Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[N+:5]([O-])[CH:4]=[C:3]([CH2:8][C:9]#[N:10])[CH:2]=1.C[Si]([C:15]#[N:16])(C)C.CN(C)C(Cl)=O>C(Cl)Cl>[C:9]([CH2:8][C:3]1[C:4]([C:15]#[N:16])=[N:5][CH:6]=[CH:1][CH:2]=1)#[N:10]
Reactant: N#CCc1ccc[n+]([O-])c1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: ClCCl
Product: N#CCc1cccnc1C#N
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.9 %

Procedure:
To a suspension of (1-oxy-pyridin-3-yl)-acetonitrile (10 g, 75 mmol) in anhydrous CH2Cl2 under a nitrogen atmosphere was added trimethylsilylcyanide (10.95 mL, 82 mmol) and dimethylcarbamoylchloride (7.55 mL, 82 mmol). The reaction mixture was stirred at room temperature for 72 hours and then concentrated. EtOAc (100 mL) was added to the residue and the organic phase was washed with 1 M NaOH (150 mL), dried over Na2SO4, filtered and concentrated. The resulting solid was purified by column chromatography (50% EtOAc/hexanes) affording 7.08 g (66%) of a yellow solid: mp 48-51° C.; MS(+)APCI m/z 144 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([O:10][C:11]([C:13]12[C:24]3([CH:26]=[O:27])[CH2:25][CH:16]([C:17]1([CH2:29][O:30][C:31]14[CH:43]([O:44][Si](C(C)(C)C)(C)C)[CH:37]5[CH:38]([O:39][CH2:40][CH2:41][CH3:42])[CH:33]([CH:34]([O:36]5)[O:35]1)[O:32]4)[CH2:18][CH:19]1[CH:23]3[CH2:22][CH2:21][CH:20]1[CH3:28])[CH:15]=[C:14]2[CH:52]([CH3:54])[CH3:53])=[O:12])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[CH3:1][C:2]([O:10][C:11]([C:13]12[C:24]3([CH:26]=[O:27])[CH2:25][CH:16]([C:17]1([CH2:29][O:30][C:31]14[CH:43]([OH:44])[CH:37]5[CH:38]([O:39][CH2:40][CH2:41][CH3:42])[CH:33]([CH:34]([O:36]5)[O:35]1)[O:32]4)[CH2:18][CH:19]1[CH:23]3[CH2:22][CH2:21][CH:20]1[CH3:28])[CH:15]=[C:14]2[CH:52]([CH3:53])[CH3:54])=[O:12])([CH3:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(C)(C)c4ccccc4)OC2OC1C3O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(C)(C)c4ccccc4)OC2OC1C3O
Reaction time: 2 h
Yield: 89.6 %

Procedure:
21 mg of compound (30) was mixed with 53.2 μl of 1M tetrabutylammonium fluoride-tetrahydrofuran solution, and the reaction was conducted at room temperature under stirring for 2 hours. The reaction solution was charged onto a silica gel column (Kieselgel 60, Merck, 1.0φ×30 cm) and eluted with n-hexane-ethyl acetate (2:1). The fraction containing the desired product was concentrated to dryness to give 16 mg of compound (31).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([C:13]#[C:14][NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9]C=1>CN1CCCC1=O.O>[C:13]1([C:14]2[NH:15][C:16]3[C:17]([CH:1]=2)=[CH:18][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:20][CH:21]=3)[CH:9]=[CH:10][CH:11]=[CH:12][CH:7]=1
Reactant: FC(F)(F)Oc1ccc(NC#Cc2ccccc2)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: FC(F)(F)Oc1ccc2[nH]c(-c3ccccc3)cc2c1
Yield: 83.8 %

