Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([Cl:19])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.O1C2C=CC=CC=2CC(=O)N1.[CH3:38][Si:39]([CH2:42][S:43][CH2:44][CH:45]([NH2:47])[CH3:46])([CH3:41])[CH3:40]>O1CCCC1>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:10]([C:11]([NH:47][CH:45]([CH3:46])[CH2:44][S:43][CH2:42][Si:39]([CH3:41])([CH3:40])[CH3:38])=[O:13])=[CH:14][C:15]([Cl:19])=[CH:16][C:17]=2[CH3:18])=[O:12])[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: CC(N)CSC[Si](C)(C)C
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Agent: O=C1Cc2ccccc2ON1
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=O)NC(C)CSC[Si](C)(C)C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 80 °C

Procedure:
To a solution of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the benzoxazinone product of Step E) (0.23 g, 0.51 mmol) in tetrahydrofuran was added 1-trimethylsilylmethylthio-2-propylamine (0.103 g, 0.58 mmol), and the reaction mixture was heated to 80° C. for 3 hours and then cooled to room temperature. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was chromatographed on silica gel with hexanes/ethyl acetate as eluent (5:1) to afford the title compound, a compound of the present invention, as a white solid (73 mg), m.p. 151–153° C.
Reaction SMILES: N1C2C(=CC=CC=2)C=NC=1.O[C@@H](CO)C[CH2:14][O:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[C:18]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:17]=1.[OH:34][CH:35](C(O)C)[CH2:36][O:37]C1C2C(=CC=CC=2)N=C(N2CCNCC2)N=1.O[C@H]([C@@H](O)C)COC1C2C(=CC=CC=2)N=C(N2CCNCC2)N=1.O[C@@H]([C@H](O)C)COC1C2C(=CC=CC=2)N=C(N2CCNCC2)N=1.Cl.C([O-])(=O)C.C([O-])(=O)/C=C/C([O-])=O>>[OH:34][C@H:35]([CH2:36][OH:37])[CH2:14][O:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[C:18]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:17]=1
Reactant: CC(O)C(O)COc1nc(N2CCNCC2)nc2ccccc12
Reactant: OC[C@H](O)CCOc1nc(N2CCNCC2)nc2ccccc12
Agent: CC(=O)[O-]
Agent: C[C@@H](O)[C@H](O)COc1nc(N2CCNCC2)nc2ccccc12
Agent: C[C@H](O)[C@@H](O)COc1nc(N2CCNCC2)nc2ccccc12
Product: OC[C@@H](O)COc1nc(N2CCNCC2)nc2ccccc12

Procedure:
Among the above quinazoline compounds (I-B), preferred ones are (10B) 4-[(3R)-(3,4-dihydroxybutan-1-yl) oxy]-2-(1-piperazinyl)quinazoline, (6B) 4-[(2RS,3RS)-(2,3-dihydroxybutan-1-yl)oxy]-2-(1-piperazinyl)quinazoline, (7B) 4-[(2S,3S)-(2,3-dihydroxybutan-1-yl)oxy]-2-(1-piperazinyl)quinazoline, (8B) 4-[(2R,3R)-(2,3-dihydroxybutan-1-yl)oxy]-2-(1-piperazinyl)quinazoline, and their salts such as hydrochloride, acetate, fumarate, particularly hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27]I>>[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[C:10]([OH:12])=[O:11]
Reactant: ClCCCCI
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: O=C(O)C(CCCCCl)c1ccc(F)c(F)c1
Yield: 88 %

Procedure:
Step AG (1): 2-(3,4-Difluorophenyl)acetic acid (2.5 g, 14.52 mmol) was deprotonated with NaHMDS (1.0 M in THF, 29.0 mL, 29.0 mmol) and reacted with 1-chloro-4-iodobutane (1.78 mL, 14.5 mmol) using a procedure analogous to Step AC (1) to afford 6-chloro-2-(3,4-difluorophenyl)hexanoic acid (3.35 g, 88% yield). LC-MS (M−H)− 261.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[C:12](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH3:12])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.1 %

