Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][C:40]=1[N:41]1[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]1)[NH2:37]>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:37][C:36]5[CH:38]=[CH:39][C:40]([N:41]6[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]6)=[C:34]([F:33])[CH:35]=5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCN(c2ccc(N)cc2F)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Product: COc1cc(C(=O)Nc2ccc(N3CCN(C)CC3)c(F)c2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was prepared in a manner analogous to the compound 149 from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid and 3-fluoro-4-(4-methylpiperazin-1-yl)aniline with yield 52.4 mg (41%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.60 (br. s., 6H) 1.99 (s, 2H) 2.22 (s, 3H) 2.40-2.51 (m, 4H) 2.98 (br. s., 4H) 3.97 (s, 3H) 4.22 (t, 2H) 4.79 (m, 1H) 7.03 (t, J=9.35 Hz, 1H) 7.45 (dd, J=8.72, 1.64 Hz, 1H) 7.54-7.78 (m, 3H) 8.04 (s, 1H) 8.28 (s, 1H) 8.36 (d, J=8.34 Hz, 1H) 10.11 (s, 1H). [M+H] calc'd for C32H37F2N8O3, 639. found 639.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH2:10]Cl)=[CH2:9])[N:3]=1.[I-:12].[K+].CC(C)=O.CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH2:10][I:12])=[CH2:9])[N:3]=1
Reactant: [I-]
Reactant: C=C(CCl)c1cccc(Cl)n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: O
Product: C=C(CI)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.6 %

Procedure:
A mixture of 0.50 g of 2-chloro-6-(1-chloromethylvinyl) pyridine, 0.88 g of potassium iodide, 5 ml of acetone and 0.5 ml of N,N-dimethylformamide was stirred at 50° to 60° C. for 5 hours. After the reaction mixture was cooled to room temperature, water was added thereto to extract the mixture with ethyl acetate. The extract was subsequently washed with an aqueous solution of 10% sodium thiosulfate, water, saturated saline solution in that order, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluted with dichloromethane) to obtain 0.45 g of the objective compound.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([N:9]1[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:19][CH3:20])[C:10]1=[O:21])[CH2:2]2.[H][H].O>CO.[Pd]>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@H:3]([N:9]1[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:19][CH3:20])[C:10]1=[O:21])[CH2:2]2
Reactant: CCc1cccc2c(=O)n([C@@H]3CN4CCC3CC4)ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CCc1cccc2c1CCN([C@@H]1CN3CCC1CC3)C2=O
Yield: 112 %

Procedure:
(S)-2-(1-Azabicyclo[2.2.2]oct-3-yl)-5-ethyl-1(2H)-isoquinolinone (0.49 g, 1.5 mmol), from Example 2, was dissolved in methanol (10 ml) and reduced with hydrogen and 10% palladium on carbon at 50 psi for 5 hours. Filtration to remove the catalyst and evaporation of the methanol gave (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)-5-ethyl-3,4-dihydro-1(2H)-isoquinolinone (0.48 g, 1.68 mmol), m.p. >290° C., [α]D25 -40.3° (c=0.64 H2O ).
Reaction SMILES: [SH:1][C:2]1[C:11]([C:12]([NH:14][CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CN(C=O)C>[CH2:28]([S:1][C:2]1[C:11]([C:12]([NH:14][CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCI
Reactant: O=C(NCc1cccs1)c1cc2ccccc2nc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCSc1nc2ccccc2cc1C(=O)NCc1cccs1
Reaction time: 0.5 h
Yield: 40 %

