Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([CH3:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][C:6]=1[CH3:14].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[F:1][C:2]([F:16])([CH3:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:12])=[CH:7][C:6]=1[CH3:14]
Reactant: CC(=O)c1ccc(OCC(C)(F)F)c(C)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)ccc1OCC(C)(F)F
Yield: 88 %

Procedure:
The title compound is prepared in 88% yield (693 mg, pale yellow oil) from 1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethanone (539 mg, 2.36 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (716 mg, 5.90 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([NH:14][C:15]2[N:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH:32]([CH3:34])[CH3:33])[CH:26]=3)[C:23](=[O:35])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[O:13])[CH:6]=1)C.[Li+].[OH-].Cl>O1CCOCC1>[CH:32]([O:31][C:27]1[CH:26]=[C:25]([N:24]2[C:23](=[O:35])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]2[NH:14][C:12](=[O:13])[NH:11][C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:4]([OH:36])=[O:3])[CH:30]=[CH:29][CH:28]=1)([CH3:34])[CH3:33]
Reactant: CCOC(=O)c1cccc(NC(=O)Nc2nc3ccccc3c(=O)n2-c2cccc(OC(C)C)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Oc1cccc(-n2c(NC(=O)Nc3cccc(C(=O)O)c3)nc3ccccc3c2=O)c1
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To a solution of 3-{3-[3-(3-Isopropoxy-phenyl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-ureido}-benzoic acid ethyl ester (200 mg, 0.41 mmol) in 1,4-dioxane (10 mL) was added 1N LiOH (3 mL) and stirred overnight. The reaction mixture was acidified with 1N HCl and concentrated. It was then diluted with ethyl acetate and washed with water. The organic layer was dried over MgSO41 concentrated and chromatographed using ethyl acetate:hexane (1:1 v/v) to isolate pure product as a white solid (150 mg, 80.2%), mp 158°-160° C.
Reaction SMILES: [Br:1][C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([F:12])[CH:5]=1.CC(C)([O-])C.[K+].C1(C)C=CC=CC=1>O>[Br:1][C:2]#[C:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([F:12])[CH:5]=1
Reactant: COc1ccc(C=C(Br)Br)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C#CBr)cc1F
Temperature: 80 °C
Yield: 81.4 %

Procedure:
A mixture of 1-(2,2-dibromo-vinyl)-3-fluoro-4-methoxybenzene (0.5 g, 0.00161 mol), potassium tertbutoxide (0.36 g, 0.00322 mol) and toluene (6 mL) were heated at 80° C. for 4 h. After completion, the reaction mixture was cooled to RT, diluted with water (15 mL), and extracted with EtOAc (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduce pressure to obtain product as a yellow oil (0.3 g, 81%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]([C:24]5[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=5)[CH2:22][CH2:21][CH:20]4[C:31]4[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=4)=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:38][O:39][C:40]([NH:42][C@@H:43]([CH:47]([CH3:49])[CH3:48])[C:44](O)=[O:45])=[O:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CS(C)=O.CO>[NH2:28][C:27]1[CH:29]=[CH:30][C:24]([CH:23]2[N:19]([C:16]3[CH:15]=[CH:14][C:13]([C:10]4[CH:11]=[N:12][C:7]([N:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)=[CH:8][CH:9]=4)=[CH:18][CH:17]=3)[CH:20]([C:31]3[CH:32]=[CH:33][C:34]([NH:35][C:44](=[O:45])[C@@H:43]([NH:42][C:40](=[O:41])[O:39][CH3:38])[CH:47]([CH3:49])[CH3:48])=[CH:36][CH:37]=3)[CH2:21][CH2:22]2)=[CH:25][CH:26]=1
Reactant: Nc1ccc(C2CCC(c3ccc(N)cc3)N2c2ccc(-c3ccc(N4CCOCC4)nc3)cc2)cc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)N[C@H](C(=O)Nc1ccc(C2CCC(c3ccc(N)cc3)N2c2ccc(-c3ccc(N4CCOCC4)nc3)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.1 %

