Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=1.[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19].Cl>C(O)C>[F:15][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=1)[O:4][CH2:3][CH2:2][NH:20][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCN
Reactant: CS(=O)(=O)c1cc(F)cc(OCCBr)c1
Agent: Cl
Solvent: CCO
Product: CCCCNCCOc1cc(F)cc(S(C)(=O)=O)c1

Procedure:
Preparation according to Example 1 but performed in one portion: 1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.3 g, 1.01 mmol) and butan-1-amine 0.61 ml, 0.5907 mmol) in ethanol (4 ml). Yield: 290 mg (99%). The amine was converted to the hydrochloric acid salt and re-crystallized from ethanol/diethyl ether: M.p. 204° C. MS m/z (relative intensity, 70 eV) 289 (M+, 1), 246 (35), 86 (bp), 56 (12), 87 (12).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[C:21]([C:22](C(O)=O)=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1)(=[O:15])=[O:14].C(N(CC)CC)C.ClC(OC)=O.C(=O)(O)[O-].[Na+]>ClCCl>[O:14]=[S:13]1(=[O:15])[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:21]2[C:22](=[O:23])[N:12]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1
Reactant: O=C(O)C(=O)c1cccnc1S(=O)(=O)NCCCCOC1CCCCO1
Agent: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1c2cccnc2S(=O)(=O)N1CCCCOC1CCCCO1
Reaction time: 2 h
Yield: 113.5 %

Procedure:
To a stirred solution of 3 g of N-(4-(2-tetrahydropyranyloxy)butyl) 3-carboxycarbonylpyridine-2-sulfonamide and 2.3 mL of triethylamine in 100 mL of dichloromethane at 0° C. was added 0.8 mL of methyl chloroformate dropwise. After 2 h, the mixture was shaken with 10 mL of saturated sodium bicarbonate, dried over MgSO4 and concentrated under reduced pressure. Chromatography of the dark brown oil over silica gel, eluting with 1:1 ethyl acetate: hexane gave 3 g of homogeneous 1,1-dioxido-2-(4-(2-tetrahydropyranyloxy)butyl)-isothiazolo[5,4-b]pyridin-3(2H)-one as an amber oil.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][C:28]1[C:35]([F:36])=[C:34]([F:37])[CH:33]=[CH:32][C:29]=1[CH2:30][OH:31]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:31][CH2:30][C:29]2[CH:32]=[CH:33][C:34]([F:37])=[C:35]([F:36])[C:28]=2[F:27])[CH:7]=1
Reactant: OCc1ccc(F)c(F)c1F
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3ccc(F)c(F)c3F)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.184 mmol), intermediate 42.1, and 2,3,4-trifluorobenzyl alcohol (119 mg; 0.736 mmol), example 72 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH:16]([CH3:18])[CH3:17].[Cl:19][C:20]1[N:21]=[C:22]([C:27](O)=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:19][C:20]1[N:21]=[C:22]([C:27]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH:16]([CH3:18])[CH3:17])=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CC(C)O[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC(C)C)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
20% palladium hydroxide (wet, 60 mg) was added to a solution of tert-butyl cis(±)-4-(benzylamino)-3-isopropoxypiperidine-1-carboxylate obtained in Example (147d) (120 mg, 0.345 mmol) in methanol (1.2 mL), and the mixture was catalytically hydrogenated at room temperature for three hours. The catalyst was filtered off, and then the filtrate was concentrated under reduced pressure. A 1 N aqueous sodium hydroxide solution was added to the resulting residue, and the organic substance was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 74 mg of tert-butyl cis(±)-4-amino-3-isopropoxypiperidine-1-carboxylate as a colorless oily substance (83%). The resulting amine was dissolved in DMF (1 mL). 4-Chloro-5-ethyl-1H-imidazole-2-carboxylic acid (described in Example 1d, 54 mg, 0.29 mmol) was added, and the mixture was cooled in an ice water bath. 1-Hydroxybenzotriazole (44 mg, 0.31 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (60 mg, 0.31 mmol) were added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, sequentially washed with brine, water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: chloroform/methanol) to obtain 60.6 mg of the title compound as a colorless solid (50%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C:5]1[C:6](Cl)=[N:7][CH:8]=[N:9][C:10]=1[C:11]([F:14])([F:13])[F:12]>CO>[Br:4][C:5]1[C:6]([O:2][CH3:1])=[N:7][CH:8]=[N:9][C:10]=1[C:11]([F:14])([F:13])[F:12]
Reactant: C[O-]
Reactant: FC(F)(F)c1ncnc(Cl)c1Br
Agent: [Na+]
Solvent: CO
Product: COc1ncnc(C(F)(F)F)c1Br
Yield: 91 %

