Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-])=O>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17]
Reactant: COC(=O)c1ccccc1Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1Nc1ccccc1N
Reaction time: 20 h
Yield: 92 %

Procedure:
2-(2-Nitro-phenylamino)-benzoic acid methyl ester (200 mg, 0.74 mmol) is suspended in EtOAc (5.0 mL)) and 10% Pd/C wet (78 mg, 0.073 mmol) is added into it. A H2 balloon is attached to the reaction flask and the reaction mixture is stirred under H2 for 20 hrs. Then the Pd/C is filtered and the filtrated is concentrated to give 165 mg (93%) of 2-(2-Amino-phenylamino)-benzoic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[CH3:11]>S(=O)(=O)(O)O>[CH3:11][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:8]
Reactant: Cc1c(Cl)cccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: Cc1c(N)cccc1Cl
Temperature: 100 °C
Yield: 96.1 %

Procedure:
To a mixed solution of 150 g of stannous chloride and 200 ml of concentrated sulfuric acid under ice-cooling is added 29 g of 2-chloro-6-nitrotoluene. Then, the solution is heated at 100° C. for 1 hour, resulting in white crystals. The crystals are recovered by filtration and dissolved in a mixed solution of 400 ml of water and 50 ml of a 40% NaOH solution, followed by extracting with 500 ml of chloroform. After washing the extract with 400 ml of water, the chloroform layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure for concentration. Distillation of the resultant residue yields 23 g of 2-methyl-3-chloroaniline as the fraction of 115°-116° C./10 mmHg.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][SH:7])[CH3:3].[OH-].[Na+].[Cl:12][CH2:13][CH2:14][N:15]([CH2:39][CH2:40][Cl:41])[P:16]([N:32]([CH2:36][CH2:37][Cl:38])[CH2:33][CH2:34][Cl:35])(=[O:31])[O:17][CH2:18][CH2:19]OS(C1C=CC(Br)=CC=1)(=O)=O>CO>[Cl:41][CH2:40][CH2:39][N:15]([CH2:14][CH2:13][Cl:12])[P:16]([N:32]([CH2:36][CH2:37][Cl:38])[CH2:33][CH2:34][Cl:35])(=[O:31])[O:17][CH2:18][CH2:19][S:7][CH2:6][CH2:5][N:4]([CH2:8][CH3:9])[CH2:2][CH3:3]
Reactant: CCN(CC)CCS
Reactant: O=P(OCCOS(=O)(=O)c1ccc(Br)cc1)(N(CCCl)CCCl)N(CCCl)CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)CCSCCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl
Yield: 42.4 %

Procedure:
To a solution of 2-(diethylamino)ethanethiol hydrochloride (840 g, 5 mmol) in methanol (20 mL) was added NaOH (3.8 mL of 4M solution in methanol, 15 mmol, 3 eq.) and 2-(4-bromobenzenesulfonyloxy)ethyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate (7.0 mL of 0.7M solution in toluene, 4.9 mmol, 0.98 eq.). The mixture was stirred at room temperature until all the 2-(4-bromobenzenesulfonyloxy)ethyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate was consumed, as determined by HPLC-ELSD. The mixture was acidified to pH 7 with 1.0 M aqueous H3PO4 and concentrated under vacuum to a thick slurry. The slurry was taken up in ethyl acetate (400 mL) and washed with 5% aqueous NaHCO3 (2×400 mL) and then with aqueous HCl (2×400 mL). The acidic aqueous layers were combined and brought to pH>9 with solid NaHCO3, then extracted with ethyl acetate (2×800 mL). The ethyl acetate solution was separated, dried over anhydrous MgSO4, filtered, and concentrated under vacuum to give 2-{[2-(diethylamino)ethyl]thio}ethyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate as a clear oil (1.05 g, 42% yield). The 2-{[2-(diethylamino)ethyl]thio}ethyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate was oxidized to 2-{[2-(diethylamino)ethyl]sulfonyl}ethyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate and isolated as the hydrochloride salt using the procedure of Synthetic Example 1. MS (ES+): m/z=536 [C16H35Cl4N3O4PS+H]; 1H NMR (CD3OD): δ=1.36 (t, J=7.4 Hz, 6H), 3.28-3.34 (m, 2H), 3.40-3.50 (m, 10H), 3.65-3.77 (m, 14H), 4.51 (dd, J=5.1, 6.3 Hz, 2H); 31P NMR (CD3OD): δ=18.02.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:41])=[N:14][C:15]([CH3:40])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:41])=[N:14][C:15]([CH3:40])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][N:37]=[CH:38][CH:39]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3ccncc3)cc2)c1N1CCC(C)(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCc2ccncc2)cc1
Yield: 82.6 %

