Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN[O:18][CH3:19].Cl.C(N=C=NCCC[N:29]([CH3:31])C)C.O.OC1C2N=NNC=2C=CC=1.CCN(CC)CC>>[CH3:19][O:18][CH2:31][NH:29][C:12]([C:10]1[NH:11][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][CH:9]=1)=[O:14]
Reactant: O=C(O)c1ccc(-c2ccccc2)[nH]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CNOC
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: COCNC(=O)c1ccc(-c2ccccc2)[nH]1

Procedure:
To a 200 mL round bottomed flask with a stirring bar and an argon inlet was added 5-phenyl-1H-pyrrole-2-carboxylic acid AV-5-1 (2.45 g, 13.09 mmol), N,O-dimethylhydroxylamine hydrochloride (1.40 g, 14.40 mmol), N-ethyl-N′-dimethylaminopropylcarbodiimide hydrochloride (2.76 g, 14.40 mmol), hydroxybenztriazole hydrate (1.94 g, 14.40 mmol) and dry, degassed DMF (25 mL). This well stirred mixture was warmed gently until all of the solids dissolved. Et3N (5.6 mL, 40.00 mmol) was added in one portion. The resulting mixture was stirred at ambient temperature 18 h. The solvents were removed in vacuo at +80° C. The residue was partitioned between saturated aqueous NaHCO3 and EtOAc. The layers were separated and the organic phase was washed with H2O (2×) and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave a solid. This material was chromatographed on silica gel using 35% EtOAc in hexane as eluant to give 5-phenyl-1H-pyrrole-2-carboxylic acid methoxymethylamide AV-6-1 as a solid. 1H NMR (CDCl3) δ 3.36 (3H, s), 3.80 (3H, s), 6.58 (1H, dd, j=2.2, 4.0 Hz), 6.94 (1H, dd, j=2.2, 4.0 Hz), 7.30 (1H, m), 7.41 (2H, m), 7.58 (2H, m), 9.63 (1H, br s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]2[CH2:23][CH2:22][C:21]3[CH:24]=[CH:25][O:26][C:20]=3[CH2:19]2)=[O:17])=[CH:11][C:10]=1[O:27][CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][NH:30][CH3:31].[CH2:32]=O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]2[CH2:23][CH2:22][C:21]3[CH:24]=[C:25]([CH2:29][N:30]([CH3:32])[CH3:31])[O:26][C:20]=3[CH2:19]2)=[O:17])=[CH:11][C:10]=1[O:27][CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC
Reactant: C=O
Reactant: COc1cc(CC(=O)N2CCc3ccoc3C2)ccc1OCc1ccccc1
Solvent: CC(=O)O
Product: COc1cc(CC(=O)N2CCc3cc(CN(C)C)oc3C2)ccc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 0.67 h

Procedure:
To a solution of 0.290 g (0.768 mmol) of 2-(4-benzyloxy-3-methoxyphenyl)-1-(5,7-dihydro-4H-furo[2,3-c]pyridin-6-yl)ethan-1-one in 20 ml of acetic acid, 0.104 ml (1.15 mmol) of 50% aqueous dimethylamine and 0.094 ml (1.15 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 40 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous sodium hydrogen carbonate and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform to chloroform/methanol=50/1 to 25/1) to yield the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:17])=O>[OH-].[Na+]>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([Cl:17])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: N#Cc1c(N)nc2ccccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1c(N)nc2ccccc2c1Cl
Temperature: 110 °C

Procedure:
The mixture of 10 g of 2-amino-3-cyano-4-hydroxyquinolin and 15 ml of phosphoryl chloride is heated under stirring at 110° C. The reaction mixture is cooled down, poured onto 100 ml of ice-water and neutralized with 60 ml of 10% sodium hydroxide solution. The resulting yellow precipitate is filtered off, washed with 50 ml of water. After drying 7.5 g of the title compound is obtained, mp.: 210° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[S:22][CH2:21][CH2:20][C:19]([C:23]([O:25]C)=[O:24])=[CH:18][C:17]=4[CH:27]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C.C1COCC1>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[S:22][CH2:21][CH2:20][C:19]([C:23]([OH:25])=[O:24])=[CH:18][C:17]=4[CH:27]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2SCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2SCC1
Reaction time: 144 h
Yield: 94.8 %

