Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][CH2:7][C:8]#[N:9])C.[C:13]([O:17][C:18]([NH:20][C@H:21]([C:29]([OH:31])=O)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:22]([C@H:21]1[C:29](=[O:31])[N:6]([CH2:7][C:8]#[N:9])[CH:5]=[CH:4][N:20]1[C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCOC(CNCC#N)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C=CN(CC#N)C(=O)[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
To a mixture of 3.0 g of 2,2-diethoxyethylaminoacetonitrile, 4.85 g of N-t-butoxycarbonyl-L-phenylalanine and 50 ml of methylene chloride was added 3.6 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, which was stirred for 4 hours at room temperature. The reaction mixture was concentrated under reduced pressure. To the concentrate were added 100 ml of ethyl acetate and 50 ml of water. The mixture was shaken. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and, then, concentrated under reduced pressure. The concentrate (7.0 g) was dissolved in 100 ml of ethyl acetate. To the solution was added 0.5 g of p-toluenesulfonic acid, and the mixture was stirred for 4 hours at 75° to 85° C. The reaction mixture was cooled and washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was purified by means of a silica-gel column chromatography (eluent: hexane-ethyl acetate=3:1), followed by recrystallization from ethyl acetate to afford 3.7 g of colorless prisms, m.p.160°-162° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4OC[CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)[C@@]2(C3C(=CC4OCCOC=4C=3)[O:33][CH2:32]2)C1=O.Cl[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][N:48]=1.BrCCCCC>>[F:54][C:53]([F:56])([F:55])[C:50]1[CH:51]=[CH:52][C:47]([CH2:46][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[CH2:32][O:33][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])=[N:48][CH:49]=1
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: FC(F)(F)c1ccc(CCl)nc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Solvent: CCCCCBr
Product: O=C1N(Cc2ccc(C(F)(F)F)cn2)c2ccccc2C12COc1cc3c(cc12)OCOC3

Procedure:
Following the procedure as described in EXAMPLE 7.3 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1H)-one, and 2-(chloromethyl)-5-(trifluoromethyl)pyridine to replace 1-bromopentane, 1′-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (53%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.83 (s, 1H), 7.89 (dd, J=8.2, 2.0 Hz, 1H), 7.42-6.81 (m, 5H), 6.50 (s, 1H), 6.28 (s, 1H), 5.13 (ABq, 2H), 4.80 (ABq, 2H), 4.22-4.07 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.6, 159.4, 155.2, 146.5, 146.5, 144.7, 141.7, 138.3, 134.3, 134.3, 134.2, 132.1, 128.9, 126.1, 125.6, 125.1, 124.0, 123.7, 121.4, 120.8, 111.6, 109.2, 99.4, 80.0, 64.5, 63.9, 58.1, 45.7; MS (ES+) m/z 454.9 (M+1).
Reaction SMILES: [C:1]([O:23][CH2:24][CH2:25][C:26]([F:38])([F:37])[C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])(=[O:22])/[CH:2]=[CH:3]\[C:4]([O:6][CH2:7][CH2:8][C:9]([F:21])([F:20])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[O:5].Cl.CN([CH:43]([SH:45])C)C.C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl.[CH3:56][N:57]([CH3:60])[CH:58]=O>>[CH3:56][N:57]([CH2:58][C:43](/[C:2](=[CH:3]/[C:4]([O:6][CH2:7][CH2:8][C:9]([F:21])([F:20])[C:10]([F:18])([F:19])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[O:5])/[C:1]([O:23][CH2:24][CH2:25][C:26]([F:37])([F:38])[C:27]([F:35])([F:36])[C:28]([F:33])([F:34])[C:29]([F:32])([F:31])[F:30])=[O:22])=[S:45])[CH3:60]
Reactant: CN(C)C=O
Reactant: O=C(/C=C\C(=O)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(S)N(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CN(C)CC(=S)/C(=C/C(=O)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 60 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
In an amount of 25.1 g (41 mmol) of 1,4-di(3,3,4,4,5,5,6,6,6-nonafluorohexyl) maleate, 6.4 g (45 mmol) of N,N-di-methylaminoethanethiol hydrochloride and 5.7 g (41 mmol) of potassium carbonate were dissolved in 60 mL of N,N-dimethylformamide and stirred at 60° C. for 4 hours. Then, the reaction mixture was added with 500 mL of chloroform and the organic phase was washed with a saturated aqueous sodium hydrogencarbonate solution. Subsequently, the organic layer was collected, and the organic solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:2 to 0:10 (volume ratio)) to obtain 15.8 g (yield: 54%) of the target compound.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[N:7]=1)([CH3:5])([CH3:4])[CH3:3].Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]>>[C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:17](=[O:18])[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[N:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)Cn1nc(C(C)(C)C)cc1N
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Product: CC(C)Cn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1

