Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Li])=[CH:3][O:4]CC.BrC(=[C:12]1[C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C:26](=[CH:27][CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[CH2:18][CH2:17]3)[CH2:14][CH2:13]1)C=O>>[Cl:1][C:2](=[C:12]1[C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C:26](=[CH:27][CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:31])[CH:22]=[CH:23]2)[CH2:18][CH2:17]3)[CH2:14][CH2:13]1)[CH:3]=[O:4]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=C(Br)C=O)CC[C@@H]12
Reactant: [Li]C(Cl)=COCC
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=C(Cl)C=O)CC[C@@H]12

Procedure:
reacting androsta-1,3,5,9(11)-tetraene-17-one-3-diethylenamine with a cis-trans mixture of 2-chloro-2-lithio-1-ethoxyethylene to give a compound of the formula: ##STR38## (2) hydrolysis of the product of step (1) with acid to give 20-chloropregna 1,4,9(11),17(20)-tetraen-3-one-21-al (IVb) and
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]>>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:10](=[O:11])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: NCCCCCC(=O)O
Product: O=C(O)CCCCCN1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Yield: 94.2 %

Procedure:
3-nitrophthalic anhydride (0.5 g, 0.0026 mol) and 6-aminohexanoic acid (0.34 g, 0.0026 mol) were refluxed as above overnight. The clear solution was purified as per 120 to yield 0.75 g (95%) 124 as a pale yellow powder: mp=144° C.; Rf 0.68 (A): Rf 0.89 (C): Rf 0.71 (D): IR (cm−1): 2800–3180 (OH), 3096 (C═CH), 2620 (C—H), 1777 (C═O), 1723 (bs, C═O), 1617 (C═C), 1543 (N═O), 1468 (C═C), 1442 (C═C), 1395 (C—O), 1359 (N═O), 1057 (C—O), 723 (C═CH); MS m/z (rel intensity) 305 (100), 191 (17).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:17][C:18]2[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(-c2ccccc2)[nH]n1
Reactant: OCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(-c2ccccc2)n(Cc2ccc(CO)cc2)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
A mixture of 3-tert-butyl-5-phenyl-1H-pyrazole (2.0 g, 10 mmol), 4-(chloromethyl)benzyl alcohol (1.70 g, 10.8 mmol), potassium carbonate (2.76 g, 20 mmol) and N,N-dimethylformamide (20 mL) was stirred at 120° C. for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (5%-80% ethyl acetate/hexane) to give the title compound (640 mg, yield 20%) as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([NH:20][NH2:21])=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([CH:30]1[CH2:35][C:34](=O)[O:33][C:31]1=[O:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C1(C)C=CC=CC=1>O>[C:12]([C:9]1[CH:8]=[C:7]([CH2:16][CH2:17][C:18]([NH:20][N:21]2[C:34](=[O:33])[CH2:35][CH:30]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:31]2=[O:32])=[O:19])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: CCCCCCCCC1CC(=O)OC1=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCC1CC(=O)N(NC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O

Procedure:
A mixture of 3-(3,5-di-t-butyl-4hydroxyphenyl)propanoic acid hydrazide (I2.1 g, 41.1 mmol), 2-octylsuccinic anhydride (9.0 g, 41.1 mmol) and 20 ml of toluene was refluxed for one hour under a nitrogen atmosphere with the azeotropic removal of water (Dean-Stark assembly). The solvent was removed under vacuum while heating the reaction mass. 18.7 g of a very viscous, clear yellow liquid was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([N:16]2[CH:20]=[CH:19][CH:18]=[C:17]2[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][C:9]=1[NH2:25])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:33][C:32]([C:34]2[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=2)[C:37]#[N:38])=[CH:31][C:30](=O)[O:29]1>>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([N:16]2[CH:20]=[CH:19][CH:18]=[C:17]2[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][C:9]=1[NH:25][C:30](=[O:29])[CH2:31][C:32]([C:34]1[CH:41]=[CH:40][CH:39]=[C:36]([C:37]#[N:38])[CH:35]=1)=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(N)cc1-n1cccc1C(C)(C)C
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(C#N)c2)cc1-n1cccc1C(C)(C)C

