Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][N:14]1[CH:18]=[CH:17][C:16]([C:19](O)=[O:20])=[N:15]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:19]([C:16]3[CH:17]=[CH:18][N:14]([CH3:13])[N:15]=3)=[O:20])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: Cn1ccc(C(=O)O)n1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cn1ccc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.1 %

Procedure:
TEA (1.21 mL, 8.69 mmol) was added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (400 mg, 1.74 mmol, Example 1, Step H), 1-methyl-1H-pyrazole-3-carboxylic acid (260 mg, 2.09 mmol) and BOP-Cl (60 mg, 2.61 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 1 hour, and then a LiOH solution (3 mL, 2N) was added. The mixture was stirred for 30 minutes, and water (10 mL) was added. The solid formed was collected by filtration, washed with DCM (5 mL) and dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-1H-pyrazole-3-carboxamide (30 mg, 66% yield) as a solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[C:10]([O:15][CH:16]2[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]2)=[N:11][CH:12]=[CH:13][CH:14]=1.FC1C=CC=C(OC)C=1C1C=CN=CC=1N(CC(F)(F)F)[C:43](=[O:58])[C:44]1[CH:49]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:47]=[C:46]([S:54]([CH3:57])(=[O:56])=[O:55])[CH:45]=1.CCN(C(C)C)C(C)C.CS(C1C=C(C=C(C(F)(F)F)C=1)C(Cl)=O)(=O)=O.[NH4+].[Cl-]>C(Cl)Cl>[C:23]([O:22][C:20]([N:18]1[CH2:19][CH:16]([O:15][C:10]2[C:9]([C:8]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[N:2]([C:43](=[O:58])[C:44]3[CH:49]=[C:48]([C:50]([F:53])([F:51])[F:52])[CH:47]=[C:46]([S:54]([CH3:57])(=[O:56])=[O:55])[CH:45]=3)[CH3:1])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:17]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: COc1cccc(F)c1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Reactant: CNc1cnccc1-c1cccnc1OC1CN(C(=O)OC(C)(C)C)C1
Agent: CS(=O)(=O)c1cc(C(=O)Cl)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1cccnc1OC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl 3-(3′-(methylamino)-3,4′-bipyridin-2-yloxy)azetidine-1-carboxylate (0.149 g, 418 μmol) in CH2Cl2 (4 mL) were added 3-(methylsulfonyl)-5-(trifluoromethyl)benzoyl chloride (240 mg, 836 μmol, example 223, intermediate d) and DIPEA (216 mg, 292 μL, 1.67 mmol) and the light yellow solution was stirred at room temperature for 24 hours. Another batch of 3-(methylsulfonyl)-5-(trifluoromethyl)benzoyl chloride (164 mg, 573 μmol) and DIPEA (162 mg, 219 μL, 1.25 mmol) was added and stirring was continued at room temperature for 24 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and CH2Cl2 and the layers were separated. The aqueous layer was extracted three times with CH2Cl2. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was twice purified by silica gel chromatography on a 20 g column using an MPLC system eluting with EtOAc. Light yellow gum (0.105 g; 41%). MS (ESI): m/z=607.18 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:11]1([Mg]Br)[CH2:13][CH2:12]1.C1(C(C2C=CC(Cl)=CC=2)O)CC1>O1CCCC1>[CH:11]1([CH:4]([C:3]2[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=2[F:1])[OH:5])[CH2:13][CH2:12]1
Reactant: Br[Mg]C1CC1
Reactant: O=Cc1ccc(F)cc1F
Agent: OC(c1ccc(Cl)cc1)C1CC1
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1F)C1CC1

