Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:25])([O:23][CH3:24])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([C:12]#[C:13][CH2:14][N:15]([CH3:17])[CH3:16])=[CH:5][C:4]=1[CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)(=O)C.O.CO.[Zn]>[C:1](=[O:25])([O:23][CH3:24])[O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([C:12]#[C:13][CH2:14][N:15]([CH3:17])[CH3:16])=[CH:5][C:4]=1[CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(C#CCN(C)C)cc1C1CCCC1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)Oc1cc(N)c(C#CCN(C)C)cc1C1CCCC1
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
2-Cyclopentyl-4-(3-(dimethylamino)prop-1-ynyl)-5-nitrophenyl methyl carbonate (800 mg, 2.31 mmol) was dissolved in a mixture of glacial acetic acid (10 mL) and water (2.5 mL). Zn dust (1511 mg, 23.10 mmol) was added at room temperature. The solution was stirred for 10 min then diluted with methanol (5 mL) and filtered. The solution was concentrated and redissolved in ethyl acetate. The ethyl acetate solution was washed with 50% saturated NaHCO3 (2×20 mL) and brine, dried over Na2SO4, filtered, and dried down to a light orange solid. Purification by silica gel chromatography (5-15% methanol/dichloromethane) provided 5-amino-2-cyclopentyl-4-(3-(dimethylamino)prop-1-ynyl)phenyl methyl carbonate as a light orange oil (420 mg, 57% yield). 1H NMR (400.0 MHz, DMSO-d6) 7.07 (s, 1H), 6.47 (s, 1H), 5.31 (s, 2H), 3.83 (d, J=5.7 Hz, 3H), 3.48 (d, J=4.6 Hz, 2H), 2.86-2.81 (m, 1H), 2.23 (s, 6H), 1.87-1.80 (m, 2H), 1.74-1.66 (m, 2H), 1.62-1.55 (m, 2H), 1.45-1.38 (m, 2H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[C:46]([F:47])=[CH:45][CH:44]=[C:43]([O:48][CH3:49])[C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[C:43]([O:48][CH3:49])=[CH:44][CH:45]=[C:46]([F:47])[C:41]=2[F:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: COc1ccc(F)c(F)c1B(O)O
Product: COc1ccc(F)c(F)c1-c1nc(C(=O)Nc2cnn(C)c2[C@@H]2CC[C@@H](N)[C@@H](F)CO2)c(N)s1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,3-difluoro-6-methoxyphenyl)boronic acid gave 277. 1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 7.84 (s, 1H), 7.47 (t, J=9.4 Hz, 1H), 7.39 (s, 2H), 7.01 (ddd, J=9.4, 4.0, 1.9 Hz, 1H), 5.02-4.76 (m, 2H), 4.18-3.93 (m, 2H), 3.92 (s, 3H), 3.72 (s, 3H), 2.23-2.13 (m, 1H), 1.90-1.60 (m, 4H). LCMS (ES+) m/z 497 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C:10](=O)[CH3:11])[CH:5]=[CH:4][N:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1.Cl.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:21]([C:18]3[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=3)[N:22]=[C:10]([CH3:11])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CC(=O)CC(=O)c1ccnc(Cl)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ccnc(Cl)c2)n(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Yield: 38.9 %