Procedure:
The title compound was prepared from [2-amino-4-(2-tert.-butyl-pyrrol-1-yl)-5-methoxy-phenyl]-carbamic acid tert.-butyl ester (Example J5) (89 mg, 0.25 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) (63 mg, 0.275 mmol) according to the general procedure M. Obtained as an off-white solid (72 mg).
Reaction SMILES: [S:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][C:14]([F:17])([F:16])[F:15])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([OH:3])=[O:2].[C:18](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:18][S:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][C:14]([F:15])([F:16])[F:17])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])(=[O:3])=[O:2]
Reactant: O=C(O)c1cc(S(=O)O)ccc1OC(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CS(=O)(=O)c1ccc(OC(F)(F)F)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To 5-Sulfino-2-trifluoromethoxy-benzoic acid (0.82 g) in DMF (5 mL) was added 1.3 g of potassium carbonate, and the reaction mixture was stirred for 5 minutes before methyl iodide (0.66 mL) was added. The reaction mixture was then stirred at room temperature for 60 hours. After such time the reaction mixture was concentrated in vacuo, and the residue was treated with 1N NaOH (10 mL) and THF (4 mL). The reaction mixture was stirred for a further 2 hours at room temperature. After such time the solution was acidified with concentrated HCl solution. THF was then removed in vacuo) and the precipitate was isolated by filtration and washed several times with water to yield the title compound. MS (m/e): 283.0 (M−H, 100%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[NH:15][C:14](=[O:16])[C:13]2[C:8](=[CH:9][C:10]([Cl:18])=[C:11]([CH3:17])[CH:12]=2)[N:7]=1)(=[O:3])[CH3:2].[H-].[Na+].I[CH3:22]>CN(C=O)C.ClCCl>[C:1]([O:4][CH2:5][C:6]1[N:15]([CH3:22])[C:14](=[O:16])[C:13]2[C:8](=[CH:9][C:10]([Cl:18])=[C:11]([CH3:17])[CH:12]=2)[N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1nc2cc(Cl)c(C)cc2c(=O)[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)OCc1nc2cc(Cl)c(C)cc2c(=O)n1C
Reaction time: 0.02 h
Yield: 66.8 %

