Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]([OH:29])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=[CH:18][CH:19]=1>O.S(=O)(=O)(O)O.CCOCC>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:20](=[O:29])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: COc1cccc(C(O)CCc2ccccc2)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: COc1cccc(C(=O)CCc2ccccc2)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
14.9 g (0.05 mole) of potassium dichromate in a mixture of 50 ml of water and 10 ml of concentrated sulfuric acid were added to a solution of 34 g (0.14 mole) of 1-(3-methoxyphenyl)-3-phenylpropan-1-ol in 500 ml of ether while cooling with ice and stirred overnight at 20° C. The aqueous, green phase was separated and extracted twice with 100 ml of ether each time. The combined ether extracts were dried over sodium sulfate and the solvent was then removed in vacuo. 28.0 g (83%) of the compound 1-(methoxyphenyl)-3-phenylpropan-1-one were obtained as a yellow oil, which was reacted further without prior purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:21])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[CH:4][CH:3]=1.C([Li])CCC.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:11]([CH3:21])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: Cn1cnc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1-methylimidazole (100 mg, 0.30 mmol) from Step C in THF (4 mL) cooled to −70° C. in a dry ice/acetone bath was added 1.6N n-butyl lithium in hexanes (0.22 mL, 0.36 mmol). The reaction was stirred for 1 hr and then ethyl chloroformate (0.060 mL, 60 mmol) was added via syringe. The reaction was allowed to warm to rt for 1 hr and was then quenched with aq. sodium bicarbonate and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by Prep TLC (2×1 mm, silica) (25% ethyl acetate in hexanes) to afford the title compound.
Reaction SMILES: BrC1C=C(N2C3=NC=CC(C4C=C5C=CN(C[O:29]C)C5=NC=4)=C3C(C(C)C)=N2)C=CC=1C#N.[OH:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42]2[CH:49]=[C:48]([N:50]3[C:54]4=[N:55][CH:56]=[CH:57][C:58]([C:59]5[CH:60]=[C:61]6[CH:67]=[CH:66][N:65]([CH2:68][O:69][CH3:70])[C:62]6=[N:63][CH:64]=5)=[C:53]4[C:52]([CH:71]([CH3:73])[CH3:72])=[N:51]3)[CH:47]=[CH:46][C:43]=2[C:44]#[N:45])[CH2:37][CH2:36]1>>[OH:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42]2[CH:49]=[C:48]([N:50]3[C:54]4=[N:55][CH:56]=[CH:57][C:58]([C:59]5[CH:60]=[C:61]6[CH:67]=[CH:66][N:65]([CH2:68][O:69][CH3:70])[C:62]6=[N:63][CH:64]=5)=[C:53]4[C:52]([CH:71]([CH3:73])[CH3:72])=[N:51]3)[CH:47]=[CH:46][C:43]=2[C:44]([NH2:45])=[O:29])[CH2:37][CH2:36]1
Reactant: COCn1ccc2cc(-c3ccnc4c3c(C(C)C)nn4-c3ccc(C#N)c(Br)c3)cnc21
Reactant: COCn1ccc2cc(-c3ccnc4c3c(C(C)C)nn4-c3ccc(C#N)c(N[C@H]4CC[C@H](O)CC4)c3)cnc21
Product: COCn1ccc2cc(-c3ccnc4c3c(C(C)C)nn4-c3ccc(C(N)=O)c(N[C@H]4CC[C@H](O)CC4)c3)cnc21

Procedure:
According to Example 1(6), a crude product of 2-(trans-4-hydroxycyclohexylamino)-4-{(3-isopropyl-4-(1-methoxymethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile was prepared using compound (15a) instead of compound (1e) and was used in the subsequent reaction without being purified. According to Example 1(7), compound (15) (the second stage yield: 45%) was prepared as a white solid using 2-(trans-4-hydroxycyclohexylamino)-4-{3-isopropyl-4-(1-methoxymethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile instead of compound (1f).
Reaction SMILES: C(C=C(F)F)(F)(F)[F:2].[C:9]([CH2:13][C:14](F)([F:16])[F:15])([F:12])([F:11])[F:10]>>[FH:2].[C:9]([CH:13]=[C:14]([F:16])[F:15])([F:12])([F:11])[F:10]
Reactant: FC(F)(F)CC(F)(F)F
Agent: FC(F)=CC(F)(F)F
Product: F

