Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[O:5][N:4]=1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:35][C@H:36]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[C:56]([Cl:58])[CH:55]=[CH:54][C:53]=2[F:59])=[CH:48][CH:47]=1)[CH2:37][C@:38]([CH2:43][OH:44])([CH3:42])[C:39]([OH:41])=[O:40].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:58][C:56]1[CH:55]=[CH:54][C:53]([F:59])=[C:52]([C:49]2[CH:48]=[CH:47][C:46]([CH2:45][C@@H:36]([NH:35][C:8]([C:6]3[O:5][N:4]=[C:3]([CH2:1][CH3:2])[CH:7]=3)=[O:10])[CH2:37][C@:38]([CH2:43][OH:44])([CH3:42])[C:39]([OH:41])=[O:40])=[CH:51][CH:50]=2)[CH:57]=1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1)C(=O)O
Reactant: CCc1cc(C(=O)O)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(C(=O)N[C@H](Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@](C)(CO)C(=O)O)on1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.4 %

Procedure:
3-Ethylisoxazole-5-carboxylic acid (8 mg, 55 μmol) and HATU (20.8 mg, 55 μmol) were combined in DMF (0.2 mL) and allowed to stand at room temperature for 10 minutes. (2S,4R)-4-Amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methylpentanoic acid (20 mg, 55 μmol) in DMF and DIPEA (28.6 μL, 164 μmol) were added, and the resulting mixture was stirred for 20 minutes at room temperature. The mixture was concentrated under reduced pressure and the residue was dissolved in AcOH purified by preparative HPLC to yield the title compound (3.6 mg). MS m/z [M+H]+ calc'd for C25H26ClFN2O5, 489.15. found 490.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C1C=CC2N(O)N=NC=2C=1.[C:24]([C:28]1[CH:44]=[CH:43][C:31]([CH2:32][NH:33][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:24]([C:28]1[CH:44]=[CH:43][C:31]([CH2:32][N:33]([CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[C:11]([C:8]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]3[C:7]=2[NH:6][CH:5]=[CH:4]3)=[O:13])=[CH:30][CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)cc2)cc1
Reactant: O=C(O)c1ccc(Cl)c2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)cc2)C(=O)c2ccc(Cl)c3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.8 %

Procedure:
To a solution of 64 mg (0.33 mmol) of 4-chloro-1H-indole-7-carboxylic acid in 2 ml DCM 50 mg of HOBT (0.33 mmol) were added and the reaction mixture was stirred for 15 min at rt under nitrogen. 85 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(4-fluoro-phenyl)-ethyl]-amine in 1 ml DCM were added and then 63 mg (0.33 mmol) of EDC.HCl. The reaction mixture was stirred over night at rt to yield a slight turbid yellow solution. The solvent was evaporated and the residue was dissolved in 1,2-dichloro ethane. The reaction mixture was stirred at reflux for 3 h. The solvent was evaporated and the residue was purified by column chromatography (25 g silica gel, heptane/EtOAc 7:3) to yield 90 mg (65%) product as a light yellow viscous oil. MS (ISP) 463.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[NH:17][C:18]4[C:24]([NH:25][C:26](=O)[C:27]5[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=5)=[CH:23][C:22]([C:37]([F:40])([F:39])[F:38])=[CH:21][C:19]=4[N:20]=3)[C@H:12]([CH3:41])[CH2:11]2)=[N:4][CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1>C1COCC1.CO.