Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C@H:8]2[C@H:13]3[CH2:14][C@H:10]([CH2:11][CH2:12]3)[C@H:9]2[C:15](OC)=[O:16])=[CH:4][CH:3]=1.[CH3:21][S:22]([NH:25][C:26]1[CH:41]=[CH:40][C:29]2[NH:30][C:31]([CH2:36][C:37](O)=[O:38])=[CH:32][S:33](=[O:35])(=[O:34])[C:28]=2[CH:27]=1)(=[O:24])=[O:23].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[O-]CC.[Na+]>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:37](=[O:38])[C:36]([C:31]3[NH:30][C:29]4[CH:40]=[CH:41][C:26]([NH:25][S:22]([CH3:21])(=[O:23])=[O:24])=[CH:27][C:28]=4[S:33](=[O:35])(=[O:34])[CH:32]=3)=[C:15]([OH:16])[C@H:9]3[C@@H:8]2[C@H:13]2[CH2:14][C@@H:10]3[CH2:11][CH2:12]2)=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)C=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)C=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Yield: 5.8 %

Procedure:
Methyl (1S,2R,3S,4R)-3-[(4-fluorobenzyl)amino]bicyclo[2.2.1]heptane-2-carboxylate (prepared as described in Example 6d, 0.20 g, 0.69 mmol) was dissolved in anhydrous N,N-dimethylformamide (7 mL). (7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid (0.23 g, 0.69 mmol) was added followed by N-methylmorpholine (0.17 mL, 1.52 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.15 g, 0.76 mmol) was added and the mixture was stirred at 25° C. for 16 h. The reaction was quenched via addition of saturated aqueous sodium bicarbonate solution (20 mL). The mixture was extracted with ethyl acetate (3×30 mL). The organic layers were combined and washed with saturated aqueous brine solution (20 mL). The resulting solution was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. The oil was dissolved in ethanol (10 mL). A 21 wt. % solution of sodium ethoxide in ethanol (0.65 mL, 1.74 mmol) was added. The reaction was stirred at 60° C. for 16 h. The reaction was quenched via the addition of 1.0 M aqueous hydrochloric acid solution (10 mL). The mixture was extracted with ethyl acetate (3×20 mL). The organic layer was further washed with saturated aqueous sodium bicarbonate solution (2×20 mL), saturated aqueous brine solution (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a clear oil. Purification by flash column chromatography (Teledyne Isco RediSep column; 22 to 75% ethyl acetate in hexanes) afforded the desired product, N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-7-yl}-methanesulfonamide (0.020 g, 0.04 mmol, 5.3%), as a yellow powder. 1H NMR (400 MHz, CDCl3) δ: 1.21-1.64 (6H, m), 2.52-2.71 (3H, m), 3.07 (3H, s), 3.39-3.52 (1H, m), 5.15-5.28 (2H, m), 6.60 (1H, s), 7.02-7.06 (2H, m), 7.22-7.26 (2H, m), 7.54-7.66 (3H, m). LC-MS (ESI) calcd for C26H26FN3O6S2 559.63, found 560.5 [M+H+].
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:9])=[CH:5][C:6](=[O:8])[CH3:7].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O.[Cl-].C([N+](CC)(CC)CCCCCCCCCCCC)C>[CH2:10]([C:5](=[C:4]([CH3:9])[CH3:3])[C:6](=[O:8])[CH3:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)C=C(C)C
Reactant: ClCc1ccccc1
Agent: CCCCCCCCCCCC[N+](CC)(CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(=O)C(Cc1ccccc1)=C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.9 %

Procedure:
A solution of 2.7 g (65 millimole) of NaOH in 2.5 ml of water was added to 8.5 g (90 millimole) of 4-methyl-3-pentene-2-one and stirred at 40° C. while 200 mg of triethyldodecyl ammonium chloride was added. The red solution was treated with 5.4 g (45 millimole) of benzyl chloride and the stirring continued for 4 hours at 50° C. The resulting yellow brown solution was cooled to room temperature and diluted with 10 ml of water, followed by extraction with 50 ml of ether. The organic extract was washed with 10 ml of water, 10 ml of 10% HCl, and then another 10 ml of water, followed by drying over magnesium sulfate. Evaporation of solvent and flash column chromatography gave 4.4 g (52% yield) of 3-benzyl-4-methyl-3-pentene-2-one.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C([Li])CCC.[CH:17]1([O:22][C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=2[O:31][CH3:32])[CH:26]=[O:27])[CH2:21][CH2:20][CH2:19][CH2:18]1.Cl>C1COCC1.CCOCC.O>[CH:17]1([O:22][C:23]2[CH:24]=[C:25]([CH:26]([OH:27])[CH2:7][C:5](=[O:6])[CH2:4][C:3]([O:9][CH2:10][CH3:11])=[O:8])[CH:28]=[CH:29][C:30]=2[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)c1ccc(OC)c(OC2CCCC2)c1
Reaction time: 0.17 h
Yield: 52.8 %

