Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)[O:5][B:4]([C:9]2[CH:10]=[C:11]([C@@H:15]([NH:17][C:18](=[O:20])[CH3:19])[CH3:16])[CH:12]=[CH:13][CH:14]=2)[O:3]1>CO>[C:18]([NH:17][C@H:15]([C:11]1[CH:10]=[C:9]([B:4]([OH:5])[OH:3])[CH:14]=[CH:13][CH:12]=1)[CH3:16])(=[O:20])[CH3:19]
Reactant: CC(=O)N[C@@H](C)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Solvent: CO
Product: CC(=O)N[C@@H](C)c1cccc(B(O)O)c1

Procedure:
A4a.1 (1.23 g, 5 mmol), bis-pinacolatodiborane (1.33 g, 5 mmol), potassium acetate (1.47 g, 15 mmol) and palladium acetate (224 mg, 1 mmol) were added to degassed DMF (anhydrous). The reaction mixture was heated at 80° C. overnight. The next day additional palladium acetate was added (610 mg, 2.5 mmol) was added and the reaction mixture heated overnight. The reaction mixture was cooled to room temperature and filtered through a pad of silica gel (washing with ethyl acetate). The filtrate was concentrated under reduced pressure with provided approximately 1.41 g of (S)—N-(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)acetamide (LCMS (M+H)+=290.31). The product was dissolved in methanol and purified by reverse phase column chromatography (during which time the boronate ester underwent hydrolysis) to yield 875 mg (˜70%) of the chiral boronic acid. (M+H)+=208.17
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[C:22]([CH3:23])=[N:21][N:20]=[C:19]2[CH2:24]O)=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])=[O:8].P(Br)(Br)[Br:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[C:22]([CH3:23])=[N:21][N:20]=[C:19]2[CH2:24][Br:27])=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])=[O:8]
Reactant: BrP(Br)Br
Reactant: Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Product: Cc1nnc(CBr)n1-c1ccc(Cl)cc1C(=O)c1c(F)cccc1F

Procedure:
In the manner given in Example 7, 5-chloro-2',6'-difluoro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone is treated with phosphorus tribromide to give 5-chloro-2',6'-difluoro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.O.[NH3:17]>O1CCCC1>[O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([S:12]([NH2:17])(=[O:14])=[O:13])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Reactant: N
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(-c2cnco2)cc1
Yield: 87 %

Procedure:
To a stirred solution of 4-(1,3-oxazol-5-yl)benzenesulfonyl chloride (1.00 g, 4.10 mmol) in tetrahydrofuran (15.0 mL) was added 25% ammonia water solution (5.00 mL) at room temperature. After 1 h the reaction mixture was partitioned between ethyl acetate (100.0 mL) and 1.0 N hydrochloric acid (10.0 mL) and separated. The organic layer was washed with water (2×40 mL), saturated sodium chloride (80 mL), dried (MgSO4), filtered. The filtrate was concentrated under reduced pressure to provide 4-(1,3-oxazol-5-yl)benzenesulfonamide (800 mg, 87%) as a solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:23][C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:38]#[N:39])[C:21]=3[NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)[CH:16]=2)=[CH:11][CH:10]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O.C(O)(=O)C>[N:1]1([CH2:7][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[S:23][C:22]4[C:17](=[N:18][CH:19]=[C:20]([C:38]#[N:39])[C:21]=4[NH:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[CH:27][CH:26]=4)[CH:16]=3)=[CH:13][CH:14]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#Cc1cnc2cc(-c3ccc(C=O)cc3)sc2c1Nc1ccc(Oc2ccccc2)cc1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: N#Cc1cnc2cc(-c3ccc(CN4CCOCC4)cc3)sc2c1Nc1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33.8 %

