Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:59])[C@H:3]([NH:54][C:55](=[O:58])[O:56][CH3:57])[C:4](=[O:53])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[NH:35][C:34]([C@@H:36]6[CH2:40][CH2:39][CH2:38][N:37]6[C:41]([C@H:43]6[C:52]7[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=7)[CH2:46][CH2:45][NH:44]6)=[O:42])=[N:33][CH:32]=5)=[CH:27][CH:26]=4)[CH:21]=3)[CH:16]=2)=[CH:13][N:14]=1.[CH2:60]=O>[Zn].C(O)(=O)C>[CH3:1][CH:2]([CH3:59])[C@H:3]([NH:54][C:55](=[O:58])[O:56][CH3:57])[C:4]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[NH:35][C:34]([C@@H:36]6[CH2:40][CH2:39][CH2:38][N:37]6[C:41]([C@H:43]6[C:52]7[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=7)[CH2:46][CH2:45][N:44]6[CH3:60])=[O:42])=[N:33][CH:32]=5)=[CH:27][CH:26]=4)[CH:21]=3)[CH:16]=2)=[CH:13][N:14]=1)=[O:53]
Reactant: C=O
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)[C@@H]6NCCc7ccccc76)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)[C@H]6c7ccccc7CCN6C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (S)-3-methyl-1-oxo-1-((S)-2-(5-(6-(4-(2-((S)-1-((R)-1,2,3,4-tetrahydroisoquinoline-1-carbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (135 mg, 0.17 mmol), acetic acid (1.7 mL), zinc dust (111 mg, 1.7 mmol), and formaldehyde were all mixed in round bottom flask and stirred at room temperature overnight. The crude mixture was filtered through a celite plug and the filtrate was concentrated down to dryness on rotovap. The residue was then taken up in EtOAc and washed with 10% Na2CO3 and brine and dried over MgSO4. The filtrate was then concentrated down and the residue was purified on reverse phase HPLC. (13 mg, 10%). MS (ESI) m/z 805.77 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(O)C.[C:27]1([C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[C:33]([NH:35][C:36]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[C:17]([F:23])[CH:18]=1)=[S:37])(=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (64 mg, yield 85%).
Reaction SMILES: [C:1]1([C@@H:7]2[NH:11][C@H:10]([CH2:12][O:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:46])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][C:35]=1[O:44][CH3:45].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:46])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]([N:11]2[C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][C@H:10]2[CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[O:42])=[CH:36][C:35]=1[O:44][CH3:45]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Reaction time: 8 h
Yield: 103.7 %

Procedure:
To a stirred solution of methyl 4-[5-(R)-phenyl-2-(S)-pirrolidinylmethoxy]benzoate (135 mg, 0.43 mmol), 4-[N′-(2-methylphenyl)ureido]-3-methoxyphenylacetic acid (136 mg, 0.43 mmol) and N,N-dimethylaminopyridine (52.9 mg, 0.43 mmol) in DMF (10 ml) was added EDC.HCl (90.8 mg, 0.48 mmol) at rt, and the resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, drying over anhydrous Na2SO4, then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (1:5) as eluent to give methyl 4-[1-[4-[N′-(2-methylphenyl)ureido]-3-methoxyphenyl acetyl]-5-(R)-phenyl-2-(S)-pyrrolidinylmethoxy]benzoate (271 mg, quant.) as a colorless amorphous solid. 1H-NMR (CDCl3) δ 2.00–2.18 (m, 3 H), 2.31–2.41 (m, 1 H), 2.27 (s, 3 H), 3.31 (s, 2 H), 3.67 (s, 3 H), 3.89 (s, 3 H), 4.35–4.48 (m, 2H), 4.60 (br s, 1 H), 4.92 (t, J=6.8 Hz, 1 H), 6.51 (d, J=8.4 Hz, 1 H), 6.62 (s, 1 H), 6.96 (d, J=8.8 Hz, 1 H), 7.11–7.40 (series of m, 8 H), 7.51 (d, J=8.0 Hz, 1 H), 7.97–8.00 (m, 2 H); MS (ESI) m/z, 608 (M++H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38]Br)[CH:32]=2)[O:11][C@@H:10]1[CH2:40][O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:49]#[N:50].[K+]>C(O)C.O>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH:12]2[C@H:13]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:10]([CH2:40][O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[O:11]2)=[CH:32][C:33]=1[CH2:38][C:49]#[N:50]
Reactant: [C-]#N
Reactant: Clc1ccc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1CBr
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of the (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(3-(bromomethyl)-4-chlorophenyl)-tetrahydro-2H-pyran in ethanol (260 mL) and water (130 mL) was added potassium cyanide (31.8 g, 488 mmol). The reaction mixture was refluxed overnight. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. Purification was accomplished by chromatography to provide the titled compound 39 (105 g, 80%, ca. 2:1 mixture of anomers β:α).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[CH:38]=2)[N:33]([CH3:42])[CH:32]=1)=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[CH:38]=4)[N:33]([CH3:42])[CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: COc1ccc2c(c1)c(C(=O)CCCCCBr)cn2C
Agent: Cl
Product: COc1ccc2c(c1)c(C(=O)CCCCCN1CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC1)cn2C