Procedure:
Sodium hydride (6.0 g of 60% sodium hydride in mineral oil, 0.15 mol) was placed in a 3-neck flask equiped with a mechanical stirrer under nitrogen and washed twice with hexanes. THF (200 mL) was added and the mixture was cooled in an ice bath. Ethyl acetoacetate (17.6 g, 0.135 mol) was added dropwise and the mixture was stirred for 10 minutes after the addition. Butyllithium (0.35 mol, 84 mL of 1.6M solution in hexanes) was added dropwise to give an orange solution. A solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (29.6 g, 0.135 mol) in THF (100 mL) was added dropwise. After 10 minutes, the cold solution was treated with concentrated hydrochloric acid (26 mL, 0.29 mol), water (65 mL) and ether (500 mL). The ether layer was separated and washed with saturated brine (3×300 mL). The ether was evaporated to give 46.5 g of crude title compound. The crude product was dissolved in a small amount of 30% methylene chloride/hexanes and purified by chromatography over 400 g of flash chromatography silica gel. Elution with methylene chloride/hexane mixtures removed 9 g of starting aldehyde. Elution with 1% methanol/methylene chloride afforded the ethyl 5-(3-cyclopentyloxy-4-methoxyphenyl)-3-oxo-5-hydroxypentanoate (25.0 g, 53%) as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11](O)=[O:12])=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]1[C@@H:41]2[C@@H:36]([CH2:37][CH2:38][CH2:39][CH2:40]2)[CH2:35][CH2:34][NH:33]1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:7]2[O:6][C:5]([C:3](=[O:4])[C:2]([CH3:21])([CH3:1])[CH3:20])=[C:9]([CH2:10][C:11]([N:33]3[CH2:34][CH2:35][C@H:36]4[C@H:41]([CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:32]3)=[O:12])[C:8]=2[CH:14]=1
Reactant: C1CC[C@@H]2CNCC[C@@H]2C1
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)N3CC[C@@H]4CCCC[C@@H]4C3)c2c1
Temperature: 40 °C

Procedure:
Dissolve a mixture of 17 mg [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid from the Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 12.3 mg cis-decahydroisoquinoline followed by 23.0 mg EDC and 35 μL DIEA. This solution was heated at 40° C. for 2 hours. It was purified directly on RP-HPLC using 65-100% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.41 min. (m/Z=412.3, 328.2, 434.2).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH2:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]2[CH:21]=[C:22]([CH:24]=O)[N:23]=[C:13]2[C:12]1=[O:26])[CH3:10]>O.C(O)C>[CH2:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]2[CH:21]=[C:22]([CH:24]=[N:2][OH:3])[N:23]=[C:13]2[C:12]1=[O:26])[CH3:10]
Reactant: CCn1c(=O)c2nc(C=O)cn2c2ccccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCn1c(=O)c2nc(C=NO)cn2c2ccccc21
Temperature: 90 °C
Reaction time: 4 h
Yield: 81.9 %

Procedure:
A solution of 0.2 g of hydroxylamine hydrochloride and 0.25 g of sodium acetate in 2 ml of water was added to a suspension of 0.5 g of the product of Example 22 in 10 ml of ethanol and the mixture was stirred at 90° C. for 4 hours and was then filtered. The recovered product was washed with water and dried in vacuo to obtain 0.435 g of pure 4,5-dihydro-5-ethyl-4-oxo-imidazo-[1,2-a]-quinoxaline-2-carboxaldehyde oxime melting at 286°-288° C.
Reaction SMILES: C(OC[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:20][N:21]([C:25]3[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=3)[CH2:22][C:23]#[CH:24])[CH:16]=2)[N:11]=[CH:10]1)(=O)C(C)(C)C.[NH2:34][CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>>[O:19]=[C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:20][N:21]([C:25]3[CH:26]=[CH:27][C:28]([C:29]([NH:34][CH2:35][C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)=[O:30])=[CH:32][CH:33]=3)[CH2:22][C:23]#[CH:24])[CH:16]=2)[N:11]=[CH:10][NH:9]1
Reactant: C#CCN(Cc1ccc2ncn(COC(=O)C(C)(C)C)c(=O)c2c1)c1ccc(C(=O)O)cc1
Reactant: NCc1cccnc1
Product: C#CCN(Cc1ccc2nc[nH]c(=O)c2c1)c1ccc(C(=O)NCc2cccnc2)cc1
Yield: 61 %

