Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:23])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCN(c2cccc([N+](=O)[O-])c2)CC1
Yield: 73 %

Procedure:
A solution of 3-iodo-nitrobenzene (3.0 g, 12.0 mmol), piperazine (1.6 g, 18.1 mmol), copper (I) iodide (0.23 ml, 1.2 mmol) and potassium carbonate (3.3 g, 24.1 mmol) in 40 ml DMSO was stirred at 45° C. for 16 hours. The run was quenched with 10 ml water and extracted with ethyl acetate (3×30 ml). The extraction was washed with water (2×30 ml) and dried over anhydrous sodium sulfate. 1-(3-Nitrophenyl)piperazine hydrochloride (2.0 g, 80%) was obtained when bubbling the HCl gas in ether solution. A solution of 1-(3-nitrophenyl)piperazine (1.50 g, 7.2 mmol), benzoyl chloride, and triethylamine (5.0 ml, 36.1 mmol) was stirred at 0° C. for 2 hours. The mixture was washed with water (2×30 ml) and dried over anhydrous sodium sulfate. (4-(3-Nitrophenyl)piperazin-1-yl)(phenyl)methanone (1.2 g, 73%) was obtained by flash column chromatograph (50% ethyl acetate in hexanes). The obtained (4-(3-nitrophenyl)piperazin-1-yl)(phenyl)methanone (1.2 g, 3.8 mmol) was dissolved in 30 ml ethanol and 10 ml THF, followed by the addition of platinum oxide (0.12 mg, 10%) and stirred under hydrogen gas for 16 hours. The reaction was filtered with the aid of celite. (4-(3-aminophenyl)piperazin-1-yl)(phenyl)methanone (0.81 g, 80%) was obtained by flash column chromatograph (90% ethyl acetate in hexanes), and its hydrochloride was made by bubbling HCl gas in ether solution. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 3.25 (s, br, 4H), 3.53 (d, br, 4H), 6.83 (dd, J=1.2, 7.7 Hz, 1H), 6.99 (s, 1H), 7.04 (d, J=8.4 Hz, 1H), 7.34 (t, J=8.2 Hz, 1H), 7.44-7.48 (m, 5H), 10.35 (s, br, 2H). 13C NMR (125 MHz, DMSO-d6): δ (ppm) 42.4, 48.1, 110.0, 112.8, 115.1, 120.2, 127.1, 127.2, 128.4, 129.6, 129.9, 130.2, 135.7, 151.0, 169.1.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][N:9]2[C:18]3[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.I.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](SC)=[NH:27]>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[N:1]1([CH2:6][CH2:7][CH2:8][N:9]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:26]([C:22]4[S:21][CH:25]=[CH:24][CH:23]=4)=[NH:27])=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc2c(c1)CCCN2CCCN1CCCC1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(Nc1ccc2c(c1)CCCN2CCCN1CCCC1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
To a stirred solution of 1-(3-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-amine (115 mg, 0.443 mmol) in ethanol (6 ml) under argon was added methyl thiophene-2-carbimidothioate hydroiodide (253 mg, 0.887 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was then diluted with water and sodium carbonate and extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed on silica gel using ethyl acetate, followed by 5-10% (2M NH3 in methanol) in dichloromethane as eluent to give the desired N-(1-(3-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximidamide (119 mg, 0.323 mmol, 72.8% yield). 1H NMR (DMSO-d6) δ 7.67 (d, J=3.6 Hz, 1H), 7.55 (d, J=5 Hz, 1H), 7.06 (dd, J=5, 3.6 Hz, 1H), 6.58 (brs, 2H), 6.48 (s, 1H), 6.27 (brs, 2H), 3.26-3.17 (m, 4H), 2.66 (t, J=6.3 Hz, 2H), 2.45-2.40 (m, 6H), 1.89-1.81 (m, 2H), 1.70-1.62 (m, 6H). ESI-MS (m/z, %) 369 (MH+, 47), 185 (100). ESI-HRMS calculated for C21H29N4S (MH+), calculated: 369.2122, observed: 369.2107. HPLC purity: >95%.
Reaction SMILES: F[C:2]1[C:9]([F:10])=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:26][NH2:27]>C(O)C>[NH2:5][C:4]1[C:3]2[C:2](=[C:9]([F:10])[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:13][CH:12]=3)=[CH:7][CH:6]=2)[NH:27][N:26]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C#N)c(F)c2F)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc3c(N)n[nH]c3c2F)cc1
Reaction time: 19 h

