Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([S:22]([NH:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][N:27]=1)(=[O:24])=[O:23])=[CH:17]2.[NH:32]1[CH:36]=[CH:35][N:34]=[CH:33]1.CC(C)([O-])C.[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1>[N:32]1([C:2]2[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=2[C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16]([S:22]([NH:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][N:27]=2)(=[O:23])=[O:24])=[CH:17]3)[CH:36]=[CH:35][N:34]=[CH:33]1
Reactant: O=S(=O)(Nc1ccncn1)c1ccc2c(-c3ccc(C(F)(F)F)cc3F)cccc2c1
Reactant: c1c[nH]cn1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: C1COCCO1
Product: O=S(=O)(Nc1ccncn1)c1ccc2c(-c3ccc(C(F)(F)F)cc3-n3ccnc3)cccc2c1
Temperature: 180 °C
Yield: 48.8 %

Procedure:
A microwave vial charged with 5-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)naphthalene-2-sulfonamide (0.111 g, 0.248 mmol), 1H-imidazole (0.051 g, 0.744 mmol), 1 mL dioxane, and lithium tert-butoxide (1N in THF) (0.992 ml, 0.992 mmol) was heated to 180° C. in the microwave for 90 minutes. LC/MS showed incomplete reaction, so the reaction mixture was heated to 180° C. for an additional 90 minutes. LC/MS showed mostly product, so the reaction mixture was poured into 1N citric acid solution and was extracted with EtOAc. The organics were concentrated. Purification of the crude residue by reverse phase column chromatography [10 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 5-(2-(1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)naphthalene-2-sulfonamide (0.060 g, 0.121 mmol, 48.8% yield). 1H NMR (DMSO-d6) δ ppm: 8.57 (s, 1H), 8.54 (s, 1H), 8.20 (d, J=8.3 Hz, 1H), 7.95-8.04 (m, 2H), 7.70-7.80 (m, 2H), 7.62-7.68 (m, 1H), 7.56-7.62 (m, 1H), 7.53 (d, J=9.0 Hz, 1H), 7.48 (s, 1H), 6.98 (d, J=6.3 Hz, 1H), 6.94 (s, 1H), 6.60 (s, 1H). m/z (ESI) 496.0 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[OH:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:33]([CH3:35])[CH3:34]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH:33]([CH3:35])[CH3:34])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:5])[CH3:2]
Reactant: CC(C)Br
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2O)Cc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
To a suspension of 2-(2-hydroxy-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (3) (300 mg, 0.88 mmol), anhydrous Cs2CO3 (573 mg, 1.76 mmol), and KI (30 mg, 0.18 mmol) in DMF (10 mL) is added 2-bromo-propane (330 μL, 3.52 mmol). The resulting reaction suspension is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (20 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 10-40% EtOAc in heptane) to give a pure product (6) as white solid (174 mg, 52%).
Reaction SMILES: [CH3:1][N:2]([CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=1)[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:14]([O-])=O)[CH:10]=2)[N:5]=1>C(O)C.O=[Pt]=O>[NH2:14][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([CH2:3][N:2]([CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=1)[CH3:1])[CH:13]=[CH:12]2
Reactant: CN(CCCOc1ccc([N+](=O)[O-])cc1)Cc1ccc2cc([N+](=O)[O-])ccc2n1
Agent: O=[Pt]=O
Solvent: CCO
Product: CN(CCCOc1ccc(N)cc1)Cc1ccc2cc(N)ccc2n1
Reaction time: 4 h
Yield: 98.6 %

Procedure:
N-Methyl-6-nitro-N-[(4-nitrophenoxy)propyl]-2-quinoline methanamine (2.60 g, 6.57 mmol) was dissolved in ethanol (170 mL) containing PtO2 (0.39 g). The mixture was charged with H2 (g) (1 atm), stirred for 4 hours, and filtered through a pad of solka floc. The filtrate was concentrated to afford 2.18 g of product as a yellow oil that was used directly without purification.
Reaction SMILES: C[Si](C)(C)[N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10].CC1(C)CCCC(C)(C)N1.C([Li])CCC.Cl[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36]>O1CCCC1.CCCCCC.O1CCCC1.CCCCCC.C(OCC)(=O)C.O>[CH3:36][O:35][C:30]1[CH:29]=[C:34]([CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9][NH:3][C:4]2=[O:10])[CH:33]=[CH:32][CH:31]=1
Reactant: COc1ccccc1Cl
Reactant: C[Si](C)(C)N1CCCCCC1=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C2CCCCNC2=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 23.9 %

