Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][C:12]=3[S:13][C:7]=2[N:6]=[CH:5]1.[N:19]1([C:25]2[C:29]3[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:28]=3[O:27][N:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C.[Br-].[Na+]>CN1CCCC1=O>[CH3:18][N:15]1[CH2:16][CH2:17][C:11]2[C:8]3[C:9](=[O:10])[N:4]([CH2:3][CH2:2][N:22]4[CH2:23][CH2:24][N:19]([C:25]5[C:29]6[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:28]=6[O:27][N:26]=5)[CH2:20][CH2:21]4)[CH:5]=[N:6][C:7]=3[S:13][C:12]=2[CH2:14]1
Reactant: CN1CCc2c(sc3ncn(CCCl)c(=O)c23)C1
Reactant: Cc1ccc2onc(N3CCNCC3)c2c1
Agent: [Br-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2onc(N3CCN(CCn4cnc5sc6c(c5c4=O)CCN(C)C6)CC3)c2c1
Yield: 16.9 %

Procedure:
3-(2-Chloroethyl)-7-methyl-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4(3H)-one (2.5 g, 8.81 mol; preparation: Example A3) was stirred together with 3-piperazin-1-yl-5-methyl-1,2-benzisoxazole (2.49 g, 11.45 mmol), diisopropylethylamine (15.4 ml, 88.1 mmol), sodium bromide (4.53 g, 44.05 mmol) and N-methyl-2-pyrrolidone (40 ml) at 70° C. for 4 days. After cooling, N-methyl-2-pyrrolidone and excess diisopropylethylamine were removed under high vacuum, the residue was added to water, the aqueous phase was extracted several times with ethyl acetate, and the organic phases were washed with water, dried over magnesium sulfate and concentrated in vacuo. The very impure crude product was chromatographed on silica gel (eluent: methylene chloride with slowly increasing methanol content (0-50%)). This resulted in 0.9 g of 7-methyl-3-{2-[4-(5-methyl-1,2-benzisoxazol-3-yl)piperazin-1-yl]ethyl}-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4(3H)-one (yield: 22%) being obtained as a solid product which was converted into the corresponding dihydrochloride with ethereal hydrochloric acid.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:11]([Cl:13])Cl>>[CH2:11]([Cl:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:6][CH2:5][CH2:4][CH:3]=[CH2:2]
Reactant: c1ccncc1
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Product: C=CCCCCCCCCCCl

Procedure:
A 1-liter, 3-neck flask equipped with a mechanical stirrer, reflux condenser, argon inlet and addition funnel was placed in an oil bath at 50° C. To the flask was added methylene chloride (400 milliliters), undecylenol (100 grams) and then pyridine (55.7 grams). Thionyl chloride (78.9 grams) in methylene chloride (100 milliliters) was added dropwise under reflux over 5 hours. The mixture was filtered, the solvent was removed from the filtrate using a rotary evaporator, and the resultant oil was refiltered and then distilled using a column packed with glass Raschig rings to yield two distillate portions. The fraction collected between 100° C. and 110° C. at 1 millimeter of mercury was retained and redistiiled using a Kugelrohr apparatus available from Aldrich. The yield of undecylenyl chloride was 40 grams of oil collected between 80° C. and 85° C. at 1 millimeter of mercury, which was identified using 13C NMR spectrometry.
Reaction SMILES: Cl[O-].[Na+].[Cl:4][C:5]1[C:14]([CH:15]=[CH2:16])=[C:13]([Cl:17])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH3:18][C:19]([CH3:24])([CH3:23])[CH:20]=[N:21][OH:22].Cl[O-]>ClCCl.O>[Cl:4][C:5]1[C:14]([CH:15]2[O:22][N:21]=[C:20]([C:19]([CH3:24])([CH3:23])[CH3:18])[CH2:16]2)=[C:13]([Cl:17])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: C=Cc1c(Cl)ccc(C(=O)OC)c1Cl
Reactant: CC(C)(C)C=NO
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)c(C2CC(C(C)(C)C)=NO2)c1Cl
Reaction time: 2 h

