Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COCCOC.O1CCCC1.[NH:12]1[CH2:17][CH2:16][CH:15]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=3)[CH:20]=[CH:19]2)[CH2:14][CH2:13]1.[CH3:31][O:32][C:33]1[C:42]([CH2:43][CH:44]=O)=[C:41]2[C:36]([C:37](=[O:48])[CH2:38][C:39]([CH3:47])([CH3:46])[O:40]2)=[CH:35][CH:34]=1>C(O)(=O)C>[CH3:31][O:32][C:33]1[C:42]([CH2:43][CH2:44][N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=4)[CH:20]=[CH:19]3)[CH2:16][CH2:17]2)=[C:41]2[C:36]([C:37](=[O:48])[CH2:38][C:39]([CH3:47])([CH3:46])[O:40]2)=[CH:35][CH:34]=1
Reactant: COc1ccc2c(c1CC=O)OC(C)(C)CC2=O
Reactant: COC(=O)c1ccc2ccn(C3CCNCC3)c2c1
Solvent: COCCOC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2ccn(C3CCN(CCc4c(OC)ccc5c4OC(C)(C)CC5=O)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.7 %

Procedure:
28 mL of DME, 14 mL of tetrahydrofuran and 1.24 mL of acetic acid were added to 2.80 g of methyl 1-piperidin-4-yl-1H-indole-6-carboxylate and 3.16 g of (7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)acetaldehyde. Although crystals precipitated, the reaction mixture was stirred for one hour as it was. The reaction mixture was cooled with an ice-water bath, and 2.75 g of sodium triacetoxyborohydride was added portionwise divided into three to the reaction mixture. The reaction mixture was warmed to room temperature and added with 3 mL of tetrahydrofuran and about 1.5 hours later, progress of the reaction was confirmed. The reaction mixture cooled with an ice-water bath again and added with 68 mL of toluene and 29 mL of water and, after clarification and filtration, added with 30 mL of toluene and the aqueous layer was discarded. The organic layer was washed with 29 mL of 1 N aqueous sodium hydroxide, 29 mL×2 of 5% sodium chloride solution and 29 mL of water. The solvent was evaporated and 5.62 g of the crude title compound was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([C:20]3([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=4)[C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[NH:22][C:21]3=[O:30])[CH2:15]2)=[O:13])=[CH:7][N:6]=1)=[O:4].O.[OH-].[Li+]>O1CCCC1.O>[Cl:29][C:25]1[CH:24]=[C:23]2[C:28]([C:20]([CH:16]3[CH2:17][CH2:18][CH2:19][N:14]([C:12]([NH:11][C:8]4[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=4)=[O:13])[CH2:15]3)([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=3)[C:21](=[O:30])[NH:22]2)=[CH:27][CH:26]=1
Reactant: COC(=O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of rac-5-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carbonyl}-amino)-pyridine-2-carboxylic acid methyl ester (67 mg, 0.12 mmol) (from Example 83 d supra) in tetrahydrofuran (2 mL) was added the suspension of lithium hydroxide monohydrate (51 mg, 1.2 mmol) (Aldrich) in water (2 mL). The mixture was stirred at room temperature for overnight. The solvent was removed and the residue was partitioned between ethyl acetate and water. The aqueous layer was acidified to “pH”<5 with dilute HCl, then extracted with ethyl acetate several times. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated to give rac-5-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carbonyl}-amino)-pyridine-2-carboxylic acid as a white solid. (Yield 45 mg, 69.2%).
Reaction SMILES: [Cl:1][CH:2]([CH3:16])[CH2:3][CH:4]([CH3:15])[O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1.[C:17]([C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1)#[N:18].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:11][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][C:6]([O:5][C@@H:4]([CH3:15])[CH2:3][C@@H:2]([Cl:1])[CH3:16])=[CH:7][CH:8]=2)=[CH:21][CH:20]=1)#[N:18]
Reactant: CC(Cl)CC(C)Oc1ccc(C(=O)O)cc1
Reactant: N#Cc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C[C@H](Cl)C[C@H](C)Oc1ccc(C(=O)Oc2ccc(C#N)cc2)cc1

