Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:13]([OH:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:13](=[O:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](O)[C@H](CC(C)(C)C)NC(=O)OCc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)[C@H](CC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pyridine-SO3 complex (285 mg, 1.79 mmol) is added to a solution of the compound of Example 68A (50 mg, 0.18 mmol) and N,N-diisopropylethylamine (310 μl, 1.79 mmol) in 2 ml of DMSO at 10° C. with and the mixture is slowly warmed to RT. After 2 h, 50 ml of ice/water are added to the reaction mixture. The mixture is extracted four times with diethyl ether. The combined organic phases are washed three times with a 10% citric acid solution, then three times with water and twice with a satd. sodium chloride solution, dried over magnesium sulfate and concentrated at 20° C. on a Rotavapor. The crude product (30 mg, 60% of th.) is reacted further without additional purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[CH2:10][OH:11].C([Cu])#N.CN([CH:18]=[O:19])C>O>[OH:8][C:5]1[C:4]([CH3:9])=[C:3]2[C:2](=[CH:7][CH:6]=1)[C:18](=[O:19])[O:11][CH2:10]2
Reactant: Cc1c(O)ccc(Br)c1CO
Reactant: CN(C)C=O
Agent: N#C[Cu]
Solvent: O
Product: Cc1c(O)ccc2c1COC2=O
Temperature: 145 °C
Reaction time: 2 h

Procedure:
To a 2 L 3 neck flask equipped with overhead stirrer, N2 inlet, and condenser were charged 4-bromo-3-hydroxymethyl-2-methyl phenol (100 g, 461 mmol), CuCN (83.0 g, 921 mmol), and DMF (500 mL). The solution was sparged with N2 for 15 min then heated to 145° C. to obtain a homogeneous solution. The solution was aged at 145° C. for 2 h, then the reaction mixture was cooled to 95° C. 41.5 mL water was added (sparged with N2), and the reaction aged for 20 h. The reaction was cooled to RT then the solids filtered through solka flok and the cake washed with 50 mL DMF. To a 3 L flask containing 1 L EtOAc was added the DMF filtrate. A precipitate coating formed in bottom of flask. The DMF/EtOAc suspension was filtered through Solka-Flok® and the cake was washed with 250 mL EtOAc. The resulting filtrate was washed with 5% brine solution (3×500 mL). The aqueous layers were extracted with 500 mL EtOAc and the combined organics were dried over MgSO4, filtered and evaporated. The solids were slurried in 250 mL MTBE at RT then filtered and washed with 100 mL MTBE. The solids were dried under vacuum at RT, providing 5-hydroxy-4-methyl-3H-isobenzofuran-1-one.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14]1(=O)[CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:12][C:10]1[CH:11]=[C:2]([NH:1][CH:14]2[CH2:17][CH2:16][CH2:15]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)cc(N)c1C
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)cc(NC2CCC2)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.2 %

Procedure:
To a stirred solution of methyl 3-amino-5-chloro-2-methylbenzoate (2.0 g, 10 mmol) and cyclobutanone (1.4 g, 20 mmol) in dichloroethane (20 mL), acetic acid (3.6 g, 60 mmol) was added and reaction stirred at room temperature for 10 minutes. Then sodium triacetoxyborohydride (6.3 g, 30 mmol) was added at 0° C. and the reaction stirred for 3 h at room temperature. On completion, the solvent was removed under reduced pressure and the crude material was purified by column chromatography to afford the title compound (1.4 g, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[S:38][C:37]([NH2:39])=[N:36][C:35]=1[CH3:40])(=[O:33])=[O:32])([CH3:29])[CH3:28]>>[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[S:38][C:37]([NH:39][C:22]([C:21]2[CH:20]=[N:19][N:12]3[C:13]([C:15]([F:17])([F:18])[F:16])=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)=[N:10][C:11]=23)=[O:24])=[N:36][C:35]=1[CH3:40])(=[O:33])=[O:32])([CH3:29])[CH3:28]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(C)(C)CO
Product: Cc1nc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)sc1S(=O)(=O)NC(C)(C)CO

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.9) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to general procedure II. Yellow solid. MS (ISP) 621.0 [(M−H)−]; mp 265° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[CH:27]=[N:26][CH:25]=[CH:24][N:23]=2)[CH2:21][O:20]1.O>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:18][C:19]([C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)([OH:20])[CH3:21])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC1(c2cnccn2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cnccn2)CCN(C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.4 %