Procedure:
To a solution of methyl 7-(4-morpholinophenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate (0.55 g) in ethanol/THF (30/30 ml) was added at room temperature 1N sodium hydroxide solution (1.8 ml), and the mixture was stirred for 6 days and then refluxed for 2 hours. To the mixture was added 1N hydrochloric acid (1.8 ml). The resulting solid was collected by filtration, which was washed with ethanol and diethylether to give yellow powder of 7-(4-morpholinophenyl)-2,3-dihydro-1-benzo-thiepine-4-carboxylic acid (502.2 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH:7]1[C:12]([S:13](Cl)(=[O:15])=[O:14])=[CH:11][CH:10]=[C:9]([I:17])[CH:8]=1.Cl.S1C(N)=NC=N1>N1C=CC=CC=1>[I:17][C:9]1[CH:8]=[CH:7][C:12]([S:13]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)(=[O:15])=[O:14])=[CH:11][CH:10]=1
Reactant: Nc1nccs1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Agent: Cl
Agent: Nc1ncns1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1nccs1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 37.9 %

Procedure:
Prepared using general procedure 42. To a stirring solution of 2-aminothiazole (13.2 g, 132.2 mmol) and pyridine (20 mL) under N2, at 0° C., was added pipsyl chloride (20.0 g, 55.1 mmol). The mixture was stirred at ambient temperature for 17 hours. CH2Cl2/MeOH-2/1 (100 mL) was added. The mixture was filtered and the filtrate was purified via silica gel chromatography using 5% MeOH in CH2Cl2. The solid was triturated with CH2Cl2 to obtain the desired sulfonamide as a white solid (8.4 g, 20.9 mmol, 38% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 7.94-7.90 (m, 2H), 7.57-7.54 (m, 2H), 7.26 (d, J=4.6 Hz, 1H), 6.86 (d, J=4.6 Hz, 1H).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:9]1([Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1.C(OCC)(=O)C>[C:9]1([CH:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[OH:8])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1cccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(c1ccccc1)c1cccnc1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
To a stirring solution of nicotinaldehyde 75 (0.876 mL, 9.34 mmol) in THF (20 mL) at 0° C. was slowly added a 1M phenylmagnesium bromide solution (9.34 mL, 9.34 mmol) and the reaction mixture was allowed to warm to room temperature over 30 minutes. The crude solution was diluted with ethyl acetate and washed with water, dried over Na2SO4, filtered and concentrated to afford compound 76 (1.7 g, 98% yield) after purification by flash chromatography (50 to 100% EtOAc in hexanes).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#N)([F:4])[CH3:3].[OH-:13].[Na+].Cl.[OH2:16]>>[F:1][C:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]([OH:16])=[O:13])([F:4])[CH3:3]
Reactant: CC(F)(F)c1cccc(C#N)c1
Reactant: [OH-]
Reactant: O
Agent: Cl
Agent: [Na+]
Product: CC(F)(F)c1cccc(C(=O)O)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
To a suspension (100 ml) of 3-(1,1-difluoroethyl)benzonitrile (5.10 g, 30.5 mmol) in water was added sodium hydroxide (3.05 g, 76.25 mmol), and the mixture was stirred at 100° C. for 5 hrs. After completion of the reaction, the reaction solution was acidified with 6N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 3-(1,1-difluoroethyl)benzoic acid (5.10 g, 90%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@H:8]([CH:18]=[O:19])[CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=O)=[O:6])[CH:2]=[CH2:3].C([O-])(=O)C.[Na+].[NH2:25][NH:26][C:27]([NH2:29])=[O:28]>CO>[CH2:1]([O:4][C:5]([NH:7][C@H:8]([CH:18]=[O:19])[CH2:9][CH2:10][C:11](=[N:25][NH:26][C:27]([NH2:29])=[O:28])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:6])[CH:2]=[CH2:3]
Reactant: NNC(N)=O
Reactant: C=CCOC(=O)N[C@H](C=O)CCC(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)N[C@H](C=O)CCC(=NNC(N)=O)OC(C)(C)C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To a solution of 207a (2.39 g, 8.8 mmol), in MeOH (20 ml) was added sodium acetate (0.72 g, 8.8 mmol) and semicarbazide (0.98 g, 8.8 mmol) stirred overnight, concentrated and diluted with CH2Cl2 (100 ml), washed with water, dried and concentrated. Flash chromatography (2% MeOH in CH2Cl2) afforded 208a (2.10 g, 73%) as an oil: [α]D20 −21 (c 2.55°, CH2Cl2); 1H NMR (CDCl3) δ 9.98 (1H, s), 7.27 (1H, d), 5.8 (1H, m), 5.5 (1H, d), 5.35-5.19 (2H, m), 4.58 (2H, m), 4.14 (1H, m), 2.37 (2H, t), 2.09 (1H, m), 2.0-1.75 (2H, m); Anal. Calcd for C14H24N4O5: C, 51.21; H, 7.37; N, 17.06. Found: C, 50.2; H, 7.3; N, 16.1
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].N[C@H]1COC2C=C(C)C=CC=2NC1=O.C(OC([NH:29][C@@H:30]([C@@H:34]([OH:36])[CH3:35])[C:31](O)=[O:32])=O)(C)(C)C.F[C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][C:39]=1[N+:48]([O-])=O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:29][C@H:30]1[C@H:34]([CH3:35])[O:36][C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][C:39]=2[NH:48][C:31]1=[O:32]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: C[C@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cc1ccc2c(c1)OC[C@H](N)C(=O)N2
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1Oc2ccc(C(F)(F)F)cc2NC(=O)[C@H]1N
Reaction time: 8 h

