Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH2:35][C@@H:34]2[CH2:38][NH:39][CH2:40][C@H:33]12)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH2:35][CH:34]2[CH2:38][N:39]([C:10]([C:2]3[NH:1][C:9]4[C:4]([CH:3]=3)=[CH:5][CH:6]=[CH:7][CH:8]=4)=[O:12])[CH2:40][CH:33]12)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]2CNC[C@@H]21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC2CN(C(=O)c3cc4ccccc4[nH]3)CC21
Reaction time: 72 h
Yield: 32.2 %

Procedure:
To a solution of indole-2-carboxylic acid (67.4 mg, 0.42 mmol) in THF (2.8 mL) was added CDI (68.3 mg, 0.42 mmol) and cis-octahydro-pyrrolo[3,4-b]pyridine-1-carboxylic acid tert-butyl ester (100 mg, 0.44 mmol). After 72 h at rt, the mixture was diluted with satd. aq. NaHCO3 and extracted with CH2Cl2 (3×). The combined organic layers were washed with satd. aq. NaCl, dried (Na2SO4), and concentrated to give a yellow liquid, which was purified by FCC (EtOAc/hexanes) to give a yellow solid (50 mg, 44%). 1H NMR (mixture of rotamers; CDCl3): 7.79-7.72 (m, 1H), 7.72-7.64 (m, 1H), 7.49-7.39 (m, 1H), 7.34-7.29 (m, 1H), 7.25-7.19 (m, 1H), 7.17-7.09 (m, 1H), 6.94-6.89 (m, 1H), 6.89-6.85 (m, 1H), 4.20-3.95 (m, 2H), 3.95-3.86 (m, 0.5H), 3.86-3.69 (m, 2H), 3.69-3.59 (m, 0.5H), 2.91-2.71 (m, 1H), 2.40-2.30 (m, 0.4H), 2.30-2.19 (m, 0.6H), 1.89-1.67 (m, 2H), 1.54-1.42 (m, 9H), 1.41-1.21 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][C:5]1[C:10]([F:11])=[CH:9][C:8](Br)=[CH:7][C:6]=1[F:13].[Li]CCCC.[CH3:19][C:20]([CH3:22])=[O:21].O>C(OC)(C)(C)C>[F:13][C:6]1[CH:7]=[C:8]([C:20]([OH:21])([CH3:22])[CH3:19])[CH:9]=[C:10]([F:11])[C:5]=1[CH:4]=[CH:3][O:2][CH3:1]
Reactant: CC(C)=O
Reactant: COC=Cc1c(F)cc(Br)cc1F
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Solvent: O
Product: COC=Cc1c(F)cc(C(C)(C)O)cc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled (−78° C.) solution of 2-(4-bromo-2,6-difluorophenyl)vinyl methyl ether (45 g, 0.18 mol) in methyl tert-butyl ether (300 mL) was added n-BuLi (75 mL of 2.5M in hexanes, 0.19 mol), and the mixture was stirred at −78° C. for one hour. A solution of acetone (13.6 g, 0.24 mol) in methyl tert-butyl ether (100 mL) was added dropwise to the reaction mixture and the resulting solution was stirred at −78° C. for two hours. Water (90 ml) was added to quench the reaction. The resulting biphasic mixture was extracted with ethyl acetate (2×). The organic layers were dried and concentrated in vacuo. Purification via flash chromatography afforded the title compound.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:25][N:24]=[C:23]([C:26](=O)[C:27]([OH:29])=[O:28])[N:22]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:31][CH2:32][O:33][NH2:34].[OH-].[Na+]>C(O)C.O>[C:1]([NH:20][C:21]1[S:25][N:24]=[C:23](/[C:26](=[N:34]/[O:33][CH2:32][F:31])/[C:27]([OH:29])=[O:28])[N:22]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)C(=O)c1nsc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NOCF
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)/C(=N\OCF)c1nsc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
2-(5-Tritylamino-1,2,4-thiadiazol-3-yl)-2-oxoacetic acid (1 g) was added to a mixture of a solution of fluoromethoxyamine (0.58 g) in ethanol (25 ml) and water (0.45 ml). After adjusting the pH of the resulting mixture to 4-5 with a 10% aqueous solution of sodium hydroxide, the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, followed by addition of water (20 ml) and sodium chloride (10 g) to the residue. The pH of the resulting solution was adjusted to 1 with concentrated hydrochloric acid. The solution was extracted four times with ethyl acetate (30 ml). After washing the extract with saturated saline, anhydrous magnesium sulfate was added to the extract to dry the same. The dry was distilled off and the residue was crystallized from a 1:10 mixture of acetone and isopropyl ether, thereby obtaining the target product (0.55 g).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[C@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([N+:23]([O-:25])=[O:24])[C:14]=2I)[O:9][C:8]1=[O:27].[F:37][C:38]1[C:43]([CH:44]([CH3:46])[CH3:45])=[CH:42][C:41](B(O)O)=[C:40]([O:50][CH3:51])[CH:39]=1>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[C@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([N+:23]([O-:25])=[O:24])[C:14]=2[C:41]2[CH:42]=[C:43]([CH:44]([CH3:46])[CH3:45])[C:38]([F:37])=[CH:39][C:40]=2[O:50][CH3:51])[O:9][C:8]1=[O:27]
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Reactant: C[C@@H]1[C@@H](c2cc(C(F)(F)F)cc([N+](=O)[O-])c2I)OC(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COc1cc(F)c(C(C)C)cc1-c1c([C@H]2OC(=O)N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)cc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Following the procedure described in EXAMPLE 81, 48 mg of (4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-3-nitro-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one and 48 mg of (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (EXAMPLE 78) provided two atroposiomers, which were separable by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 CV of 5% EtOAc in hexanes followed by a linear gradient of 5→100% EtOAc in hexanes over 10 CV, providing atropoisomer A [mass spectrum (ESI) 683.4 (M+1)] and atropoisomer B [mass spectrum (ESI) 683.3 (M+1)].
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:56][C:57]1[CH:62]=[CH:61][N:60]([CH2:63][CH2:64][O:65][Si:66]([C:69]([CH3:72])([CH3:71])[CH3:70])([CH3:68])[CH3:67])[C:59](=[O:73])[CH:58]=1>ClCCl>[C:69]([Si:66]([CH3:68])([CH3:67])[O:65][CH2:64][CH2:63][N:60]1[CH:61]=[CH:62][C:57]([NH:56][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:30])=[CH:58][C:59]1=[O:73])([CH3:72])([CH3:71])[CH3:70]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)cc1=O
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)c(=O)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.4 %

