Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:16][C:15]3[CH2:14][CH2:13][NH:12][C:11](=[O:17])[C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[CH:25]1([CH:31]=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[CH:25]1([CH2:31][NH:1][C:2]2[N:7]=[C:6]([C:8]3[NH:16][C:15]4[CH2:14][CH2:13][NH:12][C:11](=[O:17])[C:10]=4[CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Nc1nccc(-c2cc3c([nH]2)CCNC3=O)n1
Reactant: O=CC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCc2[nH]c(-c3ccnc(NCC4CCCCC4)n3)cc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 40.3 %

Procedure:
2-(2-Amino-pyrimidin-4-yl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (140 mg, 0.61 mmol), trifluoroacetic acid (565 μl, 7.33 mmol), and cyclohexanecarbaldehyde (151 μl, 1.25 mmol) were mixed in DMF (10 ml). Sodium triacetoxyborohydride (390 mg, 1.84 mmol) was added to the above solution and the reaction mixture stirred at room temperature under N2 for 20 h. Additional cyclohexanecarbaldehyde (151 μl, 1.25 mmol) and sodium triacetoxyborohydride (390 mg, 1.84 mmol) were added and the reaction mixture was stirred 20 hours longer. The reaction was quenched with 0.33N NaOH (50 ml), and the product was extracted with DCM (50 ml). The DCM extract was dried (MgSO4), and the solvent was evaporated. The residue was purified by flash chromatography (DCM-MeOH, 95:5) to give the product as a beige solid (80 mg, 40% yield).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>O1CCCC1>[F:23][C:24]1[CH:25]=[C:26]([CH2:27][CH2:13][C:14]2[N:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1ncccc1C(=O)O
Reactant: Fc1cccc(CBr)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cccnc1CCc1cccc(F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Dissolve diisopropylamine (3.8 mL, 27.3 mmol) in dry tetrahydrofuran (75 mL). Chill the resulting mixture to −78° C. and add butyl lithium (1.6M solution in hexanes, 17.1 mL, 27.3 mmol). Warm the reaction mixture to 0° C. and add a fine slurry of 2-methyl-nicotinic acid (1.5 g, 10.9 mmol) in THF (25 mL) portionwise during 10 min. Stir the resulting slurry for 1 h, then add 3-fluorobenzyl bromide (2.0 mL, 16.4 mmol) and stir 5 min. Quench the reaction with water (100 mL). Extract the reaction mixture with diethyl ether (100 mL). Adjust the pH of the aqueous layer to 3.1 with concentrated aqueous hydrochloric acid solution. Treat the resulting slurry with ethyl acetate and stir to dissolve all solids. Separate the layers and extract the aqueous layer with ethyl acetate. Concentrate the combined extracts to dryness. LCMS (APCI-pos): 244.1 (M+H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH2:16][OH:17])=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:17][CH2:16][CH2:15][CH2:14][CH:13]([NH:18][C:19]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:25])[C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)NC(CCCO)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(CCCOS(C)(=O)=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
Methanesulfonyl chloride (0.511 mL, 6.60 mmol) was added dropwise to tert-butyl 1-(4-chlorophenyl)-4-hydroxybutylcarbamate (Intermediate 55) (1.80 g, 6.00 mmol) and triethylamine (1.004 mL, 7.20 mmol) in DCM (30.0 mL) at 25° C. over a period of 15 minutes under nitrogen. The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was evaporated to dryness and the residue was suspended in DCM, filtered and the filtrate purified by flash silica chromatography, elution gradient 20 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 4-(tert-butoxycarbonylamino)-4-(4-chlorophenyl)butyl methanesulfonate (2.270 g, 100%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH:10]([C:13]1[CH:14]=[CH:15][C:16]([S:19](Cl)(=[O:21])=[O:20])=[N:17][CH:18]=1)([CH3:12])[CH3:11]>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][S:19]([C:16]2[CH:15]=[CH:14][C:13]([CH:10]([CH3:12])[CH3:11])=[CH:18][N:17]=2)(=[O:20])=[O:21])=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)nc1
Reactant: COc1ccc(N)cn1
Product: COc1ccc(NS(=O)(=O)c2ccc(C(C)C)cn2)cn1