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[N:4][C:3]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]2[NH:17][C:18]3[C:24]([NH:25][CH2:26][C:27]4[CH:28]=[C:29]([F:35])[C:30]([F:34])=[C:31]([F:33])[CH:32]=4)=[CH:23][C:22]([C:37]([F:39])([F:38])[F:40])=[CH:21][C:19]=3[N:20]=2)[C@H:12]([CH3:41])[CH2:11]1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(NC(=O)c3cc(F)c(F)c(F)c3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(NCc3cc(F)c(F)c(F)c3)c2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-{2-[(2R)-4-(3-chloro-5-hydroxymethyl-pyridin-2-yl)-2-methyl-piperazin-1-yl]-6-trifluoromethyl-3H-benzoimidazol-4-yl}-3,4,5-trifluoro-benzamide (120 mg, 0.2 mmol, Example 170c) in THF (1 mL) was added BH3. THF (0.6 mL, 0.6 mmol, Aldrich) dropwise with stirring at 0° C. The mixture was heated at reflux for 5 h, cooled to room temperature and diluted with 1:1 mixture of MeOH and 1N NaOH (2 mL). The mixture was stirred at room temperature for 30 min and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography, eluting with 5% MeOH/CH2Cl2 to give the title compound as a white solid. MS (ESI, pos. ion) m/e: 586 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:12][C:13]([F:23])([F:22])[S:14][C:15]1[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:21][C:18]1[CH:19]=[N:20][C:15]([S:14][C:13]([F:23])([F:22])[F:12])=[CH:16][CH:17]=1)=[O:9]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: Nc1ccc(SC(F)(F)F)nc1
Product: O=C(Nc1ccc(SC(F)(F)F)nc1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 9.3 using 5-bromo-6-chloronicotinic acid and 6-(trifluoromethylthio)pyridin-3-amine to afford an off-white powder. HPLC (Condition 4) tR=6.43 min, UPLC-MS (Condition 3) tR=1.15 min, m/z=411.9 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:18]([CH3:19])=[N:17][N:16]([CH3:20])[C:10]=2[N:11]=[C:12](S)[CH2:13][N:14]=1.O1CCCC1.[CH2:26]([NH2:29])[C:27]#[CH:28]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:18]([CH3:19])=[N:17][N:16]([CH3:20])[C:10]=2[N:11]=[C:12]([NH:29][CH2:26][C:27]#[CH:28])[CH2:13][N:14]=1
Reactant: Cc1nn(C)c2c1C(c1ccccc1Cl)=NCC(S)=N2
Reactant: C#CCN
Solvent: CO
Solvent: C1CCOC1
Product: C#CCNC1=Nc2c(c(C)nn2C)C(c2ccccc2Cl)=NC1

Procedure:
A mixture of 4.65 g. of 4-(2-chlorophenyl)-1,6-dihydro-1,3-dimethylpyrazolo[3,4-e][1,4]diazepine-7-thiol (prepared as disclosed in U.S. Pat. No. 3,770,762), 250 ml. of tetrahydrofuran, 3.0 g. of 2-propynylamine and 20 ml. of methanol is allowed to stand at room temperature (20°-30° C.) for 3 days, then evaporated at reduced pressure to give a residue of 4-(2-chlorophenyl-1,6-dihydro-1,3-dimethyl-7-(2-propynylamino)pyrazolo[3,4-e][1,4]diazepine; m.p. 165°-167° C. after crystallization from acetonitrile. For further purification, the product is dissolved in 9:1 tolueneacetonitrile and chromatographed on a column of neutral alumina. The column is eluted with 9:1 methanol-acetonitrile and the eluate is evaporated at reduced pressure to give a residue of m.p. 176°-178° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[Si:13]([O:20][CH2:21][CH2:22][CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C(O)(C)C>[Si:13]([O:20][CH2:21][CH2:22][CH2:23]/[C:24](=[N:7]\[NH:6][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:2]=1[F:1])/[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: NNC(=O)c1cc(F)ccc1F
Reactant: CC(C)(C)[Si](C)(C)OCCCC(=O)c1ccccc1
Solvent: CC(C)O
Product: CC(C)(C)[Si](C)(C)OCCC/C(=N\NC(=O)c1cc(F)ccc1F)c1ccccc1

Procedure:
