Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:20])[C:4]([C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH3:18])[CH:11]=1)=[CH:5]OCC.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([C:4]2[C:3](=[O:20])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:5]=2)=[O:19])=[CH:11][C:12]=1[CH3:18]
Reactant: Nc1ccccc1
Reactant: CCOC=C(C(=O)OC)C(=O)c1ccc(OC)c(C)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Yield: 101 %

Procedure:
Experimental conditions analogous to those described for Step 1 of Example 1 were used with 1 g (3.78 mmol) of 3-ethoxy-2-(4-methoxy-3-methyl-benzoyl)-acrylic acid methyl ester, 0.214 g (3.78 mmol) of aniline, and 20 mL of diphenyl ether to yield 1.12 g of 3-(4-Methoxy-3-methyl-benzoyl)-1H-quinolin-4-one.
Reaction SMILES: [C:1]1([C:7]2([C:10]3[CH:26]=[CH:25][C:13]([C:14]([N:16]4[CH2:21][CH2:20][C:19]5[CH:22]=[CH:23][O:24][C:18]=5[CH2:17]4)=[O:15])=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.[CH2:32]=O>C(O)(=O)C>[C:1]1([C:7]2([C:10]3[CH:26]=[CH:25][C:13]([C:14]([N:16]4[CH2:21][CH2:20][C:19]5[CH:22]=[C:23]([CH2:32][N:27]6[CH2:31][CH2:30][CH2:29][CH2:28]6)[O:24][C:18]=5[CH2:17]4)=[O:15])=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCNC1
Reactant: C=O
Reactant: O=C(c1ccc(C2(c3ccccc3)CC2)cc1)N1CCc2ccoc2C1
Solvent: CC(=O)O
Product: O=C(c1ccc(C2(c3ccccc3)CC2)cc1)N1CCc2cc(CN3CCCC3)oc2C1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.454 g (1.322 mmol) of 6-[4-(1-phenylcyclopropyl)benzoyl]-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 10 ml of acetic acid, 0.17 ml (1.98 mmol) of pyrrolidine and 0.16 g (1.98 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 1 hour. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: ON=[CH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14])=[O:5].C(N)(=[O:19])C>>[F:14][C:13]([F:16])([F:15])[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[NH:6][C:4](=[O:5])[C:3]2=[O:19]
Reactant: CC(N)=O
Reactant: O=C(C=NO)Nc1ccccc1C(F)(F)F
Product: O=C1Nc2c(cccc2C(F)(F)F)C1=O

Procedure:
Following the procedure of example 36.B. except using 2-hydroxyimino-N-(2-trifluoromethyl-phenyl)-acetamide as the acetamide component afforded the title compound as a solid. ESI (−) MS m/e=214 (MH−).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2C3C(=CC=CC=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(N[C@H]2[C@@H](O)C[N:42]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:41]2)=NC=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@H:18]2[C@@H:19]([OH:27])[CH2:20][N:42]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:41]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1nc(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting benzyl(3R,4S)-3-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine 1-carboxylate and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.49, 7.39–7.25, 5.18, 4.99, 4.89, 4.71, 4.55, 4.04, 3.75–3.58, 3.36, 2.69, 2.49, 1.30, 1.15; HRMS (FAB) calcd for C26H28Cl2N4O3+H 515.1616, found 515.1641.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[C:12]([Si:15]([CH3:18])([Cl:17])[Cl:16])(Cl)Cl>>[C:1]1([C:12]([Si:15]([CH3:18])([Cl:17])[Cl:16])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](Cl)(Cl)C(Cl)(Cl)Cl
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: C[Si](Cl)(Cl)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 23.3 %

