Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][C@@H:7]([CH2:11][CH2:12][C@@H:13]([C:17](=[O:35])[NH:18][C@H:19]2[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])[C:20]2=[O:34])[CH2:14][CH2:15][CH3:16])[C:8](O)=[O:9])=[CH:4][CH:3]=1.[NH2:38][C@H:39]1[CH2:45][CH2:44][S:43][C@H:42]2[CH2:46][CH2:47][CH2:48][C@@H:49]([C:50]([O:52][CH3:53])=[O:51])[N:41]2[C:40]1=[O:54]>>[F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][C@@H:7]([CH2:11][CH2:12][C@@H:13]([C:17](=[O:35])[NH:18][C@H:19]2[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])[C:20]2=[O:34])[CH2:14][CH2:15][CH3:16])[C:8]([NH:38][C@H:39]2[CH2:45][CH2:44][S:43][C@H:42]3[CH2:46][CH2:47][CH2:48][C@@H:49]([C:50]([O:52][CH3:53])=[O:51])[N:41]3[C:40]2=[O:54])=[O:9])=[CH:4][CH:3]=1
Reactant: CCC[C@@H](CC[C@H](Cc1ccc(F)cc1)C(=O)O)C(=O)N[C@H]1CCCCN(c2ccccc2OC)C1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N21
Product: CCC[C@@H](CC[C@H](Cc1ccc(F)cc1)C(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)OC)N2C1=O)C(=O)N[C@H]1CCCCN(c2ccccc2OC)C1=O

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5S)-2-(4-fluorobenzyl)-5-((S)-1-(2-methoxyphenyl)-2-oxoazepan-3-ylcarbamoyl)octanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 76 (10 mg, 0.020 mmol) and (4S,7S,10aS)-methyl 4-amino-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate (5.5 mg, 0.021 mmol) to give a white solid (10 mg, 70% yield). Anal. Calcd. for C40H53FN4O7S m/z 752.7. found: 753.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.53-7.43 (1H, m), 7.31 (1H, t, J=8.0 Hz), 7.28-7.18 (1H, m), 7.14-7.04 (3H, m), 7.01-6.95 (2H, m), 6.88 (2H, t, J=8.8 Hz), 5.35-5.27 (1H, m), 5.15-5.09 (1H, m), 5.04-4.95 (1H, m), 4.94-4.85 (1H, m), 4.05-3.90 (1H, m), 3.82 (3H, s), 3.69 (3H, s), 3.53-3.36 (1H, m), 3.22-3.06 (1H, m), 2.86-2.65 (3H, m), 2.45-2.32 (2H, m), 2.25-2.14 (1H, m), 2.12-1.87 (5H, m), 1.87-1.30 (14H, m), 1.30-1.20 (2H, m), 0.87 (3H, t, J=7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[C:5]2[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1.[C:12]([O:15]C(=O)C)(=[O:14])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([O:15][C:12](=[O:14])[CH3:13])[CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: [O-][n+]1cc(Cl)cc2c1CCC2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC1CCc2cc(Cl)cnc21

Procedure:
A solution of 3-chloro-6,7-dihydro-5H-[1]pyrindine 1-oxide (2.07 g, 12.2 mmol) in acetic acid anhydride (62.2 ml, 659 mmol) was stirred at 110° C. for 20 hours. For the workup, the solvent was removed at reduced pressure and the residue quenched with saturated aqueous solution of sodium hydrogen carbonate. The aqueous phase was extracted with dichloromethane, the resulting organic layers combined and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 70:30 as the eluent. The acetic acid 3-chloro-6,7-dihydro-5H-[1]pyrindin-7-yl ester was obtained as a red liquid (1.57 g, 61%); (calculated) C10H10ClNO2 [211.65]; (found) [M+H]+=212.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6]C)=O)#[C-:2].Cl.[F:9][C@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.C(N(CC)CC)C>CO>[F:9][C@H:10]1[CH2:14][CH2:13][N:12]([C:4](=[O:6])[CH2:3][N+:1]#[C-:2])[CH2:11]1
Reactant: [C-]#[N+]CC(=O)OC
Reactant: F[C@H]1CCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: [C-]#[N+]CC(=O)N1CC[C@H](F)C1
Yield: 79.1 %

