Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][CH:5]=1)([O-:3])=[O:2].FC(F)(F)S(O[C:25]1[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH:30]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH:26]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C
Yield: 71.8 %

Procedure:
A mixture of 4-nitrophenylboronic acid pinacol ester (4.5 g; 18.1 mmol; 1.2 eq.), tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate (5.0 g; 15.1 mmol; 1.0 eq.) and sodium carbonate (1.07 g, 10.1 mmol, 5 eq.) were dissolved in DME (50 mL) and water (25 mL). The mixture was degassed for 5 min with nitrogen before the addition of Pd(PPh3)4 (349 mg; 0.30 mmol; 0.02 eq.) and heated at 80° C. O/N. Water (100 mL) was added and aqueous phase was extracted with EtOAc (twice). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified by flash chromatography on silica (EtOAc:heptane, 10.90) to give the title compound as a yellow solid (3.3 g, 72%). 1H NMR (300 MHz, DMSO-d6) δ 8.24-8.17 (m, 2H), 7.65-7.68 (m, 2H), 6.45 (brs, 1H), 4.06 (m, 2H), 3.56 (t, 2H), 2.55-2.48 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[CH:9]=[CH:10][N:11]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12](=[O:16])[C:13]=2[C:14]=1[OH:15])=[O:4].CC1C=C(C)N=C(C)C=1.CC1C([IH+:40])=C(C)N=C(C)C=1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([I:40])[C:8]2[CH:9]=[CH:10][N:11]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12](=[O:16])[C:13]=2[C:14]=1[OH:15])=[O:4]
Reactant: COC(=O)c1ncc2ccn(Cc3ccccc3)c(=O)c2c1O
Reactant: Cc1cc(C)c([IH+])c(C)n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: COC(=O)c1nc(I)c2ccn(Cc3ccccc3)c(=O)c2c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.3 %

Procedure:
A mixture of 6-benzyl-4-hydroxy-5-oxo-5,6-dihydro-[2,6]naphthyridine-3-carboxylic acid methyl ester (130 mg, 0.42 mmol) and bis(2,4,6-trimethylpyridine)iodine(I) hexafluorophosphate (1.08 g, 2.10 mmol) in 5 mL of CH2Cl2 was stirred at r.t. for 16 h. The mixture was diluted with CH2Cl2 (50 mL) and washed with dilute sodium bisulfite and 1 M HCl. The organic layer was dried over MgSO4 and concentrated to give 180 mg of the title compound as a pale yellow solid. 1H NMR (CDCl3, 200 MHz): δ=13.56 (s, 1H), 7.20-7.50 (m, 6H), 6.77 (d, 1H, J=7.4 Hz), 5.30 (s, 2H), 3.99 (s, 3H).
Reaction SMILES: Cl.[C:2]([C:5]1[S:9][C:8]2[CH2:10][CH2:11][CH2:12][CH:13]([NH2:14])[C:7]=2[CH:6]=1)(=[O:4])[CH3:3].[O-:15][C:16]#[N:17].[K+]>O>[C:2]([C:5]1[S:9][C:8]2[CH2:10][CH2:11][CH2:12][CH:13]([NH:14][C:16]([NH2:17])=[O:15])[C:7]=2[CH:6]=1)(=[O:4])[CH3:3]
Reactant: N#C[O-]
Reactant: CC(=O)c1cc2c(s1)CCCC2N
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(=O)c1cc2c(s1)CCCC2NC(N)=O
Temperature: 70 °C

Procedure:
A sample of 6.3 grams of 2-acetyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride is dissolved in 35 ml. of water and cooled to 15° C. A solution of 2.64 grams of potassium cyanate in 35 ml. of water is added, and after 0.5 hour the mixture is heated at 70° C. for about 40 minutes. The mixture is cooled, and the solid is collected and washed with water. On drying, 5.55 grams, melting point 218° C. to 220° C., of 2-acetyl-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea is obtained.
Reaction SMILES: [CH2:1]([O:3][NH:4][CH2:5][C:6]1[C:7]([F:29])=[C:8]([F:28])[C:9]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[C:10]([CH:18]=1)[C:11]([NH:13][O:14][CH2:15][CH2:16][OH:17])=[O:12])[CH3:2].[C:30](ON1C(=O)C2C=CC=CC=2N=N1)(=[O:32])[CH3:31]>C(O)(=O)C>[C:30]([N:4]([CH2:5][C:6]1[C:7]([F:29])=[C:8]([F:28])[C:9]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[C:10]([CH:18]=1)[C:11]([NH:13][O:14][CH2:15][CH2:16][OH:17])=[O:12])[O:3][CH2:1][CH3:2])(=[O:32])[CH3:31]
Reactant: CCONCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: CC(=O)On1nnc2ccccc2c1=O
Solvent: CC(=O)O
Product: CCON(Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F)C(C)=O
Yield: 71 %

