Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:35][NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([N:36]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:35])=[O:12])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNCc1ccccc1
Reactant: O=C(N[C@@H](Cc1cccnc1)C(=O)O)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)C(=O)[C@H](Cc1cccnc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
2.5 g of Z-Pal-OH (8.7 mMol) are dissolved in 50 ml of THF, mixed with 1.55 g CDI (9.5 mMol), stirred for 45 minutes at ambient temperature, then mixed with 1.12 ml of N-methyl-benzylamine (8.7 mMol) and stirred for a further 64 hours at ambient temperature. The reaction mixture is concentrated on the rotary evaporator, the residue is taken up in ethyl acetate, extracted once with cold water and once with 10% NaCl solution. The organic phase is filtered, concentrated and chromatographed over a silica gel column by means of ether as eluant. Z-Pal-N(Me)Bzl is obtained as colourless oil from the eluant.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:5]=[CH:4][N:3]=1.[CH3:21][P:22]([C:25]1[N:30]=[C:29]([O:31][CH3:32])[C:28]([NH2:33])=[CH:27][CH:26]=1)([CH3:24])=[O:23]>>[CH3:24][P:22]([C:25]1[N:30]=[C:29]([O:31][CH3:32])[C:28]([NH:33][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:5]=[CH:4][N:3]=2)=[CH:27][CH:26]=1)([CH3:21])=[O:23]
Reactant: COc1nc(P(C)(C)=O)ccc1N
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1ccnc(Cl)n1
Product: COc1nc(P(C)(C)=O)ccc1Nc1nccc(Nc2ccccc2S(=O)(=O)C(C)C)n1

Procedure:
This compound can be prepared as in Example 32 by reacting 2-Chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-pyrimidin-4-amine with 6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (prepared in Example 32).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]2[S:10][C:9]([N:11]3[CH2:15][CH2:14][CH2:13][C:12]3=[O:16])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[N:34][NH:35]3)O1>>[NH:35]1[C:36]2[C:32](=[C:31]([C:2]3[N:3]=[C:4]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:5]4[S:10][C:9]([N:11]5[CH2:15][CH2:14][CH2:13][C:12]5=[O:16])=[CH:8][C:6]=4[N:7]=3)[CH:39]=[CH:38][CH:37]=2)[CH:33]=[N:34]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: O=C1CCCN1c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: O=C1CCCN1c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
1-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyrrolidin-2-one (35 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole via Procedure A. The product was purified by reverse phase HPLC to yield 19.5 mg of 438. MS (Q1) 421 (M)+
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[C:20](=O)[NH:19][C:18]([CH3:22])=[N:17][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:27])=O>C(Cl)Cl>[Cl:27][C:20]1[C:6]2[C:5]3[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][C:4]=3[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][CH2:8][C:7]=2[N:17]=[C:18]([CH3:22])[N:19]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2c(c(=O)[nH]1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Solvent: ClCCl
Product: Cc1nc(Cl)c2c(n1)CN=C(c1ccccc1)c1cc(Cl)ccc1-2

Procedure:
A solution of 3.5 g (10.4 mmol) of 9-chloro-3-methyl-7-phenyl-5H-pyrimido[4,5-d][2]benzazepin-1(2H)-one and 22 mL of phosphorous oxychloride in 100 mL of methylene chloride was stirred at room temperature for 18 hr. The reaction mixture was concentrated at reduced pressure to a solid residue. The residue was partitioned between ice cold saturated aqueous sodium bicarbonate and methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to a yellow residue. Purification by column chromatography (silica gel, 40.0 g; eluent:methylene chloride ether, 10:1) gave a pale yellow solid, mp 190°-192°. A portion was recrystallized from a mixture of ether and petroleum ether to yield colorless prisms, mp 191°-193°.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:24])[S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:25]1[S:26][CH:27]([CH2:30][C:31](O)=[O:32])[CH2:28][N:29]=1)=[CH:9]2.Cl.C[N:36](C)CCCN=C=NCC.CN(C)C=O>O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:24])[S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:25]1[S:26][CH:27]([CH2:30][C:31]([NH2:36])=[O:32])[CH2:28][N:29]=1)=[CH:9]2
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C3=NCC(CC(=O)O)S3)cc2c1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C3=NCC(CC(N)=O)S3)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.1 %