Procedure:
Morpholine (51 μL, 0.58 mmol) is added to a suspension of 2-(4-formylphenyl)-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile (200 mg, 0.45 mmol) in 8 mL of dichloromethane and 2 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0° C. and sodium triacetoxyborohydride (474 mg, 2.24 mmol) is added. After stirring at 0° C. for 10 minutes, 2 drops of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred for 4 hours. The reaction is quenched by the addition of water and then partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with ethyl acetate to provide 79 mg of 2-[4-(morpholin-4-ylmethyl)phenyl]-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as white crystals, mp 254-256° C.; 1H NMR (DMSO-d6) δ 2.36 (s, 4H), 3.51 (s, 2H), 3.58 (s, 4H), 7.04-7.18 (m, 5H), 7.34-7.45 (m, 6H), 7.67 (d, J=8 Hz, 2H), 7.86 (s, 1H), 8.59 (s, 1H), 9.58 (s, 1H); MS 519.2 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:22]([F:25])([F:24])[F:23])=[C:8]2[C:13](=[C:14]([CH3:16])[CH:15]=1)[S:12](=[O:18])(=[O:17])[CH2:11][C:10]([CH3:20])([CH3:19])[C:9]2=[O:21])=[O:5])C.[OH-].[K+]>C(O)C.O>[C:4]([C:6]1[C:7]([C:22]([F:24])([F:25])[F:23])=[C:8]2[C:13](=[C:14]([CH3:16])[CH:15]=1)[S:12](=[O:18])(=[O:17])[CH2:11][C:10]([CH3:20])([CH3:19])[C:9]2=[O:21])([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc(C)c2c(c1C(F)(F)F)C(=O)C(C)(C)CS2(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)O)c(C(F)(F)F)c2c1S(=O)(=O)CC(C)(C)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
2.4 Grams (6.3 mmol) of 6-ethoxycarbonyl-5-trifluoromethyl-3,3,8-trimethylthiochroman-4-one-1,1-dioxide was dissolved in 25 ml of ethanol, and than a solution of 0.62 g (9.5 mmol) of potassium hydroxide in 3 ml of water was added. The mixture was stirred at room temperature for 2 hours, then diluted with water and washed with chloroform, and an aqueous layer was acidified with a 5 wt % hydrochloric acid aqueous solution. An organic precipitate was extracted with ethyl acetate, and an organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 1.9 g (yield 86%) of the titled compound.
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=O)[CH:5]=[CH:4][N:3]=[N:2]1.[F:10][C:11]1[CH:41]=[CH:40][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C@@H:25]3[CH2:29][C@@H:28]([CH2:30][C:31]4[C:36]([F:37])=[CH:35][C:34]([F:38])=[CH:33][C:32]=4[F:39])[CH2:27][NH:26]3)=[O:24])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1>>[N:1]1([CH2:6][C:7]([N:26]2[CH2:27][C@H:28]([CH2:30][C:31]3[C:36]([F:37])=[CH:35][C:34]([F:38])=[CH:33][C:32]=3[F:39])[CH2:29][C@H:25]2[C:23]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:14]3[CH:13]=[CH:12][C:11]([F:10])=[CH:41][CH:40]=3)=[CH:21][CH:20]=2)=[O:24])=[O:9])[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2c(F)cc(F)cc2F)CN1
Reactant: O=C(O)Cn1ccnn1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2c(F)cc(F)cc2F)CN1C(=O)Cn1ccnn1

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,3-triazol-1-yl)acetic acid and (2S,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-(2,4,6-trifluorobenzyl)pyrrolidine-2-carboxamide, gave Compound 170, (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(2,4,6-trifluorobenzyl)pyrrolidine-2-carboxamide. Major isomer: 1H-NMR (400 MHz, CDCl3): δ 8.93 (s, 1H), 7.80-7.74 (m, 2H), 7.44-7.38 (m, 2H), 7.03-6.85 (m, 6H), 6.74-6.62 (m, 2H), 5.31 (d, 1H), 5.20 (d, 1H), 4.76 (d, 1H), 3.79-3.73 (m, 1H), 3.34 (t, 1H), 2.98-2.76 (m, 3H), 2.55 (dd, 1H), 1.83-1.74 (m, 1H). MS (EI) for C28H23F4N5O3 found 554 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=2)[CH:28]=[N:29][CH:30]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:24][C:25]2[CH:26]=[C:27]([C:31]3[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=3)[CH:28]=[N:29][CH:30]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Product: COc1ccc(N(Cc2cncc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
4-(p-anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Preparation Example 9 to give pale yellow amorphous of the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[N:30]=[C:29]3[C:25]([N:26]=[CH:27][N:28]3[C@@H:31]3[CH2:35][C@H:34]([N:36]4[CH:40]=[C:39]([CH2:41][OH:42])[CH:38]=[N:37]4)[C@@H:33]([OH:43])[C@H:32]3[OH:44])=[C:24]([NH:45][CH2:46][CH:47]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:23]=2)[CH2:17][CH2:16]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[OH-].[Pd+2].[OH-]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:54]1([CH:47]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:46][NH:45][C:24]2[N:23]=[C:22]([NH:21][CH:18]3[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]3)[N:30]=[C:29]3[C:25]=2[N:26]=[CH:27][N:28]3[C@@H:31]2[CH2:35][C@H:34]([N:36]3[CH:40]=[C:39]([CH2:41][OH:42])[CH:38]=[N:37]3)[C@@H:33]([OH:43])[C@H:32]2[OH:44])[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NC5CCN(Cc6ccccc6)CC5)nc43)[C@H](O)[C@@H]2O)c1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NC5CCNCC5)nc43)[C@H](O)[C@@H]2O)c1

