Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](/[CH:25]=[CH:26]/[C:27]([OH:29])=O)[CH:16]=[CH:17][C:18]=1[N:19]1[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]1.[C:30]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:33])[NH:31][NH2:32].C(N(C(C)C)CC)(C)C.O.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[CH3:11][O:12][C:13]1[CH:14]=[C:15](/[CH:25]=[CH:26]/[C:27]([NH:32][NH:31][C:30]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:29])[CH:16]=[CH:17][C:18]=1[N:19]1[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]1
Reactant: CC(C)(C)OC(=O)NN
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCCl
Product: COc1cc(/C=C/C(=O)NNC(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.5 %

Procedure:
HOBT (420 mg) and EDC (590 mg) were sequentially added to a solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (530 mg), tert-butyl carbazate (271 mg) and IPEA (0.71 mL) in DMF (10 mL), and the reaction solution was stirred at room temperature for 15 hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting solid was recrystallized from a mixed solution of ethyl acetate and ethanol to obtain 668 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: ClCCl.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[CH2:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])(=[O:13])=[O:12])=[CH:7][CH:6]=1.FC(F)(F)C(O)=O>C(OCC)(=O)C>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH:14]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])(=[O:13])=[O:12])=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)CCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C(O)CCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.7 %

Procedure:
To a dichloromethane solution (10 ml) of t-butyl 4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)butyrate (1.25 g, 3.33 mmol) was added trifluoroacetic acid (5 ml). The resulting mixture was stirred at room temperature for 4 hours. The solid obtained by concentrating the reaction mixture was recrystallized from ethyl acetate, whereby the title compound (595 mg, 1.59 mmol, 48%) was obtained as colorless needle crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][CH:11]([N:13]([CH3:15])[CH3:14])[CH3:12].[CH:16](O)=O.C=O.N>O>[CH3:16][N:9]([CH2:10][CH:11]([N:13]([CH3:15])[CH3:14])[CH3:12])[C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:8]
Reactant: O=CO
Reactant: Cc1cccc(C)c1NCC(C)N(C)C
Agent: C=O
Agent: N
Solvent: O
Product: Cc1cccc(C)c1N(C)CC(C)N(C)C
Reaction time: 6 h
Yield: 98 %

Procedure:
A mixture of 1.5 g (7.3 mmoles) of 1-(2,6-dimethylphenyl-amino)-2-dimethylamino-propane, prepared as described in Example 8, 1.5 ml of 99% formic acid and 1.5 ml of a 36% aqueous formaldehyde solution is boiled for 6 hours. The mixture is cooled, poured onto 30 ml of water, the aqueous solution is rendered alkaline (pH=9) with concentrated aqueous ammonia, and extracted then thrice with 10 ml of benzene, each. The benzene solutions are combined, dried over anhydrous potassium carbonate, and the solvent is evaporated under reduced pressure. 1.58 g (98,8%) of 1-[N-methyl-N-(2,6-dimethylphenyl)-amino]2-dimethylamino-propane are obtained as a light yellow oil; b.p.: 102°-104° C./133.3 Pa.
Reaction SMILES: C[O:2][C:3]1[C:8]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.Cl.N1C=CC=CC=1>>[NH:17]1[CH2:18][CH2:19][CH:14]([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([O:9][C:10]([F:12])([F:13])[F:11])[C:3]=2[OH:2])[CH2:15][CH2:16]1
Reactant: COc1c(OC(F)(F)F)cccc1C1CCNCC1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1c(OC(F)(F)F)cccc1C1CCNCC1

Procedure:
Preparation according to Example 29: 4-[2-methoxy-3-(trifluoromethoxy)phenyl]piperidine (1.31 g, 4.7 mmol), pyridine hydrochloride (4 g). Yield: 0.5 g. MS m/z (relative intensity, 70 eV) 261 (M+, bp), 260 (31), 244 (11), 215 (6), 56 (93).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15]C)=[CH:12][CH:13]=2)[C:8]([OH:17])=[N:7]1.Br.O.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[C:8]([OH:17])=[N:7]1
Reactant: COc1ccc2c(c1)c(O)nn2Cc1ccc(Cl)c(Cl)c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc2c(c1)c(O)nn2Cc1ccc(Cl)c(Cl)c1

