Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].O.Cl.[Cl:5][C:6]1[CH:7]=[C:8]([CH:13]([CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][C:30](COC(NCC)=O)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:29][CH2:28]2)[CH2:14][N:15]([CH3:24])[C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=[CH:10][C:11]=1[Cl:12].O.O.[Cl:48]C1C=C(C(CCN2CCC(C3C=CC=CC=3)(COC(NCC)=O)CC2)C[N:58](C)[C:59](=[O:66])C2C=CC=CC=2)C=CC=1Cl.Cl.C([O-])([O-])=O.[K+].[K+]>O.C(#N)C.Cl>[OH2:23].[ClH:5].[Cl:5][C:6]1[CH:7]=[C:8]([CH:13]([CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][C:30]([NH:58][CH:59]=[O:66])([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:31][CH2:32]2)[CH2:14][N:15]([CH3:24])[C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=[CH:10][C:11]=1[Cl:12].[Cl:5][C:6]1[CH:7]=[C:8]([CH:13]([CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([NH:58][CH:59]=[O:66])[CH2:31][CH2:32]2)[CH2:14][N:15]([CH3:24])[C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=[CH:10][C:11]=1[Cl:12].[ClH:48]
Reactant: CCNC(=O)OCC1(c2ccccc2)CCN(CCC(CN(C)C(=O)c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(CC(CCN1CCC(NC=O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Yield: 203.5 %

Procedure:
0.55 g of the compound obtained in PREPARATION 1.3 is dissolved in water, the mixture is alkalinized by adding concentrated NaOH solution, the product is extracted with DCM, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuum. The product obtained is taken up in 20 ml of acetonitrile, 0.85 g of the compound obtained in step C of EXAMPLE 15 and 1 g of K2CO3 are added and the reaction mixture is heated to reflux for 2 hours 30 minutes. It is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with water and with 5% NaOH solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H, eluting with DCM and then with a DCM/MeOH (90:10; v/v) mixture. The product obtained is taken up in ethereal hydrogen chloride and the precipitate formed is drained. 0.51 g of the expected product is obtained.
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][CH2:20][C:21](=[O:23])[NH2:22])=[CH:15][CH:14]=1)(C)(C)C>>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][CH2:20][C:21]([NH2:22])=[O:23])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(NCC(N)=O)cc1
Agent: Cl
Product: NCCCCc1ccc(NCC(N)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
12N HCl (5 mL) was added to {4-[4-(carbamoylmethylamino)phenyl]butyl}carbamic acid tert-butyl ester 390 (0.2 g, 0.62 mmol). The reaction was stirred at room temperature for 1 hour. The solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 4:1:0.1 chloroform/methanol/concentrated ammonium hydroxide, v/v) to provide 400 (0.10 g, 70%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.55 (m, 4H), 2.50 (t, 2H), 2.68 (t, 2H), 3.70 (s, 2H), 6.52 (d, 2H), 6.97 (d, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)[CH3:2].[Br:22]N1C(=O)CCC1=O.Br>C(Cl)(Cl)(Cl)Cl>[Br:22][CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C#N)cc2)cc1
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)c1ccc(Oc2ccc(C#N)cc2)cc1

Procedure:
To a solution of 1.17 g of ethyl[p-(p-cyanophenoxy)phenyl]acetate in 20 ml of carbon tetrachloride is added 0.75 g of N-bromosuccinimide and a drop of 48% HBr. The mixture is stirred and refluxed for 42 hours. The solvent is removed under vacuum to give the product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:34])([CH2:28][N:29]1[CH:33]=[N:32][N:31]=[N:30]1)[C:10]([C:13]1[N:18]=[CH:17][C:16]([O:19][C:20]2[CH:27]=[CH:26][C:23](C#N)=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)([F:12])[F:11].C1(B(O)O)C=CC=CC=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:34])([CH2:28][N:29]1[CH:33]=[N:32][N:31]=[N:30]1)[C:10]([F:12])([F:11])[C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:26][CH:27]=2)=[CH:17][N:18]=1
Reactant: N#Cc1ccc(Oc2ccc(C(F)(F)C(O)(Cn3cnnn3)c3ccc(F)cc3F)nc2)cc1
Agent: OB(O)c1ccccc1
Product: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(Oc2ccccc2)cn1