Procedure:
A mixture of 1-(2-chloro-4-pyridinyl)-1,3-butanedione (from step 2, Example 29) (2.5 g, 12.69 mmol), p-chlorophenylhydrazine·HCl (2.7 g, 15.11 mmol) and triethylamine (2.1 mL, 15.11 mmol) in ethanol (50 mL) was heated to reflux overnight (about eighteen hours). The resulting dark colored solution was cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated to give 2-chloro-4-[1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl]pyridine as an orange colored solid (1.5 g, 39%). MP: 110.05° C. This product was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[C:15]([NH2:29])=[N:16][CH:17]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:19]=2)=[N:12][N:11]=[N:10]1.Br[C:31]1[S:35][C:34]([CH:36]2[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]2)=[N:33][CH:32]=1>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[C:15]([NH2:29])=[N:16][CH:17]=[C:18]([C:31]3[S:35][C:34]([CH:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[N:33][CH:32]=3)[CH:19]=2)=[N:12][N:11]=[N:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc(Br)s2)CC1
Reactant: CC1(C)OB(c2cnc(N)c(-c3nnnn3-c3cccc(F)c3F)c2)OC1(C)C
Product: Nc1ncc(-c2cnc(C3CCNCC3)s2)cc1-c1nnnn1-c1cccc(F)c1F

Procedure:
Using the same protocol used to prepare compound I-A-492, 3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine and tert-butyl 4-(5-bromothiazol-2-yl)piperidine-1-carboxylate were reacted together in a PdCl2(dppf)-2-mediated coupling to produce 3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-(2-(piperidin-4-yl)thiazol-5-yl)pyridin-2-amine; 1H NMR (DMSO-d6): 8.46 (d, J=2.3 Hz, 1H), 7.90-7.48 (m, 5H), 3.40-3.22 (m, 3H), 3.11-2.92 (m, 2H), 2.22-2.10 (m, 2H), 1.99-1.83 (m, 2H); ES-MS: m/e=441.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:10][C:9]2[NH:8][CH:7]=[C:6]([CH2:11][CH3:12])[C:5]=2[C:4](=[O:13])[CH2:3]1.[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:14][C:2]1([CH3:1])[CH2:10][C:9]2[N:8]([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([F:15])[CH:21]=3)[CH:7]=[C:6]([CH2:11][CH3:12])[C:5]=2[C:4](=[O:13])[CH2:3]1
Reactant: OB(O)c1cccc(F)c1
Reactant: CCc1c[nH]c2c1C(=O)CC(C)(C)C2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cn(-c2cccc(F)c2)c2c1C(=O)CC(C)(C)C2
Yield: 20.2 %

Procedure:
6,6-Dimethyl-3-ethyl-4,5,6,7-tetrahydro-1H-indol-4-one (50 mg, 0.26 mmol), copper acetate (71 mg, 0.39 mmol), 3-fluorophenyl boronic acid (73 mg, 0.52 mmol) and triethylamine (73 μL, 0.52 mmol) and triethylamine (73 μL, 0.52 mmol) in DCM (1 mL) was stirred at room temperature for 48 h. The crude reaction mixture was poured onto a bond elut tube (Anachem 1225-6034 10 g/60 mL) and eluted using isohexane : EtOAc (100:0→5:1) to afford a yellow solid. The solid was triturated in ether to afford the title compound (15 mg, 20%) as a colourless solid. 1H NMR (360 MHz, CDCl3) δ 1.08 (6H,s), 1.22 (3H,t, J=7.4Hz), 2.36 (2H,s), 2.62 (2H,s), 2.81 (2H,q, J=7.4 Hz), 6.57 (1H,s), 7.02-7.11 (3H,m), 7.41-7.45 (1H,m). MS (ES+) 286 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13](=[O:36])[CH2:14][CH:15]([NH:22][S:23]([C:26]1[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=1)(=[O:25])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][CH2:6]2)=O.[NH:37]([CH3:39])[CH3:38]>>[CH3:38][N:37]([CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13](=[O:36])[CH2:14][CH:15]([NH:22][S:23]([C:26]1[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=1)(=[O:24])=[O:25])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:7][CH2:6]2)[CH3:39]
Reactant: CNC
Reactant: O=Cc1ccc2c(c1)CCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Product: CN(C)Cc1ccc2c(c1)CCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1