Procedure:
The title compound was prepared starting from 1.50 g (10.55 mmol) of 2,4-difluorobenzaldehyde and 31.7 ml (15.83 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran in analogy to the synthesis of the compound from Example 153A. 0.33 g (17% of theory) of the title compound was obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH2:12][CH2:13][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:15][CH:16]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(N(C(C)C)C(C)C)C>O1CCCC1>[CH3:20][S:17]([N:14]1[CH2:15][CH:16]=[C:11]([C:9]2[NH:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:3]=3[CH:10]=2)[CH2:12][CH2:13]1)(=[O:19])=[O:18]
Reactant: C1COCCN1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CC=C(c2cc3c(N4CCOCC4)ncnc3[nH]2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of Example 41A (100 mg, 0.320 mmol) and morpholine (2.52 mL, 3 mmol) in 3 mL tetrahydrofuran/1 mL N,N-dimethylformamide was added N-ethyl-N-isopropylpropan-2-amine (0.084 mL, 0.480 mmol). The resulting reaction was stirred at 60° C. overnight. The solvent was removed in vacuo and the residue dried under high-vacuum for 2 hours. The crude solid was triturated with ethyl acetate, collected by filtration, and dried under high-vacuum to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ 11.93 (s, 1H) 8.17 (s, 1H) 6.68 (s, 1H) 6.41 (s, 1H) 3.66-3.93 (m, 8H) 3.37 (t, J=5.65 Hz, 2H) 3.02-3.12 (m, 2H) 2.89-2.98 (m, 3H) 2.62 (s, 2H). MS (ESI+) m/z 364.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](O)[CH:6]=[C:5]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1.O=P(Cl)(Cl)[Cl:24]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:24])[CH:6]=[C:5]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1
Reactant: Oc1cc(Nc2ccc(Cl)c(Cl)c2)c2cc(F)ccc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc2nc(Cl)cc(Nc3ccc(Cl)c(Cl)c3)c2c1
Yield: 29 %

Procedure:
Prepared using general procedure 3; 6-Fluoro-2-hydroxy-4-(3,4-dichlorophenyl)aminoquinoline (2.136 g, 6.6 mmol) and 30 mL of POCl3 were heated to 120° C. for 4 h. Isolation afforded 0.654 g of material (1.914 mmol, 29%). 1H NMR (300 MHz, DMSO): 9.55(s, 1H), 8.27(dd, 1H, J=10.50, 2.02 Hz), 7.92(dd, 1H, J=8.88, 5.65 Hz), 7.70(m, 3H), 7.45(dd, 1H, J=8.48, 2.02 Hz), 6.90(s, 1H).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[Br:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[O:27][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[O:11])=[CH:6][CH:5]=1
Reactant: O=C(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(C(=O)c1ccc(Oc2cccc(Br)c2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68.4 %