A solution of 2,5-difluorobenzohydrazide (1-2, 90 mg, 0.52 mmol, 1 equiv) and 4-{[tert-butyl(dimethyl)silyl]oxy}-1-phenylbutan-1-one (3-3) (146 mg, 0.523 mmol, 1.00 equiv) in isopropanol (10 mL) was heated at 75° C. for 1 day. The reaction mixture was concentrated to give N′-((1E)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-phenylbutylidene)-2,5-difluorobenzohydrazide (3-4); LRMS m/z (M+H) 433.4 found, 433.2 required. A solution of 3-4 in acetic anhydride (5 mL) was heated at reflux for 1.5 h. The reaction mixture was concentrated and the residue was purified by reverse-phase LC(H2O/CH3CN gradient w/0.1% TFA present) to provide 3-[3-acetyl-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-oxadiazol-2-yl]propan-1-ol (3-5) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.57 (m, 2H), 7.52 (m, 1H), 7.39 (m, 3H), 7.18 (m, 2H), 3.75 (t, 2H, J=6.4 Hz), 3.07 (m, 1H), 2.64 (m, 1H), 2.39 (s, 3H), 1.72 (m, 2H). LRMS m/z (M+H) 361.3 found, 361.1 required.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C@@H:8]([C@@H:17]1[C@@H:21]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)[CH2:20][N:19]([C:30]([C:32]2[CH:37]=C(C)N=[N:34][CH:33]=2)=[O:31])[CH2:18]1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)(C)(C)C.CC[CH2:43][CH2:44][N+:45](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C@H:8]([C@@H:17]2[C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)[CH2:20][N:19]([C:30]([C:32]3[CH:37]=[N:45][C:44]([CH3:43])=[N:34][CH:33]=3)=[O:31])[CH2:18]2)[CH2:7][OH:6])=[N:11][CH:12]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: Cc1cc(C(=O)N2C[C@H]([C@H](CO[Si](C)(C)C(C)(C)C)Oc3ccc(Cl)cn3)[C@@H](c3ccc(F)c(F)c3)C2)cnn1
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ncc(C(=O)N2C[C@H]([C@H](CO)Oc3ccc(Cl)cn3)[C@@H](c3ccc(F)c(F)c3)C2)cn1
Temperature: 25 °C
Yield: 84 %

Procedure:
To a solution of [(3R,4S)-3-[(R)-2-(tert-butyl-dimethyl-silanyloxy)-1-(5-chloro-pyridin-2-yloxy)-ethyl]-4-(3,4-difluoro-phenyl)-pyrrolidin-1-yl]-(6-methyl-pyridazin-4-yl)-methanone (0.050 g, 0.085 mmol) dissolved in THF (4 mL) was added 0.10 mL of TBAF (1.0M in THF). The reaction mixture was stirred over night at room temperature. The mixture was diluted with ethyl acetate and washed with water and aq. sodium bicarbonate solution subsequently. The separated organic phase was dried over sodium sulfate and concentrated in vaccuo after filtration. The residue was purified by TLC (SiO2, MeOH/DCM, 1:10) yielded 40 mg (84%) of the title compound as a light yellow oil. ES-MS m/e: 475.1 (M+H+).
Reaction SMILES: [ClH:1].[CH2:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH2:5][CH2:4][NH:3]1.[C:21]1(NN)C=CC=CC=1>>[ClH:1].[Cl:1][C:10]1[C:11]([CH3:21])=[CH:12][C:13]2[C:14]3[CH2:2][NH:3][CH2:4][CH2:5][C:6]=3[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]=2[CH:9]=1
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CNCC2
Reactant: NNc1ccccc1
Agent: Cl
Product: CCOC(=O)Cn1c2c(c3cc(C)c(Cl)cc31)CNCC2

Procedure:
The title compound is prepared using a procedure analogous to Intermediate 1, substituting 3-chloro-4-methylhydrazine for phenylhydrazine in Step 1a).
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[Cl:17][CH2:18][CH2:19][CH2:20]I.O>CN(C=O)C>[Cl:17][CH2:18][CH2:19][CH2:20][NH:2][C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: ClCCCI
Reactant: CCOC(=O)C(C)(C)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)NCCCCl
Reaction time: 8 h
Yield: 102.5 %

Procedure:
A solution of ethyl aminoisobutyrate hydrochloride (10 g) in DMF (50 mL) was cooled to 0° C. To the solution were added potassium carbonate (18 g) and 1-chloro-3-iodopropane (12 g), and the mixture was stirred overnight at 0° C. to room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate toluene organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 12.5 g of crude ethyl 2-(3-chloropropylamino)isobutyrate.
