Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([CH2:12][N:13]([CH3:20])[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH:3]=1.[NH2:21][C:22]1[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]2[C:25]([CH:26]3[CH2:36][CH:27]3[CH2:28][O:29]2)=[CH:24][CH:23]=1>C(Cl)Cl.N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:21][C:22]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]3[C:25]([CH:26]4[CH2:36][CH:27]4[CH2:28][O:29]3)=[CH:24][CH:23]=2)(=[O:10])=[O:9])=[C:4]([CH2:12][N:13]([CH3:20])[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH:3]=1
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Reactant: CN(Cc1cc(F)ccc1S(=O)(=O)Cl)C(=O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2CN(C)C(=O)C(F)(F)F)ccc2c1OCC1CC21
Yield: 109.1 %

Procedure:
A mixture of 4-fluoro-2-[N-methyl-N-(2,2,2-trifluoroacetyl)aminomethyl]benzenesulfonyl chloride (Intermediate 158, 0.182 g) was added to a solution of methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42, 0.100 g) in DCM (3 mL) and pyridine (1 mL) and the resultant mixture was stirred at room temperature for 1 hour. The mixture was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-40% to give methyl (1aRS,7bSR)-5-(4-fluoro-2-[N-methyl-N-(2,2,2-trifluoroacetyl)aminomethyl]benzenesulfonyl-amino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.257 g) as a solid.
Reaction SMILES: [C:1]([CH2:4][C:5]([NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)=[O:6])([OH:3])=O.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[CH2:46]([O:48][C:49]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)=[O:50])[CH3:47]>C(Cl)Cl.C(OCC)(=O)C>[CH2:46]([O:48][C:49]([N:51]1[CH2:52][CH2:53][N:54]([C:1]([CH2:4][C:5]([NH:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)=[O:6])=[O:3])[CH2:55][CH2:56]1)=[O:50])[CH3:47]
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=C(O)CC(=O)Nc1ccc2ccccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(C(=O)CC(=O)Nc2ccc3ccccc3c2)CC1
Reaction time: 0.08 h
Yield: 62.5 %

Procedure:
To a solution of 2-((carboxy)methylcarbonylamino)naphthalene (1.2 g, 5.2 mmol) in CH2Cl2 (40 mL) was added triethylamine (2.2 mL, 15.6 mmol) and 1-hydroxybenzotriazole (HOBT) (0.84 g, 6.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (1.2 g, 6.2 mmol). After 5 minutes, 1-ethoxycarbonylpiperazine (0.84 mL, 5.3 mmol) was added and the reaction was stirred overnight. The reaction mixture was evaporated in vacuo to afford an oil, which was dissolved in ethyl acetate, and washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated in vacuo to afford 2-[((4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl)carbonyl]aminonaphthalene (1.2 g), as a solid that was used without further purification.
Reaction SMILES: [O:1]([C:8]1[CH:27]=[CH:26][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](O)(=[O:32])/[CH:29]=[CH:30]/[CH3:31]>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([NH:22][C:28](=[O:32])/[CH:29]=[CH:30]/[CH3:31])[CH:23]=[CH:24][CH:25]=2)=[CH:26][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Reactant: C/C=C/C(=O)O
Product: C/C=C/C(=O)Nc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Yield: 56 %

