Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][NH2:11])=[CH:2]1.[CH3:12]CN(CC)CC.Cl[C:20]([O:22]C)=[S:21]>CO.O>[CH3:12][S:22][C:20]([NH:11][CH2:10][C:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[NH:1][CH:2]=1)=[O:21]
Reactant: NCc1c[nH]c2ccccc12
Reactant: CCN(CC)CC
Reactant: COC(=S)Cl
Solvent: CO
Solvent: O
Product: CSC(=O)NCc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 6 h
Yield: 94.3 %

Procedure:
Freshly made 25 (190 mg, 1.3 mmol) and Et3N (271 μL, 1.95 mmol) was dissolved in anhydrous MeOH (10 mL). The flask was cooled to 0° C. and methyl chlorothioformate (116 μL, 1.36 mmol) was added dropwise followed by stirring at room temperature for 6 hours. A few drops of H2O were added to quench excess reagent and the volatiles were evaporated. The residue was dissolved in EtOAc (35 mL) and washed with 0.5 M HCl (2×20 mL), sat. NaHCO3 (20 mL), and brine (15 mL). The organic solution was dried with Na2SO4, filtered and concentrated to afford a crude brownish-orange solid (270 mg). After recrystallization from CH2Cl2/hexanes, beige crystals: 125 mg, 44% yd. mp 110-111° C. 1H NMR (CDCl3) δ 8.15 (br s, 1H, NH), 7.64 (d, 1H, ArH J=7.9), 7.39 (d, 1H, ArH J=7.1), 7.23 (m, 1H, ArH), 7.18 (m, 1H, ArH), 7.13 (m, 1H, ArH), 5.52 (br s, 1H, CH2NHC), 4.67 (d, 2H, ArCH2, J=5.1), 2.38 (s, 3H, SCH3). 13C NMR (CDCl3) δ 167.6, 136.3, 126.3, 123.3, 122.5, 119.9, 118.7, 112.1, 111.3, 36.9, 12.4. EI-MS m/z (%) 220 (37, M+), 205 (9), 172 (12, M+-SCH3), 130 (100). NP-HPLC r.t.=9.827 min. RP-HPLC (1/1 CH3CN/H2O+0.1% TFA) r.t.=9.512 min.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.Br.Br[CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>>[CH3:16][C:6]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:2]([CH3:1])[N:3]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:23][CH2:24][N:25]([CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[CH2:26][CH2:27]2)=[O:20])[N:5]=1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Reactant: BrCc1cccnc1
Agent: Br
Product: Cc1nc(OCC(=O)N(C)C2CCN(Cc3cccnc3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31 and 3-(bromomethyl)pyridine hydrobromide in the same manner as in Example 32.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([OH:13])=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:15][C:16]1[C:17]([F:27])=[C:18]([CH:24]=[CH:25][CH:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20].CC#N.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C1COCC1>[F:27][C:17]1[C:16]([CH2:15][O:13][C:10]2[CH:11]=[N:12][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[N:8][CH:9]=2)=[CH:26][CH:25]=[CH:24][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1cccc(CBr)c1F
Reactant: Oc1cnc(N2CCOCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(COc2cnc(N3CCOCC3)nc2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
2-(Morpholin-4-yl)pyrimidin-5-ol (300 mg) and ethyl 3-(bromomethyl)-2-fluorobenzoate (850 mg) were mixed with MeCN (5 ml), THF (2 ml) and DMF (1 ml), and potassium carbonate was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and EtOAc and water were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain ethyl 2-fluoro-3-({[2-(morpholin-4-yl)pyrimidin-5-yl]oxy}methyl)benzoate (378 