Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:16]=2)=[O:14])[CH:10]=[CH:9][C:8]=1[OH:26])[CH3:2].[Br:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:16]=2)=[O:14])[CH:10]=[CH:9][C:8]=1[O:26][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][Br:28])[CH3:2]
Reactant: BrCCCCCCBr
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1OCCCCCCBr
Yield: 76 %

Procedure:
A mixture of 0.393 g (1.06 mmol) of 5-[[3-(ethoxycarbonyl)phenyl]carbonyl]-2-hydroxybenzenepropanoic acid ethyl ester, 2.06 g (8.44 mmol) of 1,6-dibromohexane, 0.882 g (6.39 mmol) of anhydrous granular potassium carbonate and 15 mL of 2-butanone was stirred and refluxed for 18.5 hrs. The resulting slurry was filtered with suction and the solids were washed thoroughly with ethyl acetate. The filtrate and washes were combined and concentrated in vacuo and the residue was purified by flash chromatography on 75 g of silica gel, eluting with 5:1 hexane-ethyl acetate, giving 0.43 g (75.8%) of the title compound as a colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]3[C:27]4=[N:28][CH:29]=[CH:30][C:31]([CH3:32])=[C:26]4[N:25]=[C:24]3[CH2:33][CH3:34])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OCC)(=O)C.Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:33]([C:24]1[N:23]([CH2:22][C:19]2[CH:20]=[CH:21][C:16]([NH:15][CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:17][CH:18]=2)[C:27]2=[N:28][CH:29]=[CH:30][C:31]([CH3:32])=[C:26]2[N:25]=1)[CH3:34]
Reactant: CCc1nc2c(C)ccnc2n1Cc1ccc(NCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCc1nc2c(C)ccnc2n1Cc1ccc(NCC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
A solution of Compound 164 (1.44 g, 3.04 mmol) in chloroform (15 mL) was added with a 4 mol/L hydrogen chloride-ethyl acetate solution (7.0 mL) followed by stirring at room temperature for 2 hours. The reaction mixture was added with a 2 mol/L aqueous sodium hydroxide solution to control the pH to 12, and extracted with chloroform three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain Compound 165 (1.03 g, 2.84 mmol, 93%).
Reaction SMILES: C(O[C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[NH:11][CH2:12][CH2:13][O:14][CH:15]([CH3:17])[CH3:16])=[O:5])C.C(OC([N:23]=[C:24]=[S:25])=O)C>>[CH:15]([O:14][CH2:13][CH2:12][N:11]1[C:10]2[CH:9]=[CH:8][NH:7][C:6]=2[C:4](=[O:5])[NH:23][C:24]1=[S:25])([CH3:16])[CH3:17]
Reactant: CCOC(=O)N=C=S
Reactant: CCOC(=O)c1[nH]ccc1NCCOC(C)C
Product: CC(C)OCCn1c(=S)[nH]c(=O)c2[nH]ccc21
Yield: 23.1 %

Procedure:
The title compound (0.17 g, 23%) was prepared in accordance with the general method B using 3-[(2-isopropoxyethyl)amino]-1H-pyrrole-2-carboxylic acid ethyl ester (0.7 g, 2.91 mmol) and ethoxycarbonyl isothiocyanate (0.40 mL, 3.50 mmol).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=2)=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[NH:5][CH:6]=1.O([Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])S(C(F)(F)F)(=O)=O>>[Br:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=2)=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]([Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH:6]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: CNc1nccc(-c2c(Br)c[nH]c2-c2ccc(F)cc2)n1
Product: CNc1nccc(-c2c(Br)cn([Si](C(C)C)(C(C)C)C(C)C)c2-c2ccc(F)cc2)n1
Yield: 67 %

Procedure:
In a similar manner to the procedures described in Example 7(ii) above, 4-bromo-2-(4-fluorophenyl)-3-(2-methylaminopyrimidin-4-yl)-1H-pyrrole [prepared as described in step 1(vii) above] was reacted with triisopropylsilyl triflate to afford the title compound (yield 67%) as a pale brown amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.C1CCN2C(=[N:15]CCC2)CC1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:15])=[O:7])=[CH:4][N:3]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(Cl)nc1
Temperature: 65 °C
Yield: 107 %

