Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:16])([CH3:15])[C:5](=[O:14])[NH:6]2>[Pd].CO>[NH2:11][C:10]1[C:2]([F:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5](=[O:14])[C:4]2([CH3:15])[CH3:16]
Reactant: CC1(C)C(=O)Nc2ccc([N+](=O)[O-])c(F)c21
Agent: [Pd]
Solvent: CO
Product: CC1(C)C(=O)Nc2ccc(N)c(F)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
A suspension of 4-fluoro-3,3-dimethyl-5-nitro-1,3-dihydro-2H-indol-2-one (3.5 g), palladium on carbon (containing water (50%), 2.0 g) in methanol (150 mL) was stirred at room temperature for 3 hr under a hydrogen atmosphere. The palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (2.9 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[NH2:16])=[O:14])[CH3:2].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH2:29][C:30](=O)[CH3:31])(=[O:28])=[O:27])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[N:16]=[C:30]([CH3:31])[CH2:29][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=1)(=[O:28])=[O:27])=[O:14])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Reactant: CC(=O)CS(=O)(=O)c1ccc(C)cc1
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)CS(=O)(=O)c1ccc(C)cc1
Yield: 124.4 %

Procedure:
To a 25 ml volume three-necked flask with Dean-Stark, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39) (500 mg), toluene (1.75 ml), and 1-(4-methylphenylsulfonyl)-2-propanone (7-2-4) (470 mg) were added. Water was removed by azeotropic distillation at 45-50° C. under 100 mmHg for 1.5 hours. To the mixture, toluene (1.75 ml) was added, and water was removed by azeotropic distillation at 60° C. under 120 mmHg for 6 hours. The reaction mixture was concentrated under reduced pressure to give 1.109 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-[1-(4-methylphenylsulfonyl)-2-propylidene]hydrazine ((4-36)-(1)-39).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:10][C@@H:9]1[C@@:11]([CH3:27])([NH:20][S@@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[C:12]([C:15](OCC)=[O:16])([F:14])[F:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].C(O)(=O)C.O>O1CCCC1.[Cl-].[Na+].O.C(OCC)(=O)C>[C:1]([O:5][C:6]([C@H:8]1[CH2:10][C@@H:9]1[C@@:11]([CH3:27])([NH:20][S@@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[C:12]([F:13])([F:14])[CH2:15][OH:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(F)(F)[C@](C)(N[S@](=O)C(C)(C)C)[C@H]1C[C@@H]1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)[C@H]1C[C@@H]1[C@@](C)(N[S@](=O)C(C)(C)C)C(F)(F)CO
Temperature: 0 °C
Reaction time: 3 h
Yield: 59.4 %

Procedure:
A solution of (1S,2S)-rel-2-[(R)-2-ethoxycarbonyl-2,2-difluoro-1-methyl-1-((R)-2-methyl-propane-2-sulfinylamino)-ethyl]-cyclopropanecarboxylic acid tert-butylester (2.23 g, 5.42 mmol) in tetrahydrofuran (20 ml) was treated dropwise under nitrogen at 0° C. with a solution of lithium borohydride (2M in tetrahydrofuran; 5.42 ml, 10.8 mmol), at such a rate that the temperature was kept below 6° C. The orange reaction mixture was stirred at 0° C. for 3 hours. For the workup, acetic acid (654 mg, 623 μl, 10.8 mmol) was added dropwise, keeping the temperature below 10° C., followed by water (0.8 ml). After 70 minutes of stirring, brine and ethyl acetate were added and the mixture was extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulphate and evaporated. A light green oil was obtained (2.31 g) which was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 0:100 as the eluent. The (1S,2S)-rel-2-[(R)-2,2-difluoro-3-hydroxy-1-methyl-1-((R)-2-methyl-propane-2-sulfinylamino)-propyl]-cyclopropanecarboxylic acid tert-butyl ester (1.19 g, 59% yield) was obtained as a colorless oil. MS (ISP): m/z=370.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Br-].[CH2:28]([Zn+])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl.N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Reactant: [Zn+]Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Cc5ccccc5)ccc(F)c43)ccc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (84 mg), benzylzinc bromide (0.5 mol/L in tetrahydrofuran, 1.2 ml) and tetrakis(triphenylphosphine)palladium (23 mg). Degassed tetrahydrofuran (1 mL) is added under Ar atmosphere, and the mixture is heated to 60° C. and shaken at this temperature overnight. The reaction mixture is acidified with 4 N aqueous hydrochloric acid (1 mL) and then neutralized with saturated aqueous ammonia solution. The organic phase is separated, diluted with N,N-dimethylformamide (1 mL), and purified by HPLC on reversed phase (MeCN/water) to give the title compound. LC (method 6): tR=1.19 min.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:16][CH2:15]2)=[CH:10][C:9]=1[NH:17][C:18](=[O:30])[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:14]1([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:20]([C:22]4[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=4)[C:28]#[N:29])[CH2:19][C:18](=[O:30])[NH:17][C:9]=3[CH:10]=2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2CC2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(C4CC4)cc3NC(=O)C2)c1