Procedure:
The title compound was prepared from N-(5-formyl-indan-1-yl)-3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionamide (Step G) and Me2NH, using essentially the same procedure described in Example 1, Step H, yielding a white solid. MS (ESI) m/z 528 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:13][Si:23]([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24])=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)c1ccc(O)c(C=O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(O[Si](C)(C)C(C)(C)C)c(C=O)c1
Reaction time: 15 h
Yield: 114.3 %

Procedure:
To a stirred solution of 5-tert-butyl-2-hydroxybenzaldehyde (570 mg, 3.2 mmol) in DMF (5 mL) was added imidazole (435 mg, 6.4 mmol) and TBSCl (576 mg, 3.8 mmol). The reaction mixture was stirred for 15 h and quenched with saturated aqueous NH4Cl. The resulting mixture was extracted with EtOAc (2×20 mL). The combined organic layer was washed with H2O, brine, dried with Na2SO4 and concentrated under reduced pressure to provide 5-tert-butyl-2-(tert-butyldimethylsilyloxy)benzaldehyde (1.07 g, quantitative).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15]([OH:17])=O)[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:15]([N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1)=[O:17])[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)O
Product: CN1CCN(C(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)CC1

Procedure:
In the same manner as in Reference Example 2, N-tert-butoxycarbonyl-L-glutamine and 1-methylpiperazine were condensed to obtain a crystal of 1-(N-tert-butoxycarbonyl-L-glutaminyl)-4-methylpiperazine (7.0 g).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([CH2:28][CH3:29])=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([O:30][CH3:31])[N:19]=3)=[CH:14][N:13]2[CH:32]=1)(C(C)(C)C)(C)C.Cl>CO>[CH2:28]([C:27]1[C:18]([C:15]2[CH:16]=[CH:17][C:12]3[N:13]([CH:32]=[C:10]([CH2:9][OH:8])[N:11]=3)[CH:14]=2)=[N:19][C:20]([O:30][CH3:31])=[C:21]([CH:26]=1)[C:22]([O:24][CH3:25])=[O:23])[CH3:29]
Reactant: CCc1cc(C(=O)OC)c(OC)nc1-c1ccc2nc(CO[Si](C)(C)C(C)(C)C)cn2c1
Agent: Cl
Solvent: CO
Product: CCc1cc(C(=O)OC)c(OC)nc1-c1ccc2nc(CO)cn2c1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
To solution of methyl 6-(2-((tert-butyldimethylsilyloxy)methyl)imidazo[1,2-a]pyridin-6-yl)-5-ethyl-2-methoxynicotinate (0.911 g, 2.00 mmol) in MeOH (8 mL) was added 1M HCl (aqueous, 3.0 mL, 3.0 mmol). Reaction mixture was stirred at room temperature until starting material was completely consumed according to LC/MS. After ˜2 h MeOH was concentrated and residue was treated with NaHCO3 solution (aqueous saturated, 10 mL). Product was extracted with DCM (3×20 mL). Organic phase was washed with NaCl (aqueous saturated, 20 mL) and dried over Na2SO4. Removal of the solvent afforded methyl 5-ethyl-6-(2-(hydroxymethyl)imidazo[1,2-a]pyridin-6-yl)-2-methoxynicotinate (0.650 g) in 95% yield.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[C:21]([C:22](C(O)=O)=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1)(=[O:15])=[O:14].C(N(CC)CC)C.ClC(OC)=O.C(=O)(O)[O-].[Na+]>ClCCl>[O:14]=[S:13]1(=[O:15])[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:21]2[C:22](=[O:23])[N:12]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1
Reactant: O=C(O)C(=O)c1cccnc1S(=O)(=O)NCCCCOC1CCCCO1
Agent: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2cccnc2S(=O)(=O)N1CCCCOC1CCCCO1
Reaction time: 2 h
Yield: 113.5 %

