Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:18][C:19]([CH3:24])=[C:20]([CH2:22]O)[N:21]=3)=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.S(Cl)([Cl:27])=O>C(Cl)Cl>[Cl:27][CH2:22][C:20]1[N:21]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[CH:2]3)=[CH:12][CH:13]=2)[O:18][C:19]=1[CH3:24]
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccc(Cn3cnc4ccccc43)cc2)nc1CO
Solvent: ClCCl
Product: Cc1oc(-c2ccc(Cn3cnc4ccccc43)cc2)nc1CCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of {2-{4-[(1H-benzimidazol-1-yl)methyl]phenyl}-5-methyl-1,3-oxazole-4-yl}methanol (0.045 g, 0.14 mmol) in CH2Cl2 was treated with a solution of thionyl chloride (0.10 mL, 1.4 mmol) in CH2Cl2 (2 mL), heated to reflux temperature, stirred for 30 min, cooled to room temperature and concentrated in vacuo. The resultant residue was partitioned between CH2Cl2 and water. The organic phase was separated, washed with water, brine, dried over Na2SO4, and evaporated to dryness under reduced pressure to give the title product, LCMS (ESI+) 337 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=O.[F:12][C:13]([F:26])([F:25])[O:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([NH:20][NH2:21])=[O:19]>C(O)C>[Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:5]=[N:21][NH:20][C:18](=[O:19])[C:17]2[CH:22]=[CH:23][CH:24]=[C:15]([O:14][C:13]([F:12])([F:26])[F:25])[CH:16]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: NNC(=O)c1cccc(OC(F)(F)F)c1
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Solvent: CCO
Product: O=C(NN=Cc1cc(Cl)cc(Cl)c1O)c1cccc(OC(F)(F)F)c1
Temperature: 60 °C
Yield: 99.8 %

Procedure:
A suspension of 3,5-dichloro-2-hydroxy-benzaldehyde (0.200, 1.05 mmol) and 3-trifluoromethoxy-benzoic acid hydrazide (0.243 g, 1.05 mmol) in ethanol (3.3 mL) was heated to 60° C. for 18 hours. The reaction mixture was cooled to room temperature to precipitate the product. The solid was collected via suction filtration and rinsed with ethanol to furnish 3-trifluoromethoxy-benzoic acid [1-(3,5-dichloro-2-hydroxy-phenyl)-methylidene]-hydrazide as an off-white solid (0.412 g, 99%): mp 180-182° C.; 1H NMR (400 MHz, DMSO) δ 12.63 (s, 1H), 12.39 (s, 1H), 8.60 (s, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.91 (s, 1H), 7.76-7.63 (m, 4H); ESIMS m/z 393 ([M+H]+), 391 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH-].[Na+].[CH3:13]I>C1C=CC=CC=1>[CH3:13][N:6]1[C:7]2[C:3](=[C:2]([Cl:1])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: CI
Reactant: Clc1cccc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: Cn1ccc2c(Cl)cccc21
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A mixture of 60 g of 4-chloro-1H-indole, 400 ml of benzene, 200 ml of 50% sodium hydroxide solution, 68 g of n-tetrabutylammonium hydrogen sulfate and 68 ml of methyl iodide was stirred at 40° C. for 4 hours and was then cooled. The decanted aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with aqueous sodium chloride, dried over magnesium sulfate and distilled to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-2 cyclohexanebenzene mixture to obtain 63.85 g of 1-methyl-4-chloro-1H-indole.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]1([S:11][CH2:12][CH2:13][OH:14])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>N1C=CC=CC=1>[C:1]([O:14][CH2:13][CH2:12][S:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: OCCSc1ccccc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)OCCSc1ccccc1

Procedure:
Acetylchloride (7.9g), β-phenylthioethyl-alcohol (15.4g) and pyridine (9.5g) were treated according to Example 1. On fractionation, a fraction (17.5g), b.p. 76.0°-77.0° C./0.04mmHg, of β-phenylthioethyl acetate was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.[CH2:22](O)CCC>C(OCC)(OCC)OCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:22]=[N:13][N:12]=[C:10]3[CH2:9][CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1
Reactant: CCCCO
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=CC1
Solvent: CCOC(OCC)OCC
Product: Fc1ccccc1C1=CCc2nncn2-c2ccc(Cl)cc21

