Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@@:17]3([C:35]4[C:26](=[CH:27][C:28]5[O:33][CH2:32][CH2:31][O:30][C:29]=5[CH:34]=4)[O:25][CH2:24]3)[C:16]2=[O:36])[CH2:9]1)C1C=CC=CC=1.C(N1CCOC(CN2C3C(=CC=CC=3)C3(C4C(=CC5OCCOC=5C=4)OC3)C2=O)C1)C1C=CC=CC=1>>[NH:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@@:17]3([C:35]4[C:26](=[CH:27][C:28]5[O:33][CH2:32][CH2:31][O:30][C:29]=5[CH:34]=4)[O:25][CH2:24]3)[C:16]2=[O:36])[CH2:9]1
Reactant: O=C1N(C[C@@H]2CN(Cc3ccccc3)CCO2)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Agent: O=C1N(CC2CN(Cc3ccccc3)CCO2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Product: O=C1N(C[C@@H]2CNCCO2)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure described in EXAMPLE 11.102 and making non-critical variations using (8S)-1′-{[(2S)-4-benzylmorpholin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 1′-[(4-benzylmorpholin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, (8S)-1′-[(2S)-morpholin-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (56%): MS (ES+) m/z 395.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[CH3:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]([CH3:24])[C:18]=1[OH:25].C[O:27][C:28](=[O:37])[CH:29](Br)[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:31]1([CH2:30][CH:29]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:25][C:18]3[C:19]([CH3:24])=[CH:20][CH:21]=[C:22]([CH3:23])[C:17]=3[CH3:16])[CH:6]=[N:5]2)[C:28]([OH:27])=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: Cc1ccc(C)c(O)c1C
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: COC(=O)C(Br)CC1CCCC1
Product: Cc1ccc(C)c(Oc2cnn(C(CC3CCCC3)C(=O)O)c(=O)c2)c1C

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2,3,6-trimethyl-phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[6-oxo-4-(2,3,6-trimethyl-phenoxy)-6H-pyridazin-1-yl]-propionic acid as a white solid (11.5 g, 58% for the final step); LC-MS 371 [M+1]+, tR=3.92 min. Purity on HPLC: 98.5% (214 nm), 99.2% (254 nm), tR=9.92 min. 1H NMR (300 MHz, CDCl3): δ 7.94 (d, 1H, J=2.7 Hz), 7.02 (s, 2H), 5.74 (d, 1H, J=2.7 Hz), 5.52 (dd, 1H, J1=10.2 Hz, J2=5.4 Hz), 2.34˜2.32 (m, 1H), 2.20˜2.16 (m, 1H), 2.29 (s, 3H), 2.18 (s, 3H), 2.05 (s, 3H), 1.79˜1.49 (m, 7H), 1.25˜1.14 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[Na+].[S:24]1[CH2:30][C:28](=[O:29])[NH:27][C:25]1=[S:26].CCCCCC>C(O)(=O)C.C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[C:30]3[S:24][C:25](=[S:26])[NH:27][C:28]3=[O:29])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(OCCCc2ccccc2)cc1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: O=C1NC(=S)SC1=Cc1ccc(OCCCc2ccccc2)cc1
Temperature: 100 °C

Procedure:
Under nitrogen purge in a three-neck round bottom flask 4-(3-phenylpropoxy)benzaldehyde (0.79 g, 3.29 mmol) was dissolved in acetic acid (16 ml). To this solution was added sodium acetate (0.94 g, 11.5 mmol) and rhodanine (0.44 g, 3.30 mmol). The reaction mixture was then heated to 100° C. and maintained at this temperature for about three days. The progress of the reaction was monitored by thin layer chromatography (4:1 hexane:ethyl acetate).