Procedure:
The present process produces a 1:1 molar mixture of HF and CF3CH═CF2 in the reactor exit stream. The reactor exit stream can also contain unconverted reactant, CF3CH2CF3. The components of the reactor exit stream can be separated by conventional means, such as distillation. Hydrogen fluoride and CF3CH═CF2 form a homogenous low-boiling azeotrope containing about 60 mole percent CF3CH═CF2. The present process reactor exit stream can be distilled and the low-boiling HF and CF3CH═CF2 azeotrope taken off as a distillation column overhead stream, leaving substantially pure CF3CH2CF3 as a distillation column bottom stream. Recovered CF3CH2CF3 reactant may be recycled to the reactor. CF3CH═CF2 can be separated from its azeotrope with HF by conventional procedures, such as pressure swing distillation or by neutralization of the HF with caustic.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]([CH2:8][CH2:9][C:10](O)=O)=[CH:6][CH:7]=1)#[N:2].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:20](=[O:30])[C:21]1[CH:26]=[CH:25][C:24]([NH:27][CH3:28])=[C:23]([NH2:29])[CH:22]=1>ClCCl.CO>[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:20]([C:21]1[CH:26]=[CH:25][C:24]2[N:27]([CH3:28])[C:10]([CH2:9][CH2:8][C:5]3[S:4][C:3]([C:1]#[N:2])=[CH:7][CH:6]=3)=[N:29][C:23]=2[CH:22]=1)=[O:30]
Reactant: N#Cc1ccc(CCC(=O)O)s1
Reactant: CCOC(=O)CCN(C(=O)c1ccc(NC)c(N)c1)c1ccccn1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)s1)n2C)c1ccccn1
Yield: 18 %

Procedure:
Prepared analogously to Example 25c from 3-(2-cyanothiophen-5-yl)-propionic acid and 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide. Yield: 18% of theory, Rf value: 0.66 (silica gel; dichloromethane/methanol=9:1)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CN(C)C=O>[CH:12]1([NH:18][C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)cc1NC1CCCCC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 19.1 %

Procedure:
A mixture of 15.09 g (78 mmol) 2,4-dichloronitrobenzen, 7.7 g (78 mmol) cyclohexylamine, 7.9 g (78 mmol) triethylamine and 100 ml dimethylformamide was stirred at 80° C. for 3 h. After cooling to 25° C. the mixture was evaporated, dissolved in 200 ml ether and filtered. The ether solution was washed with water and evaporated to the half volume. The precipitate was filtered off to give 3.8 g (19%) N-cyclohexyl-2-nitro-5-chloraniline. M.p. 124.5° C. 1H-NMR (CDCl3): 8.2 (2H, m), 6.8 (1H, d), 6.5 (1H, dd), 3.5 (1H, broad s), 2.4-0.8 (10H, m).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:20]=[CH:19][C:9]2[N:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:11](=[O:13])[O:12][C:8]=2[CH:7]=1)(=[O:4])=[O:3].Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[O:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][N:5]([C:6]2[CH:20]=[CH:19][C:9]3[N:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:11](=[O:13])[O:12][C:8]=3[CH:7]=2)[S:2]([CH3:1])(=[O:3])=[O:4])[CH2:26][CH2:27]1
Reactant: ClCCN1CCOCC1
Reactant: COC(=O)Cn1c(=O)oc2cc(NS(C)(=O)=O)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cn1c(=O)oc2cc(N(CCN3CCOCC3)S(C)(=O)=O)ccc21
Temperature: 100 °C
Yield: 82.3 %

