Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:10]2[NH:15][C:14](=[O:16])[C:13]3([CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17]3)[N:12]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1.Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]([CH:10]2[N:15]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:14](=[O:16])[C:13]3([CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22]3)[N:12]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CC(c2cccc(F)c2)NC(=O)C12COCCOC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C2(COCCOC2)N(C(=O)OC(C)(C)C)CC1c1cccc(F)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
28 mg (0.66 mmol) sodium hydride were added to 0.21 g (0.55 mmol) tert-butyl 3-(3-fluorophenyl)-5-oxo-8,11-dioxa-1,4-diazaspiro[5.6]dodecane-1-carboxylate in 20 ml DMF. After 20 min at RT 63 μl (0.65 mmol) methyl bromoacetate were added dropwise at 0° C. Then the mixture was stirred for 30 min in the ice bath and then for 5 h at RT. The reaction mixture was poured onto water poured and extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated down.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH3:6])[CH3:5].[CH2:7]([O:9][C:10](=[O:22])[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)=[O:12])[CH3:8].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:7]([O:9][C:10](=[O:22])[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:2][CH2:3][N:4]([CH3:6])[CH3:5])[CH:14]=1)=[O:12])[CH3:8]
Reactant: CCOC(=O)C(=O)c1c[nH]c2ccccc12
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)C(=O)c1cn(CCN(C)C)c2ccccc12
Yield: 61.7 %

Procedure:
The general procedure 1 was then followed using 1-chloro-2-dimethylaminoethane (6 mmol, 0.65 g), ethyl-2-(1H-indol-3-yl)-2-oxoacetate (6 mmol, 1.3 g) and Cs2CO3 (6.6 mmol, 2.15 g). The purification was achieved by column chromatography (petrolether:ethylacetate:diethylamine 6:3:1) to yield ethyl-2-{1-[2-(dimethylamino)-ethyl]-1H-indol-3-yl}-2-oxoacetate (3.7 mmol, 62%) as pale yellow crystals. Mp=71-72° C. IR {tilde over (ν)} [cm−1]=3139; 3044; 2977; 2946; 2797; 2772; 1727; 1641. EI-MS m/z (rel. int.)=288 (19.15%; M+•.). 1H NMR (300 MHz, CDCl3) 8.45 (m; 2H; indole-H); 7.37 (m; 3H; indole-H); 4.41 (q; 3J=7.1 Hz; 2H; OCH2CH3); 4.26 (t; 3J=6.9 Hz; 2H; indole-CH2CH2N); 2.76 (t; 3J=6.9 Hz; 2H; indole-CH2CH2N); 2.31 (s; 6H); 1.44 (t; 3H; 3J=7.1 Hz; OCH2CH3).
Reaction SMILES: [F:1][C:2]1([F:6])[CH2:5][NH:4][CH2:3]1.[Cl:7][C:8]1[CH:9]=[N:10][N:11]([C:13]2([C:16]3[NH:33][C:19]4=[N:20][C:21]([N:24]5[CH2:29][CH2:28][CH2:27][C@@H:26]([C:30](O)=[O:31])[CH2:25]5)=[CH:22][CH:23]=[C:18]4[N:17]=3)[CH2:15][CH2:14]2)[CH:12]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl>[Cl:7][C:8]1[CH:9]=[N:10][N:11]([C:13]2([C:16]3[NH:33][C:19]4=[N:20][C:21]([N:24]5[CH2:29][CH2:28][CH2:27][C@@H:26]([C:30]([N:4]6[CH2:5][C:2]([F:6])([F:1])[CH2:3]6)=[O:31])[CH2:25]5)=[CH:22][CH:23]=[C:18]4[N:17]=3)[CH2:15][CH2:14]2)[CH:12]=1
Reactant: O=C(O)[C@@H]1CCCN(c2ccc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)C1
Reactant: FC1(F)CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C([C@@H]1CCCN(c2ccc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)C1)N1CC(F)(F)C1
Reaction time: 2 h
Yield: 43.3 %