Procedure:
In a similar manner to that described for the preparation of (S)-3-amino-8-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one trifluoroacetate except in Step 1 the mixture was stirred overnight and in Step 2 the mixture was stirred 3 h, (2S,3S)-2-(tert-butoxycarbonylamino)-3-hydroxybutanoic acid discyclohexylamine salt (2.0 g, 5.00 mmol) and 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (1.04 g, 5.00 mmol) were converted to the title compound (58 mg) which was used without purification.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.Cl.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C>C(#N)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:24]1[CH2:25][CH2:26][CH2:27][CH:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[CH:17]=2)[CH2:23]1
Reactant: COc1cccc(C2CCCNC2)c1
Reactant: BrCC1COc2ccccc2O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cccc(C2CCCN(CC3COc4ccccc4O3)C2)c1
Temperature: 145 °C
Yield: 31.3 %

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (36 mg, 0.16 mmol), 3-(3-methoxyphenyl)piperidine HCl (36 mg, 0.16 mmol) and triethylamine (40 mg, 0.39 mmol) in acetonitrile (2 mL) was heated in a microwave reactor at 140-150° C. for 300 min. After evaporation to dryness, the crude product was purified by flash chromatography using a gradient of heptane and EtOAc as eluent to give 17 mg of the title compound.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[C:13]1[C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=1.[C:35]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)#[N:36]>O>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:19][C:18]1[C:13]([C:41]2[CH:42]=[C:37]([CH:38]=[CH:39][CH:40]=2)[C:35]#[N:36])=[N:14][C:15]([CH3:34])=[CH:16][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cccc(C#N)c3)c2cc1OC
Temperature: 70 °C
Reaction time: 5 h
Yield: 91.4 %

Procedure:
N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonate solution (1 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg) and 3-cyanophenylboronic acid (52 mg) under an argon atmosphere, and the mixture was stirred at 70° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was 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 (43 mg, yield 92%).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7](Cl)=[O:8])(=[O:3])[CH3:2].[NH2:14][C@H:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([NH:14][C@H:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:8])(=[O:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: CC(=O)SCC(CC(C)C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)C(CSC(C)=O)CC(C)C

Procedure:
2-Acetylthiomethyl-4-methylpentanoyl chloride and (L)-leucine, ethyl ester are reacted in methylene chloride in the presence of diisopropylethylamine at a temperature below 0° according to the procedure of Example 26 to yield (±)-N-[2-(acetylthiomethyl)-4-methyl-1-oxopentyl]-L-leucine, ethyl ester.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[N+:16]([C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([N+]([O-])=O)[C:20]=1[C:21]#[N:22])([O-:18])=[O:17].C(OC(C)(C)C)=O>>[C:21]([C:20]1[C:19]([N+:16]([O-:18])=[O:17])=[CH:26][CH:25]=[CH:24][C:23]=1[O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[N:22]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Agent: CC(C)(C)OC=O
Product: CC(C)(C)OC(=O)N1CCCC(COc2cccc([N+](=O)[O-])c2C#N)C1
Yield: 58 %