Procedure:
A solution of 0.8 g of 2,3-difluoro-4-(4-tert-butoxycarbonylaminophenyl)benzonitrile in 25 mL of absolute ethanol is admixed with 0.35 mL of hydrazine hydrate. The reaction mixture is stirred for 19 hours at the reflux of the solvent and then concentrated under reduced pressure. The solid residue is stirred with 25 mL of distilled water, filtered and washed with 2×5 mL of dichloromethane. After suction treatment, 0.54 g of 3-amino-7-fluoro-6-(4-tert-butoxycarbonylaminophenyl)-1H-indazole is obtained, whose characteristics are as follows:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:6][C:5]([C:18]#[N:19])=[CH:4][C:3]=1[NH:20]C(=O)OC(C)(C)C.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[NH2:20][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[C:2]=1[Cl:1])[C:18]#[N:19].[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]
Reactant: CN1CCN(CCCc2cc(C#N)cc(NC(=O)OC(C)(C)C)c2Cl)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(CCCc2cc(C#N)cc(N)c2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl (2-chloro-5-cyano-3-(3-(4-methylpiperazin-1-yl)propyl)phenyl)carbamate (49 mg, 0.125 mmol) was taken up in DCM (0.8 mL) and TFA (0.192 mL, 2.494 mmol) was added. The reaction was stirred at room temperature for 1 h. The solvent was removed in vacuo and the material azeotroped 2× with toluene. The material was dried under vacuum overnight. 3-amino-4-chloro-5-(3-(4-methylpiperazin-1-yl)propyl)benzonitrile, TFA (88 mg) was obtained as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[O:6][C@@H:5]2[O:7][C@H:8](/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:32]=[N:33][CH:34]=[N:35][CH:36]=4)=[CH:27][CH:26]=3)[C@H:9]([CH2:10][CH2:11][N:12]3[C:17](=[O:18])[C:16]4[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=4[N:14]=[N:13]3)[C@@H:4]2[O:3]1.O1CCCC1.[H][H]>[Pd].CO>[CH3:1][C:2]1([CH3:37])[O:6][C@@H:5]2[O:7][C@H:8]([CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]4[CH:32]=[N:33][CH:34]=[N:35][CH:36]=4)=[CH:29][CH:30]=3)[C@H:9]([CH2:10][CH2:11][N:12]3[C:17](=[O:18])[C:16]4[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=4[N:14]=[N:13]3)[C@@H:4]2[O:3]1
Reactant: CC1(C)O[C@@H]2O[C@H](/C=C/c3ccc(-c4cncnc4)cc3)[C@H](CCn3nnc4ccccc4c3=O)[C@@H]2O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2O[C@H](CCc3ccc(-c4cncnc4)cc3)[C@H](CCn3nnc4ccccc4c3=O)[C@@H]2O1