Procedure:
To a 250 ml flask fitted with reflux condenser, thermometer, and nitrogen inlet were added 4-nitrobenzil (10.83 g, 42.49 mmol), 3-bromophenol (7.35 g, 42.49 mmol) and dimethylsulfoxide (150 ml). After stirring at room temperature for 20 minutes under a nitrogen atmosphere, potassium carbonate (11.73 g, 84.98 mmol) was added to the flask and the flask was heated to an internal temperature of 95° C. for 19 h under nitrogen. When cooled to room temperature the solution was very slowly poured into 12N HCL (500 ml) and extracted with methylene chloride (2×100 ml). The organic layer was washed with water (3×500 ml), dried over anhydrous magnesium sulfate, and evaporated to dryness by rotary evaporation. The light orange oil was then dissolved in 4:1 hexane:methylene chloride and chromatographed on a silica gel column (Woelm DCC, 211.94 g, 5 cm dia×24 cm H). The purified product was recrystallized twice from methylene chloride:methanol (25 ml:150 ml) to afford light yellow crystals (11.08 g, 69%): mp 75°-76° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]([C:28]1[S:29][CH:30]=[CH:31][N:32]=1)[S:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26])=[N:15][CH:14]=[C:13]2[F:27])(=[O:9])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:46][C:47]#[N:48]>CN(C=O)C.C(OCC)(=O)C>[C:47]([CH2:46][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:16]1[C:17]2[C:12](=[CH:11][C:10]([S:7]([N:6]([CH2:5][C:4]3[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:3]=3[O:2][CH3:1])[C:28]3[S:29][CH:30]=[CH:31][N:32]=3)(=[O:8])=[O:9])=[CH:19][CH:18]=2)[C:13]([F:27])=[CH:14][N:15]=1)#[N:48]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4O)ncc(F)c3c2)c(OC)c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4OCC#N)ncc(F)c3c2)c(OC)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
N-(2,4-dimethoxybenzyl)-4-fluoro-1-(2-hydroxyphenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.078 g, 0.141 mmol) was dissolved in DMF (0.7 mL) and cesium carbonate (0.148 g, 0.456 mmol) was added, followed by bromoacetonitrile (10.58 μl, 0.152 mmol). The reaction was heated to 60° C. and stirred overnight. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 12 g, gradient elution 0-100% EtOAc:Heptane) to afford 1-(2-(cyanomethoxy)phenyl)-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide. (ESI) 591.2 (M+H)+.
Reaction SMILES: [Si](O[C@H:9]([C@H:32]1[CH2:36][C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H:10]([NH:20][C:21](=O)C1C=CC=C(C(=O)N)C=1)CC1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C.C(OC([N:55]1[CH2:59][C@H:58]([O:60][CH2:61][CH2:62][CH3:63])[CH2:57][C@@H:56]1[C@@H:64]([O:87][Si](C(C)(C)C)(C)C)[C@@H:65]([NH:75][C:76]([C:78]1[CH:79]=[C:80]([CH:84]=[CH:85][CH:86]=1)[C:81]([OH:83])=O)=[O:77])[CH2:66][C:67]1[CH:72]=[C:71]([F:73])[CH:70]=[C:69]([F:74])[CH:68]=1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CNCCCC>ClCCl>[CH2:10]([N:20]([CH3:21])[C:81](=[O:83])[C:80]1[CH:84]=[CH:85][CH:86]=[C:78]([C:76]([NH:75][C@@H:65]([CH2:66][C:67]2[CH:68]=[C:69]([F:74])[CH:70]=[C:71]([F:73])[CH:72]=2)[C@H:64]([OH:87])[C@H:56]2[CH2:57][C@@H:58]([O:60][CH2:61][CH2:62][CH3:63])[CH2:59][NH:55]2)=[O:77])[CH:79]=1)[CH2:9][CH2:32][CH3:36]
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(N)=O)c2)N(C(=O)OC(C)(C)C)C1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(=O)O)c2)N(C(=O)OC(C)(C)C)C1
Agent: CCCCNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCCCN(C)C(=O)c1cccc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@@H](OCCC)CN2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Step 3 (A): Preparation of (2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-2-(3-(carbamoyl)benzamido)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of 3-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)benzoic acid (Step 1 (C), 66 mg, 0.10 mmol) in dichloromethane (2 mL) were added HATU (46 mg, 0.12 mmol) and N-methylbutan-1-amine (12 mg, 0.13 mmol) and the reaction mixture was stirred at rt overnight. The crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 40% to 60% to 80% EtOAc/Hexane step gradient) to give 60 mg of the title compound (80% yield): 1H NMR (CDCl3, 500 MHz) δ 0.02 (3H, s), 0.05 (3H, s), 0.75 (2H, m), 0.83 (9H, s), 0.88 (3H, m), 0.93-0.96 (2H, m), 1.12 (1H, m), 1.35-1.41 (1H, m), 1.48-1.53 (11H, m), 1.61 (1H, m), 2.01-2.06 (1H, m), 2.19 (1H, d, J=10 Hz), 2.66 (1H, m), 2.89-2.93 (3H, m), 3.04 (1H, s), 3.21 (1H, brd s), 3.27-3.36 (3H, m), 3.51 (1H, brd s), 3.75 (1H, dd, J=5, 15 Hz), 3.97 (1H, m), 4.05-4.11 (2H, m), 4.60 (1H, m), 6.59 (1H, m), 6.76 (2H, d, J=5 Hz), 7.41-7.48 (2H, m), 7.87 (2H, s), 8.13 (1H, brd s). MS (ESI) (M+H)+ 746.36.
Reaction SMILES: N[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:12]1[F:19].[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:22]>O>[F:19][C@@H:12]1[C@H:13]([OH:14])[C@@H:15]([CH2:17][OH:18])[O:16][C@H:11]1[N:6]1[CH:5]=[N:4][C:3]2[C:2](=[O:22])[NH:10][CH:9]=[N:8][C:7]1=2
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: O
Product: O=c1[nH]cnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Reaction time: 24 h

