Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH2:15][C:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32](=[O:34])[NH2:33])=[CH:28][N:27]=2)=[CH:21][CH:20]=1)([CH3:18])[CH3:17])(C)(C)C>ClCCl>[NH2:14][CH2:15][C:16]([C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([NH2:33])=[O:34])=[CH:28][N:27]=2)=[CH:23][CH:24]=1)([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCC(C)(C)c1ccc(Oc2ccc(C(N)=O)cn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CN)c1ccc(Oc2ccc(C(N)=O)cn2)cc1
Yield: 71 %

Procedure:
Add trifluoroacetic acid (2.0 mL, 26.0 mmol) to a stirred solution of {2-[4-(5-carbamoyl-pyridin-2-yloxy)-phenyl]-2-methyl-propyl}-carbamic acid tert-butyl ester (0.5000 g, 1.297 mmol) in dichloromethane (8 mL). Stir the reaction at room temperature under nitrogen for 2.5 h. Load the reaction contents directly onto a 10 g prepacked SCX cartridge, flush with methanol (200 mL), and elute the product with 2 M ammonia in methanol (75 mL). Concentrate the eluant on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 1.5% concentrated ammonium hydroxide/15% ethanol/chloroform to yield 0.2626 g (71%) of 6-[4-(2-amino-1,1-dimethyl-ethyl)-phenoxy]-nicotinamide: mass spectrum (ion spray): m/z=286.1 (M+1); 1H NMR (DMSO-d6): 8.59 (d, 1H), 8.23 (dd, 1H), 8.01 (s, 1H), 7.46 (s, 1H), 7.40-7.36 (m, 2H), 7.08-7.02 (m, 3H), 3.32 (br s, 2H), 2.64 (s, 2H), 1.22 (s, 6H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:10]=3[N:9]=[CH:8]2)[CH2:3][CH2:2]1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]2[N:9]=[CH:8][N:7]([CH:4]3[CH2:3][CH2:2][N:1]([CH2:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]([OH:34])([C:26]([F:27])([F:28])[F:29])[C:30]([F:31])([F:32])[F:33])=[CH:23][CH:24]=4)[CH2:6][CH2:5]3)[C:11]=2[CH:12]=1
Reactant: Nc1ccc2ncn(C3CCNCC3)c2c1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc2ncn(C3CCN(Cc4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4)CC3)c2c1
Yield: 35.9 %

Procedure:
1-(Piperidin-4-yl)-1H-benzo[d]imidazol-6-amine (4.62 mmol, 1 g), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (4.62 mmol, 1.558 g) and potassium carbonate (9.25 mmol, 1.278 g) were combined and stirred in acetonitrile (25 mL) at room temperature for 3 days. The reaction mixture was concentrated at reduced pressure, taken up in dichloromethane, washed with water and concentrated under vacuum. The resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 6% methanol/dichloromethane) to afford the title compound (784 mg). MS (ESI) m/z 473.2 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21]OS(C)(=O)=O)[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][NH2:29]>C(O)C>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][NH:29][CH3:28])[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Solvent: CCO
Product: CNCCc1ccc2[nH]c(C)c(C(=O)OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A mixture of 5-(2-methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (500 mg, 1.29 mmol, Example 56, Step D) in 29% methylamine in ethanol solution (6 mL) was stirred at room temperature overnight and then partitioned between methylene chloride and water. The organic phase was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a residue, which was triturated with diethyl ether to give 410 mg (99%) of the desired product as a white foam: mp 65-68° C.; MS(APCI+): m/z 323.1 (MH+); Anal. Calcd for C20H22N2O2.0.5H2O: C, 72.48; H, 7.00; N, 8.45. Found: C, 72.21; H, 6.85; N, 8.34.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:27]([O-])([OH:29])=[O:28].[OH-].[Na+].C([O-])(O)=O.[Na+]>CC(OC(C)=O)=O>[CH2:1]([O:8][C:9]1[C:24]([O:25][CH3:26])=[CH:23][C:22]([N+:27]([O-:29])=[O:28])=[C:11]([CH:10]=1)[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C(=O)OCc2ccccc2)cc1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: COc1cc([N+](=O)[O-])c(C(=O)OCc2ccccc2)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.3 %

