Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16](C)[C:17](=O)OC(C)(C)C)=[N:13][C:12]=1[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][CH3:17])=[N:13][C:12]=1[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N(C)C(=O)OC(C)(C)C)sc1C(=O)NCc1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1nc(C)c(C(=O)NCc2ccccc2)s1

Procedure:
To a solution of tert-butyl 5-(benzylcarbamoyl)-4-methylthiazol-2-yl(methyl)carbamate (0.030 g, 0.083 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL) and the resultant mixture was stirred at ambient temperature for 4 h. Toluene (0.5 mL) was added and the reaction mixture was concentrated in vacuo. The residue was triturated with diethyl ether and concentrated in vacuo and dried in vacuum. The crude N-benzyl-4-methyl-2-(methylamino)thiazole-5-carboxamide was obtained and used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].Br[CH2:11][CH2:12][CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24].C([O-])([O-])=O.[Cs+].[Cs+].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[O:9][CH2:11][CH2:12][CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Oc1c(Cl)cccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCOc1c(Cl)cccc1Cl
Temperature: 50 °C
Reaction time: 16 h
Yield: 93.8 %

Procedure:
A solution of 2,6-dichlorophenol (500 mg, 3.07 mmol), tetrabutyl ammonium iodide (227 mg, 0.613 mmol) and 2-(3-bromopropyl)isoindoline-1,3-dione (905 mg, 3.37 mmol) was stirred in THF (5 mL) at rt. Cs2CO3 (1.80 g, 5.52 mmol) was added. The resulting mixture was stirred at 50° C. for 16 h. H2O was added to the reaction mixture and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by triturating with Et2O to yield Intermediate 9A (1010 mg, 2.88 mmol, 94% yield) as a white powder. LC-MS (ESI) 365 (M+H), RT=2.23 min (Method B).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.[Br:13]N1C(=O)CCC1=O>CN(C)C=O>[Br:13][C:11]1[C:2]([Cl:1])=[C:3]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:12])[CH2:5][CH2:4]2
Reactant: O=C1CCc2c(Cl)cccc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: O=C1CCc2c(ccc(Br)c2Cl)N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 5-chloro-3,4-dihydroquinolin-2(1H)-one (143-4; 0.4 g, 0.022 mol) in N,N-dimethylformamide (10 mL) was added N-bromosuccinimide (0.47 g, 0.0026 mol) portion wise at 0° C. Reaction mixture was allowed to stir at room temperature for 12 h. The reaction mixture was concentrated and diluted with ice cold water (100 mL) with constant stirring and the solid residue was filtered and dried to obtain the title compound. MS (M+1): 259.9.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:4]([CH:5]=[C:6]([O:11][CH3:12])[C:7]([F:10])([F:9])[F:8])[CH:3]1[C:13](O)=[O:14].S(Cl)([Cl:19])=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:16])[CH:4]([CH:5]=[C:6]([O:11][CH3:12])[C:7]([F:10])([F:9])[F:8])[CH:3]1[C:13]([Cl:19])=[O:14]
Reactant: COC(=CC1C(C(=O)O)C1(C)C)C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=CC1C(C(=O)Cl)C1(C)C)C(F)(F)F
Yield: 64 %

