Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:3])C.[CH:4]1([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][N+:8]=2[O-])[CH2:6][CH2:5]1.C[Si](C#N)(C)C>C(N(CC)CC)C>[CH:4]1([C:7]2[N:8]=[C:9]([C:1]#[N:3])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=2)[CH2:6][CH2:5]1
Reactant: [O-][n+]1ccc(C(F)(F)F)cc1C1CC1
Reactant: CC#N
Agent: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Product: N#Cc1cc(C(F)(F)F)cc(C2CC2)n1
Temperature: 25 °C

Procedure:
To 7 ml of acetonitrile were added 0.7 g of 2-cyclopropyl-4-trifluoromethylpyridine N-oxide, 0.96 ml of triethylamine, and 1 g of trimethylsilyl cyanide, and the mixture was heated to reflux for 20 hours. Thereafter, the reaction solution was allowed to cool to room temperature, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.6 g of 6-cyclopropyl-4-trifluoromethylpyridine-2-carbonitrile.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([F:9])[C:6]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)=[C:5]([F:22])[CH:4]=1)=[CH2:2].B1C2CCCC1CCC2.[OH-:32].[Na+].OO>C1COCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:6]2[C:5]([F:22])=[CH:4][C:3]([CH2:1][CH2:2][OH:32])=[CH:8][C:7]=2[F:9])=[CH:12][C:13]=1[C:18]([F:19])([F:21])[F:20]
Reactant: C=Cc1cc(F)c(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1cc(F)c(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a solution of 4-chloro-3-(trifluoromethyl)phenyl 4-ethenyl-2,6-difluorophenyl ether (3.2 g, 9.56 mmol) in THF (10 mL) was added dropwise 9-BBN (38.2 mL, 19.12 mmol) at 0° C. The reaction mixture was stirred at room temperature for overnight. It was mixed with NaOH (19.12 mL, 57.4 mmol) and H2O2 (5.86 mL, 57.4 mmol), the mixture was stirred at 55° C. for 4 h. It was quenched by Na2SO3 and extracted with EA (100 ml×3). Organic phases were collected, combined, dried with anhydrous Na2SO4, and concentrated to afford the title compound (3.10 g, 92% yield). LCMS: rt=4.72 min, [M+H+]=352
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH3:23][O:24][C:25]1[CH:38]=[CH:37][C:28]([CH2:29][C:30](=[S:34](=[O:36])=[O:35])[CH2:31][CH2:32]Cl)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:32][CH2:31][C:30](=[S:34](=[O:36])=[O:35])[CH2:29][C:28]3[CH:37]=[CH:38][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1ccc(CC(CCCl)=S(=O)=O)cc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(CC(CCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)=S(=O)=O)cc1
Yield: 54 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (10.0 g) as a starting compound, 3-(4-methoxybenzyl)-sulfonylpropyl chloride (8.50 g) and potassium carbonate (16.8 g) were reacted and purified in the same manner as in Example 199 to give 7.60 g of 4-amino-5-chloro-2-methoxy-N-((1-(3-(4-methoxybenzyl)-sulfonylpropyl)piperidin-4-yl)methyl)benzamide, m.p. 111°-112° C.
Reaction SMILES: [H-].[Na+].C1COCC1.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[N:13]=[C:12](S(C)(=O)=O)[N:11]=1.[CH3:22][C:23]([CH3:25])=[O:24]>O>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[N:13]=[C:12]([CH2:22][C:23](=[O:24])[CH3:25])[N:11]=1
Reactant: CC(C)=O
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)nc(CC(C)=O)n1
Temperature: 30 °C
Yield: 22.4 %

