Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[S:10]([OH:13])(=[O:12])=[O:11].Cl>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([S:10]([OH:13])(=[O:12])=[O:11])[CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=S(=O)(O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(O)c1cc(F)ccc1O
Reaction time: 0.5 h

Procedure:
200 g (1.78 mol) of 4-fluorophenol are dissolved under a nitrogen atmosphere in 1300 ml of CHCl3 (distilled, dried over CaCl2). Added dropwise to this solution, over a period of 1 hour at room temperature with stirring, are 131 ml(229 g=1.96 mol) of chlorosulfonic acid, a vigorous release of HCl being observed initially, which dies down 30 min after completion and ceases entirely after a further 3 hours. After a reaction time of 24 hours, the precipitated product is filtered off with suction at room temperature under inert gas, washed twice with 200 ml of CHCl3 each time, and dried in vacuo at 1333 Pa and room temperature for 3 hours.
Reaction SMILES: [N+:1]([C:4](=[C:10]1[NH:15][CH2:14][CH2:13][CH2:12][S:11]1)C(OCC)=O)([O-:3])=[O:2].[OH-].[Na+]>C(O)(=O)C>[N+:1]([CH:4]=[C:10]1[NH:15][CH2:14][CH2:13][CH2:12][S:11]1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(=C1NCCCS1)[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=[N+]([O-])C=C1NCCCS1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2.3 g of 5A was added to 10 ml of 20% aqueous sodium hydroxide and the mixture was stirred at room temperature for 12 hours. The resulting solution was treated dropwise with 3.5 g of acetic acid. The addition was accompanied by vigorous gas evolution. The resulting mixture was extracted with methylene chloride and the extract was dried (magnesium sulfate) and concentrated under reduced pressure to give tetrahydro-2-(nitromethylene)-2H-1,3-thiazine (5B) as a pale yellow solid, m.p.: 76°-78°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:31][C:32]([O:34]C)=[O:33])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:27]=[CH:26][C:16]2[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][O:19][C:15]=2[C:14]=1[CH2:28][CH2:29][CH3:30].[OH-].[Li+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:31][C:32]([OH:34])=[O:33])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:27]=[CH:26][C:16]2[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][O:19][C:15]=2[C:14]=1[CH2:28][CH2:29][CH3:30]
Reactant: CCCc1c(OCCCSc2ccc(CC(=O)OC)cc2Cl)ccc2c(-c3ccccc3)coc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCSc2ccc(CC(=O)O)cc2Cl)ccc2c(-c3ccccc3)coc12