Procedure:
In the same apparatus and procedures as EXAMPLE 1 above, 50.4 ml (564 mmol) of benzene and 2.92 g (21.9 mmol) of aluminum chloride were alkylated with 10.0 g (43.0 mmol) of (trichloromethyl)methyldichlorosilane under dry nitrogen atmospheric pressure for 5 hours at room temperature. The aluminum chloride catalyst was quenched with PoCl3 and then stirred for another 1 hour to complete the deactivation. Freshly distilled hexane (100 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic soultion. After hexane and benzene were distilled, recrystallization from chloroform yielded 3.58 g of (triphenylmethyl)methyldichlorosilane (mp: 170-172° C., yield; 23%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[NH:8][C:7](=[O:12])[C:6]=2[CH:13]=1.CN(C=O)C.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br.C(N(C(C)C)CC)(C)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[N:8]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][Br:19])[C:7](=[O:12])[C:6]=2[CH:13]=1
Reactant: BrCCCCCCCCCCBr
Reactant: O=c1[nH]c(=O)c2cc(Cl)ccc2o1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1oc2ccc(Cl)cc2c(=O)n1CCCCCCCCCCBr
Yield: 49.9 %

Procedure:
A slurry of 9.77 g of 6-chloro-2H-1,3-benzoxazine-2,4(3H)-dione (50 mmol) and 60 ml of DMF was treated with a solution of 1,10-dibromodecane (52.52 g, 0.175 mol) and DMF (60 ml) was added. Diisopropylethylamine (9.6 ml, 55 mmol) was added dropwise. A thermometer and condenser were attached, and the flask was placed in an oil bath. The reaction was heated to 60 C for approximately 3 hrs, cooled to 47 C and hexanes (150 ml) were added. The mixture was diluted with water (175 ml). The resulting solids were removed by filtration. The aqueous layer was washed with warm hexanes. The resulting solids were filtered from the hexane layer and recrystallized from warm hexanes to give 10.39 g of 6-chloro-3-(10-bromodecyl)-2H-1,3-benzoxazine-2,4(3H)-dione.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:20]1([CH2:23][C:24]2[C:29]([C:30]3[CH:35]=[CH:34][N:33]=[C:32](S(C)=O)[N:31]=3)=[CH:28][N:27]=[C:26]([NH:39][CH3:40])[N:25]=2)[CH2:22][CH2:21]1>C1COCC1>[CH:20]1([CH2:23][C:24]2[C:29]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([NH:9][C:6]4[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:31]=3)=[CH:28][N:27]=[C:26]([NH:39][CH3:40])[N:25]=2)[CH2:21][CH2:22]1
Reactant: COc1ccc(N)cn1
Reactant: CNc1ncc(-c2ccnc(S(C)=O)n2)c(CC2CC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1ncc(-c2ccnc(Nc3ccc(OC)nc3)n2)c(CC2CC2)n1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 54.2 %

Procedure:
To a solution of 6-methoxypyridin-3-amine (61.4 mg, 0.494 mmol) in THF (5 mL) cooled to −78° C., lithium bis(trimethylsilyl)amide (1M in THF, 0.494 mL, 0.494 mmol) was added dropwise under nitrogen. After the reaction was stirred at −78° C. for 10 minutes, a solution of 4′-(cyclopropylmethyl)-N-methyl-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-amine (5-1) (30 mg, 0.099 mmol) in THF (1 mL) was added to the reaction at −78° C. The reaction was slowly warmed up to rt, then the reaction was allowed to stir for 1 hour. The reaction was quenched with saturated ammonium chloride solution, then concentrated in vacuo. The reaction was taken up in acetonitrile, purified by reverse-phase HPLC [10-90% organic phase over 15 minutes], then further purified by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 7% MeOH/DCM] to afford the title compound as a white solid (19.49 mg, 46.0% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.04 (br. s., 2 H) 0.34 (d, J=7.58 Hz, 2 H) 1.01 (br. s., 1 H) 2.77 (d, J=6.57 Hz, 2 H) 2.86 (d, J=4.55 Hz, 3 H) 3.74-3.86 (m, 3 H) 6.78 (d, J=9.09 Hz, 1 H) 6.97 (d, J=5.05 Hz, 1 H) 7.36 (d, J=4.04 Hz, 1 H) 7.99 (dd, J=8.59, 2.53 Hz, 1 H) 8.35-8.50 (m, 3 H) 9.46 (s, 1 H). HRMS (ES+) for C19 H21N7O.H+ [MH+]: calcd, 364.1886. found, 364.1891. UV-LC: 94.60/100% UV purity at 254/214 nm; tR=5.08 minutes over 7.75 minutes.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([NH2:16])=[CH:8][CH:7]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:26]=1)[C:21](O)=[O:22].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(OCC)(=O)C>[Cl:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([NH:16][C:21](=[O:22])[C:20]2[CH:24]=[C:25]([N:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)[CH:26]=[C:18]([F:17])[CH:19]=2)=[CH:8][CH:7]=1
Reactant: O=C(O)c1cc(F)cc(N2CCCCC2)c1
Reactant: Nc1ccc(OCCCl)c2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OCCCl)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Yield: 81.9 %

