Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][C:9]([OH:11])=O)=[C:6]([CH3:12])[NH:5][N:4]=1.[NH2:13][C@@H:14]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16]>>[CH2:34]([O:33][CH2:32][C@H:14]([NH:13][C:9](=[O:11])[CH2:8][C:7]1[C:3]([CH3:2])=[N:4][NH:5][C:6]=1[CH3:12])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1n[nH]c(C)c1CC(=O)O
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: Cc1n[nH]c(C)c1CC(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 42 %

Procedure:
Proceeding as in Example 1, but substituting 2-(3,5-dimethyl-1H-pyrazol-4-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 152, (S)-3-(benzyloxy)-2-(2-(3,5-dimethyl-1H-pyrazol-4-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (28 mg, 42%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 11.96 (br s, 1H) 10.20 (br s, 1H), 8.12-8.10 (d, 1H), 7.63-7.59 (d, 2H), 7.33-7.27 (m, 5H), 7.23-7.19 (t, 2H), 7.04-6.96 (m, 4H), 4.71-4.66 (m, 1H), 4.51 (s, 2H), 3.68-3.61 (d, 2H), 3.22 (s, 2H), 2.07 (s, 6H). MS (EI) for C29H29FN4O4. found 517.0 (MH+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16](OCC)=[O:17]>O1CCCC1>[OH:17][CH2:16][C:8]1[NH:7][C:15]2[C:10]([CH:9]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc2ccccc2[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of lithium aluminum hydride (2.0 g, 0.20 mol) in tetrahydrofuran (100 mL) was cooled with stirring to 0° C. under nitrogen. A solution of ethyl indole-2-carboxylate (10.0 g, 0.052 mol) in tetrahydrofuran was added dropwise, maintaining the reaction temperature between 0°-5° C. After 1 h, the reaction was quenched with saturated sodium potassium tartrate solution. The reaction was filtered and the filter cake washed well with tetrahydrofuran. The tetrahydrofuran was evaporated in vacuo and the residue partitioned between ethyl acetate and water. The ethyl acetate solution was washed with water, saturated brine, dried over magnesium sulfate, filtered and freed of solvent. The title compound was obtained as a yellowish solid. NMR (CDCl3): δ8.18 (1H, bs), 7.57 (1H, d, J=8 Hz), 7.35 (1H, d, J=8 Hz), 7.26 (1H, s), 7.18 (1H, dt, J=1, 8 Hz), 7.10 (1H, dt, J=1, 8 Hz), 6.41 (1H, bs), 4.84 (2H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH3:15])[CH:7]=1.[CH:17](OC)=[O:18].CC(C)([O-])C.[K+]>C1COCC1>[OH:18]/[CH:17]=[C:4](/[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH3:15])[CH:7]=1)\[C:3]([O:2][CH3:1])=[O:16]
Reactant: COC=O
Reactant: COC(=O)CCc1cn(C)c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)/C(=C\O)Cc1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of 1-methylindole-3-propionic acid methyl ester (700 mg, 3.22 mmol) and methyl formate (0.397 mL, 6.44 mmol) in THF (20 mL) was added potassium tert-butoxide (723 mg, 6.44 mmol). The mixture was stirred at room temperature for 1 h. concentration in vacuo then afforded the title compound. LCMS: rt=2.81 min, [M+H+]=246
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:3]=1[C:4]([NH:6][C@H:7]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([O:21]C)=[CH:19][CH:18]=[CH:17][C:16]=2[O:23][CH3:24])=[CH:11][CH:10]=1)=[O:5].B(Br)(Br)Br>C(Cl)Cl>[CH2:28]([O:27][C:25](=[O:26])[C@H:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([O:23][CH3:24])=[CH:17][CH:18]=[CH:19][C:20]=2[OH:21])=[CH:11][CH:10]=1)[NH:6][C:4](=[O:5])[C:3]1[C:2]([Cl:1])=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:34])[CH3:29]
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(O)cccc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: -78 °C
Reaction time: 2 h

