Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:7]2[OH:19].[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH:27]([CH3:30])[CH2:28]Cl)[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:7]2[O:19][CH2:28][CH:27]([CH3:30])[CH2:26][N:23]1[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1
Reactant: O=c1oc2c(Cl)cccc2c(O)c1-c1ccccc1
Reactant: CC(CCl)CN1CCOCC1
Product: CC(COc1c(-c2ccccc2)c(=O)oc2c(Cl)cccc12)CN1CCOCC1
Yield: 69 %

Procedure:
Prepared by alkylation of 8-chloro-4-hydroxy-3-phenylcoumarin by 3-morpholino-2-methyl-1-chloropropane, in accordance with the method of Example 8. By recrystallisation from ethanol, a solid melting at 120°-122° C. is obtained. Yield 69%.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C([Li])CCC>CCCCCC.O1CCCC1>[C:1]1([C:7]2[N:16]=[C:15]([C:17]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Reactant: C1CCNCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1nc(-c2ccccc2)nc2ccccc12)N1CCCCC1

Procedure:
The procedure of Example 24 is followed using ethyl 2-phenylquinazoline-4-carboxylate (3.3 g), piperidine, (2.5 ml), a 1.6M solution of butyllithium in hexane (15 ml) and tetrahydrofuran (20 ml) as the starting materials. After recrystallisation from ethanol, 1-[(2-phenylquinazolin-4-yl)-carbonyl]-piperidine (2.6 g), melting at 160° C., is obtained.
Reaction SMILES: C[O-].[Na+].C(O[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[N:10][CH:9]=1)C.[C:16]([O:19][CH2:20][CH3:21])(=[O:18])[CH3:17].Cl>O.C1(C)C=CC=CC=1>[CH2:20]([O:19][C:16](=[O:18])[CH2:17][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[N:10][CH:9]=1)[CH3:21]
Reactant: CCOC(=O)c1ccc(C)nc1
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(C)nc1
Temperature: 20 °C
Yield: 33.6 %

Procedure:
35.8 g (0.52 mol) of sodium methylate and 200 ml of toluene were put in a 750-ml sulfonation flask. The reaction mixture was heated to reflux temperature. A mixture of 55.7 g (0.33 mol) of 6-methyl nicotinic acid ethyl ester (produced according to Swiss Patent No. 654 577) and 60.3 g (0.68 mol) of ethyl acetate was added drop by drop to the stirred suspension over 7 hour period. The suspension was stirred at reflux temperature for 22 hours and then cooled to 20° C. 200 ml of water and 25 ml of concentrated hydrochloric acid were added and the phases were separated. The water phase was extracted with toluene and the combined organic phases were evaporated. Then the evaporation residue was distilled under vacuum. 25.9 g of 6-methyl nicotinoyl acetic acid ethyl ester, having a boiling point of 112°-130° C./0.2-0.4 mbar and a content according to HPLC of 89.7 percent, was obtained (yield 33.6 percent, in relation to the 6-methyl nicotinic acid ethyl ester).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[N:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][N:10]=1>N1C=CC=CC=1>[NH:2]([C:5]1[N:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][N:10]=1)[NH2:3]
Reactant: NN
Reactant: Clc1ncc(-c2ccccc2)nn1
Solvent: O
Solvent: c1ccncc1
Product: NNc1ncc(-c2ccccc2)nn1
Temperature: 0 °C
Yield: 92.9 %

Procedure:
Hydrazine hydrate (1.50 mL, 0.0308 mol) was added to suspension of 3-chloro-6-phenyl-1,2,4-triazine (2.20 g, 0.0115 mol) in pyridine (12.0 mL) at 0° C. and stirred at 0° C. until a precipitate formed. The mixture was then heated at 65° C. for 30 min. The solvent was evaporated under reduced pressure. The residue was triturated with water, filtered, and washed with water. The crystalline formed was collected and dried under high vacuum to give the desired product (2.0 g, 93%). Analytical LCMS: (M+H)+=188.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[C:5]([CH3:12])[CH:4]=1.[ClH:13].[H][H]>C(O)C.[Pd]>[ClH:13].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[C:5]([CH3:12])[CH:4]=1
Reactant: COc1ccc(CC#N)c(C)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc(CCN)c(C)c1
Reaction time: 20 h
Yield: 50 %

