Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Br)c1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(F)c(Br)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.3 %

Procedure:
3-Bromo-4-fluorobenzene-1-sulfonyl chloride (0.44 g, 1.609 mmol) in tetrahydrofuran (10 mL) was treated with morpholine (0.294 g, 3.38 mmol). The reaction mixture was stirred for 16 hours at ambient temperature. The solvent was removed, and the residue was loaded onto a silica gel column and eluted with 20% ethyl acetate in hexanes to give the title compound (0.45 g, 1.388 mmol, 86% yield).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][C@@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[C@H:8]([OH:17])[CH2:7]1)=[O:4].[Li][CH2:21][CH2:22][CH2:23]C.C(Br)C=C>C1COCC1>[CH2:23]([O:17][C@H:8]1[C:9]2[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C@@H:6]([NH:5][C:3](=[O:4])[C:2]([F:18])([F:19])[F:1])[CH2:7]1)[CH:22]=[CH2:21]
Reactant: COc1ccc2c(c1)[C@@H](NC(=O)C(F)(F)F)C[C@H]2O
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCO[C@@H]1C[C@H](NC(=O)C(F)(F)F)c2cc(OC)ccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
Step U (1): A solution of 2,2,2-trifluoro-N-((1S,3R)-3-hydroxy-6-methoxy-2,3-dihydro-1H-inden-1-yl)acetamide (enantiomer A, 2.65 g, 9.63 mmol) from step T (1) was cooled to −78° C. in THF. Added n-BuLi (7.7 mL, 19.3 mmol, 2.5M in Hex, Aldrich). Allowed the precipitous mixture to stir at −78° C. for 30 min. Added allyl bromide (4.6 mL, 48.2 mmol, Aldrich), warmed to rt and the reaction became homogeneous. The mixture was stirred for 18 h. Quenched with 1M HCl. Extracted with EtOAc. Washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to afford 1.38 g (46% yield) of N-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide as white solid. LC-MS (M+Na)+=337.9; [α]D −115.43 (c=6.79 mg/mL, dioxane); Anal. Calcd for C15H16F3NO3: C, 57.14; H, 5.11; N, 4.44. Found: C, 57.19; H, 4.88; N, 4.31. 1H NMR (500 MHz, CDCl3) δ ppm 1.55 (s, 2H) 2.09 (d, J=14.04 Hz, 1H) 2.61-2.73 (m, 1H) 3.80 (s, 2H) 4.06 (dd, J=3.05, 1.53 Hz, 2H) 4.79 (dd, J=5.49, 1.83 Hz, 1H) 5.19 (dd, J=10.53, 1.37 Hz, 1H) 5.28 (dd, J=17.24, 1.68 Hz, 1H) 5.39 (s, 1H) 5.83-5.97 (m, 1H) 6.85-6.98 (m, 2H) 7.32 (d, J=8.24 Hz, 1H).
Reaction SMILES: Cl.N1([C:14](=[O:15])[C:13]2[N:11](C)C=N[C:8]=2N(C)C1=O)C.[CH:16]1(C)[CH2:21][CH2:20][CH:19](C(C)C)[CH:18]([OH:25])[CH2:17]1>O>[CH:18]([O:25][C:14](=[O:15])[C@H:13]([CH2:8][C:21]1[CH:16]=[CH:17][C:18]([OH:25])=[CH:19][CH:20]=1)[NH2:11])([CH3:19])[CH3:17]
Reactant: CC1CCC(C(C)C)C(O)C1
Reactant: Cn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: Cl
Solvent: O
Product: CC(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1