Procedure:
Following the procedure described for Example 330A Step 2, reaction of 3-tert-butyl-1-isobutyl-1H-pyrazol-5-amine hydrochloride with phenyl chloroformate, afforded phenyl 3-tert-butyl-1-isobutyl-1H-pyrazol-5-ylcarbamate which was used in the subsequent step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].C(Cl)CCl.Cl.C1C=NC2N(O)N=NC=2C=1.[NH2:40][C:41]1[C:46]([C:47](O)=[O:48])=[CH:45][N:44]=[CH:43][N:42]=1>ClCCl.C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:47]([C:46]2[C:41]([NH2:40])=[N:42][CH:43]=[N:44][CH:45]=2)=[O:48])=[CH:21][CH:22]=1)[NH:5][C:6](=[O:15])[C:7]1[C:8]([Cl:14])=[CH:9][CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: Nc1ncncc1C(=O)O
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2cncnc2N)cc1)NC(=O)c1c(Cl)cccc1Cl
Reaction time: 8 h
Yield: 10.9 %

Procedure:
The mixture of N-(2,6-dichlorobenzoyl)-4-amino-L-phenylalanine methylester (1.0 g), EDC/HCl (783 mg), HOAt (555 mg), triethylamine (747 μL), 4-aminopyrimidine-5-carboxylic acid (417 mg) and dichloromethane (15 mL) was stirred overnight. After diluting the mixture with dichloromethane and washing with saturated sodium bicarbonate water, the organic layer thereof was dried over sodium sulfate and concentrated. The residue was washed with dichloromethane to obtain 145 mg of a crude material of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[C:10]([C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[NH:1][S:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=1)(=[O:28])=[O:27])(=[O:11])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(N)c(C(=O)c2ccccc2)c1
Product: COc1ccc(S(=O)(=O)Nc2ccc(OC)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-Amino-5-methoxy-phenyl)-phenyl-methanone and 103 mg of 4-Methoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 3.60 (s, 3H), 3.72 (s, 3H), 6.55 (d, 2H, J=8.8 Hz), 6.78 (d, 1H, J=2.8 Hz), 7.07 (dd, 1H, J=8.8 Hz, 2.8 Hz), 7.28-7.37 (m, 4H), 7.42 (d, 2H, J=6.8 Hz), 7.54 (m, 1H), 7.72 (d, 1H, J=8.8 Hz), 9.05 (s, 1H). MS: m/z 398.3 (M++1).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([C:8]2[C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH:7]=1.BrC1C=CC([N+]([O-])=O)=CC=1[C:26](OCC)=[O:27].COC1C=CC(OC)=CC=1B(O)O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][O:21][C:5]1[CH:4]=[CH:3][C:2]([O:27][CH3:26])=[CH:7][C:6]=1[C:8]1[C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(F)ccc1OC
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(OC)c(B(O)O)c1
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(OC)ccc1OC
Yield: 69 %

Procedure:
This compound was prepared in a manner similar to that of methyl 5'-fluoro-2'-methoxy-4-nitro-2-biphenylcarboxylate (EXAMPLE 107) from ethyl 2-bromo-5-nitrobenzoate (2.46 g, 9.46 mmol), (PPh3)4Pd (0.33 g, 0.28 mmol), and 2,5-dimethoxyphenylboronic acid (2.42 g, 13.3 mmol) to afford 2.08 g (69%) of methyl (2', 5'-dimethoxy-4-nitro-2-biphenylcarboxylate) as a white solid. Data for methyl (2',5'-dimethoxy-4-nitro-2-biphenylcarboxylate): 1H NMR (400 MHz, CDCl3) 8.70 (d, J=2.4, 1H), 8.37 (dd, J=8.4, 2.5, 1H), 7.52 (d, J=8.5, 1H), 6.92 (dd, J=8.8, 3.0, 1H), 6.84 (m, 1H), 3.82 (s, 3H), 3.75 (s, 3H), 3.67 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][C:22]([NH:24][CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26])=[O:23])[C:18]([OH:20])=[O:19]>>[C:18]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22](=[O:23])[NH:24][CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26])([OH:20])=[O:19]
Reactant: CC(NC(=O)CC(N)C(=O)O)c1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: CC(NC(=O)CC(Nc1nc2ccc(Cl)cc2cc1C(=O)O)C(=O)O)c1ccccc1

