Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[CH3:20][C:21]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([C:33](O)=[O:34])=[CH:23][N:22]=1>>[CH3:20][C:21]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([C:33]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:34])=[CH:23][N:22]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Reactant: Cc1ncc(C(=O)O)c(-c2ccccc2)n1
Product: Cc1ncc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2ccccc2)n1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-Methyl-4-phenyl-pyrimidine-5-carboxylic acid. LC-MS (basic): tR=1.19 min; [M+H]+=473.1.
Reaction SMILES: [Mg].II.Br[CH:5]=[CH:6][CH3:7].[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O>C1COCC1>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:10]=1[NH:15][CH:5]=[C:6]2[CH3:7]
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: CC=CBr
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1c[nH]c2c(Br)cccc12
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Magnesium turnings (1.45 g) in dry THF (10 ml) were stirred at room temperature under nitrogen and an iodine crystal added, followed by a few milliliters of a solution of 1-bromo-1-propene (7.25 g, 0.06 mole) in dry THF (50 ml). After warming to initiate the reaction, the remaining bromopropene solution was added dropwise at a rate to maintain reflux. After addition, the reaction was heated at reflux for a further hour, cooled and added rapidly to a stirred solution of 2-bromonitrobenzene (4.04 g, 0.02 mole) in dry THF (70 ml) at -40° C. under nitrogen. The reaction mixture was stirred for a further 30 minutes at -40° C., then was quenched with saturated aqueous ammonium chloride and extracted into diethyl ether. The combined organic extracts were washed with water, dried, filtered and evaporated in vacuo. The crude product was purified by flash chromatography on silica, eluting with 25% diethyl ether in hexane, to yield a yellow-orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH2:13][OH:14])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[CH:20][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH2:13][O:14][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([F:15])[CH:21]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(Cl)cnc1CO
Reactant: Oc1cccc(F)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(Cl)cnc1COc1cccc(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.9 %

Procedure:
To a mixture of ethyl 5-chloro-2-(hydroxymethyl)nicotinate (step 4, 340 mg, 1.59 mmol), 3-fluorophenol (325 mg, 2.90 mmol), and triphenylphosphine (761 mg, 2.9 mmol) in tetrahydrofuran (10 ml) was added 40% solution of diethylazodicarboxylate in toluene (506 mg, 2.9 mmol) and the reaction mixture was stirred at room temperature for 5 hours. To the reaction mixture was added water and the whole mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (4/1) to afford 300 mg (56%) of the title compound:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[O:25]1[CH2:29][CH2:28][C@@H:27]([NH2:30])[CH2:26]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:30][C@@H:27]4[CH2:28][CH2:29][O:25][CH2:26]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: N[C@@H]1CCOC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N[C@@H]3CCOC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-tetrahydrofuran-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79-1.94 (m, 1H) 2.03-2.19 (m, 1H) 2.36 (s, 3H) 3.56 (dd, J=9.09, 4.04 Hz, 1H) 3.66 (td, J=8.15, 5.94 Hz, 1H) 3.75-3.88 (m, 2H) 4.42 (dtt, J=8.07, 6.29, 6.29, 4.20, 4.20 Hz, 1H) 7.54-7.63 (m, 1H) 7.66 (s, 1H) 7.71 (br. s., 1H) 8.11 (br. s., 1H) 8.20-8.62 (m, 2H) 8.71 (d, J=6.32 Hz, 1H) 8.80-8.90 (m, 1H) 13.12 (br. s., 1H). MS m/z [M+H]+ 390.2
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[Si:16]([CH3:19])([CH3:18])[CH3:17].CCN(CC)CC>CN(C=O)C.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([O:14][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 26.1 %