Procedure:
HCl (120 g) was dissolved in water (1 L). Caffeine (100 g) and menthol (20 g) were added into the mixture and the mixture was stirred for a few minutes. The mixture was filled into either spray bottles or roll-on bottles.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=2)[O:9][N:8]=1.[O:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:21]3[CH:22]=[CH:23][O:19][CH:20]=3)[CH:17]=2)[O:9][N:8]=1
Reactant: OB(O)c1ccoc1
Reactant: Brc1cncc(-c2nc(-c3ccccn3)no2)c1
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: COCCOC
Product: c1ccc(-c2noc(-c3cncc(-c4ccoc4)c3)n2)nc1
Yield: 32.4 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(5-bromo-pyrid-3-yl)-1,2,4-oxadiazole (152 mg, 0.5 mmol), 3-furylboronic acid (111.9 mg, 1.0 mmole) and Pd(PPh3)4 (57.8 mg, 0.05 mmole) in a solution of 2M sodium carbonate (3 mL) and ethylene glycol dimethyl ether (3 mL) was heated overnight at 105° C. Standard work up afforded 47 mg (32%) of 3-(2-pyridyl)-5-[5-(3-furyl)-pyrid-3-yl]-1,2,4-oxadiazole.
Reaction SMILES: O[C:2]1[C:3]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.P(Br)(Br)([Br:29])=O.C(=O)(O)[O-].[Na+].C(Cl)Cl>C1(C)C=CC=CC=1>[Br:29][C:2]1[C:3]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnc(O)c(C(=O)Nc3ccccc3)n2)cc1
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2cnc(Br)c(C(=O)Nc3ccccc3)n2)cc1
Temperature: 25 °C
Yield: 120.8 %

Procedure:
A solution of 3-hydroxy-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide (84.3 mg, 0.1712 mmol) in toluene (3.000 mL) was treated with POBr3 (196.3 mg, 0.6848 mmol) and the resultant mixture was heated to 100° C. for 16 hours. The reaction mixture was allowed to cool to ambient temperature and treated with sodium bicarbonate/DCM. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo to give the impure desired product as a yellow solid (89.4 mg, 95% Yield). MS (ES+) 433.88.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11](Cl)=[O:12])=[CH:2]1.[C:15]1([CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][NH2:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC#N>[C:24]1([CH:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:22][NH:23][C:11](=[O:12])[C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:14])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: O=C(NCC(c1ccccc1)c1ccccc1)C(=O)c1c[nH]c2ccccc12

Procedure:
N-(2,2-Diphenylethyl)-2-(1H-indol-3-yl)-2-oxo-acetamide was synthesized following the scheme I above starting from (1H-indol-3-yl)-oxo-acetyl chloride and 2,2-diphenyl-ethylamine. Yield (48%). HPLC ret. time 3.55 min, 10-99% CH3CN, 5 min run; NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 8.70 (t, J=5.9 Hz, 1H), 8.50 (s, 1H), 8.17 (m, 1H), 7.52 (m, 1H), 7.36-7.18 (m, 12H), 4.43 (t, J=8.0 Hz, 1H), 3.90 (dd, J=8.0, 6.0 Hz, 2H); ESI-MS 369.3 m/z (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Mg+2].[Cl-].[CH2:15]=[O:16].C(N(CC)CC)C>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:15]=[O:16])[C:6]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1O
Reactant: C=O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cccc(C=O)c1O
Yield: 90 %

Procedure:
To a stirred suspension of 2-tert-butylphenol (6)(4.55 g, 30 mmol), magnesium chloride (5.71 g, 60 mmol) and paraformaldehyde (2.08 g, 66 mmol) in THF (120 mL) at room temperature, was added triethylamine (8.35 mL, 60 mmol) dropwise. The reaction was heated to reflux for 3 hours to give an orange suspension. The crude was extracted using EtOAc (3×50 mL). A small amount of diluted HCl can be added if a permanent emulsion is formed. The organic layers were dried over MgSO4 and the volatiles evaporated under low pressure to yield a pale yellow oil which did not need any further purification. It can become dark green on storage. Yield: 90%. Pale yellow oil. 1H-NMR δH (CDCl3, 300 MHz): 1.44 (9H, s, 3×CH3), 6.97 (1H, t, J=7.5 Hz, HAr), 7.41 (1H, dd, J=1.5 Hz, J=7.5 Hz, HAr), 7.54 (1H, dd, J=1.2 Hz, J=7.5 Hz, HAr), 9.88 (1H, s, CHO), 11.82 (1H, s, OH).
Reaction SMILES: C([O:4][CH2:5][CH:6]([O:22][CH2:23][P:24]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][O:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][C:12]([NH:19]C=O)=[N:13][C:14]=2Cl)(=O)C.[NH3:32]>>[NH2:19][C:12]1[N:11]=[C:10]2[C:15]([N:16]=[CH:17][N:9]2[O:8][CH2:7][CH:6]([O:22][CH2:23][P:24]([O:26][CH2:27][CH3:28])([O:29][CH2:30][CH3:31])=[O:25])[CH2:5][OH:4])=[C:14]([NH2:32])[N:13]=1
Reactant: N
Reactant: CCOP(=O)(COC(COC(C)=O)COn1cnc2c(Cl)nc(NC=O)nc21)OCC
Product: CCOP(=O)(COC(CO)COn1cnc2c(N)nc(N)nc21)OCC
Temperature: 25 °C

