Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[CH2:8]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH:16]1[CH2:28]Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C.CCOC(C)=O>[CH2:8]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH:16]1[CH2:28][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: c1nc[nH]n1
Reactant: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(CN2CCN(Cc3ccccc3)C(Cn3cncn3)C2)cc1
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
To a solution of 1,2,4-triazole (48.3 mg, 0.70 mmol) in DMF (2 ml) was added NaH (18.3 mg, 0.76 mmol). After 10 minutes stirring, 1,4-dibenzyl-2-(chloromethyl)piperazine (200 mg, 0.64 mmol) and KI (156 mg, 0.70 mmol) were added to the mixture. The mixture was stirred at 60° C. overnight. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography on NH-silica gel (Hex/AcOEt=¼) to give 1,4-dibenzyl-2-(1H-1,2,4-triazol-1-ylmethyl)piperazine (220.0 mg, 99.7%): HPLC-MS (ESI): Calcd for C21H25N5 [M+H]+ 348, found: 348.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:19][C:18]2[C@:13]([CH3:21])([CH:14]=[CH:15][C:16](=[O:20])[CH:17]=2)[C@@H:12]2[C@@H:3]1[C@H:4]1[C@@:8]([CH2:10][CH2:11]2)([CH3:9])[C:7](=[O:22])[CH2:6][CH2:5]1.[CH3:23][C@@H:24]1[C:41]2[C@:36]([CH3:43])([CH:37]=[CH:38][C:39](=[O:42])[CH:40]=2)[C@@H:35]2[C@H:26]([C@H:27]3[C@@:31]([CH2:33][CH2:34]2)([CH3:32])[C:30](=[O:44])[CH2:29][CH2:28]3)[CH2:25]1.[CH3:45][C@]12CC[C@H]3[C@@H](CCC4[C@]3(C)C=CC(=O)C=4)[C@@H]1CCC2=O>>[CH3:1][C@@H:2]1[CH2:19][C:18]2[C@:13]([CH3:21])([C@@H:14]3[CH2:23][C@@H:15]3[C:16](=[O:20])[CH:17]=2)[C@@H:12]2[C@@H:3]1[C@H:4]1[C@@:8]([CH2:10][CH2:11]2)([CH3:9])[C:7](=[O:22])[CH2:6][CH2:5]1.[CH3:23][C@@H:24]1[C:41]2[C@:36]([CH3:43])([C@@H:37]3[CH2:45][C@@H:38]3[C:39](=[O:42])[CH:40]=2)[C@@H:35]2[C@H:26]([C@H:27]3[C@@:31]([CH2:33][CH2:34]2)([CH3:32])[C:30](=[O:44])[CH2:29][CH2:28]3)[CH2:25]1
Reactant: C[C@@H]1CC2=CC(=O)C=C[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Reactant: C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)C=CC(=O)C=C12
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@@H]1CC2=CC(=O)[C@H]3C[C@H]3[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Product: C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@]2(C)C1=CC(=O)[C@H]1C[C@H]12