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(5-methoxy-1-methyl-1 H-indol-3-yl)-l-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(5-methoxy-1-methyl-1 H-indol-3-yl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [S:1]1[C:5]([CH2:6][O:7][C:8]([NH:10][C@H:11]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:12][NH:13][CH2:14][C@@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:9])=[CH:4][N:3]=[CH:2]1.[CH3:40][CH:41]([CH3:44])[CH:42]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:40][CH:41]([CH3:44])[CH2:42][N:13]([CH2:14][C@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]1[S:32][CH:31]=[N:30][CH:29]=1)=[O:25])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:12][C@@H:11]([NH:10][C:8]([O:7][CH2:6][C:5]1[S:1][CH:2]=[N:3][CH:4]=1)=[O:9])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)C=O
Reactant: O=C(N[C@H](CNC[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)Cc1ccccc1)OCc1cncs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)CN(C[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Yield: 51.9 %

Procedure:
The product from Example 26D (87.5 mg, 0.155 mmol), 2-methylpropanal (17 μl, 0.186 mmol), acetic acid (11 μl, 0.181 mmol), and sodium triacetoxyborohydride (53 mg, 0.248 mmol) were processed as described in Example 27 to provide the title compound (50 mg, 52%). 1H NMR (CDCl3) δ 8.72 (s, 2H), 7.78 (s, 2H), 7.29-7.06 (m, 10H), 5.20 (s, 4H), 4.77 (br s, 2H), 3.83 (br s, 2H), 2.88 (dd, 2H), 2.70 (m, 2H), 2.42 (m, 4H), 2.15 (d, 2H), 0.83 (d, 6H); MS (ESI+) m/z 622 (M+H)+.
Reaction SMILES: OC1C=CC(/[CH:8]=[CH:9]/[CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23]C4C=CC=CC=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=CC=1OC.[F:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH:40](CC)CBr)=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:37][CH:38]=1
Reactant: CCC(CBr)Oc1ccc(F)cc1
Reactant: COc1cc(/C=C/CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)ccc1O
Product: Fc1ccc(OCCCCN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)cc1

Procedure:
The same procedure was followed as in Example 11 using the compound (9) synthesized in Example 2 and 2-(4-fluorophenyl)oxybutyl bromide to produce the above.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]3[C:27](=[O:31])[NH:28][C:29](=[O:30])[C:16]=3[C:15]=2[C:14]2[CH:13]=[C:12]([OH:32])[CH:11]=[CH:10][C:9]1=2)(=O)=O.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[OH:32][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:7][CH2:6][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[C:20]3[CH:19]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:17]4[C:27](=[O:31])[NH:28][C:29](=[O:30])[C:16]=4[C:15]=3[C:14]=2[CH:13]=1
Reactant: CS(=O)(=O)OCCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4)cc21)C(=O)NC3=O
Reactant: C1COCCN1
Product: O=C1NC(=O)c2c1c(-c1ccccc1)cc1c2c2cc(O)ccc2n1CCN1CCOCC1
Yield: 75 %