Procedure:
1.00 g of 4-(3'-chloro-1'-methylbutoxy)benzoic acid, 0.50 g of 4-cyanophenol, 0.93 g of dicyclohexylcarbodiimide, 0.10 g of 4-pyrrolydinopyridine and 10 ml of methylene chloride were stirred together at room temperature for five hours. The dicyclohexyl urea thus precipitated was filtered and the filtrate was desolvated. The crude product thus obtained was purified by silica gel column chromatography with the use of a mixture of ethyl acetate and n-hexane (1:4) as a developing solvent to thereby give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:17]=[N:18][C:19](=[O:22])[CH2:20][CH:21]=3)[C:13]([CH2:23][OH:24])=[N:12][C:11]=2[CH:25]([CH3:27])[CH3:26])[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC(Cl)(Cl)[C:30]([N:32]=C=O)=[O:31].C(N(CC)CC)C.O>O1CCCC1.CO>[C:30]([O:24][CH2:23][C:13]1[N:14]([CH2:15][C:16]2[CH:17]=[N:18][C:19](=[O:22])[CH2:20][CH:21]=2)[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:25]([CH3:27])[CH3:26])[N:12]=1)(=[O:31])[NH2:32]
Reactant: CC(C)c1nc(CO)n(CC2=CCC(=O)N=C2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)c1nc(COC(N)=O)n(CC2=CCC(=O)N=C2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: -40 °C
Yield: 82 %

Procedure:
In 10 ml of tetrahydrofuran was dissolved 51 mg of 5-(3,5-dichlorophenylthio)-2-hydroxymethyl-1-(5,6-dihydro-6-oxopyridin-3-ylmethyl)-4-isopropyl-1H-imidazole (116a), and the mixture was cooled to -40° C. Under stirring, 22 μl of trichloroacetylisocyanate was added, the mixture was allowed to stand to reach room temperature, and stirred for 30 minutes. There were added 500 μl of triethylamine, 1 ml of water and 2 ml of methanol, and the mixture was stirred at 70° C. for 1 hour. After completion of the reaction, the solution was distilled off under reduced pressure, an aqueous sodium hydrogen carbonate solution was added, extracted with ethyl acetate, the extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:methanol=10:1)to give 46 mg of Compound I-131 was obtained (yield 82%).
Reaction SMILES: [F-:1].[K+].I([C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[C:9]([NH:11][CH2:12][C:13]([O:15][CH2:16][C:17]([Cl:20])([Cl:19])[Cl:18])=[O:14])=[O:10])(=O)=O.C1OCCOCCOCCOCCOCCOC1>CS(C)=O>[F:1][C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[C:9]([NH:11][CH2:12][C:13]([O:15][CH2:16][C:17]([Cl:20])([Cl:19])[Cl:18])=[O:14])=[O:10]
Reactant: O=C(CNC(=O)c1ccc([N+](=O)[O-])c(I(=O)=O)c1)OCC(Cl)(Cl)Cl
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(CNC(=O)c1ccc([N+](=O)[O-])c(F)c1)OCC(Cl)(Cl)Cl
Temperature: 97.5 °C
Reaction time: 0.25 h
Yield: 66.3 %

