Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH2:7])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1.[C:14](OCC)(=[O:16])[CH3:15].C(=O)(O)[O-].[Na+].C(OC(=O)C)(=O)C>O>[Cl:1][C:2]1[C:6]([NH:7][C:14](=[O:16])[CH3:15])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1
Reactant: CCOC(C)=O
Reactant: Nc1cn(-c2cccnc2)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1cn(-c2cccnc2)nc1Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A 100 mL three-neck round bottom flask was charged with 3-chloro-1(pyridin-3-yl)-1H-pyrazol-4-amine (1.00 g, 5.14 mmol) and ethyl acetate (10 mL). Sodium bicarbonate (1.08 g, 12.9 mmol) was added, followed by dropwise addition of acetic anhydride (0.629 g, 6.17 mmol) at <20° C. The reaction was stirred at 20° C. for 2 hours to afford a suspension, at which point thin layer chromatography analysis [Eluent: ethyl acetate] indicated that the reaction was complete. The reaction was diluted with water (50 mL) and the resulting suspension was filtered. The solid was rinsed with water (10 mL) followed by methanol (5 mL). The solid was further dried under vacuum at 20° C. to afford the desired product as a white solid (0.804 g, 66%): mp 169-172° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 9.05 (dd, J=2.8, 0.8 Hz, 1H), 8.82 (s, 1H), 8.54 (dd, J=4.7, 1.4 Hz, 1H), 8.20 (ddd, J=8.4, 2.8, 1.4 Hz, 1H), 7.54, (ddd, J=8.3, 4.7, 0.8 Hz, 1H), 2.11 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 168,12, 147,46, 139,42, 135.46, 133.60, 125.47, 124.21, 122.21, 120,16, 22.62; EIMS m/z 236 ([M]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]([CH3:28])[C:12](=[O:27])[C:13]([CH3:26])=[CH:14][C:15]=1[C:16](ON1C(=O)CCC1=O)=[O:17].C1COCC1.CC(C)=O.[N-:38]=[N+:39]=[N-:40].[Na+]>O>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]([CH3:28])[C:12](=[O:27])[C:13]([CH3:26])=[CH:14][C:15]=1[C:16]([N:38]=[N+:39]=[N-:40])=[O:17]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(C(=O)ON2C(=O)CCC2=O)c(Nc2ccc(I)cc2F)n(C)c1=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(C(=O)N=[N+]=[N-])c(Nc2ccc(I)cc2F)n(C)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.6 %