Procedure:
To stirred and cooled (0° C.) methyl isocyanoacetate (96% technical grade, 1.18 g, 11.9 mmol) was slowly added (S)-(+)-3-fluoropyrrolidine hydrochloride (97%, 1.5 g, 11.9 mmol), triethylamine (1.67 mL, 11.9 mmol) and MeOH (3 mL). The mixture was stirred for 15 h at RT and concentrated. The mixture was stirred for 15 h at RT and concentrated. Water was added (50 mL) and the mixture was extracted with EtOAc (3×50 mL), dried over MgSO4, filtered and evaporated to obtained crude 1-((S)-3-fluoropyrrolidin-1-yl)-2-isocyanoethanone VIB 01166 (1.47 g, 79% yield) as a brown oil which was used in the next step without purification.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([N:26]5[CH:30]=[CH:29][CH:28]=[CH:27]5)[CH:24]=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[S:6][CH:7]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.[I-].[K+]>CO.O>[N:31]1([CH2:2][C:3]2[N:4]=[C:5]([C:8]3[CH:9]=[C:10]([C:14]4[CH2:20][C:19](=[O:21])[NH:18][C:17]5[CH:22]=[C:23]([N:26]6[CH:30]=[CH:29][CH:28]=[CH:27]6)[CH:24]=[CH:25][C:16]=5[N:15]=4)[CH:11]=[CH:12][CH:13]=3)[S:6][CH:7]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: O=C1CC(c2cccc(-c3nc(CCl)cs3)c2)=Nc2ccc(-n3cccc3)cc2N1
Reactant: C1COCCN1
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C1CC(c2cccc(-c3nc(CN4CCOCC4)cs3)c2)=Nc2ccc(-n3cccc3)cc2N1
Temperature: 40 °C

Procedure:
A mixture of 4-[3-(4-(chloromethyl)-thiazol-2-yl)-phenyl]-8-pyrrol-1-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (cf. Example 35) (65 mg, 0.15 mmol), morpholine (0.11 mL, 1.2 mmol) and potassium iodide (5 mg, 0.03 mmol) in methanol (1 mL) was heated to 40° C. for 1 h. The mixture was diluted with H2O and the precipitate formed was collected by filtration and chromatographed on silica gel using EtOAc/methanol (10:1) as eluent to give the title compound as a light-brown solid.
Reaction SMILES: C([N:17]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]#[N:42])[CH:36]=1)CCCCCCCCCCCCCCCC)CCCCCCCCCCCCCCC.CCCCCC.N>C(O)C>[NH2:17][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][NH2:42])[CH:36]=1
Reactant: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C#N)c1
Agent: N
Solvent: CCCCCC
Solvent: CCO
Product: NCc1cccc(CN)c1
Reaction time: 4 h
Yield: 290.7 %

