Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21](O)[CH2:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].S(Br)([Br:45])=O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Br:45][CH:21]([CH2:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=S(Br)Br
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)COCCCCCCCCCCCCCCCCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOCC(Br)COCCCCCCCCCCCCCCCCCC
Temperature: 100 °C

Procedure:
To a solution of 11.0 g of 1,3-dioctadecyloxy-2-propanol in 400 ml of dry dimethylformamide 20 g of thionyl bromide were added dropwise, while stirring well and boiling, after which the reaction mixture was heated at 100° C for 5 hours. After cooling down said mixture was slowly poured out into 400 ml of 5% sodium bicarbonate solution. The aqueous solution was extracted with 4 × 150 ml of hexane, after which the hexane extract was consecutively washed with water, 5% sodium bicarbonate solution, and water. After drying on sodium sulphate 0 aq the solvent was removed under vacuum. The resulting coarse product was purified by means of column chromatography. After evaporation and drying in vacuum (P = 0.001 mm Hg, t = 40° C) 8 gram were obtained, melting point 47.9° - 48.7° C.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16](O)[CH:17]([OH:19])[CH3:18].B(F)(F)F.CCOCC.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:15][C:12]1[N:11]=[CH:10][C:9]([C:1]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[O:19][CH:17]([CH3:18])[CH2:16][O:8]2)=[CH:14][CH:13]=1
Reactant: CC(O)CO
Reactant: O=C(c1ccccc1)c1ccc(Cl)nc1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1COC(c2ccccc2)(c2ccc(Cl)nc2)O1

Procedure:
To 25 ml of a solution of 1.5 g of 3-benzoyl-6-chloropyridine and 3.2 g of 1,2-propanediol in toluene, 1.2 g of boron trifluoride etherate was added. The resulting mixture was heated under reflux for six hours while removing the water thus formed therefrom. Then the reaction mixture was cooled, poured into an aqueous solution of sodium hydroxide and extracted with ether. The organic phase was washed with water and dried over anhydrous sodium sulfate. After filtering off the sodium sulfate and distilling off the solvent in vacuo, 2-(6-chloropyridin-3-yl)-4-methyl-2-phenyl-1,3-dioxolane was obtained, m.p.: 44°-51° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][CH:11]=[CH:10]2)=[O:5])[CH3:2].[H-].[Na+].Cl.[CH2:24]([N:26]([CH2:30][CH3:31])[CH2:27][CH2:28][Cl:29])[CH3:25]>CN(C)C=O>[ClH:29].[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:25][CH2:24][N:26]([CH2:30][CH3:31])[CH2:27][CH3:28])[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][CH:11]=[CH:10]2)=[O:5])[CH3:2]
Reactant: CCN(CC)CCCl
Reactant: CCOC(=O)c1[nH]c(-c2ccccc2)c2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2ccccc2c(-c2ccccc2)n1CCN(CC)CC
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A solution of 26.5 g. of 3-phenylisoindole-1-carboxylic acid ethyl ester in 600 ml. of dimethylformamide is treated under nitrogen at -10° C. with 0.40 mol. of sodium hydride (17.5 g. of a 55% dispersion in mineral oil) and stirred at the same temperature for 15 minutes. Then, at -10° C. to -5° C. there are added 34.5 g. of 2-diethylaminoethyl chloride hydrochloride. The mixture is stirred for 1 hour at room temperature and subsequently heated for 3 hours at 60° C. The mixture is cooled and poured into 8 liters of ice-water. After the addition of 300 g. of sodium chloride, the oily precipitate is separated by decantation and immediately dissolved in methylene chloride. The solution, shielded from daylight, is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated to dryness. The resulting oil is dissolved in 200 ml. of ether, treated with 280 ml. of 0.5 -N hydrochloric acid and thoroughly shaken. After cooling in an ice-bath, the separated hydrochloride is removed by filtration under suction, washed with water and ether and then dissolved in methylene chloride. The aqueous layer is separated and the methylene chloride solution is dried over sodium sulfate and filtered. After the addition of ether, there is obtained 2-[2-(diethylamino)ethyl]-3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride; melting point 230°-232° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[C:15]([C:17]([C:24]#[N:25])=[C:18]([CH:21]1[CH2:23][CH2:22]1)OC)#[N:16].[H-].[Na+]>CO>[NH2:25][C:24]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[N:14]=[C:18]([CH:21]2[CH2:23][CH2:22]2)[C:17]=1[C:15]#[N:16]
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: COC(=C(C#N)C#N)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1c(C2CC2)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N