Procedure:
To a solution of potassium tert-butoxide (173 mg) in 1-methyl-2-pyrrolidone (3.7 mL) was added dropwise a solution of 2-phenylethynyl-4-trifluoromethoxyaniline (204 mg) in 1-methyl-2-pyrrolidone (3.7 mL) at room temperature under stirring, and the mixture was stirred for 6 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (171 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29]C)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=1[CH:15]=[N:16][NH:17]3)[C:7]([C:23]([F:26])([F:25])[F:24])([OH:22])[CH2:6][C:5]2([CH3:28])[CH3:27].B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]([NH:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[N:16][NH:17]4)[C:7]([C:23]([F:25])([F:26])[F:24])([OH:22])[CH2:6][C:5]([CH3:27])([CH3:28])[C:4]=2[C:3]=1[OH:29]
Reactant: COc1c(Cl)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2[nH]ncc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3[nH]ncc23)c2ccc(Cl)c(O)c21
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.5 %

Procedure:
69.9 mg (0.159 mmol) of 6-chloro-1-[(1H-indazol-4-yl)amino]-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol is mixed with 1.45 ml of a one-molar solution of BBr3 in dichloromethane, and it is stirred for five hours at room temperature. After the usual working-up, the residue is chromatographed on a Flashmaster. 28.1 mg (41.5%) of the desired compound is isolated.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([N+:18]([O-])=O)=[CH:13][C:12]=1[OH:21])[CH2:8]2>CCO.[Pd]>[CH:3]12[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]([CH2:10]3)[CH:2]1[C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([NH2:18])=[CH:13][C:12]=1[OH:21])[CH2:9]2
Reactant: Cc1cc(C2C3CC4CC(C3)CC2C4)c(O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C2C3CC4CC(C3)CC2C4)c(O)cc1N
Reaction time: 8 h

Procedure:
To a solution of 2-admantyl-4-methyl-5-nitrophenol (231 mg, 1.6 mmol) in EtOH (2 mL) was added Pd-5% wt on carbon (10 mg). The mixture was stirred under H2 (1 atm) overnight and then filtered through Celite. The filtrate was evaporated to dryness to provide 2-admantyl-4-methyl-5-aminophenol (C-12), which was used without further purification. HPLC ret. time 2.52 min, 10-99% CH3CN, 5 min run; ESI-MS 258.3 m/z (MH+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[O:6][C:7]1[N:16]=[CH:15][C:14]2[CH:13]=[CH:12][C:11]3[C:17]([C:21]([NH2:23])=[O:22])=[N:18][N:19]([CH3:20])[C:10]=3[C:9]=2[N:8]=1)=O.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C([BH3-])#N.[Na+]>CN(C)C=O.C(O)(=O)C.C(OCC)(=O)C>[CH3:20][N:19]1[C:10]2[C:9]3[N:8]=[C:7]([O:6][C:5]4[CH:24]=[CH:25][CH:26]=[C:3]([CH2:1][N:31]5[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]5)[CH:4]=4)[N:16]=[CH:15][C:14]=3[CH:13]=[CH:12][C:11]=2[C:17]([C:21]([NH2:23])=[O:22])=[N:18]1
Reactant: Cn1nc(C(N)=O)c2ccc3cnc(Oc4cccc(C=O)c4)nc3c21
Reactant: CN1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCN(Cc2cccc(Oc3ncc4ccc5c(C(N)=O)nn(C)c5c4n3)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 8-(3-formylphenoxy)-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide 30 mg (0.086 mmol) in N,N-dimethylformamide (2 ml) and acetic acid (50 μl), N-methyl piperazine (13 μl, 0.13 mmol), and sodium cyanoborohydride (6 mg, 0.26 mmol) were added. The solution was stirred at r.t. for 3 hours, monitored by both TLC and LC/MS (method 1). The reaction was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4 filtered and concentrated. The residue was purified by column (DCM/MeOH/NH4OH 95/5/0.1) to give 1-methyl-8-{3-[(4-methylpiperazin-1-yl)methyl]phenoxy}-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide as major (15 mg 40%) LC/MS (254 nm) HPLC method 2 Rt 4.14 min. 1H NMR (401 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.23 (d, J=8.79 Hz, 1H), 7.83 (s, 1H), 7.78 (d, J=8.79 Hz, 1H), 7.49-7.50 (m, 1H), 7.46 (t, J=7.81 Hz, 1H), 7.26 (dt, J=1.71, 7.69 Hz, 3H), 4.27 (s, 3H), 3.53 (s, 2H), 2.30-2.47 (m, 8H), 2.17 (br. s., 3H). HRMS (ESI) calcd for C23H25N7O2 [M+H]+ 432.2143 found 432.2141; and
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:16])=O>CN(C)C1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:16])=[N:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nc2cc(Br)ccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cc1nc(Cl)c2ccc(Br)cc2n1
Temperature: 60 °C
Yield: 60.2 %

