Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:3]=O)=O.[NH2:5][C:6]1[C:27]([NH2:28])=[CH:26][C:9]2[CH2:10][C@@H:11]3[C:16]([CH3:18])([CH3:17])[C@:15]([CH3:19])([C:8]=2[CH:7]=1)[CH2:14][CH2:13][N:12]3C(=O)C(F)(F)F>C(O)C>[CH3:19][C@@:15]12[C:16]([CH3:18])([CH3:17])[C@@H:11]([CH2:10][C:9]3[CH:26]=[C:27]4[N:28]=[CH:1][CH:3]=[N:5][C:6]4=[CH:7][C:8]=31)[NH:12][CH2:13][CH2:14]2
Reactant: O=CC=O
Reactant: CC1(C)[C@H]2Cc3cc(N)c(N)cc3[C@]1(C)CCN2C(=O)C(F)(F)F
Solvent: CCO
Product: CC1(C)[C@H]2Cc3cc4nccnc4cc3[C@]1(C)CCN2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Glyoxal (40% in water, 95 μL) is added to 1-[(2R,6S)-8,9-diamino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone (260 mg) dissolved in ethanol (3 mL) and chilled in an ice bath. The cooling bath is removed and the solution is stirred at ambient temperature overnight. Then, the solution is concentrated and the residue is taken up in methanol (1 mL) and treated with 4 M aqueous NaOH solution (0.38 mL). After stirring at ambient temperature overnight, brine is added and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (MgSO4), and the solvent is removed under reduced pressure to give the crude title compound that is used without further purification.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([S:9](Cl)(=[O:11])=[O:10])=[N:7][CH:8]=1.[NH2:13][CH2:14][CH2:15][OH:16].CCN(CC)CC>C(#N)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH:13][CH2:14][CH2:15][OH:16])(=[O:11])=[O:10])=[N:7][CH:8]=1
Reactant: NCCO
Reactant: O=S(=O)(Cl)c1ccc(Br)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=S(=O)(NCCO)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 4 mL vial equipped with a magnetic stir bar were combined 5-bromopyridine-2-sulfonyl chloride hydrochloride (50 mg, 0.171 mmol), 2-aminoethanol (0.015 mL, 0.256 mmol), Et3N (0.071 mL, 0.512 mmol), and acetonitrile (1 mL). The resulting yellow solution stirred at room temperature overnight. The reaction mixture was subsequently partitioned between water (10 mL) and ethyl acetate (15 mL). The layers were separated and the aqueous layer was back-extracted with ethyl acetate (15 mL). The combined organic layers were concentrated to give the title compound as a clear liquid, which was used without further purification (55 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14](/[CH:16]=[CH:17]/[C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:15][C:14](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)/C=C/c1ccc(-c2ccc(C(C)(C)C)cc2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2ccc(/C=C/C(=O)O)s2)cc1
Reaction time: 18 h
Yield: 82.6 %

Procedure:
To a solution of methyl (E)-3-[5-(4-tert-butylphenyl)-thiophen-2-yl]acrylate (190 mg) of THF/ethanol (15/15 ml) was added at room temperature 2N sodium hydroxide solution (2.0 ml), and the mixture was stirred 18 hours. To the mixture was added 1N hydrochloric acid (5 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the precipitated crystals were collected by filtration, which were washed with hexane to give yellow crystals of (E)-3-[5-(4-tert-butylphenyl)thiophen-2-yl]acrylic acid (149.7 mg). This compound was used for the following reaction, without subjecting further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]([CH3:28])[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH:26]=O)=[CH:20]2.N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:26][C:21]1[NH:22][C:23]2[C:19]([CH:20]=1)=[CH:18][C:17]([O:16][CH2:15][CH2:14][N:13]([CH3:12])[CH3:28])=[CH:25][CH:24]=2
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CN(C)CCOc1ccc2[nH]c(C=O)cc2c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)CCOc1ccc2[nH]c(C=C3C(=O)Nc4ccc(Br)cc43)cc2c1
Temperature: 100 °C
Yield: 80.4 %