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][NH:15][C:16]([C@@H:18]2[CH2:24][CH2:23][C@@H:22]3[CH2:25][N:19]2[C:20](=[O:31])[N:21]3[O:26][S:27]([O-:30])(=[O:29])=[O:28])=[O:17])[CH2:9]1)=O)(C)(C)C.C([N+](CCCC)(CCCC)CCCC)CCC.FC(F)(F)C(O)=O>C(Cl)Cl>[O:31]=[C:20]1[N:19]2[CH2:25][C@@H:22]([CH2:23][CH2:24][C@H:18]2[C:16]([NH:15][O:14][C@@H:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[O:17])[N:21]1[O:26][S:27]([OH:30])(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)[O-])C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NO[C@@H]1CCCNC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a solution of N,N,N-tributylbutan-1-aminium ({[(2S,5R)-2-({[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl]oxy}carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl)oxidanide 15 (0.30 g, 0.42 mmol) in DCM (17 mL) was added trifluoroacetic acid (0.84 mL, 10.9 mmol) dropwise at 0° C. The reaction mixture was stirred for 1 h, then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with acetonitrile (2×) and the white solid was collected by centrifugation. The white solid was purified by HPLC and freeze-dried to give (2S,5R)-7-oxo-N-[(3R)-piperidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide Compound 3 (Table 1) (0.045 g, 29.41%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]2[NH:14]C(=O)N[C:11]2=[O:16])=[CH:5][C:4]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=[O:32]>C(O)(=O)C.CO.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([C:11]([OH:16])=[O:32])[NH2:14])=[CH:5][C:4]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: COc1ccc(CC2NC(=O)NC2=O)cc1OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CC(N)C(=O)O)cc1OCc1ccccc1

Procedure:
This compound is prepared from the corresponding hydantoin derivative (Example 7) by a procedure similar to that in Example 9; tlc (1: 5: 20 acetic acid-methanol-chloroform system); Rf 0.4 (ninhydrin).
Reaction SMILES: CO[C:3]([C:5]1[CH:9]=[C:8]([Br:10])[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]=1[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([F:23])[CH:17]=1)O)=[O:4].[NH2:24][C:25]1[CH:26]=[C:27]([Cl:33])[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=1.COC(C1C=C(Br)N(C(C)C)C=1C(C1C=CC(Cl)=CC=1)O)=O.CN1C(N)=CC(C)=N1.ClC(N(C)C)=C(C)C>CCOC(C)=O.CCN(CC)CC>[Br:10][C:8]1[N:7]([CH:11]([CH3:12])[CH3:13])[C:6]2[CH:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([F:23])[CH:17]=3)[N:24]([C:25]3[CH:26]=[C:27]([Cl:33])[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=3)[C:3](=[O:4])[C:5]=2[CH:9]=1
Reactant: Cn1cc(N)cc(Cl)c1=O
Reactant: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)c(F)c1
Agent: CC(C)=C(Cl)N(C)C
Agent: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: Cc1cc(N)n(C)n1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)c(F)c1)N(c1cc(Cl)c(=O)n(C)c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Intermediate AW but in the step corresponding to Step AW2, 5-bromo-2-[(4-chloro-3-fluoro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (Step AZ1) and 5-amino-3-chloro-1-methyl-1H-pyridin-2-one (Step E5) were used instead of 5-bromo-2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester and 2,5-dimethyl-2H-pyrazol-3-ylamine respectively. Moreover, in this step, the procedures described for Steps H3 and H2 using 1-chloro-N,N,2-trimethylpropenylamine and Et3N were used. The title compound (containing some of the corresponding 2-chloro analog) was obtained as a white foam. tR: 1.18 min (HPLC 3); ESI-MS: tR=1.10 min, [M+H]+ 512/514/516 (LC-MS 1); TLC: Rf=0.19 (EtOAc).
