Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16]Cl)=[C:7]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:6]=1)(=O)C.N1CCCCC1.[CH3:37][S:38]([NH:41][CH2:42][CH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:40])=[O:39]>>[ClH:11].[NH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][N:46]2[CH2:45][CH2:44][CH:43]([CH2:42][NH:41][S:38]([CH3:37])(=[O:39])=[O:40])[CH2:48][CH2:47]2)=[C:7]([O:19][CH2:20][C:21]2[CH:22]=[C:23]([O:29][CH3:30])[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=2)[CH:6]=1
Reactant: CS(=O)(=O)NCC1CCNCC1
Reactant: COc1cc(COc2cc(NC(C)=O)c(Cl)cc2C(=O)CCCCCl)cc(OC)c1
Solvent: C1CCNCC1
Product: COc1cc(COc2cc(N)c(Cl)cc2C(=O)CCCCN2CCC(CNS(C)(=O)=O)CC2)cc(OC)c1
Product: Cl

Procedure:
Proceeding as in Example 4, Step (c), but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentan-1-one with 1-[4-acetylamino-5-chloro-2-(3,5-dimethoxybenzyloxy) phenyl]-5-chloropentan-1-one and piperidine with 4-(methylsulfonyl)aminomethylpiperidine, gave 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzyloxy)phenyl]-5-[4-(methylsulfonyl) aminomethyl-piperidin-1-yl]pentan-1-one hydrochloride, m.p. 211°-213° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH:26][C:27](=[O:29])[CH3:28])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:32]I>CN(C)C=O.O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([N:26]([CH3:32])[C:27](=[O:29])[CH3:28])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CCC(NC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)N(C)C(C)=O
Yield: 17.3 %

Procedure:
To a solution of N-{1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propyl}acetamide (72.0 mg, 0.159 mmol) in N,N-dimethylformamide (1.6 mL) was added sodium hydride (60%, 7.6 mg, 0.19 mmol). After the resultant mixture was stirred at room temperature for 30 min, methyl iodide (0.0119 mL, 0.191 mmol) was added, and the resultant mixture wad stirred at 60° C. for 2 hr. After sodium hydride (60%, 7.6 mg, 0.19 mmol) and methyl iodide (0.0119 mL, 0.191 mmol) were added again, the resultant mixture was stirred at 60° C. for 2 hr, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-90% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous solid (12.8 mg, 0.0275 mmol, 17%).
Reaction SMILES: [CH2:1]([NH:4][C:5](/[CH:7]=[CH:8]/[C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[CH2:18][C:19]2[CH:37]=[CH:36][C:22]([C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])(=[O:28])=[O:27])=[O:24])=[CH:21][C:20]=2[O:38][CH3:39])=[CH:11][CH:10]=1)=[O:6])[CH2:2][CH3:3].C(N(CC)CC)C.[H][H]>[Pd].C(O)C>[CH2:1]([NH:4][C:5]([CH2:7][CH2:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[CH2:18][C:19]2[CH:37]=[CH:36][C:22]([C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])(=[O:28])=[O:27])=[O:24])=[CH:21][C:20]=2[O:38][CH3:39])=[CH:11][CH:10]=1)=[O:6])[CH2:2][CH3:3]
Reactant: CCCNC(=O)/C=C/c1ccc2ccn(Cc3ccc(C(=O)NS(=O)(=O)c4ccccc4C)cc3OC)c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCNC(=O)CCc1ccc2ccn(Cc3ccc(C(=O)NS(=O)(=O)c4ccccc4C)cc3OC)c2c1
Yield: 79.7 %

Procedure:
Palladium on carbon (10% w/w, 0.01 g) was added to a solution of E-4-[6-[2-(propylcarbamoyl)vinyl]indol-1-ylmethyl]-3-methoxy-N-(2-methylphenylsulfonyl)benzamide (0.1 g) and triethylamine (0.026 ml) in ethanol (5 ml). The mixture was vigorously stirred and hydrogenated at atmospheric pressure. When hydrogen uptake had ceased, the catalyst was removed by filtration through diatomaceous earth, the filter pad washed with ethanol, the filtrate diluted with water (10 ml) and acidified to pH 4 with 1M hydrochloric acid. The ethanol was evaporated; and the white solid which precipitated from the aqueous residue was isolated by filtration, washed with water and dried to give the title compound (80 mg, 80%) as a white solid; mp 110°.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[O-]S(C(F)(F)[F:17])(=O)=O.F[N+]1C=CC=CC=1>ClC(Cl)CCl>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[F:17])(=[O:3])[CH3:2]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: CC(=O)Nc1ccc(Br)cc1
Agent: F[n+]1ccccc1
Solvent: ClCC(Cl)Cl
Product: CC(=O)Nc1ccc(Br)cc1F
Temperature: 100 °C
Yield: 28 %