Procedure:
A solution of 9-[3-acetoxy-2-(diethoxyphosphorylmethoxy)propoxy]-6-chloro-2-formamidopurine (0.16 g, 0.33 mmol) in ethanolic ammonia (5 ml) was heated in a sealed vessel at 120° C. for 5 hours. The solution was allowed to cool to ambient temperature and the solvent was removed under reduced pressure to leave a brown residue. The residue was purified by preparative t.l.c. (dichloromethane:methanol 80:20) to give 2,6-diamino-9-[2-(diethoxyphosphorylmethoxy)-3-hydroxypropoxy]purine as a colourless gum (0.065 g). The gum (0.06 g, 0.15 mmol) was dissolved in dry DMF (1 ml) and trimethylsilyl bromide (0.3 ml, 1.53 mmol) added. After 3 hours at ambient temperature, the solvent was removed under reduced pressure and the residue obtained dissolved in 50% aqueous acetone. Evaporation of the solvent gave a solid which after crystallisation from hot water, gave the title compound as a cream solid (0.014 g, 27%). 1H NMR: δH [(CD3) 2 SO] 3.46-3.60 (2H, m, CH2OH), 3.65-3.85 (3H, m, CHOCH2P), 4.24 (1H, m, NOCHB), 4.42 (1H, m, NOCHA), 6.03 (2H, br. s, D2O exchangeable NH2), 6.88 (2H, br. s, D2O exchangeable NH2), 8.02 (1H, s, H-8), 3.3 (br.s, D2O exchangeable OH, PO(OH)2, water in solvent). m/z (FAB, thioglycerol matrix) 335 (MH+, 6%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=1.Cl[C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:12]=[C:11]([N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=[C:22]2[CH:30]([F:32])[F:31])[N:10]=1.O>CS(C)=O>[F:32][CH:30]([F:31])[C:22]1[N:21]([C:11]2[N:12]=[C:13]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[N:14]=[C:9]([NH:1][C:2]3[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=3)[N:10]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1
Reactant: Cn1cc(N)cn1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: O
Solvent: CS(C)=O
Product: Cn1cc(Nc2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)cn1
Temperature: 125 °C
Yield: 17.9 %

