Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16](F)[C:15]=2[F:23])=[CH:10][C:9]=1[F:24])([CH3:4])([CH3:3])[CH3:2].O.[NH2:27][NH2:28]>C(O)C>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([F:23])=[C:16]3[C:17]([C:20]([NH2:21])=[N:27][NH:28]3)=[CH:18][CH:19]=2)=[CH:10][C:9]=1[F:24])([CH3:3])([CH3:4])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C#N)c(F)c2F)cc1F
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc3c(N)n[nH]c3c2F)cc1F

Procedure:
A solution of 1.49 g of tert-butyl(4′-cyano-3,2′,3′-trifluorobiphenyl-4-yl)carbamate in 40 mL of ethanol is admixed with 2.14 g of hydrazine hydrate and then the mixture is heated at reflux for 18 h. The reaction medium is concentrated to dryness under reduced pressure, the residue is taken up in distilled water and the solid thus obtained is isolated by filtration and then dried. This gives 1.5 g of tert-butyl[4-(3-amino-7-fluoro-1H-indazol-6-yl)-2-fluorophenyl]carbamate in the form of a white solid, whose characteristics are as follows:
Reaction SMILES: O[CH:2]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].[OH2:18]>P(=O)(O)(O)O.P([O-])([O-])(O)=O.[K+].[K+]>[OH:14][CH:15]1[CH:16]=[CH:17][C:13](=[O:18])[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: O
Reactant: COC(=O)CCCCCCC(O)c1ccco1
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])O
Agent: [K+]
Product: COC(=O)CCCCCCC1C(=O)C=CC1O
Yield: 80.7 %

Procedure:
Into a four necked-flask equipped with a stirrer and a thermometer, 2-(1-hydroxy-7-methoxycarbonylheptyl)-furan 114 g), water (4560 g) and potassium monohydrogen phosphate-phosphoric acid buffer (3.8 g) were charged, and the resulting mixture (pH 4.2) was stirred at 100° C. under nitrogen stream until the starting compound was consumed perfectly. The reaction mixture was cooled and extracted with methylisobutylketone (600 ml) two times. The extracts were combined together and concentrated under reduced pressure to give a mixture (92 g) of 3-hydroxy-2-(6-methoxycarbonylhexyl)-4-cyclopentenone and 4-hydroxy-2-(6-methoxycarbonylhexyl)-2-cyclopentenone. Yield, 80.7%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:35])=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][S:6][C:7]1[N:12]=[C:11]([NH:13][S:14]([N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH:10]=[C:9]([O:30][CH3:31])[N:8]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:35])=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][S:6][C:7]1[N:12]=[C:11]([NH:13][S:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)(=[O:15])=[O:16])[CH:10]=[C:9]([O:30][CH3:31])[N:8]=1
Reactant: COc1cc(NS(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)nc(SCc2cccc(Cl)c2F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(NS(=O)(=O)N2CCNCC2)nc(SCc2cccc(Cl)c2F)n1

Procedure:
The title compound was prepared according to the procedure outlined in example 15 using tert-butyl 4-[({2-[(3-chloro-2-fluorobenzyl)thio]-6-methoxypyrimidin-4-yl}amino)sulfonyl]piperazine-1-carboxylate (the product from step ii) (0.26 g), trifluoroacetic acid (0.5 mL) and DCM (10 mL). Purification was by reverse phase HPLC (Symmetry as the stationary phase and TFA/acetonitrile as the mobile phase) then triturated with MeOH followed by Et2O to give the title compound as a white solid. Yield: 40 mg
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH2:25][CH3:26])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32]>>[CH2:25]([C:21]1[CH:22]=[C:23]([CH3:24])[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:5]3[CH:4]=[CH:3][C:2]([N:27]4[CH2:31][CH2:30][CH2:29][C:28]4=[O:32])=[CH:9][C:6]=3[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=1)[CH3:26]
Reactant: O=C1CCCN1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C#N)CC2)c(C)c1