Procedure:
prepared by reaction of 6-methoxy-pyridin-3-ylamine with 5-isopropyl-pyridine-2-sulfonyl chloride
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:8])[C:6]=1[CH3:7].[C:9]([Cu])#[N:10].CCOCC>CN(C=O)C>[Br:8][C:5]1[C:6]([CH3:7])=[C:2]([C:9]#[N:10])[S:3][CH:4]=1
Reactant: N#C[Cu]
Reactant: Cc1c(Br)csc1Br
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1c(Br)csc1C#N

Procedure:
A mixture of 2,4-dibromo-3-methylthiophene (20.0 g, 78.1 mmol) and CuCN (6.30 g, 70.3 mmol) in 150 mL of DMF was stirred at reflux for 4 hours before cooling down. The reaction mixture was poured into 1 L of ether with stirring and the precipitate was removed by filtration. The filtrate was washed with water (100 mL×3), brine (100 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica column chromatography (petrol ether:EtOAc=50:1) to afford 4-bromo-3-methylthiophene-2-carbonitrile.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].C([O-])(O)=O.[Na+].[C:14](=O)([O:27]C1C=CC=CN=1)[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.O=C1C=CC=CN1C(OCCCCCC1CCCCC1)=O>O.C1COCC1>[CH:21]1([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:14]([NH:1][C@H:2]([C@@H:3]([OH:4])[CH3:5])[C:6]([OH:8])=[O:7])=[O:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(OCCCCCC1CCCCC1)Oc1ccccn1
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: O=C(OCCCCCC1CCCCC1)n1ccccc1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](O)[C@@H](NC(=O)OCCCCCC1CCCCC1)C(=O)O
Reaction time: 15 h
Yield: 81 %

Procedure:
To a stirred mixture of D-threonine (0.15 g, 1.25 mmol) and NaHCO3 (0.16 g, 1.89 mmol) in H2O (3.5 mL), the crude mixture containing 5-cyclohexylpentyl 2-pyridyl carbonate and 5-cyclohexylpentyl 2-oxopyridine 1-carboxylate (0.55 g, 1.5 mmol) in THF (3.5 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×5 mL). The aqueous phase was acidified with 2M HCl solution to pH 2-3 and subsequently extracted with AcOEt (3×10 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.32 g, 81%) as transparent oil, which was used in the next step without further purification. MS (ESI) m/z: 316 [M−H]+; (ESI) m/z: 314 [M−H]−. 1H NMR (DMSO-d6): δ 0.77-0.93 (m, 2H), 1.02-1.37 (m, 13H), 1.45-1.72 (m, 7H), 3.88-3.99 (m, 3H), 4.01-4.11 (m, 1H), 6.66 (d, J=9.0 Hz, 1H), 11.77 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9]Br)=[CH:4][CH:3]=1.O(CCCCBr)C1C=CC=CC=1.[OH:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33][OH:34])[CH:29]=[CH:30][CH:31]=1.OC1C=CC(CCO)=CC=1>>[F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][O:25][C:26]2[CH:27]=[C:28]([CH2:32][CH2:33][OH:34])[CH:29]=[CH:30][CH:31]=2)=[CH:4][CH:3]=1
Reactant: OCCc1cccc(O)c1
Reactant: Fc1ccc(OCCCBr)cc1
Agent: BrCCCCOc1ccccc1
Agent: OCCc1ccc(O)cc1
Product: OCCc1cccc(OCCCOc2ccc(F)cc2)c1
Yield: 95 %