Procedure:
To a solution of methyl 3-chloro-4-(3-(3-phenyl-7-propylbenzofuran-6-yloxy)propylthio)-phenylacetate (3.72 g, 7.31 mmol) prepared in last step and aqueous lithium hydroxide(1.0M; 14.62 ml; 14.62 mmol) in methanol (25 ml) was refluxed for 1 hr. The mixture was partitioned between isopropyl acetate and pH4 buffer. The organic was dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by chromatography (silica gel, 50% methylene chloride in hexane) to afford the title compound. M.P: 143° C. ESI-MS: m/e-495(M+1)
Reaction SMILES: [CH:1]1([C@H:6]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:7][C:8]([O:10]C)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>C1COCC1.O>[CH:1]1([C@H:6]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:7][C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C[C@H](C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H](CC(=O)O)C4CCCC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
To a stirred solution of (3R)-methyl 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanoate ((R)-22, 2.47 g, 5.26 mmol) in THF (30 mL) at room temperature was added a solution of lithium hydroxide monohydrate (LiOH—H2O, 265 mg, 6.31 mmol, 1.2 equiv) in water (15 mL). The reaction mixture was stirred at room temperature for 3 h. When LCMS showed the reaction was complete, the reaction mixture was then acidified with 1 N aqueous HCl solution to pH 5 before it was extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine, dried over magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure to afford (3R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanoic acid ((R)-23, 2.40 g, 2.40 g theoretical, 100% yield) as a colorless oil, which solidified upon standing at room temperature in vacuo. For (R)-23: 1H NMR (CDCl3, 300 MHz) δ ppm 8.95 (s, 1H), 8.95 (bs, 1H), 8.36 (s, 1H), 7.57 (d, 1H, J=3.7 Hz), 6.99 (d, 1H, J=3.7 Hz), 5.74 (s, 2H), 4.65 (dt, 1H, J=3.1, 10.3 Hz), 3.58 (t, 2H, J=8.2 Hz), 3.24 (dd, 1H, J=16.5, 10.3 Hz), 3.04 (dd, 1H, J=16.2, 3.1 Hz), 2.59 (m, 1H), 2.00 (m, 1H), 1.77-1.24 (m, 7H), 0.97 (t, 2H, J=8.2 Hz), 0.00 (s, 9H); C23H33N5O3Si (MW, 455.63), LCMS (EI) m/e 456.1 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[BrH:18].C1(S[C:26]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[NH:27])C=CC=CC=1>CO>[BrH:18].[O:11]=[C:10]1[NH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[NH:6][C:5]2[CH:16]=[CH:17][C:2]([NH:1][C:26]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)=[NH:27])=[CH:3][C:4]1=2
Reactant: Nc1ccc2c(c1)C(=O)Nc1ccccc1N2
Reactant: N=C(Sc1ccccc1)c1cccs1
Agent: Br
Solvent: CO
Product: N=C(Nc1ccc2c(c1)C(=O)Nc1ccccc1N2)c1cccs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Amino-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-one (Example 6, 54 mg, 0.24 mmol) was dissolved in methanol (10 mL) and thiophene-2-carboximidothioic acid phenyl ester hydrobromide (79 mg, 0.26 mmol) added. The reaction was stirred at room temperature for 4 hr. The solvent was evaporated and the residue recrystallized from a mixture of methanol and ether to give a yellow solid. The solid was washed several times with ether (84 mg, 0.20, 84%).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[C:12]2[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]([CH:16](Cl)[CH3:17])[O:15][C:11]=2[C:10]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]([CH3:35])[C:25]2=[O:36])=[C:9]([F:37])[CH:8]=1.[C-:38]#[N:39].[K+].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:6][C:7]1[C:12]2[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]([CH:16]([C:38]#[N:39])[CH3:17])[O:15][C:11]=2[C:10]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[N:26]([CH3:35])[C:25]2=[O:36])=[C:9]([F:37])[CH:8]=1
Reactant: [C-]#N
Reactant: CCOC(=O)c1c(C(C)Cl)oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C(C)C#N)oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.3 %

Procedure:
20 ml of N,N-dimethylformamide was added to 0.8 g (1.6 mmol) of 3-[4-chloro-2-(1-chloroethyl)-3-ethoxycarbonyl-6-fluorobenzofuran-7-yl]-1-methyl-6-trifluoromethyluracil, 0.16 g (2.5 mmol) of potassium cyanide and 0.40 g (2.9 mmol) of potassium carbonate, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.58 g (yield: 74%) of the desired product as a yellow glassy substance. Refractive index: 1.5348 (20° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:11])[CH2:10][CH2:9]2)=[C:4]([F:12])[CH:3]=1.N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>CC(C)=O>[F:12][C:4]1[CH:3]=[C:2]([NH:1][C:20](=[O:21])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=[CH:6][C:5]=1[C:8]1([OH:11])[CH2:9][CH2:10]1
Reactant: Nc1ccc(C2(O)CC2)c(F)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C2(O)CC2)c(F)c1)Oc1ccccc1
Reaction time: 1 h
Yield: 74.8 %

Procedure:
To a stirred solution of 1-(4-amino-2-fluorophenyl)cyclopropanol (0.7 mg, 4.19 mmol, 1.0 eq) in acetone (10 mL) was added pyridine (0.33 mL, 4.19 mmol, 1.0 eq) and phenyl chloroformate (0.5 mL, 4.19 mmol, 1.0 eq) and stirred at 0° C. to RT for 1 h. The solvent was evaporated, the residue diluted with water (10 mL×2), extracted with EtOAc (25 mL), brine (10 mL) and dried over Na2SO4 and evaporated under vacuum; the resulting residue was purified by CC using EtOAc/PE (1:4 as eluent to get phenyl 3-fluoro-4-(1-hydroxycyclopropyl)phenylcarbamate (0.9 g, 75%, off white solid; TLC system: EtOAc/PE (1:1), Rf: 0.6).
Reaction SMILES: C[O:2][CH:3](Cl)[CH:4]([C:10]([Cl:13])([CH3:12])[CH3:11])[CH2:5][C:6]([O:8][CH3:9])=[O:7].C(=O)(O)[O-].[Na+]>>[Cl:13][C:10]([CH3:12])([CH3:11])[CH:4]([CH:3]=[O:2])[CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CC(C(Cl)OC)C(C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)CC(C=O)C(C)(C)Cl