Procedure:
3,3-Difluoroazetidine (33 mg, 0.2 mmol) was added to a mixture of (R)-1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylic acid (100 mg, 0.25 mmol), diisopropylethylamine (0.1 mL, 0.77 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HATU) (118 mg, 0.31 mmol) in anhydrous dichloromethane (5 mL) at room temperature. The reaction mixture was stirred for 2 h, then partitioned between dichloromethane and water. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via preparative TLC to afford the title compound (40 mg, 43% yield). MS (ES+) (M+H) 462.2; LCMS retention time 2.163 minutes (Method N1). 1H NMR (300 MHz, CDCl3) δ 1.17-1.39 (m, 1H), 1.71-2.24 (m, 7H), 2.35-2.58 (m, 1H), 2.83-3.13 (m, 2H), 4.04-4.78 (m, 6H), 6.63 (d, 1H), 7.62 (s, 2H), 7.69-7.80 (m, 1H), 9.15 (br s, 1H).
Reaction SMILES: [C:1]([CH2:4][S:5][C:6]1[CH:34]=[CH:33][C:9]2[CH:10](O)[C:11]3[CH:18]=[C:17]([O:19][CH2:20][C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][C:25]([Cl:31])=[CH:26][CH:27]=5)[N:22]=4)[CH:16]=[CH:15][C:12]=3[O:13][CH2:14][C:8]=2[CH:7]=1)([OH:3])=[O:2].[SH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39]>>[C:38]([CH2:37][CH2:36][S:35][CH:10]1[C:9]2[CH:33]=[CH:34][C:6]([S:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:7][C:8]=2[CH2:14][O:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][C:25]([Cl:31])=[CH:26][CH:27]=4)[N:22]=3)=[CH:18][C:11]1=2)([OH:40])=[O:39]
Reactant: O=C(O)CCS
Reactant: O=C(O)CSc1ccc2c(c1)COc1ccc(OCc3ccc4ccc(Cl)cc4n3)cc1C2O
Product: O=C(O)CCSC1c2ccc(SCC(=O)O)cc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21

Procedure:
8-carboxymethylthio-2-(7-chloroquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[NH:14][N:13]=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[NH:14][N:13]=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(-c2nnn[nH]2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(-c2nnn[nH]2)c1

Procedure:
5-(3-Nitrophenyl)-1H-tetrazole (4.41 g) was hydrogenated in ethanol (50 ml) over 10% palladium on carbon (0.4 g) under 3 atmospheric pressure of hydrogen at ambient temperature. The reaction mixture was filtered through Celite® (Johns Manville) and washed with ethanol. The filtrate and the washings were combined and evaporated to give 5-(3-aminophenyl)-1H-tetrazole as a crystalline powder, which was triturated in diisopropyl ether and collected by filtration to afford the desired product as a white powder (3.19 g, 85.8%). This was used in a following reaction without further purification.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].C[Si](C)(C)N[Si](C)(C)C.C(O[C@@H:23]1[O:45][C@H:44]([CH2:46][O:47][C:48](=[O:55])[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:34]([O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:24]1[O:25][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=O)C>>[C:26]([O:25][C@@H:24]1[C@H:34]([O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@H:44]([CH2:46][O:47][C:48](=[O:55])[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[O:45][C@H:23]1[N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: Cc1cn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)[nH]c1=O

Procedure:
The title compound was prepared by a 5-step sequence reaction. Thymine (12,6 g) was treated with hexamethyldisilazane and 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (50 g) was added. The 1-(2',3',5'-tri-O-benzoyl-β-D-ribofuranosyl)thymine obtained was treated with sodium methoxide and gave 1-(β-D-ribofuranosyl)thymine (23 g). Then said substance was treated with tritylchloride and methylsulfonylchloride and 1-(2',3'-di-O-methylsulfonyl-5'-O-trityl-β-D-ribofuranosyl)thymine (39 g) was obtained. Said substance was treated with sodium hydroxide and gave the title compound 1-(2'-3'-anhydro-5'-O-trityl-β-D-lyxofuranosyl)thymine (VSB-020) 19.2 g. Yield 43%. 1H-NMR (DMSO-d6) δ: 1.66 (s, 3H, 5-CH3), 3.24-3.34 (m, 2H, 5'-H), 4.08 (s, 2H, 2'-H and 3'-H), 4.25 (t, 1H, 4'-H), 6.13 (s, 1H, 1'-H), 7.30-7.45 (m, 16H, trityl H and 6-H), 14.46 (s, 1H, N--H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11].C([O-])([O-])=O.[K+].[K+].[NH:18]1[CH:22]=[CH:21][CH:20]=[N:19]1>CS(C)=O.O>[F:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:18]1[CH:22]=[CH:21][CH:20]=[N:19]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2cccn2)c(F)c1
Temperature: 90 °C
Yield: 79.9 %