Procedure:
In an oven-dried 5-mL round bottom flask purged with nitrogen, dissolved the product of Example 108B (70 mg, 0.142 mmol) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (26.2 mg, 0.150 mmol) in anhydrous DMSO (1.5 mL), added HATU (58.6 mg, 0.150 mmol) and diisopropylethylamine (0.050 mL, 0.285 mmol), and stirred dark yellow solution at 25° C. for 15 min. Diluted the reaction with MeOH (1.5 mL) and purified by RP-C18 HPLC (Waters Prep LC, 40 mm Module with Nova Pak HR C18 6 μm 40×100 mm Prep Pak cartridge) eluting with a 30 min gradient of 95:5 0.1% TFA in H2O/AcCN to 25:75 0.1% TFA in H2O/AcCN, then 10 min to 100% AcCN at 20 mL/min. Pure fractions were concentrated by rotary evaporation (water bath 35°) to a small volume, partitioned between 20% iPrOH/CHCl3 (50 mL), and sat'd aq NaHCO3 (15 mL), separated layers, dried organic extract over anhydrous MgSO4, filtered, and concentrated by rotary evaporation to afford the title compound as a light yellow solid (48 mg, 52%). 1H NMR showed the material to be ˜3:1 trans:cis mixture; MS (ESI+) m/z 649 (M+H)+, 1297 (2M+H)+.
Reaction SMILES: [BH4-].[Li+].CO.C([O:7][C:8](=O)[C:9]([CH3:29])([CH3:28])[CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:27])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:26])([CH3:25])[C:20](OCC)=[O:21])C.[Cl-].[NH4+]>ClCCl>[CH3:25][C:19]([CH3:26])([CH2:18][CH2:17][CH2:16][CH2:15][CH:14]([OH:27])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]([CH3:29])([CH3:28])[CH2:8][OH:7])[CH2:20][OH:21]
Reactant: CCOC(=O)C(C)(C)CCCCC(=O)CCCCC(C)(C)C(=O)OCC
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(CO)CCCCC(O)CCCCC(C)(C)CO
Reaction time: 8 h
Yield: 74.5 %

Procedure:
Under nitrogen atmosphere, to a suspension of lithium borohydride (2.65 g, 122 mmol) in dichloromethane (60 mL) was added methanol (4.0 g, 125 mmol) dropwise at room temperature over 30 min. The reaction mixture was heated at reflux and 2,2,12,12-tetramethyl-7-oxo-tridecanedioic acid diethyl ester (10.0 g, 27 mmol) was introduced. Heating at reflux temperature was continued overnight. The reaction mixture was cooled to room temperature and hydrolyzed with saturated ammonium chloride solution (100 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with 2 N hydrochloric acid (100 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude product. The crude compound was purified by chromatography on silica (hexanes:ethyl acetate=40:60) to yield the pure product (5.8 g, 74%) as a white solid. M.p.: 72-74° C. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 3.58 (br. m, 1H), 3.30 (s, 4H), 1.80-1.64 (m, 3H), 1.56-1.15 (m, 16H), 0.86 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 71.87, 71.72, 38.71, 37.46, 35.11, 26.66, 24.18, 24.05, 23.97. HRMS (LSIMS, gly): Calcd. for C17H37O3 (MH+): 289.2743, found: 289.2756. HPLC: 90.6% purity.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C[O-].[Na+].Cl[CH2:10][CH:11]([OH:22])[CH2:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1.O>CN(C)C=O>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[Cl:20])[NH:13][CH2:12][CH:11]([OH:22])[CH2:10][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: OC(CCl)CNc1ccc(Cl)c(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OC(CNc1ccc(Cl)c(Cl)c1)Cn1ccnc1
Temperature: 110 °C
Reaction time: 12 h
Yield: 39 %