Procedure:
A solution of 300 mg (1.0 mmol) 2-mercapto-N-(thiophen-2-ylmethyl)quinoline-3-carboxamide (precursor VVV02) in DMF (2.3 ml) was mixed with 151 mg (1.1 mmol) K2CO3 at room temperature and stirred for 30 min. Then 131 μl (1.0 mmol) 1-iodopentane were added and the mixture was stirred for a further 3 days at RT. Then the mixture was concentrated to small volume under vacuum and the residue was taken up with EE and washed with water. The aqueous phase was extracted with EE and the combined organic phases were dried over MgSO4, filtered and concentrated to small volume under vacuum. Crystallisation of the residue from EE yielded 146 mg (0.4 mmol, 39%) 2-(pentylthio)-N-(2-thienylmethyl)-3-quinoline carboxamide. MS: m/z 371.1 [M+H]+.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[CH:11]1([CH2:16][C@H:17]([CH2:21][NH:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:18]([OH:20])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl>[CH:11]1([CH2:16][C@H:17]([CH2:21][N:22]([CH:1]=[O:2])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:18]([OH:20])=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C(O)[C@@H](CNOCc1ccccc1)CC1CCCC1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 99.8 %

Procedure:
Under a nitrogen atmosphere, formic acid (192 mL, 5 mol) was dissolved in CH2Cl2 (450 mL) and cooled to 0° C. Acetic anhydride (73 mL, 0.77 mol) was then added, and the reaction mixture was stirred for 45 min. After this time, a solution of (2R)-3-cyclopentyl-2-({[(phenylmethyl)oxy]amino}methyl)propanoic acid (22.85 g crude material, assumed 77.1 mmol) in CH2Cl2 (450 mL) was added, and the resulting mixture was stirred for 1.5 h at 0° C. The volatiles were then removed, the crude residue was dissolved in EtOAc (500 mL), and the mixture was washed with brine (4×100 mL). The organics were dried (MgSO4) and concentrated to provide (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (23.5 g, 100%) as a thick syrup. LCMS: (M+H)+: 306.1.
Reaction SMILES: [Cl:1][C:2]1[C:3](O)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[C:7]2[CH3:12].[Cl:14]P(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[Cl:14][C:3]1[C:2]([Cl:1])=[C:11]2[C:6]([C:7]([CH3:12])=[CH:8][N:9]=[CH:10]2)=[CH:5][CH:4]=1
Reactant: Cc1cncc2c(Cl)c(O)ccc12
Reactant: ClP(Cl)(c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1cncc2c(Cl)c(Cl)ccc12
Reaction time: 4 h

Procedure:
8-Chloro-7-hydroxy-4-methylisoquinoline (0.04 mole) and dichlorotriphenylphosphorane (0.04 mole) are heated to 240° C. under a nitrogen atmosphere. After four hours, the mixture is allowed to cool and is partitioned between chloroform and concentrated hydrochloric acid. The acidic extract is washed with chloroform, basified and extracted with chloroform. The chloroform extract is washed with water, dried over sodium sulfate and evaporated to yield 7,8-dichloro-4-methylisoquinoline. The product is purified by chromatography on silica gel eluted with chloroform and finally by precipitation of the hydrochloride from ethanol-ether.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O-:9])=O.[NH2:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])=[CH:13][CH:12]=1
Reactant: O=C([O-])c1ccccn1
Reactant: NCc1ccc(N)cc1
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: Nc1ccc(CNC(=O)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
Pyridine-2-carboxylate (Aldrich; 0.35 g, 2.84 mmol), 4-aminobenzylamine (Aldrich; 0.51 g, 4.26 mmol) and HATU (1.65 g, 4.26 mmol) were dissolved in DMF (7.5 ml). N,N-Diisopropylethylamine (1.5 ml, 8.53 mmol) was added and the mixture stirred at room temperature for 2 h. The mixture was absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and the residue purified by normal phase chromatography (2% MeOH/DCM) to give a yellow solid (440 mg). which was suspended in DCM/Et2O and filtered to give the title compound as a pale yellow solid (235 mg, 36%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:23](OCCC(C)C)=O.[ClH:31]>C(Cl)(Cl)Cl.CO>[Cl:31][C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[C:9]2[C:2]=1[NH:1][N:23]=[CH:10]2
Reactant: Cc1cc(C#N)ccc1N
Reactant: Cl
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: N#Cc1cc(Cl)c2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 18 %