Procedure:
Using 5-bromo-2-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (827 mg) described in Preparation Example 246 and pyrrolidin-2-one (230 μL) and by the reaction and treatment in the same manner as in Example 262, the title compound (817 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@@H:13]3[CH2:15][C@H:14]3[CH2:16][OH:17])=[CH:10][CH:11]=2)[N:6]([CH3:18])[C:5]1=[O:19].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([O:17][CH2:16][C@@H:14]1[CH2:15][C@H:13]1[C:9]1[N:8]=[C:7]2[N:6]([CH3:18])[C:5](=[O:19])[N:4]([CH2:3][C:2]([CH3:21])([CH3:20])[CH3:1])[C:12]2=[CH:11][CH:10]=1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc([C@@H]3C[C@H]3CO)nc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc([C@@H]3C[C@H]3COS(C)(=O)=O)nc21
Temperature: -10 °C
Reaction time: 0.02 h

Procedure:
1-(2,2-Dimethylpropyl)-5-[(1R,2R)-2-(hydroxymethyl)cyclopropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (31-4, 53.2 mg, 0.18 mmol, 1.0 equiv) was added to anhydrous DCM (1.8 mL) and cooled to −10° C. Triethylamine (108 μL, 0.77 mmol, 4.2 equiv) and methanesulfonyl chloride (32 μL, 0.40 mmol, 2.2 equiv) were added sequentially and the resulting reaction mixture was stirred for 1 min. Following this duration, TLC showed complete consumption of 31-4. The reaction mixture was partitioned between ethyl acetate (5 mL) and saturated NaHCO3 (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give a clear, yellow oil. The crude product was carried forward without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+].[C:9]([C:11]([CH2:21][CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12](Cl)=[O:13])#[N:10]>C(Cl)Cl>[C:9]([C:11]([CH2:21][CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:13])#[N:10]
Reactant: CCC(C#N)(C(=O)Cl)c1ccccc1
Reactant: C1COCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCC(C#N)(C(=O)N1CCOCC1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
4.4 g (0.05 mole) of morpholine are dissolved in 50 ml of methylene chloride, 20 ml of a 20% aqueous sodium hydroxide solution are added to it, and the mixture is cooled to a temperature below -10° C. with salted ice. 10.5 g (0.05 mole) of 2-cyano-2-ethyl-2-phenylacetyl chloride are added to the mixture in portions, under vigorous stirring. The reaction mixture is stirred at 0° C. for one hour, thereafter the phases are separated from each other, the organic phase is washed twice with dilute aqueous hydrochloric acid, dried over a mixture of anhydrous magnesium sulfate and potassium carbonate, filtered, and the solvent is evaporated. 10.3 g (81%) of 2-cyano-2-ethyl-2-phenylacetic acid morpholide are obtained; m.p.: 87°-89.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[N-:13]=[N+:14]=[N-:15].[Na+].C(O)C>O>[CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:13]=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(CCl)cccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1c(CN=[N+]=[N-])cccc1[N+](=O)[O-]
Temperature: 45 °C
Yield: 48.3 %

Procedure:
A mixture of 2-methyl-3-nitrobenzylchloride (0.70 g, 3.77 mmol), sodium azid (1 g, 15.4 mmol), ethanol (10 ml) and water (2 ml) was heated at 45° C. over night. The mixture was filtered, the filtrate was concentrated, and the residue was purified by chromatography on silica (heptane/EtOAc) to give the compound 2-methyl-3-nitrobenzylazide 0.35 g, which was hydrogenated over 5% palladium-charcoal 80 mg in EtOAc/EtOH 1:1 (14 ml), over night. The mixture was filtered through Celite, and the filtrated was concentrated to give 0.23 g (45%) of the title compound as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][C:31](/[CH:35]=[CH:36]/[C:37]([O:39]CC)=[O:38])=[CH:32][CH:33]=4)[N:28]([CH3:42])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[Na+]>O1CCCC1.CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][C:31](/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38])=[CH:32][CH:33]=4)[N:28]([CH3:42])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:18]=[CH:19][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=3)(=[O:15])=[O:16])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)/C=C/c1ccc2c(C(C(=O)NS(=O)(=O)c3ccc(C(C)C)cc3)c3ccc4c(c3)OCO4)cn(C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(/C=C/C(=O)O)ccc23)cc1