Procedure:
(E)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-enamide was prepared from 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline and (E)-but-2-enoic acid using Method E (56% yield). HPLC: 98%, RT=4.292 min. MS: m/z=423 [M+H]+, RT=4.28 min. 1H-NMR (DMSO-d6) δ 9.91 (s, 1H), 8.52 (s, 1H), 8.43 (d, 1H), 7.92 (s, 1H), 7.68 (d, 1H), 7.40-7.37 (m, 3H), 7.30 (d, 1H), 7.18-7.12 (m, 3H), 7.08 (d, 2H), 7.02 (d, 2H), 6.83-6.76 (m, 2H), 6.14 (d, 1H), 1.86 (d, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])=[O:24])[C:5]1=[O:32].C(N(C(C)C)CC)(C)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>CN(C=O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])=[O:24])[C:5](=[O:32])[N:4]3[CH2:3][CH2:2][NH:1][S:43]([CH3:42])(=[O:45])=[O:44])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: NCCn1c(=O)c(C(=O)NCCOCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCCn1c(=O)c(C(=O)NCCOCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-{2-[(2-hydroxyethyl)oxy]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.025 g, 0.052 mmol) and diisopropyl ethylamine (0.05 mL, 0.29 mmol) in DMF (5 mL) under nitrogen was treated with methanesulfonyl chloride (0.0053 mL, 0.068 mmol) at 40° C. for 1 h then 3½ h at ambient temperature. The reaction was concentrated in vacuo and the resulting residue was triturated with Et2O:MeOH, filtered, washed with 2:1 Et2O:MeOH. A second crop was obtained by filtration from the filtrate, dried in vacuo to provide the title compound as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.90 (s, 3 H), 3.19-3.30 (m, 2 H), 3.46-3.61 (m, 8 H), 4.14 (s, 2 H), 4.34 (t, J=6.53 Hz, 2 H), 4.60-4.64 (m, 1 H), 7.09-7.16 (m, 2 H), 7.23-7.29 (m, 1 H), 7.37-7.44 (m, 2 H), 8.11 (d, J=0.84 Hz, 1 H), 8.55 (d, J=1.54 Hz, 1 H), 10.35 (t, J=5.48 Hz, 1 H), 17.12 (s, 1 H); ES+ MS: 523 (M+H+).
Reaction SMILES: C(O[C:6](=[O:21])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.[CH2:22]([O:24][C:25](=[O:37])[CH:26](C(OCC)=O)[C:27](OCC)=[O:28])[CH3:23]>>[CH2:22]([O:24][C:25]([C:26]1[C:6](=[O:21])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]2[C:27]=1[OH:28])=[O:37])[CH3:23]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(F)c1)n1cccc1
Product: CCOC(=O)c1c(O)c2cccn2n(Cc2cccc(F)c2)c1=O

Procedure:
Prepared according to the thermal cyclization condition used in Example 1 step c) from (3-fluoro-benzyl)-pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.) and 2-ethoxycarbonyl-malonic acid diethyl ester (3.0 eq.). ESI (m/z): 331 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[N:13]([O-])=O.[Na+].C(Cl)Cl.CO>O.Cl>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[NH:1][NH2:13]
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(Cl)c(N)c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)c(NN)c1
Reaction time: 1 h

