Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]=[C:32]=[CH:33][CH3:34])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:11]([C:35]([OH:37])=O)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:38][N:39]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.NO>O.CN(C)C=O>[C:1]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH:31]=[C:32]=[CH:33][CH3:34])=[CH:27][CH:28]=2)(=[O:21])=[O:22])[CH:11]([C:35]([NH:39][OH:38])=[O:37])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: CC=C=CCOc1ccc(S(=O)(=O)N2Cc3ccccc3N(C(=O)c3ccccc3)CC2C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: O
Solvent: CN(C)C=O
Product: CC=C=CCOc1ccc(S(=O)(=O)N2Cc3ccccc3N(C(=O)c3ccccc3)CC2C(=O)NO)cc1
Yield: 54.9 %

Procedure:
The procedure of Example 45 was followed using the product from Example 44 (230 mg, 0.444 mmol), 1-hydroxybenzotriazol (72 mg, 0.533 mmol), 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (111 mg, 0.579 mmol), hydroxylamine in water 50% solution (0.217 ml, 3.55 mmol) in dimethylformamide (3 ml) to give 130 mg (55%) of the product.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:3]=1.[F:18][C@@H:19]1[C@@H:23]([CH2:24][OH:25])[O:22][C@@H:21](N2C=CC(=O)NC2=O)[CH2:20]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:21]2[O:22][C@H:23]([CH2:24][OH:25])[C@@H:19]([F:18])[CH2:20]2)=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:3]=1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CCCCCCNc1nc(N)nc2[nH]cnc12
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCCCCNc1nc(N)nc2c1ncn2[C@H]1C[C@H](F)[C@@H](CO)O1
Temperature: 45 °C
Reaction time: 216 h
Yield: 61.9 %

Procedure:
2-Amino-6-hexylamino-9H-purine (0.63 g, 2.6 mmoles) and 2',3'-dideoxy-3'-fluorouridine (0.50 g, 2.2 mmoles) were suspended in 50 ml 10 mM potassium phosphate buffer, pH 7.0, containing 0.04% potassium azide. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase (10,000 I.U.) (Krenitsky, et al., Biochemistry, 20, 3615, 1981 and U.S. Pat. No. 4,381,344) immobilized on DEAE cellulose was added to the reaction and the suspension was stirred at 45° C. After 9 days, 150 ml MeOH was added to the reaction. The reaction was applied to a column containing AG1-X2 (OH-- form, 2.5×10 cm) and eluted with MeOH. Fractions containing product were pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:acetone:methanol/97:2:1. Solvent was removed and lyophilization yielded 0.48 g of 2-amino-9(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-6-hexylamino-9H-purine (61%): mp 50°-51° C.; TLC Rf 0.86 (silica gel, MeCN:15N NH4OH:H2O/85:5:10); [α]D20 -13.2° (c=0.5, DMF); UV λmax (ε×10-3) at pH 7, 281 (15.4); at pH 13, 281 (15.4); 1H NMR (400 MHz, DMSO-d6) δ7.89 (s, 1H, H8), 7.30 (b, 1H, NH), 6.19 (dd, 1H, H1', J=9.7 Hz, J=5.6 Hz), 5.77 (b, 2H, NH2), 5.56 (m, 1H, OH5'), 5.38 (dd, 1H, H3', J=53.7 Hz, J=4.2 Hz), 4.17 (dm, 1H, H4', J=27.5 Hz, 3.57 (t, 2H, H5' and H5", J=5.0 Hz, 3.35 (b, 2H, NCH2CH2 (CH2)3CH3), 2.78-2.97 and 2.47-2.60 (m, 2H, H2, and H2") 1.52 (m, 2H, NCH2CH2 (CH2)3CH3), 1.27 (b, 6H, NCH2CH2 (CH2)3CH3), and 0.84 (t, 3H, NCH2CH2 (CH2)3CH3, J=6.8 Hz); MS (ci) 353 (M+1), 333 (M-F), 235 (MH2 --C5H8FO2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH:28]3[CH2:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)[C:11]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[CH:4][CH:3]=1.[CH2:32]=O.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH:28]3[CH2:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)[C:11]([C:13]2[C:18]([NH:19][CH3:32])=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: C=O
Reactant: Cc1ccc(N)c(C(=O)N(CCc2ccc(Cl)cc2)Cc2ccc(C3CCC3)cc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNc1ccc(C)nc1C(=O)N(CCc1ccc(Cl)cc1)Cc1ccc(C2CCC2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
A mixture of 3-amino-6-methyl-pyridine-2-carboxylic acid [2-(4-chloro-phenyl)-ethyl]-(4-cyclobutyl-benzyl)-amide (151 mg, 0.348 mmol), 37% aq. formaldehyde solution (0.16 mL, 2.09 mmol) and ethanol (2 mL) was stirred at 50° C. for 3 h, then after removal of volatile material by distillation, sodium borohydride (55 mg, 1.39 mmol) was added, and stirring at 50° C. was continued over 3 h. After cooling, the reaction mixture was partitioned between ethyl acetate and water, the organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) produced the title compound (126 mg, 81%). Colourless gum, MS (ISP) 448.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].Br[CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(O)C>[CH:4]([C:3]1[C:6]([O:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:2]=1[O:1][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])=[O:5]
Reactant: COc1cccc(O)c1C=O
Reactant: N#CCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: COc1cccc(OCCCCC#N)c1C=O
Reaction time: 2 h