Procedure:
By following the procedure of example 9 and using 3-(4-fluorophenoxy)propyl bromide rather than 4-phenoxybutyl bromide and 2-(3-hydroxyphenyl)ethanol rather than 2-(4-hydroxyphenyl)ethanol, the title compound was prepared.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([F:13])[C:3]=1[OH:14].[C:15]1([N:25]=[C:26]=S)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>CO>[C:15]1([NH:25][C:26]2[O:14][C:3]3[C:4]([F:13])=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=3[N:1]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1ccc(N)c(O)c1F
Reactant: S=C=Nc1cccc2ccccc12
Solvent: CO
Product: COC(=O)Cc1ccc2nc(Nc3cccc4ccccc34)oc2c1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.5 %

Procedure:
Methyl (4-amino-2-fluoro-3-hydroxyphenyl)acetate (996 mg, 5.00 mmol) was dissolved in methanol (50 ml). To the resulting solution was added 1-naphthyl isothiocyanate (926 mg, 5.00 mmol). After the resulting mixture was stirred at room temperature for 2 days, mercuric oxide (yellow) (1.08 g, 5.00 mmol) was added thereto. The mixture was stirred at 70° C. for 3.5 hours. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with methanol. The filtrate was distilled under reduced pressure to remove the solvent. The crude crystals thus obtained were recrystallized from chloroform/n-hexane to give methyl (2-(1-naphthylamino)-7-fluoro-6-benzoxazolyl)acetate (1.41 g, 81%) as a pale gray crystalline powder.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)[CH2:13]C[O:11][CH2:10]1)C1C=CC=CC=1.N[CH2:48]C1(N(CC2C=CC=CC=2)CC2C=CC=CC=2)COC1>>[NH2:8][C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][C:36]([CH3:48])=[CH:37][C:31]=4[S:30](=[O:38])(=[O:39])[CH2:29][CH2:28]3)[CH:17]=2)[CH2:10][O:11][CH2:13]1
Reactant: NCC1(N(Cc2ccccc2)Cc2ccccc2)COC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Product: Cc1ccc2c(c1)S(=O)(=O)CCN(c1cc(NCC3(N)COC3)c3cc(C)ccc3n1)C2

Procedure:
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro-6-methylquinolin-2-yl)-8-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 8-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-dichloro-6-methylquinoline) and 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 7.82 (d, J=7.83 Hz, 1 H), 7.68 (d, J=3.03 Hz, 2 H), 7.41 (d, J=6.57 Hz, 1 H), 7.33 (d, J=8.59 Hz, 1 H), 7.25 (dd, J=8.59, 1.52 Hz, 1 H), 6.42 (t, J=5.56 Hz, 1 H), 6.19 (s, 1 H), 5.05 (brs, 2 H), 4.45 (d, J=5.81 Hz, 3 H), 4.39 (d, J=6.06 Hz, 3 H), 3.60 (t, J=4.55 Hz, 2 H), 3.55 (d, J=5.31 Hz, 2 H), 2.37 (s, 3 H), 2.31 (s, 3 H).
Reaction SMILES: [CH2:1]([CH:8]([CH2:12][C:13](=[O:26])[C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][C@@H:28]([CH2:49][C:50]1[N:51]=[CH:52][NH:53][CH:54]=1)[C:29]([NH:31][C@@H:32]([CH2:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)[C@@H:33]([OH:41])[CH2:34][C@@H:35]([CH:38]([CH3:40])[CH3:39])[CH:36]=[CH2:37])=[O:30]>>[CH:43]1([CH2:42][C@H:32]([NH:31][C:29]([C@@H:28]([NH:27][C:9]([C@H:8]([CH2:12][C:13]([C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:26])[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:11])[CH2:49][C:50]2[N:51]=[CH:52][NH:53][CH:54]=2)=[O:30])[C@@H:33]([OH:41])[CH2:34][C@@H:35]([CH:38]([CH3:40])[CH3:39])[CH:36]=[CH2:37])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)CC(Cc1ccccc1)C(=O)O
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)Cc1ccccc1)C(C)C