Procedure:
Hexahydro-1-trimethylsilyl-2H-azepin-2-one (9.2 g) in dry tetrahydrofuran (20 ml) was added dropwise with cooling and stirring under a nitrogen atmosphere to a solution of lithium-2,2,6,6-tetramethylpiperidide (prepared from 2,2,6,6-tetramethylpiperidine (8.48 g) and butyl lithium (0.06 mole) in hexane-tetrahydrofuran (38 ml; 10 ml). A further portion of butyl lithium (0.06 mole) in hexane (38 ml) was then added, followed by o-chloroanisole (8.54 g) keeping the reaction temperature between -10° and 5° C. After allowing to warm to room temperature the reaction was stirred for 1.5 hours then decomposed by the addition of water (100 ml). The solvents were removed under reduced pressure, the resulting product partitioned between toluene and 5 M hydrochloric acid. The toluene extracts were dried (MgSO4), the solvent removed and the product distilled affording 2.7 g b.p. 160°-170° C. at 0.1 mm, which yielded 2.6 g of the crystalline title compound from ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[C:22]([CH2:23][CH3:24])=[CH:21][N:20]([CH2:25]C)[N:19]=1>CN(C=O)C>[CH2:23]([C:22]1[C:18]([CH2:17][S:8][C:6]2[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=2)=[N:19][N:20]([CH3:25])[CH:21]=1)[CH3:24]
Reactant: Cc1cc(O)nc(S)n1
Reactant: CCc1cn(CC)nc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cn(C)nc1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (604 mg, 4.2 mmol) was dissolved in anhydrous DMF (30 mL), and then potassium carbonate (1.76 g, 12.8 mmol) and 3-(bromomethyl)-1,4-diethyl-1H-pyrazole (5.1 mmol) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 4-12% DCM/MeOH to afford 2-{[(4-ethyl-1-methyl-1H-pyrazol-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (454 mg, 41% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 1.07 (t, J=7.4 Hz, 3H), 2.17 (s, 3H), 2.37 (q, J=7.4 Hz, 2H), 3.70 (s, 3H), 4.29 (s, 2H), 6.00 (s, 1H), 7.41 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([C:16]([O:18]C)=[O:17])[CH2:5]1.[OH-].[Li+].O>C1COCC1.CO>[C:12]([O:11][C:9]([N:7]1[CH2:8][C@@H:4]([CH2:3][O:2][CH3:1])[CH2:5][C@H:6]1[C:16]([OH:18])=[O:17])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC[C@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Yield: 98 %

Procedure:
A solution of (2S,4S)-1-tert-butyl 2-methyl 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (18 g, 66.91 mmol) and lithium hydroxide (3.37 g, 80.3 mmol) in THF (50 mL), methanol (50 mL), and water (50 mL) was stirred at RT for 2 h. The reaction mixture was adjusted to ph 6 and extracted with 10:1 DCM:methanol. The organic phase was dried over sodium sulfate and concentrated to provide the title intermediate (17 g, 84% yield) as a colorless oil). 1H NMR (400 MHz, CDCl3): δ(ppm) 1.398-1.451 (d, 9H, J=21.2 Hz), 1.625-1.754 (m, 1H), 2.226-2.652 (m, 3H), 3.251-3.458 (m, 1H), 3.316 (s, 3H), 3.316-3.462 (m, 2H), 3.556-3.750 (m, 2H), 4.405-4.445 (m, 1H), 7.652 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].Cl[C:13]([F:23])([F:22])C(C1C=CC=CC=1)=O>>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH:13]([F:23])[F:22]
Reactant: O=C(c1ccccc1)C(F)(F)Cl
Reactant: O=[N+]([O-])c1ccc(O)c(Br)c1
Product: O=[N+]([O-])c1ccc(OC(F)F)c(Br)c1

