Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[C:17]([F:24])[CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[Mg].Br[CH2:27][C@H:28]1[CH2:33][CH2:32][Si@H:31]([CH2:34][CH2:35][CH2:36][CH:37]=[CH2:38])[CH2:30][CH2:29]1>[Cu]I.P(OCC)(OCC)(OCC)=O.C1COCC1>[CH2:34]([Si@H:31]1[CH2:30][CH2:29][C@H:28]([CH2:27][CH2:2][C@H:3]2[CH2:8][CH2:7][C@H:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[C:17]([F:24])[CH:16]=4)=[CH:11][CH:10]=3)[CH2:5][CH2:4]2)[CH2:33][CH2:32]1)[CH2:35][CH2:36][CH:37]=[CH2:38]
Reactant: C=CCCC[Si@H]1CC[C@H](CBr)CC1
Reactant: CCOc1ccc(-c2ccc([C@H]3CC[C@H](CBr)CC3)cc2)cc1F
Agent: [Cu]I
Agent: [Mg]
Solvent: CCOP(=O)(OCC)OCC
Solvent: C1CCOC1
Product: C=CCCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(OCC)c(F)c4)cc3)CC2)CC1

Procedure:
39.1 g (0.1 mol) of 4-(trans-4-bromomethylcyclohexyl)-3'-fluoro-4'-ethoxybiphenyl was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 26.1 g (0.1 mol) of trans-1-bromomethyl-4-(4-pentenyl)-4-silacyclohexane. After a conventional after treatment, purification was conducted by means of chromatography to obtain 35.1 g (yield 71.3%) of 4-(trans-4-(2-(trans-4-(4-pentenyl)-4-silacyclohexyl)ethyl)cyclohexyl)-3'-fluoro-4'-ethoxybiphenyl.
Reaction SMILES: [CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[N:29]4[C:20](=[N:21][C:22]5[C:27]([C:28]4=[O:30])=[C:26]([F:31])[C:25]([F:32])=[CH:24][CH:23]=5)[C:19]4[CH:33]=[CH:34][N:35]([S:36]([C:39]5[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=5)(=[O:38])=[O:37])[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[CH3:49][CH:50]([NH2:52])[CH3:51]>C1COCC1.C(OCC)(=O)C>[CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[N:29]=[C:20]([NH:21][C:22]4[C:27]([C:28]([NH:52][CH:50]([CH3:51])[CH3:49])=[O:30])=[C:26]([F:31])[C:25]([F:32])=[CH:24][CH:23]=4)[C:19]4[CH:33]=[CH:34][N:35]([S:36]([C:39]5[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=5)(=[O:38])=[O:37])[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: CC(C)N
Reactant: COc1cc2c(cc1Nc1nc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c3nc4ccc(F)c(F)c4c(=O)n13)N(C(=O)CN(C)C)CC2
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Nc1nc(Nc3ccc(F)c(F)c3C(=O)NC(C)C)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)CC2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 31 %

Procedure:
To a solution of 5-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8,9-difluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (300 mg, 0.445 mmol) in THF (5 mL) was added (1-methylethyl)amine (0.765 mL, 8.91 mmol). The resulting mixture was let stir at rt for 40 min at which time it was diluted with ethyl acetate and washed with water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure. The residue was purified via chromatography on SiO2 and afforded 6-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-2,3-difluoro-N-(1-methylethyl)benzamide (101 mg, 0.138 mmol) as a yellow solid (only 85% pure by LCMS) (ESIMS (M+H)+=733)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH3:7][O:8][C:9]1[C:22]2[C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:24])[C:13]=2[C:12](OC)=[CH:11][CH:10]=1>C(Cl)Cl>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:12]1[C:13]2[C:14](=[O:24])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21](=[O:23])[C:22]=2[C:9]([O:8][CH3:7])=[CH:10][CH:11]=1
Reactant: COc1ccc(OC)c2c1C(=O)c1ccccc1C2=O
Reactant: NCCCCN
Solvent: ClCCl
Product: COc1ccc(NCCCCN)c2c1C(=O)c1ccccc1C2=O
Yield: 50.8 %