Procedure:
A solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (3.8 g) and 1,1-dicyano-2-cyclopropyl-2-methoxyethylene (2.23 g) in methanol (30 ml) was stirred and treated with sodium hydride (80%, 30 mg). After 4 hours the solution was evaporated in vacuo and the residue was dissolved in ethyl acetate (40 ml), treated with charcoal and washed with water. The organic phase was evaporated in vacuo, the residual oil was dissolved in petroleum ether and crystals of 5-amino-4-cyano-3-cyclopropyl-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole, m.p. 197°-199° C., were obtained.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C@@H:10]([NH2:12])[CH3:11])[CH:6]=[CH:7][C:8]=1[F:9].C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[F:2][C:3]1[CH:4]=[C:5]([C@@H:10]([NH:12][C:42]([C:38]2[CH:37]=[C:36]3[C:41](=[CH:40][CH:39]=2)[N:33]([CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:21]4[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:31][CH:30]=2)[C:34]([CH3:46])=[C:35]3[CH3:45])=[O:43])[CH3:11])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: C[C@H](N)c1ccc(F)c(F)c1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(F)c(F)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(3,4-difluorophenyl)ethanamine hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 539 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:12]([CH3:13])=[CH:11][S:10][C:9]=2[CH:14]=1)=[O:4].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:12]([CH2:13][Br:15])=[CH:11][S:10][C:9]=2[CH:14]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc2c(C)csc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(CBr)csc2c1
Yield: 56.2 %

Procedure:
A mixture of 3-methylbenzo[b]thiophene-6-carboxylic acid methyl ester (1.03 g), N-bromosuccinimide (0.89 g), azobisisobutyronitrile (0.2 g) and carbon tetrachloride (25 ml) was heated under reflux for 2 hours and then cooled. The mixture was diluted with a few ml. of chloroform, washed with water, dried (Na2SO4) and evaporated to give a solid which was crystallized from ethyl acetate/petrol (b.p. 60°-80° C. to give 3-bromomethylbenzo[b]thiophene-6-carboxylic acid methyl ester (0.80 g), m.p. 108°-110° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH2:23])=[C:17]3[C:16]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:26][CH:25]=3)=[N:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[O:30]([C:27]1[CH:26]=[CH:25][C:24]([C:16]2[C:17]3[C:18](=[N:19][CH:20]=[N:21][C:22]=3[NH2:23])[N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:15]=2)=[CH:29][CH:28]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.5 %

Procedure:
1-(1-benzyl-4-piperidinyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Compound 1) (1.224 g, 2.57 mmol), 10% Palladium on carbon (1.22 g) and ammonium formate(0.81 g, 12.84 mmol) were mixed with 21 ml of methanol. After stirring at room temperature for 6 hours, the reaction mixture was filtered and washed with hot methanol. Solvent was removed and the residue was taking into dichloromethane and the organic layer was washed, dried, and evaporated to give 0.77 g of 3-(4-phenoxyphenyl)-1-(4-piperidinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (CDCl3) 2.05 (d, J=12.17 Hz, 2H), 2.26 (m, 2H), 2.87 (m, 2H), 3.29 (d, J=12.76 Hz), 4.89 (m, 1H), 5.54 (s, 2H), 7.09 (m, 2H), 7.15 (m, 3H), 7.39 (m, 2H), 7.67 (d, J=9.39 Hz, 2H), 8.37 (s, 1H); LC/MS (MH+32 387).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C@@H:6]([C:8]([OH:10])=O)[C@H:5]([C:11]([OH:13])=O)[CH2:4][C:3]=1[CH3:14].S(Cl)(Cl)=O.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>C(OCC)C>[CH2:19]([N:21]([CH2:22][CH3:23])[C:8]([C@H:6]1[C@H:5]([C:11]([N:21]([CH2:22][CH3:23])[CH2:19][CH3:20])=[O:13])[CH2:4][C:3]([CH3:14])=[C:2]([CH3:1])[CH2:7]1)=[O:10])[CH3:20]
Reactant: CC1=C(C)C[C@@H](C(=O)O)[C@H](C(=O)O)C1
Reactant: CCNCC
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: CCN(CC)C(=O)[C@@H]1CC(C)=C(C)C[C@H]1C(=O)N(CC)CC
Reaction time: 2 h