Procedure:
6-Amino-9-(2-deoxy-2-fluoro-β-D-ribofuranosyl)-9H-purine (0.29 g, 1.0 mmole), prepared as in Example 8, was dissolved in 100 ml of water. Calf intestinal adenosine deaminase (4 I.U., Boehringer Mannheim) was added and the solution incubated at 37° C. for 24 hrs. The solvent was removed under vacuum. The residue was dissolved in water/n-propanol (7/3) and chromatographed on a 5×90 cm column of Sephadex G-10 (Pharmacia LKB) with water/n-propanol (7/3) as the solvent. Product-containing fractions were combined and the solvent removed under vacuum. The residue was dissolved in water and lyophilized to obtain title compound that analyzed as a hydrate.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]([C:14]([F:17])([F:16])[F:15])=[N:5]2)[CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1>CCCCCC>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]([OH:24])[C:7]2[C:6]([C:14]([F:17])([F:16])[F:15])=[N:5][N:4]([CH:1]3[CH2:3][CH2:2]3)[C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cc(C(F)(F)F)nn1C1CC1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CCCCCC
Product: CCOC(=O)c1c(C(O)c2ccc(Cl)cc2)c(C(F)(F)F)nn1C1CC1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 40.2 using ethyl 1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (Step 44.1) and 4-chlorobenzaldehyde. tR: 1.29 min (LC-MS 2); ESI-MS: 389 [M+H]+ (LC-MS 2); Rf=0.12 (hexane/15% EtOAc).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([O:10]CC)=O)[C:3]1=[O:13].[CH3:14][C@H:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([CH3:21])[N:16]1[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26]>>[CH3:14][C@H:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([CH3:21])[N:16]1[CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:8](=[O:10])[CH2:7][N:4]1[CH2:5][CH2:6][CH:2]([OH:1])[C:3]1=[O:13]
Reactant: C[C@@H]1CCC[C@H](C)N1CCCCN
Reactant: CCOC(=O)CN1CCC(O)C1=O
Product: C[C@@H]1CCC[C@H](C)N1CCCCNC(=O)CN1CCC(O)C1=O

Procedure:
3.0 g of ethyl (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetate and 5.9 g of cis-4-(2,6-dimethyl-1-piperidinyl)butylamine are heated to 95°-100° for 3.5 hours under nitrogen. The mixture is chromatographed on 70 g of aluminum oxide (activity grade III, neutral). The (R/S)-cis-N-[4-(2,6-dimethyl-1-piperidinyl)butyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide which is eluted with ethanol has a melting point of 90°-92° after crystallization from diethyl ether.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][NH:8][C:9]([C:11]1[C:12]2[N:13]=[C:14]([O:27]C)[C:15]([O:25]C)=[N:16][C:17]=2[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[C:20]=1[CH3:21])=[O:10])(C)(C)C.[I-].[Na+].Cl[Si](C)(C)C>C(#N)C>[CH3:21][C:20]1[C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]2[NH:16][C:15](=[O:25])[C:14](=[O:27])[NH:13][C:12]=2[C:11]=1[C:9]([NH:8][CH2:7][C:6]([OH:29])=[O:5])=[O:10]
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)NCC(=O)OC(C)(C)C)c2nc1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1c([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c2c1C(=O)NCC(=O)O
Reaction time: 0.5 h

Procedure:
To a stirred mixture of [(2,3-Dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl)-amino] acetic acid tert-butyl ester (14a) 150 mg (0.37 mmol) and sodium iodide 555 mg (3.7 mmol) in 25 mL acetonitrile is added dropwise chlorotrimethylsilane 0.46 mL (3.7 mmol). After addition was complete, the reaction mixture was refluxed under an atmosphere of nitrogen for 72 hours. The reaction mixture was quenched by pouring into 100 mL water, and the aqueous mixture was concentrated to 10 mL. The residue was mixed with ethyl acetate, and after stirring for 30 minutes, the product precipitated, 35 mg (29%), mp 250° C. (dec.); 1H NMR (DMSO-d6): δ 12.55 (br s, 1H), 8.40 (t, 1H, J=6.3 Hz), 7.84 (s, 1H), 4.07 (d, 2H, J=6.3 Hz), 2.43 (s, 3H); MS (APCI): m/z 323 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([OH:14])=O)[CH:11]=1)[N:8]=[CH:7][N:6]([C:15]1[CH:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17][C:16]=1[CH3:25])[C:5]2=[O:26].[N:27]1C=CC=CC=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>O1CCOCC1>[NH2:27][C:12]([C:10]1[CH:11]=[C:2]([I:1])[CH:3]=[C:4]2[C:9]=1[N:8]=[CH:7][N:6]([C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][C:16]=1[CH3:25])[C:21]([O:23][CH3:24])=[O:22])[C:5]2=[O:26])=[O:14]
Reactant: c1ccncc1
Reactant: COC(=O)c1ccc(C)c(-n2cnc3c(C(=O)O)cc(I)cc3c2=O)c1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C)c(-n2cnc3c(C(N)=O)cc(I)cc3c2=O)c1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 6-iodo-3-[5-(methoxycarbonyl)-2-methylphenyl]-4-oxo-3,4-dihydroquinazoline-8-carboxylic acid (2.4 g) in 1,4-dioxane (50 ml) was added pyridine (0.42 ml), di-tert-butyl dicarbonate (1.47 g) and NH4HCO3 (0.53 g). The reaction mixture was stirred at 40° C. for 18 hours and concentrated. The resultant white solid was washed with methanol and dried to yield methyl 3-[8-(aminocarbonyl)-6-iodo-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoate as a white solid (2.28 g); NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 3.85 (s, 3H), 7.61 (d, 1H), 8.03 (m, 3H), 8.52 (s, 1H), 8.60 (m, 1H), 8.70 (m, 1H), 9.33 (s, 1H); Mass Spectrum: M+H+ 464.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][CH2:12][OH:13])=[CH:6][CH:5]=1.[CH3:22]I>C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:11][CH2:12][O:13][CH3:22])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NC(CCO)c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCC(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 38.1 %