Procedure:
A 100 ml round-bottom flask was charged with 2,5-dioxopyrrolidin-1-yl 2-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (1.2 g, 2.40 mmol) and a mixture of THF/acetone (15 mL/30 mL). To the mixture was added NaN3 (0.52 g, 8 mmol) is previously dissolved in H2O (10 mL). The reaction mixture was stirred art room temperature for 16 hours and the organic solvents were removed under reduced pressure yielding to the desired product as a light brown solid (0.98 g, 96%).
Reaction SMILES: I[CH2:2][O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[C:8]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2[O:27][CH3:28])([F:19])[C:7]1=[O:29])=[O:5].[C:30]([O:34][P:35]([O-:42])([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([CH3:33])([CH3:32])[CH3:31].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:30]([O:34][P:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])([O:42][CH2:2][O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[C@@:8]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2[O:27][CH3:28])([F:19])[C:7]1=[O:29])=[O:5])=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: COc1ccc(Cl)cc1C1(F)C(=O)N(C(=O)OCI)c2cc(C(F)(F)F)ccc21
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)OCOP(=O)(OC(C)(C)C)OC(C)(C)C)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
To a 25 mL flask containing 3-(5-chloro-2-methoxy-phenyl)-3-fluoro-2-oxo-6-trifluoromethyl-2,3-dihydro-indole-1-carboxylic acid iodomethyl ester ((S)-XIV) (0.200 g, 0.368 mmol) was added 5 mL anhydrous tetrahydrofuran, and tetrabutylammonium di-t-butylphosphate (0.199 g, 0.441 mmol). The reaction was heated to reflux and allowed to stir for 1 hour. The reaction was then cooled to room temperature, and the solvent was evaporated in vacuo. The crude foam was purified by flash chromatography (silica gel 4:1 Hexanes: EtOAc) producing the title compound (0.110 g, 48%) as a clear colorless oil. 1H NMR (CDCl3 400 MHz): δ=8.35 (s, 1H), 7.78 (s, 1H), 7.48 (d, 1H, J=7 Hz), 7.34 (d, 1H, J=7 Hz), 7.30 (d, 1H, J=7 Hz), 6.76 (d, 1H, J=7 Hz), 5.90 (d, 1H, J=12.4 Hz), 3.53 (s, 3H), 1.50 (s, 18H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:5]2=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[Cl:27][C:28]1[CH:29]=[C:30]([CH:41]=[CH:42][CH:43]=1)[CH2:31][NH:32][C:33]1[CH:34]=[C:35]([CH:39]=[O:40])[N:36]([CH3:38])[N:37]=1>O1CCCC1>[Cl:27][C:28]1[CH:29]=[C:30]([CH:41]=[CH:42][CH:43]=1)[CH2:31][NH:32][C:33]1[CH:34]=[C:35]([CH:39]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:9]=2)[OH:40])[N:36]([CH3:38])[N:37]=1
Reactant: Cn1nc(NCc2cccc(Cl)c2)cc1C=O
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cc(Cl)cnc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2cc(NCc3cccc(Cl)c3)nn2C)c2cc(Cl)cnc21
Temperature: -20 °C
Yield: 29.5 %

Procedure:
5-Chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (629, 0.19 g, 0.44 mmol) was dissolved in tetrahydrofuran (0.9 mL). The solution was cooled to −20° C. 2M isopropylmagnesium chloride in tetrahydrofuran (200 μL) was added dropwise to the mixture, then stirred to −5° C. After the reaction was cooled to −20° C., 5-(3-chloro-benzylamino)-2-methyl-2H-pyrazole-3-carbaldehyde (648, 0.050 g, 0.20 mmol) in 2 mL of tetrahydrofuran was added at once to the mixture. The reaction was stirred to 0° C. and then concentrated. Ethyl acetate was added and the mixture was washed with sodium bicarbonate saturated solution and brine. The organic portion was dried over anhydrous sodium sulfate and concentrated. Purification with silica gel column chromatography eluting with a gradient of ethyl acetate (5-80%) in hexane gave the desired compound (649, 0.033 g, 30%). (ESI) [M+H+]+=558.3, 560.9.
Reaction SMILES: Cl[C:2]1[CH2:3][C:4](=[O:8])[N:5]=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:17]2[CH:22]=[CH:21][C:20]([CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=2)O1>>[O:8]=[C:4]1[NH:5][N:6]=[CH:7][C:2]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=2)=[CH:3]1
Reactant: CCOC(=O)C(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=C1CC(Cl)=CN=N1
Product: CCOC(=O)C(C)c1ccc(-c2cn[nH]c(=O)c2)cc1

Procedure:
This compound was prepared by using procedure analogous to those described for the synthesis of Example 94, Step 1 starting from 5-chloropyridazin-3(4H)-one and ethyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (Example 14, Step 2). LCMS (M+H)+: m/z=273.1
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]([O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35](Br)=[CH:34][CH:33]=1)([CH3:29])([CH3:28])[CH3:27].C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[C:26]([O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35]([N:22]2[CH2:23][CH2:24][CH:19]([C:16]3[CH:15]=[CH:14][C:13]([C:12](=[O:25])[NH:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=4)=[CH:18][CH:17]=3)[CH2:20][CH2:21]2)=[CH:34][CH:33]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCNCC3)cc2)c1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CC(C)(C)OC(=O)c1ccc(N2CCC(c3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cc3)CC2)cc1