Procedure:
To a stirred solution of 3 g of N-(4-(2-tetrahydropyranyloxy)butyl) 3-carboxycarbonylpyridine-2-sulfonamide and 2.3 mL of triethylamine in 100 mL of dichloromethane at 0° C. was added 0.8 mL of methyl chloroformate dropwise. After 2 h, the mixture was shaken with 10 mL of saturated sodium bicarbonate, dried over MgSO4 and concentrated under reduced pressure. Chromatography of the dark brown oil over silica gel, eluting with 1:1 ethyl acetate: hexane gave 3 g of homogeneous 1,1-dioxido-2-(4-(2-tetrahydropyranyloxy)butyl)-isothiazolo[5,4-b]pyridin-3(2H)-one as an amber oil.
Reaction SMILES: [N:1]([C:4]1[S:8][C:7]2[CH2:9][CH2:10][CH2:11][CH2:12][C:6]=2[C:5]=1[C:13]([O:15]CC)=O)=[C:2]=[S:3].[N:18]1([CH2:23][CH2:24][CH2:25][NH2:26])[CH:22]=[CH:21][N:20]=[CH:19]1>>[N:18]1([CH2:23][CH2:24][CH2:25][N:26]2[C:13](=[O:15])[C:5]3[C:6]4[CH2:12][CH2:11][CH2:10][CH2:9][C:7]=4[S:8][C:4]=3[NH:1][C:2]2=[S:3])[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: NCCCn1ccnc1
Reactant: CCOC(=O)c1c(N=C=S)sc2c1CCCC2
Product: O=c1c2c3c(sc2[nH]c(=S)n1CCCn1ccnc1)CCCC3

Procedure:
The compound was synthesized starting from ethyl 4,5,6,7-tetrahydro-2-isothiocyanatobenzo[b]thiophene-3-carboxylate (1.09 g, 4.0 mmol) and 3-(1H-imidazol-1-yl)propan-1-amine (0.5 g, 4.0 mmol) as described above.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)(O)[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[CH:17][CH:16]=1.C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:20][CH:19]=2)=[CH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[CH:37][CH:36]=1
Reactant: COc1ccc(CC(O)(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(C=C(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
To the Grignard reagent prepared from 20 g 4-bromoanisole (107 mmol) and 2.43 g Mg turnings (107 mg-atom) in 20 mL Et2O was added 19.25 g dry (P2O5) desoxyanisoin (76 mmol) as a solid in four portions, each followed by a 50 mL wash of Et2O. The mixture was stirred at reflux 17 h, cooled to room temperature, poured onto 200 g ice and 40 mL 1N H2SO4, and filtered into a separatory funnel. 100 mL Et2O was added and the organic layer was washed with 100 mL H2O and saturated NaHCO3 (2×100 mL). The organic layer was dried (MgSO4), filtered, and the Et2O was removed under reduced pressure to give crude 1,1,2-Tris(4-methoxyphenyl)ethanol as an orange oil which crystallized (25 mL EtOH with a trace of NH4OH) as an orange solid, 18.6 g (67% crude yield), mp: 109°-127° C.; NMR δ7.47 to 6.63 (m, 12H, ArH), 3.73 (3 overlapping s, 9H, OCH3), 3.48 (s, 2H, CH2), 2.27 (s, 1H, OH). p-TsOH.H2O (2 g; 10.5 mmol) and 18.5 g of the crude carbinol (50.8 mmol) were dissolved in 50 mL C6H6, heated to reflux 2 h, cooled to room temperature, and poured onto 75 mL 5% NaHCO3. The organic layer was washed with 75 mL 5% NaHCO3. The combined aqueous layers were extracted with 25 mL C6H6. The combined organic layers were washed with 100 mL H2O, dried (Na2SO4), filtered, and the solvent removed to give a dark oil. The oil was purified on 80 g flash SiO2 (gradient elution with petroleum ether-CH2Cl 2) yielding an amber oil which solidified at room temperature to yield 1,1,2-Tris(4-methoxyphenyl)ethene as white cubes (11.3 g, 64%), mp: 100°-101° C. (lit. 100°-101° C.). NMR δ7.29 to 6.55 (m, 13H, ArH and C=CH), 3.78 (s, 3H, geminal ring OCH3), 3.75 (s, 3H, vicinal ring OCH3), 3.69 (s, 3H, central ring OCH3).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH2:32])[N:17]=[C:16](C3C=CN=CC=3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH2:39]([S:42](Cl)(=[O:44])=[O:43])[CH2:40][CH3:41]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH:32][S:42]([CH2:39][CH2:40][CH3:41])(=[O:44])=[O:43])[N:17]=[C:16]([C:7]3[CH:6]=[CH:5][CH:4]=[CH:9][N:8]=3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ccncc2)nc1OCCN
Reactant: CCCS(=O)(=O)Cl
Product: CCCS(=O)(=O)NCCOc1nc(-c2ccccn2)nc(NS(=O)(=O)c2ccc(C(C)C)cn2)c1Oc1ccccc1OC