Procedure:
A solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(4-(pyridin-4-ylmethoxy)phenyl)pyridin-3-yl)acetate (0.013 g, 0.023 mmol) and 1M NaOH (0.232 ml, 0.232 mmol) in EtOH (1 mL) was refluxed for 6 h. Then, cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(4-(pyridin-4-ylmethoxy)phenyl)pyridin-3-yl)acetic acid (0.0101 g, 0.019 mmol, 82% yield) as solid. 1H NMR (500 MHz, DMSO-d6) δ 8.58 (d, J=5.5 Hz, 2H), 7.45 (d, J=5.1 Hz, 2H), 7.25 (d, J=7.7 Hz, 1H), 7.14-7.05 (m, 3H), 5.86 (s, 1H), 5.32-5.23 (m, 2H), 3.22 (d, J=12.1 Hz, 1H), 2.78 (t, J=12.3 Hz, 1H), 2.44 (s, 3H), 2.17 (d, J=11.4 Hz, 1H), 2.06 (s, 3H), 1.95-1.86 (m, 1H), 1.53-1.44 (m, 1H), 1.33-1.23 (m, 1H), 1.19-1.14 (m, 1H), 1.13 (s, 9H), 1.00 (d, J=12.5 Hz, 1H), 0.85 (s, 3H), 0.56 (s, 3H). LCMS (M+H)=532.25.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[CH:4][C:3]=1[O:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].[Cl-].[NH4+].C(O)C.O>O1CCCC1.[Fe]>[Br:1][C:2]1[C:3]([O:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[C:6]([CH:7]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(Br)c(Oc2ccc(F)cc2F)cc1Oc1ccc(F)cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(Br)c(Oc2ccc(F)cc2F)cc1Oc1ccc(F)cc1F
Temperature: 90 °C
Yield: 96.4 %

Procedure:
The product from Example 13A (0.578 g, 1.26 mmol), iron (0.352 g, 6.31 mmol), and ammonium chloride (0.101 g, 1.89 mmol) were combined in a mixture of tetrahydrofuran (9 mL), ethanol (9 mL), water (3 mL) and heated at 90° C. for 2 hours. The mixture was cooled, filtered through Celite and the Celite pad was washed repeatedly with methanol. The filtrate was concentrated and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4), filtered, and concentrated to afford the title compound (0.52 g, 96%).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH2:23][CH3:24])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:25])[N:5]=1)[CH3:2].[CH2:28]([C@H:30]1[O:32][CH2:31]1)Cl>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:28][C@H:30]4[CH2:31][O:32]4)=[C:17]([CH2:23][CH3:24])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:25])[N:5]=1)[CH3:27]
Reactant: ClC[C@@H]1CO1
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OC[C@H]1CO1
Reaction time: 24 h
Yield: 74.8 %

Procedure:
To a solution of 4-[5-(2-diethylamino-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (500 mg, 1.36 mmol) in isopropanol (15 mL) and 3 N aq. NaOH (6 mL), (S)-epichlorohydrine (378 mg, 4.09 mmol) is added. The orange solution is stirred at rt for 24 h before another portion of (S)-epichlorohydrine is added. Stirring is continued for 24 h, the mixture is diluted with EA, washed with sat. aq. NaHCO3-solution, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give diethyl-{4-[3-((R)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridin-2-yl}-amine (430 mg) as a yellow oil; LC-MS: tR=0.96 min; [M+1]+=423.21.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([C:16](OC)=[O:17])=[C:5]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[H-].C([Al+]CC(C)C)C(C)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][OH:17])=[C:5]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1c(CC(C)C)nc2ccc(Cl)cc2c1-c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)Cc1nc2ccc(Cl)cc2c(-c2ccccc2)c1CO
Temperature: -75 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a solution of methyl 6-chloro-2-isobutyl-4-phenylquinoline-3-carboxylate (0.97 g, 2.74 mmol) in toluene (20 ml) was added 1.0 M solution (6.9 ml) of diisobutylaluminum hydride in toluene under a nitrogen atmosphere at −75° C. After stirring the mixture at −75° C. for 1 hr., a solution of sodium sulfate (0.97 g) in water (10 ml) was added. The temperature of the mixture was raised to room temperature and the mixture was further stirred for 1.5 hrs. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and crystallized from diisopropyl ether to give (6-chloro-2-isobutyl-4-phenylquinolin-3-yl)methanol (0.73 g, yield 82%) as colorless crystals.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[CH:7]=[C:6]([F:17])[C:3]=1[C:4]#[N:5].[O-:18][CH2:19][CH3:20].[Na+]>CCO>[CH2:19]([O:18][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[CH:7]=[C:6]([F:17])[C:3]=1[C:4]#[N:5])[CH3:20]
Reactant: N#Cc1c(F)cc(N2CCC(O)CC2)cc1F
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc(N2CCC(O)CC2)cc(F)c1C#N
Temperature: 70 °C
Yield: 21.6 %