Procedure:
A mixture of (2-{5-(2-methoxyethoxy)-7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (220 mg), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (100 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (120 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with aqueous citric acid solution, saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-methanol (97:3-90:10, volume ratio) to give pale-yellow crystals. The crystals were recrystallized from acetone-hexane to give the title compound (110 mg, yield 50%) as pale-yellow prism crystals. melting point 189-190° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21](=[O:40])[CH2:22][N:23]([C:25]([CH:27]2[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]2)=[O:26])[CH3:24])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:14]1([CH2:13][CH2:12][CH2:11][CH:10]([NH:20][C:21](=[O:40])[CH2:22][N:23]([C:25]([CH:27]2[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]2)=[O:26])[CH3:24])[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN(CC(=O)NC(CCCc1ccccc1)CCCc1ccccc1)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CC(=O)NC(CCCc1ccccc1)CCCc1ccccc1)C(=O)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 138 %

Procedure:
N-(N-tert-Butoxycarbonyl-piperidine-4-carbonyl)-(N-methyl)-2-aminoacetic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (67) (1.46 g; 2.66 mmol) is dissolved in methylene chloride (30 mL) at ambient temperature. Trifluoroacetic acid (15 mL) is added in a slow stream, and the solution is stirred for 2 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (1.65 g) as a clear oil. ESMS: MH+ 450.2
Reaction SMILES: C([O:3][C:4](=[O:21])/[C:5](=[N:14]/[O:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)/[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)C.[OH-].[Li+].O>C(O)C.C(Cl)(Cl)Cl>[CH:16]1([O:15]/[N:14]=[C:5](\[C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=2)/[C:4]([OH:21])=[O:3])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)/C(=N/OC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)/C(=N/OC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C

Procedure:
(E)-Cyclopentyloxyimino-(3,4-dichloro-phenyl)-acetic acid ethyl ester (332 mg, 1.01 mmol) was dissolved in ethanol (10 mL) and cooled to 0° C. A 2.0 N solution of lithium hydroxide in water (1.51 mL, 3.02 mmol) was added dropwise. The reaction mixture was allowed to gradually warm to 25° C. over 1.5 h, then diluted with chloroform (125 mL) and washed with 0.3 M potassium bisulfate solution (60 mL). The aqueous phase was extracted with chloroform (75 mL) and the combined organic phases were dried over magnesium sulfate and evaporated in vacuo to afford (E)-cyclopentyloxyimino-(3,4-dichloro-phenyl)-acetic acid as a faintly yellow semi-solid (304 mg, quant.) that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][CH:12]=[C:11]([C:14](=[N:16][NH:17][C:18]([C:20]3[S:24][C:23]([C:25]([O:27]C)=[O:26])=[CH:22][CH:21]=3)=[O:19])[CH3:15])[C:10]=2[OH:29])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][CH:12]=[C:11]([C:14](=[N:16][NH:17][C:18]([C:20]3[S:24][C:23]([C:25]([OH:27])=[O:26])=[CH:22][CH:21]=3)=[O:19])[CH3:15])[C:10]=2[OH:29])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2csc(-c3ccc(Cl)c(Cl)c3)c2O)s1
Agent: [Na+]
Agent: [OH-]
Product: CC(=NNC(=O)c1ccc(C(=O)O)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Yield: 13.7 %

Procedure:
From methyl 5-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxy-3-thienyl]ethylidene}hydrazino)carbonyl]-2-thiophenecarboxylate (56.3 mg, 0.12 mmol) and 0.2 M sodium hydroxide aqueous solution (1.89 mL, 0.38 mmol), 7.5 mg of the desired product was obtained in the same manner as in Synthetic Example 66 as a pale yellow solid (yield 14%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([I:23])[CH:17]=1>C(O)(=O)C>[I:23][C:18]1[CH:17]=[C:16]([C:15]2[NH:1][C:2]3[CH:7]=[C:6]([N:8]4[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]4)[CH:5]=[CH:4][C:3]=3[N:14]=2)[CH:21]=[CH:20][C:19]=1[CH3:22]
Reactant: Cc1cn(-c2ccc(NC(=O)c3ccc(C)c(I)c3)c(N)c2)cn1
Solvent: CC(=O)O
Product: Cc1cn(-c2ccc3nc(-c4ccc(C)c(I)c4)[nH]c3c2)cn1
Yield: 65.2 %