Procedure:
A solution of 11.9 g (63.9 mmole) of methyl 3-amino-4-chlorobenzoate (prepared as in Step A) was maintained at -5° to +5° C. and subjected to vigorous mechanical stirring as a solution of 4.41 g (63.9 mmole) of sodium nitrite in 19.3 mL of H2O was added slowly via a dropping funnel. Stirring was continued at this temperature for 1 hour, and the mixture was filtered while cold. The filtrate was immediately added to a rapidly stirred solution of 28.8 g (128 mmole) of stannous chloride dihydrate in 37.3 mL of concentrated HCl, which was also maintained at >0° C. Precipitation of a cream-colored solid began at once. After being stirred at 0° C. for 0.5 hour, the mixture was refrigerated overnight. The solid was collected on a filter and triturated with ether to give, after air-drying, approximately 22 g of cream-colored solid (mp 218°-220° C.), which was stored in the freezer. As needed, a portion of this hydrochloride salt was partitioned between 5% NaHCO3 (aqueous) and a mixture of CH2Cl2 and ethyl acetate to liberate the title compound as the free base, which was isolated by concentration of the organic phase to give a cream-colored solid, homogeneous by TLC (95:5 CH2Cl2 --MeOH); mass spectrum (EI) m/e 200 (M+). This material was used immediately in the next reaction.
Reaction SMILES: [C:1]([C:3]1([C:15]2[C:24]3[O:23][CH2:22][CH2:21][O:20][C:19]=3[C:18]([O:25][CH3:26])=[CH:17][CH:16]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([O:12]CC)=[O:11])[CH2:5][CH2:4]1)#[N:2].[OH-].[Na+].Cl>C(O)C.C1COCC1>[C:1]([C:3]1([C:15]2[C:24]3[O:23][CH2:22][CH2:21][O:20][C:19]=3[C:18]([O:25][CH3:26])=[CH:17][CH:16]=2)[CH2:4][CH2:5][C:6](=[CH:9][C:10]([OH:12])=[O:11])[CH2:7][CH2:8]1)#[N:2]
Reactant: CCOC(=O)C=C1CCC(C#N)(c2ccc(OC)c3c2OCCO3)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(C2(C#N)CCC(=CC(=O)O)CC2)c2c1OCCO2
Temperature: 70 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a suspension of Compound 10 (0.31 g, 0.87 mmol) obtained in Example 10 in ethanol (3.1 mL) and THF (3.1 mL) was added a 2 mol/L aqueous solution of sodium hydroxide (0.65 mL, 1.3 mmol), the mixture was stirred at 70° C. for 1 hour, and then a 2 mol/L aqueous solution of sodium hydroxide (0.65 mL, 1.3 mmol) was further added, followed by stirring at 70° C. for 1 hour. 1 mol/L hydrochloric acid was added dropwise under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate, the solvent was evaporated in vacuo, and the residue was triturated with ethanol to give Compound 11 (0.23 g, 82%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].I[C:16]1[CH:17]=[C:18]([CH2:22][OH:23])[CH:19]=[CH:20][CH:21]=1>>[OH:23][CH2:22][C:18]1[CH:17]=[C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Reactant: OCc1cccc(I)c1
Product: COC(=O)CCc1ccc(C#Cc2cccc(CO)c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (90 mg, 0.48 mmol) and (3-iodophenyl)methanol (0.07 mL, 0.55 mmol) according to the general procedure IB to give 40 mg (32%) of an orange oil after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:30→1:10). Rf: 0.24 (EtOAc:hexanes, 1:5); 1HNMR (CDCl3) δ 7.53 (s, 1H), 7.46-7.43 (m, 3H), 7.34-7.32 (m, 2H), 7.19-7.16 (m, 2H), 4.69 (s, 2H), 3.66 (s, 3H), 2.98-2.93 (t, 2H, J=7.8 Hz), 2.66-2.61 (t, 2H, J=7.8 Hz), 1.83 (s, 1H); 13CNMR (CDCl3) δ 173.1, 141.1, 140.9, 131.7, 130.7, 130.0, 128.6, 128.3, 126.7, 123.6, 121.1, 89.4, 88.9, 64.9, 51.6, 35.4, 30.8; ESI-MS m/z 317.1 (MNa+).
Reaction SMILES: [CH2:1]([O:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH2:18]([N:14]1[CH:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:11][CH2:12][C:13]1=[O:15])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CCCCCCCCOC1CCC(=O)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCCCCOC1CCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a mixture of 2 g of 5-n-octyloxy-pyrrolidin-2-one, 0.65 g of potassium hydroxide at 85% and 0.2 g of tetra-n-butylammonium bromide in 40 cm3 of tetrahydrofuran, there is added a solution of 1.6 g of benzyl bromide in 5 cm3 of tetrahydrofuran, without exceeding 30° C. After agitating for 2 hours at ambient temperature, filtering and evaporating to dryness, the residue is chromatographed on alumina, (eluent: ethyl acetate--cyclo-hexane, 1--1), and 2 g of the expected product is obtained.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[C:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH2:12][CH2:11][CH2:10]2)=[O:5].[CH3:27][Si](C)(C)C=[N+]=[N-]>C(OCC)C>[CH3:27][O:19][C:18](=[O:20])[C:17](=[C:13]1[C:14]2[C:9](=[CH:8][C:7]([NH:6][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:25][CH:24]=[CH:23][C:22]=3[F:26])=[CH:16][CH:15]=2)[CH2:10][CH2:11][CH2:12]1)[CH3:21]
Reactant: CC(C(=O)O)=C1CCCc2cc(NC(=O)c3c(F)cccc3F)ccc21
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)C(C)=C1CCCc2cc(NC(=O)c3c(F)cccc3F)ccc21
Reaction time: 0.25 h
Yield: 75 %

Procedure:
2-[6-(2,6-Difluoro-benzoylamino)-3,4-dihydro-2H-naphthalen-1-ylidene]-propionic acid (Compound 1) (13 mg, 0.036 mmol) was then dissolved in diethylether and excess trimethyl-silyl diazomethane (TMSCHN2) was added at room temperature. After 15 min, the reaction was quenched with acetic acid and concentrated under reduced pressure. The product, 2-[6-(2,6-difluoro-benzoylamino)-3,4-dihydro-2H-naphthalen-1-ylidene]-propionic acid methyl ester (10 mg, 75% yield) was obtained by silica gel chromatography purification using ethyl acetate/hexane as eluent.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[F:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:31][C:32](O)=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:31][C:32]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:33]
Reactant: Cc1cccc(CC(=O)O)c1F
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(CC(=O)N2CCc3cc(-c4nn(C)c5ncnc(N)c45)ccc32)c1F
Reaction time: 8 h
Yield: 82.8 %