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][C:5]([O-:7])=[O:6].[C:9]([NH2:12])(=[O:11])[CH3:10].[C:13](O)(=O)[CH3:14]>>[CH2:13]([O:7][C:5]([C:4]1[O:11][C:9]([CH3:10])=[N:12][C:3]=1[CH3:2])=[O:6])[CH3:14]
Reactant: CC(N)=O
Reactant: CC(=O)O
Reactant: O=C([O-])CC(=O)CCl
Product: CCOC(=O)c1oc(C)nc1C
Temperature: 25 °C
Yield: 9 %

Procedure:
Prepared as in J. Heterocyclic Chem. 1998, 35, 859. A solution of chloroacetoacetate (20 g, 121 mmol) and acetamide (14.4 g, 240 mmol) in glacial acetic acid (40 mL) was heated to reflux for 72 h. The mixture was cooled to rt and concentrated under vacuum. The resulting material was cooled in an ice bath and made basic (pH 9-10) with 6 N NaOH solution. The aqueous solution was extracted with Et2O (3×100 mL). The combined Et2O layers were dried (Na2SO4), filtered, and concentrated to afford a light brown oil. The crude material was purified by silica gel chromatography, eluting with a gradient of 20 % EtOAc/hexanes to 25 % EtOAc/hexanes to provide the ester (1.8 g, 9 %) as a pale yellow solid. 1H NMR 300 MHz (CDCl3): δ=4.37 (q, J=7.1 Hz, 2 H), 2.49 (s, 3H), 2.43 (s, 3H), 1.38 (t, J=7.1 Hz, 3H). MS (ESI-POS): [M+H]+=191.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl.[NH2:14][CH2:15][CH2:16][SH:17].C1(C)C=CC=CC=1>O>[CH2:2]([CH:1]1[NH:14][CH2:15][CH2:16][S:17]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCC=O
Reactant: NCCS
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCC1NCCS1

Procedure:
A mixture of 34 g. of undecylaldehyde and 22.8 g. of 2-aminoethanethiol hydrochloride in about 400 ml. of toluene was heated at reflux overnight. The water of condensation was collected in a Dean-Stark trap. The reaction mixture then was washed with aqueous sodium hydroxide and dried over anhydrous magnesium sulfate. After filtering the reaction mixture, the toluene was distilled under reduced pressure. The residue then was vacuum distilled, b.p. 130°-8°/0.1 mm, giving 2-decylthiazolidine. The following elemental microanalysis was obtained:
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].Cl.[Cl:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22]2[N:23]=[CH:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:14]=1)=[O:12]>CO.O1CCCC1.ClCCl.ClCCl>[ClH:10].[NH:4]([C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22]2[N:23]=[CH:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:14]=1)=[O:12])[C:3]([NH2:5])=[NH:2]
Reactant: O=C(Cl)c1cn(-c2cc3ccccc3cn2)c2ccccc12
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: N=C(N)NC(=O)c1cn(-c2cc3ccccc3cn2)c2ccccc12
Temperature: 22 °C
Reaction time: 2 h
Yield: 35.2 %

Procedure:
0.974 g (10.2 mmol) of guanidine hydrochloride is added to a solution of 0.55 g (10.2 mmol) of sodium methoxide in 10 cm3 of methanol at a temperature in the region of 22° C. under an argon atmosphere. After stirring at a temperature in the region of 22° C. for 2 hours, the solvent is evaporated off under reduced pressure (2.7 kPa). The residue, placed under an argon atmosphere, is taken up in 20 cm3 of a tetrahydrofuran/dichloromethane (1/1 by volume) mixture and then 0.7 g (2.04 mmol) of 3-chlorocarbonyl-1-(isoquinol-3-yl)-1H-indole hydrochloride, dissolved in 5 cm3 of the same tetrahydrofuran/dichloromethane mixture, is added thereto. After 15 hours at a temperature in the region of 22° C. and then heating at a temperature in the region of 60° C. with stirring for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in dichloromethane. The insoluble material is then filtered off and discarded, and the filtrate is concentrated under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography [eluent: ethyl acetate/methanol (9/1 by volume)]. After concentrating the fractions under reduced pressure, 0.263 g of 3-guanidinocarbonyl-1-(isoquinol-3-yl)-1H-indole hydrochloride is obtained in the form of a white solid which decomposes at 235° C. Mass spectrum (EI): m/e 329 (M+·), m/e 271. IR spectrum (KBr): 3392, 1692, 1629, 1593, 1538, 1514, 1462, 1227, 1202 and 747 cm−1.