Procedure:
Ethyl (E)-3-(3-1-(1,3-benzodioxol-5-yl)-2-[(4-isopropylphenyl)sulfonamido]-2-oxoethyl-1-methyl-1H-6-indolyl)-2-propenoate (the product of Example 57, 120 mg, 0.2 mmol) was dissolved in a 1:1 mixture of tetrahydrofuran and methanol (5 ml). Sodium hydroxide solution (0.6 ml of 1N NaOH) was added and the mixture was heated to reflux with stirring. After 3 h the solvent was removed in vacuo and the product was extracted from 1N hydrochloric acid (50 ml) with ethyl acetate (2×50 ml). The organic layers were dried (MgSO4) and concentrated. Purification by flash column chromatography (gradient elution from 100% dichloromethane to 90% dichloromethane/10% methanol/1% acetic acid) gave the product as a pale green foam (90 mg).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:9]([CH2:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:12][CH3:13].[NH2:15][CH2:16][CH:17]([NH2:19])[CH3:18]>>[CH2:12]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH3:11])[C:4]=1[CH2:3][C:2]1[NH:15][CH2:16][CH:17]([CH3:18])[N:19]=1)[CH3:13]
Reactant: CCc1cccc(CC)c1C=C(Br)Br
Reactant: CC(N)CN
Product: CCc1cccc(CC)c1CC1=NC(C)CN1

Procedure:
rac-2-(2,6-Diethyl-benzyl)-4-methyl-4,5-dihydro-1H-imidazole was prepared from 2-(2,2-dibromo-vinyl)-1,3-diethyl-benzene and 1,2-diaminopropane in analogy to Example 1 e): orange crystals; MS (EI): 230.2 (M+. ), 215.2 ((M-CH3)+.), 201.2 (((M-CH3CH2)+.), 100%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:15][NH:14][CH2:13][C@@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32]>>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:15][N:14]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])[CH2:13][C@@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](CO[Si](C)(C)C(C)(C)C)C1
Reactant: O=[N+]([O-])c1cnccc1Cl
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)CN(c2ccncc2[N+](=O)[O-])C1

Procedure:
Method 1 was followed using cis (+/−)-tert-butyl 5-((tert-butyl-dimethylsilyloxy)methyl)piperidin-3-ylcarbamate and 4-chloro-3-nitropyridine yielding cis (+/−)-tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-1-(3-nitropyridin-4-yl)-piperidin-3-ylcarbamate. LCMS (m/z): 467.0 (MH+); LC Rt=4.02 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:18]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH2:27][NH:28]C(=O)C)[CH:24]=4)[CH2:19]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:32]2[CH2:34][CH2:33]2)[CH:7]=1)=[O:5])C.[ClH:35]>C(O)C>[ClH:35].[NH2:28][CH2:27][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[CH2:19][N:18]([C:11]1[N:10]=[C:9]3[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]3[CH:32]3[CH2:34][CH2:33]3)=[CH:13][C:12]=1[F:17])[CH2:26]2
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(N3Cc4ccc(CNC(C)=O)cc4C3)c(F)cc2c1=O
Agent: Cl
Solvent: CCO
Product: NCc1ccc2c(c1)CN(c1nc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2

Procedure:
80 mg of 7-(5-acetamidomethyl-2-isoindolinyl)-1- cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester was dissolved in a mixture of 10 ml of 10% hydrochloric acid and 10 ml of ethanol. The mixture was heated under reflux for 24 hours. The precipitates deposited were collected by filtration and washed with water and ethanol in this order to obtain 68 mg of 7-(5-aminomethyl-2-isoindolinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.Br[CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[N:24]=[C:23]([CH3:25])[O:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]4[N:24]=[C:23]([CH3:25])[O:22][N:21]=4)[CH:15]=3)[C:6]=2[CH:11]=1
Reactant: Cc1nc(-c2cccc(CBr)c2)no1
Reactant: O=c1[nH]c2cc(Cl)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1nc(-c2cccc(Cn3c(=O)sc4ccc(Cl)cc43)c2)no1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A suspension of 100 mg (0.54 mmol) of 5-chloro-3H-benzothiazol-2-one, 153 mg (0.59 mmol) of 3-(3-bromomethylphenyl)-5-methyl-1,2,4-oxadiazole and 303 mg (2.16 mmol) of potassium carbonate in 20 ml of acetonitrile are stirred at 80° C. for 1 h. 30 ml of water are added to the reaction mixture, which is then extracted with MTBE, dried and evaporated to dryness. The crude product is purified by column chromatography on silica gel and stirred with ether, giving “A12”: ESI: 358 (M+H); Rt.=3.25 min (method A);
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[F:18])[C:7]([O:19][CH3:20])=[CH:6][C:5]=1[F:21].[OH-].[Na+].O.Cl>CN1CCCC1=O>[Cl:17][C:13]1[C:12]([F:18])=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH2:10][C:8]1[C:7]([O:19][CH3:20])=[CH:6][C:5]([F:21])=[C:4]([CH:9]=1)[C:3]([OH:22])=[O:2]
Reactant: COC(=O)c1cc(Cc2cccc(Cl)c2F)c(OC)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc(F)c(C(=O)O)cc1Cc1cccc(Cl)c1F
Temperature: 25 °C
Yield: 93.4 %

