Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]2[C:26]3[C:21](=[CH:22][C:23]([Br:27])=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)=O)[CH2:4][CH2:3]1>P(Cl)(Cl)(Cl)=O>[Br:27][C:23]1[CH:22]=[C:21]2[C:26]3=[C:25]([CH:24]=1)[C:8]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]3[CH2:18][CH2:19][CH2:20]2
Reactant: CN1CCN(C(=O)Nc2ccccc2N2CCCc3cc(Br)ccc32)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(C2=Nc3ccccc3N3CCCc4cc(Br)cc2c43)CC1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
A stirred mixture of 4-methyl-N-[2-(6-bromo-1,2,3,4-tetrahydro-1-quinolinyl)phenyl]piperazine-carboxamide (14.2 g, 0.0330 mole) in phosphorus oxychloride (250 ml) was heated under reflux under nitrogen for 5 hours. The reaction mixture was cooled to room temperature and excess phosphorous oxychloride was removed at aspirator pressure with heating. The residue was chilled in an ice-bath (with exclusion of moisture), and treated with ice-cold 2N sodium hydroxide solution (250 ml) and dichloromethane (500 ml). The mixture was stirred, the organic phase was separated, washed with 2N sodium hydroxide solution, twice with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was digested in boiling methanol (40 ml) to afford 10.7 g (79%) of product. Recrystallization from ethanol provided the analytical sample, mp 181°-183° C.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][N:11]1[CH2:18][CH2:17][NH:16][C:15]2[C:14](=[O:19])[C:13](=[O:20])[C:12]1=2)(=[O:8])[O:5]CC)C.Br[Si](C)(C)C>ClCCCl>[O:19]=[C:14]1[C:13](=[O:20])[C:12]2[N:11]([CH2:10][CH2:9][P:4](=[O:3])([OH:5])[OH:8])[CH2:18][CH2:17][NH:16][C:15]1=2
Reactant: CCOP(=O)(CCN1CCNc2c1c(=O)c2=O)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCCl
Product: O=c1c2c(c1=O)N(CCP(=O)(O)O)CCN2
Yield: 57.8 %

Procedure:
A solution of [2-(7,8-dioxo-2,5-diazabicyclo[4.2.0]oct-1(6)-en-2-yl)ethyl]phosphonic acid diethyl ester (0.78 g, 2.6 mmol) and bromotrimethylsilane (2.1 mL, 16 mmol) in dry 1,2-dichloroethane (30 mL) was refluxed under nitrogen for 20 minutes. The cooled reaction mixture was concentrated in vacuo, and the residue was dissolved in water (100 mL) and washed with diethyl ether (3×50 mL). After concentrating the aqueous layer, the residue was recrystallized from water (25 mL) and methanol (300 mL) to yield a solid beige impurity which was removed by filtration. The filtrate was concentrated and recrystallized from water in isopropanol to yield the title compound as a yellow solid (0.37 g, 58%, mp 220°-270° C. dec); IR (KBr, cm-1): 1800; MS (-FAB): 245 (M-H); 1H NMR (DMSO/drop of DCl, 400 MHz): δ 3.58-3.51 (m, 2H), 3.40-3.33 (m, 4H), 2.07-1.98 (m, 2H).
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([Cl:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17](Br)=[CH:16][C:15]=4[CH3:23])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.N1(C2C=CC(CC3C(OC)=NC4C(C=3Cl)=CC(Br)=CC=4C)=CC=2)C=CC=N1.[Cl:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]([C:63]2[N:67]([CH3:68])[CH:66]=[N:65][CH:64]=2)=[O:62])=[CH:57][CH:56]=1.[Li]CCCC>>[N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([Cl:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:61]([C:58]3[CH:59]=[CH:60][C:55]([Cl:54])=[CH:56][CH:57]=3)([C:63]3[N:67]([CH3:68])[CH:66]=[N:65][CH:64]=3)[OH:62])=[CH:16][C:15]=4[CH3:23])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1cc(Br)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Reactant: Cn1cncc1C(=O)c1ccc(Cl)cc1
Agent: COc1nc2c(C)cc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: [Li]CCCC
Product: Cc1cc(C(O)(c2ccc(Cl)cc2)c2cncn2C)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloro-8-methylquinoline (393 mg, 0.880 mmol, Intermediate 19: step a) and (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (194 mg, 0.880 mmol, Intermediate 1: step b) in dry degassed THF (16 mL) was cooled to −78° C. and n-BuLi (1.6 M in hexane, 0.5 mL, 0.8 mmol) was added over 1.5 minutes. Stirring was continued at −78° C. for 10 minutes and the dry ice acetone bath was replaced with an ice water bath. Stirring was continued for 1 hour and the reaction mixture was quenched with saturated aqueous NH4Cl solution. EtOAc was added and the layers were separated and the aqueous mixture again extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification using flash column chromatography (5% MeOH in dichloromethane) yielded the substantially pure title compound. MS (ESI) 588.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][CH2:9][CH:10]([F:12])[F:11])[C@H:3]1[C:14]([OH:16])=[O:15].[C:18]([CH:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)#[CH:19]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][CH2:9][CH:10]([F:11])[F:12])[C@H:3]1[C:14]([O:16][C@H:20]([C:18]#[CH:19])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)=[O:15]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)OCC(F)F
Reactant: C#CC(O)c1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: C#C[C@@H](OC(=O)[C@@H]1[C@H](/C=C\C(=O)OCC(F)F)C1(C)C)c1cccc(Oc2ccccc2)c1