Procedure:
A mixture of 1.17 g (5.0 mmol) of N-acetyl-4-bromoaniline, 1.20 g (5.0 mmol) of N-fluoropyridinium triflate, and 50 ml of 1,1,2-trichloroethane was placed in a 100 ml 3-necked round bottomed flask equipped with a magnetic stirring bar, a thermometer, and a reflux condenser. The mixture was heated to 100° C. and allowed to react at that temperature for 20 hours. The mixture was then allowed to cool and the volatiles were removed by evaporation under reduced pressure. Analysis of the residue by standardized gas-liquid chromatography using a mass spectrometer detector indicated that the title product was present in 28 percent yield and that the balance of the N-acetyl-4-bromoaniline was still present as unreacted material.
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([CH2:42][S:43][CH2:44][C@H:45]([O:61][C:62](=[O:74])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[CH2:46][O:47][C:48](=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:20](=[O:41])[NH:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1.C1(C)C=CC=CC=1>C(#N)C>[CH2:35]([O:34][P:33]([CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][NH:21][C:20](=[O:41])[C@@H:19]([NH2:18])[CH2:42][S:43][CH2:44][C@H:45]([O:61][C:62](=[O:74])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[CH2:46][O:47][C:48](=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])(=[O:40])[O:37][CH2:38][CH3:39])[CH3:36]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OC(=O)CCCCCCCCCCC
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OC(=O)CCCCCCCCCCC
Temperature: 25 °C

Procedure:
To a solution of diethyl (14R,18R)-14-(((9H-fluoren-9-yl)methoxy)carbonylamino)-18-(dodecanoyloxy)-13,21-dioxo-3,6,9,20-tetraoxa-16-thia-12-azadotriacontylphosphonate (1 eq) was added 20% piperidine (50 eq) in acetonitrile. The resulting mixture was stirred at 25° C. until the deprotection completed. To the mixture was added toluene and then concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 100% EtOAc then 0-10% MeOH/DCM to give the product as colorless oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:11])[CH:7]=[N:8]2)=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:3]=1.[CH3:20][C:21]1[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([N:22]3[C:21]([CH3:20])=[CH:25][C:24]([CH3:26])=[N:23]3)[N:10]=[C:9]3[C:5]=2[N:6]([CH3:11])[CH:7]=[N:8]3)=[CH:14][CH:15]=1
Reactant: Cn1cnc2nc(Cl)nc(Nc3ccc(Cl)cc3)c21
Reactant: Cc1cc(C)[nH]n1
Product: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)c3c(ncn3C)n2)n1

Procedure:
Was prepared according to Example 6 from (2-chloro-7-methyl-7H-purin-6-yl)(4-chloro-phenyl)-amine and 3,5-dimethylpyrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=O)[N:10]=2)[N:7]=1.Cl.[CH3:18][NH:19][CH3:20].C(N(CC)CC)C>CN(C)C=O>[CH3:18][N:19]([CH3:20])[C:12](=[O:14])[C:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][N:6]2[CH:8]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(C(=O)O)c1cn2nc(Cl)ccc2n1
Reactant: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
0.959 g of 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionic acid was dissolved in 6 ml of N,N-dimethylformamide; 0.714 g of N,N′-carbonyldiimidazole was added, followed by stirring at room temperature for 60 minutes. To this mixture, 0.392 g of dimethylamine hydrochloride and 0.665 ml of triethylamine were added under ice cooling conditions, followed by stirring at room temperature for 3 hours. Saline was added to the reaction mixture, followed by extraction with ethyl acetate; the extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol (95:5). The desired fraction was collected and concentrated; the crystal obtained was collected by filtration to yield 0.608 g of the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[N:10][C:11]([C:17]2[CH:18]=[C:19]([CH:23]([CH3:26])[C:24]#N)[CH:20]=[N:21][CH:22]=2)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:35].[Na+].[OH2:37].Cl>C(O)C.O>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[N:10][C:11]([C:17]2[CH:18]=[C:19]([CH:23]([CH3:26])[C:24]([OH:37])=[O:35])[CH:20]=[N:21][CH:22]=2)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C#N)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Reactant: [OH-]
Reactant: O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C(=O)O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Temperature: 95 °C
Yield: 39 %