Procedure:
4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (10.0 g, 501 mmol) was dissolved in DMF (20 mL). Chlorotrimethylsilane (6.6 g, 60.6 mmol) was added, followed by Et3N (12.3 g, 122 mmol). The mixture was stirred at 80° C. for 16 hours, cooled to ambient temperature, diluted with Et2O, and then washed with water, followed by brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated. Purification by flash chromatography on silica gel (EtOAc/heptanes 0-50%) afforded 4-trimethylsilanyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (4.3 g, 32% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.80 (br. s., 1H), 3.88 (br. s., 2H), 3.53 (t, J=5.81 Hz, 2H), 2.11 (br. s., 2H), 1.49 (s, 9H), 0.20 (s, 9H).
Reaction SMILES: BrBr.[F:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].[S-:11][C:12]#[N:13].[K+].C([O-])([O-])=O.[Na+].[Na+]>[Br-].[Na+].CO.O>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([S:11][C:12]#[N:13])=[CH:10][C:4]=1[F:3]
Reactant: Nc1ccccc1F
Reactant: N#C[S-]
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CO
Solvent: O
Product: N#CSc1ccc(N)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
A solution of bromine (3.02 g, 18.9 mmol) in sodium bromide-saturated methanol (11 mL) was added dropwise to a solution of 2-fluoroaniline (2.00 g, 18.0 mmol) and potassium thiocyanate (5.25 g, 54.0 mmol) in methanol (45 mL). The mixture was stirred for 0.5 hours, at room temperature, poured into water (300 mL) and made basic with solid Na2CO3. This aqueous mixture was extracted with Et2O (5×30 mL), then the combined Et2O extracts were washed with water (2×100 mL), saturated NaCl (100 mL), and dried (Na2SO4). Removal of the solvent under reduced pressure afforded a pale yellow liquid which was purified by dry flash column chromatography on silica (2.5% Et2O/hexanes as eluant) to give 4-amino-3-fluorophenyl thiocyanate as a white solid (1.60 g, 53%); m.p. 36-38° C. 1H NMR (400 MHz, CDCl3) δ 7.25 (dd, J=10.5, 2.2 Hz, 1 H), 7.18 (ddd, J=8.3, 2.2, 1.0 Hz, 1 H), 6.78 (dd, J=9.0, 8.3 Hz), 4.03 (br s, 2 H). Anal. Calcd for C7H5FN2S: C, 50.0; H, 3.0; N, 16.7. Found: C, 50.2; H, 3.0; N, 16.7. Step B: Preparation of 2-fluoro-4-methylthioaniline
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)[CH:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([OH:32])[CH:30]=3)[N:25]([S:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:24]=2)[CH:3]=1.N(C(OC(C)(C)C)=O)=NC(O[C:47](C)(C)[CH3:48])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)[CH:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([O:32][CH2:47][CH3:48])[CH:30]=3)[N:25]([S:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:24]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2cc(-c3cn(S(=O)(=O)c4ccccc4)c4ncc(O)cc34)cc(Cl)n2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1cnc2c(c1)c(-c1cc(Cl)nc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c1)cn2S(=O)(=O)c1ccccc1

Procedure:
A mixture of Example 224a (80.0 mg, 0.134 mmol), di-tert-butyl azodicarboxylate (77 mg, 0.334 mmol), triphenylphosphine on solid support (3 mmol/g, 112.0 mg, 0.427 mmol) and ethanol (0.039 mL, 0.669 mmol) in THF (3 mL) was stirred at room temperature overnight. The mixture was diluted with EtOac, filtered through celite, concentrated and purified on a 12 g column using the ISCO Companion flash system eluting with hexane/EtOAc (8:2 to 6:4) to give 76.1 mg of the title compound.
Reaction SMILES: [ClH:1].[C:2]([CH2:6][CH2:7][C:8](=[NH:11])OC)([O:4][CH3:5])=[O:3].[NH3:12]>CO>[ClH:1].[C:2]([CH2:6][CH2:7][C:8]([NH2:11])=[NH:12])([O:4][CH3:5])=[O:3]
Reactant: N
Reactant: COC(=N)CCC(=O)OC
Agent: Cl
Solvent: CO
Product: COC(=O)CCC(=N)N
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
To a suspension of 16.5 g. (0.09 mole) of methyl β-carbomethoxypropionimidate hydrochloride in 20 ml. of methanol at ice bath temperatures is added 12 ml. of the same solvent containing 1.7 g. of dissolved ammonia gas. The reaction mixture is allowed to stir at room temperature for 2 hrs., followed by filtration of some insoluble material and concentration of the filtrate to near dryness. The residual white solids are treated with ethanol, filtered and dried, 7.8 g. (51.5% yield), m.p. 132°-134° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].C(N(CC)CC)C.[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:21](Cl)=[O:22]>C(Cl)Cl>[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=1)[C:21]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([I:1])[CH:3]=1)=[O:22]
Reactant: Cc1ccc(N)cc1I
Reactant: O=C(Cl)c1cc(F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cc(F)cc(C(F)(F)F)c2)cc1I
Temperature: 0 °C
Reaction time: 16 h

