Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH:3]1[CH2:5][CH:4]1[C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9].C([N:16](CC)CC)C.CS(Cl)(=O)=O.[OH-].[NH4+]>C(Cl)Cl.C(#N)C>[NH2:16][CH2:2][CH:3]1[CH2:5][CH:4]1[C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: CCN(CC)CC
Reactant: N#Cc1ccccc1C1CC1CO
Agent: CS(=O)(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC#N
Product: N#Cc1ccccc1C1CC1CN
Temperature: 25 °C
Yield: 13 %

Procedure:
A cold solution of 2-(2-(hydroxymethyl)cyclopropyl)benzonitrile (425 mg, 2.454 mmol) in methylene chloride (15 mL), and triethyl amine (1.368 mL, 9.81 mmol) was treated with methanesulfonyl chloride (0.287 mL, 3.68 mmol) dropwise with ice bath cooling. The cooling bath was removed, the reaction warmed to rt for 1 hr. The reaction was diluted with methylene chloride washed with water and brine, dried over magnesium sulfate, and concentrated to give a wax. A solution of the material in acetonitrile (15 mL) and ammonium hydroxide (2 mL, 51.4 mmol) was stirred for 16 h at rt. The reaction was concentrated to about ½ volume and diluted with ether. The suspension was extracted with 1N HCl. The acid extracts were made basic with 50% sodium hydroxide, then extracted with methylene chloride (4×). The organics were dried potassium carbonate and concentrated. The resulting dark wax (400 mg) was then purified on silica gel using 1-20% MeOH/methylene chloride to give an orange wax. The wax was triturated with acetone to give 2-(2-(aminomethyl)cyclopropyl)benzonitrile as a white solid (55 mg, 13%). 1H NMR (400 MHz, DMSO-d6) δ 7.91 (br. s., 2H), 7.80 (dd, J=7.8, 1.0 Hz, 1H), 7.65 (td, J=7.8, 1.3 Hz, 1H), 7.40 (td, J=7.6, 1.1 Hz, 1H), 7.20 (d, J=7.8 Hz, 1H), 2.97 (t, J=6.9 Hz, 2H), 2.32-2.19 (m, 1H), 1.68-1.48 (m, 1H), 1.23 (dt, J=8.8, 5.2 Hz, 1H), 1.10 (dt, J=8.7, 5.2 Hz, 1H). LCMS: M+1=173.05.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[S:19](Cl)(=[O:21])=[O:20]>>[C:1]([C:4]1[S:8][C:7]([NH:9][S:19]([C:13]2[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])(=[O:21])=[O:20])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: CC(=O)c1sc(N)nc1C
Product: CC(=O)c1sc(NS(=O)(=O)c2c(Cl)cccc2Cl)nc1C

Procedure:
The title compound was prepared from 5-acetyl-2-amino-4-methylthiazole (42 mg) and-2,6-dichlorobenzenesulfonyl chloride (66 mg) as described in the synthetic METHOD B to give a white solid (21.4 mg) with purity >90%: MS (pos) m/z 365.3, 367.3.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O-])=[O:15].C(O)(=O)C>CO.O>[OH:15][N:14]=[C:17]1[CH:22]=[CH:21][C:20](=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[C:12]#[N:13])[CH:19]=[CH:18]1
Reactant: COc1ccc(CC#N)cc1
Reactant: O=[N+]([O-])c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C(C#N)=C2C=CC(=NO)C=C2)cc1
Temperature: 55 °C
Reaction time: 4 h
Yield: 53.2 %