Procedure:
(1R,2S,3R,1S)-3-[2-(1-benzyl-piperidin-4-ylamino)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 78) (50 mg, 0.063 mmol) is dissolved in ethanol (2 ml). Palladium hydroxide (20% on carbon) (45 mg, 0.57 mmol) and ammonium formate (20 mg, 0.057 mmol) are added and the reaction mixture is refluxed for 1.5 hours. The reaction mixture is allowed to cool, the catalyst is filtered off and the solvent is removed in vacuo. The title compound is obtained after purification by reverse phase column chromatography (Isolute™ C18, 0-100% MeCN in water—0.1% TFA). MS (ES+) m/e 610 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:13][CH3:14])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.[OH-].[Na+].C(OCCOCCO)C>O>[CH:20]([C:19]1[CH:22]=[CH:23][C:16]([O:15][CH2:2][CH2:3][N:4]([CH2:13][CH3:14])[C:5]2[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=2)=[CH:17][CH:18]=1)=[O:21]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCN(CCCl)c1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCCOCCO
Solvent: O
Product: CCN(CCOc1ccc(C=O)cc1)c1ccc(C=O)cc1

Procedure:
A mixture of 4-[[2-Chloroethyl)ethylamino]benzaldehyde 10.6 g (0.05 m), p-hydroxybenzaldehyde (6.1 g, 0.05 m), 50% NaOH (4.4 g), water (50 mL), and 2-(2-ethoxyethoxy)ethanol was heated at reflux for 6 hours and then allowed to cool. A semi-solid product was obtained which was washed with water by decantation and recrystallized from methanol. After being collected by filtration, washed with methanol, and dried in air the product weighed 6.5 g and the structure was confirmed by mass spectral analysis to be as follows: ##STR14##
Reaction SMILES: [C:1]1([C:7]2[N:8]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[N:13]=3)[CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:25]O>C(Cl)Cl>[O-:25][N+:21]1[CH:22]=[CH:23][CH:24]=[C:19]([NH:18][C:14]2[N:13]=[C:12]([N:8]3[CH:9]=[CH:10][N:11]=[C:7]3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:17]=[CH:16][N:15]=2)[CH:20]=1
Reactant: OO
Reactant: c1ccc(-c2nccn2-c2ccnc(Nc3cccnc3)n2)cc1
Solvent: ClCCl
Product: [O-][n+]1cccc(Nc2nccc(-n3ccnc3-c3ccccc3)n2)c1

Procedure:
To a solution of 4-(2-phenyl-1H-imidazol-1-yl)-N-pyridin-3-ylpyrimidin-2-amine (3-3, 0.17 mmol) in CH2Cl2 (1 mL) was added MeReO3 (1 mg) then 30% H2O2 (0.05 mL) with vigorous stirring at room temperature. After 18 hrours additional MeReO3 (1 mg) and 30% H2O2 (0.05 mL) were added. After 18 hours the mixture was concentrated. Purification by reverse phase HPLC (5-100% CH3CN/H2O+0.1% TFA) gave the title compound as a tan solid after trituration with Et2O. 1H-NMR (500 MHz, d6-DMSO) δ 10.38 (s, 1H), 8.68 (d, J=5.13 Hz, 1H), 8.57 (s, 1H), 7.99 (s, 1H), 7.87 (d, J=5.86 Hz, 1H), 7.55 (m, 6H), 7.27 (bs, 1H), 7.20 (s, 1H), 6.86 (d, J=4.64 Hz, 1H).
Reaction SMILES: FC1C=CC(F)=C2C=1C=CCO2.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[O:21][CH2:22][C:23]#[CH:24]>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]2[C:15]=1[O:21][CH2:22][CH:23]=[CH:24]2
Reactant: C#CCOc1cc(F)ccc1Br
Agent: Fc1ccc(F)c2c1C=CCO2
Product: Fc1ccc(Br)c2c1C=CCO2