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-N-(1-phenyl-ethyl)-succinamic acid to provide the title compound in good yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(#N)C.CS(O[CH:17]1[CH2:20][N:19]([CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18]1)(=O)=O>>[CH:21]([N:19]1[CH2:20][CH:17]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:18]1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Oc1ccc(F)cc1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CC#N
Product: Fc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 4-fluorophenol (0.80 g, 7.16 mmol) in acetonitrile (15 ml) potassium carbonate (1.3 g, 9.30 mmol) was added followed by the addition of 1-benzhydrylazetidin-3-yl methanesulfonate (D19) (2.5 g, 7.87 mmol) and the mixture was stirred under microwave irradiation at 100° C. for 5 mins. The reaction mixture was evaporated in vacuo and the residue was taken up in a mixture diethylether/water (10 ml/10 ml). The aqueous layer was extracted with diethylether (2×10 ml). The organics after solvent evaporation were loaded on SPE-Si (25 g) cartridge eluting with a mixture cyclohexane/ethylacetate (from 100/0 to 85/15. Collected fractions gave, after evaporation, the title compound (D21) (1.8 g).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]([CH3:28])=[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]([O-])=O.[Na+].[CH3:38]CO.COCCOC>C(O)C>[C:30]1([S:34][CH2:2][C:3]2[NH:4][C:5]([CH3:28])=[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)[C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:38]=[CH:29][CH:33]=[CH:32][CH:31]=1
Reactant: CCO
Reactant: CCOC(=O)C1=C(C)NC(CCl)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: O=C([O-])c1cccs1
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C1=C(C)NC(CSc2ccccc2)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 2-chloromethyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1, 4-dihydropyridine (5.6 g) in EtOH/DME (5/1; 20 ml) is added dropwise at +10° C. to a stirred solution of sodium thiophenate (1.8 g) in ethanol (10 ml), under N2 atmosphere. After two hours at room temperature the reaction mixture is evaporated under vacuum and the residue is partitioned between Et2O (100 ml) and water (50 ml). The organic phase is washed with a satured solution of sodium bicarbonate (2×20 ml) and water (3×20 ml), dried (Na2SO4) and evaporated to dryness. The residue is recrystallized from isopropylether to give 5.7 g of 2-(phenylthio)methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1, 4-dihydropyridine, m.p. 92°-94° C.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([C:33]2([F:39])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH:30]=[C:29]([F:40])[C:28]=1[C:41]1[N:46]=[C:45]([C:47](O)=[O:48])[CH:44]=[CH:43][C:42]=1[F:50]>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:47](=[O:48])[C:45]2[CH:44]=[CH:43][C:42]([F:50])=[C:41]([C:28]3[C:29]([F:40])=[CH:30][C:31]([C:33]4([F:39])[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)=[CH:32][C:27]=3[F:26])[N:46]=2)[CH2:6][CH2:7]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cc(C3(F)CCOCC3)cc2F)n1
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3c(F)cc(C4(F)CCOCC4)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-(4-fluorotetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropicolinic acid (see US2012/225062) gave 206. 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.30 (dd, J=8.7, 4.0 Hz, 1H), 8.17 (t, J=8.9 Hz, 1H), 7.92 (s, 1H), 7.41 (d, J=9.2 Hz, 2H), 4.81 (dd, J=10.3, 3.8 Hz, 1H), 4.17 (ddd, J=49.1, 5.9, 3.1 Hz, 1H), 4.02-3.96 (m, 1H), 3.96-3.84 (m, 3H), 3.75 (s, 3H), 3.74-3.64 (m, 2H), 3.09-2.99 (m, 1H), 2.33-2.13 (m, 2H), 2.10-1.99 (m, 1H), 1.93-1.80 (m, 2H), 1.80-1.52 (m, 5H). LCMS (ES+) m/z 566 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:4][NH:5][C:6](=[O:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:3].[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1C=CC=CC=1>[CH2:13]([O:20][C:21]([N:5]1[C:6](=[O:11])[CH2:7][C:8]([CH3:9])([CH3:10])[NH:3][C:2]([CH3:1])([CH3:12])[CH2:4]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)CC(=O)NCC(C)(C)N
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccccc1
Product: CC1(C)CC(=O)N(C(=O)OCc2ccccc2)CC(C)(C)N1

