Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][C:25]1[C:30]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:28]5[CH:29]=[C:30]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])[C:25]([CH3:24])=[N:26][CH:27]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Product: Cc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1NS(C)(=O)=O

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-methanesulfonamide (Stage 76.1.1) to give the title compound as a white solid. (HPLC: tR 2.06 min (Method A); M+H=478 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.51-9.47 (m, 1H), 8.98 (s, 1H), 8.46-8.42 (m, 1H), 8.15-8.09 (m, 2H), 7.94-7.88 (m, 1H), 7.72-7.68 (m, 1H), 7.60-7.56 (m, 1H), 3.90 (s, 3H), 3.57 (s, 3H), 3.09 (s, 3H), 3.54 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:19]>ClCCl>[N+:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][C:18](=[O:19])[NH:10][C:8]2[O:7][N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=2)=[CH:26][CH:25]=1)([O-:29])=[O:28]
Reactant: CC(C)(C)c1cc(N)on1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.4 %

Procedure:
A solution of 3-tert-butyl-isoxazol-5-ylamine (2.50 g, 17.83 mmol) in dichloromethane was treated with pyridine (2 mL, 26.7 mmol) followed by p-nitrophenyl chloroformate (3.77 g, 18.73 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with 1N HCl, filtered, and concentrated under reduced pressure. The residue was triturated with ether and collected by filtration to afford 2.2 g of product (41% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][CH2:29][NH:30][CH3:31]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][CH2:29][NH:30][CH3:31])=[CH:4][CH:3]=1
Reactant: COc1ccccc1N1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: CNCCCl
Product: CNCCn1cc(C(=O)N2CCN(c3ccccc3OC)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone (prepared herein) with (commercially available) (2-chloro-ethyl)-methyl-amine gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]([C:13](O)=[O:14])=[C:8]([C:9]([F:12])([F:11])[F:10])[C:4]=2[CH:3]=1.C(Cl)(C([Cl:22])=O)=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]([C:13]([Cl:22])=[O:14])=[C:8]([C:9]([F:12])([F:11])[F:10])[C:4]=2[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1sc2ccc(Cl)cc2c1C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1sc2ccc(Cl)cc2c1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To compound 18f in CH2Cl2 (5 mL) at room temperature was added (COCl)2, followed by 2 drops of DMF. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then concentrated to give compound 18g.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]([NH:26][NH:27][C:28]([C@@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][N:31]1[S:36]([C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)(=[O:38])=[O:37])=O)(=O)[CH3:24]>C1(C)C=CC=CC=1>[F:45][C:42]1[CH:43]=[CH:44][C:39]([S:36]([N:31]2[CH2:32][CH2:33][CH2:34][CH2:35][C@H:30]2[C:28]2[S:10][C:23]([CH3:24])=[N:26][N:27]=2)(=[O:38])=[O:37])=[CH:40][CH:41]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)NNC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Solvent: Cc1ccccc1
Product: Cc1nnc([C@@H]2CCCCN2S(=O)(=O)c2ccc(F)cc2)s1

Procedure:
Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide] (271 mg) was added to a solution of N′2-acetyl-(2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarbohydrazide (192 mg) [see Preparation 39] in toluene (10 ml). The reaction mixture was heated under reflux for 3 hours and the cooled mixture was then purified by column chromatography on silica gel eluting with a solvent gradient of 0:100 changing to 30:70 (in 10% increments), by volume, hexane:ethyl acetate, to afford 2-[(2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidyl]-5-methyl-1,3,4-thiadiazole (106 mg) as a clear oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]1[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]3[CH:36]=[CH:37][C:38]([NH:40][C:32]=3[CH:31]=2)=[O:39])[CH2:23][CH2:22][N:21]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[C:42]=2[Cl:48])[CH2:20]1>N1C=CC=CC=1>[CH2:12]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9](=[O:10])[O:39][C:38]1[CH:37]=[CH:36][C:33]2[C:32](=[CH:31][C:30]([O:29][CH2:28][CH2:27][CH2:26][CH2:25][N:24]3[CH2:23][CH2:22][N:21]([C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[C:42]=4[Cl:48])[CH2:20][CH2:19]3)=[CH:35][CH:34]=2)[N:40]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Reactant: O=C(Cl)N(Cc1ccccc1)Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Oc1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2n1)N(Cc1ccccc1)Cc1ccccc1