Procedure:
To a solution of racemic of 2-(5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)pyridin-3-yl) propanenitrile (0.08 g, 0.18 mmol) in ethanol/water (3:3 mL) was added solid NaOH (52 mg, 1.1 mmol). Upon completion of addition, the reaction mixture was heated at 95° C. for 16 h. After this time, the reaction mixture allowed to cool to RT and then water was added (5 mL). Upon completion of addition, 1.0 N HCl was added to the reaction mixture to adjust the pH to 6-7. Once at the prescribed pH, the aqueous portion was extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated under reduced pressure to yield racemic 2-(5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)pyridin-3-yl)propanoic acid (32 mg, 39% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2(O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C@H:15]([NH:19][C:20]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2([CH3:29])[CH3:28])=[CH:4][CH:3]=1.CCN(S(F)(F)[F:37])CC>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([F:37])[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C@H:15]([NH:19][C:20]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2([CH3:29])[CH3:28])=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](NC(=O)C1CCCC1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)C1CCCC1)C(=O)N1CC[C@](F)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: -78 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
N—((R)-1-((S)-4-(4-Chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)cyclopentanecarboxamide (30 mg, 0.069 mmol) was dissolved into methylene chloride (2 mL) then cooled to −78° C. and DAST (13.3 mg, 0.083 mmol) was added. The reaction was stirred overnight at rt. HPLC showed some starting material present and 2 additional drops of DAST was added at rt. Some starting material was still present and 2 additional drops DAST was added and HPLC then showed the reaction was complete. The reaction was concentrated and Example 616 was isolated as a white solid by preparative reverse-phase HPLC (15.3 mg, 51% yield), M+H=437.38.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:31])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]1[S:23][CH:24]([CH2:27][C:28]([OH:30])=O)[CH2:25][N:26]=1)=[CH:18]2)(=[O:11])=[O:10].[OH:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O>[OH:32][CH:33]1[CH2:38][CH2:37][N:36]([C:28](=[O:30])[CH2:27][CH:24]2[S:23][C:22]([C:19]3[NH:20][C:21]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[N:12]([CH3:31])[S:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])(=[O:11])=[O:10])=[N:26][CH2:25]2)[CH2:35][CH2:34]1
Reactant: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C3=NCC(CC(=O)N4CCC(O)CC4)S3)[nH]c12
Temperature: 25 °C
Yield: 74 %

Procedure:
To a mixture of (2-{7-[[(2-methoxyphenyl)sulfonyl](methyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (150 mg), 4-hydroxypiperidine (43 mg), 1H-1,2,3-benzotriazol-1-ol (67 mg) and N,N-dimethylformamide (8 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (94 mg) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 15 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:methanol=100:0-90:10), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (131 mg, yield 74%) as colorless prism crystals. MS: 543 (MH+). melting point 166-167° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:18](OCC=C)[CH:19]=[CH2:20].[C:25]1(C2C(=CC=CC=2)C([O-])=O)[C:26](=CC=C[CH:33]=1)C([O-])=O.C(Cl)C=C>ClC1C=CC=CC=1Cl>[CH2:20]([C:7]1[CH:6]=[C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[C:15]([CH2:26][CH:25]=[CH2:33])[CH:16]=2)([CH3:10])[CH3:9])[CH:4]=[CH:3][C:2]=1[OH:1])[CH:19]=[CH2:18]
Reactant: O=C([O-])c1ccccc1-c1ccccc1C(=O)[O-]
Reactant: C=CCOCC=C
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: Clc1ccccc1Cl
Solvent: C=CCCl
Product: C=CCc1cc(C(C)(C)c2ccc(O)c(CC=C)c2)ccc1O