Procedure:
N-(2,6-Dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine, ethyl ester (0.16 g, prepared in a fashion similar to that of the methyl ester described in Example 8) was dissolved in anhydrous CH2Cl2 (8 mL). The solution was cooled to −78° C. and BBr3 (0.56 mL, 1 M solution in CH2Cl2) was added. The mixture was allowed to warm to 0° C., and stirred at that temperature for 2 h. The mixture was subsequently warmed to room temperature and quenched with satd. NaHCO3 (5 mL). The mixture was stirred for 1 h, and diluted with CH2Cl2. The organic phase was dried (MgSO4) and concentrated. The residue was purified by flash column chromatography (silica gel; eluent: EtOAc/hexanes 1:2) to give 40 mg of N-(2,6-dichlorobenzoyl)-4-(2-hydroxy-6-methoxyphenyl)-L-phenylalanine ethyl ester. ESMS: m/z 488 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1.[H-].[Na+].O>CS(C)=O>[C:20]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:22][CH:23]=[C:18]([CH2:17][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH:9]3[S:13][C:12](=[O:14])[NH:11][C:10]3=[O:15])=[CH:6][CH:7]=2)[CH:19]=1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Reactant: ClCc1cccc(-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1NC(=O)C(Cc2ccc(OCc3cccc(-c4ccccc4)c3)cc2)S1
Temperature: 50 °C
Reaction time: 1 h
Yield: 256.8 %

Procedure:
To a solution of 5-[(4-hydroxyphenyl)methyl]-2,4-thiazolidinedione (0.30 g, 1.3 mmol) in dimethyl sulfoxide (20 mL) were added 3-(chloromethyl)biphenyl (0.26 g, 1.3 mmol) and 60% sodium hydride (0.11 g, 2.6 mmol), and the mixture was stirred at room temperature for 1 hr and further at 50° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=8:2) to give the title compound (1.3 g, yield 96%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:9][C:10](=[O:33])[N:11]1[CH2:16][CH2:15][N:14]2[C:17]([C:29]([F:32])([F:31])[F:30])=[N:18][C:19]([C:20](=[O:28])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[C:13]2[CH2:12]1)(C)(C)C.[Cl:45]CCl.[ClH:48]>CO>[ClH:45].[ClH:48].[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:20]([C:19]1[N:18]=[C:17]([C:29]([F:30])([F:31])[F:32])[N:14]2[CH2:15][CH2:16][N:11]([C:10](=[O:33])[CH2:9][C@H:8]([NH2:7])[CH2:34][C:35]3[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=3[F:43])[CH2:12][C:13]=12)=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)Nc3ccccn3)c2C1)Cc1cc(F)c(F)cc1F
Reactant: ClCCl
Agent: Cl
Solvent: CO
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)Nc3ccccn3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 95.2 %

Procedure:
(R)-[3-Oxo-3-[1-(pyridin-2-ylcarbamoyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 31a (0.10 g, 0.16 mmol) and 2 mL of dichloromethane were added into the reaction flask. A solution of 2.7 N hydrochloric acid in 5 mL of methanol was added to the flask. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid (pyridin-2-yl)amide dihydrochloride 31 (80 mg, yield 95.2%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24][O:25][C:26](=[O:33])[C@H:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH2:28].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(N(CC)CC)C.CN(C)C=O>[CH3:24][O:25][C:26](=[O:33])[C@H:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:28][C:20](=[O:22])[C@@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 6.65 g. of Nα -benzyloxycarbonyl-D-phenylalanine (0.022 mol) and 4.38 g. (0.022 mol) of L-leucine methyl ester hydrochloride in 60 ml. of spectrograde dimethylformamide is chilled in ice and treated with 3.0 ml. of triethylamine (2.24 g.). 1-Hydroxybenztriazole, 3.3 g., and dicyclohexylcarbodiimide, 5 g., are added and the reaction stirred to room temperature overnight and for 24 hours at room temperature. The mixture is filtered and the solvent evaporated under reduced pressure. The residue is dissolved in 200 ml. of ethyl acetate and washed with 0.1N hydrochloric acid, saturated salt solution, 5% sodium bicarbonate solution, saturated salt solution and water. The ethyl acetate solution is dried over magnesium sulfate, filtered and evaporated to a crystalline residue. The product is recrystallized twice from ethyl acetate and petroleum ether; 7.3 g.; m.p. 125°-126° C.; [α]D23 -20.3° (c 1.02, methanol).
Reaction SMILES: [O:1]([CH:8](OC1C=CC=CC=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)C1C=CC=CC=1.S(=O)(=O)(O)O.O>O1CCOCC1>[O:15]([C:11]1[N:10]=[C:9]([CH:8]=[O:1])[CH:14]=[CH:13][CH:12]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(Oc2cccc(C(Oc3ccccc3)Oc3ccccc3)n2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1cccc(Oc2ccccc2)n1