Procedure:
To a stirred solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido(4,3-b)indole (350 mg, 1.75 mmol) in DMF (4 mL) was added sodium hydride (210 mg, 5.25 mmol) followed by dropwise addition of 2-(2-methyl oxiranyl)pyrazine (310 mg, 2.275 mmol) at 10° C. and the reaction mixture was further stirred at RT for 16 h. After completion, the reaction mixture was poured into ice cooled water, extracted with EtOAc (3×75 mL). The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated yielding crude product, which was re-crystallized in ether and hexane to yield a yellow solid product (350 mg). 1H NMR (DMSO, Oxalate salt) d (ppm): 8.65 (s, 1H), 8.55 (s, 1H), 8.50 (d, 1H), 7.10 (s, 1H), 6.90 (d, 1H), 6.78 (d, 1H), 4.30 (m, 4H), 3.20 (m, 2H), 3.0 (m, 2H), 2.90 (s, 3H), 2.30 (s, 3H), 1.50 (s, 3H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.O[NH:38][C:39](=[NH:48])[C:40]1[CH:45]=[CH:44][C:43]([CH2:46][OH:47])=[CH:42][CH:41]=1>CN(C=O)C>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]2[O:11][N:48]=[C:39]([C:40]3[CH:45]=[CH:44][C:43]([CH2:46][OH:47])=[CH:42][CH:41]=3)[N:38]=2)=[CH:12][CH:13]=1)([CH3:2])[CH3:3]
Reactant: N=C(NO)c1ccc(CO)cc1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
A solution of 4-iso-propoxybenzoic acid (2.0 g, 11.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.13 g, 11 mmol), 1-hydroxybenzotriazole hydrate (1.50 g, 11.1 mmol) and DMF (14 mL) was stirred at room temperature for 30 minutes. N-hydroxyl-4-(hydroxylmethyl)benzamidine (1.84 g, 11.1 mmol) was added to the reaction mixture and stirred at 140° C. for 2 hours. The reaction mixture was cooled to room temperature, quenched with water (20 mL) and the aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were washed with 1N HCl and sat. NaHCO3, dried (Na2SO4), filtered and concentrated in vacuo to provide the title compound (2.0 g, 58% yield) as a pale yellow solid.
Reaction SMILES: C([N:3](CC)CC)C.[OH:8][CH:9]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)/[CH:10]=[CH:11]/[C@H:12]1[CH2:17][CH2:16][CH2:15][C:14](=[O:18])[N:13]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26].ClC(OCC)=O.N>C(Cl)Cl.CCOC(C)=O>[OH:8][CH:9]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)/[CH:10]=[CH:11]/[C@H:12]1[CH2:17][CH2:16][CH2:15][C:14](=[O:18])[N:13]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH2:3])=[O:26]
Reactant: O=C(O)CCCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC(=O)CCCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
Triethylamine (9 μL, 0.065 mmol) was added to a solution of 7-[(R)-2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acid (11.3 mg, 0.030 mmol) in CH2Cl2 (0.3 mL) at rt. After cooling to 0° C., ethyl chloroformate (3.2 μL, 0.033 mmol) was added. After 1 h at 0° C., a solution of ammonia (0.5 M in 1,4-dioxane, 0.3 mL, 0.15 mmol) was added and the reaction mixture was allowed to warm to rt. After 18 h at rt, the reaction mixture was diluted with EtOAc (10 mL) and washed with aqueous HCl (0.5 M, 3 mL), saturated aqueous NaHCO3 (5 mL) and brine (5 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→3% MeOH/CH2Cl2, gradient) afforded 3.5 mg (31%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.Cl[C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+]>>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=C1CCc2cc(O)ccc21
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Yield: 47.2 %

Procedure:
Using a method similar to Intermediate 1, using 5-hydroxy-1-indanone (2.44 g 16.5 mmol), 6-chloronicotinamide (2.34 g, 15.0 mmol) and K2CO3 (3.11 g, 22.5 mmol) gives the title compound (1.90 g) as a yellow solid. Mass spectrum (ion spray): m/z=269 (M+1); 1HNMR (DMSO-d6): 8.63 (s, 1H), 8.30 (d, 1H), 8.06 (s, 1H), 7.68 (d, 1H), 7.52 (s, 1H), 7.33 (s, 1H), 7.19 (d, 1H), 7.17 (d, 1H), 3.07 (t, 2H), 2.64 (t, 2H).
Reaction SMILES: [CH2:1]([NH:13][CH2:14][CH2:15][OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].I[CH2:18][CH3:19].C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH2:1]([N:13]([CH2:14][CH2:15][OH:16])[CH2:18][CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCNCCO
Reactant: CCI
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCN(CC)CCO
Yield: 73.4 %

