Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:47])[C@@H:5]([NH:15][C:16]([C:18]1[S:26][C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[O:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]3[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:39]=3[F:45])=[O:36])=[C:30]([F:46])[CH:29]=2)[CH:19]=1)=[O:17])[CH2:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([NH:3][C:4](=[O:47])[C@@H:5]([NH:15][C:16]([C:18]1[S:26][C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[O:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]3[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:39]=3[F:45])=[O:36])=[C:30]([F:46])[CH:29]=2)[CH:19]=1)=[O:17])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH3:2]
Reactant: CCNC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)[C@H](CCC(=O)O)NC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of tert-butyl (4S)-5-(ethylamino)-4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoate (70 mg, 0.10 mmol) in 5 ml of methylene chloride was added 2 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 2 hours and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5 ml) and poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give (4S)-5-(ethylamino)-4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoic acid as light yellow solid. Yield: 53 mg, 83%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>>[CH3:25][O:24][C:22]([C:4]1[N:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:27]([F:26])=[CH:28][CH:29]=1)=[CH:10][CH:9]=[C:8]([O:14][CH3:15])[CH:7]=2)=[O:23]
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(OC)cc2n1-c1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: COC(=O)c1c(CNC(=O)c2ccc(F)cc2)c(=O)c2ccc(OC)cc2n1-c1ccccc1

Procedure:
3-[(4-Fluoro-benzoylamino)-methyl]-7-methoxy-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester was prepared starting from intermediate K and 4-fluorobenzoyl chloride. MS calcd. for C26H21FN2O5 [(M+H)+] 461.1, obsd. 460.9.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]1(=[O:12])[CH2:11][CH2:10][CH2:9]1>>[OH:12][C:8]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: Brc1ccccn1
Reactant: O=C1CCC1
Product: OC1(c2ccccn2)CCC1

Procedure:
Prepared from 2-bromopyridine and cyclobutanone by the method described in Example 10 to give the title compound (7.62 g, quantitative) as an orange oil; NMR δH (400 MHz, DMSO) 8.54 (1H, m), 7.75 (1H, td, J 7.6, 1.7 Hz), 7.59 (1H, m), 7.22 (1H, m), 5.70 (1H, s), 2.58 (2H, m), 2.23 (2H, m), 1.91 (2H, m); (M+H)+ 151.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)(=[O:21])=[O:20]
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1cn(S(=O)(=O)c2ccccc2Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
A solution of 1H-indole-3-carboxaldehyde (0.290 g, 2.00 mmol) in methylene chloride (4 mL) was added with 2-chlorophenylsulfonyl chloride (0.507 g, 2.40 mmol) and diisopropylethylamine (0.310 g, 2.40 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate to terminate the reaction, and then extracted three times with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 1-(2-chlorophenylsulfonyl)-1H-indole-3-carboxaldehyde (0.580 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:12]([C:9]2[O:10][C:11]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=2)=[O:14])=[CH:18][CH:17]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COc1cccc2cc(C(=O)O)oc12
Product: COc1cccc2cc(C(=O)Nc3ccc(Cl)cc3)oc12

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-methoxybenzofuran-2-carboxylic acid, and 4-chloroaniline to give N-(4-chlorophenyl)-7-methoxybenzofuran-2-carboxamide (Compound 379a). Successively, it was formylated to give N-(4-chloropheny)-4-formyl-7-methoxybenzofuran-2-carboxamide (Compound 379b), then compound 379b was reacted with cyclobutylamine to give compound 379 as a white solid.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[Br:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[S:15][C:16]=1[Cl:17]>>[C:1]([C:4]1[S:8][C:7]([NH:9][S:18]([C:14]2[S:15][C:16]([Cl:17])=[C:12]([Br:11])[CH:13]=2)(=[O:20])=[O:19])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)s1
Reactant: CC(=O)c1sc(N)nc1C
Product: CC(=O)c1sc(NS(=O)(=O)c2cc(Br)c(Cl)s2)nc1C