Procedure:
8.7 g (0.0365 mol) of 2,2-dimethyl-3-(3,3,3-trifluoro-2-methoxy-prop-1-enyl)-cyclopropanecarboxylic acid were dissolved in 100 ml of carbon tetrachloride, and 21 g of thionyl chloride were slowly added dropwise at 60° C., while stirring. The mixture was then heated to the reflux temperature for 4 hours. After this reaction time, excess thionyl chloride and carbon tetrachloride were distilled off under a waterpump vacuum. The residue was distilled in vacuo. 6 g (64.2% of theory) of 2,2-dimethyl-3-(3,3,3-trifluoro-2-methoxy-prop-1-enyl)-cyclopropanecarboxylic acid chloride were obtained as a slightly yellow liquid with a boiling point of 80° C./2 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=O)[CH3:11].Cl.[NH2:14][OH:15].N1C=CC=CC=1>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=[N:14][OH:15])[CH3:11]
Reactant: NO
Reactant: CC(=O)Cc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(Cc1ccc(Cl)cc1Cl)=NO
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
A solution of 1-(2,4-dichlorophenyl)-propan-2-one (3.46 g, 16.7 mmole) in methanol (40 ml) was treated with hydroxylamine hydrochloride (1.40 g, 20.6 mmol) followed by pyridine (1.7 ml, 20.6 mmol). The resulting mixture was stirred at ambient temperature over night for 16 hours. The reaction mixture was poured onto water (200 ml). The solid product was collected by filtration, washed with water and dried (40° C., 100 mbar). 3.63 g (100% of theory) of 1-(2,4-dichlorophenyl)-propan-2-one oxime was obtained in form of a white solid (m.p. 120-124° C.).
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[C:6]([CH3:14])[CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].[Cl:15][C:16]1[CH:21]=[C:20]([N:22]=[C:23]=[O:24])[CH:19]=[C:18]([Cl:25])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[C:20]([NH:22][C:23]([NH:2][NH:1][C:3]2[CH:12]=[C:11]([CH3:13])[C:10]3[C:5](=[C:6]([CH3:14])[CH:7]=[CH:8][CH:9]=3)[N:4]=2)=[O:24])[CH:19]=[C:18]([Cl:25])[CH:17]=1
Reactant: Cc1cc(NN)nc2c(C)cccc12
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Product: Cc1cc(NNC(=O)Nc2cc(Cl)cc(Cl)c2)nc2c(C)cccc12

Procedure:
A solution of 2-hydrazinyl-4,8-dimethylquinoline (100 mg, 0.53 mmol) and 100 mg (1.0 eq) of 1,3-dichloro-5-isocyanatobenzene was reacted as outlined in Scheme 1 above to give the desired title compound. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.51 (s, 3 H) 2.55 (s, 3 H) 6.77-6.80 (m, 1 H) 7.09 (t, J=1.76 Hz, 1 H) 7.17 (dd, J=8.20, 7.03 Hz, 1 H) 7.40 (d, J=6.74 Hz, 1 H) 7.65-7.72 (m, 3 H) 8.40 (br. s., 1 H) 8.62 (s, 1 H) 9.25 (br. s., 1 H).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH2:6]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O)C.[N:24]#[C:25]Br>C(Cl)Cl.C1(C)C=CC=CC=1.[OH-].[Na+]>[CH2:14]([N:13]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:25]#[N:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#CBr
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: N#CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a dry 2 L round bottom flask, equipped with an overhead stirrer, charged: sodium acetate (120 gm), 1 dibenzyl amine (100 gm) and 600 mL of ethanol. To this suspension at room temperature, was added a 3 M solution of cyanogen bromide in methylene chloride over 30 minutes (340 mL). The suspension was allowed to stir at ambient temperature until reaction completion was observed via HPLC. The reaction mixture was diluted with 1 L of toluene and 1 N sodium hydroxide was added over 15 minutes. The reaction mixture was stirred for 1 hour and the layers separated. The organic layer was dried over sodium sulfate, filtered, and concentrated to an oil that solidified upon standing. Recrystallization from a 1:1 2 L mixture of IPE/Heptanes gave 101 g (89%) of product. 1H NMR (400 MHz, CD3OD) 7.42-7.15 (m, 10H), 1.31 (s, 4H). 13C NMR (400 MHz, CD3OD) δ 135.1, 128.8, 128.7, 128.5, 118.0, 54.6. C, H, N Calculated (found) 81.05 (80.71), 6.35 (6.52), 12.60 (12.65)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][CH3:23])=[C:6]([C:8]2[N:9](C(OC(C)(C)C)=O)[CH2:10][CH2:11][O:12][CH:13]=2)[CH:7]=1>[Pt]=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][CH3:23])=[C:6]([CH:8]2[CH2:13][O:12][CH2:11][CH2:10][NH:9]2)[CH:7]=1
Reactant: CCOc1ccc(Cl)cc1C1=COCCN1C(=O)OC(C)(C)C
Agent: O=[Pt]
Product: CCOc1ccc(Cl)cc1C1COCCN1
Yield: 38 %

