Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16]CC)=[O:15])[CH:12]=2)[NH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CO>[CH2:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=2)[NH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c[nH]c2ccc(C(=O)OCC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1c[nH]c2ccc(C(=O)O)cc12
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a mixture of Ethyl 3-butyl-1H-indole-5-carboxylate, Example SP-225, step 2, (0.4 g) in methanol (15 mL) was added 1N NaOH (5 mL). The mixture was stirred at 50° C. for 18 h, cooled to room temperature and poured into 1N HCl (50 mL). The mixture was extracted with ethyl acetate. The ethyl acetate extract was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give 0.145 g of the title compound: MS (ESI+) for C13H15N1O2 m/z 216.12 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16](Br)=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:10]([C:24]([F:27])([F:26])[F:25])=[N:9]2)[CH:5]=[CH:4][C:3]=1[S:28]([NH2:31])(=[O:30])=[O:29].C([Sn](CCCC)(CCCC)[C:37]1[N:38]=[CH:39][S:40][CH:41]=1)CCC.[Cl-].[Li+]>O1CCOCC1.C(OCC)(=O)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>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:37]4[N:38]=[CH:39][S:40][CH:41]=4)=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:10]([C:24]([F:27])([F:26])[F:25])=[N:9]2)[CH:5]=[CH:4][C:3]=1[S:28]([NH2:31])(=[O:30])=[O:29]
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)c(C(F)(F)F)c2)cc1F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3cscn3)c(C(F)(F)F)c2)cc1F
Temperature: 25 °C
Yield: 18 %

Procedure:
To a stirred solution of 2-fluoro-4-[5-[4-bromo-3-(trifluoromethyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (308 mg, 0.58 mmol) in dioxane (5 ml) was added 4-(tributylstannyl)thiazole (260 mg, 0.70 mmol), tetrakis(triphenylphosphine)palladium (67 mg, 0.058 mmol), lithium chloride (61 mg, 1.45 mmol), and the mixture was heated at reflux temperature for 16 hours. The reaction mixture was cooled down to room temperature, and diluted with ethyl acetate. The whole was washed with saturated potassium fluoride aqueous solution, and the precipitate was removed by filteration through celite. The resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:2) to give title compound (56 mg, 18% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C1COCC1.B.C1COCC1>C(O)C>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: B
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cc(F)ccc1CO
Temperature: 23 °C
Reaction time: 4 h
Yield: 74.2 %

Procedure:
To a solution of 2-amino-4-fluorobenzoic acid (3.00 g, 19.3 mmol) and THF (40 mL) at 0° C. under argon, borane-THF complex (1M THF solution, 77.0 mmol) was added dropwise over 30 min. After complete addition, the reaction was warmed to 23° C. After 4 h, the reaction mixture was added slowly (5 min) to ethanol (77 mL). After 20 min, the reaction was concentrated in vacuo, diluted with sat'd NaHCO3 (100 mL), extracted with ethyl acetate (2×100 mL), washed with brine (1×100 mL), and dried (MgSO4). After concentration in vacuo, the residue was purified by passing through a silica gel pad (1:1 ethyl acetate:hexane). Concentration in vacuo afforded 2.02 g of 2-amino-4-fluorobenzyl alcohol as a yellow solid which was sufficiently pure to take on to the next step: 1H NMR (CDCl3) δ4.54 (br s), 6.28-6.47 (m), 6.93-7.05 (m); 13C NMR (CDCl3) δ62.7, 101.9 (J=24 Hz), 103.4 (J=21 Hz), 121.5, 130.1 (J=10 Hz), 149.1, 163 (J=360 Hz). MS (EI) 141 (M+), 124, 110. IR (neat) 3500-3000 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([CH3:14])(=[O:13])=[O:12].S(Cl)(Cl)=O.[CH3:19]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:19])=[O:7])=[CH:4][C:3]=1[S:11]([CH3:14])(=[O:12])=[O:13]
Reactant: CO
Reactant: CS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Cl)c(S(C)(=O)=O)c1
Temperature: 0 °C