Procedure:
The title compound was prepared from 5-acety1-2-amino-4-methylthiazole (42 mg) and 4-bromo-5-chlorothiophene-2-sulfonyl chloride (80 mg) as described in the synthetic METHOD B to give a white solid (11.7 mg) with purity >90%: MS (pos) m/z 415.3, 417.3.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1)(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].[CH2:18]([O:20][C:21](=[O:26])[C:22](Br)([CH3:24])[CH3:23])[CH3:19].O>CN(C=O)C>[CH2:18]([O:20][C:21](=[O:26])[C:22]([NH:11][CH:8]1[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][CH2:9]1)([CH3:24])[CH3:23])[CH3:19]
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)NC1CCN(S(C)(=O)=O)CC1
Reaction time: 16 h
Yield: 14.2 %

Procedure:
2.40 g (13.5 mmol) of 1-methanesulfonyl-piperidin-4-ylamine are dissolved in DMF (32.8 mL). 5.58 g (40.4 mmol) of K2CO3, 3.06 mL (20.2 mmol) ethyl-2-bromoisobutyrate and 1.12 g (6.73 mmol) of KI are added at RT. The reaction is stirred 16 h. Additional ethyl-2-bromoisobutyrate (3.06 mL) and KI (1.12 g) are added and the reaction mixture is stirred for further 16 h. Water and sat. aq. K2CO3 solution is added, the aqueous layer extracted with EE. The combined organic layers are dried over MgSO4 and filtered. The solvent is removed under reduced pressure to afford the crude product, which is purified by silica gel chromatography (eluent: EE/MeOH 95/5) to afford 0.56 g of 2-(1-methanesulfonyl-piperidin-4-ylamino)-2-methyl-propionic acid ethyl ester. Yield: 14%; ESI-MS: 293 [M+H]+; HPLC (Rt): 0.97 min (method E)
Reaction SMILES: [CH2:1]([C:3]1([C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22](CCCCCCC(F)(F)C(F)(F)F)[C:23]([OH:25])=[O:24])[C:11]2[C:6](=[CH:7][C:8]([OH:39])=[CH:9][CH:10]=2)[O:5][CH2:4]1)[CH3:2].[F:47][C:48]([F:70])([C:66]([F:69])([F:68])[F:67])[CH2:49][CH2:50][CH2:51]C(CCCCCCC=C)C(OCC)=O>>[CH2:1]([C:3]1([C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([CH2:51][CH2:50][CH2:49][C:48]([F:70])([F:47])[C:66]([F:69])([F:68])[F:67])[C:23]([OH:25])=[O:24])[C:11]2[C:10](=[CH:9][C:8]([OH:39])=[CH:7][CH:6]=2)[O:5][CH2:4]1)[CH3:2]
Reactant: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Reactant: C=CCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Product: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 21 and the ethyl 2-(4,4,5,5,5-pentafluoropentyl)-9-decenoate prepared in Example 6, the same procedure as shown in Example 21 was repeated to give 11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoic acid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br)#[N:2].[CH2:11]([O:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17])[CH3:12]>>[CH2:11]([O:13][P:14]([CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([C:1]#[N:2])[CH:4]=1)(=[O:18])[O:15][CH2:16][CH3:17])[CH3:12]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cccc(C#N)c1)OCC
Yield: 79 %

Procedure:
3-Cyanobenzyl bromide (9.8 g, 50 mmol) and triethylphosphite (9.97 g, 60 mmol) were stirred at 140° C. for 3 hours. The resulting residue was evaporated, the distillate which has 145° C./1 mmHg was collected, and the title compound (10 g, 39.5 mmol, 79.1%) was obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[SH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Sc1ccccn1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2ncc(Sc3ccccn3)s2)c(C(=O)C2CCCC2)c1
Yield: 31.9 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(pyridin-2-ylsulfanyl)-thiazol-2-yl]-urea (140 mg, 32%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 2-mercaptopyridine (222 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [O-]CC.[Na+].CO[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1OC)[CH2:10][C:11]#N.C(=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[C:9]1([CH:10]=[CH:11][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:14][CH:15]=[CH:7][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(CC#N)cc1OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: C(=Cc1ccccc1)c1ccccc1
Reaction time: 3 h