Procedure:
To a solution of dibenzylcarbamoyl chloride (1.7 g, 6.7 mmol) in pyridine (15 mL) was added dehydro-aripiprazole (1.5 g, 3.4 mmol) and the reaction mixture heated at reflux for 4 h. The reaction mixture was concentrated and the residue co-evaporated with toluene (×3). The residue was dissolved in ethyl acetate (ethyl acetate), washed with water and dried over MgSO4. After evaporation the residue was further purified on silica eluting with ethyl acetate and after drying gave Compound-342 (0.71 g) as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]([C:24]([NH:26]C2C=CC=CC=2)=O)=[CH:4][C:5]2[N:6](C(CC3CCC(F)(F)CC3)=C(C(F)(F)F)[N:10]=2)[CH:7]=1.[Cl:33]C1C(C(O)=O)=CC2N(C(CC3CCC(F)(F)CC3)=C(C(F)(F)F)N=2)C=1.NC1C=CC=CC=1>>[NH2:10][C:5]1[C:4]([Cl:33])=[C:3]([C:24]#[N:26])[CH:2]=[CH:7][N:6]=1
Reactant: O=C(O)c1cc2nc(C(F)(F)F)c(CC3CCC(F)(F)CC3)n2cc1Cl
Reactant: O=C(Nc1ccccc1)c1cc2nc(C(F)(F)F)c(CC3CCC(F)(F)CC3)n2cc1Cl
Solvent: Nc1ccccc1
Product: N#Cc1ccnc(N)c1Cl

Procedure:
Compound 107 (40.9 mg, yield 69%) was obtained in the same manner as in step 4 of Example 21, using 6-chloro-3-(4,4-difluorocyclohexylmethyl)-2-trifluoromethylimidazo[1,2-a]pyridine-7-carboxylic acid obtained in step 3, and aniline.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])[O:11][C:10]([CH3:30])([CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)[CH2:9][C:8]2=[O:31])(=O)C.[BH4-].[Na+].Cl>O1CCCC1.CO>[C:15]([C:14]1[CH:13]=[C:12]2[C:7]([CH:8]([OH:31])[CH2:9][C:10]([CH3:30])([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)[O:11]2)=[CH:6][C:5]=1[OH:4])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(COc2ccc([N+](=O)[O-])cc2)CC(O)c2cc(O)c(C(C)(C)C)cc2O1

Procedure:
A solution of 3.0 g of 6-acetoxy-7-t-butyl-2-methyl-2-(4-nitrophenoxymethyl)chroman-4-one (prepared as described in Preparation 54) in 20 ml of tetrahydrofuran was dropped into a suspension containing 0.3 g of sodium borohydride in 10 ml of methanol whilst stirring over an ice bath. After the whole of the solution had been added, the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was then ice-cooled again, acidified weakly with 10% w/v aqueous hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to give crystals. Recrystallization of these crystals from a mixture of benzene and petroleum ether gave the title compound, melting at 194°-201° C.
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]([C:16]#[N:17])=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[CH:6]1)[CH2:2][CH2:3][CH3:4].C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:14](=[O:15])[CH:13]([C:16]#[N:17])[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cc2c(c(C#N)c1=O)CCCC2
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCCCN1CC2=C(CCCC2)C(C#N)C1=O
Reaction time: 0.17 h
Yield: 70.1 %