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:23])[CH:18]([NH2:22])[CH2:19][CH2:20][CH3:21])[N:13]=[CH:12]1)([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[F:24][C:25]1[CH:26]=[C:27]([CH:32]([OH:36])[C:33](O)=[O:34])[CH:28]=[C:29]([F:31])[CH:30]=1>>[CH3:1][C:2]([N:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:23])[CH:18]([NH:22][C:33](=[O:34])[CH:32]([C:27]2[CH:28]=[C:29]([F:31])[CH:30]=[C:25]([F:24])[CH:26]=2)[OH:36])[CH2:19][CH2:20][CH3:21])[N:13]=[CH:12]1)([CH3:10])[CH2:3][N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCOCC2)cn1
Product: CCCC(NC(=O)C(O)c1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CN2CCOCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide was coupled with (3,5-Difluoro-phenyl)-hydroxy-acetic acid to afford the title compound: H1 NMR (400 MHz, CDCl3) 0.8 (m, 3H), 1.40 (m, 2H), 1.48 (s, 2H), 1.70, (m, 2H), 2.20 (m, 4H), 2.42, (m, 2H), 3.58 (m, 4H), 4.80 (m, 0.5H), 4.90 (m, 0.5H), 5.12 (m, 0.5H), 5.20 (m, 0.5H), 6.72 (m, 1H) 7.08 (m, 2H), 7.39 (s, 0.5H) 7.40 (s, 0.5H), 7.46 (s, 0.5H), 7.47 (s, 0.5H); MS m/z 494.4 (M+1).
Reaction SMILES: C(N1CCOCC1)C.[NH:9]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:10]([C:15]([OH:17])=O)[C@H:11]([CH2:13][CH3:14])[CH3:12].[NH2:28][C@H:29]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C=O>[NH:9]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:10]([C:15]([NH:28][C@H:29]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:17])[C@H:11]([CH2:13][CH3:14])[CH3:12]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
1.3 ml of N-ethylmorpholine are added to the solution of 2.65 g of Z-Ile-OH, 2.58 g of H-Phe-OBut and 1.35 g of HOBt in 30 ml of dimethylformamide and 2.2 g of DCC are added to 0° C. The mixture is allowed to stand for 1 hour at 0° C. and overnight at room temperature. On the following day the precipitate is filtered off and the filtrate is concentrated. The residue is partitioned between ethyl acetate and water. The ethyl acetate phase is extracted by shaking with 20 ml of saturated NaHCO3 solution, 20 ml of K2SO4 /KHSO4 solution and 20 ml of NaHCO3 solution and is dried over Na2SO4 and concentrated. The product crystallizes from petroleum ether. Yield 3.7 g, melting point 122°-125°.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[CH3:6][C:7]1([CH3:15])[CH2:13][C:12](=O)[O:11][C:9](=[O:10])[CH2:8]1.C(OC(=O)C)(=O)C.[OH-].[Na+]>C(OCC)C>[CH3:3][CH:2]([CH3:4])[CH2:1][N:5]1[C:9](=[O:10])[CH2:8][C:7]([CH3:15])([CH3:6])[CH2:13][C:12]1=[O:11]
Reactant: CC(C)CN