Reaction SMILES: [C:1]([Si:5]([CH3:29])([CH3:28])[O:6][CH2:7][C@H:8]([CH2:19][N:20]1[CH:25]=[CH:24][C:23](=O)[NH:22][C:21]1=[O:27])[C@H:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[NH:30]1[CH:34]=[N:33][CH:32]=[N:31]1>N1C=CC=CC=1>[C:1]([Si:5]([CH3:29])([CH3:28])[O:6][CH2:7][C@H:8]([CH2:19][N:20]1[CH:25]=[CH:24][C:23]([N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)=[N:22][C:21]1=[O:27])[C@H:9]([O:11][Si:12]([C:15]([CH3:17])([CH3:16])[CH3:18])([CH3:13])[CH3:14])[CH3:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)Cn1ccc(=O)[nH]c1=O
Reactant: c1nc[nH]n1
Solvent: c1ccncc1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)Cn1ccc(-n2cncn2)nc1=O
Temperature: 0 °C
Reaction time: 72 h
Yield: 66.6 %

Procedure:
To a cold (ice/water bath) solution of 42 (2.7 g, 6.08 mmol) and 1,2,4-triazole (5.8 g, 84 mmol) in 37 ml of anhydrous pyridine was added dropwise over 5 min 4.2 g (17.11 mmol) of 4-chlorophenyldichlorophosphate (via syringe). The reaction was allowed to warm up and kept at room temperature for 3 days. The reaction was concentrated and partitioned between ethyl acetate (150 ml) and water (150 ml). The organic phase was washed with 10% citric acid, saturated NaCl and dried over Na2SO4. The crude material (brown oil) obtained after concentration of the extract was chromatographed on silica eluting with a gradient of ethyl acetate (50-66%) in hexane. Concentration of the pure product fractions afforded 2.0 g (66%) of 43 as a light tan solid. 1H NMR (DMSO-d6): δ 9.40 (s, 1H), 8.38 (s, 1H), 8.37 (d, J=7 Hz, 1H), 6.90 (d, J=7 Hz, 1H), 4.05 (m, 2H), 3.83 (m, 1H), 3.60 (d, J=6.3 Hz, 2H), 2.22 (m, 1H), 1.15 (d, J=6 Hz, 3H), 0.81 (s, 9H), 0.79 (s, 9H), 0.01 (s, 6H), −0.04 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:12][CH:13]1[N:19]=[C:18]([CH3:20])[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[N:15]([CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[C:14]1=[O:32]>CC#N>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][CH:13]2[C:14](=[O:32])[N:15]([CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[C:18]([CH3:20])=[N:19]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: CC1=NC(N)C(=O)N(CC(=O)C(C)(C)C)c2ccccc21
Solvent: CC#N
Product: CC1=NC(NC(=O)Nc2cccc(C#N)c2)C(=O)N(CC(=O)C(C)(C)C)c2ccccc21
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
3-Cyanophenyl isocyanate (278 mg) was added to a solution of 3-amino-2,3-dihydro-1-(3,3,-dimethyl-2-oxo-butyl)-5-methyl-2-oxo-1H-1,4-benzodiazepine (500 mg) in dry MeCN (13 ml) at 23° under nitrogen. After 30 min the resulting thick slurry was stirred with DE (5 ml) filtered and the filtercake washed with EA and DE then dried in vacuo at 50° to give the title compound (571 mg) as a white solid, m.p. 246°-7°
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7](Br)[C:8]#[CH:9].[C:11]([O:15][C:16]([NH:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][C:26]([C:35]2[N:36]=[CH:37][NH:38][CH:39]=2)([C:31]([O:33][CH3:34])=[O:32])[C:27]([O:29][CH3:30])=[O:28])=[CH:21][CH:20]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].O>CN(C=O)C>[C:11]([O:15][C:16]([NH:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][C:26]([C:35]2[N:36]=[CH:37][N:38]([CH2:9][C:8]#[CH:7])[CH:39]=2)([C:31]([O:33][CH3:34])=[O:32])[C:27]([O:29][CH3:30])=[O:28])=[CH:21][CH:20]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)(C(=O)OC)c1c[nH]cn1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCn1cnc(C(Cc2ccc(NC(=O)OC(C)(C)C)nc2)(C(=O)OC)C(=O)OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.4 %

Procedure:
322 mg (0.99 mmol) of cesium carbonate and sowie 20 μl (0.27 mmol, 80% pure in toluene) of propargyl bromide were successively added to a solution of 100 mg (0.25 mmol) of dimethyl 2-(6-tert-butoxycarbonylaminopyridin-3-ylmethyl)-2-(1H-imidazol-4-yl)malonate (example 12d) in 2 ml of DMF. The mixture was stirred at RT for 3 h and then poured into water and extracted with EA. Purification by chromatography on silica afforded 27 mg of the title compound.