Procedure:
Compound 11 was prepared in a similar manner to compound 5 from phenylboronic acid to afford a solid (30 mg, 8.7%). 1H NMR (500 MHz, CDCl3): δ 8.74 (s, 1H), 8.25 (s, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.49 (br s, 1H), 7.45-7.35 (m, 3H), 7.30-7.29 (m, 1H), 7.28-7.27 (m, 1H), 7.06 (d, J=7.5 Hz, 2H), 6.79-6.74 (m, 1H), 6.72-6.69 (m, 1H), 5.54 (d, J=14.0 Hz, 1H), 5.12 (d, J=14.0 Hz, 1H). MS (ESI): m/z 446.8 [M++1]. HPLC: 99.5%.
Reaction SMILES: [N:1]1([C:52](OC(C)(C)C)=O)[CH2:51][CH2:50][CH2:49][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([N:27]([CH2:29][C:30]([NH:32][C@H:33]([C:38]([NH:40][C@H:41]([C:46]([NH2:48])=[O:47])[CH2:42][CH2:43][S:44][CH3:45])=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:31])[CH3:28])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].Cl>C(O)(=O)C>[NH:1]1[CH2:52][CH2:51][CH2:50][CH2:49][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([N:27]([CH2:29][C:30]([NH:32][C@H:33]([C:38]([NH:40][C@H:41]([C:46]([NH2:48])=[O:47])[CH2:42][CH2:43][S:44][CH3:45])=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:31])[CH3:28])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CN(C)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Agent: Cl
Solvent: CC(=O)O
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CN(C)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCCN1)C(N)=O

Procedure:
Condensation of BocPro-Phe-PheNHNH2 (Example 1, 1.35 g.) and HSar-Leu-MetNH2 (0.95 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-Phe-Phe-Sar-Leu-MetNH2 in 45% yield. De-t-butoxycarbonylation of BocPro-Phe-Phe-Sar-Leu-MetNH2 (0.90 g.) using hydrogen chloride in acetic acid gave HPro-Phe-Phe-Sar-Leu-MetNH2, which was isolated as the amorphous white solid phosphate (1:1) salt sesquihydrate in 59% yield.
Reaction SMILES: [OH2:1].[OH-].[Na+].[OH:4][C:5]1[CH2:9][CH2:8][C:7](=O)[C:6]=1[CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]>C(O)(=O)C>[OH:1][CH:8]1[CH2:9][C:5](=[O:4])[C:6]([CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:7]1
Reactant: COC(=O)CC/C=C\CCC1=C(O)CCC1=O
Reactant: O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(=O)CC/C=C\CCC1=CC(O)CC1=O
Temperature: 100 °C
Reaction time: 26 h
Yield: 71 %

Procedure:
To the compound [VIII-2] (2.50 g) obtained above are added water (123.8 g) and acetic acid (0.19 g), and the pH value of the mixture is adjusted to pH 4.2 with 5% aqueous sodium hydroxide solution and the mixture is heated with stirring at 100° C. for 26 hours. After completion of the reaction, the reaction mixture is cooled and extracted twice with methyl isobutyl ketone (50 ml). The organic layer is separated and concentrated to give a mixture (1.78 g, yield; 71%) of 4-hydroxy-2-(6-methoxycarbonyl-cis-3-hexenyl)-2-cyclopentenone (racemic 4-hydroxycyclopentenone) and 3-hydroxy-2-(6-methoxycarbonyl-cis-3-hexenyl)-2-cyclopentenone [IX-2] (ratio thereof=4.9:5.1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].CN(C=O)C.[Cl:21]N1C(=O)CCC1=O>O>[Cl:21][C:8]1[CH:7]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([N+:13]([O-:15])=[O:14])[C:3]=1[NH:2][CH3:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1c(Cl)cc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
To a mixture of methyl-(2-nitro-4-trifluoromethylphenyl)-amine (4.40 g) and DMF (20 ml), N-chlorosuccinimide (3.67 g) was added under ice-cooling, and stirred for 3 hours. The mixture was heated to room temperature, and allowed to stand. Water was poured thereinto under ice-cooling, and then the precipitated solid was collected by filtration. The obtained solid was washed with water, and dried to give 3.96 g of (2-chloro-6-nitro-4-trifluoromethylphenyl)-methylamine.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.[C:21]([OH:24])(=[O:23])[CH3:22]>CCCCCC>[CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.[C:21]([O-:24])(=[O:23])[CH3:22]
Reactant: CC(=O)O
Agent: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Solvent: CCCCCC
Product: CC(=O)[O-]
Temperature: 25 °C