Procedure:
To a mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.2 g, 0.428 mmol) in dichloromethane (20 mL) was added iPr2NEt (138 mg, 1.07 mmol), followed by the addition of diphenylphosphinic chloride (Aldrich) (203 mg, 0.856 mmol). The mixture was stirred at room temperature for 30 min, then 4-amino-1-(2-(tert-butyldimethylsilyloxy)ethyl)pyridin-2(1H)-one (115 mg, 428 μmol) was added. The reaction mixture was stirred at room temperature for 3 h, then concentrated. The residue was purified by flash chromatography (silica gel, 40 g, 5% to 80% EtOAc in hexanes) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-oxo-1,2-dihydro-pyridin-4-yl)-amide as a white solid (35 mg, 11%).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=1.FC(F)(F)C(O)=O.[Br:22][C:23]1[CH:24]=[C:25]([CH2:28][NH2:29])[O:26][CH:27]=1.C(N(CC)CC)C>C(O)C>[Br:22][C:23]1[CH:24]=[C:25]([CH2:28][NH:29][C:3]([C:4]2[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=2)=[N:2][OH:1])[O:26][CH:27]=1
Reactant: NCc1cc(Br)co1
Reactant: COCCNc1nonc1C(Cl)=NO
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COCCNc1nonc1C(=NO)NCc1cc(Br)co1
Reaction time: 0.25 h
Yield: 100 %

Procedure:
N-Hydroxy-4-(2-methoxyethylamino)-1,2,5-oxadiazole-3-carbimidoyl chloride [prepared according to the procedure of Example 1, steps A through E] (4.5 g, 20.3 mmol) was stirred in ethanol (20 mL) at room temperature. To this, a solution of 1-(4-bromo-2-furyl)methanamine trifluoroacetate (6.5 g, 22.4 mmol) in ethanol (24 mL) was added and the mixture was stirred for 15 minutes. Triethylamine (6.3 mL, 44.8 mmol) was added dropwise over 10 minutes and the reaction was stirred for an additional 15 minutes. The solvent was removed in vacuo and after adding water (50 mL), the product was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated to give the desired product (7.5 g, 100%). LCMS calculated for C11H15BrN5O4 (M+H)+: m/z=359.9, 361.9.
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@@H:13]1[C:35](=[O:36])[N:15]2[C:16]([C:23]([O:25][CH:26]([O:28][C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH3:27])=[O:24])=[C:17](COC)[CH2:18][S:19][C@H:14]12.[C:37]([O-:40])(O)=O.[Na+]>C(OCC)(=O)C>[NH2:12][C@@H:13]1[C:35](=[O:36])[N:15]2[C:16]([C:23]([O:25][CH:26]([O:28][C:29]([O:31][CH:32]([CH3:33])[CH3:34])=[O:30])[CH3:27])=[O:24])=[C:17]([O:40][CH3:37])[CH:18]([CH3:1])[S:19][C@H:14]12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C([O-])O
Reactant: COCC1=C(C(=O)OC(C)OC(=O)OC(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC1=C(C(=O)OC(C)OC(=O)OC(C)C)N2C(=O)[C@@H](N)[C@H]2SC1C
Reaction time: 0.08 h