Procedure:
At room temperature, 17 ml of a 12% strength aqueous sodium hypochlorite solution were added dropwise with vigorous stirring to a solution of 2.6 g (10 mmol) of methyl 2,4-dichloro-3-ethenylbenzoate and 1 g (10 mmol) of 2,2-dimethylpropionaldoxime in 100 ml of dichloromethane. Twice, in each case after 2 hours of stirring, a further 0.5 g (5 mmol) of the oxime and 9 ml of the hypochlorite solution were added. The reaction mixture was stirred at room temperature for a further 12 hours and then stirred into 350 ml of water. After extraction with dichloromethane, drying and removal of the solvent, the residue was chromatographed.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][NH:11][C:10]3=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][CH2:24][NH:25]2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][CH2:24][N:25]2[C:10]2[C:9]3[C:14](=[CH:15][CH:16]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:8]=3)[N:13]=[CH:12][N:11]=2)=[CH:21][CH:20]=1
Reactant: Clc1ccc2c(c1)NCC2
Reactant: O=c1[nH]cnc2ccc(-c3ccccc3)cc12
Product: Clc1ccc2c(c1)N(c1ncnc3ccc(-c4ccccc4)cc13)CC2

Procedure:
The title compound was prepared in a manner analogous in the method of Example 4 using 6-Phenyl-3H-quinazolin-4-one (250 mg, 1.124 mmol) and 6-chloroindoline (172 mg, 1.124 mmol)). Three hundred eighty-nine milligrams (88%) of a yellow solid was isolated from the reaction mixture.
Reaction SMILES: O[CH:2]=[C:3]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[CH3:14])[C:4]#[N:5].[CH3:15][S:16](Cl)(=[O:18])=[O:17].O>N1C=CC=CC=1>[CH3:15][S:16]([CH:2]=[C:3]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[CH3:14])[C:4]#[N:5])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(C)c(C(C#N)=CO)c(C)c1
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(C)c(C(C#N)=CS(C)(=O)=O)c(C)c1
Reaction time: 1 h
Yield: 105.1 %

Procedure:
A solution of intermediate 1 (1 g) in 10 ml pyridine was cooled to 0° C. under nitrogen and then treated with methanesulfonyl chloride (0.67 g) with good stirring. The solution was allowed to come to room temperature and stirred for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with 1 M HCl, water and brine, dried (MgSO4) and concentrated to give 3-methanesulfonyl-2-(2,4,6-trimethylphenyl)acrylonitrile (intermediate 2) as a brown solid (1.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:15](Cl)[CH:16]([C:18]([F:21])([F:20])[F:19])[CH3:17].[CH2:23]([NH:26][C:27]#[N:28])[CH2:24][CH3:25].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:27]([NH:26][CH2:23][CH2:24][CH3:25])=[N:28][C:15]([CH:16]([C:18]([F:21])([F:20])[F:19])[CH3:17])=[N:14]1
Reactant: CC(C(Cl)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl)C(F)(F)F
Reactant: CCCNC#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCNc1nc(C(C)C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 2 h
Yield: 700.8 %