Procedure:
19.9 Grams (0.293 mol) of imidazole and 54.7 g (0.304 mol) of sodium methylate solution (30% in methanol) are mixed and concentrated to dryness at 50° C./12 Torr. 80 Ml of dimethylformamide are added to the thus-formed imidazole sodium salt. The mixture is heated to 110° C. and a solution of 50 g (0.197 mol) of N-(3-chloro-2-hydroxypropyl)-3,4-dichloroaniline in 100 ml of dimethylformamide is added dropwise at this temperature over a period of 30 minutes. This addition finished, the reaction solution is further heated and refluxed for 2 hours. The solution is then cooled to 90° C. and 650 ml of water are added. The reaction mixture is left standing for 12 hours. The solid precipitant is filtered off, washed with water and dried at 50° C./12 Torr. For purification the substance is recrystallized under filtration with active charcoal from 100 ml ethyl acetate to yield 22 g of 1-[3-(3,4-dichloroanilino)-2-hydroxypropyl]-imidazole, M.P. 98°-100° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][O:11][CH3:12])[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:2]2[N:3]=[C:4]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:5]=[C:6]([NH:8][CH2:9][CH2:10][O:11][CH3:12])[CH:7]=2)=[CH:24][CH:23]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: COCCNc1cc(Cl)nc(-c2ccc(OC)cc2)n1
Product: COCCNc1cc(Sc2ccc(Cl)cc2)nc(-c2ccc(OC)cc2)n1
Temperature: 25 °C

Procedure:
A blended mixture of 6.5 g of 4-chloro-6-(2-methoxyethylamino)-2-(4-methoxyphenyl)-pyrimidine and 15.0 g. of p-chlorothiophenol is heated to 160°C. for 3 hours. Thereafter, the reaction mixture is cooled to room temperature and triturated with 60 ml. of 30°/o sodium hydroxide. The product is separated by filtration, washed with water and recrystallized from absolute ethanol to afford 6-(4-chlorophenylthio)-4-(2-methoxyethylamino)-2-(4-methoxyphenyl)pyrimidine, m.p. 117°-118.5°C.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[OH:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15].[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[Cl:8][C:4]1[N:3]=[C:2]([O:9][CH2:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: N#Cc1cccc(CO)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: N#Cc1cccc(COc2cncc(Cl)n2)c1

Procedure:
A mixture of 2,6-dichloropyrazine (400 mg, 0.671 mmol), 3-hydroxymethyl-benzonitrile (428 mg, 0.805 mmol), KOH (181 mg, 0.805 mmol) and 18-crown-6 (28 mg, 0.027 mmol) in toluene (10 mL) was stirred at reflux for 6 h and concentrated in vacuo. The residue was partitioned between H2O and ethyl acetate. The aqueous phase was separated and extracted with ethyl acetate twice. The combined organic extracts were washed with water and brine, dried and concentrated in vacuo. The crude product I-3f (667.2 mg) was used for next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[CH:34][C:6]([CH2:7][N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18](=[O:33])[C:19]3[CH:24]=[CH:23][C:22]([CH:25](OC)[O:26]C)=[CH:21][C:20]=3[N+:30]([O-:32])=[O:31])[N:10]=[N:9]2)=[CH:5][CH:4]=1.Cl>O1CCCC1>[CH:25]([C:22]1[CH:23]=[CH:24][C:19]([C:18]([C:11]2[N:10]=[N:9][N:8]([CH2:7][C:6]3[CH:34]=[CH:35][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:33])=[C:20]([N+:30]([O-:32])=[O:31])[CH:21]=1)=[O:26]
Reactant: CCOC(=O)c1c(C(=O)c2ccc(C(OC)OC)cc2[N+](=O)[O-])nnn1Cc1ccc(OC)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(=O)c2ccc(C=O)cc2[N+](=O)[O-])nnn1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
To a solution of ethyl 1-(4-methoxybenzyl)-4-(4-dimethoxymethyl-2-nitrobenzoyl)-1,2,3-triazole-5-carboxylate (7.26 g, 15 mmole) obtained in Example 11 (b-1: LP) in tetrahydrofuran (50 ml) was added a 1N aqueous hydrochloric acid solution (30 ml), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution. The solvent was removed under reduced pressure to give ethyl 4-(4-formyl-2-nitrobenzoyl)-1-(4-methoxybenzyl)1,2,3-triazole-5-carboxylate as a yellow crystalline powder (6.2 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>ClCCl>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:3][CH:4]=1
Reactant: Nc1ccc(F)cn1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(F)cn1
Reaction time: 3 h