Procedure:
4.85 g 1-(3,4-dichlorobenzyl)-5-methoxy-1H-indazole-3-ol are heated in 30 ml acetic acid and 30 ml 50% hydrobromic acid for 4 hours under gentle reflux. After cooling, the mixture is stirred into 250 ml water, rendered alkaline with concentrated sodium hydroxide solution and extracted twice with 80 ml tert-butyl methyl ether. The aqueous phase is acidified with sulfuric acid and extracted by shaking three times with 200 ml tert-butyl methyl ether. The combined ether phases are dried over sodium sulfate and distilled to dryness under vacuum. The residue is washed with a small amount of tert-butyl methyl ether and dried.
Reaction SMILES: [NH2:1][OH:2].[F:3][C:4]1[CH:9]=[C:8]([CH2:10][C:11](Cl)=[O:12])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21]>CCOCC.O>[F:3][C:4]1[CH:9]=[C:8]([CH2:10][C:11]([NH:1][OH:2])=[O:12])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21]
Reactant: NO
Reactant: O=C(Cl)Cc1ccc(-c2ccc(F)cc2F)c(F)c1
Solvent: CCOCC
Solvent: O
Product: O=C(Cc1ccc(-c2ccc(F)cc2F)c(F)c1)NO

Procedure:
Hydroxylamine free base was added to a solution of 2,2',4'-trifluoro-4-biphenylylacetyl chloride (obtained as in Example 9) in ether. After stirring for 15 minutes the ether solution was diluted with water, separated, washed again with water, dried and evaporated. The orange residue was recrystallised twice from acetone/40-60 petroleum ether and then from toluene to give fine colourless needles of 2,2',4'-trifluoro-4-biphenylylacethydroxamic acid, m.p. 149°-150° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.Cl[C:13]([O:15][CH2:16][CH3:17])=[O:14]>N1C=CC=CC=1>[CH2:16]([O:15][C:13]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)=[O:14])[CH3:17]
Reactant: Nc1ccc2c(c1)CCC2=O
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc2c(c1)CCC2=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-Aminoindan-1-one was dissolved in the minimum of hot pyridine and the solution was cooled to 0° C. Ethyl chloroformate (1.2 mole equivalents) was added dropwise to the cold stirred solution which was then stirred for one hour at room temperature. Evaporation under reduced pressure and trituration of the residue with water afforded 5-ethoxycarbonylaminoindan-1-one, m.p. 181°-2° C. (from ethanol).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2ccccc2)c1
Temperature: 50 °C
Yield: 68.9 %

Procedure:
To 3-nitrobenzene-1-sulfonyl chloride (296.9 mg, 1.340 mmol) is added THF (20 mL), aniline (134.8 mg, 1.447 mmol) and potassium carbonate (408.5 mg, 2.955 mmol). The resulting mixture is heated at 50° C. for 16 hours. The reaction mixture is subsequently cooled and concentrated in vacuo after which the residue is treated with 10 ml of H2O and extracted with EtOAc (75 mL). The organic layer is washed with saturated aqueous NaCl (2×75 mL), dried (MgSO4), and concentrated in vacuo. The residue is purified over silica (CH2Cl2) to afford 257 mg (69% yield) of the desired compound. MS (ESI, pos. ion) m/z: 279 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:7]([O:6][C:5]([NH:4][CH2:3][CH2:2][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17])=[O:11])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCOc1cccc(C#N)c1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
5.85 g (29 mmol) of t-butyl (2-bromoethyl)carbamate was dissolved in 100 ml of dimethylformamide. 2.38 g (26.4 mmol) of 3-hydroxybenzonitrile, 3.04 g (53 mmol) of potassium carbonate and 4.31 g (53 mmol) of sodium iodide were added to the obtained solution, and they were stirred at 50° C. for 6 hours. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14].C(N(CC)CC)C>C(Cl)Cl>[O:11]=[CH:12][C@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@H](C=O)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a cooled (−78° C.) solution of oxalyl chloride (90 mL, 1.03 mol) in CH2Cl2 was added dropwise a solution of DMSO (100 mL, 1.41 mol) in CH2Cl2. The mixture was stirred at −78° C. for 1 hr, and a solution of (R)-tert-butyl 1-hydroxypropan-2-ylcarbamate (90 g, 0.51 mol) in CH2Cl2 was added. After stifling for 3 hr, 500 mL of triethylamine was added and the reaction mixture was stirred for another 3 h at −78° C. The reaction was quenched with 1% HCl and the reaction mixture was warmed to RT. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The organic layer was washed with water, dried over MgSO4, and evaporated to provide crude N.1, (R)-tert-butyl 1-oxopropan-2-ylcarbamate (76.0 g, 85.4%). 1H NMR (CDCl3) δ9.56 (s, 1H), 4.23 (br s, 1H), 1.45 (s, 9H), 1.32 (s, 3H).
Reaction SMILES: [C:1]1(O)[C:5](=[O:6])[C:3](=O)[C:2]=1[OH:7].[NH2:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]1>C(O)(C)C>[CH3:16][C:14]1([CH3:17])[CH2:15][CH:10]([NH:9][C+:1]2[C:2]([O-:7])=[C:3]([NH:9][CH:10]3[CH2:11][C:12]([CH3:19])([CH3:18])[NH:13][C:14]([CH3:17])([CH3:16])[CH2:15]3)[C+:5]2[O-:6])[CH2:11][C:12]([CH3:19])([CH3:18])[NH:13]1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: O=c1c(O)c(O)c1=O
Solvent: CC(C)O
Product: CC1(C)CC(Nc2c([O-])[c+](NC3CC(C)(C)NC(C)(C)C3)[c+]2[O-])CC(C)(C)N1
Yield: 90.4 %

