Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[CH2:12]([O:14][C:15](=[O:19])[C:16]#[C:17][CH3:18])[CH3:13].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:12]([O:14][C:15](=[O:19])[CH:16]=[C:17]([O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[CH3:18])[CH3:13]
Reactant: CC#CC(=O)OCC
Reactant: Oc1cccc(C(F)(F)F)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C)Oc1cccc(C(F)(F)F)c1
Temperature: 130 °C
Yield: 53.3 %

Procedure:
A mixture of 3-trifluoromethyl-phenol (1.09 mL, 8.96 mmol) and ethyl-2-butynoate (2.0 g, 17.83 mmol) in tetrahydrofuran (14 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.4 mL, 9.37 mmol). The reaction was then heated at 130° C. for 2 h. At this time, the reaction was concentrated in vacuo. The residue dissolved in dichloromethane (100 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a 1N aqueous sodium hydroxide solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organics were then dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 1-10% ethyl acetate/hexanes) afforded 3-(3-trifluoromethyl-phenoxy)-but-2-enoic acid ethyl ester (1.31 g, 53%) as a clear, colorless oil: HR-ES-MS m/z calculated for C13H13O3F3 [M+H]+ 275.0890, observed 275.0889; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (t, J=7.1 Hz, 3H), 2.45 (s, 3H), 4.01 (q, J=7.1 Hz, 2H), 4.68 (s, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.57 (br. s., 1H), 7.66-7.75 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([Br:17])=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1oc2ccc(Br)c(O)c2c1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
To 2 g (0.81 mmol) of 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester was added 20 mL of carbon tetrachloride, and the mixture was cooled with a water/ice bath while 1 equivalent of N-bromosuccinimide was added in small portions. After stirring at 0° C. for 3 h, the reaction mixture was filtered and the filtrate was loaded onto a column and purified by column chromatography to give 1.6 mg (59% yield) of 5-bromo-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [CH:1]1([N:6]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:7](=[O:26])[C:8]2[CH:13]=[CH:12][C:11]([CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)O)=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.S(=O)(=O)(O)O.[Pd].C(OCC)(=O)C.CCCCCC>[CH:27]1([N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:7](=[O:26])[C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)=[CH:12][CH:13]=2)[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COc1ccc(C(O)c2ccc(C(=O)N(C3CCCC3)C3CCCC3)cc2)cc1OC
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(Cc2ccc(C(=O)N(C3CCCC3)C3CCCC3)cc2)cc1OC

Procedure:
The compound prepared in Example 10 (0.40 g, 0.84 mmol) in ethyl alcohol (20 mL) containing concentrated sulfuric acid (2 drops) was hydrogenated at 60 psi and room temperature using 5% Pd/C as catalyst. The catalyst was filtered and the filtrate concentrated in vacuo to give the crude product as an oil. Chromatography of the crude product on silica gel using mixtures of ethyl acetate and hexane as eluents gave the title compound as a crystalline solid, m. pt. 138-142° C.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)(=[O:11])[CH3:10].[CH3:25][Si:26](Cl)([CH3:28])[CH3:27]>C1COCC1>[CH3:25][Si:26]([CH3:28])([CH3:27])[O:11][C:9]([CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]1)=[CH2:10]
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[Si](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(O[Si](C)(C)C)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h