Procedure:
To the solution of the compound obtained from step k above (0.3 g) in a solvent mixture of tetrahydrofuran: methanol (10 mL, 1:1), 10% palladium on charcoal (0.15 g) was added at room temperature and the reaction mixture was hydrogenated with hydrogen at 35 psi for 4 hours in a Paar apparatus. The reaction mixture was filtered through a celite pad and the residue was washed with methanol. The filtrate was concentrated to afford the title compound (0.3 g).
Reaction SMILES: [CH2:1]([CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]1C(OC1C=CC=CC=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23]C1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[CH2:1]([C:8]1[CH:13]=[C:12]([Cl:23])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Oc1ccccc1)N1C=CC=CC1Cc1ccccc1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: Clc1ccnc(Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
The crude dihydropyridine intermediate is dissolved in benzene (100 ml) and heated to 65°. A solution of 2,3-dichloro 5,6-dicyanobenzoquinone (5.0 q) in warm benzene (50 ml) is added dropwise with stirring. The reaction mixture is stirred at 65° for one hour and then cooled to room temperature. The mixture is washed with 10% aqueous sodium bicarbonate (two portions of 100 ml each) and water (100 ml), then extracted with 2N hydrochloric acid (two portions of 150 ml each). The combined acid extracts are made alkaline with dilute aqueous sodium hydroxide and extracted with diethyl ether. After drying and concentration, the title compound is obtained as an oil (0.95 g) that can be further purified by chromatography on silica gel (using 4:1 by volume hexane-ethyl acetate as eluent). Structure assignment is confirmed by nmr spectroscopy. nmr (CDCl3): δ (ppm) 4.16 (s, 2H); 7.14-7.40 (m, 7H); 8.46 (d, 1H).
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]2[C@@H:28]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=4[CH2:35][C@@H:27]3[O:26][C:25]2=[O:36])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl>C1COCC1.CO.[OH-].[Na+]>[CH3:12][O:11][C:8]1[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]2[C@@H:28]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=4[CH2:35][C@@H:27]3[O:26][C:25]2=[O:36])=[CH:6][C:5]([CH2:4][C:3]([OH:37])=[O:2])=[CH:10][CH:9]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H]3Cc4ccccc4[C@H]32)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H]2Cc3ccccc3[C@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To [6-methoxy-2′-((3aR,8aS)-2-oxo-8,8a-dihydro-3aH-indeno[1,2-d]oxazol-3-ylmethyl)-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester (0.091 g, 0.18 mmol) in THF (0.9 mL) and MeOH (0.7 mL) was added IN aqueous NaOH (0.45 mL), and the reaction was stirred at room temperature for 2 hours. The mixture was acidified with 1N aqueous HCl and extracted with CH2Cl2. The combined organic layers were washed with H2O, dried over MgSO4, filtered, and concentrated to give the title compound. M+H is 498.
Reaction SMILES: N1(S(N[C:9](=O)[C:10]2[CH:15]=C(Cl)C(OCC3(C(F)(F)F)CCCC3)=CC=2F)(=O)=O)CCC1.Cl[C:31]1[C:32]([O:45][CH2:46][C:47]2([C:50]([F:53])([F:52])[F:51])[CH2:49][CH2:48]2)=[CH:33][C:34]([F:44])=[C:35]([CH:43]=1)[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[O:37]>>[CH:15]1([C:31]2[C:32]([O:45][CH2:46][C:47]3([C:50]([F:53])([F:52])[F:51])[CH2:49][CH2:48]3)=[CH:33][C:34]([F:44])=[C:35]([CH:43]=2)[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[O:37])[CH2:10][CH2:9]1
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(OCC2(C(F)(F)F)CC2)cc1F
Reactant: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(OCC2(C(F)(F)F)CCCC2)cc1F
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CC2)cc1F
Yield: 19 %

Procedure:
Following the procedure as described in Example 165 and making variations as required to replace N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclopentyl)-methoxy)benzamide with 5-chloro-2-fluoro-N-(methylsulfonyl)-4-((1-(trifluoromethyl)-cyclopropyl)-methoxy)benzamide. Purification by reverse-phase preparative HPLC to yield the title compound (0.047 g, 19%): 1H NMR (300 MHz, DMSO-d6) 11.94 (br s, 1H), 7.14 (d, J=8.3 Hz, 1H), 6.96 (d, J=12.9 Hz, 1H), 4.23 (s, 2H), 3.31 (s, 3H), 2.09-2.00 (m, 1H), 1.16-1.11 (m, 2H), 1.07-1.02 (m, 2H), 0.93-0.86 (m, 2H), 0.72-0.66 (m, 2H); MS (ES−) m/z 394.1 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:39]=[CH:38][C:5]([CH2:6][N:7]([CH3:37])[C:8]([O:10][C@H:11]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:31])[F:30])=[C:24]([O:32][CH2:33][CH:34]3[CH2:36][CH2:35]3)[CH:23]=2)[CH2:12][C:13]2[C:18]([Cl:19])=[CH:17][N+:16]([O-:20])=[CH:15][C:14]=2[Cl:21])=[O:9])=[CH:4][CH:3]=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>N1C=CC=CC=1.C(Cl)Cl.[NH4+].[Cl-]>[Cl:19][C:18]1[CH:17]=[N+:16]([O-:20])[CH:15]=[C:14]([Cl:21])[C:13]=1[CH2:12][C@@H:11]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:30])[F:31])=[C:24]([O:32][CH2:33][CH:34]2[CH2:35][CH2:36]2)[CH:23]=1)[O:10][C:8](=[O:9])[N:7]([CH3:37])[CH2:6][C:5]1[CH:38]=[CH:39][C:2]([NH:1][S:41]([CH3:40])(=[O:43])=[O:42])=[CH:3][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(Cc1ccc(N)cc1)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(Cc1ccc(NS(C)(=O)=O)cc1)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
(S)-4-(2-((4-aminobenzyl)(methyl)carbamoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (for reference procedure see Example 3, Table 5) (73.2 mg, 0.126 mmol) was dissolved in pyridine (3 ml) and cooled at 0° C. Methanesulfonyl chloride (13.71 μl, 0.176 mmol) was added, and the reaction was stirred RT for 1 hour. The reaction was diluted with DCM and aqueous sat. NH4Cl. The aqueous phase was extracted twice with DCM, the combined organic layers were dried and evaporated. The residue was purified by flash chromatography on silica gel cartridge (DCM/AcOEt=80/20 to 50/50) to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(methyl(4-(methylsulfonamido)benzyl)carbamoyloxy)ethyl)pyridine 1-oxide (69 mg, 0.104 mmol, 83% yield, MS/ESI+ 660.0 [MH]+.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[N:21]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([N:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[N:21]3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1
Reactant: c1ccc2[nH]ncc2c1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCc1oc(-n2ncc3ccccc32)nc1-c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 44.8 %

