Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[NH:12][C:11]=3[C:10](=O)[NH:9][C:8]2=[O:20])=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24].[OH-].[Na+]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[NH:12][C:11]=3[C:10](=[S:24])[NH:9][C:8]2=[O:20])=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(C)c1nc2c([nH]1)c(=O)[nH]c(=O)n2Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)c1nc2c([nH]1)c(=S)[nH]c(=O)n2Cc1ccc(Cl)cc1
Temperature: -5 °C
Yield: 135.5 %

Procedure:
12.75 g of 3-(4-chlorobenzyl)-8-isopropyl-xanthine and 10.67 g of phosphorus pentasulfide were heated under reflux in 200 ml of pyridine for 5.5 hours. After cooling to −5° C., 52.5 ml of 2N NaOH was added over 15 minutes. The solid was filtered off and the filtrate evaporated in vacuo to dryness. The residue was suspended in 250 ml of water (pH 7), the solid collected and washed. The crude product was redissolved in 200 ml of 2N NaOH, treated with 1.4 g of charcoal, filtered and neutralized with 38 ml of 5N HCl to pH 7. The solid was collected, washed and dried to give the crude title compound (12.36 g). This was dissolved in chloroform and filtered through 60 g of silica gel, thereby affording the title compound (10.89 g) as an off-white solid mp 235-6° C. (from acetone).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([CH2:10][N:11]3[C:19]4[CH:18]=[CH:17][C:16]([F:20])=[C:15](C(O)=O)[C:14]=4[C:13]([CH3:24])=[N:12]3)[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C1(P([N:39]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C=O)C.O>[CH:1]1([C:4]2[N:9]=[C:8]([CH2:10][N:11]3[C:19]4[CH:18]=[CH:17][C:16]([F:20])=[C:15]([NH2:39])[C:14]=4[C:13]([CH3:24])=[N:12]3)[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1nn(Cc2cccc(C3CC3)n2)c2ccc(F)c(C(=O)O)c12
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(Cc2cccc(C3CC3)n2)c2ccc(F)c(N)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.3 %

Procedure:
1-((6-Cyclopropylpyridin-2-yl)methyl)-5-fluoro-3-methyl-1H-indazole-4-carboxylic acid (0.205 g, 0.630 mmol) was dissolved in 6 mL of DMF. To this was added diphenylphosphoryl azide (0.260 g, 0.945 mmol) and TEA (0.263 mL, 1.89 mmol) and the mixture was stirred at ambient temperature for 1.5 hours. Water (5 mL) was added and the mixture was warmed to 80° C. for 2 hours, then allowed to stir at ambient temperature for 16 hours. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic extracts washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Column chromatography (1:1 EtOAc:Hexanes) of the crude material afforded 0.107 g (57%) of the title compound.
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([O-])=[O:4].[H-].[Na+].[I:14][C:15]1[CH:27]=[CH:26][C:18]2[N:19](C)[C:20](=O)[O:21][C:22](=O)[C:17]=2[CH:16]=1>O1CCOCC1>[OH:21][C:22]1[C:17]2[C:18](=[CH:26][CH:27]=[C:15]([I:14])[CH:16]=2)[N:19]([CH3:20])[C:3](=[O:4])[C:2]=1[C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: Cn1c(=O)oc(=O)c2cc(I)ccc21
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1c(=O)c(C(=O)OC(C)(C)C)c(O)c2cc(I)ccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of tert-butyl malonate (5 ml, 20 mmol) in 1,4-Dioxane (70 ml) was added 60% Sodium hydride (0.8 g, 35 mmol) in portions. The mixture was stirred at room temperature for 45 min. then a solution of 6-iodo-1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (6.1 g, 20 mmol) in 1,4-Dioxane (40 ml) was added. The mixture was placed in an oil bath at 60° C. and the bath temp was raised to 120° C. over a period of 20 min after which stirring was continued for 90 min. The solvent was removed on a roto-evaporator and cold water (300 ml) was added to the residue. The mixture was washed with DCM (100 ml) then the aqueous phase was acidified with 2N HCl. The organic layer was extracted into DCM (2×100 ml) and after drying over MgSO4 the solvent was removed on a roto-evaporator. Yield=4.1 g.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[O:7]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[C:24]1[C:25]([NH2:31])=[N:26][CH:27]=[C:28]([CH3:30])[N:29]=1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:30][C:28]1[N:29]=[C:24]([C:17]2[CH:18]=[CH:19][C:14]([O:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:15][CH:16]=2)[C:25]([NH2:31])=[N:26][CH:27]=1
Reactant: Cc1cnc(N)c(Br)n1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cnc(N)c(-c2ccc(Oc3ccccc3)cc2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A mixture of sodium carbonate (122 mg), tetrakis(triphenylphosphine)palladium(0) (33.2 mg), 4-phenoxyphenylboronic acid (160 mg) and 3-bromo-5-methylpyrazin-2-amine (108 mg) in DME (10 mL) and water (3 mL) was stirred at 80° C. overnight. The mixture was added with silica gel, concentrated in vacuo, and purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (148 mg) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[N:18]=3)[CH2:9]2)[N:5]=[C:4]([NH2:26])[N:3]=1.[F:27][C:28]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:29]=1[C:30]#[N:31].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:26][C:4]1[N:3]=[C:2]([C:34]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([F:27])[CH:35]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[N:18]=3)[CH2:9]2)[N:5]=1
Reactant: Nc1nc(Cl)cc(N2CCOC(c3nc(-c4cccc(Cl)c4)c[nH]3)C2)n1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cc(N3CCOC(c4nc(-c5cccc(Cl)c5)c[nH]4)C3)nc(N)n2)cc1F
Temperature: 140 °C
Reaction time: 1 h
Yield: 23.2 %