Procedure:
To a solution of benzyl 3-(benzyloxy)-4-methoxybenzoate (6.32 g, 18.1 mmol) in Ac2O (62 mL) cooled to −10° C. under an atmosphere of N2 was added fuming HNO3 (1.5 mL, 37.1 mmol) in one portion. Stirring was continued at −10° C. for 10 minutes, then at RT for 3 hours. The reaction mixture was carefully poured into ice-water and the pH adjusted to ca. pH=5 with 5N NaOH, sat. NaHCO3 and 0.5 NaOH. The mixture was extracted with CH2Cl2 (3×200 mL). The combined organics were dried (Na2SO4), filtered and concentrated in vacuo. The residue was azeotroped with heptane to give benzyl 5-(benzyloxy)-4-methoxy-2-nitrobenzoate as red colored oil (6.55 g, 16.7 mmol, 93%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[H-].[Na+].[CH2:16](I)[CH:17]=[CH2:18].O>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[N:7]2[CH2:18][CH:17]=[CH2:16]
Reactant: O=c1ccc2c(F)cc(F)cc2[nH]1
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)ccc2c(F)cc(F)cc21
Temperature: 25 °C
Yield: 44.7 %

Procedure:
A suspension of 5,7-difluoro-2(1H)-quinolinone (640 mg, 3.54 mmol) in DMF (15 ml) under argon at 0° C. was treated with sodium hydride (60% in mineral oil, 312 mg, 7.8 mmol) and then it was warmed up at rt. After 0.5 h at rt allyl iodide (0.72 mL, 7.8 mmol) was added. After 0.5 h sodium hydride (60% in mineral oil, 200 mg, 5 mmol) and allyl iodide (0.35 ml, 3.8 mmol) were added. Water (15 ml) was added and the aqueous was extracted using DCM (3×50 ml). The combined organic phases were dried, evaporated and the residue was chromatographed on silica gel, eluting with 0-4% MeOH-DCM to afford 350 mg of the desired compound (45%).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[CH:22]([NH2:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(N(CC)CC)C>[CH:22]([NH:35][S:18]([C:4]1[CH:5]=[C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])[CH:7]=[CH:8][C:3]=1[Cl:2])(=[O:20])=[O:19])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Reactant: NC(c1ccccc1)c1ccccc1
Agent: Br
Solvent: CCN(CC)CC
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NC(c3ccccc3)c3ccccc3)c2)N1C

Procedure:
6.5 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were reacted as prescribed in Example 76 with 2.7 g of benzhydrylamine and 4 g of triethyl amine and worked up. Colorless solid body, decomposition beginning at 103° C, γ C=N 1620 cm-1.
Reaction SMILES: C(O)C.[C:4]([N:8]1[C:13](=[O:14])[C:12]([C:15]([O:17][CH3:18])=[O:16])=[C:11](Cl)[CH:10]=[N:9]1)([CH3:7])([CH3:6])[CH3:5].[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][CH:21]=1>C(N(CC)CC)C>[C:4]([N:8]1[C:13](=[O:14])[C:12]([C:15]([O:17][CH3:18])=[O:16])=[C:11]([NH:27][CH2:26][C:23]2[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=2)[CH:10]=[N:9]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: NCc1ccncc1
Reactant: COC(=O)c1c(Cl)cnn(C(C)(C)C)c1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)c1c(NCc2ccncc2)cnn(C(C)(C)C)c1=O

