Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=1)=O.Cl.[C:14]([O:18][C:19](=[O:23])[C@@H:20]([CH3:22])[NH2:21])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C.[BH4-].[Na+]>CO.C(Cl)Cl>[C:11]([C:8]1[CH:9]=[CH:10][C:5]([CH:3]([NH:21][C@@H:20]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:23])[CH3:22])[CH2:2][OH:1])=[CH:6][CH:7]=1)#[N:12]
Reactant: N#Cc1ccc(C(=O)CO)cc1
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: C[C@@H](NC(CO)c1ccc(C#N)cc1)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
To a solution of 2-Hydroxy-1-(4-cyanophenyl)ethanone (3.2 g, 0.0198 mol) in methanol and DCM (1:1) (100 ml) were added D-Alanine t-butyl ester hydrochloride (3.6 g, 0.0198 mol) and triethylamine (6.9 ml, 0.0495 mol) at RT. The reaction mixture was heated at 70° C. for 18 h. The reaction mixture was cooled to 0° C. and NaBH4 (0.9 g, 0.0237 mol) was added in portions and stirred at RT for 1 h. The reaction mixture was quenched with ice, extracted with DCM (2×100 ml), dried over sodium sulphate and evaporated. The crude material was purified by column chromatography using chloroform and methanol (90:10) as an eluent to afford (2.5 g, 43%) of title compound as brown oil. 1H NMR: (CD3OD, 400 MHz) δ 7.71-7.69 (d, J=8.36 Hz, 2H), 7.59-7.56 (d, J=8.08 Hz, 2H), 4.76-4.74 (t, J=6.32 Hz, 1H), 3.64-3.61 (q, 2H), 3.44-3.42 (d, J=7.04 Hz, 1H), 1.47 (s, 9H), 1.30-1.28 (d, J=7.04 Hz, 3H). LC/MS (Method A): 291.3 (M+H)+. HPLC (Method A) Rt 2.95 min. (Purity: 76.8%).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:11]1[CH:15]=[C:14]([NH2:16])[NH:13][N:12]=1.[C:17]([CH:20]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:21](OCC)=[O:22])(=O)[CH3:18]>CC1C=CC=CC=1C.S(O)(C1C=CC(C)=CC=1)(=O)=O.O>[OH:22][C:21]1[N:13]2[N:12]=[C:11]([C:2]3[CH:3]=[CH:4][C:5]4[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=4[CH:1]=3)[CH:15]=[C:14]2[N:16]=[C:17]([CH3:18])[C:20]=1[CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: Nc1cc(-c2ccc3c(c2)CCCC3)n[nH]1
Reactant: CCOC(=O)C(CC(=O)OC)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: COC(=O)Cc1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1O
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 85.1 %