Procedure:
1,4-Diaminobutane (1.65 g, 19 mmol) was added to a solution of 1,4-dimethoxyanthracene-9,10-dione (1.0 g, 3.7 mmol) in CH2Cl2 (700 ml). After seven, hours of irradiation, the solvent was removed and the residue chromatographed on silica gel. Starting material was eluted with CHCl3 and the product with 5% CH3OH in CHCl3. A purple solid (0.61 g, 50%) was obtained which was converted to the benzyloxycarbonyl derivative.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>ClCCCl>[Br:1][C:2]1[CH:10]=[C:9]([CH2:11][Br:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: O=C(O)c1ccc(CBr)cc1Br
Reaction time: 1 h
Yield: 51.9 %

Procedure:
2-Bromo-4-methylbenzoic acid (33.5 g, 156 mmol, 1 eq) and N-Bromosuccinimide (40.7 g, 233 mmol, 1.5 eq) were dissolved in refluxing 1,2-dichloroethane (600 ml) and a catalytic amount of AIBN was added. The mixture was left stirring under a lamp and under nitrogen for 1 hour. The solvent was removed and the mixture was partitioned between 600 ml of water and 600 ml EtOAc. The organic layer was washed twice with water (600 ml), washed once with brine (600 ml) and then dried with sodium sulfate. The solvent was removed and the crude mixture was triturated with 10% EtOAc/Hexane for 2 hours and 23.8 g (52%) of the title compound was obtained.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=CC=1.[NH2:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][OH:56]>>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[C:16]3[CH2:29][CH2:28][N:27]([C:30]4[CH:31]=[CH:32][C:33]([C:34]([NH:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][OH:56])=[O:35])=[CH:37][CH:38]=4)[C:17]=3[N:18]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:20]=2)=[CH:11][N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Reactant: NCCOCCO
Product: Nc1ncc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccc(C(=O)NCCOCCO)cc2)cn1
Yield: 10 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (38 mg) obtained in Step A in Example 1-D-19 and 2-(2-aminoethoxy)ethanol (6 μl) instead of 3-(aminomethyl)pyridine, in the same manner as Step B in Example 1-D-19, 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-N-[2-(2-hydroxy-ethoxy)-ethyl]-benzamide was obtained, and further PMB group was removed according to the above Deprotection method 3, to obtain the desired compound (D-179) as a colorless powder (3 mg, 10%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:45])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:44])[CH2:9][CH2:10][C@@:11]3([C:27]([C@@H:29]4[CH2:33][CH2:32][C@H:31]([CH2:34][N:35]5[CH2:40][CH2:39][CH:38]([C:41]([OH:43])=[O:42])[CH2:37][CH2:36]5)[CH2:30]4)=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:47])[CH3:46].N1C=CC=CC=1.[CH3:54][C:55]1([CH3:62])[CH2:59][C:58](=[O:60])[O:57][C:56]1=[O:61]>C(OCC)(=O)C>[C:56]([C:55]([CH3:62])([CH3:54])[CH2:59][C:58]([O:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:45])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:44])[CH2:9][CH2:10][C@@:11]3([C:27]([C@@H:29]4[CH2:33][CH2:32][C@H:31]([CH2:34][N:35]5[CH2:36][CH2:37][CH:38]([C:41]([OH:43])=[O:42])[CH2:39][CH2:40]5)[CH2:30]4)=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:47])[CH3:46])=[O:60])([OH:61])=[O:57]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)[C@@H]3CC[C@H](CN4CCC(C(=O)O)CC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)[C@@H]3CC[C@H](CN4CCC(C(=O)O)CC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
To a stirred solution of 1-(((1S,3R)-3-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carbonyl)cyclopentyl)methyl)piperidine-4-carboxylic acid (0.5 g, 0.80 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.2 g, 1.6 mmol) and 3,3-dimethyldihydrofuran-2,5-dione (0.82 ml) were added and the contents were refluxed for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ethyl acetate (30 ml), the organic layer was washed with 5% aqueous HCl, then water followed by brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.25 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.95-1.16 (m, 19H); 1.23-1.78 (m, 23H); 2.15-2.59 (m, 11H); 2.77-3.58 (m, 16H); 4.33-4.70 (m, 4H); 5.58-5.60 (s, 1H); 5.78-5.80 (s, 1H); 7.44-7.47 (s, 1H); ES Mass: 778 (100%), [M+1].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:22][S:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[C:28]([CH3:35])[C:27]=1[CH2:36][O:37][CH3:38])(=[O:25])=[O:24].[C:39]1(=[O:46])[CH2:44][CH2:43][CH2:42][C:41](=[O:45])[CH2:40]1>C(O)(CC)(C)C>[CH3:22][S:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([CH:40]2[C:41](=[O:45])[CH2:42][CH2:43][CH2:44][C:39]2=[O:46])=[O:32])=[C:28]([CH3:35])[C:27]=1[CH2:36][O:37][CH3:38])(=[O:24])=[O:25]
Reactant: O=C1CCCC(=O)C1
Reactant: COCc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: COCc1c(S(C)(=O)=O)ccc(C(=O)C2C(=O)CCCC2=O)c1C
Temperature: 80 °C
Reaction time: 11 h
Yield: 7.3 %

