Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH:15]([C:16]([O:18]C(C)C)=[O:17])[C:11]3=[CH:10][C:9]=2[CH3:22])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.CO.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]1([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH:15]([C:16]([OH:18])=[O:17])[C:11]3=[CH:10][C:9]=2[CH3:22])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc2n(c1C(=O)c1cccs1)CCC2C(=O)OC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cc2n(c1C(=O)c1cccs1)CCC2C(=O)O

Procedure:
A solution of 500 mg. of isopropyl 5-(2-thenoyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate in 15 ml. of methanol is treated with a solution of 1.05 g. of potassium carbonate in 8 ml. of water. The reaction mixture is refluxed under nitrogen atmosphere for 3 hours, cooled, and evaporated to dryness. The residue is taken up in 10 ml. of 10% aqueous hydrochloric acid and 50 ml. of water and the resultant mixture extracted with ethyl acetate (3 × 50 ml.). The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure, to give 5-(2-thenoyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid [(A), R = CH3, R1 = H, X = S], having a melting point of 166° C.
Reaction SMILES: CC1(C)[N:6](C(OC(C)(C)C)=O)[C@:5]([CH3:20])([C:14]2[O:15][C:16]([CH3:19])=[N:17][N:18]=2)[CH2:4][O:3]1.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>ClCCl>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[NH2:6][C@@:5]([C:14]1[O:15][C:16]([CH3:19])=[N:17][N:18]=1)([CH3:20])[CH2:4][OH:3]
Reactant: Cc1nnc([C@]2(C)COC(C)(C)N2C(=O)OC(C)(C)C)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nnc([C@@](C)(N)CO)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 220 mg of tert-butyl (4S)-2,2,4-trimethyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)-1,3-oxazolidine-3-carboxylate in 3.0 ml of dichloromethane was added 1.5 ml of trifluoroacetic acid, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was azeotropic distilled with methanol to obtain 266 mg of (2S)-2-amino-2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-1-ol trifluoroacetate as a crude product, which was used for the next reaction without further purification.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9](C)C)[CH2:3][CH2:2]1.[F:13][C:14]1[C:21]([CH3:22])=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][N:6]([C:20]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([F:13])[C:21]=3[CH3:22])[C@H:5]2[CH3:9])[CH2:2][CH2:3]1
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: Cc1c(F)ccc(C#N)c1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: Cc1c(N2CC[C@@](O)(C3CC3)[C@@H]2C)ccc(C#N)c1F

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3R)-3-cyclopropyl-2-methylpyrrolidin-3-ol 0.5 oxalate (260 mg), 2,4-difluoro-3-methylbenzonitrile (364 mg) and lithium carbonate (234 mg), the title compound was obtained as a colorless solid (yield: 106 mg, yield: 24%).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:9]1[C:17]2[C:12](=[C:13]([CH2:19][S:20][CH3:21])[CH:14]=[C:15]([F:18])[CH:16]=2)[NH:11][CH:10]=1)(=O)=O.[C-:29]#[N:30].[K+]>CN(C=O)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH:8]([C:9]2[C:17]3[C:12](=[C:13]([CH2:19][S:20][CH3:21])[CH:14]=[C:15]([F:18])[CH:16]=3)[NH:11][CH:10]=2)[CH2:7][CH2:6][C:29]#[N:30])=[CH:23][CH:24]=1
Reactant: [C-]#N
Reactant: CSCc1cc(F)cc2c(C(CCOS(C)(=O)=O)c3ccc(Cl)cc3)c[nH]c12
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCc1cc(F)cc2c(C(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Temperature: 80 °C
Reaction time: 72 h

Procedure:
445 mg (1.01 mmol) of the compound from Example 59A and 131 mg (2.01 mmol) of potassium cyanide were dissolved in 23 ml of DMF and stirred at 80° C. for three days. The mixture was concentrated, and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 102 mg (27% of theory) of the title compound. Also obtained were 180 mg (0.47 mmol) of 3-[3-chloro-1-(4-chlorophenyl)propyl]-5-fluoro-7-[(methylsulfanyl)methyl]-1H-indole.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](Cl)=[O:37]>>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:20]2[CH:19]=[CH:18][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:9]([CH3:8])[C:36](=[O:37])[C:35]4[CH:39]=[CH:40][CH:41]=[C:33]([O:32][CH3:31])[CH:34]=4)[CH:12]=3)=[CH:22][CH:21]=2)[S:28]1
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(C(=O)N(C)Cc2cccc(-c3ccc(CC4SC(=O)NC4=O)cc3)c2)c1