Procedure:
2-Butyl-3-oxol-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile (7-012) (100 mg, 0.43 mmol) was dissolved in toluene (10 mL), and to the reaction mixture was added 1 M diisobutylaluminium hydride toluene solution (0.8 mL, 0.8 mmol) under ice-cooling, and the reaction mixture was stirred for 10 min. To the reaction mixture was added 1 mol/L diluted hydrochloric acid (5 mL), and the reaction mixture was extracted with ethyl acetate (10 mL), washed with brine (5 mL), dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (toluene/ethyl acetate) to give 2-butyl-3-oxo-1,2,3,4,5,6,7,8-octahydroisoquinoline-4-carbonitrile (7-018) (70 mg, 70%) as a white powder.
Reaction SMILES: [C:1]([C:5]1[CH:45]=[CH:44][C:8]([C:9]([N:11]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[C:33][C:34]3[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][CH3:43])=[CH:36][CH:35]=3)=[CH:28][CH:27]=2)[C:12]2[CH:24]=[CH:23][C:15]3[O:16]C(C)(C)[O:18][C:19](=[O:20])[C:14]=3[CH:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:11]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[C:33][C:34]3[CH:35]=[CH:36][C:37]([CH2:40][CH2:41][CH2:42][CH3:43])=[CH:38][CH:39]=3)=[CH:28][CH:27]=2)[C:12]2[CH:24]=[CH:23][C:15]([OH:16])=[C:14]([CH:13]=2)[C:19]([OH:20])=[O:18])=[O:10])=[CH:44][CH:45]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(C(=O)c3ccc(C(C)(C)C)cc3)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)c3ccc(C(C)(C)C)cc3)c3ccc(O)c(C(=O)O)c3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure C using 4-tert-butyl-N-{4-[(4-butylphenyl)ethynyl]benzyl}-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-6-yl)benzamide and NaOH 1M aq. in the presence of EtOH as a white powder (61%). 1H NMR (McOD, 300 MHz) δ 7.63 (d, J=2.3 Hz, 1H), 7.46 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.3 Hz, 2H), 7.33 (m, 6H), 7.22 (d, J=8.3 Hz, 2H), 6.85 (brd, J=8.7 Hz, 1H), 6.62 (d, J=8.7 Hz, 1H), 5.13 (s, 2H), 2.66 (t, J=7.5 Hz, 2H), 1.64 (m, 2H), 1.41 (m, 2H), 1.26 (s, 9H), 0.97 (t, J=7.3 Hz, 3H). M− (ESI): 558.3. HPLC, Rt: 5.72 min (Purity: 97.9%).
Reaction SMILES: Cl[C@H:2]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C@H:6]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[CH2:5][CH2:4][C@H:3]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[F:31].[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C)C=O.O.C(OCC)(=O)C>[N:32]([C@@H:2]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C@H:6]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[CH2:5][CH2:4][C@H:3]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[F:31])=[N+:33]=[N-:34]
Reactant: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@@H](Cl)c2cccnc21)(C(C)C)C(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@H](N=[N+]=[N-])c2cccnc21)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
In a 100 mL round-bottom flask was dissolved (5R,6S,9R)-5-chloro-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (566 mg, 1.214 mmol) in dimethylformamide (5 mL) to give a colorless solution. Sodium azide (474 mg, 7.29 mmol) was added, and the mixture was stirred at room temperature under nitrogen for 2.5 h. LCMS indicated only partial reaction. The mixture was heated at 50° C. overnight. After 15 h, LCMS indicated complete conversion with some elimination product. The mixture was diluted with water and ethyl acetate. The layers were separated. The organic layer was washed with brine, dried, and concentrated to give a colorless oil. The crude product was carried onto the next reaction without further purification and characterization. Smaller scale purification afforded an analytical sample: MS(ESI)[M+H+]=473.27; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.52-8.63 (m, 1H) 7.75 (d, J=7.81 Hz, 1H) 7.23-7.36 (m, 1H) 6.95-7.17 (m, 2H) 6.89 (br. s., 1H) 5.28 (d, J=4.03 Hz, 1H) 4.90 (d, J=9.07 Hz, 1H) 3.79 (t, J=9.44 Hz, 1H) 1.86-2.23 (m, 4H) 1.16-1.30 (m, 3H) 0.98-1.15 (m, 18H); 19F NMR (376 MHz, CHLOROFORM-d) δ ppm −137.68-−137.36 (m, 1F) −141.78-−141.54 (m, 1F).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[C:14]=1[C:24]1[CH:28]=[C:27]([S:29][CH3:30])[N:26]([CH3:31])[N:25]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:23][C:15]1[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=[C:13]([Cl:12])[C:14]=1[C:24]1[CH:28]=[C:27]([S:29]([CH3:30])=[O:9])[N:26]([CH3:31])[N:25]=1
Reactant: CSc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nn1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1S(C)=O

Procedure:
A 0.3 g quantity of 70% m-chloroperbenzoic acid was slowly added to 0.3 g of 3-(2,6-dichloro-4-trifluoromethylphenyl)-1-methyl-5-methylsulfenylpyrazole (compound 1) in 20 ml of anhydrous chloroform at room temperature with stirring, followed by stirring for 3 hours. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate, an organic layer was then separated off, washed with 5% aqueous sodium hydroxide solution and with brine and dried over anhydrous magnesium sulfate. The solvent was thereafter distilled off under reduced pressure, giving 0.3 g of the desired compound in the form of white crystals (quantitative crude yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@@:8]([NH:14][S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])([CH2:11][CH2:12][OH:13])[CH2:9][F:10])[CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@@:8]([NH:14][S@@:15]([C:17]([CH3:19])([CH3:18])[CH3:20])=[O:16])([CH2:11][CH:12]=[O:13])[CH2:9][F:10])[CH:7]=1
Reactant: CC(C)(C)[S@@](=O)N[C@@](CF)(CCO)c1cc(Br)ccc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)N[C@@](CF)(CC=O)c1cc(Br)ccc1F
Reaction time: 2.5 h
Yield: 84 %