Procedure:
A solution of 4-fluoroaniline (1.00 ml, 10 mmol) and diisopropylethylamine (1.74 mL, 10 mmol) in anhydrous DMF (10 mL) was warmed to 60° C., then a solution of tert-butyl bromoacetate (1.47 mL, 10 mmol) in anhydrous DMF (10 ml) was added drop-wise over 1 hour. After addition, the reaction mixture was kept at 60° C. for 4 hours. The reaction mixture was then concentrated by rotary evaporation, then partitioned between EtOAc and water. The organic layer was washed with water, then evaporated to yield a dark brown liquid (1.96 g, 87%) TLC (EtOAc/hexanes, 1:4) Rf=0.31; ESI-MS m/z=225.9 [M+H]+. The disubstituted aniline derivative (0.41 g, 2.31 mmol) and was then coupled to 6-chloronicotinoyl chloride (0.52 g, 2.31 mmol) in anhydrous DMF (2 mL) using DBU (344 ml, 2.31 mmol). The reaction mixture was heated to 65° C. for 48 h. The reaction mixture was diluted with EtOAc, and the organic layer washed with H2O. The crude material was concentrated by rotary evaporation, and purified by flash chromatography (EtOAc/hex 1:2) to yield 387 mg (46%) of 6-chloronicotinamide intermediate XIV as a clear oil. TLC (EtOAc/hexanes, 1:2) Rf=0.28; ESI-MS m/z=364.9 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:12]1.[CH3:23][O:24][C:25](OC)(OC)OC.C(O)(=O)CC>>[CH3:23][O:24][C:25]1[N:15]([CH:13]2[CH2:14][N:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH2:12]2)[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:21]2[N:22]=1
Reactant: Nc1cccnc1NC1CN(c2ccc3ccccc3n2)C1
Reactant: COC(OC)(OC)OC
Solvent: CCC(=O)O
Product: COc1nc2cccnc2n1C1CN(c2ccc3ccccc3n2)C1
Temperature: 90 °C
Yield: 59 %

Procedure:
N2-(1-Quinolin-2-yl-azetidin-3-yl)-pyridine-2,3-diamine (150 mg, 0.51 mmol) was combined with tetramethylorthocarbonate (1 mL) and propionic acid (8 mg) and heated at 90° C. for 2 hours. After that, the reaction solution was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to give 2-(3-(2-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)azetidin-1-yl)quinoline (100 mg, 0.30 mmol, 59% yield). M+1: 332. 1H NMR (CDCl3, 400 MHz): δ(ppm) 8.06-8.05 (m, 1 H); 7.87-7.85 (m, 1 H); 7.72-7.68 (m, 2 H); 7.58-7.47 (m, 2 H); 7.20-7.17 (m, 1 H); 7.06-7.03 (m, 1 H); 6.62-6.60 (m, 1 H); 5.62-5.55 (m, 1 H); 4.84-4.80 (m, 2 H); 4.61-4.57 (m, 2 H); 4.10 (s, 3 H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O1CCCC1.[BH4-].[Na+]>CO>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([OH:3])[CH3:2])=[CH:9][CH:8]=2)=[CH:11][CH:12]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 96.4 %

Procedure:
120.9 g (0.4 mol) of 4'-acetyl-4-benzyloxybiphenyl, 400 ml of tetrahydrofuran and 100 ml of methanol were supplied into a four-necked flask equipped with a stirrer and a thermometer. Then 15.14 g (0.4 mol) of sodium borohydride was added at 15°-25° C. over a period of 2 hours. The mixture was kept at the same temperature for 5 hours, then poured into ice-water and extracted twice with 500 ml of chloroform. The organic layer was concentrated under reduced pressure to obtain 117.4 g of 4-benzyloxy-4'-(1-hydroxyethyl)biphenyl in a 96.5% yield.
Reaction SMILES: Cl.[N:2]1([S:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH:37]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=3)[N:36]([C:45](Cl)=[O:46])[C:35]([C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][C:49]=3[O:58][CH2:59][CH3:60])=[N:34]2)=[CH:29][CH:28]=1>C(Cl)Cl>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH:37]([C:38]3[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=3)[N:36]([C:45]([N:5]3[CH2:4][CH2:3][N:2]([S:8]([N:11]4[CH2:12][CH2:13][O:14][CH2:15][CH2:16]4)(=[O:10])=[O:9])[CH2:7][CH2:6]3)=[O:46])[C:35]([C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:55])([F:56])[F:57])=[CH:50][C:49]=3[O:58][CH2:59][CH3:60])=[N:34]2)=[CH:29][CH:28]=1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=S(=O)(N1CCNCC1)N1CCOCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(S(=O)(=O)N2CCOCC2)CC1
Reaction time: 8 h
Yield: 64 %