Procedure:
Prepared as in Example 197c from tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate and 2,6-dinitrobenzonitrile in 58% yield. MS 263 [M+H-Boc]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]([O:39][CH3:40])=[CH:31][N:30]=3)[CH2:27][C@H:21]2[C:20](=[O:41])[NH:19][C@:18]2([C:43]([OH:45])=O)[CH2:42][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH:12]([CH3:46])[CH2:11][C@H:10]1[CH3:47])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:60]1([S:64]([NH2:67])(=[O:66])=[O:65])[CH2:63][CH2:62][CH2:61]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH:60]1([S:64]([NH:67][C:43]([C@@:18]23[CH2:42][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH:12]([CH3:46])[CH2:11][C@@H:10]([CH3:47])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]4[C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[C:32]([O:39][CH3:40])=[CH:31][N:30]=4)[CH2:27][C@H:21]2[C:20](=[O:41])[NH:19]3)=[O:45])(=[O:66])=[O:65])[CH2:63][CH2:62][CH2:61]1
Reactant: COc1cnc(O[C@@H]2C[C@H]3C(=O)N[C@]4(C(=O)O)C[C@H]4C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N3C2)c2ccccc12
Reactant: NS(=O)(=O)C1CCC1
Agent: COc1cnc(O[C@@H]2C[C@H]3C(=O)N[C@]4(C(=O)NS(=O)(=O)C5CCC5)C[C@H]4/C=C\CCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N3C2)c2ccccc12
Agent: COc1cnc(O[C@@H]2C[C@H]3C(=O)N[C@]4(C(=O)O)C[C@H]4/C=C\CCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N3C2)c2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cnc(O[C@@H]2C[C@H]3C(=O)N[C@]4(C(=O)NS(=O)(=O)C5CCC5)C[C@H]4C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N3C2)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (2R,6S,7R,13aS,14aR,16aS,Z)-6-((tert-butoxycarbonyl)amino)-2-((4-methoxyisoquinolin-1-yl)oxy)-7,9-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid (70 mg, 0.108 mmol), CDI (34.9 mg, 0.215 mmol) in tetrahydrofuran (3 mL) was refluxed for 2 h. It was then cooled to rt and cyclobutanesulfonamide (32.0 mg, 0.237 mmol) was added and followed by DBU (0.036 mL, 0.237 mmol). The mixture was stirred at rt for 16 h. It was then concentrated and purified by silica gel chromatography, eluting with 40% acetone/hexane to isolate 70 mg of the diastereomers tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-14a-((cyclobutylsulfonyl)carbamoyl)-2-((4-methoxyisoquinolin-1-yl)oxy)-7,9-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate that was used as it was.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][CH:8]=[CH2:9])(=[O:3])[CH3:2].[C:10](O)(=[O:14])[C:11](C)=C.N1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:14][CH:10]=[CH2:11])(=[O:3])[CH3:2]
Reactant: C=COCCOC(C)=O
Reactant: C=C(C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=COCCOCCOC(C)=O
Yield: 93 %

Procedure:
The thus obtained acetoxyethylvinylether by 19.5 grams (0.15 mols) and methacrylic acid by 15.5 grams (0.18 mols) were dissolved into methylene chloride. Then, 0.38 grams (0.0015 mols) of p-toluenesulfonic acid pyridine salt was added into the mixture, and stirred for complete dissolution. The resultant mixture is stood at room temperature for 6 hours. Then, the mixture was washed three times with 2.5% aqueous sodium hydroxide, and six times with water. Then, the resultant mixture was dehydrated with magnesium sulfate. After filtering magnesium sulfate out, solvent was removed by means of an evaporator. Then, the resultant residue was distilled under reduced pressure, thereby there was obtained 29.6 grams of acetoxyethoxyethylvinylether (b.p. 100-105° C./0.07 mmHg). The yield was 93%.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([O:18][CH2:19][CH2:20][C:21]([OH:23])=O)[C:15]([I:17])=[CH:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[C:13]3[C:21](=[O:23])[CH2:20][CH2:19][O:18][C:14]=3[C:15]([I:17])=[CH:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2cc(I)c(OCCC(=O)O)cc2CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)N1CCc2cc(I)c3c(c2CC1)C(=O)CCO3
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
Into a 100 ml flask, the product from step (e) (312 mg, 0.72 mmol) dissolved in DCM (20 ml) was added. The solution was cooled to 0° C., and oxalyl chloride (94 μL, 1.07 mmol) was added, followed by 2 drops of DMF. After 30 minutes, volatiles were evaporated in vacuo and the residue was dissolved in fresh DCM (20 ml) and cooled to 0° C. Aluminum chloride (386 mg, 2.88 mmol) was then added and the reaction mixture stirred for 1 hour. The reaction was quenched with saturated aqueous NH4Cl, and the organic layer was extracted with DCM (3×). The combined DCM extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the crude product. Purification by silica-gel chromatography (gradient elution: 0 to 40% EtOAc in hexanes) gave the sub-title compound as a light yellow solid (170 mg). 1H NMR (300 MHz, CDCl3) δ 7.69 (s, 1H); 4.56 (t, J=6.3 Hz, 2H); 4.12 (q, J=7.2 Hz, 2H); 3.68-3.51 (m, 6H); 2.85 (t, J=6.6 Hz, 4H); 1.23 (t, J=7.2 Hz, 3H); MS: ESI (positive): 416 (M+H).
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[N:20]4[CH:21]=[C:22]([CH2:24]O)[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(Cl)([Cl:28])=O>>[C:1]12([CH2:11][NH:12][C:13]([C:15]3[N:20]4[CH:21]=[C:22]([CH2:24][Cl:28])[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[ClH:28]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccc2nc(CO)cn12
Reactant: O=S(Cl)Cl
Product: Cl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccc2nc(CCl)cn12