Procedure:
To a solution of (R)-N-((S)-2-(5-bromo-2-fluorophenyl)-1-fluoro-4-hydroxybutan-2-yl)-2-methylpropane-2-sulfinamide (4.84 g, 12.59 mmol, step 4) in DCM (100 ml) was added Dess-martin periodinane (5.88 g, 13.85 mmol, Aldrich) at RT. The reaction was stirred for 2.5 hours. The reaction was quenched with water, followed by the addition of aqueous, saturated sodium bicarbonate solution, and DCM. The organic layer was washed with sequentially with saturated sodium bicarbonate solution three times and brine before drying over magnesium sulfate and concentrating under reduced pressure. The crude residue was purified via silica gel flash chromatography using a gradient of 10-60% acetone in hexanes to afford the title compound as a clear oil (4.04 g, 10.58 mmol, 84% yield). MS m/z=382.0 M+. Calculated for C14H18BrF2NO2S: 382.264
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.[C:9](=O)([O-])[O-:10].[Cs+].[Cs+].C1COCC1.CO>O>[I:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:10][CH3:9])[CH:7]=1
Reactant: Fc1cc(I)ccn1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(I)ccn1
Temperature: 50 °C

Procedure:
To 2-fluoro-4-iodopyridine (500 mg, 2.2 mmol) and cesium carbonate (730 mg, 2.2 mmol) was added THF (5 mL) and MeOH (0.091 mL, 2.2 mmol). The resulting mixture was heated to 50° C. for 24 hours in a sealed tube. The cooled mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated to yield the title compound. MS m/z=236 [M+1]+. Calc'd for C6H61NO: 235.03.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5]O.[H-].[Na+].[CH:10]1([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH:30]([CH2:33][O:34]S(C)(=O)=O)[O:31][CH3:32])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.CCCCCC.C(OCC)(=O)C>CS(C)=O>[CH:10]1([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH:30]([CH2:33][O:34][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:7])[O:31][CH3:32])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: OCCOCCO
Reactant: COC(COCCCCCCCCCCCCC1CCCCC1)COS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(COCCCCCCCCCCCCC1CCCCC1)COCCOCCO
Temperature: 75 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
2.03 g (19.2 millimole) of diethylene glycol was dissolved in 10 ml of dimethylsulfoxide (DMSO), to which 0.576 g (14.4 millimole) of 60% sodium hydride was added, and the mixture was stirred at 75° C. for 1 hour. The mixture was cooled to room temperature, to which 1.93 g (4.62 millimole) of 1-O-(12-cyclohexyl)dodecyl-3-O-mesyl-2-O-methylglycerol in 5 ml of DMSO was added, and the reaction mixture was stirred at 75° C. for 1 hour. After the reaction, 20 ml of ice water and 50 ml of hexane-ethyl acetate (1:1) mixture were added to the reaction mixture, and the upper layer was separated after shaking thoroughly. The aqueous layer was extracted with 20 ml of hexane-ethyl acetate (1:1), and the organic layers were combined, washed with water and dried (MgSO4), followed by evaporation of the solvent. The residue was subjected to silica gel (60 g) column chromatography, and eluted with hexane-ethyl acetate (1:1), to give 1.0 g (49%) of the above-captioned compound as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=3)[N:16]=[C:15]([C:25]([OH:27])=O)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=3)[N:16]=[C:15]([C:25]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=[O:27])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1
Reactant: Cc1cc(-n2nc(C(=O)O)cc2-c2cc(Br)cc(OC(F)(F)F)c2)ccn1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: Cc1cc(-n2nc(C(=O)N3CNC(=O)C3)cc2-c2cc(Br)cc(OC(F)(F)F)c2)ccn1