Procedure:
4-(Piperazine-1-sulfonyl)-morpholine hydrochloride (0.042 mmol) was suspended in methylene chloride, and 400 uL of diisopropylethylamine was added. The mixture was added to 4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (10 mg, 0.019 mmol, example 3), and the reaction mixture was allowed to stand overnight. It was diluted with methylene chloride and washed with water. The organic layer was evaporated, and the residue purified by flash chromatography using ethyl acetate and hexanes to give [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(morpholine-4-sulfonyl)-piperazin-1-yl]-methanone (9.0 mg). LR-MS: 740.2 [(M+H)+].
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][C@H:9]1[C:15]([OH:17])=[O:16])=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:13][C:11]1([F:14])[CH2:12][NH:8][C@H:9]([C:15]([OH:17])=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)[C@@H]1CC(F)(F)CN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid (500 mg, 2.0 mmol) was dissolved in dichloromethane and treated dropwise with TFA (227 mg, 153 μL, 2 mmol). The reaction was stirred for 3 h at room temperature, the solvents evaporated to obtain (S)-4,4-difluoropyrrolidine-2-carboxylic acid, which was used in the next step without further purification. LC/MS: m/z 152.2 (M+H)+ at 0.53 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[N:8][OH:9])[CH2:4][CH2:3]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[C:27]([OH:32])(=[O:31])[CH:28]([CH3:30])[CH3:29]>>[C:27]([O:32][C:5]1([N:8]=[O:9])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)(=[O:31])[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)C(=O)O
Reactant: CN1CCC(=NO)CC1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: CC(C)C(=O)OC1(N=O)CCN(C)CC1

Procedure:
1-Methyl-4-nitrosopiperidin-4-yl isobutyrate was prepared from 1-methyl-piperidin-4-one oxime, lead tetraacetate and isobutyric acid using conditions of General Method 3. 1H NMR (400MHz, chloroform-d) δ 2.82-2.94 (2H, m), 2.65 (1H, sept, 7.0 Hz), 2.36 (3H, s), 2.23-2.35 (4H, m), 1.83-1.92 (2H, m), 1.28 (3H, s), 1.27 (3H, s).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:25]([CH3:26])[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:27])[CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[CH3:26][CH:25]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:27])[CH:23]=2)[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]1[S:9]([C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(C)cc3C2C)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(C)N(S(=O)(=O)c1ccc(O)cc1)c1ccccc1-2
Yield: 53.8 %

Procedure:
The title compound was prepared from 5-[(4-methoxyphenyl)sulfonyl]-6,8-dimethyl-5,6-dihydrophenanthridine (0.6 g, 1.58 mmol), cyclohexene (0.4 mL, 3.95 mmol), and 1.0 M boron tribromide in dichloromethane (9.5 mL, 9.49 mmol) according to the procedure and in the same manner as described in Example 1, step b. The crude product was purified by flash column chromatography on silica gel, eluting with dichloromethane to yield 4-[(6,8-dimethylphenanthridin-5(6H)-yl)sulfonyl]phenol (0.31 g, 0.85 mmol, 54%) as a white solid, m.p. 111-113° C.;
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.[C-:23]#[N:24].[Na+]>CN(C=O)C>[CH:17]1([NH:16][C:4]2[N:3]=[C:2]([C:23]#[N:24])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: [C-]#N
Reactant: Clc1nc(NC2CCCCC2)c2ncn(C3CCCC3)c2n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1nc(NC2CCCCC2)c2ncn(C3CCCC3)c2n1
Temperature: 25 °C