Procedure:
To a solution of methyl 2-(6-(methylsulfonamido)-2-oxobenzo[d]oxazol-3(2H)-yl)acetate (300 mg, 0.999 mmol) (prepared in an analogous manner as described in Example 24, Scheme 24, Steps 1, 2, 3) in CH3CN (15 ml), 4-(2-chloroethyl)morpholine hydrochloride (186 mg, 0.999 mmol) and K2CO3 (138 mg, 0.999 mmol) were added. The mixture was heated at 100° C. under microwaves irradiation for 1 hour. The solvent was removed under vacuum, and the residue was portioned between EtOAc and water. The organic phase was washed several times with brine and dried over sodium sulfate; the solvent was evaporated to dryness and the crude was purified by flash chromatography on silica gel (DCM/MeOH 98/2) to afford methyl 2-(6-(N-(2-morpholinoethyl)methylsulfonamido)-2-oxobenzo[d]oxazol-3(2H)-yl)acetate (340 mg, 0.822 mmol, 82% yield, MS/ESI+ 414.0 [MH]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([N:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN([C@H]2CC[C@H](c3ccc(F)cc3)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc([C@H]2CC[C@H](N3CCNCC3)CC2)cc1

Procedure:
This compound was prepared from trans 1,1-dimethylethyl 4-[4-(4-fluorophenyl)-1-cyclohexyl]-1-piperazine carboxylate (1.7 mmole) by treatment with TFA for 0.5 hr. The TFA was removed in vacuo and the residue dissolved in water. The solution was basified with NaOH and the basic mixture extracted with methylene chloride. The extracts were dried and concentrated in vacuo to give the product which was converted to the difumarate [95%, mp: 210° C.(dec)]. Calc'd for C16H23FN2.2C4H4O4.0.25H2O: C, 57.77%; H, 6.39%; N, 5.61%. Found: C, 57.69%; H, 6.23%; N, 5.60%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)[CH3:2].[NH2:13][C:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:29])=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:21]=2)[N:16](COCC[Si](C)(C)C)[N:15]=1.OP([O-])(O)=O.[K+].CO>C1COCC1>[Cl:29][C:19]1[CH:18]=[C:17]2[C:22]([C:14]([NH:13][C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=3)=[O:12])=[N:15][NH:16]2)=[CH:21][C:20]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[Si](C)(C)CCOCn1nc(N)c2cc(-c3ccccc3)c(Cl)cc21
Reactant: CCOc1ccc(N=C=O)cc1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(NC(=O)Nc2n[nH]c3cc(Cl)c(-c4ccccc4)cc23)cc1
Temperature: 50 °C
Yield: 71.8 %

Procedure:
36.4 mg of 4-ethoxyphenyl isocyanate are added to 80 mg of 3-amino-5-phenyl-6-chloro-1-[(2-trimethylsilylethoxy)methyl]indazole in 1 ml of THF. The mixture is heated at 50° C. for 1 h and is then hydrolyzed in a saturated KH2PO4 solution and extracted with methylene chloride. After drying and evaporating, the crude product is purified by chromatography on silica with an AcOEt/hexane mixture. The product obtained is deprotected in 2 ml of a 1/1 MeOH/2N HCL mixture at reflux for 3 h. 62.5 mg of 1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(4-ethoxyphenyl)urea are obtained.
Reaction SMILES: [F:1][CH2:2][C@H:3]1[CH2:7][N:6]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[C:5](=[O:16])[C@@:4]1([CH3:22])[C:17]([O:19]CC)=[O:18].[OH-].[Na+].O>C(O)C>[F:1][CH2:2][C@H:3]1[CH2:7][N:6]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[C:5](=[O:16])[C@@:4]1([CH3:22])[C:17]([OH:19])=[O:18]
Reactant: CCOC(=O)[C@]1(C)C(=O)N([C@H](C)c2ccccc2)C[C@@H]1CF
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@H](c1ccccc1)N1C[C@H](CF)[C@](C)(C(=O)O)C1=O
Reaction time: 0.5 h