Procedure:
Bis-A {2,2-bis-(4-hydroxyphenyl) propane} was converted to the diallyl ether via reaction of the diphenate salt with allyl chloride. The diallyl ether of Bis-A was heated in refluxing o-dichlorobenzene for 48 hrs to yield 2,2-bis(3-allyl4-hydroxyphenyl)propane. MS m/z 308 (M+ calcd for C21H24O2=308). The diphenol was converted to the dimethyl ether via reaction with methyl iodide as described in Example 2. MS m/z 336 (M+ calcd for C23H28O2=336). H NMR (300 MHz, CDCl3) d 1.70 (s, 6, CH3), 3.37 (m, 4, CH2 allyl), 3.82 (s, 6, OCH3), 4.92–5.05 (m, 4, CH2 vinyl), 5.85–6.15 (m, 2, vinyl), 6.70–7.05 (m, 6, aromatic). Oxidation of the diallyl derivative as described in Example 1 gave 2,2-{bis(3,3-epoxypropyl)4-methoxyphenyl}propane. MS m/z 353 (M+ —CH3) {Calcd for C23H28O4=368}. H NMR (300 MHz, CDCl3) d 1.60 (s, 6, CH3), 2.25 (d, 2, CH2epoxypropyl) 2.60–2.75 (m, 4, CH2 epoxypropyl), 2.85–2.95 (m, 2, CH2 epoxypropyl), 3.15–3.22 (m, 2, CH epoxypropyl) 3.83 (s, 6, OCH3), 6.75 (d, 2, aromatic), 7.10 (d, 4, aromatic).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[C:8](Cl)=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:5].ClC1C(N)=CC=CN=1.NC1C=C(C)C=CC=1C(OC)=O.S(=O)(=O)(O)O>S1(CCCC1)(=O)=O.ClCCl.C1(C)C=CC=CC=1>[CH3:18][C:16]1[CH:15]=[CH:14][C:3]2[C:4](=[O:5])[NH:6][C:7]3[CH:12]=[CH:11][CH:10]=[N:9][C:8]=3[NH:1][C:2]=2[CH:17]=1
Reactant: Cc1ccc(C(=O)Nc2cccnc2Cl)c(N)c1
Agent: COC(=O)c1ccc(C)cc1N
Agent: Nc1cccnc1Cl
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O=S1(=O)CCCC1
Solvent: ClCCl
Product: Cc1ccc2c(c1)Nc1ncccc1NC2=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
127.0 g (0.485 mol) of 2-amino-N-(2-chloro-pyridin-3-yl)-4-methyl-benzamide (m.p. 150°-152° C.) prepared analogously to Example A from 2-chloro-3-amino-pyridine and methyl 2-amino-4-methyl-benzoate (see F. Mayer and R. Schulze, Ber. Dtsch. Chem. Ges. 58, 1465 [1925]) were suspended in 500 ml of sulpholane and after the addition of 1.4 ml of conc. sulphuric acid the suspension was heated for 3 hours to 130° C. with stirring. It was then left to cool to 80° C., 500 ml of toluene were added and the mixture was left to stand overnight at ambient temperature. The crystals formed were suction filtered, suspended in 0.75 liters of dichloromethane, suction filtered once more and thoroughly washed with dichloromethane. After drying in a circulating air dryer, 70.2 g (64% of theory) of very slightly yellow crystals were obtained, m.p. 286°-288° C., which were further reacted without any further purification.
Reaction SMILES: Br[C:2]1[NH:3][C:4](=[O:11])[C:5]2[NH:6][CH:7]=[N:8][C:9]=2[N:10]=1.[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>CO>[C:12]1([S:18][C:2]2[NH:3][C:4](=[O:11])[C:5]3[NH:6][CH:7]=[N:8][C:9]=3[N:10]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=c1[nH]c(Br)nc2nc[nH]c12
Reactant: Sc1ccccc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]c(Sc2ccccc2)nc2nc[nH]c12
Temperature: 90 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
To a solution of 2-bromohypoxanthine (10.0 g, 46.5 mmol) in methanol (200 mL) was added thiophenol (9.55 mL, 93.0 mmol) and diisopropylethylamine (20.2 mL, 116.3 mmol). The reaction was stirred at 90° C. for overnight. The solvent was removed under reduced pressure and the solid was collected by filtration and washed with hexanes (100 mL×2). The collected solid was further purified by re-crystallization from methanol to afford desired product (10.1 g, 89% yield). 1H NMR (400 MHz, (CD3)2SO) δ 7.50(m, 3H), 7.62 (m, 2H), 7.97 (s, 1H); MS (ES) calc'd for C11H8N4OS [MH+] 245.05, found: 245.05.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14](Cl)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1B(O)O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CO.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>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:22]1[C:21]([Cl:20])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:27])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1c(Cl)cccc1Cl