Procedure:
A mixture of 4-chloro-6-{2-[4-(3-chlorophenyl)-1H-imidazol-2-yl]-4-morpholinyl}-2-pyrimidinamine (1.1 g, 2.81 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (0.903 g, 3.65 mmol), Na2CO3 (0.745 g, 7.03 mmol) and Pd(PPh3)4 (0.325 g, 0.281 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was heated at 140° C. under microwave condition with stirring for 1 hour. The reaction mixture was filtered, washed by ethyl acetate (100 mL) and concentrated to afford the crude title compound (310 mg) as a yellow solid. LC-MS (ES) m/z=476 [M+H]+.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)(=O)OCC)C.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[CH:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Product: COc1ccc(C=Cc2ccc(N)cc2)cc1
Yield: 69 %

Procedure:
Prepared in analogy to example 56b) from (4-nitro-benzyl)-phosphonic acid diethyl ester and 4-methoxy-benzaldehyde. Yellow solid. Yield=69%. MS: m/e=225.9 (M+).
Reaction SMILES: [C:1](/[C:3](=[CH:9]\[CH2:10][CH:11]([CH3:13])[CH3:12])/[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[N+]([CH:17]([CH3:19])[CH3:18])([O-])=O.[O-]CC.[Na+]>C(O)C>[C:1]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[C:17]1([CH3:19])[CH3:18])#[N:2]
Reactant: CC(C)[N+](=O)[O-]
Reactant: CCOC(=O)/C(C#N)=C/CC(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1(C#N)C(CC(C)C)C1(C)C
Yield: 95.4 %

Procedure:
A mixture of 490 mg (2.70 mmoles) of cyanoester 5 (produced in accordance with Example V), 0.25 mL (2.78 mmoles) of 2-nitropropane, and 4.0 mL of an 0.65M solution of sodium ethoxide (prepared from sodium metal and ethyl alcohol) in absolute ethyl alcohol was heated at reflux, protected from atmospheric moisture, for 31/2 hours. The product was isolated as described in the procedure of Example VIII, affording 575 mg (95% yield) of cyclopropanoid cyanoester 14: bp 80°-102° C. (bath temperature, 0.05 mm).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:29]4[CH:28]=[CH:27][C:26]([F:25])=[CH:31][C:30]=4[F:32])=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(F)cc1F
Yield: 16.4 %

Procedure:
Using the conditions of General Procedure C for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 2,4-difluorophenylboronic acid (available from Frontier Scientific, Inc.; 79 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′,4′-difluoro-biphenyl-2-carboxylic acid (19 mg, 17%). 1H NMR (400 MHz, DMSO-d6) δ 13.17 (br s, 1H), 8.46-8.52 (m, 2H), 8.33 (d, J=2.0 Hz, 1H), 8.26-8.31 (m, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.44-7.52 (m, 1H), 7.27-7.36 (m, 1H), 7.15-7.24 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([S:15]([CH3:18])(=[O:17])=[O:16])([CH3:14])[CH3:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[OH:19][CH2:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH3:18][S:15]([C:12]([C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([C:25]3[CH:26]=[C:21]([CH2:20][OH:19])[CH:22]=[CH:23][CH:24]=3)[CH:3]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:14])[CH3:13])(=[O:17])=[O:16]
Reactant: CC(C)(c1cc(Br)c2ncccc2c1)S(C)(=O)=O
Reactant: OCc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(c1cc(-c2cccc(CO)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 95 °C
Reaction time: 3 h