Procedure:
This compound was prepared analogously to 5,8-difluoro-2H-chromene but using (15 g, 65 mmol) of 1-bromo-4-fluoro-2-prop-2-ynyloxybenzene to give the title compound (3.7 g, 25
Reaction SMILES: [CH3:1]/[CH:2]=[C:3]1\[C@H:4]2[CH:11]=[C:10]([CH3:12])[CH2:9][C@@:8]\1([NH2:13])[C:7]1[CH:14]=[CH:15][C:16]([NH:18][C:6]=1[CH2:5]2)=[O:17].C=O.[CH2:21]1COCC1>C(O)(C)C>[CH3:21][NH:13][C@@:8]12[C:7]3[CH:14]=[CH:15][C:16](=[O:17])[NH:18][C:6]=3[CH2:5][C@@H:4](/[C:3]/1=[CH:2]\[CH3:1])[CH:11]=[C:10]([CH3:12])[CH2:9]2
Reactant: C/C=C1\[C@H]2C=C(C)C[C@@]1(N)c1ccc(=O)[nH]c1C2
Reactant: C1CCOC1
Agent: C=O
Solvent: CC(C)O
Product: C/C=C1\[C@H]2C=C(C)C[C@]1(NC)c1ccc(=O)[nH]c1C2
Reaction time: 4 h