Procedure:
The compound was prepared starting from commercially available 2-bromo-4-nitrophenol, which was reacted with 2-chloro-2,2-difluoroacetophenone (J. Hu et al., J. Org. Chem., 2006, 71, 9845) to yield 2-bromo-1-difluoromethoxy-4-nitro-benzene. Subsequent Buchwald-Hartwig coupling of 2-bromo-1-difluoromethoxy-4-nitro-benzene with tert.butyloxycarbonyl-piperazine by analogy to preparation example 3.1, reduction of the nitro group to the corresponding aniline by analogy to preparation example 3.2, subsequent coupling with commercially available 2-difluoromethoxybenzene-sulfonylchloride by analogy to preparation example 1.4, and final deprotection under acidic conditions by analogy to example 1 yielded the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH:22]2[CH2:24][CH2:23]2)[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([F:14])[CH:10]([NH:15]C(=O)C(F)(F)F)[CH2:9][CH2:8]1.C(OC([NH:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46](O)=[O:47])=O)(C)(C)C>>[NH2:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH:22]2[CH2:23][CH2:24]2)[C:6]=1[N:7]1[CH2:13][CH2:12][C@H:11]([F:14])[C@@H:10]([NH2:15])[CH2:9][CH2:8]1)=[O:47]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2cc(F)ccc2F)nc1C(=O)O
Reactant: Nc1cnn(C2CC2)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Product: Nc1sc(-c2cc(F)ccc2F)nc1C(=O)Nc1cnn(C2CC2)c1N1CC[C@H](N)[C@@H](F)CC1

Procedure:
Following the procedure for Example 107 starting from N-(1-(4-amino-1-cyclopropyl-1H-pyrazol-5-yl)-5-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonyl-amino)-2-(2,5-difluorophenyl)thiazole-4-carboxylic acid gave 276 as the monoformate salt as an off-white solid (170 mg, 40% over two steps). 1H NMR (400 MHz, d4-MeOD) δ 8.54 (s, 1H), 8.06 (ddd, J=9.4, 5.8, 3.2 Hz, 1H), 7.39 (s, 1H), 7.28 (td, J=9.9, 4.4 Hz, 1H), 7.19-7.11 (m, 1H), 4.86 (dtd, J=49.0, 9.3, 3.6 Hz, 1H), 3.62-3.49 (m, 2H), 3.50-3.38 (m, 4H), 2.45-2.31 (m, 1H), 2.26-2.06 (m, 2H), 1.99-1.86 (m, 1H), 1.21-1.12 (m, 2H), 1.15-1.05 (m, 2H). LCMS (ES+) m/z 492 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19]C)=[C:6]([CH2:8][CH2:9][C:10]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])[CH:7]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:19])=[C:6]([CH2:8][CH2:9][C:10]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])[CH:7]=1
Reactant: COc1ccc(Br)cc1CCc1c(Cl)cccc1C#N
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1cccc(Cl)c1CCc1cc(Br)ccc1O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.2 %

Procedure:
A solution of 2-[2-(5-bromo-2-methoxyphenyl)-ethyl]-3-chlorobenzonitrile (0.187 g, 1.0 equiv) in CH2Cl2 (2.5 mL) was allowed to stir under an atmosphere of argon at −78° C. To this solution was added boron tribromide (1.0 M in CH2Cl2, 2.65 mL, 5.0 equiv). After 15 min at −78° C., the solution was allowed to warm to room temperature and stir overnight. The reaction was quenched by the addition of water and the solution was extracted with EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromotagraphy (SiO2, 20% EtOAc in hexane) to give 2-[2-(5-bromo-2-hydroxyphenyl)-ethyl]-3-chlorobenzonitrile (0.144 g, 81%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:13][C:14]([F:17])([F:16])[F:15])(=O)=O.[Br:20][C:21]1[C:22]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[N:23][NH:24][C:25]=1[CH:26]=[O:27].O>CN(C)C=O>[Br:20][C:21]1[C:22]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[N:23][N:24]([CH2:13][C:14]([F:15])([F:16])[F:17])[C:25]=1[CH:26]=[O:27]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=Cc1[nH]nc(-c2cccs2)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1c(Br)c(-c2cccs2)nn1CC(F)(F)F
Temperature: 100 °C
Reaction time: 0.83 h
Yield: 32.3 %

Procedure:
Cesium carbonate (1.56 g, 4.78 mmol) and 2,2,2-triflouroethyl trifluoromethanesulfonate (0.92 mL, 6.38 mmol) were added to a solution of 4-bromo-3-(thiophen-2-yl)-1H-pyrazole-5-carbaldehyde (34c) (0.82 g, 3.19 mmol) in N,N-dimethylformamide (15 mL). The reaction mixture was stirred at 100° C. for 50 minutes. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (2×40 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 100/0 to 94/6), to provide 4-bromo-3-(thiophen-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carbaldehyde (34d) (350 mg, 1.03 mmol, 32%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[CH2:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[CH2:15][CH:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(C(=O)CC(c2ccccc2)c2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC1CCN(C(=O)CC(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[1-(3,3-Diphenyl-propionyl)-pyrrolidin-3-ylmethy-carbamic acid tert-butyl ester (1.04 g, 2.54 mmol) was dissolved in dry CH2Cl2 (15 ml) followed by addition of TFA (10 ml). The resulting solution was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure. The resulting residue was dissolved in water (15 ml) and pH of the solution was adjusted to 10. The water phase was extracted with CH2Cl2 (100 ml), and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the desired product in almost quantitative yield
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:14](=[O:15])[CH2:13][CH2:12][CH:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:10]1O.C(N(CC)CC)C.CS(Cl)(=O)=O.Cl>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10]1
Reactant: CCOC(=O)C1CCC(=O)N(c2c(Cl)cccc2Cl)C1O
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=CN(c2c(Cl)cccc2Cl)C(=O)CC1
Reaction time: 0.25 h