Procedure:
In a reactor were placed 16.0 g (0.4 moles) of 60% sodium hydride, 400 ml of THF and 43.6 g (0.2 moles) of 4,6-dimethoxy-2-methanesulfonylpyrimidine. The reactor contents were heated to 30° C. Thereto was dropwise added 39.4 g (0.68 moles) of acetone, followed by a reaction for 2 hours. After the completion of the reaction, 350 ml of water was added and extraction with 500 ml of ethyl acetate was conducted. The ethyl acetate layer was concentrated. The concentrate was subjected to distillation under reduced pressure to obtain 8.8 g (44.9 m moles) of 1-(4,6-dimethoxypyrimidine-2-yl)-2-propanone. Refractive index n20D: 1.5181
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:15][CH:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=O.O>C1(C)C=CC=CC=1>[CH3:15][C:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]=1[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: CC1C(=O)CCC1=O
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=C(Nc2ccc(C3=NNC(=O)CC3)cc2)CCC1=O

Procedure:
3.4 g of 4,5-dihydro-6-(4-aminophenyl)-3(2H)-pyridazinone and 2.0 of 2-methylcyclopentane-1,3-dione were suspended in 30 ml of toluene, to which a catalytic amount of p-toluene sulfonate-hydrate was add while the resulting suspension was heated to reflux with stirring for 8 hours, with removal of water as an azcotropic mexture. After cooled, deposited crude crystal was collected by filtrating, and purified by silica gel column chromatography (eluting solvent: chloroform:methanol=10:1), 4.7 g of the title compound was obtained. m.p. 284°-285° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:12][N:11]([C:13]3[CH:18]=[CH:17][C:16]([C@@H:19]([NH2:21])[CH3:20])=[CH:15][CH:14]=3)[CH2:10]2)=[CH:6][CH:5]=1)[CH3:2].Br[C:25]1[CH2:29][O:28][C:27](=[O:30])[CH:26]=1>C1COCC1>[CH2:1]([O:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:10][N:11]([C:13]3[CH:18]=[CH:17][C:16]([C@@H:19]([NH:21][C:25]4[CH2:29][O:28][C:27](=[O:30])[CH:26]=4)[CH3:20])=[CH:15][CH:14]=3)[CH2:12]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=C1C=C(Br)CO1
Reactant: CCOc1ccc(OC2CN(c3ccc([C@H](C)N)cc3)C2)cc1
Solvent: C1CCOC1
Product: CCOc1ccc(OC2CN(c3ccc([C@H](C)NC4=CC(=O)OC4)cc3)C2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To 0.040 g (0.13 mmol) (S)-1-{4-[3-(4-ethoxy-phenoxy)-azetidin-1-yl]-phenyl}-ethylamine (X.1) in 1.5 mL THF are added 54 μL (0.38 mmol) TEA and 0.021 g (0.13 mmol) 4-bromo-2(5H)-furanone. The mixture is stirred for 12 h at 80° C. After concentration in vacuo the residue is purified by HPLC (SunfireC18, MeOH/water (+0.3% formic acid)) to yield the desired product.
Reaction SMILES: C(O[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=2)[N:12]=[C:11]([N:22]2[CH2:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[S:25](=[O:34])(=[O:33])[CH2:24][CH2:23]2)[N:10]=1)C1C=CC=CC=1.[O:35]1[CH2:38][C:37]([CH2:41][NH2:42])([CH2:39][NH2:40])[CH2:36]1>>[NH2:40][CH2:39][C:37]1([CH2:41][NH:42][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=3)[N:12]=[C:11]([N:22]3[CH2:28][C:27]4[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=4[S:25](=[O:34])(=[O:33])[CH2:24][CH2:23]3)[N:10]=2)[CH2:38][O:35][CH2:36]1
Reactant: NCC1(CN)COC1
Reactant: O=C(O)c1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)nc(OCc3ccccc3)c2c1
Product: NCC1(CNc2nc(N3CCS(=O)(=O)c4ccccc4C3)nc3ccc(C(=O)O)cc23)COC1