Procedure:
4-Methoxy-2-methylphenylacetonitrile (3.0 g, 18.6 mmol) was dissolved in 2B ethanol (65 mL). To the solution was added con. HCl (2.4 mL) and 10% Pd/C (300 mg). The suspension was deaerated in a 500 mL Parr hydrogenation bottle and then pressurized with 55 psi H2, and shaken. After 20 h, the reaction was recharged with hydrogen and 10% Pd/C. After a total of 96 h, the reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The off-white solid residue was recrystallized from isopropanol and collected by suction filtration to afford 1.86 g (50% yield) 2-(4-methoxy-2-methylphenyl)-ethylamine hydrochloride as a white solid, melting point (M.P.) 220-222° C. (gradual softening and discoloration from 104-220° C.). The filtrate was concentrated in vacuo and the residue was washed with ethyl acetate and filtered, providing an additional 1.34 g for a total yield of 3.2 g (85% yield). GC/MS: m/z 165; 1H NMR (DMSO) 8.25 (bs, 3H), 7.09 (d, 1H), 6.75 (m, 2H), 3.71 (s, 3H), 2.87 (m, 4H), 2.27 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([OH:8])[CH2:7][CH2:6]1)=[O:4].[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.[NH+]1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.C(OCC)C>[CH3:1][O:2][C:3]([C:5]1([O:8][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][O:9]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(O)CC1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C1(OC2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
Hydroxy-cyclopropanecarboxylic acid methyl ester (5.07 g, 43.71 mmol) was dissolved in methylene chloride (75 mL) and 3,4-dihydro-2H-pyran (3.86 g, 45.90 mmol) was added followed by pyridinium-p-toluene-sulfonic acid (1.10 g, 4.37 mmol). The reaction stirred at 25° C. for 3 h. The reaction was concentrated in vacuo to give a clear oil. The oil was dissolved in diethyl ether (75 mL), washed with saturated aqueous brine solution (25 mL), dried over sodium sulfate and concentrated in vacuo to an oil. The oil was passed through a plug of silica gel (Merck silica gel 60, 40-63 μm; 100% ethyl acetate) to afford 1-(tetrahydro-pyran-2-yloxy)-cyclopropanecarboxylic acid methyl ester (7.49 g, 86%) as a clear oil: H1-NMR (400 MHz, CDCl3) δ 1.14-1.42 (4H, m), 1.88-3.46 (6H, m), 3.46-3.54 (1H, m), 3.70-3.72 (3H, m), 3.82-3.90 (1H, m), 4.81-4.96 (1H, m).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([Br:11])[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:6]=2[C:5](=[O:16])[NH:4][C:3]1=[O:17].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.O>CN(C)C=O>[S:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[CH2:25][N:4]1[C:5](=[O:16])[C:6]2[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:8]([Br:11])=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:17]
Reactant: CC#CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Reactant: BrCc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc3ccccc3s1)c(=O)n2C
Yield: 90 %

Procedure:
By utilizing the well known method, 3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine 1a (327 mg, 1 mmol) was dissolved in N,N-dimethylformamide (5 ml). Potassium carbonate (221 mg, 1.6 mmol) and 2-bromomethyl-1,3-benzothiazole (228 mg, 1 mmol) were added to give a reaction mixture. The reaction mixture was reacted overnight at room temperature and TLC was used to monitor the reaction progress. After the reaction was completed, the obtained reaction mixture was poured into water, suction filtered, and the obtained solid was washed with water, dried to give 1-[(1,3-benzothiazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine 2b (400 mg, yellow solid), yield: 90%.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([P:19]([CH2:24][CH2:25][CH3:26])([CH2:21][CH2:22][CH3:23])=[O:20])[CH:14]=2)[N:3]=1.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]([C@H:39]2[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41][CH2:40]2)=[C:32]2[C:36]=1[C:35](=[O:37])[N:34]([CH3:38])[CH2:33]2>>[CH2:21]([P:19]([C:15]1[CH:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([C@H:39]4[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41][CH2:40]4)=[C:32]4[C:36]=3[C:35](=[O:37])[N:34]([CH3:38])[CH2:33]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)[CH:18]=[CH:17][CH:16]=1)([CH2:24][CH2:25][CH3:26])=[O:20])[CH2:22][CH3:23]
Reactant: CCCP(=O)(CCC)c1cccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c1
Reactant: CN1Cc2c(c(N)ccc2[C@H]2CC[C@H](O)CC2)C1=O
Product: CCCP(=O)(CCC)c1cccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)c4c3C(=O)N(C)C4)n2)c1