Procedure:
16.7 ml of sodium methoxide (a 28% methanol solution, 86.4 mmoles) was added, at room temperature, to a solution of 21.5 g (82.2 mmoles) of 5-bromo-4-chloro-6-trifluoromethylpyrimidine dissolved in 100 ml of methanol. The mixture was stirred to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the solvent contained therein. The residue was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was washed with n-hexane to obtain 19.2 g (yield: 91.0%) of 5-bromo-4-methoxy-6-trifluoromethylpyrimidine.
Reaction SMILES: [C:1]1([CH3:34])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]#[N:20])=[CH:16][CH:17]=3)[C:12]([Sn](CCCC)(CCCC)CCCC)=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:35]([O:37][C:38]([C:40]1[CH2:44][CH2:43][CH2:42][C:41]=1OS(C(F)(F)F)(=O)=O)=[O:39])[CH3:36].C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[CH2:35]([O:37][C:38]([C:40]1[CH2:44][CH2:43][CH2:42][C:41]=1[C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=2)[N:10]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:34])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH:11]=1)=[O:39])[CH3:36]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(S(=O)(=O)c2ccc(C)cc2)c2ccc(C#N)cc12
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCC1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(C#N)cc23)CCC1
Temperature: 60 °C
Yield: 73.2 %

Procedure:
1-(Toluene-4-sulfonyl)-3-tributylstannanyl-1H-indole-5-carbonitrile (5.60 g, 9.56 mMol), 2-trifluoromethanesulfonyloxy-cyclopent-1-enecarboxylic acid ethyl ester (2.75 g, 9.56 mMol), triphenyl arsine (0.29 g, 0.96 mMol) and tris(dibenzylidenacetone)dipalladium(0) (0.44 g, 0.48 mMol) were dissolved in DMF and degassed for 5 min with a stream of nitrogen. The reaction was heated under nitrogen at 60° C. for 5 min. The reaction was poured into brine (500 mL) and extracted with ethyl acetate (2×100 mL). The organics were mixed with saturated aqueous potassium fluoride (100 mL) and the resulting solids were removed by filtration through celite. The layers of the filtrate were separated and the organic layer was dried with magnesium sulfate and evaporated in vacuo. The solid product was recrystallized from hot ethyl acetate/hexanes to provide the product as a white solid (3.04 g, 73%). 1H NMR (400 MHz, CDCl3) δ 8.05 (1H, d, J=8.7 Hz), 7.87 (1H, s), 7.79 (2H, d, J=8.5 Hz), 7.71 (1H, d, J=1.2 Hz), 7.53 (1H, dd, J=8.8, 1.5 Hz), 7.27 (2H, m), 4.01 (2H, q, J=6.9 Hz), 2.86 (4H, m), 2.36 (3H, s), 2.03 (2H, pentet, J=7.7 Hz), 0.95 (3H, t, J=7.1 Hz); MS m/e 457.0 (M+Na).
Reaction SMILES: C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].[CH3:18][C:19]1([CH3:29])[CH2:24][CH2:23][C:22](=[O:25])[CH:21]([CH2:26][CH:27]=[CH2:28])[CH2:20]1>O1CCCC1.C(OCC)(=O)C>[CH3:18][C:19]1([CH3:29])[CH2:24][CH2:23][C@@H:22]([OH:25])[C@H:21]([CH2:26][CH:27]=[CH2:28])[CH2:20]1
Reactant: C=CCC1CC(C)(C)CCC1=O
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC[C@@H]1CC(C)(C)CC[C@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To a solution of lithium tri-tert-butoxyaluminohydride (460 mg) in dry tetrahydrofuran (3.5 ml) there was added a solution of 4,4-dimethyl-2-(2-propenyl)cyclohexanone (250 mg) at 0° C., and the mixture was stirred at room temperature for 2 hrs. The reaction was quenched by addition of water. The pH of the mixture was adjusted to pH 7 with 0.1N hydrochloric acid. The mixture was extracted with diethyl ether, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the residue by silica gel column chromatography (using n-hexane:ethyl acetate=20:1 as an eluent) gave (1R*,2R*)-4,4-dimethyl-2-(2-propenyl)cyclohexanol (185 mg, 73% yield) as a colorless oil; EI-MS: m/z 168 (M+); 1H-NMR (CDCl3)d: 0.90 (3H,s), 0.93 (3H,s), 1.2-1.8 (7H,m), 1.95 (1H,m), 2.46 (1H,m), 3.23 (1H,dt,J=5 & 11 Hz), 5.02 (1H,br.d,J=10 Hz), 5.06 (1H,br.d,J=17 Hz), 5.85 (1H,m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:17]([C:18]([OH:20])=[O:19])=[C:16]([F:21])[CH:15]=[CH:14][CH:13]=2)[N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:34][Si:35]([CH3:40])([CH3:39])[CH2:36][CH2:37]O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[C:17]([C:18]([O:20][CH2:37][CH2:36][Si:35]([CH3:40])([CH3:39])[CH3:34])=[O:19])=[C:16]([F:21])[CH:15]=[CH:14][CH:13]=2)[N:6]=1
Reactant: COc1cc(OC)nc(Oc2cccc(F)c2C(=O)O)n1
Reactant: C[Si](C)(C)CCO
Agent: O=C([O-])[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(OC)nc(Oc2cccc(F)c2C(=O)OCC[Si](C)(C)C)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-(4,6-dimethoxypyrimidin-2-yl)oxy-2-fluorobenzoic acid (3.0 g) and carbonyldiimidazole (1.8 g) were dissolved in 50 ml of tetrahydrofuran, and the mixture was refluxed under heating and stirring for one hour. After cooling the reaction solution, 2-(trimethylsilyl)ethanol (6.0 g) and potassium carbonate (1.5 g) were added thereto, and the mixture was refluxed under heating and stirring for one hour. The reaction solution was poured into ice water and extracted with ethyl ether. The extract was washed with water and dried. Then, the solvent was evaporated under reduced pressure. The residue thereby obtained was purified by silica gel column chromatography to obtain the above identified compound as a pale yellow oily substance (2.4 g). Refractive index nD20 : 1.5159.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH3:7][O:8][C:9]1[CH:14]=[C:13]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:11][C:10]=1[OH:18]>>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:11][C:10]=1[O:18][CH2:2][C:3]([O:5][CH3:6])=[O:4]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: COC(=O)CBr
Product: COC(=O)COc1ccc(C(C)=O)cc1OC