Procedure:
To a solution of ethyl (3S,4R)-4-fluoromethyl-3-methyl-2-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (20.0 g, 65.1 mmol) in ethanol (400 mL), 10 mol/l aqueous solution of sodium hydroxide (65.1 mL, 651 mmol) was added dropwise, and the mixture was stirred for 30 minutes. Water (400 mL) was added to the reaction mixture in an ice bath, and the aqueous solution was washed with diethylether (500 mL). Concentrated hydrochloric acid was added to the aqueous layer in an ice bath to pH 2 to 3, and the mixture was extracted with chloroform (500 mL×3). The organic layer was dried with anhydrous sodium sulfate, and after filtration, the filtrate was concentrated under reduced pressure. The concentrate was azeotropically distilled by adding toluene (20 mL), and dried under reduced pressure to obtain 19.16 g (quantitative) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH:7]([NH2:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[CH:23]=O.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>C(O)C.C(O)(=O)C>[C:1]([O:5][C:6](=[O:16])[CH:7]([NH:15][CH2:23][C:19]1[S:20][CH:21]=[CH:22][C:18]=1[Br:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(N)Cc1ccccc1
Reactant: O=Cc1sccc1Br
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)C(Cc1ccccc1)NCc1sccc1Br
Yield: 80 %

Procedure:
To a stirred solution of 2-Amino-3-phenyl-propionic acid tert-butyl ester (50.6 mg, 0.229 mmol) in ethanol (1 mL), were added 3-Bromo-thiophene-2-carbaldehyde (50 mg, 0.208 mmol.) and acetic acid (21 μL). The reaction mixture was stirred at room temperature under nitrogen for 2 hrs as the progress of imine formation was monitored by TLC. Then, sodium cyanoborohydride (20 mg, 0.312 mmol) was added. The mixture was acidified with sodium bicarbonate and then extracted with dichloromethane. After removal of the solvent, the crude product was purified by silica plate (hexane/ethylacetate 90%:10%) to give 2-[(3-Bromo-thiophen-2-ylmethyl)-amino]-3-phenyl-propionic acid tert-butyl ester in 80% yield: 1H NMR (Varian 400 MHz, CDCl3) δ7.23 (m, 6H, ArH), 6.90 (d, 1H, J=5.3 Hz, thiophenH), 4.00 (d, 1H, J=14.6 Hz, NCH2), 3.85 (d, 1H, J=14.6 Hz, NCH2), 3.48 (m, 1H, CHCH2), 3.00 (m, 2H, CHCH2), 1.37 (s, 9H, tBu).
Reaction SMILES: [CH3:1][C@@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][CH2:12][OH:13]>ClCCl>[OH:13][CH2:12][CH2:11][NH:9][C@H:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCCBr
Reactant: C[C@@H](N)c1ccccc1
Solvent: ClCCl
Product: C[C@@H](NCCO)c1ccccc1
Temperature: 51 °C
Reaction time: 50 h
Yield: 76003 %

Procedure:
51.45 g (0.43 mmole) of (R)-(+)-α-methylbenzylamine was dissolved in 52 ml of dichloromethane and 63.78 g (0.51 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51° C. for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and the residue was subjected to fractional distillation to obtain 54 g of the title compound having pale yellow color.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]([C:19]#N)(C)[C:15](N)=[O:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:21].[Na+]>>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]([CH3:19])[C:15]([OH:16])=[O:21])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C#N)(C(N)=O)c1cccc(Oc2ccccc2)c1
Reactant: [OH-]
Agent: [Na+]
Product: CC(C(=O)O)c1cccc(Oc2ccccc2)c1
Reaction time: 20 h
Yield: 98.5 %

Procedure:
A mixture of 106.4 g. of 2-(3-phenoxy-phenyl)-2-cyano-propionic acid amide, 200 ml. of 40% aqueous sodium hydroxide and 400 ml. of alcohol is boiled under stirring for 20 hours. The alcohol is then distilled off and the residue is diluted with 200 ml. of water. The aqueous solution is acidified to pH=1 by adding concentrated hydrochloric acid. The separating oil is extracted with 3×500 ml. of benzene. The benzene solution is evaporated after drying above sodium sulphate. Thus 96 g. (98.5%) 2-(3-phenoxy-phenyl)-propionic acid are obtained; the product is suitable for the preparation of salts without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=O)=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:48][C@H:49]1[CH2:54][CH2:53][C@H:52]([OH:55])[CH2:51][CH2:50]1.C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([NH:48][C@H:49]4[CH2:54][CH2:53][C@H:52]([OH:55])[CH2:51][CH2:50]4)=[O:26])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)N[C@H]3CC[C@H](O)CC3)c2n1
Reaction time: 0.5 h