Procedure:
To a suspension of 2-acetoxymethyl-7-chloro-6-methyl-3,4-dihydroquinazolin-4-one 0.428 g, 1.6 mmol) in anhydrous DMF (13 ml) was added sodium hydride (60% dispersion, 0.070 g, 1.76 mmol) under argon. Stirring was continued at room temperature for 1 min and then iodomethane (0.20 ml, 3.2 mmol) was added into the reaction mixture with a syringe via a septum. Stirring was continued at room temperature for 1 hour and the reaction mixture was then partitioned between ethyl acetate (130 ml) and brine (80 ml). The organic layer was washed with dilute brine (80 ml), dried (Na2SO4) and concentrated in vacuo to leave an orange residue. This orange residue was dissolved in dichloromethane and to this solution silica gel (Art 7734, 1.7 g) was added. The solvent was removed in vacuo and the orange free running powder was placed on a silica gel column made up in 5% ethyl acetate in dichloromethane. The column was eluted with 5% ethyl acetate in dichloromethane to afford a pale yellow solid (0.300 g, 67%), mp 110-112° C.; 1H-NMR (DMSO-d6) 2.17 (s, 3H, CH3CO), 2.47 (s, 3H, 6-CH3), 3.54 (s, 3H, N3—CH3), 5.23 (s, 2H, 2-CH2O), 7.71, 8.09 (2×s, 2H, 5-H, 8-H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH3:17][C:18]1[C:22]([CH3:23])=[C:21]([N:24]([CH2:49][O:50][CH2:51][CH2:52][O:53][CH3:54])[S:25]([C:28]2[C:29]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4[O:41][CH:42]=[CH:43][N:44]=4)=[CH:36][C:35]=3[CH2:45][CH2:46][NH:47][CH3:48])=[CH:30][CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[O:20][N:19]=1.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[CH3:17][C:18]1[C:22]([CH3:23])=[C:21]([N:24]([CH2:49][O:50][CH2:51][CH2:52][O:53][CH3:54])[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[CH:39]=[CH:38][C:37]([C:40]3[O:41][CH:42]=[CH:43][N:44]=3)=[CH:36][C:35]=2[CH2:45][CH2:46][N:47]([CH3:48])[C:8](=[O:10])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:27])=[O:26])[O:20][N:19]=1
Reactant: CNCCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)N(COCCOC)c1onc(C)c1C
Reactant: O=C(O)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CCN(C)C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To phenylacetic acid (7.9 mg, 0.058 mmol) and 0.003 ml DMF in 1 ml CH2Cl2, oxalyl chloride (2M in CH2Cl2, 0.073 ml, 0.15 mmol) was added. The mixture was stirred at room temperature for 1.5 hr and concentrated. The residue was dissolved in 0.5 ml CH2Cl2 and cooled to 0° C. A solution of the title compound of Step (A) (29 mg, 0.053 mmol) in 0.5 ml CH2Cl2 was added and followed by Et3N (16 mg, 0.16 mmol). The reaction was stirred at room temperature for 2 hr and concentrated to give the title compound of this step.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][CH:14]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1N)[CH2:13][CH2:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.N1(CCOC2C=CC(C(Cl)=O)=CC=2)CCCCCC1.[N:48]1([CH2:55][CH2:56][O:57][C:58]2[CH:91]=[CH:90][C:61]([CH2:62][NH:63][C:64]3C=C(OC)C=C[C:65]=3C3CCC4C(=CC=C(O[Si](C(C)(C)C)(C)C)C=4)C3)=[CH:60][CH:59]=2)[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1>>[N:48]1([CH2:55][CH2:56][O:57][C:58]2[CH:59]=[CH:60][C:61]([CH2:62][NH:63][CH2:64][CH2:65][C:20]3[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=3[CH:14]3[CH2:13][CH2:12][C:11]4[C:16](=[CH:17][CH:18]=[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH:10]=4)[CH2:15]3)=[CH:90][CH:91]=2)[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]1
Reactant: COc1ccc(C2CCc3cc(O[Si](C)(C)C(C)(C)C)ccc3C2)c(NCc2ccc(OCCN3CCCCCC3)cc2)c1
Reactant: COc1ccc(C2CCc3cc(O[Si](C)(C)C(C)(C)C)ccc3C2)c(N)c1
Agent: Cl
Agent: O=C(Cl)c1ccc(OCCN2CCCCCC2)cc1
Product: COc1ccc(C2CCc3cc(O[Si](C)(C)C(C)(C)C)ccc3C2)c(CCNCc2ccc(OCCN3CCCCCC3)cc2)c1

Procedure:
Synthesized from 2-[6-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]-5-methoxyphenylamine and 4-(2-azepan-1-ylethoxy)benzoyl chloride hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl]{2-[6-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]-5-methoxyphenyl}amine (448 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]{2-[6-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]-5-methoxyphenyl}ethylamine (392 mg). This compound (390 mg) was used according to an analogous synthetic method to Example 325 described below to provide the title compound (254 mg).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[C:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:6]1(=[O:36])=[O:35])[CH2:2][CH2:3][CH3:4].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)=[C:7]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[S:6]1(=[O:35])=[O:36])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(Nc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)C3)=C(c2ccccc2)S1(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCN1C(=O)C(Nc2ccc3c(c2)CCNC3)=C(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 66.9 %