Procedure:
To a solution of LDA in THF (70 mL) under nitrogen atmosphere, cooled to −78° C. via dry ice/acetone bath, was added tert-butyl 4-acetylpiperidine-1-carboxylate (5 g, 22 mmol) in THF (30 mL) dropwise over 30 min. The resulting mixture was stirred for an additional 30 min and then TMSCl (2.81 mL) was added via syringe dropwise over 10 min and the resulting solution stirred for 1 h at −78° C. Quench with saturated sodium bicarbonate (300 mL) and extracted with ether (2×200 mL). Combined the organics, wash with brine, dry over sodium sulfate, filter, and concentrate under vacuum. The compound obtained (6.0 g, 92%) was used for the next reaction without further purification.
Reaction SMILES: [CH2:1]([N:5]([CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]1)[C:6](=[O:8])[CH3:7])[CH2:2][CH2:3][CH3:4].[O:19]1[CH2:43][CH:20]1[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH:40]3[O:42][CH2:41]3)=[CH:34][CH:33]=2)([CH3:31])[CH3:30])=[CH:25][CH:24]=1>C(O)(C)(C)C>[CH2:1]([N:5]([CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH2:41][CH:40]([OH:42])[CH2:39][O:38][C:35]2[CH:36]=[CH:37][C:32]([C:29]([C:26]3[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH:20]([OH:19])[CH2:43][N:12]4[C:13]([CH3:15])([CH3:16])[CH2:14][CH:9]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6](=[O:8])[CH3:7])[CH2:10][C:11]4([CH3:17])[CH3:18])=[CH:24][CH:25]=3)([CH3:31])[CH3:30])=[CH:33][CH:34]=2)[C:11]([CH3:17])([CH3:18])[CH2:10]1)[C:6](=[O:8])[CH3:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C(C)=O)C1CC(C)(C)NC(C)(C)C1
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Solvent: CC(C)(C)O
Product: CCCCN(C(C)=O)C1CC(C)(C)N(CC(O)COc2ccc(C(C)(C)c3ccc(OCC(O)CN4C(C)(C)CC(N(CCCC)C(C)=O)CC4(C)C)cc3)cc2)C(C)(C)C1

Procedure:
To 20 ml of t-butanol were added 5.0 g of 4-(N-butylacetamido)-2,2,6,6-tetramethylpiperidine and 2.8 g of 2,2-bis[p-(2,3-epoxypropoxy)phenyl]propane, and the mixture was reacted following the procedure described in Example 1 to give the desired Compound No. 234 in the form of a white vitreous mass. The compound had an Rf value of 0.54 on thin-layer chromatography on silica gel developed with a 20:1 by volume mixture of ethyl acetate and triethylamine.
Reaction SMILES: C(N(CCCCCCCC)CCC[NH:13][C:14]([NH2:16])=[NH:15])CCCCCCC.[S:25]([OH:29])([OH:28])(=[O:27])=[O:26].COC(=N)N>>[S:25]([O-:29])([O-:28])(=[O:27])=[O:26].[NH2:15][C:14]([NH2:16])=[NH2+:13].[NH2:15][C:14]([NH2:16])=[NH2+:13]
Reactant: O=S(=O)(O)O
Reactant: CCCCCCCCN(CCCCCCCC)CCCNC(=N)N
Agent: COC(=N)N
Product: NC(N)=[NH2+]
Product: O=S(=O)([O-])[O-]

Procedure:
Using the procedure of Process I, 590 g (2 moles) of 1-dioctylamino-3-guanidino-propane are reacted with 236 g (0.96 moles) of O-methylisourea sulfate. After working up the reaction batch, 651 g (83.7% of the theoretical yield) of guanidinium sulfate are obtained.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([O:12][C:13]([N:15]1[CH2:34][CH2:33][C:18]2([N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([OH:31])=[O:30])[CH:24]=3)[NH:20][C:19]2=[O:32])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>CO>[C:8]([O:12][C:13]([N:15]1[CH2:16][CH2:17][C:18]2([N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([O:31][CH3:1])=[O:30])[CH:24]=3)[NH:20][C:19]2=[O:32])[CH2:33][CH2:34]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)N=C(c1cccc(C(=O)O)c1)NC2=O
Solvent: CO
Product: COC(=O)c1cccc(C2=NC3(CCN(C(=O)OC(C)(C)C)CC3)C(=O)N2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
(Trimethylsilyl)diazomethane (2.0 M in hexane, 4.0 ml, 8.0 mmol) was added dropwise to a solution of 2-(3-carboxy-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester (200 mg, 0.54 mmol) in methanol (10 ml). The mixture was stirred at room temperature for one hour, and (trimethylsilyl)diazomethane (1.0 ml, 2.0 mmol) was then further added, followed by stirring for one hour. The reaction mixture was concentrated under reduced pressure, and the resulting solid was then washed with a solution of hexane/ethyl acetate=5/1 to give 2-(3-methoxycarbonyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester (91.5 mg, 44%).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][OH:21])[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:29]1[C:30]([CH3:38])=[CH:31][C:32]2[N:33]([N:35]=[CH:36][N:37]=2)[N:34]=1>O1CCCC1>[C:22]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][C:29]3[C:30]([CH3:38])=[CH:31][C:32]4[N:33]([N:35]=[CH:36][N:37]=4)[N:34]=3)[CH2:14][CH2:15]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: OCCOCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: Cc1cc2ncnn2nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2ncnn2nc1OCCOCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Yield: 48.2 %