Procedure:
In an autoclave, 114.0 g of quadratic acid (1.0 mole), 390.8 g of 4-amino-2,2,6,6-tetramethylpiperidine (2.5 moles), and 800 cc of isopropanol were heated for five hours to 140° C. and then for 15 hours to 210° C. After cooling, the solid was suctioned off and dried. The thusobtained crude product was eluted three times with boiling methanol, washed with cold methanol, and then exhaustively dried, yielding as the remainder 353.1 g of white crystals (yield: 90.4%, mp>400° C., decomposition).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:6]=1)[OH:4].[C:20]1([C@H:26]([N:28]=[C:29]=[O:30])[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C1C=CN=CC=1.C1C=CC=CC=1.CCOCC>[O:11]([C:7]1[N:6]=[C:5]([CH:3]([O:4][C:29](=[O:30])[NH:28][CH:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:27])[C:2]([F:1])([F:18])[F:19])[CH:10]=[CH:9][CH:8]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C[C@@H](N=C=O)c1ccccc1
Reactant: OC(c1cccc(Oc2ccccc2)n1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(NC(=O)OC(c1cccc(Oc2ccccc2)n1)C(F)(F)F)c1ccccc1

Procedure:
A stirred solution of 2.40 g (8.91 mmol) of α-trifluoromethyl-6-phenoxy-2-pyridinemethanol, 1.38 g (9.36 mmol) of (R)-(+)-1-phenylethyl isocyanate, and 22 mg (0.18 mmol) of 4-dimethylaminopyridine in 9 ml of benzene under a nitrogen atmosphere was heated at 50° C. for 17 hours. The reaction mixture was then diluted with 150 ml of ether and washed with 25 ml of 1N aqueous HCl, 25 ml of saturated aqueous NaHCO3, and 25 ml of saturated aqueous NaCl. The organic layer was dried (MgSO4) and concentrated under reduced pressure. Repeated chromatography of the residue on silica gel with benzene afforded first 1.77 g (48%) of the [R-(R*,R*)] diastereomer: Rf =0.10 (SiO2, benzene); 1H NMR (CDCl3) δ 1.52 (d, 6.8 Hz, 3H), 4.83 (quintet, 7.1 Hz, 1H), 6.01 (q, 6.1 Hz, 1H), 6.83 (d, 8.2 Hz, 1H), 7.11-7.37 (br m, 12H), and 7.68 (t, 7.8 Hz, 1H); and then 1.77 g (48%) of the [S-(R*,S*)] diastereomer: Rf =0.09 (SiO2, benzene); 1H NMR (CDCl3) δ 1.47 (d, 6.8 Hz, 3H), 4.80 (quintet, 7.0 Hz, 1H), 5.98 (q, 6.9 Hz, 1H), 6.86 (d, 8.3 Hz, 1H), 7.13-7.42 (br m, 12H), and 7.72 (t, 7.8 Hz, 1H).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][CH:27]=[CH:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(Sc2c(NCC=Cc3ccccc3)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(Sc2c(NCC=Cc3ccccc3)cc(C(=O)O)cc2S(N)(=O)=O)cc1

Procedure:
The mixture of 1.5 g of 4-(4-acetamidophenylmercapto)-3-cinnamylamino-5-sulfamoylbenzoic acid and 15 ml of 2 N aqueous sodium hydroxide is refluxed for 80 minutes under nitrogen. After cooling it is washed with diethyl ether, acidified with glacial acetic acid to a pH of 4-5, the precipitate collected and recrystallized from 75% aqueous ethanol, to yield the 4-(4-aminophenylmercapto)-3-cinnamylamino-5-sulfamoylbenzoic acid of the formula ##SPC15##
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[NH2:25]>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:25][C:24]4[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:22]([O:21][CH3:20])[CH:23]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: COc1cc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc(OC)c1OC

