Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[C:13]([Cl:19])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[K+]>C(O)C.O>[Cl:19][C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:20])=[O:2])[CH:16]=[CH:15][C:14]=1[S:17][CH3:18]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(SC)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
A solution of 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (4.85 g, 15.50 mol) in ethanol (108 mL) was treated with a solution of potassium hydroxide (4.35 g, 77.50 mmol) in water (25.2 mL). The reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was then concentrated in vacuo to remove ethanol. The resulting aqueous residue was acidified to pH=2 with a 1N aqueous hydrochloric acid solution and then extracted with methylene chloride (3×15 mL). The combined organic layers were then dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid (4.14 g, 89.4%) as a white solid which was used without further purification.
Reaction SMILES: C1COC2(C3[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][C:11]=3[O:13][CH3:14])[CH2:6][C:5]([OH:21])([C:17]([O:19]C)=[O:18])[CH2:4]2)O1.[CH:24]([SH:27])([SH:26])[CH3:25].B(F)(F)F.[CH3:32][CH2:33]OCC.[OH-].[Na+]>ClCCl.CO.C(OCC)C>[OH:21][C:5]1([C:17]([OH:19])=[O:18])[CH2:4][C:24]2([S:27][CH2:33][CH2:32][S:26]2)[C:25]2[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][C:11]=2[O:13][CH3:14])[CH2:6]1
Reactant: COC(=O)C1(O)Cc2c(OC)ccc(OC)c2C2(C1)OCCO2
Reactant: CCOCC
Reactant: CC(S)S
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(OC)c2c1CC(O)(C(=O)O)CC21SCCS1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 66.5 %

Procedure:
10 g of methyl rac-4,4-ethylenedioxy-1,2,3,4-tetrahydro-2-hydroxy-5,8-dimethoxynaphthalene-2-carboxylate were dissolved in 30 ml of dichloromethane and the solution was cooled to 0° C. To the solution were added 4 ml of ethanedithiol followed by 4 ml of boron trifluoride etherate. The mixture was stirred at 0° C. for 15 minutes and then poured into 200 ml of diethyl ether. The organic layer was washed with three 50 ml portions of 5% sodium hydroxide solution and evaporated to give a yellow oil which was taken up in 200 ml of methanol. 100 ml of 5% sodium hydroxide solution were added and the resulting solution was stirred at room temperature for 1.5 hours. Most of the methanol was then evaporated, the residue was diluted with 250 ml of water and washed with three 100 ml portions of ether. The aqueous layer was acidified with hydrochloric acid and the precipitated oil was left to solidify. The product was collected by filtration, washed free from acid using water and dried. The crude acid was purified by suspension in 150 ml of ethyl acetate and heating under reflux for 30 minutes. The mixture was cooled and the product was collected by filtration after 24 hours. There were obtained 7.0 g (66.5%) of 1',2',3',4'-tetrahydro-2'-hydroxy-5',8'-dimethoxyspiro[1,3-dithiolane-2,4'-naphthalene]-2'-carboxylic acid in the form of colourless crystals of melting point 189°-189.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[C:9]1([S:15]([O-:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na+].CNCCNC>CS(C)=O>[C:9]1([S:15]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Fc1cccc(I)c1