Procedure:
Mesylate (205) (70 mg, 0.16 mmol) prepared as described in example 174 was reacted with morpholine according to the procedure described in example 179 to give amine (211) (53 mg, 75%) as a yellow powder, mp 260–262° C. 1H NMR □ [(CD3)2SO) 1H NMR δ [(CD3)2SO] 11.04 (br s, 1H), 9.33 (s, 1H), 8.40 (d, J=2.5 Hz, 1H), 7.78 (s, 1H), 7.64 (m, 2H), 7.54 (d, J=8.9 Hz, 1H), 7.47 (m, 3H), 7.12 (dd, J=8.9, 2.5 Hz, 1H), 4.57 (t, J=6.4 Hz, 2H), 3.45 (t, J=4.5 Hz, 4H), 2.67 (t, J=6.4 Hz, 2H), 2.18 (br t, J=4 Hz, 4H). Found: C, 70.55; H, 5.25; N, 9.22. C26H23N3O4 requires: C, 70.74; H, 5.25; N, 9.51.
Reaction SMILES: CC1(C)[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:4]=2[O:3]1.[CH3:15][C:16]([N+:24]([O-:26])=[O:25])([CH3:23])[CH2:17]OS(C)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>COCCOCCOC>[CH3:15][C:16]([N+:24]([O-:26])=[O:25])([CH3:23])[CH2:17][O:13][C:10]1[CH:9]=[C:5]([C:6]([NH2:7])=[O:8])[C:4]([OH:3])=[CH:12][CH:11]=1
Reactant: CC(C)(COS(C)(=O)=O)[N+](=O)[O-]
Reactant: CC1(C)NC(=O)c2cc(O)ccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: O
Product: CC(C)(COc1ccc(O)c(C(N)=O)c1)[N+](=O)[O-]
Reaction time: 9 h

Procedure:
A mixture of 84.3 g of 2,3-dihydro-2,2-dimethyl-6-hydroxy-4H-1,3-benzoxazin-4-one, 144.2 g of methanesulfonic acid-(2-methyl-2-nitropropyl)-ester and 121 g of anhydrous potassium carbonate in 440 ml of diethylene glycol dimethyl ether is stirred for 9 hours in a bath at about 150°. The reaction mixture is cooled, poured into 4000 ml of water, and extracted with 3000 ml of ethyl acetate. The oil, obtained by concentrating the organic phase by evaporation, is dissolved in 250 ml of dioxane, and about 750 ml of 2N hydrochloric acid is added until an acid reaction occurs. The solution is held for 11/2 hours at 80°-100°; it is then concentrated under reduced pressure to half its volume, and extracted three times with 500 ml of ethyl acetate each time. The combined organic phases are washed with 200 ml of water, then with saturated sodium bicarbonate solution, and finally with saturated sodium chloride solution; they are subsequently dried over magnesium sulfate and concentrated by evaporation. The dark brown oil thus obtained is chromatographed on 500 g of silica gel. Elution with ether yields crystalline 5-(2-methyl-2-nitropropoxy)-salicylamide, m.p. 145°-148°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[Cl-].[Ca+2].[Cl-].[C:8](#N)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([C:8]2[O:4][CH2:3][CH2:2][N:1]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCCO
Reactant: N#Cc1ccccc1
Agent: [Ca+2]
Agent: [Cl-]
Product: c1ccc(C2=NCCO2)cc1

Procedure:
The methods (1) to (6) will be described more specifically. For example, as the method (1), potassium hydroxide or acetic anhydride is reacted to 2-chloroethylformamide to provide 2-oxazoline, and the case where 2-bromoethylbenzamide is used provides 2-phenyl-2-oxazoline (see, for example Non-patent Document 1). As the method (2), thionyl chloride is reacted to 2-formamide ethanol to provide 2-oxazoline, and N-(2-hydroxyethyl)benzamide is heated with phosphorous pentoxide to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 2). As the method (3), benzoic acid and 2-aminoethanol are heated with alumina to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 3). As the method (4), benzonitrile and 2-aminoethanol are heated with calcium chloride at 110 to 120° C. to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 4 and Patent Document 1). As the method (5), methyl benzimidate and 2-aminoethanol are heated with alumina to provide 2-phenyl-2-oxazoline (see, for example, Non-patent Document 5). Vinylbenzamide is simply heated to provide 2-phenyl-2-oxazoline. As the method (6), N-allylbenzamide is heated with sulfuric acid to provide 5-methyl-2-phenyl-2-oxazoline (see, for example, Non-patent Document 6).
Reaction SMILES: I[C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1.[CH3:24][N:25]1[C:30]2[N:31]=[C:32]([NH:35][CH3:36])[N:33]=[CH:34][C:29]=2[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[C:26]1=[O:46].O.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CN(C=O)C>[CH3:24][N:25]1[C:30]2[N:31]=[C:32]([NH:35][CH3:36])[N:33]=[CH:34][C:29]=2[CH:28]=[C:27]([C:2]2[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]=[C:7]3[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:26]1=[O:46]
Reactant: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)nccc2c1I
Reactant: CNc1ncc2cc(B3OC(C)(C)C(C)(C)O3)c(=O)n(C)c2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CNc1ncc2cc(-c3c(C)ccc4c(Nc5cccc(C(F)(F)F)c5)nccc34)c(=O)n(C)c2n1
Temperature: 160 °C
Reaction time: 0.33 h
Yield: 19.8 %