Procedure:
In a manner analogous to that described in Example 27, by condensing (αRS,S)-α-benzyl-1-t-butoxycarbonyl-γ-oxo-2-pyrrolidinebutyric acid with (S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide and subsequent epimer separation by chromatography, there were obtained t-butyl (S)-2-[[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]acetyl]-1-pyrrolidinecarboxylate (less polar isomer) and t-butyl (S)-2-[[(R)-γ-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]acetyl]-1-pyrrolidinecarboxylate. MS: 734 (M+H)+
Reaction SMILES: [CH2:1]([NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH2:25])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:27]([O:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:28]>>[CH2:1]([NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH:25][C:27]([O:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:28])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)COC(=O)Cl
Reactant: NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccc1
Product: CC(C)(C)COC(=O)NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccc1

Procedure:
From 0.45 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid phenethylamide (precursor 5a) and neopentyl chloroformate, according to the general working procedure followed by extraction with EA and purification by flash chromatography 156 mg of 2′-(2,2-dimethylpropoxycarbonylaminomethyl)biphenyl-2-carboxylic acid phenethylamide were obtained. MS (ES+): m/e=445 (M+1).
Reaction SMILES: C(O)(=O)C(O)=[O:3].[CH3:7][N:8]([CH2:10][C@H:11]1[O:32][N:14]2[C:15]3[CH:27]=[C:26]([C:28]([O:30]C)=[O:29])[CH:25]=[CH:24][C:16]=3[O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C@@H:13]2[CH2:12]1)[CH3:9].[OH-].[Na+]>C(O)C.O>[OH2:3].[CH3:9][N:8]([CH2:10][C@H:11]1[O:32][N:14]2[C:15]3[CH:27]=[C:26]([C:28]([OH:30])=[O:29])[CH:25]=[CH:24][C:16]=3[O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C@@H:13]2[CH2:12]1)[CH3:7].[CH3:9][N:8]([CH2:10][C@H:11]1[O:32][N:14]2[C:15]3[CH:27]=[C:26]([C:28]([OH:30])=[O:29])[CH:25]=[CH:24][C:16]=3[O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C@@H:13]2[CH2:12]1)[CH3:7]
Reactant: COC(=O)c1ccc2c(c1)N1O[C@H](CN(C)C)C[C@H]1c1ccccc1O2
Reactant: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)C[C@@H]1C[C@H]2c3ccccc3Oc3ccc(C(=O)O)cc3N2O1
Yield: 41.6 %

Procedure:
(±)-Methyl cis-2-[(dimethylamino)methyl]-3,3a-dihydro-2H-dibenz[b,f]isoxazolo-[2,3-d][1,4]oxazepine-11-carboxylate ethanedioate(1:1)(1.53g), prepared following the procedure in example 7, in ethanol (60 ml) was added dropwise to a mixture of sodium hydroxide (0.3 g) in water (7.5 ml) and the mixture was stirred and refluxed for 2 hours. The solvent was evaporated in vacuo and the residue was acidified with HCl (4N) to a pH of 3.6. The precipitate was filtered off, dried with P2O5 and purified by short pad column chromatography over silica gel (eluent: CH2Cl2 /(CH3OH/NH3) 7/3). The pure fractions were collected and evaporated and the residue (1 g) was treated with CH2Cl2 /C2H5OH/H2O 25ml/5ml/5ml. The precipitate was filtered off and dried, yielding 0.5 g (38%) of (±)-cis-2-[(dimethylamino)methyl]-3,3a-dihydro-2H-dibenz[b,f]isoxazolo[2,3-d][1,4]oxazepine-11-carboxylic acid hemihydrate; mp. 229.8° C. (comp. 4).
Reaction SMILES: OC1C=C(CNC=C2C3C(=CC=C(I)C=3)C(=O)NC2=O)C=CC=1C1C=CC=CC=1.[C:30]([C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[C:40](=[O:44])[NH:39][C:38](=[O:45])[C:37]2=[CH:46]OC)([CH3:33])([CH3:32])[CH3:31].[NH2:49][CH2:50][C:51]1[C:52]([F:63])=[CH:53][C:54]([C:58]2[CH:62]=[CH:61][O:60][CH:59]=2)=[C:55]([OH:57])[CH:56]=1>>[C:30]([C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[C:40](=[O:44])[NH:39][C:38](=[O:45])[C:37]2=[CH:46][NH:49][CH2:50][C:51]1[CH:56]=[C:55]([OH:57])[C:54]([C:58]2[CH:62]=[CH:61][O:60][CH:59]=2)=[CH:53][C:52]=1[F:63])([CH3:33])([CH3:32])[CH3:31]
Reactant: NCc1cc(O)c(-c2ccoc2)cc1F
Reactant: COC=C1C(=O)NC(=O)c2ccc(C(C)(C)C)cc21
Agent: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Product: CC(C)(C)c1ccc2c(c1)C(=CNCc1cc(O)c(-c3ccoc3)cc1F)C(=O)NC2=O
Yield: 60 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound is prepared from 6-tert-Butyl-4-methoxymethylene-4H-isoquinoline-1,3-dione (11 mg, 0.042 mmol) and 5-Aminomethyl-4-fluoro-2-furan-3-yl-phenol (12 mg, 0.058 mmol) in 60% yield: MS (ESI): 433.2 (M−1)−1.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[N:19][CH:18]=[C:17](Cl)[N:16]=1.C([O-])([O-])=O.[K+].[K+].CCOCC>C(#N)C>[Cl:14][C:15]1[N:16]=[C:17]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH:18]=[N:19][CH:20]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)CC1
Temperature: 65 °C
Reaction time: 15 h
Yield: 89.9 %