Procedure:
260 mg of 60% sodium hydride dispersion in mineral oil was suspended in 20 ml of tetrahydrofuran; 1.15 g of 4-(diphenylmethyl)-1-[2-(2-hydroxyethoxy)ethyl]piperazine was added, followed by heating and refluxing for 1 hour. After cooling, 540 mg of 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine was added, followed by heating and refluxing for 3 hours. After cooling, ice water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. After the dry product was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with dichloromethane-ethyl acetate-methanol (10:10:1). The desired fraction was collected; the crystal precipitated was collected by filtration, washed with ethyl ether and dried to yield 730 mg of the title compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClC(Cl)C.[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([C:15](Cl)=[O:16])=[CH:11][CH:10]=1.[CH3:19][N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][C:26]#[N:27].Cl>>[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([C:15]([C:24]2[N:20]([CH3:19])[C:21]([CH2:25][C:26]#[N:27])=[CH:22][CH:23]=2)=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cn1cccc1CC#N
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cc1ccc(C(=O)c2ccc(CC#N)n2C)cc1
Temperature: 25 °C

Procedure:
To a cooled suspension of 26.6 g. (0.2 mole) aluminum chloride in 80 ml. dichloroethane is added dropwise 30.8 g. (0.2 mole) p-toluoyl chloride. The resulting solution is added dropwise to a solution of 1-methylpyrrole-2-acetonitrile in 80 ml. dichloroethane cooled externally with an ice bath. After the addition, the resulting solution is stirred at room temperature for twenty minutes and then refluxed for three minutes. The solution is poured into ice acidified with dilute hydrochloric acid. The organic and aqueous fractions are separated. The aqueous fraction is extracted once with chloroform. The organic fractions are combined and washed successively with N,N-dimethyl-1,3-propanediamine, dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic fraction is dried over anhydrous magnesium sulfate. The solvent is then evaporated off. Upon trituration of the residue with methanol, a solid crystallizes, 5-(p-toluoyl)-1-methylpyrrole-2-acetonitrile, which is removed by filtration and purified by recrystallization from benzene. Additional product is isolated from the mother liquors which are combined, concentrated in vacuo, and the resulting oily residue column chromatographed on neutral alumina using hexane, benzene and ether as successive solvents. The product is isolated by concentrating in vacuo the first few major compound-bearing fractions (10% ether in benzene). The solids are combined and recrystallized from methanol and then from benzene-hexane, m.p. 102-105° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].[C:7]([O:11][C:12](=O)[O:13]C(C)(C)C)([CH3:10])([CH3:9])[CH3:8]>C(Cl)Cl>[CH3:1][N:2]([CH2:3][CH2:4][NH:5][CH3:6])[C:12](=[O:13])[O:11][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CNCCNC
Solvent: ClCCl
Product: CNCCN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl methyl(2-(methylamino)ethyl)carbamate was prepared as follows: N1,N2-dimethylethane-1,2-diamine (40 mmol) was dissolved in 100 mL of CH2Cl2 and cooled to 0° C. A solution of di-tert-butylcarbonate (4.0 mmol) in CH2Cl2 (10 mL) was then added dropwise at 0° C. over a period of 15 min. The resulting reaction mixture was stirred at 0° C. for 30 min and then warmed to room temperature. After stirring at room temperature for 2 h, the reaction mixture was diluted with CH2Cl2 (100 mL). The organic layer was washed with brine (3×25 mL), dried (Na2SO4) and concentrated under reduced pressure to afford tert-butyl methyl(2-(methylamino)ethyl)carbamate. This amine was subjected to the same reaction conditions outlined earlier in the preparation of (E)-methyl 4-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethylamino)-4-oxobut-2-enoate. The desired product, namely (E)-methyl 4-(methyl(2-((4Z,7Z,10Z,13Z,16Z,19Z)—N-methyldocosa-4,7,10,13,16,19-hexaenamido)ethyl)amino)-4-oxobut-2-enoate, was obtained after purification by silica gel chromatography. MS (EI) calcd for C31H46N2O4: 510.35. found 511 (M+1).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C@H:11]([N:15]1[CH:19]=[C:18]([C:20]([O:22]CC)=O)[N:17]=[CH:16]1)[CH2:12][CH2:13][OH:14])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:25]>CO>[Si:1]([O:8][C@H:9]([C@H:11]([N:15]1[CH:19]=[C:18]([C:20]([NH2:25])=[O:22])[N:17]=[CH:16]1)[CH2:12][CH2:13][OH:14])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cn([C@H](CCO)[C@H](C)O[Si](C)(C)C(C)(C)C)cn1
Reactant: N
Solvent: CO
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CCO)n1cnc(C(N)=O)c1
Temperature: 100 °C
Yield: 83.8 %