Procedure:
To a solution of 0.200 g (0.839 mmol) of the above benzonitrile in EtOH (2 mL), cooled to 0° C., was added 1.0 mL (3.1 mmol) of sodium ethoxide. The reaction was heated to 70° C. for 15 h then cooled to room temperature and an additional 1.0 mL (3.1 mmol) of sodium ethoxide was added. The mixture was heated to 70° C. for an additional 15 h. The reaction was cooled to room temperature and excess base was consumed by the addition of a saturated aqueous solution of NH4Cl. The mixture was diluted with H2O and washed with CH2Cl2. The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to provide after 0.048 g (21%) of 2-ethoxy-6-fluoro-4-(4-hydroxy-piperidin-1-yl)-benzonitrile as a white solid.
Reaction SMILES: [NH2:1]N.[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12]C2C=CC=C3C(NC(=O)C=23)=O)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1>CO>[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][NH2:1])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: O=C1NC(=O)c2c(CCCCN3CCOCC3)cccc21
Reactant: NN
Solvent: CO
Product: NCCCCN1CCOCC1

Procedure:
Hydrazine (aqueous solution at 35% by wt.) (0.15 ml; 1.6 mmoles) was added to 4-morpholinylbutylphthalimide (231 mg; 0.8 mmoles) in methanol (5 ml) and the resulting solution was refluxed. Reaction times and process as per Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[F:17])=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1ccccc1F
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccccc2F)cc1-c1c(Br)cnn1C
Yield: 91.7 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.034 g, 0.12 mmol) was treated with 2-fluorophenyl isocyanate (0.018 g, 14.4 μL, 0.12 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.10 to afford Compound 25 (0.045 g, 0.11 mmol, 91%) as a solid film. LCMS m/z (%)=419 (M+H79Br, 99), 421 (M+H81Br, 100). 1H NMR (400 MHz, CDCl3) δ: 8.08 (t, J=8.1 Hz, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 7.53-7.59 (m, 1H), 7.40 (s, 1H), 7.12 (d, J=1.5 Hz, 1H), 6.95-7.12 (m, 3H), 6.94 (d, J=5.7 Hz, 1H), 3.77 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15]([C:17]2[N:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH2:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[C:4]([NH:14][C:15]([C:17]3[N:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:16])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:27][CH:26]=1)[CH3:24]
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cccnn1
Reactant: CCc1ccc(B(O)O)cc1
Product: CCc1ccc(-c2cc(NC(=O)c3cccnn3)cnc2OCC(F)(F)F)cc1

Procedure:
The title compound was synthesized in analogy to Example 39, using pyridazine-3-carboxylic acid[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 62 a) and B-(4-ethylphenyl)-boronic acid (CAN 63139-21-9) as starting materials; LC-MS (UV peak area/ESI) 98.9%, 403.1386 (M+H)+.
Reaction SMILES: CN(C)CCCN[C:7]([C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[C:23](=[O:27])[NH:22][N:21]=[CH:20]3)=[CH:11][CH:10]=1)=[O:8].[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][OH:34].CCOCC>C1COCC1>[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][O:34][C:7]([C:9]1[CH:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[C:23](=[O:27])[NH:22][N:21]=[CH:20]3)=[CH:13][CH:14]=1)=[O:8]
Reactant: CN(C)CCCO
Reactant: CN(C)CCCNC(=O)c1ccc(/C=C/c2ccc3c(=O)[nH]ncc3c2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)CCCOC(=O)c1ccc(/C=C/c2ccc3c(=O)[nH]ncc3c2)cc1