Procedure:
To a solution of 0.5 g of 2-[bis-(phenoxy)methyl]-6-(phenoxy)pyridine in 15 ml of 1,4-dioxane was added dropwise, 5 percent sulfuric acid until the mixture just became turbid. The mixture was heated over a steam bath at 80°-90° C. for about 10 minutes. The reaction mixture was poured into 20 ml of water, producing a yellowish emulsion and then extracted with 50 ml of ethyl ether. The extract was washed with 50 ml of a 5 percent aqueous sodium hydroxide solution and thrice with 50 ml portions of water and then with 50 ml of a saturated sodium chloride solution. The extract was then dried over sodium sulfate and the solvent removed by evaporation under reduced pressure. The residue was a yellow-orange oil which solidified partially on cooling to yeild 0.3 g of the desired product. The product was confirmed by Infrared and Nuclear Magnetic resonance analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH2:18][CH3:19])[CH2:11]3)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:28][N:29]1[CH:33]=[C:32]([S:34](Cl)(=[O:36])=[O:35])[N:31]=[CH:30]1>C(#N)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH2:18][CH3:19])[CH2:11]3)[S:34]([C:32]2[N:31]=[CH:30][N:29]([CH3:28])[CH:33]=2)(=[O:36])=[O:35])=[CH:4][CH:3]=1
Reactant: CCN1Cc2cc(NCc3ccc(Cl)cc3)ccc2C1=O
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: CC#N
Solvent: c1ccncc1
Product: CCN1Cc2cc(N(Cc3ccc(Cl)cc3)S(=O)(=O)c3cn(C)cn3)ccc2C1=O
Temperature: 150 °C

Procedure:
To a stirred solution of 5-(4-Chloro-benzylamino)-2-ethyl-2,3-dihydro-isoindol-1-one (40 mg, 0.133 mmol) and pyridine (23 μM, 0.29 mmol) in dry acetonitrile (1 ml) was added 1-methyl-1H-imidazole-4-sulfonyl chloride (52 mg, 0.29 mmol) and the reaction heated to 150° C. in a microwave for 0.5 hrs. The reaction was filtered and purified by preparative HPLC (Method B) to afford the title compound as an off white solid (17 mg, 25%). HPLC retention time 4.00 min. Mass spectrum (ES+) m/z 445 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C@@H:13]2[C@H:9]1[CH2:10][CH2:11][NH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.CC(C)([O-])C.[Na+]>>[CH2:1]([N:8]1[CH2:14][C@@H:13]2[C@H:9]1[CH2:10][CH2:11][N:12]2[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2C[C@H]3NCC[C@H]32)cc1
Reactant: Brc1cccnc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: c1ccc(CN2C[C@@H]3[C@H]2CCN3c2cccnc2)cc1
Yield: 98 %

Procedure:
The product from Example 18E (260 mg, 1.0 mmol) and 3-bromopyridine were processed as described in Example 1E, except that a larger amount of sodium tert-butoxide (384 mg, 4.0 mmol) was used to neutralize the salt. The crude product was purified by chromatography (SiO2, CH2Cl2:MeOH, 95:5, Rf 0.3) to provide the title compound (0.26 g, 98% yield). 1H NMR (CD3OD, 300 MHz) δ 2.40 (m, 2H), 3.20 (m, 2H), 3.50-3.80 (m, 4H), 4.10 (m, 1H), 4.50 (m, 1H), 7.00-7.60 (m, 9H); MS (DCI/NH3) m/z 266 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][NH2:3].C([O:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[NH:11][C:10]=1[CH:16]=O)=O)C.S(=O)(=O)(O)O>C(O)C>[CH3:15][C:12]1[NH:11][C:10]2[CH:16]=[N:3][N:2]([CH3:1])[C:7](=[O:6])[C:9]=2[C:13]=1[CH3:14]
Reactant: CCOC(=O)c1c(C=O)[nH]c(C)c1C
Reactant: CNN
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cc1[nH]c2cnn(C)c(=O)c2c1C
Temperature: 25 °C
Yield: 104.2 %