Procedure:
4-chloro-3-(methylsulfonyl)benzoic acid (Enamine, 500 mg; 2.13 mmol; 1 eq.) was dissolved in MeOH (10 mL) The solution was cooled down to 0° C. Thionyl chloride (0.62 mL; 8.52 mmol; 4 eq.) was added dropwise.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([N:15]2[CH2:19][C@H:18]([CH2:20][OH:21])[O:17][C:16]2=[O:22])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.Cl[C:31]1[N:32]=[N:33][C:34]([C:37]#[N:38])=[CH:35][CH:36]=1>C(#N)C>[C:37]([C:34]1[N:33]=[N:32][C:31]([N:12]2[CH2:11][CH2:10][N:9]([C:8]3[CH:7]=[CH:6][C:5]([N:15]4[CH2:19][C@H:18]([CH2:20][OH:21])[O:17][C:16]4=[O:22])=[CH:4][C:3]=3[F:2])[CH2:14][CH2:13]2)=[CH:36][CH:35]=1)#[N:38]
Reactant: N#Cc1ccc(Cl)nn1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(N2CCNCC2)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ccc(N2CCN(c3ccc(N4C[C@H](CO)OC4=O)cc3F)CC2)nn1
Yield: 79.1 %

Procedure:
3-(3-Fluoro4-(piperazin-1-yl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one hydrochloride (6.63 g, 20 mmol) was suspended by stirring in acetonitrile (200 ml) under nitrogen, and triethylamine (4.44 g, 44 mmol) added. The mixture was stirred for 10 minutes 3-chloro-6-cyanopyridazine (2.79 g, 20 mmol) added, and the mixture heated under reflux for 18 hours. After cooling, solid was filtered, washed with water (3×150 ml) and diethyl ether (2×150 ml) to give the title product (6.3 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:36])[CH2:16][NH:17][C:18]([CH3:35])([CH3:34])[CH2:19][CH2:20][N:21]2[CH:25]=[N:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[N:22]2)=[CH:11][C:10]=1[CH2:37][OH:38])C1C=CC=CC=1>[Pd].CO.O1CCCC1>[OH:36][CH:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([CH2:37][OH:38])[CH:11]=1)[CH2:16][NH:17][C:18]([CH3:35])([CH3:34])[CH2:19][CH2:20][N:21]1[CH:25]=[N:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)=[N:22]1
Reactant: COc1ccc(-c2ncn(CCC(C)(C)NCC(O)c3ccc(OCc4ccccc4)c(CO)c3)n2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2ncn(CCC(C)(C)NCC(O)c3ccc(O)c(CO)c3)n2)cc1

Procedure:
3.8 g of 1-(4-benzyloxy-3-hydroxymethyl-phenyl)-2-{3-[3-(4-methoxy-phenyl)-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamino}-ethanol are hydrogenated with 0.6 g of palladium on charcoal (5%) as catalyst in 75 mL methanol and 75 mL tetrahydrofuran. Then the catalyst is suction filtered and the filtrate is evaporated down. The residue is dissolved in 15 mL 15% m acetonitrile, acidified with formic acid and combined with a crystallisation aid. The precipitated product is separated off and washed. Yield: 2.8 g (81%, formate); m.p.=142-145° C.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH:7]=[C:6]([CH3:10])[O:5]1)(=O)[CH3:2].[C:11]([NH:16][NH2:17])(=[O:15])[CH2:12][CH2:13][CH3:14].C(O)C>O>[CH3:10][C:6]1[O:5][CH:4]([C:1](=[N:17][NH:16][C:11](=[O:15])[CH2:12][CH2:13][CH3:14])[CH3:2])[CH2:9][CH2:8][CH:7]=1
Reactant: CC(=O)C1CCC=C(C)O1
Reactant: CCCC(=O)NN
Solvent: O
Solvent: CCO
Product: CCCC(=O)NN=C(C)C1CCC=C(C)O1
Yield: 11.6 %

Procedure:
A mixture of 5.0 gm (0.0356 mole) of 2-acetyl-6-methyl-2,3-dihydropyran, 3.64 gm (0.0356 mole) of n-butyric acid hydrazide and 100 ml of ethanol is refluxed 24 hr. The mixture is diluted with water to the cloud point and chilled. The product is collected, washed with water and dried to give 0.93 gm (12%) of the title compound having a melting point of 72.8° C.
Reaction SMILES: C([O:4][CH:5]1[CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6]1)(=O)C.[CH2:12]([N:19]1[C:27]2[C:26](=[O:28])[N:25]([CH3:29])[C:24](=[O:30])[N:23]([CH3:31])[C:22]=2[N:21]=[C:20]1Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>CC(O)C>[CH2:12]([N:19]1[C:27]2[C:26](=[O:28])[N:25]([CH3:29])[C:24](=[O:30])[N:23]([CH3:31])[C:22]=2[N:21]=[C:20]1[N:7]1[CH2:6][CH:5]([OH:4])[CH2:11][NH:10][CH2:9][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)OC1CNCCNC1
Reactant: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2)n(C)c1=O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cn1c(=O)c2c(nc(N3CCNCC(O)C3)n2Cc2ccccc2)n(C)c1=O
Yield: 97 %

