Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[N:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=2)[CH2:4][CH2:3]1>CCOC(C)=O.CO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]2[N:10]=[CH:11][C:12]([NH2:15])=[CH:13][N:14]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(Nc2ncc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCC(Nc2ncc(N)cn2)CC1
Reaction time: 8 h

Procedure:
The crude N-(1-methylpiperidin-4-yl)-5-nitropyrimidin-2-amine was combined with 10% Pd/C (500 mg) in EtOAc (8 mL) and MeOH (20 mL) was added. The mixture was purged with H2 and allowed to stir under 1 atm H2 overnight. Filtration through a pad of celite and concentration afforded N2-(1-methylpiperidin-4-yl)pyrimidine-2,5-diamine 17 as a tan solid, which may be used without further purification. MS: m/z found 285 [MH+].
Reaction SMILES: Br[C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]4=[O:23])=[CH:13][CH:12]=3)[C:6](=[O:24])[C:5]=2[N:4]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[N:3]=1.[Li+].[Cl-].Cl.C1C[O:39][CH2:38][CH2:37]1>>[C:38]([C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]4=[O:23])=[CH:13][CH:12]=3)[C:6](=[O:24])[C:5]=2[N:4]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[N:3]=1)(=[O:39])[CH3:37]
Reactant: C1CCOC1
Reactant: COc1ccc(-n2nc(Br)c3c2C(=O)N(c2ccc(-n4ccccc4=O)cc2)CC3)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Product: COc1ccc(-n2nc(C(C)=O)c3c2C(=O)N(c2ccc(-n4ccccc4=O)cc2)CC3)cc1
Temperature: 25 °C

Procedure:
To 3-bromo-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one (0.11 g, 0.22 mmol) was added THF (25 mL), 1-(ethoxyvinyl)tributyltin (0.078 mL, 0.23 mmol), and LiCl (27 mg, 0.65 mmol) and the mixture was degassed with N2 for 15 min. Tetrakistriphenylphosphine Palladium(0) (12 mg, 0.01 mmol) was added and the reaction was heated to reflux 24 h. The reaction was cooled to rt and treated with 1N HCl for 24 h. After extraction with EtOAc and drying (MgSO4), the product was purified by silica gel (mixed with KF) chromatography using 0–3% MeOH in CH2Cl2 and by HPLC to afford 6 mg (6%); High Resolution Mass Spec (M+H)+ for C26H23N4O4 455.1713.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)=[CH:5][C:4]=1[CH3:21])[CH3:2].[OH:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1>>[CH2:1]([C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([NH:11][C:12]([N:32]2[CH2:31][CH2:30][N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([OH:22])[CH:24]=3)[CH2:34][CH2:33]2)=[O:20])=[CH:5][C:4]=1[CH3:21])[CH3:2]
Reactant: CCc1nc(OC)c(NC(=O)Oc2ccccc2)cc1C
Reactant: Oc1cccc(N2CCNCC2)c1
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cccc(O)c3)CC2)cc1C
Yield: 56 %

Procedure:
Phenyl N-(6-ethyl-2-methoxy-5-methylpyridin-3-yl)carbamate and 1-(3-hydroxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8](Cl)[CH:7]=[CH:6][N:5]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>ClCCl>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][N:5]=1
Reactant: C1COCCN1
Reactant: COCc1nccc(Cl)n1
Solvent: ClCCl
Product: COCc1nccc(N2CCOCC2)n1