Procedure:
7.8 g (0.02 mol) of 2-trifluoromethylpropionyl chloride 2,6-dichloro-4-trifluoromethylphenylhydrazone and 1.9 g (0.002 mol) of propyl cyanamide were dissolved in 50 ml of tetrahydrofuran, and 2.6 g (0.026 mol) of triethylamine was dropwise added thereto under stirring and cooling with ice. After completion of the dropwise addition, the stirring was continued at room temperature for 2 hours. The solvent was distilled off under reduced pressure. The residue was dissolved in hexane, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. Then, hexane was distilled off under reduced pressure. Further, the residue was subjected to distillation under reduced pressure. The fraction having a boiling point of 110°-120° C./0.1-0.2 mmHg was subjected to recrystallization from hexane to obtain 6.1 g (yield: 70%) of the desired compound having a melting point of from 73° to 74.5° C. as white prismatic crystals.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]#[N:16])=[C:11](Cl)[C:10]2[C:18]([CH3:21])=[CH:19][S:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C(=O)C(C#N)=C([N:38]2[CH2:43][CH2:42][N:41]([C:44]([C:46]3[S:47][CH:48]=[CH:49][CH:50]=3)=[O:45])[CH2:40][CH2:39]2)C2C=CSC1=2)C1C=CC=CC=1>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]#[N:16])=[C:11]([N:38]2[CH2:43][CH2:42][N:41]([C:44]([C:46]3[S:47][CH:48]=[CH:49][CH:50]=3)=[O:45])[CH2:40][CH2:39]2)[C:10]2[C:18]([CH3:21])=[CH:19][S:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2ccsc2n(Cc2ccccc2)c1=O
Reactant: Cc1csc2c1c(Cl)c(C#N)c(=O)n2Cc1ccccc1
Product: Cc1csc2c1c(N1CCN(C(=O)c3cccs3)CC1)c(C#N)c(=O)n2Cc1ccccc1
Yield: 25 %

Procedure:
This compound was prepared from 7-benzyl-4-chloro-6,7-dihydro-3-methyl-6-oxo-thieno[2,3-b]pyrdine-5-carbonitrile (65) by applying the same method as described for the preparation of 7-benzyl-6-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile (66). Yield 25%; MP 223° C. 1H-NMR (DMSO-d6) δ 2.48 (d, J=0.8 Hz, 3H), 3.50 (m, 4H), 3.86 (b, 4H), 5.30 (s, 2H), 6.99 (d, J=1.2 Hz, 1H), 7.16 (m, 1H), 7.30 (m, 5H), 7.47 (dd, J=0.8, 3.6 Hz, 1H), 7.80 (dd, J=1.2, 5.2 Hz, 1H) ppm; EIMS m/z 475 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[P:7](Cl)([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[O:8].[C:16]([C:18]1[S:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:21][C:22]=1[OH:23])#[N:17]>C(#N)C>[C:16]([C:18]1[S:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:21][C:22]=1[O:23][P:7]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[O:8])#[N:17]
Reactant: CCCCOc1cc(O)c(C#N)s1
Reactant: CCOP(=O)(Cl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCOc1cc(OP(=O)(OCC)OCC)c(C#N)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
7.7 g of potassium carbonate and 8.6 g of O,O-diethyl chlorophosphate were added to a solution of 11 g of 2-cyano-3-hydroxy-5-n-butoxy-thiophene in 150 ml of acetonitrile and the mixture was stirred for 16 hours at room temperature and was then filtered. The filtrate was evaporated to dryness and the residue was taken up in ethyl ether. The ether phase was washed with an aqueous solution of 100 g/l of sodium chloride and then with an aqueous 0.1N sodium hydroxide solution containing 100 g/l of sodium chloride. The solution was dried, treated with activated carbon, filtered and evaporated to dryness under reduced pressure to obtain 15.5 g of 2-cyano-3-(diethoxyphosphoryloxy)-5-n-butoxy-thiophene with a refractive index of nD20 = 1.500.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([NH2:4])[CH3:3].O.[C:7]1([C:13]([CH:15]=O)=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[K+]>C(O)C>[CH3:3][C:2]1[CH:1]=[N:5][C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:15][N:4]=1
Reactant: CC(N)CN
Reactant: O=CC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cnc(-c2ccccc2)cn1