Procedure:
To trans-1,2-dimethylcyclohexene-4,5-dicarboxylic acid (1.98 g 0.01 mol) heated to 80° C., was added thionyl chloride (2.38 g, 0.02 mol) over 1 hr. The mixture was kept at this temperature for a further two hours, then cooled and added dropwise to a diethyl ether solution (45 ml) of excess diethylamine (14.6 g, 0.2 mol) cooled to ice bath temperature. The solvent was removed to give the crude product as an oil which was not purified for use in the next stage.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]([I:9])=[CH:7][N:8]=2)[CH2:3][CH2:2]1.[CH:10](Br)([CH3:12])[CH3:11]>>[CH:1]1([C:4]2[N:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([I:9])[N:5]=2)[CH2:3][CH2:2]1
Reactant: CC(C)Br
Reactant: Ic1cnc(C2CC2)[nH]1
Product: CC(C)n1cc(I)nc1C1CC1

Procedure:
The title compound, MS: m/e=277.1 (M+H+), was prepared in accordance with the general method of example 1 from 2-cyclopropyl-5-iodo-1H-imidazole (example C) and isopropylbromide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][N:10]=[C:11]3[CH:16]=[CH:15][C:14]([C:17]([C:19]4[S:20][CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[N:23]=4)=[O:18])=[CH:13][C:12]=23)[CH:5]=[CH:6][CH:7]=1>O.C1COCC1>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[S:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:23]=2)=[O:18])=[CH:13][C:12]=1[C:8](=[O:9])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C(c1ccc2noc(-c3cccc(Cl)c3)c2c1)c1nc(-c2ccccc2)cs1
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)c2nc(-c3ccccc3)cs2)cc1C(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
TiCl3 15% in water (300 ml) was added slowly at room temperature to a mixture of intermediate (15) (0.0656 mol) in THF (500 ml). The mixture was stirred at room temperature overnight, then poured out into ice water, extracted with DCM and washed with K2CO3 10%. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness, yielding 25.5 g (92.7%) of [4-amino-3-(3-chlorobenzoyl)phenyl](4-phenyl-2-thiazolyl)-methanone (intermediate 16).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[O:6][CH:7]1[CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:9]1[CH2:10][CH:7]([O:6][C:5]2[CH:18]=[CH:19][C:20]([CH2:21][N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:8]1
Reactant: COc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1CN1CCOCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC2CNC2)ccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
A solution of 7B (2.1 g, 5.47 mmol) in DCM (20 mL) was treated with TFA (10 g, 88 mmol) and stirred at RT for 2 h. The reaction mixture was concentrated and the residue was dissolved in aqueous NaHCO3 (sat.) and extracted several times with DCM and the organic solutions were filtered through a phase separator. The solvent was removed by evaporation and the residue was purified by column chromatography on SiO2 using 10% triethylamine and 10% MeOH in EtOAc as eluent. There was obtained 1.0 g (66%) of 7C as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 2.40-2.53 (m, 4H), 3.47 (s, 2H), 3.66-3.74 (m, 4H), 3.78 (s, 3H), 3.77-3.84 (m, 2H), 3.89-3.97 (m, 2H), 4.94-5.04 (m, 1H), 6.23 (d, 1H), 6.37 (s, 1H), 7.19 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH:15]([C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][C:23]([NH2:25])=[O:24])=[CH:19][CH:18]=1)=O.S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:15]([C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][C:23]([NH2:25])=[O:24])=[CH:19][CH:18]=1)=[N:1]2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: NC(=O)COc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OCC(N)=O)cc3)nc2c1
Yield: 27.3 %

