Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](O)([CH3:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Br-:12].[Li+].C[Si](Cl)(C)C>C(#N)C>[Br:12][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)([CH3:10])[CH3:9]
Reactant: [Br-]
Reactant: CC(C)(O)c1cccc(Cl)c1
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: CC#N
Product: CC(C)(Br)c1cccc(Cl)c1

Procedure:
This compound is prepared in a manner analogous to that of Step A of Example 5, using 8.5 grams (0.05 mole) of 2-(3-chlorophenyl)propan-2-ol, 8.7 grams (0.1 mole) of lithium bromide, and 13.5 grams (0.125 mole) of trimethylsilyl chloride in 100 mL of acetonitrile, yielding 2-bromo-2-(3-chlorophenyl)propane.
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([F:13])[F:12])=[CH:6][C:5]=1[N+:14]([O-])=O.[H][H]>[Ni].O1CCOCC1>[F:1][CH:2]([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([F:13])[F:12])=[CH:6][C:5]=1[NH2:14]
Reactant: O=[N+]([O-])c1cc(OC(F)F)ccc1OC(F)F
Reactant: [H][H]
Agent: [Ni]
Solvent: C1COCCO1
Product: Nc1cc(OC(F)F)ccc1OC(F)F
Yield: 98.9 %

Procedure:
A mixture of 12.6 g of 2.5-bis(difluoromethoxy)nitrobenzene, 1.3 g of Raney-nickel catalyst and 130 ml of dioxane is agitated in a hydrogen atmosphere for 15 hours at a temperature of 20°-25° C. The hydrogen consumption is 3.34 liters. After removal of the catalyst the mixture is evaporated to dryness, yielding 11.0 g of crude 2.5-bis(difluoromethoxy) aniline in form of a yellow-brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Br[C:30]([CH3:36])([CH3:35])[C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[Si:12]([O:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:30]([CH3:36])([CH3:35])[C:31]([O:33][CH3:34])=[O:32])=[CH:7][CH:6]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)[Si](OCCCc1ccc(O)cc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)C(C)(C)Oc1ccc(CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 60 °C
Yield: 93 %

Procedure:
A solution of 3-(4-hydroxyphenyl)-1-(tert-butyldiphenylsilyloxy)propane (5.00 g, 12.8 mmol and methyl 2-bromo-2-methylpropionate (4.53 g, 25.0 mmol in dry acetonitrile (25 ml) was treated with cesium carbonate (8.3 g, 25.4 mmol and the resulting mixture was heated at 60° C. for 3.5 h. The cooled mixture was diluted with ethyl acetate, washed with water, brine and dried (magnesium sulfate). Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene) gave 5.88 g (93%) of the title material as a clear oil.
Reaction SMILES: N(C(OCCOC)=O)=NC(OCCOC)=O.[CH3:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([CH3:27])=[CH:20][C:19]=1[OH:28].[CH3:29][C:30]1([CH2:33]O)[CH2:32][CH2:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([CH3:27])=[CH:20][C:19]=1[O:28][CH2:29][C:30]1([CH3:33])[CH2:32][CH2:31]1
Reactant: CC1(CO)CC1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1O
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])c(C)cc1OCC1(C)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 34.8 %