Procedure:
To a solution of 1,2-difluoro-4-nitrobenzene (3.18 g, 20 mmol) in DMSO (35 mL) were added K2CO3 (6.08 g, 44 mmol) and pyrazole (1.50 g, 22 mmol) with stirring. The reaction mixture was heated at 90° C. for 18 h, and cooled to rt. The mixture was diluted with water (50 mL) and filtered. The filtrate was extracted with DCM (50 mL×3), the combined organic phases were concentrated in vacuo. The crude product was purified by a silica gel column chromatography (PE/CH2Cl2 (V/V)=1:1) to give the title compound as a yellow solid (3.31 g, 80%).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([O:24][CH2:25][CH2:26]Cl)[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:28][C:29]1[CH:30]=[C:31]([NH:38][C:39](=[O:44])[CH2:40][N:41]([CH3:43])[CH3:42])[CH:32]=[CH:33][C:34]=1[NH:35][CH2:36][CH3:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:45][NH:46][CH3:47]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([O:24][CH2:25][CH2:26][N:46]([CH3:47])[CH3:45])[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:28][C:29]1[CH:30]=[C:31]([NH:38][C:39](=[O:44])[CH2:40][N:41]([CH3:43])[CH3:42])[CH:32]=[CH:33][C:34]=1[NH:35][CH2:36][CH3:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccc(OCCCl)cc3N2C)C(=O)N1Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Product: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccc(OCCN(C)C)cc3N2C)C(=O)N1Cc1ccccc1
Temperature: 65 °C
Yield: 20 %

Procedure:
To a pressure tube was added the product of Example 145 (150 mg, 0.23 mmol), tetra-n-butylammonium iodide (85 mg, 0.23 mmol), and 2.0 M solution of dimethylamine in THF (6 mL). The tube was sealed and heated at 65° C. for 14 h. The solution was cooled and concentrated under reduced pressure, and the crude material was purified by chromatography (silica gel, 0–20% MeOH/DCM) to provide the title compound (30 mg, 20%). 1H-NMR (CDCl3): δ 8.83 (1H, s), 7.45 (2H, d), 7.22–7.34 (5H, m), 7.11 (1H, dd), 6.71 (1H, dd), 6.63 (1H, d), 6.52 (1H, d), 5.14 (2H, s), 4.12 (2H, t), 3.70 (3H, s), 3.04 (2H, s), 2.97 (2H, q), 2.82 (2H, t), 2.40 (6H, s), 2.35 (6H, s), 1.02 (3H, t); MS(ESI): 660(MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[CH:18]=3)=[CH:15][C:14]([C@H:43]([N:45]3[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][C@@H:46]3[CH3:55])[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].OS(C(F)(F)F)(=O)=O>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[CH:18]=3)=[CH:15][C:14]([C@H:43]([N:45]3[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][C@@H:46]3[CH3:55])[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)C[C@@H]4C)cnc3Nc3cnc(OC)c(F)c3)nc(C)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc([C@@H](C)N3CCN(S(C)(=O)=O)C[C@@H]3C)cc2-c2cc(N)nc(C)n2)cc1F
Temperature: 80 °C
Yield: 29.2 %

Procedure:
A mixture of 6-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((1R)-1-((2S)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.050 g, 0.065 mmol) in TFA (1 mL) was treated with triflic acid (5.76 μL, 0.065 mmol) and heated to 80° C. for 1 h. The reaction mixture was concentrated and then ice cubes were added to the brown residue. Saturated NaHCO3 (aq.) was added followed by CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column (4 g), eluting with a gradient of 0% to 5% MeOH in CH2Cl2, to provide 6-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((1R)-1-((2S)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-2-methyl-4-pyrimidinamine (0.010 g, 0.019 mmol, 29.1% yield) as a brown solid. m/z (ESI, +ve) 531.2 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.14 (s, 1H); 8.36 (dd, J=12.91, 2.35 Hz, 1H); 8.22-8.25 (m, 1H); 8.16 (d, J=2.35 Hz, 1H); 7.95 (dd, J=1.96, 0.39 Hz, 1H); 7.04 (s, 2H); 6.79 (s, 1H); 4.02 (q, J=6.65 Hz, 1H); 3.94 (s, 3H); 3.05-3.20 (m, 2H); 2.77-2.95 (m, 5H); 2.53 (br. s., 3H); 2.45 (dd, J=11.35, 5.28 Hz, 1H); 1.40 (d, J=6.65 Hz, 3H); 1.10 (d, J=6.26 Hz, 3H).
Reaction SMILES: [OH:1][CH:2]([C:6]([O:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1)([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=1)[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].CN(C=O)C.[H-].[Na+].[CH3:43][O:44][C:45]1[CH:50]=[C:49]([CH3:51])[N:48]=[C:47](S(C)(=O)=O)[N:46]=1>O>[CH3:43][O:44][C:45]1[CH:50]=[C:49]([CH3:51])[N:48]=[C:47]([O:1][CH:2]([C:6]([O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][CH:8]=2)[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=2)[C:3]([OH:5])=[O:4])[N:46]=1
Reactant: COc1cc(C)nc(S(C)(=O)=O)n1
Reactant: CCc1ccc(C(OCCc2ccc(OC)c(OC)c2)(c2ccc(CC)cc2)C(O)C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(C(OCCc2ccc(OC)c(OC)c2)(c2ccc(CC)cc2)C(Oc2nc(C)cc(OC)n2)C(=O)O)cc1
Reaction time: 0.25 h
Yield: 23.7 %