Procedure:
To a solution of the compound prepared in Example 1 in dichloromethane (150 mL) were added triethylamine (12.27 g) and methanesulfonyl chloride (6.65 g) on ice bath and the mixture was stirred at same temperature for 15 minutes. The reaction mixture was added by hydrochloric acid (1 mol/L), then the water layer was extracted with dichloromethane. The obtained extract was dried with anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give the title compound (4.00 g) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:9]=2[F:16])=[CH:4][C:3]=1[N+:17]([O-])=O>CC(O)=O.C1COCC1.[Zn]>[NH2:17][C:3]1[CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:9]=2[F:16])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: N#Cc1ccc(-c2ccc(N)c([N+](=O)[O-])c2)c(F)c1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1ccc(-c2ccc(N)c(N)c2)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.6 %

Procedure:
To a suspension of 4′-amino-2-fluoro-3′-nitrobiphenyl-4-carbonitrile (Preparation 92, 3 g, 11.66 mmol) in AcOH/THF (70 mL/70 mL) was added zinc dust (6.9 g, 105.6 mmol) and the reaction stirred at room temperature for 18 hours. The reaction was filtered and the filtrate concentrated in vacuo. The residue was treated with saturated aqueous NaHCO3 solution (200 mL) and extracted with EtOAc (200 mL). The organic layer was collected, dried over Na2SO4 and concentrated in vacuo. The solid was triturated with MTBE (30 mL) and filtered to afford the title compound as a brown solid (1.5 g, 57%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]=O.Cl.[NH:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([NH2:19])=[O:18])=[CH:12][CH:11]=1)N>C(O)(=O)C>[Cl:1][CH2:2][CH2:3][C:4]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][C:17]([NH2:19])=[O:18])[CH:14]=2)[NH:8][CH:5]=1
Reactant: NNc1ccc(CC(N)=O)cc1
Reactant: O=CCCCCl
Agent: Cl
Solvent: CC(=O)O
Product: NC(=O)Cc1ccc2[nH]cc(CCCl)c2c1

Procedure:
A mixture of 4-chlorobutanal (1.8 g) and 2-(4-hydrazinophenyl)acetamide hydrochloride (3 g) in 50% aqueous acetic acid (200 ml) was heated at reflux for 45 min., then cooled and evaporated to give 3-(2-chloroethyl)-1H-indole-5-acetamide as a dark organe-brown foam. τ (DMSO) 6.3(2H); 6,8(2H); (CH2CH2Cl)
Reaction SMILES: [F:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([OH:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][CH:31]([CH3:37])[CH2:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:30][CH:31]([CH3:37])[CH2:32][CH2:33][C:34]([O:22][CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:21])[N:12]1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[N:11][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=1)=[O:35]
Reactant: O=C1c2ccccc2C(O)N1c1ccc2ccc(F)nc2n1
Reactant: CC(C)CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(F)nc2n1
Yield: 18 %

Procedure:
The procedure is as in Example 7, but starting with 2-(7-fluoro-1,8-naphthyridin-2yl)-3-hydroxy-1-isoindolinone (5 g) in methylene chloride (60 cc), triethylamine (6.5 g), 4-methylpentanoyl chloride (3.66 g) and 4-dimethylaminopyridine (10 mg). After recrystallization in ethanol, 2-(7-fluoro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 4-methylpentanoate (1.2 g), m.p. 154° C., is obtained.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][C:12]([NH:15][C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[N:13][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[N:11][C:12]([NH:15][C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[N:13][CH:14]=1
Reactant: CCCCCC(=O)Nc1ncc(OCc2ccccc2)cn1
Agent: [Pd]
Solvent: CO
Product: CCCCCC(=O)Nc1ncc(O)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46142.9 %