Procedure:
12.1 g of 7-chloro-5-(2-fluorophenyl)-2-hydrazino-3H-1-benzazepine are heated to boiling under reflux for 2 hours in a mixture of 330 ml of n-butanol and 110 ml of triethyl orthoformate. The mixture is evaporated in vacuo. The residue is crystallized from hexane, there being obtained crude 8-chloro-6-(2-fluorophenyl)-4H-s-triazolo[4,3-a][1]benzazepine as reddish coloured crystals. This material is purified by chromatography on 121 g of silica gel. Impurities are eluted with benzene/methanol (99:1). The product is subsequently eluted with benzene/methanol (98.5:1.5 and 98:2). After crystallization of the resulting material from ether, there is obtained 8-chloro-6-(2-fluorophenyl)-4H-s-triazolo[4,3-a][1]benzazepine of melting point 180°-182°.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Li])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[P:19]([Cl:21])Cl>>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([P:19]([C:13]3[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:11][CH:12]=3)[Cl:21])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]c1ccc(CCCc2ccccc2)cc1
Reactant: COP(Cl)Cl
Product: ClP(c1ccc(CCCc2ccccc2)cc1)c1ccc(CCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
p-(3-phenylpropyl)phenyllithium (8.1 g, 40 mmol) in 150 ml solvent (Et2O/THF 1/1) was added dropwise to CH3OPCl2 (2.66 g, 20 mmol) in 70 ml solvent (Et2O/THF 1/1) at -70° C. The addition was completed in 2 h. The reaction mixture was stirred overnight at room temperature and then brought to reflux for 2 h. The precipitate was filtered and the solvent of the solution was removed by applying vacuum. PCl3 (15 ml) was added to the resulting viscous oil and stirred for 24 h. Then the mixture was kept at 70° C. and 1 mm Hg for 2 h to remove excess PCl3 and byproduct. The product, di[p-(3-phenylpropyl)phenyl]chlorophosphine, was obtained as a pale yellow viscous oil with 90% yield. The product was characterized by 31P NMR. 83.6.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:32])[CH2:9][CH2:10][CH:11]2[C:14](=[O:15])[N:13]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[CH:12]2[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.N.[H][H]>C(O)C.[Ni]>[NH2:21][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([N:13]2[CH:12]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH:11]([CH2:10][CH2:9][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[OH:32])[C:14]2=[O:15])=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(C#N)cc2)cc1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(CN)cc2)cc1
Temperature: 60 °C