Procedure:
2-Amino-4,6-dimethoxy-benzamide (150 mg, 0.764 mmol), 2-(4-formyl-phenoxy)-acetamide (137 mg, 0.764 mmol), sodium hydrogen sulfite (150 mg, 58.5%) and p-toluenesulfonic acid monohydrate (15 mg) in N,N-dimethyl acetamide (15 mL) were heated to 150° C. overnight. N,N-dimethyl acetamide was removed under vacuum and the residue was poured into water (50 mL). The solid was filtered off and washed with methanol to yield 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide (74 mg, 27.2%). Selected data: MS (m/z): 356.09; MP 309-311° C. HPLC purity: 88.57%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[CH2:6][NH:5]2.[N+:14]([O-])([OH:16])=[O:15]>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[CH:6]=[N:5]2
Reactant: O=[N+]([O-])O
Reactant: O=C1CNc2cc(Br)c(Cl)cc2N1
Solvent: O=C(O)C(F)(F)F
Product: O=c1cnc2c([N+](=O)[O-])c(Br)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a stirred suspension of 6-bromo-7-chloro-3,4-dihydroquinoxaline-2(1H)-one (0.06 g, 0.23 mmol) in CF3COOH (0.5 mL) was added fuming HNO3 (0.02 mL, 0.46 mmol) and the resulting reddish yellow suspension was stirred at r.t. overnight. The cream colored suspension so obtained was poured into ice (2.5 mL) and the precipitated solid was filtered, washed with water (1.0 mL) and dried under vacuum to afford 0.049 g (70%) of title compound as a cream colored powder which contained ~10% impurity (1H NMR integration); 1H NMR (DMSO-d6): δ7.577 (s, 1H), 8.251 (s, 1H), 12.879 (s, 1H). The crude product was used for the next reaction.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1>C(O)(=O)C>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[N:4]1[CH:12]=[CH:16][CH:15]=[CH:14]1
Reactant: Cc1cccc(C)c1N
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: Cc1cccc(C)c1-n1cccc1

Procedure:
A solution of 2,6-dimethylaniline (60.5 g), glacial acetic acid (600 ml) and 2,5-dimethoxytetrahydrofuran (572 g) is refluxed for 5 hours. The solvent is evaporated at 60° and reduced pressure to give 1-(2,6-dimethylphenyl)-1H-pyrrole as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[O:16][C:17]1[N:22]=[CH:21][C:20]([NH:23][C:24](=[O:35])[C@H:25]([NH:27]C(=O)OC(C)(C)C)[CH3:26])=[CH:19][CH:18]=1>ClCCl>[CH3:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH3:8])[C:10]=1[O:16][C:17]1[N:22]=[CH:21][C:20]([NH:23][C:24](=[O:35])[C@@H:25]([CH3:26])[NH2:27])=[CH:19][CH:18]=1
Reactant: Cc1cccc(C)c1Oc1ccc(NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(C)c1Oc1ccc(NC(=O)[C@@H](C)N)cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a 50 mL round-bottomed flask 1,1-dimethylethyl [(1R)-2-({6-[(2,6-dimethylphenyl)oxy]-3-pyridinyl}amino)-1-methyl-2-oxoethyl]carbamate (Intermediate 43, 282 mg) was dissolved in dichloromethane (2 mL) to give a yellow solution. Trifluoroacetic acid (2 mL, 26.0 mmol) was added. The reaction mixture was stirred at room temperature. After 20 min, the solvent was evaporated under vacuum affording a yellow oil that was charged on a 5 g SCX cartridge. It was then flushed with 25 mL of MeOH followed by 25 mL of 2M solution of ammonia in MeOH. The ammonia eluate was evaporated under vacuum to afford the title compound as a yellow oil which solidified (173.8 mg).
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[S:14](Cl)(=[O:16])=[O:15])[N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[N:9]=[CH:8]2.[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][NH2:32].C(N(CC)CC)C>ClCCl>[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][NH:32][S:14]([C:13]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:6][C:5]=1[O:4][C:3]1[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:2]=1[F:1])(=[O:16])=[O:15]
Reactant: CN(C)CCCN
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(S(=O)(=O)Cl)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(S(=O)(=O)NCCCN(C)C)cc21
Reaction time: 4 h
Yield: 39.9 %