Reactant: Clc1ccc2cc(OCc3ccccc3)ccc2n1
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: Cc1ccccc1
Solvent: CO
Product: Clc1cccc(Cl)c1-c1ccc2cc(OCc3ccccc3)ccc2n1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a solution of 3 g of 6-(benzyloxy)-2-chloroquinoline 12 in toluene (294 ml) is added Pd(PPh3)4 (1 g). After 30 minutes, a solution of 2,6-dichlorophenylboronic acid (4.22 g) in methanol (186 ml) and 120 ml of a saturated aqueous solution of NaHCO3 is added. The reaction is heated under reflux for 4 h. After evaporation, the aqueous phase is extracted with AcOEt (3×20 ml). The organic phases are washed with brine, dried over MgSO4 and evaporated to dryness. The residue is purified over silica gel using AcOEt/petroleum ether 5/95 then 10/90 as eluent to give 6-(benzyloxy)-2-(2,6-dichlorophenyl)quinoline 19 as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C@@H:5]([C@@H:13]([CH3:16])[CH2:14][CH3:15])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[CH3:17][C:18]1[S:19][CH:20]=[C:21]([CH:23]=O)[N:22]=1.[BH4-].[Na+].[C:27](=O)(OC1C=CC([N+]([O-])=O)=CC=1)[O:28]C1C=CC([N+]([O-])=O)=CC=1>C1C=CC=CC=1.CO.C1(C)C=CC=CC=1>[CH3:16][C@@H:13]([CH2:14][CH3:15])[C@H:5]([N:4]1[CH2:3][CH2:2][N:1]([CH2:23][C:21]2[N:22]=[C:18]([CH3:17])[S:19][CH:20]=2)[C:27]1=[O:28])[C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7]
Reactant: CC[C@H](C)[C@H](NCCN)C(=O)OC(C)(C)C
Reactant: Cc1nc(C=O)cs1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Solvent: CO
Product: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CCN(Cc2csc(C)n2)C1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
A solution containing the product from Example 3G (1.81 g, 7.9 mmol) in a mixture of benzene (8 mL) and methanol (8 mL) was treated with the product from Example 11B (1.0 g, 7.9 mmol), stirred at 50° C. for 1 hour, cooled to 25° C. and treated with sodium borohydride (0.60 g, 15.7 mmol), stirred at 25° C. for 1 hour, quenched with sodium bicarbonate solution and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. A solution of the residue (7.9 mmol) in toluene (16 mL) was treated with bis(4-nitrophenyl) carbonate (2.87 g, 9.4 mmol), stirred at reflux for 16 hours, cooled to 25° C. and partitioned between ethyl acetate and 10% K2CO3. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 1% methanol in chloroform to give the title compound (2.0 g, 69% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH2:22])[N:16]=1>CN(C=O)C.C(#N)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][N:8]2[C:15]2[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH2:22])[N:16]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: Cc1n[nH]c2cc(Br)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1cc(-n2nc(C)c3ccc(Br)cc32)nc(N)n1
Temperature: 25 °C

Procedure:
To a solution of 6-bromo-3-methyl-1H-indazole (500 mg, 2.37 mmol) in dry DMF (5 mL) at 0° C. under an atmosphere of nitrogen was introduced sodium hydride (684 mg of a 60% dispersion in mineral oil, 7.11 mmol). After warming to RT for 30 minutes, 4-chloro-6-methylpyrimidin-2-amine (510 mg, 3.55 mmol) was added and the solution warmed to 65° C. for 18 hr. The reaction mixture was cooled to RT, quenched by dropwise addition of water (5 mL) and extracted with 2:1 chloroform/isopropanol (3×10 mL extractions). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by column chromatography (Biotage, DCM containing a 0-10% gradient of methanol) furnished a yellow semi-solid which was slurried in acetonitrile (3 mL). The precipitate was collected by filtration to furnish the title compound as a yellow solid: 1H NMR (500 MHz, DMSO) delta 2.29 (3H, s), 2.56 (3H, s), 6.79-6.93 (2H, m), 6.93-6.95 (1H, m), 7.48 (1H, dd, J=8.43, 1.66 Hz), 7.78 (1H, d, J=8.35 Hz), 9.07 (1H, d, J=1.42 Hz); LC-MS: m/z=+317.95/319.95.