Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][CH:8]=[C:9]2[CH:13]=[CH:12][NH:11][C:10]=12)=[O:4].[OH-].[K+].Cl>C1COCC1>[NH:11]1[C:10]2=[C:5]([C:3]([OH:4])=[O:2])[N:6]=[CH:7][CH:8]=[C:9]2[CH:13]=[CH:12]1
Reactant: COC(=O)c1nccc2cc[nH]c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1nccc2cc[nH]c12
Yield: 156.4 %

Procedure:
1H-Pyrrolo[2,3-c]pyridine-7-carboxylic acid methyl ester (example E1, 50 mg, 0.28 mmol) was dissolved in THF (0.57 mL) and treated with 2 M aq. potassium hydroxide solution (0.57 mL, 1.1 mmol), then after 1 h acidified with 2M aq. hydrochloric acid solution and extracted with dichloromethane. The aqueous layer was evaporated and the residue was taken up in methanol and the residue was taken up in methanol and filtered. The filtrate was evaporated to afford the title compound (71 mg), which contained an unspecified amount of potassium chloride. MS (EI) 118.1 (100), 162.1 (53, M+); 1H-NMR (300 MHz, CD3OD): 8.30-8.25 (m, 2H), 8.24 (d, J=3.0, 1H), 7.07 (d, J=3.0, 1H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:50]([O:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([NH2:65])[CH:60]=2)=[CH:55][C:54]=1[CH3:66])[CH3:51]>CN(C=O)C>[CH2:50]([O:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([NH:65][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:60]=2)=[CH:55][C:54]=1[CH3:66])[CH3:51]
Reactant: CCOc1ccc(-c2cccc(N)c2)cc1C
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)cc1C
Temperature: 25 °C
Yield: 62.6 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.016 g, 0.067 mmol) and HATU (0.028 g, 0.072 mmol) in 0.37 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-ethoxy-3′-methyl-biphenyl-3-ylamine (0.015 g, 0.067 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.018 g of product in 65% yield: LCMS (ESI) m/z 430 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[Cl:7][CH2:8][CH2:9]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:9][CH2:8][Cl:7])[CH:6]=1
Reactant: OCCCl
Reactant: Brc1cn[nH]c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClCCn1cc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-1H-pyrazole (5 g, 34.02 mmol), 2-chloroethanol (2.7 mL, 40.82 mmol) and PPh3 (10.71 g, 40.82 mmol) and in THF (68 mL) at 0° C. was added DEAD (6.4 mL, 40.8 mmol). The mixture was allowed to warm-up to room temperature and stirred overnight. It was then concentrated under reduced pressure, the residue was treated with ether and the resultant suspension was filtered. The filtrate was collected and concentrated under reduced pressure to afford the title compound 75 which was used in the next step without further purification. MS (m/z). 209.0 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]=O)=[C:6]2[CH2:7][CH2:8][CH2:9][O:10][C:5]2=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=1.[BH4-].[Na+].Cl>CO.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:11]=1[CH2:12][NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=1
Reactant: O=Cc1c(O)ccc2c1CCCO2
Reactant: CC(=O)c1ccc(N)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)c1ccc(NCc2c(O)ccc3c2CCCO3)cc1
Temperature: 25 °C
Yield: 33 %

Procedure:
A mixture of 6-hydroxy-3,4-dihydrobenzopyran-5- carboxaldehyde (308 mg, 1.73 mmol) and p-aminoacetophenone (236 mg, 1.73 mmol) in methanol (8 mL) was heated at reflux for one hour. The mixture was cooled to 15° at which time the intermediate Schiff's base crystallized. After filtration and drying a light orange product (221 mg, 43.3%) was obtained. This material was suspended in methanol (8 mL) and sodium borohydride (28 mg, 0.74 mmol) was added. After stirring at room temperature for ten minutes the mixture was poured into water (75 mL) and the resulting suspension neutralized (pH=7) with 2.5 N HCl. The product was collected by filtration and dried to afford 6-hydroxy-5-(4-acetylphenyl) aminomethyl-3,4-dihydrobenzopyran (170 mg, 76.6%), m.p. 213°-215° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:14][CH2:15][CH:16]1[CH2:18][CH2:17]1.[C:19]([CH2:23][C:24](Cl)=O)([CH3:22])([CH3:21])[CH3:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.N>C(OCC)(=O)C.O>[CH:16]1([CH2:15][N:14]2[C:3]3[CH:4]=[CH:5][C:6]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:9])=[O:10])=[CH:7][C:2]=3[N:1]=[C:24]2[CH2:23][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:18][CH2:17]1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CC(C)S(=O)(=O)c1ccc(NCC2CC2)c(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)S(=O)(=O)c1ccc2c(c1)nc(CC(C)(C)C)n2CC1CC1
Reaction time: 1 h
Yield: 55.9 %