Procedure:
To a cooled (0° C.) solution of 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-sulfonyl chloride (0.20 g, 0.50 mmol) in dichloromethane under N2 atmosphere was added 3-(dimethylamino)propylamine (0.05 g, 0.50 mmol) and triethylamine (0.15 g, 1.5 mmol) drop-wise. The reaction mixture was stirred for 4 hours and then diluted with dichloromethane (20 mL), washed with water, saturated NaHCO3 and brine and then dried over MgSO4. The mixture was concentrated under reduced pressure and chromatographed on preparatory TLC plates eluting with dichloromethane/MeOH/Et3N (95:4:1) to afford the 93 mg of final product (40% yield). MS (APCI−) m/z 466 detected; 1H NMR (400 mHz, CDCl3) δ 8.15 (s, 1H), 7.91 (s, 1H), 7.20 (m, 1H), 7.09 (s, 1H), 7.00 (m, 1H), 6.90 (m, 1H), 4.22 (d, 2H), 3.12 (t, 2H), 2.35 (m, 3H), 2.13 (s, 6H), 1.70 (m, 2H), 0.94 (d, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:56][CH:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>CN(C=O)C>[O:60]1[CH2:61][CH2:62][CH:57]([NH:56][C:21]([C:17]2[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[N:10][C:11]=3[CH3:24])[CH:16]=2)=[O:23])[CH2:58][CH2:59]1
Reactant: NC1CCOCC1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1cc(C(=O)NC2CCOCC2)n(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
To a solution of 5-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (85 mg, 0.26 mmol) and TBTU (91 mg, 0.28 mmol) in DMF (3.0 mL) was added DIPEA (220 μL, 1.28 mmol). Then 4-aminotetrahydropyran (29 mg, 0.28 mmol) was added and the mixture was stirred at room temperature under Ar for 30 min. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (72 mg, 68%) as a white solid. MS: m/e=415.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:11]=[C:12]([CH3:18])[C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[C:6]=2[CH:19]=1.CN(C)[C:22]1[O:23][C:24](=[O:32])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:27]=1.C(O)(=O)C>O>[CH3:17][O:16][C:13]1[C:12]([CH3:18])=[CH:11][C:10]([C:7]2[C:6]3[CH:19]=[C:2]([N:1]4[C:24](=[O:32])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[NH:27][C:22]4=[O:23])[CH:3]=[CH:4][C:5]=3[O:9][N:8]=2)=[CH:15][CH:14]=1
Reactant: CN(C)c1nc(C(F)(F)F)cc(=O)o1
Reactant: COc1ccc(-c2noc3ccc(N)cc23)cc1C
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2noc3ccc(-n4c(=O)cc(C(F)(F)F)[nH]c4=O)cc23)cc1C

Procedure:
A mixture of 5-amino-3-(6-methoxy-m-tolyl)-1,2-benzisoxazole (8.40 g, 0.033 mol), 2-dimethylamino-4-(trifluoromethyl)-6H-1,3-oxazin-6-one (7.60 g, 0.036 mol), and acetic acid is refluxed for three hours, cooled, poured onto ice, and diluted with water. The resultant aqueous mixture is filtered to obtain a solid. The solid is washed with water and dried to give the title product as a pink solid which is identified by NMR spectral analyses.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:5]=[N:6][CH:7]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Reactant: COc1ccc(B(O)O)cc1OC
Product: COc1ccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)cc1OC

Procedure:
The title compound was prepared from the product of Example 65A and 3,4-dimethoxyphenylboronic acid according to General Method B: 1H NMR (500 MHz, CDCl3) δ ppm 8.14 (d, 2 H), 7.19 (d, 1 H), 7.07 (d, 2 H), 6.93 (d, 1 H), 4.13 (s, 1 H), 3.91 (s, 3 H), 3.87 (s, 3 H), 3.81-3.30 (m, 7 H), 3.09-2.95 (m, 4 H), 2.34-2.18 (m, 3 H); LC-MS Method D (ESI+) m/z 366.0 (M+H)+, retention time 1.28 minutes.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][O:19][NH2:20])=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][O:19][NH:20][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])=[CH:16][CH:15]=1
Reactant: COc1ccc(CON)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(CONS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution of tosyl chloride (156.7 g) in pyridine (240 ml) was added dropwise to a solution of p-methoxybenzyloxyamine (102.3 g) in pyridine (210 ml) for 2.5 hours under cooling at 0°-5° C. and the mixture was stirred overnight at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate (1 l). The insoluble substances were filtered off, and the filtrate was washed three times with 2N hydrochloric acid, twice with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give crystalline product, which was recrystallized from a mixture of ethylacetate and petroleum ether to give N-(p-methoxybenzyloxy)-p-toluenesulfonamide (162.2 g) in the form of crystals.