Procedure:
4-(2-Chloroethoxy)-naphthalen-1-ylamine hydrochloride salt (482 mg, 1.86 mmol), 3-fluoro-5-piperidinylbenzoic acid (500 mg, 2.2 mmol), diisopropylethylamine (1.14 ml, 6.7 mmol) and HBTU (1.06 g, 2.8 mmol) are stirred at room temperature in anhydrous dimethylformamide (10 ml) for 1 day. The mixture is poured into ethyl acetate (200 ml) and washed with water (3×100 ml). The organic layer is dried over anhydrous sodium sulfate and evaporated to dryness. The residue is purified by column chromatography on silica gel eluted with 20% ethyl acetate in hexanes to give N-[4-(2-chloroethoxy)-naphthalen-1-yl]-3-fluoro-5-piperidin-1-yl-benzamide as a tan solid (650 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.CN(C1CCCCC1)C.[Cl:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([NH2:30])[C:26]=1[C:27]([OH:29])=[O:28]>C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:30][C:25]2[C:26](=[C:21]([Cl:20])[CH:22]=[CH:23][CH:24]=2)[C:27]([OH:29])=[O:28])=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CN(C)C1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(Cl)c1C(=O)O)c1ccc(F)cc1
Temperature: 30 °C
Reaction time: 0.33 h

Procedure:
17.5 parts of 4-fluorobenzoyl chloride and 14 parts of N,N-dimethylcyclohexylamine are introduced simultaneously, from 2 feeds, into a solution of 17.1 parts of 6-chloroanthranilic acid in 230 parts of ethyl acetate at from 10° to 20° C., and the mixture is then stirred for 20 minutes at 30° C. Thereafter, the reaction mixture is washed once with 1 N hydrochloric acid and then with water, a colorless precipitate being formed. The latter is dissolved in ethyl acetate, and the organic phase is again washed with 1 N hydrochloric acid and then with water, dried over magnesium sulfate and evaporated down; 29 parts of N-(4'-fluorobenzoyl)-6-chloroanthranilic acid, of melting point 228°-233° C., are obtained.
Reaction SMILES: [N:1]1([C:8]([N:10]([CH2:12][CH2:13][N:14]([CH3:36])[C:15]([O:17][C@@H:18]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:19]([O:21]CC2C=CC=CC=2)=[O:20])=[O:16])[CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[N:1]1([C:8]([N:10]([CH2:12][CH2:13][N:14]([CH3:36])[C:15]([O:17][C@@H:18]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:19]([OH:21])=[O:20])=[O:16])[CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(CCN(C)C(=O)N1CCCCCC1)C(=O)O[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(CCN(C)C(=O)N1CCCCCC1)C(=O)O[C@@H](Cc1ccccc1)C(=O)O
Yield: 93.2 %