Procedure:
Methyl bromoacetate was reacted with 2-methoxy-4-acetylphenol to give methyl 2-methoxy-4-acetylphenoxyacetate by the same procedure as was used to make isopropyl 4-acetylphenoxyacetate.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=1.[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]1>O1CCCC1>[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([O:20][C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=2)[CH2:16][CH2:15]1
Reactant: CN1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccc([N+](=O)[O-])cn2)CC1

Procedure:
To a mixture of sodium hydride (189 mg, 4.73 mmol) in anhydrous tetrahydrofuran (2 mL) at 0° C., a solution of 2-chloro-5-nitropyridine (500 mg, 3.16 mmol) and 1-methylpiperidin-4-ol (455 mg, 3.96 mmol) in anhydrous tetrahydrofuran (4 mL) was added dropwise. The reaction was heated reflux for 16 h. The THF was evaporated and water (100 mL) and EtOAc (200 mL) were added. The aqueous layer was extracted with EtOAc (200 mL). The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated to give a brown oil. Purification by silica gel column chromatography using 3% methanol/methylene chloride yielded 2-(1-methylpiperidin-4-yloxy)-5-nitropyridine as a yellow solid, (367 mg, 49%). LC/MS (m/z): 238.0 (MH+), Rt 1.59 minutes.
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11](Cl)=[O:12])=[CH:6][CH:5]=1.[C:18]([CH:20]([OH:34])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)#[N:19].N1C=CC=CC=1>C(Cl)Cl>[CH:14]([CH:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:17])[F:1])=[CH:5][CH:6]=1)[C:11]([O:34][CH:20]([C:18]#[N:19])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:22]=1)=[O:12])([CH3:16])[CH3:15]
Reactant: CC(C)C(C(=O)Cl)c1ccc(OC(F)F)cc1
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)c1ccc(OC(F)F)cc1
Reaction time: 60 h
Yield: 24.8 %