Procedure:
Prepared from {2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-cyclopropyl-phenyl}-carbamic acid tert.-butyl ester (Example K78) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (44 mg).
Reaction SMILES: [C:1]([C@@H:3]([NH:5][C:6](=[O:12])OC(C)(C)C)[CH3:4])#[N:2].[CH2:13]([C:23]1[CH:31]=[CH:30][C:26](C(O)=O)=[CH:25][CH:24]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[C:1]([C@@H:3]([NH:5][C:6](=[O:12])[C:26]1[CH:25]=[CH:24][C:23]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:31][CH:30]=1)[CH3:4])#[N:2]
Reactant: C[C@@H](C#N)NC(=O)OC(C)(C)C
Reactant: CCCCCCCCCCc1ccc(C(=O)O)cc1
Product: CCCCCCCCCCc1ccc(C(=O)N[C@@H](C)C#N)cc1

Procedure:
General procedure D was used to deprotect 0.198 g (1.2 mmols) of 4. The product was immediately carried on using general procedure F and coupled to 1.2 mmols of 7. The title product was purified with flash chromatography using a solvent system of ethyl acetate and hexanes (1:3) to yield 0.2 g (0.63 mmols). 1H NMR (500 MHz, CDCl3) δ 7.23 (d, J=8.2, 2H), 6.94 (d, J=7.3, 1H), 5.19-5.11 (m, 1H), 2.66-2.60 (m, 2H), 1.64 (dd, J=2.0, 7.2, 2H), 1.59 (dd, J=5.9, 13.3, 2H), 1.30 (dd, J=18.9, 22.5, 13H), 0.88 (t, J=6.9, 3H). 13C NMR (126 MHz, CDCl3) δ 173.67, 166.98, 147.92, 147.35, 129.98, 128.73, 127.28, 119.51, 52.38, 48.45, 36.25, 35.86, 31.88, 31.16, 29.59, 29.56, 29.45, 29.31, 29.23, 22.67, 19.47, 18.62, 14.12.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:27])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1.I[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:27])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1)[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COC(=O)Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: ICC1CCCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 31.9 %

Procedure:
A solution of diisopropylamine (3.35 mL, 23.9 mmol) in dry tetrahydrofuran (45 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (15 mL) was cooled to −78° C. and then treated dropwise with a 2.5M solution of n-butyllithium in hexanes (9.56 mL, 23.9 mmol) over a 10 min period. The pale yellow reaction mixture was stirred at −78° C. for 20 min and then slowly treated with a solution of 4-chloro-3-nitrophenylacetic acid methyl ester (5.00 g, 21.8 mmol) in a small amount of tetrahydrofuran over a 15 min period. The reaction mixture turned deep purple (almost black) in color. The reaction mixture was then stirred at −78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (4.58 g, 21.8 mol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was then stirred at −78° C. and then allowed to warm to 25° C. where it was stirred for 48 h. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution (50 mL), and the resulting reaction mixture was concentrated in vacuo to remove tetrahydrofuran. The remaining residue was diluted with ethyl acetate (150 mL) and water (50 mL). The organic phase was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 4/1 hexanes/ethyl acetate) afforded 2-(4-chloro-3-nitrophenyl)-3-cyclopentyl-propionic acid methyl ester (2.17 g, 32%) as a yellow oil: EI-HRMS m/e calcd for C15H18ClNO4 (M+) 311.0924, found 311.0927.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]=[O:13].[BH4-].[Na+]>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][OH:13]
Reactant: O=Cc1ccc2ccccc2c1Br
Agent: [BH4-]
Agent: [Na+]
Product: OCc1ccc2ccccc2c1Br