Procedure:
71 gms of sertraline base is dissolved in 350 ml of n-hexane under stirring at room temperature. 14 ml acetic acid is added to the clear solution and stirred for 10 minutes at 25° C. and refluxed at 60° C. for 30 minutes to obtain a thick white precipitate. The precipitated solid is filtered. The product is dried in a fluid bed dryer at 60° C. for 3-4 hours to give sertraline acetate.
Reaction SMILES: NC(N)=O.[CH:5]1([NH:10][S:11]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([NH2:21])[C:15]=2[OH:22])(=[O:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1.[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>>[Cl:20][C:19]1[CH:18]=[CH:17][C:16]([NH:21][C:32]([NH:31][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([Cl:30])[C:24]=2[Cl:23])=[O:33])=[C:15]([OH:22])[C:14]=1[S:11]([NH:10][CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9]1)(=[O:13])=[O:12]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: Nc1ccc(Cl)c(S(=O)(=O)NC2CCCC2)c1O
Agent: NC(N)=O
Product: O=C(Nc1ccc(Cl)c(S(=O)(=O)NC2CCCC2)c1O)Nc1cccc(Cl)c1Cl
Yield: 40.2 %

Procedure:
Following the general procedure for urea formation outlined in example 15, (N-cyclopentyl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide (0.15 g, 0.52 mmol) and 2,3-dichlorophenylisocyanate(68 μL, 0.52 mmol) were coupled to form the desired urea (0.10 g, 40%). LC-MS m/z 478(M+).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[NH:9][CH:10]=[C:11]([CH2:13][CH2:14][CH2:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:12]=1)=[O:7])C>CO>[CH:16]1([CH2:15][CH2:14][CH2:13][C:11]2[CH:12]=[C:8]([C:6]([OH:7])=[O:5])[NH:9][CH:10]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)c1cc(CCCC2CCCC2)c[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(CCCC2CCCC2)c[nH]1

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 11.23 mmol) was added to a stirring, room temperature solution of 75 (0.56 g, 2.25 mmol) in MeOH (5.6 mL, 0.4 M) under N2. The reaction was heated to reflux until the reaction was judged complete by HPLC (10 min). Upon cooling, the reaction solidified. The product was concentrated and H2O was added. When the product would not dissolve in H2O, EtOAc was added, followed by 10% HCl to acidify the aqueous layer. The organic was then removed, dried with Na2SO4, filtered, concentrated, and purified by preparative reverse phase HPLC with the following conditions: 30:70 H2O:CH3CN; 20 mL/min.; λ=254 nm. 76 was obtained as a fluffy white solid. (Note: An undesired impurity has a retention time of 12.073 min by HPLC). 1H (CD3OD, 400 MHz): δ 10.80 (1H, s), 6.72 (1H, s), 6.68 (1H, s), 2.43 (2H, t, J=7.6 Hz), 1.82-1.70 (3H, m), 1.64-1.46 (6H, m), 1.38-1.29 (2H), 1.14-1.02 (2H, m) ppm. 13C (CD3OD, 100 MHz): δ 164.45, 127.29, 122.45, 116.39, 41.31, 37.00, 33.73, 31.43, 27.96, 26.11 ppm. DEPT (CDCl3, 100 MHz): CH2 carbons: 37.00, 33.73, 31.43, 27.96, 26.11; CH carbons: 122.45, 116.39, 41.31 ppm. HPLC: 10.977 min.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8](Cl)[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:6]1=[O:50])[CH2:2][CH2:3][CH3:4].[C:51]1([SH:57])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([S:57][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:27][N:28]=[N:29][N:30]=3)=[CH:18][CH:19]=2)[C:6]1=[O:50])[CH2:2][CH2:3][CH3:4]
Reactant: Sc1ccccc1
Reactant: CCCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCn1c(=O)cc(Sc2ccccc2)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1=O
Yield: 69 %