Procedure:
A solution of 12 g of 2-methoxymethyl-4-chloropyrimidine and 15 ml of morpholine in 50 ml of dichloromethane was stirred at room temperature for 3 hours. The reaction solution was washed several times with water. The organic phase was dried and, after purification by column chromatography, yielded 13 g of 2-methoxymethyl4-morpholinopyrimidine as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:14]3[CH2:15][CH2:16][CH:10]2[CH2:11][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]3)=[N:7][CH:8]=1)#[N:2].Cl.[NH2:25][OH:26].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[OH:26][NH:25][C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:10]3[CH2:16][CH2:15][CH:14]2[CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11]3)=[N:7][CH:8]=1)=[NH:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2c1ccc(C#N)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2CCC(C1)N2c1ccc(C(=N)NO)cn1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
The product of step b) (7.6 g) is dissolved in 75 ml of ethanol, and a solution of 3.36 g of hydroxylamine hydrochloride dissolved in 38 ml of water is added, followed by addition of 5 g of sodium carbonate. The mixture is stirred at 90° C. for 4 hours. The resulting mixture is cooled and filtered. 8 g of the title compound are obtained in the form of a white solid.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][O:7][CH2:8][C@@H:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10](O)=[O:11].Cl.[CH3:31][O:32][NH:33][CH3:34].C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:27][C:24]([F:25])([F:26])[C:22]1[CH:21]=[C:5]([CH:4]=[C:3]([C:2]([F:28])([F:1])[F:29])[CH:23]=1)[CH2:6][O:7][CH2:8][C@@H:9]([NH:13][C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[C:10]([N:33]([O:32][CH3:31])[CH3:34])=[O:11]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)[C@@H](COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.5 %

Procedure:
To a solution of (2R)-3-{3,5-bis(trifluoromethyl)benzyloxy}-2-tert-butoxycarbonylaminopropionic acid (76.6 g, 176 mmol), N-methoxy-N-methylamine hydrochloride (18.53 g, 190 mmol) and triethylamine (25.6 mL, 190 mmol) in CH2Cl2 (400 mL) was added WSC.HCl (36.4 g, 190 mmol). The mixture was stirred at room temperature for 20 hours, washed with water and saturated brine in order. The organic extract was dried over sodium sulfate anhydride. Sodium sulfate was filtered off and the solvent was removed by evaporation from the filtrate under reduced pressure to give (2R)-3-(3,5-bis(trifluoromethyl)benzyloxy)-2-tert-butoxycarbonylamino-N-methoxy-N-methylpropionamide (76.4 g, 92%) as a pale brown oil.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1>>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:27]5[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)CC1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCN(c4ccc(C(F)(F)F)cn4)CC2)C3)CC1

Procedure:
The title compound is prepared from (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 39, the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5-trifluoromethyl-pyridine following a procedure analogous to that described for Example 79. LC (method 7): tR=1.63 min; Mass spectrum (ESI+): m/z=509 [M+H]+.
Reaction SMILES: Cl.[C:2]1(=N)[C:14]2[C:6]([C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:5][CH:4]=[CH:3]1.[NH4+:16].[OH-]>>[CH:2]1[C:14]2[C:13](=[NH:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: N=C1C=CC=C2C1=Cc1ccccc12
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Product: N=C1c2ccccc2-c2ccccc21
Yield: 58 %

Procedure:
The fluorenone (4.0 g, 22.2 mmol) was stirred in an autoclave of 110° C. for three days in an ammonia atmosphere (7 to 8 atm). After the reaction, it was allowed to dissolve in diethyl ether. And, hydrogen chloride was blown into it. It was stirred for one hour at room temperature. The obtained suspension was filtered, and the filtrate was cleaned with the diethyl ether. With this, fluorenone imine hydrochloride (3.4 g, 71%) was obtained. This hydrochloride was allowed to decompose with an ammonia aqueous solution. And, it was recrystallized by using the methylene chloride and hexane. And, Fluoren-9-ylideneamine (2.3 g, 58%) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[CH2:20][OH:21])[CH3:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>>[CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[CH2:20][O:21][C:31]([NH:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=1)=[O:32])[CH3:2]
Reactant: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1CO
Reactant: COc1cccc(N=C=O)c1
Product: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1COC(=O)Nc1cccc(OC)c1

Procedure:
Using dimethyl 2-[4-ethoxy-3-(hydroxymethyl)benzyl]-malonate and 3-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](Cl)=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.OC(C(F)(F)F)=O.[NH2:20][CH:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:30][CH:29]([NH:31][C:32]([CH2:34][NH:35][C:36](=[O:47])[C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=3)=[O:33])[CH2:28]2)[CH2:23][CH2:22]1>C(Cl)Cl>[F:46][C:43]([F:44])([F:45])[C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[C:36]([NH:35][CH2:34][C:32]([NH:31][CH:29]1[CH2:28][N:27]([CH:24]2[CH2:23][CH2:22][CH:21]([NH:20][C:10]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)=[O:11])[CH2:26][CH2:25]2)[CH2:30]1)=[O:33])=[O:47]
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: NC1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(NC(=O)c3ccc4c(c3)OCO4)CC2)C1
Reaction time: 2 h