Procedure:
A solution of N-(2-amino-4-(4-methyl-1H-imidazol-1-yl)phenyl)-3-iodo-4-methylbenzamide (0.16 g, 0.37 mmol) in 5 mL glacial acetic acid was refluxed for 8 hrs, and then the mixture was evaporated in vacuo, the residue was purified by chromatography on silica gel (CH2Cl2/CH3OH 97:3 to 94:6) to give 0.1 g product as pale yellow solid (65.3%). LC/MS: m/z [M+H]+ 415.0415.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:10]([O-])=O.[Cl:13][CH2:14][C:15](O)=O.Cl>CO.[Pd]>[Cl:13][CH2:14][C:15]1[NH:10][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=2[N:1]=1
Reactant: O=C(O)CCl
Reactant: COc1cccc([N+](=O)[O-])c1N
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cccc2[nH]c(CCl)nc12
Yield: 86.6 %

Procedure:
A solution of 2-amino-3-methoxy-1-nitrobenzene (0.860 g, 5.11 mmol) in MeOH (50 mL) was hydrogenated (1 atm) over palladium, 10 wt. % on activated carbon (0.163 g). The resultant crude 3-methoxy-1,2-phenylenediamine was reacted with chloroacetic acid (0.953 g, 10.08 mmol) in refluxing 4 N HCl (10 mL) overnight. After aqueous workup, 0.87 g of 2-chloromethyl-4-methoxy-1H-benzimidazole was isolated as a red-brown solid, which was used without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[C:13]([O:17][C:18]([N:20]1[CH2:24][C@H:23]([CH2:25][OH:26])[C@@H:22]([OH:27])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:24][C@H:23]([CH2:25][O:26][S:2]([CH3:1])(=[O:4])=[O:3])[C@@H:22]([OH:27])[CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H](CO)[C@@H](O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](COS(C)(=O)=O)[C@@H](O)C1
Temperature: 25 °C
Yield: 33.1 %

Procedure:
Methanesulfonyl chloride (180 μL, 23 mmol) was added dropwise to a CH2Cl2 solution of triethylamine (400 μL, 29 mmol) and (3R,4R)-1-tert-butoxycarbonyl-3-hydroxy-4-(hydroxymethyl)pyrrolidine (1) (2 g, 9.2 mmol) at 0° C. and the resulting solution allowed to warm to room temperature. The reaction was diluted with CH2Cl2, washed with water, brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography to afford (3R,4R)-1-tert-butoxycarbonyl-3-hydroxy-4-(mesyloxymethyl)pyrrolidine (900 mg) as an oil. Without further purification the product was dissolved in DMF (10 mL) and stirred with sodium thiomethoxide (400 mg, 5.7 mmol) at room temp. overnight. The reaction was diluted with toluene washed with water, brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography to afford (3R,4S)-1-tert-butoxycarbonyl-3-hydroxy-4-(methylthiomethyl)pyrrolidine (600 mg, 2.4 mmol) as a syrup, which was not further characterised. (3R,4S)-1-tert-Butoxycarbonyl-3-hydroxy-4-(methylthio)pyrrolidine was dissolved in MeOH (5.0 mL) and cHCl (1.0 mL) and concentrated in vacuo to afford (3R,4S)-3-hydroxy-4-(methylthiomethyl)pyrrolidine hydrochloride (48) as a syrup (442 mg, 26% overall yield for three steps). 13C NMR (D2O) δ 73.5, 51.5, 48.6, 45.2, 34.3, 14.9.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)[CH2:4][C@H:3]1[O:19][CH3:20].[Cl:21][C:22]1[N:23]=[C:24]([C:29](O)=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:21][C:22]1[N:23]=[C:24]([C:29]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[O:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=3)[CH2:4][C@H:3]2[O:19][CH3:20])=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCOC(=O)c1oc(N2CC[C@H](N)[C@H](OC)C2)nc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCOC(=O)c1oc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C
Yield: 69.9 %

Procedure:
The same operation as in Example (106d) was performed using ethyl cis(±)-2-(4-amino-3-methoxypiperidin-1-yl)-4-methyl-1,3-oxazole-5-carboxylate obtained in Example (107b) (0.22 g, 0.78 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.16 g, 0.92 mmol), WSC hydrochloride (0.46 g, 2.4 mmol), HOBt (0.2 g, 1.2 mmol), DMA (3 mL) and dichloromethane (3 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/2, 1/1, 2/1, 1/0, ethyl acetate/methanol=97/3, 93/7) to obtain 0.24 g of the title compound as a light yellow solid (70%).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:13](N(OC)C)=[O:14].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:13]=[O:14]
Reactant: COc1ccc2oc(C(=O)N(C)OC)c(Br)c2c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc2oc(C=O)c(Br)c2c1
Reaction time: 1 h
Yield: 27.1 %