Procedure:
A suspension of 3-(5,6,7,8-tetrahydronaphthalen-2-yl)-1H-pyrazol-5-amine (6 g, 28.1 mmol), 1-ethyl 4-methyl 2-acetylsuccinate (24.52 mL, 141 mmol) and Ts-OH.H2O (0.096 g, 0.506 mmol) in o-xylene (200 mL) was heated at 150° C. (oil bath temp) for 16 h. (Note: Mixture became homogeneous and in about 15 min slowly yellow solid started crashing out of the reaction.). Then, the reaction mixture was cooled, diluted with hexanes (300 mL), filtered, washed with hexanes and dried to afford methyl 2-(7-hydroxy-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetate (8.4 g, 23.90 mmol, 85% yield) as light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 12.35 (s, 1H), 7.78-7.62 (m, 2H), 7.15 (d, J=8.5 Hz, 1H), 6.52 (s, 1H), 3.64 (s, 3H), 3.58 (s, 2H), 2.82-2.77 (m, 4H), 2.33 (s, 3H), 1.78 (t, J=3.0 Hz, 4H). LCMS (M+H)=352.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:26][CH3:27])[C:10](=[O:25])[N:11]3[CH2:21][CH2:20][C:19](=O)[CH2:18][N:17]([CH3:23])[C:16](=[O:24])[C:12]3=2)[C:7]1=[O:28].[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.C(O)(=O)C.[BH4-].[Na+]>ClC(Cl)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:26][CH3:27])[C:10](=[O:25])[N:11]3[CH2:21][CH2:20][CH:19]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)[CH2:18][N:17]([CH3:23])[C:16](=[O:24])[C:12]3=2)[C:7]1=[O:28]
Reactant: C1CCNC1
Reactant: COc1c2c(c3n(c1=O)CCC(=O)CN(C)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1c2c(c3n(c1=O)CCC(N1CCCC1)CN(C)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-methyl-5,6,12,13-tetrahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,4,8,10(3H,11H)-tetrone (30 mg, 0.06 mmol), molecular sieves (4A), pyrrolidine (23 mg, 0.32 mmol), and acetic acid (4 mg) in dichloroethane (1 mL) was heated at 80° C. for four hrs. The mixture was cooled to room temperature, treated with sodium borohydride (12 mg, 0.19 mmol), and stirred at room temperature for 30 minutes. The product mixture was diluted with dichloromethane, washed successively with aq sodium carbonate and brine. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title compound. This material was used in the following step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH2:23]([C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:36]2[CH2:37][CH2:38][N:33]([C:30]3[CH:31]=[CH:32][C:27]([CH2:23][CH2:24][CH2:25][CH3:26])=[CH:28][CH:29]=3)[CH2:34][CH2:35]2)=[S:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2nc1NC(=S)Oc1ccccc1
Reactant: CCCCc1ccc(N2CCNCC2)cc1
Product: CCCCc1ccc(N2CCN(C(=S)Nc3nc4ccccc4nc3OC)CC2)cc1
Yield: 62.5 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)thiocarbamate and 1-(4-butylphenyl)piperazine were reacted by the same way with the example 63 to obtain the titled compound.
Reaction SMILES: [F:1][C:2]1[C:10]2[CH:9]=[C:8](C(O)=O)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.O>CC(N(C)C)=O>[F:1][C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2c(F)cccc2s1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Fc1cccc2sccc12
Temperature: 200 °C

Procedure:
A mixture of 4-fluorobenzo[b]thiophene-2-carboxylic acid (200 mg, 1.019 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.457 mL, 3.06 mmol) in DMA (1 mL) was heated at 200° C. for 1 hour. The reaction mixture was allowed to cool and was poured into water (100 mL). The product was extracted with hexane (2×20 mL) and washed with 1N HCl (100 mL) and 1N NaOH (50 mL). The organic layers were combined, dried over Na2SO4 and the solvent was removed in vacuo to give the title compound as a yellow oil, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[CH2:13]([S-:15])[CH3:14].[Na+]>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([S:15][CH2:13][CH3:14])=[N:7][N:6]=[CH:5]2
Reactant: CC[S-]
Reactant: Clc1nncc2cc(Br)ccc12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCSc1nncc2cc(Br)ccc12
Reaction time: 1 h

Procedure:
To a solution of 6-bromo-1-chlorophthalazine (0.22 g, 0.9 mmol) in acetonitile (5 mL) stirred at ambient was added sodium ethanethiolate (0.2 g, 2 mmol), and the mixture was stirred for 1 h. The mixture was diluted with ethyl acetate (100 mL), washed with sat. NH4Cl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by chromatography eluting with 1-5% 2 M ammonia methanol/dichloromethane to give the 6-bromo-1-(ethylthio)phthalazine as pale yellow solid.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:15](=[O:30])[N:16]([CH2:18][C:19]3[C:20]([CH3:29])=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=3)[N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[CH3:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C(Cl)Cl.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[CH:6]=[CH:5][N:4]3[C:15](=[O:30])[N:16]([CH2:18][C:19]4[C:20]([CH3:29])=[N:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=4)[N:17]=[C:3]3[C:2]=2[C:37]2[CH:38]=[CH:39][C:34]([CH2:33][O:32][CH3:31])=[CH:35][CH:36]=2)=[CH:9][CH:10]=1
Reactant: COCc1ccc(B(O)O)cc1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(Br)c(-c3ccc(Cl)cc3)ccn2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCc1ccc(-c2c(-c3ccc(Cl)cc3)ccn3c(=O)n(Cc4ccc(C(F)(F)F)nc4C)nc23)cc1
Temperature: 90 °C