Procedure:
To a stirred solution of 2-amino-5-fluoropyridine (50.0 g, commercially available) and triethylamine (93 ml) in dichloromethane (600 ml) was added pivaloyl chloride (56 ml) at ambient temperature. The slurry that formed was stirred for 3 hours, stored for 18 hours then washed with water (200 ml), brine (100 ml) then dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the required product as a brown oil, 86 g. 1H NMR (CDCl3) δ: 8.30 (1H, dd), 8.10 (1H, d), 8.00 (1H, bs), 7.42 (1H, m), 1.30 (9H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH:9]([NH:11][CH2:12][C:13]#[CH:14])=[O:10]>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:9]([NH:11][CH2:12][C:13]#[C:14][C:5]1[CH:6]=[CH:7][C:2]([C:14]#[C:13][CH2:12][NH:11][CH:9]=[O:10])=[N:3][CH:4]=1)=[O:10]
Reactant: Brc1ccc(Br)nc1
Reactant: C#CCNC=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: O=CNCC#Cc1ccc(C#CCNC=O)nc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
A mixture of 2,5-dibromopyridine (100 g), N-formylpropargylamine (87.7 g), PdCl2(PPh3)2 (2.96 g), and CuI (0.2 g) in diisopropylamine (3 L) was heated at 70° C. for 6 h under a nitrogen atmosphere. The mixture was cooled to 20-22° C. and filtered. The cake was dried and then slurried in water (3 L) at 0-5° C. for 3 h. The slurry was filtered, and the cake was dried to afford 95.4 g of the title compound 9-1.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[Si:11]([O:18][CH:19]([CH2:25][C:26](=[O:34])[CH2:27]P(OC)(OC)=O)[CH2:20][C:21]([O:23][CH3:24])=[O:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(O)(C)C>[Si:11]([O:18][CH:19]([CH2:25][C:26](=[O:34])/[CH:27]=[CH:4]/[C:3]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=1[Cl:1])[CH2:20][C:21]([O:23][CH3:24])=[O:22])([C:14]([CH3:16])([CH3:15])[CH3:17])([CH3:13])[CH3:12]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: COC(=O)CC(CC(=O)CP(=O)(OC)OC)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COC(=O)CC(CC(=O)/C=C/c1ccc(Cl)cc1Cl)O[Si](C)(C)C(C)(C)C
Temperature: 22 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
In 10 mL of isopropanol (water content: 9,500 ppm) were dissolved 457 mg (2.6 mmol.) of 2,4-dichlorobenzaldehyde and 1.0 g (2.6 mmol.) of methyl 3-[(tert-butyldimethylsilyl)oxy]-6-(dimethoxyphosphinyl)-5-oxohexanoate togive an alcoholic solution. To the alcoholic solution was added 362 mg (2.3mmol) of potassium carbonate, and the mixture was stirred for 3 hours at room temperature (22° C.). To the resulting reaction mixture was added 40 mL of ethyl acetate, and the mixture was stirred and washed with 20 mL of water. The washing was repeated twice. The organic phase was separated, dried over anhydrous magnesium sulfate, and filtered to give a filtrate. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=95/5, volume ratio) to give 1.06 g (yield: 94%) of methyl (E)-3-[(tert-butyldimethylsilyl)oxy]-7-(2,4-dichlorophenyl)-5-oxo-6-heptenoate.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[S:7][C:8]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14]Cl)=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[F:17][C:18]1[CH:32]=[CH:31][C:21]2[C:22]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:23][O:24][C:20]=2[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C1(C)C=CC=CC=1.CN(C)C=O>[C:1]([NH:4][CH2:5][C:6]1[S:7][C:8]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][N:28]2[CH2:27][CH2:26][CH:25]([C:22]3[C:21]4[CH:31]=[CH:32][C:18]([F:17])=[CH:19][C:20]=4[O:24][N:23]=3)[CH2:30][CH2:29]2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1ccc(C(=O)CCCCl)s1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc(C(=O)CCCN2CCC(c3noc4cc(F)ccc34)CC2)s1
Temperature: 60 °C
Reaction time: 6 h
Yield: 20.3 %