Procedure:
In a 20 mL vial with cap, to 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2HCl (70 mg, 0.206 mmol), (2-fluoro-3-methylphenyl)acetic acid (34.7 mg, 0.206 mmol), and HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144 mL, 0.825 mmol). The mixture was stirred overnight. The reaction was poured into water, off-white solid formed. The solid was filtered to give 3-{1-[(2-fluoro-3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (71 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (d, J=1.52 Hz, 3H), 3.24-3.32 (m, 2H), 3.92 (s, 2H), 3.94 (s, 3H), 4.30 (t, J=8.46 Hz, 2H), 7.04-7.11 (m, 1H), 7.16 (s, 1H), 7.21 (s, 1H), 7.44 (d, J=8.34 Hz, 1H), 7.53 (s, 1H), 8.16 (d, J=8.34 Hz, 1H), 8.25 (s, 1H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH:12]=[O:13])=[C:7]([N+:14]([O-])=O)[CH:6]=1)(=[O:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH:12]=[O:13])=[C:7]([NH2:14])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(NC=O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(NC=O)c(N)c1
Yield: 88 %

Procedure:
4-(Formylamino)-3-nitrophenyl acetate (13.5 g, 60.3 mmol, split into 1 g, 5 g, and 7.5 g batches) was dissolved in a minimal amount of ethyl acetate. The solution was hydrogenated over 10% Pd on carbon (wet, degussa type) on a Parr hydrogenator at 40 PSI of H2 for 1 hour. The catalyst was removed by filtering the reaction through Celite. The filtrate was concentrated to give 10.3 g of 3-amino-4-(formylamino)phenyl acetate. (M+1) 195.1, 1.31 min (LC/MS method A)
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:27](O)=[O:28])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:31]=[C:32]([NH2:36])[CH:33]([CH3:35])[CH3:34]>>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:20][CH:21]=3)[CH2:13][CH:12]([C:27]3[O:28][N:36]=[C:32]([CH:33]([CH3:35])[CH3:34])[N:31]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:7]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: CC(C)C(N)=NO
Product: CC(C)c1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(O)CC3)C2)n1

Procedure:
200 mg (0.480 mmol) of the compound from Example 63A and 98 mg (0.961 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 2. Yield: 62 mg (27% of theory)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[CH:11][C:10]=1[C:29]([CH3:32])([CH3:31])[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:33][C:34]1[C:35]([F:47])=[C:36]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:37](O)=[O:38]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH3:26])([CH3:28])[CH3:27])=[CH:21][CH:20]=2)[C:37](=[O:38])[C:36]2[CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=[C:34]([Cl:33])[C:35]=2[F:47])=[CH:11][C:10]=1[C:29]([CH3:32])([CH3:31])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(OCc3ccccc3)c(C(C)(C)C)c2)cc1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(Cl)c1F
Product: CC(C)(C)c1ccc(CN(CCc2ccc(OCc3ccccc3)c(C(C)(C)C)c2)C(=O)c2cc(C(F)(F)F)cc(Cl)c2F)cc1

Procedure:
The title compound was prepared in analogy to Example 1, using [2-(4-benzyloxy-3-tert-butyl-phenyl)-ethyl]-(4-tert-butyl-benzyl)-amine (S9-C48) and 3-chloro-2-fluoro-5-(trifluoromethyl)benzoic acid. MS: 654.4 [ISP (M+H)+].
Reaction SMILES: Br[C:2]1[N:3]([CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[C:4]2[N:5]=[C:6]([NH2:12])[NH:7][C:8](=[O:11])[C:9]=2[N:10]=1.C(OC(=O)C)(=[O:21])C.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:12][C:6]1[NH:7][C:8](=[O:11])[C:9]2[NH:10][C:2](=[O:21])[N:3]([CH2:13][C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[C:4]=2[N:5]=1
Reactant: Nc1nc2c(nc(Br)n2Cc2cccs2)c(=O)[nH]1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1nc2c([nH]c(=O)n2Cc2cccs2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 8-bromo-9-[(2-thienyl)methyl]guanine (see Example 5) (3.12 g; 9.56 mmol), acetic anhydride (75 ml), glacial acetic acid (75 ml) and anhydrous sodium acetate (14.9 g; 0.1816 mol) was heated to reflux for 20 hours. The dark solution which formed was then evaporated to dryness under reduced pressure. The residue was dissolved in aqueous methylamine (150 ml), stirred at room temperature for 48 hours and then heated to reflux for 2.5 hours. The methylamine was distilled off under reduced pressure and the residue was recrystallized from boiling methanol-water mixture to give 1.23 g of the analytical product, mp >300° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:30]=[CH:29][C:15]([O:16][C:17]2[C:22]([C:23]3[CH2:27][CH2:26][C:25](=[O:28])[CH:24]=3)=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:14][CH:13]=1)=[O:11].[Cl-].[Ce+3].[Cl-].[Cl-].[B-].[Na+]>O1CCCC1.CO>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([OH:11])[C:12]1[CH:30]=[CH:29][C:15]([O:16][C:17]2[C:22]([C:23]3[CH2:27][CH2:26][CH:25]([OH:28])[CH:24]=3)=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:14][CH:13]=1
Reactant: O=C1C=C(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Agent: [B-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Product: OC1C=C(c2cccnc2Oc2ccc(C(O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 0 °C