Procedure:
To a solution of 2-amino-1-(N-cyclopropylmethylamino)-4-(isopropylsulfonyl)benzene (Step E, 113 mg, 0.38 mmol) in ethyl acetate (3 mL) was added tert-butylacetyl chloride (58 μL, 0.42 mmol) at room temperature. After stirring for 1 h, p-toluenesulfonic acid monohydrate (72 mg, 0.38 mmol) was added and the mixture was stirred under reflux for 3 h. Water (5 mL) and aqueous ammonia (0.5 mL) were added and the mixture was extracted with ethyl acetate (15 mL×3) and washed with brine (5 mL). The organic extracts were dried over sodium sulfate and concentrated. The residue was purified by pTLC (hexane:ethyl acetate=1:1 then dichloromethane:methanol=10:1 as eluent) to give colorless oil (74 mg), which was recrystalized from ethyl acetate and hexane to afford the title compound (28 mg, 21%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])C)=[O:15])[CH:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1.FC(F)(F)C(O)=O.ClC(OC1C=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40]C=1)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([O:16][C:17]2[CH:20]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:19]=2)=[O:15])[CH:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)ccc2F)=CC1c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(c2cc(F)ccc2F)=CC1c1ccccc1

Procedure:
To a flame-dried flask equipped with stir bar under nitrogen was charged 2-3 (0.71 g, 1.98 mmol) and anhydrous CH2Cl2 (50 mL). The resulting solution was treated with trifluoroacetic acid (10 mL) and stirred 1 hour at 25° C. Upon completion, the reaction was concentrated, taken up in CH2Cl2 (50 mL) and washed with 5% NaHCO3 (50 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The resulting free-amine was dissolved in anhydrous CH2Cl2 (50 mL) and treated with p-nitrophenyl chloroformate (0.44 g, 2.17 mmol). The resulting solution was stirred 4 hours at 25° C. until completion. The reaction was concentrated to give 19-1 as a yellow oil: 1H NMR (300 MD, CDCl3) δ 8.22 (d, J=9.4 Hz, 1H), (d, J=9.1 Hz, 1H), 7.38 (m, 5H), 7.02 (m, 5H), 6.43 (m, 1H), 5.85 (m, 1H), 4.90 (m, 2H); LRMS m/z (M+H) 422.9 found, 423.1 required.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]([CH3:22])([CH3:21])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)[CH2:8][CH2:7]1.CO.[OH-].[Na+]>O1CCCC1>[CH3:21][C:4]([CH3:22])([CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)[CH2:10][CH2:11]1)[C:3]([OH:23])=[O:2]
Reactant: COC(=O)C(C)(C)CC1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(CC1CCN(c2ccc([N+](=O)[O-])cn2)CC1)C(=O)O
Temperature: 25 °C
Yield: 95.2 %

Procedure:
2,2-Dimethyl-3-(5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-propionic acid methyl ester (199 mg, 0.62 mmol) from above was dissolved in tetrahydrofuran (2 mL). Then methanol (4 mL) and sodium hydroxide solution (1N, 2 mL) were added. The mixture was stirred and refluxed for 8 hrs. Solvents were evaporated and the residue was dissolved in hot methanol. The solution was cooled to room temperature and hydrochloric acid (1N, 2 mL) was added. The resulting mixture was cooled in an ice bath and the solid was filtered and washed with water. The solid was dried in air to give 2,2-dimethyl-3-(5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-propionic acid (181.5 mg). The NMR spectrum obtained on the sample is compatible with its structure. LC-MS calcd for C15H21N3O4 (m/e) 307.34, obsd 308.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[SH:9].[CH3:10]I>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9][CH3:10]
Reactant: CI
Reactant: Cc1cccc(C)c1S
Product: CSc1c(C)cccc1C

Procedure:
This compound was synthesized from 2,6-dimethylthiophenol and methyl iodide according to general method 4 described earlier.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[CH:11]/[C:12]1[C:13]([O:29]CC2C=CC=CC=2)=[N:14][C:15]([CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:16]([CH2:18][CH3:19])[CH:17]=1>O1CCCC1.CO.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][C:12]1[C:13](=[O:29])[NH:14][C:15]([CH2:20][O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:16]([CH2:18][CH3:19])[CH:17]=1
Reactant: CCc1cc(/C=C/c2nc3ccccc3o2)c(OCc2ccccc2)nc1COCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(CCc2nc3ccccc3o2)c(=O)[nH]c1COCc1ccccc1
Reaction time: 20 h