Procedure:
Huperzine A 10 mg, and 37% aqueous solution of formaldehyde were refluxed for 1 hour in 2 mL of isopropanol; the solvent was stripped in vacuo; THF (dry, 5 mL) and NaBH(OOCCH3)3 0.15 g were added, the reaction mixture was allowed to stir for 4 hours; and then filtered to remove solid substances. The filtrate was purified after concentrating on prep TLC (chloroform:methanol=9:1) to yield 6 mg of pure title compound. MS: 257 (M+1).
Reaction SMILES: [CH3:1][C@@H:2]([O:7][C@@H:8]([CH2:44][CH3:45])[C@H:9]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18](=[O:35])[NH:19][C@:20]1([C:25](=[O:34])[NH:26][S:27]([C:30]2([CH3:33])[CH2:32][CH2:31]2)(=[O:29])=[O:28])[CH2:22][C@H:21]1C=C)=[O:11])[CH2:3][CH2:4][CH:5]=[CH2:6]>CC1C=C(C)C=C(C)C=1N1CCN(C2C(C)=CC(C)=CC=2C)C1=[Ru](Cl)(Cl)=CC1C=CC=CC=1OC(C)C.ClCCCl>[CH2:44]([C@H:8]1[C@H:9]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:40])([CH3:42])[CH3:41])[C:10](=[O:11])[N:12]2[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]2[C:18](=[O:35])[NH:19][C@:20]2([C:25](=[O:34])[NH:26][S:27]([C:30]3([CH3:33])[CH2:31][CH2:32]3)(=[O:29])=[O:28])[CH2:21][C@H:22]2[CH:6]=[CH:5][CH2:4][CH2:3][C@@H:2]([CH3:1])[O:7]1)[CH3:45]
Reactant: C=CCC[C@@H](C)O[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2(C)CC2)C[C@H]1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: CC[C@@H]1O[C@H](C)CC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@H]1NC(=O)OC(C)(C)C
Solvent: ClCCCl
Product: CC[C@@H]1O[C@H](C)CCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@H]1NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a round-bottom flask equipped with a stir bar was added tert-butyl ((2S,3S)-3-((R)-hex-5-en-2-yloxy)-1-((2S,4R)-4-hydroxy-2-(((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-1-oxopentan-2-yl)carbamate (all material from step 4, 569 mg, 0.869 mmol) and DCE (100 mL). The solution was sparged with nitrogen for 30 min. and then to the solution was added (1,3-Bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium (“Hoveyda-Grubbs Catalyst 2nd Generation”, 27 mg, 0.043 mmol). The solution was stirred at 80° C. for 2 h and then cooled to 45° C. and stirred for 3 days. The solution was concentrated in vacuo and the resulting residue was subjected to silica gel purification (hexanes:acetone 80:20 to 40:60). The product containing fractions were pooled; concentrated; and re-subjected to silica gel chromatography (hexanes:acetone 80:20 to 40:60) to afford tert-butyl ((2R,6S,7S,9R,13aS,14aR,16aS,Z)-7-ethyl-2-hydroxy-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-2,3,5,6,7,9,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa[i]pyrrolo[1,2-e][1,5,8]oxadiazacyclopentadecin-6-yl)carbamate as a light-brown solid foam (90 mg, 10% over 5 steps). 1H-NMR (500 MHz, CD3OD) δ 8.93 (s, 1H), 5.61 (td, J=10.1, 6.2 Hz, 1H), 5.03 (t, J=10.3 Hz, 1H), 4.58 (br. s., 1H), 4.47-4.37 (m, 2H), 3.92 (br. s., 2H), 3.86-3.79 (m, 1H), 3.58-3.49 (m, 1H), 2.75 (q, J=9.5 Hz, 1H), 2.64-2.52 (m, 1H), 2.23-2.11 (m, 2H), 1.92-1.80 (m, 2H), 1.75 (dd, J=8.5, 5.5 Hz, 1H), 1.66-1.60 (m, 1H), 1.59-1.52 (m, 2H), 1.49 (s, 4H), 1.43 (s, 9H), 1.41-1.32 (m, 2H), 1.15 (d, J=6.3 Hz, 3H), 0.95 (t, J=7.4 Hz, 3H), 0.88-0.84 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]23[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[C:21]([Cl:23])[N:20]=[C:19]([Cl:24])[CH:18]=4)[C:13](=[O:25])[N:12]2[NH:11][CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:37][O:38][C:39](Cl)=[O:40].O>C1COCC1.CN(C1C=CN=CC=1)C.CCOC(C)=O>[Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]23[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[C:21]([Cl:23])[N:20]=[C:19]([Cl:24])[CH:18]=4)[C:13](=[O:25])[N:12]2[N:11]([C:39]([O:38][CH3:37])=[O:40])[CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: COC(=O)Cl
Reactant: O=C1N(c2cc(Cl)nc(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)CCCNN12
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N1CCCC2(Cc3ccc(Br)cc3)C(=O)N(c3cc(Cl)nc(Cl)c3)C(=O)N12

Procedure:
To a solution of the compound from Example 100 (60 mg) in dry THF (2 mL) was added DIEA (0.044 mL), methylchloroformate (0.02 mL) and DMAP (catalytic amount). The reaction mixture was heated at 80° C. for 3 days during which more methylchloroformate (0.1 mL) was added after 24 hours and 48 hours. Water (10 mL) and EtOAc (10 mL) were added and the mixture shaken. The aqueous phase was separated and extracted with EtOAc. The combined organics were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel; EtOAc/hexanes; chromatotron) to give the titled compound (37 mg). MS (m/z) 529 (MH+); Mp. 81° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][O:13][C:12]3[N:16]=[CH:17][C:18]([C:20](Cl)=[O:21])=[CH:19][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[NH:24][C:25](=[NH:28])[CH2:26][CH3:27].CCN(C(C)C)C(C)C>C(Cl)Cl.C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[CH2:26]([C:25]1[N:28]=[C:20]([C:18]2[CH:17]=[N:16][C:12]3[O:13][CH2:14][CH2:15][N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[C:11]=3[CH:19]=2)[O:21][N:24]=1)[CH3:27]
Reactant: CCC(=N)NO
Reactant: O=C(Cl)c1cnc2c(c1)N(S(=O)(=O)c1ccccc1)CCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1noc(-c2cnc3c(c2)N(S(=O)(=O)c2ccccc2)CCO3)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.4 %

