Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][C:11]([OH:13])=O)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:16])=O>ClC(Cl)(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][C:11]([Cl:16])=[O:13])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(CC(=O)O)on1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(CC(=O)Cl)on1

Procedure:
5 mmoles of 3(t-butyl)isoxazole-5 yl acetylchloride were prepared from 3(t-butyl)isoxazole-5-yl-acetic acid and thionylchloride in tetrachloromethane.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[CH:6]1([C:9]2[N:14]=[C:13]([C:15]([NH:17][C:18]3[CH:26]=[N:25][CH:24]=[CH:23][C:19]=3[C:20](O)=[O:21])=[O:16])[C:12]([NH:27][C:28]3[CH:29]=[N:30][CH:31]=[N:32][CH:33]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1>>[CH:1]1([NH:5][C:20]([C:19]2[CH:23]=[CH:24][N:25]=[CH:26][C:18]=2[NH:17][C:15]([C:13]2[C:12]([NH:27][C:28]3[CH:29]=[N:30][CH:31]=[N:32][CH:33]=3)=[CH:11][CH:10]=[C:9]([CH:6]3[CH2:8][CH2:7]3)[N:14]=2)=[O:16])=[O:21])[CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCC1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: O=C(NC1CCC1)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 35 %

Procedure:
According to the general method described in step 3 of example 53, reaction of cyclobutylamine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (35%) as amorphous yellow solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][Br:27].[Cl-].[NH4+]>C1COCC1>[Br:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:14]([CH3:16])([CH3:15])[C:13]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(C)C
Reactant: BrCCCCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)CCCCCBr
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (5.82 mL) in THF (30 mL) was added n-butyllithium (2.5M in hexanes, 16.4 mL) at 0° C. and the mixture was stirred for 30 min at this temperature before being cooled to −78° C. Ethyl isobutyrate (5 mL) was added dropwise and the resultant mixture was stirred at −78° C. for 1 h before addition of 1,5-dibromopentane (5.61 mL). The reaction mixture was stirred at −78° C. for 1 h then at RT for 2.5 h before being poured into saturated ammonium chloride solution. The solution was extracted with ethyl acetate (×2), then the combined organics were washed with water and dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 0-25% ethyl acetate in cyclohexane to give the subtitled compound as a yellow liquid. Yield 4.45 g.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[OH:27]>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[C:21]([OH:27])[CH:22]=1
Reactant: Nc1ccc(F)cc1O
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)cc1O
Yield: 22.3 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 815 mg of 2-amino-5-fluorophenol in place of the 2,4-difluoroaniline. After purification by silica column chromatography, eluent: CH2Cl2/MeOH 95/5, 149 mg of N-(4-fluoro-2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a grey solid, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][C:15]([C:28]#[CH:29])([O:18][C:19]([O:21]C3C=CC=CC=3)=O)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1C=CC=CC=1>[CH2:37]([NH:44][C:19]([O:18][C:15]1([C:28]#[CH:29])[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH:9]=[C:8]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:17][CH2:16]1)=[O:21])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NCc1ccccc1
Reactant: C#CC1(OC(=O)Oc2ccccc2)CCN(CCC=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Solvent: c1ccccc1
Product: C#CC1(OC(=O)NCc2ccccc2)CCN(CCC=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 10 h
Yield: 75.7 %

Procedure:
9.8 g of 1-[4,4-bis(4-fluorophenyl)-3-butenyl]-4-ethynyl -4-phenoxycarbonyloxypiperidine are stirred with 9 ml of benzylamine at 42° C. under nitrogen for 30 minutes, then at room temperature for 10 hours. Thereafter, benzene is added to the reaction mixture and washed first with an aqueous sodium hydroxide solution of 1 ml/liter concentration, then with water and dried over anhydrous magnesium sulfate. After evaporating the solution under reduced pressure, the residue is boiled in hexane and after filtration it is recrystallization from diisopropyl ether to give the title product in 75.7% yield, m.p.: 94°-95° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]([OH:20])([CH3:19])[CH3:18])[CH2:13][CH2:12]3)=[N:9][N:10]=2)[CH:7]=1.FC(F)(F)S(O[Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])(=O)=O.CCN(CC)CC.O>C(Cl)Cl.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:12][CH2:13][CH:14]([C:17]([CH3:18])([O:20][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[CH3:19])[CH2:15][CH2:16]3)=[N:9][N:10]=2)[CH:7]=1
Reactant: CC(C)(O)C1CCN(c2nnc3ccc(F)cn23)CC1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)[Si](OC(C)(C)C1CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Yield: 79.2 %

