Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[OH:39][C:40]1[CH:41]=[C:42]([NH:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH:43]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[OH:39][C:40]1[CH:41]=[C:42]([NH:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH:43]=[C:44]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:45]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cc(O)cc(NS(C)(=O)=O)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(O)cc(NS(C)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 37 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.13 mmol) was treated with N-(3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (101 mg, 0.32 mmol), sodium carbonate (34 mg, 0.32 mmols) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (8 mg, 0.01 mmol) using 1,2-dimethoxyethane (0.96 ml) and water (0.24 ml) as solvents according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 80%, hexane-ethyl acetate) to give 46 mg (37% yield, 76% purity) of the title compound.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[C:8]1([CH3:16])[C:9]([CH:14]=O)=[CH:10][CH:11]=[CH:12][CH:13]=1.Cl>C(O)C>[CH3:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH:16]=[C:3]1[C:4](=[O:7])[C:5](=[CH:16][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[CH2:6][S:1][CH2:2]1
Reactant: Cc1ccccc1C=O
Reactant: O=C1CCSCC1
Agent: Cl
Solvent: CCO
Product: Cc1ccccc1C=C1CSCC(=Cc2ccccc2C)C1=O
Yield: 87.8 %

Procedure:
Tetrahydro-4H-thiopyran-4-one (9.3 g, 0.08 mole) and o-tolualdehyde (25 g, 0.20 mole) are dissolved in 60 ml of ethanol and treated with concentrated hydrochloric acid (6 ml). After heating at reflux temperature for 4 hours, the mixture is cooled and product is collected by filtration. The combined filtrate and washings (ethanol) are concentrated to the original volume and additional concentrated hydrochloric acid (4 ml) is added and the mixture is refluxed for 4 hours. This procedure is repeated 3 times. The combined crude material (23 g) is recrystallized from chloroform/ethanol/H2O to give 22.5 g (88%) of product, m.p. 123°-125°.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][CH2:13][C:14]1[N:15]([CH2:27][C:28]2([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:12][CH2:13][C:14]1[N:15]([CH2:27][C:28]2([OH:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:19]([O-:6])=[CH:18][C:17]=2[N:26]=1
Reactant: OC1(Cn2c(CCl)nc3cnc4ccccc4c32)CCCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cc2nc(CCl)n(CC3(O)CCCCC3)c2c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Chloroperoxybenzoic acid (8.37 g of 70% pure material, 34 mmol) was added to a suspension of 1-{[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol (8.0 g, 24 mmol) in chloroform (100 mL), and the reaction was stirred at room temperature for four hours. Saturated aqueous sodium bicarbonate (100 mL) was added, and the mixture was stirred for 15 minutes. A precipitate formed and was isolated by filtration to provide 1-{[2-(chloromethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol as a white solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.[CH3:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.C(N(CC)CC)C>O1CCOCC1>[CH3:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:7][C:5]2[S:6][C:2]([CH3:1])=[CH:3][N:4]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1cnc(N)s1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2ncc(C)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Methyl-thiazol-2-ylamine (22.8 mg, 0.200 mmol) and 4-methyl-benzoyl chloride (30.9 mg, 0.200 mmol) were dissolved in 1,4-dioxane (2 mL) containing triethylamine (84.1 μL, 0.600 mmol). The reaction mixture was stirred overnight at room temperature. The crude product was filtered, evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (9.29 mg, 0.400, 20.0%). ESI-MS m/z calc. 232.1, found 233.2 (M+1)+ Retention time 2.65 minutes.
Reaction SMILES: [C:1]1([CH2:7][NH:8][C@@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C.[Br-].[CH3:30][CH:31]1[O:35][C:34](=[N+:36]([CH3:38])[CH3:37])[C:33]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:32]1>O>[OH:15][C@H:10]1[C@H:9]([NH:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:14][CH2:13][N:12]([CH:31]([CH3:30])[CH2:32][C:33]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:34]([N:36]([CH3:37])[CH3:38])=[O:35])[CH2:11]1
Reactant: O[C@@H]1CNCC[C@H]1NCc1ccccc1
Reactant: CC1CC(c2ccccc2)(c2ccccc2)C(=[N+](C)C)O1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CC(CC(C(=O)N(C)C)(c1ccccc1)c1ccccc1)N1CC[C@@H](NCc2ccccc2)[C@H](O)C1
Reaction time: 24 h
Yield: 45 %