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[S:9])[O:8][C:4]=2[CH:3]=1.IC.[C:14](=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([S:9][CH3:14])[O:8][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc2[nH]c(=S)oc2c1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CSc1nc2ccc(C)cc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Methyl-1,3-benzoxazole-2(3H)-thione (375 mg, 2.27 mmol) was dissolved in THF (2.0 mL), and iodomethane (1610.8 mg, 11.35 mmol) and potassium carbonate (627.36 mg, 4.54 mmol) were added. This reaction mixture was stirred vigorously at rt overnight. The reaction mixture was filtered and the solid was rinsed with additional THF. The filtrate was concentrated in vacuo to a yellow solid. The solid was partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried with MgSO4, and concentrated. The solid was dried for 1 h in a 50° C. oven. The product 6-methyl-2-(methylsulfanyl)-1,3-benzoxazole was obtained as yellow solid (145 mg, 35.6%). 1H NMR (300 MHz, DMSO-d6) δ 7.50 (d, 1 H), 7.20 (s, 1 H), 7.10 (d, 1 H), 2.78 (s, 3 H), 2.42 (s, 3 H); LC-MS ret. time 2.90 min (method 2), m/z 180.1 (MH+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:14])[O:8][C@H:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[CH2:2]1.Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=2)[N:19]=[C:18]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[OH:33])[N:17]=1.C(N(CC)CC)C>C(Cl)Cl>[F:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[OH:33])[N:17]=[C:16]2[N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:14])[O:8][C@H:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[CH2:2]1
Reactant: Oc1ccccc1-c1nc(Cl)c2cc(F)ccc2n1
Reactant: O=C(N[C@@H]1CCNC1)O[C@H]1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)C1)O[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
A mixture of (S)-tetrahydrofuran-3-yl (R)-pyrrolidin-3-ylcarbamate (225 mg, 1.12 mmol), 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (250 mg, 0.86 mmol), and triethylamine (0.240 mL, 1.72 mmol) in CH2Cl2 (10 mL) was stirred at room temperature. The reaction was complete in one hour. The reaction was quenched with water, the aqueous layer was extracted twice with CH2Cl2, and the combined organic extracts were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc/CH2Cl2 gave (S)-tetrahydrofuran-3-yl (R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamate (250 mg, 66%). LC/MS: m/z 439.5 (M+H)+ at 2.40 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.43 (dd, J=7.8, 1.5 Hz, 1H), 7.99 (d, J=2.6 Hz, 1H), 7.87-7.91 (m, 1H), 7.74-7.79 (m, 1H), 7.70 (d, J=6.2 Hz, 1H), 7.35-7.39 (m, 1H), 6.91-6.96 (m, 2H), 5.15 (s, 1H), 4.21-4.25 (m, 2H), 4.12-4.14 (m, 1H), 4.01-4.06 (m, 1H), 3.87-3.89 (m, 1H), 3.65-3.78 (m, 4H), 2.02-2.26 (m, 3H), 1.82-1.89 (m, 1H) ppm.
Reaction SMILES: [NH2:1][CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5][C@@H:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1)=[O:4].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:14]1([CH:2]([NH:1][S:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:28])=[O:27])[C:3]([O:5][C@@H:6]2[CH:11]3[CH2:10][CH2:9][N:8]([CH2:13][CH2:12]3)[CH2:7]2)=[O:4])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Solvent: ClCCl
Product: O=C(O[C@H]1CN2CCC1CC2)C(NS(=O)(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
(R)-quinuclidin-3-yl 2-amino-2-phenylacetate (I30) (100 mg, 0.38 mmol) was dissolved in DCM (4 ml) and TEA (0.11 ml, 0.77 mmol). Benzenesulfonyl chloride (59 μl, 0.46 mmol) was added and the solution was stirred at RT for 1 hour. The volatiles were evaporated and the residue was purified by flash chromatography (DCM/MeOH/NH4OH=95/5/0.3) to obtain (R)-quinuclidin-3-yl 2-phenyl-2-(phenylsulfonamido)acetate (101 mg; 66% yield).