Procedure:
To a solution of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation K, 30 mg, 0.084 mmol) in anhydrous CH2Cl2 (2 mL) was added HOBt (34 mg, 0.25 mmol) followed by EDCI (48 mg, 0.25 mmol). The solution was stirred for 30 minutes, then treated with (trans)-4-aminocyclohexanol (29 mg, 0.25 mmol) followed by triethylamine (35 μL, 0.25 mmol). After stirring at ambient temperature for 5 hours, the reaction mixture was diluted with EtOAc, washed with saturated NH4Cl (20 mL), saturated NaHCO3, and brine, then dried (Na2SO4), filtered and concentrated. The crude material was purified by silica chromatography (4% MeOH/CH2Cl2) to yield the final product as white solid (23 mg, 60%). LCMS (apci) m/z=455.1 (M+H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[C:8]([F:33])=[C:9]([CH:30]=[CH:31][CH:32]=1)[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:28][CH3:29])=[C:18]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)[CH:19]=2)[N:14]=[CH:13][N:12]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:6][C:7]1[C:8]([F:33])=[C:9]([CH:30]=[CH:31][CH:32]=1)[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:28][CH3:29])=[C:18]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][N:24]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:23]3)[CH:19]=2)[N:14]=[CH:13][N:12]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCNC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCN(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonyl chloride (42 mg) was added to a solution of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline (134 mg) and diisopropylethylamine (65 mg) in methylene chloride (5 ml) at ambient temperature. The reaction mixture was stirred for 16 hours at ambient temperature. The reaction mixture was adsorbed onto silica and the residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 95/5). The fractions containing the title product were combined and evaporated under vacuum and the residue triturated with diethyl ether, filtered and dried under vacuum to give the title product as a mixture of the 3R and 3S isomers (0.10 g); 1H NMR Spectrum: (DMSO d6 and CD3COOD) 1.54-2.07 (m, 4H), 2.95 (s, 3H), 3.10-120 (m, 1H), 3.21-3.37 (m, 2H), 3.50-3.59 (m, 1H), 3.93 (s, 3H), 4.70 (m, 1H), 7.20-7.29 (m, 2H), 7.40-7.55 (m, 2H), 7.89 (s, 1H), 8.37 (s, 1H); Mass Spectrum: (M+H)+ 481.
Reaction SMILES: CS(O[C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=O)=O.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CC(O)(C)C>[F:17][C:18]([F:26])([F:27])[C:19]1[CH:20]=[CH:21][C:22]([NH:23][C:6]2[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:24][CH:25]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1cccc(OS(C)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cccc(Nc2ccc(C(F)(F)F)cc2)c1
Temperature: 110 °C
Yield: 93.1 %

Procedure:
Following general procedure A, a mixture of ethyl 3-(methylsulfonyloxy)benzoate (122 mg, 0.5 mmol), 4-(trifluoromethyl)aniline (75 μL, 0.6 mmol), K2CO3 (97 mg, 0.7 mmol), 10 (4 mg, 1 mol %), 1 (2.5 mg, 1 mol %), and t-BuOH (6 mL) was heated to 110° C. for 16 h. The crude product was purified via the Biotage SP4 (silica-packed 25+M; 0-30% EtOAc/hexanes) to provide the title compound as a white solid (144 mg, 93%), mp 106-108° C. 1H NMR (300 MHz, CDCl3) δ: 7.81 (s, 1H), 7.71 (d, J=7.0 Hz, 1H), 7.49 (d, J=8.5 Hz, 2H), 7.36 (m, 2H), 7.07 (d, J=8.5 Hz, 2H), 6.13 (s 1H), 4.38 (q, J=7.0 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 166.7, 146.3, 141.8, 132.1, 130.1, 129.8, 127.1, 127.0, 127.0, 126.9, 126.6, 123.8, 123.8, 123.0, 122.6, 122.2, 120.6, 116.0, 61.5, 14.5 ppm. IR (neat, cm−1): 3358, 1701, 1620, 1543, 1333, 1158, 1108, 1070, 751. Anal. Calcd. for C16H14F3O2N: C, 62.13; H, 4.56. Found: C, 61.97; H, 4.46.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([CH:10]=[O:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][Mg]Br.O>O1CCCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([CH:10]([OH:11])[CH3:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Mg]Br
Reactant: CC(C)(C)c1cc(C=O)no1
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1cc(C(C)(C)C)on1
Reaction time: 1 h