Procedure:
A mixture of spray-dried KF (135 mg, 2.3 mmol), intermediate 8 (120 mg, 0.23 mmol) and catalytic amount of 18-crown-6 in DMSO (5 mL) was stirred at 95-100° C. for 15 min. Work-up of the reaction mixture as described in example 1 gave the product as a yellow color solid (57 mg, 65%), mp 142-144° C. 1H NMR (400 MHz, CDCl3): δ 8.15 (1H, t, J=7.8 Hz), 7.78 (1H, dd, J=10.8, 1.6 Hz), 7.71 (1H, d, J=8.4 Hz), 6.70 (1H, br s), 4.86 (2H, s), 4.44 (2H, d, J=5.2 Hz); LC-MS (negative ion mode): m/z 371, 373 (M−H)−.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:17][CH:10]3[CH2:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH2:13][CH:9]3[CH:8]2[CH2:18][O:19][CH3:20])[C:3]1=[O:21].Cl[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=2)[N:26]=[CH:25][N:24]=1.C(N(CC)CC)C>C(O)C>[CH:14]([N:12]1[CH2:13][CH:9]2[CH:8]([CH2:18][O:19][CH3:20])[CH:7]([N:4]3[CH2:5][CH2:6][CH:2]([NH:1][C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=5)[N:26]=[CH:25][N:24]=4)[C:3]3=[O:21])[CH2:17][CH:10]2[CH2:11]1)([CH3:16])[CH3:15]
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: COCC1C2CN(C(C)C)CC2CC1N1CCC(N)C1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: COCC1C2CN(C(C)C)CC2CC1N1CCC(Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O

Procedure:
A mixture of 3-amino-1-(2-isopropyl-4-methoxymethyloctahydrocyclopenta[c]pyrrol-5-yl)-pyrrolidin-2-one, 4-chloro-6-trifluoromethylquinazoline (see Armarego et al., J. Chem. Soc. B, 1967, 449) and triethylamine in ethanol is heated at reflux until the reaction is complete. The resulting solution is concentrated under vacuum yielding a residue. The residue is purified by reverse phase HPLC and lyophilization providing the title product.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([CH:11]1[O:16][C:15](=[O:17])[CH:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][CH3:38])[CH2:32][CH2:31]4)=[C:26]([F:39])[C:25]=3[F:40])=[C:20]([F:41])[C:19]=2[F:42])[CH2:13][CH2:12]1)[CH2:9][CH3:10].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C(O)=O>[CH2:8]([CH:11]1[O:16][CH:15]([OH:17])[CH:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][CH3:38])[CH2:32][CH2:31]4)=[C:26]([F:39])[C:25]=3[F:40])=[C:20]([F:41])[C:19]=2[F:42])[CH2:13][CH2:12]1)[CH2:9][CH3:10]
Reactant: CCCC1CCC(c2ccc(-c3ccc(C4CCC(CCC)OC4=O)c(F)c3F)c(F)c2F)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O=CO
Product: CCCC1CCC(c2ccc(-c3ccc(C4CCC(CCC)OC4O)c(F)c3F)c(F)c2F)CC1
Reaction time: 3 h
Yield: 100.1 %

Procedure:
Toluene (50 ml) was added to 6-propyl-3-(2,2′,3,3′-tetrafluoro-4′-(4-propylcyclohexyl)biphenyl-4-yl)tetrahydro-2H-pyran-2-one (16) (4.18 g) prepared in the first step. A diisobutylaluminum hydride-toluene solution (0.99 M; 12.5 ml) was added dropwise at −50° C. or lower, and the stirring was continued for 3 hours. The reaction mixture was poured into a 10% aqueous solution of formic acid (50 ml) to give two layers. The water layer was extracted with toluene (20 ml) twice and the combined organic layer was washed with water. The solution was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to leave 6-propyl-3-(2,2′,3,3′-tetrafluoro-4′-(4-propylcyclohexyl)biphenyl-4-yl)tetrahydro-2H-pyran-2-ol (17) (4.2 g) in 99% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([OH:12])([CH3:11])[CH3:10].[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14]>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:13](=[O:14])[O:12][C:9]([CH3:10])([CH3:11])[C:3]=2[CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(O)c1cc(Br)ccc1N
Solvent: C1CCOC1
Product: CC1(C)OC(=O)Nc2ccc(Br)cc21
Temperature: 50 °C