Reaction SMILES: B(C1CCCCC1)C1CCCCC1.[CH3:14][C:15]([CH3:19])([CH3:18])[C:16]#[CH:17].[Zn](CC)CC.[CH:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC([O:36]C([C@H](O)[C@@H](O)C(OC(C)C)=O)=O)C>CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:15]([CH:16]1[O:36][CH:17]1[CH:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:32])([CH3:19])([CH3:18])[CH3:14]
Reactant: C#CC(C)(C)C
Reactant: O=Cc1ccccc1
Reactant: CC(C)OC(=O)[C@H](O)[C@@H](O)C(=O)OC(C)C
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: B(C1CCCCC1)C1CCCCC1
Agent: CC[Zn]CC
Product: CC(C)(C)C1OC1C(O)c1ccccc1
Yield: 77 %

Procedure:
The product was prepared by General procedure T using 50 mg (0.28 mmol) Cy2BH, 35 μL (0.28 mmol) 3,3-dimethyl-1-butyne, 0.39 mL (0.78 mmol, 2.0 M in hexanes) Et2Zn, 2.4 mg (0.01 mmol) (−)-MIB, 25 μL (0.25 mmol) benzaldehyde, 50 μL (0.05 mmol, 1.0 M in hexanes) Ti(OiPr)4, and 10.6 μL (0.05 mmol) (+)-DIPT. The crude product was purified by column chromatography (5% ethyl acetate in hexanes) to afford the title compound in 77% yield (40 mg, 0.19 mmol). threo-diastereomer: White solid. m.p.: 70-73° C. [α]D20=−25.6 (c=0.16, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 0.83 (s, 9H), 2.32 (br s, 1H), 2.82 (d, 1H, J=1.6 Hz), 3.01 (dd, 1H, J=5.3, 1.9 Hz), 4.46 (t, 1H, J=4.4 Hz), 7.26 (t, 1H, J=6.9 Hz), and 7.31-7.36 (m, 4H) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 25.7, 30.6, 59.3, 65.1, 74.2, 126.0, 128.0, 128.6, and 140.5 ppm; IR (film): 3413, 3049, 3025, 2955, 2919, 2861, 2355, 1719, 1602, 1478, 1455, 1390, 1360, 1273, 1237, and 1196 cm−1; HRMS-CI m/z 189.1288. [(M−OH)+; calcd for C3H17O: 189.1279]. erythro-diastereomer: White solid. m.p.: 57-59° C.; [α]D20=−27.1 (c=0.31, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 0.82 (s, 9H), 2.20 (br s, 1H), 2.96 (d, 1H, J=2.0 Hz), 3.01 (t, 1H, J=2.7 Hz), 4.82 (br s, 1H), and 7.26-7.32 (m, 5H) ppm; 13 C{1H} NMR (CDCl3, 125 MHz): δ 25.8, 30.4, 58.3, 62.8, 71.2, 126.5, 128.3, 128.6, and 139.8 ppm; IR (film): 3413, 3037, 2955, 2931, 2861, 1719, 1643, 1602, 1449, 1367, and 1327 cm−1; HRMS-CI m/z 189.1288 [(M−OH)+; calcd for C13H17O: 189.1279].
