]([NH:11][C:12]([N:14]1[C:18]2[CH2:19][CH2:20][O:21][CH2:22][C:17]=2[C:16](C2C=CC(F)=C(F)C=2)=[N:15]1)=[O:13])[C:7]([CH3:10])([CH3:9])[CH3:8].[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([F:42])=[C:37]([CH:41]=1)C(Cl)=O>>[Cl:32][C:33]1[CH:41]=[CH:37][C:36]([F:42])=[C:35]([C:16]2[C:17]3[CH2:22][O:21][CH2:20][CH2:19][C:18]=3[N:14]([C:12]([NH:11][C@@H:6]([C:7]([CH3:8])([CH3:10])[CH3:9])[C:5]([NH:4][CH2:3][CH2:2][OH:1])=[O:31])=[O:13])[N:15]=2)[CH:34]=1
Reactant: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(=O)NCCO
Reactant: O=C(Cl)c1cc(Cl)ccc1F
Product: CC(C)(C)[C@H](NC(=O)n1nc(-c2cc(Cl)ccc2F)c2c1CCOC2)C(=O)NCCO

Procedure:
Compound 86 was prepared according to the procedure for the synthesis of compound 36 by replacing 3,4-difluorobenzoyl chloride with 5-chloro-2-fluorobenzoyl chloride. LCMS (+ESI) m/z=453.3 [M+H]+. 1H NMR (CDCl3) δ 7.81 (d, J=9.1 Hz, 1H), 7.60-7.62 (dd, J=2.7, 6.21 Hz, 1H), 7.27-7.32 (m, 1H), 7.07 (t, J=9.3 Hz, 1H), 6.56 (br, 1H), 4.57 (s 2H), 4.12 (d, J=9.2 Hz, 1H), 3.87 (t, J=5.6 Hz, 2H), 3.66 (s, 3H), 3.36-3.41 (m, 2H), 3.08-3.12 (m, 2H), 1.03 (s, 9H). Purity: 97%.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH3:9])=[CH2:5])[CH3:2].[OH-].[K+].C1OCCOCCOCCOCCOCCOC1.[Cl:30][CH:31](Cl)[F:32]>O.CCOCC>[CH2:6]([C:4]1([O:3][CH2:1][CH3:2])[CH2:5][C:31]1([Cl:30])[F:32])[CH2:7][CH2:8][CH3:9]
Reactant: FC(Cl)Cl
Reactant: C=C(CCCC)OCC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCCCC1(OCC)CC1(F)Cl
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a solution of 61.0 g. of 2-ethoxy-1-hexene, 135 ml. of 13.5 M potassium hydroxide and 217 g. of "18-crown -6" ether at -15° C. is added dropwise over 30 minutes at 0°, a 90 ml. portion of dichlorofluoromethane. After the addition, the mixture is placed in an ice bath. An exotherm raises the temperature to 20° C., whereupon the mixture is placed in a dry-ice/carbon tetrachloride bath to maintain the temperature at -5° C. to 0° C. After three hours at this temperature, the reaction mixture is diluted with water and extracted with ether. The ether extracts are combined, washed with water, then brine, dried over potassium carbonate and concentrated in vacuo to an oil. This oil is distilled through a 6 inch Vigreux column to provide 82 g. of the desired compound as a colorless liquid, b.p. 70°-71° C., 16 mm.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:35]=[C:36]([OH:41])[C:37]([OH:40])=[CH:38][CH:39]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([OH:41])[CH:35]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: NCCc1ccc(O)c(O)c1
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(O)c(O)c3)n2)c1

Procedure:
Intermediate 4 from above was coupled with 4-(2-Amino-ethyl)-benzene-1,2-diol following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 472. 1H NMR (Varian 300 MHz, CDCl3—CD3OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.1 (m, 2H) 8.0 (d, 1H) 7.7 (d, 1H) 7.5 (m, 1H) 7.2 (m, 1H) 6.7 (d, 1H) 6.6 (m, 2H) 4.7 (s, 2H) 3.8 (m, 2H) 3.6 (m, 2H) 2.9 (s, 3H) 2.8 (m, 4H) 1.8 (m, 2H).