Procedure:
Using the procedure described in Example 10, p-[N-(3,4-dihydro-3-pivaloyloxymethyl-4-oxoquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzoic acid was reacted with 3-aminomethylpyridine to give p-[N-(3,4-dihydro-4-oxoquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]-N-(3-pyridylmethyl)benzamide (containing 4.5 equivalents of water, 61%), m.p. 137°-139° C.
Reaction SMILES: [S:1]([O:11][CH2:12][C:13]1([CH2:35][O:36][S:37]([C:40]2[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=2)(=[O:39])=[O:38])[CH2:26][C@@H:25]2[C@:16]34[CH2:29][CH2:28][N:27]([CH3:30])[C@@H:24]2[CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:31][CH3:32])=[C:18]([O:33][C@H:15]3[C:14]1=[O:34])[C:17]4=2)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[BH4-].[Na+].CC(O)=O>CCO.C(Cl)(Cl)Cl>[S:37]([O:36][CH2:35][C:13]1([CH2:12][O:11][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:2])=[O:3])[CH2:26][C@@H:25]2[C@:16]34[CH2:29][CH2:28][N:27]([CH3:30])[C@@H:24]2[CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:31][CH3:32])=[C:18]([O:33][C@H:15]3[C@H:14]1[OH:34])[C:17]4=2)([C:40]1[CH:41]=[CH:42][C:43]([CH3:44])=[CH:45][CH:46]=1)(=[O:39])=[O:38]
Reactant: COc1ccc2c3c1O[C@H]1C(=O)C(COS(=O)(=O)c4ccc(C)cc4)(COS(=O)(=O)c4ccc(C)cc4)C[C@H]4[C@@H](C2)N(C)CC[C@]314
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2c3c1O[C@H]1[C@@H](O)C(COS(=O)(=O)c4ccc(C)cc4)(COS(=O)(=O)c4ccc(C)cc4)C[C@H]4[C@@H](C2)N(C)CC[C@@]341

Procedure:
A solution of 10 (20.0 g, 30 mmole) in a mixture of 95% EtOH (200 mL) and CHCl3 (100 mL) was cooled in an ice bath and NaBH4 (3.4 g, 90 mmole) added portionwise over 10 min. The mixture was stirred for 90 min. in the cold, excess HOAc added to destroy the hydride and the solution evaporated. The residue was partitioned between CHCl3 and dilute NH4OH and further processed in the usual fashion. Evaporation gave a quantitative yield of 11 as a foam which contained traces of 6β-ol 2 and other impurities; NMR δ 4.41 (d, 1H, H5, J=5.5 Hz). This material was converted to 12 without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([O:13][C:14]([N:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[Cl:25])[CH2:17]2)=[O:15])[CH2:10][C@H:9]1[C:26]([OH:28])=O)=O)(C)(C)C.Cl.[NH2:30][C@:31]1([C:37]([NH:39][S:40]([CH:43]2[CH2:45][CH2:44]2)(=[O:42])=[O:41])=[O:38])[CH2:33][C@H:32]1[CH:34]1[CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[ClH:25].[CH:43]1([S:40]([NH:39][C:37]([C@@:31]2([NH:30][C:26]([C@H:9]3[NH:8][CH2:12][C@H:11]([O:13][C:14]([N:16]4[CH2:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][C:22]=5[Cl:25])[CH2:17]4)=[O:15])[CH2:10]3)=[O:28])[CH2:33][C@H:32]2[CH:34]2[CH2:36][CH2:35]2)=[O:38])(=[O:42])=[O:41])[CH2:45][CH2:44]1
Reactant: N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C1CC1
Reactant: CC(C)(C)OC(=O)N1C[C@H](OC(=O)N2Cc3cccc(Cl)c3C2)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C1CC1)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(Cl)c3C2)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 163.7 %