Procedure:
N-(Adamantan-1-ylmethyl)-2-(hydroxymethyl)imidazo[1,2-a]pyridine-5-carboxamide (4.4 g, 12.96 mmol) is treated with 10 mL of thionyl chloride at RT for 1 h. The excess thionyl chloride is removed in vacuo to give the title compound as its HCl salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1/[CH:12]=[CH:13]/[C:14]([O:16][CH3:17])=[O:15])[C:5]([O:7][CH3:8])=[O:6].[S:18](=[O:21])([OH:20])[O-:19].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[CH:10][C:11]=1[CH:12]([S:18]([OH:21])(=[O:20])=[O:19])[CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: O=S([O-])O
Reactant: COC(=O)/C=C/c1ccc(C(=O)OC)cc1Br
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)CC(c1ccc(C(=O)OC)cc1Br)S(=O)(=O)O
Temperature: 165 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
Methyl 3-bromo-4-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]benzoate (300 mg, 1.00 mmol) dissolved in ethanol (2.0 mL) was added to sodium bisulfite (209 mg, 2.00 mmol) in water (2.0 mL). The reaction mixture was heated in the microwave at 165° C. with stirring for 30 minutes. The colorless solution was purified by preparative LCMS to afford product as a white solid (0.26 g, 68%). 1H NMR (400 MHz, CDCl3): δ 8.19 (d, J=1.5 Hz, 1H), 7.93 (dd, J=8.2, 1.8 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H), 5.18 (dd, J=10.0, 5.1 Hz, 1H), 3.88 (s, 3H), 3.55 (s, 3H), 3.38 (dd, J=16.5, 5.1 Hz, 1H), 3.08 (dd, J=16.5, 10.0 Hz, 1H). LCMS found for C12H12BrO7S (M−H)−: m/z=378, 380.
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][CH2:7][CH2:8][NH2:9])[C:3]([OH:5])=[O:4].[O-2].[Mg+2].[CH3:12][O:13][C:14]1[CH:26]=[CH:25][C:17]([CH2:18][O:19][C:20](N=[N+]=[N-])=[O:21])=[CH:16][CH:15]=1>O.O1CCOCC1>[CH2:1]=[C:2]([CH2:6][CH2:7][CH2:8][NH:9][C:20]([O:19][CH2:18][C:17]1[CH:25]=[CH:26][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)=[O:21])[C:3]([OH:5])=[O:4]
Reactant: C=C(CCCN)C(=O)O
Reactant: COc1ccc(COC(=O)N=[N+]=[N-])cc1
Agent: [Mg+2]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: O
Product: C=C(CCCNC(=O)OCc1ccc(OC)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 105.4 %

Procedure:
To a solution of 8.8 g of 2-methylene-5-aminopentanoic acid hydrochloric in 100 ml of water is added with stirring 6.36 g of magnesium oxide, followed by a solution of 12.2 g of p-methoxybenzyloxycarbonyl azide in 100 ml of dioxane, and the resulting mixture is stirred at room temperature for two days. The reaction mixture is filtered, and the filtrate diluted with 200 ml of ethyl acetate, two equivalents of Dowex 50 ion exchange resin is added, and the mixture is stirred at room temperature for two hours. The resin is then filtered off and washed with water. The layers in the filtrate are separated and the aqueous layer is extracted twice with ethyl acetate. The combined organic layers are dried and concentrated in vacuo to give 18.2 g of 2-methylene-5-(p-methoxybenzyloxycarbonyl)aminopentanoic acid as an amber oil which crystallizes on standing. This is used without further purification.