Procedure:
The title product was prepared according to the procedure for Example 102 using 4-chloro-N-[3-(dipropylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (Compound 1688) and 7-amino-4-(trans-4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one. 1H NMR (400 MHz, DMSO-d6) δ 0.93 (t, J=7.33 Hz, 6H), 1.24-1.40 (m, 4H), 1.42-1.58 (m, 4H), 1.79 (d, J=12.88 Hz, 2H), 1.82-1.89 (m, 2H), 1.89-1.98 (m, 4H), 3.08 (s, 3H), 3.42-3.54 (m, 1H), 4.54 (s, 2H), 4.64 (br. s., 1H), 7.26 (br. s., 1H), 7.63-7.72 (m, 2H), 7.79 (d, J=6.57 Hz, 2H), 8.52 (s, 1H), 8.62 (br. s., 1H), 10.14 (s, 1H), 10.59 (br. s., 1H). MS (ES+): m/z=630.27 [MH+]. HPLC: tR=3.17 min (ZQ3, polar—5 min).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[N:7]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[N:17]=3)[C:6]=2[CH:23]=1.[CH3:24][C:25]1[O:29][N:28]=[C:27]([C:30]([OH:34])([C:32]#[CH:33])[CH3:31])[CH:26]=1>CS(C)=O.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:22][C:18]1[N:17]=[C:16]([N:7]2[C:6]3[CH:23]=[C:2]([C:33]#[C:32][C:30]([C:27]4[CH:26]=[C:25]([CH3:24])[O:29][N:28]=4)([OH:34])[CH3:31])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:21]=[CH:20][N:19]=1
Reactant: Nc1nccc(-n2c(OCC(F)(F)F)nc3ccc(Br)cc32)n1
Reactant: C#CC(C)(O)c1cc(C)on1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc(C(C)(O)C#Cc2ccc3nc(OCC(F)(F)F)n(-c4ccnc(N)n4)c3c2)no1
Yield: 38.7 %

Procedure:
A mixture of 4-[6-bromo-2-(2,2,2-trifluoroethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (120 mg, 0.31 mmol), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (120 mg, 0.79 mmol) and bis(triphenylphosphine)palladium(II) dichloride (200 mg, 0.28 mmol) in dimethylsulfoxide (2 mL) and triethylamine (1 mL) kept in a 10-mL vial under nitrogen was irradiated with microwave radiation for 2 h at 70° C. The reaction mixture was concentrated in vacuo. The crude product (120 mg) was purified by preparative HPLC to give 55 mg (39%) of 4-[1-(2-aminopyrimidin-4-yl)-2-(2,2,2-trifluoroethoxy)-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol as a light yellow solid: 1H NMR (400 MHz, DMSO) delta 8.45 (d, J=5.2 Hz, 1H), 8.17 (s, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.17 (s, 2H), 6.86 (d, J=5.2 Hz, 1H), 6.46 (s, 1H), 6.38 (s, 1H), 5.37-5.30 (m, 2H), 2.41 (s, 3H), 1.82 (s, 3H); LC-MS: m/z=+459 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:7][CH2:6][C:5]2[C:8]([CH:13](O)[C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:9][N:10]=[C:11]([CH3:12])[C:4]=2[O:3]1.N1C=CC=CC=1.S(Cl)([Cl:31])=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:22])[O:7][CH2:6][C:5]2[C:8]([CH:13]([Cl:31])[C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:9][N:10]=[C:11]([CH3:12])[C:4]=2[O:3]1
Reactant: O=S(Cl)Cl
Reactant: Cc1ncc(C(O)c2ccc(Cl)cc2)c2c1OC(C)(C)OC2
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ncc(C(Cl)c2ccc(Cl)cc2)c2c1OC(C)(C)OC2