Procedure:
In a round-bottom flask, 380 mg (5.64 mmol, 0.1 eq.) of sodium ethoxide was added to a suspension of 10.0 g (56.43 mmol) of 3,4-dimethoxybenzyl cyanide and 5.99 g (56.43 mmol, 1.0 eq.) of benzaldehyde in 150 mL of ethanol under an argon atmosphere at room temperature while stirring, and the resulting mixture was heated to reflux (the oil bath temperature: 85° C.). After three hours, the disappearance of the raw materials was confirmed, and the resulting reaction liquid was cooled on ice to precipitate a solid. The solid was then collected by suction filtration using a Büchner funnel and a filtering flask, which was then washed with 100 mL of methanol twice. The solid was dried under reduced pressure at 60° C. to give 13.70 g (92%) of light yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:20]([O:18][C:17](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 63 h
Yield: 82.4 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-L-phenylalanine (30.0 g, 113 mmol) and benzyl alcohol (14.0 mL, 136 mmol) in methylene chloride (200 mL), were added successively 4-dimethylaminopyridine (1.38 g, 11.3 mmol) and WSCI.HCl (26.0 g, 136 mmol) under ice-cooling, and the mixture was stirred for 63 hr while gradually raising the temperature to room temperature. The solvent was distilled away from the reaction solution under reduced pressure, and water (200 mL) was added to the residue. The mixture was extracted with ethyl acetate (400 mL). The obtained extract solution was washed with 0.5N hydrochloric acid, water, saturated aqueous sodium hydrogencarbonate solution, water and saturated brine (each 200 mL), and dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. The obtained residue was recrystallized from hexane to give the title compound (33.1 g, 82%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:24].Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:24]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1Cl
Reaction time: 0.05 h
Yield: 53.8 %

Procedure:
40% Methanolic Triton B (0.15 mL, 0.34 mM) was added to a solution of the 9-[(2-chlorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (80 mg, 0.23 mM) in 5 mL DMF at room temperature. After 3 minutes, t-butyl bromoacetate (182 mg, 0.91 mM) was added and the resultant mixture stirred at room temperature for 72 hours. The mixture was diluted with ethyl acetate, washed five times with H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 57 mg (53%) of the {9-[(2-chlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester as a white solid. 1H NMR (DMSO-d6) δ7.6 (d, 1H, J=8 Hz), 7.5-6.9 (m, 9H), 6.55 (d, 1H, J=8 Hz), 6.35 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.75 (s, 2H), and 1.45 (s, 9H). IR (KBr, cm−1) 1753 and 1678. MS (FD) m/e 464.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[CH3:26][O:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:26][O:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][N:33]([C:22]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:25])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:17])([CH3:16])[C:10]=3[CH:18]=2)=[O:23])[CH2:32][CH2:31]1
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: COCCN1CCNCC1
Product: COCCN1CCN(C(=O)c2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1

Procedure:
Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and 1-(2-methoxyethyl)piperazine.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([O:15][CH3:16])[C:10]([O:13][CH3:14])=[N:11][CH:12]=2)[CH:2]=1.[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:38])(=O)=O)=CC=1>C1COCC1.CCCCCC>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:8]([F:38])=[C:9]([O:15][CH3:16])[C:10]([O:13][CH3:14])=[N:11][CH:12]=2)[CH:2]=1
Reactant: COc1cc(-c2cccc(-c3ccccc3)c2)cnc1OC
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ncc(-c2cccc(-c3ccccc3)c2)c(F)c1OC
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 29 %