Procedure:
Sodium hydride (35.0 mg, 0.87 mmol) was added to tert-butyl 1-(4-chlorophenyl)-3-hydroxypropylcarbamate (Intermediate 30) (200 mg, 0.70 mmol) in THF (10 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 15 minutes. Methyl iodide (0.044 mL, 0.70 mmol) was added dropwise, and the resulting suspension was stirred at 22° C. for 4 hours. The reaction was quenched with KHSO4 solution (1M, 0.5 mL) and water (15 mL). The mixture was extracted with diethyl ether (3×20 mL); the combined extracts were washed with saturated brine (20 mL), dried over MgSO4, filtered and evaporated to give crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 60% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 1-(4-chlorophenyl)-3-methoxypropylcarbamate (80 mg, 38.1%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[F:9][C:10]([F:14])([F:13])[CH2:11]I.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:9][C:10]([F:14])([F:13])[CH2:11][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: FC(F)(F)CI
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccccc1Br
Temperature: 25 °C

Procedure:
A solution of 0.35 g (2 mmol) of 2-bromophenol, 0.63 g (3 mmol) of 2,2,2-trifluoroethyliodide, 0.55 g (4 mmol) of potassium carbonate in 2 Ml of DMF was reacted at 150° C. in a microwave system (Personal Chemistry, Smithcreator) for 30 min. After cooling to RT, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic fraction was dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (5%, 10% successively EtOAc:hexanes) to give the title compound.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:19][C:20]([C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])=[CH:21][N:22]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Xe](F)[F:29]>C(#N)C.C(OCC)(=O)C>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:19][C:20]([C:23](=[O:27])[CH:24]([CH3:25])[CH3:26])=[C:21]([F:29])[N:22]=2)[C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C(=O)c1cnc(C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)[nH]1
Reactant: F[Xe]F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)C(=O)c1[nH]c(C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)nc1F
Yield: 13.2 %

Procedure:
To a solution (13 mL) of 1-(2-{2-cyclopentyl-1-[4-(methylsulfonyl)phenyl]ethyl}-1H-imidazol-5-yl)-2-methylpropan-1-one (0.507 g) in acetonitrile was added xenon difluoride (0.440 g), and the mixture was heated under reflux for 4 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-40:60, volume ratio) and recrystallized from diethyl ether-hexane to give the title compound (0.07 g, yield 13%) as colorless crystals. melting point 161-162° C.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:32][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([C:34]([F:45])([F:44])[F:33])[CH:40]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(C(F)(F)F)c1)N1CCC(N2CCCC2)CC1
Yield: 53 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 169), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a brown oil (53%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C:9]=2[S:8][C:7]=1[NH2:22])=O)C.C(O)(=O)C.[CH:27](N)=[NH:28]>CN(C=O)C>[C:18]([O:17][C:15]([N:11]1[CH2:10][C:9]2[S:8][C:7]3[N:22]=[CH:27][NH:28][C:4](=[O:3])[C:6]=3[C:14]=2[CH2:13][CH2:12]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOC(=O)c1c(N)sc2c1CCN(C(=O)OC(C)(C)C)C2
Reactant: N=CN
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(sc3nc[nH]c(=O)c23)C1
Temperature: 100 °C
Yield: 90.7 %

Procedure:
A mixture of 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-dicarboxylic acid 6-tert-butyl ester 3-ethyl ester (18.5 g) and formamidine acetate (8.85 g) in DMF (100 mL) were heated at 100° C. for 16 h. The reaction mixture was cooled and concentrated. The residues was partitioned between water and ethyl acetate. The organic layer was washed with water 3 times and concentrated to give the title compound (15.8 g, 90%). 1H NMR (400 MHz, CDCl3): δ 7.88 (s, 1H), 4.56-4.62 (brs, 2H), 3.62-3.70 (brs, 2H), 3.02-3.08 (brs, 2H), 1.42 (s, 9H). LC-MS (ESI) m/z 308.1 (M+H).