Procedure:
A mixture of 17.6 parts of trans-4-[(phenylmethyl)amino]-3-piperidinol, 27 parts of sodium carbonate and 680 parts of 4-methyl-2-pentanone was stirred and refluxed for 45 minutes using a water separator. After cooling, 33.8 parts of N-(dihydro-5-methyl-3,3-diphenyl-2(3H)-furanylidene)-N-methylmethanaminium bromide were added and stirring was continued for 24 hours at reflux. The mixture was cooled and washed with water. The organic layer was dried, filtered and evaporated. The residue was dissolved in 1,1'-oxybisethane and acidified with 2-propanol, saturated with hydrogen chloride. The liquid was decanted and the half solid precipitated product was dissolved in water and treated with ammonium hydroxide. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (90:10 by volume) as eluent. The desired fractions were collected and the eluent was evaporated. The residue was solidified on scratching in petroleum ether. The product was filtered off and crystallized twice from acetonitrile. The product was filtered off and dried, yielding 18.8 parts (45%) of trans-3-hydroxy-N,N,γ-trimethyl-α,α-diphenyl-4-[(phenylmethyl)amino]-1-piperidinebutanamide; mp. 134.5° C. (interm. 18).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][CH:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]#[N:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.[BH3-]C#N.[Na+].CC(O)=O.[O:28]=[C:29]1[C:33]2[CH:34]=[CH:35][C:36]([CH2:38][CH:39]=O)=[CH:37][C:32]=2[CH2:31][O:30]1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[O:1]=[C:2]1[CH2:7][N:6]([CH2:39][CH2:38][C:36]2[CH:35]=[CH:34][C:33]3[C:29](=[O:28])[O:30][CH2:31][C:32]=3[CH:37]=2)[CH2:5][CH2:4][N:3]1[CH2:8][CH:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]#[N:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: N#Cc1ccc2c(c1)CCC2CN1CCNCC1=O
Reactant: O=CCc1ccc2c(c1)COC2=O
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#Cc1ccc2c(c1)CCC2CN1CCN(CCc2ccc3c(c2)COC3=O)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-[(2-Oxopiperazin-1-yl)methyl]-2,3-dihydro-1H-indene-5-carbonitrile (42 mg, 0.16 mmol), NaBH3CN (40 mg, 0.66 mmol) and HOAc (40 mg, 0.66 mmol) in 20 mL DCM was added (1-Oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (29 mg, 0.16 mmol) and the mixture was stirred at RT overnight. Then saturated Na2CO3 (50 mL) was added and stirred for 30 min and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by prep-TLC to give the title product. 1H-NMR (400 MHz, CDCl3) δ ppm 7.84 (d, J=8.6 Hz, 2H), 7.50 (s, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.32 (s, 1H), 7.27 (d, J=7.8 Hz, 1H), 5.28 (s, 2H), 3.50˜3.61 (m, 3H), 3.20˜3.32 (m, 4H), 2.99˜3.08 (m, 1H), 2.84˜2.95 (m, 3H), 2.67˜2.77 (m, 4H), 2.21˜2.30 (m, 1H), 1.87˜1.95 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([N+:11]([O-])=O)=[CH:4][N:3]=1.[H][H]>C1COCC1.[Ni]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([NH2:11])=[CH:4][N:3]=1
Reactant: CCNc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: CCNc1nc(Cl)ncc1N
Yield: 92 %