Procedure:
The solution of Step A was poured into an iced aqueous sodium bicarbonate solution and the mixture was extracted with methylene chloride. The organic phase was evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 4-1 hexane-ethyl acetate mixture yielded 600 mg of methyl 4-chloro-4-methyl-3-formylpentanoate which crystallized at -20° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([O:9][CH2:10][CH2:11][CH3:12])[N:3]1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][C:15]=1[F:28].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)=[O:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[F:28][C:15]1[CH:16]=[C:17]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:18]=[CH:19][C:14]=1[CH2:13][N:3]1[C:4]([O:9][CH2:10][CH2:11][CH3:12])=[CH:5][C:6](=[O:8])[N:7]([CH2:30][C:31]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[O:32])[C:2]1=[O:1]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCCOc1cc(=O)[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOc1cc(=O)n(CC(=O)c2ccc(OC)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
To a mixture of 4′-[(2,4-dioxo-6-propoxy-3,4-dihydropyrimidin-1(2H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (0.55 g), 2-bromo-1-(4-methoxyphenyl)ethanone (0.4 g) and N,N-dimethylformamide (25 mL) was added 60% sodium hydride (0.087 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.45 g, 59%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:5]=[N:6][CH:7]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Reactant: OB(O)c1cccc(F)c1
Product: Fc1cccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)c1

Procedure:
The title compound was prepared from the product of Example 65A and 3-fluorophenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 324.0 (M+H)+, retention time 1.31 minutes.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[C:10]([CH3:11])=[C:9]([S:12][CH2:13][CH2:14][CH2:15][CH2:16][SH:17])[CH:8]=[CH:7][N:6]=1.Cl[CH2:19][CH2:20][N:21]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][N:23]=[C:22]1[CH3:29]>CN(C=O)C.C(O)(=O)C>[OH:3][CH2:4][C:5]1[C:10]([CH3:11])=[C:9]([S:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17][CH2:19][CH2:20][N:21]2[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][N:23]=[C:22]2[CH3:29])[CH:8]=[CH:7][N:6]=1
Reactant: Cc1ncc([N+](=O)[O-])n1CCCl
Reactant: Cc1c(SCCCCS)ccnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1c(SCCCCSCCn2c([N+](=O)[O-])cnc2C)ccnc1CO
Temperature: 0 °C

Procedure:
0.43 g (15 mmol) of sodium hydride are initially introduced in 25 ml of DMF with ice-cooling. 3.33 g (13.7 mmol) of 2-hydroxymethyl-4-(4-mercaptobutylthio)-3-methylpyridine are added. After the evolution of gas has ended, 2.62 g (13.7 mmol) of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole in 10 ml of DMF are added dropwise. The mixture is stirred with ice- cooling for 1 h. It is then diluted with 200 ml of ice-water and neutralized with acetic acid. The mixture is extracted 3 times with dichloromethane. The combined organic phases are washed 4 times with water, dried over magnesium sulfate, filtered and concentrated. The crude product is chromatographed on silica gel using ethyl acetate/methanol/conc. ammonia=89/10/1. The title compound is obtained on concentrating as a yellow crystallizate which is washed by stirring with diethyl ether. M.p. 86°-87° C.; yield 4 g (75% of theory).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=1)[CH2:10][N:11](C(OC(C)(C)C)=O)[C:12]1[S:13][C:14]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)=[C:15]([C:17]([O:19]C)=O)[N:16]=1)=O)(C)(C)C.[NH2:49][CH2:50][CH2:51][OH:52].C(O)(C(F)(F)F)=O>>[NH2:8][C@@H:9]([CH2:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]([F:47])([F:46])[F:48])=[CH:43][CH:44]=1)[CH2:10][NH:11][C:12]1[S:13][C:14]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)=[C:15]([C:17]([NH:49][CH2:50][CH2:51][OH:52])=[O:19])[N:16]=1
Reactant: COC(=O)c1nc(N(C[C@H](Cc2ccc(C(F)(F)F)cc2)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)sc1-c1ccc2cnccc2c1
Reactant: NCCO
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CNc1nc(C(=O)NCCO)c(-c2ccc3cnccc3c2)s1)Cc1ccc(C(F)(F)F)cc1