Reaction SMILES: [OH:1][CH:2]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[OH-].[K+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.C(OCC)(=O)C>CS(C)=O>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][CH:2]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][N:4]2[CH:8]=[CH:7][N:6]=[CH:5]2)=[CH:22][CH:21]=1
Reactant: CCCCCOCC(O)Cn1ccnc1
Reactant: COc1ccc(CCl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCCOCC(Cn1ccnc1)OCc1ccc(OC)cc1
Reaction time: 0.5 h

Procedure:
1-[2-Hydroxy-3-(pentoxy)propyl]-1H-imidazole (Example 29b; 2.12 g, 0.01 mol) was added to a stirred suspension of powdered potassium hydroxide (2.24 g, 0.040 mol) in dimethylsulphoxide (10 ml) at 18° C. and stirred for 0.5 hours. 4-Methoxybenzyl chloride was then added and stirring was continued for 2 hours. Ethyl acetate (350 ml) was added and the solution was washed with water and dried (MgSO4). The solvent was evaporated off under reduced pressure and the crude product was purified by column chromatography (silica gel, chloroform) to give 1-[2-[(4-methoxyphenyl)methoxy]-3-(pentoxy)propyl]-1H-imidazole as a pale-yellow oil.
Reaction SMILES: C1(C2N(S[CH2:13][N:14]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[CH2:26][CH3:27])[S:15]3(=[O:17])=[O:16])N=NN=2)C=CC=CC=1.[Na].[C:29]1([N:35]2[C:39]([SH:40])=[N:38][N:37]=[N:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C)C=O>[C:29]1([N:35]2[C:39](=[S:40])[N:38]([CH2:13][N:14]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[CH2:26][CH3:27])[S:15]3(=[O:16])=[O:17])[N:37]=[N:36]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCc1cccc2c1C(=O)N(CSn1nnnc1-c1ccccc1)S2(=O)=O
Reactant: Sc1nnnn1-c1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cccc2c1C(=O)N(Cn1nnn(-c3ccccc3)c1=S)S2(=O)=O
Yield: 60 %

Procedure:
A solution of 2-(5-phenyl-1-tetrazolyl)thiomethyl-4-ethylsaccharin (Example 30AE, 0.020 g) and 1-phenyltetrazol-5-thiol sodium salt (0.0026 g) in dimethylformamide (1 mL) was heated at 100° C. for three days, then poured into water. Recrystallization of the resulting solid from ethanol-water afforded 2-(4-phenyl-5-thioxo-1-tetrazolyl)methyl-4-ethylsaccharin, 0.012 g, 60% yield, mp 127°-129° C.