Procedure:
Benzo[1,3]dioxole-5-carbonyl chloride (Aldrich, 74 mg, 0.404 mmol) was added into a solution of N-{[1-(4-amino-cyclohexyl)-azetidin-3-ylcarbamoyl]-methyl}-3-trifluoromethyl-benzamide TFA salt (as prepared in the previous step 200 mg, 0.404 mmol) and TEA (170 μL, 1.21 mmol) in DCM (5 mL) at 0° C. The reaction was stirred for an additional 2 hours and quenched with saturated sodium bicarbonate. The reaction was then partitioned between DCM and water. The organic layer was separated and the aqueous layer was extracted 3 times with a chloroform/IPA “cocktail” (˜3:1, v/v). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]2)(=[O:17])=[O:16])=[CH:11][C:5]=1[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH2:1]([O:3][C:4]1[N:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]2)(=[O:16])=[O:17])=[CH:11][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)c1cc(S(=O)(=O)N2CCN(CC)CC2)cnc1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
Ethyl 2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinoate (10.2 g, 0.0275 mol) was dissolved in toluene (50 mL) and a solution of sodium hydroxide (1.1 g, 0.0275 mol) in water (20 mL) added to it. This two phase mixture was then stirred vigorously at ambient temperature overnight. The aqueous phase was separated off and adjusted to pH=5.6 by addition of c. hydrochloric acid. The precipitated product was slurried with ice cooling for 15minutes, filtered, water washed and dried under vacuo at 50° C. to afford the title compound (4.1 g, 43%) as an off-white solid. Mpt 206-207° C. d (CDCl3): 1.25 (3H, t), 1.39 (3H,t), 2.82 (2H, q), 3.03 (4H, m), 3.25 (4H, m), 4.50 (2H, q), 8.25 (1H, d), 8.56 (1H, d). m/z (Found:344 [M+H]+, 100%. C14H22N3O5S requires 344.38).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C:11]2=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CO[C:22](OC)([N:24]([CH3:26])[CH3:25])[CH3:23]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[C:22]([N:24]([CH3:26])[CH3:25])[CH3:23])[C:11]2=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COC(C)(OC)N(C)C
Reactant: COc1ccc(N2C(=O)Cc3ccccc32)cc1Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(N2C(=O)C(=C(C)N(C)C)c3ccccc32)cc1Cl
Yield: 94.4 %

Procedure:
1-(3-Chloro-4-methoxyphenyl)-2(1H,3H)-indolone (0.67 g, 2.45 mmole), dimethylacetamide dimethylacetal (90%, 0.45 ml, 2.7 mmole) and 10 ml CHCl3 were refluxed under nitrogen for 3 hours. The reaction mixture was cooled and evaporated in vacuo to a viscous oil. The oil was column chromatographed on silica gel, eluting impurities with ethyl acetate and then product with 2-4% methanol in ethyl acetate, initially isolated as an oil (793 mg). Crystallization from ether gave purified title product, 625 mg, m.p. 138°-141°.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:9]([NH:11][CH2:12][C:13]([NH:15][C@H:16]([C:24]([NH:26][NH:27][C:28]([CH3:30])=[O:29])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])=[O:10])[CH2:3][CH2:4][S:5]([CH3:8])(=[O:7])=[O:6].[CH3:38][C:39]([O:42][C:43]([NH:45][C@H:46]([C:55]([O:57]CC1C=CC([N+]([O-])=O)=CC=1)=O)[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[CH:50][CH:49]=1)=[O:44])([CH3:41])[CH3:40]>>[NH:45]([C:43]([O:42][C:39]([CH3:38])([CH3:40])[CH3:41])=[O:44])[C@H:46]([C:55]([NH:1][C@@H:2]([C:9]([NH:11][CH2:12][C:13]([NH:15][C@H:16]([C:24]([NH:26][NH:27][C:28]([CH3:30])=[O:29])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])=[O:10])[CH2:3][CH2:4][S:5]([CH3:8])(=[O:7])=[O:6])=[O:57])[CH2:47][C:48]1[CH:49]=[CH:50][C:51]([OH:54])=[CH:52][CH:53]=1
Reactant: CC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](CCS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: CC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](CCS(C)(=O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C