Procedure:
A mixture of 5-fluoro-2-nitrophenol (3.0 g, 19.1 mmol), potassium carbonate (2.50 g, 21.0 mmol) and dimethyl sulfate (2.65 g, 21.0 mmol) in acetone was stirred at ambient temperature for 24 hours. The solvents were removed under reduced pressure and then water (30 mL) and dichloromethane (30 mL) was added to the residue. The combined organics solutions were dried over magnesium sulfate then filtered and the filtrate concentrated under reduced pressure to provide an oil. This was purified by flash chromatography on silica gel using dichloromethane/heptane (7:3) as an eluent to provide the title compound as a crystalline solid (3.24 g, 100%): 1H NMR (CDCl3, 400 MHz) δ 7.96 (M, 1H), 6.80 (m, 1H), 6.73 (m, 1H), 3.96 (s, 3H); RP-HPLC (Hypersil HS C18, 5 μm, 100 A, 250×4.6 mm; 5%-100% acetonitrile-0.05 M ammonium acetate over 25 min, 1 μL/min) tr 17.82 min; MS: MH+ 172.2
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[O:12]1[CH2:17][CH2:16][CH2:15][CH:14]([CH:18]=O)[CH2:13]1.N1CCCC1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:18]([CH:14]1[CH2:15][CH2:16][CH2:17][O:12][CH2:13]1)[CH2:9][C:8]2=[O:10]
Reactant: O=CC1CCCOC1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: CO
Solvent: C1CCNC1
Product: O=C1CC(C2CCCOC2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.6 %

Procedure:
To a solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (6.069 g, 28.23 mmol) and tetrahydro-2H-pyran-3-carbaldehyde (3.218 g, 28.23 mmol) in MeOH (50 mL) was added pyrrolidine (1.5 mL). The resulting solution was heated to reflux and monitored with LC-MS. 50% conversion was achieved after 2 h. After 12 h, there was no improvement in conversion. The reaction mixture was cooled down to room temperature and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel and eluted with EA in hexane (0-30%) to produce 1.981 g of 6-bromo-2-(tetrahydro-2H-pyran-3-yl)chroman-4-one. 1.321 g of 6-bromo-2-(tetrahydro-2H-pyran-3-yl)chroman-4-one was further purified by preparative HPLC to give (S/R)-6-bromo-2-((S/R)-tetrahydro-2H-pyran-3-yl)chroman-4-one (A) (669 mg, polar isomer on preparative HPLC) and (S/R)-6-bromo-2-((R/S)-tetrahydro-2H-pyran-3-yl)chroman-4-one (B)(512 mg, less polar isomer on preparative HPLC). MS ESI+ve m/z 311 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](=O)[CH3:8])[CH:4]=[N:3]1.[CH2:10]([NH2:13])[CH2:11][NH2:12].C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.O1CCCC1.C(O)(=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([CH:7]([NH:12][CH2:11][CH2:10][NH2:13])[CH3:8])[CH:4]=[N:3]1
Reactant: CC(=O)c1cnn(C)c1
Reactant: NCCN
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(NCCN)c1cnn(C)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.1 %

Procedure:
1-(1-Methyl-1H-pyrazol-4-yl)-ethanone (250 mg) and ethylenediamine (362 mg) were dissolved in methanol (10 ml), the solution was added with acetic acid (1.21 g) and sodium cyanoborohydride (189 mg), and the mixture was stirred at room temperature for 48 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate and tetrahydrofuran, the layers were separated, and then the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol:28% aqueous ammonia=10:1:0.1) to obtain the title compound (163 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][C:12]([NH2:15])=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([S:26](Cl)(=[O:28])=[O:27])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>N1C=CC=CC=1>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([S:26]([NH:15][C:12]2[N:11]=[CH:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[CH:14][N:13]=2)(=[O:27])=[O:28])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc(-c2cnc(N)nc2)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(-c2cnc(NS(=O)(=O)c3ccc(OC)c(OC)c3)nc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.2 %