Procedure:
1.22 g of 4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile (4) were dissolved in 90 ml of ethanol. 10 ml of conc. ammonia solution and an excess of Raney nickel were added, and the mixture was stirred at 60° C. and a hydrogen pressure of 10 bar for 8 h. Overnight, the reaction mixture cooled to room temperature. The next day, the catalyst was removed, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography using dichloromethane/methanol/ammonia solution 10/1/0.1. This produced 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)-azetidin-2-one (5) of molecular weight 434.51 (C26H27FN2O3); MS (ESI): 418.2 (MH+-NH3).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[O:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[CH2:34][O:35][CH2:36][CH2:37][NH2:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[O:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[CH2:34][O:35][CH2:36][CH2:37][NH:38][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: NCCOCC1CCCO1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCOCC3CCCO3)ccc21
Yield: 21.4 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(tetrahydro-furan-2-ylmethoxy)-ethyl]amide (21 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (75 mg), 2-(tetrahydro-furan-2-ylmethoxy)-ethylamine (29 mg), HBTU (84 mg), and DIEA (48 uL). LC/MS: m/z 536.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.39 (s, 1H), 8.46 (s, 1H), 8.09 (s, 1H), 7.92 (s, 1H), 7.83-7.65 (m, 2H), 7.49 (d, 1H), 7.36 (d, 1H), 3.98-3.90 (m, 1H), 3.79-3.68 (m, 2H), 3.64 (bs, 3H), 3.61-3.52 (m, 2H), 3.49-3.38 (m, 5H), 1.94-1.68 (m, 2H), 1.60-1.47 (m, 1H).
Reaction SMILES: [C:1]([C:3]([C:19]#[N:20])=[C:4]([OH:18])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)#[N:2].[CH:21](N(C(C)C)CC)(C)C.C[Si](C=[N+]=[N-])(C)C>C(#N)C.CO>[C:1]([C:3]([C:19]#[N:20])=[C:4]([O:18][CH3:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)#[N:2]
Reactant: N#CC(C#N)=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Solvent: CO
Product: COC(=C(C#N)C#N)c1ccc(Oc2ccccc2)cc1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
1,1-Dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene (56.5 g) in acetonitrile (780 mL) and methanol (85 mL) is stirred under nitrogen at 0° C. while adding diisopropylethylamine (52.5 mL) followed by 2M trimethylsilyldiazomethane (150 mL) in TI-IF. The reaction is stirred for 2 days at 20° C., and then 2 g of silica is added (for chromatography). The brown-red solution is evaporated in vacuo, the residue dissolved in ethyl acetate and washed well with water then brine, dried and evaporated. The residue is extracted with diethyl ether (3×250 mL), decanting from insoluble oil. Evaporation of the ether extracts gives 22.5 g of 1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene as a pale orange solid. The insoluble oil is purified by flash chromatography to give 15.0 g of a red-orange oil.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C:12]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH:13]=2)(=O)=O)=CC=1.[I-:21].[Na+].O>CC(C)=O>[I:21][CH2:11][CH:12]1[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)OCC2=Cc3ccccc32)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: ICC1Cc2ccccc21
Yield: 88 %

Procedure:
6 g of benzocyclobuten-1-ylmethyl para-toluenesulfonate (prepared according to the process described in J.A.C.S., (1975), 154, p. 347) are mixed with 6.2 g of sodium iodide in 85 ml of acetone. The reaction medium is brought to reflux for 8 hours, then introduced into 150 ml of water and extracted several times with ethyl ether. The organic phase is then washed with normal sodium thiosulfate solution, dried over anhydrous magnesium sulfate and concentrated to obtain the expected compound in the form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]O)=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].P(Br)(Br)[Br:15]>C(Cl)Cl.O.[Cl-].[Na+].O>[Br:15][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COc1ccc(CO)cc1[N+](=O)[O-]
Reactant: BrP(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CBr)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 191.1 %

Procedure:
(4-methoxy-3-nitrophenyl)methanol (215 mg, 1.174 mmol) was dissolved, under N2 atmosphere, in dry DCM and cooled to 0° C. PBr3 (55.4 μl, 0.587 mmol) was added, and the reaction was stirred RT for 1 hour. Ice and DCM were added to the reaction mixture. The mixture was diluted with WATER and brine and extracted twice with DCM. The organic layers were dried and evaporated to dryness to give 4-(bromomethyl)-1-methoxy-2-nitrobenzene (276 mg, 1.122 mmol, 96% yield) that was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:4][CH3:5])[C:2]#[CH:3].I[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1/[C:9](=[CH:17]/[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24])/[C:10](=[O:16])[NH:11]2>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.CN(C=O)C.CCN(CC)CC>[CH3:5][O:4][CH2:1][C:2]#[C:3][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1/[C:9](=[CH:17]/[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24])/[C:10](=[O:16])[NH:11]2
Reactant: C#CCOC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, methyl propargyl ether (34 mg, 0.49 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.41 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 18 h to yield (Z)-1,3-dihydro-4-(3-methoxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 69 mg, 55%).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[NH3:36]>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:24]=[C:23]([C:25]([NH2:36])=[O:26])[CH:22]=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(-c2cccc(C(=O)O)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: N
Product: C[C@@H](c1ccc(-c2cccc(C(N)=O)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylic acid and ammonia (32% in water) following a procedure analogous to that described in Example 203. Mass spectrum (ESI+): m/z=474 [M+H]+.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:31].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>C1COCC1>[CH3:32][N:33]1[CH2:34][CH2:35][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])[CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)c1
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)C(=CNc2ccc(N4CCN(C)CC4)cc2)C(=O)N3)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-amide (as prepared in Example 1, 30 mg, 0.072 mmol) and THF (1 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (20.7 mg, 0.1082 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. The reaction mixture was concentrated in vacuo and purified via flash silica gel chromatography (5% MeOH/95% CHCl3) providing the title compound in 57% yield (24 mg, 0.0407 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](N(OC)C)=[O:14])=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25](=[O:32])(=[O:31])[N:26]=CN(C)C)=[CH:21][CH:20]=3)[C:9]=2[N:33]([CH3:35])[CH3:34])=[CH:4][CH:3]=1.[CH2:36]1COC[CH2:37]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13](=[O:14])[CH2:36][CH3:37])=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH2:26])(=[O:31])=[O:32])=[CH:21][CH:20]=3)[C:9]=2[N:33]([CH3:34])[CH3:35])=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1sc(-c2ccc(Cl)cc2)c(N(C)C)c1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Product: CCC(=O)c1sc(-c2ccc(Cl)cc2)c(N(C)C)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 72.5 °C
Yield: 64.43 %