Procedure:
Scheme 3 also shows a general synthetic route to compounds of formula I. Reaction of 1-bromo-2-naphthaldehyde with sodium borohydride provided 1-bromo-2-naphthalenemethanol (xiv). Alcohol (xiv) was reacted with BOC-protected sulfonamide (xc), triphenylphosphine and diethyl azodicarboxylate to provide sulfonamide (xv). The sulfonamide was reacted with tert-butyllithium at a temperature between about -90° C. and about 10° C. in THF to provide (xvi). The nitrogen of compound (xvi) was protected as the benzyl carbamate by treating (xvi) with sodium hydride and benzylchloroformate, and the tert-butyl ester was then hydrolyzed with trifluoroacetic acid to provide carboxylic acid (xvii). The carboxylic acid (xvii) was converted to the hydroxamate (xviii) following the procedure outlined in Scheme 1. Hydrogenation of (xvii) in the prescence of a palladium catalyst provided a compound of formula I.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33](=[O:40])[O:32]1>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH:31]1[C:39]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:33](=[O:40])[O:32]1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1OC(Br)c2ccccc21
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: O=C1OC(Oc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c2ccccc21

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 3-Bromo-3H-isobenzofuran-1-one following the procedure of Example 478: MS (ESI) m/z 526; HRMS: calcd for C31H18F3NO4+H+, 526.12607; found (ESI, [M+H]+), 526.1287.
Reaction SMILES: ON1C(=O)CCC1=O.N1C=CC=CC=1.[CH2:15]([O:22][CH2:23][C@@:24]1([N:49]2[CH:57]=[C:55]([CH3:56])[C:53](=[O:54])[NH:52][C:50]2=[O:51])[O:48][C@H:28]([CH2:29][O:30][Si:31]([C:44]([CH3:47])([CH3:46])[CH3:45])([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:26]([OH:27])[CH2:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH:58]1[CH:63]=[CH:62][C:61]([O:64][C:65](Cl)=[S:66])=[CH:60][CH:59]=1>C1(C)C=CC=CC=1>[CH2:15]([O:22][CH2:23][C@@:24]1([N:49]2[CH:57]=[C:55]([CH3:56])[C:53](=[O:54])[NH:52][C:50]2=[O:51])[O:48][C@H:28]([CH2:29][O:30][Si:31]([C:44]([CH3:47])([CH3:46])[CH3:45])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C@@H:26]([O:27][C:65]([O:64][C:61]2[CH:62]=[CH:63][CH:58]=[CH:59][CH:60]=2)=[S:66])[CH2:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Reactant: S=C(Cl)Oc1ccccc1
Agent: O=C1CCC(=O)N1O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](OC(=S)Oc3ccccc3)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 75.1 %

Procedure:
N-hydroxysuccinimide (3.9 g, 34 mmol) and pyridine (24.3 mL, 300 mmol) were added to a solution of the alcohol 3 (90.0 g, 150 mmol) in 1 L of toluene. The mixture was warmed up to 80° C. and stirred for 10 min. Phenyl chlorothionoformate (30 g, 174 mmol) was added to the solution and the resultant reaction mixture was stirred at 80° C. for 8 h. The hot toluene solution was decanted from solids. The solids were rinsed with AcOEt (2×30 mL) and the combined toluene solution and AcOEt washes were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes/AcOEt 9:1 then 3:1) to give 83.0 g (75.2%) of the title compound, 17, as a light yellow foam. Rf (hexanes/AcOEt 9:1) 0.24. 13C-NMR (CDCl3): 12.97 (5-CH3), 19.49 (2'-C), 27.16 (Me3C), 38.32 (Me3C), 64.87 (O--C--Ph), 70.75 (N--C--O), 72.28 (5'-C), 84.21 (4'-C), 84.90 (3'-C), 85.39 (1'-C), 110.82 (5-C), 121.95, 126.94, 127.72, 128.27, 128.40, 129.81 (Ar--C), 130.35 (6-C), 131.93, 132.79, 133.76, 135.38, 135.76, 138.30 (Ar--C), 151.05 (2-C), 153.42 (Ar--C), 163.40 (4-C), 194.36 (thioformate-C).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11]CC(=O)O)=[O:8])CC(=O)O.N[C@H](C(N[C@H](C(N[C@H](C(O)=O)CC(C)C)=O)[C@H](CC)C)=O)C(C)C>>[NH2:1][CH2:2][C:7]([NH:9][C@H:10]([C:16]([OH:18])=[O:17])[CH3:11])=[O:8]
Reactant: N[C@@H](CC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)O
Agent: CC[C@H](C)[C@H](NC(=O)[C@@H](N)C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O
Product: C[C@H](NC(=O)CN)C(=O)O