Procedure:
The acid chloride (25 g) of Example 29 above was dissolved in THF (1250 ml) and 3-dimethylaminopropanol (250 ml) was added dropwise. After stirring overnight at room temperature ether (2 l) was added and the resulting precipitate was filtered. The crude ester (13.6 g) was purified via the hydrochloride salt, mp 288° C.
Reaction SMILES: [Na].[F:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]([CH2:17][C:18]([OH:20])=O)[NH:13][C:14](=[O:16])[CH:15]=2)[CH2:5]1.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][NH:26]2>>[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][N:26]2[C:18](=[O:20])[CH2:17][C:12]1[NH:13][C:14](=[O:16])[CH:15]=[C:10]([N:6]2[CH2:7][CH2:8][O:9][CH:4]([CH2:3][F:2])[CH2:5]2)[N:11]=1
Reactant: Fc1cccc2c1CCN2
Reactant: O=C(O)Cc1nc(N2CCOC(CF)C2)cc(=O)[nH]1
Agent: [Na]
Product: O=C(Cc1nc(N2CCOC(CF)C2)cc(=O)[nH]1)N1CCc2c(F)cccc21

Procedure:
The product is prepared by following the procedure described in step 3b of example 1b, but using 670 mg of the sodium salt of [4-(2-fluoromethylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid and 345 mg of 4-fluoro-2,3-dihydro-1H-indole. 161 mg of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-(2-fluoromethylmorpholin-4-yl)-3H-pyrimidin-4-one are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[C:12]2[CH:13]=[C:14]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]3=[O:29])[CH:15]=[CH:16][C:11]=2[S:10][N:9]=1.C(Cl)Cl.[CH3:33][OH:34]>[Ag]>[CH3:33][O:34][CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[C:12]2[CH:13]=[C:14]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]3=[O:29])[CH:15]=[CH:16][C:11]=2[S:10][N:9]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(-c4sccc4CBr)c3c2)c1=O
Reactant: CO
Agent: [Ag]
Solvent: ClCCl
Product: COCc1ccsc1-c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
To a mixture of 3-[3-[3-(bromomethyl)-2-thienyl]-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)uracil(1.00 g, 1.99 mmol), methylene chloride and methanol is added silver trifluorormethanesulfonate. The resultant white suspension is stirred overnight at room temperature and filtered through a pad of diatomaceous earth with methylene chloride wash. The filtrate is washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to a pale yellow solid, which is recrystallized from diethyl ether to afford the title compound (0.790 g, 87.7%, mp 131-133° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH2:16][CH2:15][C@H:14]([CH3:17])[C@H:13]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[CH2:12]2)[N:3]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]([N:11]2[CH2:16][CH2:15][C@H:14]([CH3:17])[C@H:13]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[CH2:12]2)[N:3]=1
Reactant: C[C@H]1CCN(c2ncc([N+](=O)[O-])c(N)n2)C[C@H]1C(=O)N1CCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1CCN(c2ncc(N)c(N)n2)C[C@H]1C(=O)N1CCCC1

Procedure:
A suspension of 10% palladium-on-carbon (350 mg) in ethanol was added to a solution of cis-(1-(4-amino-5-nitropyrimidin-2-yl)-4-methylpiperidin-3-yl)(pyrrolidin-1-yl)methanone (600 mg, 1.79 mmol) in ethanol (20 mL) at room temperature under nitrogen. The mixture was hydrogenated using a balloon filled with hydrogen gas at room temperature for 2 h. The suspension was filtered through a pad of Celite under a nitrogen atmosphere and the filtrate was used for the next without further purification.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:2].[Na+].[CH:15]1([N:18]2[C:22]3[CH:23]=[C:24]([C:28]4[C:33]([F:34])=[CH:32][N:31]=[C:30]([NH:35][C:36]5[CH:41]=[CH:40][C:39]([CH2:42][CH:43]6[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]6)=[CH:38][N:37]=5)[N:29]=4)[CH:25]=[C:26]([F:27])[C:21]=3[N:20]=[C:19]2[CH3:49])[CH2:17][CH2:16]1.ClCCCl>C(O)(=O)C>[CH:15]1([N:18]2[C:22]3[CH:23]=[C:24]([C:28]4[C:33]([F:34])=[CH:32][N:31]=[C:30]([NH:35][C:36]5[CH:41]=[CH:40][C:39]([CH2:42][CH:43]6[CH2:48][CH2:47][N:46]([CH2:1][CH3:2])[CH2:45][CH2:44]6)=[CH:38][N:37]=5)[N:29]=4)[CH:25]=[C:26]([F:27])[C:21]=3[N:20]=[C:19]2[CH3:49])[CH2:17][CH2:16]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1nc2c(F)cc(-c3nc(Nc4ccc(CC5CCNCC5)cn4)ncc3F)cc2n1C1CC1
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCN1CCC(Cc2ccc(Nc3ncc(F)c(-c4cc(F)c5nc(C)n(C6CC6)c5c4)n3)nc2)CC1
Temperature: 60 °C
Yield: 68.7 %

