Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH2:11]([O:13][CH:14]([O:23][CH2:24][CH3:25])[C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:12]>N1CCCCC1.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[C:16]([C:15]([CH:14]([O:13][CH2:11][CH3:12])[O:23][CH2:24][CH3:25])=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Reactant: COc1ccccc1C=O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1ccccc1OC)C(=O)C(OCC)OCC

Procedure:
A solution of 2-methoxybenzaldehyde (2.7228 g), ethyl 4,4-diethoxyacetoacetate (4.3648 g) and piperidine (4 or 5 drops) in benzene (20 ml) was refluxed under azeotropic dehydration for 3 hours. The resultant solution was washed with water and dried. The solvent was removed from the extract to give oily ethyl 2-(2-methoxybenzylidene)-4,4-diethoxyacetoacetate. The mixture of the compound obtained above and ethyl 3-aminocrotonate (2.5832 g) was heated in an oil bath (about 100° C.) for 7 hours. After cooling, the reaction mixture was extracted with diethyl ether, and the extract was washed with water twice and dried over magnesium sulfate. The solvent was removed to give a red oil. The oil was purified by a column chromatography on silica gel with an eluent (benzene: ethyl acetate=20:1) to give diethyl 2-methyl-4-(2-methoxyphenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (5.0779 g). The product was recrystallized from n-hexane to give pale yellowish prisms, m.p. 105° to 107° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:9]2[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13][C:8]=2[S:7][C:6]=1[C:21]([OH:23])=O)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:36][C:37]1[NH:41][N:40]=[N:39][N:38]=1.O>CN(C=O)C>[NH:38]1[C:37]([NH:36][C:21]([C:6]2[S:7][C:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C:9]=3[C:5]=2[O:4][CH:1]([CH3:3])[CH3:2])=[O:23])=[N:41][N:40]=[N:39]1
Reactant: CC(C)Oc1c(C(=O)O)sc2c1CN(C(=O)OC(C)(C)C)CC2
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1c(C(=O)Nc2nnn[nH]2)sc2c1CN(C(=O)OC(C)(C)C)CC2
Temperature: 85 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To a stirred solution of 1.43 g (4.2 mmol) of 3-isopropoxy-5-tert-butoxycarbonyl-6,7-dihydro-4H-thieno[3,2-c]pyridine-2-carboxylic acid in 15 mL of DMF were added 1.07 g (6.6 mmol) of 1,1'-carbonyldiimidazole. The reaction mixture was heated at 85° C. for 2 hours. 5-Aminotetrazole (0.655 g, 7.7 mmol) was added to the reaction mixture in one portion, and the mixture was stirred at 85° C. for 8 hours. The solution was cooled to 24° C. and stirred at that temperature for 18 hours. The reaction mixture was diluted by addition of 100 mL of water and was extracted three times with 50 mL portions of chloroform. The extracts were washed with 50 mL of 2N HCl, water, brine, dried over Na2SO4, and concentrated to dryness by evaporation of the solvent under reduced pressure. The residue was crystallized from 500 mL of diethyl ether to give 1.02 g of 3-isopropoxy-5-tert-butoxycarbonyl-6,7-dihydro-4H-thieno[3,2-c]pyridine-2-carboxylic acid (1H-tetrazol-5-yl) amide, mp 189°-191° C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:18]([NH:20][C@H:21]([C:26]([NH2:28])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:17])[NH:13][N+:14]([O-:16])=[O:15])=[O:5])[CH3:3].[NH:29](C(OC(C)(C)C)=O)[C@H:30]([C:41](O)=[O:42])[CH2:31][CH2:32][CH2:33][NH:34][C:35](=[NH:40])[NH:36][N+:37]([O-:39])=[O:38].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(O)(C(F)(F)F)=O.C(Cl)Cl>CN(C=O)C>[NH2:29][C@H:30]([C:41]([NH:1][C@H:2]([C:4]([NH:6][C@H:7]([C:18]([NH:20][C@H:21]([C:26]([NH2:28])=[O:27])[CH2:22][CH:23]([CH3:24])[CH3:25])=[O:19])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:17])[NH:13][N+:14]([O-:16])=[O:15])=[O:5])[CH3:3])=[O:42])[CH2:31][CH2:32][CH2:33][NH:34][C:35](=[NH:40])[NH:36][N+:37]([O-:39])=[O:38]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)[C@H](C)N)C(N)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCNC(=N)N[N+](=O)[O-])C(N)=O