Procedure:
2.53 g (4.6 mmol) of diastereomer mixture from Example 1 were taken up in a mixture of ethyl acetate and 5% strength aq. NaHCO3 solution and stirred for 5 min. The phases were separated, and the organic phase was washed with satd. aq. NaCl solution, dried with MgSO4 and concentrated in vacuo.
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.ClCCl.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>CN(C1C=CN=CC=1)C.O>[CH2:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]
Reactant: COC(=O)c1ccc2c(c1)CCNC2
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc2c(c1)CCN(C(=O)OCc1ccccc1)C2
Temperature: 0 °C

Procedure:
A mixture of 10 g methyl 1,2,3,4-tetrahydroisoquinoline-6-carboxylate hydrochloride, 10 ml triethylamine, and 15 ml dichloromethane with 525 mg DMAP is stirred at 0° C. and 9.3 ml of benzyl chloroformate are added dropwise. After stirring overnight at ambient temperature, the reaction mixture is added to cold water. The organic phase is washed, dried, and evaporated. The crude product is purified by a silica gel chromatography.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11].[CH2:13]=O.[ClH:15].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.Cl>C(O)(C)C.O>[ClH:15].[CH3:11][CH:10]([CH2:13][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])=[O:12]
Reactant: C1CCNC1
Reactant: C=O
Reactant: CCC(=O)c1cccc(C)c1C
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: Cc1cccc(C(=O)C(C)CN2CCCC2)c1C
Yield: 67.3 %

Procedure:
A mixture of 1-(2,3-dimethylphenyl)-1-propanone (11.2 g), paraformaldehyde (2.70 g), pyrrolidine-hydrochloride (9.7 g), and hydrochloric acid (0.5 ml) in isopropyl alcohol (15 ml) was refluxed for 8.5 hours. The reaction mixture was evaporated in vacuo to give the residue. The residue was dissolved in water and then washed with ethyl acetate. The aqueous layer was extracted with dichloromethane and then dried over anhydrous magnesium sulfate. The mixture was filtered and then the filtrate was evaporated in vacuo to give the residue. The residue was recrystallized from CH2Cl2 --AcOEt to give 2-methyl-1-(2,3-dimethylphenyl)-3-pyrrolidino-1-propanone hydrochloride (13.1 g, Y: 64.7%) as colorless prisms, m.p. 149°-151° C. ##STR319##
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[O:3].[C:14]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=2)[NH2:26])[CH2:19][CH2:18]1)(=[O:16])[CH3:15].O>CN1C(=O)CCC1>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:26][C:25]2[CH:27]=[CH:28][CH:29]=[C:23]([N:20]3[CH2:19][CH2:18][N:17]([C:14](=[O:16])[CH3:15])[CH2:22][CH2:21]3)[CH:24]=2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)N1CCN(c2cccc(N)c2)CC1
Reactant: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)c1ccc(Nc2cccc(N3CCN(C(C)=O)CC3)c2)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
A mixture of 1b (0.75 g, 4.1 mmol) and 2d (0.9 g, 4.1 mmol) in anhydrous NMP (2 ml) was heated to 80° C. overnight under a stream of nitrogen. After cooling water (20 ml) was added and the mixture was extracted with dichloromethane. The organic extract was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by column-chromatography on silica gel using ethyl acetate as the eluent to yield 4-acetyl-N-(3-(1-acetylpiperazin-4-yl)phenyl)-2-nitroaniline as an oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11]P(=O)(OCC)OCC.[Li]CCCC.[CH:25]([C:27]1[N:28]=[C:29]2[C:34]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:33][CH:32]=[N:31][N:30]2[C:41]=1[C:42]1[CH:54]=[CH:53][C:45]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[CH:44][CH:43]=1)=O.[NH4+].[Cl-]>C1COCC1.O>[O:38]1[CH2:37][CH2:36][N:35]([C:34]2[C:29]3[N:30]([C:41]([C:42]4[CH:54]=[CH:53][C:45]([C:46]([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:47])=[CH:44][CH:43]=4)=[C:27](/[CH:25]=[CH:11]/[C:2]4[CH:3]=[CH:4][C:5]5[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=5[N:1]=4)[N:28]=3)[N:31]=[CH:32][CH:33]=2)[CH2:40][CH2:39]1
Reactant: CCOP(=O)(Cc1ccc2ccccc2n1)OCC
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(-c2c(/C=C/c3ccc4c(n3)CCCC4)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of compound 58a (125 mg, 0.441 mmol) in 2.5 mL of THF at RT was added n-BuLi (275 μL, 0.441 mmol, 1.6M in hexane) dropwise. After stirring at rt for 15 min, the mixture was added slowly to a suspension of compound 5f (150 mg, 0.367 mmol) in 2.5 mL of THF. The resulting mixture was stirred at rt for 30 min, then 2 mL of saturated NH4Cl was added. The mixture was diluted with 10 mL of water, then extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (15 mL) and dried with Na2SO4, filtered and concentrated. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel (0:1-1:4 EtOAc/DCM) to afford compound 60a as a pale yellow solid. 1H-NMR (CDCl3; 400 MHz) δ 8.16 (d, J=8.1 Hz, 2H), 7.98 (d, J=5.6 Hz, 1H), 7.79 (d, J=8.6 Hz, 2H), 7.73 (d, J=15.7 Hz, 1H), 7.50-7.58 (m, 1H), 7.29-7.35 (m, 1H), 7.21-7.26 (m, 1H), 6.11 (d, J=5.6 Hz, 1H), 4.02-4.09 (m, 4H), 3.93-4.02 (m, 4H), 2.93 (t, J=6.3 Hz, 2H), 2.77 (t, J=6.1 Hz, 2H), 1.86-1.95 (m, 2H), 1.77-1.86 (m, 2H), 1.63 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C32H35N5O3, 538.1 (M+H). found 538.0.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH3:22])([CH3:21])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([OH:20])[CH2:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]1([S:7]([C:10]([CH3:22])([CH3:21])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([O:20][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:15]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(CCCN1CCCC(O)C1)S(=O)(=O)c1ccccc1
Product: CC(C)(CCCN1CCCC(OCc2ccccc2)C1)S(=O)(=O)c1ccccc1