Procedure:
A solution of Intermediate 74a (480 mg, 1.72 mmol), triisopropylsilyl trifluoromethane-sulfonate (0.579 mL, 2.16 mmol) and Et3N (0.361 mL, 2.59 mmol) in dry DCM (5 mL) under N2 was stirred at reflux for 2 h. The mixture was cooled to RT, then Et3N (0.361 mL, 2.59 mmol) and triisopropylsilyl trifluoromethanesulfonate (0.579 mL, 2.16 mmol) were added and the orange solution stirred at reflux for 3 h. To the cooled solution, water (5 mL) was added and the mixture shaken. The aqueous was extracted with DCM (5 mL), then the combined organics passed through a hydrophobic frit and concentrated in vacuo to leave an orange oil. FCC, using 1-3% MeOH in DCM, gave the title compound as a pale yellow solid (592 mg, 79%). LCMS (Method 3): Rt 5.66 min, m/z 435 [MH+].
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:8]([OH:10])=[O:9])[N:6]=1.[C:21](OC(=O)C)(=[O:23])C>C(O)=O>[CH:21]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:8]([OH:10])=[O:9])[N:6]=1)=[O:23]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCON=C(C(=O)O)c1csc(N)n1
Solvent: O=CO
Product: CCCCCCCCON=C(C(=O)O)c1csc(NC=O)n1
Yield: 97.4 %

Procedure:
2-(2-Aminothiazol-4-yl)-2-n-octyloxyiminoacetic acid (syn isomer, 20 g.), acetic anhydride (27.3 g.) and formic acid (12.3 g.) were treated in a similar manner to that of Example F-(5) to give 2-(2-formamidothiazol-4-yl)-2-n-octyloxyiminoacetic acid (syn isomer, 21.3 g.), mp. 122° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH:18]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][CH2:14][NH:13][C:12]=2[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:26]([N:13]1[C:12]2[CH:17]=[C:8]([CH2:7][C:6]3[CH:18]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[Cl:19])[CH:9]=[CH:10][C:11]=2[O:16][CH2:15][CH2:14]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Clc1ccc(Br)cc1Cc1ccc2c(c1)NCCO2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(Br)cc1Cc1ccc2c(c1)N(Cc1ccccc1)CCO2
Temperature: 60 °C
Yield: 69 %

Procedure:
To a stirred solution of 6-(5-bromo-2-chloro-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (8.0 g, 23.66 mmol) in DMF (35 mL) was added potassium carbonate (6.53 g, 47.3 mmol), and benzyl bromide (4.33 mL, 35.50 mmol). The reaction mixture was heated to 60° C. for 8 h, then cooled to room temperature and quenched by the addition of ice-cold water (50 mL). The resulting mixture was extracted with ethyl acetate (3×30 mL), and the combined organic layers were washed with water (50 mL) and brine (50 mL), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated to crude product which was purified by silica gel column chromatography to furnish 4-benzyl-6-(5-bromo-2-chloro-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (7.0 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([OH:9])[CH:8]=1)#[N:2].[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:15]([O:9][C:7]1[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=1[N+:10]([O-:12])=[O:11])[CH:14]=[CH2:13]
Reactant: N#Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(C#N)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.8 %