Procedure:
2-Hydroxy-6-methoxybenzaldehyde (3.04 g, 0.02 M), 5-bromopentanonitrile (3.81 g, 0.02 M), anhydrous potassium carbonate (2.97 g), sodium iodide (0.12 g) and ethanol (15 ml) were refluxed with stirring for 41/2 hr. The cooled reaction mixture was filtered and the solid washed well with ethanol. The filtrate was evaporated to dryness and the residue partitioned between ether and water. The organic layer was separated and washed with 2 N sodium hydroxide solution water, dried (sodium sulphate) and evaporated to give 5-(2-formyl-3-methoxyphenoxy)pentanonitrile, 2.92 g, 63%, m.p. 71°-72° C. from benzene/petrol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)=[CH:4][CH:3]=1.[C:23](O)(=[O:25])[CH3:24].C(OC(=O)C)(=O)C>O>[C:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)=[CH:4][CH:3]=1)(=[O:25])[CH3:24]
Reactant: CC(C)(C)c1cc(-c2ccc(N)cc2)cc(C(C)(C)C)c1O
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1

Procedure:
A solution of 15 g. (0.050 mole) of 4-(4'-aminophenyl)-2,6-di(t-butyl)phenol in 100 ml. of glacial acetic acid is treated with 5.2 g. (0.050 mole) of acetic anhydride. The resulting solution is heated gently for 10 minutes, diluted with water, cooled, and the solid product is separated by filtration. Recrystallization from a benzene-hexane mixture provides 4-(4'-acetamidophenyl)-2,6-di(t-butyl)phenol, m.p. 173°-174.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[F:14])[CH3:2]>CO.[Pt](=O)=O>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[F:14])[CH3:2]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cc1F
Agent: O=[Pt]=O
Solvent: CO
Product: CCOC(=O)c1ccc(N)cc1F

Procedure:
A solution of 2-fluoro-4-nitrobenzoic acid ethyl ester (770 mg, 3.62 mmol) in methyl alcohol (15 mL) was treated with platinum (IV) oxide (75 mg) at 40 psi of H2. After 0.5 h the reaction mixture was filtered through celite and concentrated in vacuo to give 700 mg (Y: 99%) of the title product; 1H-NMR (CDCl3): δ 7.76 (t, J=8.3 Hz, 1H), 6.42 (d, J=8.5 Hz, 1H), 6.35 (d, J=12.9 Hz, 1H), 4.33 (q, J=7.1 Hz, 2H), 4.20 (bs, 2H), 1.36 (t, J=7.1 Hz, 3H); MS (DCI) m/e: 184 (MH+).
Reaction SMILES: C[O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]3[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]3[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2oc(-c3nccn3C)cc12
Agent: BrB(Br)Br
Product: Cn1ccnc1-c1cc2c(O)cccc2o1
Yield: 64.5 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 5 using 4-methoxy-2-(1-methylimidazol-2-yl)benzo(b)furan (2.00 g) and boron tribromide (2.0 ml), the title compound (1.21 g) was obtained as pale-yellow crystals, melting point >265° C. (decomposition)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]1[N:12]2[C:13]3[CH:19]=[CH:18][C:17]([C:20](OCC)=[O:21])=[CH:16][C:14]=3[N:15]=[C:11]2[CH2:10][CH2:9][CH2:8]1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O1CCCC1>[CH2:7]1[N:12]2[C:13]3[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:14]=3[N:15]=[C:11]2[CH2:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)c1ccc2c(c1)nc1n2CCCC1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)nc1n2CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
Lithium aluminum hydride (1.97 g, 51.9 mmol) was suspended in tetrahydrofuran (30 ml); and under an ice cooling, a solution (20 ml) of ethyl 1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate (6.34 g, 26.0 mmol) prepared in the Step 3-1-3 in tetrahydrofuran was slowly added thereto. After the mixture was stirred under an ice cooling for one hour, a saturated sodium bicarbonate solution (5 ml) was slowly added to the mixture at the same temperature while paying attention to the generation of heat. Further, ethyl acetate was slowly added to the mixture. The mixture was allowed to cool to a room temperature and filtered. The filtrate was thoroughly washed with chloroform. The filtrate was concentrated and purified by silica gel column chromatography (chloroform:methanol=20:1 to 10:1) to give the title compound (4.20 g, 80%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13]C(OC(C)(C)C)=O)=[C:8]([F:21])[CH:7]=1>C(O)=O>[NH2:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([O:2][CH3:1])=[O:22])=[CH:7][C:8]=1[F:21]
Reactant: COC(=O)COc1ccc(CNC(=O)OC(C)(C)C)c(F)c1
Solvent: O=CO
Product: COC(=O)COc1ccc(CN)c(F)c1
Temperature: 60 °C
Yield: 86.7 %