Procedure:
A solution of benzyl (2S)-2-[N-[2-{N-(hexahydro-1H-azepin-1-ylcarbonyl)-N-methylamino}ethyl]-N-methylaminocarbonyl]oxy-3-phenylpropionate (1.43 g) in methanol (20 ml) was hydrogenated over 10% palladium on carbon (0.2 g) at 3 atmospheric pressure of hydrogen gas for 1 hour at ambient temperature. The solution was filtered and concentrated in vacuo to give (2S)-2-[N-[2-{N-(hexahydro-1H-azepin-1-ylcarbonyl)-N-methylamino}ethyl]-N-methylaminocarbonyl]oxy-3-phenylpropionic acid (1.09 g) as an oil. Rf: 0.44 (chloroform:methanol:acetic acid, 16:1:1, V/V)
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:52])([F:51])[C:17]1[CH:18]=[C:19]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:20][N:21]([C:38]1[N:39]=[N:40][N:41]([CH3:43])[N:42]=1)[C@H:22]1[CH2:28][CH2:27][CH2:26][NH:25][C:24]2[CH:29]=[C:30]([C:34]([F:37])([F:36])[F:35])[C:31]([CH3:33])=[CH:32][C:23]1=2.[CH3:53][O:54][C:55](=[O:65])[C:56]1[CH:61]=[C:60]([CH:62]=O)[CH:59]=[CH:58][C:57]=1[OH:64].C(O)(=O)C>C(#N)C.ClCCl>[CH3:53][O:54][C:55](=[O:65])[C:56]1[CH:61]=[C:60]([CH2:62][N:25]2[CH2:26][CH2:27][CH2:28][C@H:22]([N:21]([CH2:20][C:19]3[CH:44]=[C:45]([C:47]([F:50])([F:48])[F:49])[CH:46]=[C:17]([C:16]([F:51])([F:15])[F:52])[CH:18]=3)[C:38]3[N:39]=[N:40][N:41]([CH3:43])[N:42]=3)[C:23]3[CH:32]=[C:31]([CH3:33])[C:30]([C:34]([F:35])([F:36])[F:37])=[CH:29][C:24]2=3)[CH:59]=[CH:58][C:57]=1[OH:64]
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: COC(=O)c1cc(C=O)ccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cc(CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)ccc1O
Reaction time: 24 h
Yield: 59.8 %

Procedure:
Add sodium triacetoxyborohydride (0.115 g, 0.543 mmol) portionwise to a solution of (S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine (Example 3, Step 18) (0.200 g, 0.362 mmol), 5-formyl-2-hydroxy-benzoic acid methyl ester (0.195 g, 1.08 mmol) and glacial acetic acid (1 mL) in acetonitrile (10 mL) at room temperature under an atmosphere of nitrogen and stir for 24 h. Quench the reaction with saturated sodium bicarbonate (5 mL) and dilute with dichloromethane (15 mL). Separate the layers and wash the organic layer with saturated sodium bicarbonate and brine (20 mL each). Dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (80:20), to provide the title compound as an off-white foam (0.155 g, 60%). 1H NMR (CDCl3, 300 MHz) δ 10.63 (s, 1H), 7.89 (s, 1H), 7.67 (s, 1H), 7.56 (m, 2H), 7.28 (s, 1H), 6.96 (m, 2H), 5.56 (m, 1H), 4.85-4.98 (m, 2H), 4.14 (s, 3H), 3.89 (s, 3H), 2.95-3.00 (m, 1H), 2.73-2.80 (m, 1H), 2.30 (s, 3H), 2.00-2.13 (m, 2H), 1.43-1.72 (m, 2H), 1.21-1.34 (m, 3H); ESI MS m/z 717 [C32H29F9N6O3+H]+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[O:9][C:10]1[CH:22]=[CH:21][C:13]2[C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][O:16][C:12]=2[C:11]=1[CH2:23][CH2:24][CH3:25].CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[CH3:33][S:34]([O:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[O:9][C:10]1[CH:22]=[CH:21][C:13]2[C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][O:16][C:12]=2[C:11]=1[CH2:23][CH2:24][CH3:25])(=[O:36])=[O:35]
Reactant: CCCc1c(O[C@@H]2CCCC[C@@H]2CO)ccc2c(C(F)(F)F)noc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1c(O[C@H]2CCCC[C@H]2COS(C)(=O)=O)ccc2c(C(F)(F)F)noc12
Reaction time: 4 h