Procedure:
The title compound was prepared by a procedure similar to that in Example 41. Namely, 5-(ethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide obtained in Example 17 was reacted with 4-oxo-4H-benzo[d][1,2,3]triazin-3-yl acetate prepared from acetic acid to give 5-[(acetyl-ethoxy-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (19.3 mg, 71%).
Reaction SMILES: [OH-].[Na+].[CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:23]=[C:24]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[CH:25]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[CH:15][N:14]=1)=[O:11])([CH3:5])[CH3:4].O.Cl>C1COCC1>[CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:23]=[C:24]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[CH:25]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][N:14]=1)=[O:11])([CH3:5])[CH3:4]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(COc3ccccc3F)cc(OC(C)C)c2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1cc(COc2ccccc2F)cc(C(=O)Nc2ccc(C(=O)O)cn2)c1
Yield: 96.8 %

Procedure:
2M NaOH (0.55 ml, 1.1 mM) was added to methyl 2-[3-isopropyloxy-5-(2-fluorophenoxy) methyl benzoyl]amino-5-pyridine carboxylate (0.16 g, 0.36 mM) in THF (10 ml)/water (10 ml) at ambient temperature. After 4 hrs the reaction mixture was neutralised to pH=4–5 with 2M HCl, concentrated, filtered, washed with water, and dried under high-vacuum to give the title compound as a colourless solid (0.15 g, 98%); 1H NMR δ (d6-DMSO): 1.28 (d, 6H), 4.74 (m, 1H), 5.20 (s, 2H), 6.87–6.97 (m, 1H), 7.10 (m, 1H), 7.16–7.26 (m, 3H), 7.54 (s, 1H), 7.66 (s, 1H), 8.28 (s, 2H), 8.84 (s, 1H), 11.78 (bs, 1H).
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][O:15][C@@H:14]([CH2:18][N:19]3[CH2:24][CH2:23][N:22]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=4)=[O:26])[CH2:21][CH2:20]3)[CH2:13]2)[CH2:9]1.[CH3:36][C:37](OC(C)=O)=[O:38]>C(Cl)Cl>[C:37]([N:8]1[CH2:9][CH:10]([N:12]2[CH2:17][CH2:16][O:15][C@@H:14]([CH2:18][N:19]3[CH2:20][CH2:21][N:22]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=4)=[O:26])[CH2:23][CH2:24]3)[CH2:13]2)[CH2:11]1)(=[O:38])[CH3:36]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@H]2CN(C3CNC3)CCO2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(N2CCO[C@@H](CN3CCN(C(=O)Nc4ccc(Cl)c(Cl)c4)CC3)C2)C1
Reaction time: 3 h

Procedure:
Triethylamine (61 uL) was added to a stirring solution of 4-{[(25)-4-azetidin-3-ylmorpholin-2-yl]methyl}-N-(3,4-dichlorophenyl)piperazine-1-carboxamide (125 mg) in DCM (5 ml) followed by Ac2O (30 uL) and the reaction was stirred for 3 h. The reaction was then quenched by addition of 1M NaOH (aq.) (10 ml) and DCM (15 ml). The organic layer was separated and dried (MgSO4), filtered and evaporated. Purification by column chromatography 5-10% MeOH:DCM afforded the title compound (31 mg) as a white foam.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([N+:16]([O-])=O)[CH:10]=1)#[N:2]>C(O)C.[Pd]>[NH2:16][C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[CH:15]=[CH:14][C:12]=1[NH2:13]
Reactant: N#Cc1ccccc1-c1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: N#Cc1ccccc1-c1ccc(N)c(N)c1