Procedure:
To a solution of 5-(4-methoxyphenyl)pyrimidin-2-amine (302 mg, 1.5 mmol) in 10 mL of dry pyridine was added 3,4-dimethoxybenzenesulfonyl chloride (398 mg, 1.68 mmol). The solution was stirred at room temperature under Argon. After 24 h, the pyridine was removed in vacuo and flashed off with toluene. The residue was partitioned between EtOAc and 1M HCl. EtOAc phase was washed with water to neutral, dried over Na2SO4 and evaporated in vacuo to give 0.20 g of a solid which was taken up in 4 mL of hot HOAc, diluted with 2 mL of water which initiated crystallization to give 181 mg of product with mp 218-220° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](=O)[CH2:10][C:11]([O:13]C)=[O:12].[C:16]1([N:22]=[N+:23]=[N-:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH3:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[N:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:23]=[N:24][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: [N-]=[N+]=Nc1ccccc1
Reactant: COCCCCC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCCc1c(C(=O)O)nnn1-c1ccccc1
Yield: 52.4 %

Procedure:
A solution of sodium hydride (60% in oil, 2 g) in DMF (50 ml) was cooled to 0° C.-5° C., methyl 7-methoxy-3-oxoheptanoate (9.4 g) was added, and the mixture was stirred at 0° C.-5° C. for min. Phenyl azide (6 g) was added, and the mixture was stirred at room temperature for 15 hr. The solvent was concentrated under reduced pressure, and methanol (100 ml) was added to the residue and 4N aqueous sodium hydroxide solution (20 ml) was further added. The mixture was stirred at 60° C. for 1 hr. The solvent was evaporated under reduced pressure and water (100 ml) was added to the residue. 6N Hydrochloric acid was added for neutralization and the mixture was extracted with ethyl acetate (100 ml×2). The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (7.2 g) as a white powder.
Reaction SMILES: C([O:8][C:9]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=1[C:11]#[N:12])C1C=CC=CC=1>CO>[F:17][C:14]1[CH:15]=[CH:16][C:9]([OH:8])=[C:10]([CH:13]=1)[C:11]#[N:12]
Reactant: N#Cc1cc(F)ccc1OCc1ccccc1
Solvent: CO
Product: N#Cc1cc(F)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 106 %

Procedure:
Dry 10% Pd/C (2.48 g) was placed in a 5 L flask under N2. A solution of 2-(benzyloxy)-5-fluorobenzonitrile (148 g, 651 mmol) in methanol (2.34 L) was added slowly under N2. The air of the flask was removed by vacuum and the flask was charged with H2 (balloon) three times. The mixture was stirred at room temperature for 1 hour. The above process was repeated two more times to push the reaction to completion. The mixture was stirred at room temperature for another 2 hours. The mixture was filtered through a Celite pad under N2 and washed with EtOAc (150 mL×2). The palladium waste was rinsed with water (50 mL) and discarded. The filtrates were concentrated to give (94.6 g, 106%) of the desired compound as a yellow solid. MS (APCI−) m/z 137 (M−1) was detected. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (br, 1H), 7.58 (dd, 1H, J=3.2 Hz, J=8.2 Hz), 7.43 (m, 1H), 6.91-7.03 (dd, 1H J=4.5 Hz, J=9.2 Hz).
Reaction SMILES: [C@H:1]1([C:9]([OH:11])=O)[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.C1(C(O)=O)C2(CCCCC2)C1.[NH2:23][CH2:24][C@@H:25]([OH:27])[CH3:26].Cl.NCC(N)=O>>[OH:27][C@@H:25]([CH3:26])[CH2:24][NH:23][C:9]([C@H:1]1[C:3]2([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:2]1)=[O:11]
Reactant: C[C@H](O)CN
Reactant: O=C(O)[C@@H]1CC12CCCCC2
Agent: Cl
Agent: NCC(N)=O
Agent: O=C(O)C1CC12CCCCC2
Product: C[C@H](O)CNC(=O)[C@@H]1CC12CCCCC2