Procedure:
A suspension of 0.45 g (1.87 mmol) of 7-bromo-2-methyl-3H-quinazolin-4-one in 0.48 ml N,N-dimethylaniline was treated with 1.41 ml (15.4 mmol) phosphorous oxychloride and heated at 60° C. for 2 h. The reaction mixture was evaporated in vacuo and the residue taken up in 20 ml water, neutralized with 10 ml saturated aqueous sodium bicarbonate and twice extracted with 25 ml dichloromethane. The organic layer is washed with 25 ml water, 25 ml brine, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by chromatography on silica gel with heptane/ethylacetate (2:1) to give 0.29 g (59%) of 7-bromo-4-chloro-2-methyl-quinazoline as an orange solid. Mp. >82° C. EI mass spectrum, m/e: 258 (M calculated for C9H6BrClN2: 258).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][CH3:15])[CH2:12][O:11][C@H:10]([C:16]([OH:18])=O)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH2:14]([C@H:13]1[N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9][C@@H:10]([C:16]([NH:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])[O:11][CH2:12]1)[CH3:15]
Reactant: CC[C@@H]1CO[C@H](C(=O)O)CN1C(=O)OC(C)(C)C
Reactant: NCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC[C@@H]1CO[C@H](C(=O)NCc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.1 %

Procedure:
To (2S,5R)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-5-ethyl-2-morpholinecarboxylic acid (0.390 g, 1.504 mmol) in CH2Cl2 (10 mL) were added benzylamine (0.164 mL, 1.504 mmol), HOAt (0.205 g, 1.504 mmol) and EDC (0.346 g, 1.805 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was washed with H2O (3×) and the organics were then dried over Na2SO4 and concentrated to afford the title compound (0.551 g). LC-MS (ES) m/z=249 [M+H-Boc]+.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH:17]=O)[CH2:6][CH2:5][C:4](=[O:19])[NH:3]1>O>[N:16]1[C:11]2[C:10](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][N:8]([CH:7]2[CH2:6][CH2:5][C:4](=[O:19])[NH:3][C:2]2=[O:1])[CH:17]=1
Reactant: O=CNc1ccccc1CNC1CCC(=O)NC1=O
Solvent: O
Product: O=C1CCC(N2C=Nc3ccccc3C2)C(=O)N1