Procedure:
A suspension of 3-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)cyclopent-2-enone (2125 mg, 5.37 mmol) and cerium (iii) chloride (1325 mg, 5.37 mmol) in tetrahydrofuran (300 mL) and methanol (30.0 mL) was cooled to 0° C. under nitrogen. Sodium borohydrate (813 mg, 21.50 mmol) was added in 4 lots over 20 min. The reaction was warmed to 23° C. over 2 h. After a total reaction time of 4 h, the reaction was quenched with saturated ammonium chloride solution (10 ml, slowly—effervescence). The solution was diluted with EtOAc (500 mL) and washed with saturated ammonium chloride solution (100 mL) and brine (100 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 1-8% methanol/dichloromethane), affording the product as a yellow film.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[C:4]([Br:9])[CH:3]=1.C([Li])CCC.[B:15](OC)([O:18]C)[O:16]C.Cl>C(OCC)C.CCCCCC>[Br:1][C:2]1[CH:7]=[C:6]([B:15]([OH:18])[OH:16])[CH:5]=[C:4]([Br:9])[CH:3]=1
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OB(O)c1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To 9.44 g of 1,3,5-tribromobenzene in 200 mL of diethyl ether was added 19.4 mL of 1.55M n-butyllithium in hexane at -78° under nitrogen. The suspension was stirred for 30 min, then added to 30 mL of trimethyl borate in 300 mL of diethyl ether at the same temperature. The now clear solution was stirred at -78° for 30 min then warmed to room temperature overnight. Fifty mL of 1 N hydrochloric acid were added and allowed to react for 2 h. The aqueous layer was discarded and the ether layer was extracted with 2 N sodium hydroxide solution (5 times with 100 mL). The extract was washed once with 50 mL of ether, then acidified with 6N HCl to pH 2 at 0°. A white precipitate was collected by filtration after the solution had been kept at 0° for 2 h. After air drying, 8.49 g (95%) of the title product was obtained. Melting point was >300° and the purity was confirmed by chromatography.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17]C)=[O:16].O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]=[CH:4][C:3]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1cnn(CCc2ccccc2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)cnn1CCc1ccccc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 36.2 %

Procedure:
A mixture of methyl 5-methyl-1-phenethyl-1H-pyrazole-4-carboxylate (177 mg, 0.72 mmol), lithium hydroxide monohydrate (111 mg, 2.62 mmol), tetrahydrofuran (5 mL), methanol (1 mL) and water (1 mL) was stirred at 20° C. for 4 hours. The mixture was acidified to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuum and separated by HPLC (condition: column AD-H (20 mm*250 mm*5 μm), hexane: ethanol (0.2% DEA)=50:50, flow rate: 13 mL/min) to give 5-methyl-1-phenethyl-1H-pyrazole-4-carboxylic acid (60 mg, 36%). LRMS (M+H+) m/z: calcd. 230.11. found 230.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]2[O:11][CH2:12][CH2:13][O:14][C:9]=2[CH:8]=[C:7](N=[N-])[CH:6]=1)=[O:4].[F:17][B+]F>ClC1C=CC(Cl)=CC=1Cl>[F:17][C:7]1[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:10]2[O:11][CH2:12][CH2:13][O:14][C:9]=2[CH:8]=1
Reactant: F[B+]F
Reactant: COC(=O)c1cc(N=[N-])cc2c1OCCO2
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: COC(=O)c1cc(F)cc2c1OCCO2
Temperature: 110 °C
Reaction time: 3 h
Yield: 54.5 %

Procedure:
A suspension of difluoroboranylium {8-[(methyloxy)carbonyl]-2,3-dihydro-1,4-benzodioxin-6-yl}diazenide (1.0 g, 3.46 mmol) in 1,2,4-trichlorobenzene (10 mL) was heated to 110° C. and allowed to stir for 3 h. The reaction mixture was then cooled to room temperature and purified immediately by flash column chromatography (SiO2, 100% hexanes, 30% ethyl acetate/hexanes) to yield 400 mg (54%) of methyl 7-fluoro-2,3-dihydro-1,4-benzodioxine-5-carboxylate as a white powder: 1H NMR (400 MHz, CDCl3): 7.11 (dd, J=3.2, 8.8 Hz, 1H), 6.78 (dd, J=3.2, 8.8 Hz, 1H), 4.35-4.28 (m, 4H), 3.89 (s, 3H).