Procedure:
A solution of methylhydrazine (1.82 g) and 3-ethoxycarbonyl-4,5-dimethyl-2-formylpyrrole (3.85 g) in ethanol (40 ml) was refluxed for 2 hours. After cooling to room temperature, concentrated sulfuric acid (0.7 ml) was added and the mixture was further refluxed for 13 hours. The mixture was cooled to room temperature and the resulting precipitate was collected by filtration, washed with ethanol and ether, and dried under reduced pressure to provide the title compound as light-yellow powder (3.64 g; yield 100%). 1H-NMR (DMSO-d6) δ: 2.26(6H,s), 3.62(3H,s), 7.98(1H,s), 11.6-11.7(1H,m).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[N:5]1.Cl.Cl[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N+:21]=1[O-:26].C(=O)(O)[O-].[Na+]>C(O)CCC>[OH:26][N:21]1[CH:20]=[CH:25][CH:24]=[CH:23][CH:22]1[NH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[N:5]1
Reactant: [O-][n+]1ccccc1Cl
Reactant: CCOC(=O)c1ccc2c(cnn2CCN)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: CCOC(=O)c1ccc2c(cnn2CCNC2C=CC=CN2O)c1
Reaction time: 24 h
Yield: 43.6 %

Procedure:
Ethyl 1-(2-aminoethyl)-1H-indazole-5-carboxylate (584 mg, 2.5 mmol, prepared as in step B), was added to dry n-butanol along with 2-chloropyridine-N-oxide hydrochloride (847 mg, 5.1 mmol) and anhydrous sodium bicarbonate (850 mg, 10.1 mmol). The reaction mixture was vigorously stirred and heated at 100 C for 21 hr. Additional aliquots of 2-chloropyridine-N-oxide hydrochloride (847 mg, 5.1 mmol) and anhydrous sodium bicarbonate (850 mg, 10.1 mmol) were added and heating continued for 24 hours. The reaction was cooled and filtered and the filtrate concentrated. The residue was purified by flash chromatography (5% methanol-dichloromethane) and the product fractions concentrated to afford the product as an orange solid (358 mg, 44%). LRMS (ES): 327.1 ([M+H]+, 100%), 653.3 ([2M+H]+, 40%) 1HNMR (600.1343 MHz, CDCl3): 8.44 (s, 1H), 8.12 (s, 1H), 7.97 (d of t, 2H), 7.56 (bs, 1H), 7.45 (d, 1H), 7.06, (m, 1H), 6.45 (m, 1H), 6.35 (t, 1H), 4.68 (t, 2H), 4.37 (q, 2H), 3.90 (q, 2H), 1.39 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[S:13][C:14]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[F:21][C:18]1[CH:19]=[CH:20][C:14]2[S:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[CH:17]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2cc(F)ccc2s1
Product: Fc1ccc2sc(CCC#Cc3ccccn3)nc2c1
Yield: 9.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (220 mg, 1.39 mmol) and 2-but-3-ynyl-5-fluoro-benzo[d]thiazole (286 mg, 1.39 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 38 mg (0.13 mmol, 10%) of 5-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as an orange solid.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH:15]3[CH2:16][CH2:17][CH:11]2[CH2:12][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]3)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH:11]3[CH2:17][CH2:16][CH:15]2[CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12]3)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2c1ccc([N+](=O)[O-])nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2CCC(C1)N2c1ccc(N)nc1
Yield: 99.9 %

Procedure:
To a solution of tert-butyl 8-(6-nitropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (330 mg, 987 umol) in 10 ml of Methanol was added 10% Palladium in carbon (10 mg. The reaction mixture was hydrogenated 2 hr under 50 psi hydrogen. The reaction mixture was filtered through pack of celite and concentrated to afford 300 mg (100%) of tert-butyl 8-(6-aminopyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate as colorless oil. This product was used in subsequent steps without further purification.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11](Br)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[Li]CCCC.[CH:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)=[O:26]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([CH:25]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[OH:26])[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: O=Cc1cccnc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN1CCN(c2nc(C(O)c3cccnc3)cc3ccccc23)CC1
Temperature: 25 °C
Yield: 35.3 %