Procedure:
A mixture of the 8-Bromo-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline from Step 2 above (26 g, 79 mmol), 3-(hydroxymethyl)phenyl-boronic acid (14 g, 92 mmol), sodium carbonate (120 mL, 2M, H2O), PdCl2(Ph3P)2 (2 g) in DME (300 mL) was heated at 90-100° C. for 8 h. The resulting reaction mixture was filtered on a large plug/column of silica gel and the eluted with EtOAc. The organic extracts were concentrated and the resulting suspension diluted with Et2O and stirred vigorously for 3 h. The desired {3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-methanol was isolated as a white solid by filtration.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17](I)[CH:18]=[CH:19][C:20]=1[Cl:21]>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:18]2[CH:17]=[CH:16][C:15]([Cl:14])=[C:20]([Cl:21])[CH:19]=2)[CH:3]=1
Reactant: COc1ccc2c(Cl)ccnc2c1
Reactant: Clc1ccc(I)cc1Cl
Product: COc1ccc2c(Cl)cc(-c3ccc(Cl)c(Cl)c3)nc2c1

Procedure:
The title compound, m. p. 122-131° C., MS: m/e=338 (M+), was prepared from 4-chloro-7-methoxyquinoline and 3,4-dichloroiodobenzene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[CH3:12][NH2:13].O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:13][CH3:12])(=[O:10])=[O:9]
Reactant: CN
Reactant: O=S(=O)(Cl)c1ccccc1Br
Solvent: C1CCOC1
Solvent: O
Product: CNS(=O)(=O)c1ccccc1Br
Temperature: 0 °C

Procedure:
2-Bromobenzenesulfonyl chloride (manufactured by Fluorochem Co., 25 g) was dissolved in tetrahydrofuran (40 mL), and under stirring at 0° C., 40% methylamine aqueous solution (TCI, 25 mL) was added dropwise thereto over ten minutes. After stirring the mixture at room temperature for 2 hours and 40 minutes, water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. To the residues, hexane and a small amount of ethyl acetate were added, followed by stirring. Solids were filtered to obtain the target compound (23.26 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[CH2:9]([OH:14])[CH:10]=[CH:11][C:12]#[CH:13]>C(NC(C)C)(C)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:14][CH2:9]/[CH:10]=[CH:11]/[C:12]#[C:13][C:4]1[CH:3]=[C:2]([C:13]#[C:12]/[CH:11]=[CH:10]/[CH2:9][OH:14])[CH:7]=[CH:6][CH:5]=1
Reactant: Ic1cccc(I)c1
Reactant: C#CC=CCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Product: OC/C=C/C#Cc1cccc(C#C/C=C/CO)c1
Reaction time: 1 h
Yield: 70.8 %