Procedure:
From 515 g of H-Ala-Arg(NO2)-Leu-NH2 in 2.5 l of DMF and 333 g of Boc-Arg(NO2)-OH and 500 g of BOP, 607 g (85%) of a white solid monitored by TLC and NMR are obtained by employing the operational conditions described in Example I-1, after treatment with the mixture TFA-CH2Cl2.
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19]1[CH:20]=[C:21]([CH:25]([NH2:27])[CH3:26])[CH:22]=[CH:23][CH:24]=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:4]1([CH:3]=[CH:2][C:1]([NH:27][CH:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([O:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[CH:20]=2)[CH3:26])=[O:11])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: CC(N)c1cccc(Oc2ccccn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)C=Cc1ccccc1)c1cccc(Oc2ccccn2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of cinnamic acid (0.11 mmol), 1-[3-(pyridine-2-yloxyl)phenyl]-ethylamine (16.3 mg, 0.11 mmol), EDAC.HCl (42 mg, 0.22 mmol), DMAP (13 mg, 0.11 mmol) and Et3N (0.1 mL, 0.44 mmol) in CH2Cl2 (2 mL) was stirred at room temperature for 12 h. The reaction mixture was purified by flash column chromatography on silica gel eluting with 1:1/Hexane:EtOAc to give the title compound.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:15][CH2:16][C:17]([OH:19])=O)[CH3:14].[CH2:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:21]>C(Cl)Cl>[CH2:20]([N:22]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:17](=[O:19])[CH2:16][O:15][CH2:13][CH3:14])[CH3:21]
Reactant: CCOCC(=O)O
Reactant: CCNCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCOCC(=O)N(CC)Cc1ccccc1
Reaction time: 1 h
Yield: 89.1 %

Procedure:
A suspension of 1,1′-carbonyldiimidazole (4.68 g, 28.86 mmol) in dry DCM (15 mL) was added portion-wise over 15 min to a solution of ethoxyacetic acid (2.09 mL, 22.12 mmol) in DCM (30 mL) under nitrogen at room temperature. The resulting solution was stirred under nitrogen for 1 h and then treated with a solution of N-ethylbenzylamine (6.60 mL, 44.37 mol) in dry dichloromethane (30 mL) drop-wise over 15 min. The resultant solution was stirred under nitrogen at room temperature for 18 h and then partitioned with aqueous HCl (2M, 2×75 mL) and the combined organic layer dried (MgSO4), filtered and reduced in vacuo to give an oil. Purification by SPE (silica, 2×50 g cartridges), eluting with cyclohexane:EtOAc gradient 15:1 to 1:1 afforded the title compound as a pale yellow oil (4.36 g).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16].[CH3:18][S-:19].[Na+]>>[CH3:18][S:19][CH2:2][CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: C[S-]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCCl
Agent: [Na+]
Product: CSCCNc1c([N+](=O)[O-])cnc2ccccc12
Yield: 78.9 %

Procedure:
Using the general method of Example 21 Part D, N-(2-chloroethyl)-3-nitroquinolin-4-amine (6.0 g, 23.84 mmol) was reacted with sodium thiomethoxide (2.11 g of 95%, 28.61 mmol) to provide 4.95 g of N-[2-(methylthio)ethyl]-3-nitroquinolin-4-amine as a dull yellow solid.
Reaction SMILES: Cl.[C:2]1([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[CH2:32][C:33](O)=[O:34]>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][C:23]=1[CH2:32][C:33]([N:18]1[CH2:19][CH2:20][CH:15]([C:12]2[S:13][CH:14]=[C:10]([CH2:9][CH2:8][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:11]=2)[CH2:16][CH2:17]1)=[O:34]
Reactant: c1ccc(CCc2csc(C3CCNCC3)n2)cc1
Reactant: O=C(O)Cc1cc(C(F)(F)F)ccc1Cl
Agent: Cl
Product: O=C(Cc1cc(C(F)(F)F)ccc1Cl)N1CCC(c2nc(CCc3ccccc3)cs2)CC1