Procedure:
The title compound was prepared as described in Example 3 substituting the product from Example 9 for the product from Example 1B and substituting (S)-1-amino-2-propanol, purchased from Aldrich, for 2-aminoacetamide hydrochloride. 1H NMR (400 MHz, CD3OD) δ 3.80 (m, 1H), 3.16 (m, 2H), 1.20-1.70 (m, 11H), 1.13 (d, 3H), 1.02 (dd, 1H), 0.69 (dd, 1H); MS (CI) m/z 212 (M+H)+.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH2:7][C:6]1=[O:15].[CH2:17]([CH:22]1[CH2:28][CH:27]2[NH:29][CH:24]([CH2:25][CH2:26]2)[CH2:23]1)[CH2:18][CH2:19][CH2:20][CH3:21]>CC#N>[CH3:16][C@H:3]([CH2:2][N:29]1[CH:24]2[CH2:25][CH2:26][CH:27]1[CH2:28][CH:22]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:23]2)[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH2:7][C:6]1=[O:15]
Reactant: CCCCCC1CC2CCC(C1)N2
Reactant: C[C@H](CI)CN1C(=O)CSc2ccccc21
Solvent: CC#N
Product: CCCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)CSc2ccccc21
Temperature: 40 °C
Reaction time: 120 h
Yield: 48.6 %

Procedure:
The compound (S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]thiazin-3-one (108LM37-34) (0.080 g, 0.231 mmol) and 3-pentyl-8-azabicyclo[3.2.1]octane (104KS32-2) (0.050 g, 0.276 mmol) in MeCN (½ mL) were reacted according to GP10 shaking at 40° C. for 5 days. Purified by cation exchange CC and flash CC (SiO2; MeOH/DCM 1:50+1% Et3N) to give the title compound (108LM52-49) (0.045 g, 49%). 1H NMR (CDCl3) δ 7.36 (d, J=7.6 Hz, 1H), 7.32 (d, J=7.7 Hz, 1H), 7.22 (t, J=7.6 Hz, 1H), 7.00 (t, J=7.6 Hz, 1H), 4.16 (d, J=7.3 Hz, CH2), 3.34 (s, CH2), 3.10-2.95 (m, 2H), 2.25-2.17 (m, 1H), 2.15-2.03 (m, 3H), 1.94-1.75 (m, 3H), 1.70-1.60 (m, 1H), 1.60-1.50 (m, 2H), 1,40-1.15 (m, 10H), 0.90-0.80 (m, 6H); 13C NMR (CDCl3) δ 166.1, 139.2, 128.7, 127.1, 124.7, 123.4, 119.1, 60.5, 59.0, 57.4, 47.5, 38.4, 36.4, 32.2, 32.1, 31,4, 29.9, 28.5, 28.4, 27.9, 27.2, 22.9, 16.7, 14.3; HPLC-MS (ammonium acetate) [M+H]+=401.3.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.[O:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[O:40][NH2:41]>C(Cl)CCl.CN(C=O)C>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([NH:41][O:40][CH:35]3[CH2:36][CH2:37][CH2:38][CH2:39][O:34]3)=[O:19])=[CH:11]2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1)NOC1CCCCO1

Procedure:
Starting materials: (E)-3-[1-(biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-acrylic acid (compound B2) (0.300 g), HOBtH2O (0.130 g), triethylamine (668 μl), DMF (20 ml), EDC?HCl (0.508 g), O-(tetrahydro-2H-pyran-yl)hydroxylamine (0.089 g). Reaction conditions: room temperature, 1 hour; room temperature, 18 hours.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4([OH:23])[CH2:22][CH2:21][CH2:20]4)[N:14]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[CH3:24][O:25][C:26]1[CH:31]=[C:30]([C:2]2[C:3]3[N:11]=[N:10][N:9]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]5([OH:23])[CH2:22][CH2:21][CH2:20]5)[N:14]=4)[C:4]=3[N:5]=[C:6]([NH2:8])[N:7]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Nc1nc(Cl)c2nnn(Cc3cccc(C4(O)CCC4)n3)c2n1
Product: COc1cccc(-c2nc(N)nc3c2nnn3Cc2cccc(C3(O)CCC3)n2)c1
Yield: 16 %