Procedure:
To a stirred solution of propylenediamine (2.94 g, 0.04 mol) in ethanol was added phenylglyoxal-monohydrate (5.00 g, 0.03 mol) at 0° C. within 30 minutes. After stirring for 1.5 hours at room temperature KOH (2.10 g, 0.04 mol) was added and the reaction mixture was refluxed for 12 hours. Then the solvent was removed under vacuum and the residue was extracted with ether. The organic phases were washed with brine and dried over MgSO4. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (7:3→3:7) as eluent. After flash chromatography the product was recrystallized from hexane. White solid. Yield: 780 mg, 15%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=2.57 (s, 3H), 7.38-7.50 (m, 3H), 7.91-7.99 (m, 2H), 8.43-8.49 (m, 1H), 8.87 (d, J=1.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=21.2, 126.6, 128.9, 129.4, 136.5, 140.9, 143.8, 149.8, 151.9; (ESI): m/z=170.94 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].[CH3:30][O:31][CH2:32][CH2:33][NH2:34]>O1CCCC1>[CH3:30][O:31][CH2:32][CH2:33][NH:34][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22][C@H:21]([OH:27])[CH2:20][CH2:19][C@@H:14]1[C@@H:13]2[C:12](=[CH:11][C@H:10]([CH3:29])[CH2:9][C@@H:8]2[O:7][C:5](=[O:6])[C@@H:3]([CH3:4])[CH2:2][CH3:1])[CH:17]=[CH:16][C@@H:15]1[CH3:18]
Reactant: COCCN
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Solvent: C1CCOC1
Product: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)NCCOC)[C@H]21
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Lovastatin (50 gm) is mixed with tetrahydrofuran (100 ml) and methoxy ethylamine (140 ml) to obtain a clear solution, the solution is heated to 50° C. and stirred for 4 hours at the same temperature. Then the solvent is distilled off at reduced pressure not allowing the temperature to raise above 50° C., tetrahydrofuran (200 ml) is added to the residue thus obtained, stirred for 30 minutes and distilled off the solvent to give 58 gm of N-methoxyethyl-7-[1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-[[2(S)-methylbutanoyl]oxy]-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanamide as residue (HPLC Purity 97.3%).
Reaction SMILES: [NH2:1][C@@:2]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([Br:16])[N:10]=1)([CH3:8])[C:3]([F:7])([F:6])[CH2:4][OH:5].C([O-])(O)=O.[Na+].[N:22]#[C:23]Br>CCO>[Br:16][C:11]1[N:10]=[C:9]([C@:2]2([CH3:8])[C:3]([F:6])([F:7])[CH2:4][O:5][C:23]([NH2:22])=[N:1]2)[C:14]([F:15])=[CH:13][CH:12]=1
Reactant: N#CBr
Reactant: C[C@@](N)(c1nc(Br)ccc1F)C(F)(F)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C[C@]1(c2nc(Br)ccc2F)N=C(N)OCC1(F)F
Temperature: 85 °C

Procedure:
To a solution of (R)-3-amino-3-(6-bromo-3-fluoro-pyridin-2-yl)-2,2-difluoro-butan-1-ol (9.49 g, 31.7 mmol) in EtOH (256 ml) was added NaHCO3 (1.066 g, 12.69 mmol) and cyanogen bromide (10.08 g, 95 mmol) and the mixture was warmed to 85° C. over night. After cooling to rt the solvent was evaporated and the residue taken up in 1N HCl and TBME, the layers were separated and the organic layer was washed with 1N HCl. The aq. layers were combined, basified by addition of solid Na2CO3 and extracted with TBME (2×). The combined TBME extracts were washed with sat. aq. NaCl, dried with K2CO3 to provide the desired product as yellow resin. This material was used for the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9](OC(=O)C)(=[O:11])[CH3:10]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 96 %

