Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3=[N:19][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:21](=[O:22])[C:11]3=[N:10]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:35]1[N:36]=[CH:37][S:38][CH:39]=1)CCC.[F-].[Cs+]>CN(C)C=O.C(OCC)(=O)C.[Cu]I.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>[CH3:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:20]1[C:21](=[O:22])[C:11]2=[N:10][N:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([C:35]4[N:36]=[CH:37][S:38][CH:39]=4)=[CH:3][CH:4]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]2=[N:19]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(Br)nc3)nc-2c1=O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-c4cscn4)nc3)nc-2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-[(6-Bromopyridin-3-yl)methyl]-2-(2-methylphenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one [(Example 22), 77 mg, 0.17 mmol] and 4-(tributylstannyl)thiazole (77 mg, 0.21 mmole, 1.2 equiv) were dissolved in degassed N,N-dimethylformamide (1 mL) and treated with cesium fluoride (52 mg, 0.34 mmol, 2 equiv), copper(I) iodide (13 mg, 0.069 mmol, 0.4 equiv), and tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.035 mmol, 0.2 equiv). The mixture was stirred at ambient temperature for one hour, diluted with ethyl acetate (15 mL) and filtered. The filtrate was concentrated in vacuo and the residue was purified by preparative reverse phase HPLC (15:85 to 65:35; acetonitrile containing 0.01% trifluoroacetic acid:water containing 0.01% trifluoroacetic acid), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 9.13 (1H, s), 8.95 (1H, s), 8.50 (1H, s), 8.35 (2H, br d, J=7.9 Hz), 8.08 (1H, d, J=8.5 Hz), 7.73-7.60 (3H, m), 7.45 (1H, br s), 7.39-7.31 (3H, m), 5.97 (2H, s), 2.73 (3H, s) ppm; low resolution mass spectrometry (ES+) m/z 451.3 [(M+H)+; calculated for C25H19N6OS: 451.3].
Reaction SMILES: C1C2C(COC(=O)[NH:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24]([C:26]3[CH:50]=[CH:49][C:29]4[N:30]([CH3:48])[C:31]([NH:33][C:34]5[S:35][C:36]6[CH:42]=[C:41]([O:43][C:44]([F:47])([F:46])[F:45])[CH:40]=[CH:39][C:37]=6[N:38]=5)=[N:32][C:28]=4[CH:27]=3)=[O:25])C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[NH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24]([C:26]1[CH:50]=[CH:49][C:29]2[N:30]([CH3:48])[C:31]([NH:33][C:34]3[S:35][C:36]4[CH:42]=[C:41]([O:43][C:44]([F:45])([F:46])[F:47])[CH:40]=[CH:39][C:37]=4[N:38]=3)=[N:32][C:28]=2[CH:27]=1)=[O:25]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCOCCNC(=O)OCC3c4ccccc4-c4ccccc43)ccc21
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCOCCN)ccc21
Yield: 95.7 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(2-amino-ethoxy)-ethyl]-amide (70 mg) was prepared by following General Procedure 0 starting from [2-(2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-ethoxy)-ethyl]-carbamic acid 9H-fluoren-9-ylmethyl ester (106 mg), 20% (v/v) piperidine in DMF (1.5 mL). LC/MS: m/z 494.5.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH3:9])=[CH:4][C:3]=1[CH3:10].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.B([O-])[O-].[C:39]([O:43][C:44](=[O:65])[NH:45][C:46]([C:48]1[S:49][C:50]([S:63][CH3:64])=[C:51]([S:53]([C:56]2[CH:61]=[CH:60][CH:59]=[C:58](Br)[CH:57]=2)(=[O:55])=[O:54])[CH:52]=1)=[NH:47])([CH3:42])([CH3:41])[CH3:40].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(O)C.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.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>[C:39]([O:43][C:44](=[O:65])[NH:45][C:46](=[NH:47])[C:48]1[S:49][C:50]([S:63][CH3:64])=[C:51]([S:53]([C:56]2[CH:61]=[C:60]([C:2]3[CH:7]=[CH:6][C:5]([NH:8][CH3:9])=[CH:4][C:3]=3[CH3:10])[CH:59]=[CH:58][CH:57]=2)(=[O:55])=[O:54])[CH:52]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CNc1ccc(Br)c(C)c1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: CCO