Procedure:
1.29 g of 5-t-butyl-isoxazole-3-carbaldehyde was dissolved in 10 ml of tetrahydrofuran, and 10 ml of a 0.93 M solution of methylmagnesium bromide in tetrahydrofuran was then added. The mixture was stirred for 1 hour under ice-cooling. After water was added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.18 g of 1-(5-t-butyl-isoxazol-3-yl)ethanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[CH3:12][C:13]1([CH3:20])[O:17][CH:16]([CH2:18]O)[CH2:15][O:14]1>>[I:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[N:7]([CH2:18][CH:16]2[CH2:15][O:14][C:13]([CH3:20])([CH3:12])[O:17]2)[N:6]=1
Reactant: Fc1ccc2[nH]nc(I)c2c1
Reactant: CC1(C)OCC(CO)O1
Product: CC1(C)OCC(Cn2nc(I)c3cc(F)ccc32)O1
Yield: 52 %

Procedure:
The title compound was prepared from 5-fluoro-3-iodo-indazole and 1,2-isopropylideneglycerol in 52% yield according to the general procedure for Preparation 31A. The minor isomer was not isolated or characterized. 1H NMR (300 MHz, CDCl3): δ 1.27 (3H, s), 1.31 (3H, s), 3.83-3.87 (1H, m), 4.07-4.11 (1H, m), 4.48-4.55 (3H, m), 7.10 (1H, dd, J=8.3, 2.3 Hz), 7.22 (1H, td, J=8.9, 2.3 Hz), 7.45 (1H, dd, J=9.1, 4.0 Hz). [M+H] calc'd for C13H14FN2O2, 377; found, 377.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:11][C:12](=[O:18])[C@H:13]([CH:15]([CH3:17])[CH3:16])[NH2:14])[CH:5]=[CH:4][CH:3]=1.[CH:19]1[C:31]2[CH:30]([C:32]([NH:34][CH2:35][C:36](O)=[O:37])=[O:33])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1>>[CH:28]1[C:29]2[CH:30]([C:32]([NH:34][CH2:35][C:36]([NH:14][C@H:13]([C:12]([NH:11][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:7]=3[C:8]([OH:10])=[O:9])=[O:18])[CH:15]([CH3:16])[CH3:17])=[O:37])=[O:33])[C:31]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]=2[CH:25]=[CH:26][CH:27]=1
Reactant: Cc1cccc(NC(=O)[C@@H](N)C(C)C)c1C(=O)O
Reactant: O=C(O)CNC(=O)C1c2ccccc2-c2ccccc21
Product: Cc1cccc(NC(=O)[C@@H](NC(=O)CNC(=O)C2c3ccccc3-c3ccccc32)C(C)C)c1C(=O)O
Yield: 33.4 %

Procedure:
84 mg of 2-[[[N-(9-fluorenylcarbonyl)glycyl]-L-valyl]amino]-6-methylbenzoic acid was prepared exactly as in step c) of Example 3, except that 126 mg of 6-methyl-2-(L-valylamino)benzoic acid was subjected to a condensation reaction with 188 mg of N-(9-fluorenylcarbonyl)glycine in place of 9-fluorenyloxyacetic acid used in Example 3.