Procedure:
To a solution (40 mL) of 3-bromo-N,5-dimethoxy-N-methyl-1-benzofuran-2-carboxamide (4.00 g) synthesized above in tetrahydrofuran was added lithium aluminum hydride (241 mg) at 0° C., and the mixture was stirred for 1 hr. Lithium aluminum hydride (241 mg) was additionally added, and the mixture was stirred at 0° C. for 1 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the title object compound (880 mg, 27%) as a pale-yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[C:16](=[N:17][N:18]([S:22]([CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)(=[O:24])=[O:23])[CH:19]=3)[CH2:15]2)[CH2:11][O:10][C@@H:9]1[C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])CCC.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[F:37][C:31]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=1[C@@H:9]1[C@@H:8]([NH2:7])[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[C:16](=[N:17][N:18]([S:22]([CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)(=[O:23])=[O:24])[CH:19]=3)[CH2:15]2)[CH2:11][O:10]1
Reactant: CCCCOC(=O)N[C@H]1C[C@@H](N2Cc3cn(S(=O)(=O)C4CCCC4)nc3C2)CO[C@@H]1c1cc(F)ccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1C[C@@H](N2Cc3cn(S(=O)(=O)C4CCCC4)nc3C2)CO[C@@H]1c1cc(F)ccc1F
Reaction time: 1.5 h

Procedure:
A solution of the intermediate obtained in Step A above (90 mg, 0.16 mmol) in dichloromethane (6 mL) was treated with trifluoroacetic acid (3 mL) at room temperature. After 1.5 h, the reaction mixture was concentrated to give the title compound. 1H NMR (500 MHz, CD3OD): δ 1.61-1.74 (m, 4H); 1.92-2.08 (m, 4H); 2.11 (q, 1H, J=12 Hz); 2.78-2.84 (m, 1H); 3.68 (td, 1H, J=12, 4 Hz); 3.78 (t, 1H, J=12 Hz); 3.88-3.96 (m, 1H); 4.02-4.10 (m, 1H); 4.49-4.67 (m, 5H); 4.71 (d, 1H, J=12 Hz); 7.19-7.27 (m, 2H); 7.28-7.33 (m, 1H); 8.09 (s, 1H). LC-MS: 453.04 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br>O>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=3)[CH2:10][CH2:11]2)=[CH:20][CH:19]=1
Reactant: COc1ccc(N2CCN(c3ccc(N)cc3)CC2)cc1
Agent: Br
Solvent: O
Product: Nc1ccc(N2CCN(c3ccc(O)cc3)CC2)cc1
Yield: 44 %

Procedure:
A mixture of 30 parts of 4-[4-(4-methoxyphenyl)-1-piperazinyl]benzenamine and 300 parts of a hydrobromic acid solution 48% in water is stirred and refluxed for 10 days. The reaction mixture is evaporated and the residue is alkalized with sodium hydroxide. The mixture is filtered and the filtrate is acidified with acetic acid. The precipitated product is filtered off and crystallized from 1,4-dioxane, yielding 12 parts (44%) of 4-[4-(4-aminophenyl)-1-piperazinyl]phenol.
Reaction SMILES: [CH3:1][CH:2]([C:11](=[O:21])[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[F:22][C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:24]=1[NH2:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[F:22][C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:24]=1[N:25]1[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][C:11](=[O:21])[C:2]([CH3:1])=[C:3]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C(=O)CC(=O)c1ccccc1)C(=O)c1ccccc1
Reactant: Nc1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: Cc1c(-c2ccccc2)n(-c2c(F)cccc2F)c(-c2ccccc2)cc1=O
Yield: 18.7 %