Procedure:
To a solution of ethyl 1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-hydroxy-3-pentyl]imidazole-4-carboxylate (1.0 g, 2.8 mmol) in methanol (15 ml) was added aqueous 28% NH3 solution (15 ml). And the mixture was heated at 100° C. in a sealed steel tube for 15 h. After cooling, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel (35 g) chromatography eluting with chloroform/methanol (25:1 to 15:1) to give 1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-hydroxy-3-pentyl]imidazole-4-carboxamide (769.5 mg, 83.8%) as a white amorphous solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[C:8]2[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=3)=[N:10][CH2:11][C:12](=S)[NH:13][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:27]([O:30][CH2:31][C:32]([NH:34][NH2:35])=O)[CH2:28][CH3:29]>C(O)CCC>[F:26][C:2]([F:25])([F:1])[C:3]1[C:8]2[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=3)=[N:10][CH2:11][C:12]3[N:13]([C:32]([CH2:31][O:30][CH2:27][CH2:28][CH3:29])=[N:34][N:35]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)c1cccc(C2=NCC(=S)Nc3cccc(C(F)(F)F)c32)c1
Reactant: CCCOCC(=O)NN
Solvent: CCCCO
Product: CCCOCc1nnc2n1-c1cccc(C(F)(F)F)c1C(c1cccc(S(C)(=O)=O)c1)=NC2

Procedure:
In the manner given in Example 1, a solution of 1,3-dihydro-6-trifluoromethyl-5-[m-(methylsulfonyl)phenyl]-2H-1,4-benzodiazepine-2-thione in n-butyl alcohol was heated to reflux with propoxyacetic acid hydrazide to give 7-trifluoromethyl-1-(propoxymethyl)-6-[m-(methylsulfonyl)phenyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][CH:6]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[CH2:5][C:4]([CH3:20])([CH3:19])[NH:3]1.[N:22]1[C:29]([Cl:30])=[N:28][C:26](Cl)=[N:25][C:23]=1[Cl:24].[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:19][C:4]1([CH3:20])[CH2:5][CH:6]([N:8]([C:26]2[N:28]=[C:29]([Cl:30])[N:22]=[C:23]([Cl:24])[N:25]=2)[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[CH2:7][C:2]([CH3:21])([CH3:1])[NH:3]1
Reactant: CC1(C)CC(NC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CC1(C)CC(N(c2nc(Cl)nc(Cl)n2)C2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
29.5 g (0.1 mol) of bis(2,2,6,6-tetramethyl-4-piperidyl)amine are slowly added to a solution, cooled to -10° C., of 18.45 g (0.1 mol) of cyanuric chloride in 160 ml of xylene, maintaining the temperature at about 0° C. After the end of the addition, the mixture is stirred for 3 hours at room temperature, 4.4 g (0.11 mol) of powdered sodium hydroxide are added and stirring is continued for a further 2 hours at room temperature.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+].Cl>O1CCCC1CO.O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)CCC(=O)c1ccc(-c2ccc(SC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCC1CCCO1
Product: CSc1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.1 %