Procedure:
According to the procedure described in Example 4a) 100 mg 5-isopropyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with 1-propanesulfonylchloride to give 76 mg 5-isopropyl-N-[6-(2-(1-propanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(2-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=4.56 min, [M+1]+=643.65, [M−1]−=641.70.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11]C2)[S:6][N:5]=1.[CH2:16]([C:23]1[CH:28]=[C:27]([CH3:29])[N:26]=[C:25](Cl)[N:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.O>[CH2:16]([C:23]1[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([NH:15][C@@H:12]2[CH2:13][CH2:14][N:9]([C:7]3[S:6][N:5]=[C:4]([CH3:3])[N:8]=3)[CH2:11]2)[N:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1nsc(N2CCC(N)CC2)n1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1cc(Cc2ccccc2)nc(N[C@@H]2CCN(c3nc(C)ns3)C2)n1

Procedure:
A solution of 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-ylamine dihydrochloride (54.2 mg, 0.2 mmol), 4-benzyl-2-chloro-6-methyl-pyrimidine (48.1 mg, 0.22 mmol)) and N,N-diisopropylethyl amine (120 L, 0.7 mmol) in dioxane (0.6 mL) was heated at 200° C. in a microwave oven for 1 hour. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with EtOAc as eluent. The title compound was obtained as a yellow viscous oil (22 mg, 29%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:22]([CH3:24])[CH3:23].O>CN(C=O)C>[CH:22]([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)([CH3:24])[CH3:23]
Reactant: CC(C)I
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 100 °C

Procedure:
In a microwave vial, a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 g, 5.15 mmol) in DMF (10 mL) was added cesium carbonate (5.04 g, 15.46 mmol) and 2-iodopropane (2.58 mL, 25.8 mmol). The mixture was heated at 100° C. overnight. After cooling to RT, H2O (300 mL) was added and the aqueous layer was extracted with EtOAC (2×200 mL). The organic extracts were combined, dried over Na2SO4, filtered, and solvent was removed in vacuo. The resulting crude material was reconstituted in MeOH (1.0 mL) and purified by HPLC. The fractions were collected and stripped to dryness via rotary evaporation to yield the title compound. [M+H] calc'd for C12H21BN2O2, 237. found 237.
Reaction SMILES: [CH:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[N:18]O)[CH:15]=3)[CH2:10][CH2:9][N:8]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCO.C(O)(=O)C.O.[Pd]>[NH2:18][CH2:17][C:14]1[CH:15]=[C:16]2[C:11]([CH2:10][CH2:9][N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:7]2[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C=NO)cc2C1C1CCCCC1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2ccc(CN)cc2C1C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
Tert-butyl 1-cyclohexyl-7-[(hydroxyimino)methyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (995 mg) was dissolved in EtOH-acetic acid-water (8:1:1, 20 mL). To the reaction mixture was added 10% palladium-supported carbon (480 mg), followed by stirring under a hydrogen atmosphere, at room temperature and normal pressure, for 4 hours. Then, the reaction mixture was filtered through celite and the solvent was evaporated to obtain tert-butyl 7-(aminomethyl)-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (956 mg).
Reaction SMILES: Cl[C:2]1[N:18]=[C:5]2[C:6]([C:10]3[CH:15]=[N:14][C:13]([O:16][CH3:17])=[CH:12][N:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:2]3[N:18]=[C:5]4[C:6]([C:10]5[CH:15]=[N:14][C:13]([O:16][CH3:17])=[CH:12][N:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: COc1cnc(-c2cccn3nc(Cl)nc23)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: COc1cnc(-c2cccn3nc(Nc4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc23)cn1