Procedure:
A solution of 1-(4-ethylpiperazin-1-yl)-3-bromoisoquinoline (0.39 g) obtained in Example 28-2, in tetrahydrofuran (10 ml) was cooled to −78° C., followed by the dropwise addition of 2.5M n-BuLi (0.6 ml). Fifteen minutes later, a solution of 3-formylpyridine (0.2 g) in tetrahydrofuran (3 ml) was added dropwise thereto. The temperature of the reaction solution was gradually raised to room temperature. The reaction solution was diluted with ethyl acetate, washed with brine, water and an aqueous solution of saturated sodium chloride, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give the title compound (0.15 g) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17]2[S:18][CH:19]=[C:20](Br)[N:21]=2)[C:9]1=[O:23])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CO.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:1]([O:5][C:6](=[O:24])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17]2[S:18][CH:19]=[C:20]([C:6]([O:5][CH3:1])=[O:24])[N:21]=2)[C:9]1=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Cn1c(=O)n(-c2nc(Br)cs2)c2ccccc21
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1csc(-n2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)n1

Procedure:
To a suspension of tert-butyl[3-(4-bromo-1,3-thiazol-2-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate from Step A (250 mg, 0.609 mmol) and triethylamine (0.850 mL, 6.09 mmol) in MeOH (5 mL) was added bis(triphenylphosphine)palladium (II) chloride (86.0 mg, 0.122 mmol). The reaction mixture was heated at reflux under an atmosphere of carbon monoxide (ca 1 atm) for 48 h, then partitioned between CHCl3 (20 mL) and saturated aqueous NaHCO3 (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 60:40, to give the title compound. MS: m/z=412 (M+23).
Reaction SMILES: [CH2:1]=O.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[CH2:8][CH2:9][NH2:10].[ClH:14]>>[ClH:14].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:1][NH:10][CH2:9][CH2:8]2
Reactant: C=O
Reactant: COc1cccc(CCN)c1
Agent: Cl
Product: COc1ccc2c(c1)CCNC2
Yield: 61 %

Procedure:
Formaldehyde solution (20%) (50 g) was added dropwise with stirring to 3-methoxyphenethylamine (50 g, 0.33M) over 15 minutes. The reaction was then heated for 1 hour on a steam bath. Excess concentrated hydrochloric acid was added and the mixture was then evaporated to dryness in vacuo. The residual solid was recrystallised from MeOH:isopropanol:ether to yield 6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (41 g, 61%), m.p. 234°-5° C. (lit.* 233°-4° C.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[CH3:34][CH:35]([NH2:38])[CH2:36][OH:37].[I-].[Na+]>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][NH:38][CH:35]([CH3:34])[CH2:36][OH:37])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: CC(N)CO
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCNC(C)CO)CC2)nc1N
Temperature: 150 °C
Yield: 65.2 %

Procedure:
The reaction mixture of [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (100 mg, 0.198 mmol, Example 226), dl-2-amino-1-propanol (158 uL, 1.980 mmol, TCI) and sodium iodide (30 mg, 0.198 mmol) in tetrahydrofuran (4 mL) was heated at 150° C. for 1 hour using a Smith Creator microwave synthesizer. Upon cooling to room temperature, the solvent was removed and acetonitrile (3 mL) was added. The mixture was filtered and trifluoroacetic acid (0.25 mL) was added. Purification by reverse phase HPLC (C18, eluting with acetonitrile and water) gave (4-amino-2-[1-[3-(2-hydroxy-1-methyl-ethylamino)-propane-1-sulfonyl]-piperidin-4-ylamino]-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone (70 mg, 65% yield) as off-white solids. HR-MS (ES, m/z) calculated for C23H33N6O5SF2 [(M+H)+] 543.2196, observed 543.2202.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH:1][N:2]2[N:11]=[C:10]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:20])=[O:30])=[CH:24][CH:23]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Nn1nc(Cc2ccc(Cl)nc2)c2ccccc2c1=O
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(Cc2ccc(Cl)nc2)c2ccccc2c1=O

Procedure:
The product from Example 30A and 2-(4-chlorophenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.60 (s, 1H), 8.42 (d, J=2.5 Hz, 1H), 8.32 (dd, J=7.9, 1.3 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.97 (ddd, J=8.1, 7.2, 1.4 Hz, 1H), 7.90 (ddd, J=8.0, 7.2, 1.3 Hz, 1H), 7.73 (dd, J=8.2, 2.5 Hz, 1H), 7.46 (dd, J=8.2, 0.8 Hz, 1H), 7.39-7.43 (m, 2H), 7.35-7.38 (m, 2H), 4.39 (s, 2H), 3.68 (s, 2H); MS (APCI) M/Z 439 (M+H)+.