Procedure:
3-Iodo-4-methylaniline (2.42 g, 10.4 mmol) was dissolved in DCM (20.00 mL) and triethylamine (TEA) (1.70 mL, 12.2 mmol) was added and the resulting mixture was cooled to 0° C. To the mixture was added dropwise 3-fluoro-5-(trifluoromethyl)benzoyl chloride (1.60 mL, 10.5 mmol) and the resulting mixture was stirred at 0° C. for 45 minutes and at 25° C. for 16 hours. The reaction was extracted with ethyl acetate and the organic extracts were washed with water sat. Na2CO3, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The reaction product was used in the next reaction without purification. 1H NMR (CDCl3): 8.98 (d, 1H), 7.78 (s, 1H), 7.72 (m, 2H), 7.55 (m, 2H), 7.23 (d, 1H), 2.42 (s, 3H). MS (EI) m/z=424 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:12]=[C:13]([C:17]2[CH:18]=[C:19]3[C:24](=[N:25][CH:26]=2)[NH:23][CH2:22][CH2:21][CH2:20]3)[CH:14]=[N:15][CH:16]=1.[C:27]([N:35]=C=O)(=[O:34])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:12]=[C:13]([C:17]2[CH:18]=[C:19]3[C:24](=[N:25][CH:26]=2)[N:23]([C:27]([NH2:35])=[O:34])[CH2:22][CH2:21][CH2:20]3)[CH:14]=[N:15][CH:16]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Cn1c(-c2cncc(-c3cnc4c(c3)CCCN4)c2)cc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cn1c(-c2cncc(-c3cnc4c(c3)CCCN4C(N)=O)c2)cc2ccccc21
Yield: 60.3 %

Procedure:
To a solution of 6-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-1,2,3,4-tetrahydro-[1,8]naphthyridine (110 mg; 0.32 mmol) in anhydrous DCM (5.0 mL) is added benzoyl isocyanate (71 mg; 0.48 mmol). The mixture is heated to reflux for 3 hrs. The solvent is removed and the residue is dissolved in EtOH (5.0 ml). K2CO3 (76 mg; 0.55 mmol) is added and the mixture is heated to reflux for 1 hr. Then the solvent is removed and the residue is purified by preparative HPLC to give 74 mg of the titled product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][N:19]=2)[C:13]=1[C:24]#[N:25])[C:5](O)=[O:6].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:57][CH2:58][C:59]1[C:60]([OH:67])=[N:61][C:62]([CH3:66])=[CH:63][C:64]=1[CH3:65]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][N:19]=2)[C:13]=1[C:24]#[N:25])[C:5]([NH:57][CH2:58][C:59]1[C:60]([OH:67])=[N:61][C:62]([CH3:66])=[CH:63][C:64]=1[CH3:65])=[O:6]
Reactant: N#Cc1c(Oc2ccc(C(=O)O)cc2Cl)cccc1-c1ccncn1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3cccc(-c4ccncn4)c3C#N)c(Cl)c2)c(O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-chloro-4-(2-cyano-3-(pyrimidin-4-yl)phenoxy)benzoic acid (80 mg, 0.23 mmol), 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (130 mg, 0.34 mmol) and triethylamine (70 mg, 0.69 mmol) in dichloromethane (20 mL) was stirred at room temperature for 2 hours. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (42 mmg, 0.28 mmol) was added. The resultant mixture was stirred at room temperature for additional 15 hours. To the reaction mixture, water (30 mL) was added. The mixture was extracted with dichloromethane (30 mL×3). The organic layers were combined and concentrated to give a residue in vacuo. The residue was purified by preparative-HPLC to give 3-Chloro-4-(2-cyano-3-(pyrimidin-4-yl)phenoxy)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide I-8 as a white solid (80 mg, 72%). LRMS (M+H+) m/z: calcd 485.13. found 485. HPLC purity (214 nm): 96%. 1H NMR (300 MHz, d6-DMSO): δ 11.49 (s, 1H), 9.39 (s, 1H), 9.04 (d, J=5.1 Hz, 1H), 8.57-8.56 (m, 1H), 8.17 (d, J=1.2 Hz, 1H), 8.05 (d, J=5.1 Hz, 1H), 7.93 (d, J=9 Hz, 1H), 7.83-7.73 (m, 2H), 7.39 (d, J=8.4 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 5.87 (s, 1H), 4.30 (d, J=4.8 Hz, 2H), 2.18 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18]>CO.[Pd]>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)/C=C/c1cc(OC)c2ccccc2c1OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1cc(OC)c2ccccc2c1OC
Yield: 86.6 %