Procedure:
1-(Dihexadecyl)aminomethyl-3-cyanobenzene (1,814 g.) was placed in an autoclave (15 gal.) with a mixture of hexane (1.98 l.), ethanol (17.82 l.) and ammonia (3,627 g.). Said mixture was prepared in advance by saturating the ethanol-hexane mixture with ammonia gas. The saturated mixture was refrigerated until it was ready for use. Raney nickel (3,689 g., wet weight) was added. The Raney nickel W2 is weighed as a wet slurry, the form in which it is obtained from W. R. Grace as Raney nickel No. 28. This differs from the standard W2 Raney nickel in that it is slurried in water rather than benzene. For the present process, the difference is inconsequential. The mixture was contacted with hydrogen gas maintained at a pressure of 50 psig. for four hours at room temperature. After the uptake of hydrogen ceased, the mixture was filtered and the filtrate concentrated to an oil by vacuum distillation. The oil was dissolved in methylene chloride (4.0 l.) and washed once with water (2.0 l.) and three times with a saturated sodium chloride solution (1.0 l.). The clear methylene chloride solution was then dried over magnesium sulfate (454 g.), filtered and concentrated to an oil again to yield 1-dihexadecyl)aminomethyl-3-aminomethylbenzene (1,236 g., 68% yield). The purity of the product was determined by thin layer chromatography. The dihydrochloride salt was prepared by dissolving the 1-(dihexadecyl)aminomethyl-3-aminomethylbenzene (1,236 g.) in ethanol (5.0 l.) and ethanol (5.0 l.) containing dissolved hydrogen chloride gas (800 g.) was added. The mixture was stirred for one hour at room temperature and the solvent removed by vacuum distillation. Ether (8.0 l.) was added to the residue until a clear solution was obtained. Cooling with a dry ice/acetone bath followed by the slow addition of acetonitrile effected the precipitation of 1-(dihexadecyl)aminomethyl-3-aminomethylbenzene diamine dihydrochloride as a fine white crystalline material. The overall yield for the two processes was 62.5%.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([N:6]=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.[CH2:28]=[C:29]([CH3:31])[CH3:30]>C(#N)C>[CH3:28][C:29]1([CH3:31])[C:4]2[C:5](=[CH:17][CH:18]=[C:2]([CH3:1])[CH:3]=2)[NH:6][CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[CH2:30]1
Reactant: C=C(C)C
Reactant: Cc1ccc(N=Cc2ccccc2[N+](=O)[O-])cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC#N
Product: Cc1ccc2c(c1)C(C)(C)CC(c1ccccc1[N+](=O)[O-])N2
Temperature: 90 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To a suspension of 4-methyl-N-(2-nitrobenzylidene)aniline (10 g) and boron trifluoride etherate (3 mL) in anhydrous acetonitrile was added isobutene (70 mL, pre-cooled to −78° C.) at ice-bath. After addition, the resulting mixture was stirred at 90° C. in sealed tube overnight. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give 4,4,6-trimethyl-2-(2-nitrophenyl)-1,2,3,4-tetrahydroquinoline (10.5 g, yield 85.4%). LC/MS m/e obsd. (ESI+) [(M+H)+] 297.2.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([F:20])[CH:13]=2)[CH:9]=[N:8][CH:7]=1.Br[CH2:22][CH2:23][O:24][CH2:25][CH2:26]Br>C(#N)C.C(N(CC)CC)C>[F:20][C:14]1[CH:13]=[C:12]([CH2:11][N:10]2[C:6]([CH2:5][CH2:4][N:3]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:7][N:8]=[CH:9]2)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: N#Cc1ccc(Cn2cncc2CCN)cc1F
Reactant: BrCCOCCBr
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Cn2cncc2CCN2CCOCC2)cc1F

Procedure:
To a solution of 4-[5-(2-amino-ethyl)-imidazol-1-ylmethyl]-2-fluoro-benzonitrile dihydrochloride (0.92 g, 0.0029 mmol) in acetonitrile (150 mL) and triethylamine (3.2 mL) was added 2-bromoethyl ether (0.839 mL, 0.0067 mmol) and the mixture was refluxed for 48 hr. The solvents were removed in vacuo and the residue was dissolved in EtOAc which was washed twice with 1M HCl (100 mL). The HCl layers were combined and adjusted to pH=9 with solid Na2CO3 and extraxcted 3 times with EtOAc. The EtOAc layers were combined and dried with brine and MgSO4. Removal of the EtOAc in vacuo yielded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[C:11](F)=[N:12][C:13]([O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])=[CH:14][C:15]=1[NH:16][CH2:17][C@@H:18]([OH:20])[CH3:19])=O.[NH2:31][NH2:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:10]2[C:11](=[N:12][C:13]([O:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])=[CH:14][C:15]=2[NH:16][CH2:17][C@@H:18]([OH:20])[CH3:19])[NH:32][N:31]=1
Reactant: C[C@H](O)CNc1cc(Oc2ccc(F)cc2F)nc(F)c1C(=O)c1ccccc1Cl
Reactant: NN
Product: C[C@H](O)CNc1cc(Oc2ccc(F)cc2F)nc2[nH]nc(-c3ccccc3Cl)c12