Procedure:
A mixture of 4-(4′-methylsulfanyl-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester (0.3742 g, 0.001190 mol) and 1.0 M aqueous sodium hydroxide (1.3 mL, 0.0013 mol) in tetrahydrofuran-methanol (5 mL/5 mL) was stirred at room temperature for 3 days. The volatiles were rotary evaporated, and the residue was suspended in water. The suspension was acidified with 1.0 M aqueous hydrochloric acid (1.4 mL, 0.0014 mol), and the mixture was extracted with tetrahydrofuran-dichloromethane (50/50 v/v). The organics were washed with brine, dried (Na2SO4) and rotary evaporated to give 0.34 g of crude 4-(4′-methylsulfanyl-biphenyl-4-yl)-4-oxo-butyric acid as an off-white solid. A portion of this material (0.3383 g, 0.0011 mol) was stirred with hydroxylamine hydrochloride (0.0931 g, 0.00134 mol) in the presence of sodium carbonate (0.1438 g, 0.001357 mol) in absolute ethanol (7 mL) at reflux for 20 hours and allowed to cool. The volatiles were rotary evaporated, and the residue was partitioned between dichloromethane-tetrahydrofuran (50/50, v/v) and 0.10 M aqueous hydrochloric acid (25 mL). The organics were washed with brine, dried (Na2SO4) and rotary evaporated. The residue was dissolved in tetrahydrofuran, silica gel (4.0 g) was added, and the mixture was rotary evaporated to dryness. The resulting powder was chromatographed on silica gel (48 g, 230-400 mesh), eluting with dichloromethane-diethyl ether (24:1, 13×50 mL); dichloromethane-methanol (24:1, 13×50 mL; 20:1, 10×50 mL) to give 0.0525 g of 4-hydroxyimino-4-(4′-methylsulfanyl-biphenyl-4-yl)-butyric acid as a white solid; mp 162-164° C.
Reaction SMILES: Br[C:2]1[C:3]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])=[CH:12][CH:11]=1)=[O:8].[F:30][C:31]1[CH:32]=[N:33][CH:34]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:36]=1>>[F:30][C:31]1[CH:36]=[C:35]([C:2]2[C:3]([N:24]3[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:22])([F:21])[CH:18]([F:19])[F:20])=[CH:14][CH:15]=3)=[O:8])[CH:23]=2)[CH:34]=[N:33][CH:32]=1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)C(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)C(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)nicotinamide (Stage 212.1) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford a solid. UPLC-MS (Condition 3), tR=0.96 min, m/z=495.3; 1H-NMR (400 MHz, DMSO-d6), δ ppm 1.75 (br. s, 1H) 1.86 (d, J=8.21 Hz, 1H) 2.88 (d, J=12.12 Hz, 1H) 3.17-3.29 (m, 3H) 3.35-3.46 (m, 1H) 4.21 (br. s, 1H) 4.88 (br. s, 1H) 6.79 (m, 1H) 7.26 (d, J=8.99 Hz, 2H) 7.83 (d, J=9.38 Hz, 3H) 8.08 (d, J=2.35 Hz, 1H) 8.51 (s, 1H) 8.60 (d, J=2.74 Hz, 1H) 8.76-8.81 (m, 1H) 10.15 (s, 1H).
Reaction SMILES: C(C1C=CC=CC=1)(C)(C)C.[Cl-].[Al+3].[Cl-].[Cl-].[C:15]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:29][CH3:30])[C:24]=2Br)[CH:19]=1)(=[O:17])[CH3:16].BrC1C2C(=CC=CC=2)C=CC=1OC>>[C:15]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:29][CH3:30])[CH:24]=2)[CH:19]=1)(=[O:17])[CH3:16]
Reactant: COc1ccc2cc(C(C)=O)ccc2c1Br
Agent: COc1ccc2ccccc2c1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(C)(C)c1ccccc1
Product: COc1ccc2cc(C(C)=O)ccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
57 Ml of tert-butylbenzene and 8.2 g of anhydrous aluminum chloride are added to the solution of 2-acetyl-5-bromo-6-methoxynaphthalene obtained as in example 1a), while keeping the temperature at -10° C. The reaction mixture is kept for 16 hours under stirring at room temperature and then it is worked as in example 1 obtaining 41.8 g of product with a yield equal to 85.3% calculated on the basis of the starting material 1-bromo-2-methoxynaphthalene.
Reaction SMILES: [C:1](#[N:6])[CH2:2][C:3]([CH3:5])=[O:4].C(O[CH:12]([N:16]([CH3:18])[CH3:17])N(C)C)(C)(C)C.[CH3:19][N:20]([CH:22](OC)OC)[CH3:21]>>[CH3:18][N:16]([CH3:17])[CH:12]=[CH:5][C:3](=[O:4])[C:2](=[CH:19][N:20]([CH3:22])[CH3:21])[C:1]#[N:6]
Reactant: COC(OC)N(C)C
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(=O)CC#N
Product: CN(C)C=CC(=O)C(C#N)=CN(C)C
Temperature: 100 °C
Yield: 67.5 %