Procedure:
0.47 g of methyl trans-3-(1,4-dimethoxy-2-naphthyl)acrylate [prepared as described in step (b) above] was dissolved in 20 ml of methanol and hydrogenated under an atmosphere of hydrogen and in the presence of 0.20 g of 10% w/w palladium-on-charcoal, to give 0.41 g of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.[CH:31]1([NH2:35])[CH2:34][CH2:33][CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O1CCCC1.O>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH2:25][NH:35][CH:31]3[CH2:34][CH2:33][CH2:32]3)[CH:8]=2)[N:3]=1
Reactant: NC1CCC1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3C=O)ccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: O
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3CNC3CCC3)ccc2n1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
200 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzaldehyde are dissolved in 3 ml of 1,2-dichloroethane and 3 ml of tetrahydrofuran. 106 μl of cyclobutylamine and 35 μl of glacial acetic acid are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 226 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])=[C:6]([CH:9]=1)[CH2:7]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:36]N1C(=O)CCC1=O>C1COCC1>[I:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])=[C:6]([CH:9]=1)[CH2:7][Br:36]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCOCOc1ccc(I)cc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOCOc1ccc(I)cc1CBr
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-iodo-2-(2-methoxy-ethoxymethoxy)-benzyl alcohol (7.5 g, 22 mmol) in 60 mL of THF at 15° C. is added triphenylphosphine (6.35 g, 24 mmol) followed by N-bromosuccinimide (4.3 g, 24 mmol). The solution is stirred for 5 minutes. The solution is allowed to warm to ambient temperature. After 20 minutes, the solution is concentrated. The crude product is purified by column chromatography eluting with EtOAc:CH2Cl2 :hexane (3:1:6).
Reaction SMILES: OS(O)(=O)=O.N[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[CH2:15][CH3:16].N([O-])=[O:18].[Na+]>O>[CH2:15]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:7]=1[OH:18])[C:11]#[N:12])[CH3:16]
Reactant: CCc1cc(C#N)ccc1N
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCc1cc(C#N)ccc1O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Concentrated H2SO4 (3.4 mL) was added dropwise to a solution of 4-amino-3-ethylbenzonitrile (6.84 mmol) in H2O (12 mL) at 0° C. A solution of NaNO2 (7.52 mmol) in H2O (5 mL) was added dropwise at 0° C. to the resulting mixture. The reaction was stirred at 0° C. for 30 min and at 100° C. for 2 h. The mixture was cooled to room temperature and extracted with EtOAc. The organic layer was washed (H2O), dried and concentrated to yield the desired product.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([NH2:24])[N:18]=1>CN(C=O)C>[NH2:24][C:19]1[N:20]=[C:21]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:10]=3)[C:6]([C:11]([OH:13])=[O:12])=[N:7]2)[CH:22]=[C:17]([Cl:16])[N:18]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: O=C(O)c1n[nH]c2cc(I)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc(Cl)cc(-n2nc(C(=O)O)c3ccc(I)cc32)n1
Temperature: 25 °C