Procedure:
4-[4-(2-Phenylethyl)-1,3-thiazol-2-yl]piperidine hydrochloride (II-1, 309 mg) is reacted analogously to Example I-63 with [2-chloro-5-(trifluoromethyl)phenyl]acetic acid (262 mg). After chromatographic purification, this gives 2-[2-chloro-5-(trifluoromethyl)phenyl]-1-{4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone (210 mg).
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[Cl:47][C:48]1[N:53]2[CH:54]=[CH:55][N:56]=[C:52]2[C:51](I)=[CH:50][CH:49]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:64]([N:67]1[CH2:72][CH2:71][N:70]([C:73]2[CH:78]=[CH:77][C:76]([NH2:79])=[CH:75][CH:74]=2)[CH2:69][CH2:68]1)([CH3:66])[CH3:65]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:47][C:48]1[N:53]2[CH:54]=[CH:55][N:56]=[C:52]2[C:51]([NH:79][C:76]2[CH:75]=[CH:74][C:73]([N:70]3[CH2:69][CH2:68][N:67]([CH:64]([CH3:66])[CH3:65])[CH2:72][CH2:71]3)=[CH:78][CH:77]=2)=[CH:50][CH:49]=1
Reactant: Clc1ccc(I)c2nccn12
Reactant: CC(C)N1CCN(c2ccc(N)cc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)N1CCN(c2ccc(Nc3ccc(Cl)n4ccnc34)cc2)CC1

Procedure:
Palladium acetate (4.67 mg, 0.021 mmol) and rac-BINAP (12.95 mg, 0.021 mmol) are sonicated in toluene (4.5 mL) under nitrogen, at room temperature for 5 minutes in a microwave tube. 5-Chloro-8-iodo-imidazo[1,2-a]pyridine (116 mg, 0.417 mmol), Cs2CO3 (679.7 mg, 2.09 mmol) and 4-(4-isopropyl-piperazin-1-yl)-phenylamine (109.59 mg, 0.502 mmol) are then added at room temperature. The reaction mixture is then allowed to proceed at reflux for 16 hours at which point no starting material is visible by LC-MS. After concentration, the mixture is diluted in dichloromethane, and washed with 10% aqueous citric acid solution. The aqueous phase is then basified to pH 7 with saturated aqueous NaHCO3, and extracted with dichloromethane. The combined organic layers are dried (MgSO4) and the solvent is removed under reduced pressure to yield title compound, which is used as such for the next step.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][CH2:8][CH2:9][CH2:10][C:11]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)([O:15][CH3:16])[C:12]([OH:14])=O.[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[NH:25][NH2:26].O>C(Cl)Cl.CN(C=O)C.C(OCC)(=O)C>[Cl:7][CH2:8][CH2:9][CH2:10][C:11]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)([O:15][CH3:16])[C:12]([NH:26][NH:25][C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:14]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COC(CCCCl)(C(=O)O)c1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(CCCCl)(C(=O)NNC(=O)OC(C)(C)C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
Oxalyl chloride (44 μL) was added a mixed solution of 5-chloro-2-(4-fluorophenyl)-2-methoxyvaleric acid (108 mg) in methylene chloride (1 mL) and DMF (1 drop) under ice-cooling, and then the reaction solution was stirred at room temperature for 30 minutes. The acid chloride solution was added dropwise to a solution of tert-butyl carbazate (82 mg) and TEA (0.3 mL) in methylene chloride (2 mL) under ice-cooling, and the reaction solution was stirred at the same temperature for 10 minutes and at room temperature for 30 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was sequentially washed with 1 N hydrochloric acid, water, a saturated sodium bicarbonate solution and brine. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 90 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.COCOCCCCCCCCCC(O)=O.[CH:42]1([N:48]=[C:49]=[N:50][CH:51]2[CH2:56][CH2:55][CH2:54]CC2)CCCCC1>O1CCCC1>[CH3:1][N:48]([C:49]1[CH:54]=[CH:55][CH:56]=[CH:51][N:50]=1)[CH3:42]
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: COCOCCCCCCCCCC(=O)O
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 400 mg of radicicol, 595 mg of 10-(methoxymethoxy)decanoic acid, 6 ml of dry tetrahydrofuran, 567 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 739 mg of the title compound were obtained.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([CH3:5])=[O:4].[C-:8]#[N:9].[C-]#N.[Na+].Cl>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:4])([CH3:5])[C:8]#[N:9]
Reactant: [C-]#N
Reactant: CC(=O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Product: CC(O)(C#N)C(F)(F)F

Procedure:
In Scheme 2, 1,1,1-trifluoroacetone (1) is reacted with a cyanide such as sodium cyanide in the presence of an acid such as hydrochloric acid to form racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropanenitrile (2). The racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropanenitrile (2) is then hydrolyzed with, for example, hydrochloric acid or sulfuric acid to provide racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (3). Racemic (3) is then selectively crystallized with a resolving agent such as (lR,2S)-norephedrine (4) to form a salt (5) which may be recrystallized to diastereomeric purity. The purified salt (6) contains (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (7). (S)-3,3,3-Trifluoro-2-hydroxy-2-methylpropanoic acid (7) after liberation from the salt is reacted with 4-aminobenzophenone (8) and SOCl2 using an organic base such as triethylamine or Hunig's base to form (S)-(−)-N-(4-benzoylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (9), which can then be purified by recrystallization.
Reaction SMILES: [C:1]1(=[O:22])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][S:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[C:4](=[O:17])[C:3]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]12.[BH4-].[Na+]>C(O)C>[OH:22][CH:1]1[C:2]2[C:3](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:4](=[O:17])[N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCSc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1c2ccccc2C(O)N1CCCCSc1ccncc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 27.5 %

