Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][C:36]=1[NH:50][S:51]([CH3:54])(=[O:53])=[O:52].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:12]=[N:13][N:14]([CH2:16][C:17]5[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=5)[CH:15]=4)=[CH:9][N:8]([S:24]([C:27]4[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=4)(=[O:25])=[O:26])[C:5]3=[N:6][CH:7]=2)=[CH:37][C:36]=1[NH:50][S:51]([CH3:54])(=[O:53])=[O:52]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Reactant: CC1(C)OB(c2ccc(F)c(NS(C)(=O)=O)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(F)c(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 94.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of Step-i of example 9) (166 mg, 0.317 mmol) was coupled with N-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (Intermediate 65) (100 mg, 0.317 mmol) using sodium carbonate (101 mg, 0.952 mmol) and Pd(PPh3)2Cl2 (12 mg, 0.015 mmol) in DME/water (15/2 mL). This afforded 190 mg (94.5% yield) of the titled compound. MS: m/z=634.0 (M+1).
Reaction SMILES: [C:1]([NH:3][C:4]([NH:29][CH3:30])=[N:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21]CC2C=CC=CC=2)=[CH:14][CH:13]=[CH:12][N:11]=1)#[N:2]>[Pd]>[C:1]([NH:3][C:4]([NH:29][CH3:30])=[N:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:13]=[CH:12][N:11]=1)#[N:2]
Reactant: CNC(=NCCSCc1ncccc1OCCCCOCc1ccccc1)NC#N
Agent: [Pd]
Product: CNC(=NCCSCc1ncccc1OCCCCO)NC#N

Procedure:
N-Cyano-N'-methyl- N"-[2-((3-(4-benzyloxybutoxy)-2-pyridyl)methylthio)ethyl]guanidine which may be hydrogenolysed using palladium on charcoal catalyst to give N-cyano-N'-methyl-N"-[2-((3-(4-hydroxybutoxy)-2-pyridyl)methylthio)ethyl]guanidine
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[NH2:27][CH:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:27][CH:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(NC(=O)c1ccc(Cl)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
1.00 g of 4-chlorobenzoic acid and 1.45 g of dicyclohexylcarbodiimide (DCC) were solved in 30 ml of tetrahydrofuran, and the resulting solution was stirred at the room temperature for 2 hours. Subsequently, 1.35 g of diethyl aminomalonate hydrochloride and 0.65 g of triethylamine were added to 20 ml of tetrahydrofuran, and after stirring for about 20 minutes, the previously prepared solution was added to the this resulting solution. The mixed solution was then stirred at the room temperature for 2 hours to complete the reaction. After filtration of the solution and concentration of the filtrate, the concentrated filtrate was diluted with 50 ml of chloroform, washed with 20 ml of water twice and subjected to dry filtration to yield 1.72 g (86%) of diethyl 4-chlorobenzamidomalonate.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[N:8]=[C:7]2[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1)=[N+:2]=[N-:3].[C:38]([C@@H:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:41]1)#[CH:39].[Na+].[Cl-]>CC(O)(C)C.O>[N:35]1[CH:34]=[CH:33][C:32]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N:1]4[CH:39]=[C:38]([C@@H:40]5[CH2:45][CH2:44][CH2:43][N:42]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:41]5)[N:3]=[N:2]4)[CH:5]=3)[N:9]([C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:8]=2)=[CH:37][CH:36]=1
Reactant: [N-]=[N+]=Nc1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C#C[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](c2cn(-c3ccc4c(c3)c(-c3ccncc3)nn4C(c3ccccc3)(c3ccccc3)c3ccccc3)nn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
5-azido-3-(pyridin-4-yl)-1-trityl-1H-indazole (1.0 g, 2.1 mmol) and (S)-tert-butyl 3-ethynylpiperidine-1-carboxylate (0.43 g, 2.1 mmol) were suspended in t-BuOH:H2O (1:1 10 mL:10 mL) and then CuSO4.5H2O (5 mg, 0.002 mmol) and Na-Ascorbic acid (40 mg, 0.21 mmol) were added sequentially. Reaction mixture was stirred vigorously at room temperature overnight. After the completion of reaction, added sat. NaCl (30 mL), extracted with EtOAc (3×50 mL), evaporated the organic solvent to give (R)-tert-butyl 3-(1-(3-(pyridin-4-yl)-1-trityl-1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate (1.26 g) which was used for next step with out purification.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[N+](C1C=C(S(O[CH2:26][C@@:27]2([CH3:30])[CH2:29][O:28]2)(=O)=O)C=CC=1)([O-])=O>>[CH3:26][C@:27]1([CH2:30][O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:29][O:28]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: C[C@]1(COS(=O)(=O)c2cccc([N+](=O)[O-])c2)CO1
Product: C[C@]1(CON2C(=O)c3ccccc3C2=O)CO1