Procedure:
To a solution of 6-{[cis-2-(hydroxymethyl)cyclohexyl]oxy}-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole (388 mg, 1.09 mmol), from this Example step 3, in CH2Cl2 (11 mL) was added Et3N (0.230 ml, 1.635 mmol) at 0° C., followed by methanesulfonyl chloride (0.093 mL, 1.2 mmol). The reaction mixture was stirred from 0° C. to room temperature for four hours. The mixture was diluted with CH2Cl2, washed with 5% HCl, followed by H2O then NaHCO3. Organic extracts were dried over NaSO4 and filtered. The solvent was evaporated in vacuo to give title compound.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Al](C)C.C[O:13][C:14]([C:16]1[C:20]([CH3:21])=[C:19]([C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[N:18]([CH2:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[C:17]=1[CH3:43])=O>C1(C)C=CC=CC=1>[CH:1]1([NH:7][C:14]([C:16]2[C:20]([CH3:21])=[C:19]([C:22]3[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=3)[N:18]([CH2:36][CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]3)[C:17]=2[CH3:43])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: COC(=O)c1c(C)c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n(CC2CCCCC2)c1C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1c(C(=O)NC2CCCCC2)c(C)n(CC2CCCCC2)c1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
A solution of 59.5 μl (0.52 mmol) of cyclohexylamine in toluene (2 ml) was treated at RT dropwise with 0.26 μl of a 2 M solution of trimethylaluminum in toluene (0.52 mmol). The reaction solution was stirred 1 h at RT, 200 mg (0.43 mmol) of 5-(3,5-bis-trifluoromethyl-phenyl)-1-cyclohexylmethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid methyl ester in toluene (2 ml) were added and reaction mixture was heated at 110° C. for 3 h. The mixture was then partitioned between water and ethyl acetate, the organic layer was isolated, dried over sodium sulfate and concentrated in vacuo and purified by column chromatography to give 114 mg of the title compound, MS (ISP) 529.3 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]2)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[H-].[Na+].[CH3:30]I.[Cl-:32].[Na+]>CN(C)C=O>[ClH:32].[CH3:30][N:23]1[C:24]2[C:19](=[CH:18][C:17]([C:2](=[O:1])[CH2:3][CH2:4][N:5]3[CH2:10][CH2:9][CH:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:7][CH2:6]3)=[CH:26][CH:25]=2)[CH2:20][CH2:21][C:22]1=[O:27]
Reactant: O=C1CCc2cc(C(=O)CCN3CCC(c4ccccc4)CC3)ccc2N1
Reactant: CI
Reactant: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CCc2cc(C(=O)CCN3CCC(c4ccccc4)CC3)ccc21
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.8 Grams of 6-[1-oxo-3-(4-phenyl-1-piperidyl)-propyl]-3,4-dihydrocarbostyril and 0.24 g of sodium hydride (50% in mineral oil) were mixed in 50 ml of dimethylformamide and the mixture was stirred at a room temperature for 3 hours. Then 0.8 g of methyl iodide was added thereto and stirred at a room temperature for 3 hours. The reaction mixture was poured into 150 ml of saturated sodium chloride aqueous solution and the organic layer was extracted with chloroform. The chloroform layer was washed with water, dried and chloroform was removed by distillation. The residue thus obtained was isolated and purified by preparative thin-layer chromatography and the desired product was converted into the hydrochloride then recrystallized from ethanol-water to obtain 1.5 g of 1-methyl-6-[1-oxo-3-(4-phenyl-1-piperidyl)-propyl]-3,4-dihydrocarbostyril monohydrochloride in light yellow plate-like crystals.
Reaction SMILES: CCO.C([Cl:7])(=O)C.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[C:18]1[N:23]([CH2:24][CH2:25][NH:26]C(=O)OC(C)(C)C)[C:22](=[S:34])[NH:21][C:20](=[O:35])[CH:19]=1>CCOC(C)=O>[ClH:7].[NH2:26][CH2:25][CH2:24][N:23]1[C:18]([C:11]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=2[O:9][CH3:8])=[CH:19][C:20](=[O:35])[NH:21][C:22]1=[S:34]
Reactant: COc1ccc(-c2cc(=O)[nH]c(=S)n2CCNC(=O)OC(C)(C)C)c(OC)c1
Reactant: CC(=O)Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc(=O)[nH]c(=S)n2CCN)c(OC)c1
Product: Cl
Reaction time: 0.75 h
Yield: 99.4 %