Product: CNc1ccc(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(C)c1
Yield: 62 %

Procedure:
The procedure in Example 294: step e was followed using (4-bromo-3-methyl-phenyl)-methyl-amine ((Example 262: step a) 600 mg, 3 mmol), palladium acetate (34 mg, 0.15 mmol), and 2-(dicyclohexylphosphino)biphenyl (210 mg, 0.6 mmol) in dioxane (20 mL). Analogous workup yielded the crude pinacolboronate ester (720 mg, 98%) which was used without further purification. Following the procedure in Example 294: step f the crude boronate (540 mg, 2.18 mmol) was reacted with {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 27: step c) 715 mg, 1.46 mmol), aq Na2CO3 (2M, 4.4 mL, 8.8 mL), and Pd(PPh3)4 (407 mg, 0.37 mmol) in ethanol (4.4 mL) and toluene (8.8 mL). Analogous workup and SiO2 flash column chromatography yielded the title compound (482 mg, 62%) as a yellow glass. 1H-NMR (CDCl3): δ 8.0 (s, 1H), 7.95 (m, 1H), 7.90 (m, 1H), 7.55 (m, 1H), 7.51 (m, 1H), 7.05 (m, 1H), 6.53 (m, 2H), 2.9 (s, 3H), 2.56 (s, 3H), 2.56 (s, 3H), 2.22 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Cl-].[Al+3].[C:11](Cl)(=[O:16])/[C:12](=[CH:14]/[CH3:15])/[CH3:13]>Cl>[CH3:13][CH:12]1[CH:14]([CH3:15])[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[C:11]1=[O:16]
Reactant: C/C=C(\C)C(=O)Cl
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC1C(=O)c2ccccc2C1C
Temperature: 7 °C
Yield: 91.8 %

Procedure:
Under an argon atmosphere benzene (335 ml, 3.74 mol) and aluminum trichloride (90.78 g, 0.68 mol) were introduced into a 1 liter three necked round bottomed flask fitted with a magnetic stirring apparatus, an addition funnel and a reflux condenser. The stirred orange mixture was cooled to 7° C. and tigloyl chloride (33) (40 g, 0.34 mol) was added dropwise via an addition funnel. After completion of the addition, the mixture was allowed to come to room temperature and then refluxed overnight. Then the reaction mixture was allowed to come to room temperature and poured onto mixture of ice (300 g) and conc. HCl (50 ml). The organic layer was separated and washed with a saturated solution of sodium bicarbonate (3×100 ml), then dried over magnesium sulfate and filtered. The excess benzene was removed under reduced pressure to afford (34) (50.02 g, 92%) as a yellow liquid. The 1H NMR spectrum was identical with the literature (T. E. Ready, J. C. W. Chien, M. D. Rausch, J. Org. Chem. 1999 583, 11-27; J. Sarrazin, A. Tallec, Tetrahedron Letters, 1977, 18, 1579-1582; M. Hiscock, G. B. Porter, J. Chem. Soc. (B), 1971, 1631-1634). 1H NMR (200 MHz, CDCl3): δ [ppm] 7.76-7.34 (m, 4H, arom), 2.94 (dq, 3J=4.9 Hz, 3J=7.0 Hz, 1H, H-position 2), 2.24 (dq, 3J=7.3 Hz, 3J=4.7 Hz, 1H, H-position 3), 1.46 (d, 3J=6.9 Hz, 3H, CH3-position 2), 1.32 (d, 3J=7.3 Hz, 3H, CH3-position 3).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[CH2:21]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cccc(NC(=O)OC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(N(Cc2ccccc2)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 3-(tert-butoxycarbonylamino)benzoate (1.08 g) described in a document (Bioorg. Med. Chem. 2010, 18, 3175.) in DMF (40 mL) was added sodium hydride (258 mg). The reaction mixture was stirred at room temperature for 15 min, and benzyl bromide (613 μL) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (125 mg).