Procedure:
Following essentially the same procedure and substituting 7α-methyl-1,4-androstadiene-3,17-dione and 6α-methyl-1,4-androstadiene-3,17-dione for the 1,4-androstadiene-3,17-dione above results in the preparation of 7α-methyl-1β,2β-methylene-4-androstene-3,17-dione and 6α-methyl-1β,2β-methylene-4-androstene-3,17-dione.
Reaction SMILES: O[C:2]([CH3:14])([CH3:13])[CH2:3][C:4]1[C:5]([CH3:12])=[C:6]([OH:11])[C:7]([CH3:10])=[CH:8][CH:9]=1.[C-:15]#[N:16].[Na+].[Cl-]>O>[CH3:13][C:2]1([CH3:14])[CH2:3][C:4]2[C:9](=[CH:8][C:7]([CH3:10])=[C:6]([OH:11])[C:5]=2[CH3:12])[CH:15]=[N:16]1
Reactant: Cc1ccc(CC(C)(C)O)c(C)c1O
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Cc1cc2c(c(C)c1O)CC(C)(C)N=C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tertiary alcohol 33 (12.5 g, 64.4 mmol) is subjected to the Ritter reaction according to general procedure B. The substrate is added to the acid/cyanide mixture (at rt) over a 2.5 h period, and the resulting red reaction mixture is stirred overnight at rt. Because of the high water solubility of the product, during the work-up the aqueous phase is saturated with NaCl, and extracted six times with EtOAc to obtain an acceptable recovery of material. The organic phase is dried (Na2SO4), filtered and concentrated. The residue is filtered through silica gel with 10:1 CH2Cl2 /MeOH, and the appropriate fractions are combined and diluted with hexane to produce 38 as yellow crystals, mp 220-234° C. (dec.). A lower Rf product is also isolated. This product displays the same type of TLC behavior (blue fluorescence), and a very similar 1H NMR spectrum, and is thought to be a symmetrical dimer. Upon standing in solution, this product is slowly converted into 38, which then precipitates. Three crops of the yellow crystals are collected for a total yield of 6.8 g (52%). 1H NMR (CD3OD, 3.30 ppm) 7.76 (s, 1), 7.10 (s, 1), 4.93 (s, 1), 2.82 (s, 2), 2.10 (s, 3), 2.07 (s, 3), 1.33 (s, 6); 13C NMR (CD3OD, 49.05 ppm) 158.21, 136.17, 134.91, 127.55, 126.90, 54.34, 38.15, 27.25, 17.02, 11.39; MS (MW=203.3, CI/CH4, eE=70 eV) m/z 204 [(M+H)+, base peak)], 188, 177, 122.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7].[Li].C(OCC)(=O)C.CCCCCC>CCOCC>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C@H:15]([CH2:16][C:17](=[O:27])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Li]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.17 h
Yield: 41.8 %

Procedure:
Into a solution of 3-oxo-4-cholenic acid methyl ester 3002 (13.0 g, 23.68 mmol) in dry ether (50 ml) was added distilled liquid ammonia (70 ml) at -78° C. Lithium (1.0 g, 144.1 mmol) was added in small portions until a blue coloration persisted for 10 minutes, after which the solution was quenched with solid NH4Cl (50 g). Ammonia was evaporated, and the resulting residue was partitioned between water (100 ml) and ether (150 ml). The aqueous solution was extracted further with ether (3×50 ml). The combined extracts were washed with brine (1×70 ml), dried (MgSO4), filtered and concentrated in vacuo to get the crude product. Flash chromatography of the crude product in silica gel using ethyl acetate:hexane (2:8) gave pure 3-oxo-5α-cholanic acid methyl ester 3003 (3.85 g, 29%). 1H NMR (400 MHz, CDCl3) δ: 0.69 (3H, s, 18-CH3, 0.91 (3H, d, 21-CH3), 1.02 (3H, s, 19-CH3) and 3.66 (3H, s, CO2CH3).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][N:34]=1>>[CH3:25][S:22]([CH2:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[N:3][C:2]([C:36]4[CH:35]=[N:34][C:33]([NH2:32])=[N:38][CH:37]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19])(=[O:24])=[O:23]
Reactant: Nc1ncc(B(O)O)cn1
Reactant: CS(=O)(=O)CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CS(=O)(=O)CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonylmethanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 416. NMR (CDCl3): 2.67-2.70 (4H, m), 3.24 (3H, s), 3.49-3.54 (4H, m), 3.90 (2H, s), 3.90-3.93 (4H, m), 4.03-4.06 (4H, m), 4.42 (2H, s), 5.24 (2H, br s), 7.30 (1H, s), 9.30 (2H, s). MS (ESI+): MH+569.17 (100%)
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([OH:24])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:41][C:42]#[C:43][C:44]([O:47][Si:48]([CH2:53][CH3:54])([CH2:51][CH3:52])[CH2:49][CH3:50])([CH3:46])[CH3:45].[H-].[Na+].C1OCCOCCOCCOCCOC1>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24][CH2:41][C:42]#[C:43][C:44]([O:47][Si:48]([CH2:49][CH3:50])([CH2:51][CH3:52])[CH2:53][CH3:54])([CH3:45])[CH3:46])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC[Si](CC)(CC)OC(C)(C)C#CCBr
Reactant: CC(C)(O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)C#CCOC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 62 %