Procedure:
88 mg (0.275 mmole) of (+)-2,2,8-trimethyl-5-(4-chloro-α-hydroxybenzyl)-pyrido-[4,3-e]-1,3-dioxane are poured into a 5 ml flask, dissolved in 1 ml of methylene chloride and the flask is sealed under an atmosphere of nitrogen. 22 μl (0.27 mmole) of anhydrous pyridine are injected via a glass syringe. 36 μl (0.54 mmole) of thionyl chloride are then added dropwise. At disappearance (2 hours later) of the starting material (checked by TLC), the solvent is evaporated off under reduced pressure.
Reaction SMILES: [CH3:1][C:2]([OH:13])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][CH2:4][CH:5]=C.[O:14]=[O+][O-].O=O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[O:13][C:5](=[O:14])[CH2:4][CH2:3]1
Reactant: O=[O+][O-]
Reactant: C=CCCC(C)(O)CCCCCC
Agent: O=[Cr](=O)=O
Agent: O=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CCCCCCC1(C)CCC(=O)O1
Yield: 89 %

Procedure:
A solution of 5-methyl-1-undecen-5-ol (9.2 g., 0.05 mol) in acetone (100 ml) was cooled in a dry-ice-isopropanol bath while a stream of ozone was bubbling through it. When reaction was complete, excess ozone was expelled with oxygen and the reaction mixture was treated with Jones' reagent until an orange color persisted. Acetone was removed by evaporation and the residue was distributed between water and methylene chloride. The organic solution was separated, washed with water, and evaporated. The residue was distilled to give 4-methyl-4-decanolide (8.2 g., 89% yield; b.p. 108°-113°/0.5 torr).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([NH:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1.C(Cl)Cl.B(Br)(Br)Br>C(OCC)(=O)C>[OH:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([NH:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)(=[O:24])=[O:25])=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc(C(F)(F)F)ccc1-c1ncnc2cc(S(=O)(=O)Nc3nccs3)ccc12
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=S(=O)(Nc1nccs1)c1ccc2c(-c3ccc(C(F)(F)F)cc3O)ncnc2c1
Reaction time: 8 h

Procedure:
A vial was charged with 4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide (Example 261; 0.100 g, 0.214 mmol) and DCM (2.144 ml) to give a clear solution. Boron tribromide (0.101 ml, 1.072 mmol) was added in one portion at room temperature to give a dark red suspension. The mixture was stirred overnight. The reaction was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 40 g, gradient elution 0-10% MeOH:DCM) to afford 4-(2-hydroxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=13.02 (s, 1H), 10.65 (s, 1H), 9.49 (s, 1H), 8.41 (d, J=1.5 Hz, 1H), 8.02-7.96 (m, 1H), 7.94-7.88 (m, 1H), 7.63 (d, J=7.7 Hz, 1H), 7.38 (d, J=8.1 Hz, 1H), 7.34 (s, 1H), 7.31 (d, J=4.6 Hz, 1H), 6.90 (d, J=4.5 Hz, 1H). m/z (ESI) 453.2 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH:3]1[C:8]2[CH:9]=[CH:10][S:11][C:7]=2[CH2:6][CH2:5][O:4]1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[Na+].[I-].Cl>CN(C=O)C.O>[S:11]1[C:7]2[CH2:6][CH2:5][O:4][CH:3]([CH2:2][N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:8]=2[CH:9]=[CH:10]1
Reactant: C1CCNC1
Reactant: ClCC1OCCc2sccc21
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1cc2c(s1)CCOC2CN1CCCC1
Temperature: 130 °C
Reaction time: 6 h