Procedure:
Prepared from N-hydroxyphthalimide and [(2R)-2-methyloxiran-2-yl]methyl 3-nitrobenzenesulfonate (Chen, J.; Shum, W., Tetrahedron Letters, 1993, 34(48), 7663-6) by the method of Example 93 Step I.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:11]([CH3:34])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH3:23])=[C:17]([CH2:24][C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=O)[C:16]=3[CH:15]=[CH:14][C:13]=2[N:33]=1.B.CSC.Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:11]([CH3:34])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH3:23])=[C:17]([CH2:24][CH2:25][N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[C:16]=3[CH:15]=[CH:14][C:13]=2[N:33]=1
Reactant: Cc1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1CC(=O)N1CCOCC1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: Cc1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 38.7 %

Procedure:
A stirred suspension of the product of Example 7 (85 mg, 0.17 mmol) in THF (9 mL) was heated to reflux and borane-methylsulfide (0.09 mL, 0.9 mmol) added. Stirring was continued for 3.5 h at reflux and overnight at room temperature. 6M HCl was added and the solution stirred for 2 h. The solution was applied to a Varian SCX column, washed with MeOH/CH2Cl2 50:50, then the product eluted with MeOH/CH2Cl2/NH4OH 50:50:1. The product was further purified on a silica column eluting with CH2Cl2/MeOH 98:2 to give the title compound 32 mg, 39%, mp 285-290° C.; MS (ES) 486, 488 (MH+).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1.Cl.O>C1COCC1>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[CH:2]=[O:1]
Reactant: c1ccc(Nc2cccc(C3OCCO3)c2)nc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cccc(Nc2ccccn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve (3-[1,3]dioxolan-2-yl-phenyl)-pyridin-2-yl-amine (10.32 g, 42.6 mmol) in THF (150 mL). Add concentrated HCl solution (37.5 mL) and stir the solution at room temperature overnight. Concentrate the reaction, treat with water, and extract with CH2Cl2. Wash the organic extract with water, dry (Na2SO4) and concentrate to give the crude product. Purification by flash chromatography (hexanes/EtOAc (7:3)) provides the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:11][CH3:12])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[CH2:13](N)[CH2:14][NH2:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:9]2[NH:15][CH2:14][CH2:13][N:10]=2)[CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: NCCN
Reactant: CCC(C#N)c1cccc(Cl)c1
Product: CCC(C1=NCCN1)c1cccc(Cl)c1

Procedure:
rac-2-[1-(3-Chloro-phenyl)-propyl]-4,5-dihydro-1H-imidazole was prepared from 2-(3-chloro-phenyl)-butyronitrile and ethylene diamine in analogy to Example 22: colourless powder;MS (ISP): 223.0 ((M+H)+.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Cl[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[N:16][CH:17]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: Clc1ccc(Cl)nc1
Product: COC(=O)c1ccc(-c2ccc(Cl)cn2)cc1

Procedure:
Repeating the operations of Production Example 14 using 4-(methoxycarbonyl)phenylboronic acid and 2,5-dichloropyridine, methyl 4-(5-chloro-2-pyridyl)benzoate was obtained. Hydrolyzing the same with 5N aqueous sodium hydroxide solution, the title compound was obtained as white solid.
Reaction SMILES: [CH2:1]([S:7][CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9]([O-:11])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:18][C:19]1[C:20]([S:28][CH3:29])=[N:21][C:22]([CH3:27])=[CH:23][C:24]=1[S:25][CH3:26].C[Al](C)C.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:29][S:28][C:20]1[C:19]([NH:18][C:9](=[O:11])[CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[C:24]([S:25][CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=1
Reactant: CCCCCCSC(C(=O)[O-])c1ccccc1
Reactant: CSc1cc(C)nc(SC)c1N
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCCCSC(C(=O)Nc1c(SC)cc(C)nc1SC)c1ccccc1
Yield: 7.6 %