Procedure:
The title compound was prepared in analogy to Example 108-1 in Scheme 54 by using 4-(benzyloxy)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazoline-6-carboxylic acid and oxetane-3,3-diyldimethanamine, MS obsd. (ESI+) [(M+H)+] 484, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.95 (brs, 1 H), 8.68 (m, 1 H), 8.04 (d, J=9.1 Hz, 1 H), 7.77-7.73 (m, 2 H), 7.68-7.63 (m, 1 H), 7.48-7.43 (m, 1 H), 7.24-7.19 (m, 1 H), 5.11 (brs, 2 H), 4.59-4.30 (brs, 6 H), 4.20 (m, 1 H), 4.0 (m, 1 H), 3.58 (brs, 2 H), 3.12 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[N:9]=[CH:8][NH:7][C:6]2=O.CN(C=O)C.S(Cl)([Cl:29])=O>C1(C)C=CC=CC=1>[Cl:29][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccncc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc2c(Cl)ncnc2cc1OCc1ccncc1
Yield: 55 %

Procedure:
A suspension of 6-methoxy-7-(4-pyridylmethoxy)-3,4-dihydroquinazolin-4-one (300 mg, 1.06 mmol) in thionyl chloride (5 ml) containing DMF (50 μl) was heated at reflux for 1 hour. The mixture was allowed to cool, diluted with toluene and the volatiles were removed by evaporation. The residue was dissolved in methylene chloride and a cooled solution of aqueous sodium hydrogen carbonate was added. The resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-chloro-6-methoxy-7-(4-pyridylmethoxy)quinazoline (175 mg, 55%).
Reaction SMILES: [F:1][C:2]1([F:14])[CH:9]2[CH2:10][C:5]3([CH2:12][OH:13])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[Cl:15][C:16]1[C:17](F)=[CH:18][C:19]([F:29])=[C:20]([CH:28]=1)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[Cl:15][C:16]1[C:17]([O:13][CH2:12][C:5]23[CH2:10][CH:9]4[CH2:8][CH:7]([CH2:11][CH:3]([C:2]4([F:14])[F:1])[CH2:4]2)[CH2:6]3)=[CH:18][C:19]([F:29])=[C:20]([CH:28]=1)[C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCC12CC3CC(C1)C(F)(F)C(C3)C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CC4CC(C2)C(F)(F)C(C4)C3)cc1F
Temperature: 70 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
To a solution of (4,4-difluoroadamantan-1-yl)methanol (1.00 g, 4.90 mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (1.84 g, 7.40 mmol) in anhydrous dimethylsulfoxide (20 mL) was added cesium carbonate (3.22 g, 9.90 mmol). The mixture was stirred at 70° C. for 16 hours. The mixture was then cooled to ambient temperature, and mixed with water (50 mL). The white solid was filtered and washed with hexanes and dried by air give the title compound as colorless solid (1.70 g, 80%): MS (ES+) m/z 431.1, 433.1 (M+1); 375.0, 377.0 (M−55).
Reaction SMILES: Cl.C[O:3][C:4]([C:6]1[S:7][C:8]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:9][C:10]=1[N:11]([C:18]([CH:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:5].[O:33]1[CH:37]2[O:38][CH2:39][CH2:40][CH:36]2[C@@H:35]([O:41][C:42](=[O:52])C2C=CC([N+]([O-])=O)=CC=2)[CH2:34]1.O1CCC(O)CC1>>[O:33]1[CH:37]2[O:38][CH2:39][CH2:40][CH:36]2[C@@H:35]([O:41][C:42]([N:15]2[CH2:16][CH2:17][CH:12]([N:11]([C:10]3[CH:9]=[C:8]([C:27]#[C:28][C:29]([CH3:32])([CH3:30])[CH3:31])[S:7][C:6]=3[C:4]([OH:3])=[O:5])[C:18]([CH:20]3[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]3)=[O:19])[CH2:13][CH2:14]2)=[O:52])[CH2:34]1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCNCC1
Reactant: O=C(O[C@H]1COC2OCCC21)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: OC1CCOCC1
Product: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C2CCN(C(=O)O[C@H]3COC4OCCC43)CC2)CC1