Procedure:
A mixture of 4-(chloromethyl)-6,7-dihydro-4H-thieno[3,2-c]pyran (1 g, 5.305 mmol, 1 eq), pyrrolidine (11.3 g, 159.1 mmol, 30 eq) and NaI (50 mg) in DMF (50 mL) in a sealed tube was stirred at 130° C. for 6 hr. The reaction mixture was cooled and poured into H2O and the pH was adjusted to ˜2 with 2N HCl. The resulting solution was washed with EtOAc. The aqueous layer was then adjusted to pH 9-10 and extracted with EtOAc. The EtOAc layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting crude product was purified by preparative HPLC. After removal of organic volatiles of the collected HPLC fractions, the pH of remaining aqueous phase was adjusted to ˜8 with saturated Na2CO3 solution. The aqueous solution was extracted with EtOAc (3 times). The combined EtOAc extract was washed with brine, dried with Na2SO4, and concentrated to give the desired product.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:8]=1[C:17]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:18]=1[F:24].C(=O)([O-])[O-].[Cs+].[Cs+].[F:32][C:33]([F:37])([F:36])[CH2:34]I>CN(C=O)C.O>[CH3:1][C:2]1([CH3:25])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:8]=1[C:17]1[CH:22]=[C:21]([O:23][CH2:34][C:33]([F:37])([F:36])[F:32])[CH:20]=[CH:19][C:18]=1[F:24]
Reactant: COC(=O)c1ccc(-c2cc(O)ccc2F)c(C2CCCC2(C)C)c1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2cc(OCC(F)(F)F)ccc2F)c(C2CCCC2(C)C)c1
Reaction time: 5 h
Yield: 91.8 %

Procedure:
To a flask containing 66.23A (0.100 g, 0.29 mmol) and cesium carbonate (0.29 g, 0.88 mmol) in DMF (2 mL) was added 1,1,1-trifluoro-2-iodoethane (0.12 g, 0.58 mmol) (commercially available from Aldrich), and stirring was continued for 5 hours. The reaction was diluted with water and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-10% EtOAc in hexanes) to yield 66.23B as a colorless oil (0.113 g, 91% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1(O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.S(=O)(=O)(O)O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:10]2([CH3:9])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC1(O)CCCCC1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC1(c2cc(F)ccc2O)CCCCC1
Temperature: 25 °C
Reaction time: 50 h