Procedure:
2.98 g of Bis(2-methoxyethyl) azodicarboxylate was added to a mixture of 1.59 g of 2,5-dimethyl-4-nitrophenol, 0.81 g of (1-methylcyclopropyl)methanol, 2.98 g of triphenylphosphine and 50 mL of toluene at 0° C., and the mixture was stirred at 80° C. for 4 hours. After cooling, a saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate, and then the organic layer was washed with water and saturated salt water and dried over anhydrous magnesium sulfate. The resulting residue was subjected to silica gel column chromatography to obtain 0.77 g of 2,5-dimethyl-1-[(1-methylcyclopropyl)methoxy]-4-nitrobenzene.
Reaction SMILES: [C:1]1([C@@H:11]([NH2:13])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:21]([CH2:26]Br)[C:22]([O:24][CH3:25])=[O:23]>C(#N)C>[CH3:25][O:24][C:22]([CH:21]1[CH2:26][N:13]1[CH:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:12])=[O:23]
Reactant: COC(=O)C(Br)CBr
Reactant: C[C@H](N)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1CN1C(C)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a solution of (S)-(−)-1-(1-naphthyl)ethylamine (20.8 g, 120 mmol) in acetonitrile (HPLC grade, 600 mL) is added K2CO3 (52.7 g, 360 mmol) and methyl 2,3-dibromopropionate (30 g, 120 mmol). The solution is stirred overnight at room temperature. The solution is evaporated to dryness, then H2O/EtOAc (1:1) (600 mL) is added, and the mixture is extracted with EtOAc (4×100 mL). The organic extracts are combined, dried and concentrated under vacuum. The residue is purified by flash chromatography (silica gel; Hexane/EtOAc 1:2) to provide 24 g (78%) of the title compound as a mixture of two diastereomers in an equimolecular ratio. M+H+=256.10.
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH:1]1([CH2:7][O:8][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Cyclohexylmethanol (1.25 mL, 10.0 mmol) was dissolved in CH2Cl2 (50 mL), treated with diisopropylethylamine (7.0 mL, 40.0 mmol), cooled to 0° C., treated with methanesulfonyl chloride (0.85 mL, 11.0 mmol), and stirred for 1 hour at room temperature. The reaction was diluted with CH2Cl2 (200 mL), washed with saturated bicarbonate solution and brine, dried over Na2SO4, and concentrated to give 2.42 g (125% crude yield) of the desired product which was used immediately without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:9]2)([O-])=O.C(O)C>[C].[Pd].O1CCCC1>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[NH:11][C:12]2[C:8]([CH:9]=1)=[CH:7][CH:6]=[CH:5][C:4]=2[NH2:1]
Reactant: O=[N+]([O-])c1cccc2cc(-c3ccccn3)[nH]c12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cccc2cc(-c3ccccn3)[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
A mixture of 7-nitro-2-(pyridin-2-yl)-1H-indole (0.47 g), 10% palladium-carbon (50% water, 0.05 g), ethanol (4 mL) and tetrahydrofuran (10 mL) was stirred at room temperature overnight under a hydrogen atmosphere. Palladium-carbon was filtered off, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography and the title compound (0.35 g, yield 85%) was obtained as pale-yellow crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). melting point 165-166° C.
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][C:8]([CH3:12])([OH:11])[C:9]#[CH:10])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[CH:17]=[CH:18][C:19]2[N:23]=[C:22]([CH3:24])[N:21]([C:25]3[N:30]=[CH:29][N:28]=[C:27]([NH2:31])[N:26]=3)[C:20]=2[CH:32]=1.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].[Cu]I>[NH2:31][C:27]1[N:28]=[CH:29][N:30]=[C:25]([N:21]2[C:20]3[CH:32]=[C:16]([C:10]#[C:9][C:8]([CH3:12])([OH:11])[CH2:7][O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:14])[CH3:13])[CH:17]=[CH:18][C:19]=3[N:23]=[C:22]2[CH3:24])[N:26]=1
Reactant: C#CC(C)(O)CO[Si](C)(C)C(C)(C)C
Reactant: Cc1nc2ccc(Br)cc2n1-c1ncnc(N)n1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: Cc1nc2ccc(C#CC(C)(O)CO[Si](C)(C)C(C)(C)C)cc2n1-c1ncnc(N)n1
Temperature: 120 °C
Yield: 68 %