Procedure:
To a solution of 6.25 g (20.0 mmol) of 4-(4-phthalimidobutylthio)pyridine in 300 ml of ethanol, 1.51 g (40 mmol) of sodium borohydride was added, and the mixture was stirred at room temperature for 2.5 hours. The solvent was distilled off and saturated saline was added to the residue. The mixture was extracted with chloroform and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate) to give 1.73 g of the desired compound (27.5% yield, colorless crystals), mp. 144°-145° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9]Cl)=[CH:3][CH:2]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CS(C)=O.CCOC(C)=O>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][N:11]=[N+:12]=[N-:13])=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: ClCCCc1ccncc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCCc1ccncc1
Temperature: 65 °C

Procedure:
A solution of 2-3 (7 g, 41.2 mmol) in DMSO (150 mL) was treated with sodium azide (2 g, 45.3 mmol) and heated to 65° C. for 72 h. The solution was diluted with EtOAc, washed with H2O and saturated NaHCO3. The H2O washing was basified to pH11 and extracted with EtOAc. The organic layers were combined, dried with brine and MgSO4, filtered and evaporated to give 2-4 as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:15]1([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([O:21][C:2]2[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: OC1CCCCC1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(OC2CCCCC2)c(C(=O)O)c1

Procedure:
Prepared in analogy to Example A1 (b) from 2-chloro-5-methanesulfonyl-benzoic acid (Example A1(a)) and cyclohexanol. The crude material was purified by preparative HPLC to yield the title compound as a white solid. MS (m/e): 297.3 ([M−H]−, 100%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([NH:11][C@@H:12]([C:19]([OH:21])=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:3][CH:2]=1.[C:22]([N:29]1[CH2:34][CH2:33][CH:32]([CH:35]2[CH2:40][CH2:39][N:38]([C:41]([NH2:43])=[O:42])[CH2:37][CH2:36]2)[CH2:31][CH2:30]1)(OC(C)(C)C)=O.C([BH3-])#N.[Na+].N>C(#N)C.C=O>[CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([NH:11][C@@H:12]([C:19]([OH:21])=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:3][CH:2]=1.[CH3:22][N:29]1[CH2:30][CH2:31][CH:32]([CH:35]2[CH2:40][CH2:39][N:38]([C:41]([NH2:43])=[O:42])[CH2:37][CH2:36]2)[CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(C(N)=O)CC2)CC1
Agent: C=O
Agent: N
Agent: O=C(N[C@@H](C(=O)O)c1ccccc1)OCc1ccccc1
Solvent: CC#N
Product: CN1CCC(C2CCN(C(N)=O)CC2)CC1
Reaction time: 3 h