Procedure:
[4-(tert-Butoxycarbonylamino-methyl)-3-fluoro-phenoxy]-acetic acid methyl ester (0.94 g, 3.0 mmol) was dissolved in formic acid (13 mL) and heated to 60° C. for 1 hour. The solvent was removed under vacuo and the residue repeatedly co-evaporated with chloroform and ethanol. The residue was dissolved in ethyl acetate washed with saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to give the title compound (0.56 g, 2.6 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH3:23][N:24]([CH3:45])[C:25]([CH:27]1[CH2:31][C:30]2[CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=[CH:35][C:29]=2[O:28]1)=[O:26].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:33]3[CH:34]=[CH:35][C:29]4[O:28][CH:27]([C:25]([N:24]([CH3:23])[CH3:45])=[O:26])[CH2:31][C:30]=4[CH:32]=3)[C:16]2=[CH:15][N:14]=1
Reactant: CN(C)C(=O)C1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2O1
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(OC)c(Cl)c(-c2ncc3c(-c4ccc5c(c4)CC(C(=O)N(C)C)O5)n[nH]c3n2)c1Cl
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (18.0 mg, 0.0400 mmol), N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-2-carboxamide (19.0 mg, 0.0600 mmol), tetrakis(triphenylphosphine)palladium(0) (2.77 mg, 0.00240 mmol), and sodium carbonate (12.7 mg, 0.120 mmol) in 1,4-dioxane (0.42 mL) and water (0.14 mL) in a reaction vial was sealed, and degassed and recharged with nitrogen for three times. The mixture was stirred at 120° C. for 3 h. After cooling, the mixture was diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+=514.0/516.0. 1H NMR (300 MHz, DMSO-d6) δ: 9.77 (s, 1H), 8.02 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.06 (s, 1H), 6.97 (d, J=8.4 Hz, 1H), 5.76 (d, J=9.1, 7.4 Hz, 1H), 3.99 (s, 6H), 3.55-3.49 (m, 2H), 3.13 (s, 3H), 2.90 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.N(C(OCC)=O)=NC(OCC)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:17]2[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=2[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 72.7 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (3.62 g), 2-methyl-4-nitrophenol (2.55 g) and triphenylphosphine (5.25 g) in dichloromethane (100 ml), diethyl azodicarboxylate (3.2 ml) was added dropwise with stirring under ice-cooling, and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using dichloromethane as the eluent to afford the title compound (4.07 g) containing impurities as a pale yellow oil.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36]N>>[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)(=[O:22])=[O:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N3CCCC3)c2)ccc1=O
Reactant: NNc1ccccc1F
Product: O=c1ccn(-c2cccc(S(=O)(=O)N3CCCC3)c2)nc1-c1ccnn1-c1ccccc1F