Procedure:
Using the procedure of Step F of Example 9, (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2,2-difluoroethoxy)1-propenyl]-cyclopropane-carboxylic acid and α-ethynyl-3-phenoxy-benzyl alcohol were reacted to obtain (R)α-ethynyl-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2,2-difluoroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+47°±1.5° (c=1% in CHCl3).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:14]([NH2:16])=[O:15].Br[C:18]1[N:23]=[C:22]([C:24]([OH:28])([CH3:27])[CH2:25][OH:26])[CH:21]=[CH:20][CH:19]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)(CC)(C)C.C(OCC)(=O)C.CO>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:6][C:2]([NH:1][C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([C:24]([OH:28])([CH3:27])[CH2:25][OH:26])[N:23]=3)=[C:3]([C:14]([NH2:16])=[O:15])[N:4]=2)=[CH:12][CH:11]=1
Reactant: NC(=O)c1nc(-c2ccc(Cl)cc2)sc1N
Reactant: CC(O)(CO)c1cccc(Br)n1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCC(C)(C)O
Product: CC(O)(CO)c1cccc(Nc2sc(-c3ccc(Cl)cc3)nc2C(N)=O)n1

Procedure:
A suspension containing 5-amino-2-(4-chlorophenyl)-1,3-thiazole-4-carboxamide (Example 1, Step 1) (200 mg, 0.788 mmol), 2-(6-bromopyridin-2-yl)propane-1,2-diol (179 mg, 0.773 mmol), 2-dicylohexylphosphino-2′,4′,6′-triisopropyl-1,1-biphenyl (92 mg, 0.193 mmol), dibenyzlideneacetone bis(triphenylphosphine) (35.4 mg, 0.039 mmol) and potassium carbonate (117 mg, 0.850 mmol) in tert-amyl alcohol (3.0 mL) was sealed in a 5 mL microwave reaction vessel and was purged of oxygen by doing 5 vacuum/argon flush cycles. After heating the reaction at 100° C. for 16 hours, the mixture was cooled, diluted with ethyl acetate (100 mL) and methanol (5 mL), washed with saturated aqueous sodium bicarbonate (30 mL), and filtered both layers through filter paper. The layers were separated, and the organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The resulting solid was diluted with acetonitrile (40 mL) and methanol (10 mL), and this solution was extracted with hexanes (2×50 mL) and then concentrated. The crude product was purified by reverse phase HPLC (40-90% acetonitrile/water with 0.05% trifluoroacetic acid), and then the appropriate fractions were diluted with ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (30 mL). The layers were separated, and the organic layer was washed with saturated aqueous sodium bicarbonate (15 mL) and water (2×15 mL), dried over sodium sulfate, filtered and concentrated to yield the title compound as a light yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1.[CH:10](Cl)([Cl:12])[Cl:11].[OH-].[Na+]>CN1CCCC1=O>[Cl:8][C:7]1[C:2]([CH:10]([Cl:12])[Cl:11])=[N:3][C:4]([Cl:9])=[CH:5][CH:6]=1
Reactant: Clc1ccc(Cl)c(Cl)n1
Reactant: ClC(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Clc1ccc(Cl)c(C(Cl)Cl)n1
Reaction time: 8 h