Procedure:
To a mixture of 4-amino-5-methyl-benzonitrile (3.0 g, 18.0 mmol) in chloroform (50 mL) was added acetic anhydride (3.92 mL, 41.4 mmol). The mixture was heated at reflux for 5 hours and then cooled to room temperature. To the mixture was added potassium acetate (530 mg, 5.4 mmol) and isoamyl nitrite (5.28 mL, 39.6 mmol). The reaction was heated at reflux for 16 hours. The reaction mixture was coded to room temperature, extracted with saturated aqueous sodium bicarbonate, the organics were dried over sodium sulfate, and concentrated in vacuo to afford a brown oil. The oil was dissolved in methanol (25 mL) and concentrated hydrochloric acid (25 mL) was added. The reaction was stirred at room temperature for 22 hours and the methanol was concentrated in vacuo. The remaining aqueous layer was adjusted to a pH of 7 and the resultant precipitate was filtered to afford a brown solid which was purified by flash chromatography using 50% dichloromethane in heptane as eluent to afford 7-chloro-1H-indazole-5-carbonitrile as a solid (585 mg, 18%): −ESI MS (M−1) 176.0; 1H NMR (400 MHz, CDC3) 5 ppm 8.29 (br. s., 2H), 8.08 (s, 1H), 7.61 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[N:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]1=[O:18].ClCC[CH2:22][N:23]1N=C[C:30]2[C:25](=CC(OC)=[C:28](OC)[CH:29]=2)[C:24]1=O.C1(N2CCNCC2)C=CC=CC=1.[F:50][C:51]1[CH:64]=[CH:63][C:54]([C:55](N2CCNCC2)=[O:56])=[CH:53][CH:52]=1>C(OCC)(=O)C>[ClH:1].[F:50][C:51]1[CH:52]=[CH:53][C:54]([C:55]([CH:30]2[CH2:25][CH2:24][N:23]([CH2:22][CH2:2][CH2:3][N:4]3[N:13]=[CH:12][C:11]4[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=4)[C:5]3=[O:18])[CH2:28][CH2:29]2)=[O:56])=[CH:63][CH:64]=1
Reactant: O=C(c1ccc(F)cc1)N1CCNCC1
Reactant: COc1cc2cnn(CCCCl)c(=O)c2cc1OC
Reactant: COc1cc2cnn(CCCl)c(=O)c2cc1OC
Agent: c1ccc(N2CCNCC2)cc1
Solvent: CCOC(C)=O
Product: COc1cc2cnn(CCCN3CCC(C(=O)c4ccc(F)cc4)CC3)c(=O)c2cc1OC
Product: Cl

Procedure:
Working as described in Example 3 but replacing 2-(2-chloroethyl)-6,7-dimethoxy-1(2H)-phthalazinone with an equivalent amount of 2-(3-chloropropyl)-6,7-dimethoxy-1(2H)-phthalazinone obtained as described in Example 13, and replacing N-phenylpiperazine with an equivalent amount of 4-(4-fluorobenzoyl)-piperazine, 2-{3-[4-(4-fluorobenzoyl)-piperidin-1-yl]-propyl}-6,7-dimethoxy-1(2H)-phthalazinone hydrochloride is obtained (m.p. 250°-252° C., from ethyl acetate).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[C:8]([C:9]([O:11]C)=[O:10])=[CH:7][CH:6]=[C:5]([C:13]([F:16])([F:15])[F:14])[N:4]=1.[OH-].[K+].O>C(O)C>[F:17][C:2]([F:1])([F:18])[C:3]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=[C:5]([C:13]([F:16])([F:14])[F:15])[N:4]=1
Reactant: COC(=O)c1ccc(C(F)(F)F)nc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(C(F)(F)F)nc1C(F)(F)F
Yield: 90.1 %