Procedure:
Using BOC-(D)-Met(O2)-Gly-Phe-NHNH-COCH3 (0.52 g) and BOC-Tyr-ONB(0.46 g), the desired compound is obtained in a similar manner to (V) of Example 26. m.p. 176°-177° C. [α]D23 -2.9°(c=0.24, DMF), Rf1 =0.23.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27](=[O:41])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][C:37]([OH:39])=O)=[C:30]([CH3:40])[CH:29]=1.Cl.[CH3:43][C:44]([CH3:54])([CH3:53])[CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.CCN(C(C)C)C(C)C>ClCCl>[CH3:25][O:26][C:27](=[O:41])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][C:37]([N:50]2[CH2:51][CH2:52][N:47]([CH2:46][CH2:45][C:44]([CH3:54])([CH3:53])[CH3:43])[CH2:48][CH2:49]2)=[O:39])=[C:30]([CH3:40])[CH:29]=1
Reactant: COC(=O)c1ccc(CCCC(=O)O)c(C)c1
Reactant: CC(C)(C)CCN1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CCCC(=O)N2CCN(CCC(C)(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94 %

Procedure:
HBTU (910 mg, 2.4 mmol) was added to a solution of 4-(3-carboxy-propyl)-3-methyl-benzoic acid methyl ester from Example E30 (378 mg, 1.6 mmol) and 1-(3,3-dimethyl-butyl)-piperazine hydrochloride from Example E4 (467 mg, 1.9 mmol) in dichloromethane (15 ml) and DIEA (0.836 ml, 4.8 mmol). The mixture was stirred for 20 h at room temperature, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; 5% methanol:95% dichloromethane) to yield the title compound (582 mg, 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22](O)=[O:23])=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[CH:7][CH:8]=2)[N:3]=1.[CH3:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([NH:20][CH2:21][C:22]([N:27]([CH3:26])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:23])=[O:19])[CH2:16][CH2:17]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CNc1ccccc1
Reactant: Nc1cc(N2CCN(C(=O)NCC(=O)O)CC2)c2ccc(Cl)cc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)CNC(=O)N1CCN(c2cc(N)nc3cc(Cl)ccc23)CC1)c1ccccc1

Procedure:
As described for example 171, [[[4-(2-amino-7-chloro-4-quinolinyl)-1-piperazinyl]carbonyl]amino]-acetic acid, N-methyl-benzenamine, iPr2NEt, and HATU are reacted to afford the product. LC-MS: 452 (M++1). 1H NMR (CDCl3): δ 3.0–3.2 (m, 4H), 3.3 (s, 3H), 3.6–3.76 (m, 4H), 3.76–3.9 (d, 2H), 4.8–5.0 (s, 2H), 5.6–5.8 m, 1H), 6.1–6.2 (s, 1H), 7.13–7.18 (m, 1H), 7.2–7.25 (m, 2H), 7.36–7.48 (m, 3H), 7.6 (d, 1H), 7.68–7.72 (d, 1H).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)(=[O:5])[CH3:4]>CO>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:3]([OH:5])[CH3:4]
Reactant: CC(=O)c1ccccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.3 %

