Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH2:11][C:12]#[N:13].[CH2:14](Br)[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16]>C(#N)C>[Cl:1][C:2]1[N:10]=[C:5]2[N:6]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:16])[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH2:11][C:12]#[N:13]
Reactant: N#CCc1c(Cl)[nH]c2ncccc12
Reactant: O=C(CBr)c1ccccc1
Solvent: CC#N
Product: N#CCc1c2cccn(CC(=O)c3ccccc3)c-2nc1Cl
Yield: 9 %

Procedure:
A solution of 0,66 g (3,4 mmol) 2-chloro-3-cyanomethyl-pyrrolo[2,3-b]pyridine, and 0,65 g (3,8 mmol) phenacyl bromide in 40 ml acetonitrile was refluxed for 20 h. The mixture was allowed to cool and the precipitated product was filtred off and recrystallized from acetonitrile. Chromatography on silica gel eluting with ethyl acetate gave the desired product (0,094g, 9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1.[Al+3].[Cl-].[Cl-].[Cl-]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][C:8]=1[C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:17]
Reactant: O=C1CCC(=O)O1
Reactant: COc1cccc(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)CCC(=O)O)c(OC)c1
Yield: 68 %

Procedure:
1,3-Dimethoxybenzene 10 h (99%, 6 eq) was reacted with succinic anhydride (99%, 1 eq) and AlCl3 (95%, 2 eq) for 19 h according to the general procedure. Recrystallization in EtOH gave white crystals of 11 h in 68% yield. 1H-NMR: 7.89 (d, 1H, J=8.7 Hz, Ar--H; 6.55 (dd, 1H, J=8.7 and 2.3 Hz, Ar--H); 6.46 (d, 1H, J=2.3 Hz, Ar--H); 3.91 (s, 3H, OCH3); 3.86 (s, 3H, OCH3); 3.30 (t, 2H, J=6.6 Hz, CH2CH2COOH); 2.73(t, 2H, J=6.6 Hz, CH2CH2COOH). 13C-NMR: 197.62; 164.79; 161.23; 132.96; 105.29; 98.31; 55.54; 55.47; 38.42; 28.67.
Reaction SMILES: Cl.[CH3:2][C:3]1([OH:8])[CH2:7][CH2:6][NH:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[CH3:2][C:3]1([OH:8])[CH2:7][CH2:6][N:5]([CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:16])[CH2:4]1
Reactant: BrCCc1ccccc1
Reactant: CC1(O)CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(c1ccccc1)N1CCC(C)(O)C1
Reaction time: 12 h
Yield: 75.2 %

Procedure:
According to Example 15, 3-methylpyrrolidin-3-ol hydrochloride was synthesized. To a 100 mL reaction flask were added 3-methylpyrrolidin-3-ol hydrochloride (1 g, 7.2 mmol), anhydrous potassium carbonate (2.5 g, 18 mmol) and acetonitrile (15 mL). To the resulting mixture was slowly added a solution of 2-bromoethylbenzene (1.2 g, 6.48 mmol) in acetonitrile dropwisely at 85° C. The reaction was conducted for 12 hours. After the completion of reaction monitored by TLC, the resulting mixture was evaporated under reduced pressure to remove acetonitrile. To the residue was added a mixed solution of dichloromethane and water for extraction. The organic phase was dried over anhydrous sodium sulfate, and evaporated to remove the solvent to produce a crude product. The crude product was purified by column chromatography (silica gel column, eluted with petroleum ether:ethyl acetate=30:1 (volumetric ratio)) to produce 3-methyl-1-phenylethylpyrrolidin-3-ol (1 g) in a yield of 75.2%.
Reaction SMILES: C([O:8][C:9]1[CH:46]=[CH:45][C:12]([O:13][CH2:14][C@@H:15]([OH:44])[CH2:16][NH:17][CH2:18][CH2:19][C:20]2[CH:43]=[CH:42][C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:32])[CH2:27][CH2:26]3)=[CH:22][CH:21]=2)=[CH:11][C:10]=1[NH:47][S:48]([CH3:51])(=[O:50])=[O:49])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:34]([NH:33][C:31]([N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:23]2[CH:22]=[CH:21][C:20]([CH2:19][CH2:18][NH:17][CH2:16][C@H:15]([OH:44])[CH2:14][O:13][C:12]3[CH:45]=[CH:46][C:9]([OH:8])=[C:10]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:11]=3)=[CH:43][CH:42]=2)[CH2:26][CH2:27]1)=[O:32])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: [H][H]
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)c(NS(C)(=O)=O)c3)cc2)CC1
Yield: 38.6 %