Procedure:
(2S,4R)-1-(tert-butoxycarbonyl)-4-(4-chloroisoindoline-2-carbonyloxy)pyrrolidine-2-carboxylic acid 26 (0.35 g, 0.852 mmol), (1R,2S)-1-amino-2-cyclopropyl-N-(cyclopropylsulfonyl)cyclopropanecarboxamide hydrochloride 25 (0.287 g, 1.02 mmol) and HATU (0.389 g, 1.02 mmol) were dissolved in DriSolve DMF (8.5 mL), and cooled in an ice bath. DIEA (d 0.742) (0.445 ml, 2.56 mmol) was then added to reaction drop-wise. The reaction was allowed to warm up to rt slowly and stirred overnight. After reaching completion, the reaction was diluted with water (120 mL) and extracted with EtOAc (3×150 mL). The combined organic extract was washed with 0.5 N HCl (200 mL), brine (150 mL) and dried over Na2SO4. Removal of solvent yielded the crude product as a light yellowish foamy solid, which was purified by reverse phase chromatography (eluent: 5 to 95% MeCN/water), giving pure desired product as a white solid (0.40 g, 70% yield). LCMS (APCI+): 537.2 (MH+−Boc).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][NH2:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:11][C:12]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[CH2:20][CH2:19]1)=[O:17])([CH3:14])[CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:28]([C:27]2[CH:26]=[C:25]([CH2:24][CH:21]3[CH2:22][CH2:23][N:18]([C:16]([O:15][C:12]([CH3:14])([CH3:13])[CH3:11])=[O:17])[CH2:19][CH2:20]3)[CH:33]=[CH:32][CH:31]=2)=[O:29])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NCc1ccc(F)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(C(=O)O)c2)CC1
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
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Cc2cccc(C(=O)NCc3ccc(F)c(Br)c3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a solution of [(3-bromo-4-fluorophenyl)methyl]amine (0.802 g, 3.33 mmol) in DMF (12.0 mL) was added 3-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)methyl]benzoic acid (1.060 g, 3.32 mmol), HATU (1.389 g, 3.65 mmol), and diisopropylethylamine (2.9 mL, 16.6 mmol). The reaction was allowed to stir at room temperature overnight. The reaction was diluted with EtOAc (300 mL), washed with 1N HCl (2×75 mL), then saturated NaHCO3 (3×75 mL), then brine (2×75 mL). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give the desired product (1.58 g, 94.2%). EI-MS m/z 506(M−H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[C:15]1([C:21]2[O:25][N:24]=[C:23]([C:26](Cl)=[O:27])[CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:26]([C:23]1[CH:22]=[C:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:25][N:24]=1)=[O:27]
Reactant: O=C(Cl)c1cc(-c2ccccc2)on1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cc(-c2ccccc2)on1
Yield: 33.8 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0419 g, 0.178 mmol), 5-phenylisoxazole-3-carbonyl chloride (0.041 g; 0.178 mmol), and triethylamine (0.0624 mL; 0.444 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 2 to 16% of ethyl acetate in dichloromethane gave 0.022 g (34%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-phenylisoxazole-3-carboxamide as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:27])([CH3:26])[NH:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:26][C:4]1([CH3:27])[CH2:5][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][OH:24])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:7][C:2]([CH3:28])([CH3:1])[NH:3]1
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(CCC(=O)O)cc3)n2)CC(C)(C)N1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC1(C)CC(Nc2nccc(-c3ccc(CCCO)cc3)n2)CC(C)(C)N1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-{4-[2-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-phenyl}-propionic acid (50 mg, 0.13 mmol) (Step A of Example 185) in 1 ml THF was added LAH (1M in THF, 393 μl, 0.393 mmol). The mixture was stirred at 60° C. for 1 hour. A saturated solution of sodium sulfate was added and the aqueous phase was extracted with EtOAc. The crude product was purified using preparative HPLC. Yield: 19 mg (39%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[OH:21])[CH:16]=O.Cl.O>CO>[CH3:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:18]=[CH:19][C:20]=1[OH:21]
Reactant: Cc1cc(C=O)ccc1O
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1cc(C=C2Oc3cc(O)ccc3C2=O)ccc1O
Temperature: 25 °C
Yield: 68.3 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-methyl-4-hydroxybenzaldehyde 1.00 g were dissolved in methanol 70 ml, concentrated hydrochloric acid 60 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and water 250 ml was added. Precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.22 g.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:24])([CH3:23])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26](O)=[O:27])[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.Cl.[CH3:61][O:62][C:63](=[O:66])[CH2:64][NH2:65]>C1COCC1.CN(C=O)C>[OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:23])([CH3:24])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([NH:65][CH2:64][C:63]([O:62][CH3:61])=[O:66])=[O:27])[CH:3]=1
Reactant: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(O)cc(C(=O)O)c4[C@]3(C)CC[C@@H]12
Reactant: COC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)c1cc(O)cc2c1[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.4 %