Procedure:
1.8 g (3.8 mmol) of 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-ethylphenyl)propionic acid were introduced into 20 ml of DMF, and 554 mg of NaH (50% suspension) were added. After the mixture had stirred for 15 minutes, 855 mg (4.2 mmol) of 4-methoxy-6-methyl-2-methylsulfonylpyrimidine were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the mixture, which was then extracted with ether. The aqueous phase was acidified with 1 N aqueous HCl, extracted with ether and dried over magnesium sulfate. The solvent was distilled off and 540 mg (23%) of colorless powder were isolated after recrystallization from ether/n-hexane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.Cl.[CH3:14][O:15][C@@H:16]1[C@@H:20]([O:21][CH3:22])[CH2:19][NH:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:18]1[CH2:19][C@H:20]([O:21][CH3:22])[C@@H:16]([O:15][CH3:14])[CH2:17]1
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: CO[C@H]1CNC[C@@H]1OC
Agent: Cl
Product: CO[C@H]1CN(c2ccnc3ccc(Br)cc23)C[C@@H]1OC
Yield: 35.7 %

Procedure:
697 mg 6-bromo-4-chloroquinoline and 482 mg (3S,4S)-3,4-dimethoxytetrahydro-1H pyrrole monohydrochloride were reacted by the same method as in Production Example 82, to give 346 mg of the title compound as pale brown crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[C:9](=[O:16])[NH:10][C:11](SC)=[N:12][CH:13]=1.[CH3:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH2:23][S:24][CH2:25][CH2:26][NH2:27]>>[CH3:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH2:23][S:24][CH2:25][CH2:26][NH:27][C:11]1[NH:10][C:9](=[O:16])[C:8]([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:13][N:12]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CSc1ncc(Cc2ccccn2)c(=O)[nH]1
Product: Cc1[nH]cnc1CSCCNc1ncc(Cc2ccccn2)c(=O)[nH]1

Procedure:
An intimate mixture of 5-(2-pyridylmethyl)-2-methylthio-4-pyrimidone (4.7 g) and 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (3.4 g) was heated at 130°-135° for 7 hours. The cooled residue was triturated with hot water to give 2-[2-(5-methyl-4-imidazolylmethythio)ethylamino]-5-(2-pyridylmethyl)-4-pyrimidone and this product was treated with dilue ethanolic HCl to give the title compound m.p. 207°-210° (aqueous ethanol)
Reaction SMILES: [H-].[Na+].[N:3]1[C:11]([NH2:12])=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[N:5][CH:4]=1.[C:13]1([C:19]2[C:20]3[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=3[S:22][C:23]=2[CH2:24]OS(C)(=O)=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[C:13]1([C:19]2[C:20]3[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=3[S:22][C:23]=2[CH2:24][N:7]2[CH:8]=[N:9][C:10]3[C:6]2=[N:5][CH:4]=[N:3][C:11]=3[NH2:12])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ncnc2[nH]cnc12
Reactant: CS(=O)(=O)OCc1sc2ccccc2c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1sc2ccccc2c1-c1ccccc1
Reaction time: 0.08 h