Procedure:
A mixture of 5-cyano-2-nitro-phenol (3.0 g, 18.9 mmol), allyl bromide (1.82 ml, 21.0 mmol) and cesium carbonate (7.39 g, 22.7 mmol) in DMF (20 ml) was stirred at rt for 18 hrs under Ar. The reaction mixture was partitioned between t-butyl-methylether and water. The layers were separated and the aqueous portion was further extracted (×3). The combined organic extracts were washed twice with water, then brine and dried over MgSO4 and filtered. Removal of solvent at reduced pressure afforded the title compound (3.89 g, 100%). 1H NMR(400 MHz, CDCl3) δ 7.87 (d, J=8.5 Hz, 1H), 7.35 (dd, J=8.4 Hz J=1.2 Hz 1H), 7.35 (d, J=1.5 Hz, 1H), 6.02 (m, 1H), 5.52 (d, 1H), 5.43 (d, 1H), 4.73 (dd, J=3.6 Hz J=1.2 Hz 2H);
Reaction SMILES: [CH2:1]=[O:2].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1.[OH-].[Na+]>C(O)C>[OH:2][CH2:1][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH:7]2[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]2)=[N:11]1
Reactant: C=O
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCC(c2nn(CO)c3ccccc23)CC1
Yield: 38 %

Procedure:
A solution of 0.52 g of paraformaldehyde, 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole, 15 ml of ethanol and 0.34 ml of 5% aqueous sodium hydroxide was refluxed for 3 hrs. The ethanol was removed in vacuo and the residue diluted with water. The aqueous suspension was extracted with dichloromethane (2x, 50 ml) and the combined extracts were washed with water and dried over anhydrous magnesium sulfate. The dichloromethane was evaporated in vacuo to yield an oil, which crystallized upon standing. The solid was recrystallized twice from ethyl acetate to yield 1.3 g (57.8%) of product, mp 128°-130° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:15])=[CH:4][C:5]2[N:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[NH:7][C:6]=2[CH:14]=1.[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([N:7]1[C:6]2[CH:14]=[C:2]([Cl:1])[C:3]([I:15])=[CH:4][C:5]=2[N:9]=[C:8]1[S:10]([CH3:13])(=[O:12])=[O:11])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CS(=O)(=O)c1nc2cc(I)c(Cl)cc2[nH]1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1nc2cc(I)c(Cl)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-chloro-5-iodo-2-methanesulfonyl-1H-benzoimidazole (12.1 g, 34 mmol) in DMF (100 ml) at 0° C. was added NaH (60% dispersion in mineral oil, 1.5 g, 38 mmol). After 10 minutes, the mixture was warmed to rt and stirred for 45 minutes. Benzyl bromide (6.4 g, 38 mmol) was then slowly added and the reaction was stirred overnight at rt. The volatiles were then removed by rotary evaporation and the residue was partitioned between EtOAc and half-saturated ammonium chloride solution. The resulting emulsion was filtered through celite to obtain a cleaner partition. The EtOAc layer was washed with H2O, brine, and dried with MgSO4. After rotary evaporation, the oily residue was stirred in diethyl ether overnight. The mixture was filtered and the beige solid thus obtained was dried under vacuum at rt for 24 hours to yield the title compound. The filtrate was evaporated to an oil and purified by flash chromatography (SiO2, 220 g). A second crop of the title compound was eluted from the column with 40% EtOAc in hexane.
Reaction SMILES: [NH4+:1].[Cl-].C[Al](C)C.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH2:19][C:20]#[N:21])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2([CH2:19][C:20]([NH2:1])=[NH:21])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:12][CH:13]=1
Reactant: N#CCC1(c2ccc(Br)cc2)CCCC1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: N=C(N)CC1(c2ccc(Br)cc2)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
To a suspension of NH4Cl (1.21 g, 43.65 mmol) in toluene (30 mL) was added dropwise a solution of trimethyl aluminium (1.64 g, 43.65 mmol, 2M in toluene) at 0° C. and stirred for 2 h at room temperature prior to the addition of a solution of [1-(4-bromophenyl)-cyclopentyl]-acetonitrile (228) (2.0 g, 7.57 mmol) in toluene (10 mL). The resulting solution was heated to 80° C. for 16 h. The cooled reaction mixture was poured into a slurry of silica gel (10 g) in CHCl3 (20 mL), followed by vigorous stirring for 30 min. The silica gel was filtered off and the cake was rinsed in turn with methanol. The solvent was evaporated and the crude product was taken up in 10% methanol in dichloromethane (200 mL) and stirred for 30 min. The solid suspension was removed by filtration and the filtrate was evaporated. The crude product was triturated in diethyl ether and the solid was collected by filtration and dried under vacuum to afford HCl-salt of 2-[1-(4-bromophenyl)-cyclopentyl]-acetamidine (229) (1.78 g, 74%) as a white solid.
Reaction SMILES: [CH:1]1([CH:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH:5]2C(=O)OC(C)(C)[O:7][C:6]2=[O:14])[CH2:3][CH2:2]1.O.[Cl-].[Na+]>CN(C=O)C>[CH:1]1([CH:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH2:5][C:6]([OH:14])=[O:7])[CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)C(C(c2cccc(O)c2)C2CC2)C(=O)O1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CC(c1cccc(O)c1)C1CC1
Temperature: 90 °C
Reaction time: 7 h
Yield: 85.8 %