Procedure:
Prepared from 7-chloro-3-{6-[1-hydroxy-1-cyclobutyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and 3-methoxyphenylboronic acid by the method described in Example 7 to give the title compound (0.04 g, 16%).
Reaction SMILES: Cl.C(OC(=O)[NH:8][C:9]1[C:14]([CH2:15][CH3:16])=[CH:13][C:12]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:11][C:10]=1[CH2:24][CH3:25])(C)(C)C>CO>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:12]2[CH:11]=[C:10]([CH2:24][CH3:25])[C:9]([NH2:8])=[C:14]([CH2:15][CH3:16])[CH:13]=2)=[CH:18][CH:19]=1
Reactant: CCc1cc(-c2ccc(Cl)cc2)cc(CC)c1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CCc1cc(-c2ccc(Cl)cc2)cc(CC)c1N
Temperature: 60 °C
Yield: 61.6 %

Procedure:
Concentrated hydrochloric acid (22 ml) is added to a solution of (4′-chloro-3,5-diethylbiphen-4-yl)carbamic acid tert-butyl ester (22 g, 0.06 mol) in methanol (110 ml), and the reaction mixture is heated to 60° C. for 2 hours. The mixture is cooled to room temperature and most of the methanol is removed by evaporation under reduced pressure. The mixture is diluted with water, made basic by addition of 2N aqueous potassium hydroxide solution and extracted with ethyl acetate (3×200 ml). The organic extracts are combined and the solvents are removed under reduced pressure to give 4′-chloro-3,5-diethylbiphen-4-ylamine (9.6 g).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11](=[O:22])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)[CH3:2]>S(Cl)(Cl)=O>[CH2:20]([C:16]1[CH:15]=[C:14]([CH2:13][CH2:12][C:11]2[O:22][C:1]([CH3:2])=[N:4][C:5]=2[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:19]=[CH:18][CH:17]=1)[CH3:21]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)CCc1cccc(CC)c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1nc(C)oc1CCc1cccc(CC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (80 ml) was added to the product from step (v) (21.0 g) at 0° C. The mixture was stirred at room temperature for 1 hour and heated at reflux for 1 hour. The residue after evaporation was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase was dried (MgSO4) and evaporated.
Reaction SMILES: [OH-].[Li+].O1CCCC1.C[O:9][C:10](=[O:38])[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[C:14]([CH2:22][C:23]2[S:27][CH:26]=[N:25][C:24]=2[S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:30])=[O:29])=[C:13]1[CH3:37]>O>[C:31]1([S:28]([C:24]2[N:25]=[CH:26][S:27][C:23]=2[CH2:22][C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[N:12]([CH2:11][C:10]([OH:38])=[O:9])[C:13]=2[CH3:37])(=[O:29])=[O:30])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)Cn1c(C)c(Cc2scnc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cc2scnc2S(=O)(=O)c2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A mixture of lithium hydroxide (0.10 g), tetrahydrofuran (1.0 mL) and water (1.0 mL) was treated [3-(4-benzenesulfonylthiazol-5-ylmethyl)-5-fluoro-2-methylindol-1-yl]acetic acid methyl ester (0.20 g), and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was diluted with water, concentrated to low bulk under reduced pressure and acidified by the addition of 1.0 M aqueous hydrochloric acid solution. The resulting precipitate was collected by filtration, washed with water and dried to afford the title compound as a white solid (0.19 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=O)[CH:7]=1.[CH3:17][NH:18][NH2:19]>O1CCOCC1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:18]([CH3:17])[N:19]=[C:8]2[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(c1cccnc1)c1cc(Br)ccc1F
Reactant: CNN
Solvent: C1COCCO1
Product: Cn1nc(-c2cccnc2)c2cc(Br)ccc21
Temperature: 100 °C