Procedure:
Add sodium triacetoxyborohydride (720 mg) to a mixture of [4-(3-cyclopropyl-7-fluoro-2-methyl-3H-benzoimidazol-5-yl)-5-fluoro-pyrimidin-2-yl]-(5-piperidin-4-ylmethyl-pyridin-2-yl)-amine (110 mg), 1,2 dichloroethane (1.14 mL) and acetic acid (2709 μL). Heat at 60° C. for 1 h. Remove the solvent under vacuum. Purify by strong cation exchange cartridge (SCX) eluting with methanol and then methanol-NH3 2M followed by silica gel column chromatography eluting with DCM/methanol-NH3 2M (3%) to afford 80 mg of the title compound. MS (ES+): m/z=504 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1B(O)O>>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: N#Cc1cc(-c2ccc(Cl)cc2Cl)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, light brown solid (46 mg, 52%), MS (ISP) m/z=356.4 [(M+H)+], mp 284.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 2,4-dichloro-phenylboronic acid (62.0 mg, 0.325 mmol).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:8][CH2:7][CH2:6][CH2:5][CH:4]=1.[CH2:9](Br)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[OH-].[K+]>C1(C)C=CC=CC=1>[CH2:24]([O:1][CH2:2][C:3]1[O:8][CH2:7][CH2:6][CH2:5][CH:4]=1)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: OCC1=CCCCO1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOCC1=CCCCO1
Yield: 84.9 %

Procedure:
5.71 g of 6-hydroxymethyl-3,4-dihydro-2H-pyran, 16.79 g of hexadecyl bromide and 8.22 g of pulverized 85% potassium hydroxide were mixed in 160 ml of toluene and heated under reflux for 2 hours. The mixtured was then cooled, washed with water, dried and condensed by evaporation under reduced pressure. The resulting oily residue, 17 g, was subjected to column chromatography through 400 g of silica gel. The fraction eluted with a 1:5 by volume mixture of diethyl ether and hexane gave 14.38 g of the title compound as a colorless oily substance.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([C:14]#[N:15])=[CH:9][C:8]=1[F:16])(=O)=O.[N-:17]=[N+:18]=[N-:19].[Na+]>O.CN(C=O)C>[N:17]([CH2:6][C:7]1[C:8]([F:16])=[CH:9][C:10]([C:14]#[N:15])=[C:11]([F:13])[CH:12]=1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCc1cc(F)c(C#N)cc1F
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(CN=[N+]=[N-])cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-cyano-2,5-difluorobenzyl methanesulfonate (4.5 g, 0.0182 mol; see step (iv) above) and sodium azide (2.0 g, 0.031 mol) in 20 mL of water and 40 mL of DMF was stirred at room temperature for 2 h. It was subsequently poured into 300 mL of water and extracted three times with diethyl ether. The combined ethereal phase washed several times with water, dried (Na2SO4) and evaporated. A small sample was evaporated for NMR purposes and the product crystallised. The rest was evaporated cautiously but not until complete dryness. Yield (theoretically 3.5 g) is assumed to be almost quantitative based on NMR and analytical HPLC.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)#[N:24].C([O-])([O-])=O.[Na+].[Na+]>>[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]2[C:7]([NH:9][C:10]2([C:13]3[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)=[O:8])=[CH:27][CH:26]=1)#[N:24]
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3)CC2)cc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3Cc3ccc(C#N)cc3)CC2)cc1
Yield: 74.6 %

Procedure:
The title compound (D121) (35 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from (R)-methyl 4-(1-(piperidine-2-carboxamido)cyclopropyl)benzoate (D87) (34 mg) and 4-Cyanobenzylbromide (33 mg). (Na2CO3: 4 eq; reaction time: 18 hrs; 68° C.)