Procedure:
A mixture of methyl 3-[2-chloro-4-(4-chlorophenyl)-5-oxazolyl]propionate (1.50 g), 1H-indazole (1.18 g), potassium carbonate (1.38 g) and N,N-dimethylformamide (20 mL) was stirred at 120° C. for 3 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The obtained crystals were collected by filtration, dried and dissolved in a mixed solvent of tetrahydrofuran (20 mL) and ethanol (20 mL). A 1N aqueous sodium hydroxide solution (10 mL) was added, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was acidified with 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The obtained crystals were collected by filtration using isopropyl ether and dried to give 3-[4-(4-chlorophenyl)-2-(1H-indazol-1-yl)-5-oxazolyl]propionic acid (824 mg, yield 45%) as pale-yellow prism crystal. melting point: 204–205° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[N:9]([O-])=[O:10].[Na+].C(O)(=O)C>O>[OH:10][N:9]=[C:5]([C:6]#[N:7])[C:4]([O:3][CH2:1][CH3:2])=[O:8]
Reactant: O=N[O-]
Reactant: CCOC(=O)CC#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=NO

Procedure:
Ethylcyanoacetate (11.3 g, 100 mmol) is added to a solution of sodium nitrite (8.3 g, 120 mmol) in distilled water (50 ml) and acetic acid (8.0 ml=8.4 g, 140 mmol) is added to the stirred mixture. The ester disappears and soon yellow crystals of the sodium derivative start to separate. Next day the crystals are collected and then dissolved in 2N HCl (50 ml). The product is extracted with ether (four times, 50 ml each time) and the extracts dried over anhydrous Na2SO4. Removal of the solvent by evaporation in vacuo leaves a crystalline residue, ethyl 2-hydroxyimino-2-cyanoacetate, melting at 133° C. (12.4 g, 87%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:16]2[CH2:17][CH2:18][N:19]([CH:22]3[CH2:25][O:24][CH2:23]3)[CH2:20][CH:21]=2)=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:6][CH:7]=1.CCOC(C)=O>CCO.[Pd]>[F:1][C:2]1[C:3]([CH:16]2[CH2:17][CH2:18][N:19]([CH:22]3[CH2:25][O:24][CH2:23]3)[CH2:20][CH2:21]2)=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(F)c1C1=CCN(C2COC2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cncc(F)c1C1CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 46 h
Yield: 96.7 %

Procedure:
Pd on C, wet, Degussa (70 mg, 0.06578 mmol) was added to a stirred solution of tert-butyl N-[5-fluoro-4-[1-(oxetan-3-yl)-3,6-dihydro-2H-pyridin-4-yl]-3-pyridyl]carbamate (180 mg, 0.5152 mmol) in EtOH (5 mL)/EtOAc (5 mL). The reaction was placed under an atmosphere of hydrogen and stirred at ambient temperature for 46 hours. The catalyst was removed by filtration through a pad of celite and the filtrate concentrated in vacuo to give tert-butyl (5-fluoro-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-3-yl)carbamate as an off-white solid (175 mg, 97% Yield). MS (ES+) 352.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12](O)=[O:13])[C:5](=[CH:9][C:10]=1[Cl:11])[C:6](O)=[O:7].B.CSC>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[C:5]([CH2:6][OH:7])=[CH:9][C:10]=1[Cl:11]
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1C(=O)O
Agent: B
Solvent: CSC
Product: OCc1cc(Cl)c(Cl)cc1CO
Temperature: 0 °C