Procedure:
4-{4-[8-(5-Methoxy-pyrazin-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(5-methoxy-pyrazin-2-yl)-[1,2,4]triazolo[1,5-a]pyridine and 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester with 2,2′-bis-dicyclohexylphosphanyl-biphenyl as the ligand in a manner analogous to Example 2d (0.039 g, 19%). MP=193-195° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.75 (s, 1H), 9.69 (s, 1H), 8.87 (d, 1H), 8.49 (m, 1H), 8.35 (m, 1H), 7.65 (m, 2H), 7.20 (m, 3H), 4.08 (m, 2H), 4.02 (s, 3H), 2.80 (m, 2H), 2.62 (m, 1H), 1.72 (m, 2H), 1.51 (m, 2H), 1.40 (s, 9H). MS=502 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:16](=[O:17])[CH:15]2[CH:10]([CH:11]3[C:18](=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]2[C:13]([C:32]([OH:45])([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:12]3)[C:8]1=[O:9])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].ClCC(O[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62]CC)=O>CN(C)C=O>[OH:45][C:32]([C:13]1[CH:14]2[C:18](=[C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:11]([CH:12]=1)[CH:10]1[C:8]([N:7]([CH2:6][C:4]([O:3][CH2:1][CH2:2][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])=[O:5])[C:16](=[O:17])[CH:15]21)=[O:9])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCCCCCCCOC(=O)CCl
Reactant: CCOC(=O)CN1C(=O)C2C3C=C(C(O)(c4ccccc4)c4ccccn4)C(C3=C(c3ccccc3)c3ccccn3)C2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOC(=O)CN1C(=O)C2C3C=C(C(O)(c4ccccc4)c4ccccn4)C(C3=C(c3ccccc3)c3ccccn3)C2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
A similar procedure (Hursthouse, M. B.; Khan, A.; Marson, C. M.; Porter, R. A. Tetrahedron Lett. 1995, 36, 33, 5979-5982) to that described for the preparation of 207 was followed using NRB (0.37 g, 0.7 mmol) and potassium carbonate (0.25 g, 1.8 mmol) in dimethylformamide (5 mL), and octyl chloroacetate (0.32 g, 1.5 mmol) in dimethylformamide (2 mL), and the mixture stirred at room temperature for 2 h. Purification by flash chromatography (hexane/ethyl acetate 2:1) afforded 369 as a white solid (0.34 g, 0.5 mmol, 71%). 1H NMR (400 MHz, CDCl3) δ 0.87-0.90 (3H, m, O(CH2)7CH3), 1.26-1.30 (10H, m, OCH2CH2(CH2)5CH3), 1.61-1.63 (2H, m, OCH2CH2(CH2)5CH3), 3.40-4.56 (8H, m, OCH2(CH2)6CH3, NCH2, H-1, H-2, H-3, H-4), 5.48 (0.5H, s, OH), 5.52 (0.3H, m, V/H-6), 5.53 (0.5H, s, OH), 5.55 (0.4H, m, Y/H-6), 6.02 (0.1H, m, U/H-6), 6.04 (0.2H, m, W/H-6), 6.70-7.60 (16H, m, Ar), 8.40-8.60 (2H, m, αPyr).