Procedure:
The title compound was prepared by procedure described in Example 144, by substituting 2-ethynylbicyclo [2.2.1]heptan-2-ol with 1-(tert-butyl-dimethyl-silanyloxy)-2-methyl-but-3-yn-2-ol. A mixture of 4-(6-bromo-2-methyl-benzoimidazol-1-yl)-[1,3,5]triazin-2-ylamine (300 mg, 0.98 mmol), 1-(tert-butyl-dimethyl-silanyloxy)-2-methyl-but-3-yn-2-ol (380 mg, 1.9 mmol) in DMF (2.5 mL) was treated with Pd(OAc)2 (20 mg, 0.1 mmol), dppp (60 mg, 0.2 mmol), CuI (5 mg, 0.05 mmol) and K2CO3 (280 mg, 2.0 mmol), then the mixture was heated at 120° C. for 40 min under microwave. After filtrated and concentrated by vacuum, the residue was purified by silica gel chromatography (DCM: MeOH=20:1) to get the title compound 4-[3-(4-amino-[1,3,5]triazin-2-yl)-2-methyl-3H-benzoimidazol-5-yl]-1-(tert-butyl-dimethyl-silanyloxy)-2-methyl-but-3-yn-2-ol (7-b) (300 mg, yield 68%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=2)=[CH:9][CH2:10][S:11][C:12]2[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[C:14]([CH3:23])[CH:13]=2)=[CH:4][CH:3]=1.[C:31]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.[F-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Br:30][C:27]1[CH:28]=[CH:29][C:24]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([C:43]3[CH:44]=[CH:45][C:40]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:41][CH:42]=3)=[CH:7][CH:6]=2)=[CH:9][CH2:10][S:11][C:12]2[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[C:14]([CH3:23])[CH:13]=2)=[CH:25][CH:26]=1
Reactant: Cc1cc(SCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)ccc1OCC(=O)O
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cc(SCC=C(c2ccc(Br)cc2)c2ccc(-c3ccc(-c4ccccc4)cc3)cc2)ccc1OCC(=O)O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of {4-[3,3-bis-(4-bromo-phenyl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid (example 1) (225 mg, 0.410 mmol), 4-biphenylboronic acid (163 mg, 0.82 mmol), KF (79 mg, 1.35 mmol), Pd2(dba)3 (23 mg, 0.025 mmol) and Pd(P(t-Bu)3)2 (25 mg, 0.049 mmol) was evacuated for air and kept under nitrogen. THF (6 ml) was added and the reaction mixture was stirred at 70° C. overnight. A saturated aqueous NH4Cl (5 ml) solution was added, and the mixture was extracted with methylene chloride (2×20 ml). The combined organic phases were dried an evaporated. The isolated products were further purified on column chromatography using methylene chloride:THF (40:1) as eluent. The isolated products were further purified on HPLC using acetonitril:water (7:3) increasing to pure acetonotril as eluent. The title product was isolated as an E/Z mixture in 40 mg (16%) yield.
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[C:7]1([C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[CH:15]=O)[CH2:11][CH2:10][CH2:9][CH:8]=1.[CH3:20][C:21]1([CH3:34])[CH2:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH2:31][CH2:32][NH2:33])[C:23]=2[O:22]1.[BH4-].[K+]>ClCCCl>[CH3:20][C:21]1([CH3:34])[CH2:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH2:31][CH2:32][NH:33][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[C:12]([C:7]4[CH2:11][CH2:10][CH2:9][CH:8]=4)[CH:13]=3)[C:23]=2[O:22]1
Reactant: CC1(C)Cc2cccc(OCCN)c2O1
Reactant: O=Cc1cccc(C2=CCCC2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: ClCCCl
Product: CC1(C)Cc2cccc(OCCNCc3cccc(C4=CCCC4)c3)c2O1
Temperature: 60 °C
Reaction time: 3 h
Yield: 51.5 %

Procedure:
1.5 g of magnesium sulfate are added to a solution of 3-cyclopenten-1-ylbenzaldehyde (2a) (0.56 g, 3.26 mmol) and of [2-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl-oxy)]ethylamine (3a) (0.68 g, 3.26 mmol) in 15 ml of 1,2-dichloroethane and the mixture is heated at 60° C. for 17 hours. The mixture is cooled to room temperature, the solid is filtered and the solvent is evaporated under reduced pressure. The residue is diluted with 15 ml of methanol and then cooled to 0° C. 0.35 g of potassium borohydride (6.52 mmol) is then introduced and the reaction mixture is stirred for 3 hours at 0° C. The mixture is then poured into ice-cold water, extracted with ethyl acetate and washed with a saturated aqueous sodium chloride solution. The combined organic phases are dried over magnesium sulfate, filtered and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on silica gel (methylene chloride/methanol/aqueous ammonia: 98/1.5/0.5). The title product (0.61 g) is isolated in the form of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:16])=[C:11]([Cl:24])[CH:10]=2)=[C:4]([CH2:25][O:26][CH2:27][CH2:28]O)[CH:3]=1.[C:30]([O:33][C@H:34]1[C@@H:39]([O:40][C:41](=[O:43])[CH3:42])[C:38](=[O:44])[NH:37][C:35]1=[O:36])(=[O:32])[CH3:31]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:16])=[C:11]([Cl:24])[CH:10]=2)=[C:4]([CH:3]=1)[CH2:25][O:26][CH2:27][CH2:28][N:37]1[C:38](=[O:44])[C@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@H:34]([O:33][C:30](=[O:32])[CH3:31])[C:35]1=[O:36]
Reactant: CC(=O)O[C@@H]1C(=O)NC(=O)[C@@H]1OC(C)=O
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2COCCO)cc1Cl
Product: CC(=O)O[C@@H]1C(=O)N(CCOCc2cc(Br)ccc2Nc2ccc(C(=O)c3ccccc3C)c(Cl)c2)C(=O)[C@@H]1OC(C)=O