Procedure:
A mixture of (1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carboxylic acid (65) (0.20 g, 0.49 mmol), HATU (0.37 g, 0.98 mmol), N-methyl morpholine (0.2 mL, 3 mmol) and glycine methyl ester hydrochloride (0.09 g, 2 mmol) in THF (10 mL) and DMF (2.0 mL) was stirred at room temperature for 18 h. The THF was evaporated under reduced pressure, the residue was quenched with water and the resulting solid was collected by filtration. The crude product was purified by flash column chromatography on silica gel (CH2Cl2/MeOH, 10:1) to give methyl 2-{[(1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-yl]formamido}acetate (90) (0.05 g, 54%) as a cream solid. 1H NMR (CDCl3): δ 7.37 (s, 1H), 7.21 (d, 1H), 6.89 (d, 1H), 6.70 (m, 1H), 4.19 (m, 2H), 3.81 (s, 3H), 3.40 (m, 2H), 2.62 (m, 1H), 2.16 (m, 1H), 1.76-1.34 (m, 10H), 1.20-1.00 (m, 2H), 0.98-0.92 (m, 4H), 0.89 (s, 3H), 0.82 (s, 3H). MS m/z 476 (C25H35NO6S−H+).
Reaction SMILES: [OH-].[Na+].[F:3][C@@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([C:16]([O:18]C)=[O:17])[CH2:5]1>CO>[C:12]([O:11][C:9]([N:7]1[CH2:8][C@@H:4]([F:3])[CH2:5][C@H:6]1[C:16]([OH:18])=[O:17])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)[C@@H]1C[C@H](F)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(=O)O
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To an aqueous solution of 2 mol/L NaOH (86 ml) was added dropwise under ice cooling a solution of 30.2 g of the compound obtained in Step 14-1 in MeOH (181 ml) under stirring over 60 minute, then the reaction mixture was stirred at room temperature for 16 hours. MeOH was evaporated under reduced pressure, to the solution was added toluene and stirred, then the aqueous layer was separated and the solution was stirred under ice cooling. To the solution was added dropwise 2 mol/L hydrochloric acid over 40 minutes, then extracted with EtOAc, the combined organic layer was washed with saturated brine, dried over Na2SO4, then, the drying agent was separated by filtration, and the solvent was evaporated under reduced pressure to obtain 25.1 g of a colorless solid. IPE (91 ml) was added, the suspension was stirred for 2 hours at room temperature, then, crystals were collected by filtration as 20.2 g of the title compound (colorless solid). The filtrate was concentrated under reduced pressure, IPE (9 ml) was added, stirred for 2 hours at room temperature, then, crystals were collected by filtration to 540 mg of the title compound (colorless solid).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][N:5]2[N:9]=[C:10]([NH:12][C:13]3[C:14](=[O:29])[N:15]([CH3:28])[CH:16]=[C:17](B4OC(C)(C)C(C)(C)O4)[CH:18]=3)[CH:11]=[C:4]2[CH2:3]1.Cl[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([N:37]2[CH2:48][CH2:47][C:46]3[C:45]4[CH2:44][C:43]([CH3:50])([CH3:49])[CH2:42][C:41]=4[S:40][C:39]=3[C:38]2=[O:51])[C:32]=1[CH:52]=[O:53].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[CH3:49][C:43]1([CH3:50])[CH2:42][C:41]2[S:40][C:39]3[C:38](=[O:51])[N:37]([C:33]4[C:32]([CH:52]=[O:53])=[C:31]([C:17]5[CH:18]=[C:13]([NH:12][C:10]6[CH:11]=[C:4]7[CH2:3][N:2]([CH3:1])[C:7](=[O:8])[CH2:6][N:5]7[N:9]=6)[C:14](=[O:29])[N:15]([CH3:28])[CH:16]=5)[CH:36]=[CH:35][N:34]=4)[CH2:48][CH2:47][C:46]=3[C:45]=2[CH2:44]1
Reactant: CC1(C)Cc2sc3c(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Reactant: CN1Cc2cc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)nn2CC1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CN1Cc2cc(Nc3cc(-c4ccnc(N5CCc6c(sc7c6CC(C)(C)C7)C5=O)c4C=O)cn(C)c3=O)nn2CC1=O
Temperature: 25 °C
Yield: 35.9 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 317a (100 mg, 0.28 mmol), 4-chloro-2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.02,6]dodeca-1(8),2(6)-dien-10-yl}pyridine-3-carbaldehyde 109a (112 mg, 0.28 mmol), Pd(dppf)Cl2 (22.9 mg, 0.028 mmol), K3PO4 (118.7 mg, 0.56 mmol), sodium acetate (45.9 mg, 0.56 mmol), water (0.5 mL), and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 1 hour. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (50:1 to 30:1) to afford 317b as a yellow solid (60 mg, 36%). MS-ESI: [M+H]+ 597.8.