Procedure:
[1,4]Diazepan-6-ol acetate (2B) (116 mg, 0.49 mmol) and 7-benzyl-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione (100 mg, 0.33 mmol) were dissolved in 2-propanol (20 ml) and triethylamine (0.68 ml, 4.9 mmol) and the mixture was subjected to micro waves (150° C., 6 bar, 300 W, 8 hours). The solvents were evaporated and the remaining was redissolved in dichloromethane (20 ml) and water (20 ml). The aqueous layer was acidified with potassium hydrogen sulfate until pH=2. The aqueous layer was separated and aqueous sodium hydroxide was added until pH=12. The aqueous layer was extracted with 3×50 ml of dichloromethane, and the combined organic material were added excess trifluoroacetic acid, and evaporated, to afford 123 mg of the title compound as a brown oil in 75% yield.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24]Cl.C(N(CC)CC)C>C1COCC1>[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24][O:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: COCCOCCl
Reactant: CCCCOC(=O)C12CC3CC(CC(O)(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCOC(=O)C12CC3CC(CC(OCOCCOC)(C3)C1)C2
Yield: 94.1 %

Procedure:
A mixture of 200 mmol of n-butyl 3-hydroxy-1-adamantanecarboxylate, 220 mmol of 2-methoxyethoxymethyl chloride, 220 mmol of triethylamine and 200 ml of THF was refluxed for 3 hours. The reaction mixture was concentrated and subjected to column chromatography on a silica gel to give n-butyl 3-(2-methoxyethoxymethoxy)-1-adamantanecarboxylate (yield: 94.1%) at a conversion rate from n-butyl 3-hydroxy-1-adamantanecarboxylate of 99%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[CH:13]=[N:14][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:17]=3)[CH:11]=[C:4]2[N:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:5]2[N:9]=[C:10]([C:12]3[CH:13]=[N:14][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:17]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: C1COCCN1
Reactant: Clc1cc(Cl)n2nc(-c3ccc(N4CCOCC4)nc3)cc2n1
Solvent: O
Solvent: C1COCCO1
Product: Clc1cc(N2CCOCC2)n2nc(-c3ccc(N4CCOCC4)nc3)cc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The resulting 5,7-dichloro-2-(6-morpholin-4-yl-pyridin-3-yl)-pyrazolo[1,5-a]-pyrimidine was dissolved in 1,4-dioxane (4 mL), morpholine (500 μL, 5.74 mM) was added to the solution and then the mixture was stirred at room temperature for one hour. The solvent was distilled off from this reaction mixture, the residue obtained was diluted with water, the precipitated solid was recovered through filtration and then dried under reduced pressure to thus give the title compound (59.6 mg, overall yield of these three steps: 5.1%).
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([C:16]2([C:40]([F:43])([F:42])[F:41])[O:20][N:19]=[C:18]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[C:26]3([CH2:32][N:31]([C:33]([CH:35]5[CH2:38]S(=O)[CH2:36]5)=[O:34])[CH2:30]3)[O:25][CH2:24]4)[CH2:17]2)[CH:11]=[C:12]([Cl:15])[C:13]=1[F:14]>O.CO>[Cl:15][C:12]1[CH:11]=[C:10]([C:16]2([C:40]([F:41])([F:43])[F:42])[O:20][N:19]=[C:18]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[C:26]3([CH2:32][N:31]([C:33]([CH:35]5[CH2:38][S:3](=[O:5])(=[O:2])[CH2:36]5)=[O:34])[CH2:30]3)[O:25][CH2:24]4)[CH2:17]2)[CH:9]=[C:8]([Cl:7])[C:13]=1[F:14]
Reactant: O=C(C1CS(=O)C1)N1CC2(C1)OCc1cc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)ccc12
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(C1CS(=O)(=O)C1)N1CC2(C1)OCc1cc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)ccc12
Temperature: 0 °C
Yield: 15.9 %

Procedure:
To a 20 mL vial containing a solution of oxone (320 mg, 0.52 mmol) in water (2 mL) at 0° C. was added (5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)(1-oxidothietan-3-yl)methanone from Example 4 (100 mg, 0.17 mmol) as a solution in methanol (4 mL). The reaction was stirred at 0° C. and allowed to warm to room temperature while stirring over 2 hours. Next, the reaction mixture was concentrated to remove excess MeOH and diluted with water. The crude product was extracted with CH2Cl2 (75 mL) and the organic phase was dried (Na2SO4) and concentrated under vacuum. The residue was purified by preparative HPLC to afford the final product (16 mg, 16%) as a solid. 1HNMR (CDCl3) δ ppm: 7.69 (1H), 7.63-7.60 (3H), 7.49 (1H), 5.19 (2H), 4.61-4.45 (4H), 4.36 (2H), 4.24-4.09 (3H), 3.72 (1H), 3.30 (1H); m/z (CI) 593 [M+H]+.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)C(=O)[C:2]1=[O:3].[CH:12]([O:17][CH3:18])([O:15][CH3:16])OC>CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:18][O:17][C:12]1([O:15][CH3:16])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:1][C:2]1=[O:3]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC1(OC)C(=O)Nc2ccccc21
Yield: 76.2 %