Procedure:
To a solution of EtOH (50 mL, 860 mmol) in EtOAc (390 mL), cooled in an ice/water bath, was slowly added acetyl chloride (55 mL, 770 mmol) over 3 minutes. After 5 minutes the cooling bath was removed, and after stirring for 45 min, the solution was added to tert-butyl 2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)ethylcarbamate (31.7 g, 77.8 mmol). A suspension formed over time, and after stirring for 5 h, the solid was collected by vacuum filtration, rinsing with EtOAc. The solid was pulled dry and dried further under vacuum to afford 26.6 g (99.3%) of the desired product as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:32]=[CH:31][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[O:28][CH:27]=[C:26]([CH:29]=O)[CH:25]=4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][S:34]([CH2:37][CH2:38][NH2:39])(=[O:36])=[O:35]>>[CH2:1]([O:8][C:9]1[CH:32]=[CH:31][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[O:28][CH:27]=[C:26]([CH2:29][NH:39][CH2:38][CH2:37][S:34]([CH3:33])(=[O:36])=[O:35])[CH:25]=4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1coc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)c1
Reactant: CS(=O)(=O)CCN
Product: CS(=O)(=O)CCNCc1coc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)c1

Procedure:
Prepared according to Procedure D from 5-(4-{4-benzyloxyanilino}-6-quinazolinyl)-furan-3-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). 1HNMR 400 MHz, d6DMSO 9.51 (bs,2H), 9.11 (s, 1H), 8.79 (s, 1H), 8.29 (d, 1H), 8.06 (s, 1H), 7.90 (d, 1H), 7.60 (d, 2H), 7.5–7.3 (m, 5H), 7.11 (d, 2H), 5.14 (s, 2H), 4.14 (bs, 2H), 3.6–3.5 (m, 3H), 3.12 (s, 3H); MS m/z 529 (M+1).
Reaction SMILES: Br[C:2]1[S:6][N:5]=[CH:4][C:3]=1[N+:7]([O-:9])=[O:8].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C.O>O1CCOCC1>[N+:7]([C:3]1[CH:4]=[N:5][S:6][C:2]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)([O-:9])=[O:8]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cnsc1Br
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnsc1N1CCOCC1
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-4-nitroisothiazole (P) (500 mg, 2.39 mmol) and morpholine (6B2) (620 mg, 7.12 mmol) in dioxane (10 mL) at room temperature (25° C.) was added DIEA (851 μL, 4.78 mmol). The solution was stirred for 30 min and HPLC showed the reaction was complete. Water (10 mL) was then added. A precipitate was formed, filtered and air dried at room temperature to get the product 6C6 (500 mg, 2.32 mmol).
Reaction SMILES: [C-:1]#[N:2].[K+].[C:4](Cl)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[CH:21]=[N:20][CH:19]=[CH:18]2>C(Cl)Cl>[C:4]([N:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][CH3:13])[CH:16]=2)[CH:21]1[C:1]#[N:2])(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc2ccncc2cc1OC
Reactant: [C-]#N
Agent: [K+]
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(C#N)N(C(=O)c1ccccc1)C=C2
Temperature: 25 °C
Yield: 33.7 %

Procedure:
An aqueous potassium cyanide (1.0 g, 16 mmol) solution (2.3 ml) and benzoyl chloride (1.1 ml, 9.5 mmol) were added to a solution of 6,7-dimethoxyisoquinoline (1.0 g, 5.3 mmol), which was synthesized according to Tetrahedron, 37 (23), 3977 (1981), in methylene chloride (6.0 ml), and this reaction mixture was stirred while heating under reflux for 2 hours. The reaction mixture was cooled to room temperature, filtered through celite, and washed with methylene chloride and water. After the obtained filtrate was separated, the methylene chloride layer was washed successively with water, 2 N hydrochloric acid, water, and 2 N sodium hydroxide, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (573 mg).