Procedure:
4-(2-Cyanophenyl)-2-nitroaniline (0.042 moles, 10 g.) was dissolved in 200 ml ethanol and hydrogenated at 40 psi over 10 g of 10% Pd/C. The solution was filtered, concentrated, and purified by HPLC eluted with a gradient of 0-50% ethyl acetate in toluene. (MS)
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].C(OC([N:15]1[C@H:19]([CH2:20][OH:21])[CH2:18][C@H:17]([O:22][C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[NH:30][C:31]2[C:32]3[C:39]([CH3:40])=[C:38]([C:41](N)=[O:42])[S:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH2:16]1)=O)(C)(C)C>ClCCl>[CH3:3][O:4][C:41]([C:38]1[S:37][C:33]2[N:34]=[CH:35][N:36]=[C:31]([NH:30][C:24]3[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=3[O:22][C@H:17]3[CH2:18][C@@H:19]([CH2:20][OH:21])[NH:15][CH2:16]3)[C:32]=2[C:39]=1[CH3:40])=[O:42]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3C[C@@H](CO)N(C(=O)OC(C)(C)C)C3)c12
Solvent: ClCCl
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CN[C@H](CO)C3)c2c1C
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (1 ml) was added to a solution of 4-[2-((3S,5S)-1-tert-butoxycarbonyl-5-hydroxymethyl-pyrrolidin-3-yloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid amide (754 mg) in dichloromethane (10 ml). The reaction mixture was stirred for 4 h and a further aliqout of trifluoroacetic acid was added. The reaction mixture was stirred for 1 h again. The solvent was removed in vacuo. The mixture was diluted with dichloromethane and washed with 10% aq. K2CO3. The organic layer was concentrated and the residue was purified by flash column chromatography (silica gel, solvent: 100% dichloromethane→20:1:0,1 dichloromethane: MeOH: NH4OH)
Reaction SMILES: [N:1]1[C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[C:4](O)=[N:3][CH:2]=1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:22]>ClCCCl>[Cl:22][C:4]1[C:5]2[CH2:9][CH2:8][CH2:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2c1CCC2
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncnc2c1CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.9 %

Procedure:
To a solution of 6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (9.87 g, 72.5 mmol) in DCE (200 ml) was added DIEA (15 mL, 86.1 mmol). The mixture was stirred at room temperature for 30 minutes and then added POCl3 (15 mL, 163.9 mmol) was added slowly. The mixture was stirred at room temperature for 1 hour and then refluxed for 12 hour. After cooling, the solvent was removed and the residue was dissolved in CHCl3 (200 ml). The mixture was basified by adding ice-cooled concentrated aqueous ammonia (15 mL). The organic phase was separated. The aqueous phase was washed with CHCl3 (3×100 mL). The organic phase was combined, dried and concentrated. The residue was subject to chromatography on silica gel, eluted by Hexanes/ethyl acetate (4:1) to afford 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (5.7 g, 51%). 1H NMR (CDCl3, 400 MHz) δ 8.76 (s, 1H), 3.12-3.01 (m, 4H), 2.23-2.14 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]C(=O)C2C=CC=CC=2)=[O:9])=[CH:5][C:4]([CH3:25])=[N:3]1.[OH-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.CO>[CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:9])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[SH:16])=[CH:5][C:4]([CH3:25])=[N:3]1
Reactant: Cc1cc(NC(=O)c2ccccc2SC(=O)c2ccccc2)n(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(NC(=O)c2ccccc2S)n(C)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67 %

Procedure:
The thiobenzoic acid S-[2-(2,5-dimethyl-2H-pyrazol-3-ylcarbamoyl)-phenyl]ester (as prepared in step 2 above; 0.966 g, 2.75 mmol) was dissolved in THF (50 mL) and MeOH (100 mL). Under N2(g), a 0.2M solution of NaOH (80 mL) was added and the mixture was stirred for 1.5 h at rt. A saturated solution of NaHCO3(aq) (100 mL) was added and the aqueous layer was extracted with CHCl3 (3×100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated in vacuo. The crude mixture was then purified over silica (5% MeOH/CHCl3) to give the title compound in 67% yield (0.455 g, 1.84 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([O:15][B:16](OC(C)C)[O:17]C(C)C)(C)C.C([Li])CCC.CCCCCC>O1CCCC1>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[N:4][CH:3]=[C:2]([B:16]([OH:17])[OH:15])[CH:7]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)(F)c1cncc(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1cncc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)pyridine (2.5 g, 11.06 mmol) and triisopropylborate (3.06 mL, 13.27 mmol) in anhydrous tetrahydrofuran (20 mL) at −78° C. under nitrogen was added dropwise a solution of n-butyl lithium in hexane (2.5 M, 4.9 mL, 12.17 mmol) The reaction was stirred at −78° C. for 3 hours then allowed to warm slowly to −10° C. The reaction mixture was then quenched by the addition of water (20 mL) and the tetrahydrofuran removed under reduced pressure. The resulting aqueous phase was diluted with water (40 mL) and washed with ether (2×40 mL). The aqueous phase was then acidified to pH 5 by the addition of acetic acid and the resulting suspension extracted with ethyl acetate (80 mL). The organic phase was separated, dried (MgSO4), filtered and concentrated under reduced pressure to give 3-(trifluoromethyl)pyridine-5-boronic acid (2.022 g, 96% yield) as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl.O>C(O)C>[ClH:26].[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:10]1
Reactant: Cc1ccnc2c1C(=O)CC(c1cc(F)ccc1F)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1cc(F)ccc1F)C2
Yield: 99.6 %