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3,4,5-trimethoxyaniline were reacted to produce N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:19])[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=1B(O)O>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=1[C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:19])[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: COc1cccc(OC)c1B(O)O
Product: COc1cccc(OC)c1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1

Procedure:
Intermediate 1-1 (566 mg, 2.0 mmol) and 2,6-dimethoxyphenylboronic acid (437 mg, 2.4 mmol) were reacted according to GENERAL METHOD 1-5 for Suzuki coupling. 6-(2,6-Dimethoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine was obtained as a beige solid (375 mg, 49% yield) after flash column chromatography purification. MS (M+1)=385.4.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([C:19]([F:22])([F:21])[F:20])=[N:17][CH:18]=3)[CH:15]=2)=[CH:6][CH:5]=1.C1C(=O)N([Br:32])C(=O)C1>C(Cl)Cl>[Br:32][C:18]1[N:17]=[C:16]([C:19]([F:20])([F:21])[F:22])[N:14]2[CH:15]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:23])[F:24])=[CH:9][CH:8]=3)[CH:11]=[CH:12][C:13]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: FC(F)(F)Oc1ccc(-c2ccc3cnc(C(F)(F)F)n3c2)cc1
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(-c2ccc3c(Br)nc(C(F)(F)F)n3c2)cc1

Procedure:
6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)imidazo[1,5-a]pyridine (1.2001 g, 3.466 mmol) was dissolved in CH2Cl2 (20 mL) in a 250 mL round bottomed flask. The solution was treated with NBS (925.4 mg, 5.199 mmol, 1.5 equiv.) at 0° C. for 30 min. And then the solvent was removed by rota-vap to give a crude mixture. Obtained crude mixture was purified by a column chromatography (SiO2=80 g, EtOAc/hexane=1:7 Rf=0.5) to give 1-bromo-6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)imidazo[1,5-a]pyridine as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[C:5]2[CH:16]=[CH:17][C:18]([S:20][CH2:21][CH3:22])=[CH:19][C:4]=2[N:3]=1.[C:23](OCC)(=[O:26])[C:24]#[CH:25]>C(O)C>[CH2:21]([S:20][C:18]1[CH:17]=[CH:16][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=3)=[N:7][CH2:8][C:2]3[N:3]([CH:25]=[CH:24][C:23](=[O:26])[N:1]=3)[C:4]=2[CH:19]=1)[CH3:22]
Reactant: CCSc1ccc2c(c1)N=C(N)CN=C2c1cccc(F)c1
Reactant: C#CC(=O)OCC
Solvent: CCO
Product: CCSc1ccc2c(c1)-n1ccc(=O)nc1CN=C2c1cccc(F)c1

Procedure:
In the manner given in Example 1, 2-amino-8-ethylthio-5-(m-fluorophenyl)-3H-1,4-benzodiazepine, ethyl propiolate and ethanol were refluxed. The mixture was chromatographed to give 10-ethylthio-7-(m-fluorophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[N:23][CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1O)[C:12]([F:18])([F:17])[O:11][C:10]2([F:20])[F:19])=[O:5].O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:24]=[N:23][CH:22]=[CH:21][C:3]=1[C:4]1[O:5][C:15]2[CH:14]=[C:13]3[C:12]([F:17])([F:18])[O:11][C:10]([F:19])([F:20])[C:9]3=[CH:8][C:7]=2[N:6]=1
Reactant: O=C(Nc1cc2c(cc1O)C(F)(F)OC2(F)F)c1ccncc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: FC1(F)OC(F)(F)c2cc3oc(-c4ccncc4Cl)nc3cc21
Reaction time: 1.5 h
Yield: 85.1 %

Procedure:
To a mixture of 0.68 g of 3-chloro-N-(1,1,3,3-tetrafluoro-6-hydroxy-1,3-dihydroisobenzofuran-5-yl)isonicotinamide, 8 ml of tetrahydrofuran and 0.55 g of triphenylphosphine, 0.90 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature, and the reaction mixture was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.55 g of 2-(3-chloropyridin-4-yl)-5,5,7,7-tetrafluoro-5,7-dihydro-furo[3′,4′:4,5]benzo[1,2-d]oxazole (hereinafter, referred to as “active compound 86”).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]2=[O:15])[CH:5]=[CH:6][C:7]=1[NH2:8].[NH2:16][C:17]1[C:22]([CH:23]=O)=[CH:21][C:20]([I:25])=[CH:19][N:18]=1.S([O-])(O)=O.[Na+].O>CN(C=O)C>[NH2:16][C:17]1[C:22]([C:23]2[NH:1][C:2]3[CH:3]=[C:4]([N:9]4[CH2:14][CH2:13][O:12][CH2:11][C:10]4=[O:15])[CH:5]=[CH:6][C:7]=3[N:8]=2)=[CH:21][C:20]([I:25])=[CH:19][N:18]=1
Reactant: Nc1ncc(I)cc1C=O
Reactant: Nc1ccc(N2CCOCC2=O)cc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc(I)cc1-c1nc2ccc(N3CCOCC3=O)cc2[nH]1
Temperature: 150 °C
Reaction time: 18 h