Procedure:
AspGlu; ValIleLeu;
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:5][CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:3]=1
Reactant: CCOC(=O)C1=C(C)NC(c2ccccc2)=CC1c1cccc([N+](=O)[O-])c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(-c2cccc([N+](=O)[O-])c2)cc(-c2ccccc2)nc1C
Temperature: 25 °C
Yield: 50.3 %

Procedure:
To a solution of ethyl 1,4-dihydro-2-methyl-4-(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylate (0.5 g) in chloroform (5 ml) was added activated manganese dioxide (2 g) and the mixture was refluxed for 1 hour with stirring vigorously. After allowing to cool to ambient temperature, manganese dioxide was filtered off and the filtrate was evaporated in vacuo. The residual precipitates were recrystallized from ethanol, washed with ethanol and dried in vacuo to give ethyl 2-methyl-4-(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylate (0.25 g)
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[K+].[C:11]([O:15][C:16]([N:18]1[CH:22]2[CH2:23][CH2:24][CH:19]1[CH:20]([CH2:25]OS(C)(=O)=O)[CH2:21]2)=[O:17])([CH3:14])([CH3:13])[CH3:12].O>CN(C=O)C>[CH3:1][C:2]1[C:7]([O:8][CH2:25][CH:20]2[CH2:21][CH:22]3[N:18]([C:16]([O:15][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:17])[CH:19]2[CH2:24][CH2:23]3)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1O
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(COS(C)(=O)=O)C2
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncccc1OCC1CC2CCC1N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To 2-methylpyridin-3-ol in DMF was added KOH. The solution was stirred for 30 min at rt, then the title compound from step A was added and the reaction was heated at 80° C. After 5 h, H2O was added and the mixture extracted with EtOAc. The combined organic layers were dried (MgSO4). Purification via silica gel chromatography (0-7% MeOH in DCM) gave the title compound (201 mg, 90%). MS (ESI) mass calcd. for C18H26N2O3, 318.2; m/z found 319.0 [M+1]+.
Reaction SMILES: [Al].[C:2]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9](=[O:16])[C:8](O[Si](CC)(CC)CC)([C:17]([F:20])([F:19])[F:18])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3]>O>[C:12]([C:10]1[CH:11]=[C:6]([C:2]([CH3:3])([CH3:4])[CH3:5])[CH:7]=[C:8]([C:17]([F:19])([F:20])[F:18])[C:9]=1[OH:16])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC[Si](CC)(CC)OC1(C(F)(F)F)C=C(C(C)(C)C)C=C(C(C)(C)C)C1=O
Agent: [Al]
Solvent: O
Product: CC(C)(C)c1cc(C(C)(C)C)c(O)c(C(F)(F)F)c1
Temperature: 70 °C
Yield: 83.2 %

Procedure:
A strip of aluminum foil weighing 267 mg (9.9 mmol) was amalgmated by immersion in a solution of 2% mercuric chloride in water for 15 seconds, washed with absolute ethanol followed by diethyl ether, cut into small pieces, and added to a solution of 400 mg (0.99 mmol) of 4,6-di-tert-butyl-2-triethylsiloxy-2-trifluoromethyl-3,5-cyclohexadien-1-one in 25 mL of 10% water -90% tetrahydrofuran. The resulting mixture was heated at 70° C. for 1.5 hours, allowed to cool to room temperature, and filtered. The filter cake was washed with 10 mL of tetrahydrofuran. Concentration of the combined filtrates gave a residue which was poured into 25 mL of water. The aqueous mixture was extracted with tree 10 mL portions of dichloromethane. Combination, drying and concentration of the organic layers gave a residue which was purified by PTLC (one 2 mm silica gel plate eluted with petroleum ether), affording 226 mg (83% yield) of 2,4-di-tert-butyl-6-trifluoromethylphenol as a colorless liquid: 1H NMR (CDCl3)δ1.31 (s, 9H), 1.45 (s, 9H), 5.56 (q,1H, JHF =4 Hz), 7.39 (d,1H, J=2 Hz), 7.54 (d, lH, J=2 Hz); IR (neat) 3624, 2959, 2906, 2868, 1481, 1458, 1448, 1363, 1340, 1263, 1251, 1170, 1126, 1097, 887, 694 cm-1 ; mass spectrum (70 eV) m/z (relative intensity) 274 (20, M+), 259 (100), 239 (68), 98 (20), 57 (22), 41 (34).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:25]([NH:29][S:30]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:37]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[S:34][C:35]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=4)[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)ccn2)s1