Procedure:
A solution of 0.91 g of the product from stage 2 in 5 ml of distilled water was stirred for 24 hours at 20° C. The reaction solution was then evaporated to dryness in vacuo. The remaining solid was triturated with diethyl ether, 0.85 g (99% of theory) of the title compound remaining as a yellow powder.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[CH:13]=[N:14][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:16][CH:17]=3)=[C:7]2[N:6]=[C:5]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:4]=1[C:30](=[O:32])[CH3:31].CCN(C(C)C)C(C)C.[C:42](O)(=[O:46])[C@@H:43]([CH3:45])[OH:44].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[C:30]([C:4]1[C:5]([CH:24]2[CH2:25][CH2:26][N:27]([C:42](=[O:46])[C@H:43]([OH:44])[CH3:45])[CH2:28][CH2:29]2)=[N:6][C:7]2[N:8]([N:9]=[CH:10][C:11]=2[C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:17]=2)[C:3]=1[NH2:2])(=[O:32])[CH3:31]
Reactant: C[C@@H](O)C(=O)O
Reactant: CC(=O)c1c(C2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)c1c(C2CCN(C(=O)[C@@H](C)O)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-(7-amino-3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone hydrochloride (0.5 mmol), DIEA (350 μL, 2 mmol) in DMF (5 mL) was added a solution of D-lactic acid (45 mg, 0.5 mmol), HOBt (68 mg, 0.5 mmol), EDCI (144 mg, 0.75 mmol) in DMF (1 mL). The reaction was stirred at rt for 20 min. Another solution of solution of D-lactic acid (45 mg, 0.5 mmol), HOBt (68 mg, 0.5 mmol), EDCI (144 mg, 0.75 mmol) in DMF (2 mL) was added and stirred for 5 minutes. LC-MS indicated the reaction was complete and reaction mixture was directly purified by HPLC to furnish the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([C:17]3[N:18]=[CH:19][N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:21]=3)=[O:16])[CH:11]=2)[CH:6]=1)=[O:4].[CH2:41]([Mg]Br)[CH:42]([CH3:44])[CH3:43]>C1COCC1>[OH:16][C:15]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:14]=[CH:13]2)([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)[CH2:41][CH:42]([CH3:44])[CH3:43]
Reactant: CC(C)C[Mg]Br
Reactant: CNC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2cc(C(O)(CC(C)C)c3c[nH]cn3)ccc2c1

Procedure:
The similar reaction as described in Example 50-(i) was carried out by using N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide (500 mg) and isobutyl-magnesium bromide in THF (1M; 5 mL) to give the titled compound (188 mg) as colorless powder.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]([CH3:20])[C:8]([NH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)=[O:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:45][C:46]1[CH:51]=[C:50]([F:52])[CH:49]=[CH:48][C:47]=1[NH:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57].CN1CCOCC1>CN(C=O)C.O.C(#N)C>[F:52][C:50]1[CH:49]=[CH:48][C:47]([NH:53][C:54](=[O:60])[O:55][C:56]([CH3:57])([CH3:59])[CH3:58])=[C:46]([NH:45][C:15](=[O:17])[C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[CH:7]([N:3]3[CH2:4][CH2:5][CH2:6][C:2]3=[O:1])[CH3:20])=[CH:19][CH:18]=2)[CH:51]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1N
Reactant: CC(C(=O)Nc1ccc(C(=O)O)cc1)N1CCCC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: CC(C(=O)Nc1ccc(C(=O)Nc2cc(F)ccc2NC(=O)OC(C)(C)C)cc1)N1CCCC1=O
Temperature: 55 °C
Reaction time: 40 h

Procedure:
To the 4-(2-(2-oxopyrrolidin-1-yl)propanamido)benzoic acid (210 mgs, 0.76 mmol) in DMF (2 mL), was added HATU (375 mg, 0.99 mmol), tert-butyl 2-amino-4-fluorophenylcarbamate (172 mg, 0.76 mmol) and NMM (0.3 mL, 2.3 mmol) and stirred at 55° C. for 40 hours. The reaction mixture was then diluted with water and acetonitrile and the precipitate formed was then filtered, washed with water and dried. The solid was then purified by column chromatography on silica gel with elution using 80% ethyl acetate/hexanes to give tert-butyl 4-fluoro-2-(4-(2-(2-oxopyrrolidin-1-yl)propanamido)benzamido)phenylcarbamate.
Reaction SMILES: [OH:1][C@@H:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:4]=2[C@H:3]1[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[CH:18][C:17]1=[O:31].N1C=CC=CC=1.[C:38](OC(=O)C)(=[O:40])[CH3:39].O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:38]([O:1][C@@H:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:4]=2[C@H:3]1[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[CH:18][C:17]1=[O:31])(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](n2ccc(CO[Si](C)(C)C(C)(C)C)cc2=O)[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1[C@H](n2ccc(CO[Si](C)(C)C(C)(C)C)cc2=O)c2cc(C#N)ccc2OC1(C)C