Procedure:
To a solution of 5-iodo-6-methyl-N-(3-(trifluoromethyl)phenyl)isoquinolin-1-amine (0.1680 g, 0.392 mmol) in 10:1 DMF:Water (1.5 ml), charged to a 5 mL mircowave reaction vessel, 8-methyl-2-(methylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.149 g, 0.471 mmol), dichlorobis(triphenyl-phosphine)palladium (ii) (0.0110 g, 0.0157 mmol), and sodium carbonate hydrate (0.102 g, 0.824 mmol) were added. The reaction mixture was stirred at 160° C. for 20 min. The reaction mixture was diluted with EtOAc and partioned with saturated sodium bicarbonate. The aqueous layer was extracted twice with EtOAc. The combined organics were washed with brine, dried over magnesium sulfate and concentrated under vacuum. The resulting residue was loaded on to silica and purified by silica gel chromatgraphy (ISCO 2×12.0 g, 0-6% MeOH in DCM, 45 min.) and HPLC to give 8-methyl-6-(6-methyl-1-(3-(trifluoromethyl)phenylamino)isoquinolin-5-yl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (.0381 g, 19.8% yield). MS (M+H)+ 491.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][OH:10].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[O:10]
Reactant: CSc1ccccc1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CSc1ccccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
To a solution of (2-methylsulfanylphenyl)methanol (0.20 g, 1.3 mmol) obtained in Step 1 in dichloromethane (4.0 mL), Celite (0.40 g) and pyridinium chlorochromate (0.42 g, 1.9 mmol) were added, followed by stirring at room temperature for 1.0 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 80/20) to obtain 2-methylsulfanylbenzaldehyde (0.14 g, 69%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][NH:13][CH2:14][C:15]#[CH:16]>ClCCl.C(N(CC)CC)C>[CH3:12][N:13]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH2:14][C:15]#[CH:16]
Reactant: C#CCNC
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCN(C)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 80 %