Procedure:
7 g (0.026 mole) of the product of Example 7, 5 g of potassium hydroxide, 10 ml of H2O and 35 ml ethanol were stirred overnight at reflux. The solvent was then removed under vacuum. H2O was added to the residue. This aqueous layer was extracted 2X with ether (ether layer discarded). The aqueous layer was then acidified with conc. HCl. The product was extracted with ether. The ether layer was washed 2X with H2O and dried over MgSO4. The ether was then removed under vacuum and the resulting solid was dried to yield 6.07 g (91%) of a white solid. M.P. 102°-104° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:22](COCC[Si](C)(C)C)[C:21]([O:31][C@H:32]3[C@H:36]4[O:37][CH2:38][CH:39]([CH2:40][C:41]([NH2:43])=[O:42])[C@H:35]4[O:34][CH2:33]3)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C(Cl)Cl>C(O)(C(F)(F)F)=O.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:31][C@H:32]3[C@H:36]4[O:37][CH2:38][CH:39]([CH2:40][C:41]([NH2:43])=[O:42])[C@H:35]4[O:34][CH2:33]3)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@@H]3C(CC(N)=O)CO[C@@H]32)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: NC(=O)CC1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1

Procedure:
2-[(3aR,6R,6aS)-6-[6-chloro-5-(4-phenylphenyl)-1-(2-trimethylsilylethoxymethyl)-imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]acetamide was dissolved in TFA (0.5 mL) and DCM (0.5 mL) and stirred at room temperature for 2 hours. The reaction mixture was evaporated to give an oil. The oil was dissolved in methanol (0.5 mL) and purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-80% acetonitrile/water+0.05% TFA gradient. The desired fractions were lyophilized to give the title compound as a solid. Major isomer LC-MS: calculated for C26H23ClN4O4 490.14 observed m/e: 491.23 (M+H)+ (Rt 0.53/2 min); 1H NMR δ (ppm) (CD3OD): 7.94 (s, 1H), 7.76 (ABq, 4H), 7.71 (d, 2H), 7.48 (dd, 2H), 7.38 (dd, 1H), 5.58 (qt, 1H), 5.00 (t, 1H), 4.56 (t, 1H), 4.12 (dd, 1H), 4.02 (m, 2H), 3.54 (dd, 1H), 2.64 (dd, 1H), 2.58 (m, 1H) and 2.38 (dd, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[C:11]2=[O:26])[S:5][C:6]=1[C:7]([NH2:9])=O.CO[C:29](OC)([N:31](C)C)[CH3:30].C(O)(=O)C.O.[NH2:41]N>O1CCOCC1>[CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[C:11]2=[O:26])[S:5][C:6]=1[C:7]1[NH:31][C:29]([CH3:30])=[N:41][N:9]=1
Reactant: NN
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(N)=O
Reactant: COC(C)(OC)N(C)C
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: Cc1nnc(-c2sc(N3CCN(Cc4ccc(C(F)(F)F)cc4)C3=O)nc2C)[nH]1
Temperature: 100 °C
Reaction time: 4 h
Yield: 56.8 %

Procedure:
To a solution of 4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiazole-5-carboxamide (0.19 g, 0.50 mmol) in anhydrous 1,4-dioxane (5.0 mL) was added N,N-dimethylacetamide dimethylacetal (0.50 g, 3.50 mmol). The resulting mixture was refluxed for 16 h and concentrated in vacuo and acetic acid (5.0 mL) and hydrazine monohydrate (0.15 g, 3.00 mmol) was slowly added to the residue. The reaction mixture was stirred at 100° C. for 4 h and concentrated in vacuo. The residue was suspended in saturated aqueous sodium bicarbonate solution (150 mL) and extracted with ethyl acetate (3×80 mL). The organic layer was dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography eluted with 2-10% methanol in dichloromethane to afford the title compound as a colorless solid (0.12 g, 58%): mp 273-274° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 13.64 (s, 1H), 7.74 (d, J=8.2 Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 4.55 (s, 2H), 4.06-4.00 (m, 2H), 3.52-3.47 (m, 2H), 2.57 (s, 3H), 2.38 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 156.4, 156.3, 155.3, 153.0, 145.0, 141.6 (d, JC-F=1 Hz), 128.4, 128.1 (q, 2JC-F=32 Hz), 125.5 (q, 3JC-F=4 Hz), 124.3 (q, 1JC-F=272 Hz), 115.3, 46.5, 42.0, 41.9, 16.7, 11.5; MS (ES+) m/z 422.9 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[C:4](=[O:13])[CH2:5][CH2:6][NH:7]2.[C:14](Cl)(=[O:16])[CH3:15].O>ClCCl.N1C=CC=CC=1>[C:14]([NH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[C:4](=[O:13])[CH2:5][CH2:6][NH:7]2)(=[O:16])[CH3:15]
Reactant: Cc1ccc(N)c2c1NCCC2=O
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1ccc(C)c2c1C(=O)CCN2