Procedure:
The title compound was prepared from 1-(4-benzenesulfonyl-4-methylpentyl)-3-hydroxypiperidine and benzyl bromide.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][C:26]=3[O:40][CH3:41])[N:15]=2)=[C:6]2[C:10]=1[CH2:9][N:8]([CH3:11])[C:7]2=[O:12].[C:42]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:44])[CH3:43]>>[C:42]([N:45]1[CH2:50][CH2:49][N:48]([C:2]2[CH:3]=[CH:4][C:5]([NH:13][C:14]3[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]4[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][C:26]=4[O:40][CH3:41])[N:15]=3)=[C:6]3[C:10]=2[CH2:9][N:8]([CH3:11])[C:7]3=[O:12])[CH2:47][CH2:46]1)(=[O:44])[CH3:43]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CC(=O)N1CCNCC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCN(C(C)=O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 199 using Diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl) pyrimidin-2-yl}amino)-3-methoxybenzyl]phosphonate and 1-acetylpiperazine. MS (ES+): m/z 706.38 (100) [MH+]; HPLC: tR=0.99 min (UPLC, purity).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][N:4]=1)#[CH:2].CO[C:12](=[O:27])[C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:16](Cl)=[N:15][CH:14]=1.[NH2:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[OH:35]>>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]2[C:16]([CH2:2][CH2:1][C:3]3[CH:8]=[CH:7][C:6]([F:9])=[CH:5][N:4]=3)=[N:15][CH:14]=[C:13]([CH:18]=2)[C:12]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[OH:35])=[O:27])=[CH:24][CH:23]=1
Reactant: COC(=O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Reactant: C#Cc1ccc(F)cn1
Reactant: N[C@@H]1CCCC[C@H]1O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(CCc2ccc(F)cn2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 140, using 2-ethynyl-5-fluoro-pyridine (CAN 884494-34-2), 6-chloro-5-(4-chloro-phenyl)-nicotinic acid methyl ester, and (1R,2R)-2-amino-cyclohexanol (commercially available) as starting materials, LC at 215 nm; Rt 4.12: 99%, m/z (ES+): 454.5 (M+H).
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([SH:7])=[CH:3][CH:2]=1.[OH-].[K+].[CH2:11]([O:13][C:14]([CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18](Br)[CH2:17]1)=[O:15])[CH3:12]>C(O)C>[CH2:11]([O:13][C:14]([CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18]([S:7][C:4]2[CH:5]=[CH:6][C:1]([CH3:8])=[CH:2][CH:3]=2)[CH2:17]1)=[O:15])[CH3:12]
Reactant: CCOC(=O)C1CCC(=O)C(Br)C1
Reactant: Cc1ccc(S)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1CCC(=O)C(Sc2ccc(C)cc2)C1