Procedure:
2-Chloro-6-cyclohexylamino-9-cyclopentyl-purine (6.3 mmol) and sodium cyanide (36 mmol) are heated up in DMF (30 ml) to 160° C. for 70 hours. After cooling down to RT the mixture is poured on water and extracted 3 times with ethyl acetate. The combined organic phases are washed with brine and the extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with ethyl acetate as mobile phase. The product containing fractions are combined and evaporated. A pale yellow oil with Rf=0.33 (ethyl acetate) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[C:6]([CH:11]=1)[O:7][CH2:8][C:9]#[N:10].[Cl-].[NH4+].[N-:34]=[N+:35]=[N-:36].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[C:6]([O:7][CH2:8][C:9]2[N:34]=[N:35][NH:36][N:10]=2)[CH:11]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1OCC#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1OCc1nn[nH]n1
Temperature: 100 °C
Reaction time: 12 h
Yield: 14.7 %

Procedure:
To a solution of (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-acetonitrile (0.11 g, 0.25 mmol) in dimethylformamide (0.50 mL) was added ammonium chloride (0.058 g, 1.1 mmol) and sodium azide (0.055 g, 0.85 mmol). The resulting mixture was stirred at 100° C. for 12 hours. The reaction was cooled and diluted with ethyl acetate and washed with water. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. Trituration with diethyl ether and methylene chloride gave the title compound (0.018 g, LRMS 489.4, 491.5).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 120 °C
Yield: 95 %

Procedure:
To a solution of 4-(trifluoromethyl)phenol (3 g, 18.51 mmol) and 4-fluorobenzaldehyde (2.3 g, 18.53 mmol) in DMF (20 mL), was added Cs2CO3 (7.24 g, 22.21 mmol). The mixture was heated with a microwave condition at 120° C. for 4 h. After cooling, the reaction mixture was diluted in water, extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4 and evaporated in vacuo to afford the title compound (4.68 g, 95% yield) as a brown oil. LCMS: rt=3.58 min, [M+H+]=267
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].ClC1C=CC(NC(=O)C2C=C(F)C=CC=2)=NC=1.C(O[CH:30]([N:65]=C=O)[CH2:31][O:32][C:33]1[CH:58]=[C:57]([N:59]2[CH2:64][CH2:63][O:62][CH2:61][CH2:60]2)[CH:56]=[CH:55][C:34]=1[C:35]([NH:37][C:38]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:39]=1[C:40]([NH:42][C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][N:44]=1)=[O:41])=[O:36])(C)(C)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:65][CH2:30][CH2:31][O:32][C:33]1[CH:58]=[C:57]([N:59]2[CH2:64][CH2:63][O:62][CH2:61][CH2:60]2)[CH:56]=[CH:55][C:34]=1[C:35]([NH:37][C:38]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:39]=1[C:40]([NH:42][C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][N:44]=1)=[O:41])=[O:36]
Reactant: CC(C)(C)OC(COc1cc(N2CCOCC2)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1)N=C=O
Agent: O=C(Nc1ccc(Cl)cn1)c1cccc(F)c1
Solvent: O=C(O)C(F)(F)F
Product: NCCOc1cc(N2CCOCC2)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Yield: 74 %