Procedure:
A mixture of 17 parts of 2,2,7,7-tetramethyl-1,4-diazaheptan-5-one, 19 parts of benzylchloroformate and 250 parts of dry benzene was heated at reflux for 16 hours. The solvent was then evaporated in vacuo to yield an almost colourless oil. Addition of 20 parts of petroleum ether (of boiling range 40° to 60°C) produced 4-benzyloxycarbonyl-2,2,7,7-tetramethyl-1,4-diazacycloheptan-5-one as a colourless solid of melting point 86° -88°C. This material gave the following elemental analysis by weight:
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][CH:7]=[C:8]([C:9]([OH:11])=[O:10])[C:4]=2[CH:3]=1.SC1C=C[C:18]([OH:21])=[CH:17]C=1.N1C=CC=CC=1.O>C(OC(=O)C)(=O)C>[C:18]([O:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][CH:7]=[C:8]([C:9]([OH:11])=[O:10])[C:4]=2[CH:3]=1)(=[O:21])[CH3:17]
Reactant: O=C(O)c1csc2ccc(O)cc12
Reactant: Oc1ccc(S)cc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1ccc2scc(C(=O)O)c2c1
Reaction time: 3 h
Yield: 97.3 %

Procedure:
5-Hydroxybenzo[b]thiophene-3-carboxylic acid (11) (1,140 mg) prepared in above (1) was dissolved in acetic anhydride (2 ml), pyridine (4 ml). After 3 hours, water was added and the mixture was continuously stirred under ice-cooling for 1.5 hours. The deposited crystals were filtered, washed with water and dried to provide 1,349 mg of the title compound (12). Yield: 97.3% mp 239-240° C.
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[C:3]([O:5][CH3:6])=[O:4].O1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.Cl[CH2:20]Cl>FC(F)(F)C(O)=O>[CH:14]1([O:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[C:3]([O:5][CH3:6])=[O:4])[CH2:20][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1=COCCC1
Reactant: ClCCl
Reactant: C=CCCCCC(O)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Product: C=CCCCCC(OC1CCCCC1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 2-hydroxyoct-7-enoate (6.88 g, 0.040 mmol), dichloromethane (40 mL), 3,4-dihydro-2H-pyran (7.4 mL, 0.082 mol), and 6 drops of trifluoroacetic acid was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo to yield methyl 2-(cyclohexyloxy)oct-7-enoate, which was used in the next step without further purification. A solution of methyl 2-(cyclohexyloxy)oct-7-enoate (500.0 mg, 1.95 mmol) dissolved in toluene (33 mL) containing 4-methyl-5-vinylthiazole (1.11 mL, 19.5 mmol) and Grubb's 2nd generation catalyst (166 mg, 0.195 mmol) was flushed with argon and heated in a sealed tube at 100° C. for 20 h. After cooling to room temperature, the solvent was removed in vacuo and the resulting residue was purified via flash silica gel chromatography (Analogix IF-280, SF25-115 g column, gradient 90:10-80:20 Heptane:EtOAc) to yield (E)-methyl 2-(cyclohexyloxy)-8-(4-methylthiazol-5-yl)oct-7-enoate. MS (ES+) 354 (M+1).
Reaction SMILES: C(OC(=O)COC1C=CC(S)=CC=1C)C.[CH2:16]([O:18][C:19](=[O:34])[CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([S:29](Cl)(=O)=O)=[CH:24][C:23]=1[CH3:33])[CH3:17]>>[CH2:16]([O:18][C:19](=[O:34])[CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([SH:29])=[CH:24][C:23]=1[CH3:33])[CH3:17]
Reactant: CCOC(=O)COc1cc(C)c(S(=O)(=O)Cl)cc1C
Agent: CCOC(=O)COc1ccc(S)cc1C
Product: CCOC(=O)COc1cc(C)c(S)cc1C