Procedure:
4-(4-(2-[((2S)-3-(4-(Benzyloxy)-3-[(methylsulfonyl)amino]phenoxy)-2-hydroxypropyl)amino]ethyl}anilino)-N-octyl-1-piperidinecarboxamide (0.15 g, 0.207 mmol) was dissolved in ethanol (70 mL) and 10% palladium on carbon (0.043 g) added. The solution was shaken in a Parr apparatus at 50 psi hydrogen atmosphere for 16 hours, filtered through a Celite pad and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel Merck-60 (eluant: 10:1 going to 5:1 chloroform-methanol containing 2% triethylamine) to give the title compound (0.052 g, 0.08 mmol).
Reaction SMILES: [C:1]([C@@H:4]1[CH2:7][C@H:6]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]1([CH3:20])[CH3:19])(=[O:3])C.[OH2:21]>O1CCOCC1>[CH2:11]([O:10][C:9]([NH:8][C@H:6]1[CH2:7][C@@H:4]([C:1]([OH:3])=[O:21])[C:5]1([CH3:20])[CH3:19])=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)[C@@H]1C[C@H](NC(=O)OCc2ccccc2)C1(C)C
Reactant: O
Solvent: C1COCCO1
Product: CC1(C)[C@@H](NC(=O)OCc2ccccc2)C[C@H]1C(=O)O
Reaction time: 5 h
Yield: 92 %

Procedure:
To a stirred solution of benzyl (1S,3R)-3-acetyl-2,2-dimethylcyclobutylcarbamate (Step 2, 1.3 g, 4.72 mmol) in dioxane (90 ml): water (30 ml) aq. NaOBr solution (80 ml) was added slowly at about −5° C. and stirred at the same temperature for about 5 hours. After completion of the reaction (monitored by TLC), the reaction mixture was washed with methyl t-butyl ether and the aqueous layer was adjusted pH (2-3) with 1N HCl and extracted with EtOAc, dried over Na2SO4 and the solvent was evaporated then the resulting crude was purified by silica gel column (100-200 mesh, elution: 20% EtOAc in Hexane) to afford the title compound as a semi solid. Wt: 1.2 g: Yield: 92%; 1H NMR (300 MHZ, CDCl3): δ 7.38-7.31 (m, 5H), 5.09 (q, 2H, J=10.8 Hz), 4.89 (d, 1H, J=8.4 Hz), 3.98-3.89 (m, 1H), 2.64-2.53 (m, 1H), 2.51-2.26 (m, 2H), 1.32 (s, 3H), 0.98 (s, 3H). IR (KBr, cm−1): 3411, 3351, 2961, 1705, 1532, 1456, 1412, 1343, 1256, 1044, 1003, 776, 697; Mass: [M+Na]+ 300 (100%).
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].[H-].[Na+].COC[O:11][C:12]1[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=1[CH:14]=[CH:15][C:16](OCC)=O>O1CCCC1>[OH:11][C:12]1[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=1[CH:14]=[CH:15][C:16]1[O:5][N:4]=[C:1]([CH3:2])[N:3]=1
Reactant: CC(N)=NO
Reactant: CCOC(=O)C=Cc1ccccc1OCOC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(C=Cc2ccccc2O)n1
Temperature: 50 °C
Yield: 58.4 %