Procedure:
In 15 ml of anhydrous methylene chloride, is dissolved 1.32 g of trans-3-hydroxy-6-cyano-3,4-dihydro-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-t-butyldimethylsilyloxymethyl-1-pyridinyl)-2H-benzo[b]pyran obtained in Example 1. Then, 0.49 ml of pyridine and 73 mg of 4-dimethylaminopyridine are added. Then, 0.43 ml of acetic anhydride is dropped thereinto at 0° C. and reacted at room temperature for 30 minutes. After stopping the reaction by adding water to the reaction mixture, it is extracted with ether. The organic layer is successively washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography using 1/3 mixture of ethyl acetate/methylene chloride as a developing solvent to obtain 1.45 g of trans-3-acetoxy-6-cyano-3,4-dihydro-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-t-butyldimethylsilyloxymethyl-1-pyridinyl)-2H-benzo[b]pyran.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:6]=1)([F:4])[CH3:3].[C:19](=[O:28])([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)N>>[F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:19](=[O:28])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:6]=1)([F:4])[CH3:3]
Reactant: NC(=O)Oc1ccccc1
Reactant: COc1ccc(-n2nc(C(C)(F)F)cc2N)cc1
Product: COc1ccc(-n2nc(C(C)(F)F)cc2NC(=O)Oc2ccccc2)cc1
Yield: 64 %

Procedure:
3-(1,1-difluoroethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-amine was converted to the phenyl carbamate using the procedure for Example 282A Step 2. Purification using silica gel chromatography eluting with EtOAc/hexane (5-40%) afforded phenyl 3-(1,1-difluoroethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-ylcarbamate in 64% yield. LC-MS (ESI) m/z 374 (M−H)−
Reaction SMILES: C[O:2][C:3](=[O:44])[CH:4]=[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12](S(C1C=CC=CC=1)(=O)=O)[CH:11]=[C:10]2[C:25]1[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:28]=[C:27]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:26]=1[O:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH3:6].[OH-].[Na+]>CO.O1CCOCC1.Cl>[CH2:40]([O:39][C:26]1[C:27]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:28][C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:30][C:25]=1[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:5]([CH3:6])=[CH:4][C:3]([OH:44])=[O:2])[CH:8]=2)[NH:12][CH:11]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCOc1c(-c2cn(S(=O)(=O)c3ccccc3)c3ccc(C(C)=CC(=O)OC)cc23)cc(C(C)(C)C)cc1C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1c(-c2c[nH]c3ccc(C(C)=CC(=O)O)cc23)cc(C(C)(C)C)cc1C(C)(C)C
Yield: 115.5 %