Procedure:
4-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperidin-1-yl}-benzoic acid tert-butyl ester was synthesized from N-(3-tert-butyl-phenyl)-4-piperidin-4-yl-benzamide and 4-bromo-benzoic acid tert-butyl ester in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C33H40N2O3 (m/e) 512, obsd 513 (M+H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:19]([O:20]C(=O)C)[C@H:18]([O:24]C(=O)C)[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=1)(=O)C.C[O-].[Na+]>CO>[O:7]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=1)[C@@H:6]1[S:16][CH2:17][C@@H:18]([OH:24])[C@H:19]([OH:20])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(C#N)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1cccc(O[C@@H]2SC[C@@H](O)[C@H](O)[C@H]2O)c1
Yield: 84.7 %

Procedure:
If the procedure described in Preparation LXXXIV is followed starting from 2.12 g (5.4.10-3 mol) of 3-cyanophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 0.2 ml of a solution of sodium methylate in methanol (8% w/v of Na), reacted in 60 ml of methanol for 30 min, 1.22 g (yield: 85%) of the expected product are obtained after precipitation in ether and lyophilization.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2C(O)=O)=[CH:4][CH:3]=1.C1(P([N:31]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.O>C1(C)C=CC=CC=1.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:31])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)O
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1noc(-c2ccc(Br)cc2)c1N
Temperature: 120 °C
Reaction time: 0.42 h

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid (1.1 g, 4.1 mmol), diphenylphosphoryl azide (1.2 mL, 4.3 mmol), and triethylamine (1.14 mL, 8.2 mmol) were combined in toluene and stirred at 120° C. for 25 minutes. After cooling to room temperature, H2O (2 mL) in THF (2 mL) was added and the reaction was stirred at 88° C. for 2 hours. The mixture was cooled to room temperature and extracted with EtOAc. The combined organic layers were concentrated to give the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3]1.CCN(CC)CC.[Cl:26][CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31]>C(Cl)Cl>[Cl:26][CH2:27][CH2:28][CH2:29][C:30]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3]1)=[O:31]
Reactant: O=C(Cl)CCCCl
Reactant: N[C@@H]1CCC[C@H](NC(=O)OCc2ccccc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCCl)N[C@@H]1CCC[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
To a stirred slurry of benzyl N-[(1S,3R)-3-aminocyclohexyl]carbamate, 18e, (0.97 g, 3.41 mmol) in CH2Cl2 (34 mL), was added Et3N (1.00 mL, 7.15 mmol), followed by 4-chlorobutanoyl chloride (0.40 mL, 3.58 mmol). After stirring at room temperature, the mixture was diluted with CH2Cl2, washed with 1N HCl (2×), 1N NaOH (2×), and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give 1.07 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:14][C:15]2[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=2)[CH2:9][C:10](OC)=[O:11])[C:5]([N+:25]([O-])=O)=[C:4]([Cl:28])[N:3]=1>C(O)(=O)C.[Fe]>[NH2:1][C:2]1[N:3]=[C:4]([Cl:28])[C:5]2[NH:25][C:10](=[O:11])[CH2:9][N:8]([CH2:14][C:15]3[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=3)[C:6]=2[N:7]=1
Reactant: COC(=O)CN(Cc1ncc(C)c(OC)c1C)c1nc(N)nc(Cl)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1c(C)cnc(CN2CC(=O)Nc3c(Cl)nc(N)nc32)c1C
Temperature: 65 °C
Yield: 7.6 %