Procedure:
A mixture of tert-butyl 6-[(2-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]-3,4-dihydroisoquinoline-2(1H)-carboxylate (example 24) (0.585 g, 1.144 mmol) in DCM (10 ml) and TFA (2 ml) was stirred at rt for 2.5 h. The reaction mixture was basified by addition of saturated aqueous NaHCO3. The organic phase was washed with saturated aqueous NaHCO3 and brine. The mixture was evaporated and the residue was purified by flash chromatography using 0-20% MeOH in DCM as eluent to give the title compound (0.315 g, 67%). 1H NMR (500 MHz DMSO-d6); δ 9.44 (bs, 1H), 7.26 (td, 1H), 7.19 (td, 2H), 7.05 (d, 2H), 6.76-6.68 (m, 3H), 6.29 (s, 1H), 3.78 (s, 2H), 3.69 (t, 2H), 2.86 (t, 2H), 2.27 (t, 3H), 1.78-1.68 (m, 2H), 1.46-1.36 (m, 2H), 0.93 (t, 3H); 13C NMR (125 MHz CDCl3): 159.5, 134.4, 134.3, 130.7, 129.6, 129.5, 128.3, 126.6, 125.4, 122.9, 119.9, 111.2, 46.9, 43.1, 40.5, 30.5, 28.1, 20.3, 13.8: Mass Spectrum: M+H+ 412.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][CH3:23])[CH:15]=3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]1([CH3:32])[O:29][C@@H:28]([CH2:30]O)[CH2:27][O:26]1>C(Cl)(Cl)Cl>[CH3:24][C:25]1([CH3:32])[O:29][C@@H:28]([CH2:30][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:9]=[N:10][C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][CH3:23])[CH:15]=4)=[N:12][CH:13]=3)=[CH:6][CH:7]=2)[CH2:27][O:26]1
Reactant: CC1(C)OC[C@H](CO)O1
Reactant: CCCOc1cccc(-c2ncc(-c3ccc(O)cc3)cn2)c1
Solvent: ClC(Cl)Cl
Product: CCCOc1cccc(-c2ncc(-c3ccc(OC[C@H]4COC(C)(C)O4)cc3)cn2)c1

Procedure:
The synthesis is carried out analogously to Example 17 from 5-(4-hydroxyphenyl)-2-(3-propoxyphenyl)pyrimidine and (4S )-2,2-dimethyl-1,3-dioxolan-4-ylmethanol (commercially available). ##STR46## [α]D20 (CHCl3)=+5.0
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[CH3:8][NH:9][CH:10]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[S:25][C:24]3[C:19](=[N:20][CH:21]=[CH:22][C:23]=3[Cl:26])[CH:18]=2)=[O:16])[CH2:11]1>>[CH3:8][N:9]([CH:10]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[S:25][C:24]3[C:19](=[N:20][CH:21]=[CH:22][C:23]=3[Cl:26])[CH:18]=2)=[O:16])[CH2:11]1)[S:3](=[O:5])(=[O:4])[N:2]([CH3:7])[CH3:1]
Reactant: CNC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: CN(C)S(=O)(=O)Cl
Product: CN(C)S(=O)(=O)N(C)C1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1

Procedure:
The title compound was prepared from dimethylsulfamoyl chloride and (3-methylamino-pyrrolidin-1-yl)-(7-chloro-thieno[3,2-b]pyridin-2yl)-methanone by a procedure analogous to Example 64C. MS: 403/405 (MH+); HPLC Rf: 4.76 min.; HPLC purity 98%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:38][NH:39][C@H:40]([CH2:59][C:60]1[CH:69]=[CH:68][C:67]2[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH:61]=1)[C:41]([NH:43][C@@H:44]([C:56](=[S:58])[NH2:57])[CH2:45][C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=1)=[O:42].C(N(C(C)C)CC)(C)C>C(Cl)Cl.C(OC)(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[N:39]([CH3:38])[C@@H:40]([C:41](=[O:42])[NH:43][C@@H:44]([C:56](=[S:58])[NH2:57])[CH2:45][C:46]2[CH:55]=[CH:54][C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[CH:47]=2)[CH2:59][C:60]2[CH:69]=[CH:68][C:67]3[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=3)[CH:61]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccc2ccccc2c1)C(N)=S
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CN(C(=O)C1CCN(C(=O)OC(C)(C)C)CC1)[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccc2ccccc2c1)C(N)=S
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.4 %