Procedure:
In a manner similar to that of Example 37(e), by reacting 540 mg (1.2 mmol) of 5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dione trifluoroacetate with 300 μl (2 mmol) of 3-methoxybenzoyl chloride, and after purification, 400 mg (70%) of N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)-biphenyl-3-ylmethyl]-3-methoxy-N-methylbenzamide are obtained in the form of a white solid with a melting point of 173° C.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.[CH3:16][CH:17]([SiH:19]([CH:21]([CH3:23])[CH3:22])Cl)[CH3:18]>CCCCCC>[CH3:16][CH:17]([SiH:19]([CH:21]([CH3:23])[CH3:22])[O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:18]
Reactant: CC(C)[SiH](Cl)C(C)C
Reactant: CCCCCCCCO
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CCCCCCCCO[SiH](C(C)C)C(C)C
Temperature: -5 °C
Reaction time: 8 h

Procedure:
Di(2-propyl)octyloxysilane was prepared in the following manner. Dry octanol (52.5 g, 0.40 mole) and dry pyridine (32.9 g, 0.42 mole) were added to a 500 ml round-bottom flask. The solution was cooled to -5° C. with stirring. Di(2-propyl)chlorosilane (67.1 g, 0.44 mole) was added in a dropwise fashion over 60 minutes. After this addition, the temperature of the reaction mixture was maintained at -5° C. for another 30 minutes, then allowed to come to room temperature overnight. Hexane (100 ml) was then added to this reaction mixture. The organic phase was extracted with 500 ml 0.1N aq. HCl and 500 ml water. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled to produce di(2-propyl)octyloxysilane.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[CH3:27][C:28]1[N:33]=[C:32](B(O)O)[CH:31]=[CH:30][CH:29]=1>>[OH:25][CH2:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:27])[N:33]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: Cc1cccc(B(O)O)n1
Product: Cc1cccc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccccc4)OC3=O)cc2)n1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one and 6-methylpyridine-2-boronic acid following procedures analogous to those described in Example 75 Step 1. LC-MS Method 2 tR=0.986 min, m/z=431.1; 1H NMR (CDCl3) 1.33 (m, 2H), 1.52 (d, 3H), 1.69 (m, 1H), 1.97 (m, 2H), 2.12-2.30 (m, 3H), 2.56 (s, 3H), 2.85 (m, 1H), 3.52 (t, 2H), 5.67 (m, 1H), 6.95 (d, 2H), 7.03 (d, 1H), 7.22-7.37 (m, 6H), 7.55 (t, 1H), 7.64 (d, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH3:29])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH2:27][CH3:28])[N:6]=2.[CH3:30][S:31]([CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][C:37]1([CH3:43])[CH3:42])(=[O:33])=[O:32].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:42][C:37]1([CH3:43])[N:36]([CH2:35][CH2:34][S:31]([CH3:30])(=[O:32])=[O:33])[CH2:41][CH2:40][N:39]([CH2:2][C:3]2[N:4]([CH3:29])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH2:27][CH3:28])[N:6]=3)[CH2:38]1
Reactant: CC1(C)CNCCN1CCS(C)(=O)=O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCl)n(C)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(CCS(C)(=O)=O)C(C)(C)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.8 %