Procedure:
Using methods substantially equivalent to those described in Example 34, 2-2-(2-aminoethoxy)-4-(morpholin-4-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide trifluoroacetate was prepared in a 74% yield from 2-[2-(2-tert-butoxy-carbonylaminoethoxy)-4-(morpholin-4-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C@H:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1.[O:16]=[S:17]1(=[O:40])[CH2:22][CH2:21][CH:20]([O:23][C:24]2[CH:29]=[C:28]([CH3:30])[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37]O)[CH:32]=3)=[C:26]([CH3:39])[CH:25]=2)[CH2:19][CH2:18]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[O:16]=[S:17]1(=[O:40])[CH2:22][CH2:21][CH:20]([O:23][C:24]2[CH:29]=[C:28]([CH3:30])[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][O:1][C:2]4[CH:15]=[CH:14][C:5]5[C@H:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=5[CH:3]=4)[CH:32]=3)=[C:26]([CH3:39])[CH:25]=2)[CH2:19][CH2:18]1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: Cc1cc(OC2CCS(=O)(=O)CC2)cc(C)c1-c1cccc(CO)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCS(=O)(=O)CC5)cc4C)c3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
A solution of methyl [(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate (0.208 g, 1.00 mmol), {4′-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-2′,6′-dimethylbiphenyl-3-yl}methanol (0.360 g, 1.00 mmol) and tributylphosphine (0.324 g, 1.60 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.404 g, 1.60 mmol) was added, and the mixture was stirred at room temperature for 3 hr under nitrogen atmosphere. Hexane (8 mL) was added to the reaction mixture, the precipitated insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-70:30) to give the title compound (0.432 g, yield 79%) as a colorless oil.
Reaction SMILES: [ClH:1].[O:2]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:38])[C@@H:17]2[CH2:21][C@@H:20]([CH2:22][NH:23]C(OC(C)(C)C)=O)[CH2:19][N:18]2C(OC(C)(C)C)=O)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCOCC1>[ClH:1].[ClH:1].[O:2]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:38])[C@@H:17]2[CH2:21][C@@H:20]([CH2:22][NH2:23])[CH2:19][NH:18]2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: NC[C@H]1CN[C@H](C(=O)Nc2ccc(Oc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 4 N hydrochloric acid in 1,4-dioxane (6 mL) was added to a solution of trans-4-(N-tert-butoxycarbonylaminomethyl)-N-tert-butoxycarbonyl-L-proline 4-phenoxyphenylamide (A, 182 mg) in 1,4-dioxane (6 mL) at room temperature. After stirring at room temperature for 20 min, the reaction mixture was concentrated in vacuo. The residue was washed with ether to give the title compound (95 mg) as a colorless solid: 1H NMR (400 MHz, D2O) δ 2.36 (m, 1 H), 2.60 (m, 1H), 2.82 (m, 1 H), 3.23 (m, 3 H), 3.85 (dd, J=7.5, 11.5 Hz, 1 H), 4.73 (dd, J=3.9, 9.3 Hz, 1 H), 7.08 (d, J=6.84 Hz, 2 H), 7.10 (d, J=6.84 Hz, 2 H), 7.22 (t, J=7.0 Hz, 1H), and 7.45 (m, 4 H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[CH:12][CH:11]=3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:24][N:25]([CH3:30])[S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1>[CH3:24][N:25]([CH3:30])[S:26](=[O:28])(=[O:27])[NH:23][C:20]1[CH:21]=[CH:22][C:17]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[N:16]3)=[CH:18][CH:19]=1
Reactant: Nc1ccc(-c2ccc3ncc(N4CCOCC4)nc3c2)cc1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)Nc1ccc(-c2ccc3ncc(N4CCOCC4)nc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
A mixture of 4-(3-morpholin-4-yl-quinoxalin-6-yl)-phenylamine [intermediate example 4.1] (100 mg) and pyridine (0.5 mL) was treated with a solution of dimethylsulfamyl chloride (75 mg, 0.65 mmol) in pyridine (0.6 mL) and stirred at room temperature overnight. The reaction was partitioned between dichloromethane and water, the phases separated and the organic layer concentrated in vacuo. The residue was purified by preparative reverse phase HPLC to give the title compound (71 mg). 1H-NMR (300 MHz, d6-DMSO) δ=10.06 (1H, br s), 8.76 (1H, s), 7.84 (1H, d), 7.66-7.79 (4H, m)), 7.27 (2H, d), 3.72 (8H, s), 2.70 (6H, s).
Reaction SMILES: [C:1]1([C:7](=O)[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH:17][NH3+:18].C(OCC)(=O)C.O>N1C=CC=CC=1>[OH:17][N:18]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9]
Reactant: COCCOC(=O)C(=O)c1ccccc1
Reactant: [NH3+]O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COCCOC(=O)C(=NO)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.9 %

Procedure:
61.7 g (0.296 mol) of 2-methoxyethyl phenylglyoxalate are dissolved in 360 ml pyridine. 22.7 g (0.0.326 mol) of hydroxylammonium hydrochloride are added in portions to this solution. When the addition is complete, the reaction mixture is stirred at room temperature for 2 hours. After addition of ethyl acetate and water, the organic layer is separated, washed with diluted HCl and water and dried over magnesium sulfate. Evaporation of the solvent gives 68 g (100%) of crude 2-methoxyethyl α-(hydroxyimino)-2-phenylacetate as a slightly brownish liquid. This compound is used without further purification in the next step.