Procedure:
To a solution of 1,3-diiodobenzene (2.64 g, 8.0 mmol) in diisopropylamine (25 mL) under a nitrogen atmosphere were added copper(I) iodide (75 mg, 0.4 mmol) and tetrakis(triphenylphosphine)palladium (80 mg, 0.07 mmol). After the mixture stirred for 1 h, a solution of 2-penten-4-yn-1-ol (2.0 g, 24.0 mmol) in diisopropylamine (10 mL) was added. After stirring at 60° C. for 16 h, the reaction mixture was filtered and the filtrate evaporated to dryness. The product was purified by flash chromatography using toluene/ethyl acetate (9:1) graduated to ethyl acetate as eluent to give 1.35 g (71%) of (E)(E) 5-[3-(5-hydroxy-pent-3-en-1-ynyl)-phenyl]-pent-2-en-4-yn-1-ol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:6]([CH2:8]O)[CH:7]=1.[Br-:20].[C:21]1([PH+:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[Br-:20].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:6]([CH:7]=1)[CH2:8][P+:27]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1ccc(CCc2ccc(F)cc2CO)cc1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CC#N
Product: COc1ccc(CCc2ccc(F)cc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
A solution of 5.95 g (22.86 mmol) of {5-fluoro-2-[2-(4-methoxyphenyl)ethyl]phenyl}methanol in 130 ml of acetonitrile is mixed with 7.45 g (21.71 mmol) of triphenylphosphonium bromide and heated under reflux for 3 hours. The reaction solution is then concentrated to dryness, and the resulting oil is triturated in diethyl ether. The product crystallizes as a white solid during this. After filtration, the solid is dried in a drying oven at 50° C. overnight. 11.5 g (77% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[C:14]1[C:22]2[C:17](=[C:18]([O:23]C)[N:19]=[CH:20][CH:21]=2)[N:16]([CH3:25])[CH:15]=1.Cl>O1CCOCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[C:14]1[C:22]2[CH:21]=[CH:20][NH:19][C:18](=[O:23])[C:17]=2[N:16]([CH3:25])[CH:15]=1
Reactant: COc1nccc2c(-c3cc([N+](=O)[O-])ccc3Oc3ccc(F)cc3F)cn(C)c12
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc([N+](=O)[O-])ccc2Oc2ccc(F)cc2F)c2cc[nH]c(=O)c21
Temperature: 70 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
A solution of Example 2C (1.133 g, 2.75 mmol) in dioxane (35 mL) was treated with 4 N HCl in dioxane (35 mL, 140 mmol) and stirred at 70° C. overnight. The solution was cooled, diluted with 200 mL ethyl acetate, then washed with 200 mL of 1:1 saturated aqueous sodium chloride/sodium bicarbonate and dried over anhydrous sodium sulfate. Filtration and solvent removal provided 1.085 g of the product as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][CH:7]=[C:8]([CH2:9][P:10]([CH3:15])(=[O:14])[O:11][CH2:12][CH3:13])[C:4]=2[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:28](=[O:30])=[O:29].CC(OC)(C)C>C1COCC1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][CH:7]=[C:8]([CH:9]([P:10]([O:11][CH2:12][CH3:13])([CH3:15])=[O:14])[C:28]([OH:30])=[O:29])[C:4]=2[CH:3]=1
Reactant: O=C=O
Reactant: CCOP(C)(=O)Cc1csc2ccc(Cl)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCOP(C)(=O)C(C(=O)O)c1csc2ccc(Cl)cc12
Temperature: -20 °C

Procedure:
To a dry 4N 300 ml flask equipped with magnetic stirrer, nitrogen inlet, temperature probe and addition port was added ethyl (5-chlorobenzo[b]thiophen-3-yl)methyl(methyl)phosphinate (12.7, 43.99 mmol) and dry THF (15 mL) under nitrogen. The resulting solution was cooled to −20° C. To the mixture was then added a 40% (2.2 M) NaHMDS solution in THF (25 mL), maintaining the temperature below 10° C. Following the base addition, CO2 was bubbled cautiously until no exotherm was observed, while maintaining the temperature of the reaction mixture below 15° C. The resulting mixture was then degassed with nitrogen and NaHMDS (10 mL) was added, followed by additional CO2 bubbling. The addition of NaHMDS ad CO2 was repeated 3 more times. The resulting solution was cooled to 0° C. and MTBE (80 mL) was added. To the resulting mixture was then added, slowly, 2N HCl (20 mL), followed by 6N HCl (40 mL), at which point the pH of the mixture was measured to be about 2. Throughout the addition of the acid, the temperature of the mixture was maintained between 0 and 15° C. Initial precipitation was observed upon acidification, while on completion of the acid addition, the mixture resolved in two clear layers. The layers were split, and the organic layer evaporated to yield an oil. The oil was digested overnight with MTBE (20 mL) to yield the title compound as a filterable solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[CH:8]=[C:7]([N+:9]([O-])=O)[N:6]=[N:5]1.[Cl-].[NH4+].CO>[Zn].O1CCCC1>[CH3:1][O:2][CH2:3][N:4]1[CH:8]=[C:7]([NH2:9])[N:6]=[N:5]1
Reactant: COCn1cc([N+](=O)[O-])nn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: COCn1cc(N)nn1
Reaction time: 18 h
Yield: 79.6 %