Procedure:
2-[Dodecylamino]ethanol (2.0 g, 8.73 mmol), 1-iodoethane (1.63 g, 10.48 mmol) and N,N-diisopropylethylamine (2.51 g,17.5 mmol) in isopropanol (25 ml )were heated under reflux for 4 h. The solvent was then evaporated in vacuo and the residue was diluted with ethyl acetate washed with aqueous sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent followed by chromatography on silica gel (ethyl acetate/methanol 90:10 to 80:20) afforded the title compound (1.65 g, 73%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])[CH3:2].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH:1]([C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1cccc(C(=O)c2ccccc2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 200 ml reactor equipped with a reflux condenser and a stirrer, 60 ml of carbon tetrachloride and 10 g of the above mentioned fraction containing 3-ethylbenzophenone were introduced. While stirring the resultant mixture at room temperature, 8.6 g of N-bromosuccinimide and 0.14 g of benzoyl peroxide were added thereto, and reflux was perfomed for 8 hours while stirring the reaction solution. After the reaction solution had been cooled to room temperature, the succinimide was filtered out, and carbon tetrachloride was distilled off from a filtrate under a reduced pressure. The spectrum data of the obtained product were in accord with those of 3-(1-bromoethyl)benzophenone.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(C)(C)C.[Li]C(C)(C)C.CCCCC.CON(C)[C:28]([CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:29]>CCOCC>[NH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[C:28]([CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:29]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1
Reactant: CON(C)C(=O)C1CCCC1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: Nc1ccccc1C(=O)C1CCCC1
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 87.8 %

Procedure:
To a stirred solution of phenyl-carbamic acid tert-butyl ester (1.2 g, 6.2 mmol) in Et2O (12 mL) under a nitrogen atmosphere was added dropwise a 1.7 M solution of t-BuLi in pentan (8.4 mL, 14.3 mmol) over a 10-min period at −20° C. The mixture was stirred at −10° C. for 2.5 h and then cyclopentanecarboxylic acid methoxy-methyl-amide (1.07 g, 6.8 mmol) was added over 5 min. The mixture was allowed to warm to room temperature and stirred for further 1 h before it was quenched with aqueous NH4Cl. The organic phase was isolated and the aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried and concentrated in vacuo. The crude material was dissolved CH2Cl2 (18 mL) and TFA (6 mL) and stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo, and added aqueous NaHCO3 to pH 7 and extracted with CH2Cl2. The combined organic phases were dried and concentrated in vacuo to give 1.03 g (68%) of (2-amino-phenyl)-cyclopentyl-methanone as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:16].Cl[CH2:18][C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:16][CH2:18][C:19]#[N:20]
Reactant: Oc1ccc(Oc2cccc(Cl)c2)cc1Cl
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCOc1ccc(Oc2cccc(Cl)c2)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
A mixture of 14.99 g of 2-chloro-4-(3-chlorophenoxy)phenol, 4.44 g of chloro acetonitrile and 8.94 g of potassium carbonate in 150 ml dimethylformamide was stirred at a temperature of 70° to 80° C. in an oil bath for 5 hours. The reaction mixture was cooled to room temperature, poured into water and extracted twice with 100 ml of ethyl acetate. The extracts were conbined together, washed twice with 200 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 14.0 g of [2-Chloro-4-(3-chlorophenoxy)phenoxy] acetonitrile as a crude product.
Reaction SMILES: [OH:1][C:2]([CH3:14])([CH3:13])[CH2:3][CH2:4][CH2:5][C@H:6]([CH3:12])[CH2:7][CH2:8][CH2:9][CH:10]=[O:11].C(Cl)Cl.[Si:18](Cl)([CH3:21])([CH3:20])[CH3:19]>CN(C1C=CN=CC=1)C.CCN(CC)CC>[CH3:12][C@@H:6]([CH2:5][CH2:4][CH2:3][C:2]([CH3:13])([O:1][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[CH2:7][CH2:8][CH2:9][CH:10]=[O:11]
Reactant: C[Si](C)(C)Cl
Reactant: C[C@H](CCCC=O)CCCC(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](CCCC=O)CCCC(C)(C)O[Si](C)(C)C
Reaction time: 0.5 h

Procedure:
3.10 g of (S)-9-hydroxy-5,9-dimethyl-decanal was dissolved in 60 ml of abs. CH2Cl2 and treated successively at 0° with 57 mg of DMAP, 7.0 ml of NEt3 and 3.1 ml of TMS-Cl. The reaction mixture was kept for 30 minutes at RT and then poured onto crushed ice, extracted twice with ether, washed twice with water and brine, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=95/5) yielded 3.90 g of (S)-5,9-dimethyl-9-trimethylsilanyloxy-decanal as colorless oil, 98.6% pure according to GC.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[C:1]1([CH2:7][CH2:8][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCc1ccccc1
Reactant: Cc1cccc(N)c1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: Cc1cccc(NCCc2ccccc2)c1
Temperature: 236 °C
Yield: 90 %