Procedure:
To a solution of 10.0 g (50 mmol, 1.0 eq.) of 2-chloro-N-ethyl-5-nitropyrimidin-4-amine (I-1) in 300 mL of THF was added ˜4.0 g of Raney Nickel. The solution was stirred under 1 atm. of hydrogen at room temperature for 12 h. The reaction mixture was filtered through Celite® and the pad was washed with 100 mL of THF. The solvent was removed in vacuo to provide 8.0 g (46 mmol, 92%) of 2-chloro-N4-ethylpyrimidine-4,5-diamine (I-5).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.[F:20][C:21]([F:46])([F:45])[C:22]1[CH:23]=[CH:24][C:25]2[N:31]3[C:32]([CH2:35]Cl)=[N:33][N:34]=[C:30]3[CH2:29][N:28]=[C:27]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:43])[C:26]=2[CH:44]=1>CC(N(C)C)=O>[F:46][C:21]([F:20])([F:45])[C:22]1[CH:23]=[CH:24][C:25]2[N:31]3[C:32]([CH2:35][O:1][N:2]4[C:3](=[O:12])[C:4]5=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]5[C:6]4=[O:7])=[N:33][N:34]=[C:30]3[CH2:29][N:28]=[C:27]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:43])[C:26]=2[CH:44]=1
Reactant: FC(F)(F)c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1, N-hydroxyphthalimide and triethylamine in dimethylacetamide is treated with 8-trifluoromethyl-6-(o-chlorophenyl)-1-(chloromethyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 8-trifluoromethyl-6-(o-chlorophenyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N:2]=1.[NH2-:11].[Na+]>C1(C)C(C)=CC=CC=1>[NH2:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: [NH2-]
Reactant: c1cc2c(cn1)CCCC2
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: Nc1nccc2c1CCCC2
Temperature: 150 °C
Reaction time: 8 h
Yield: 5.4 %

Procedure:
Using the method described in Example 63, Step B, a mixture of 2.0 g (15.0 mmol) of 5,6,7,8-tetrahydroisoquinoline and 644 mg (16.5 mmol) of sodium amide in 2.5 mL of xylene was stirred at 150° C. overnight. The crude material was purified by flash column chromatography on silica gel eluting with 0-100% ethyl acetate/dichloromethane, and the partially purified material was distilled using a Kugelrohr apparatus at 100-105° C. (0.3 mm). Recrystallization of the distallate from a hexane/toluene mixture gave 120 mg of 1-amino-5,6,7,8-tetrahydroisoquinoline as a white solid containing approximately 7% of 1-aminoisoquinoline.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:7]=2[S:8][C:9]=1[OH:10])=[O:4].C(Cl)Cl.[O:19](S(C(F)(F)F)(=O)=O)[S:20]([C:23]([F:26])([F:25])[F:24])(=O)=[O:21]>CCN(CC)CC>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:7]=2[S:8][C:9]=1[O:10][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:21])=[O:19])=[O:4]
Reactant: COC(=O)c1c(O)sc2cc(Cl)ccc12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)sc2cc(Cl)ccc12
Reaction time: 1 h
Yield: 69 %

Procedure:
6-chloro-2-hydroxy-benzo[b]thiophene-3-carboxylic acid methyl ester (2.46 g, 10.1 mmol) was cooled to 0° C. in a solution of DCM (25 ml) and Et3N (25 ml). Tf2O (2.56 ml, 15.2 mmol, 1.5 equiv) was added dropwise, then stirred for 1 hr. The resulting solution was washed twice with water, saturated NaHCO3, then water, followed by drying over MgSO4. This was filtered and the solvent removed in vacuo. The crude material was purified by column chromatography leaving 2.61 g (68%) of 6-chloro-2-trifluoromethanesulfonyloxy-benzo[b]thiophene-3-carboxylic acid methyl ester as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[C:13]([Cl:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)=[N:6][C:7]=1Cl.[CH2:20](COC)[O:21]C.C[O-].[Na+]>CO.C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[C:13]([Cl:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)=[N:6][C:7]=1[O:21][CH3:20]
Reactant: COCCOC
Reactant: Cn1nc(-c2ccc(Cl)c(Cl)n2)c(Cl)c1C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: COc1nc(-c2nn(C)c(C(F)(F)F)c2Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 48 h