Procedure:
A heavy wall pressure flask was charged with (5-bromo-2-fluorophenyl)(pyridin-3-yl)methanone (3.417 g, 12.2 mmol) and dioxane (30 mL). Methylhydrazine (1.4 mL, 26.6 mmol) was then added, and the mixture was heated to 100° C. for 16 hours. The crude mixture was concentrated, and purified by column chromatography (gradient 0 to 55% EtOAc in hexanes) to give the product. 1H NMR (400 MHz, CDCl3) δ 9.19 (d, J=2.1 Hz, 1H), 8.65 (dd, J=4.9, 1.5 Hz, 1H), 8.28 (d, J=8.0 Hz, 1H), 8.13 (d, J=1.6 Hz, 1H), 7.54 (dd, J=8.9, 1.7 Hz, 1H), 7.49 (dd, J=8.0, 4.9 Hz, 1H), 7.35 (d, J=8.9 Hz, 1H), 4.15 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[CH:32]=[C:31]([CH3:33])[N:30]=[C:29]([NH2:34])[N:28]=2)=[CH:22][CH:21]=1.N>O1CCOCC1>[NH2:34][C:29]1[N:28]=[C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:8](=[O:9])[C:7]3[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[CH:21][CH:22]=2)[CH:32]=[C:31]([CH3:33])[N:30]=1
Reactant: Cc1cc(Nc2ccc(N)cc2)nc(N)n1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: N
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2ccc(NC(=O)c3ccc([N+](=O)[O-])cc3)cc2)nc(N)n1
Temperature: 50 °C
Yield: 46.7 %

Procedure:
4-Nitrobenzoyl chloride (11.00 g, 0.06 mol) and dry pyridine (9.08 mL, 0.11 mol) were sequentially added to a solution of amine E3 (4.85 g, 0.02 mol) in dry dioxane (200 mL), and the resulting solution heated at ˜50° C. for 5 d. After this time, the reaction mixture was cooled to room temperature, and then basified by addition of aqueous ammonia solution. The resulting suspension was filtered through a pad of Celite to afford amide E4 as an amorphous yellow solid (3.40 g, 41%). 1H NMR [(CD3)2SO]: 2.09 [s, 3H, ArCH3], 5.87 [s, 1H, ArNHAr], 6.08 [br s, 6.08, ArNH2], 7.68 [m, 4H, ArH], 8.18 [d, J=8.80 Hz, 2H, ArH], 8.36 [d, J=8.80 Hz, 2H, ArH], 8.95 [s, 1H, ArH], 10.45 [s, 1H, ArC(O)NHAr]. LCMS (APCI+): 365 (100%).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([C:26]2[O:30][N:29]=[C:28]([CH:31]=O)[CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:31][C:28]2[CH:27]=[C:26]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:30][N:29]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cc(-c2ccccc2)on1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cc(-c2ccccc2)on1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 5-phenylisoxazole-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.85 min.; [M+H]+: 393.12 g/mol.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:42]/[CH:43]=[CH:44]\[C:45]([CH3:55])([O:47][Si:48]([CH2:53][CH3:54])([CH2:51][CH3:52])[CH2:49][CH3:50])[CH3:46]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:42]/[CH:43]=[CH:44]\[C:45]([CH3:55])([O:47][Si:48]([CH2:51][CH3:52])([CH2:53][CH3:54])[CH2:49][CH3:50])[CH3:46])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC[Si](CC)(CC)OC(C)(C)/C=C\CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)/C=C\CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 97.8 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-Butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5(10 μl) and (Z)-1-bromo-4-methyl-4-triethylsilyloxy-2-pentene (125 mg, 0.428 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=30:1, developed once) to give the title compound as a colorless oil (80.7 mg, 98%).