Procedure:
In 500 ml of methanol were dissolved 14.7 g of isatin and 10.6 g of trimethyl orthoformate, and 100 mg of p-toluenesulfonic acid was added thereto. The mixture was heated under reflux for 7 hours, followed by concentration. To the residue was added chloroform, and the mixture was washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (eluent: chloroform/ethyl acetate=10/1) to give 14.7 g (76%) of the title compound as an oil.
Reaction SMILES: Cl.[C:2]([NH:7][CH2:8][CH2:9][CH2:10][NH2:11])(=[O:6])[C:3]([CH3:5])=[CH2:4].[N:12]1[C:19]([Cl:20])=[N:18][C:16](Cl)=[N:15][C:13]=1[Cl:14].C(=O)(O)[O-].[Na+]>O.CC(C)=O>[C:2]([NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:16]1[N:18]=[C:19]([Cl:20])[N:12]=[C:13]([Cl:14])[N:15]=1)(=[O:6])[C:3]([CH3:5])=[CH2:4]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C=C(C)C(=O)NCCCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C=C(C)C(=O)NCCCNc1nc(Cl)nc(Cl)n1
Temperature: 25 °C

Procedure:
To a solution of 71.6 g. (0.4 mole) of 3-methacrylamidopropylamine hydrochloride in 400 ml. of water being stirred at 0°-5° C. was added dropwise a solution of 79 g. (0.4 mole) of cyanuric chloride in 400 ml. of acetone. To this mixture was then added in portions 67.2 g. (0.8 mole) of sodium bicarbonate over the course of 1 hr. The mixture was stirred at room temperature for an additional hour and then 2 l of water was added. The product was collected by filtration and dried in vacuo at room temperature to yield 75.8 g. The product was recrystallized from 600 ml. of ethyl acetate to give 53.2 g. (46%) (mp 138°-140° C.).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH2:24][CH:25]([CH3:27])[CH3:26])[NH:14][C:13](=[O:28])[N:12]=3)[CH:9]=2)[NH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[C:38](O)(=[O:41])[CH2:39][CH3:40].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O>[CH3:27][CH:25]([CH3:26])[CH2:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[NH:14][C:13](=[O:28])[N:12]=[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[NH:1][C:38](=[O:41])[CH2:39][CH3:40])[CH:16]=1
Reactant: CC(C)COc1ccccc1-c1cc(-c2ccc3[nH]nc(N)c3c2)nc(=O)[nH]1
Reactant: CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCC(=O)Nc1n[nH]c2ccc(-c3cc(-c4ccccc4OCC(C)C)[nH]c(=O)n3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.3 %

Procedure:
To a solution of commercially available 4-(3-amino-1H-indazol-5-yl)-6-(2-isobutoxyphenyl)pyrimidin-2(1H)-one (60 mg, 0.15 mmol) in dimethylacetamide (4 mL) and diisopropylethylamine (130 pt, 0.76 mmol, 5 eq) was added propionic acid (56 μL, 0.76 mmol, 5 eq) followed by HATU (290 mg, 0.76 mmol, 5 eq). The reaction mixture was stirred at room temperature for 16 h. Formation of product was confirmed by LC/MS and the product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to yield 17 mg (26%) of the title compound: 1H-NMR (400 MHz, d6-DMSO): δ 11.85 (s, 1H), 8.79 (s, 1H), 8.28-8.35 (m, 1H), 7.64 (s, 1H), 7.49-7.58 (m, 1H), 7.20 (d, 1H), 7.08-7.13 (m, 1H), 6.63 (s, 2H), 4.07-4.14 (m, 1H), 3.83-3.91 (m, 2H), 3.15-3.19 (m, 1H), 2.93-3.03 (m, 2H), 1.95-2.08 (m, 1H), 1.14-1.21 (m, 3H), 0.90-0.96 (m, 6H). MS (EI) for C24H25N5O3: 431 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[C:6]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[N:7][C:8]([NH2:12])=[N:9][C:10]=1[CH3:11].[CH:19]([C:21]1[CH:22]=[C:23]([CH:30]=[CH:31][CH:32]=1)[O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=O>C1COCC1.[BH4-].[Na+]>[NH2:12][C:8]1[N:9]=[C:10]([CH3:11])[C:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:19][C:21]2[CH:22]=[C:23]([CH:30]=[CH:31][CH:32]=2)[O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:6]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:7]=1
Reactant: CCCCCNc1nc(N)nc(C)c1CCCN
Reactant: COC(=O)COc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCNc1nc(N)nc(C)c1CCCNCc1cccc(OCC(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.2 %