Procedure:
The title compound was synthesized by treating the intermediate methyl 2-(((S)-2-(tert-butoxycarbonylamino)-3-(4-(trifluoromethyl)phenyl)propyl)(tert-butoxycarbonyl)amino)-5-(isoquinolin-6-yl)thiazole-4-carboxylate with 2-aminoethanol followed with a TFA treatment to remove the tert-butoxycarbonyl protecting groups. LCMS (M+H) calc. for C25H25F3N5O2S 516.2. 1H NMR (400 MHz, CD3OD) δ ppm 9.70 (s, 1H) 8.53-8.60 (m, 1H) 8.38-8.46 (m, 2H) 8.36 (s, 1H) 8.10-8.19 (m, 1H) 7.73 (d, J=6.85 Hz, 2H) 7.58 (d, J=6.85 Hz, 2H) 4.52-4.61 (m, 1H) 3.93 (s, 1H) 3.78-3.87 (m, 1H) 3.71 (t, J=5.48 Hz, 2H) 3.63 (dd, J=14.67, 6.46 Hz, 1H) 3.44-3.51 (m, 2H) 3.06-3.23 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][N:24]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([Si:32]([CH3:33])([CH3:35])[CH3:34])=[CH:30][CH:31]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:20][CH:21]=1
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Reactant: C[Si](C)(C)c1ccc(CNCCc2ccc(Cl)cc2)cc1
Product: C[Si](C)(C)c1ccc(CN(CCc2ccc(Cl)cc2)C(=O)c2c(F)c(Cl)cc3cc[nH]c23)cc1

Procedure:
5-Chloro-6-fluoro-1H-indole-7-carboxylic acid [2-(4-chloro-phenyl)-ethyl]-(4-trimethylsilanyl-benzyl)-amide was prepared in analogy to example 1 from 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and [2-(4-chloro-phenyl)-ethyl]-(4-trimethylsilanyl-benzyl)-amine. MS (ISP) 513.3/515.3 (100/69) (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:14]C2N=NC=CC=2C=1O)=[O:5])[CH3:2].C(O[C:19](=[O:30])[C:20]1[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[N:22][C:21]=1Cl)C>>[CH2:1]([O:3][C:4]([C:6]1[O:14][C:21]2=[N:22][C:23]([CH3:28])=[CH:24][C:25]([O:26][CH3:27])=[C:20]2[C:19]=1[OH:30])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(OC)cc(C)nc1Cl
Reactant: CCOC(=O)c1oc2nnccc2c1O
Product: CCOC(=O)c1oc2nc(C)cc(OC)c2c1O

Procedure:
This compound was prepared using a method analogous to that of 5-hydroxyfuro[2,3-c]pyridazine-6-carboxylic acid ethyl ester (A.2.3.1), 2-chloro-4-methoxy-6-methylnicotinic acid ethyl ester replacing 3-chloropyridazine-4-carboxylic acid ethyl ester;
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]2[CH3:28])=[N:4][C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:6][C:7]=1[CH2:8][OH:9].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(OC([NH:57][C@H:58]([C:62](O)=[O:63])[CH:59]([CH3:61])[CH3:60])=O)(C)(C)C.C(N(CC)CC)C>>[CH3:1][C:2]1[C:3]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]2[CH3:28])=[N:4][C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:6][C:7]=1[CH2:8][O:9][C:62](=[O:63])[C@H:58]([CH:59]([CH3:61])[CH3:60])[NH2:57]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1c(CO)nc(Nc2ccc(F)cc2)nc1N1CCc2ccccc2C1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: Cc1c(COC(=O)[C@@H](N)C(C)C)nc(Nc2ccc(F)cc2)nc1N1CCc2ccccc2C1C