Procedure:
Crude (S)-(2-Chloro-phenyl)-[6-(2,4-difluoro-phenoxy)-2-fluoro-4-(2-hydroxy-propylamino)-pyridin-3-yl]-methanone (837 mg, 1.92 mmol) was treated with hydrazine using the procedure of step 5 of Example 9 to afford 148 mg of (S)-1-[3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-b]pyridin-4-ylamino]-propan-2-ol. Mass spec., M+1=432. Mp=237.9-238.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:15])[NH:12][CH2:13][CH2:14][C:3]=12.[H-].[Na+].Cl[CH2:19][C:20]1[N:21]=[CH:22][N:23]([C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]=1[CH3:25]>CN(C)C=O.O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:15])[N:12]([CH2:19][C:20]3[N:21]=[CH:22][N:23]([C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:24]=3[CH3:25])[CH2:13][CH2:14][C:3]=12
Reactant: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1c2n(c3ccccc13)C(=O)NCC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c2n(c3ccccc13)C(=O)N(Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Temperature: 5 °C
Reaction time: 0.67 h
Yield: 64.6 %

Procedure:
To a solution of 3,4-dihydro-5-methylpyrimido[1,6-a]-indol-1(2H)-one (0.67 g) in N,N-dimethylformamide (8 ml) at 5° C. was added sodium hydride (60% in mineral oil, 0.16 g). The mixture was stirred at 5° C. for 40 minutes and then at room temperature for 15 minutes and again cooled to 5° C. 4-Chloromethyl-5-methyl-1-trityl-1H-imidazole (1.50 g) was added to the solution in small portions over two minutes. After being stirred at 5° C. for 2 hours, the reaction mixture was diluted with chilled water to give precipitates. The precipitates collected were dissolved in dichloromethane. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. Column chromatography (silica, gel, 0.5% methanol in chloroform as an eluent) of the residue, followed by recrystallization from toluene-hexane, gave 3,4-dihydro-5-methyl-2-[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrimido[1,6-a]indol-1 (2H)-one (1.16 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:17]O>>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: Cc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C)c1Cl

Procedure:
53.02 g (0.21 mol) of 2-chloro-3-methyl-4-methylsulfonylbenzoic acid were dissolved in 400 ml of methanol and HCl was passed in at reflux temperature for 3 h. The mixture was then allowed to cool and completely concentrated on a rotary evaporator.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[C:12]2[S:11][C:10]([C:13]([NH:15][C@@H:16]3[CH:21]4[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]4)[CH2:17]3)=[O:14])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[ClH:1].[NH:37]([C:38]([NH:3][C:4]1[C:12]2[S:11][C:10]([C:13]([NH:15][C@@H:16]3[CH:21]4[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]4)[CH2:17]3)=[O:14])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc12
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)Nc1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc12
Reaction time: 18 h