Procedure:
To a solution of 5-(biphenyl-3-yl)-2,3-dimethoxypyridine (52 mg, 0.178 mmol) in THF (2 mL) at −78° C. was added n-BuLi solution in hexane (2.5 M, 0.157 mL) and then the −78° C. bath was replaced with a 0° C. cooling bath. After stirring at this temperature for 50 min, the reaction mixture was cooled down to −78° C. and then solid N-fluorobenzenesulfonimide was added to it. The reaction was quenched after 10 min by adding saturated aqueous NH4Cl solution and then partitioned between EtOAc and saturated aqueous NaHCO3 solution. Layers were separated and the aqueous solution was extracted with EtOAc (2×). Combined organic solutions were dried over Na2SO4 and concentrated. Purification by preparative HPLC (10-85% CH3CN/H2O over 20 min, 0.05% added TFA) afforded 16 mg (29%) of 5-(biphenyl-3-yl)-4-fluoro-2,3-dimethoxypyridine as a colorless viscous material. LC/MS (M+H)+ 310.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[N:14][C:15]([C:18]([O:20]CC)=O)=[C:16]([OH:17])[C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:23][CH2:24][C:25]([OH:27])=[O:26].[O-]CC.[Na+].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[N:14][C:15]([C:18]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:20])=[C:16]([OH:17])[C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ncc2c(-c3ccc(F)cc3)noc2c1O
Reactant: NCC(=O)O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CNC(=O)c1ncc2c(-c3ccc(F)cc3)noc2c1O
Temperature: 25 °C
Yield: 57.9 %

Procedure:
Ethyl 3-(4-fluorophenyl)-7-hydroxyisoxazolo[4,5-c]pyridine-6-carboxylate (0.11 g, 0.36 mmol) was dissolved in 10 mL of DMF. Glycine (0.55 g, 7.28 mmol) and sodium ethoxide (0.37 g, 5.46 mmol) were added and the mixture was refluxed for 14 h. The mixture was cooled to room temperature and diluted with 60 mL of water. Concentrated hydrochloric acid was added dropwise until pH was 3. The resulting suspension was filtered and the solid was dried under vacuum to give 69 mg of the title compound. MS: (+) m/z 332.00 (M+1).
Reaction SMILES: Cl[C:2]1[C:12]([N+:13]([O-])=O)=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CS(C)=O.O>[NH2:13][C:12]1[C:2]([NH:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:3][CH:4]=[C:5]([CH:11]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: NC1CCCCC1
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cnc(NC2CCCCC2)c(N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
Ethyl 6-chloro-5-nitronicotinate (1.00 g, 4.33 mmol) prepared according to A. H. Berrie et al. (J. Chem. Soc. 1951, 2590) was dissolved in DMSO (2 mL) and cyclohexylamine (0.54 g, 5.4 mmol) was added. The mixture was stirred for 1 h at room temperature, diluted with water and the yellow precipitated collected by filtration. The product was washed with water and dried (0.95 g, 74% yield).
Reaction SMILES: [OH:1][C:2]1([C:15](O)=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[CH2:43]([O:50][C:51](=[O:57])[C@@H:52]1[CH2:56][CH2:55][CH2:54][NH:53]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:43]([O:50][C:51](=[O:57])[C@@H:52]1[CH2:56][CH2:55][CH2:54][N:53]1[C:15]([C:2]1([OH:1])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:16])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: O=C(O)C1(O)c2ccccc2-c2ccccc21
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)C1(O)c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 9-hydroxy-9-fluorene carboxylic acid (5.04 g, 22.3 mmol) in N,N-dimethylformamide (30 mL), cooled to 0° C. under nitrogen, was added (O-7-azabenzotriazol-1-y)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), (9.32 g, 24.5 mmol), L-proline-benzyl ester hydrochloride (5.93 g, 24.5 mmol), and N,N-diisopropylethylamine (8.5 mL, 48.8 mmol). The mixture was stirred at 0° C. for 3 hours, then concentrated and purified on silica gel (ethyl acetate-hexane, 1:2) to give 9-hydroxy-9-fluorenylcarbonyl-L-proline benzyl ester. HPLC=96%, R.T.=3.7 min; Mass spec.(electrospray) M+1=414.1.
Reaction SMILES: CS([C:5]1[S:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15](C(OC(C)(C)C)=O)[CH:14]=[C:13]3[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[N:27]=2)=[N:7][N:6]=1)(=O)=O.[OH-:38].[Na+].Cl>>[O:35]1[CH2:34][CH2:33][N:32]([C:28]2[N:27]=[C:26]([C:13]3[C:12]4[C:16](=[CH:17][CH:18]=[C:10]([C:8]5[S:9][C:5]([OH:38])=[N:6][N:7]=5)[CH:11]=4)[NH:15][CH:14]=3)[CH:31]=[CH:30][CH:29]=2)[CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cccc(N3CCOCC3)n2)c2cc(-c3nnc(S(C)(=O)=O)s3)ccc21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Oc1nnc(-c2ccc3[nH]cc(-c4cccc(N5CCOCC5)n4)c3c2)s1
Temperature: 120 °C
Yield: 14.2 %