Procedure:
3-[1-Benzenesulfonyl-3-(2-butoxy-3,5-di-tert-butyl-phenyl)-1H-indol-5-yl]-but-2-enoic acid methyl ester (187 mg, 0.3 mmol) was dissolved in methanol (2 mL)/dioxane (3.5 mL) and treated with 1N NaOH (2 mL) at 60° C. for 4 h. Diluted with 1N HCl (3 mL) and extracted with ethyl acetate (3×10 mL). The combined organic portions were washed with water (10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to provide 160 mg of an orange solid. The material was purified using radial chromatography (eluet: hexane/ethyl acetate gradient) to provide 85 mg (62%) of a yellow foam. 1H NMR (250 MHz, CDCl3): δ 8.24 (bs, 1H), 7.88 (s, 1H), 7.40-7.35 (m, 3H), 7.28 (d, 2H), 6.18 (s, 1H), 3.37 (t, 2H, J=6.5), 2.61 (s, 3H), 1.41 (s, 9H), 1.28 (s, 9H), 1.19-0.98 (m, 4H), 0.56 (t, 3H, J=7.2). MS [EI+] 462 M+H)+, [EI−] 460 (M−H)+. Anal. Calcd for C30H39NO3: C, 78.05; H, 8.52; N, 3.03. Found: C, 78.10; H, 8.30; N, 3.02.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:15]=[C:14]([OH:16])[CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:16][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:9])[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc(Cl)n1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cccc(OCc2ccccc2)n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Add benzyl bromide (1 mL, 8.38 mmol) to a solution of 6-chloropyridin-2-ol (2 g, 15.4 mmol), potassium carbonate (3.41 g, 24.7 mmol) in DMF (20 mL) heat to 80° C. and stir for two hours. Quench reaction mixture with water, then extract three times with 20 mL EtOAc. Combine the organic washings and wash with water (20 mL); dry over sodium sulphate; filter; collect the filtrate; and concentrate under vacuum. Purify via normal phase silica gel flash column chromatography using a gradient of 0-50% ethyl acetate in petroleum ether to give the title compound as a clear oil. MS: (m/z): 220 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Cl[CH2:16][CH2:17][O:18][CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:19][O:18][CH2:17][CH2:16][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: COCCCl
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Yield: 100 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 0.52 mmol), 1-chloro-2-methoxyethane (0.056 mL, 0.62 mmol) and cesium carbonate (252 mg, 0.73 mmol) in DMF (1 mL) were heated in microwave reactor at 160° C. for 30 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (ISCO, hexanes/ethyl acetate 0-100% over 15 min) to isolate Compound B162a (130 mg, 100% yield). HPLC: RT=1.0 min (LCMS Method M). MS (ES): m/z=253.0 [M+H]+. 1H NMR (500 MHz, CHLOROFORM-d) δ 8.04 (s, 1H), 7.83 (d, J=18.4 Hz, 1H), 4.37 (t, J=5.2 Hz, 1H), 3.78 (t, J=5.2 Hz, 1H), 3.38-3.31 (m, 2H), 2.98 (s, 3H), 2.90 (s, 3H), 1.34 (s, 6H), 1.26 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[C:9]1[C:18]1[C:19]2[S:32][C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:30][C:20]=2[N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:45][CH2:46][CH2:47][CH2:48]Br>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:48][CH2:47][CH2:46][Br:45])[CH:15]=2)[CH:10]=[C:9]1[C:18]1[C:19]2[S:32][C:31]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:30][C:20]=2[N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:22]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(O)cc3n2C(=O)OC(C)(C)C)c2sc(-c3ccccc3)cc21
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(OCCCBr)cc3n2C(=O)OC(C)(C)C)c2sc(-c3ccccc3)cc21
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
A mixture of 2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-hydroxy-indole-1-carboxylic acid tert-butyl ester [950 mg, 1.79 mmol, Intermediate (49)], cesium carbonate (1.75 g, 5.37 mmol), and 1,3-dibromopropane (6.0 mL) was heated at 90° C. under nitrogen. After 1.5 hours, the mixture was cooled to ambient temperature, filtered, and the insolubles washed twice with dichloromethane (10 mL). The filtrate was concentrated in vacuo to yield a cloudy oil. The crude product was chromatographed on silica, eluting first with 80% dichloromethane/heptane and then 100% dichloromethane to give 6-(3-bromo-propoxy)-2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester [760 mg, 65%, intermediate 50] as a white foam. TLC Rf 0.37 (silica, dichloromethane); LC/MS: 674 (M+Na), RT=2.60 minutes.
Reaction SMILES: [CH3:1][C:2]1([C:5](O)=O)[CH2:4][CH2:3]1.[NH2:8][NH:9][C:10]([NH2:12])=[S:11].P(Cl)(Cl)(Cl)=O>>[CH3:1][C:2]1([C:5]2[S:11][C:10]([NH2:12])=[N:9][N:8]=2)[CH2:4][CH2:3]1
Reactant: NNC(N)=S
Reactant: CC1(C(=O)O)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(c2nnc(N)s2)CC1

Procedure:
Commercially available, 1-methyl-cyclopropane-1-carboxylic acid (Aldrich), thiosemicarbazide (Aldrich) and phosphorus oxychloride (Aldrich) were processed as described for Example 1A to obtain the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.84-0.93 (m, 2H), 0.93-1.03 (m, 2H), 1.41 (s, 3H), 6.94 (s, 2H); MS (ESI+) m/z 156 (M+H)+.