Procedure:
Acetamide oxime (7.5 g), molecular sieves (4A) (10 g) and sodium hydride (5 g) were added to tetrahydrofuran (200 ml) and the mixture was refluxed under heating. To this reaction mixture was added dropwise ethyl 2-(methoxymethyloxy)cinnamate (12 g) and the mixture was continuously heated for 2 hr. After cooling, the mixture was poured on ice and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. Thereto were added tetrahydrofuran (10 ml) and 6N hydrochloric acid (20 ml) and the mixture was stirred with heating at 50° C. for 30 min to allow precipitation of crystals. The crystals were collected by filtration and dried to give the title compound (6.0 g) as white crystals, melting point 184–186° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)[NH:11][C:10]1[CH2:9][CH:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:7][CH2:6][C:5]2=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[CH:6][C:5]2=1
Reactant: CCOC(=O)C1CCc2c([nH]c3c(C(N)=O)cc(Br)cc23)C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Br)cc12
Temperature: 25 °C
Yield: 118.4 %

Procedure:
A stirred suspension of ethyl 6-bromo-8-carbamoyl-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylate (3.93 g, 10.76 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (5.37 g, 23.67 mmol) in toluene (60 mL) was heated at reflux for 4 h. The reaction mixture was cooled to room temperature and the solid was filtered, washed with toluene, and air-dried. The solid was suspended in ethyl acetate, the solid filtered, washed with MeOH and air-dried to furnish 4.6 g of ethyl 6-bromo-8-carbamoyl-9H-carbazole-2-carboxylate which was taken as such to the next reaction. MS (ESI) m/z 361.1/363.1 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.76 (s, 1H), 8.60 (d, J=1.76 Hz, 1H), 8.36 (d, J=0.88 Hz, 1H), 8.25 (d, J=8.35 Hz, 1H), 8.23 (br. s., 1H), 8.13 (d, J=1.76 Hz, 1H), 7.73 (dd, J=8.24, 1.43 Hz, 1H), 7.59 (br. s., 1H), 4.29 (q, J=7.18 Hz, 2H), 1.30 (t, J=7.14 Hz, 3H).
Reaction SMILES: CO.C(OC(=O)[N:9]([CH2:31][C:32]1[CH:41]=[CH:40][C:35]2[O:36][CH2:37][CH2:38][O:39][C:34]=2[CH:33]=1)[CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=3)[C:21]([CH3:29])=[CH:20][C:19]2=[O:30])[CH2:12][CH2:11]1)(C)(C)C.[ClH:43].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:43].[O:36]1[C:35]2[CH:40]=[CH:41][C:32]([CH2:31][NH:9][CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=5)[C:21]([CH3:29])=[CH:20][C:19]4=[O:30])[CH2:12][CH2:11]3)=[CH:33][C:34]=2[O:39][CH2:38][CH2:37]1
Reactant: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(F)ccc12
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2cc(F)ccc12
Reaction time: 4 h

Procedure:
To 1.5 mL of methanol solution containing 0.17 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-fluoro-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 1.5 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added, and stirred for 4 hours. Ethyl acetate was added, and the resulting solid was filtered to give 0.15 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-4-methylquinolin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[C:8](Cl)=[N:9][C:10](Cl)=[N:11][CH:12]=1)[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[C:8]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:9][C:10]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1cnc(Cl)nc1Cl)c1ccncc1
Reactant: Nc1ccccc1
Product: CCOC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1ccncc1
Temperature: 120 °C

Procedure:
A mixture of 3-(2,4-dichloro-pyrimidin-5-yl)-2-pyridin-4-yl-propionic acid ethyl ester (0.68 g, 2.0 mmol) (from Example 9a supra) and aniline (3.0 mL) (Aldrich) was heated at 120° C. for 2 hours. The reaction mixture was washed with hexanes (50 mL×3) and the supernatant was decanted off after each time. The residue was then dissolved in ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (30 mL), water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was triturated with ethyl acetate-hexanes. The resulting solid was collected by filtration and washed with diethyl ether to give 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-pyridin-4-yl-propionic acid ethyl ester as a brown solid which was used in the next step without further purification. (Yield 0.54 g, 83.1%).
Reaction SMILES: [O:1]=[C:2]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][C:26]2=[O:35])[CH2:21][CH2:20]1)[CH2:3][CH:4]([CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:5](O)=[O:6].[N:36]1([CH2:48][C:49]([O:51][CH3:52])=[O:50])[CH2:41][CH2:40][CH:39]([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:38][CH2:37]1>>[O:1]=[C:2]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][C:26]2=[O:35])[CH2:23][CH2:24]1)[CH2:3][CH:4]([CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:5]([N:45]1[CH2:46][CH2:47][CH:42]([CH:39]2[CH2:40][CH2:41][N:36]([CH2:48][C:49]([O:51][CH3:52])=[O:50])[CH2:37][CH2:38]2)[CH2:43][CH2:44]1)=[O:6]
Reactant: COC(=O)CN1CCC(C2CCNCC2)CC1
Reactant: O=C(O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)Cc1ccc2c(c1)CCCC2
Product: COC(=O)CN1CCC(C2CCN(C(=O)C(CC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)Cc3ccc4c(c3)CCCC4)CC2)CC1