Procedure:
4-Fluorophenol (41.8 g, 373 mmol) and 1-methylcyclohexanol (63.8 g, 560 mmol) dissolved in 600 mL of dried CH2Cl2, were treated with concentrated sulfuric acid (98%, 22.3 mL, 418 mmol). The mixture was stirred at room temperature for 50 hours. The reaction mixture was then extracted by CH2C2 (250 mL×3). The organic layer was washed with saturated a.q. NaHCO3, dried over MgSO4, and evaporated under vacuum. The residue was purified by column chromatography on silica gel to give 4-fluoro-2-(1-methylcyclohexyl)phenol as a dark green oil—47.6 g. 1H NMR (400 MHz, CDCl3) δ 7.00 (dd, J=3.2, 11.2 Hz, 1H), 6.76-6.71 (m, 1H), 6.62-6.59 (m, 1H), 5.27 (brs, 1H), 2.13-2.07 (m, 2H), 1.70-1.37 (m, 8H), 1.32 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:16]([O:18][C:19](=[O:37])[CH:20](Br)[C:21]1[CH:26]=[CH:25][C:24]([S:27]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)(=[O:29])=[O:28])=[CH:23][CH:22]=1)[CH3:17]>C(#N)C.O>[CH2:16]([O:18][C:19](=[O:37])[CH:20]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:21]1[CH:22]=[CH:23][C:24]([S:27]([N:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)(=[O:28])=[O:29])=[CH:25][CH:26]=1)[CH3:17]
Reactant: CCOC(=O)C(Br)c1ccc(S(=O)(=O)N2CCCCC2)cc1
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)N2CCCCC2)cc1
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
2,4-Difluorophenol (0.38 ml, 3.89 mmol) and cesium carbonate (0.76 gm, 2.33 mmol) were taken in acetonitrile (30 ml) under argon atmosphere and was stirred for 30 minutes. Bromo-[4-(piperidine-1-sulfonyl)-phenyl]-acetic acid ethyl ester (1.4 gm, 3.86 mmol) in acetonitrile (15 ml) was added to the mixture and stirred at 25° C. for 3 hour. Reaction mixture was diluted with water (30 ml), extracted with ethyl acetate (3×20 ml), organic layer was washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a gummy mass which was purified by flash column chromatography using over silica gel using 40-60% ethyl acetate in hexane as eluent to give (2,4-difluoro-phenoxy)-[4-(piperidine-1-sulfonyl)-phenyl]-acetic acid ethyl ester (1.31 gm).
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]([C:7]([NH2:9])=[O:8])=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[N:28]=[C:29]=[O:30]>O1CCCC1>[Cl:1][C:2]1[NH:6][C:5]([C:7]([NH2:9])=[O:8])=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:29]([NH:28][C:19]3[CH:20]=[C:21]([C:24]([F:25])([F:27])[F:26])[CH:22]=[CH:23][C:18]=3[F:17])=[O:30])=[CH:12][CH:11]=2)[CH:3]=1
Reactant: NC(=O)c1[nH]c(Cl)cc1-c1ccc(N)cc1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Product: NC(=O)c1[nH]c(Cl)cc1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To 0.055 g (0.233 mmol) of 5-chloro-3-(4-aminophenyl)-1H-pyrrole-2-carboxamide dissolved in 5 cm3 of tetrahydrofuran is added, at a temperature in the region of 20° C. under an argon atmosphere, 0.035 cm3 (0.245 mmol) of 2-fluoro-5-trifluoromethylphenyl isocyanate. After stirring for 2 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue, which is recrystallized from 4 cm3 of acetonitrile. After filtering through a No. 3 sinter funnel, the solid is washed with 2 cm3 of acetonitrile and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 35° C. for 4 hours to give 0.076 g of 5-chloro-3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]-phenyl}-1H-pyrrole-2-carboxamide in the form of a yellow solid; 1H NMR (400 MHz, DMSO d6, δ in ppm): 6.16 (s, 1H); 6.45 (broad m, 1H); 7.12 (broad m, 1H); 7.38 (partially masked m, 1H); 7.40 (d, J=9.0 Hz, 2H); 7.45 (d, J=9.0 Hz, 2H); 7.49 (dd, J=9.0 and 11.0 Hz, 1H); 8.63 (dd, J=2.0 and 7.5 Hz, 1H); 8.90 (d, J=2.5 Hz, 1H); 9.22 (s, 1H); 12.1 (broad m, 1H); ES+: m/z=291: [M+Na]+.
Reaction SMILES: [C:1](N1C(N)=C(C2C=CN=CC=2)C=N1)(=N)N.[C:16]([N:19]1[C:23]([NH2:24])=[C:22]([C:25]2[CH:30]=[N:29][CH:28]=[CH:27][N:26]=2)[CH:21]=[N:20]1)(=[NH:18])[NH2:17]>>[NH2:18][C:16]1[N:19]2[N:20]=[CH:21][C:22]([C:25]3[CH:30]=[N:29][CH:28]=[CH:27][N:26]=3)=[C:23]2[N:24]=[CH:1][N:17]=1
Reactant: N=C(N)n1ncc(-c2ccncc2)c1N
Reactant: N=C(N)n1ncc(-c2cnccn2)c1N
Product: Nc1ncnc2c(-c3cnccn3)cnn12
Yield: 75 %

Procedure:
By replacing the 1-amidino-4-(4-pyridyl)-5-amino-pyrazole employed in Example 1C with an equivalent quantity of 1-amidino-4-(2-pyrazinyl)-5-aminopyrazole and following substantially the same procedure described in Example 1C there is obtained a 75% yield of 4-amino-8-(2-pyrazinyl)-pyrazolo[1,5-a][1,3,5]triazine. The product separates from boiling dimethylformamide in crystals melting above 360° C.