Procedure:
In a 2 l. three-necked flask provided with a condenser, nitrogen inlet, dropping funnel and stirrer were placed 73.5 g. of p-toluenethiol and a solution of 33 g. of 85% potassium hydroxide in 500 ml. of ethanol. The solution was brought to reflux, and a solution of 146.4 g. of 3-bromo-4-ketocyclohexanecarboxylic acid ethyl ester in 500 ml. of ethanol was added over a period of one hour. After the addition, the solution was stirred at reflux for one hour. After removal of the ethanol in vacuo on the steam bath, 300 ml. of water was added, and the product was extracted three times with 200 ml. of ether. The ether solution was dried over anhydrous magnesium sulfate, and then the solvent was removed on the steam bath. The residue was crystallized from heptane; yield 66 g. of 3-(4-methylphenylthio)-4-ketocyclohexanecarboxylic acid ethyl ester, m.p. 87°-89°.
Reaction SMILES: [I-].[Na+].[C:3](OC(=O)C)(=[O:5])[CH3:4].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][C:18]2[C:26]3[C:25](=[N:27]O)[CH2:24][CH2:23][CH2:22][C:21]=3[N:20]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:19]=2[CH3:35])=[CH:13][CH:12]=1>C1(C)C(C)=CC=CC=1.C(O)(=O)C>[C:3]([NH:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:18]([S:17][C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=1)=[C:19]([CH3:35])[N:20]2[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])(=[O:5])[CH3:4]
Reactant: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c1CCCC2=NO
Reactant: CC(=O)OC(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c(NC(C)=O)cccc21
Temperature: 97 °C
Reaction time: 2 h

Procedure:
In flask 1, a mixture of sodium iodide (171.6 mg, 1.14 mmol) in xylene (12.5 mL), acetic acid (12.5 ml) and acetic anhydride (4.2 mL, 44.54 mmoles) was heated to 97° C. In flask 2, acetic anhydride (4.2 mL, 44.5 mmol) was added to a stirred slurry of ethyl [3-(4-chlorophenylsulfanyl)-4-(hydroxyimino)-2-methyl-4,5,6,7-tetrahydro-1H-indol-1-yl]acetate (10 g, 22.3 mmol corrected for assay) in xylene (12.5 mL) and acetic acid (12.5 ml) at ambient temperature. The mixture in flask 2 was added to the mixture in flask 1 over 2-3 hours maintaining the temperature at 97° C. The reaction was held at this temperature for a further 2 hours following the end of the addition. The reaction was cooled to 60° C. and split into 2 equal size portions. One of these portions was cooled to r.t. and propan-1-ol (25 mL) was added, following by water (25 mL), added over 15 minutes, effecting a precipitation. After stirring for 1 h, the solid product was collected by filtration, washed with propan-1-ol (2×10 mL) and dried in vacuo at 40° C. to afford crude ethyl [4-acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-1H-indol-1-yl]acetate as a solid; 4.32 g (91% based on work up of half of the reaction mixture). Purity by HPLC 97.15 area %.
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][OH:8])[CH2:5][OH:6])[CH2:2][CH3:3].[CH:9]([C@@H:11]1[CH2:16][O:15][C@@H:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:13][O:12]1)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C@H:14]2[CH2:13][O:12][C@H:11]([C@H:9]3[O:8][CH2:7][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][O:6]3)[CH2:16][O:15]2)=[CH:18][CH:19]=1
Reactant: CCCC(CO)CO
Reactant: COc1ccc([C@H]2CO[C@H](C=O)CO2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC[C@H]1CO[C@H]([C@@H]2CO[C@@H](c3ccc(OC)cc3)CO2)OC1

Procedure:
A mixture of 1.2 g. 2-propylpropan-1,3-diol, 2.2 g. trans-5-formyl-2-p-methoxyphenyl-1,4-dioxane (obtainable by reaction of 1,1-ethylenedioxypropan-2,3-diol with p-methoxystyrene oxide and hydrolysis), 0.01 g. p-toluene sulphonic acid and 15 ml. toluene is boiled on a water separator for 3 hours, cooled, washed with water and evaporated. One obtains trans-2-p-methoxyphenyl-5-(trans-5-propyl-1,3-dioxan-2-yl)-1,4-dioxane.