Procedure:
1α,3β-Bis(tert-Butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene (100 mg, 0.175 mmol), 1-bromo-4-triethylsilyloxy-4-methyl-2-pentyne (203 mg, 0.697 mmol), sodium hydride (60% in oil, 42 mg, 1.05 mmol), 15-crown-5 (38 mg, 0.173 mmol) and tetrahydrofuran (3 ml) were reacted using a procedure similar to that of Example 5 (1) (reflux under heating for 17 hours), worked-up and purified by column chromatography (hexane:toluene=2:1) to give the titled compound (85 mg, 62%) as a colorless oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6]C(O)=O)=[CH:2]1.C([N:12]([CH2:15]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:24])C=CC=CC=1>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:12]=[C:15]=[O:24])=[CH:2]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Reactant: O=C(O)Cc1ccsc1
Solvent: Cc1ccccc1
Product: O=C=NCc1ccsc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 204.8 %

Procedure:
To 3-thiopheneacetic acid (2.84 g, 20 mmol) in dry toluene (22.5 mL) was added dry triethylamine (2.93 mL, 4.2 mmol) and diphenyl phosphorylazide (4.31 mL, 4 mmol). The mixture was stirred at room temperature for 0.5 hours, and then heated at reflux for a further 3 hours. After cooling, the mixture was concentrated under reduced pressure and purified by distillation using an oil pump to give thiophen-3-ylmethyl isocyanate (1.14 g, 40%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][C:18]3ON=C(CC4C=CC(F)=CC=4F)N=3)[C:6](=[O:32])[NH:5][C:4]=2[N:3]=1.ClC1[N:42]([CH2:43][CH:44]=[CH2:45])[C:41]2[C:40](=O)N(CCCC(OCC)=O)[C:38](=[O:55])[NH:37][C:36]=2[N:35]=1>>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][CH2:18][C:38]3[O:55][N:35]=[C:36]([C:41]4[CH:40]=[CH:45][CH:44]=[CH:43][N:42]=4)[N:37]=3)[C:6](=[O:32])[NH:5][C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)n(CCCc3nc(Cc4ccc(F)cc4F)no3)c(=O)c21
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)n(CCCC(=O)OCC)c(=O)c21
Product: C=CCn1c(Cl)nc2[nH]c(=O)n(CCCCc3nc(-c4ccccn4)no3)c(=O)c21

Procedure:
Similarly prepared was 8-chloro-1-(3-{3-[(2,4-difluorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione using ethyl 4-[8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-1-yl]butanoate.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:34][C:35]1[N:39]=[CH:38][NH:37][CH:36]=1)[NH:5][C:6](=[O:33])[C@H:7]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:8][C:9](=[O:25])[C@H:10]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].[BH4-].[Na+].Cl>O1CCCC1.CO>[OH:2][CH2:3][CH:4]([NH:5][C:6](=[O:33])[C@H:7]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[NH:8][C:9](=[O:25])[C@H:10]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:34][C:35]1[N:39]=[CH:38][NH:37][CH:36]=1
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)C(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NC(CO)Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.8 %

Procedure:
N-Pivaloyl-L-phenylalanyl-L phenylalanyl-L-histidine methyl ester (1.90 g) is dissolved in tetrahydrofuran (12 ml), and a solution of sodium borohydride (0.20 g) in methanol (2.5 ml) is added dropwise thereto. The mixture is stirred at room temperature for four hours, and 5% hydrochloric acid (4 ml) is added to the mixture and then the solvent is distilled off. The residue is made alkaline with an aqueous sodium bicarbonate solution and then extracted with ethyl acetate. The extract is washed with an aqueous sodium chloride solution, dried, and concentrated to remove solvent. The residue is triturated with ethyl acetate to give 4-{2-hydroxymethyl-2-[N-(N-pivaloyl-L-phenylalanyl-L-phenylalanyl)amino]ethyl}imidazole (1.24 g) as white powder. Yield: 68.8%
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([N:20]4[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[C:21]4=[O:27])=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH2:28]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH:39]1[CH:51]([NH2:53])[CH3:52])=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])[CH2:40][CH:39]1[CH:51]([NH:53][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([N:20]4[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[C:21]4=[O:27])=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)[CH3:52])=[O:37])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(N)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Reactant: CCN1CCN(c2ccc3c(c2)ncn3-c2ccnc(S(C)(=O)=O)n2)C1=O
Product: CCN1CCN(c2ccc3c(c2)ncn3-c2ccnc(NC(C)C3CN(C(=O)OC(C)(C)C)CCN3C(=O)OCc3ccccc3)n2)C1=O