Procedure:
NaH (60% in mineral oil, 15 mg, 0.377 mmol) was added in one portion to a mixture of 9H-purin-6-ylamine (47 mg, 0.345 mmol) in DMF (3 mL) at RT. After 5 min stirring, a solution of methanesulfonic acid 3-phenylbenzo[b]thiophen-2-ylmethyl ester from Example 26 (100 mg, 0.314 mmol) in DMF (2 mL) was added dropwise and stirring at RT was continued for 30 min. The reaction mixture was then quenched by addition of water and a solid formed. The precipitated was collected by filtration and was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) and triturated from diethyl ether affording 166 as a white solid (52 mg, 46%). LCMS: RT 3.99 min [M+H]+ 358.1. 1H NMR (DMSO, 400 MHz): δ 8.15 (1H, s), 8.06 (1H, s), 7.98-7.92 (1H, m), 7.64-7.59 (4H, m), 7.57-7.46 (2H, m), 7.42-7.37 (2H, m), 7.27 (2H, s), 5.63 (2H, s)
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[S:7][CH:8]=[CH:9][C:4]=2[C:3]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12].C(O[K])(C)(C)C.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>C1COCC1>[CH3:1][C:2]1[N:6]([S:31]([C:28]2[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:30][CH:29]=2)(=[O:33])=[O:32])[C:5]2[S:7][CH:8]=[CH:9][C:4]=2[C:3]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)Cc1c(C)[nH]c2sccc12
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(S(C)(=O)=O)cc2)c2sccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(5-methyl-6H-thieno[2,3-b]pyrrol-4-yl)acetate (0.059 g, 0.282 mmol) in THF at about 0° C. was added tBuOK (0.044 g, 0.395 mmol), followed by the 4-(methylsulfonyl)-benzene-1-sulfonyl chloride (0.086 g, 0.338 mmol). The reaction mixture was stirred at ambient temperature for about 1 h to give the crude title compound, which was used without further purification. LC/MS (Table 1, Method b) Rt=2.25 min; MS m/z 428 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:25])[CH:3]=1.[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[C:30]([CH3:37])[CH:29]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[CH:32]=[N:33][C:28]([O:27][CH3:26])=[CH:29][C:30]=5[CH3:37])[CH:3]=[C:4]([CH3:25])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1cc(Cl)nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)c1
Reactant: COc1cc(C)c(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(C)c(-c2cc(C)cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)n2)cn1
Temperature: 80 °C
Yield: 52.4 %

Procedure:
To N-(6-chloro-4-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (59 mg, 0.16 mmol), 6-methoxy-4-methylpyridin-3-ylboronic acid (40 mg, 0.24 mmol) and tetrakis(triphenylphosphine)palladium (0) (9 mg, 0.008 mmol) in 1,2-dimethoxyethane (1.63 mL), aqueous saturated Na2CO3 (163 uL) was added. The reaction mixture was stirred and heated at 80° C. for 18 hours under N2 atmosphere. The reaction mixture was diluted with 1,2-dimethoxyethane, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-4,4′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (38 mg, 52%). ESI-MS m/z calc. 453.44. found 454.5 (M+1)+. Retention time 2.01 minutes.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=2)[C:11]2[CH:16]=[C:15]([Cl:17])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:11]3[CH:16]=[C:15]([Cl:17])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(Cl)cc23)cc1Cl
Reactant: Cc1ncc[nH]1
Product: COc1ccc(CNc2nc(-n3ccnc3C)nc3sc(Cl)cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2,6-dichloro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-chloro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].[OH:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[I:17])[C:10]([O:12][CH3:13])=[O:11].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:2]([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[I:17])[C:10]([O:12][CH3:13])=[O:11])[CH2:3][CH2:4][CH3:5]
Reactant: COC(=O)c1ccc(I)c(O)c1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCOc1cc(C(=O)OC)ccc1I
Yield: 99 %

Procedure:
In a manner similar to that of Example (25a), by reaction of 21.5 mL (0.189 mol, 1.5 eq) of 1-iodobutane and 35.03 g (0.126 mol, 1 eq) of methyl 3-hydroxy-4-iodobenzoate in 350 ml of methyl ethyl ketone in the presence of 52.24 g (0.378 mol, 3 eq) of potassium carbonate at 85° C. for 2 hours 30 minutes, and after washing with heptane, 41.78 g of methyl 3-butoxy-4-iodobenzoate are obtained in the form of white crystals. Yield=99%
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]=[C:37]=[O:38].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([C:37]([NH:36][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[Cl:29])=[O:38])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: O=C=Nc1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C(=O)Nc4ccccc4Cl)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 7-[(R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0237 mmol), 2-chlorophenylisocyanate (0.00669 g, 0.0436 mmol), DIPEA (0.033 mL, 0.19 mmol) in DMF (1 mL) was stirred at rt for 15 min. Purification by HPLC afforded the title compound as a light yellow solid. 1H NMR (400 MHz, CD3OD): δ=1.89 (d, J=6.6 Hz, 3H), 2.59 (br. s., 2H), 3.78 (t, J=5.8 Hz, 2H), 4.28 (d, J=2.5 Hz, 2H), 6.32 (br. s., 1H), 6.45-6.55 (m, 1H), 7.08-7.17 (m, 1H), 7.18-7.32 (m, 2H), 7.36-7.46 (m, 2H), 7.60 (dd, J=8.1, 1.5 Hz, 1H), 7.69 (s, 1H), 8.23 (br. s., 1H). MS (ES+): m/z 575.03/577.01 (98/100) [MH+]. HPLC: tR=3.63 min (ZQ3, polar—5 min).