Procedure:
To 150 ml of xylene were added 2.8 g (0.010 mole) of 2-methyl-1,5-diphenyl-1,3,5-pentanetrione, 12.9 g (0.010 mole) of 2,6-diflouroaniline, 3.0 g (0.016 mole) of para-toluenesulfonic acid and 30.0 g of Molecular Sieves 5A, followed by refluxing the resulting mixture for 3 hours. After cooling the reaction mixture, solid matter was filtered off and the filtrate was washed successively with 50 ml of 10% hydrochloric acid, 50 ml of 10% aqueous solution of sodium hydroxide and water. The filtrate was then dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate by filtration, the solvent was distilled off and the residue was crystallized from a 2:1 mixed solvent of acetone and hexane to give 0.7 g of 1-(2,6-diflourophenyl)-3-methyl-2,6-diphenyl-4(1H)-pyridinone having a melting point of 219°-221° C.
Reaction SMILES: [OH-].[K+].CC1C=CC(S([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][C:21]([C:23]2[C:24]3[CH:25]=[CH:26][NH:27][C:28]=3[CH:29]=[CH:30][CH:31]=2)=[O:22])(=O)=O)=CC=1.O.Cl>C(O)C>[OH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([C:23]1[C:24]2[CH:25]=[CH:26][NH:27][C:28]=2[CH:29]=[CH:30][CH:31]=1)=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Oc2ccccc2NC(=O)c2cccc3[nH]ccc23)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccccc1O)c1cccc2[nH]ccc12

Procedure:
250 ml of a solution of potassium hydroxide in ethanol at 10 g per 100 ml were added to a suspension of 25 g of N-[2-[(4-methylphenyl)sulfonyloxy]phenyl]-1H-indol-4-carboxamide in 50 ml of ethanol at 95° C. with stirring under an inert atmosphere and the mixture was stirred for 21 hours. 1 liter of iced water was added, and the mixture was acidified with a concentrated aqueous solution of hydrochloric acid, followed by stirring for a further 15 minutes, filtering, drying and triturating at reflux in 1.5 liters of methylene chloride. After concentrating to about 300 ml, filtering and drying at 80° C. under reduced pressure, 13 g of N-(2-hydroxyphenyl)-1H-indol-4-carboxamide melting at ≃208° C. were obtained.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:8]([O:13][C@H:14]3[CH2:19][CH2:18][C@H:17]([NH:20][C:21]4[S:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[N:25]=4)[CH2:16][CH2:15]3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8]([O:13][C@H:14]3[CH2:15][CH2:16][C@H:17]([NH:20][C:21]4[S:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[N:25]=4)[CH2:18][CH2:19]3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: C1=C(c2nccnc2O[C@H]2CC[C@H](Nc3nc4ccccc4s3)CC2)CCOC1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: c1ccc2sc(N[C@H]3CC[C@H](Oc4nccnc4C4CCOCC4)CC3)nc2c1
Temperature: 65 °C

Procedure:
A mixture of N-(trans-4-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yloxy)cyclohexyl)benzo[d]thiazol-2-amine. As prepared in Example 30b, (0.22 g, 0.54 mmol), palladium hydroxide on carbon (20 wt % Pd dry basis, wet, Degussa type E101 NE/W) (0.60 g), and ammonium formate (0.51 g, 8.11 mmol) in methanol (3 mL) was heated to 65° C. for 12 h, then cooled to RT. The palladium was filtered off and the filtrate was concentrated in vacuo to give a white solid. This solid was partitioned between ethyl acetate and water, the layers were separated, and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give an oil. The oil was then purified by silica gel chromatography to give N-(trans-4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)cyclohexyl)benzo[d]thiazol-2-amine (0.030 g, 0.073 mmol, 14% yield) as a white solid. [M+1] 411.2. IC50 (uM): 0.0635.
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23].C(N(CC)CC)C.O>ClCCl>[N+:22]([C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:12]=1[NH:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)([O-:24])=[O:23]
Reactant: NCCOc1ccccc1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCOc1ccccc1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
Under a nitrogen atmosphere, 2-phenoxyethylamine (17.6 ml, 0.13 mol) was added dropwise to a chilled (ice bath) solution of 4-chloro-3-nitroquinoline (21.5 g, 0.1 mol), triethylamine (21.5 ml, 0.16 mol) in dichloromethane (500 ml). The reaction was maintained at ambient temperature overnight. Water was added and the phases were separated. The organic phase was dried (MgSO4), filtered, and the bulk of the solvent was removed under vacuum. Hexane was added and the solution was chilled in a refrigerator. The resulting precipitate was recovered by vacuum filtration to provide 19.1 g of 3-nitro-N-(2-phenoxyethyl)quinolin-4-amine as a yellow solid.