Procedure:
80 g of KOH are dissolved in 400 ml of methanol and heated up to 55° C. To the solution are added 50 ml (0.37 mol) of p-methoxyphenylacetonitrile, followed by 35 ml (0.34 mol) of nitrobenzene. The reaction mixture is stirred at 55° C. for 4 hrs. After cooling, 500 ml of water are added with stirring. The resulting solution is acidified by addition of 110 ml of acetic acid in 100 ml of water, leading to a precipitate. The mixture is then filtered, and the solid is washed with a mixture of methanol and water. The crude product is dried in air and recrystallized from 500 ml of ethyl acetate. 45.6 g (53%) of (4-Hydroxyimino-cyclohexa-2,5-dienylidene)-(4-methoxyphenyl)-acetonitrile are obtained in the form of orange crystals having a melting point of 161-163° C. (dec.).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C[Si]([C:23]#[C:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32]([O:34][CH3:35])=[O:33])(C)C>C(Cl)Cl>[C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32]([O:34][CH3:35])=[O:33])#[CH:23]
Reactant: COC(=O)Cc1ccccc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: C#Cc1ccccc1CC(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TBAF (1.0 M in THF; 28.5 mL, 28.5 mmol) was added to a solution of methyl 2-(2-((trimethylsilyl)ethynyl)phenyl)acetate (I2) (4.63 g, 19.0 mmol) in DCM (200 mL) at 0° C. The solution was stirred at room temperature for 1 hour before washing with 10% aqueous NaHCO3 (100 mL). The organic layer was dried (MgSO4) before removing the volatiles in vacuo to give a dark brown/black residue which was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 0-10% EtOAc in petroleum benzine 40-60° C.) to give the title compound K1 as a red liquid (2.76 g, 83%); 1H NMR (400 MHz, CDCl3) δ 7.52 (dd, J=7.6, 1.1 Hz, 1H), 7.43-7.16 (m, 3H), 3.88 (d, J=9.6 Hz, 2H), 3.77-3.52 (m, 3H), 3.28 (s, 1H).
Reaction SMILES: F[C:2]1[C:3](I)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=C\C1NC=CC=1OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[N:7]1[C:6](=[O:11])[CH:5]=[C:4]2[C:8]=1[CH:9]=[CH:10][CH:2]=[CH:3]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1C=c2ccccc2=N1

Procedure:
Using Method C above, Ethyl-[(3R,4S,5R)-4-ethynyl-2,2,6-trimethyl-[1,3]-dioxan-5-yl]-carbamic acid tert-butyl ester (148.5 mg, 0.50 mmol) (Example 123C above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (96 mg, 0.25 mmol) (Starting Material 6) using (Ph3P)4Pd (23.1 mg, 8 mol %) and CuI (5 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 5 h to give the coupling product (137.2 mg, 99.2% after flash column purification). This coupling product (125 mg) was then treated with 50% of trifluoroacetic acid/CH2Cl2 (5 mL) and 0.5 mL of water at r.t. for 1 h. The reaction mixture was concentrated to about 2 mL and diluted with AcOEt (50 mL) and then quenched with 2 N NaOH. The organic layer was washed with brine and dried with Na2SO4. After concentration, the crude product (113.6 mg) was triturated with AcOEt/hexanes and the precipitate was collected by filtration to offer (Z)-1,3-Dihydro-4-[(3R,4S,5R)-3,5-dihydroxy-4-ethylamino-1-hexynyl]-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (LLLLL) as a brown-orange solid. (Yield 29.5 mg, 31.6%). The filtrate was then purified via flash column chromatography (5%-10% MeOH in CH2Cl2) to give (R)-(Z)-1,3-Dihydro-4-[(5-ethylamino-6-methyl)-6H-pyran-2-yl]-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene)]-2H-indol-2-one (MMMMM). (Yield 33.6 mg, 37.6%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2].C1C(=O)N([I:19])C(=O)C1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([I:19])=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]cnc1C
Reactant: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c(I)nc1C

Procedure:
A solution of 5 g 5-Methyl-3H-imidazole-4-carboxylic acid ethyl ester and 7.2 g NIS in 50 ml THF were refluxed for 10 h. After cooling, the solvent was removed under reduced pressure and the residue taken-up in ethyl acetate, washed with sat. NaS2O3 solution and dried over MgSO4. After removal of the solvent under reduced pressure the product was purified by recrystallisation from ethyl acetate. Yield: 7 g
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:14]=[C:15]1[N:21]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C@@H:31]([C:44](O)=[O:45])[CH2:32][C:33]3[CH:42]=[C:41]([CH3:43])[C:36]4[NH:37][C:38](=[O:40])[O:39][C:35]=4[CH:34]=3)=[O:29])[CH2:24][CH2:23]2)[CH2:20][CH2:19][C:18]2[CH:47]=[CH:48][CH:49]=[CH:50][C:17]=2[NH:16]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:14]=[C:15]1[N:21]([CH:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C@H:31]([CH2:32][C:33]3[CH:42]=[C:41]([CH3:43])[C:36]4[NH:37][C:38](=[O:40])[O:39][C:35]=4[CH:34]=3)[C:44]([N:11]3[CH2:12][CH2:13][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)=[O:45])=[O:29])[CH2:26][CH2:27]2)[CH2:20][CH2:19][C:18]2[CH:47]=[CH:48][CH:49]=[CH:50][C:17]=2[NH:16]1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2oc(=O)[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(c3ccc(F)cc3)CC2)cc2oc(=O)[nH]c12
Temperature: 25 °C