Procedure:
7 ml of an absolute ethanol solution of 170 mg of 2-tert-butyl-5-chloro-4-methoxycarbonylpyridazin-3-(2H)-one, 76 mg of 4-picolylamine and 80 mg of triethylamine, was reacted for 4 hours under heating and refluxing and then left to cool. Ethanol was distilled off under reduced pressure, and 0.3 g of the obtained oil was subjected to column chromatography. Using an eluent (ethyl acetate:methanol=20:1), 0.13 g of the desired product (Compound No. 22) having a melting point of from 99° to 100° C., was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[OH:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:30]1[CH2:31][CH2:32][N:27]([OH:26])[CH2:28][CH2:29]1)=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: ON1CCNCC1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCN(O)CC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 4-hydroxypiperazine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.80 minutes; C21H21Cl2N5O3 (462.34); mass spectrum: (M−H)−=461/463/465 (chlorine isotope).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH2:23])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1.[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36]([C:39](O)=[O:40])=[CH:35][N:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH:23][C:39]([C:36]5[CH:35]=[N:34][C:33]([O:32][CH3:31])=[N:38][CH:37]=5)=[O:40])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1
Reactant: Cn1nnc(-c2c(F)cc(Cl)cc2-c2cnc3c(c2)CCC3NC(=O)C2(N)CC2)n1
Reactant: COc1ncc(C(=O)O)cn1
Product: COc1ncc(C(=O)NC2(C(=O)NC3CCc4cc(-c5cc(Cl)cc(F)c5-c5nnn(C)n5)cnc43)CC2)cn1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-3-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-6,7-dihydro-5H-[1]pyrindin-7-yl}-amide (example 55) was coupled with 2-methoxy-pyrimidine-5-carboxylic acid to yield the title compound as light yellow solid. MS: 562.2 (M−H−, 1Cl).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O.[H][H]>C(O)C.[Pt](=O)=O>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12]
Reactant: O=[N+]([O-])c1ccccc1OCCCCl
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: Nc1ccccc1OCCCCl

Procedure:
1-(3-Chloro-propoxy)-2-nitro-benzene (˜60 mmol) is dissolved in ethanol (200 ml) and platinum dioxide (0.5 g) is added. The stirred mixture is treated with hydrogen under normal pressure until the hydrogen uptake stopped. The catalyst is filtered off and the filtrate is evaporated. A pale yellow oil with Rf=0.3 (CH2Cl2) is obtained, which is used in the next step without further purification.
Reaction SMILES: Cl.Br[CH:3]([CH2:6][NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])C#N.[N:13](CCO)(CCO)[CH2:14]CO>>[C:14]([CH:9]([CH2:10][CH2:11][CH3:12])[CH2:8][N:7]1[CH2:6][CH2:3]1)#[N:13]
Reactant: OCCN(CCO)CCO
Reactant: CCCCCNCC(Br)C#N
Agent: Cl
Product: CCCC(C#N)CN1CC1
Yield: 43 %

Procedure:
reaction of 2-bromo-3-n-pentylaminopropionitrile hydrochloride (prepared by reacting 2,3-dibromopropionitrile with n-pentylamine; m.p. 133°-135° C.) with triethanolamine gives 2-cyano-n-pentylaziridine; b.p.0.3 : 50°-52° C.; yield 43% of theory;
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.[CH:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:8].C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[O:4]1[CH:5]=[CH:6][C:2]([C:12]2[CH:13]=[CH:14][C:9]([CH:7]=[O:8])=[CH:10][CH:11]=2)=[CH:3]1
Reactant: Brc1ccoc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2ccoc2)cc1
Temperature: 150 °C
Yield: 59.2 %

Procedure:
In a microwave vial, 3-bromo-furan (590 mg, 4.02 mmol), 4-formyl phenylboronic acid (600 mg, 4.02 mmol) and 7 ml of actonitrile were mixed. 8 ml of 1N aqueous sodium carbonate was then added to the mixture, followed by 5 mole percent of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 7 minutes with microwave irradiation. After cooling, 50 ml of ethyl acetate was added, the organic layer was separated, washed with water, dried over sodium sulfate. The organic solvent was evaporated to give crude product, which was purified by ISCO to give 410 mg of 4-furan-3-yl-benzaldehyde, yield: 60%.
Reaction SMILES: [C:1]([CH:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](=O)[CH3:17])=[CH:11][CH:10]=1)[CH3:7])([O:3][CH2:4][CH3:5])=[O:2].[OH:19][CH:20]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([CH2:30][OH:31])[CH:24]=1)[CH2:21][NH2:22]>>[C:1]([CH:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:22][CH2:21][CH:20]([OH:19])[C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([CH2:30][OH:31])[CH:24]=2)[CH3:17])=[CH:11][CH:10]=1)[CH3:7])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C(C)Oc1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1ccc(O)c(CO)c1
Product: CCOC(=O)C(C)Oc1ccc(CC(C)NCC(O)c2ccc(O)c(CO)c2)cc1