Reaction SMILES: B(F)(F)F.CCOCC.[CH2:10]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1)[CH2:11][CH:12]([CH3:14])[CH3:13].[C:26](OC(=N)C(Cl)(Cl)Cl)([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[CH2:10]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:20][CH:21]=1)[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: CC(C)CCOc1ccc(CC(=O)O)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)CCOc1ccc(CC(=O)OC(C)(C)C)cc1
Reaction time: 16 h
Yield: 41.7 %

Procedure:
Boron trifluoride etherate (0.65 mL) was added in one portion to a stirred solution of [4-(isopentyloxy)phenyl]acetic acid (crude from preparation of intermediate 11; 7.31 g, 32.9 mmol) and t-butyltrichloroacetimidate (14.4 g, 11.8 mL, 65.8 mmol) in THF (70 mL) at room temperature under nitrogen. The resulting solution was stirred for 16 h then quenched with saturated aqueous sodium hydrogen carbonate solution (50 mL). The resulting suspension was extracted with ethyl acetate (3×50 mL) then the organic_extracts combined, dried_(magnesium sulfate) and evaporated to dryness. The residue was chromatographed on silica gel (5-10% diethyl ether: cyclohexane) to give the title compound as a colourless oil (3.82 g, 42% over 2 steps). LC/MS: 3.94 min; z/e 296, calcd (M+18) 296. 1H NMR (400 MHz: CDCl3): 7.25 (2H), 6.90 (2H), 4.05 (2H), 3.55 (2H), 1.90 (1H), 1.75 (2H), 1.50 (9H), 1.05 (6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([C:19]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=2)=[O:20])=[CH:4][N:3]=1.[C-]#N.[K+].OC1CC[NH:40][CH2:39]C1.O>CN(C)C=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd](Cl)Cl>[C:39]([C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([C:19]([C:21]2[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[C:25]([O:27][CH3:28])[CH:26]=2)=[O:20])=[CH:4][N:3]=1)#[N:40]
Reactant: COc1ccc(CNc2nc(Cl)ncc2C(=O)c2cc(OC)c(OC)c(OC)c2)cc1Cl
Reactant: OC1CCNCC1
Agent: Cl[Pd]Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CNc2nc(C#N)ncc2C(=O)c2cc(OC)c(OC)c(OC)c2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 101 mg of 2-chloro-5-(3,4,5-trimethoxyphenylcarbonyl)-4-(3-chloro-4-methoxybenzylamino)pyrimidine prepared in above Example 1-(3), potassium cyanide 27.5 mg and palladium chloride triphenylphosphine 3 mg in dimethylformamide 3 ml is stirred at 120° C. for 7 hours. To the reaction mixture is added 4-hydroxypiperidine, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is poured into water and is twice extracted with ethyl acetate. The extract is washed with water and brine in order, dried over anhydrous sodium sulfate and evaporated to dryness to give 2-cyano-5-(3,4,5-trimethoxyphenylcarbonyl)-4-(3-chloro-4-methoxybenzylamino)pyrimidine as a yellow solid, 7.5 mg. mp 140-143° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:17][N:18]3[CH2:21][CH:20]([N:22]4[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]4)[CH2:19]3)[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[N:3]=1.[CH2:35]([C:37]1[NH:38][C:39]2[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=1)[CH3:36].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:35]([C:37]1[N:38]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:17][N:18]4[CH2:19][CH:20]([N:22]5[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]5)[CH2:21]4)[N:8]3[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)=[C:4]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[N:3]=2)[C:39]2[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=1)[CH3:36]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: O=C1CN(C2CN(Cc3nc4c(N5CCOCC5)nc(Cl)nc4n3C3CCCCO3)C2)CCN1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCNC(=O)C4)C3)n(C3CCCCO3)c2n1