Procedure:
This compound was prepared from tert-butyl 5-(5-chloro-2-ethoxyphenyl)-2H-1,4-oxazine-4(3H)-carboxylate using procedures similar to those described in Example 3b above. Platinum oxide was used as a catalyst. The product was isolated as a brown solid (38% yield); 1H-NMR (d6-DMSO) 1.34 (3H, s), 2.87-3.00 (3H, m), 3.42 (2H, m), 3.72-3.76 (2H, m), 4.02-4.11 (3H, m), 6.97 (1H, d), 7.25 (1H, d), 7.47 (1H, brs); 13C-NMR (d6-DMSO) 14.6, 45.9, 52.9, 63.7, 66.5, 71.1, 113.2, 126.9, 127.5; MS ES(+) 242.8 (M++1); HRMS m/z calcd for C12H16ClNO2+H+ 242.0948 [M+H+]. Found 242.0958. IR λmax=1491, 1103, 806 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>>[F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:6]
Reactant: O=C(O)c1ccc(O)cc1F
Reactant: C1CN[C@H](CN2CCCC2)C1
Product: O=C(c1ccc(O)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure A from 2-fluoro-4-hydroxybenzoic acid [CAS 65145-13-3] and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine. MS (ES+) m/e 293.1
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[C:4](=[O:16])[C:3]=1[Br:17].C(N(CC)CC)C.[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:27]=1[C:28](Cl)=[O:29].[OH-].[Na+]>CN(C)C1C=CN=CC=1.C(#N)C>[Br:17][C:3]1[C:4](=[O:16])[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH:6]=[CH:7][C:2]=1[NH:1][C:28](=[O:29])[C:27]1[C:26]([F:25])=[CH:34][CH:33]=[CH:32][C:31]=1[F:35]
Reactant: Nc1ccn(Cc2cccc(F)c2)c(=O)c1Br
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1ccn(Cc2cccc(F)c2)c(=O)c1Br)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43 %

Procedure:
4-amino-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one (from step 3) (0.30 g, 1.01 mmol) and 4-dimethylaminopyridine (0.002 g, 0.01 mmol) were suspended in acetonitrile (5 mL) followed by dropwise addition of triethylamine (0.2 mL, 1.41 mmol). This reaction mixture was stirred for 10 minutes at room temperature before being cooled to 0° C. 2,6-difluorobenzoyl chloride (0.37 g, 2.12 mmol) was added dropwise and the reaction was heated at reflux overnight. The reaction was cooled to room temperature and 1N NaOH (10 mL) was added. The reaction was then stirred for 45 minutes at room temperature. The reaction mixture was extracted with ethyl acetate (3×25 mL) and the organic layer washed with 1N NaOH (2×25 mL), H2O (until pH neutral), brine (50 mL), dried over MgSO4, concentrated, and subjected to chromatography (on C-18, acetonitrile/H2O with 0.1% trifluoracetic acid) to afford a white solid (0.19 g, 43%). 1H NMR (400 MHz, CDCl3) δ 8.42 (br s, 1H), 7.67 (d, J=7.65 Hz, 1H), 7.49 (app tt, J=6.31, 8.60 Hz, 1H), 7.33-28 (m, 2H), 7.10-6.97 (m, 5H), 5.17 (s, 2H). ES-HRMS m/z 437.0083 (M+H C19H12BrF3N2O2 requires 437.0107).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1>C1COCC1.[Ni]>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1)[NH2:8]
Reactant: CS(=O)(=O)c1cc(Br)cc([N+](=O)[O-])c1
Agent: [Ni]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(N)cc(Br)c1

Procedure:
1-Bromo-3-methylsulfonyl-5-nitro-benzene (100 mg; 0.4 mmol) was dissolved in THF (10 ml). Raney-Nickel was added and the mixture hydrogenated at 1 bar. The reaction mixture was filtrated and concentrated. 30 mg (0.16 mmol; 40%) of target compound were obtained as a yellow solid.
Reaction SMILES: C([O-])=O.[NH4+].C([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1([N+:19]([O-])=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)(=O)C>[Pd].[C].CO>[NH:19]1[C:13]2([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:12][O:11][CH2:10][C:9]1=[O:8]
Reactant: CC(=O)OCCOCC1([N+](=O)[O-])CCCCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C1COCC2(CCCCC2)N1
Temperature: 50 °C