Procedure:
A mixture of tert-butyl 1-piperazinecarboxylate (5.07 g, 27.2 mmol), 2,6-dichloropyrazine (3.38 g, 22.7 mmol), and K2CO3 (4.09 g, 30.0 mmol) in acetonitrile (20 mL) was stirred at 65° C. for 12.5 h and for a further 15 h at room temperature. Ether was added and the suspension was filtered. Concentration in vacuo fumished the crude product as an oil that crystallized upon standing. Purification by chromatography on silica gel using ethyl acetate/n-hexane (6:4) as eluent gave 6.1 g (90%) of the title compound as a solid. HRMS m/z calcd for C13H19ClN4O2 (M)+ 298.1197, found 298.1211. Anal. (C13H19ClN4O2) C, H, N.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[C:5]([O:9][CH2:10][CH3:11])(=[O:8])[NH:6][NH2:7]>C(OCC)C>[CH2:10]([O:9][C:5]([NH:6][NH:7][C:1]([Cl:4])=[O:2])=[O:8])[CH3:11]
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)NN
Solvent: CCOCC
Product: CCOC(=O)NNC(=O)Cl
Reaction time: 1 h
Yield: 90.1 %

Procedure:
Phosgene (100 ml, 1.41 mole) was condensed into a 2 l flask and anhydrous diethyl ether (160 ml) was added. The solution was kept at 0° C. in an ice bath and ethyl carbazate (103 g, 1 mole) in anhydrous diethyl ether (800 ml) was added dropwise over a period of 3 hr to the stirred phosgene solution. Stirring was continued for 1 hr after the end of the addition and ether and excess phosgene were removed by distillation. The crude solid product was re-dissolved in warm anhydrous ether (800 ml) and filtered in a dry atmosphere to remove insoluble by-products. Evaporation of the filtrate gave 2-ethoxycarbonylhydrazinecarbonyl chloride (150 g, 90%) m.p. 78°-80° C. Recrystallisation of a sample from a mixture of anhydrous diethyl ether and petroleum ether (1:2.5) gave a colourless crystalline solid mp 82°-6° C. (Lit 78°-80° C.). The ir spectrum of the product was in agreement with the published spectrum.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]1[CH2:22][CH2:21][C:14]2[N:15]=[C:16]([S:19][CH3:20])[N:17]=[CH:18][C:13]=2[CH2:12]1.[CH:23]([C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:23]([C:26]1[CH:27]=[C:28]([NH:29][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N:11]3[CH2:22][CH2:21][C:14]4[N:15]=[C:16]([S:19][CH3:20])[N:17]=[CH:18][C:13]=4[CH2:12]3)[CH:4]=2)[CH:30]=[CH:31][CH:32]=1)([CH3:25])[CH3:24]
Reactant: CSc1ncc2c(n1)CCN(c1cc(C(=O)O)ccc1C)C2
Reactant: CC(C)c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1ncc2c(n1)CCN(c1cc(C(=O)Nc3cccc(C(C)C)c3)ccc1C)C2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4-methyl-3-[2-(methylsulfanyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-yl]benzoic acid (67 mg, 0.212 mmol), 3-isopropylaniline (0.03 ml, 0.212 mmol) and N,N′-diisopropylethylamine (0.18 ml, 1.06 mmol) in DMF (1.0 ml) was treated with HATU (89 mg, 0.233 mmol). After stirring at room temperature for 1.5 hours, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with sat′d NaCl (aq.), dried (MgSO4), filtered, and concentrated. Trituration of the residue with cold MeOH yielded the title compound as a white, crystalline solid (50 mg, 55%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([Cl:31])=[C:12]([CH:30]=2)[C:13]([NH:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([NH2:29])=[O:28])[CH:17]=2)=[O:14])[C:5]([F:32])=[CH:4][CH:3]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].O.