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[NH2:7][S:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[N:12]([CH3:20])[C:11]=1[C:21]([O:23]CC)=O)=[O:9]>O.CC(C)=O>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]2[N:12]([CH3:20])[C:11]3[C:21](=[O:23])[NH:7][S:8](=[O:9])(=[O:2])[C:10]=3[C:18]=2[CH:17]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCOC(=O)c1c(S(N)=O)c2cc(Cl)ccc2n1C
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cn1c2c(c3cc(Cl)ccc31)S(=O)(=O)NC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 15.8 gm (0.1 mols) of potassium permanganate in 300 ml of water was added dropwise over a period of 2.5 hours to a solution of 37.6 gm (0.125 mols) of ethyl 3-aminosulfinyl-5-chloro-1-methyl-indole-2-carboxylate in 2500 ml of acetone at 20° C. After stirring overnight at room temperature, the precipitate which had formed was filtered off and washed with warm water and acetone. The filtrate then was evaporated in vacuo at 25°-30° C. to a volume of about 350 ml. The crystallized product, ethyl 5-chloro-1-methyl-3-sulfamoyl-indole-2-carboxylate, was filtered off, washed with water and dried. Yield: 30.5 gm (77% of theory); M.p.: 207°-208° C. After acidification of the filtrate to pH 3, another product, 7-chloro-4-methyl-2H-isothiazolo[4,5-b]indole-3-(4H)-one-1,1-dioxide, was obtained, which was filtered off, washed with water and dried. Yield: 3.9 gm (12% of theory); M.p.: 288° C. (decomposition).
Reaction SMILES: Br.[CH2:2]([NH:4][C:5](=[O:14])[C@H:6]([CH3:13])[NH:7][C:8](=[O:12])[C@H:9]([CH3:11])[NH2:10])[CH3:3].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH2:2]([NH:4][C:5](=[O:14])[C@H:6]([CH3:13])[NH:7][C:8](=[O:12])[C@H:9]([CH3:11])[NH:10][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:3]
Reactant: CCNC(=O)[C@H](C)NC(=O)[C@H](C)N
Reactant: O=C(Cl)c1ccccc1
Agent: Br
Solvent: c1ccncc1
Product: CCNC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
2.35 g (0.0087 mol) of L-alanyl-L-alanine ethylamide hydrobromide were suspended in 40 ml of pyridine and 2.04 ml (0.02 mol) of benzoyl chloride were added. The mixture was then stirred for 2 hours at room temperature. The solvent was evaporated and the residue recrystallised from isopropanol to yield 1.3 g (51%) of N-benzoyl-L-alanyl-L-alanine ethylamide of melting point 237°-239° C; [α]D20 =-17.8° (c=1.01% in methanol).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:10][C:11]([CH:13]2[CH2:17][CH:16](OS(C3C=CC(Br)=CC=3)(=O)=O)[CH2:15][N:14]2[C:29](=[O:45])[CH:30]([NH:35][C:36]([O:38][CH:39]2[CH2:44][CH:43]3[CH:41]([CH2:42]3)[CH2:40]2)=[O:37])[C:31]([CH3:34])([CH3:33])[CH3:32])=[O:12])[CH2:7][CH:6]1[CH2:8][CH3:9])=[O:4].[Cl:46][C:47]1[C:48]([O:67][CH2:68][CH:69]([O:72][CH3:73])[O:70][CH3:71])=[CH:49][CH:50]=[C:51]2[C:56]=1[N:55]=[C:54]([C:57]1[N:58]=[C:59]([NH:62][CH:63]([CH3:65])[CH3:64])[S:60][CH:61]=1)[CH:53]=[C:52]2[OH:66].C(=O)([O-])[O-].[Cs+].[Cs+].[Li+].