Procedure:
Grignard reagent (ethyl magnesium bromide, 0.62 g, 4.66 ml 1M solution in THF, 4.67 mmol) was added drop wise to a stirred solution of 5-(4-chlorophenyl)-4-(dimethylamino)-3-(4-(N-((dimethylamino)methylene)sulfamoyl)phenyl)-N-methoxy-N-methylthiophene-2-carboxamide (compound 34g, 0.5 g, 0.93 mmol) in anhydrous THF (30 ml) at 25° C. The reaction mixture was then heated at about 70 to 75° C. for 2 hr. The progress of the reaction was monitored by TLC. After cooling the reaction mixture to 0° C., the reaction mixture was quenched by addition of saturated solution of ammonium chloride (10 ml). The mixture so obtained was then extracted with ethyl acetate (2×30 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (0.27 g, 64.43%). The title compound was then purified by preparative HPLC (0.135 g, 32.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[N:9]=[CH:8][NH:7][C:6]2=O.CN(C)C=O.S(Cl)([Cl:30])=O>>[Cl:30][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCC1CCN(C)CC1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Yield: 98 %

Procedure:
A solution of 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-3,4-dihydroquinazolin-4-one (2.8 g, 9.24 mmol) in thionyl chloride (28 ml) containing dimethylformamide (0.28 ml) was heated at reflux for 1 hour. The reaction was cooled, the volatiles were removed in vacuo and the resultant solid was triturated with diethyl ether, filtered, washed with diethyl ether and dried in vacuo. The solid was dissolved in dichloromethane and washed with saturated aqueous sodium hydrogen carbonate, water and brine. Evaporation of the solvent and drying in vacuo yielded 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (2.9 g, 98% yield):
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[C:3]=1I.[C:11]([C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)#[CH:12].C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[NH2:8][C:6]1[N:5]=[C:4]([NH2:9])[C:3]([C:12]#[C:11][C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)=[C:2]([Cl:1])[N:7]=1
Reactant: Nc1nc(N)c(I)c(Cl)n1
Reactant: C#Cc1cccc(O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nc(N)c(C#Cc2cccc(O)c2)c(Cl)n1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 500 mg (1.8 mmol) 6-chloro-5-iodo-pyrimidine-2,4-diamine, 827 mg (7.0 mmol) 3-ethynyl-phenol, 35 mg (0.19 mmol) CuI, 129 mg (0.19 mmol) PdCl2(PPh3)2 and 4.1 mL triethylamine in 4 mL dry DMF. Yield after purification by RP-HPLC: 511 mg (100%).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[F:13][C:14]([F:22])([F:21])[C:15]1([C:18](O)=[O:19])[CH2:17][CH2:16]1.CCCP(=O)=O>CN(C=O)C>[CH3:5][O:4][N:3]([CH3:2])[C:18]([C:15]1([C:14]([F:22])([F:21])[F:13])[CH2:17][CH2:16]1)=[O:19]
Reactant: CNOC