Procedure:
Compound 158 (67 mg, 0.1 mmol) and 2,3-cis-diacetoxysuccinimide (30 mg, 0.14 mmol) were treated as described in the preparation of compound 219. Purification was done by flash chromatography (CH2Cl2/ethyl acetate 1:20) to provide the title compound as yellow oil.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[NH2:11][C:12](=[N:29][N+:30]([O-:32])=[O:31])[NH:13][CH2:14][CH2:15][CH2:16][C@H:17]([C:26]([OH:28])=O)[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[NH2:33][C:34]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][NH2:45])=[CH:40][CH:39]=1)=[O:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:33][C:34]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][NH:45][C:26](=[O:28])[C@@H:17]([CH2:16][CH2:15][CH2:14][NH:13][C:12]([NH2:11])=[N:29][N+:30]([O-:32])=[O:31])[NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[CH:40][CH:39]=1)=[O:35]
Reactant: NCc1ccc(CNC(N)=O)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Product: CC(C)(C)OC(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)NCc1ccc(CNC(N)=O)cc1
Yield: 80 %

Procedure:
Prepared analogously to Example 14c), but with the addition of HOBt, from (R)-N5 -[amino(nitroimino)methyl]-N2 -[(1,1-dimethylethoxy)-carbonyl]-ornithine, 4-(aminocarbonylaminomethyl)-benzenemethanamine and TBTU in a yield of 80% of theory. Colourless crystals, Mp. 172° C.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[S:7])[CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[NH:3]1.[C:12](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[CH3:1][N:2]1[C:6]([S:7][CH3:12])=[CH:5][C:4]([C:8]([F:11])([F:9])[F:10])=[N:3]1
Reactant: Cn1[nH]c(C(F)(F)F)cc1=S
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CSc1cc(C(F)(F)F)nn1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.4 %

Procedure:
3.87 g of compound (8-5) and 4.40 g of potassium carbonate were suspended in 100 ml of acetonitrile. The suspension was stirred at room temperature for 15 minutes. A solution of 3.62 g of methyl iodide in 10 ml of acetonitrile was added dropwise, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure. After water was added to the residue, the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to produce 3.60 g of 1-methyl-5-methylthio-3-(trifluoromethyl)pyrazole (14).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1.[NH2:25][C@H:26]([C:28]([O:30][CH3:31])=[O:29])[CH3:27]>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([NH:25][C@H:26]([C:28]([O:30][CH3:31])=[O:29])[CH3:27])=[O:21])[C:9]2[C:10]([CH3:16])=[CH:11][CH:12]=[CH:13][C:14]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](C)N
Reactant: Cc1cccc(C)c1N(CCCC(=O)O)C(=O)c1ccc(Cl)cc1
Product: COC(=O)[C@H](C)NC(=O)CCCN(C(=O)c1ccc(Cl)cc1)c1c(C)cccc1C

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyric acid and methyl L-alaninate and suitable processing produces methyl N-[N-(p-chlorobenzoyl)-4-(2,6dimethylanilino)butyryl]-L-alaninate (M.P. 91° to 92°), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyryl]-L-alanine (M.P. 159° to 161°).
Reaction SMILES: C(NC(C)C)(C)C.CC(C)([O-])C.[K+].[F:14][CH:15]1[C:21](=[O:22])[C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([S:27]([C:30]2[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH2:17][CH2:16]1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:47])(=O)=O)=CC=1.Cl>O1CCCC1.CCCCCC>[F:14][C:15]1([F:47])[C:21](=[O:22])[C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([S:27]([C:30]2[CH:31]=[CH:32][C:33]([CH3:34])=[CH:35][CH:36]=2)(=[O:29])=[O:28])[CH2:17][CH2:16]1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(F)C(=O)c3ccccc32)cc1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1ccc(S(=O)(=O)N2CCC(F)(F)C(=O)c3ccccc32)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 30.4 %