Reactant: O=S([O-])c1ccccc1
Agent: CNCCNC
Agent: [Na+]
Solvent: CS(C)=O
Product: O=S(=O)(c1ccccc1)c1cccc(F)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A mixture of 1-fluoro-3-iodobenzene (2.22 g, 10 mmol), sodium phenylsulfinate (2.16 g, 13 mmol), copper (1) trifluoromethylsulfonate-benzene complex (0.15 g, 0.3 mmol), N,N′-dimethylethylenediamine (0.95 g, 1.09 mmol) and dimethyl sulfoxide (20 mL) was heated at 90° C. under nitrogen with stirring for 2 h then at 115° C. for 18 h. Mixture was cooled then partitioned between water (150 mL) and 1:1 Et2O− EtOAc (100 mL) and the organic phase was washed with water (3×100 mL), dried (Na2SO4) and evaporated in vacuo to give a beige solid. Chromatography (SiO2; gradient elution with 0-40% Et2O in petrol) gave the title compound (1.725 g, 73%) as a colourless solid. 1H NMR (CDCl3): 8.02-7.93 (2H, m), 7.81-7.71 (1H, m), 7.71-7.46 (5H, m), 7.28 (1H, m).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([NH:25]C(=O)OCCCC)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].O1CCC(=O)CC1.C1(=O)CCCCC1.Cl>C(O)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([NH2:25])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCCCOC(=O)NC1(Cn2c(COCC)nc3cnc4ccccc4c32)CCOCC1
Agent: Cl
Agent: O=C1CCOCC1
Solvent: CCO
Solvent: O=C1CCCCC1
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(N)CCOCC1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a mixture of tent-Butyl {4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydropyran-4-yl}carbamate (3.0 g, prepared according to the general methods of Parts A through F of Example 54 using tetrahydro-4H-pyran-4-one in lieu of cyclohexanone in Part A), hydrochloric acid (12.2 mL of 2.8 M in ethanol), and ethanol (18 mL) was heated at reflux for 4 hours. The reaction mixture was allowed to cool to ambient temperature and was then concentrated under reduced pressure. The residue was combined with isopropanol (100 mL). A solid was isolated by filtration to provide 2.56 g of 4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydropyran-4-amine as a tan solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]/[C:17](=[C:26]2\[C:27](=[O:38])[NH:28][C:29]3[C:34]\2=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=3)/[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39](OC(=O)C)(=[O:41])[CH3:40]>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]/[C:17](=[C:26]2\[C:27](=[O:38])[NH:28][C:29]3[C:34]\2=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=3)/[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:39](=[O:41])[CH3:40])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccc(CN)cc2)cc1
Solvent: C1COCCO1
Product: CC(=O)NCc1ccc(/C(Nc2ccc(CNC(=O)OC(C)(C)C)cc2)=C2/C(=O)Nc3ccc([N+](=O)[O-])cc32)cc1