Procedure:
N-tert-Butyloxycarbonylpiperidin-4-carboxylic acid (97 mg; 0.424 mmol) was dissolved in methylene chloride (2 ml). HOAt (58 mg; 0.424 mmol) and EDAC (85 mg; 0.444 mmol) were added. The reaction mixture was stirred 15 min at RT. (2R)-2-Methylamino-3-(2-naphthyl)-N-((1R)-2-(2-naphthyl)-1-thiocarbamoylethyl)propionamide (17 mg; 0.386 mmol) was dissolved in methylene chloride (2 ml) and added. Diisopropylethylamine (0.073 ml; 0.424 mmol) was added and the reaction mixture was stirred 12 hours at room temperature. Tert-butylmethylether (25 ml) was added and the reaction mixture was washed with water (25 ml), aqueous sodium hydrogencarbonate (15 ml), aqueous sodiumhydrogensulfate (10%; 15 ml), water (15 ml) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (3.5×30 cm) using gradient elution, starting with ethyl acetate/heptane (1:1) increasing to ethyl acetate/heptane (2:1) to afford 0.190 g of 4-(N-methyl-N-((1R)-2-(2-naphtyl)-1-((1R)-2-(2-naphthyl)-1-thiocarbamoylethylcarbamoyl)ethyl)carbamoyl)piperidine-1-carboxylic acid tert-butylester.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:15])[N:6]=1)=[O:4].[F:16][C:17]1[CH:18]=[CH:19][C:20]([O:35][CH3:36])=[C:21]([C:23]([CH3:34])([CH3:33])[CH2:24][C:25]([OH:32])([C:28]([F:31])([F:30])[F:29])[CH:26]=O)[CH:22]=1.C(O)(=O)C.CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:15]=[CH:26][C:25]([OH:32])([C:28]([F:29])([F:31])[F:30])[CH2:24][C:23]([C:21]2[CH:22]=[C:17]([F:16])[CH:18]=[CH:19][C:20]=2[O:35][CH3:36])([CH3:33])[CH3:34])[N:6]=1)=[O:4]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: CNC(=O)c1ccc2c(N)cccc2n1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CNC(=O)c1ccc2c(N=CC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1

Procedure:
Analogously to Example 37, 220 mg (1.08 mmol) of 5-aminoquinoline-2-carboxylic acid-methylamide is reacted with 550 mg (1.78 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 3.0 ml of concentrated acetic acid in 30 ml of toluene. After chromatography on silica gel with hexane-ethyl acetate (0-70%), 259 mg (48% of theory) of the product is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([CH:10]=[CH:11][C:12]([OH:17])=[CH:13]2)=[C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].[CH2:26](I)[CH2:27][CH2:28][CH3:29].Cl>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([CH:10]=[CH:11][C:12]([O:17][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13]2)=[C:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccccc2)c2ccc(O)cn2c1=O
Reactant: CCCCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOc1ccc2c(-c3ccccc3)cc(C(=O)OCC)c(=O)n2c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-ethoxycarbonyl-7-hydroxy-1-phenyl-4H-quinolizin-4-one (5 g) in N,N-dimethylformamide (100 ml) was added sodium hydride (63.6% in mineral oil, 732 mg) at 50° C. After stirring for 30 minutes at 50° C., n-butyliodide (2.77 ml) was added. After stirring for 1 hour at 50° C., the mixture was cooled to room temperature and added to a mixture of aqueous hydrogen chloride and an ice. The mixture was extracted with chloroform and the chloroform extract was washed with 10% aqueous sodium hydrogen carbonate and aqueous saturated sodium chloride. After drying over magnesium sulfate, the chloroform extract was filtered and concentrated in vacuo. The residue was chromatographed on silica gel (Merck 70-230 mesh, 100 g), eluting with chloroform and then 10% methanol in chloroform to give 3-ethoxycarbonyl-7-(n-butoxy)-1-phenyl-4H-quinolizin-4-one (2.37 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@:8]([NH:17][S@@](C(C)(C)C)=O)([CH3:16])[C:9]([F:15])([F:14])[C:10]([OH:13])([CH3:12])[CH3:11])[C:5]([F:24])=[CH:4][CH:3]=1.[N:25]#[C:26]Br>C(O)C>[Br:1][C:2]1[N:7]=[C:6]([C@:8]2([CH3:16])[C:9]([F:14])([F:15])[C:10]([CH3:11])([CH3:12])[O:13][C:26]([NH2:25])=[N:17]2)[C:5]([F:24])=[CH:4][CH:3]=1
Reactant: N#CBr
Reactant: CC(C)(C)[S@@](=O)N[C@](C)(c1nc(Br)ccc1F)C(F)(F)C(C)(C)O
Solvent: CCO
Product: CC1(C)OC(N)=N[C@](C)(c2nc(Br)ccc2F)C1(F)F
Temperature: 85 °C
Yield: 48.9 %