Procedure:
A mixture of 0.405 g (4.27 mmol) of 4-amino-1-methylpyrazole and 0.695 g (1.90 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in DMSO (5 mL) was heated at 125° C. for 15 min. The reaction mixture was cooled to room temperature and water was added. The solid was collected by filtration, washed with water, and dried. Chromatography on alumina, eluting with hexanes/EtOAc (1:1) gave a brown powder. Recrystallization from ethanol/CH2Cl2 gave 0.145 g (18% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-(1-methyl-1H-pyrazol-4-yl)-6-(4-morpholinyl)-1,3,5-triazin-2-amine: mp 225-226° C.; 1H NMR (DMSO-d6) (rotamers) δ 10.00 (s, 1H), 9.73 (s, 0.2H), 8.60 (d, J=8.0 Hz, 1H), 8.29 (d, J=7.6 Hz, 0.2H), 7.92 (t, JHF=52.8 Hz, 1H), 7.86-7.80 (m, 2.6H), 7.68 (t, JHF=52.6 Hz, 0.2H), 7.59 (s, 1H), 7.52-7.42 (m, 2.9H), 3.85-3.82 (m, 8.4H), 3.75-3.73 (m, 4.8H); Anal. Calcd. for C19H19F2N9O 0.06EtOAc 0.24H2O: C, 52.9; H, 4.6; N, 28.8. Found: C, 52.9; H, 4.5; N, 28.6%.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH2:5].[N:8]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=1)=[C:9]=[S:10].Cl>O1CCOCC1>[SH:10][C:9]1[N:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=2)[CH:3]=[CH:4][N:5]=1
Reactant: N#Cc1ccc(N=C=S)c2ccccc12
Reactant: COC(CN)OC
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(-n2ccnc2S)c2ccccc12
Temperature: 105 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
Aminoacetaldehyde dimethyl acetal (5.98 mL, 55.36 mmol) was added to a stirring slurry of 4-isothiocyanato-1-naphthonitrile (11.64 g, 55.36 mmol) in dioxane (55 mL), and stirring continued for 1 h (sizeable exotherm observed). HCl was added (4.8 mL, 58.13 mmol) and the mixture heated to 105° C. for 18 h. The mixture was then concentrated, methanol added (100 mL), concentrated again, more methanol added (100 mL) and sonicated. Filtration provided 4-(2-mercapto-1H-imidazol-1-yl)-1-naphthonitrile as a tan solid (8.33 g, 60%).
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[C:26]([CH2:27][C:28]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:29])=[C:25]([CH3:37])[NH:24][C:23]=1[CH:38]=O.N1CCCCC1>C(O)C>[CH3:21][C:22]1[C:26]([CH2:27][C:28]([N:30]2[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]2)=[O:29])=[C:25]([CH3:37])[NH:24][C:23]=1/[CH:38]=[C:14]1\[C:15](=[O:20])[NH:16][C:17]2[C:13]\1=[CH:12][C:11]([S:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:10])=[O:9])=[CH:19][CH:18]=2
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)N1CCN(C)CC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4)cc32)c(C)c1CC(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-phenylmethanesulfonyl-1,3-dihydro-indol-2-one (100 mg, 0.35 mmol), 3,5-dimethyl-4-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-pyrrole-2-carbaldehyde (174 mg, 0.68 mmol) and piperidine (0.5 eq.) in ethanol (2 mL) was stirred at rt for 48 hours. The reaction was concentrated and triturated with acetone to give the titled compound as a pale orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)#[N:14]>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]2[CH:19]=[CH:20][C:15]([C:13]#[N:14])=[CH:16][CH:17]=2)=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Product: N#Cc1ccc(-c2ccc(N)cc2C(F)(F)F)cc1

Procedure:
The title compound is prepared as described in Example 13 but using 5-amino-3-bromobenzotrifluoride (OAKWOOD PRODUCTS; Inc.) and 1.5 equiv of 4-cyanophenylboronic acid (MATRIX SCIENTIFIC). Silica gel column chromatography purification (Hexane/EtOAc, 4:1) provides the title compound as a white solid: ES-MS: 262.0 [M-H]−; single peak at tR=4.37 min (System 1); Rf=0.09 (Hexane/EtOAc, 4:1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12](Br)=[CH:11][C:10]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([NH:21][C:22](=[CH2:27])[C:23]([O:25][CH3:26])=[O:24])(=[O:20])[CH3:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:18]([NH:21][C:22](=[CH:27][C:12]1[CH:13]=[C:14]([CH3:15])[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([CH3:17])[CH:11]=1)[C:23]([O:25][CH3:26])=[O:24])(=[O:20])[CH3:19]
Reactant: Cc1cc(Br)cc(C)c1OCc1ccccc1
Reactant: C=C(NC(C)=O)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C(=Cc1cc(C)c(OCc2ccccc2)c(C)c1)NC(C)=O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere a mixture of 40.0 g (137 mmol) 2-benzyloxy-5-bromo-1,3-dimethylbenzene and 24.1 g (165 mmol) methyl 2-acetylamino-acrylate in 420 mL triethylamine and 200 mL acetonitrile was combined with 3.5 g (11.2 mmol) tri-o-tolyl-phosphane and 2.5 g (11.1 mmol) Pd(OAc)2 and the mixture was stirred for 18 h at 80° C. The precipitate was suction filtered, the filtrate was evaporated down i. vac. and combined with 800 mL DCM and 800 mL water. The organic phase was separated off, suction filtered through Na2SO4, the solvent was removed i.vac., the residue was stirred with EtOAc, suction filtered and dried i. vac.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([S:13][CH3:14])[N:5]=[C:4]([CH3:15])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:22]([C:24]1[CH:37]=[CH:36][CH:35]=[CH:34][C:25]=1[O:26][C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1)#[N:23].O>CN(C=O)C.[Cu](I)I>[CH3:15][C:4]1[N:5]=[C:6]([S:13][CH3:14])[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:2]([O:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([O:26][C:25]3[CH:34]=[CH:35][CH:36]=[CH:37][C:24]=3[C:22]#[N:23])[CH:28]=2)[N:3]=1
Reactant: COC(=O)Cc1c(Cl)nc(C)nc1SC
Reactant: N#Cc1ccccc1Oc1cccc(O)c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1c(Oc2cccc(Oc3ccccc3C#N)c2)nc(C)nc1SC