Procedure:
3.72 g (22.0 mmol) of p-nitrobenzyl chloride in 20 ml of dichloromethane is added, dropwise, at 0° C. to a solution of 1 g (1.45 mmol) of N-methylpropargylamine in 15 ml of dichloromethane and 3.1 ml of triethylamine. After stirring overnight, the reaction mixture is concentrated to dryness under vacuum, and the residue is diluted with dichloromethane and 40 ml of a saturated solution of NaCl. After stirring and decanting, the organic phase is separated and dried over magnesium sulphate, filtered and concentrated under vacuum. The expected product is obtained after chromatography on a silica column, eluent: (20% ethyl acetate in heptane), the pure fractions, after evaporation, produce a brown solid with a yield of 80%. Melting point 47-49° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[O:12][C:13]1[N:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=1[Cl:20].[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[O:12][C:13]1[N:18]=[CH:17][C:16]([NH:19][S:33]([C:27]2[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=2[Cl:25])(=[O:35])=[O:34])=[CH:15][C:14]=1[Cl:20]
Reactant: Nc1cnc(Oc2ccccc2-c2nc3ccccc3s2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Product: O=S(=O)(Nc1cnc(Oc2ccccc2-c2nc3ccccc3s2)c(Cl)c1)c1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared by reacting 6-(2-(benzo[d]thiazol-2-yl)phenoxy)-5-chloropyridin-3-amine (obtained as per procedure described in preparation 4) and 2,4-dichlorobenzene-1-sulfonyl chloride.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:24][CH3:25])[CH2:4][N:5]1[CH:10]=[CH:9][C:8](=[O:11])[C:7]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]1[C:20]([O:22][CH3:23])=[O:21].C1C(=O)N([Br:33])C(=O)C1>ClCCl>[CH3:25][O:24][CH:3]([O:2][CH3:1])[CH2:4][N:5]1[CH:10]=[C:9]([Br:33])[C:8](=[O:11])[C:7]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)ccn1CC(OC)OC
Solvent: ClCCl
Product: COC(=O)c1c(OCc2ccccc2)c(=O)c(Br)cn1CC(OC)OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 2 L flask equipped with a mechanic stirrer were charged with methyl 1-[2,2-bis(methyloxy)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 23 as obtained above and 500 mL of dichloromethane. To this flask was added NBS (30 g, 0.17 mole) portion-wise. The reaction was stirred at room temperature until its completion (monitored by TLC, ˜6 hours). The mixture was then diluted with dichloromethane and washed with NaHCO3 (ss). The organic phase was dried over Na2SO4 before evaporation of the solvents. The crude product was purified by column chromatargraphy (silcal gel, EtOH/DCM: 0-40%) to afford methyl 1-[2,2-bis(methyloxy)ethyl]-5-bromo-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 24 as a light brown solid (50 g, 60% over three steps). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.7 (s, 1H), 7.4 (m, 2H), 7.3 (d, J=7.9 Hz, 3H), 5.3 (s, 2H), 4.4 (s, 1H), 3.8 (d, J=4.8 Hz, 2H), 3.8 (s, 3H), 3.4 (s, 6H). LC-MS (M+H+): calcd 426, obsd 426.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][N:31]([CH3:33])[CH3:32])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[CH2:39][C:40](Cl)=[O:41]>>[CH3:32][N:31]([CH2:30][C:26]1[CH:25]=[C:24]([NH:23][C:19]2[N:18]=[C:17]([C:16]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:40](=[O:41])[CH2:39][C:35]5[S:34][CH:38]=[CH:37][CH:36]=5)[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=34)[CH:22]=[CH:21][N:20]=2)[CH:29]=[CH:28][CH:27]=1)[CH3:33]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CN(C)Cc1cccc(Nc2nccc(-c3c(-c4cccc(N)c4)nn4ccccc34)n2)c1
Product: CN(C)Cc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)c1
Yield: 88 %

Procedure:
The title compound was prepared from 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-{3-[(dimethylamino)methyl]phenyl}-2-pyrimidinamine and 2-thiopheneacetyl chloride using acylation conditions described in Example 1, Step F to generate the product in 88% yield. 1H NMR (400 MHz, DMSO-d6): δ 2.11 (s, 6H), 3.26 (s, 2H), 3.86 (s, 2H), 6.46 (d, 1H, J=5.3 Hz), 6.85 (d, 1H, J=7.5 Hz), 6.96 (m, 2H), 7.10-7.19 (m, 2H), 7.26 (d, 1H, J=7.9 Hz), 7.36-7.48 (m, 3H), 7.62 (d, 1H, J=8.2 Hz), 7.69 (s, 1H), 7.73 (d, 1H, J=9.1 Hz), 7.89 (s, 1H), 8.23 (d, 1H, J=5.3 Hz), 8.51 (d, 1H, J=8.8 Hz), 8.82 (d, 1H, J=6.9 Hz), 9.52 (s, 1H), 10.35 (s, 1H); ES-LC/MS m/z=560 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-:19])=O)=[C:10]([C:14]([O-:16])=O)[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[NH2:23][CH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH2:31])=[O:30])=[CH:27][CH:26]=1.Cl>>[CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:6][C:7]2=[CH:8][C:9]3[C:17](=[O:19])[N:23]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([C:29]([NH2:31])=[O:30])=[CH:32][CH:33]=4)[C:14](=[O:16])[C:10]=3[CH:11]=[C:12]2[CH2:13]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Reactant: NCc1ccc(C(N)=O)cc1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccc(C(N)=O)cc1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with 4-(aminomethyl)benzamide (0.26 g, 1.4 mmol). Purification using silica gel, eluting with 19:1 CH2Cl2 /MeOH, afforded an oil that was converted to an HCl salt and recrystallized from hot MeOH to give 111 as a white solid (m.p. 294° C.).