Procedure:
1.3 g of potassium carbonate and 3.0 g of N,N'-dicyclohexylcarbodiimide were added to a solution mixture comprising 2.0 g of 4-methanesulfonyl-3-methoxymethyl-2-methylbenzoic acid, 0.9 g of 1,3-cyclohexanedione and 100 ml of t-amyl alcohol. The mixture was stirred at 80° C. for 11 hours. It was concentrated under reduced pressure, and then an aqueous potassium carbonate solution was added. Then, insoluble substances were removed by filtration. The filtrate was washed with chloroform, then acidifed by an addition of concentrated hydrochloric and extracted with chloroform. The chloroform layer was washed with water and with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.1 g of a crude desired product. This crude product was recrystallized from ethanol to obtain 0.2 g of the desired product. Melting point: 192°-198° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@@H:20]3[C@@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:29][CH2:30][S:31]([CH2:34][CH2:35]Br)(=[O:33])=[O:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@@H:20]3[C@@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:35][CH2:34][S:31]([CH:30]=[CH2:29])(=[O:33])=[O:32])[CH2:24][CH2:23]3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Reactant: O=S(=O)(CCBr)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CS(=O)(=O)CCN1CCC(N2N=C(c3ccc(OC)c(OC)c3)[C@H]3CC=CC[C@H]3C2=O)CC1
Reaction time: 18 h

Procedure:
A solution of 10 mmol of compound 5c, 10 mmol of 1-bromo-2-(2-bromo-ethanesulfonyl)-ethane and 30 mmol of potassium carbonate in 30 ml of dimethylformamide is stirred at RT. After 18 h, the mixture is poured into water (150 ml) and subsequently extracted with ethyl acetate. Crystallisation from diethyl ether. M. p. 165-166° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([Cl:12])[C:9]2[NH:8][C:7](=[O:13])[CH:6]3[CH2:14][O:15][CH2:16][CH2:17][N:5]3[C:4]=2[N:3]=1.IC.[CH3:20]C([O-])(C)C>CS(C)=O>[Cl:1][C:2]1[N:11]=[C:10]([Cl:12])[C:9]2[N:8]([CH3:20])[C:7](=[O:13])[CH:6]3[CH2:14][O:15][CH2:16][CH2:17][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1Nc2c(Cl)nc(Cl)nc2N2CCOCC12
Solvent: CS(C)=O
Solvent: CI
Product: CN1C(=O)C2COCCN2c2nc(Cl)nc(Cl)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.8 %

Procedure:
2,4-Dichloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (500 mg, 1.818 mmol) and iodomethane (1.134 mL, 18.18 mmol) were mixed in DMSO (3 mL). 2-Methylpropan-2-olate (699 mg, 7.27 mmol) was added and the suspension was stirred overnight at room temperature. Ten more equivalents of iodomethane were added and the solution was heated at 50° C. for about 18 hours. The reaction was purified by mass-triggered preparative HPLC 20-60% of ACN (containing 0.035% TFA) in water (containing 0.05% TFA) on a Phenomenex Gemini 5 μm C18, 75×30 mm column)) to give 20 mg of 2,4-dichloro-5-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one as a tan solid. MS [M+H] Found 289.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:19])=[C:5]([CH3:18])[C:6]2[O:11][C:10]([C:13](O)=[O:14])([CH3:12])[CH2:9][CH2:8][C:7]=2[C:16]=1[CH3:17].S(Cl)([Cl:22])=O>CN(C)C=O.ClCCCl>[CH3:1][O:2][C:3]1[C:4]([CH3:19])=[C:5]([CH3:18])[C:6]2[O:11][C:10]([C:13]([Cl:22])=[O:14])([CH3:12])[CH2:9][CH2:8][C:7]=2[C:16]=1[CH3:17]
Reactant: O=S(Cl)Cl
Reactant: COc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)O)O2
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)Cl)O2