Procedure:
Sodium borohydride (344 mg; 9.08 mmol) was added portionwise to a solution of 2-acetylpyridine (500.0 mg; 8.25 mmol) in methanol. The reaction mixture was stirred overnight at room temperature. Quenched with water and extracted with ethyl acetate and solvent removed to yield 125 milligrams of 1-(2-pyridyl)ethanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH:11][C:12](=[O:32])[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:8][NH:7]1)=[O:5])[CH3:2].[C:33]([C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([C:48]([CH3:51])([CH3:50])[CH3:49])[C:45]=1[O:46][CH3:47])[C:40](O)=[O:41])([CH3:36])([CH3:35])[CH3:34].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH:11][C:12](=[O:32])[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:8][N:7]1[C:40](=[O:41])[C:39]1[CH:43]=[C:44]([C:48]([CH3:49])([CH3:50])[CH3:51])[C:45]([O:46][CH3:47])=[C:37]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:38]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H](NC(=O)CCCCC(c2ccc(F)cc2)c2ccc(F)cc2)CN1
Reactant: COc1c(C(C)(C)C)cc(C(=O)O)cc1C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)[C@@H]1C[C@H](NC(=O)CCCCC(c2ccc(F)cc2)c2ccc(F)cc2)CN1C(=O)c1cc(C(C)(C)C)c(OC)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To the solution of (2S,4S)-4-[6,6-Bis-(4-fluoro-phenyl)-hexanoylamino]-pyrrolidine-2-carboxylic acid ethyl ester (32) (0.39 g, 0.88 mmol) in dry CH2Cl2 (20 ml) was added 3,5-di-tert-butyl-4-methoxy benzoic acid (0.23 g, 0.88 mmol). To the reaction was added EDC (0.34 g, 1.76 mmol) and DMAP (cat), and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate: water (10:1) (150 ml). The organic was washed with water (30 ml, 2×) and 10% NaOH (10 ml), dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using pet ether: EtOAc (1:1) to give 0.46 g of desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[C:8]([CH:11]=1)[C:9]#[N:10])([O-:3])=[O:2].[OH:19][CH2:20][CH2:21][NH2:22].C([BH3-])#N.[Na+].Cl>O1CCCC1.CO>[OH:19][CH2:20][CH2:21][NH:22][CH:15]1[CH2:16][CH2:17][N:12]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]=2[C:9]#[N:10])[CH2:13][CH2:14]1
Reactant: NCCO
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N1CCC(=O)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CCC(NCCO)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Nitro-2-(4-oxopiperidin-1-yl)benzonitrile (5.0 g), 2-hydroxyethylamine (1.5 g) and sodium cyanoborohydride (1.3 g) were added to a mixed solvent of methanol (100 ml) and tetrahydrofuran (50 ml) and the mixture was stirred at room temperature for 1 h. An aqueous hydrochloric acid solution was added to keep the reaction mixture acidic. The solvent was evaporated under reduced pressure. Aqueous sodium hydroxide solution was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow precipitation, whereby the title compound (3.6 g) was obtained, melting point: 115° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:21](O)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([C:21]([N:1]3[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]3)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:14][CH:15]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCC1
Reactant: OCC1CCCNC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N1CCCC(CO)C1)C1(c2ccc(Cl)cc2)CCCC1
Temperature: 25 °C
Yield: 156.9 %

Procedure:
A solution of piperdin-3-yl methanol (0.342 g, 2.97 mmol), 1-(4-chloro-phenyl)-cyclopentylcarboxylic acid (1.0 g, 4.45 mmol), diisopropylethyl amine (1.9, 15.00 mmol) in dichloromethane (7 mL) was stirred at room temperature. PyBroP (2.07 g, 4.45 mmol) was added and the reaction mixture continued stirring at room temperature. After 12 h the reaction mixture was quenched with 10% KOH. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to yield a crude oil. The crude material was purified using silica gel chromatography (95:5 hexane:ethyl acetate) to yield the desired compound (1.50 g). C18H24ClNO2, LRMS (m/z)=322 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([SH:24])[CH:21]=[CH:22][CH:23]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[S:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH3:16])[CH:19]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COc1cccc(S)c1
Product: COc1cccc(Sc2ccnc3cc(OC)c(OC)cc23)c1
Temperature: 180 °C
Reaction time: 0.01 h
Yield: 98.4 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (50 mg) and commercially available 3-methoxybenzenethiol (77 mg) were mixed and stirred at 180° C. for 30 seconds. Purification was carried out in the same manner as described in Example 18 to obtain 72 mg of the title compound (yield: 100%).