Temperature: 115 °C
Reaction time: 16 h
Yield: 39.1 %

Procedure:
A mixture of 4-{1-[2-chloro-6-morpholin-4-yl-9-(tetrahydropyran-2-yl)-9H-purin-8-ylmethyl]azetidin-3-yl}piperazin-2-one (990 mg, 2.00 mmol), 2-ethylbenzimidazole (322 mg, 2.20 mmol), tris(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol), XPhos (95 mg, 0.20 mmol) and Cs2CO3 (980 mg, 3.01 mmol) in dioxane (30 mL) was purged with argon then heated at 115° C. for 6 h then stirred at r.t. for 16 h. The reaction mixture was filtered through Celite®, washing with dioxane, and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording the title compound (470 mg, 39%). LCMS (method A): RT 2.01 and 1.92 min [M+H]+ 601.6
Reaction SMILES: [CH2:1]([CH:3]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([O:15][CH3:16])=[C:8]([Cl:14])[C:9]=2[Cl:13])[C:4]1=[O:17])[CH3:2].[C:18](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH2:1]([C:3]1([CH3:18])[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([O:15][CH3:16])=[C:8]([Cl:14])[C:9]=2[Cl:13])[C:4]1=[O:17])[CH3:2]
Reactant: CCC1C(=O)c2cc(OC)c(Cl)c(Cl)c2C1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CCC1(C)C(=O)c2cc(OC)c(Cl)c(Cl)c2C1=O
Reaction time: 0.25 h

Procedure:
A stirred solution of 2-ethyl-4,5-dichloro-6-methoxyindan-1,3-dione (1.3 g.) in dimethylformamide (15 ml.) is treated with potassium carbonate (1.26 g.) and metyl iodide. After 15 minutes, the reaction is poured into water (75 ml.) affording 1.3 g. of 2-ethyl-2-methyl-4,5-dichloro-6-methoxyindan-1,3-dione which melts at 157°C. after recrystallization from ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[O:4][C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].CN(C=O)C.C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][N:24]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][C:30]([O:39][CH3:40])=[CH:31][C:32]=2[CH:36]([CH3:38])[CH3:37])[S:25]1(=[O:27])=[O:26]>O>[Cl:1][C:2]1[C:3](=[O:10])[O:4][C:5]([CH3:9])=[CH:6][C:7]=1[O:8][CH2:23][N:24]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][C:30]([O:39][CH3:40])=[CH:31][C:32]=2[CH:36]([CH3:38])[CH3:37])[S:25]1(=[O:26])=[O:27]
Reactant: Cc1cc(O)c(Cl)c(=O)o1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C)oc(=O)c1Cl)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
A mixture of 3-chloro-4-hydroxy-6-methyl-2H-pyran-2-one (0.493 g, 3.07 mmol), DMF and K2CO3 (0.467 g, 3.38 mmol) was stirred at room temperature under N2 for 0.5 hours then 2-chloromethyl-4-isopropyl-6-methoxysaccharin (0.978 g, 3.22 mmol) was added in one portion. The mixture was stirred at room temperature for 3 hours, and then at 75° C. for 3 hours. The mixture was poured into water, extracted with ethyl acetate and the organic layer was washed with brine and dried. The solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with 30% ethyl acetate/hexane to afford 0.25 g (18.1%) of 2-(3-chloro-6-methyl-2-oxo-2H-pyran-4yl)oxymethyl-4-isopropyl-6-methoxysaccharin, m.p. 182.5°-183.5° C. after recrystallization from ether/hexane.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)=[C:6]([C:21]#[N:22])[CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.O>[OH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][N:12]=2)=[C:6]([CH:5]=1)[C:21]#[N:22]
Reactant: COC(=O)c1ccc(Oc2ccc(C(F)(F)F)cn2)c(C#N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(CO)ccc1Oc1ccc(C(F)(F)F)cn1