Procedure:
To a solution composed of 3.0 g of (3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)carboxylic acid, 2 drops of N,N-dimethylformamide and 50 ml of 1,2-dichloroethane was added 1.1 ml of thionyl chloride and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was evaporated under reduced pressure to remove the low-boiling substances. This procedure gave (3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)carbonyl chloride in a quantitative yield of 3.39 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:25])([CH3:24])[CH:9]=[CH:10][Sn](CCCC)(CCCC)CCCC)=[CH:4][CH:3]=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C(OC(=O)C)(=O)C.CCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:25])([CH3:24])[C:9]#[CH:10])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](C=CC(C)(C)c1ccc(Cl)cc1)(CCCC)CCCC
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CCCCC
Solvent: CC(=O)OC(C)=O
Product: C#CC(C)(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.4 %

Procedure:
A mixture of 4.0 grams (0.0085 mole) of 3-(4-chlorophenyl)-3-methyl-1-tributylstannyl-1-butene and 4.3 grams (0.0096 mole) of lead tetraacetate in 30 mL of anhydrous acetic anhydride is stirred at ambient temperature for about 18 hours. After this time, the reaction mixture is diluted to 100 mL with pentane. The mixture was then filtered through a pad of diatomaceous earth. The pad of diatomaceous earth is washed with about 300 mL of pentane. The wash and the filtrate are combined and concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel, using petroleum ether as the eluant. The product-containing fractions are combined and concentrated under reduced pressure, yielding about 1.1 grams of 3-(4-chlorophenyl)-3-methyl-1-butyne. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:21]([Si:25]([CH3:34])([CH3:33])S(C(F)(F)F)(=O)=O)([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH2:7][CH2:8][CH:9]=[C:10]([O:11][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:34])[CH3:33])[C:4]=2[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)S(=O)(=O)C(F)(F)F
Reactant: O=C1CCCOc2ccc(Br)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1=CCCOc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
To a 7-bromo-3,4-dihydrobenz o[b]oxepin-5(2H)-one (3 g, 12.6 mmol) and triethylamine (10 mL, 18.9 mmol) in DCM (100 mL) was added tert-butyldimethyl(trifluoromethylsulfonyl) silane (3.06 g, 12.4 mmol) dropwise under argon at room temperature, the mixture was stirred for 1 hour at room temperature. The mixture was washed with NaHCO3, dried over Na2SO4, concentrated to give crude (7-bromo-2,3-dihydrobenzo[b]oxepin-5-yloxy)(tert-butyl)dim ethylsilane (3.40 g, 81%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[C:26]([S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[C:26]([S:31]([CH:34]([CH3:36])[CH3:35])(=[O:32])=[O:33])=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: CC(C)S(=O)(=O)c1ncccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: CC(C)S(=O)(=O)c1ncccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 3-bromo-2-(isopropylsulfonyl)pyridine yielding 52 mg (88%) of the title compound. MS (ESI): mass calcd. for C18H17FN4O2S, 372.11; m/z found, 373.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.69 (dd, J=4.6, 1.7, 1H), 8.60 (dd, J=2.1, 1.5, 1H), 8.10 (d, J=1.5, 1H), 8.08-7.98 (m, 1H), 7.81 (dd, J=7.8, 1.6, 1H), 7.58 (dd, J=7.8, 4.6, 1H), 7.38 (dd, J=8.0, 1.8, 1H), 7.32 (dd, J=11.7, 1.7, 1H), 4.71 (s, 2H), 4.19 (hept, J=6.8, 1H), 1.31 (d, J=6.9, 6H).
Reaction SMILES: [OH:1][CH:2]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)/[CH:3]=[CH:4]/[CH:5]1[CH2:12][CH2:11][CH:10]2[CH:6]1[CH2:7][CH2:8][C:9]2=[O:13].[C:22]([Si:26]([CH3:29])([CH3:28])Cl)([CH3:25])([CH3:24])[CH3:23].N1C=CN=C1.O>CN(C)C=O>[Si:26]([O:1][CH:2]([CH2:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)/[CH:3]=[CH:4]/[CH:5]1[CH2:12][CH2:11][CH:10]2[CH:6]1[CH2:7][CH2:8][C:9]2=[O:13])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCC2C(/C=C/C(O)COc3ccccc3)CCC12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC(/C=C/C1CCC2C(=O)CCC12)COc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.9 %