Procedure:
A mixture of acetoacetonitrile (41 g, 493 mmol), t-butoxybis(dimethyl amino)methane (86 g, 493 mmol) and DMF-DMA (263 mL, 1.97 mol) was heated at 100° C. overnight and evaporated to remove the volatiles. The residue was triturated with hexanes/ether (1:1) and the solids were collected by filtration and washed with hexanes/ether (1:1) and a minimum amount of EtOAc to give 64.3 g (67%) of 5-(dimethylamino)-2-[(dimethylamino)methylene]-3-oxopent-4-enenitrile as a light yellow solid, which was used for the next step without further purification.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].[CH:11]#[C:12][CH2:13][CH3:14]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[CH:11]=[C:12]([CH2:13][CH3:14])[O:10][C:3]=2[CH:4]=1
Reactant: COc1ccc(I)c(O)c1
Reactant: C#CCC
Product: CCc1cc2ccc(OC)cc2o1
Yield: 81 %

Procedure:
This material was prepared from 2-iodo-5-methoxyphenol (1 g, 4 mmole) and 1-butyne in a manner as previously described for example 12a to give 570 mg (81%) of a brown oil. 1H NMR (CDCl3) δ 7.33 (1H, d, J=8.6 Hz), 6.97 (1H, d, J=2.2 Hz), 6.80 (1H, dd, J=2.2, 8.6 Hz), 6.26 (1H, s), 3.83 (3H, s), 3.04 (2H, q, J=7.3 Hz), 1.28 (3H, t, J=7.3 Hz).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[OH:11])=[O:3].[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN1C(=O)CCC1.O>[OH:11][C:5]1[CH:6]=[C:7]([S:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:9][C:4]=1[C:2](=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: Sc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)c1ccc(Sc2ccccc2)cc1O
Temperature: 110 °C
Yield: 101.9 %

Procedure:
To a solution of 4-fluoro-2-hydroxyacetophenone (3.083 g, 20 mmol) in NMP (50 mL) were added thiophenol (2.054 ml, 20 mmol) and K2CO3 (8.293 g, 60 mmol). The reaction was heated at 110° C. overnight. Upon cooling the mixture was poured into water, acidified by addition of HCl (diluted) and extracted with Et2O. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 1-(2-hydroxy-4-phenylsulfanyl-phenyl)-ethanone (4.980 g of oil) that was used for the next step without further purification.