Procedure:
Prepared analogously to Example 31 from (Z)-3-[1-(4-tert.butoxycarbonylaminomethyl-phenylamino)-1-(4-aminomethyl-phenyl)-methylidene]-5-nitro-2-indolinone and acetic anhydride in dioxane.
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].[Cl:32]C1C=CC(CCI)=CC=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[Cl:32][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][N:16]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][C:2]([CH3:1])([CH3:6])[C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)=[CH:20][CH:21]=1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: Clc1ccc(CCI)cc1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCc2ccc(Cl)cc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-Methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl -ureido]-thiazol-5-ylsulfanyl}-propionic acid using 1-chloro-4-(2-iodo-ethyl)-benzene (J. Med. Chem. 1998, 41,3, 358-378) and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: FC(F)(F)C(O)=O.[BH4-].[Na+].[N+:10]([C:13]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:17][C:14]=1[C:15]#[N:16])([O-:12])=[O:11].Cl>O1CCCC1>[N+:10]([C:13]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:17][C:14]=1[CH2:15][NH2:16])([O-:12])=[O:11]
Reactant: N#Cc1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: NCc1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 85 %

Procedure:
A mixture consisting of 2.4 ml of trifluoroacetic acid and 10 ml of tetrahydrofuran was added dropwise to a suspension of 1.2 g of sodium borohydride in 6 ml of tetrahydrofuran under ice-cooling. To the resulting mixture was added a solution of 1.48 g of 2-nitro-5-piperidinobenzonitrile which was prepared in Reference Example 1-(a) in 15 ml of tetrahydrofuran, followed by stirring overnight. 20 ml of a 10% hydrochloric acid aqueous solution was added dropwise to the reaction mixture under ice-cooling, and the resulting mixture was heat-refluxed for 1 hour. The tetrahydrofuran was removed from the reaction mixture by distillation under reduced pressure. The aqueous layer was washed with chloroform, neutralized with sodium hydrogencarbonate and extracted with chloroform. The extracted layer was washed with water, dried and concentrated to dryness under reduced pressure. Purification of the residue by silica gel chromatography gave 1.28 g of 2-nitro-5-piperidinobenzylamine as an oily substance.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[NH:4][CH2:5][C:6](=[O:16])[N:7]2[CH2:12][CH2:13][O:14][CH3:15].ClC([O:20][C:21](Cl)(Cl)Cl)=O.C(N(C(C)C)CC)(C)C.[NH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([N:44]2[C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=3[CH2:48][N:47]3[CH:55]=[CH:56][CH:57]=[C:46]3[CH2:45]2)=[O:43])=[CH:38][C:37]=1[CH3:58]>C1(C)C=CC=CC=1.C1COCC1>[CH:57]1[CH:56]=[CH:55][N:47]2[CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=3[N:44]([C:42]([C:39]3[CH:40]=[CH:41][C:36]([CH2:35][NH:34][C:21]([N:4]4[C:3]5[C:8](=[CH:9][CH:10]=[CH:11][C:2]=5[F:1])[N:7]([CH2:12][CH2:13][O:14][CH3:15])[C:6](=[O:16])[CH2:5]4)=[O:20])=[C:37]([CH3:58])[CH:38]=3)=[O:43])[CH2:45][C:46]=12
Reactant: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1CN
Reactant: COCCN1C(=O)CNc2c(F)cccc21
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COCCN1C(=O)CN(C(=O)NCc2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2C)c2c(F)cccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-fluoro-1-(2-methoxyethyl)-3,4-dihydro-1H-quinoxalin-2-one from Example 16A (100 mg, 0.44 mmol) in toluene (7.0 ml) were added trichloromethyl chloroformate (54 μl, 0.45mmol), diisopropylethylamine (81 μl, 0.45 mmol) and a spatula full of activated carbon. The mixture was heated at reflux for 2 h. The mixture was cooled to room temperature, filtered through Celite® and evaporated. The residue was taken up in THF (5.0 ml) and added to a solution of (4-aminomethyl-3-methylphenyl)-(5H,11H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)methanone from Example G (145 mg, 0.44 mmol) in THF (5.0 ml) and diisopropylethylamine (81 μl, 0.45 mmol) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature, stirred for 18 h and evaporated in vacuo. The residue was purified by flash column chromatography on silica (eluant EtOAc:pet. ether 90:10) to give an off-white solid; yield 200 mg, 78%.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([F:25])[CH2:23][CH:22]2[NH2:24])=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C@@:21]2([F:25])[CH2:23][C@H:22]2[NH:24][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[C:2]([F:13])([F:12])[F:1])=[CH:19][CH:20]=1
Reactant: NC1CC1(F)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1C[C@]1(F)c1ccc(Cl)cc1)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-trifluoromethylbenzoyl chloride (0.10 g; 0.54 mmol) in dichloromethane (2 ml) added dropwise to a stirred solution of the amine from example P5 (compound Z1.004; 2-(4-chlorophenyl)-2-fluoro-cyclopropylamine; 0.100 g; 0.54 mmol) and triethylamine (0.15 ml; 1.08 m) in dichloromethane (3 ml). Stirred for 1 hr at room temperature then allowed to stand for 18 hr. The white precipitate was filtered off, washed with 2M HCl, saturated NaHCO3 and water and air dried giving the pure cis isomer. 0.065 g (34%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.CN(C(ON1N=[N:40][C:35]2[CH:36]=[CH:37]C=N[C:34]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CC1(N)CC1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([NH:40][C:35]4([CH3:34])[CH2:37][CH2:36]4)=[O:24])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Agent: CC1(N)CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(NC(=O)c2cnn3ccc(N4CCC[C@@H]4c4cncc(F)c4)nc23)CC1
Reaction time: 0.17 h
Yield: 81.9 %