Procedure:
A solution of 7-(2,5-difluorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.2 g) and aminoguanidine hydrochloride (0.58 g) in ethanol (30 ml) was combined with concentrated hydrochloric acid (1.1 ml) and water (1.1 ml), and the mixture was heated under reflux for 14 hours. The solvent was distilled off under reduced pressure, and the resultant crystal was recrystallized from ethanol to obtain 7-(2,5-difluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound K) (1.6 g) as a colorless crystal.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[O:16][CH2:17][C:18]([OH:20])=O)[CH3:2].[CH:21]([NH:24][NH:25][C:26]([C:28]1[CH:32]=[CH:31][S:30][CH:29]=1)=[O:27])([CH3:23])[CH3:22].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[F:15][C:13]1[CH:12]=[CH:11][C:10]([O:16][CH2:17][C:18]([N:24]([CH:21]([CH3:23])[CH3:22])[NH:25][C:26]([C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)=[O:27])=[O:20])=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:1][CH3:2])[CH:14]=1
Reactant: CC(C)NNC(=O)c1ccsc1
Reactant: CCc1ccccc1-c1cc(F)ccc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1ccccc1-c1cc(F)ccc1OCC(=O)N(NC(=O)c1ccsc1)C(C)C
Yield: 73.4 %

Procedure:
A solution of (2′-ethyl-5-fluoro-biphenyl-2-yloxy)-acetic acid (100 mg, 0.36 mmol), and tiophene-3-carboxylic acid-N′-isopropyl hydrazide (32 mg, 0.1268 mmol) in DMF (5 mL), was treated with triethylamine (0.152 ml, 1.09 mmol), HOBT (59 mg, 0.44 mmol), and EDCI (84 mg, 0.44 mmol) for 12 hours at room temperature. The reaction mixture was partitioned between 1N HCl and DCM. The organic layer was successively washed with 1N NaOH and brine, then dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a solid (41 mg, 26%). MS m/e 441.30 (M+H+)
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C(OC(=O)[NH:35][C:36]([CH3:49])([CH3:48])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]=O)=[CH:41][C:40]=1[F:47])(C)(C)C>>[NH2:35][C:36]([CH3:49])([CH3:48])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[C@@H:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:41][C:40]=1[F:47]
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(COc1ccc(C=O)cc1F)NC(=O)OC(C)(C)C
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCC(C)(C)N)c(F)c2)c1
Yield: 73.6 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and tert-butyl[2-(2-fluoro-4-formylphenoxy)-1,1-dimethylethyl]carbamate (72 mg) according to an analogous synthetic method to Example 238 and purified by LC-MS, the title compound (19 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:21].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:21])[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc2cc(OCc3ccccc3)ccc21
Reaction time: 0.5 h
Yield: 90 %

Procedure:
5-benzyloxyindole (2.00 g, 8.96 mmol) was dissolved in DMF (20 mL) and the solution cooled in ice. Sodium hydride (60% oil dispersion, 1.2 equivalent, 10.7 mmol, 0.43 g) was added and the mixture stirred for 30 min. Iodomethane (1.2 equivalent, 10.7 mmol, 0.67 mL) was added and the reaction stirred at room temperature overnight. The reaction was then poured into water (150 mL) and the precipitated solid collected by filtration. After washing with water and drying, 5-benzyloxy-1-methylindole (1.913 g, 90% yield) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)c1sc(Br)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(Oc2ccccc2)nc1C
Temperature: 95 °C
Yield: 66.2 %

Procedure:
A mixture of 2-bromo-4-methyl-thiazole-5-carboxylic acid ethyl ester (1.89 g, 7.57 mmol), phenol (855 mg, 9.09 mmol) and potassium carbonate (1.36 g, 9.84 mmol) in dimethylformamide (18 mL) was heated at 95° C. for 15 h before it was cooled to room temperature and partitioned between ethyl acetate and water, the organic layer was washed with water, aqueous sodium hydroxide (2×), brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (1.32 g): MS: (+) m/z 264.0 (M+1).
Reaction SMILES: [N:1]1[N:5]2[C:6]3[C:11]([NH:12][CH2:13][C:4]2=[N:3][N:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[CH3:14]I.[H-].[Na+]>C(COC)OC>[CH3:14][N:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[N:1]=[N:2][N:3]=[C:4]2[CH2:13]1
Reactant: c1ccc2c(c1)NCc1nnnn1-2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CN1Cc2nnnn2-c2ccccc21