Procedure:
To a stirring solution of 8-bromo-7-(4-chlorophenyl)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (60 mg, 0.12 mmol) in THF (2 mL) at room temperature under argon was added 4-methoxymethylphenylboronic acid (60.0 mg, 0.36 mmol), Pd(dppf)Cl2.CH2Cl2 (11.0 mg, 0.012 mmol), and K3PO4 (77 mg, 0.36 mmol). The resulting suspension was purged of oxygen by bubbling with argon for 15 min, sealed in a vial under argon, heated at 90° C. for 12 h, and then cooled to room temperature. Analysis by HPLC/MS indicated that starting material was absent and one major new product had formed. The reaction mixture was diluted with EtOAc and washed once with brine. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by automated silica gel chromatography (eluted with EtOAc/hexanes). Pooling of the desired fractions, washing with saturated aq. NaHCO3 solution to eliminate any possible boronic acid contaminant, drying the organic phase (MgSO4), filtering and evaporation provided the title compound as a yellow solid, 38 mg, 59%. HPLC/MS: retention time=3.94 min, [M+H]+=539. 1H NMR (CDCl3): δ 7.82 (d, J=7.7 Hz, 1H), 7.67 (d, J=8.2 Hz, 1H), 7.48 (d, J=7.7 Hz, 1H), 7.25 (m, 5H), 7.05 (d, J=7.7 Hz, 2H), 6.64 (d, J=7.2 Hz, 1H), 5.23 (s, 2H), 4.44 (s, 2H), 3.41 (s, 3H), 2.74 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:26][O:27][NH:28][CH3:29]>C1COCC1>[CH3:26][O:27][N:28]([CH3:29])[C:10]([C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1)=[O:12]
Reactant: CNOC
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
To a stirred suspension of 1H-Indole-6-carboxylic acid (5.65 g, 35.1 mmol) in 55 mL of THF was added 1,1′-carbonyldiimidazole (6.25 g, 38.6 mmol). The suspension was stirred for 2 h at room temperature followed by addition of O,N-dimethyl-hydroxylamine hydrochloric acid (4.10 g, 42.1 mmol) in an ice-bath. The mixture ws stirred at room temperature overnight. The mixture was extracted with EtOAc (2×50 mL). The combined EtOAc extracts were washed brine (50 mL), dried over MgSO4, filtered and concentrated to an oil, which was purified by flash column chromatography (EtOAc/Hexane) to give 1H-Indole-6-carboxylic acid methoxy-methyl-amide as an oil (5.54 g, 77% yield): 1H NMR (CDCl3) δ 3.39 (s 3H, NCH3), 3.58 (s, 3H, OCH3), 6.55-6.57 (m, 1H, Ar), 7.29-7.84 (m, 4H, Ar), 8.85 (brs, 1H, NH). The product was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.Cl[C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([CH3:21])[N:14]=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH:7]2[C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([CH3:21])[N:14]=1
Reactant: COc1nc(C)nc(Cl)n1
Reactant: O=C1Cc2cccc(F)c2N1
Product: COc1nc(C)nc(C2C(=O)Nc3c(F)cccc32)n1

Procedure:
7-Fluoro-1,3-dihydro-2H-indol-2-one (3.05 g) and 2-chloro-4-methoxy-6-methyl-1,3,5-triazine (6.59 g) are reacted analogously to Example 1 Variant A. This gives the title compound as solid in an HPLC purity of 85% area (4.73 g, 73% of theory).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[Cl:19][C:20]1[N:21]([CH2:28][C@:29]2([CH3:32])[CH2:31][O:30]2)[CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[N:24]=1>>[Cl:19][C:20]1[N:21]([CH2:28][C@@:29]([CH3:32])([OH:30])[CH2:31][N:12]2[CH2:13][CH2:14][CH:9]([CH2:8][C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:17])([F:1])[F:18])=[CH:16][CH:15]=3)[CH2:10][CH2:11]2)[CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[N:24]=1
Reactant: FC(F)(F)Oc1ccc(CC2CCNCC2)cc1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Product: C[C@](O)(CN1CCC(Cc2ccc(OC(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl

Procedure:
Using 4-(4-trifluoromethoxybenzyl)piperidine and (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 gave (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethoxybenzyl)piperidin-1-yl]propan-2-ol (crude) as a yellow oil in the same manner as in Example 270.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])=[C:4]2[N:9]([C:10]=1[C:11](OCC)=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:35]1(C)[CH:40]=CC=C[CH:36]=1>COC(OC)(C)C.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>[OH:12][C:11]1[C:10]2[N:9]3[C:4]([CH:5]=[CH:6][CH:7]=[CH:8]3)=[C:3]([C:16]3[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=3[CH3:22])[C:2]=2[N:1]=[C:35]([CH3:40])[CH:36]=1
Reactant: CCOC(=O)c1c(N)c(-c2c(C)cc(C)cc2C)c2ccccn12
Reactant: Cc1ccccc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: COC(C)(C)OC
Product: Cc1cc(C)c(-c2c3nc(C)cc(O)c3n3ccccc23)c(C)c1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
To a solution of 2-amino-3-ethoxycarbonyl-1-(2,4,6-trimethylphenyl)-indolizine (19.2 g; 59.6 mmol) in 2,2-dimethoxypropane (100 mL) is added dl-camphorsulfonic acid (0.2 g). The mixture is stirred at reflux for 30 minutes and then distilled slowly to remove ca. 60 mL of volatiles over a 30-minute period. The solution is cooled to ambient temperature under an inert atmosphere, diluted with anhydrous toluene (50 mL), and concentrated in vacuo. The residue is dissolved in toluene (50 mL) and to the stirred solution is then added a 0.5M solution of potassium bis(trimethylsilyl)amide in toluene (250 mL; 125 mmol) dropwise over a 1-hour period. After the addition is complete, the mixture is further stirred for 2 hours at room temperature before being concentrated in vacuo to a small volume and then diluted with aqueous ammonium chloride. The resulting emulsion-like biphasic mixture is suction-filtered and washed succesively with water, methanol, and ethyl ether. Air- and vacuum drying provides 10.1 g of the title compound as a pale yellow solid (54%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(C1C=CC(/C=C/[C:36]([NH:38][C:39]2C=CC(Cl)=C([N+]([O-])=O)C=2)=[O:37])=CC=1)(C)(C)C.CCO.[In]>[NH4+].[Cl-]>[C:19]([C:16]1[CH:15]=[CH:14][C:13](/[CH:12]=[CH:11]/[C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([NH:1][C:36]([NH:38][CH3:39])=[O:37])[CH:3]=2)=[O:23])=[CH:18][CH:17]=1)([CH3:20])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1ccc(/C=C/C(=O)Nc2ccc(Cl)c(N)c2)cc1
Reactant: CC(C)(C)c1ccc(/C=C/C(=O)Nc2ccc(Cl)c([N+](=O)[O-])c2)cc1
Agent: [Cl-]
Agent: [In]
Agent: [NH4+]
Solvent: CCO
Product: CNC(=O)Nc1cc(NC(=O)/C=C/c2ccc(C(C)(C)C)cc2)ccc1Cl