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[3-(pyrrolidine-1-sulfonyl)-phenyl]-1H-pyridazin-4-one (A-29) and 2-fluoro-phenylhydrazine according to the method described for example 91. MS: M=466.1 (M+H)+
Reaction SMILES: C(O[C:4](=[O:28])[C:5]1[C:6](=[CH:18][C:19]([CH3:27])=[C:20]([C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH:21]=1)[N:7]([CH2:16][CH3:17])[C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])C.[Na].Cl>C(O)C>[CH2:13]([O:12][C:10]([C:9]1[C:8](=[O:15])[N:7]([CH2:16][CH3:17])[C:6]2[C:5]([C:4]=1[OH:28])=[CH:21][C:20]([C:22](=[O:26])[CH2:23][CH2:24][CH3:25])=[C:19]([CH3:27])[CH:18]=2)=[O:11])[CH3:14]
Reactant: CCCC(=O)c1cc(C(=O)OCC)c(N(CC)C(=O)CC(=O)OCC)cc1C
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCCC(=O)c1cc2c(O)c(C(=O)OCC)c(=O)n(CC)c2cc1C
Temperature: 0 °C

Procedure:
19.6 g of N-ethyl-5-butyryl-4-methyl-N-(1'-oxo-2'-ethoxycarbonylethyl)-anthranilic acid ethyl ester in 60 ml of absolute ethanol are added dropwise, at room temperature, to a solution of 1.15 g of sodium in 30 ml of absolute ethanol. The yellow solution is refluxed for 3 hours. The resulting suspension is then freed of ethanol in vacuo. The residue is dissolved in ice-water and acidified with hydrochloric acid. The separated oil is extracted with methylene chloride and the methylene chloride solution is washed with water, dried over sodium sulphate, filtered and concentrated to dryness by evaporation in vacuo. An oil is obtained, which is caused to crystallise from methanol. In this manner 1-ethyl-6-butyryl-4-hydroxy-7-methylcarbostyril-3-carboxylic acid ethyl ester having a melting point of 124°-126° is obtained.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]([O:17][C:18]3[CH:23]=[N:22][C:21]([C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)=[CH:20][N:19]=3)[CH3:16])[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:3].C(=O)=O>CO>[CH3:3][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:10][CH2:11][CH:12]([C@H:15]([O:17][C:18]3[CH:23]=[N:22][C:21]([C:24]4[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=4)=[CH:20][N:19]=3)[CH3:16])[CH2:13][CH2:14]2)[O:6][N:5]=1)[CH3:1]
Reactant: CC(C)c1noc(N2CCC(C(C)Oc3cnc(-c4ccc(S(C)(=O)=O)cc4)cn3)CC2)n1
Agent: O=C=O
Solvent: CO
Product: CC(C)c1noc(N2CCC([C@@H](C)Oc3cnc(-c4ccc(S(C)(=O)=O)cc4)cn3)CC2)n1

Procedure:
The racemic 2-[(1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]-5-[4-(methylsulfonyl)phenyl]pyrazine (prepared as in Example 156) was subjected to Chiral HPLC [column: AS-H, column mobile phase: 70% CO2: 30% MeOH (2 mL/min), pressure 140 bar, temperature 40° C., 215 nm] analysis and then separated to give two (R and S) enantiomers. The title compound was isolated as an off-white solid with Tr of 23.42 min (first eluting peak). The (R) absolute stereochemistry was assigned by Ab initio VCD analysis.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][N:6]([CH3:20])[CH2:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)=[O:9].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][N:6]([CH3:20])[CH2:7][CH:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[OH:9]
Reactant: CN(CC(=O)c1ccc2ccccc2c1)Cc1cccc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(Cc1cccc(Br)c1)CC(O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.6 %

Procedure:
To a solution of Compound 15 (˜110 mmol) in methanol (600 mL), sodium borohydride (5.4 g, 142.8 mmol) was added in portions at 0° C. The reaction mixture was first stirred overnight while warming up to room temperature. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (200 mL) and the solution was extracted with methylene chloride (3×300 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure to afford the crude desired product Compound 16 (42.6 g) as a yellow oil, which was used without further purification in the next step: 1H NMR (300 MHz, CDCl3) δ 7.86-7.79 (m, 4H), 7.52-7.38 (m, 5H), 7.28-7.15 (m, 2H), 4.93 (dd, J=9.5, 4.4 Hz, 1H), 4.05 (s, 1H), 3.71 (d, J=13.3 Hz, 1H), 3.52 (d, J=13.3 Hz, 1H), 2.72-2.61 (m, 2H), 2.34 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([N+:12]([O-])=O)[C:5]([C:15]2[CH:19]=[CH:18][O:17][C:16]=2[CH:20]=O)=[CH:4][CH:3]=1.CO.N>Cl.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]2[C:5]([C:15]3[CH:19]=[CH:18][O:17][C:16]=3[CH:20]=[N:12]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(N)ccc(-c2ccoc2C=O)c1[N+](=O)[O-]
Agent: [Fe+2]
Agent: Cl
Agent: N
Solvent: CO
Solvent: O
Product: COC(=O)c1c(N)ccc2c1ncc1occc12
Temperature: 70 °C
Yield: 16 %