Procedure:
In a mixed solvent of 20 ml of dichloromethane and 1.3 ml of pyridine was dissolved 2.0 gm of 5-amino-8-methyl-2,3-dihydroquinoline-4-one. 1.2 ml of acetyl chloride was added to the solution under ice-cooling while stirring, followed by further stirring for 4 hours. After the addition of water, the reaction mixture was extracted with chloroform, washed with saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was crystallized in ether to obtain 1.24 gm of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=O.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[F:23])[NH:19][C:18]([C:24]1[CH:25]=[CH:26][C:27]([O:31][CH3:32])=[C:28]([NH2:30])[CH:29]=1)=[CH:17]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[F:23])[NH:19][C:18]([C:24]1[CH:25]=[CH:26][C:27]([O:31][CH3:32])=[C:28]([NH:30][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([OH:1])[CH:3]=3)[CH:29]=1)=[CH:17]2
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NCc1ccc([N+](=O)[O-])c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
3-Hydroxy-4-nitrobenzaldehyde (0.334 g, 2.0 mmol) was added to a stirred mixture of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.548 g, 2.0 mmol) in methylene chloride (125 mL), followed by acetic acid (0.2 g). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.46 g, 2.2 mmol) was added in one portion, and the resulting homogeneous solution was stirred at room temperature for 3 days. Saturated aqueous sodium bicarbonate solution (100 mL), was added and the mixture was stirred for 2 hours. The mixture was shaken; the organic layer was separated and dried over Na2SO4. The solvent was evaporated to give a red-orange gum. Recrystallization from methanol gave the product (350 mg), mp 170-171° C.
Reaction SMILES: C([O:8][C:9]1[CH:40]=[CH:39][C:12]([O:13][CH2:14][CH:15]([CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](=[O:38])[C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[C:28](=[O:37])[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[OH:16])=[CH:11][CH:10]=1)C1C=CC=CC=1.N1C=CC=CC=1.FC(F)(F)C(O)=O.C1CCC(N=C=NC2CCCCC2)CC1>CS(C)=O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]([C@@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](=[O:38])[C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[C:28](=[O:37])[CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:16])=[CH:39][CH:40]=1
Reactant: O=C([C@@H]1CCCN1C(=O)CCc1ccccc1)N1CCCC1C(O)COc1ccc(OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: O=C(COc1ccc(O)cc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
To a solution of (2S)-2-{2-(2-[4-(benzyloxy)phenoxy]-1-hydroxyethyl}-1-[N-(3-phenylpropionyl)-L-prolyl]pyrrolidine (1.81 g) in DMSO (30 ml) were added pyridine (0.3 ml), trifluoroacetic acid (0.15 ml) and DCC (1.2 g), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, saturated aqueous solution of sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluate: chloroform-methanol) to give 1.45 g of the title compound.
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH2:7][CH2:8][N:9]([CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])(C)(C)C>[F-].C([NH3+])(C)(C)C>[OH:29][CH2:28][CH2:27][CH2:26][CH2:25][N:9]([CH2:8][CH2:7][OH:6])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: CC(C)(C)[Si](OCCN(CCCCO)S(=O)(=O)c1ccc(-c2ccccc2)cc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[NH3+]
Agent: [F-]
Product: O=S(=O)(c1ccc(-c2ccccc2)cc1)N(CCO)CCCCO
Reaction time: 0.5 h