Procedure:
A mixture of 5-bromo-2-oxindole (46 mg, 0.215 mmol), 5-(2-dimethylamino-ethoxy)-1H-indole-2-carbaldehyde (50 mg, 0.21 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 72 mg (78%) of the title compound as a red solid.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]=[C:9]1[CH2:32][CH:31]=[CH:30][C:29](=[CH2:33])[CH:10]1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:19](=[O:28])[CH:20](Br)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:16]=[CH:17][CH:18]=1>C(Cl)(Cl)(Cl)Cl>[CH3:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:9]([CH3:8])[C:10]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:19](=[O:28])[CH:20]=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:16]=[CH:17][CH:18]=1
Reactant: C=C1C=CCC(=C)C1COc1cccc(C(=O)C(Br)CC(=O)OCC)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C=CC(=O)c1cccc(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Triethylamine (5.95 g, 58.9 mmol) was added to a solution of Ethyl 4-(3-(2,6-dimethlylbenzyloxy)phenyl)-4-oxo-3-bromo-butyrate (Step D, 2.47 g, 5.8 mmol) in carbon tetrachloride (50 ml). After stirring for 4 hours at room temperature, the reaction mixture was filtered through a pad of silica gel few times, and concentrated to give the title compound.
Reaction SMILES: [O:1]([C:8]([NH:10][C:11](=[S:24])[C:12](=[CH:18]N(CC)CC)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][S:26]([C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=1)[C:32](=[O:35])[CH2:33]Br)(=[O:28])=[O:27].C(O)(C)C>O>[F:25][S:26]([C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=1)[C:32]([C:33]1[S:24][C:11]([NH:10][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:9])=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:18]=1)=[O:35])(=[O:28])=[O:27]
Reactant: O=C(CBr)c1cccc(S(=O)(=O)F)c1
Reactant: CCOC(=O)C(=CN(CC)CC)C(=S)NC(=O)Oc1ccccc1
Solvent: O
Solvent: CC(C)O
Product: CCOC(=O)c1cc(C(=O)c2cccc(S(=O)(=O)F)c2)sc1NC(=O)Oc1ccccc1
Reaction time: 1 h
Yield: 75 %

Procedure:
A mixture of 130 g of ethyl 2-[[(phenoxycarbonyl)-amino]thioxomethyl]-3-(diethylamino)propenoate (0.37 mole), 104 g of m-fluorosulfonylphenacyl bromide (0.37 mole), and 350 ml of isopropanol was heated to reflux and held one hour. During this time, the reactants dissolved and the product precipitated. The mixture was cooled to 20°-25°, filtered, washed with isopropanol and then water to yield 133 g of white solid, ethyl 5-[3-(fluorosulfonyl)benzoyl]-2-[(phenoxycarbonyl)-amino]-3-thiophenecarboxylate, (75% yield), melting point 161°-163°. Ir: 2.88, 5.72, 5.98, 6.18, 7.12, 8.10, 8.40μ; NMR (CDCl3) δ10.75 (s,1,N-H); 8.4 (m,1); 8.2 (m,2); 7.8 (m,1); 7.7 (s,1, thiophene-proton); 4.4 (q,2); 1.4 (t,3).
Reaction SMILES: [CH:1]1[N:2]=[C:3]([CH2:10][C:11](OC)=[O:12])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[BH4-].[Na+].O>CO>[CH:1]1[N:2]=[C:3]([CH2:10][CH2:11][OH:12])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: COC(=O)Cc1ncc2ccccn12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCCc1ncc2ccccn12
Temperature: 60 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
Methyl 2-(imidazo[1,5-a]pyridin-3-yl)acetate (1.85 g) was dissolved in methanol (30 ml). To the solution was added sodium borohydride (3.68 g), and the mixture was stirred for one hour at 60° C. To the reaction mixture was added water (20 ml), which was concentrated under reduced pressure. The concentrate was subjected to extraction twice with ethyl acetate (40 ml). The organic layers were combined and dried over anhydrous magnesium sulfate, followed by concentration to afford the title compound (1.39 g).
Reaction SMILES: S([O-])(O)=O.[Na+].[C:6]([NH:16][C@H:17]([CH:22]=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[C-:24]#[N:25].[K+]>O.C(OCC)(=O)C>[C:6]([NH:16][CH:17]([CH2:18][CH:19]([CH3:20])[CH3:21])[CH:22]([OH:23])[C:24]#[N:25])([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: [C-]#N
Reactant: CC(C)C[C@@H](C=O)NC(=O)OCc1ccccc1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)CC(NC(=O)OCc1ccccc1)C(O)C#N
Reaction time: 14 h
Yield: 81.6 %