Procedure:
A solution of 44 mg (0.12 mmol) of 7-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 32.8 μl (0.24 mmol) of triethylamine and 28 mg (0.24 mmol) of phenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 20 mg (36.1% of theory) of the title compound are obtained.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(OC([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=O)(C)(C)C.[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([CH:60]2[CH2:62][CH2:61]2)[NH2:59])=[CH:54][CH:53]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[NH2:32][C:33]1([C:48]([NH:59][CH:58]([C:55]2[CH:54]=[CH:53][C:52]([Cl:51])=[CH:57][CH:56]=2)[CH:60]2[CH2:62][CH2:61]2)=[O:50])[CH2:34][CH2:35][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: NC(c1ccc(Cl)cc1)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: NC1(C(=O)NC(c2ccc(Cl)cc2)C2CC2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.228 g) was added to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (0.181 g), (4-chlorophenyl)(cyclopropyl)methanamine (Intermediate 3) (0.091 g) and DIPEA (0.261 mL) in DMA (5 mL) at 25° C. The resulting solution was stirred at 50° C. for 1 hour. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness. This crude material was suspended in dichloromethane (25 mL), and TFA (5 mL) was added. The reaction mixture was stirred for 1 hour, then the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness to afford the crude material as a white solid. This material was triturated under cold methanol to give the pure product, 4-amino-N-((4-chlorophenyl)(cyclopropyl)methyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide as a white solid (0.167 g, 79%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](Cl)=[O:15])[CH:5]=[CH:4][C:3]1=2.Br[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1>C(COC)OC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Zn]>[C:24]([C:23]1[CH:28]=[CH:29][C:20]([CH2:19][C:14]([C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:17])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=3[CH:7]=2)=[O:15])=[CH:21][CH:22]=1)([O:26][CH3:27])=[O:25]
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Cl)ccc21
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Zn]
Solvent: COCCOC
Product: COC(=O)c1ccc(CC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
A solution of 4 g (16 mmol) of 5,6,7, 8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carbonyl chloride and 4 g (16 mmol) of methyl 4-bromomethylbenzoate in 20 ml of dimethoxyethane was added dropwise to a solution or suspension of 0.56 g of bis(triphenylphosphine)palladium(II) dichloride and 2.1 g of zinc powder in 40 ml of dimethoxyethane at room temperature. The reaction mixture was then refluxed for 6 h. After cooling, solids were filtered off and the filtrate was heated with active carbon and filtered hot. The filtrate was concentrated and yielded after recrystallization 3x from methanol and finally from isopropanol 0.9 g of the title compound of melting point 103°-104° C.
Reaction SMILES: [CH3:1][C:2]1([S:12][CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].Cl[CH2:15][CH2:16][O:17]C1CCCCO1.CC1(C)C2C(=CC=CC=2)N(CCO)C1=O>>[OH:17][CH2:16][CH2:15][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])([S:12][CH3:13])[C:3]1=[O:11]
Reactant: CSC1(C)C(=O)Nc2ccccc21
Reactant: ClCCOC1CCCCO1
Agent: CC1(C)C(=O)N(CCO)c2ccccc21
Product: CSC1(C)C(=O)N(CCO)c2ccccc21