Procedure:
234 mg (1.30 mmol) 1-(4-fluoro-phenyl)-piperazine were added to a solution of 600 mg (1.18 mmol) (R)-1-carboxy-2-(4-methyl-2-oxo-2,3-dihydrobenz-oxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5,-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 417 mg (1.30 mmol) TBTU, 183 μL (1.30 mmol) triethylamine in 10 mL DMF and the reaction mixture was shaken at RT. The reaction solution was purified by HPLC without any further working up, the fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH3:1][C:2]([C:7]1[S:11][C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:15][CH2:16][CH3:17])=[N:9][N:8]=1)([CH3:6])[CH2:3][CH:4]=[CH2:5].ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)Cl>[CH3:1][C:2]([C:7]1[S:11][C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:15][CH2:16][CH3:17])=[N:9][N:8]=1)([CH3:6])[CH2:3][CH:4]1[CH2:5][O:39]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCC(C)(C)c1nnc(NC(=O)C(CCC)NC(=O)Cc2cc(F)cc(F)c2)s1
Solvent: ClCCl
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)CC2CO2)s1
Reaction time: 4 h

Procedure:
A mixture of 2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide (196 mg, 0.45 mmol) and ˜60% pure m-chloroperbenzoic acid (109 mg, 0.45 mmol) in methylene chloride was stirred for 4 hr. The mixture was quenched with water, saturated Na2S2O3 and extracted with methylene chloride. The organic layer was washed with brine, separated, dried, and concentrated to give 114 mg of crude material with a mixture of desired title compound and undesired N-oxide and recovered starting material. The crude material was purified by HPLC and the title compound was isolated, LC-MS, RT=2.3 min, M=1=453.5
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:24]([OH:26])=[O:25])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1O)([O-:29])=[O:28].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1.CCOC(C)=O.C(O)(C)C>[N+:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:25][C:24](=[O:26])[C@@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)Oc1ccccc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A solution Nα -Boc-Nδ -Cbz-(R)-ornithine (25.0 g; 68.2 mmol) and o-nitrophenol (19.0 g; 136.4 mmol) in pyridine (250 mL) was cooled to 0° C. Dicyclohexylcarbodiimide (13.4 g; 64.8 mmol) was added at 0° C. The solution was stirred at 0° C. for several hours, warmed to room temperature and stirred overnight. The resulting heterogeneous solution was diluted with EtOAc and filtered. The filtrate was concentrated under reduced pressure to afford a thick oil. The oil was dissolved in a minimal amount of warm isopropanol and stirred. The resultant precipitate was collected via vacuum filtration and washed with isopropanol, then diethyl ether. Concentration of the isopropanol/ether filtrate and crystallization from isopropanol provided a second crop. The combined product was dissolved in EtOAc at room temperature and filtered. Concentration of the EtOAc gave the sub-title compound as a solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]([CH2:25][O:26][C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[CH3:34])=[C:23]3[C:18]([NH:19][C:20]([CH3:38])([CH3:37])[C:21](=[O:36])[N:22]3[CH3:35])=[CH:17][CH:16]=2)=[C:11]([O:39][CH3:40])[CH:10]=1)(=[O:7])=[O:6].[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.[I-].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:41]([NH:48][CH2:2][CH2:3][CH2:4][S:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]([CH2:25][O:26][C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[CH3:34])=[C:23]3[C:18]([NH:19][C:20]([CH3:38])([CH3:37])[C:21](=[O:36])[N:22]3[CH3:35])=[CH:17][CH:16]=2)=[C:11]([O:39][CH3:40])[CH:10]=1)(=[O:7])=[O:6])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COc1cc(OS(=O)(=O)CCCCl)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Reactant: NCc1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(OS(=O)(=O)CCCNCc2ccccc2)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 50 °C
Reaction time: 5 h
Yield: 38.2 %