Procedure:
To a solution of 8-chloromethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (107 mg, 0.26 mmol) and 1-(2-methanesulfonylethyl)-2,2-dimethylpiperazine (68 mg, 0.31 mmol) in DMF (3 mL) was added K2CO3 (106 mg, 0.77 mmol). The resulting mixture was allowed to stir at room temperature for 16 h. The reaction mixture was dissolved in EtOAc, washed with H2O (×4) then dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) and (Si—PCC, MeOH:DCM 0-5%). The resulting residue was further purified by reverse phase HPLC (Phenomenex Luna C18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 95:5 to 5:95) to afford 310 as a white solid (40 mg, 26%). LCMS (Method G): RT 6.68 min, [M+H]+ 596.3. 1H NMR (CDCl3, 400 MHz): δ 8.04-7.99 (m, 1 H); 7.77-7.72 (m, 1 H); 7.28-7.23 (m, 2 H); 4.35 (m, 4 H); 3.87 (m, 7 H); 3.69 (s, 2H); 3.36 (q, J=7.5 Hz, 2 H); 3.11-3.03 (m, 5 H); 2.92 (m, 2 H); 2.62 (m 2 H); 2.51 (m, 2H); 2.37-2.22 (m, 2 H); 1.45 (t, J=7.5 Hz, 3 H) and 1.09 (s, 6 H)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH:23]=O)[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH:29]([CH2:30][CH3:31])[CH2:32][CH3:33])[CH2:23][N:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:7](=[O:8])[C:6]2[CH:16]=[C:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)[CH2:15][CH2:14]1)[CH3:18]
Reactant: Cc1cncc(C(=O)NC2CCNCC2)c1
Reactant: CCOc1cc(C=O)ccc1OC(CC)CC
Product: CCOc1cc(CN2CCC(NC(=O)c3cncc(C)c3)CC2)ccc1OC(CC)CC
Yield: 36 %

Procedure:
The title compound (14 mg, 36%) was prepared analogously to example 30 from 5-methyl-N-(piperidin-4-yl)-nicotinamide and 3-ethoxy-4-(1-ethyl-propoxy)-benzaldehyde. MS: 440.6 (MH+)
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:11]2[C@@:6]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])([N:7]=[C:8]([NH:12]C(=O)C3C=CC=CC=3)[S:9][CH2:10]2)[CH2:5][O:4]1.N12CCCN=C1CCCCC2>CO>[F:1][CH2:2][C@@H:3]1[C@@H:11]2[C@@:6]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])([N:7]=[C:8]([NH2:12])[S:9][CH2:10]2)[CH2:5][O:4]1
Reactant: O=C(NC1=N[C@@]2(c3ccccc3F)CO[C@H](CF)[C@H]2CS1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: NC1=N[C@@]2(c3ccccc3F)CO[C@H](CF)[C@H]2CS1
Temperature: 80 °C
Yield: 89.2 %

Procedure:
N-((4aS,5S,7aS)-5-(fluoromethyl)-7a-(2-fluorophenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (70.56 g, 181.65 mmol) was dissolved in methanol (420 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (55.73 mL, 372.69) was added, and the solution was heated to reflux (heating block temperature 80° C.) for 5 h. The reaction mixture was concentrated under reduced pressure, and the residue purified by silica gel column chromatography (10% to 50% EtOAc in hexanes) to afford the title compound (46.05 g, 89%). 1H NMR (400 MHz, CDCl3) δ ppm 2.79 (dd, J=13.39, 4.04 Hz, 1H) 2.98-3.05 (m, 1H) 3.12 (dd, J=13.39, 3.54 Hz, 1H) 3.87 (dd, J=8.46, 2.65 Hz, 1H) 4.46 (br. s., 2H) 4.48-4.67 (m, 4H) 7.06 (ddd, J=12.57, 8.15, 1.26 Hz, 1H) 7.15 (td, J=7.58, 1.26 Hz, 1H) 7.24-7.31 (m, 1H) 7.44 (td, J=8.08, 2.02 Hz, 1H).
Reaction SMILES: [CH3:1][NH2:2].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[C:10][CH2:11][CH2:12]O)[CH:4]=1>O>[CH3:1][NH:2][CH2:12][CH2:11][C:10]#[C:9][C:5]1[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=1
Reactant: OCCC#Cc1cccnc1
Reactant: CN
Solvent: O
Product: CNCCC#Cc1cccnc1
Reaction time: 3 h
Yield: 546.1 %

Procedure:
An aqueous methylamine solution (5 mL, 40%, 58.7 mmole) was mixed with XII (200 mg, 0.08 mmole) and stirred for 3 hr. in a sealed tube at 45° C. After the reaction was complete, water (10 mL) was added to the cooled reaction mixture, and the reaction mixture was extracted with chloroform (10×5 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was chromatographed on a silica gel column using methanol:chloroform (1:9) and then with a chloroform: methanol mixture containing 1% triethylamine as eluent. About 70 mg of XIII was obtained as a slightly yellow syrup, which was distilled at 110-112° C., 0.04 mm Hg. XIII was converted to its mono fumarate salt form, which exhibits a melting point of 103-104° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[NH2:22][CH:23]([CH3:27])[C:24]([NH2:26])=[O:25]>CO.C(Cl)Cl>[C:24]([CH:23]([NH:22][CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:27])(=[O:25])[NH2:26]
Reactant: CC(N)C(N)=O
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CC(NCc1ccc2[nH]c(C(N)=O)c(Sc3ccccc3)c2c1)C(N)=O