Procedure:
4-[[2-carboxy-5-(3,3-dimethyl-but-1-ynyl)-thiophen-3-yl]-(4-methyl-cyclohexanecarbonyl)-amino]-piperidine-1-carboxylic acid hexahydro-furo[2,3-b]furan-3-(R)-yl ester was prepared in a similar fashion to 5-(3,3-dimethyl-but-1-ynyl)-3-{(4-trans-methyl-cyclohexanecarbonyl)-[4-(tetrahydro-pyran-4-yloxycarbonylamino)-cyclohexyl]-amino}-thiophene-2-carboxylic acid using method B, except the HCl salt of 5-(3,3-dimethyl-but-1-ynyl)-3-[(4-methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-thiophene-2-carboxylic acid methyl ester was used instead of 3-[(4-amino-cyclohexyl)-(4-trans-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester, and 4-nitro-benzoic acid hexahydro-furo[2,3-b]furan-3-(R)-yl ester was used in place of the chloroformate of tetrahydro-pyran-4-ol.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:13]=1[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])=[O:15])[C:8](=[O:11])[CH2:9]Br)(=[O:3])[CH3:2].[CH2:28]([N:30](CC)CC)[CH3:29].C(CN)O>C1C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:13]=2[C:14]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[O:15][CH2:29][CH2:28][N:30]2[CH2:9][C:8]1=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCN(C(=O)CBr)c1ccc(Cl)cc1C(=O)c1ccccc1F
Reactant: CCN(CC)CC
Solvent: c1ccccc1
Solvent: NCCO
Product: CC(=O)OCCN1C(=O)CN2CCOC2(c2ccccc2F)c2cc(Cl)ccc21
Reaction time: 65 h

Procedure:
A solution containing 1.5g (0.0033 M) of 2-[N-(2-acetoxyethyl)-N-(2-bromoacetyl)amino]-5-chloro-2'-fluorobenzophenone, 0.5 ml of triethylamine and 0.23g (0.0036 M) of ethanolamine in 15 ml of benzene was kept at room temperature for 65 hours and then was partitioned between 25 ml of ethyl acetate and 25 ml of water. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was partioned between 20 ml of ether and 20 ml of 1N hydrochloric acid. The acid layer was separated and extracted with 25 ml of ethyl acetate. The organic layer was then washed with 20 ml of dilute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated to dryness. The residual oil was crystallized from ether and recrystallized from a mixture of methanol and water to give the above named product as white prisms, m.p. 120°-123°.
Reaction SMILES: [CH2:1]([CH:3]1[CH:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][CH:5]([CH2:20][CH2:21][CH2:22][C:23](OCC)=[O:24])[CH2:4]1)[CH3:2].[NH3:28]>>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][CH:5]([CH2:20][CH2:21][CH2:22][C:23]([NH2:28])=[O:24])[CH2:4]1)[CH3:2]
Reactant: N
Reactant: CCOC(=O)CCCC1CC(CC)C(c2nnc3cnc4[nH]ccc4n23)C1
Product: CC[C@@H]1CC(CCCC(N)=O)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Temperature: 85 °C
Yield: 100.2 %

Procedure:
Ethyl 4-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)butanoate (0.080 g, 0.217 mmol, prepared using III from Preparation #25 and (E)-ethyl 4-(diethoxyphosphoryl)but-2-enoate, W) and ammonia (7 N in MeOH, 6.2 mL, 43.3 mmol). The reaction vessel was sealed and heated to about 85° C. After about 2 days the tube was cooled to rt and the reaction mixture was concd in vacuo to provide 4-((3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)butanamide (0.074 g, 100%) as a solid which was used without further purification: LC/MS (Table 1, Method c) Rt=0.50 min.; MS m/z: 341 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.[C:38](OC(=O)CN)(C)(C)C.Cl.C(OC(=O)[C@H](C)N)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@H:19]([CH2:31][CH3:32])[C:20]([NH:22][C@@H:23]([CH3:38])[C:24]([OH:26])=[O:25])=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Agent: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)N[C@@H](C)C(=O)O