Procedure:
The compound was prepared as in Example 1 from 1-(4-(1-carboethoxy)ethoxyphenyl) propan-2-one (1.22 g) and 2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl) ethanamine (0.95 g), and crystallised from benzene m.p. 53°-55° as a 53:47 mixture of diastereoisomers.
Reaction SMILES: CO[C:3]([C:5]1([C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH2:9])[CH2:7][CH2:6]1)=[O:4].[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19]>C1(C)C=CC=CC=1>[CH3:13][O:12][C:10]([CH:8]1[C:5]2([CH2:6][CH2:7]2)[C:3](=[O:4])[N:19]([CH2:18][C:17]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:16]=2[O:15][CH3:14])[CH2:9]1)=[O:11]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: C=C(C(=O)OC)C1(C(=O)OC)CC1
Solvent: Cc1ccccc1
Product: COC(=O)C1CN(Cc2ccc(OC)cc2OC)C(=O)C12CC2

Procedure:
To a solution of 1-(1-methoxycarbonylvinyl)cyclopropanecarboxylic acid methyl ester (720 mg) in toluene (3.6 ml) was added 2,4-dimethoxybenzylamine (587 μl) at room temperature, and then the mixture was stirred at reflux for 20 hours. This reaction mixture was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to give the titled compound (567 mg).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>C(O)C>[NH:10]([C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1)[NH2:11]
Reactant: NN
Reactant: Fc1cc(I)ccn1
Solvent: O
Solvent: CCO
Product: NNc1cc(I)ccn1
Temperature: 24.5 °C
Reaction time: 20 h

Procedure:
A solution of 2-fluoro-4-iodopyridine (prepared as described in Rocca, P. et al J. Org. Chem. 1993, 58, 7832-7838) (8.72 g, 39.1 mmol) in 80 mL of ethanol was treated with 20 mL of hydrazine hydrate and the mixture was stirred at room temperature (24-25° C.) for 20 hours. At the end of the reaction, the mixture was concentrated in vacuum and the resulting solid triturated with a mixture of hexanes/diethyl ether affording (8.52 g, 93%) the desired compound that was used in the following steps without further purification.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[CH:6]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH:1]1([NH:4][C@H:14]2[CH2:15][CH2:16][C@H:11]([C:7]3[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=3)[CH2:12][CH2:13]2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: O=C1CCC(c2cccnc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: c1cncc([C@H]2CC[C@H](NC3CC3)CC2)c1
Temperature: 0 °C
Reaction time: 21 h

Procedure:
Cyclopropyl amine (11.4 mL, 165 mmol) was added to a solution of 4-(3-pyridyl)cyclohexanone (19.2 g, 110 mmol) in DCE (360 mL) and acetic acid (12.6 mL, 220 mmol). The reaction mixture was cooled to 0° C. and NaBH(OAc)3 (46 g, 220 mmol) was added protionwise. After being stirred for 21 h at 23° C., the reaction was re-cooled to 0° C. and quenched with 1 M NaOH (200 mL). The aqueous layer was extracted with CH2Cl2 (2×200 mL) and the combined organic layers were washed with brine (300 mL), dried with MgSO4, filtered, and concentrated in vacuo. The crude mixture of cis and trans amines was purified by flash column chromatography (gradient elution, 40% EtOAc/hexanes (2.5% TEA)→70% EtOAc/hexanes (2.5% TEA)) to provide trans-N-cyclopropyl-4-(pyridine-3-yl)cyclohexylamine.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([OH:19])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])=[C:24]([O:42][CH3:43])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([O:19][CH2:21][C:22]2[CH:41]=[CH:40][C:25]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])=[C:24]([O:42][CH3:43])[CH:23]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)nc1O
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 55.7 %