Procedure:
To a DMF (0.6 mL) solution of (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I, 10.5 mg, 0.0321 mmol) and HATU (14.6 mg, 0.0385 mmol) was added 1-methylcyclopropanamine hydrochloride (4.14 mg, 0.0385 mmol) and DIEA (0.0168 mL, 0.0962 mmol). After stirring for 10 minutes, the reaction mixture was directly purified by reverse-phase chromatography (5 to 50% acetonitrile/water) to yield the final product as white solid (10 mg, 82%). LCMS (apci) m/z=381.1 (M+H).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]#[N:13])[CH:5]=[CH:4][C:3]1=2.[Br:14]N1C(=O)CCC1=O.O.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Br:14][CH:11]1[CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]#[N:13])[CH:5]=[CH:4][C:3]=2[C:2]1=[O:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc2c(c1)CCCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CCC(Br)C2=O
Temperature: 60 °C
Yield: 86.2 %

Procedure:
5-Oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (1.0 g, 5.8 mmol), 1-bromopyrrolidine-2,5-dione (1.04 g, 5.8 mmol) and 4-methylbenzenesulfonic acid hydrate (0.111 g, 0.58 mmol) were ground in a porcelain mortar. The resulting powder was placed in a vial, and heated at 60° C. for 12 mins. The mixture became a muddy liquid at 60° C. After cooling to room temperature, the mixture was dissolved in CH2Cl2 (80 mL). The solution was washed with saturated NaHCO3, water, brine, and dried (MgSO4). Solvent was evaporated off to give racemic 6-bromo-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (1.25 g, 5.0 mmol, 86% yield) as a yellow solid: LCMS=249.98 [M+H]+.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[S:11][CH2:10][CH2:9][C:8]2([CH3:16])[CH3:15])[OH:4])#[CH:2].[OH:17][C:18]1[CH:27]=[C:26](I)[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21].C(N(CC)CC)C>O.C(OCC)C.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.[Cu](I)I>[OH:17][C:18]1[CH:27]=[C:26]([C:2]#[C:1][CH:3]([OH:4])[C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[S:11][CH2:10][CH2:9][C:8]3([CH3:16])[CH3:15])[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCS2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCS3)cc1O
Reaction time: 4 h

Procedure:
2.5 g (10.8 mmol) of α-ethynyl-4,4-dimethyl-6-thiochromanmethanol, 3 g (10.8 mmol) of methyl 2-hydroxy-4-iodobenzoate and 50 ml of triethylamine were introduced into a three-necked flask. The reaction mixture was degassed with nitrogen for 30 min. and then 600 mg (0.86 mmol) of bis(triphenylphosphine)palladium(II) chloride and 240 mg (1.3 mmol) of copper iodide were added successively. Stirring was carried out at room temperature for four hours, the reaction mixture was evaporated to dryness and the residue obtained was taken up in water and ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with dichloromethane. 3.2 g (80%) of methyl 2-hydroxy-4-[3-hydroxy-3-(4,4-dimethylthiochroman-6-yl)-1-propynyl]benzoate, with a melting point of 105°-106° C., were recovered.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:15][C:16]1[CH:20]=[CH:19][NH:18][N:17]=1.O=[C:22]([CH2:29][CH2:30][CH3:31])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH:1]1([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]2[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:22]([CH2:29][CH2:30][CH3:31])[NH:15][C:16]3=[N:17][NH:18][CH:19]=[C:20]23)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccccc1OC1CCCC1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: Nc1cc[nH]n1
Product: CCCC1=C(C(=O)OCC)C(c2ccccc2OC2CCCC2)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2-cyclopentyloxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=O)#[N:2].[OH:12][NH2:13].C([O-])(=O)C.[Na+]>C(O)C.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=[N:13][OH:12])#[N:2]
Reactant: NO
Reactant: N#Cc1cc(C=O)ccc1F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1cc(C=NO)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
To a solution of 3-cyano-4-fluorobenzaldehyde (2.50 g) in ethanol (40 mL) was added a solution of hydroxyamine (1.46 g) in water (10 mL), a solution of sodium acetate (2.75 g) in water (10 mL). The mixture was stirred at rt, overnight. Ethanol was removed and the white precipitate was filtered, washed with water and air dried to leave 3-cyano-4-fluorobenzaldehydeoxime (2.05 g). CI mass spectrum z (rel. intensity) 165 (M+H, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[C:24]([C:27]1[S:31][C:30]([C:32](O)=[O:33])=[CH:29][CH:28]=1)(=[O:26])[CH3:25].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:24]([C:27]1[S:31][C:30]([C:32]([NH:1][C:2]2[CH:23]=[CH:22][CH:21]=[C:4]([O:5][C:6]3[CH:7]=[CH:8][C:9]4[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]5[CH2:20][CH2:19]5)=[O:17])[N:14]=4)[N:11]=3)[CH:3]=2)=[O:33])=[CH:29][CH:28]=1)(=[O:26])[CH3:25]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: CC(=O)c1ccc(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)s1
Yield: 48.6 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.49 mmol), 5-acetylthiophene-2-carboxylic acid (85 mg, 0.50 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (98 mg, 0.51 mmol), 1-hydroxybenzotriazole (69 mg, 0.51 mmol) and N,N-dimethylformamide (6.0 mL) as starting materials and in the same manner as in Example 318, the title compound (110 mg, 48%) was obtained as a white powder.
Reaction SMILES: [F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@H:8]([CH3:18])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[C:28]2[C:23]=1[CH:24]=[N:25][C:26]([CH3:34])=[N:27]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:32][C:30]1[C:29]([F:33])=[C:28]2[C:23]([CH:24]=[N:25][C:26]([CH3:34])=[N:27]2)=[C:22]([N:21]=[CH:11][C@:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH2:9][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=2[O:19][CH3:20])[CH3:18])[CH:31]=1
Reactant: Cc1ncc2c(N)cc(F)c(F)c2n1
Reactant: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=O)C(F)(F)F
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=Nc1cc(F)c(F)c2nc(C)ncc12)C(F)(F)F