Procedure:
A solution of 2-(4-difluoromethoxyphenyl)-3-methylbutyryl chloride (4.82 g) in methylene chloride (10 ml) is added to a methylene chloride solution (10 ml) of α-cyano-m-phenoxybenzyl alcohol (4.05 g) and pyridine (1.5 ml). The mixture is stirred for approximately 60 hours and filtered. The filtrate and the washings are evaporated and the residual oil (6.29 g) is purified on a silica column using 1:1 methylenechloride-hexane as an eluant. The solvent is evaporated and the residue treated with sodium borohydride. The resulting crude material is purified on a silica gel column to yield 2.01 g of product.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]([CH2:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH2:13])[C:8]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:7]=3[C:6]=2[CH:5]=[C:4]([CH3:26])[CH:3]=1.[C:27]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:32]=CC=C[CH:28]=1.C([Sn](CCCC)(CCCC)CCCC)C=C>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>[CH2:32]([C:2]1[C:10]2[N:9]([CH2:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH2:13])[C:8]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:7]=3[C:6]=2[CH:5]=[C:4]([CH3:26])[CH:3]=1)[CH:27]=[CH2:28]
Reactant: C=C(Cn1c2c(c3cc(C)cc(Br)c31)CN(C)CC2)c1ccc(F)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=CC[Sn](CCCC)(CCCC)CCCC
Product: C=CCc1cc(C)cc2c3c(n(CC(=C)c4ccc(F)cc4)c12)CCN(C)C3
Temperature: 100 °C
Reaction time: 8 h

Procedure:
6-Bromo-5-(2-(4-fluorophenyl)allyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (185 mg, 0.23 mmol) and tetrakis(triphenylphosphine (5.3 mg, 0.046 mmol) were charged in a reaction bottle, which was evacuated and backfilled with nitrogen. Dry toluene (2 mL) was added under nitrogen and the flask purged with nitrogen for 2 min. Allyltributyltin (151 mg, 0.46 mmol) was added dropwise. The reaction mass was stirred at 100° C. overnight. The reaction mixture was concentrated under vacuum and purified on silica gel (100-200 mesh) using 0-3% MeOH:DCM as eluent. Yield: 30 mg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20](F)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[K])(C)(C)C.[OH:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][C:36]1=[O:40]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][C:36]4=[O:40])=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCCN1CCCO
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCN4CCCC4=O)ccc23)CC1
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester 66.9 mg, 0.20 mmol), as prepared in Example 65b, and tert-BuOK (33.4 mg, 0.30 mmol) was added 1-(3-hydroxypropyl)-2-pyrrolidone (34.7 mg, 0.24 mmol) in anhydrous THF (3 mL). The mixture was stirred at 85° C. for 15 min and the solvent was evaporated under reduced pressure to give a light brown residue, which is used for the next step reaction without purification. 1H NMR (300 MHz, CDCl3) δ 9.10 (s, 1H), 8.03 (d, J=9.13 Hz, 1H), 7.26 (m, 1H), 7.23 (dd, J=9.05 and 2.43 Hz, 1H), 4.14 (t, J=6.08 Hz, 2H), 3.58 (m, 1H), 3.50 (t, J=6.60 Hz, 4H), 3.42 (t, J=6.98 Hz, 4H), 2.37 (t, J=8.45 Hz, 2H), 1.80-2.15 (m, 8H), 1.46 (s, 9H). LC-MS (ESI) calcd for C25H35N4O4 (MH+) 455.3, found 455.2.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:4]=1)=C.[O:17]=[O+][O-].CSC>CO>[CH:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:4]=1)=[O:17]
Reactant: O=[O+][O-]
Reactant: C=Cc1cc(NC(=O)OC(C)(C)C)ncn1
Solvent: CO
Solvent: CSC
Product: CC(C)(C)OC(=O)Nc1cc(C=O)ncn1
Yield: 100 %