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[N:15]=2)[CH2:10]1.Cl[C:33]([O:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:34].ClC([O-])=O>C1COCC1>[OH:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:16]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][C@@H:9]([NH:8][C:33](=[O:34])[O:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:10]2)[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[N:17]=1
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)(C)COC(=O)Cl
Agent: O=C([O-])Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)OCC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Temperature: -60 °C
Yield: 89.2 %

Procedure:
At RT, triethylamine (260 μL, 1.86 mmol) was added to a solution of (R)-2-(4-(3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (300 mg, 0.93 mmol) in THF (6 mL), and the reaction was cooled to −60° C. external temperature. Neopentyl chloroformate (132 μL in 1.0 mL THF, 0.89 mmol) was added dropwise over a period of 5 minutes. Once the addition of the chloroformate was complete, the reaction mixture was warmed to RT, quenched with H2O, and extracted with CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated. The residue was purified via silica gel chromatography using 0-10% EtOAc in CH2Cl2 to give (R)-neopentyl 1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (compound 9) (345 mg, 85%). 1H NMR (400 MHz, DMSO-d6) δ 8.44-8.42 (m, 1H), 8.18 (d, J=8.6 Hz, 1H), 7.59 (d, J=0.5 Hz, 2H), 7.38-7.32 (m, 2H), 6.94-6.90 (m, 2H), 4.28-4.19 (m, 3H), 4.12-4.01 (m, 1H), 3.89 (d, J=9.0 Hz, 1H), 3.71-3.64 (m, 2H), 2.49 (s, 3H), 2.25-2.20 (m, 1H), 2.06-2.00 (m, 1H), 0.89 (s, 9H) ppm. LC/MS: m/z 435.5 (M+H)+ at 2.73 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:24])=[C:18]([S:20](Cl)(=[O:22])=[O:21])[CH:19]=1>>[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:24])=[C:18]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:21])[CH:19]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cc(F)ccc2C)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 5-fluoro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (32.7 mg) with purity >90%. LCMS (pos) m/z 359.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[CH3:11][C:12]1([CH3:19])[C:16](=[O:17])[CH:15]=[C:14]([CH3:18])[O:13]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:18][C:14]2[O:13][C:12]([CH3:19])([CH3:11])[C:16](=[O:17])[CH:15]=2)[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: CC1=CC(=O)C(C)(C)O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(C=Cc2ccc(F)c(F)c2)=CC1=O
Temperature: 50 °C
Yield: 49.6 %

Procedure:
To a solution of 3,4-difluorobenzaldehyde (1.9 g, 13.2 mM) and 2,2,5-trimethyl-3(2H)-furanone (2.0 g, 15.9 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.6 mL, 1.6 mM). The reaction solution was heated at 50° C. for four hours. After the reaction solution was cooled to room temperature, saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a yellow solid. The crude product was triturated with 10% diethyl ether/pet. ether (50 mL) to give a pale yellow solid (1.66 g, 50% yield), m.p. 105°-106° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.C1C(=O)N([Br:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:20])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: Cc1ccc(Br)cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(Br)ccc1CBr

Procedure:
A solution of commercially available 4-bromo-1-methyl-2-(trifluoromethyl)benzene (1 eq.), NBS (1.1 eq.) and a catalytic amount of benzoyl peroxide in CCl4 (0.21M) was stirred at room temperature for 1 h under a 150 W spot lamp. The mixture was concentrated, purification by column chromatography on silica gel, eluting with Hex, afforded the desired material as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.B(O)(O)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1>>[ClH:1].[Cl:11][C:4]1[CH:3]=[C:2]([C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: Cc1cccc(B(O)O)c1
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Product: Cc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Product: Cl
Yield: 54.4 %

Procedure:
Following General Procedure F, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.300 g, 1.60 mmol) was reacted with 3-tolyboronic acid (0.282 g, 2.07 mmol), followed by the formation of the hydrochloride salt to afford the title compound (0.244 g, 82%) as a white solid. MW=280.19. 1H NMR (CDCl3, 500 MHz) δ 13.97 (s, 1H), 7.97 (s, 1H), 7.91 (d, J=7.5 Hz, 1H), 7.74 (s, 1H), 7.49 (t, J=7.5 Hz, 1H), 7.41 (d, J=7.5 Hz, 1H), 3.84 (t, J=7.6 Hz, 2H), 3.15 (t, J=7.6 Hz, 2H), 2.49 (s, 3H), 2.41-2.37 (m, 2H); APCI MS m/z 244 [M+H]+.
Reaction SMILES: Cl[C:2]1([C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:7])[C:5]([CH3:8])=[CH:4][S:3]1.[CH3:13][OH:14]>>[OH:7][C:6]1[C:5]([CH3:8])=[C:4]([O:14][CH3:13])[S:3][C:2]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: CO
Reactant: COC(=O)C1(Cl)SC=C(C)C1=O
Product: COC(=O)c1sc(OC)c(C)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of (d) above (3 g) was dissolved in 15 ml of methanol and stirred 8 hours at room temperature. The precipitate was filtered and recrystallised from methanol, m.p. 63°-65° C.