Procedure:
N-[5-(Benzyloxy)pyrimidin-2-yl]hexanamide (87.1 g, 0.29 mmol) was dissolved in methanol (2.4 L), the solution was added with 10% palladium/carbon (20 g), and the mixture was stirred at room temperature for 3 hours under hydrogen atmosphere. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to obtain N-(5-hydroxypyrimidin-2-yl)hexanamide (28.0 g, 46%) as pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:17][C:16]([C:18]([O:20]CC)=[O:19])=[C:15]([CH3:23])[CH:14]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:17][C:16]([C:18]([OH:20])=[O:19])=[C:15]([CH3:23])[CH:14]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(-n2cnn(Cc3ccc(F)cc3)c2=O)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Temperature: 0 °C
Yield: 82 %

Procedure:
A mixture of ethyl 5-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylate (0.17 g, 0.47 mmol) and 1 N aqueous sodium hydroxide solution (3.0 mL, 3.0 mmol) in ethanol (6 mL) was stirred at reflux for 1 h, cooled to 0° C. and acidified with 10% aqueous hydrochloric acid to pH ˜2. The resulting precipitate was filtered, washed with water and hexanes, and dried in vacuo to afford the title compound as a colorless solid in 82% yield (0.13 g): 1H NMR (300 MHz, DMSO-d6) δ 12.94 (br s, 1H), 8.70 (s, 1H), 7.36-7.29 (m, 2H), 7.23 (s, 1H), 7.19-7.11 (m, 2H), 4.92 (s, 2H), 2.43 (s, 3H); MS (ES−) m/z 332.1 (M−1).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[F:5][C:6]1[CH:30]=[CH:29][C:9]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][NH2:28])[CH:25]=4)[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1>C(OCC)(=O)C>[F:5][C:6]1[CH:30]=[CH:29][C:9]([CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][NH:28][C:3]([NH:2][CH3:1])=[O:4])[CH:25]=4)[CH:20]=[CH:19]3)[CH2:16][CH2:17]2)=[CH:8][CH:7]=1
Reactant: CN=C=O
Reactant: NCc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Solvent: CCOC(C)=O
Product: CNC(=O)NCc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Yield: 67.3 %

Procedure:
Under ice cooling, methyl isocyanate (0.02 g) was added dropwise into a solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindoline (0.09 g) obtained in Example 132 in ethyl acetate (10 ml) and the resultant mixture was stirred at room temperature for 1 hr. The resulting precipitate was collected by filtration, washed with ether/hexane and dried to give the title compound (0.07 g) as a white powder (yield: 67%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].CN.[CH2:16]([N:18](CC)CC)C>ClCCl.O>[CH3:16][NH:18][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11]
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: CN
Solvent: ClCCl
Solvent: O
Product: CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a solution of 2-nitrobenzene-1-sulfonyl chloride (30 g, 0.14 mol) in dichloromethane (500 mL) was slowly added a solution of methylamine in water (30%, 15.3 g) and triethylamine (38 mL, 0.27 mol) respectively. The mixture was stirred at room temperature for 1 hour and then evaporated. The residue was subjected to silica gel chromatography to afford the product N-methyl-2-nitrobenzenesulfonamide (26 g, yield 90%).
Reaction SMILES: O.Cl.[F:3][CH2:4][CH2:5][NH2:6].[CH2:7]1[C:12](=[O:13])[O:11][CH2:10][C:8]1=O.C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:3][CH2:4][CH2:5][NH:6][C:8]1[CH2:10][O:11][C:12](=[O:13])[CH:7]=1
Reactant: NCCF
Reactant: O=C1COC(=O)C1
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1C=C(NCCF)CO1
Yield: 41.6 %

Procedure:
On a water separator, 550 mg (4.97 mmol) of 2-fluoroethylamine hydrochloride, 547 mg (5.47 mmol) of tetronic acid, 408 mg (4.97 mmol) of sodium acetate and 9 mg (0.05 mmol) of 4-toluenesulphonic acid in 50 ml of toluene are heated for 5 hours under reflux. The reaction mixture is concentrated under reduced pressure, the residue is taken up in ethyl acetate and the mixture is washed with 1 N aqueous sodium hydroxide solution. The aqueous phase is extracted repeatedly with ethyl acetate and the combined organic phase is dried over sodium sulphate. The organic phase is concentrated under reduced pressure and the residue is purified by recrystallisation from ethyl acetate/cyclohexane, giving 300 mg (42% of theory) of 4-[(2-fluoroethyl)amino]furan-2(5H)-one.