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[C:34]([C:40]([F:43])([F:42])[F:41])[CH:33]=1.Cl>CC(N(C)C)=O>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:23])[N:9]([CH2:36][C:35]3[CH:38]=[CH:39][C:32]([F:31])=[CH:33][C:34]=3[C:40]([F:42])([F:41])[F:43])[C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Fc1ccc(CBr)c(C(F)(F)F)c1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(Cc2ccc(F)cc2C(F)(F)F)c1=O
Reaction time: 8 h
Yield: 37.8 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles) and 4-fluoro-2-trifluoromethylbenzyl bromide (455 mg, 1.77 mmoles) in dimethylacetamide (6 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (3.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from hexane gave the title compound (184 mg, 38%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (br. s., 1 H), 10.11 (br. s., 1 H), 7.67 (dd, J=9.09, 2.78 Hz, 1 H), 7.45 (ddd, J=8.40, 2.65 Hz, 1 H), 7.29 (dd, J=8.59, 5.31 Hz, 1 H), 5.13 (s, 2 H), 4.64 (t, J=12.00 Hz, 1 H), 4.13 (d, j=5.81 Hz, 2 H), 2.24 (q, 2 H), 1.78 (d, J=12.63 Hz, 2 H), 1.53-1.73 (m, 3 H), 1.28 (q, J=12.72 Hz, 2 H), 1.10 (q, J=12.63 Hz, 1 H)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2([CH3:16])[N:13]=[C:12](OC)[CH2:11][O:10][CH2:9]2)[CH:7]=1.[N:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[N:20][CH:19]=1.[NH:27]=O.[Cl-].[NH4+]>[Pd]>[F:17][C:5]1[CH:4]=[CH:3][C:2]([C:22]2[CH:23]=[N:18][CH:19]=[N:20][CH:21]=2)=[CH:7][C:6]=1[C:8]1([CH3:16])[CH2:9][O:10][CH2:11][C:12]([NH2:27])=[N:13]1
Reactant: N=O
Reactant: OB(O)c1cncnc1
Reactant: COC1=NC(C)(c2cc(Br)ccc2F)COC1
Agent: [Pd]
Agent: [Cl-]
Agent: [NH4+]
Product: CC1(c2cc(-c3cncnc3)ccc2F)COCC(N)=N1

Procedure:
In close analogy to the reaction sequence described in Example 31 (method B), the palladium-catalyzed coupling of (RS)-3-(5-bromo-2-fluoro-phenyl)-5-methoxy-3-methyl-3,6-dihydro-2H-[1,4]oxazine (intermediate XI-2) with pyrimidine-5-boronic acid followed by the treatment of the corresponding imino-ether with ammonium chloride yielded the 5-(2-fluoro-5-pyrimidin-5-yl-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine as a white foam. MS (ISP): m/z=302.2 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]#[C:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C)C=O.O>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:10]#[C:9][CH2:8][CH2:7][CH2:6][N:19]=[N+:20]=[N-:21])=[CH:12][CH:13]=1)#[N:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCCC#Cc1ccc(C#N)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C#CCCCN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of the product of step B (13.40 g, 50.9 mmol) in dimethylformamide (35 mL) was added NaN3 (16.5 g, 255 mmol). The reaction was stirred at room temperature for 18 hours then at 60° C. for 2 hours, cooled to room temperature, diluted with water (400 mL) and extracted with ethyl acetate. The organic layer was washed with water (2×) then with brine and dried (Na2SO4). Evaporation under reduced pressure afforded 10.70 g (100%) of product as a tan oil.
Reaction SMILES: C([Li])CCC.[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[NH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26](Cl)=[O:27])=[CH:22][CH:21]=1>CCCCCC.O1CCCC1>[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[N:14]1[C:26](=[O:27])[CH2:25][O:24][C:23]1[CH:29]=[CH:30][C:20]([CH3:19])=[CH:21][CH:22]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: Cc1ccc(OCC(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(OCC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (8.83 ml) and N,N-dimethylformamide (3 drops) were added at room temperature to a solution of 4-methylphenoxyacetic acid (6.73 g) in dichloromethane (70 ml), and the reaction mixture was stirred for 1.5 hours. The reaction solution was concentrated under