Temperature: -55 °C
Reaction time: 0.33 h
Yield: 60.7 %

Procedure:
To a solution of 3-cyano-4-(5-trifluoromethyl-pyridin-2-yloxy)-benzoic acid methyl ester (23 g, 0.070 mol) in anhydrous THF (200 mL), was added LiAlH4 (4.07 g, 0.11 mmol) portionwise at −78° C. The reaction mixture was warmed to −55° C. slowly and stirred for 20 mins, diluted with water (3 mL 0.16 mmol, slow addition), filtered and concentrated. Purification via FC (PE/EtOAc=10/1 to 5/1) afforded the title product as a colorless oil (12.5 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC[N+]1C=CC(C2C=C[N+](CC)=CC=2)=CC=1.[Br-].[Br-]>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CCOC(=O)CCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: CC[n+]1ccc(-c2cc[n+](CC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Product: CCOC(=O)CCNc1c(N)cnc2ccccc12
Reaction time: 8 h

Procedure:
Ethyl N-(3-nitroquinolin-4-yl)-β-alaninate (41.6 g, 144 mmol, prepared as described in Part A of Example 15) was treated with sodium hydrosulfite (87.62 g, 503.3 mmol), potassium carbonate (78.5 g, 568 mmol), and ethyl viologen dibromide (0.54 g, 1.4 mmol) according to a modification of the method described in Part A of Example 8. After the reaction was stirred overnight, additional sodium hydrosulfite (5.0 g, 29 mmol) was added, and the reaction was stirred for one additional hour. The organic layer was separated, washed with water (5×200 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 33.3 g of ethyl N-(3-aminoquinolin-4-yl)-β-alaninate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])[CH3:2].[NH2:13][C:14]1[C:15]([C:23]([NH2:25])=[O:24])=[N:16][CH:17]=[CH:18][C:19]=1[CH2:20][CH2:21][CH3:22]>N1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:13][C:14]1[C:15]([C:23]([NH2:25])=[O:24])=[N:16][CH:17]=[CH:18][C:19]=1[CH2:20][CH2:21][CH3:22])=[O:7])[CH3:2]
Reactant: CCCc1ccnc(C(N)=O)c1N
Reactant: CCOc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Product: CCCc1ccnc(C(N)=O)c1NC(=O)c1ccccc1OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.9 %

Procedure:
2-Ethoxybenzoyl chloride (2.96 g, 0.016 mol) was added dropwise to a stirred solution of 3-amino-4-n-propylpyridine-2-carboxamide (Preparation 6; 1.43 g, 0.008 mol) in pyridine (40 ml) at 0° C. The mixture was stirred at ambient temperature for 4 hours and then the solvent evaporated under vacuum. The residue was dissolved in dichloromethane (100 ml), the solution washed with saturated aqueous sodium carbonate solution (100 ml) and the aqueous phase then washed with dichloromethane (2×25 ml). The combined organic extracts were dried (MgSO4) and evaporated under vacuum, then the residue purified by chromatography on silica gel (15 g), using a methanol in dichloromethane elution gradient (0-3% methanol), followed by crystallization from ethyl acetate to give the product as a light brown solid (1.36 g, 60%), 129-131° C.
Reaction SMILES: [ClH:1].[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:20]4[CH:28]=[C:27]([C:29]5[O:33][C:32]([C:34]([OH:36])=O)=[CH:31][CH:30]=5)[N:26]=[CH:25][C:21]=4[N:22]=[CH:23][N:24]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl.[CH3:50][S:51]([CH2:54][CH2:55][NH2:56])(=[O:53])=[O:52].C(N(CC)CC)C.Cl>C1COCC1.CO>[ClH:1].[CH3:50][S:51]([CH2:54][CH2:55][NH:56][C:34]([C:32]1[O:33][C:29]([C:27]2[N:26]=[CH:25][C:21]3[N:22]=[CH:23][N:24]=[C:19]([NH:18][C:14]4[CH:13]=[C:12]5[C:17](=[CH:16][CH:15]=4)[N:9]([CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:10]=[CH:11]5)[C:20]=3[CH:28]=2)=[CH:30][CH:31]=1)=[O:36])(=[O:53])=[O:52]