Procedure:
To a solution of 5-(cyclopropyl(3-hydroxyphenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (164 g) in DMF (1.64 L) was added water (164 mL), and the mixture was stirred at 90° C. for 7 hr. Water and sodium chloride were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was back-extracted with saturated aqueous sodium hydrogen carbonate solution, and hydrochloric acid was added until the aqueous layer became pH 4. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (100 g) as a brown oil. This compound was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[CH3:11][C:12](O)=[O:13]>CC(OC(C)=O)=O>[C:12]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1)(=[O:13])[CH3:11]
Reactant: Nc1ccc2c(c1)CCO2
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2c(c1)CCO2
Yield: 88 %

Procedure:
The product (5.2 g, 38.5 mmol) obtained in Step 2 was dissolved in AcOH (20 mL) and Ac2O (5 mL), heated to 60° C., reacted for 12 h, and concentrated to obtain a crude product (6 g, 88.0%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])/[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].[NH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:9])[CH2:4][C@@H:5]([C:6]([OH:8])=[O:7])[NH:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NCCCN1CCCCC1
Reactant: COC(=O)/C=C\C(=O)O
Solvent: CCN(CC)CC
Product: COC(=O)C[C@H](NCCCN1CCCCC1)C(=O)O

Procedure:
In a manner analogous to that described in Example 1, 28.6 g (0.2 mol+10% excess) of maleic acid-monomethyl ester, 40 ml of triethylamine and 88.4 g (0.2 mol) of N-(3'-aminopropyl)-piperidine are reacted and the reaction product is purified. The yield is 36.7 g (67.4% of theory) and the melting point of the product obtained is 172°-173° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([Br:16])=[C:12]([O:17][CH3:18])[C:9]=2[C:10]=1[CH3:11])=[O:5])C.[Li+].[OH-]>C1COCC1>[Br:16][C:13]1[CH:14]=[CH:15][C:8]2[O:7][C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[C:9]=2[C:12]=1[O:17][CH3:18]
Reactant: CCOC(=O)c1oc2ccc(Br)c(OC)c2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1c(Br)ccc2oc(C(=O)O)c(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
To 170 mg of 5-bromo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester was added 1 mL of THF and 3 mL of LiOH solution (3.6 g LiOH/50 mL MeOH/50 mL H2O). The mixture was stirred at room temperature overnight. The solvents were removed under vacuum and the residue was dissolved in 5 mL of water. The solution was acidified and the resulting suspension was filtered. The solid product was dried under vacuum to give 156 mg (100% yield) of 5-bromo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid, obtained as a white solid.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20])(C(C)(C)C)(C)C.Cl.Cl[C:25]1[N:30]=[C:29]([NH:31][C@@H:32]2[CH2:40][C@H:39]3[N:35]([CH2:36][CH2:37][CH2:38]3)[C:34]([CH3:42])([CH3:41])[CH2:33]2)[C:28]([F:43])=[CH:27][N:26]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(O)C>[CH3:41][C:34]1([CH3:42])[CH2:33][C@H:32]([NH:31][C:29]2[C:28]([F:43])=[CH:27][N:26]=[C:25]([NH:16][C:15]3[CH:17]=[CH:18][C:12]([O:11][CH2:10][CH2:9][OH:8])=[C:13]([C:19]([F:20])([F:21])[F:22])[CH:14]=3)[N:30]=2)[CH2:40][C@H:39]2[N:35]1[CH2:36][CH2:37][CH2:38]2
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(N)cc1C(F)(F)F
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CC1(C)C[C@H](Nc2nc(Nc3ccc(OCCO)c(C(F)(F)F)c3)ncc2F)C[C@@H]2CCCN21
Yield: 57.2 %