Procedure:
A mixture of (E)-2-(3-hydroxy-4-phenoxybut-1-enyl)bicyclo[3,3,0]octan-6-one (49 mg), the less polar component prepared as described in Reference Example 45 and in the form of (±)-(E)-2β-(3β-hydroxy-4-phenoxybut-1-enyl)bicyclo[3,3,0]octan-6-one, tert-butyldimethylchlorosilane (31 mg), and imidazole (29 mg) in dimethylformamide (0.116 ml) was stirred at the ambient temperature for 2 hours. The mixture was then treated with water (10 ml) and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure, to give (E)-2-(3-tert-butyldimethylsilyloxy-4-phenoxybut-1-enyl)bicyclo[3,3,0]octan-6-one (76 mg), in the form of (±)-(E)-2β-(3β-tert-butyldimethylsilyloxy-4-phenoxybut-1-enyl)bicyclo[3,3,0]octan-6-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:28])[CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]#[N:26])=[CH:24][C:19]=4[O:18][C:17]3=[O:27])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:29][CH3:30].[NH2:31][OH:32].Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:28])[CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]([NH:31][OH:32])=[NH:26])=[CH:24][C:19]=4[O:18][C:17]3=[O:27])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:29][CH3:30]
Reactant: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(C#N)ccc43)CC2)ccc1Cl
Reactant: NO
Agent: Cl
Solvent: CCO
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(C(=N)NO)ccc43)CC2)ccc1Cl

Procedure:
A mixture of 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-dihydro-benzooxazole-6-carbonitrile (49) (150 mg, 0.35 mmol, 1 eq), NH2OH.HCl (73 mg, 1.05 mmol, 3 eq), TEA (270 ml), in ethanol (2 ml) was stirred at 60° C. overnight. The resultant mixture was cooled and precipitated material was removed by filtration. The reaction solution was washed with ethyl acetate to provide 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-N-hydroxy-2-oxo-2,3-dihydro-benzooxazole-6-carboxamidine (50).
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:31])[C:19]([CH3:30])([S:21]([CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)(=[O:23])=[O:22])[CH3:20])[O:14][N:13]=1)([CH3:11])[CH2:3][O:4]C1CCCCO1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.C(O)C>[OH:4][CH2:3][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:31])[C:19]([CH3:30])([S:21]([CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)(=[O:23])=[O:22])[CH3:20])[O:14][N:13]=1)([CH3:11])[CH3:1]
Reactant: CC(C)(COC1CCCCO1)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(CO)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Yield: 82.7 %

Procedure:
A solution of 98 g (0.21 mol) of N-{3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl}-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide in DCM/ethanol (1/1, 1.2 L) is treated with 129 g (0.42 mol) of MP-TsOH resin (loading 3.3 mmol/g) at room temperature for 18 h. The resin is removed by filtration and washed alternating with DCM (0.5 L) and methanol (0.5 L) twice. The combined filtrates are concentrated under reduced pressure and the resulting tan residue is slurried in heptanes/ethyl acetate (7/3, 4×1 L) to yield 65 g of N-[3-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)propionamide as a white powder. Yield 82%; ES-MS: m/z 375 [M+H], mp 191-192° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:18]([N:20]1[CH2:25][CH2:24][C@@:23]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)([OH:26])[C:22]([CH3:35])([CH3:34])[CH2:21]1)=[O:19])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH:36]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1.CCN(C(C)C)C(C)C>ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C@@:23]2([OH:26])[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C@H:3]([NH:2][C:41]([CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[O:42])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:21][C:22]2([CH3:35])[CH3:34])=[CH:32][CH:31]=1
Reactant: CC1(C)CN(C(=O)[C@H](N)CCCNC(=O)OCc2ccccc2)CC[C@]1(O)c1ccc(Cl)cc1
Reactant: O=C(Cl)C1CCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)CN(C(=O)[C@@H](CCCNC(=O)OCc2ccccc2)NC(=O)C2CCCC2)CC[C@]1(O)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
Benzyl (R)-4-amino-5-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-5-oxopentylcarbamate hydrochloride (50.5 mg, 0.096 mmol) was dissolved in dichloromethane (0.5 mL) and added cyclopentane carbonylchloride (14 μL, 0.12 mmol) followed by DIPEA (42 μL, 0.24 mmol). The solution was stirred for 2 h, concentrated, and partitioned between EtOAc (2 mL) and aq NaHCO3 (0.5 mL). The EtOAc layer was separated, dried over magnesium sulfate, and concentrated to give benzyl (R)-5-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-4-(cyclopentanecarboxamido)-5-oxopentylcarbamate which was used without further purification.