Procedure:
75 mg (0.17 mmol) of the compound of Example 48A is reacted analogously to the synthesis of the compound of Example 1 with 23 mg (0.19 mmol) of 4-imidazolinone-hydrochloride. 72 mg (83% of theory) of the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C:12]2[C:13]([C:26]([OH:28])=O)=[N:14][N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:16]=2)[CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([N:10]2[CH:11]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:12]3[C:13](=[N:14][N:15]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[CH:16]=3)[C:26]2=[O:28])[CH:3]=1
Reactant: COc1ccc(Cn2cc(C(Nc3cc(Cl)c(=O)n(C)c3)c3ccc(Cl)cc3)c(C(=O)O)n2)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(Cn2cc3c(n2)C(=O)N(c2cc(Cl)c(=O)n(C)c2)C3c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-ylamino)(4-chlorophenyl)methyl)-1-(4-methoxy-benzyl)-1H-pyrazole-3-carboxylic acid (Step 9.5). tR: 4.58 min (HPLC 1); tR: 1.01 min (LC-MS 2); ESI-MS: 495/497 [M+H]+ (LC-MS 2); Rf=0.55 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH:10]=2)[O:5][CH:4]([C:19]2[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][OH:26])=[CH:21][CH:20]=2)[C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[CH:30]=1.C(N(CC)CC)C.[CH3:49][S:50](Cl)(=[O:52])=[O:51].[Cl-].[NH4+]>C(Cl)Cl.O>[CH3:49][S:50]([O:26][CH2:25][CH2:24][O:23][C:22]1[CH:27]=[CH:28][C:19]([CH:4]2[C:3]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[CH:30]=3)=[C:2]([CH3:1])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]4[CH2:18][CH2:17][CH2:16][CH2:15][O:14]4)[CH:10]=3)[O:5]2)=[CH:20][CH:21]=1)(=[O:52])=[O:51]
Reactant: CC1=C(c2cccc(OC3CCCCO3)c2)C(c2ccc(OCCO)cc2)Oc2ccc(OC3CCCCO3)cc21
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC1=C(c2cccc(OC3CCCCO3)c2)C(c2ccc(OCCOS(C)(=O)=O)cc2)Oc2ccc(OC3CCCCO3)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of 2-(4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)ethanol (Intermediate 4, 0.7 g, 1.25 mmol) in DCM (25 mL) at 0° C., triethylamine (0.26 mL, 1.87 mmol) and methanesulfonyl chloride (0.146 mL, 1.87 mmol) were added respectively. The reaction mixture was stirred at 0° C. for 1 h, and then diluted with DCM. To this mixture, water (20 mL), and sat'd ammonium chloride (20 mL) were added. The layers were separated and the organic layer was washed with water, washed with saturated NaHCO3, washed with brine, dried over Na2SO4, and concentrated to give 2-(4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)ethyl methanesulfonate (0.7 g). 1H NMR (DMSO-d6): δ 7.25 (d, 3H), 6.99-6.98 (m, 1H), 6.93-6.87 (m, 3H), 6.85-6.78 (m, 2H), 6.77-6.75 (dd, 1H), 6.61 (d, 1H), 5.98 (d, 1H), 5.43 (d, 1H), 5.34 (br, 1H), 4.47-4.45 (m, 2H), 4.16 (br, 2H), 3.83-3.70 (m, 2H), 3.56-3.47 (m, 2H), 3.18 (s, 3H), 2.05 (s, 3H), 1.92-1.65 (m, 6H), 1.60-1.40 (m, 6H).
Reaction SMILES: O.[OH:2][CH:3]([CH2:20][S:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8](=[O:19])[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[O:11]2.[OH-].[Na+:27]>>[OH:2][CH:3]([CH2:20][S:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8](=[O:19])[CH:9]=[C:10]([C:16]([O-:18])=[O:17])[O:11]2.[Na+:27]
Reactant: CCCCSCC(O)COc1cccc2oc(C(=O)O)cc(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCSCC(O)COc1cccc2oc(C(=O)[O-])cc(=O)c12
Reaction time: 0.17 h

Procedure:
A mixture of 3.7 g of 5-(2-hydroxy-3-butylthiopropoxy)chromone-2-carboxylic acid monohydrate and 10 ml of N sodium hydroxide is stirred for 10 minutes and the precipitate which forms is filtered, washed with a little acetone and dried. Thus, 3.5 g sodium 5-(2-hydroxy-3-butylthiopropoxy)chromone-2-carboxylate is obtained.