Procedure:
A solution of 1 g. of 4,5-dihydrotetrazolo[1,5-a]quinoxaline and 2 g. of methyl iodide in 50 ml. of dimethoxyethane was stirred with 1.5 g. of sodium hydride, as a 50 percent suspension in mineral oil, overnight at room temperature. The reaction mixture was then filtered and evaporated under vacuum. The residue was dissolved in ethyl acetate and extracted twice with water. The brown residue which resulted on evaporation of the dried organic layer was washed with cyclohexane, leaving 0.87 g. of crude product. Two recrystallizations from ethanol produced pure 4,5-dihydro-5-methyltetrazolo[1,5-a]quinoxaline, m.p. 107°-10°C., which was identified by NMR analysis and elemental micro-analysis with the following results.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].[CH3:27][C:28]([CH3:30])=O>>[CH:28]([NH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:21])([F:22])[F:23])=[CH:12][C:11]=1[O:24][CH3:25])([CH3:30])[CH3:27]
Reactant: CC(C)=O
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1CCCCC1NC(C)C

Procedure:
The title compound, off-white foam, MS: m/e=427.2 [(M+H)+], was prepared in accordance with the general method of example 11 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and acetone.
Reaction SMILES: Cl.[Br:2][C:3]1[N:7]([CH2:8][CH3:9])[C:6]([CH2:10]Cl)=[N:5][C:4]=1[CH3:12].C([O-])([O-])=O.[K+].[K+].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[NH:27][CH:28]=[CH:29][N:30]=2)[N:21]=1.O>CN(C=O)C>[Br:2][C:3]1[N:7]([CH2:8][CH3:9])[C:6]([CH2:10][N:30]2[CH:29]=[CH:28][N:27]=[C:26]2[C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[N:21]=2)=[N:5][C:4]=1[CH3:12]
Reactant: CCn1c(CCl)nc(C)c1Br
Reactant: Fc1cccc(-c2ncc[nH]2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(Cn2ccnc2-c2cccc(F)n2)nc(C)c1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 74 mg (0.27 mmol) of 5-bromo-2-chloromethyl-1-ethyl-4-methyl-1H-imidazole hydrochloride in 1.5 ml of DMF is added 224 mg (1.62 mmol) of K2CO3 and 45 mg (0.27 mmol) of 2-fluoro-6-(1H-imidazol-2-yl)-pyridine. The mixture is stirred at room temperature for 24 hours. 5 ml water is added and the mixture was extracted with EtOAc (3×15 ml). The combined extracts are washed with 15 ml brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue is purified by preparative TLC, developing with 10:0.4:0.05 CH2Cl2—MeOH—NH4OH solution. The purified compound is then dissolved in 3 ml of EtOAc and to it is added 2 ml of 2N HCl in ether. The resulting suspension is stirred at room temperature for 15 minutes. Evaporation of the solvent provided the title compound as a white powder. LC-MS (M+1) 364.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([NH:30][NH2:31])=[O:29])=[CH:22][CH:21]=2)=[C:4]([CH3:32])[CH:3]=1.[C:33](N1C=CN=C1)(N1C=CN=C1)=[O:34].Cl>C1COCC1.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]3[O:29][C:33](=[O:34])[NH:31][N:30]=3)=[CH:22][CH:21]=2)=[C:4]([CH3:32])[CH:3]=1
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)NN)cc3)c(-c3ccc(F)cc3C)sc2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(/C=C/c4n[nH]c(=O)o4)cc3)c(-c3ccc(F)cc3C)sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a 30 mL screw cap vial, (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylohydrazide (38 mg, 0.085 mmol) was dissolved in THF (2 mL). The vial was charged with 1,1′-carbonyldiimidazole (16.49 mg, 0.102 mmol) and the reaction was stirred at room temperature for 1 h. The reaction mixture was acidified with 6 N HCl which caused a precipitate to form. The mixture was diluted with DCM to dissolve the precipitate. The organic phase was collected (phase separator) and concentrated to afford (E)-5-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-1,3,4-oxadiazol-2(3H)-one (31 mg, 0.065 mmol, 77% yield) as an off white solid which was used without further purification. LC/MS (m/z, M-H): 473.0