Procedure:
1M Hydrochloric acid (14 drops) was added to a solution of iron (II) sulfate heptahydrate (18.44 g) in water (50 mL) and the resultant solution was added to methyl 6-amino-3-(2-formylfuran-3-yl)-2-nitrobenzoate (Intermediate 30, 2.02 g). The resultant mixture was stirred and heated at reflux for 10 minutes then cooled to 70° C. Methanol (50 mL) was added followed by aqueous ammonia (33%, 19.2 mL) and the mixture was stirred and heated at reflux for 5 hours. After cooling, methanol (50 mL) was added and the mixture was filtered through Celite and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a DMAW 350 followed by DMAW 240 and DMAW 120 to give methyl 7-aminofuro[2,3-c]quinoline-6-carboxylate (0.27 g) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([S:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[N:5]=[C:4]([O:21][C:22]([F:30])([F:29])[CH:23]([F:28])[C:24]([F:27])([F:26])[F:25])[C:3]=1[Cl:31].[C:32](OC(=O)C)(=O)C>>[Cl:31][C:3]1[C:4]([O:21][C:22]([F:29])([F:30])[CH:23]([F:28])[C:24]([F:25])([F:26])[F:27])=[N:5][N:6]([C:7]2[CH:12]=[C:11]([S:13][CH2:14][C:15]([F:16])([F:18])[F:17])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[C:2]=1[NH:1][CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)C(F)(F)F)c(Cl)c2N)cc1SCC(F)(F)F
Product: CNc1c(Cl)c(OC(F)(F)C(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reaction time: 3 h

Procedure:
0.8 g of 5-amino-4-chloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)pyrazole was dissolved in 20 mL of acetic anhydride. After stirring for 3 hours under reflux with heating, acetic anhydride was distilled off under reduced pressure, the obtained residue was dissolved in 20 mL of tetrahydrofuran, and 20 mL of a 25 mass % ammonia water was added under cooling with ice. After stirring for one hour under cooling with ice, the solvent was distilled off under reduced pressure, extraction with ethyl acetate was carried out, and the organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in 5 mL of dimethylformamide, and the solution was dropwise added to a suspension having 50 mg of sodium hydride suspended in 10 mL of dimethylformamide under cooling with ice. After completion of the dropwise addition, stirring was carried out at room temperature for 30 minutes. The reaction solution was cooled with ice again, and 0.18 g of methyl iodide was added, followed by stirring at room temperature for one hour. Water was injected, extraction with ethyl acetate was carried out, and after washing with water, the organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in 10 mL of ethanol, and 10 mL of a 35 mass % hydrochloric acid aqueous solution was added, followed by stirring under reflux with heating for one hour. The reaction mixture was poured into water, extraction with ethyl acetate was carried out, and after washing with water, the organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 0.34 g of 4-chloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)-5-methylaminopyrazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[NH2:10].CC1C=CC=CC=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>O>[Cl:18][CH2:19][C:20]([NH:10][C:4]1[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:21]
Reactant: COc1ccc(C)cc1N
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C)cc1NC(=O)CCl
Reaction time: 1.5 h
Yield: 66 %

Procedure:
To a stirred solution of 49.2 parts of 2-methoxy-5-methylbenzenamine and 270 parts of methylbenzene were added dropwise 22.5 parts of 2-chloroacetyl chloride while cooling (ice-bath) at 10°-20° C. Upon completion, stirring was continued for 1.50 hours at room temperature. 200 Parts of water were added. The organic phase was separated, washed with water, dried, filtered and evaporated. The oily residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 28.2 parts (66%) of 2-chloro-N-(2-methoxy-5-methylphenyl)acetamide; mp. 83.9° C. (intermediate 66).