Procedure:
(2E)-N-(3-Amino-4-chlorophenyl)-3-[4-(tert-butyl)phenyl]prop-2-enamide. To a round-bottomed flask equipped with a magnetic stir bar, was added (2E)-3-[4-(tert-butyl)phenyl]-N-(4-chloro-3-nitrophenyl)prop-2-enamide, Example 156, (250 mg, 0.69 mmol), EtOH (8 mL), indium (800 mg, 6.9 mmol, Aldrich) and satd NH4Cl (10 mL). The reaction mixture was stirred at reflux for 5 h. The solvents were removed in vacuo, the residue was dissolved in EtOAc (20 mL), washed with water (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to yield the title product. MS (ESI, pos. ion) m/z: 329 (M+1).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.C1(C(C2C=CC=CC=2)[N:25]2[CH2:28][CH:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:26]2)C=CC=CC=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[O:17]=[C:15]([N:25]1[CH2:28][CH:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:26]1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CCCCCOC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCOC1CN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 9.1 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (40 mg, 0.16 mmol), DMF (3.8 mL), 1-(diphenylmethyl)-3-(pentyloxy)azetidine (34 mg, 0.19 mmol; which may be prepared as described in Step 2), DIPEA (63 μL, 0.38 mmol) and EDAC (36 mg, 0.19 mmol). The reaction mixture was stirred at room temperature for 48 h and concentrated to dryness. The residue was purified on preparative TLC (eluent: dichloromethane/MeOH, 9/1) to give a beige solid. This solid was triturated in acetone to give the title compound (5 mg, 9%) as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:13]=O.[BrH:15]>>[BrH:15].[CH2:13]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]([C:10]([OH:12])=[O:11])[NH:1]1
Reactant: C=O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Br
Product: O=C(O)C1Cc2ccccc2CN1
Temperature: 65 °C
Reaction time: 7 h
Yield: 86.4 %

Procedure:
To 10 g of L-phenylalanine suspended in 108 ml of 47% hydrobromic acid, 23 ml of 37% formalin aqueous solution was added dropwise. The reaction mixture was stirred at 65° C. for 7 hours, and subjected to crystallization under ice cooling for 3 hours. The precipitate was filtered off, and dried at 55° C. under reduced pressure to obtain 13.5 g of Compound 2 (yield 86.4%, optical purity 97% ee).
Reaction SMILES: N[C:2]1[CH:15]=[CH:14][C:5]2[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:7][O:8][C:4]=2[CH:3]=1.N([O-])=[O:17].[Na+]>S(=O)(=O)(O)O.O.[N+]([O-])([O-])=O.[Cu+2].[N+]([O-])([O-])=O.[Cu-]=O>[OH:17][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=N[O-]
Reactant: CCOC(=O)c1noc2cc(N)ccc12
Agent: O=[Cu-]
Agent: [Cu+2]
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1noc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
Ethyl 6-aminobenzo[d]isoxazole-3-carboxylate (2.43 mmol) was diluted with a solution of sulfuric acid (2.5 mL) in water (2.5 mL) and the resulting mixture was maintained at rt for 30 min. A solution of sodium nitrite (2.67 mmol) in water (2.5 ml) was added dropwise at 0° C. and the resulting mixture was maintained for 30 min at 0° C. This aqueous solution was added to a cold (0° C.) solution of copper (II) nitrate (149 mmol) in water (80 mL) and the reaction mixture was allowed to warm to rt. After 5 min., copper (I) oxide (2.78 mmol) was added to the mixture and the reaction mixture was maintained for 1 h at rt. The reaction mixture was extracted with ethyl acetate (3×100 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide crude ethyl 6-hydroxybenzo[d]isoxazole-3-carboxylate in 99% yield as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:19]#[N:20])(C(OC)=O)[CH2:10][C:11]([O:13][CH3:14])=[O:12]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:19]#[N:20])[CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CC(C#N)(Cc1ccccc1Cl)C(=O)OC
Solvent: CS(C)=O
Product: COC(=O)CC(C#N)Cc1ccccc1Cl

Procedure:
In the same manner as Example 1-(c), 50 g of methyl 4-(2-chlorophenyl)-3-cyano-3-methoxycarbonylbutyrate was decarboxylated in dimethylsulfoxide to obtain methyl 4-(2-chlorophenyl)-3-cyanobutyrate.
Reaction SMILES: FC1C=CC(S)=CC=1.[H-].[Na+].[OH:11][C:12]([CH3:26])([CH2:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:13]([O:15]C)=[O:14].[OH-].[K+]>C(O)C>[OH:11][C:12]([CH3:26])([CH2:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:13]([OH:15])=[O:14]
Reactant: COC(=O)C(C)(O)CSc1ccc(F)cc1
Agent: Fc1ccc(S)cc1
Agent: [H-]
Agent: [K+]
Solvent: CCO
Product: CC(O)(CSc1ccc(F)cc1)C(=O)O