Procedure:
22.4 320 mg (1.544 mmol) of 4-(3,4-diaminophenyl)morpholin-3-one are dissolved in 4 ml of DMF, and 382.99 mg (1.544 mmol) of 2-amino-5-iodopyridine-3-carbaldehyde and 0.913 ml (4.633 mmol) of 38-40% sodium hydrogensulfite solution are added at room temperature. The mixture is stirred at 150° C. for 18 hours. The batch is cooled to room temperature, poured into 20 ml of water, the precipitate which deposits in the process is separated off and washed well with about 10 ml of water. The precipitate is triturated with about 25 ml of acetonitrile, and the undissolved crystals are separated off and dried, giving 4-[2-(2-amino-5-iodopyridin-3-yl)-3H-benzimidazol-5-yl]morpholin-3-one; HPLC-MS [M+H]+ 436.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[CH3:21])=[CH:18]/[CH2:19][OH:20])=[CH:13][CH:12]=1.[CH2:22]([O:24][C@@H:25]([CH2:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:23]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[CH:12]=[CH:13][C:14](/[C:17](/[CH3:21])=[CH:18]/[CH2:19][O:20][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][C@H:25]([O:24][CH2:22][CH3:23])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:37][CH:36]=2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: COc1ccc(OC)c(-c2ccc(/C(C)=C/CO)cc2)c1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(OC)ccc3OC)cc2)cc1)OCC
Yield: 60.6 %

Procedure:
The title compound (0.765 g, 61%) was prepared as a colourless gum from (E)-3-(2′,5′-dimethoxy-biphenyl-4-yl)-but-2-en-1-ol (0.711 g, 2.50 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.655 g, 2.75 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([C:13]3[C:14](=[O:23])[NH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:12]=2)[CH:5]=[CH:4][N:3]=1.NCC[N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[N:27]1([C:2]2[CH:7]=[C:6]([C:8]3[S:9][CH:10]=[C:11]([C:13]4[C:14](=[O:23])[NH:15][C:16]5[C:21]([CH:22]=4)=[CH:20][CH:19]=[CH:18][CH:17]=5)[N:12]=3)[CH:5]=[CH:4][N:3]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=c1[nH]c2ccccc2cc1-c1csc(-c2ccnc(Cl)c2)n1
Reactant: NCCN1CCCCC1
Product: O=c1[nH]c2ccccc2cc1-c1csc(-c2ccnc(N3CCCCC3)c2)n1
Temperature: 128 °C

Procedure:
A mixture of 3-[2-(2-chloro-pyridin-4-yl)-thiazol-4-yl]-1H-quinolin-2-one (Example 85, 60 mg, 0.18 mmol) and 1-(2-aminoethyl)piperidine (Aldrich-Sigma Company, 2 mL) was heated at 128° C. for 48 h. The reaction was quenched by addition of 10 mL of H2O. The precipitates were collected by filtration and purified by Gilson preparative HPLC to provide the title compound as a yellow solid after lyophilization. MS m/z: 389.3 (M+1). HRMS m/z: 389.1398 (M+H+, C22H20N4OS Calc'd 389.1431).
Reaction SMILES: CON(C)[C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[O:15][CH2:16][CH3:17].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH2:16]([O:15][C:6]1[CH:7]=[C:8]([C:11]([F:12])([F:13])[F:14])[CH:9]=[CH:10][C:5]=1[CH:4]=[O:18])[CH3:17]
Reactant: CCOc1cc(C(F)(F)F)ccc1C(=O)N(C)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCOc1cc(C(F)(F)F)ccc1C=O
Yield: 89.1 %

Procedure:
N-Methoxy-N-methyl-2-ethoxy-4-trifluoromethyl-benzamide (1.04 g) was reacted with 1 M LAH (1 ml) at −40° C. for 2 hrs as described above to yield title compound (729 mg, 65%)