Procedure:
A solution containing 3.43 g of sodium hydrogen sulfite in 20 ml of water was added to 2.81 g of N-carbobenzoxy-L-leucinal, and the mixture was stirred for 14 hours under ice-cooling. A solution of 1.41 g of potassium cyanide in 50 ml of water and 200 ml of ethyl acetate were added to the reaction mixture, and the mixture was stirred for 4 hours at room temperature. The ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give 2.54 g of 3-carbobenzoxyamino-2-hydroxy-5-methylhexanenitrile as a colorless oil. A mixture of 20 ml of dioxane and 20 ml of concentrated hydrochloric acid was added to 500 mg of the nitrile, and the mixture was heated under reflux for 12 hours. The reaction mixture was evaporated under reduced pressure, and the residual crystals were purified by cation exchange column chromatography (eluent: a 2N aqueous NH4OH solution) to obtain 254 mg of (2RS, 3S)-3-amino-2-hydroxy-5-methylhexanoic acid as colorless crystals (a mixture in ratio of 2R and 2S being about 7:3).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[Cl:24][C:25]1[CH:26]=[C:27]([S:34](Cl)(=[O:36])=[O:35])[CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32]>C(Cl)Cl>[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([S:34]([C:27]2[CH:28]=[CH:29][C:30]([N+:31]([O-:33])=[O:32])=[C:25]([Cl:24])[CH:26]=2)(=[O:36])=[O:35])[CH2:19][CH2:18]1)([CH3:13])([CH3:11])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
Diisopropylethylamine (1.74 ml, 9.98 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (0.25 g, 1.25 mmol) in DCM (5 ml) at room temperature. To this mixture was added 3-chloro-4-nitrobenzene sulfonyl chloride (0.32 g, 1.25 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with DCM (100 ml) and washed sequentially with HCl (1M solution, 50 ml), NaOH (1M solution, 50 ml) and brine (50 ml), the organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting residue was purified by flash column chromatography (elution: % EtOAc: % Heptane) to give the title compound (0.44 g, 84% yield) as a white solid. δH (500 MHz, DMSO) 7.97-8.12 (m, 3 H) 6.93 (d, J=7.72 Hz, 1 H) 3.64 (d, J=12.77 Hz, 2 H) 3.43 (d, J=3.94 Hz, 2 H) 2.88-3.00 (m, 2 H) 1.78 (d, J=10.40 Hz, 2 H) 1.25-1.46 (m, 11 H). Tr=2.22 min, m/z (ES+) (M+Na)+ 442.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:12]([O:29]2)[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(Cl)cc2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(c3ccc(Cl)cc3)OC2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.5 %

Procedure:
To a cooled (0° C.) solution of 4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (7.10 g, approx. 24.1 mmol) in methylene chloride (150 mL) was added a solution of 3-chloroperbenzoic acid (75%, 8.34 g, 36.2 mmol) in methylene chloride (120 mL) over 40 min. The mixture was warmed to rt and allowed to stir over night (16 h). The solution was washed twice with a half-saturated aqueous solution of sodium bisfulfite to destroy excess oxidant. The mixture was then twice washed with half-saturated aqueous potassium carbonate, and brine. The extracts were dried over magnesium sulfate, filtered and concentrated to afford a crude oil which was purified by silica gel chromatography (100% hexanes—80% hexanes/20% ethyl acetate gradient) to afford pure 6-(4-Chloro-phenyl)-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (5.34 g, 71%) as a clear, colorless oil which solidified on standing.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:17]([CH3:19])=[O:18])[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:20][C:13]1[S:12][C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=2)=[C:15]([OH:16])[C:14]=1[C:17]([CH3:19])=[O:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)c1c(Br)sc(-c2ccc(C(C)(C)C)cc2)c1O
Yield: 85.5 %

Procedure:
2-(4-t-butylphenyl)-3-hydroxy-4-methylcarbonylthiophene (2.66 g, 9.7 mmol), N-bromosuccinimide (1.73 g, 9.7 mmol) and benzoyl peroxide (153 mg, 0.63 mmol) were heated with reflux for 2 hours in 65 ml of chloroform. Water was added, and the reaction solution was extracted three times with chloroform, and the organic layer was washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. The obtained organic layer was concentrated, and then purified with a silica gel column chromatography (n-hexane/chloroform=3/2) to obtain the desired product as a yellow solid (2.93 g, yield 86%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.C[N:18](C=O)C>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:18])=[O:6]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cccc(I)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)c1cccc(I)c1
Reaction time: 2 h
Yield: 99 %