Procedure:
A 1.24 g portion of 4,5-dichlorophthalic acid is dissolved in 40 mL anhydrous tetahydrofuran and the solution is cooled to 0° C. To this solution is slowly added 4 mL of borane-methyl sulfide. The reaction flask is first warmed to room temperature, then heated to reflux for 12 hours. The product mixture is cooled to 0° C., then slowly quenched with 50 mL methyl alcohol. Following removal of the solvent, the residue is partitioned between 40 mL water, and 100 mL 1:1 ethyl acetate tetrahydrofuran. The organic layer is washed with 30 mL brine, then dried over magnesium sulfate. Purification by silica gel chromatography (2:1 ethyl acetate/hexane) affords 1.01 g of the desired product as a white solid, m.p. 128°-136° C.
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[OH-].[Na+].S(OC)(O[CH3:18])(=O)=O>CS(C)=O.O>[CH3:18][O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10]
Reactant: OCCCCCCCCCO
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COCCCCCCCCCO
Temperature: 40 °C
Yield: 21.9 %

Procedure:
a 500-mL, one-necked, round-bottom flask equipped with a magnetic stirrer and stir bar was charged with 1,9-nonanediol (10.00 g, 62.3 mmol) in dimethyl sulfoxide (100 mL) and H2O (100 mL). To this was added slowly a solution of sodium hydroxide (5.0 g, 125.0 mmol) in H2O (10 mL) at room temperature. During addition of sodium hydroxide the reaction mixture generated heat and the temperature rose to ˜40° C. The mixture was stirred for one hour, and then dimethyl sulfate (16.52 g, 131 mmol) was added in four portions while maintaining the temperature of the reaction mixture at ˜40° C. The reaction mixture was stirred at room temperature overnight. Progress of the reaction was monitored by TLC (Note 1). TLC monitoring indicated that the reaction was 25% conversion. At this stage additional dimethyl sulfate (24.78 g, 196.44 mmol) was added and the resulting mixture was stirred at room temperature for an additional 24 h. After completion of the reaction, sodium hydroxide (10% solution in water) was added to the reaction mixture to adjust the pH of the solution to 11-13. The mixture was stirred at room temperature for 2 h and extracted with dichloromethane (3×100 mL). The combined organic layers were washed with H2O (200 mL), brine (150 mL), dried over anhydrous sodium sulfate (20 g), filtered and concentrated in vacuo to obtain a crude product (14 g). The crude product was purified by column chromatography using 250-400 mesh silica gel. A solvent gradient of ethyl acetate in hexanes (10-50%) was used to elute the product from the column. All fractions containing the desired pure product were combined and concentrated in vacuo to give pure 9-methoxy-1-nonanol (lot D-1027-155, 2.38 g, 21.9%). Completion of the reaction was monitored by thin layer chromatography (TLC) using a thin layer silica gel plate; eluent: 60% ethyl acetate in hexanes.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:30]([N:32]=[C:33]=[O:34])[CH3:31]>>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:33]([NH:32][CH2:30][CH3:31])=[O:34])[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: CCN=C=O
Agent: Cl
Product: CCNC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Yield: 55.6 %

Procedure:
The compound (0.20 g) obtained in Example 1 and ethyl isocyanate (0.047 g) were reacted and treated in the same manner as in the method described in Example 6 to obtain the title compound as colorless oil (0.12 g, 74%).
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][C:4]=1[C:5](O)=[O:6])[CH3:2].[CH:31]1[C:44]2[C:35](=[N:36][C:37]3[C:42]([C:43]=2[NH:45][C:46]2[CH:47]=[C:48]([NH:54][C:55](=[O:59])[CH:56]([NH2:58])[CH3:57])[CH:49]=[C:50]([CH2:52][OH:53])[CH:51]=2)=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:34]=[CH:33][CH:32]=1>>[CH:41]1[C:42]2[C:37](=[N:36][C:35]3[C:44]([C:43]=2[NH:45][C:46]2[CH:47]=[C:48]([NH:54][C:55]([CH:56]([NH:58][C:5]([C:4]4[CH:8]=[C:9]([NH:14][C:15]([N:17]5[CH2:18][CH2:19][N:20]([C:23]6[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=6)[CH2:21][CH2:22]5)=[O:16])[C:10]([O:12][CH3:13])=[N:11][C:3]=4[CH2:1][CH3:2])=[O:6])[CH3:57])=[O:59])[CH:49]=[C:50]([CH2:52][OH:53])[CH:51]=2)=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:38]=[CH:39][CH:40]=1
Reactant: CC(N)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Reactant: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(C)cc(C)c3)CC2)cc1C(=O)O
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(C)cc(C)c3)CC2)cc1C(=O)NC(C)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 52.3 %

Procedure:
The same reaction procedure to the example 1 were carried out using 2-ethyl-5-{[4-(3,5-dimethylphenyl)-piperazine-1-carbonyl]-amino}-6-methoxy-nicotinic acid and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-2-aminopropaneamide to give the titled compound.