Procedure:
A mixture of ethyl (1-benzyl-3-hydroxy-1H-pyrazol-4-yl)acetate (521 mg), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyloxazole (687 mg), potassium carbonate (553 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 5 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl [1-benzyl-3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-yl]acetate (632 mg, yield 56%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 86–87° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.[C:25]([O:28][CH:29]([CH3:33])[C:30](Cl)=[O:31])(=[O:27])[CH3:26]>CN(C=O)C>[C:25]([O:28][CH:29]([CH3:33])[C:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:6][CH:7]=1)=[O:31])(=[O:27])[CH3:26]
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Reactant: CC(=O)OC(C)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CN(C)c1ccccc1
Product: CC(=O)OC(C)C(=O)Nc1ccc(C2=NNC(=O)NC2C)cc1
Yield: 72.5 %

Procedure:
To a stirred mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.0 g) and N,N-dimethylaniline (0.93 ml) in DMF (10 ml) was added dropwise 2-acetoxypropionyl chloride (0.98 g) under ice cooling. The stirring was continued for one night at ambient temperature. The mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate after addition of saline solution. The extract was washed successively with 1N hydrochloric acid, water and saline solution, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (170 ml) with a mixture of chloroform and methanol (10:1) as an eluent. The eluates containing the object compound were evaporated in vacuo to give 1.13 g of 6-[4-(2-acetoxypropionylamino)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH2:11][CH:12]=[CH2:13])[C:6](OCC)=[O:7])C.C[O-].[Na+].C(O)(=O)C.[CH:22]([NH2:24])=[NH:23]>C(O)C>[CH2:11]([C:5]1[C:6](=[O:7])[NH:24][CH:22]=[N:23][C:4]=1[OH:3])[CH:12]=[CH2:13]
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Reactant: N=CN
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: C=CCc1c(O)nc[nH]c1=O
Reaction time: 0.17 h
Yield: 57 %

Procedure:
2-Allyl-malonic acid diethyl ester (Preparation 205, 100 g, 0.5 mol) was added dropwise to a mixture of sodium methoxide (27 g, 0.5 mol) in ethanol (1 L) at 0-5° C. and the mixture was stirred at this temperature for 10 min. Formamidine acetate (51.9 g, 0.5 mol) was added and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo, and aqueous hydrochloric acid (36.5%) and water were added to adjust the pH to approximately 3 at 0-20° C. The resulting mixture was filtered to afford the title compound as a colorless solid in 57% yield, 87.12 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[C:21]([CH2:25][C:26](Cl)=O)([CH3:24])([CH3:23])[CH3:22]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:26]([CH2:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: NNC1=Nc2ccc(Br)cc2C(c2ccccc2)=NC1
Product: CC(C)(C)Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2

Procedure:
Following the procedure of Example 5, 2.0 g of 7-bromo-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine is reacted with 1.01 ml of tert-butyl acetylchloride to yield 1.17 g of title product with melting point 229.5°-232° C. and 0.30 g of title product with melting point 205°-219° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(#N)C>O>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:5]
Reactant: CCCCCCCBr
Reactant: O=C(O)c1cc(O)ccc1O
Solvent: CC#N
Solvent: O
Product: CCCCCCCOC(=O)c1cc(O)ccc1O

Procedure:
A mixture of 2,5-dihydroxybenzoic acid (28 g), 1,8-diazobicyclo[5.5.0]undec-7-ene (27.6 g), 1-bromo-heptane (39 g) and acetonitrile (380 ml) was heated, under reflux for 18 h. The cooled reaction mixture was added to water (1000 ml) and extracted with ethyl acetate (3×400 ml). The combined organic layers were washed with 1N-hydrochloric acid (300 ml) and water (2×400 ml), dried over magnesium sulphate and filtered. The solvent was removed in vacuum. The residue (40 g) was purified by column flash chromatography on silica gel using toluene/ethyl acetate (9:1) as eluent, to give heptyl 2,5-dihydroxybenzoate.