Procedure:
1.0 g of 3-(5,6-dichloro-2-pyridyl)-4-chloro-5-trifluoromethyl-1-methyl-[1 H]-pyrazole (Example H20) is initially introduced into 5 ml of dry dimethoxyethane. After the solution has been cooled to 0° C., 0.61 ml of a 5.4 molar solution of sodium methylate in methanol is added dropwise and the mixture is subsequently stirred at 25° C. for 2 days. The reaction mixture is taken up in diethyl ether and washed successively with 0.5 N hydrochloric acid, water and brine. After drying over sodium sulfate, the mixture is filtered and the filtrate is concentrated to dryness in vacuo. 0.94 g of the desired title compound is obtained as a white solid.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:7]2.O1CCCC1.[CH3:23][O:24][CH2:25][CH2:26][O:27][CH2:28]Cl>CN(C)C=O>[CH3:23][O:24][CH2:25][CH2:26][O:27][CH2:28][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:7]2
Reactant: COCCOCCl
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCOCOc1ccc2cc(C(=O)OC)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
3.3 g (83 mmol) of 60% sodium hydride in oil are added portionwise to a solution of 14 g (69 mmol) of methyl 6-hydroxynaphthalene-2-carboxylate in 180 ml of an equivolume mixture of tetrahydrofuran and dimethylformamide. After the evolution of gas has ceased, 8.7 ml (76 mmol) of methoxyethoxymethyl chloride are added dropwise. The reaction medium is stirred at room temperature for 3 hours, immersed into ice-cold water and extracted with ethyl ether. The organic phase is dried over sodium sulfate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture. 17 g of methyl 6-(2-methoxyethoxymethoxy)naphthalene-2-carboxylate are obtained in the form of a colorless oil, in a yield of 85%.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[Na].[N+](C1C=CC(S[C:17]2[C:22]([C:23]#[N:24])=[CH:21][C:20]([CH:25]=[CH:26][C:27]3[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:34])=[CH:19][N:18]=2)=CC=1)([O-])=O.C(OCC)C>C(O)(C)(C)C>[NH2:4][C:3]1[N:5]=[C:23]([NH2:24])[C:22]2[CH:21]=[C:20]([CH:25]=[CH:26][C:27]3[C:28]([Cl:34])=[CH:29][CH:30]=[CH:31][C:32]=3[Cl:33])[CH:19]=[N:18][C:17]=2[N:2]=1
Reactant: N=C(N)N
Reactant: N#Cc1cc(C=Cc2c(Cl)cccc2Cl)cnc1Sc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na]
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: Nc1nc(N)c2cc(C=Cc3c(Cl)cccc3Cl)cnc2n1
Temperature: 24 °C

Procedure:
To a solution of 2.24 g (23.4 mM) of guanidine hydrochloride in 30 ml of tert.-butanol were added 0.538 g (23.4 mM) of sodium metal. The mixture was heated at 50° C. for 90 minutes, at which time 2.0 g (4.67 mM) of the 2-(4-nitrophenylthio)-3-cyano-5-(2,6-dichlorophenyl)ethenylpyridine from above were added in one portion. The mixture was heated at reflux for three hours, then cooled to 24° C., diluted by addition of 200 ml of diethyl ether, and filtered. The filter cake was washed with 30 ml of water and dried. The solid product was next washed with 20 ml of acetone and dried to afford 1.45 g (93.5% yield)
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[NH:15]2)[CH:9]=1)([CH3:6])[CH3:5].Cl>O1CCCC1.[OH-].[Li+].O>[CH3:24][C:23]1([CH3:25])[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:26]([F:28])([F:27])[F:29])[CH:20]=2)[NH:15][CH:14]1[C:10]1[CH:9]=[C:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:30])=[O:2])[CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(C(F)(F)F)cc3CC2(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Nc1cccc(C2Nc3ccc(C(F)(F)F)cc3CC2(C)C)c1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 0.8 %

Procedure:
A mixture of 2-[3-(3,3-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid methyl ester (400 mg, 0.95 mmol) in tetrahydrofuran (30 mL), 2M lithium hydroxide in water (15 mL) was stirred at 25° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(3,3-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (3 mg, 0.7%) as a light yellow oil: LC/MS m/e calcd for C22H25F3N2O2 (M+H)+: 407.45, observed: 407.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.C(N(C(C)C)C(C)C)C.[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:26])[CH3:25])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(Br)ccc1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Br)ccc1O[Si](C)(C)C(C)(C)C
Reaction time: 0.08 h
Yield: 99.3 %