Procedure:
To a stirred solution α-hexylthio-phenylacetate (204 mg) and 3-amino-2,4-bis(methylthio)-6-methyl-pyridine (146 mg) in methylene chloride (5 ml) was added dropwise 2M solution of trimethylaluminum in toluene (0.4 ml), and the mixture was refluxed for 16 hours. After cooling to 0° it was acidified slowly with 1N hydrochloric acid, and extracted with ethyl acetate twice. The combined extracts were washed with water and brine, dried (magnesium sulfate) and evaporated to give a solid residue. It was purified by a column chromatography on silica gel with elution by 2:8 ethyl acetate-hexane to give a solid residue. Crystallization from ethyl ether and hexane to provide pure N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]-α-hexylthio-phenylacetamide (24 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][C:33](=[O:49])[NH:34][CH2:35][CH2:36][CH2:37][C@H:38]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:39][NH2:40])([CH3:31])([CH3:30])[CH3:29].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([CH2:13][C:14]([NH:40][CH2:39][C@@H:38]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37][CH2:36][CH2:35][NH:34][C:33]([O:32][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:49])=[O:16])[CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CC(=O)O)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CN)NC(=O)OC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCC[C@@H](CC(=O)NC[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.1 g (0.26 mmol) of (3S)-3-{[(benzyloxy)carbonyl]amino}-6-[(tert-butoxycarbonyl)amino]hexanoic acid (J. Med. Chem. (2002) 45:4246-4253) and 0.11 g (0.34 mmol) of tert-butyl{(4S)-5-amino-4-[(tert-butoxycarbonyl)amino]pentyl}carbamate (Example 86A) are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 0.065 g (0.34 mmol) of EDC and 0.011 g (0.079 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is dried to constant weight under high vacuum.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[N:26]1([C:31]2[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=2)[NH2:34])[CH:30]=[CH:29][N:28]=[CH:27]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:34][C:33]3[CH:35]=[CH:36][CH:37]=[C:31]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)[CH:32]=3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: Nc1cccc(-n2ccnc2)c1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)Nc3cccc(-n4ccnc4)c3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and 3-(1H-imidazol-1-yl)aniline and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [C:1]1([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:21])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[C:23]#[CH:24]>CN(C=O)C.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH2:27]([O:26][C:22](=[O:25])/[CH:23]=[CH:24]/[N:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:12]([CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:13]1=[O:21])[CH3:28]
Reactant: C#CC(=O)OCC
Reactant: O=c1[nH]c2ccccc2n1Cc1cccc2ccccc12
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/n1c(=O)n(Cc2cccc3ccccc23)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 101.4 %

Procedure:
To a solution of 1-Naphthalen-1-ylmethyl-1,3-dihydro-benzimidazol-2-one (0.5 g, 1.8 mmol) in DMF (4 mL) were added ethyl propiolate (0.28 mL, 2.7 mmol) and DMAP (0.22 mL), 1.8 mmol). The reaction mixture was stirred at room temperature for 10 min. The reaction mixture turned dark brown in color. The reaction mixture was diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated to afford 0.68 g of the desired product as a dark brown foam. This crude product was used for the next reaction without further purification. LCMS (ESMS): m/z 373.33 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:8][N:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11]N=2)[CH2:6][C@H:5]1[NH:15][C:16]1[C:21]([CH2:22][CH3:23])=[N:20][C:19]([C:24]2[C:25]([CH3:32])=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[C:18]([CH2:33][CH3:34])[N:17]=1)[CH3:2].Br[C:36]1C=CC=CN=1>>[CH2:1]([O:3][C@H:4]1[CH2:8][N:7]([C:9]2[CH:36]=[CH:11][CH:12]=[CH:13][N:14]=2)[CH2:6][C@H:5]1[NH:15][C:16]1[C:21]([CH2:22][CH3:23])=[N:20][C:19]([C:24]2[C:25]([CH3:32])=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[C:18]([CH2:33][CH3:34])[N:17]=1)[CH3:2]
Reactant: CCO[C@H]1CN(c2ncccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C)nc1CC
Reactant: Brc1ccccn1
Product: CCO[C@H]1CN(c2ccccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C)nc1CC