Procedure:
A mixture of 7-[4-(3-chloropropylsulfonyloxy)-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 1-40, 50.0 mg, 0.0846 mmol), benzylamine (92.4 μL, 0.846 mmol), and potassium iodide (16.9 mg, 0.102 mmol) was suspended in anhydrous N,N-dimethylformamide (0.4 mL) and stirred at 50° C. for 5 hours. After cooling down, ethyl acetate (50 mL) was added thereto. The organic layer was washed with water (50 mL) and saturated brine (30 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (21.4 mg) as a colorless amorphous product. (Yield 38%)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>CC#N>[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12]([CH:4]([OH:5])[CH2:3][CH2:2][Cl:1])(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)C(O)CCCl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.8 %

Procedure:
To 3-Chloro-1-propanol (5.02 mL, 60 mmol) was added CH3CN (200 mL), p-toluenesulfonyl chloride (17 g, 90 mmol) and pyridine (7.3 mL, 90 mmol). The reaction mixture was stirred at room temperature for 12 hours under an atmosphere of argon. Saturated NaHCO3 (200 mL, aq) was added and stirring was continued for 15 minutes. The mixture was then poured into a separatory funnel and extracted several times with CH2Cl2. The CH2Cl2 extracts were combined and dried over Na2SO4. The CH2Cl2 layer was filtered and concentrated in vacuo to give 12.35 g (83.8%) of the title compound. TLC (Rf: 0.5; 20% EtOAc/Hexane). 1H NMR (CDCl3) δ2.1 (m, 2H, CH2), 2.5 (s, 3H, CH3), 3.6 (t, 2H, CH2), 4.2 (t, 2H, CH2), 7.6 (d & d, 4H, Ar). 13C NMR (CDCl3) δ21.4 (CH3), 31.5 (CH2), 40.2 (CH2), 66.7 (CH2), 127.8 (Ar), 129.8 (Ar), 132.5 (Ar), 144.9 (Ar).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[NH:5][C:4](=[O:13])[CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].N1CCNCC1>C(O)CCC>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=3)[NH:5][C:4](=[O:13])[CH:3]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=c1cc(Cl)c2ccc(Cl)cc2[nH]1
Agent: C1CNCCN1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCN(c2cc(=O)[nH]c3cc(Cl)ccc23)CC1
Reaction time: 18 h

Procedure:
4,7-Dichloro-2-quinolone (192 mg, 0.88 mmol) and 1-tert-butoxycarbonylpiperazine (580 mg, 3.1 mmol) in n-butanol (10 mL) are heated in a sealed tube for 2 h at 150° C., when additional piperazine (200 mg) is added and heating is continued for further 18 h. After removing the solvent, the residue is purified by column chromatography with CH2Cl2-MeOH—NH4OH yielding the title product as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([NH:11][CH2:12][CH2:13][F:14])=[O:10])[CH:5]=[CH:4][C:3]=1[C:15]1[N:16]=[C:17]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]2C)[C:18]2[CH2:23][N:22]([C:24]([O:26][CH2:27]C)=[O:25])[CH2:21][C:19]=2[N:20]=1.ClC1N=C(N2CCOCC2)C2CN(C(OC)=O)CC=2N=1>>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([NH:11][CH2:12][CH2:13][F:14])=[O:10])[CH:5]=[CH:4][C:3]=1[C:15]1[N:16]=[C:17]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[C:18]2[CH2:23][N:22]([C:24]([O:26][CH3:27])=[O:25])[CH2:21][C:19]=2[N:20]=1
Reactant: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)NCCF)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Agent: COC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Product: COC(=O)N1Cc2nc(-c3ccc(NC(=O)NCCF)cc3F)nc(N3CCOCC3)c2C1
Yield: 16 %