Procedure:
Under the nitrogen gas atmosphere, ammonium formate (5.75 g, 91.1 mmol) and 10% Pd-carbon (4.5 mg) was added in the methanol (90 mL) solution of (1-nitro-cyclohexylmethoxy)-ethyl acetate (4.5 g, 18.2 mmol) which had been obtained in 2), and the mixture was heated and stirred at 50° C. over-night. After that, the mixture was filtered with Celite, the filtrate was concentrated under reduced pressure, the residue was refined with silica gel column chromatography (Highflash 3L, manufactured by Yamazen Corporation, and the mixtures of hexane and ethyl acetate of 5:1, 1:1, and 1:2 in mixing ratio), and an orange-colored crystal of 4-oxa-1-aza-spiro[5.5]-undecan-2-one (1.67 g, 54%) was obtained.
Reaction SMILES: Br[CH:2]1[CH:7]2[CH:8]([OH:13])[CH:9]([OH:12])[CH:10]([OH:11])[C:3]1([CH2:15][OH:16])[O:4][C:5](=[O:14])[NH:6]2.[H][H]>O.[Pd]>[OH:13][CH:8]1[CH:9]([OH:12])[CH:10]([OH:11])[C:3]2([CH2:15][OH:16])[CH2:2][CH:7]1[NH:6][C:5](=[O:14])[O:4]2
Reactant: O=C1NC2C(O)C(O)C(O)C(CO)(O1)C2Br
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Product: O=C1NC2CC(CO)(O1)C(O)C(O)C2O
Reaction time: 8 h