Procedure:
Following the procedure for the preparation of N-[(3R,4S)-4-ethoxy-1-pyrimidin-2-ylpyrrolidin-3-yl]-3,6-diethyl-5-(6-methoxy-2-methylpyridin-3-yl)pyrazin-2-amine but substituting 2-bromo pyridine provided the title compound as an amporphous solid:
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]([O:15]C)=O)#N.CC(C[AlH]CC(C)C)C.Cl.C1C[O:30]CC1>>[OH:15][CH2:13][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][CH:12]=[C:3]2[CH:1]=[O:30]
Reactant: COC(=O)c1cccc2c(C#N)cccc12
Reactant: C1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Product: O=Cc1cccc2c(CO)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a cooled (0° C.) solution of methyl 5-cyano-1-naphthylcarboxylate (1 g, 5 mmol) in 20 mL anhydrous THF was added DIBAL (1M in hexane, 20 mL, 20 mmol) via syringe. The mixture was then kept between 50-60° C. overnight. The mixture was then cooled to room temperature. The mixture was poured into a cold (0° C.) solution of 2 N HCl (100 mL). The product was extracted with ether (2×). The organic layer was washed with brine, dried over MgSO4 and concentrated. Silica gel column chromatography using hexane/ethyl acetate (2/1) gave the 0.85 g (91%) of the product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].I([Cl:15])(=O)=O.I(Cl)(=O)=O.I(Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[C:9]([Cl:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=I(=O)Cl
Reactant: Cc1ccc(C(C)(C)C)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Product: Cc1ccc(C(C)(C)C)cc1Cl
Temperature: 70 °C
Reaction time: 24 h
Yield: 62.3 %

Procedure:
A solution of 2 g (13.49 mmol) of 4-tert-butyltoluene is mixed with 5.65 g (13.49 mmol) of benzyltrimethylammonium tetrachloroiodate and stirred at 70° C. for 24 hours. After cooling, the precipitate is filtered off with suction and the filtrate is concentrated. The resulting residue is purified over silica gel (mobile phase: cyclohexane). 1.53 g (8.4 mmol) of the title compound are obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:16][NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.[Pd]>[CH3:16][NH:17][C:18]1[CH:19]=[C:20]([C:2]2[C:3]3[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: CNc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCOC(=O)c1c[nH]c2ncnc(Cl)c12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(NC)c3)c12
Temperature: 150 °C

Procedure:
To a nitrogen purged mixture of ethyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (300 mg, 1.33 mmol) and N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (465 mg, 1.99 mmol) in 2 M aqueous sodium carbonate solution (3.32 mL, 6.65 mmol) and dioxane (10 mL) was added SiliaCat® heterogeneous catalysts DPP-Pd (loading=0.28 mmol/g, 950 mg, 0.266 mmol). The reaction mixture was heated by microwave irradiation at 150° C. in a sealed microwave vessel for 30 minutes. Water (5 mL) was added to the reaction mixture and then the biphasic mixture was filtered. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (×3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica eluting with 0-100% ethyl acetatehexane to give ethyl 4-(3-(methylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C16H17N4O2[M+H]+: 297, found 297.
Reaction SMILES: [OH:1][CH:2]1[CH:8]2[CH:9]=[CH:10][CH:3]1[CH:4]1[CH:7]2[N:6]=[N:5]1.[C:11](OC(=O)C)(=[O:13])[CH3:12].C(N(CC)CC)C>CCOCC>[C:11]([O:1][CH:2]1[CH:8]2[CH:9]=[CH:10][CH:3]1[CH:4]1[CH:7]2[N:6]=[N:5]1)(=[O:13])[CH3:12]
Reactant: OC1C2C=CC1C1N=NC21
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)OC1C2C=CC1C1N=NC21