Procedure:
260 parts of phenylethyl alcohol, 428 parts of m-toluidine and 20 parts of triphenyl phosphite are mixed and heated, using a water separator, initially to 210° C, at which temperature the elimination of water commences. The internal temperature is raised to 236° C in the course of 8 hours. After this time, the elimination of water has ended (36 parts of water). After distilling off excess alcohol and amine, the N-(2-phenylethyl)-m-toluidine distils at a boiling point of 167° C/5 mm Hg. 402 parts of N-(2-phenylethyl)-m-toluidine (90% of theory) are obtained.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=[O:9]>C(O)(=O)C.O>[Br:1][C:11]1[CH:12]=[C:13]([CH3:14])[C:5]([O:4][CH3:3])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COc1cc(C(=O)O)ccc1C
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C(=O)O)c(Br)cc1C
Temperature: 60 °C

Procedure:
Br2 (0.74 mL, 14.4 mmol) was added to a rt suspension of 3-methoxy-4-methylbenzoic acid (2.00 g, 12 mmol) in acetic acid (15 mL) and water (15 mL), then the mixture was heated to 60° C. for 2 h. The mixture was allowed to reach rt and the solids were filtered off and rinsed with cold water (40 mL) to yield 2-bromo-5-methoxy-4-methylbenzoic acid as a white solid which was used further without purification. LC-MS A: tR=0.76 min, [M+H]+=no ionization. 1H NMR (DMSO) δH: 7.49 (s, 1H), 7.29 (s, 1H), 3.82 (s, 3H), 2.17 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[O:9][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cc1cc(O)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 110 °C
Yield: 85.2 %

Procedure:
To a solution of 3-bromo-5-methylphenol (2.0 g, 0.0106 mol) in DMF (15 mL) was added K2CO3 (2.93 g, 0.02 mol) at RT. 2-Chloro-5-(trifluoromethyl)pyridine (1.94 g, 0.0106 mol) was added and the reaction was refluxed at 110° C. for 12 h. The reaction mixture was quenched with water and extracted with EtOAc three times. The total organic extract was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (3 g, 84.5%). 1H NMR (500 MHz, CDCl3): δ 8.45 (s, 1H), 7.92 (d, J=8.6 Hz, 1H), 7.26 (d, J=14.95 Hz, 1H), 7.13 (s, 1H), 7.03 (d, J=10 Hz, 1H), 6.90 (s, 1H), 2.36 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:19][C:20]3[CH:33]=[CH:32][C:23]([C:24]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[O:25])=[CH:22][CH:21]=3)=[CH:8][C:9](C3C=CC=CC=3)=[N:10]2)=[CH:5][CH:4]=1.[F:36][C:37]([F:49])([F:48])[C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>C(N(CC)CC)C>[F:36][C:37]([F:49])([F:48])[C:38]1[CH:43]=[CH:42][C:41]([S:44]([N:29]2[CH2:30][CH2:31][N:26]([C:24](=[O:25])[C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:34])[F:35])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:33][CH:32]=3)[CH2:27][CH2:28]2)(=[O:46])=[O:45])=[CH:40][CH:39]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: O=C(c1ccc(Nc2cc(-c3ccccc3)nc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In the manner given in Example 15, 4-[4-[[7-(trifluoromethyl)phenyl-4-quinolinyl]amino]benzoyl]piperazine is reacted with p-trifluoromethylphenylsulfonyl chloride in the presence of triethylamine to give 1-[4-(trifluoromethyl)phenylsulfonyl]-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)[N:7]([CH:9]([C:13]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21](=[O:30])[C:20]3[C:15](=[CH:16][C:17]([Cl:31])=[CH:18][CH:19]=3)[N:14]=2)[CH:10]([CH3:12])[CH3:11])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48]>CN(C=O)C.O>[C:50]([O:49][C:47](=[O:48])[CH2:46][NH:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)[N:7]([CH:9]([C:13]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21](=[O:30])[C:20]3[C:15](=[CH:16][C:17]([Cl:31])=[CH:18][CH:19]=3)[N:14]=2)[CH:10]([CH3:12])[CH3:11])[CH:8]=1)([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ccc(-c2nc(CCN)cn2C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc(CCNCC(=O)OC(C)(C)C)cn2C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Yield: 49.6 %

Procedure:
A solution of 2-{1-[4-(2-Amino-ethyl)-2-p-tolyl-imidazol-1-yl]-2-methyl-propyl}-3-benzyl-7-chloro-3H-quinazolin-4-one (181 mg, 0.343 mmol), potassium carbonate (47 mg., 0.343 mmol), and tert-butyl bromoacetate (67 mg., 0.343 mmol) in DMF (2.0 mL) was stirred at room temperature for 4.5 h. The reaction was diluted with water and the resulting white precipitate was filtered and purified by flash chromatography (silica gel, 95:5 methylene chloride:methanol) to provide the title compound as a white solid (109 mg., 50%). MS(ES+) m/e 640 [M+H]+.