Procedure:
The title compound was prepared according to the method described for preparing compound 10.3, using compound 21.2 as the starting material. 1H NMR (300 MHz) (CDCl3) δ 7.11 (1H, s); 6.54 (1H, s); 4.59 (2H, s); 4.26 (2H, q, J=7.2 Hz); 3.10(1H, s); 2.29 (3H, s); 2.21 (3H, s); 1.30 (3H, t, J=7.2 Hz).
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([F:41])=[C:19]([C@@:21]23[N:30]=[C:29]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[S:28][CH2:27][C@@H:26]2[CH2:25][C@H:24]([CH2:39]O)[O:23][CH2:22]3)[CH:20]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([F:41])=[C:19]([C@@:21]23[N:30]=[C:29]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:35])[CH3:36])[S:28][CH2:27][C@@H:26]2[CH2:25][C@H:24]([CH2:39][F:11])[O:23][CH2:22]3)[CH:20]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(Br)ccc3F)CO[C@@H](CO)C[C@H]2CS1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(Br)ccc3F)CO[C@@H](CF)C[C@H]2CS1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[Bis(2-methoxyethyl)amino]sulfur trifluoride (155 μl) was added dropwise to a solution of tert-butyl [(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-hydroxymethyl-4,4a,5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl]carbamate (200 mg) in dichloromethane (5.0 ml) at −78° C. The mixture was stirred overnight with gradual heating to room temperature. A sodium bicarbonate solution was added to the reaction mixture to terminate the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (145 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=[O:5].C[Si]([C:12]#[N:13])(C)C>[I-].[Zn+2].[I-].CO>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]([OH:5])[C:12]#[N:13]
Reactant: CC(C)(C)CC=O
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: CO
Product: CC(C)(C)CC(O)C#N

Procedure:
Tert-butylacetic acid (b) is reduced with a hydride reducing agent, preferably lithium aluminum hydride, to provide 3,3-dimethyl-1-butanol (c). Oxidation of alcohol (c) with 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (TEMPO), provides 3,3-dimethylbutyraldehyde (d), which is isolated by co-distillation with tetrachloroethane. Aldehyde (d) is treated sequentially with trimethylsilyl cyanide and a catalytic amount of zinc iodide, followed by methanol to afford (±)-4,4-dimethyl-2-hydroxypentanenitrile (e). This nitrile is hydrolyzed first with hydrochloric acid, followed by 50% NaOH to provide racemic pentanoic acid (f). Sequential treatment of racemate (f) with neat acetyl chloride, followed by either oxalyl chloride or thionyl chloride and N,N-dimethylformamide, provides 4,4-dimethyl-2-acetoxypentanoyl chloride (g), which is then coupled with (R)-(−)-4-phenyl-2-oxazolidinone in the presence of 4-dimethylaminopyridine and N,N-diisopropylethylamine in dichloromethane to give a mixture of the acetoxy diastereomers. This diastereomeric mixture of acetates is separated by column chromatography to provide the single diastereomeric acetate (h). The acetate (h) is treated with sodium hydroxide in a solution of tetrahydrofuran/methanol/water to give the desired (2S)-(−)-4,4-dimethyl-2-hydroxypentanoic acid IV. The crude pentanoic acid IV is converted to an ester, preferably the allyl ester, and is then purified by chromatography to provide allyl (2S)-(−)-4,4-dimethyl-2-hydroxypentanoate (i).
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[CH2:8]([O:10][C:11](=[O:22])[C:12]([C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=1[F:21])=O)[CH3:9]>O1CCCC1.C(OCC)(=O)C.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH2:8]([O:10][C:11](=[O:22])/[C:12](/[C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=1[F:21])=[N:7]\[S@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[CH3:9]
Reactant: CCOC(=O)C(=O)c1cc(Br)ccc1F
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C(=N\[S@@](=O)C(C)(C)C)c1cc(Br)ccc1F
Temperature: 70 °C
Reaction time: 3.5 h

Procedure:
A solution of (S)-(−)-2-methyl-2-propanesulfinamide (2.35 g, 19.4 mmol) and (5-bromo-2-fluoro-phenyl)-oxo-acetic acid ethyl ester (5.33 g, 19.4 mmol) in tetrahydrofuran (80 ml) was treated at room temperature with titanium(IV) ethoxide (8.04 ml, 38.8 mmol). The light brown solution was stirred at 70° C. for 3.5 hours. For the workup, the cooled reaction mixture was poured into ice water, diluted with ethyl acetate, and filtered through a pad of Dicalite. The organic layer was separated, washed with brine, dried over sodium sulfate, and finally evaporated at reduced pressure. The crude product (6.7 g) was purified by chromatography on silica gel using a gradient of cyclohexane and dichloromethane=100/0 to 0/100 as the eluent. (S)-(5-bromo-2-fluoro-phenyl)-[(Z)-2-methyl-propane-2-sulfinylimino]-acetic acid ethyl ester was obtained as a yellow oil (4.9 g, 66% of theory). Mass (calculated) C14H17BrFNO3S [378.260]; (found) [M+H]+=378, [M+2-H]+=380.