Procedure:
2,3,6-Trichloropyridine (1.0 g, 0.0055 mole) was combined with 4 g N-methylpyrrolidone, 4 g (0.033 mole) of chloroform, and 1.0 g of 50 percent aqueous sodium hydroxide (0.013 mole). The resulting mixture was stirred and warmed mildly for about 1 hour at which time the product was found to be present in the reaction mixture by gas chromatography and mass spectrometry using an authentic sample of the product as a standard. After standing overnight at ambient temperature the title compound represented about 1.7 percent of the pyridines in the mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[C:20]2[CH:21]=[CH:22][N:23]=[C:24]([O:25][CH3:26])[C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[N:16][CH:17]=2)[N:12]=1.[CH3:27][N:28](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[C:20]2[CH:21]=[CH:22][N:23]=[C:24]([O:25][CH3:26])[C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[N:16][CH:17]=2)[N:12]=1)[C:27]#[N:28]
Reactant: CN(C)C=O
Reactant: COc1nccc2c(Nc3c(Cl)cc(I)cc3Cl)nc3ccncc3c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1nccc2c(Nc3c(Cl)cc(C#N)cc3Cl)nc3ccncc3c12
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
To a solution of N-(2,6-dichloro-4-iodophenyl)-10-methoxypyrido[4,3-c]-1,6-naphthyridin-6-amine (Example 152, Step 1) (1.0 g, 2.01 mmol) in DMF (10 mL) was added zinc cyanide (283 mg, 2.41 mmol) and Pd(Ph3P)4 (465 mg, 0.402 mmol). The reaction was stirred at 80 ° C. for 2.5 h in a sealed tube. After cooling to room temperature, the reaction was diluted with ethyl acetate and washed with water followed by brine. The organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with methanol in dichloromethane to afford the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8]([CH2:9][NH:10][C:11](=[O:16])[CH2:12][C:13](=O)[CH3:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:19][C:20]1[N:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:21]=1[CH:22]=O.N1CCCCC1.CCOC(C)=O>CCO>[C:1]([C:5]1[CH:18]=[CH:17][C:8]([CH2:9][NH:10][C:11]([C:12]2[C:13]([CH3:14])=[N:19][C:20]3[C:21]([CH:22]=2)=[C:24]([CH3:28])[CH:25]=[CH:26][N:27]=3)=[O:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccnc(N)c1C=O
Reactant: CC(=O)CC(=O)NCc1ccc(C(C)(C)C)cc1
Solvent: C1CCNCC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nc2nccc(C)c2cc1C(=O)NCc1ccc(C(C)(C)C)cc1
Temperature: 120 °C

Procedure:
In a screw cap pressure tube were N-(4-tert-butylbenzyl)-3-oxobutanamide (94.5 mg, 0.38 mmol), 2-amino-4-methylnicotinaldehyde (52.0 mg, 0.38 mmol) and piperidine (151.0 μl, 1.53 mmol) suspended in EtOH (0.5 ml). The tube was sealed and the mixture heated to 120° C. for 1.5 h. The mixture was allowed to cool. EtOAc was added and the mixture washed with H2O, dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography CH2Cl2/MeOH 96/4 yielding 61.5 mg of the title compound (47%).
Reaction SMILES: CC1C=CC(CCN)=CC=1.C(Cl)(=O)CC.[CH2:16]([CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([CH3:28])[CH:26]=2)[CH2:21][CH2:20][NH:19]1)[CH3:17].C1C2C(=CC=CC=2)C=CN=1.[OH-].[Na+].[Cl:41][CH:42]([Cl:46])[C:43](Cl)=[O:44]>C(Cl)Cl>[Cl:41][CH:42]([Cl:46])[C:43]([N:19]1[CH2:20][CH2:21][C:22]2[C:27](=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:18]1[CH2:16][CH3:17])=[O:44]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CCC1NCCc2ccc(C)cc21
Agent: CCC(=O)Cl
Agent: Cc1ccc(CCN)cc1
Agent: [Na+]
Solvent: c1ccc2cnccc2c1
Solvent: ClCCl
Product: CCC1c2cc(C)ccc2CCN1C(=O)C(Cl)Cl