Procedure:
Prepared from 3-methyl-3-methylthioindol-2(3H)-one and 2-(2-chloroethoxy)tetrahydro-2H-pyran as described for 3,3-dimethyl-1-(2-hydroxy-1-ethyl)-1,3-dihydro-2H-indol-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=O.[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>O=S(Cl)Cl.CN(C=O)C>[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[C:4]=3[N+:16]([O-:18])=[O:17])[N:9]=[CH:8][N:7]=2)=[CH:22][CH:21]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COc1cc2nc[nH]c(=O)c2c([N+](=O)[O-])c1OC
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(Cl)cc3)c2c([N+](=O)[O-])c1OC
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 6,7-dimethoxy-5-nitro-3H-quinazolin-4-one (0.5 g, 1.99 mmol) (from Example 1, Step A, supra) in SOCl2 (20 mL) (Aldrich) was added a few drops of DMF (0.05 mL). The reaction mixture was then heated with stirring at 90° C. for 3 hours. The solvents were evaporated and the residue was dried in vacuo. This residue was dissolved in 2-propanol (30 mL), then 4-chloroaniline (0.25 g, 1.99 mmol) (Aldrich) was added. The reaction mixture was heated at 110° C. for 3 hours. The solvents were removed and the residue was purified by chromatography using EtOAc/CH2Cl2/NEt3 (1:2:0.05) as eluent to give the desired (4-chloro-phenyl)-(6,7-dimethoxy-5-nitro-quinazolin-4-yl)-amine as a yellow solid. (Yield 0.5 g, 70%).
Reaction SMILES: Cl.[CH3:2][O:3][N:4]1[CH2:10][CH2:9][NH:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.C([O:20][C:21](=O)[CH:22]([C:28]1[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=1[CH3:36])[C:23](OCC)=[O:24])C.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:2][O:3][N:4]1[CH2:10][CH2:9][N:8]2[C:21](=[O:20])[CH:22]([C:28]3[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=3[CH3:36])[C:23](=[O:24])[N:7]2[CH2:6][CH2:5]1
Reactant: CCOC(=O)C(C(=O)OCC)c1c(C)cc(C)cc1C
Reactant: CON1CCNNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: CON1CCN2C(=O)C(c3c(C)cc(C)cc3C)C(=O)N2CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A degassed suspension of 5-methoxy-[1,2,5]triazepane hydrochloride salt (350 mg, 1.71 mmol) and triethylamine (1.0 ml, 726 mg, 7.17 mmol) in xylene (8 ml) was stirred under argon at 60° C. for one hour. After further addition of 2-(2,4,6-trimethyl-phenyl)-malonic acid diethyl ester (482 mg, 1.73 mmol), the reaction mixture was heated at 150° C. (oil bath temperature) for 18 hours. The cooled reaction mixture was poured on ice, the pH made alkaline by addition of 5N aqueous sodium hydroxide, the aqueous layer extracted twice with ethyl acetate and the combined organic layers discarded. The aqueous alkaline phase was acidified with cooling to pH 2-3 by addition of a 4N HCl solution and the product thoroughly extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The base-acidification workup protocol is repeated a second time. Yield: 24 mg of 3-methoxy-8-(2,4,6-trimethyl-phenyl)-tetrahydro-pyrazolo[1,2-a][1,2,5]triazepine-7,9-dione (compound P2.1) as a beige solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]2)=[C:4]([F:27])[CH:3]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.O1CCOCC1>[F:27][C:4]1[CH:3]=[C:2]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)c1nn(Cc2ccc(Br)cc2F)c(=O)c(C(=O)NCC(=O)O)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1nn(Cc2ccc(-c3ccccc3)cc2F)c(=O)c(C(=O)NCC(=O)O)c1O
Yield: 25.6 %

Procedure:
To a 5 ml microwave tube was added N-{[2-[(4-bromo-2-fluorophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 46(b), 40 mg, 0.09 mmol), phenylboronic acid (13.2 mg, 0.11 mmol), potassium carbonate (38 mg, 0.272 mmol), tetrakis (triphenylphosphine)palladium (0) (3 mg, 2.7 μmol), 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes. The reaction mixture was diluted with water (5 ml), acidified with 1N HCl (2 ml), and extracted with ethyl acetate (20 ml). The organic phase was dried over MgSO4, filtered. and solvents removed under reduced pressure. The crude residue was purified by HPLC chromatography (ODS silica, gradient 15-95% acetonitrile/water (0.1% TFA)) to afford the title compound (10 mg, 0.023 mmol, 25% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.91 (s, 1H), 12.97 (br. s., 1H), 10.16 (t, J=5.56 Hz, 1H), 7.69 (d, J=7.33 Hz, 2H), 7.55 (dd, J=11.62, 1.52 Hz, 1H), 7.51-7.43 (m, 3H), 7.38-7.42 (m, 1H), 7.35 (t, J=7.96 Hz, 1H), 5.34 (s, 2H), 4.10 (d, J=5.81 Hz, 2H), 3.18 (sept, J=6.82 Hz, 1H), 1.19 (d, J=6.82 Hz, 6H). MS (ES+) m/e 440 [M+H]+.