Procedure:
To a solution of 1-(phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carbonyl chloride (40 mg, 0.118 mmol; Example 1, Step 1) in DCM (2 mL) was added N-hydroxypropionimidamide (20.81 mg, 0.236 mmol) and DIPEA (50 μL, 0.286 mmol). The reaction was stirred at room temperature for 16 hours. LCMS analysis of the reaction mixture indicated consumption of starting material. The reaction mixture was treated with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (3×10 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting solid was diluted with THF (5 mL) and TBAF in THF (118 μL, 0.118 mmol) was added. The reaction was then stirred overnight. The reaction mixture was concentrated in vacuo and the resulting paste was purified by flash column chromatography using a gradient elution of hexanes with 30-100% EtOAc to provide 7-(3-ethyl-1,2,4-oxadiazol-5-yl)-1-(phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (29.7 mg, 0.076 mmol, 64.2% yield) as a white solid. LCMS (+ESI) m/z=373.0 [M+H]+; 1H-NMR (CDCl3) δ 8.87 (d, 1H), 8.77 (d, 1H), 7.71 (m, 2H), 7.63 (tt, 1H) 7.51 (m, 2H), 4.01 (m, 2H), 3.92 (m, 2H), 2.84 (q, 2H), 1.39 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([SH:20])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:28]([C:30]1[CH:31]=[C:32]([CH:43]=[CH:44][CH:45]=1)[C:33]([C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Br)=[CH:37][CH:36]=1)=[O:34])#[N:29]>CS(C)=O.CCCCCC.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:39][C:38]3[CH:37]=[CH:36][C:35]([C:33](=[O:34])[C:32]4[CH:43]=[CH:44][CH:45]=[C:30]([C:28]#[N:29])[CH:31]=4)=[CH:42][CH:41]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(S)c2CC1
Reactant: N#Cc1cccc(C(=O)c2ccc(CBr)cc2)c1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(C(=O)c4cccc(C#N)c4)cc3)c2CC1
Temperature: 40 °C
Yield: 76.5 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.52 mmol) in methanol (12 mL) and add potassium hydroxide (0.935 g, 16.66 mmol). Heat at 60° C. for 4 h. Cool the reaction mixture to ambient temperature, add aqueous saturated ammonium chloride and concentrate in vacuo. Partition the residue between EtOAc and water. Dry the organic phase over anhydrous Na2SO4 and concentrate in vacuo to give 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.16 g, 5.2 mmol). Dissolve the crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.16 g, 0.52 mmol) in anhydrous DMSO (5 mL) and add triethylamine (0.435 mL, 3.12 mmol) and 4-(3-cyano-benzoyl)benzyl bromide (289 mg, 0.96 mmol). Heat the solution at 40° C. overnight. Cool to ambient temperature, dilute the mixture with hexane/EtOAc (1:1, 100 mL), and wash the organic solution sequentially with brine and ice-cold water. Dry the organic layer over anhydrous Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (9:1, 4:1) to give 3-tert-butoxycarbonyl-7-chloro-6-[4-(3-cyanobenzoyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as oil (212 mg, 77%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH3:26])=[C:12]([NH:14][C:15]([C:17]3[N:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]4=[N:19][CH:18]=3)=[O:16])[CH:13]=2)[N:4]=1.CCN(C(C)C)C(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH3:36][S:37]([O:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH3:26])=[C:12]([NH:14][C:15]([C:17]3[N:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]4=[N:19][CH:18]=3)=[O:16])[CH:13]=2)[N:4]=1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(-c2noc(CO)n2)cc1NC(=O)c1cnc2ccccn12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2noc(COS(C)(=O)=O)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.2 %

Procedure:
To a solution of N-(5-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (43) (210 mg, 0.6 mmol) and DIEA (0.32 mL, 1.8 mmol) in DCM (5 mL) was added MsCl (138 mg, 1.2 mmol). The mixture was stirred at room temperature for 10 minutes then subjected to standard aqueous work up. The crude product was purified by silica chromatography to yield (3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-ylmethyl methanesulfonate (44) (180 mg, 70% yield). MS m/z 428.1 (M+1)+.