Procedure:
To a dichloromethane solution (15 ml) of 3-bromoaniline (1 g), acetic anhydride (659 μl) was added, followed by stirring at room temperature for 14 hours. This was washed with water (20 ml), and the organic layer was dried over sodium sulfate. After filtering off the sodium sulfate, the solvent was distilled off under reduced pressure. This was purified by silica gel column chromatography (dichloromethane/methanol=200/1), to obtain the desired compound (1.19 g, 96%).
Reaction SMILES: [C:1](#[N:5])[CH2:2][CH2:3][CH3:4].[CH2:6]([OH:8])[CH3:7].[ClH:9]>>[ClH:9].[C:1](=[NH:5])([O:8][CH2:6][CH3:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC#N
Reactant: CCO
Agent: Cl
Product: CCCC(=N)OCC
Reaction time: 18 h
Yield: 30 %

Procedure:
A solution of butyronitrile (34.5 g; 0.5 mol) in ethanol (25 g; 0.54 mol) was cooled in an ice bath. The cold solution was then saturated with hydrogen chloride gas. The reaction mixture was refrigerated for 18 hours. The excess ethanol was evaporated under vacuum. The residual oil was then treated with a small amount of diethyl ether. Collection of the colorless solid provided the title compound (23 g, 30% yield) which was used in the reaction described in step 2 of this example. 1H-NMR (DMSO-d6; 200 MHz): δ12.22 (br s, 1H), 11.33 (br s, 1H), 4.46 (q, 2H), 2.62 (t, 2H), 1.65 (m, 2H), 1.32 (t, 3H), and 0.92 ppm (t, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3](Br)=[C:4](Br)[C:5]([Br:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCCC1>[C:16]1([S:22][C:4]2[C:5]([Br:13])=[C:6]3[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]3=[C:2]([Br:1])[C:3]=2[S:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Sc1ccccc1
Reactant: O=C1OC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1OC(=O)c2c(Br)c(Sc3ccccc3)c(Sc3ccccc3)c(Br)c21

Procedure:
2 g (4.31 millimols) of tetrabromophthalic anhydride, 0.975 g (8.84 millimols) of thiophenol, 2.41 g (17.47 millimols) of potassium carbonate and 20 ml of tetrahydrofuran are stirred at 0° C. for 2 hours and at 25° C. for 2 hours. The mixture is acidified with 2N HCl solution and extracted with tetrahydrofuran/toluene. The extracts are dried over sodium sulfate and evaporated. After recrystallisation from toluene/cyclohexane, 1.68 g (75% of theory) of 4,5-bis-(phenylthio)-3,6-dibromophthalic anhydride are obtained; melting point 183°-4° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:22]=[CH:21][C:8]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:12]=2[CH3:20])=[C:7]([F:23])[CH:6]=1)[CH:2]=[CH2:3].[F:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:26]=1[CH2:27]Br>>[CH2:1]([O:4][C:5]1[CH:22]=[CH:21][C:8]([CH2:9][N:10]([CH2:27][C:26]2[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:25]=2[F:24])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:12]=2[CH3:20])=[C:7]([F:23])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: C=CCOc1ccc(CNc2cccc([N+](=O)[O-])c2C)c(F)c1
Product: C=CCOc1ccc(CN(Cc2ccc(F)cc2F)c2cccc([N+](=O)[O-])c2C)c(F)c1