Procedure:
The methyl 2-methyl-oxirane-carboxylate of formula (1), which was obtained by epoxidation, was reacted with 4-fluorothiophenol [formula (2)] in the presence of sodium hydride under the conditions listed in Scheme-2. The obtained methyl 2-hydroxy-2-methyl-3-(4-fluorophenylthio)-propionate of formula (3) was hydrolyzed with potassium hydroxide in aqueous ethanol over a period of 22 hours to yield the 2-hydroxy-2-methyl-3-(4-fluorophenylthio)-propionic acid of formula (4), which was converted into acid chloride of formula (5) with thionyl chloride in dimethyl acetamide at −15° C.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[C-:10]#[N:11].[Na+]>CN1CCCC1=O>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:10]#[N:11])=[CH:3][C:4]=1[F:9]
Reactant: Nc1ccc(Br)cc1F
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(N)c(F)c1

Procedure:
6.8 Parts of 4-bromo-2-fluoroaniline were dissolved in 75 parts of N-methylpyrrolidone. This solution was treated with 4.2 parts of cuprous cyanide. The reaction mixture was heated to 190° for 2 hours. The reaction mass was poured onto a mixture of 200 parts of ice and 15 parts of sodium cyanide. This mixture was then heated on a steam bath for 2 hours at 60°-70°. This aqueous solution was then extracted with four 100 ml portions of toluene. The toluene extracts were combined and washed with four 300 ml portions of water followed by 100 ml of saturated aqueous NaCl solution. The toluene solution of the product was dried over sodium sulfate and stripped to give 2.6 parts of the desired product, m.p. 71°-73°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:35])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:19]([N:27]3[CH2:32][C@@H:31]([CH3:33])[NH:30][CH2:29][C@@H:28]3[CH3:34])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[CH:14]=2)[CH2:8][CH2:7]1)[CH3:2].[CH:37]1([CH:40]=O)[CH2:39][CH2:38]1>>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:35])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:19]([N:27]3[CH2:32][C@@H:31]([CH3:33])[N:30]([CH2:40][CH:37]4[CH2:39][CH2:38]4)[CH2:29][C@@H:28]3[CH3:34])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[CH:14]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CN1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)NC[C@@H]3C)c2)CC1
Reactant: O=CC1CC1
Product: CCOC(=O)CN1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)N(CC4CC4)C[C@@H]3C)c2)CC1
Yield: 43.9 %

Procedure:
The title compound was made by a procedure identical to that of Example 66 except that a shorter reaction time (2 hours) was used to combine 1.50 g of (4-{3-[(R)-((2S,5R)-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperazin-1-yl)-acetic acid ethyl ester (3.03 mmol) and 0.43 g of cyclopropanecarboxaldehyde (6.07 mmol, 2 equiv.) to give 0.73 g (44%) of the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO): □ 0.02-0.03 (t, 2H); 0.38-0.41 (d, J=7.7 Hz, 2H); 0.73-0.75 (m, 1H); 0.85-0.87 (d, J=5.8 Hz, 3H); 1.07-1.09 (d, J=6.0 Hz, 3H); 1.14-1.19 (t, 3H), 1.76-1.79 (m, 1H); 2.07-2.20 (ddd, 2H); 2.30-2.36 (dd, 1H); 2.48-2.51 (m, 6H); 2.86-2.89 (dd, 1H); 3.24 (s, 2H); 3.37-3.59 (m, 5H); 4.02-4.09 (q, 2H); 5.03 (s, 1H); 6.62-6.66 (m, 3H); 7.09-7.20 (m, 2H); 7.32-7.37 (m, 3H); 9.35 (s, 1H). Calculated for C32H44N4O4.0.20 CH2Cl2: C, 68.37; H, 7.91; N, 9.90. Found: C, 68.38; H, 7.97; N, 9.91.