Procedure:
3-Iodobenzoic acid (2.00 g, 8.06 mmol) was dissolved in THF (20 mL) then oxalyl chloride (1.4 mL, 16 mmol) and DMF (0.05 mL) were added and the resulting mixture stirred for 2 hours. The volatiles were evaporated under reduced pressure and the residue was dissolved in THF (20 mL) and concentrated aqueous ammonia (10 mL). After 60 minutes water (200 mL) was added and after a further 30 minutes the resulting precipitate was collected by filtration and air dried to give the title compound (I142) (1.97 g, 99% yield) as a white powder; 1H NMR (400 MHz, d4-MeOH) δ 8.23 (t, J=1.8 Hz, 1H), 7.90 (ddd, J=7.9, 1.7, 1.0 Hz, 1H), 7.86 (ddd, J=7.8, 1.7, 1.0 Hz, 1H), 7.24 (t, J=7.8 Hz, 1H). LCMS Method C: rt 5.29 min, m/z 248.1 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:22][CH2:21][C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:23])[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2)#[N:2].[OH:32][Li].O.OO>CO>[C:1]([CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:18][CH2:19][C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:23])[CH2:21][CH2:22]4)[C:6]=3[C:5]1=2)(=[O:32])[NH2:2]
Reactant: [Li]O
Reactant: CC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CC#N)CC4)CC1
Agent: OO
Solvent: CO
Solvent: O
Product: CC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Reaction time: 8 h
Yield: 71.8 %

Procedure:
A 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with tert-butyl N-(4-[[(3R)-3-(cyanomethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-methylcyclohexyl)carbamate (600 mg, 1.36 mmol, 1.00 equiv) in methanol (8.0 mL). Then LiOH.H2O (171 mg, 4.08 mmol, 3.00 equiv) and H2O2 (30%, 1.0 mL) were added at 0° C. and the resulting solution was stirred overnight at this temperature. The reaction was then quenched by the addition of 40 mL of NaHSO3 (aq.) and extracted with 3×60 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/1) to afford tert-butyl N-(4-[[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-methylcyclohexyl)carbamate (450 mg, 72%) as a white solid.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])(=[O:4])=[O:3].[CH3:14][C:15]([CH3:20])=[CH:16][C:17]([OH:19])=[O:18].S(=O)(=O)(O)O>>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][C:10]([C:15]([CH3:20])([CH3:14])[CH2:16][C:17]([OH:19])=[O:18])=[CH:11][C:6]=1[O:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: COc1ccccc1OS(C)(=O)=O
Reactant: CC(C)=CC(=O)O
Agent: O=S(=O)(O)O
Product: COc1ccc(C(C)(C)CC(=O)O)cc1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 23.4 %

Procedure:
To a mixture of 2-methoxyphenyl methanesulfonate (Example 50b) (82 g, 406.4 mmol) and 3-methylbut-2-enoic acid (20.3 g, 203.2 mmol), was added concentrate sulfuric acid (11 mL, 96%, 206.3 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 min, then heated to 70° C. and stirred under nitrogen overnight. Upon completion, the reaction was cooled to room temperature, quenched with ice water (500 mL) and extracted with ether (1×). The phases were separated, and the organic layer was washed with 2N NaOH (1×). The combined aqueous layers were acidified to pH 1 with 12N HCl at 0° C. and extracted with ether (1×). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a red-brown oil (14.4 g, contained <20% 3-methylbut-2-enoic acid) 1H NMR (400 MHz, DMSO-d6) δ 1.33 (s, 6H), 2.53 (s, 2H), 3.31 (s, 3H), 3.79 (s, 3H), 7.08-7.31 (m, 3H), 11.87 (s, 1H).
Reaction SMILES: [C:1]1([C:6]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>CN(C)C=O.CN(C1C=CN=CC=1)C>[C:18]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]([C:6](=[O:7])[C:1]2[S:5][CH:4]=[CH:3][CH:2]=2)[C:9]1=[O:17])(=[O:20])[CH3:19]
Reactant: O=C1Nc2ccccc2C1C(=O)c1cccs1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)N1C(=O)C(C(=O)c2cccs2)c2ccccc21
Reaction time: 0.02 h
Yield: 52.6 %

Procedure:
To a stirred solution of 486 mg (2.0 mmole) of 3-(2-thenoyl)-2-oxindole in 4 ml of N,N-dimethylformamide was added 538 mg (4.4 mmole) of 4-(N,N-dimethylamino)pyridine. The resulting mixture was cooled in an ice-bath, and then a solution of 225 mg (2.2 mmole) of acetic anhydride in 2 ml of N,N-dimethylformamide was added dropwise, with stirring during about 1 minute. The cooling bath was removed and stirring was continued for 1 hour, and then the reaction mixture was poured onto a mixture of 50 ml of water and 1.7 ml of 3N hydrochloric acid. The resulting mixture was cooled in an ice-bath, and the solid was recovered by filtration. This afforded 528 mg of a yellow solid. The yellow solid was recrystallized from ca. 15 ml of ethanol, giving 300 mg of the title compound as yellow crystals, m.p. 139°-140° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=3)[CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C=O.[C:32]([O-])([O-])=[O:33].[K+].[K+]>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=2)([CH2:32][OH:33])[CH2:10][OH:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1cccc(C2(c3cccc(Br)c3)CO2)c1
Agent: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: OCC(CO)(c1cccc(Br)c1)c1cccc(Br)c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 113.9 %