Procedure:
The general displacement procedure described herein was used with 4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3-(trifluoromethyl)aniline (481 mg, 1.4 mmol), (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine hydrochloride (480 mg, 1.4 mmol) and pTsOH.H2O (546 mg, 2.9 mmol) in IPA (10 mL) at reflux to give the product (387 mg, 56% yield) as a solid, after workup and purification by column chromatography on silica gel using DCM/2M NH3 in MeOH (1:0 to 9:1) as eluent.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[S:31][C:30]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[S:31][C:30]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:29][CH:28]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.10) (178 mg, 0.5 mmol) and commercially available 5-bromo-thiophene-2-sulfonamide (121 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (102 mg, 40%). MS (ISN) 515.0 [(M−H)−]; mp 250° C.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6]([C:11]2[S:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)[N:5]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][OH:27])=[CH:24][CH:23]=1.C([O-])(O)=O.[Na+]>>[Cl:10][C:8]1[CH:9]=[C:4]([O:27][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[N:5]=[C:6]([C:11]2[S:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)[N:7]=1
Reactant: COc1ccc(CO)cc1
Reactant: FC(F)(F)c1csc(-c2nc(Cl)cc(Cl)n2)n1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(COc2cc(Cl)nc(-c3nc(C(F)(F)F)cs3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
NaH (60% in oil) (1.49 g, 1 eq.) was added portionwise to a stirred solution of compound 284 (11.2 g, 1 eq.) and 4-methoxybenzyl alcohol (5.15 g, 1 eq.). The reaction mixture was stirred at 0° C. for 1 hr and saturated NaHCO3 solution was added. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was triturated in pentane to yield compound 285 as a beige solid in 89% yield. MS (ESI, EI+): m/z=402 (MH+).
Reaction SMILES: [CH:1](Br)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=1>O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH:1]([CH3:3])[CH3:2])[C:21]#[N:22])=[CH:16][CH:15]=1
Reactant: CC(C)Br
Reactant: COc1ccc(CC#N)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C(C#N)C(C)C)cc1

Procedure:
A mixture comprising: isopropyl bromide, sodium hydroxide pels, and optionally the catalyst triethylamine (i.e., approximately 0.5 to 12 mol or weight percent) is stirred and heated to 50°-60° C. Over approximately a 30-minute period 4-methoxyphenylacetonitrile is added to the reaction mixture. Following this addition, the mixture is stirred and heated at reflux for several hours. After cooling, water is added to the reaction mixture which is then stirred briefly. The organic phase containing the product is then separated. This solution can be used in subsequent reaction steps or the product can be isolated by removal of the solvents.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]([O:16]CC)=O)=[C:5]2[OH:19].[C:20]([NH:29][NH2:30])(=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]([NH:30][NH:29][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:16])=[C:5]2[OH:19]
Reactant: CCCCCCCC(=O)NN
Reactant: CCOC(=O)c1c(O)c2cc(Cl)ccc2n(C)c1=O
Product: CCCCCCCC(=O)NNC(=O)c1c(O)c2cc(Cl)ccc2n(C)c1=O

Procedure:
Reagents: Comp 37 (0.36 mmols, 0.1 g); octanoyl hydrazine (0.39 mmols, 0.062 g). Yield: 0.12 g (86%), white solid, m.p.=187° C.-188° C.