Procedure:
Prepared analogously to Example 76e) from 4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-2-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-butanoic acid and methyl [4,4′]bipiperidinyl-1-yl-acetate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:17]2[CH2:21][NH:20][C:19](=[O:22])[CH2:18]2)[C:5]([O:14][CH2:15][CH3:16])=[C:6]([C:8]2([CH3:13])OCC[O:9]2)[CH:7]=1.Cl.O>CO>[C:8]([C:6]1[C:5]([O:14][CH2:15][CH3:16])=[C:4]([CH:17]2[CH2:21][NH:20][C:19](=[O:22])[CH2:18]2)[C:3]([F:23])=[C:2]([Cl:1])[CH:7]=1)(=[O:9])[CH3:13]
Reactant: CCOc1c(C2(C)OCCO2)cc(Cl)c(F)c1C1CNC(=O)C1
Agent: Cl
Solvent: O
Solvent: CO
Product: CCOc1c(C(C)=O)cc(Cl)c(F)c1C1CNC(=O)C1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
The separated enantiomers from step 4 were each processed individually to the final compounds. A solution of 4-[3-chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]pyrrolidin-2-one (1.7 g, 5.0 mmol) (from Step 4) in methanol (17 mL) was treated with 6.0 M hydrogen chloride in water (11 mL, 69 mmol) dropwise and stirred 20° C. for 30 min. The reaction mixture was added dropwise to ice cooled saturated sodium bicarbonate solution (75 ml) and extracted with ethyl acetate (2×100 ml). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the desired products [from peak 1 (1.5 g, 99%); from peak 2 (1.5 g, 99%)] that were used without further purification. From peak 1: 1H NMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.70 (d, J=8.6 Hz, 1H), 4.16-3.99 (m, 1H), 3.83 (q, J=7.0 Hz, 2H), 3.65-3.54 (m, 1H), 3.30-3.23 (m, 1H), 2.55 (s, 3H), 2.33 (dd, J=16.8, 8.4 Hz, 1H), 1.30 (t, J=7.0 Hz, 3H). LCMS for C14H16ClFNO3 (M+H)+: m/z=300.1; Found: 300.0. From peak 2: 1H NMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.70 (d, J=8.6 Hz, 1H), 4.13-4.00 (m, 1H), 3.87-3.77 (m, 2H), 3.65-3.55 (m, 1H), 3.31-3.23 (m, 1H), 2.55 (s, 3H), 2.32 (ddd, J=16.9, 8.4, 1.6 Hz, 1H), 1.30 (t, J=7.0 Hz, 3H). LCMS for C14H16ClFNO3 (M+H)+: m/z=300.1; Found: 300.1.
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[C:3]1=O.[S:15]1[CH2:20]CC(=O)[CH2:17][CH2:16]1.N>CO>[N+:8]([C:6]1[CH:7]=[N:2][C:3]2[CH2:17][CH2:16][S:15][CH2:20][C:4]=2[CH:5]=1)([O-:10])=[O:9]
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Reactant: O=C1CCSCC1
Agent: N
Solvent: CO
Product: O=[N+]([O-])c1cnc2c(c1)CSCC2
Yield: 99.5 %