Procedure:
In 100 ml of water is dissolved 2.0 g of 9-bromo-6,7,8-trihydroxy-1-hydroxymethyl-3-oxo-2-oxa-4-azabicyclo[3.3.1]nonane, and 400 mg of palladium black is added to the solution, followed by stirring for 8 hours in a stream of hydrogen at room temperature. The catalyst is filtered off and washed with water. The filtrate and washings are combined, adjusted to pH 6 by adding a saturated aqueous solution of sodium hydrogen carbonate, and concentrated under reduced pressure. The residue is chromatographed on a column of 250 ml of MCI Gel CHP 20P (produced by Mitsubishi Chemical Ind., Ltd., Japan), followed by elution with water. The eluate is chromatographed on a column of activated carbon (250 ml), and the column is washed with water, followed by elution with a water-methanol gradient. The eluate containing the objective compound is concentrated under reduced pressure, and methanol is added to the residue, which is then allowed to stand overnight in a refrigerator to give crystals of 6,7,8-trihydroxy-1-hydroxymethyl-3-oxo-2-oxa-4-azabicyclo[3.3.1]nonane. Yield of 780 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@:19]([CH2:32][OH:33])([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17]2)=[CH:12][C:11]=1[O:34][CH3:35].[CH3:36]I.[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[C@:19]([CH2:32][O:33][CH3:36])([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17]2)=[CH:12][C:11]=1[O:34][CH3:35]
Reactant: CI
Reactant: COC(=O)[C@]1(CO)CC[C@H](c2ccc(OCc3ccccc3F)c(OC)c2)N1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@@]1(C(=O)OC)CC[C@H](c2ccc(OCc3ccccc3F)c(OC)c2)N1C(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 85.1 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2R,5R)-5-[4-{[(2-fluorophenyl)methyl]oxy}-3-(methyloxy)phenyl]-2-(hydroxymethyl)-1,2-pyrrolidinedicarboxylate (D62, 170 mg, 0.35 mmol) and methyl iodide (44 μl, 0.70 mmol) in dry DMF (2 ml) at 0° C. was added NaH (60% dispersion in mineral oil) (21 mg, 0.52 mmol) and the mixture was stirred for 1.5 h from 0° C. to r.t. The reaction was quenched with brine and extracted with ethyl acetate. The organic layer was washed three times with ice cold brine, dried (Na2SO4) and evaporated and the residue was purified by chromatography on silica gel using cyclohexane/ethyl acetate (1:0 to 85:15) to afford the title compound as a colourless oil (150 mg, 86%); Rt (HPLC): 6.62 min; MS: (ES/+) m/z: 526 [M+Na] C27H34FNO7 requires 503.
Reaction SMILES: Cl.Cl.[F:3][CH2:4][C:5]([NH2:14])([CH2:10][CH2:11][CH2:12][NH2:13])[C:6](OC)=[O:7].C[O-].[Na+]>CO>[NH2:14][C:5]1([CH2:4][F:3])[CH2:10][CH2:11][CH2:12][NH:13][C:6]1=[O:7]
Reactant: COC(=O)C(N)(CF)CCCN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC1(CF)CCCNC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
To a solution of methyl 2-fluoromethyl-2,5-diaminopentanoate dihydrochloride (2.5 g) in methanol (30 ml) is added under nitrogen a solution of sodium methylate (prepared from 0.46 g of sodium) in methanol (20 ml). The reaction mixture is stirred for 1 hour at room temperature and then concentrated in vacuo. The residue is taken up in CH2Cl2. The insoluble material is removed by filtration, and the filtrate is concentrated to give 1 g of 3-amino-3-fluoromethyl-2-piperidone: m.p. 132° C. (from CH2CL2 /pentane).
Reaction SMILES: NCC1N2C3C=CC=C(F)C=3C=C2C2N=C([C:21]3[C:22]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])=[CH:23][C:24]4[O:28][C:27]([C:29]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=5)=[C:26]([C:36]([NH:38][CH3:39])=[O:37])[C:25]=4[CH:40]=3)C=CC=2O1.N1C=CC=CC=1.C(Cl)(=O)C>ClCCl.O>[F:35][C:32]1[CH:33]=[CH:34][C:29]([C:27]2[O:28][C:24]3[CH:23]=[C:22]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:43])=[O:44])[CH:21]=[CH:40][C:25]=3[C:26]=2[C:36]([NH:38][CH3:39])=[O:37])=[CH:30][CH:31]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CN)O4)cc12
Solvent: ClCCl
Solvent: CC(=O)Cl
Solvent: c1ccncc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)ccc12
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A mixture of 5-(6-(aminomethyl)-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (50 mg, 0.08 mmol), and pyridine (11 mg, 0.14 mmol) in dichloromethane (1 mL) was stirred at room temperature under N2 protection. Then acetyl chloride (11 mg, 0.14 mmol) was added and the solution was stirred at room temperature for 1.5 hours. Then the mixture was diluted with water (50 mL) and extracted with EtOAc (10 mL*3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-TLC (dichloromethane:MeOH=10:1) to provide 546-(acetamidomethyl)-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (30 mg, yield: 56.3%). And after SFC separation, two enantiomers were obtained. Column: Chiralpak AD-3 50*4.6 mm I.D., 3 um. Mobile phase: 60% ethanol (0.05% DEA) in CO2. Flow rate: 3 mL/min. Wavelength: 220 nm. Compound 129: RT=0.449 min, Compound 130: RT=1.264 minutes.
Reaction SMILES: [N:1]([CH:4]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[Cl:19])[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=[N+]=[N-].ClC1C(Cl)=CC=CC=1C=CC1C=CN=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[K+].Cl>C1COCC1.O>[Cl:19][C:13]1[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=1[CH:4]([NH2:1])[CH2:5][C:6]1[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=1
Reactant: [N-]=[N+]=NC(Cc1ccncc1)c1cccc(Cl)c1Cl
Agent: Cl
Agent: Clc1cccc(C=Cc2ccncc2)c1Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: NC(Cc1ccncc1)c1cccc(Cl)c1Cl
Reaction time: 0.25 h
Yield: 61.1 %

Procedure:
A mixture of (8) (81% pure, 3.82 g, 10.6 mmol) and (9) in THF (30 mL) was added triphenylphosphine (2.86 g, 10.9 mmol) at room temperature. After the solution was stirred for 15 minutes, potassium hydroxide (0.61 g, 10.9 mmol) in water (6 mL) was added. The resulting mixture was stirred at room temperature overnight. The mixture was acidified to pH˜3 with HCl (2M). The aqueous layer was washed numerous times with diethyl ether, and basified to pH>7 with NaOH (2M). The basic layer was extracted with ethyl acetate. The pooled organic layer was dried over magnesium sulfate. The mixture was filtered. Silica gel was added to the filtrate, and the solvent was removed under vacuum. Purification by chromatography on silica gel (2 to 10% methanol in dichloromethane) gave 1-(2,3-dichlorophenyl)-2-(pyridin-4-yl)ethanamine (10) as a solid (1.71 g, 6.48 mmol, 60% yield).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][C:44]=1[CH3:45])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1>CN(C)C=O.CN(C)C(=O)C>[Cl:1][C:2]1[S:3][C:4]([C:8]([NH:22][C:23]2[CH:24]=[C:25]([O:26][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]5[CH2:40][CH2:41]5)=[O:38])[N:35]=4)[N:32]=3)[CH:42]=[CH:43][C:44]=2[CH3:45])=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cc1nc(Cl)sc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1sc(Cl)nc1C
Yield: 90.2 %