Procedure:
Method as (S)-Ethyl 2-(2-fluoro-4-(3-(2-fluoroethyl)ureido)phenyl)-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (Example 168) using methyl 2-chloro-4-morpholino-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 25). Residue was then purified by prep. HPLC at low pH to afford a colourless solid (16%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]([C:17]([O:30][CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([O:15]C)=[O:14])[N:4]=1.[OH-].[K+]>O1CCOCC1.O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][CH:12]([C:17]([O:30][CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:13]([OH:15])=[O:14])[N:6]=1
Reactant: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(OC)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(OC)nc(OC(C(=O)O)C(OC)(c2ccccc2)c2ccccc2)n1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
2.12 g (5 mmol) of methyl 2-(4,6-dimethoxy-pyrimidin-2-yl-oxy)-3-methoxy-3,3-diphenylpropionate were dissolved in 50 ml of dioxane, 10 ml of 1N KOH solution were added, and the mixture was stirred at 100° C. for 3 h. The solution was diluted with 300 ml of water and extracted with ethyl acetate to remove unreacted ester. The aqueous phase was then adjusted to pH 1-2 with dilute hydrochloric acid and extracted with ethyl acetate. After drying over magnesium sulfate and removal of the solvent by distillation, the residue was mixed with an ether/hexane mixture, and the precipitate which formed was filtered off with suction. After drying, 1.85 g (90%) of a white powder remained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:18]2[CH2:27][C:26]([CH3:29])([CH3:28])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:30]#[N:31])[CH:24]=3)[NH:19]2)[CH:15]=[CH:16][CH:17]=1.N1C=CC=CC=1>ClCCl>[C:30]([C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]([C:14]1[CH:13]=[C:12]([NH:11][S:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)(=[O:9])=[O:8])[CH:17]=[CH:16][CH:15]=1)[CH2:27][C:26]2([CH3:29])[CH3:28])#[N:31]
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C#N)cc21
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3cccnc3)c2)Nc2ccc(C#N)cc21
Reaction time: 8 h
Yield: 44.2 %

Procedure:
Pyridine-3-sulfonyl chloride (144 mg, 0.81 mmol) was added dropwise to a mixture of 2-(3-amino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (150 mg, 0.54 mmol) and pyridine (77 mg, 0.97 mmol) in dichloromethane (5 mL). The resultant mixture was allowed to stir overnight. The reaction mixture was washed by water, dried over magnesium sulfate. Filtered and concentrated to provide the crude product. It was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=3:1) to afford pyridine-3-sulfonic acid [3-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide as off-white solid (100 mg, yield: 44.2%). MS (ESI+APCI) M+1=419.1.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:38][CH3:39])([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]4([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[C:24]([CH3:37])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:40])=[CH:9][CH:8]=1.[Cl-].[NH4+]>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C:5]([OH:41])=[O:4])=[CH:12][CH:11]=2)=[C:14]([CH3:40])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]2([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:24]([CH3:37])[CH:23]=1)[CH2:38][CH3:39])[CH3:21]
Reactant: CCC(CC)(c1ccc(CCC2(O)CCCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(CCC2(O)CCCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.151 mL, 0.151 mmol) was added to a solution of [4′-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-propyl)-2′-methyl-biphenyl-4-yl]-acetic acid methyl ester (Example 57-(1); 26.5 mg, 0.050 mmol) in methanol-tetrahydrofuran (1:1, 3 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (24.6 mg, 96%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].[H-].[Na+].[C:11]([O:15][C:16](=[O:19])[CH2:17]Br)([CH3:14])([CH3:13])[CH3:12].O>C1COCC1>[C:11]([O:15][C:16](=[O:19])[CH2:17][O:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: OCc1ccccn1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)COCc1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.5 mL (5.18 mmol) 2-pyridylmethanol in 20 mL THF at 0° C. was added 270 mg (6.75 mmol) NaH and the reaction stirred for 0.25 h. Then 0.82 mL t-butylbromoacetate was added and the reaction warmed to rt and stirred for 12 days. The reaction was poured into 100 mL H2O, extracted with CH2Cl2 (2×100 mL), the combined organic layers washed with brine, dried over MgSO4, filtered, and the solvent removed under reduced pressure to give 1.16 g (61%) as a brown oil.