Procedure:
In the same way as in Example 1, 150 mg (0.5 mmol) of (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 100 mg (0.51 mmol) of 5-amino-7,8-difluoro-2-methylquinazoline and 0.2 ml of titanium tetraethoxide are reacted to give (2R*,4R*)-1-[(7,8-difluoro-2-methylquinazolin-5-yl)imino]-4-(3-fluoro-2-methoxyphenyl)-2-(trifluoromethyl)pentan-2-ol. 240 mg of resultant crude imine are cyclized in the same way as in Example 1 at −30° C. using 4 ml (4 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 50%) yields 30 mg of product.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.N1C=CC=CC=1>C(Cl)Cl>[N:8]1([C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Cl)OC(=O)N1CCOCC1

Procedure:
In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate (2.64 g, 2 mL, 18.5 mmol) was reacted with morpholine (1.69 g, 1.7 mL, 19.4 mmol) and pyridine (1.68 g, 1.72 mL, 21.2 mmol) in methylene chloride (25 mL) at room temperature overnight to give the crude product, 1-chloroethyl morpholine-4-carboxylate. A portion of 1-chloroethyl morpholine-4-carboxylate (670.1 mg, 3.46 mmol) was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (200.5 mg, 0.325 mmol) in the presence of cesium carbonate (1.094 g, 3.36 mmol) in dimethylformamide (7 mL) overnight to give, 1-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)ethyl morpholine-4-carboxylate as an off-white solid (186.5 mg, 74% yield). MS (ES+) m/z calcd. for C38H41Cl2F2N4O7: [(M+H)+]: 773, found: 773
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][Si](C)(C)C)[N:4]=1.C1C=CC(O[C:22](Cl)=[S:23])=CC=1>C1(C)C=CC=CC=1>[N:10]([C:5]1[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([CH3:9])[N:6]=1)=[C:22]=[S:23]
Reactant: COc1cc(C)nc(N[Si](C)(C)C)n1
Reactant: S=C(Cl)Oc1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc(C)nc(N=C=S)n1
Temperature: 80 °C
Reaction time: 5.5 h
Yield: 63.9 %

Procedure:
To 30 ml of toluene is added 4.2 g of 4-methoxy-6-methyl2-trimethylsilylaminopyrimidine and 3.5 g of phenyl chlorothionocarbonate, and the mixture is stirred for 5.5 hours while heating at about 80° C. After cooling the reaction mixture to room temperature, the precipitates are removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent, ethyl acetate:toluene =1:3) to yield 2.3 g of the title compound.