Procedure:
The same procedures as in Example 167 were repeated using 5-methyl-6-hydroxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(50 mg, 0.132 mmol), 1-hydroxybenzotriazole(26.8 mg, 0.198 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (32.9 mg, 0.171 mmol), N-t-butyloxycarbonyl-valine (34.4 mg, 0.158 mmol), and triethylamine(23.9 μl, 0.171 mmol) to afford the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.[CH2:28]1[C@@H:31]([C:32]([OH:34])=[O:33])[NH:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2)[CH2:5][N:30]1[CH2:29][CH2:28][C@H:31]1[C:32]([OH:34])=[O:33]
Reactant: O=C(O)[C@@H]1CCN1
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Product: O=C(O)[C@@H]1CCN1Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (93.3 mg, 0.249 mmol) and L-azetidine-2-carboxylic acid (76 mg, 0.748 mμmol) according to Reference R and the general procedure for reductive amination gave (S)-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)-azetidine-2-carboxylic acid as a light yellow solid. MS (ESI) m/z: Calculated: 459.1; Observed: 460.0 (M++1).
Reaction SMILES: C([O:4][CH:5]([CH2:45][O:46]C(=O)C)[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([N:17]2[C:22](=[O:23])[CH2:21][O:20][CH2:19][CH:18]2[CH2:24][O:25]C(=O)C)[C:13]([I:29])=[C:12]([C:30]([NH:32][CH2:33][CH:34]([O:40]C(=O)C)[CH2:35][O:36]C(=O)C)=[O:31])[C:11]=1[I:44])=[O:9])(=O)C.C[O-].[Na+].[Na]>CO.O>[OH:40][CH:34]([CH2:35][OH:36])[CH2:33][NH:32][C:30]([C:12]1[C:13]([I:29])=[C:14]([N:17]2[C:22](=[O:23])[CH2:21][O:20][CH2:19][CH:18]2[CH2:24][OH:25])[C:15]([I:16])=[C:10]([C:8]([NH:7][CH2:6][CH:5]([OH:4])[CH2:45][OH:46])=[O:9])[C:11]=1[I:44])=[O:31]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(N2C(=O)COCC2COC(C)=O)c1I)OC(C)=O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Product: O=C(NCC(O)CO)c1c(I)c(C(=O)NCC(O)CO)c(I)c(N2C(=O)COCC2CO)c1I
Reaction time: 3 h
Yield: 60 %

Procedure:
To a solution of N,N'-bis[2,3-bis(acetyloxy)propyl]-5-[3-(Acetyloxy)methyl-5-oxo-4-morpholinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide (5.15 g, 5 mmol) in anhydrous methanol (100 ml), was added a solution of sodium methoxide, prepared from sodium (25 mg) and anhydrous methanol (5 ml), and the mixture was stirred for 3 hours. The solution was adjusted to pH 7 by a slow addition of Dowex-50 (H+) resin and then filtered. The filtrate was concentrated in vacuo to obtain the crude product (3.85 g) as a white solid. The material was dissolved in water (40 ml) and loaded onto a column of CHP-20 diaion resin. The column was first eluted with water (1 L) and then with a stepwise gradient of ethanol in water (1-8%). The fractions containing the pure product were combined and the solvents removed in vacuo to obtain N,N'-Bis(2,3-dihydroxypropyl)-5-[3-(hydroxymethyl)-5-oxo-4-morpholinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide as a white microcrystalline solid (2.45 g, 60% yield, 99% purity). Recrystallization from ethanol/isopropanol (95/5) afforded the analytical sample as a white solid, m.p. 227°-230°.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.Br[CH:27]([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C)C=O>[NH2:3][C:4]1[C:5]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:17][CH:18]=3)=[CH:11][N:10]([CH:27]([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)n1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (120 mg, of a 60% dispersion in mineral oil) was added to a mixture of 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine (906 mg) in dry dimethyformamide (30 ml) and the mixture was stirred under nitrogen for 30 minutes at ambient temperature. A solution of ethyl 2-bromopropionate (543 mg) in dry DMF (10 ml) was added dropwise via a syringe over 10 minutes. The mixture was stirred at ambient temperature for 2 hours and then left for 18 hours. The mixture was evaporated under vacuum and the residue was washed with water to give a solid which was triturated with ether and filtered to give ethyl 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]propionate, m.p. 139-140° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.O.Cl.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:17]1[CH2:18][CH2:19][NH:14][CH2:15][CH:16]=1
Reactant: COc1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: COc1ccc2[nH]cc(C3=CCNCC3)c2c1
Yield: 78.6 %

Procedure:
Beginning with 5.0 gm (34.0 mMol) 5-methoxy-1H-indole and 10.0 gm (65.0 mMol) 4-piperidone hydrochloride monohydrate, 6.1 gm (79%) of the title compound were recovered as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[C:12]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[O:16])=[C:11](I)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[C:12]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[O:16])=[C:11]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cn1c(-c2ccc(Cl)c(Cl)c2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1cncnc1
Product: Cn1c(-c2ccc(Cl)c(Cl)c2)nc(-c2cncnc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [2-(3,4-dichloro-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 105) was reacted with pyrimidine-5-yl-boronic acid to give the title compound as colorless amorphous solid. MS: 485.3 (MH+, 2Cl).