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[C:33]([NH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([Cl:31])=[C:12]([CH:30]=2)[C:13]([NH:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([NH2:29])=[O:28])[CH:17]=2)=[O:14])[C:5]([F:32])=[CH:4][CH:3]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1cc(NC(=O)c2cc(-c3nc(N)ccc3F)ccc2Cl)n(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(F)c(-c2ccc(Cl)c(C(=O)Nc3cc(C(N)=O)nn3-c3ccccc3)c2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
To a solution of 5-(5-(6-amino-3-fluoropyridin-2-yl)-2-chlorobenzamido)-1-phenyl-1H-pyrazole-3-carboxamide (Preparation 1, 23 mg, 0.05 mmol) in acetic acid (2 mL) was added acetic anhydride (0.5 mL) and the reaction was stirred at room temperature for 18 hours. The reaction was poured into water (50 mL) and basified by the addition of solid potassium carbonate. The aqueous solution was extracted with ethyl acetate (50 mL) and the organic layer was washed with brine (50 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 40-60% EtOAc in heptanes followed by trituration in TBME to afford the title compound as a white solid (10 mg, 40%).
Reaction SMILES: C(OC(=O)[N:10]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:46])[C:26]2[CH:31]=[CH:30][C:29]([CH2:32][N:33]([CH2:40][C:41]3[NH:42][CH:43]=[CH:44][N:45]=3)[CH2:34][C:35]3[NH:36][CH:37]=[CH:38][N:39]=3)=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)C1C=CC=CC=1.[H][H]>CO.C(O)C.[C].[Pd]>[NH:36]1[CH:37]=[CH:38][N:39]=[C:35]1[CH2:34][N:33]([CH2:32][C:29]1[CH:30]=[CH:31][C:26]([C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([CH2:17][NH:10][CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)=[CH:19][CH:20]=2)=[O:46])=[CH:27][CH:28]=1)[CH2:40][C:41]1[NH:45][CH:44]=[CH:43][N:42]=1
Reactant: O=C(Nc1ccc(CN(C(=O)OCc2ccccc2)C2CCCCC2)cc1)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: O=C(Nc1ccc(CNC2CCCCC2)cc1)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound (282 mg) obtained in Example 88-1 was dissolved in methanol (14 ml). After having been cooled with ice, the solution was added with a suspension of 10% palladium-carbon (140 mg) in ethanol (3.0 ml). After having been subjected to hydrogen displacement, the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. After the reaction, the reaction solution was filtrated through Celite and the solvent was then distilled off. Then, the residue was purified through silica gel column chromatography (chloroform/methanol/water) and treated with hydrochloric acid, thereby obtaining hydrochloride (47.1 mg) of the subject compound as a white solid.