reduced pressure, then the resulting acidic gas was removed as the toluene azeotrope, and the product was dried under reduced pressure to give 4-methylphenoxyacetyl chloride. A 1.61N solution of n-butyl lithium in hexane (25.2 ml) was added dropwise at −78° C. to a solution of (S)-4-benzyl-2-oxazolidinone (7.08 g) in tetrahydrofuran (70-ml), and after the completion of the dropwise addition, the reaction mixture was stirred at −78° C. for 30 minutes. To this resulting solution was added at −78° C. a solution of 4-methylphenoxyacetyl chloride obtained above in tetrahydrofuran (70 ml) followed by stirring at 0° C. for 1 hour. The resulting reaction mixture was partitioned between ethyl acetate and water, and the ethyl acetate layer was washed successively with a 1N aqueous solution of hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column (eluant; hexane/ethyl acetate =3/1˜1/1) to afford the target compound (9.00 g) as a colorless oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6][CH2:5]2.C1CCCCC1.[CH3:19][O:20][CH2:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[NH2:27].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[N:27][N:23]1[CH2:24][CH2:25][CH2:26][C@H:22]1[CH2:21][O:20][CH3:19])[CH2:7][CH2:6][CH2:5]2
Reactant: COC[C@@H]1CCCN1N
Reactant: O=C1CCCc2cc(I)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC[C@@H]1CCCN1N=C1CCCc2cc(I)ccc21
Yield: 98.7 %

Procedure:
To a stirred mixture of 6-iodo-3,4-dihydronaphthalen-1(2H)-one (I-8A, 20.90 g, 77 mmol), p-toluenesulfonic acid monohydrate (0.584 g, 3.07 mmol), and cyclohexane (40 mL) was added (S)-2-(methoxymethyl)pyrrolidin-1-amine (10 g, 77 mmol) dropwise at room temperature under nitrogen. The mixture was heated with azeotropic removal of water for 5 h. The reaction mixture was diluted with ethyl acetate (20 mL) and mixed with saturated aqueous sodium bicarbonate solution (15 mL). The aqueous layer was separated and extracted with ethyl acetate (2×30 mL). The combined organic solutions were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Flash chromatography purification (330 g silica gel column, gradient elution from 0% to 20% EtOAc in hexanes) afforded (S)—N-(6-iodo-3,4-dihydronaphthalen-1(2H)-ylidene)-2-(methoxymethyl)pyrrolidin-1-amine (29.1 g, 76 mmol) as a yellow liquid. LC/MS M+1=385.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.I[CH:10]([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH:10]([CH3:12])[CH3:11])[CH:7]=1
Reactant: Oc1ccc(Br)cn1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1cc(Br)ccc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
To a solution of 5-bromopyridin-2-ol (1 g, 5.75 mmol) in DMF (10 mL) were added 2-iodopropane (4.9 g, 28.75 mmol) and K2CO3 (4 g, 28.75 mmol). The mixture was stirred at rt overnight. The mixture was diluted with water (20 mL) extracted with EtOAc (3×25 mL), the combined organic phase was washed with brine, dried over Na2SO4, concentrated and purified by prep TLC to give 5-bromo-1-isopropylpyridin-2(1H)-one (380 mg, 31%). 1H NMR (CDCl3): 1.35 (d, 6H), 5.65-5.75 (m, 1H), 6.48 (d, 1H), 7.30 (m, 1H), 7.41 (d, 1H).
Reaction SMILES: C([Mg]Cl)(C)C.[OH:6][CH2:7][C@H:8]([CH3:35])[C@@H:9]([NH:16][C:17]1[C:18](=[O:34])[N:19]([C:23]2[CH:24]=[C:25]([CH:30]=[CH:31][C:32]=2[CH3:33])[C:26]([O:28]C)=O)[CH:20]=[CH:21][N:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH:36]1([NH2:39])[CH2:38][CH2:37]1>O1CCCC1>[CH:36]1([NH:39][C:26](=[O:28])[C:25]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:23]([N:19]3[CH:20]=[CH:21][N:22]=[C:17]([NH:16][C@@H:9]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[C@@H:8]([CH3:35])[CH2:7][OH:6])[C:18]3=[O:34])[CH:24]=2)[CH2:38][CH2:37]1
Reactant: COC(=O)c1ccc(C)c(-n2ccnc(N[C@@H](c3ccccc3)[C@@H](C)CO)c2=O)c1