Procedure:
Biphenyl-4-sulfonic acid [2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-(4-hydroxy-butyl)-amide (1 g) was dissolved in tertiarybutylammonium fluoride (15 mL of 1 M in tetrahydrafuran) and stirring for 30 minutes. The solvent was evaporated and the residue dissolved in methylene chloride, washed with water and dried over Na2SO4. The product was purified by column chromatography (ethyl acetate: light petroleum) to give the title compound. δC (DMSO, 62.9 MHz): 25.1, 29.5, 48.9, 51.2, 57.9, 60.3, 127.1, 127.2, 127.6, 128.6, 129.2, 138.1, 138.4 and 144.1.
Reaction SMILES: C(O[C:6]([NH:8][NH:9][CH2:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1[OH:18])=O)(C)(C)C.CCO.[CH3:22][O:23][C:24](=[O:33])/[C:25](=C\N(C)C)/[C:26](=O)[CH3:27]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:22][O:23][C:24]([C:25]1[CH:6]=[N:8][N:9]([CH2:10][C:11]2[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=2[OH:18])[C:26]=1[CH3:27])=[O:33]
Reactant: CC(C)(C)OC(=O)NNCc1cc(Br)ccc1O
Reactant: COC(=O)/C(=C\N(C)C)C(C)=O
Solvent: ClCCl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cnn(Cc2cc(Br)ccc2O)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.6 %

Procedure:
A suspension of N′-(5-bromo-2-hydroxy-benzyl)-hydrazinecarboxylic acid tert-butyl ester 1 2 g (6.3 mmol) in a mixture of CH2Cl2 (8 mL) and TFA (8 mL) was stirred at RT for 2 hours. The volatiles were removed in vacuo. The residue was dissolved in abs. EtOH (7 mL) and added to 2-[1-Dimethylamino-meth-(Z)-ylidene]-3-oxo-butyric acid methyl ester (12 mmol) at RT. The resulting mixture was stirred at RT for 1 hour, refluxed for 2 h, let cool down and stirred at RT for 16 h. The oily residue obtained after removing the volatiles in vacuo was purified by MPLC (10 g SiO2 cartridge, eluent 90% iso-hexane-10% EtOAc) to give 0.38 g of 1-(5-Bromo-2-hydroxy-benzyl)-5-methyl-1H-pyrazole-4-carboxylic acid methyl ester, 5 and 1-(5-Bromo-2-hydroxy-benzyl)-3-methyl-1H-pyrazole-4-carboxylic acid methyl ester 6 as a mixture.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]#[C:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=3)=[CH:9][N:8]([C@@H:23]3[CH2:27][N:26](C(OC(C)(C)C)=O)[C@H:25]([C:35]([O:37][CH3:38])=[O:36])[CH2:24]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[C:3]2[C:10]([C:11]#[C:12][C:13]3[CH:14]=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=3)=[CH:9][N:8]([C@@H:23]3[CH2:27][NH:26][C@H:25]([C:35]([O:37][CH3:38])=[O:36])[CH2:24]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COC(=O)[C@@H]1C[C@H](n2cc(C#Cc3cc(OC)cc(OC)c3)c3c(N)ncnc32)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@H](n2cc(C#Cc3cc(OC)cc(OC)c3)c3c(N)ncnc32)CN1

Procedure:
A solution of (2S,4S)-1-tert-butyl 2-methyl 4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1,2-dicarboxylate (24 mg) obtained in Step 6 above in methylene chloride (2.0 ml) and TFA (2.0 ml) was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the resulting residue was purified by basic silica gel column chromatography (developing solvent: chloroform/methanol). The title compound was thus obtained as a light-yellow, amorphous substance (11.9 mg). Physical properties: m/z [M+H]+ 422.1