Procedure:
The product from example 1 step (v) (0.2 g) was dissolved in THF (10 mL) then methyl 2-(3-formylphenoxy)acetate (0.154 g) was added and stirred at rt overnight. Sodium borohydride (0.0301 mg) was added and stirred for 3 hr. The reaction was quenched with water and extracted with EtOAc, dried and solvent removed under reduced pressure. The residue was purified by RPHPLC to afford the title compound 0.038 g.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[CH:15][C:7]2[C:8]([CH3:14])=[C:9]([C:11]([OH:13])=O)[O:10][C:6]=2[C:5]=1[O:17][CH2:18][CH3:19])[CH3:2].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:34]=[CH:35][C:36]([NH:39][C:11]([C:9]3[O:10][C:6]4[C:5]([O:17][CH2:18][CH3:19])=[C:4]([O:3][CH2:1][CH3:2])[CH:16]=[CH:15][C:7]=4[C:8]=3[CH3:14])=[O:13])=[CH:37][CH:38]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOc1ccc2c(C)c(C(=O)O)oc2c1OCC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Product: CCOc1ccc2c(C)c(C(=O)Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)oc2c1OCC

Procedure:
With a procedure similar to the example above, 4-{4-[(6,7-diethoxy-3-methyl-benzofuran-2-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester was prepared from 6,7-diethoxy-3-methyl-benzofuran-2-carboxylic acid and 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester. LCMS calcd for C29H37N3O6 (m/e) 523, obsd 524 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Mg].[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([OH:14])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: Brc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(O)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
A solution of 5.00 g of N-t-butoxycarbonyl-3-oxopiperidine in 10 ml of tetrahydrofuran was added dropwise under ice-cooling to a Grignard reagent solution prepared from 4.73 g of bromobenzene and 0.79 g of magnesium in 50 ml of tetrahydrofuran. The mixture was stirred at room temperature for 1 hour, followed by cooling with ice, and 100 ml of a saturated aqueous solution of ammonium chloride was added thereto dropwise. The reaction mixture was extracted with ethyl acetate, and the extract was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=3/1) to give 4.21 g of N-t-butoxycarbonyl-3-hydroxy-3-phenylpiperidine.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:14])[CH:12]2[CH:7]([CH:8]([OH:13])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5][CH2:4]1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(OCC)C>O1CCCC1>[Si:15]([O:14][CH:3]1[CH2:4][CH2:5][CH2:6][CH:7]2[CH:12]1[CH2:11][CH2:10][CH2:9][CH:8]2[OH:13])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: OC1CCCC2C(O)CCCC12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CCCC2C(O)CCCC12
Temperature: 56 °C
Reaction time: 8 h

Procedure:
A suspension of 0.45 gm (12 mmole) of sodium hydride dispersion (60%) in 75 mL of tetrahydrofuran was treated with 2.0 gm (12 mmole) of 1,5-decalindiol in an inert atmosphere. This mixture was stirred overnight at about 56° C. then cooled to room temperature and 1.8 gm (12 mmole) of t-butyldimethylsilyl chloride added. The mixture was stirred at room temperature for 4 days then 200 mL of diethyl ether added followed by washing the resulting mixture with 10% aqueous potassium carbonate. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was subjected to flash chromatography on 40 microns silica gel to give 5-(t-butyldimethylsilyloxy)-1 -hydroxydecalin as a clear, colorless oil. Satisfactory ir, cmr and pmr spectra were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21](I)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1.[C:24]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([C:21]2[N:20]=[CH:19][N:18]([C:10]3[N:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)[CH:22]=2)=[CH:34][CH:33]=1)(=[O:31])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cnc(I)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)cc1

Procedure:
N-tert-Butyl-4-{1-[6-(4-chloro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 4-(4-chloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (example E.70) (0.68 g, 1.5 mmol) and commercially available 4-(tert.-butylsulfamoyl)-phenylboronic acid (0.46 g, 1.8 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.26 g) which was subsequently deprotected.