Procedure:
A mixture of 1-methyl-3,5-dinitro-2-pyridone (0.6 g, 3.0 mmol), tetrahydrothiopyran-4-one (0.35 g, 3.0 mmol) and ammonia solution in methanol (2.0M, 30 mL) was refluxed for 6 h. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The soluble portico was flash chromatographed over silica pel (eluent: 90:1 v/v ethyl acetate-hexane) to give a yellow solid (0.586 g, 99% yield).
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH3:5].O.O.[SH2:16].[Na].[Cl-].[NH4+]>CO>[CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12](=[S:16])[NH2:13])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNc1nc[nH]c1C#N
Reactant: S
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: O
Solvent: CO
Product: CCCCCNc1nc[nH]c1C(N)=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
A mixture of 4-(pentylamino)-1H-imidazole-5-carbonitrile (25 g, 0.14 mol), sodium hydrogen sulfide dihydrate (26 g, 0.28 mol) and ammonium chloride (7.5 g, 0.14 mol) in methanol (400 mL) was stirred at room temperature overnight. The conversion was about 60% according to analytical LCMS. The mixture was then stirred at 50° C. for 3 hours. The methanol was removed and the residue was diluted with water and EtOAc. The organic layer was washed with water and brine respectively, dried and concentrated to yield the crude product (30.0 g), which was used for next step without further purification. LCMS calculated for C9H17N4S (M+H): 213.1. found: 213.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[Br:9]Br>C(Cl)(Cl)Cl>[Br:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Nc1cccc(Cl)n1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Nc1nc(Cl)ccc1Br
Reaction time: 8 h
Yield: 26.7 %

Procedure:
6-Chloro-pyridin-2-ylamine (5 g, 38.89 mmol) is dissolved in chloroform (250 mL) and a solution of bromine (1.33 mL, 26 mmol) in chloroform (50 mL) is slowly added over a one hour period. During the addition a precipitate (hydrobromide salt of the starting material) forms. After stirring overnight the reaction mixture is filtered, the filtrate is evaporated and the residue is partitioned between ethyl acetate and 1 M sodium carbonate solution. The organic phase is separated, evaporated and the solid residue purified by flash chromatography (silica gel, 15% ethyl acetate in petroleum ether) affording the title compound (1.44 g, 17%) as a solid. The material is carried through the next three reaction steps.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:13]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[NH:21][N:20]=[C:19]3[NH2:23])[N:11]=[C:10]2[N:24]([CH3:27])[N:25]=[CH:26][C:9]=12.[CH3:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>CN(C=O)C>[CH3:27][N:24]1[C:10]2=[N:11][C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:22]=3[NH:21][N:20]=[C:19]4[NH2:23])=[CH:13][C:8]([O:38][C:35]3[CH:34]=[CH:33][C:32]([S:29]([CH3:28])(=[O:31])=[O:30])=[CH:37][CH:36]=3)=[C:9]2[CH:26]=[N:25]1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4c(N)n[nH]c34)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ncc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(-c3cccc4c(N)n[nH]c34)nc21
Temperature: 155 °C
Yield: 44 %

Procedure:
Potassium carbonate (0.14 g, 1.04 mmol) was added to a solution of 7-(4-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-1H-indazol-3-amine 16 (0.30 g, 0.1046 mmol) and 4-methylsulfonyl phenol 8a (0.036 g, 0.2 mmol) in 2 mL DMF. Nitrogen was bubbled through the solution. The reaction mixture was heated in a microwave at 155° C. for 40 minutes. The crude compound was purified by mass directed purification to obtain 20 mg, 40% of 105 as a yellow solid. 1H NMR (400 MHz, DMSO) δ 11.53 (s, 1H), 8.21-7.64 (m, 6H), 7.64-7.40 (m, 3H), 7.40-6.91 (m, 1H), 5.51 (s, 2H), 4.12 (m, 3H), 3.21 (m, 3H). MS (ESI) m/z 435.1 (M+1)+
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:25])[CH2:14][S:15][C:16]1[N:21]=[C:20]([Cl:22])[CH:19]=[C:18]([NH:23][NH2:24])[N:17]=1)[CH3:11]>C(O)(=O)C>[CH2:10]([O:12][C:13](=[O:25])[CH2:14][S:15][C:16]1[N:21]=[C:20]([Cl:22])[CH:19]=[C:18]([NH:23][N:24]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:17]=1)[CH3:11]
Reactant: CCOC(=O)CSc1nc(Cl)cc(NN)n1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CC(=O)O
Product: CCOC(=O)CSc1nc(Cl)cc(NN=Cc2ccc(Cl)cc2)n1