Reactant: O=C(O)C1(C(F)(F)F)CC1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of N,O-dimethyl hydroxylamine hydrochloride (0.48 g, 4.87 mmol, Aldrich) in DMF (15 mL, Aldrich) was added triethylamine (0.68 mL, 4.87 mmol, Aldrich). After completed addition the reaction was stirred at RT for 5 min. 1-trifluoromethylcyclopropane-1-carboxylic acid (0.5 g, 3.24 mmol, Alfa Aesar, A Johnson Matthey Company) was added and the reaction was stirred at room temperature for 1 min. The reaction was cooled to 0° C. and propylphosphonic anhydride solution (50 wt. % in DMF; 3.10 mL, 4.87 mmol, Acros Organics) was added dropwise. The resulting mixture was stirred at room temperature for 5 days. The reaction was quenched with saturated NaHCO3 and stirred at RT for 5 min. The reaction was extracted with diethyl ether (2×40 mL) and the combined organic extracts were washed with saturated ammonium chloride, water, dried over MgSO4, and concentrated to give 229 mg of the title compound as a light yellow liquid. MS (ESI, positive ion) m/z: 198.1 (M+H).
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1.Cl[C:40]1[N:45]=[CH:44][C:43]([C:46]([NH:48][CH3:49])=[O:47])=[CH:42][CH:41]=1>CN(C)C=O>[CH3:49][NH:48][C:46](=[O:47])[C:43]1[CH:42]=[CH:41][C:40]([O:21][C:19]2[CH:18]=[CH:17][C:15]3[N:16]=[C:12]([N:9]4[CH2:10][CH2:11][C@@H:7]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[CH2:8]4)[S:13][C:14]=3[CH:20]=2)=[N:45][CH:44]=1
Reactant: CNC(=O)c1ccc(Cl)nc1
Reactant: Oc1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(Oc2ccc3nc(N4CC[C@@H](N5CCCCC5)C4)sc3c2)nc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of (R)-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-6-ol (Example 47) in N,N-dimethylformamide (˜0.06 M) under a dry nitrogen atmosphere is placed in a microwave vial and stirred. Sodium hydride or a 1 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (1.2 equivalents) is added to the reaction mixture and stirring is continued for 45 minutes. 6-Chloro-N-methyl-3-pyridinecarboxamide (CAS #54189-82-1, 1.2 equivalents) is added to the reaction mixture and stirring is continued for 2-3 hours at 100° C. under microwave irradiation with the cooling air remaining on for the duration of the heating cycle. The reaction mixture is cooled to ambient temperature, dried (MgSO4), and filtered. The filtrate is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel, eluting with 98:2 dichloromethane/2 M NH3 in methanol. Fractions containing product are combined and concentrated under reduced pressure to give (R)—N-methyl-6-(2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-6-yloxy)nicotinamide.
Reaction SMILES: C([C:3]1[C:4](=[O:13])[NH:5][C:6]([CH2:11][CH3:12])=[CH:7][C:8]=1[CH2:9][CH3:10])#N.C(CC(=O)CC)(=O)CC.C(CC(N)=O)#N.C(NCC)C.Cl>C(O)C>[CH2:9]([C:8]1[CH:7]=[C:6]([CH2:11][CH3:12])[NH:5][C:4](=[O:13])[CH:3]=1)[CH3:10]
Reactant: CCc1cc(CC)c(C#N)c(=O)[nH]1
Agent: CCC(=O)CC(=O)CC
Agent: Cl
Agent: N#CCC(N)=O
Solvent: CCO
Solvent: CCNCC
Product: CCc1cc(CC)[nH]c(=O)c1

Procedure:
Basu [J. Indian Chem. Soc. 7, 815 (822-3) (1930)] describes the preparation of 3-cyano-4,6-diethyl-2(1H)-pyridinone (p. 822, VI) by reacting dipropionylmethane with cyanoacetamide in ethanol in the presence of diethylamine. In this same paper Basu heated 3-cyano-4,6-diethyl-2(1H)-pyridinone with concentrated hydrochloric acid to produce 4,6-diethyl-2(1H)-pyridinone (pp. 822-3).