Procedure:
Methyl 2-[(2-amino-6-chloro-5-nitro-pyrimidin-4-yl)-[(4-methoxy-3,5-dimethyl-pyridin-2-yl)methyl]amino]acetate (Intermediate 25)(2.0 g) was dissolved in acetic acid (120 mL) and warmed to 65° C. Iron powder (5 g) was added and the mix heated at 85° C. for 40 minutes. The reaction mixture allowed to cool, filtered and the filtrate was evaporated to dryness. The residue was purified by flash chromatography on silica, eluting with increasingly polar mixtures of methanol DCM (1/99-10/90) to give crude product. The crude product was triturated with methanol (3 mL) and the resulting solid filtered off then redissolved in 5N aqueous HCl (5 mL) and heated at 80° C. for 30 minutes. The reaction mixture was cooled, evaporated to dryness and the residue triturated with aqueous ammonia solution (d=0.880). The resulting solid was filtered off to give the title compound (129 mg) as a beige coloured solid; 1H NMR spectrum (400 MHz, DMSO) 2.20 (6H, s), 3.74 (3H, s), 4.05 (2H, s), 4.79 (2H, s), 6.17 (2H, s), 8.15 (1H, s), 9.92 (1H, s);
Reaction SMILES: Cl[CH:2]([CH2:7][C:8]1[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)[C:3]([O:5]C)=[O:4].[OH-].[K+]>C(O)C>[CH3:15][O:14][C:11]1[N:10]=[CH:9][C:8]([CH:7]=[CH:2][C:3]([OH:5])=[O:4])=[CH:13][CH:12]=1
Reactant: COC(=O)C(Cl)Cc1ccc(OC)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C=CC(=O)O)cn1
Yield: 17.9 %

Procedure:
A mixture of 4.5 g of methyl 2-chloro-3-(6-methoxy-3-pyridyl)propionate, 46 ml of 4N potassium hydroxide solution, and 46 ml of ethanol is refluxed for 2 hours and concentrated under reduced pressure. To the residue is added 30 ml of water, and the mixture is neutralized with acetic acid. The resulting precipitate is collected and recrystallized from isopropyl alcohol to give 0.63 g of the title compound, m.p. 177°-180° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:23]([OH:25])=[O:24])=[CH:6][N:7]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22].[NH2:27][C@H:28]1[C@@H:32]([N:33]2[CH:37]=[CH:36][N:35]=[N:34]2)[CH2:31][NH:30][CH2:29]1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:30]2[CH2:31][C@H:32]([N:33]3[CH:37]=[CH:36][N:35]=[N:34]3)[C@H:28]([NH2:27])[CH2:29]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:23]([OH:25])=[O:24])=[CH:6][N:7]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22]
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Reactant: N[C@@H]1CNC[C@@H]1n1ccnn1
Product: Nc1c(F)c(N2C[C@@H](N)[C@@H](n3ccnn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Yield: 66 %

Procedure:
Prepared by following the same procedure as described for Example 17 by using 5-amino-1-(2,4-difluorophenyl) -6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and cis-3-amino-4-(1,2,3-triazol-1-yl)-pyrrolidine. Yield: 66%, m.p. 279°-281° C. 1H NMR (TFA) δ: 4.48-4.82 (m, 4H), 5.02 (m, 1H), 6.26 (m, 1H), 7.17 (m, 2H), 7.62 (m, 1H), 8.6 (s, 1H), 8.82 (d, 2H).
Reaction SMILES: [C:1]1([C:7]2[C:8](=O)[O:9][CH2:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+:23]>>[C:1]1([C:7]2[C:8](=[O:9])[NH:23][CH2:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1OCC(c2ccccc2)=C1c1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: O=C1NCC(c2ccccc2)=C1c1ccccc1

Procedure:
Analogous to the reaction of 3,4-diphenyl-2(5H)-furanone with ammonium acetate, forming 3,4-diphenyl-1,5-dihydro-pyrrol-2-on in Rio, G. and Sekiz, B. (see above):
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:9](Cl)(Cl)Cl)[CH:8]=1>>[F:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH:8]=1)[C:9]#[N:1]
Reactant: Fc1cccc(C(Cl)(Cl)Cl)c1
Reactant: N
Product: N#Cc1cccc(F)c1