Procedure:
A solution of cis/trans 3-[2-(benzoxazol-2-yl)ethenyl]-5-ethyl-6-benzyloxymethyl-2-benzyloxypyridine (1.40 g, 2.94 mmol) in dry tetrahydrofuran (20 mL) and methanol (15 mL) containing 10% Pd on charcoal (215 mg) as a catalyst was hydrogenated at atmospheric pressure for 20 hours. The catalyst was filtered off and the solution evaporated to give a white residue. This residue was triturated with diethyl ether to give pure product with m.p. of 140°-142° C.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[F:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[F:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1
Reactant: COc1cccc(B(O)O)c1F
Reactant: Cc1oc(Br)cc1C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cccc(-c2cc(C=O)c(C)o2)c1F
Reaction time: 8 h
Yield: 93.1 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.3 g), 2-fluoro-3-methoxyphenylboronic acid (1.4 g), tetrakis(triphenylphosphine)palladium(0) (0.4 g), 2N aqueous sodium carbonate solution (9 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 30% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.5 g, 93%) as a yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[OH:24].IC.[C:28]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:15][CH2:16]2)=[CH:6][C:5]=1[O:24][CH3:28]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1O
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-hydroxybenzoic acid methyl ester (10 g, 28 mmol) from Step 1 was dissolved in DMF (100 mL) and cooled to 0° C. To the stirred solution was added iodomethane (6.1 g, 43 mmol) and Cs2CO3 (10 g, 31 mmol). The mixture was stirred at 0° C. for 1 h and then at ambient temperature for 12 h. The solids were removed by filtration and the filtrate solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using a gradient elution of 20-40% EtOAc-hexane. 4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-methoxybenzoic acid methyl ester was obtained as an oil.
Reaction SMILES: ClC1C=CC(S[CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=CC=1.S(Cl)([Cl:24])(=O)=O>>[Cl:24][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: FC(F)(F)c1cccc(OCSc2ccc(Cl)cc2)c1
Product: FC(F)(F)c1cccc(OCCl)c1
Yield: 89 %

Procedure:
The title compound was prepared as described in Preparation 3 (b) by reaction of 1-(4-chlorophenylthio) methoxy-3-trifluoromethyl-benzene and sulfuryl chloride; yield 89%, b.p. 88°-90° C./15 mmHg. 1H NMR (CDCl3): δ 5.82 (CH2), 7.26 (Ph). MS [70 eV; m/z (% rel.int.)]: 212/210 (10/34,M); 191 (12), 175 (100), 145 (76), 133 (13), 127 (19), 114 (11), 113 (11).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][NH2:37]>>[Cl:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][NH:37][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:18]([C:16]2[CH:15]=[N:14][C:10]3[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]4[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:28]([F:30])([F:29])[F:31])[C:9]=3[CH:17]=2)=[CH:19][CH:20]=1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: NCc1cccc(Cl)c1
Product: O=C(NCc1cccc(Cl)c1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 3-chlorobenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=570.90 (M+H+); retention time=0.98 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][C:6]([Si](C)(C)C)=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[Si](C)(C)c1[nH]c2c([N+](=O)[O-])cc(Cl)cc2c1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Cl)cc2c(-c3ccccc3)c[nH]c12
Yield: 101.2 %

Procedure:
5-Chloro-7-nitro-3-phenyl-2-trimethylsilyl-1H-indole (1.5 g, 4.35 mmol) prepared in Step A was dissolved in tetrahydrofuran (30 mL), and tetrabutylammonium fluoride 1M solution (5.2 mL, 5.2 mmol) was added in drops thereto at 0° C. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (1.2 g, Yield 100%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.FC(F)(F)S(O[C:17]1[CH2:21][CH2:20][CH2:19][C:18]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=O)=O.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:17]1[CH2:21][CH2:20][CH2:19][C:18]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCC1
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C1=C(c2ccccc2F)CCC1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
2-Fluorobenzeneboronic acid (4.48 g) and tetrakis(triphenylphosphine)palladium (740 mg) were added to a solution of ethyl 2-trifluoromethanesulfonyloxycyclopent-1-enecarboxylate obtained in Preparation Example 3-(1) in toluene. Then, ethanol (100 mL) and a 1 N sodium carbonate solution (32 mL) were added to the reaction solution, followed by replacement of the reaction atmosphere with nitrogen. The reaction solution was heated to 85° C. and stirred overnight. The reaction solution was cooled to room temperature, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (7.60 g).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([N:15]2[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][C:17](=[O:25])[NH:16]2)=[N:11][CH:12]=[CH:13][CH:14]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N(CC)CC)C>[Cl:8][C:9]1[C:10]([N:15]2[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][C:17]([O:25][S:32]([C:29]3[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=3)(=[O:34])=[O:33])=[N:16]2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CC(OS(=O)(=O)c2ccc(C)cc2)=NN1c1ncccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
Triethylamine (3.75 g, 37.1 mmol) was added dropwise to a mixture of ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. the product of Example 8, Step A) (10.0 g, 37.1 mmol) and p-toluenesulfonyl chloride (7.07 g, 37.1 mmol) in dichloromethane (100 mL) at 0° C. Further portions of p-toluenesulfonyl chloride (0.35 g, 1.83 mmol) and triethylamine (0.19 g, 1.88 mmol) were added. The reaction mixture was then allowed to warm to room temperature and was stirred overnight. The mixture was then diluted with dichloromethane (200 mL) and washed with water (3×70 mL). The organic phase was dried and evaporated to leave the title product as an oil (13.7 g, 87% yield), which slowly formed crystals. Product recrystallized from ethyl acetate/hexanes melted at 99.5-100° C.
Reaction SMILES: [CH3:1][C@@:2]12[O:9][C@@H:6]([CH2:7][CH2:8]1)[C:5](=[O:10])[CH2:4][C:3]2=[O:11].C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[CH3:28][C:29]1[C:34]([Pb+3])=[C:33]([CH3:36])[CH:32]=[C:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:30]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH3:28][C:29]1[CH:30]=[C:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:32]=[C:33]([CH3:36])[C:34]=1[CH:4]1[C:5](=[O:10])[C@H:6]2[O:9][C@:2]([CH3:1])([CH2:8][CH2:7]2)[C:3]1=[O:11]
Reactant: Cc1cc(-c2ccccc2)cc(C)c1[Pb+3]
Reactant: C[C@]12CC[C@H](O1)C(=O)CC2=O
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccccc2)cc(C)c1C1C(=O)[C@@H]2CC[C@@](C)(O2)C1=O
Temperature: 80 °C
Yield: 32 %