Procedure:
To 300 ml of tetrahydrofuran solution containing 2.62 g of diisopropylamine and 2.91 g of potassium t-butoxide was added dropwise 16.2 ml of 1.6N n-hexane solution of n-butyllithilum at -78° C., followed by 30 minutes of stirring at -78° C. To this reaction solution was added 70 ml of tetrahydrofuran solution containing 7.2 g of 4-fluoro-1-tosyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one, followed by 1 hour of stirring at -78° C. The reaction solution was mixed with 70 ml of tetrahydrofuran solution containing 10.22 g of N-fluorobenzenesulfonimide, and the mixture was stirred for 2 hours at -78° C. and then for 1 hour at room temperature. The reaction solution was mixed with 500 ml of 0.1N hydrochloric acid aqueous solution and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with 10% sodium thiosulfate, 1N sodium hydroxide and saturated sodium chloride aqueous solution in that order and dried over anhydrous magnesium sulfate, subsequently evaporating the solvent. The resulting residue was applied to silica gel column chromatography, which was eluted with a mixed solvent of n-hexane and ethyl acetate (4:1, v/v) to obtain 2.31 g of 4,4-difluoro-1-tosyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[C:12]([O-:17])(=[O:16])[C:13]([CH3:15])=[CH2:14].[K+]>C(P(CCCC)CCCC)CCC.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[C:12]([O:17][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: C=C(C)C(=O)[O-]
Agent: CCCCP(CCCC)CCCC
Agent: [K+]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=C(C)C(=O)OCCC[Si](OC)(OC)OC
Reaction time: 10 h
Yield: 89 %

Procedure:
Using a method analogous to Example 1, 198.7 g (1 mol) of 3-chloropropyltrimethoxysilane are reacted in the presence of 6.1 g (0.03 mol) of tri-n-butylphosphine and 0.1 g of phenothiazine with 130.4 g (1.05 mol) of potassium methacrylate at 90° C. The reaction is complete 10 hours after all the potassium methacrylate has been introduced. Work-up gives 221.0 g (89%) of 3-methacryloxypropyltrimethoxysilane having a purity of 98.3%.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.O>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(OCc2ccccc2)cc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
Sodium hydroxide (1.80 g, 45 mmol) was added to a solution of methyl 4-(benzyloxy)benzoate (2.18 g, 9 mmol) in methanol (5 mL) and water (10 mL). The reaction mixture was stirred at 65° C. for 3 hours. After the reaction, the solvent was removed in vacuo. 3N hydrochloric acid was added to make pH 2, and the product was extracted with dichloromethane (100 mL×3). The combined organics phase was washed with brine (20 mL×3), dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 4-(benzyloxy)benzoic acid (1.95 g, 95%). LRMS (M+H+) m/z: calcd 227.08. found 227.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH3:7])[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.OC(C(F)(F)F)=O.[F:48][C:49]1[CH:75]=[C:74]([F:76])[CH:73]=[CH:72][C:50]=1[O:51][CH:52]1[CH2:57][CH2:56][N:55]([C:58]2[N:59]=[C:60]3[CH2:71][CH2:70][NH:69][CH2:68][C:61]3=[N:62][C:63]=2[NH:64][CH:65]([CH3:67])[CH3:66])[CH2:54][CH2:53]1>CC(N(C)C)=O>[F:48][C:49]1[CH:75]=[C:74]([F:76])[CH:73]=[CH:72][C:50]=1[O:51][CH:52]1[CH2:53][CH2:54][N:55]([C:58]2[N:59]=[C:60]3[CH2:71][CH2:70][N:69]([C:4](=[O:6])[CH:3]([O:2][CH3:1])[CH3:7])[CH2:68][C:61]3=[N:62][C:63]=2[NH:64][CH:65]([CH3:67])[CH3:66])[CH2:56][CH2:57]1
Reactant: COC(C)C(=O)O
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(C)C(=O)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NC(C)C)nc2C1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-methoxypropanoic acid (10.8 μL, 0.113 mmol) in DMA (0.4 mL) at room temperature was added DIPEA (45.5 μL, 0.261 mmol) and HATU (42.9 mg, 0.113 mmol). To this was added a solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (45.0 mg, 0.087 mmol) in DMA (0.47 mL). The resulting reaction mixture was stirred at 60° C. for 45 min. The reaction mixture was allowed to cool to room temperature and was purified directly by HPLC Method B, with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column was used, using a 50% to 80% ACN gradient to give the title compound, as a TFA salt, as a pale yellow solid (11.2 mg, 21.4%). 1H NMR (400 MHz, methanol-d4) δ ppm 1.36 (m, 9H), 1.98 (m, 2H), 2.14 (m, 2H), 2.83 (m, 2H), 3.16 (m, 2H), 3.35 (s, 3H), 3.49 (m, 2H), 3.90 (m, 1H), 3.93 (t, J=5.8 Hz, 1H), 4.12 (m, 1H), 4.35 (m, 1H), 4.52 (m, 1H), 4.59-4.79 (m, 2H), 6.88 (m, 1H), 6.99 (ddd, J=11.4, 8.6, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 490.5.