Procedure:
By procedures described in Example 1 (Method A), 4-methyl-phenethylamine and propionyl chloride were converted to 1-ethyl-7-methyl-1,2,3,4-tetrahydroisoquinoline. A reaction vessel was charged with 3.0 g of this isoquinoline compound, 10 ml 10% sodium hydroxide and 50 ml methylene chloride. With this mixture stirred, 2 ml dichloroacetyl chloride was added dropwise to the mixture. The mixture was stirred for 5 minutes and then made alkaline with aqueous sodium hydroxide. The organic extract was dried with magnesium sulfate, stripped of solvent and subjected to Kugelrohr distillation (105° C. @ 0.1 mm Hg) to provide 4.8 g of a yellow oil product having the elemental analysis reported in Table I.
Reaction SMILES: C[Si](C)(C)CC[S:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[C:8]([F:18])[CH:7]=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].C1COCC1.CCOC(C)=O>CN(C=O)C>[F:18][C:8]1[CH:7]=[C:6]([SH:5])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=1
Reactant: C[Si](C)(C)CCSc1cc(F)cc(-c2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cc(S)cc(-c2ccccc2)c1
Reaction time: 1.5 h

Procedure:
To S-(2-trimethylsilylethyl)-3-fluoro-5-phenylthiophenol (2.4 g) in DMF (50 mL) was added Bu4NF (16 mL of a 1M THF solution). After 90 min., EtOAc was added and this solution was washed with 1N HCl, H2O and brine. Concentration and chromatography (silica gel; hexane/EtOAc (9:1)) provided the title compound as a liquid.
Reaction SMILES: C(P(C1C=CC=CC=1)(=O)OC1C=CC=CC=1)(O)=O.[C:19]1([P:25]([Cl:27])Cl)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:28]([C:30]1[CH:35]=[CH:34][C:33]([N+]#N)=[CH:32][CH:31]=1)#[N:29].F[B-](F)(F)F.[Al]>>[C:28]([C:30]1[CH:35]=[CH:34][C:33]([P:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[Cl:27])=[CH:32][CH:31]=1)#[N:29]
Reactant: ClP(Cl)c1ccccc1
Reactant: N#Cc1ccc([N+]#N)cc1
Agent: F[B-](F)(F)F
Agent: O=C(O)P(=O)(Oc1ccccc1)c1ccccc1
Agent: [Al]
Product: N#Cc1ccc(P(Cl)c2ccccc2)cc1
Yield: 47 %

Procedure:
P-CARBOXYPHENYL-PHENYLPHOSPHINIC ACID IS ALREADY KNOWN AND HAS BEEN PREPARED BY L. D. Quinn et al. with unsatisfactory yields (L. D. Quinn et al., J. org. Chem. 27, 4120 (1962): ##STR2## In this process, the reaction product of phenyldichlorophosphine and p-cyanophenyl-diazonium-tetrafluoroborate has to be subjected to a reduction with aluminum in order to obtain the p-cyanophenyl-phenylchlorophosphine. The yield is 47 % of the theoretical yield. This process can be carried out only with difficulty on a large scale, and the formation of large amounts of fluorine containing waste secondary products creates the problem of the pollution-free destruction thereof.
Reaction SMILES: Br[CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[CH2:23][NH:22][CH2:21][CH2:20]2.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[CH2:23][N:22]([CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)[CH2:21][CH2:20]2
Reactant: O=[N+]([O-])c1ccc(SCCBr)cc1
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc2c(cc1OC)CN(CCSc1ccc([N+](=O)[O-])cc1)CC2
Temperature: 80 °C
Reaction time: 14 h
Yield: 53.8 %

Procedure:
6.9 g of the compound obtained in Step 1, 6.1 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride and 7.7 g of potassium carbonate were added to 80 ml of acetonitrile, and stirred at 80° C. for 14 hours. After washing with 250 ml of distilled water and with 300 ml of aqueous NaCl, the resulting organic layer was dried over MgSO4, filtrated, and distilled under a reduced pressure to obtain 5.3 g of 6,7-dimethoxy-2-[2-(4-nitro-phenylsulfanyl)-ethyl]-1,2,3,4-tetrahydro-isoquinoline. The compound was stirred with 3.4 g of Iron, 6.74 ml of 35% HCl and 35 ml of methanol under 1 atmospheric nitrogen atmosphere for 20 hours. The reaction mixture was filtrated through a cellite pad, the pad was washed with methanol, and the filtrate and wash solution were combined, and distilled under a reduced pressure to obtain a residue that gave 3.0 g of the title compound (yield 33%).
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.C(N(C(C)C)CC)(C)C.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.O>C(Cl)Cl>[CH3:1][O:2][CH2:3][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)=[CH:19][CH:20]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COCOc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.4 %