Reactant: NC1CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(N[C@@H](c2ccccc2)[C@@H](C)CO)c1=O

Procedure:
A solution of iso-propylmagnesium chloride (2M in tetrahydrofuran, 5.5 mL) was added dropwise to a stirred mixture of 3-[3-[[(1R,2R)-3-hydroxy-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoic acid, methyl ester (Example 136c, 500 mg), cyclopropylamine (0.3 mL) and tetrahydrofuran (20 mL) at 0° C. After 15 min the reaction was quenched with sat. aqueous NH4Cl and extracted into ethyl acetate. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to give a crude title product (525 mg). Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25]>C1C=CC=CC=1>[C:22]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)(=[O:26])[CH2:23][CH2:24][CH3:25]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1
Reaction time: 0.03 h

Procedure:
0.390 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 4.0 ml. of absolute pyridine and cooled to -10° with stirring. 0.255 G. of butyric acid chloride are added dropwise thereto over a period of 2 minutes. The temperature rises to 0° and pyridine hydrochloride precipitates out. Subsequently, the mixture is stirred overnight at room temperature and the suspension poured on to a mixture of 12 g. of ice and 12 ml. of 20% hydrochloric acid. Thereafter, this mixture is extracted three times with ethyl acetate, washed with water, dried over sodium sulfate and evaporated in vacuum. The 0.552 g. of yellowish crystals obtained as the residue are dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.521 g. of yellowish crystals which are recrystallized from acetone-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl butyrate obtained melts at 77.9°-78.2° and is liquid crystalline (monotrope) upon cooling to 74.7°. UV (EtOH): ε272 = 26,100.
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:31])[C@@H:8]([N:15]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=2)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:32]([O:36][CH:37]([O:39][NH:40][C:41]([C:43]1[S:47][C:46]2[CH:48]=[C:49]([CH:52]=O)[CH:50]=[CH:51][C:45]=2[CH:44]=1)=[O:42])[CH3:38])[CH:33]([CH3:35])[CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)Cl>ClCCCl.C(O)(=O)C>[CH:1]1([O:6][C:7](=[O:31])[C@@H:8]([N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH2:52][C:49]3[CH:50]=[CH:51][C:45]4[CH:44]=[C:43]([C:41](=[O:42])[NH:40][O:39][CH:37]([O:36][CH2:32][CH:33]([CH3:34])[CH3:35])[CH3:38])[S:47][C:46]=4[CH:48]=3)[CH:25]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)COC(C)ONC(=O)c1cc2ccc(C=O)cc2s1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(N)c1)[C@H](C(=O)OC1CCCC1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)COC(C)ONC(=O)c1cc2ccc(CNc3cccc(CN(C(=O)OC(C)(C)C)[C@H](C(=O)OC4CCCC4)c4ccccc4)c3)cc2s1
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To (S)-[(3-Amino-benzyl)-tert-butoxycarbonyl-amino]-phenyl-acetic acid cyclopentyl ester (0.317 g, 0.75 mmol) was added 6-Formyl-benzo[b]thiophene-2-carboxylic acid (1-isobutoxy-ethoxy)-amide (Scheme 7) (0.210 g, 0.65 mmol) in DCE (8 ml). 2 drops of glacial acetic acid were added, and then sodium triacetoxyborohydride (0.170 g, 0.8 mmol). The mixture was stirred for 2 h and then poured into DCM (150 ml). The solution was washed with saturated sodium bicarbonate (50 ml), then dried (MgSO4), concentrated and purified by flash column chromatography to yield the desired product as a pale yellow foam (0.346 g, 73% yield). 1H NMR (300 MHz, CDCl3), δ: 8.35-8.43 (1H, m), 7.56-8.05 (2H, m), 7.01-7.41 (8H, m), 6.90-7.01 (1H, m), 6.42 (1H, dd, J=2.6, 7.9 Hz), 5.25-5.31 (1H, m), 5.12 (1H, q, J=5.2 Hz), 4.40 (1H, d, J 5.4 Hz), 4.00 (1H, dd, J=3.1, 15.8 Hz), 3.60-3.70 (1H, m), 3.35-3.40 (1H, m), 1.33-1.94 (21H, m), 0.98 (3H, d, J=6.6 Hz), 0.97 (3H, d, J=6.6 Hz)