Procedure:
To a solution of 4-bromo-2-methoxyphenol (2.87 g, 14.13 mmol) in DMF (20 ml) was added ethyldiisopropylamine (6.15 ml, 35.32 mmol). The clear solution was stirred for 5 min. followed by addition of tert-butylchlorodimethylsilane (2.56 g, 16.95 mmol). The crude was purified via flash column chromatography (100% in hexane) to give (4-bromo-2-methoxy-phenoxy)-tert-butyl-dimethyl-silane as a clear oil (4.45 g, 99%): 1HNMR (CDCl3) δ 6.95 (s, wide, 1H, Ar), 6.92 (d, J=2 Hz, 1H, Ar), 6.71 (d, J=7 Hz, 1H, Ar), 3.79 (s, 3H, OCH3), 0.98 (s, 9H, 3CH3), 0.13 (s, 6H, 2CH3). The product was carried over to the next step.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[C:4]([OH:10])=[C:3]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].S(OC)(O[CH3:20])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[C:4]([O:10][CH3:20])=[C:3]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1c(O)c([N+](=O)[O-])cn1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1c(OC)c([N+](=O)[O-])cn1C
Yield: 88.6 %

Procedure:
A mixture of ethyl 1-methyl-4-nitro-3-hydroxypyrrole-2-carboxylate (0.071 g, 0.3315 mmol), dimethyl sulfate (0.055 g, 0.436 mmol) and anhydrous potassium carbonate (0.5 g, 3.90 mmol) in dry acetone (20 mL) was refluxed under a nitrogen atmosphere for 22 h. Potassium carbonate was removed by filtration and the filtrate was evaporated under reduced pressure to afford an orange crystalline solid. Excess dimethyl sulfate was destroyed by treating the residue with aqueous ammonia (1 mL). Water (2 mL) was added and the residue was extracted with ether (30 mL). The combined ether extracts were washed with aqueous sodium hydroxide solution and water. Removal of ether under reduced pressure afforded a cream residue. The residue was dissolved in CH2Cl2 (25 mL), dried with anhydrous Na2SO41 filtered and evaporated under reduced pressure to yield a cream microcrystalline solid (0.067 g, 89%). Recrystallization from acetone/hexane afforded colorless needles, mp 145-147° C.; 1H NMR (300 MHZ, CDCl3) d 1.40 (t, J=7.2 Hz, 3H, CH3—CH2—), 3.90 (s, 3H, CH3—N—), 3.95 (s, 3H, CH3O—), 4.36 (q, J=7.0 Hz, 2H, CH3—CH2—), 7.47 (s, 1H, H-5); 13C NMR (100 MHZ, CDCl3) d 14.22, 38.92, 60.67, 63.02, 114.73, 125.76, 127.79, 146.18, 160.09; MS (EI, 70 eV) m/z (relative intensity) 229 (M+1, 3), 228 (M+, 30), 211 (12), 183 (12), 167 (20), 153 (25), 152 (100), 141 (7), 109 (12), 84 (8), 67 (6), 53 (31), 42 (17), Calcd for C9H12N2O5: 228.20. HRMS (M+H): Calcd for C9H13N2O5 [M+H+]: 229.0824, Found 229.0834. Anal. Calcd for C9H12N2O5: C, 47.37; H, 5.29; N, 12.27. Found. C, 47.44; H, 5.36; N, 12.28. TLC (ethyl acetate/Hexane, 1:3) Rf 0.23.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[C:33]1([NH:43]N)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:43][C:33]3[C:34]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:35][CH:36]=[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=32)=[CH:4][CH:3]=1
Reactant: NNc1cccc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(I)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(I)cc4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-naphthylhydrazine hydrochloride: ESMS m/e: 656.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=[C:9]1[CH2:19][CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:22]Br.CC([O-])=O.[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=[C:9]1[CH:19]([Br:22])[CH2:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CCCc1nc2snc(C)c2c(=O)n1Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC(Br)c1nc2snc(C)c2c(=O)n1Cc1ccccc1
Temperature: 0 °C

Procedure:
A mixture of 31 (430 mg, 1.44 mmol), bromine (345 mg, 2.16 mmol) and NaOAc (236 mg, 2.88 mmol) in acetic acid (10 mL) was heated at 40–45° C. for 14 h. The reaction mixture was poured into ice water, a yellow solid was collected by filtration. The crude product 32 was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.06–7.31 (m, 5H), 6.13 (d, J=16.41 Hz, 1H), 4.80 (d, J=16.41 Hz, 1H), 4.56 (t, J=7.26 Hz, 1H), 2.77 (s, 3H), 2.33 (m, 1H), 2.13 (m, 1H), 0.67 (t, J=7.27 Hz, 3H).