Procedure:
A solution of methyl 2-(4-chloro-2-methyl-6-methylthio-pyrimidin-5-yl)-acetate (5.5 g) in DMF (80 ml) is added to a suspension of anhydrous potassium carbonate (5.6 g) and 3-(2-cyanophenoxy)phenol (5.1 g) and copper iodide (1 g) in DMF at room temperature. The mixture was heated to +120° C. for 2 hours and then cooled. The mixture is poured into water and extracted successively with ethyl acetate (2×50 ml) and the organic phase dried over anhydrous sodium sulfate. Evaporation and drying under high vacuum gives the methyl 2-[2-methyl-4-methylthio-6-(3-(2-cyanophenoxy)-phenoxy)-pyrimidin-5-yl]-acetate, as a crude product in form of a yellow oil. NMR (CDCl3): 6.18-6.84 (m, 3H); 3.74 (s, 2H); 3.69 (s, 3H); 2.85 (m, 1H); 2.51 (s, 3H); 2.45 (s, 3H); 2.34 (s, 3H); 1.22 (d, 6H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)[CH3:2].[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[N:38]1[C:42](=[O:43])[CH2:41][S:40]/[C:39]/1=[N:44]\[C:45](=O)[O:46]C1C=CC([N+]([O-])=O)=CC=1)([CH3:30])[CH3:29]>>[CH2:1]([N:3]([CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=3)[N:13]=2)=[CH:10][CH:11]=1)[C:45](/[N:44]=[C:39]1\[S:40][CH2:41][C:42](=[O:43])[N:38]\1[C:32]1[CH:33]=[C:34]([CH3:37])[CH:35]=[CH:36][C:31]=1[CH:28]([CH3:29])[CH3:30])=[O:46])[CH3:2]
Reactant: CCNCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Product: CCN(CCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)C(=O)/N=C1\SCC(=O)N1c1cc(C)ccc1C(C)C

Procedure:
The title compound was prepared as described in Example 95 using N-ethyl-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethanamine (CB25) and (Z)-4-nitrophenyl (3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50), purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolated as a red solid (0.075 g, 56%).
Reaction SMILES: Br[CH2:2][C@H:3]1[CH2:8][CH2:7][Si@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:5][CH2:4]1.[Mg].I[CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>[Cu]I.P(OCC)(OCC)(OCC)=O.C1COCC1>[CH2:9]([Si@H:6]1[CH2:7][CH2:8][C@H:3]([CH2:2][CH2:16][C@H:17]2[CH2:18][CH2:19][C@H:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)[CH2:21][CH2:22]2)[CH2:4][CH2:5]1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCC[Si@H]1CC[C@H](CBr)CC1
Reactant: FC(F)(F)c1ccc(-c2ccc([C@H]3CC[C@H](CI)CC3)cc2)cc1
Agent: [Cu]I
Agent: [Mg]
Solvent: CCOP(=O)(OCC)OCC
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)CC2)CC1