Procedure:
Chloromethyl methyl ether (0.5 ml, 6.59 mmol) and diisopropylethylamine (1.44 ml, 8.24 mmol) were added to a solution of 4′-hydroxy-1,1′-biphenyl-4-carbonitrile (1.07 g, 5.49 mmol) in methylene chloride (10 ml), and the mixture was stirred at room temperature for 16 hours. After water was added to the reaction mixture and the mixture was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=5/1) to give 4′-methoxymethoxy-1,1′-biphenyl-4-carbonitrile (1.03 g, yield: 78%).
Reaction SMILES: [CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]2)[CH:9]=1.C1C(=O)N([Br:53])C(=O)C1>CC#N.C(Cl)Cl>[CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]2)[C:9]=1[Br:53]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=O)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Solvent: CC#N
Solvent: ClCCl
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(Br)c(C2CCC(=O)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a solution of 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone (128 mg, 0.199 mmol) in CH3CN/DCM (3/1 mL) was added NBS (42.5 mg, 0.239 mmol) and stirred at rt for 30 min. TLC showed complete conversion. All the volatiles were removed under reduced pressure and the residue was purified by a SiO2 column (0-15% EtOAc/Hexanes, Rf=0.6 in 20% EtOAc) to afford 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone as a pale yellow oil (125 mg).
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([N:13]=O)[C:8](=[O:9])[N:7]([CH2:15][CH:16]=[CH2:17])[C:5]1=[O:6])[CH:2]=[CH2:3].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O>[CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([NH2:13])[C:8](=[O:9])[N:7]([CH2:15][CH:16]=[CH2:17])[C:5]1=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCn1c(N)c(N=O)c(=O)n(CC=C)c1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCn1c(N)c(N)c(=O)n(CC=C)c1=O
Reaction time: 1 h
Yield: 104.2 %

Procedure:
The 1,3-diallyl-5-nitroso-6-aminouracil (4.5 g) was suspended in 150 ml of ethyl acetate and treated with 23.6 g of sodium dithionite in 64 ml of water. After 1 hour, the layers were separated and the aqueous phase was extracted with ethyl acetate (4×100 ml). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated and the residue was purified by flash chromatography (10% methanol in chloroform) to yield 4.41 g of 1,3-diallyl-5,6-diaminouracil.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:17][CH:18]([CH3:20])[CH3:19])=[C:4]([C:13]([O:15]C)=[O:14])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].O.Cl>CO>[Br:1][C:2]1[C:3]([O:17][CH:18]([CH3:20])[CH3:19])=[C:4]([C:13]([OH:15])=[O:14])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1sc(-c2ccccc2)c(Br)c1OC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)Oc1c(C(=O)O)sc(-c2ccccc2)c1Br
Yield: 98.4 %

Procedure:
Methyl 4-bromo-3-(1-methylethoxy)-5-phenyl-2-thiophenecarboxylate (4.8 g, 14 mmoles) is stirred in methanol (5 mL), 1N NaOH (27 mL) is added, and the mixture is stirred and heated under reflux. After 3 hours the mixture is stirred into water (300 mL) and acidified with concentrated HCl. The precipitate is filtered off, rinsed with water and dried to afford the product (4.7 g); mp 159°-160° C.
Reaction SMILES: CS(Cl)(=O)=O.OCC[N:9](CCO)[S:10]([C:13]1[CH:18]=[CH:17][C:16](C)=[CH:15][CH:14]=1)(=[O:12])=[O:11].C(N(CC)CC)C>ClCCl>[C:13]1([S:10]([NH2:9])(=[O:12])=[O:11])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)N(CCO)CCO)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccccc1
Yield: 85.7 %

Procedure:
A solution of 11.4 g (0.1 mole) of methanesulfonyl chloride in 17.1 ml of dichloromethane is cooled to 5° C. A solution of 13 g (0.05 mole) of N,N-bis(2-hydroxyethyl)-4-methylbenzenesulfonamide and 10.1 g (0.1 mole) of triethylamine in 52 ml of dichloromethane is then added dropwise with stirring. The resulting mixture is allowed to return to ambient temperature and stirred for a further 3 hours. The reaction mixture is then extracted three times with 40 ml water. The organic phase is dried over sodium sulfate, filtered and concentrated in a rotating evaporator. The resulting oil is then crystallized from ethanol. 17.8 g of 4-methyl-N,N-bis[2-methylsulfonyloxy)ethyl]benzenesulfonamide are obtained.