Procedure:
To a solution of 2.1 g of p-chlorobenzaldehyde in 25 ml. of glacial acetic acid was added a solution of 3.9 g of (4-chloro-6-hydrazino-2-pyrimidinylthio) acetic acid ethyl ester in 100 ml. of glacial acetic acid. The reaction mixture was warmed on a steam bath for a few minutes and then cooled in ice. The resulting precipitate was collected, washed with petroleum ether and recrystallized twice from ethanol affording 3.6 g of product, mp. 162°-165°C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[N:10]([CH2:27][CH:28]2[CH2:30][CH2:29]2)[C:11](=[O:26])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([CH:24]=[O:25])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].O1CCC[CH2:33]1>[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[N:10]([CH2:27][C:28]([CH3:30])([CH3:33])[CH3:29])[C:11](=[O:26])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([CH:24]=[O:25])=[CH:14][CH:13]=2)([CH3:3])([CH3:2])[CH3:4]
Reactant: C1CCOC1
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC2CC2)c(=O)c2ccc(C=O)cc12
Agent: [Mn+4]
Agent: [O-2]
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.6 %

Procedure:
To a solution of tert-butyl(4-butoxy-2-cyclopropylmethyl-6-formyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (2.27 g, 6.2 mmol) in tetrahydrofuran (30 mL) was added manganese dioxide (8.1 g) and the mixture was stirred at room temperature for 12 h. Manganese dioxide was filtered off and the mother liquor was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl(4-butoxy-6-formyl-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (2.52 g, 91.6%) as crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[C:17]([F:26])[CH:16]=3)[CH2:12][N:11]([C:27]([O:29]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:10]2)[O:6][N:5]=1)[CH3:2].Cl.[OH:40][CH:41]1[CH2:44][NH:43][CH2:42]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[C:17]([F:26])[CH:16]=3)[CH2:12][N:11]([C:27]([N:43]3[CH2:44][CH:41]([OH:40])[CH2:42]3)=[O:29])[CH2:10]2)[O:6][N:5]=1)[CH3:2]
Reactant: OC1CNC1
Reactant: CCOc1noc(C2CC(c3ccc(OC(F)(F)F)c(F)c3)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1noc(C2CC(c3ccc(OC(F)(F)F)c(F)c3)CN(C(=O)N3CC(O)C3)C2)n1

Procedure:
145 mg (0.23 mmol) of the compound from Example 65A, 76 mg (0.68 mmol) of 3-hydroxyazetidine hydrochloride and 62 mg (0.45 mmol) of potassium carbonate were initially charged in 4.5 ml of DMF and reacted in the microwave at 150° C. for 15 minutes. The reaction mixture was purified by means of preparative HPLC. Yield: 41 mg (36% of theory)
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[CH2:14][CH2:13]1)=[O:11])=O)(C)(C)C.Cl>CCOC(C)=O>[ClH:36].[NH2:8][C@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:10]([N:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[CH2:16][CH2:17]1)=[O:11]
Reactant: CN(C)C(=O)c1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1

Procedure:
(2-{4-[(2R)-2-Amino-3-(4-chlorophenyl)propanoyl]-piperazinyl}phenyl)-N,N-dimethylcarboxamide HCl salt was prepared according to the procedure described in Preparation XVI by using [2-(4-{(2R)-2-[(tert-butoxy)carbonylamino]-3-(4-chlorophenyl)propanoyl}-piperazinyl)phenyl]-N,N-dimethylcarboxamide (Step 4) (240 mg, 0.46 mmol) and a satd soln of HCl in EtOAc (10 mL). The white solid that formed was isolated by filtration (200 mg). MS (ESI, pos.ion) m/z: 415 (M+H). Calc'd for C22H28Cl2N4O2: 451.39.