Procedure:
A mixture of 2-acetylaminomethyl-5-(4-chlorobutyryl)thiophene (2.6 g), 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (2.7 g), potassium carbonate (3.0 g), potassium iodide (1.6 g), dimethylformamide (20 ml), and toluene (20 ml) was stirred at 60° C. for 6 hours. The reaction mixture was poured into water, and the precipitated crystals were filtered off, followed by recrystallization from ethanol to give 0.9 g of 3-(1-(4-(5-acetylaminomethyl -2-thienyl)-4-oxobutyl)piperidin-4-yl)-6-fluoro-1,2-benzisoxazole as white crystals, m.p. 140-142° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11]([Cl:14])(Cl)Cl.[C]=[O:16].Cl>[Fe](Cl)(Cl)Cl.C(O)=O>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11]([Cl:14])=[O:16]
Reactant: Fc1cc(C(Cl)(Cl)Cl)c(F)c(F)c1F
Reactant: [C]=O
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: O=CO
Product: O=C(Cl)c1cc(F)c(F)c(F)c1F

Procedure:
268 g of 2,3,4,5-tetrafluorobenzotrichloride were placed in a stirred apparatus and 5.3 [lacuna] of iron(III) chloride were added, 45 g of formic acid (98-100%) were pumped in over 8 hours at 60° C. Vigorous gas development (carbon monoxide, hydrogen chloride) began immediately. The gas stream was fed to an absorption tower via a cooler. After addition was complete, the mixture was stirred until the end of gas development. The product was then distilled. 195 g of 2,3,4,5-tetrafluorobenzoyl chloride were obtained (91.5% of theory); b.p.: 70°-72° C./20 mbar, nD25 : 1.4773.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:48])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:47])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:46])[NH:31][C@@H:32]4[CH2:35][C@H:34]([C:36]([N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)=[O:37])[C:33]4([CH3:45])[CH3:44])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:50])[CH3:49])(=O)C>CO.C1COCC1.[OH-].[Na+]>[CH3:44][C:33]1([CH3:45])[C@@H:34]([C:36]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[O:37])[CH2:35][C@H:32]1[NH:31][C:30]([C@:14]12[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]1[C@@H:16]1[C@@:11]([CH3:47])([CH2:12][CH2:13]2)[C@@:10]2([CH3:48])[C@@H:19]([C@:20]3([CH3:23])[C@@H:7]([CH2:8][CH2:9]2)[C:6]([CH3:49])([CH3:50])[C@@H:5]([OH:4])[CH2:22][CH2:21]3)[CH2:18][CH2:17]1)=[O:46]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N4CCOCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N4CCOCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1R,3S)-2,2-dimethyl-3-(morpholine-4-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 16, 0.300 g, 0.43 mmol) in MeOH:THF (2:1) (15 ml), 2N NaOH (5 ml) was added at about 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the volatiles were evaporated and the aqueous layer was extracted with ethyl acetate and dried over Na2SO4. The solvent was evaporated and purified by silica gel column (100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.230 g: Yield: 81.8%; 1H NMR (300 MHz, CDCl3): δ 5.83 (d, 1H, J=7.8 Hz), 4.72 (s, 1H), 4.57 (s, 1H), 4.18-4.07 (m, 1H), 3.80-3.41 (m, 8H), 3.22-3.05 (m, 2H), 2.86 (t, 1H, J=8.1 Hz), 2.52-2.23 (m, 3H), 1.99-1.87 (m, 2H), 1.79-1.11 (m, 28H), 0.93, 0.89, 0.81, 0.74 (s, 18H); Mass: [M+1]+ 673 (100); IR (KBr, cm−1): 3419, 2951, 2864, 1624, 1527, 1459, 1374, 1271, 1249, 1112, 1068, 1044, 875, 861; M.R: 213.5° C.-216.5° C.; HPLC: 95.6%.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH:9]([C:16]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[O:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[O:17][C:16]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)=[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccc(C)cc1)C(=O)c1ccco1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccc(C)cc2)oc1-c1ccco1
Yield: 42.3 %