Procedure:
To a solution of CBz-D-phenylglycine-4-[1-(Boc)piperidin-4-yl]piperidinamide (1.1 g, 2.5 mmol) in acetonitrile (40 ml) and aq. formaldehyde (10 ml) was added sodium cyanoborohydride (315 mg, 5 mmol) portionwise over 10 min. The reaction mixture was left to stir for 3 hours and then poured onto water (50 ml), containing conc ammonia solution (5 ml) and left to stir for 15 min. Extraction with ethyl acetate (100 ml), washing with brine and drying gave the title compound as a colourless oil (1.1 g, 97%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][O:13][CH2:14][CH2:15][NH:16][CH3:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH3:12][O:13][CH2:14][CH2:15][N:16]([CH3:17])[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=1
Reactant: CNCCOC
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCCN(C)c1ccc([N+](=O)[O-])c(N)c1
Temperature: 117.5 °C
Reaction time: 48 h
Yield: 73.4 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (2.2 g, 12.7 mmol), (2-methoxy-ethyl)-methyl-amine (3.0 g, 33.7 mmol) and anhydrous potassium carbonate (1.93 g, 14 mmol) in N,N-dimethylacetamide (5 ml) was stirred at 115-120° C. under nitrogen for 2 days. Sample NMR analysis showed complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured into cold water (20 ml) and stirred vigorously and cooled at 5° C. overnight. The resulting yellow brown precipitate was collected by filtration, washed well with water then dried on the filter funnel. The resulting yellow brown solid was slurried in diethyl ether (20 mL), filtered, washed with additional diethyl ether, dried to afford N1-(2-methoxy-ethyl)-N1-methyl-4-nitro-benzene-1,3-diamine (2.1 g, 72%) as a yellow brown powder.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[NH:7][C:8](=[O:14])[CH:9]=[CH:10]OCC)([OH:3])=[O:2].[OH-].[Na+]>S(=O)(=O)(O)O>[C:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:6]2[C:5]=1[CH:10]=[CH:9][C:8](=[O:14])[NH:7]2)([OH:3])=[O:2]
Reactant: CCOC=CC(=O)Nc1cccc(C(=O)O)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cccc2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8 Grams of m-carboxy-N-(β-ethoxyacryloyl)aniline was added in 80 ml of concentrated sulfuric acid and stirred at a room temperature for 2 hours, then stirred at 50° C. for 1 hour. The reaction mixture was poured into ice and the pH of the mixture was adjusted to pH 3-4 by adding 10N-sodium hydroxide aqueous solution. The precipitated crystals were collected by filtration and washed with water, recrystallized from dimethylformamide to obtain 4.26 g of 5-carboxycarbostyril. Light yellow powdery crystals. Melting point: over 320° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:25]([NH:27][CH:28]([CH3:30])[CH3:29])[CH3:26]>>[CH2:25]([N:27]([CH:28]([CH3:30])[CH3:29])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)[CH3:26]
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: CCNC(C)C
Product: CCN(CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1)C(C)C

Procedure:
The product from Example 1C and ethyl(isopropyl)amine were processed as described in Example 1D to provide the titled compound. MS (DCI) m/z 333 (M+H)+;
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].S(O[CH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1)(=O)(=O)C>CC(N(C)C)=O>[C:46]([O:45][C:43]([N:40]1[CH2:41][CH2:42][CH:37]([CH2:36][O:17][C:11]2[CH:10]=[C:9]3[C:14]([C:5]([O:4][C:3]4[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:2]=4[F:1])=[CH:6][CH:7]=[N:8]3)=[CH:13][C:12]=2[O:15][CH3:16])[CH2:38][CH2:39]1)=[O:44])([CH3:49])([CH3:47])[CH3:48]
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
To a solution of the 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-hydroxyquinoline (609 mg, 1.8 mmol) in DMA (9 mL) was added K2CO3 (1.24 g, 9.0 mmol) and N-Boc-4-piperidinemethanol mesylate (732 mg, 2.5 mmol). The mixture was then stirred at 80° C. for 2.5 h. After it was cooled to rt, the mixture was loaded directly to a Biotage column, and eluted with solvents (hexanes:EtOAc=1:3). The resulting product, 4-[4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester, was obtained as a solid (556 mg, 56%).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][N:11]([CH3:22])[C:12]2[NH:17][C:16]([Cl:18])=[N:15][C:14](=[N:19][NH2:20])[C:13]=2[F:21])[N:9]=1.[CH:23]1([CH2:28][C@H:29]([CH2:33][N:34]([CH:42]=[O:43])[O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[C:30](O)=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24]1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[NH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][N:11]([CH3:22])[C:12]2[N:17]=[C:16]([Cl:18])[N:15]=[C:14]([NH:19][NH:20][C:30](=[O:31])[C@H:29]([CH2:28][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH2:33][N:34]([O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[CH:42]=[O:43])[C:13]=2[F:21])[N:9]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Reactant: CN(Cc1csc(N)n1)c1[nH]c(Cl)nc(=NN)c1F
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CN(Cc1csc(N)n1)c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-[[(2-Amino-1,3-thiazol-4-yl)methyl](methyl)amino]-2-chloro-5-fluoro-4(1H)-pyrimidinone hydrazone trihydrochloride (150 mg, 0.29 mmol), (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (120 mg, 0.4 mmol), and HOAt (59 mg, 0.43 mmol) were dissolved in 10 mL of DMF. NMM (0.2 mL, 1.8 mmol) was added, followed by EDC (85 mg, 0.43 mmol). After stirring overnight at room temperature, the reaction mixture was purified by RP-HPLC [(2R)-3-(2-{6-[[(2-amino-1,3-thiazol-4-yl)methyl](methyl)amino]-2-chloro-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (110 mg, 52%). LCMS: (M+H)+: 585.2.