Reactant: CC1(C)CC(=O)OC(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CC(C)CN1C(=O)CC(C)(C)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Isobutylamine (7.3 g, 0.1 mol) was added slowly to 3,3-dimethylglutaric anhydride (14.2 g, 0.1 mol) stirring at room temperature in a two neck round bottom flask fitted with a water condenser. After 30 minutes, acetic anhydride (20.4 g, 0.2 mol) was added, and the resulting mixture was boiled for two hours. After cooling, the mixture was poured slowly on to an aqueous NaOH solution (2N, 100 ml) stirring at room temperature. After one hour, the mixture was diluted with diethyl ether (50 ml), and the organic layer was separated. The aqueous layer was washed with more diethyl ether (2×50 ml), and the combined organic layer dried and concentrated to give the title compound as a pale yellow oil which solidified on standing, m.p. 48°-52° C., yield 18.5 g (94%). The product was suffuciently pure by NMR spectroscopy to be used directly in the following procedure.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19]([N:28]4[CH2:33][CH2:32][CH2:31][C@@H:30]([N:34]5C(=O)C6=CC(C)=CC=C6C5=O)[CH2:29]4)=[N:18][C:17]=3[N:16]([CH3:46])[C:14]2=[O:15])[N:3]=1.C(CN)O>O>[CH3:27][C:26]#[C:25][CH2:24][N:20]1[C:19]([N:28]2[CH2:29][C@H:30]([NH2:34])[CH2:31][CH2:32][CH2:33]2)=[N:18][C:17]2[N:16]([CH3:46])[C:14]([N:13]([CH2:12][C:4]3[N:3]=[C:2]([CH3:1])[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N:5]=3)[C:22](=[O:23])[C:21]1=2)=[O:15]
Reactant: CC#CCn1c(N2CCC[C@@H](N3C(=O)c4ccc(C)cc4C3=O)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Solvent: NCCO
Solvent: O
Product: CC#CCn1c(N2CCC[C@@H](N)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Temperature: 95 °C

Procedure:
In a clean round bottom flask, 10.0 gms of 1[(4-Methylquinazolin-2yl) methyl]-3-methyl-7-(2-butin-1yl)-8-(3(R)-4-methyl phthalimidopiperidine-yl)-xanthine and 50 ml ethanolamine were charged. The reaction mass was heated to 90-100° C. for 1 hr and cooled to room temperature. 100 ml water was added and the solid was filtered. 150 ml of toluene was added and completely distilled out under vacuum at 45-50° C. to get pale yellow solid. Dry wt: 6.0 gm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14].Cl>ClCCl.C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(NCc3cccc(Cl)c3)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(N2CCNCC2)cc1NCc1cccc(Cl)c1
Reaction time: 4 h
Yield: 79.4 %

Procedure:
To a solution of t-butyl 4-(3-(3-chlorobenzylamino)-4-nitrophenyl)piperazine-1-carboxylate (104 mg, 0.23 mmol) in dry dichloromethane (1.0 mL) was added a saturated solution of HCl in diethyl ether (15 mL). The reaction mixture was stirred for 4 hours. The solvent was evaporated and the precipitate was recrystallized from methanol (0.3 mL), dichloromethane (0.5 mL) and diethyl ether (5 mL). The product was collected by filtration and dried in vacuo to afford the title compound (35.0 mg, 39% yield after recrystallization). 1H NMR (400 MHz, CD3OD): δ 8.07 (d, 1H), 7.42 (s, 1H), 7.33 (m, 2H), 7.28 (m, 1H), 6.40 (d, 1H), 6.03 (s, 1H), 4.61 (s, 1H), 3.56 (m, 4H), 3.27 (m, 4H); MS (ESI) m/z: Calculated for C17H20ClN4O2: 347.13; Observed: 347.5 (M++1) [corresponding to the free base].