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (50 mg, 0.17 mmol) with 2-aminopropionamide (62.3 mg, 0.50 mmol) as described in General Procedure X to afford Iaf (39 mg, 62.9%) as an ivory colored solid, tlc Rf=0.5 (10% MeOH/CH2Cl2−0.2% Et3N), m/z obs=369 (M+1).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17].[C:19]([OH:23])([CH3:22])([CH3:21])[CH3:20]>>[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:12])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)O
Agent: [Li]CCCC
Product: CC(C)(C)OC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyl lithium (1.6 M, 101 mL) was added dropwise to stirring anhydrous tert-butanol (200 mL) under nitrogen in a room temperature water bath. After 0.5 hours, 4-chloro-3-nitrobenzoyl chloride (10.0 g) was added, and the dark solution was stirred for 1.5 hours at room temperature. The reaction was evaporated under vacuum, and the residue was crystallized from hexane to yield the title compound as an orange solid. Mp: 66°-67° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=1)[C:21]([N:23]([CH2:33][C:34]1[C:35]2[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=2[S:37][CH:38]=1)[C@@H:24]([CH3:32])[CH:25]([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[O:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:9])[NH:10][N:11]([CH2:13][C:14]([NH:19][C@@H:20]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:52])[CH3:53])=[CH:46][CH:45]=2)[C:21]([N:23]([CH2:33][C:34]2[C:35]3[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=3[S:37][CH:38]=2)[C@@H:24]([CH3:32])[CH:25]([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[O:22])=[O:16])[CH3:12])=[CH:17][CH:18]=1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 79 mg (0.29 mmol) was coupled with (S)-2-amino-N-(benzo[b]thiophen-3-ylmethyl)-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)propanamide (Compound IV-6) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:3]1.[F:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22](=[CH:28]O)[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22](=[CH:28][NH:16][C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH:4]4[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]4)=[CH:15][CH:14]=3)[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1
Reactant: O=C1Nc2cc(F)ccc2C1=CO
Reactant: CN1CCCC(COc2ccc(N)cc2)C1
Product: CN1CCCC(COc2ccc(NC=C3C(=O)Nc4cc(F)ccc43)cc2)C1
Yield: 54.8 %

Procedure:
In a manner similar to that described in Example 231, 4-(1-methyl-piperidin-3-ylmethoxy)-phenylamine (590 mg, 1.2 equiv.) and 6-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (400 mg, 2.23 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (466 mg, 55%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][OH:11]>C(OCC)C>[O:4]1[CH2:5][CH2:6][N:1]([CH2:8][CH2:9][CH2:10][OH:11])[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: OCCCBr
Solvent: CCOCC
Product: OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
To a solution of 31.4 ml (360 mmol) of morpholine in 500 ml of diethyl ether were added slowly 10 g (71.94 mmole) of 3-bromopropanol and the mixture was stirred for one hour at room temperature. The reaction mixture was evaporated under vacuum and 300 ml of methylene chloride and 400 ml of a saturated aqueous solution of sodium bicarbonate were added. The mixture was shaken and the organic layer was separated and washed twice with 300-ml portions of saturated aqueous sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and evaporated to yield 10.3 g of 3-morpholinopropanol.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(#N)C.[OH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=1>O>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=1)[CH3:13]
Reactant: CCOC(=O)CBr
Reactant: NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)COc1ccc(C(N)=O)cc1
Temperature: 80 °C