Procedure:
Instead of the starting material compound of Example 220, that is, the glycine tert-butyl ester hydrochloride, L-alanine tert-butyl ester hydrochloride was used for the similar procedure as in Example 220 and Example 245 to obtain the title compound.
Reaction SMILES: [C:1]([Si:5]([CH3:26])([CH3:25])[O:6][C@@H:7]([C@@H:9]1[C@@H:12]([C@H:13]([C:15]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[S:16])[CH3:14])[NH:11][C:10]1=[O:24])[CH3:8])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:34](=[O:41])[C:35]([O:37][CH2:38][CH:39]=[CH2:40])=[O:36]>ClCCl>[CH2:38]([O:37][C:35](=[O:36])[C:34]([N:11]1[C@H:12]([C@H:13]([C:15]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[S:16])[CH3:14])[C@@H:9]([C@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:26])[CH3:25])[CH3:8])[C:10]1=[O:24])=[O:41])[CH:39]=[CH2:40]
Reactant: C=CCOC(=O)C(=O)Cl
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=S)Sc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)C(=O)N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](C)C(=S)Sc1ccccc1
Reaction time: 2 h

Procedure:
To a mixture of (3S,4S)-3-[(1R)-1-(tertbutyldimethylsilyloxy)ethyl] -4-[(1R)-1-{(phenylthio)thiocarbonyl}ethyl]-2-oxoazetidine (5.12 g) in dichloromethane (50 ml) were added pyridine (1.8 ml) and allyl chloroglyoxylate (2.3 ml) successively at 0° C. After stirring for 2 hours at the same temperature, to the solution were added pyridine (0.9 ml) and allyl chloroglyoxylate (0.75 ml). After stirring for 1 hour at 0° C., the solution was washed with water, 1N hydrochloric acid and brine, and dried. The solvent was removed under reduced pressure and the residue was purified by column chromatography (ethyl acetate:hexane=1:9) to afford (3S,4S)-1-(allyloxyoxalyl)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-{(phenylthio)thiocarbonyl}ethyl]-2-oxoazetidine (4.77 g).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[N:13]=[N:14][C:15]([Cl:19])=[CH:16][C:17]=2Cl)=[C:7]([CH3:20])[CH:6]=1)(=O)C.[OH-].[Na+].CS(C)=[O:25].Cl>O1CCOCC1>[Cl:19][C:15]1[N:14]=[N:13][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][C:7]=2[CH3:20])=[C:17]([OH:25])[CH:16]=1
Reactant: CC(=O)Oc1ccc(Oc2nnc(Cl)cc2Cl)c(C)c1
Reactant: CS(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(O)ccc1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 1,4-dioxane(1.4 mL) was dissolved 173 mg (0.553 mmol) of 4-[(4,6-dichloro-3-pyridazinyl)oxy]-3-methylphenyl acetate obtained in Example 630(3), 0.7 mL (2.1 mmol) of 3 mol/L sodium hydroxide solution and dimethylsulfoxide (2.8 mL) were added to the solution and the resulting mixture was stirred at room temperature overnight. To the reaction mixture was added 4 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine. After drying over anhydrous magnesium sulfate, the solvent was removed. The obtained residue was purified by preparative thin-layer chromatography (developed by dichloromethane:methanol=36:1) to obtain 66.8 mg of 6-chloro-3-(4-hydroxy-2-methylphenoxy)-4-pyridazinol.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[CH:9][N:8]([C@@H:11]3[O:23][C@H:22]([CH3:24])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[C:7]=2[CH:25]=1.[Br:28]C1N([C@@H]2O[C@H](C)[C@@H](OC(=O)C)[C@H]2OC(=O)C)C2C=CC(C(F)(F)F)=CC=2N=1>CCOC(C)=O.CCCCCC>[Br:28][C:9]1[N:8]([C@@H:11]2[O:23][C@H:22]([CH3:24])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]2[O:13][C:14](=[O:16])[CH3:15])[C:7]2[CH:25]=[C:3]([C:2]([F:1])([F:26])[F:27])[CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cnc2ccc(C(F)(F)F)cc21
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2cc(C(F)(F)F)ccc21
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2ccc(C(F)(F)F)cc21
Yield: 52 %