Procedure:
To a solution of 2-(2-amino-5-bromophenyl)propan-2-ol (18 g, 78 mmol) in dry THF (150 mL) was added 1,1′-carbonyldiimidazole (15.5 g, 94 mmol) under nitrogen. The reaction solution was heated at 50° C. overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (100 mL). The solution was washed with 1N aqueous hydrochloride solution (2×40 mL), brine (20 mL), and dried with MgSO4. After removal of solvent in vacuo, 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one was obtained as a white solid (20 g, 100%): mp 199–200° C.; 1H-NMR (DMSO-d6) δ 10.32 (s, 1H, D2O exchangeable), 7.48 (d, 1H, J=2.1 Hz), 7.43 (dd, 1H, J=8.5, 2.1 Hz), 6.84 (d, 1H, J=8.4 Hz), 1.61 (s, 6H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:8][N:7]=1.Cl[CH2:17][C:18]1[CH:36]=[CH:35][C:21]([O:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[S:27][CH:28]=2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:29]1([C:26]2[S:27][CH:28]=[C:24]([CH2:23][O:22][C:21]3[CH:20]=[CH:19][C:18]([CH2:17][N:8]4[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([C:2]5[S:1][CH:5]=[CH:4][CH:3]=5)=[N:7]4)=[CH:36][CH:35]=3)[N:25]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: ClCc1ccc(OCc2csc(-c3ccccc3)n2)cc1
Reactant: CCOC(=O)c1c[nH]nc1-c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A mixture of ethyl 3-(2-thienyl)-1H-pyrazole-4-carboxylate (5.60 g), 4-(4-chloromethylphenoxy)methyl-2-phenylthiazole (7.96 g), potassium carbonate (6.98 g), and N,N-dimethylformamide (75 ml) was stirred at 80° C. for 8 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carboxylate as colorless crystals (10.93 g, yield: 87%) from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 94˜95° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:17]([O:19]C)=O)[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:21])[O:4][N:3]=1.[CH:22]1([Mg]Cl)[CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1>[CH:22]1([C:17]([C:9]2[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:21])[CH:8]=2)=[O:19])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Reactant: Cl[Mg]C1CCCC1
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1cc(C(=O)C2CCCC2)c2[nH]c(=O)[nH]c2c1

Procedure:
To a mixture containing methyl 6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate (60 mg, 0.21 mmol, 1 equiv.) and THF (3 mL) is added cyclopentyl magnesium chloride (0.88 mL, 1.46 mmol, 7 equiv.) at 0° C. for 5 min. After completion, the reaction was quenched and extracted with EtOAc and washed with water, saturated NH4Cl. After drying with MgSO4, it was filtered and concentrated to dryness. Purification was carried out by reverse phase HPLC.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[N:6][CH:7]=1.[CH3:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1B(O)O>>[CH3:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[C:2]1[CH:3]=[C:4]([O:8][S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[N:6][CH:7]=1
Reactant: Cn1c(B(O)O)cc2ccccc21
Reactant: CN1CCN(S(=O)(=O)Oc2cncc(Br)c2)CC1
Product: CN1CCN(S(=O)(=O)Oc2cncc(-c3cc4ccccc4n3C)c2)CC1

Procedure:
4-Methyl-piperazine-1-sulfonic acid 5-bromo-pyridin-3-yl ester and N-methyl-indoleboronic acid are processed according to the method described in Example 100 to give 4-Methyl-piperazine-1-sulfonic acid 5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl ester. MS (ESI) m/z 387.1 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[NH2:8].C(=O)([O-])[O-].[K+].[K+].[C:18](Cl)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O.O1CCOCC1>[CH2:21]([O:20][C:18]([NH:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(Cc1cccs1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NC(Cc1cccs1)C(=O)O)OCc1ccccc1
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To a mixture of 3.0 g (16.9 mmol) of β-thienyl-D,L-alanine in 75 mL of water and 60 mL of dioxane, was added 5.6 g (40.6 mmol) of anhydrous potassium carbonate, followed by 2.85 mL (20 mmol) of carbobenzyloxychloride. The resulting mixture was stirred rapidly for approximately one hour. When the reaction was substantially complete, as indicated by thin layer chromatography (21/7/7/9, EtOAc/AcOH/CH3 CN/H2O), the reaction mixture was concentrated. The resultant layers were separated and the aqueous layer was washed with 75 mL of diethyl ether and then layered with 150 mL of methylene chloride. The resultant mixture was acidified with rapid stirring to pH=2.0 using 5N hydrochloric acid. The layers were then separated, and the organic layer was dried with sodium sulfate (Na2SO4), filtered and concentrated to provide 5.05 g of desired compound (98%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:38])([F:37])[C:13]([CH2:32][NH:33][CH2:34][CH2:35][CH3:36])([OH:31])[CH2:14][NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:33]([CH2:34][CH2:35][CH3:36])[CH2:32][C:13]([OH:31])([CH2:14][NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]([F:37])([F:11])[F:38])=[O:6]
Reactant: O=C(O)c1ccccc1F
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Product: CCCN(CC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1F