Procedure:
5 parts of 9-hydroxy-3,4-diazatricyclo[4,2,1,02,5 ]nona-3,7-diene, 5 parts of acetic anhydride, 1 part of triethylamine and 100 parts of ether were refluxed for 24 hours, after which the reaction mixture was extracted twice with 50 parts of water, and the organic phase was dried with MgSO4 and evaporated down in a rotary evaporator to give 6.2 parts (95 mole %) of 9-acetoxy-3,4-diazatricyclo[4,2,1,02,5 ]nona-3,7-diene of melting point 58° C.
Reaction SMILES: [CH3:1][C:2]1([C:32](OCC)=[O:33])[C:10]2[C:9]([NH:11][CH3:12])=[N:8][C:7]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[N:15]([CH2:22][CH2:23][C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[N:14]=3)=[N:6][C:5]=2[NH:4][C:3]1=[O:31].[CH:37]1([NH2:40])[CH2:39][CH2:38]1>CO>[CH:37]1([NH:40][C:32]([C:2]2([CH3:1])[C:10]3[C:9]([NH:11][CH3:12])=[N:8][C:7]([C:13]4[C:21]5[C:16](=[N:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH2:22][CH2:23][C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[N:14]=4)=[N:6][C:5]=3[NH:4][C:3]2=[O:31])=[O:33])[CH2:39][CH2:38]1
Reactant: NC1CC1
Reactant: CCOC(=O)C1(C)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(NC)c21
Solvent: CO
Product: CNc1nc(-c2nn(CCC(F)(F)C(F)(F)F)c3ncccc23)nc2c1C(C)(C(=O)NC1CC1)C(=O)N2
Temperature: 80 °C

Procedure:
The intermediate from Step B above (65 mg, 0.127 mmol) and cyclopropylamine (0.088 mL, 1.266 mmol) in MeOH (1 mL) were sealed in a microwave tube and heated at 80° C. for 2 days.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]([C:28]1[NH:32][C:31]([C:33]([OH:35])=O)=[C:30]([Cl:36])[CH:29]=1)=[O:27].[NH2:37][CH2:38][C:39]1[C:40]([F:56])=[C:41]([O:46][C:47]2[CH:48]=[C:49]([CH:52]=[C:53]([Cl:55])[CH:54]=2)[C:50]#[N:51])[C:42]([Cl:45])=[CH:43][CH:44]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:36][C:30]1[CH:29]=[C:28]([C:26]([NH2:25])=[O:27])[NH:32][C:31]=1[C:33]([NH:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([O:46][C:47]2[CH:48]=[C:49]([C:50]#[N:51])[CH:52]=[C:53]([Cl:55])[CH:54]=2)[C:40]=1[F:56])=[O:35]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: NC(=O)c1cc(Cl)c(C(=O)O)[nH]1
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: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(C(N)=O)cc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
HATU (0.061 g, 0.161 mmol) was added to a solution of 5-(aminocarbonyl)-3-chloro-1H-pyrrole-2-carboxylic acid (0.030 g, 0.161 mmol), 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol), and DIPEA (0.028 mL, 0.161 mmol) in DMF (2 mL). This solution was stirred overnight at RT. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with a 15% solution of Na2CO3, dried over MgSO4, filtered and evaporated. Purification was accomplished by silica gel column chromatography (EtOAc/hexanes) to afford the title compound (0.023 g, 28%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.08 (br. s., 1H), 8.48-8.74 (m, 1H), 7.72-7.98 (m, 2H), 7.27-7.62 (m, 5H), 6.83 (d, 1H), 4.48 (d, 2H). LCMS: m/z 481.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2[CH2:16][CH2:17][CH2:18][CH2:19][C:11]1=2>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([N:5]2[C:13](=[O:14])[C:12]3[CH2:16][CH2:17][CH2:18][CH2:19][C:11]=3[C:10]2=[O:15])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1ccc(Cl)c(O)c1
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)c(O)c1

Procedure:
Employed 47.5 g of 3-hydroxy-4-chloroaniline (0.33 mol); 38.2 of 3,4,5,6-tetrahydrophthalic anhydride (0.25 mol) and 350 ml of glacial acetic acid.