Procedure:
5-(3-Chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoic acid methyl ester (100 g) obtained in Example 2, Step III was dissolved in 1-methyl-2-pyrrolidinone (500 ml), and 2.5% V/W aqueous alkali solution prepared from 8N-aqueous sodium hydroxide solution (54.7 ml) and water (192.6 ml) was added dropwise with stirring at room temperature. After the dropwise addition, the mixture was stirred for 3.5 hr, and acidified by dropwise addition of 2N-hydrochloric acid (240 ml) with stirring at room temperature. The precipitated crystals were stirred for 2 hr and collected by filtration. The filtrate was washed with 50% methanol aqueous solution (100 ml) and dried at an outer temperature of 70° C. to give 5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoic acid (89.4 g, yield 93.4%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:63][N:64]1[CH2:69][CH2:68][N:67]([CH3:70])[CH2:66][CH2:65]1>C(Cl)Cl>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:63][N:64]5[CH2:69][CH2:68][N:67]([CH3:70])[CH2:66][CH2:65]5)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3F)ncc21
Reactant: CN1CCN(N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC3(CC3)C(=O)N4C)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.5 %

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-fluorobenzoic acid (Intermediate 9) (0.27 g, 0.63 mmol, 1 eq), DIPEA (0.21 mL, 1.26 mmol, 2 eq) and TBTU (0.22 g, 0.69 mmol, 1.1 eq) were added to 5 mL DCM and the resulting solution stirred at rt for 30 min before the addition of 1-amino-4-methylpiperazine (91 μl, 0.75 mmol, 1.2 eq). The RM was then stirred at rt for 4 hours before washing with water, concentrating in vacuo and purifying the residue by preparative RP-HPLC-MS (Preparative—1) to provide 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-fluoro-N-(4-methylpiperazin-1-yl)benzamide (0.14 g, 44%).
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:24]([O:25]C(=O)C)=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1.Cl.Cl.[NH2:33][CH2:34][CH2:35][NH:36][C:37]([NH2:39])=[NH:38].CC(N(C)C)=O.C(N(CC)C(C)C)(C)C>>[OH:25][C:24]1[C:4]2[O:3][C:2]([NH:33][CH2:34][CH2:35][NH:36][C:37]([NH2:39])=[NH:38])=[C:6]([C:7](=[O:20])[C:8]3[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=3)[C:5]=2[CH:21]=[CH:22][C:23]=1[O:29][CH3:30]
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reactant: N=C(N)NCCN
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)c2c(NCCNC(=N)N)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 30 h
Yield: 28.5 %

Procedure:
To a mixture of 0.02 g (0.046 mmol) of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran and 0.02 g (0.11 mmol) of N-(2-aminoethyl)guanidine dihydrochloride (prepared by Fontand & Pignatti, J. Label. Compd. Radiopharm., 2002, 45, 899-909) in 0.5 ml of anhydrous dimethylacetamide 0.032 ml (0.184 mmol) of N,N-diisopropylethylamine was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 30 h at room temperature, then evaporated to dryness in vacuo. The residue was purified by flash column chromatography (silica gel, acetonitrile/water 9:1) to give the title compound as a yellowish solid (0.006 g, 28%); 1H NMR (CD3OD) δ 3.55 (tr, 2H, CH2, J=6 Hz); 3.7-3.86 (m, 14H, OMe×4, CH2); 4.82 (s, H2O); 6.32 (d, 1H, CH aromatic, J=8.47 Hz); 6.69 (d, 1H, CH aromatic, J=8.47 Hz); 6.94 (s, 2H, CH aromatic). MS (m/z) 458.9; 459.9, 460.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([Cl:15])=[O:12])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CSc1ccc(F)cc1
Product: O=C(Cl)CSc1ccc(F)cc1
Yield: 87.6 %