Procedure:
To a stirred solution of tert-butyl 6-vinylpyrimidin-4-ylcarbamate (4.4 g, 0.020 mol) in MeOH (200 mL) at −78° C. was bubbled O3 for 1 hour. N2 was bubbled through the mixture for 10 minutes and then dimethylsulfide (1.24 g, 0.020 mol) was added dropwise. After addition, the solvent was removed under reduced pressure to give the crude desired product (4.6 g, over 100% yield) which was used in the next step without purification. LCMS (ESI) m/z: 224.1 [M+H+].
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=O)=[CH:3][CH:2]=1.[CH3:17][O:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:17][O:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:8](=[O:10])[CH2:7][C:4]2[CH:3]=[CH:2][C:1]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:6][CH:5]=2)[CH:21]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(NC(=O)Cc2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
To a solution of the 4-biphenyl acetic acid (106.1 mg, 0.50 mmol), 3-amino benzoic acid methyl ester (113.4 mg, 0.75 mmol), EDCHCl (143.8 mg, 0.75 mmol) and HOBT (101.4 mg, 0.75 mmol) were dissolved in DMF (5.0 mL), and DIPEA (0.13 mL, 0.75 mmol) were added. The reaction mixture was stirred at room temperature overnight and then partitioned between Ethyl acetate and brine. The organic phase was dried (anhydrous MgSO4), and concentrated. Purification by silica gel column chromatography (n-Hexane: Ethyl acetate:MeOH=6:3:1) gave 3-(2-biphenyl-4-yl-acetyl-amino)benzoic acid methyl ester as a white solid (174 mg, 100% yield).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:7]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@H]1CNCCN1
Solvent: ClCCl
Product: C[C@H]1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(S)-methylpiperazine (2.62 g, 26.2 mmol) in dichloromethane (100 mL) was trityl chloride (7.30 g, 26.2 mmol) added and the mixture was stirred at ambient temperature for 1.5 h. The organic phase was washed (×1) with 1 M aqueous K2CO3, water, and brine. Drying (MgSO4) and solvent removal in vacuo furnished a quantitative yield of the title compound as a glassy oil which solidified upon standing. This material was used directly in the next step.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH3:20])[CH:14]=3)[CH:10]=[C:9]([C:21]([F:24])([F:23])[F:22])[N:8]=2)[CH:6]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:10]=[C:9]([C:21]([F:24])([F:23])[F:22])[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:29]4[CH:30]=[CH:31][C:26]([NH2:25])=[N:27][CH:28]=4)[N:3]=[CH:4]3)[N:12]=2)=[CH:14][C:15]=1[CH3:20]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)ccc1Cl
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4ccc(N)nc4)c3)n2)ccc1Cl

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(4-chloro-3-methyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.40) (0.21 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a yellow solid (0.096 g, 45%). MS (ISP) 431.2 [(M+H)+]; mp 276° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[C:14]([C:16]4[CH:17]=[C:18]([C:21]([OH:23])=O)[S:19][CH:20]=4)[CH:13]=[N:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:27])=O>ClCCl>[C:1]1([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[C:14]([C:16]4[CH:17]=[C:18]([C:21]([Cl:27])=[O:23])[S:19][CH:20]=4)[CH:13]=[N:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cc(-c2cnc3c(-c4ccccc4)cnn3c2)cs1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)c1cc(-c2cnc3c(-c4ccccc4)cnn3c2)cs1

Procedure:
A solution of 4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)thiophene-2-carboxylic acid (5-3, 1.0 g, 3.11 mmol, 1 equiv) and oxalyl chloride (2.17 mL, 24.9 mmol, 8.00 equiv) in dichloromethane (400 mL) was stirred at 23° C. for 72 hours. The reaction mixture was concentrated to give 4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)thiophene-2-carbonyl chloride (5-4) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.89 (d, 1H, J=2.4 Hz), 8.79 (d, 1H, J=2.2 Hz), 8.50 (s, 1H), 8.22 (d, 1H, J=1.6 Hz), 8.05 (br d, 2H, J=7.8 Hz), 8.00 (d, 1H, J=1.6 Hz), 7.48 (br t, 2H, J=7.7 Hz), 7.31 (t, 1H, J=7.5 Hz).
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[H][H]>[Pd].CC1CCCCC1>[CH3:2][O:3][CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1
Reactant: COc1ccc(O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CC1CCCCC1
Product: COC1CCC(=O)CC1

Procedure:
0.5 g of borax and 0.5 g of water were mixed and 6 g of a catalyst which was moist with water (water content=50 %) and comprised 5% by weight of palladium on carbon were then mixed in. The resulting mixture was added to a solution of 100 g of p-methoxyphenol in 150 g of methylcyclohexane and this reaction mixture was hydrogenated in a stirred reactor at from 150 to 180° C. and from 3 to 8 bar of hydrogen pressure until no more hydrogen was absorbed. After a hydrogenation time of 72 minutes, 96.2% by weight of the p-methoxyphenol had reacted and p-methoxycyclohexanone had been formed in a yield of 83% by weight.