Procedure:
To a solution of 6-iodo-1H-indazole-3-carboxylic acid (3.00 g, 10.42 mmol) in dry DMF (50 mL) at 0° C. under an atmosphere of nitrogen was introduced sodium hydride (1.25 g of a 60% dispersion in mineral oil, 31.25 mmol). The reaction mixture was warmed to RT for 15 mins. 4,6-Dichloropyrimidin-2-amine (2.56 g, 15.62 mmol) was then added, and the solution warmed to 60° C. for 18 hr. After cooling to 0° C., the reaction was carefully quenched with water (50 mL) and acidified by addition of 0.5M aqueous citric acid. The resulting precipitate was collected by filtration, washed on the filter with 1:1 methanol/EtOAc and dried under vacuum to furnish the title compound as a beige solid: LC-MS: m/z=+415.85/417.90 (M+H)+. This compound, with LC-MS purity=70% UV, was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]2[N:15]=[N:14][C:13]([N:16]([CH3:27])[CH:17]3[CH2:22][C:21]([CH3:24])([CH3:23])[NH:20][C:19]([CH3:26])([CH3:25])[CH2:18]3)=[CH:12][CH:11]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][NH:41][CH:42]=2)O1>>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([C:38]2[CH:39]=[N:40][NH:41][CH:42]=2)[CH:3]=[C:4]([O:28][CH3:29])[C:5]=1[C:10]1[N:15]=[N:14][C:13]([N:16]([CH3:27])[CH:17]2[CH2:22][C:21]([CH3:24])([CH3:23])[NH:20][C:19]([CH3:26])([CH3:25])[CH2:18]2)=[CH:12][CH:11]=1
Reactant: COc1cc(Br)cc(OC)c1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: COc1cc(-c2cn[nH]c2)cc(OC)c1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Yield: 70 %

Procedure:
6-(4-Bromo-2,6-dimethoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (63 mg, 0.136 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (52.8 mg, 0.272 mmol) were reacted according to GENERAL METHOD 1-5 for Suzuki coupling. The title compound was obtained as a yellow solid after column chromatography (43 mg, 70% yield). MS (M+1)=451.5.
Reaction SMILES: [N:1]1[NH:2][CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6][C:5]=12.[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)(=[O:21])=[O:20].N1C=CC=CC=1>ClCCl.CO.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([N:2]2[CH:3]=[C:4]3[C:5]([CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]3)=[N:1]2)=[CH:24][CH:23]=1)(=[O:21])=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCc2c[nH]nc2CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(S(C)(=O)=O)cc3)nc2CC1

Procedure:
A solution of 1,1-dimethylethyl 4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 9) (75 mg, 0.32 mmol), [4-(methylsulfonyl)phenyl]boronic acid (128 mg, 0.64 mmol), copper acetate (116 mg, 0.64 mmol), molecular sieves (4 Å, 0.2 g) and pyridine (52 μl, 0.64 mmol) in dichloromethane (2.5 ml) was stirred at room temperature open to atmosphere for 60 hours. The mixture was then diluted with methanol and filtered through a celite pad washing with methanol. The solvent was evaporated in vacuo. Residue was taken up into ethyl acetate and washed with water and 5% aq. sodium hydrogen carbonate, then dried over magnesium sulphate and evaporated in vacuo. The resulting residue was purified by MDAP to afford the title compound (D32). MS (ES+) m/e 392 [M+H]+.
Reaction SMILES: CS(O[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[S:13][C:14]3[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:7]1)(=O)=O.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Br:21][C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:12]([N:8]3[CH2:9][CH2:10][CH2:11][C@H:6]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[CH2:7]3)[S:13][C:14]=2[CH:20]=1
Reactant: CS(=O)(=O)O[C@@H]1CCCN(c2nc3ccc(Br)cc3s2)C1
Reactant: C1CCNC1
Product: Brc1ccc2nc(N3CCC[C@H](N4CCCC4)C3)sc2c1

Procedure:
The title compound was prepared by the method of Example 34, substituting (R)-1-(6-bromobenzo[d]thiazol-2-yl)piperidin-3-yl methanesulfonate (Reference Example 12) in place of (S)-1-(6-bromobenzo[d]thiazol-2-yl)piperidin-3-yl methanesulfonate (Reference Example 10) and substituting pyrrolidine in place of azetidine to give (S)-6-bromo-2-(3-(pyrrolidin-1-yl)piperidin-1-yl)benzo[d]thiazole. 1H NMR (300 MHz, CD3OD) δ ppm 1.47-1.75 (m, 2H), 1.77-1.95 (m, 5H), 2.11-2.20 (m, 1H), 2.28-2.39 (m, 1H), 2.67-2.76 (m, 4H), 3.06-3.25 (m, 2H), 3.87-3.96 (m, 1H), 4.25-4.32 (m, 1H), 7.33 (d, J=9 Hz, 1H), 7.39 (dd, J=2, 9 Hz, 1H), 7.79 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 366 (M+H)+.