Procedure:
A mixture of 5.3 g of (4-fluorophenylthio)acetic acid and 6.8 g of thionyl chloride is refluxed for 2 hours. Excess of thionyl chloride is evaporated in vacuo and the residue distilled. There are obtained 5.1 g (88%) of oily (4-fluorophenylthio)acetyl chloride, b.p. 76°-77° C./0.25 Torr.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12][S:13][C:14]2[NH:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[C:5]([CH3:23])=[CH:4][CH2:3]1.ClC1C=CC=C(C(OO)=[O:32])C=1>ClCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12][S:13]([C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)=[O:32])[C:5]([CH3:23])=[CH:4][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1=CCN(C)c2c(CSc3nc4ccccc4[nH]3)cccc21
Solvent: ClCCl
Product: CC1=CCN(C)c2c(CS(=O)c3nc4ccccc4[nH]3)cccc21
Yield: 47.6 %

Procedure:
1,4-Dimethyl-8-(2-benzimidazolyl)thiomethyl-1,2-dihydroquinoline (0.4 g) was dissolved in dichloromethane (30 ml). To this solution was added dropwise a solution of m-chloroperbenzoic acid (0.27 g) in dichloromethane (5 ml) at -40° C. with stirring. After the mixture was stirred for 20 minutes at the same temperature, the reaction mixture was washed with an aqueous solution of sodium carbonate and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off. Diethyl ether was added to the resulting residue to precipitate crystals. The resulting crystals were recrystallized from dichloromethane-diethyl ether to give 1,4-dimethyl-8-(2-benzimidazolyl)sulfinylmethyl-1,2-dihydroquinoline (0.2 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:29]=[CH:28][C:8]2[N:9]([CH2:26][CH3:27])[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].CO>C1COCC1>[CH2:26]([N:9]1[C:8]2[CH:28]=[CH:29][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[C:10]1[NH:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:16]=2[N:17]=1)[CH3:27]
Reactant: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Yield: 94.8 %

Procedure:
1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (770.0 mg) was prepared by following General Procedure E starting from 1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (840.0 mg) and sodium hydroxide (2.0 N solution, 2.0 mL) MeOH (1.0 mL) and THF (2.0 mL).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:23])=[CH:6][C:7]([CH3:22])([CH3:21])[NH:8]2.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[C:3]([CH2:2][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:22])([CH3:21])[CH:6]=[C:5]2[CH3:23]
Reactant: C1CCNC1
Reactant: COc1ccccc1-c1ccc2c(c1CCl)C(C)=CC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1-c1ccc2c(c1CN1CCCC1)C(C)=CC(C)(C)N2
Temperature: 50 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A mixture of 5-chloromethyl-6-(2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 5-1, 41.2 mg, 0.126 mmol), pyrrolidine (52.6 μL, 0.630 mmol) and potassium carbonate (34.8 mg, 0.252 mmol) was suspended in anhydrous N,N-dimethylformamide mL), and the reaction mixture was stirred at 50° C. for 1 hour. After cooling down, it was diluted with ethyl acetate (50 mL). The whole was washed with water (50 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (36.1 mg) as a colorless solid: (Yield 79%)
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[F:17][C:18]([F:36])([F:35])[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][N:28]=[CH:27][C:26]=2[CH2:30][CH2:31][C:32](O)=[O:33])=[CH:21][CH:20]=1.ON1C2N=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH2:12]([O:11][P:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][C:26]2[CH:27]=[N:28][O:29][C:25]=2[C:22]2[CH:23]=[CH:24][C:19]([C:18]([F:35])([F:17])[F:36])=[CH:20][CH:21]=2)=[CH:16][CH:15]=1)([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: O=C(O)CCc1cnoc1-c1ccc(C(F)(F)F)cc1
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2cnoc2-c2ccc(C(F)(F)F)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (72.9 mg), 3-[5-(4-trifluoromethylphenyl)-4-isoxazolyl]propionic acid (57 mg), 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (40 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (45 mg) and N,N-dimethylformamide (0.3 ml) was stirred at room temperature overnight. The reaction mixture was directly introduced into preparative HPLC and purified to give N-[4-(diethylphosphonomethyl)phenyl]-3-[5-(4-trifluoromethylphenyl)-4-isoxazolyl]propionamide.