Procedure:
A solution of (R)-2-methyl-propane-2-sulfinic acid [(R)-1-(6-bromo-3-fluoro-pyridin-2-yl)-2,2-difluoro-3-hydroxy-1,3-dimethyl-butyl]-amide (2.95 g, 6.84 mmol) and cyanogen bromide (2.24 g, 20.52 mmol) in dry ethanol (68 ml) was sealed with a glass stopper and heated at 85° C. for 9 hr. The reaction solution was evaporated in vacuo and the crude product was taken up with ethyl acetate and 2M aq. ammonia. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The crude product (2.74 g) was chromatographed over silica gel (toluene/ethyl acetate 6:4) to give the title compound as a colourless solid. 1.19 g (48.9% yield).
Reaction SMILES: [C:1](OC(=O)C)(=O)C.N1C=CC=CC=1.[CH2:14]([O:21][CH2:22][CH2:23][CH:24]([NH:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][C:31]=1[F:37])[C:25]([OH:27])=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][CH2:22][CH2:23][CH:24]([NH:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][C:31]=1[F:37])[C:25](=[O:27])[CH3:1])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(NC(CCOCc1ccccc1)C(=O)O)c1ccc(Br)cc1F
Solvent: c1ccncc1
Product: CC(=O)C(CCOCc1ccccc1)NC(=O)c1ccc(Br)cc1F
Temperature: 90 °C

Procedure:
Add acetic anhydride (0.97 mmol) and pyridine (0.58 mmol) to a round bottom flask containing 4-benzyloxy-2-(4-bromo-2-fluoro-benzoylamino)-butyric acid (1.0 mmol) (See Intermediate 35) and heat to 90° C. for two hours. After this time, remove the heat and concentrate in vacuo. Wash crude with 1N hydrochloric acid and water while extracting with diethyl ether. Concentrate the organics in vacuo and purify on an Isco CombiFlash® chromatography system eluting with ethyl acetate and hexane. MS (m/e) (79Br/81Br): 408.3/410.3 (M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1.C(N(CC)CC)C.[CH3:18][CH:19]([CH2:23][CH2:24][Cl:25])[C:20](Cl)=[O:21]>C(OCC)(=O)C>[Cl:25][CH2:24][CH2:23][CH:19]([CH3:18])[C:20]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1)=[O:21]
Reactant: CC(CCCl)C(=O)Cl
Reactant: CC(C)(C)c1cc(N)no1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(CCCl)C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.2 %

Procedure:
To a stirred solution of 7 g of 3-amino-5-(1,1-dimethylethyl)isoxazole and 5.05 g triethylamine dissolved in 100 ml ethyl acetate was added 7.75 g of 2-methyl-4-chlorobutyric acid chloride dropwise. The mixture was stirred for about 16 hours at room temperature and the precipitated salt was collected by filtration and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was chromatographed over silica gel while eluting with a 1:1 (v/v) mixture of toluene:diethyl ether. Fractions containing the major component as indicated by thin layer chromatography were combined and concentrated under vacuum to provide 7 g of 4-chloro-N-[5-(1,1-dimethylethyl)-3-isoxazolyl]-2-methylbutanamide. Yield 54%. This material was used in the following reaction without additional purification.