Procedure:
The product from Example 53C and 2,4-diflurobenzyl bromide were processed as described in Example 6B to provide the title compound. MS (ESI+) m/z 443 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:23][C@H:24]1[CH2:29][CH2:28][C@@H:27](O)[CH2:26][CH2:25]1)[CH2:10][N:11]([CH3:22])[C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[F-].[F:39]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.C1COCC1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([F:39])[CH2:26][CH2:25]1)[CH2:10][N:11]([CH3:22])[C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CN(C[C@H](C[C@H]1CC[C@@H](O)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [F-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C[C@H](C[C@H]1CC[C@H](F)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
A mixture of benzyl (S)-2-(t-butoxycarbonylamino)-3-(cis-4-hydroxycyclohexyl)-propyl(methyl)carbamate (1 g, 2.38 mmol), base Et3N (5 mL, 28 mmol), a fluoride source NEt3(HF)3 (1.9 mL, 9.52 mmol) and perfluorobutanesulfonyl fluoride (2.1 mL, 9.52 mmol) were stirred in THF (24 mL, 1 mmol/10 mL) in a capped vial or flask at 50° C. until LC revealed complete conversion. The reaction mixture was quenched with water and extracted with EtOAc (2×100 mL), dried over MgSO4, and evaporated. The residue was then purified by preparative HPLC to give benzyl (S)-2-(t-butoxycarbonylamino)-3-(trans-4-fluorocyclohexyl)propyl-(methyl)carbamate (200 mg, 20%) as a white solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[Cl:24][C:25]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[Cl:24][C:25]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH:22][CH:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[CH:9]([C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=1)[OH:23])=[O:28]
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of (1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) in ethyl acetate (5 ml) were added 2,3-dichlorobenzoyl chloride (135 mg, 0.64 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) and recrystallized from ethyl acetate-hexane to give the title compound (161 mg, 77%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20]Br)[CH:15]=2)[CH:10]=[C:9]1[C:22]1[C:23]2[S:36][C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:34][C:24]=2[N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][N:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[CH:15]=2)[CH:10]=[C:9]1[C:22]1[C:23]2[S:36][C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:34][C:24]=2[N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(OCCCBr)cc3n2C(=O)OC(C)(C)C)c2sc(-c3ccccc3)cc21
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(OCCCN4CCCCC4)cc3n2C(=O)OC(C)(C)C)c2sc(-c3ccccc3)cc21
Temperature: 70 °C
Reaction time: 20 h

Procedure:
A mixture of 6-(3-bromo-propoxy)-2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester [300 mg, 0.460 mmol, Intermediate 50)], piperidine (60.2 mg, 0.707 mmol), potassium carbonate (191 mg, 1.38 mmol), potassium iodide (40.0 mg, 0.241 mmol), and anhydrous acetonitrile (5.0 mL) was heated at 70° C. with shaking at 200 rpm. After 20 hours, the reaction was cooled to ambient temperature, filtered, the insolubles washed three times with dichloromethane (5 mL), and the filtrate concentrated under reduced pressure to give a dark residue. The residue was chromatographed on silica, eluting with 10%-1 M ammonia in methanol/90% dichloromethane, to give 2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-[3-(piperidin-1-yl)-propoxy]-indole-1-carboxylic acid tert-butyl ester (310 mg) as a brittle green foam: LC/MS: 657.3, (M+H), RT=3.92 minutes, 50% UV purity). A mixture of this material (300 mg), 4 M aqueous potassium carbonate (5.0 mL), tetrahydrofuran (5.0 mL) and methanol (5.0 mL) was heated at 60° C. for 2 hours. After cooling to room temperature, the solvent was removed in vacuo to give a solid. The crude solid was suspended in water (25 ml) and the mixture stirred at room temperature for 0.5 hours. The solid was collected by filtration and dried to give a grey solid. Trituration of the solid with 20% methanol/ether provided 2-(5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-(3-piperidin-1-yl-propoxy)-1H-indole [90.0 mg, 43%, Example 58] as a grey solid. TLC Rf 0.37 (silica, 14% 1 M ammonia in methanol/86% dichloromethane); LC/MS: 457.3 (M+H), RT=2.93 minutes; 1H NMR [300 Mhz, (CD3)2SO]: δ 13.30 (br s 1H), 11.39 (br s, 1H), 7.78 (d, J=7 Hz, 2H), 7.64 (s, 1H), 7.49-7.35 (m, 4H), 6.92 (s, 1H), 6.65 (d, J=8.5 Hz, 1H), 6.59 (s, 1H), 3.98 (t, J=6 Hz, 2H), 2.43-2.33 (m, 6H), 1.88 (m, 2H), 1.50-1.39 (m, 6H).