Procedure:
The concentration of the aqueous ammonia is preferably from 25 to 40%. It is used usually in an amount of from 10 to 40 moles, preferably from 20 to 30 moles, per mole of the 5-fluorobenzotrichloride. The reaction temperature is preferably from 90° to 120° C., and the reaction time is preferably form 5 to 20 hours. After completion of the reaction, the ammonia is recovered, and then the mixture is filtered. The filtrate is distilled to obtain the desired 5-fluorobenzonitrile.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C@H:11]([CH:19]=[O:20])[C@H:12]([CH3:18])[CH2:13][C:14]([F:17])([F:16])[F:15])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:21][Mg]Br.CCOC(C)=O.CCCCCC>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C@H:11]([CH:19]([OH:20])[CH3:21])[C@H:12]([CH3:18])[CH2:13][C:14]([F:15])([F:16])[F:17])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: C[C@H](CC(F)(F)F)[C@@H](C=O)NS(=O)(=O)c1ccc(Cl)s1
Reactant: C[Mg]Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)[C@@H](NS(=O)(=O)c1ccc(Cl)s1)[C@H](C)CC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
A solution of 5-chloro-N-[(1S,2R)-4,4,4-trifluoro-1-formyl-2-methylbutyl]thiophene-2-sulfonamide (prepared as in Example 16, 1.0 g, 2.86 mmol) in THF (10 mL) was stirred under nitrogen at 0° C. Methyl magnesium bromide (3.0 M in ethyl ether, 1.9 mL, 5.71 mmol.) was added dropwise and the resulting solution was stirred for 1 h at 25° C. After this time period, the reaction was complete by TLC (1:2 EtOAc/hexane). The solution was quenched with saturated aqueous NH4Cl (10 mL) and extracted with ether (40 mL). The organic layer was washed with brine (20 mL) and then dried over MgSO4 to obtain a crude oil (0.867 g). The crude product was purified by the Biotage Flash™ 60 chromatography system, eluent: 1:6 EtOAc-hexanes, to afford 5-chloro-N-[(1S,2R)-4,4,4-trifluoro-1-(1-hydroxyethyl)-2-methyl butyl]thiophene-2-sulfonamide as a colorless oil (0.495 g, 49.5%). Mass Spectrum (−ESI): 364 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])[CH:24]=[CH:23]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[O:11]=[C:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[C:25]([NH:30][C:31]([C:33]3[CH:37]=[CH:36][S:35][CH:34]=3)=[O:32])[CH:24]=[CH:23]4)[CH:3]=2)[NH:7]1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Reactant: O=C1Cc2cc(Br)ccc2N1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1Cc2cc(-c3ccc4cc(NC(=O)c5ccsc5)ccc4c3)ccc2N1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 8.9 %

Procedure:
5-bromoindolin-2-one (23.6 mg, 0.111 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (75.0 mg, 0.198 mmol), Fibercat palladium catalyst (Johnson-Matthey, 36.3 mg), and K2CO3 (2 M in water, 0.25 ml, 0.5 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (1.1 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 80 C, first for 10 minutes, and then for 20 minutes. The reaction was cooled to room temperature, diluted with water (5 ml), and extracted with dichloromethane (3×10 ml) and EtOAc (6×10 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified two times on HPLC (10%->95% MeCN/water with 0.1% TFA) to afford title compound (3.8 mg, 9%). MS (ESI pos. ion) m/z: 385 (M+H). Calc'd Exact Mass for C23H16N2O2S: 384.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[CH:15][N:16]=[CH:17][CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[C:27](B(O)O)=[C:28]2[CH2:33][CH2:32][CH2:31][N:29]2[N:30]=1>>[C:1]1([S:7]([N:10]2[C:14]3=[CH:15][N:16]=[CH:17][CH:18]=[C:13]3[C:12]([C:27]3[C:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=4)=[N:30][N:29]4[CH2:31][CH2:32][CH2:33][C:28]=34)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2ccncc21
Reactant: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Product: O=S(=O)(c1ccccc1)n1cc(-c2c(-c3ccccn3)nn3c2CCC3)c2ccncc21