Reactant: CS(=O)(=O)CCN
Reactant: O=C(O)c1ccc(-c2cc3c(Nc4ccc5c(cnn5Cc5ccccc5)c4)ncnc3cn2)o1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)CCNC(=O)c1ccc(-c2cc3c(Nc4ccc5c(cnn5Cc5ccccc5)c4)ncnc3cn2)o1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
5-[4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido-[3,4-d]pyrimidin-6-yl]-furan-2-carboxylic acid hydrochloride (0.125 g, 0.25 mmol) and carbonyl diimidazole (0.052 g, 0.33 mmol) were suspended in dry THF (3 ml) under a nitrogen atmosphere and stirred at room temperature for 7 hours. 2-(Methanesulphonyl)ethylamine hydrochloride (0.080 g, 0.50 mmol) and triethylamine (0.15 ml, 0.11 g, 1.08 mmol) were added, together with further THF (2 ml), and the resulting mixture was stirred at room temperature for 18 hours. The mixture was adsorbed onto silica gel and purified by column chromatography, eluting with 2-10% MeOH/DCM. Concentration of the relevant fractions gave a pale yellow solid. This was resuspended in methanol and treated with ethanolic HCl to give the product as an orange solid, which was collected by filtration, washed with methanol, acetone and ether, and dried in vacuo (0.093 g, 0.154 mmol, 61%); δH [2H6]DMSO 12.00 (1H,s), 9.76 (1H,s), 9.19-9.29 (2H,m), 8.75 (1H,s), 8.28 (1H,s), 8.22 (1H,s), 7.78-7.90 (2H,m), 7.23-7.38 (7H,m), 5.71 (2H,s), 3.50-3.90 (2H obscured by water signal), 3.48 (2H,t), 3.07 (3H,s); m/z (M+1+) 568.
Reaction SMILES: N[NH-].[C:3](Cl)(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[NH2:19][C:20]1[CH:38]=[CH:37][C:23]2[N:24]=[C:25]([NH:28][C:29]3[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:36])[N:26]([CH3:27])[C:22]=2[C:21]=1[C:39]([NH2:41])=[O:40]>C1COCC1>[Cl:36][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([Cl:35])[C:29]=1[NH:28][C:25]1[N:26]([CH3:27])[C:22]2=[C:21]3[C:20](=[CH:38][CH:37]=[C:23]2[N:24]=1)[N:19]=[C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH:41][C:39]3=[O:40]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cn1c(Nc2c(Cl)cccc2Cl)nc2ccc(N)c(C(N)=O)c21
Agent: [NH-]N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(Nc2c(Cl)cccc2Cl)nc2ccc3nc(-c4ccccc4)[nH]c(=O)c3c21
Reaction time: 1 h

Procedure:
The above amino amide (50 mg, 0.15 mmol) was added to a solution of benzoyl chloride (32 mg, 0.23 mmol) in THF (1 mL). Triethylamine (0.03 mL, 0.23 mmol) was added and the mixture stirred for 1 h. TLC showed conversion to the benzamide. The solvent was evaporated and the residue dissolved in MeOH (1 mL). Sodium methoxide in MeOH (25%, 0.2 mL) was added and the solution heated to reflux for 45 min. The cooled mixture was partitioned between 1M NH4C1 and CH2Cl2. The residue from the organic layer was stirred and refluxed with MeOH (2 mL) for 1 h, cooled, filtered and washed with MeOH to yield the title compound, 7 (52 mg, 79%) Mp>300° C. MS (ES+) 436, 438 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][S:18]([OH:21])(=O)=[O:19])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>>[Cl:24][S:18]([CH2:17][CH:13]1[CH2:14][CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1)(=[O:21])=[O:19]
Reactant: O=S(Cl)Cl
Reactant: O=C(OCc1ccccc1)N1CCCC(CS(=O)(=O)O)C1
Product: O=C(OCc1ccccc1)N1CCCC(CS(=O)(=O)Cl)C1

Procedure:
The title compound was prepared by the method of Preparation 58 from 1-[(benzyloxy)carbonyl]-3-piperidylmethanesulfonic acid [see Preparation 61]and thionyl chloride to afford benzyl 3-[(chlorosulfonyl)methyl]-1-piperidinecarboxylate as an oil.