Procedure:
A glass microwave reaction vessel was charged with tert-butyl 5-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)-3-(6-morpholinopyridin-2-yl)-1H-indole-1-carboxylate (160.0 mg, 0.296 mmol) and aq. 10 M NaOH (1.5 mL, 15.0 mmol). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 120° C. for 30 min. The mixture was neutralized with aq. 5 N HCl and the mixture was extracted with CHCl3/iPrOH (4:1). The combined organic layers were dried, filtered and concentrated. The crude product was dissolved in MeOH/p-dioxane (2:1, 3 mL) and catalytic amount of Pd/C was added. The mixture was stirred under H2 for 2 h, then filtered through a plug of celite. The filtrate was concentrated and the residue was purified with RP-HPLC to give 5-(3-(6-morpholinopyridin-2-yl)-1H-indol-5-yl)-1,3,4-thiadiazol-2-ol (16.0 mg, 0.042 mmol, 14%) as a pink solid. MS (ESI, pos. ion) m/z 380 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.87 (1H, br. s.), 11.71 (1H, br. s.), 8.83 (1H, s), 8.12 (1H, d, J=2.5 Hz), 7.46-7.63 (3H, m), 7.20 (1H, d, J=7.6 Hz), 6.63 (1H, d, J=8.2 Hz), 3.76-3.87 (4H, m), 3.53-3.65 (4H, m).
Reaction SMILES: [C:1]1([N:7]2[C:15](=[O:16])[C:14]3[C:9]([C:10]4[CH2:20][S:19][CH2:18][CH2:17][C:11]=4[NH:12][CH:13]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:22].[Na+]>CO.O>[O:22]=[S:19]1[CH2:18][CH2:17][C:11]2[NH:12][CH:13]=[C:14]3[C:15](=[O:16])[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]3[C:10]=2[CH2:20]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=c1c2c[nH]c3c(c-2nn1-c1ccccc1)CSCC3
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=c1c2c[nH]c3c(c-2nn1-c1ccccc1)CS(=O)CC3
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 0.3 g of 2,3,5,6,7,9-hexahydro-2-phenylthiopyrano[4,3-b]pyrazolo[3,4-d]pyridin-3-one in 200 mL of methanol, a solution of 0.8 g of sodium metaperiodate in 25 mL of water is added. The mixture is stirred at room temperature for 48 hours, then evaporated to dryness. The residue is washed with 50 mL of water, filtered, and dried in a vacuum oven at 80° overnight obtaining 2,3,5,6,7,9-hexahydro-8-oxo-2-phenylthiopyrano[4,3-b]pyrazolo[3,4-d]pyridin-3-one, m.p. 218°-220° (dec).