Procedure:
10 g of ethyl 3-(4-methylbenzoylamino)-3-(2-furylcarbonyl)propionate, 40 ml of chloroform and 23.3 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 4.0 g of ethyl 2-[2-(4-methylphenyl)-5-(2-furyl)-4-oxazolyl]acetate are thereby obtained. Yield: 42.3%
Reaction SMILES: [Br:1]N1C(C)(C)C(=O)N(Br)C1=O.[NH:12]1[C:20]2[CH2:19][CH2:18][CH2:17][C:16](=[O:21])[C:15]=2[CH:14]=[CH:13]1>CN(C=O)C>[Br:1][C:13]1[NH:12][C:20]2[CH2:19][CH2:18][CH2:17][C:16](=[O:21])[C:15]=2[CH:14]=1
Reactant: O=C1CCCc2[nH]ccc21
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: CN(C)C=O
Product: O=C1CCCc2[nH]c(Br)cc21
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 166.7 %

Procedure:
1,3-Dibromo-5,5-dimethylhydantoin (Fluka, St. Louis, Mo.) (532 mg, 1.86 mmol) was added to a solution of 6,7-dihydro-1H-indol-4(5H)-one (Aldrich) (503.0 mg, 3.72 mmol) in DMF (13 mL) at 60° C. and the resulting mixture was stirred at 60° C. for 10 min. The mixture was then concentrated in vacuo (65° C., 24 Torr), and the residual oil was chromatographically purified (silica gel, 0-80% EtOAc/hexanes). The isolated product was taken up in EtOAc (100 mL) and sequentially washed with saturated aq. NaHCO3 (3×40 mL) and brine (40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-bromo-6,7-dihydro-1H-indol-4(5H)-one (664 mg, 3.10 mmol, 83% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ ppm 8.43 (1H, br. s.), 6.51 (1H, d, J=2.3 Hz), 2.79 (2H, t, J=6.2 Hz), 2.48 (2H, t, J=6.6 Hz), 2.15 (2H, quin, J=6.3 Hz). m/z (ESI, +ve) 214.1/216.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:21])([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([CH3:18])([CH3:17])[CH2:12][CH2:11][C:10]2([CH3:20])[CH3:19])[C:3]([O:5]C)=[O:4].O.[OH-].[Na+]>CO>[F:1][C:2]([F:21])([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([CH3:17])([CH3:18])[CH2:12][CH2:11][C:10]2([CH3:20])[CH3:19])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(F)(F)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C(F)(F)C(=O)O)ccc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
Methyl 2,2-difluoro-2-(1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalen-6-yl)acetate 15 (1.38 g, 4.65 mmol) was dissolved in methanol (129 mL). Water (12.9 mL) and NaOH (1.04 g, 18.57 mmol) were successively added at RT. The mixture was stirred at 70° C. for 1 h. The mixture was evaporated in vacuo. The crude product was dissolved in water and extracted with diethyl ether (2×50 mL). The aqueous layer was acidified by HCl (1M) to about pH=1 and extracted with diethyl ether (3×100 mL). The organic layer was dried over MgSO4, filtered and evaporated to obtain 2,2-difluoro-2-(1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalen-6-yl)acetic acid 16 (1.27 g, 96.5% yield) as an orange solid.