Procedure:
In the same manner as in Example 259 and using 2-chloro-4-methyl-1,3-thiazole-5-carboxylic acid (140 mg, 0.80 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (170 μL, 2.0 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (270 mg, 91%) was obtained as a pale-green solid.
Reaction SMILES: [CH3:1]N(C)C=CC(C1N(C2CCC2)C(C)=NC=1)=O.[S:18]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:49]=[CH:48][C:31]([NH:32][C:33]3[N:38]=[C:37]([C:39]4[N:43]([CH:44]([CH3:46])[CH3:45])[C:42]([CH3:47])=[N:41][CH:40]=4)[CH:36]=[CH:35][N:34]=3)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)([CH3:21])(=[O:20])=[O:19]>COCCO>[S:18]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:49]=[CH:48][C:31]([NH:32][C:33]3[N:38]=[C:37]([C:39]4[N:43]([CH:44]5[CH2:46][CH2:1][CH2:45]5)[C:42]([CH3:47])=[N:41][CH:40]=4)[CH:36]=[CH:35][N:34]=3)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)([CH3:21])(=[O:19])=[O:20]
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(N4CCN(S(C)(=O)=O)CC4)cc3)n2)n1C(C)C
Reactant: Cc1ncc(C(=O)C=CN(C)C)n1C1CCC1
Solvent: COCCO
Product: Cc1ncc(-c2ccnc(Nc3ccc(N4CCN(S(C)(=O)=O)CC4)cc3)n2)n1C1CCC1
Temperature: 110 °C

Procedure:
5-(3-Dimethylaminoprop-2-en-1-oyl)-1-cyclobutyl-2-methylimidazole (Method 37 of WO 03/076435; 233 mg 1 mmol) and N-{4-[4-(methylsulphonyl)piperazin-1-yl]phenyl}guanidine (Method 1; 390 mg 1.3 mmol) in 2-methoxyethanol (8 ml) was stirred and heated for 18 hours at 110° C. The reaction mixture was evaporated under reduced pressure and the residue purified by chromatography on silica gel with MeOH:DCM (3:97 to 8:92). After evaporation and trituration with ether, the title compound was obtained as a yellow solid. (227 mg 48.5%). NMR: 1.60-1.71 (2×m, 2H), 2.36 (m, 4H), 2.49 (s, 3H), 2.91 (s, 3H), 3.18 (m, 4H), 3.25 (m, 4H), 5.51 (quintet, 1H), 6.91 (d, 1H), 6.97 (d, 2H), 7.30 (s, 1H), 7.54 (d, 2H), 8.33 (d, 1H), 9.23 (s, 1H); m/z 468.
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:8][C:9]1[C:14]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=2[F:23])=[C:13]([CH3:24])[C:12](=[O:25])[N:11]2[CH2:26][CH2:27][O:28][C:10]=12.C(OC(=O)C)C>N1C=CC=CC=1>[F:23][C:17]1[CH:18]=[C:19]([I:22])[CH:20]=[CH:21][C:16]=1[NH:15][C:14]1[C:9]([NH:8][S:4]([CH:1]2[CH2:3][CH2:2]2)(=[O:6])=[O:5])=[C:10]2[O:28][CH2:27][CH2:26][N:11]2[C:12](=[O:25])[C:13]=1[CH3:24]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCO2
Reactant: O=S(=O)(Cl)C1CC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC2)c2n(c1=O)CCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 3 %

Procedure:
Cyclopropane sulfonyl chloride (50 mg, 0.35 mmol) was added to a solution of 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one (I-7f: 80 mg, 0.199 mmol) in dry pyridine (1 mL) at 0° C. The resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (1.5% MeOH in DCM) afforded 3 mg of the product (3% yield).