Procedure:
A mixture of the crude 2,2-bis(3-bromophenyl)oxirane (7.4 g, 20.90 mmol) and p-toluenesulfonic acid monohydrate (360 mg, 2.1 mmol) in toluene (25 mL) was stirred at 95° C. for 1 h. The solution was washed with aq NaHCO3 (10 mL) and water (20 mL). The organic layer was dried and concentrated. The residue was dissolved in EtOH (20 mL). To the solution was added formaldehyde (15.56 mL, 209 mmol, 37% aqueous solution) and K2CO3 (1.44 g, 10.45 mmol). The mixture was stirred at 85° C. for 12 h. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (60 mL×4). The combined organic layers were dried and concentrated. The residue was purified by column chromatography (on silica gel, eluent with Petroleum ether˜Petroleum ether: EtOAc=2:1) to afford 4.6 g of 2,2-bis(3-bromophenyl)propane-1,3-diol (11.9 mmol, 57% after two steps). LC/MS: [M−18+1]=368. 1HNMR (CDCl3), 400 MHz: δ 2.53 (brs, 2H), 2.41 (s, 4H), 7.09-7.20 (m, 4H), 7.36-7.40 (m, 4H).
Reaction SMILES: [CH:1]1([C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12]3[C:13]4[N:14]([CH:21]=[N:22][CH:23]=4)[CH:15]=[CH:16][C:17]=3[C:18]([OH:20])=O)=[C:7]([F:24])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:55]([O:57][CH2:58][CH2:59][O:60][NH2:61])=[CH2:56]>C1COCC1>[CH:55]([O:57][CH2:58][CH2:59][O:60][NH:61][C:18]([C:17]1[CH:16]=[CH:15][N:14]2[CH:21]=[N:22][CH:23]=[C:13]2[C:12]=1[NH:11][C:8]1[CH:9]=[CH:10][C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:6][C:7]=1[F:24])=[O:20])=[CH2:56]
Reactant: O=C(O)c1ccn2cncc2c1Nc1ccc(C2CCC2)cc1F
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=COCCONC(=O)c1ccn2cncc2c1Nc1ccc(C2CCC2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.9 %

Procedure:
A suspension of 8-(4-cyclobutyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid (154 mg, 0.46 mmol), EDCI (105 mg, 0.55 mmol), HOBt (74 mg, 0.55 mmol), DIPEA (0.19 mL, 1.14 mmol) and O-(2-vinyloxy-ethyl)-hydroxylamine (52 mg, 0.50 mmol) in THF (2.5 mL) was stirred at room temperature for 18 hours. The reaction mixture was partitioned between DCM (20 mL) and saturated aqueous NaHCO3. The organic layer was isolated then washed with water (20 mL), followed by brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The resultant gum was subjected to flash chromatography (Si-PPC, gradient 0% to 100%, ethyl actetate in cyclohexane) to afford the title compound as a brown gum (149 mg, 80%). LCMS (method B): RT=3.49 min, [M+H]+=411.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6]1)#[CH:4].Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:16][O:15][C:13](=[O:14])[CH2:12][O:10][C:5]1([C:3]#[CH:4])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)CBr
Reactant: C#CC1(O)CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#CC1(OCC(=O)OC)CCCC1
Reaction time: 1 h

Procedure:
A mechanically stirred suspension of sodium hydride (60% dispersion in mineral oil, 1.5 g, 38 mmol) in tetrahydrofuran (10 mL) at 0 C. under nitrogen was treated with a solution of 1-ethynylcyclopentanol (5.0 g, 45 mmol) in tetrahydrofuran (20 mL) over 15 minutes. After stirring at 0 C. for 1 hour, the mixture was treated with methyl bromoacetate (5.4 mL, 56 mmol). after stirring at ambient temperature for 16 hours, the mixture was treated with 2M HCl (25 mL) and then treated with ethyl acetate (25 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered, concentrated and used without purification in the next step.