Procedure:
(1R*,5S*)-1-Methyl-8-oxabicyclo[3.2.1]octane-2,4-dione (0.20 g, 1.30 mmol) and 4-dimethylaminopyridine (0.792 g, 6.49 mmol) are added to a mixture of chloroform (4 ml) and toluene (1 ml). The reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 3,5-Dimethylbiphen-4-yllead triacetate (0.805 g, 1.43 mmol) is added in one portion and the reaction mixture is stirred and heated to 80° C. under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases are separated. The aqueous phase is extracted with dichloromethane (2×5 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1R*,5S*)-3-(3,5-dimethyl-biphenyl-4-yl)-1-methyl-8-oxabicyclo[3.2.1]octane-2,4-dione as a white solid (0.139 g).
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].C(N(C(C)C)CC)(C)C.Cl[C:36]([O:38][CH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1)=[O:37]>C(#N)C>[CH:39]1([O:38][C:36]([N:9]2[CH2:10][C@H:11]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:23])[F:24])(=[O:15])=[O:14])[CH2:12][C@H:8]2[C:6](=[O:7])[NH:5][CH2:4][C:2]#[N:3])=[O:37])[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Reactant: O=C(Cl)OC1CCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)OC1CCCC1
Reaction time: 2 h

Procedure:
L21. To a suspension of (2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride (0.13 mmole) from experiment K2 in acetonitrile (1 ml) was added at 22° C. diisopropyl ethyl amine (0.40 mmole) and cyclopentyl chloroformate (0.15 mmole) and stirring was continued for 2 h. The mixture was quenched with methanol, acidified with acetic acid and subjected to prep. HPLC (RP-18) using a mixture of acetonitrile and water to give (2S,4R)-2-(cyanomethyl-carbamoyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-1-carboxylic acid cyclopentyl ester as a colorless oil. MS: 474.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([CH3:20])([CH3:19])[CH2:10][C:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=O.[NH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[CH3:31]>[Ti](Cl)(Cl)(Cl)Cl>[CH3:31][N:26]1[C:27]2[C:23](=[C:22]([NH:21][CH:12]3[C:5]4[C:4](=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][CH:6]=4)[C:9]([CH3:20])([CH3:19])[CH2:10][C:11]3([C:14]([F:15])([F:17])[F:16])[OH:18])[CH:30]=[CH:29][CH:28]=2)[CH:24]=[N:25]1
Reactant: COc1ccccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Cn1ncc2c(N)cccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COc1cccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c1cnn2C
Yield: 23.4 %

Procedure:
Analogously to Example 3, the corresponding imine is produced starting from 296 mg of 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 150 mg of 4-amino-1-methylindazole. By reaction of 100 mg of the imine with 0.5 ml of titanium tetrachloride, 100 mg of the title compound is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[CH:5]=[CH:6][C:7](O)=[O:8].S(Cl)([Cl:16])=O>ClC(Cl)C.CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][C:7]([Cl:16])=[O:8])[CH:10]=[CH:11][C:12]=1[F:13]
Reactant: O=C(O)C=Cc1ccc(F)c(F)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: O=C(Cl)CCc1ccc(F)c(F)c1

Procedure:
To 0.27 mol of 3,4-difluorocinnamic acid dissolved in dichloroethane there are added 20 drops of dimethylformamide and 100 ml of thionyl chloride.