Procedure:
Prepared similarly to Example 1 from 2-fluorobenzoic acid and 1,1,1-trifluoro-3-[(1-phenyl-1H-indazol-4-yl)amino]-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [O-]CC.[Na+].[F:5][C:6]1[CH:26]=[CH:25][C:9]([C:10]([C:12]2[C:17]([O:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:16][CH:15]=[CH:14][N:13]=2)=O)=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[C:20]([C:19]1[O:18][C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C:10]=1[C:9]1[CH:25]=[CH:26][C:6]([F:5])=[CH:7][CH:8]=1)([OH:22])=[O:21]
Reactant: CCOC(=O)COc1cccnc1C(=O)c1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O)c1oc2cccnc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.9 %

Procedure:
Sodium ethoxide (1.51 g, 22.6 mmol) was suspended in toluene (25 ml) and ethyl 2-[2-(4-fluorobenzoyl)pyridin-3-yloxy]acetate (3.5 g, 11.5 mmol) was added. The reaction was heated at reflux under an argon atmosphere. After 12 h, the reaction mixture was cooled to room temperature and the product was extracted into water. The aqueous layer was acidified with hydrochloric acid to give 2-carboxy-3-(4-fluorophenyl)-furo[3,2-b]pyridine as a solid (1.8 g).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:14][C:15]1[C:20]([F:21])=[CH:19][C:18]([NH2:22])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1.O.[OH-].[Li+].C(OCC)(=O)C>CS(C)=O>[F:14][C:15]1[C:20]([F:21])=[CH:19][C:18]([NH:22][C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[C:4]#[N:5])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cc(C(F)(F)F)ccc1Nc1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
Heat a solution of 2-fluoro-5-trifluoromethyl-benzonitrile (1.0 g, 5.74 mmol) with 4,5-difluoro-2-nitro-phenylamine (1.09 g, 5.74 mmol) and lithium hydroxide monohydrate (0.48 g, 11.49 mmol) in DMSO (12 ml) to 55° C. for 16 hours. Cool the reaction to ambient temperature and then add approximately 150 ml of ice water and stir the mixture for one hour. Extract with three 200 ml portions of dichloromethane. Combine organic layers, dry over sodium sulfate and evaporate solvent. Purify the residue via flash chromatography eluting with a linear gradient starting with 100% hexanes and going to 70% hexanes: 30% ethyl acetate to obtain 0.995 g (2.90 mmol, 50% yield) of the title compound as a yellow amorphous solid: Mass Spectrum (m/e): 344 (M+1).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[C:11]([NH:14][C@@H:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16](O)=[O:17])(=[O:13])[CH3:12].CCN=C=NCCCN(C)C.Cl.[NH2:38][C@@H:39]([CH2:48][C:49]1[CH:54]=[CH:53][C:52]([N:55]2[CH2:59][C:58](=[O:60])[N:57]([CH2:61][C:62]3[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][CH:63]=3)[S:56]2(=[O:71])=[O:70])=[CH:51][CH:50]=1)[C:40]([NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:41]>C(Cl)Cl>[C:11]([NH:14][C@@H:15]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:16]([NH:38][C@H:39]([C:40](=[O:41])[NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:48][C:49]1[CH:50]=[CH:51][C:52]([N:55]2[CH2:59][C:58](=[O:60])[N:57]([CH2:61][C:62]3[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][CH:63]=3)[S:56]2(=[O:70])=[O:71])=[CH:53][CH:54]=1)=[O:17])(=[O:13])[CH3:12]
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCCCCNC(=O)[C@@H](N)Cc1ccc(N2CC(=O)N(Cc3ccc(OC)cc3)S2(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCCCNC(=O)[C@H](Cc1ccc(N2CC(=O)N(Cc3ccc(OC)cc3)S2(=O)=O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(C)=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
HOBt (16 mg, 0.102 mmol), (S)-2-acetylamino-3-phenyl-propionic acid (21 mg, 0.102 mmol) and EDCl (21 mg, 0.112 mmol) are added to a solution of the title B compound, (S)-2-amino-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-N-pentyl-propionamide (50 mg, 0.102 mmol) in CH2Cl2 (3 mL) and the reaction is stirred at RT for 2.5 h, then concentrated. The residue is taken up in EtOAc, washed with 1N aqueous HCl, saturated NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated to yield (S)-2-acetylamino-N-((S)-2-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-1-pentylcarbamoyl-ethyl)-3-phenyl-propionamide as a white foam: [M+1]+=678.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)[OH:4].[C:15](=[S:17])=[S:16].C(N(CC)CC)C.C(Cl)C1C=CC=CC=1>N1C=CC=CC=1>[CH3:14][O:13][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH2:2][NH:1][C:15](=[S:16])[SH:17])[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: S=C=S
Reactant: COc1ccc(C(O)CN)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(C(O)CNC(=S)S)cc1OC
Reaction time: 1 h