Procedure:
Using Preparation 3A, 1-benzenesulfonyl-3-iodo-1H-pyrrolo[2,3-c]pyridine (Preparation 8) is reacted with 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 2) to provide the titled product. MS (ES) m/z=442 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[NH:16][CH:15]=[CH:14][C:13]=3[NH:12][C:11]([CH3:20])=[C:10]2[C:21]([O:23][CH2:24][CH2:25][C:26]#[N:27])=[O:22])=[C:5]([O:28][CH3:29])[CH:4]=1)#[N:2].C(OCC)(OCC)O[CH2:32][CH3:33]>S(=O)(=O)(O)O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[N:16][C:17]=3[O:19][CH2:32][CH3:33])[NH:12][C:11]([CH3:20])=[C:10]2[C:21]([O:23][CH2:24][CH2:25][C:26]#[N:27])=[O:22])=[C:5]([O:28][CH3:29])[CH:4]=1)#[N:2]
Reactant: COc1cc(C#N)ccc1C1C(C(=O)OCCC#N)=C(C)Nc2cc[nH]c(=O)c21
Reactant: CCOC(OCC)OCC
Agent: O=S(=O)(O)O
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1OC)C(C(=O)OCCC#N)=C(C)N2
Temperature: 130 °C
Reaction time: 8 h

Procedure:
10.00 g (25.62 mmol) of the compound from Example 20A are suspended in 250 ml of triethyl orthoformate and heated to 130° C. Then, over a total period of 8 hours, 15 drops of concentrated sulfuric acid are added each hour to the reaction mixture. It is then stirred at the same temperature overnight. After cooling, excess orthoester is removed in a rotary evaporator, and the crude product is purified by column chromatography (silica gel; mobile phase: cyclohexane/ethyl acetate 1:1). 7.20 g (65% of theory) of the title compound are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([NH:13][N:14]([CH3:16])[CH3:15])=[O:12])[S:10][C:3]=12.[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[OH:27].C([O-])([O-])=O.[K+].[K+].O(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl>[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[O:27][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([NH:13][N:14]([CH3:16])[CH3:15])=[O:12])[S:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: CN(C)NC(=O)c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CN(C)NC(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 170 °C
Reaction time: 12 h
Yield: 65.5 %

Procedure:
A mixture of 7-chloro-N′,N′-dimethylthieno[3,2-b]pyridine-2-carbohydrazide (237) (798 mg, 3.13 mmol), 2-fluoro-4-nitrophenol (740 mg, 4.70 mmol), K2CO3 (830 mg, 6.26 mmol) and Ph2O (4.2 mL) was stirred in a sealed tube for 12 h at 170° C. The mixture was diluted with DCM, extracted with water, the organic phase dried with anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (EtOAc/hexanes 1:1) giving 238 (772.5 mg, 2.05 mmol, 66% yield) as a brown foam. MS (m/z): (M+1) 377.0 (100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[N+:18]([O-])=O)=[CH:8][N:7]1[C:21](=[O:23])[CH3:22])=[O:5])[CH3:2].C(O)C>O1CCCC1.CO.[Pt]>[CH2:1]([O:3][C:4]([C:6]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[NH2:18])=[CH:8][N:7]1[C:21](=[O:23])[CH3:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CC(c2ccc(Cl)cc2[N+](=O)[O-])=CN1C(C)=O
Agent: [Pt]
Solvent: CO
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)OCC)CC(c2ccc(Cl)cc2N)=CN1C(C)=O
Reaction time: 22 h

Procedure:
A solution of 82.2 g (0.20 mol) of the compound of Example 10 in 300 ml of tetrahydrofuran and 700 ml of methanol was hydrogenated in the presence of 4 g of 5% sulfided platinum on carbon at room temperature and 1500 psi for 22 hours. The reaction mixture was concentrated and the solid residue (76 g) was recrystallized from ethanol (320 ml) to afford 61.4 g (81%) of light orange crystals, m.p. 151.5-153°. The analytical sample was prepared by a second recrystallization from ethanol: white crystals, m.p, 152-153.5°.