Procedure:
Starting with 6-trifluoromethyl-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole, this compound was prepared in a manner analogous to that described for 2-bromo-5-trifluoromethyl-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole. Following flash column chromatography on silica with EtOAc/hexane (2:3), a 52% yield of the title compound was obtained as an oil. 1H NMR (DMSO-d6) δ1.48 (d, 3H, CH3), 2 (s, 3H, COCH3), 2.1 (s, 3H, COCH3), 4.2-4.3 (m, 1H, CH), 5.2 (t, 1H, CH), 5.63 (t, 1H, CH), 6.22 (d, 1H, CH), 7.6 (d, 1H, aromatic), 7.8 (d, 1H, aromatic), 8.1 (s, 1H, aromatic).
Reaction SMILES: O[CH2:2][CH2:3][S:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].C(OCC)C.P(Br)(Br)[Br:17]>N1C=CC=CC=1>[Br:17][CH2:2][CH2:3][S:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)CCSCCO
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCOCC
Product: COC(=O)CCSCCBr
Temperature: 25 °C
Reaction time: 5 h

Procedure:
8.2 g. of this ester are dissolved in 27 ml. anhydrous diethyl ether, 0.8 ml. pyridine is added thereto and then 1.9 ml. phosphorus tribromide is added dropwise, while cooling with ice. The reaction mixture is subsequently stirred for 5 hours at ambient temperature. Ice water is then added thereto, followed by extraction with diethyl ether. The extract is washed with water, dried and evaporated to give 10.1 g. of an oil which is chromatographed with 480 g. of silica gel, using ligroin-diethyl ether (2:1 v/v) as elution agent, 7.1 g. methyl 3-(2-bromoethylthio)-propionate being obtained in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[N:17]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C([O:26][C:27]([C:29]1[C:30]([S:41][CH3:42])=[N:31][N:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:33]=1[NH2:34])=O)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:27](=[O:26])[C:29]3[C:30]([S:41][CH3:42])=[N:31][N:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:33]=3[N:34]=[C:9]2[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[N:17]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(SC)nn(-c2ccccc2)c1N
Reactant: O=C(Nc1ccc(Cl)cc1)c1ccc(-c2ccnc(Cl)n2)cc1
Product: CSc1nn(-c2ccccc2)c2nc(-c3ccc(-c4ccnc(Cl)n4)cc3)n(-c3ccc(Cl)cc3)c(=O)c12

Procedure:
5-(4-Chloro-phenyl)-6-[4-(2-chloro-pyrimidin-4-yl)-phenyl]-3-methylsulfanyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one is prepared from N-(4-chloro-phenyl)-4-(2-chloro-pyrimidin-4-yl)-benzamide and 5-amino-3-methylsulfanyl-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester by following a similar procedure as described in example 2. 1H NMR (CDCl3) δ (ppm) 8.68(d, 1H), 8.15(d, 2H), 8.01(d, 2H), 7.63(d, 1H), 7.49(m, 4H), 7.32(m, 3H). 7.11(d, 2H), 2.73(s, 3H). HPLC-MS calculated C28H18Cl2N6OS (M+1+): 557.1. Found: 557.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:39][OH:40].C(=O)([O-])O.[Na+]>>[CH3:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:39]/[OH:40])/[CH2:9][C@H:10]([C:18]2[CH:19]=[CH:20][C:21]([CH:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)=[CH:22][CH:23]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(C3CCNCC3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from (R)-tert-butyl 4-(4-(3-(2-methylpyridin-4-yl)-3-oxo-1-o-tolylpropyl)phenyl)piperidine-1-carboxylate and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=414.4 ([M+H]+).