Procedure:
10 mmol of 2-amino-1-(3,4-dimethoxyphenyl)-ethanol is dissolved in 6 ml. of pyridine and, under cooling to 0°, combined dropwise with 11 mmol of carbon disulfide in 10 mmol of triethylamine. During this step, the temperature rises greatly. The mixture is agitated for one hour at 0° and then, at the same temperature, 10 mmol of benzyl choride is added dropwise thereto. After agitation overnight at 0°, the batch is taken up in 40 ml. of 3 N sulfuric acid and extracted three times with respectively 50 ml. of chloroform. The combined chloroform phases are washed in succession with sodium bicarbonate and water, dried, filtered, and concentrated. The residue, which crystallizes spontaneously, is recrystallized from benzene and ethyl acetate, thus obtaining in a quantitative yield the benzyl ester of [2-(3,4-dimethoxyphenyl)-2-hydroxyethyl]-dithiocarbamic acid, m.p. 130°-132°.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[CH:21]=[CH:22][S:23][C:16]=12>O1CCOCC1.[Cu]Br>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[CH:21]=[CH:22][S:23][C:16]=12)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Brc1ccnc2ccsc12
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1ccnc2ccsc12
Temperature: 0 °C
Yield: 57 %

Procedure:
Charge a flask containing sodium hydride (17.45 g, 0.44 moles) with anhydrous dioxane (500 ml) while cooling at 0° C. Add diethyl malonate (69.88 g, 0.44 moles) dropwise over one hour. Upon reaching ambient temperature, add copper (I) bromide (62.59 g, 0.44 moles). Add 7-bromothieno[3,2-b]pyridine (18.68 g, 87.26 mmol) as a solution in dioxane (50 mL). Heat the reaction to reflux for 18 hours. Concentrate the reaction solution to ˜175 mL. Pour the concentrate into concentrated ammonium hydroxide (2.5 L). Extract the aqueous phase with ethyl acetate (6×300 mL). Wash the organic layers exhaustively with 2 N sodium hydroxide until the blue color dissipates. Treat the organic layers with magnesium sulfate, filter and concentrate. Purification on silica utilizing a solution of 1:1:3 of ether, ethyl acetate and hexane as eluent yields the desired compound (14.6 gm, 57%).