Procedure:
The title compound was prepared from 2-methanesulfonyl-4-[5-(3-ethyl-imidazolidin-2-on-1-yl)benzimidazol-1-yl]pyrimidine (EXAMPLE 29; 95 mg) and 1-benzyloxycarbonyl-2-(1-aminoethyl)-4-tert-butyloxycarbonylpiperazine, diastereomer 1 (EXAMPLE 14 Step D; 100 mg) according to the procedure described in EXAMPLE 14, Step E. Mass spectrum (ESI) 670.5 (M+1).
Reaction SMILES: [CH:1]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[C:12]1[O:13]CC(C)(C)N=1)([CH3:3])[CH3:2].[OH-:19].[Na+]>S(=O)(=O)(O)O>[CH:1]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[C:12]([OH:13])=[O:19])([CH3:2])[CH3:3]
Reactant: COc1cccc(C2=NC(C)(C)CO2)c1C(C)C
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COc1cccc(C(=O)O)c1C(C)C
Yield: 35.6 %

Procedure:
A solution of 2-(2-isopropyl-3-methoxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole (6.18 g, 25 mmol) in 35% solution of sulfuric acid (40 mL) was stirred at reflux for 48 hours. Upon cooling, solid sodium hydroxide (18.15 g) was slowly added. The reaction mixture was extracted with diethyl ether, and the combined organic extracts were extracted with sodium bicarbonate solution. The bicarbonate extracts were then acidified with 3N hydrochloric acid, filtered and dried to give 2-isopropyl-3-methoxybenzoic acid as a white crystalline solid (1.73 g, 35.7%).
Reaction SMILES: [O:1]=[C:2]1[N:7]([NH:8]C(OCC2C=CC=CC=2)=O)[CH2:6][CH2:5][CH2:4][N:3]1[C:19]([NH2:21])=[O:20]>CN(C)C=O.[Pd]>[NH2:8][N:7]1[CH2:6][CH2:5][CH2:4][N:3]([C:19]([NH2:21])=[O:20])[C:2]1=[O:1]
Reactant: NC(=O)N1CCCN(NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CN(C)C=O
Product: NC(=O)N1CCCN(N)C1=O
Yield: 99.2 %

Procedure:
Tetrahydro-2-oxo-3-[[(phenylmethoxy)carbonyl]amino]-1(2H)-pyrimidinecarboxamide (37.45 g. 128.1 mmol), dissolved in 650 ml N,N-dimethylformamide, was hydrogenated over 15 g palladium on activated carbon for 2 hours. The catalyst was removed by filtration and the solvent evaporated in vacuo. Trituration with ether furnished 20.1 g of the desired product, melting point 153°-156° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:15][NH2:16])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[CH:22](O)=O>>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:22]=[N:16][CH:15]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ncccc1OCc1ccccc1
Reactant: O=CO
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(COc2cccn3cncc23)cc1

Procedure:
This compound is prepared according to the same procedure as in preparation II (stage C) from 2.8 g (13.25 mmol) of 1-[3-(benzyloxy)pyridin-2-yl]methanamine [described in Inorg. Chem., (2003), 42(14), 4401] by formylation with formic acid and then cyclization by reaction with phosphoryl chloride. 1.74 g of a brown oil are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1.[C:29]([N:32]1[CH2:36][CH2:35][NH:34][C:33]1=[O:37])(=[O:31])[CH3:30]>>[C:29]([N:32]1[CH2:36][CH2:35][N:34]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=2)[C:33]1=[O:37])(=[O:31])[CH3:30]
Reactant: CC(=O)N1CCNC1=O
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C(C)=O)C4=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 77.6 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (1.17 g) described in Preparation Example 254 and 1-acetylimidazolidin-2-one (0.38 g) and by the reaction and treatment in the same manner as in Example 1, the title compound (1.00 g) was obtained.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([N:15]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)O1.Br[C:35]1[CH:40]=[N:39][C:38]([Br:41])=[CH:37][N:36]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:41][C:38]1[N:39]=[CH:40][C:35]([C:9]2[CH:10]=[CH:11][C:12]([N:15]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)=[N:36][CH:37]=1
Reactant: Cc1ccccc1N(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1cccc2ccccc12
Reactant: Brc1cnc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccccc1N(c1ccc(-c2cnc(Br)cn2)cc1)c1cccc2ccccc12
Temperature: 80 °C
Yield: 75 %