Procedure:
Potassium carbonate (1.04 g) and ethyl bromoacetate (0.610 ml) were added to an acetonitrile (15 ml) solution containing 4-hydroxybenzamide (686 mg), followed by heating at 80° C. for 2 hours. The reaction solution was cooled, water (45 ml) was added thereto, and the precipitated solid was collected by filtration, washed with water and dried to obtain ethyl[4-(aminocarbonyl)phenoxy]acetate (893 mg) as pale brown powder.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[S:16][CH2:17][CH:18]=[CH:19][CH2:20]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.Cl.[OH:25][NH2:26]>N1C=CC=CC=1>[OH:25][N:26]=[CH:20][CH:19]1[C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]=2[S:16][CH2:17][CH2:18]1
Reactant: OCC=CCSc1cc2ccccc2n1-c1ccccc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: ON=CC1CCSc2c1c1ccccc1n2-c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 84.7 %

Procedure:
A solution of the product of the above (2) (3.71 g) in pyridine (75 ml) is heated at 110° C. for 70 minutes. After cooling, methanol (25 ml) and hydroxyamine hydrochloride (2.2 g) are added thereto. The mixture is stirred at room temperature for 50 minutes and evaporated. The residue is acidified with ice-cooled 3 N-hydrochloric acid and extracted with chloroform. The extract is evaporated to give oily residue. The residue is chromatographed on a column of silica gel and eluted with benzene. The eluate is evaporated to give 4-hydroxyiminomethyl-9-phenyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole (3.28 g). The product is dissolved into tetrahydrofuran (55 ml) and lithium aluminium hydride (1.4 g) is added thereto at room temperature. The mixture is refluxed for 1 hour. Ethyl acetate, an 10% aqueous solution of sodium hydroxide and water are successively added thereto. The precipitate is collected by filtration, washed with ethyl acetate and chloroform, and added to the filtrate. The organic layer is separated, washed with water, dried and evaporated to give the free base of the title compound as an oil.
Reaction SMILES: C([Li])(C)(C)C.CCCCC.[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][CH:14]=1.[B:27](OC)([O:30]C)[O:28]C>CCOCC>[B:27]([C:15]1[CH:14]=[C:13]([O:12][CH3:11])[CH:26]=[CH:25][C:16]=1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])([OH:30])[OH:28]
Reactant: COB(OC)OC
Reactant: COc1ccc(NC(=O)OC(C)(C)C)cc1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: COc1ccc(NC(=O)OC(C)(C)C)c(B(O)O)c1
Temperature: -20 °C
Reaction time: 5 h
Yield: 54.8 %

Procedure:
A solution of t-butyllithium in pentane (1.70M, 200 mL, 340 mmol, 2.50 equiv) was added via cannula to a solution of tert-butyl 4-methoxycarbanilate (30.4 g, 136 mmol, 1 equiv) in ether (500 mL) at -20° C., producing a cloudy yellow solution. After stirring at -20° C. for 5 h, trimethyl borate (46.3 mL, 408 mmol, 3.00 equiv) was added. The resulting viscous solution was swirled by hand for 5 min, then was allowed to warm to 23° C. and was held at that temperature for 12 h. The product solution was partitioned between saturated aqueous ammonium chloride solution (500 mL) and ethyl acetate (500 mL). The aqueous layer was separated and further extracted with ethyl acetate (2×500 mL). The combined organic layers were dried over sodium sulfate and were concentrated. The product was purified by flash column chromatography (2.5% methanol-dichloromethane initially, grading to 10% methanol-dichloromethane) to provide the tert-Butyl 2-Borono-4-methoxycarbanilate (8) as a yellow powder (19.9 g, 55%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:3]=1.[NH:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1.C1(O)C=CC=CC=1>O>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[CH:3]=[C:2]2[N:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1
Reactant: NC(=O)C1CCNCC1
Reactant: Cc1ccc(-c2cc(Cl)c3cc(C)ccc3n2)cc1
Solvent: Oc1ccccc1
Solvent: O
Product: Cc1ccc(-c2cc(N3CCC(C(N)=O)CC3)c3cc(C)ccc3n2)cc1
Yield: 74 %

Procedure:
A mixture of 3.2 g of 4-chloro-6-methyl-2-(4-methylphenyl)quinoline, 3.06 g (24 mmol) of isonipecotamide, and 6 g of phenol was stirred and heated in an oil bath at 160° for 4 hr. It was then cooled and diluted with water. Crystallization was induced by the addition of ethanol and scratching. The solid was collected and washed with ether to give 3.18 g of crude product. Recrystallization from n-butanol gave off-white prisms, mp 242°-244° dec.