Procedure:
5-{4-[4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butyl amide was prepared from 2-(2-chloro-pyridin-4-yl)-4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidine (example E.103) (0.24 g, 0.68 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.28 g, 0.81 mmol) according to the general procedure VI. Obtained as light brown solid (0.27 g), which was subsequently deprotected.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:21]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:20]=3[O:19][CH2:18]1)[C:5](=[O:17])[N:6]2[CH2:11][C:12]([O:14]CC)=[O:13].O=C1C2(C3=CC4OCOC=4C=C3OC2)C2C(=CC=CC=2)N1CC(OCC)=O>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:21]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:20]=3[O:19][CH2:18]1)[C:5](=[O:17])[N:6]2[CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)CN1C(=O)C2(COc3cc(F)c(F)cc32)c2c(Br)cccc21
Agent: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Product: O=C(O)CN1C(=O)C2(COc3cc(F)c(F)cc32)c2c(Br)cccc21
Yield: 100 %

Procedure:
Following the procedure as described in EXAMPLE 2, and making non-critical variations using ethyl (4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)acetate to replace ethyl (2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetate, the title compound was obtained in 100% yield. The product was used directly in the next step.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([F:25])[C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[CH:7]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[CH3:60][C:61]1[CH:65]=[C:64]([Sn](C)(C)C)[S:63][N:62]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[F:25][C:4]1[C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[CH:7]=[C:2]([C:64]2[S:63][N:62]=[C:61]([CH3:60])[CH:65]=2)[CH:3]=1
Reactant: COc1ccc2c(OCc3nnc4c(F)cc(Cl)cn34)ccnc2c1
Reactant: Cc1cc([Sn](C)(C)C)sn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: COc1ccc2c(OCc3nnc4c(F)cc(-c5cc(C)ns5)cn34)ccnc2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
Dioxane (3.6 mL) was added to 4-((6-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline (175 mg, 488 μmol), X-Phos (32.6 mg, 68.3 μmol), 3-methyl-5-(trimethylstannyl)isothiazole (153 mg, 585 μmol), palladium acetate (7.67 mg, 34.1 μmol). The flask was purged with argon and sealed. The reaction mixture was stirred at 80° C. for 2d. More X-Phos (32.6 mg, 68.3 μmol), palladium acetate (7.67 mg, 34.1 μmol) and 3-methyl-5-(trimethylstannyl)isothiazole (153 mg, 585 μmol) were added and stirring was continued at 80° C. overnight. The reaction mixture was cooled at RT, concentrated in vacuo and purified by MPLC(CH2Cl2/MeOH: 100/0 to 90/10). Further purification by MPLC (ISCO, EtOAc/MeOH: 9/1, isocratic) afforded the title compound (105 mg, 51% yield). MS m/z=422.0 [M+H]+. Calc'd for C21H16FN5O2S: 421.46
Reaction SMILES: [CH3:1][C:2]1[C@H:6]([O:7][N+]([O-])=O)[CH2:5][C:4](=[O:11])[C:3]=1[CH2:12][C:13]#[CH:14].O>C(Cl)(Cl)Cl>[OH:7][C@H:6]1[CH2:5][C:4](=[O:11])[C:3]([CH2:12][C:13]#[CH:14])=[C:2]1[CH3:1]
Reactant: C#CCC1=C(C)[C@H](O[N+](=O)[O-])CC1=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: C#CCC1=C(C)[C@@H](O)CC1=O
Reaction time: 4 h
Yield: 90 %

Procedure:
A mixture of 1.95 g of crude (R)-3-methyl-4-nitroxy-2-(2-propynyl)-2-cyclopenten-1-one and 30 ml of water was stirred at a temperature of 85°-90° C. for 4 hours. Thereafter, with the same operations as in Example 3, 1.35 g of (S)-4-hydroxy-3-methyl-2-(2-propynyl)-2-cyclopenten-1-one (chemical purity: 90.2%, [α]D24 : +13.1° (C=1.07, in chloroform), (R)-isomer/(S)-isomer=16.2/83.8) was obtained.