Procedure:
A mixture of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(o-tolyl)naphthalen-1-amine (Compound 22) (0.55 g, 1.26 mmol), 2,5-dibromopyrazine (0.77 g, 3.0 mmol), Pd(PPh3)4 (0.1 g, 0.09 mmol), K2CO3 (0.414 g, 3 mmol) in dioxane/water (40 mL/8 mL) was degassed and heated at 80° C. overnight. The resulting mixture was worked up with ethyl acetate/brine, dried over Na2SO4, loaded on silica gel and purified by flash column using eluents of hexanes/dichloromethane 9:1 to 3:2. After removal of solvents, a yellow solid (Compound 23) was obtained, 0.44 g in 75% yield.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([NH:11][C:12](=[O:14])[CH3:13])=[CH:9][C:8]([Cl:15])=[C:7]([NH2:16])[CH:6]=1)(=[O:3])[CH3:2].CO[CH:19]1[CH2:23][CH2:22][CH:21](OC)O1>C(O)(=O)C>[Cl:15][C:8]1[CH:9]=[C:10]([NH:11][C:12](=[O:14])[CH3:13])[C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][C:7]=1[N:16]1[CH:19]=[CH:23][CH:22]=[CH:21]1
Reactant: COC1CCC(OC)O1
Reactant: CC(=O)Nc1cc(N)c(Cl)cc1NC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(Cl)c(-n2cccc2)cc1NC(C)=O

Procedure:
3 g (12.4 mmol) of 4,5-diacetamido-2-amino-1-chlorobenzene and 1.6 g (12.4 mmol) of 2,5-dimethoxytetrahydrofuran in 150 ml of acetic acid were refluxed for 30 minutes. The reaction mixture was concentrated, the residue was washed with water and ethyl acetate, and the organic phase was worked up.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:4]([CH:5]=[CH:6][C:7](=[O:20])[C:8]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[CH:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30])#[CH:22].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.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.[Cu]I>[F:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=1[C:8]1[C:7](=[O:20])[CH:6]=[CH:5][N:4]2[C:9]=1[CH:10]=[CH:11][C:2]([C:22]#[C:21][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30])=[CH:3]2
Reactant: C#Cc1ccc(F)cc1F
Reactant: O=c1ccn2cc(Br)ccc2c1-c1c(F)cccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1ccn2cc(C#Cc3ccc(F)cc3F)ccc2c1-c1c(F)cccc1F
Temperature: 100 °C

Procedure:
To a solution of 7-bromo-1-(2,6-difluorophenyl)-2H-quinolizin-2-one (100 mg) was added 1ethynyl-2,4-difluorobenzene (82 mg), triethylamine (0.17 ml), dichlorobis(triphenylphosphine)palladium (25 mg), CuI (6 mg) in DMF was heated to 100° C. until reaction complete. The mixture was diluted with ethyl acetate, washed with water (4×), brine, dried over MgSO4, and concentrated to yield crude material. The crude material was purified by silica gel chromatography (100% ethyl acetate) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]([O:9]C)=[O:8])[N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.O.[OH-].[Li+]>O1CCOCC1.O>[ClH:1].[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: COC(=O)c1cc(Cl)nn1-c1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cl
Product: O=C(O)c1cc(Cl)nn1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 191.1 %

Procedure:
Methyl 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (3.83 g, 16.1 mmol) was stirred in dioxane (53.7 mL). The orange suspension was heated until a solution was achieved. Lithium hydroxide hydrate (1.01 g, 24.2 mmol) in water (26.9 mL) was added to afford a darker red solution. The reaction was stirred at room temperature for 1 hours, at which point LCMS showed the corresponding acid to be the major product. The orange mixture was concentrated to dryness and the residue was mixed with 4 N hydrochloric acid in dioxane (100 mL). The suspension was heated to reflux for 1 h and allowed to cool to room temperature. The resulting suspension was filtered and the filter cake was rinsed with dioxane. The solid was vacuum dried at 50° C. to afford the desire product as a white solid (4.00 g, 91%): mp 244-246° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.00 (dd, J=2.5, 0.7 Hz, 1H), 8.82 (dd, J=5.2, 1.4 Hz, 1H), 8.35 (ddd, J=8.3, 2.4, 1.4 Hz, 1H), 7.85 (ddd, J=8.3, 5.2, 0.7 Hz, 1H), 7.25 (s, 1H); 13C NMR (101 MHz, DMSO-d6) δ 158.71, 146.00, 143.44, 140.36, 137.00, 136.83, 125.19, 111.71; ESIMS m/z 224 ([M+H]+).