[Cl-]>CN1C(=O)CCC1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1([NH:10][C:11]([CH:13]2[CH2:17][CH:16]([O:66][C:52]3[C:51]4[C:56](=[C:47]([Cl:46])[C:48]([O:67][CH2:68][CH:69]([O:70][CH3:71])[O:72][CH3:73])=[CH:49][CH:50]=4)[N:55]=[C:54]([C:57]4[N:58]=[C:59]([NH:62][CH:63]([CH3:65])[CH3:64])[S:60][CH:61]=4)[CH:53]=3)[CH2:15][N:14]2[C:29](=[O:45])[CH:30]([NH:35][C:36]([O:38][CH:39]2[CH2:44][CH:43]3[CH:41]([CH2:42]3)[CH2:40]2)=[O:37])[C:31]([CH3:33])([CH3:34])[CH3:32])=[O:12])[CH2:7][CH:6]1[CH2:8][CH3:9])=[O:4]
Reactant: CCC1CC1(NC(=O)C1CC(OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)C(NC(=O)OC1CC2CC2C1)C(C)(C)C)C(=O)OC
Reactant: COC(COc1ccc2c(O)cc(-c3csc(NC(C)C)n3)nc2c1Cl)OC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCC1CC1(NC(=O)C1CC(Oc2cc(-c3csc(NC(C)C)n3)nc3c(Cl)c(OCC(OC)OC)ccc23)CN1C(=O)C(NC(=O)OC1CC2CC2C1)C(C)(C)C)C(=O)OC
Temperature: 65 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
To a mixture of 1-{[1-[2-(bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethyl-butyryl]-4-(4-bromobenzenesulfonyloxy)pyrrolidine-2-carbonyl]amino}-2-ethyl-cyclopropanecarboxylic acid methyl ester (15 g, 35 mmol) and 8-chloro-7-(2,2-dimethoxyethoxy)-2-(2-isopropylaminothiazol-4-yl)-quinolin-4-ol (27.5 g, 38.5 mmol) in NMP (200 ml) was added cesium carbonate (25.1 g, 77 mmol). The mixture was stirred at 65° C. for 5 h. The reaction was cooled to room temperature and EtOAc (600 ml) and an aqueous solution of 3% LiCl (600 ml) were added to the mixture. The organic layer was washed with aqueous 3% LiCl (1×600 ml), brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography to produce 1-({1-[2-(bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethylbutyryl]-4-[8-chloro-7-(2,2-dimethoxyethoxy)-2-(2-isopropylaminothiazol-4-yl)-quinolin-4-yloxy]pyrrolidine-2-carbonyl}amino)-2-ethylcyclopropanecarboxylic acid methyl ester as a yellow solid (23.6 g, 75% yield). LCMS found 900.1 [M+H]+.
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][CH:3]=1.[Li]CCCC.[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18]>CCOCC>[Br:7][C:6]1[C:2]([CH:17]([C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Cl:13])[CH:15]=2)[OH:18])=[CH:3][S:4][CH:5]=1
Reactant: Brc1cscc1Br
Reactant: O=Cc1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC(c1cccc(Cl)c1)c1cscc1Br
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
3,4-Dibromothiophene (15.5 g, 64.1 mmol) was added dropwise to a solution of n-BuLi (2.5M in hexane, 25.6 mL, 64.1 mmol) in Et2O (50 mL) at −78° C. After 1.5 h, 3-chlorobenzaldehyde (7.29 mL, 64.1 mmol) was added dropwise to the beige suspension. The resulting solution was stirred at −78° C. for 1 h and allowed to warm to 0° C. After 1 h, the reaction was quenched by the addition of 25% aq. NH4OAc. The aqueous layer was extracted with EtOAc and the combined organics were washed with water and brine, dried (Na2SO4) and concentrated to afford the desired product as a pale yellow oil. The crude product was used directly without further purification.