Procedure:
1-(methoxymethyl)-4-nitro-1H-1,2,3-triazole (5.517 g, 34.891 mmol), zinc powder (22.697 g, 349.185 mmol) and ammonium chloride (18.678 g, 349.187 mmol) were added successively into a mixed solvent of methanol (100 mL) and tetrahydrofuran (100 mL), and stirred for 18 hours. The insoluble was removed by suction filtration. After concentration, 1-(methoxymethyl)-4-amino-1H-1,2,3-triazole was obtained as 3.56 g of a brown-yellow oil, at a yield of 79.6%.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[N:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[N:6]2.[Cu][C:20]#[N:21]>CS(C)=O>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:4]1[N:5]2[N:6]=[CH:7][CH:8]=[CH:9][C:10]2=[C:2]([C:20]#[N:21])[N:3]=1
Reactant: Fc1ccccc1Cc1nc(Br)c2cccnn12
Reactant: N#C[Cu]
Solvent: CS(C)=O
Product: N#Cc1nc(Cc2ccccc2F)n2ncccc12
Temperature: 170 °C

Procedure:
1.00 g (3.266 mmol) of the compound obtained in Example 5A were initially charged in dry DMSO (25 ml), 1.170 g (13.066 mmol) of copper(I) cyanide were then added and, with stirring, the mixture was heated to 170° C. for 3.5 h. The mixture was filtered through Celite, and the filter cake was washed with ethyl acetate and tetrahydrofuran. The filtrate was then extracted four times with a mixture of saturated aqueous ammonium chloride solution/aqueous ammonia (33%) (3:1, v/v) and washed once with saturated aqueous sodium chloride solution. The phases were separated and the organic phase was dried with sodium sulfate, filtered and concentrated. The residue was treated with ethanol in an ultrasonic bath, and water was then added. The precipitate formed was filtered off, washed with ethanol and then dried under high vacuum. This gave 586 mg of the target compound (71% of theory).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][C:25]([O:27]CC)=[O:26])[CH2:20][CH2:19]3)[C:8]=2[CH:30]=1>CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]([N:18]3[CH2:19][CH2:20][N:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][CH2:23]3)[C:8]=2[CH:30]=1
Reactant: CCOC(=O)CN1CCN(C2=Nc3ccccc3Sc3ccc(Cl)cc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN1CCN(C2=Nc3ccccc3Sc3ccc(Cl)cc32)CC1
Yield: 97.4 %

Procedure:
2N Aqueous sodium hydroxide solution (5 ml) was added to a solution of 2.08 g of ethyl 4-(2-chlorodibenzo[b,f][1,4]thiazepin-11-yl)-1-piperazineacetate in 21 ml of methanol. The solution was refluxed for 30 min and then concentrated. The residue was dissolved in hot water and the solution was neutralized with 0.5N hydrochloric acid. The yellowish viscous precipitates were extracted with chloroform. The chloroform layer was washed with water, dried and concentrated to give 1.89 g of pale yellow crystals, which were recrystallized from ethanol to give pale yellow crystals, mp 139°-141° C.
Reaction SMILES: C[O:2][C:3](=[O:19])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)\[CH:8]([CH3:10])[CH3:9].[OH-].[Na+]>CO>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11](/[C:7](/[CH:8]([CH3:10])[CH3:9])=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:19])=[O:2])=[CH:16][CH:15]=1
Reactant: COC(=O)/C=C/C=C(/c1ccc(OC)cc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C(=C/C=C/C(=O)O)C(C)C)cc1
Yield: 74 %

Procedure:
As described in Example 99, (E,E)-5-(4-methoxyphenyl)-6-methyl-2,4-heptadienoic acid methyl ester (4 g) was saponified in a refluxing mixture of methanol (15 mL) and 2N NaOH (15 mL). After 2 hours reaction was worked up in the usual way and the crude acid was crystallized from cyclohexane-hexane to provide 2.8 g of (E,E)-5-(4-methoxyphenyl)-6-methyl-2,4-heptadienoic acid, mp 140.5°-141.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([C:13](C)(C)[O:14][SiH2]C(C)(C)C)[CH:7]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:22])[NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([CH2:13][OH:14])[CH:7]=1
Reactant: COC(=O)NCc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)NCc1ccc(Cl)c(CO)c1
Temperature: 80 °C
Yield: 97.9 %

Procedure:
A mixture of [3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzyl]-carbamic acid methyl ester (5.39 g, 15.7 mmol) in MeOH (160 mL) and aq. 1M NaOH (80 mL) was heated to 80° C. for 1.5 h. The mixture was allowed to cool to rt, and was partially evaporated under reduced pressure. The aq. residue was extracted with EtOAc (3×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the crude title compound (3.53 g, 98%) that was used further without purification. LC-MS: tR=0.72 min; ES+: 230.25.