Procedure:
26.3 g (0.1 mol) of trans-1-bromomethyl-4-n-pentyl-4-silacyclohexane was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 44.4 g (0.1 mol) of 4-(trans-4-iodomethylcyclohexyl)-4'-trifluoromethylbiphenyl. After a conventional after treatment, purification was conducted by means of chromatography to obtain 38.5 g (yield 76.9%) of 4-(trans-4-(2-(trans-4-n-pentyl-4-silacyclohexyl)ethyl)cyclohexyl)-4'-trifluoromethylbiphenyl was obtained.
Reaction SMILES: [CH2:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]([OH:12])=[O:11])[CH:6]=1)[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>>[CH2:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]([OH:12])=[O:11])[C:6]=1[N+:18]([O-:20])=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])O
Reactant: CCCCc1cc(C(=O)O)n[nH]1
Agent: O=S(=O)(O)O
Product: CCCCc1[nH]nc(C(=O)O)c1[N+](=O)[O-]
Temperature: 60 °C
Yield: 76.7 %

Procedure:
5-Butyl-1H-pyrazol-3-carboxylic acid (22.6 g, 134 mmol) was added portionwise to concentrated sulfuric acid (100 ml) at room temperature with stirring. The reaction mixture was then heated to 60° C. and concentrated nitric acid (70%, 23.7 ml, 376 mmol) was added dropwise, keeping the temperature at 60° C. The reaction was then stirred at 60° C. for 3 hours, cooled to room temperature and poured onto 50 ml of ice with stirring. After 15 minutes the pale yellow precipitate was isolated by filtration, washed with water and dried under reduced pressure to give 5-butyl-4-nitro-1H-pyrazol-3-carboxylic acid (21.9 g) as a pale yellow solid. 1H NMR (400 MHz, DMSO-D6): δ=2.83-2.92 (2H, t), 1.56-1.64 (2H, quin), 1.22-1.36 (2H, sext), 0.84-0.90 (3H, t) ppm. LRMS (electrospray): m/z [M−H]+ 212. Anal. Found C, 30.19; H, 5.41; N, 13.12. C8H11N3O4. 6 mol H2O requires C, 29.91; H, 7.22; N, 13.08%.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[C:9]([C:18]([O:20]CC)=O)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2.[C:23](#[N:25])[CH3:24].O>C1(C)C=CC=CC=1>[CH3:7][C:8]1[C:9]([C:18](=[O:20])[CH2:24][C:23]#[N:25])=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: CCOC(=O)c1nc2ccccc2nc1C
Reactant: CC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc2ccccc2nc1C(=O)CC#N
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of potassium tert-butoxide (72.7 g, 647 mmol) in toluene (810 mL) was added a solution of ethyl 3-methylquinoxaline-2-carboxylate (70.0 g, 324 mmol) and acetonitrile (38.3 mL, 809 mmol) in toluene (270 mL) dropwise over 50 min at 5° C. After being stirred for 5 min at 0° C., water (585 mL) was added. The organic layer was extracted with water (100 mL) and the aqueous layer was combined and acidified to pH 3-4 with 10% aqueous hydrochloric acid. The resulting precipitate was collected and dissolved to tetrahydrofuran. And then the organic layer was dried over sodium sulfate, filtrated and concentrated in vacuo. The crude solid was purified by silica gel column chromatography (silica gel 2.2 kg, chloroform to chloroform:ethyl acetate=19:1) to give 3-(3-methylquinoxalin-2-yl)-3-oxopropanenitrile. MS (APCI): m/z 212 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC1C=CC(S(O[CH2:27][C:28]2([CH3:32])[CH2:31][O:30][CH2:29]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:27][C:28]1([CH2:32][O:1][C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=2)[C:12]([O:14][CH3:15])=[O:13])[CH2:31][O:30][CH2:29]1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)COC2)cc1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCC2(C)COC2)cc(C(=O)OC)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture of dimethyl 5-hydroxyisophthalate (500 mg), (3-methyloxetan-3-yl)methyl 4-methylbenzenesulfonate (915 mg), and potassium carbonate (850 mg) in N,N-dimethylformamide (3 mL) is stirred at 50° C. for 5 h. The reaction mixture is diluted with water and the precipitate is filtered off, washed with water, and dried to give the title compound. LC (method 7): tR=0.97 min; Mass spectrum (ESI+): m/z=295 [M+H]+.