Reaction SMILES: OO.FC(F)(F)C(C(F)(F)F)=[O:6].[F:13][C:14]([F:34])([CH:17]([F:33])[O:18][C:19]([F:32])([F:31])[C:20]([F:30])([F:29])[C:21]([F:28])([F:27])[O:22][C:23]([F:26])([F:25])[F:24])[CH2:15][OH:16]>C(Cl)(Cl)Cl>[F:13][C:14]([F:34])([CH:17]([F:33])[O:18][C:19]([F:32])([F:31])[C:20]([F:29])([F:30])[C:21]([F:27])([F:28])[O:22][C:23]([F:24])([F:25])[F:26])[C:15]([OH:6])=[O:16]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: OCC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Agent: OO
Solvent: ClC(Cl)Cl
Product: O=C(O)C(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 2.3 mL (22 mmol) of 30% H2O2 in 20 mL of chloroform, 13.28 g (80 mmol) of hexafluoroacetone (pre-generated from HFA-hydrate) was added followed by 2,2,3-trifluoro-3-(1,1,2,2,3,3-hexafluoro-3-trifluoromethoxy-propoxy)-propan-1-ol (3.64 g, 10 mmol). The mixture was stirred 2 days at room temperature. After separation of phases and evaporation of solvent, the residue was examined by 19F NMR spectroscopy. Yield of the raw product 52%.
Reaction SMILES: [OH-].[Na+].[C:3]([O:14]CC)(=[O:13])/[CH:4]=[CH:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>O1CCCC1>[C:3]([OH:14])(=[O:13])/[CH:4]=[CH:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCC/C=C\C=C\C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCC/C=C\C=C\C(=O)O
Temperature: 25 °C

Procedure:
An aqueous solution of sodium hydroxide (10%, 22 ml) was added to a solution of technical grade ethyl (2E,4Z)-2,4-decadienoate (10 g) in tetrahydrofuran (100 ml). The mixture was heated under reflux for 5 hours with rapid stirring in a nitrogen atmosphere. After allowing to cool to room temperature, tetrahydrofuran was removed on a rotary evaporator, the residue was diluted with water (100 ml), and acidified to pH 2 with 6N HCl. The acid was extracted with ether (3×100 ml) and the combined extracts were washed with water (2×50 ml) and brine (50 ml) and dried using anhydrous magnesium sulfate. Removal of ether under reduced pressure gave (2E,4Z)-2,4-decadienoic acid. This product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C(N(CC)CC)C.Cl[C:20]([O:22][CH3:23])=[O:21]>C(#N)C>[CH3:23][O:22][C:20](=[O:21])[NH:11][S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:10])=[O:9]
Reactant: COC(=O)Cl
Reactant: NS(=O)(=O)c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)NS(=O)(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 25.0 g 2-chloro-benzenesulfonamide was added 75 mL acetonitrile and 45.2 mL (2.5 eq) triethylamine. The mixture was cooled with an ice bath and 15.1 mL methyl chloroformate was slowly added dropwise. The mixture was stirred overnight at room temperature and concentrated in vacuo. Water was added and de aqueous layer was washed two times with ether. Acidification of the aqueous layer with 2 M HCl led to formation of a white precipitate. The suspension was filtered, the residue was washed with H2O and dried in vacuo to yield 19.1 g of a white solid. 1H NMR (400 MHz, DMSO-d6) δ 3.58 (s, 3H), 7.52-7.61 (m, 1H), 7.62-7.72 (m, 2H), 8.10 (dd, J=8 and 1.5 Hz, 1H), 12.42 (br s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4](=[O:12])[C:3]=1[CH2:13][CH2:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH4-].[Na+].C(O)(=O)C>CO>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4](=[O:12])[C:3]=1[CH2:13][CH2:14][CH:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(CCc1c(O)c2ccccc2oc1=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=c1oc2ccccc2c(O)c1CCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A rapidly stirred suspension of the product obtained in Example 16 (0.21 g, 0.71 mmol) in 10 mL of methanol was treated portionwise with 0.08 g (2.1 mmol) of sodium borohydride. The reaction mixture was stirred at room temperature for 36 hours. Glacial 30 acetic acid (3 mL) was added, and the mixture was concentrated. The residue was partitioned between ethyl acetate and water, and the organic layer was dried and concentrated. The product was chromatographed on silica gel, eluting with 4:1 chloroform: ethyl acetate, to give the title compound, m.p. 138°-140° C. NMR (CDCl3) δ1.25 (m, 2H), 2.88 (m, 2H), 4.66 (dd, 1H), 7.32 (m, 7H), 7.52 (t, 1H), 7.90 (d, 1H).