Procedure:
A mixture of 3-butyl-6-chloro-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.52 g), thiophenol (0.1 ml) and potassium carbonate (0.15 g) in acetonitrile (10 ml) was heated under reflux for 4 hours with stirring. The reaction mixture was allowed to cool and the insoluble material was removed from the reaction mixture by filtration. The filtrate was concentrated to dryness. The resulting residue was dissolved in methanol (15 ml) and 1N hydrochloric acid (1 ml) and the mixture stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness and the residue was extracted with methylene chloride-water. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless amorphous powders (0.27 g, 69%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([C:15]3[C:16]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:14])=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:31]([OH:33])=O)[CH3:2].Cl.[NH2:35][C@@H:36]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:37]([NH:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:40]([NH:39][C:37](=[O:38])[C@@H:36]([NH:35][C:31]([C:4]1[N:3]([CH2:1][CH3:2])[C:11]2[C:6]([CH:5]=1)=[CH:7][C:8]([NH:12][C:13]([C:15]1[C:16]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=3)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:14])=[CH:9][CH:10]=2)=[O:33])[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CCn1c(C(=O)O)cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Reactant: N[C@H](C(=O)NCc1ccccc1)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCn1c(C(=O)N[C@H](C(=O)NCc2ccccc2)c2ccccc2)cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Reaction time: 8 h
Yield: 71 %

Procedure:
1-Ethyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid (0.05 g, 0.11 mmol) and (S)-2-Amino-N-benzyl-2-phenyl-acetamide hydrochloride (0.031 g, 0.11 mmol) were combined in DCM (3 mL) and DIEA (1.1 mL) was added to the above mixture. PyBroP (0.077 g, 0.17 mmol) was added to the above mixture in one portion. The mixture which was resulted was stirred overnight. The crude mixture was then purified by HPLC to furnish the desired product (52.7 mg). HPLC retention time 16.892 min.; Mol. Wt. (calc) 674.7; MS (found) 675.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=1)[C:6]([CH3:25])=[C:5]2[CH:26]=O.Cl.[NH2:29][OH:30].CO>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=1)[C:6]([CH3:25])=[C:5]2[CH:26]=[N:29][OH:30]
Reactant: Cc1c(C=O)c2cc(F)ccc2n1-c1ccc(OCc2ccccc2)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: Cc1c(C=NO)c2cc(F)ccc2n1-c1ccc(OCc2ccccc2)cc1
Yield: 88 %

Procedure:
A mixture of 5-fluoro-1-(4-benzyloxyphenyl)-2-methyl-1H-indole-3-carbaldehyde (0.97 g, 2.7 mmol), hydroxylamine hydrochloride (0.25 g, 3.6 mmol), methanol (25 mL) and pyridine (1 mL) was reacted according to the procedure in Example 3a to afford white solid (88%): mp 183-185° C.; 1H NMR (DMSO-d6): δ 2.30 (3H, s), 5.20 (2H, s) d, 6.94-6.97 (2H, m), 7.23 (2H, d, J=8.9 Hz), 7.37-7.46(5H, m), 7.52(2H, d, J=6.8 Hz), 7.71 (1H, d, J=10.1 Hz), 8.41 (1H, s), 10.72 (1H, s); MS m/z (M+H)+ 375. Anal. for C23H19FN2O2: Calc'd: C, 73.78; H, 5.11 N, 7.48. Found: C, 73.55; H, 5.03; N, 7.35.
Reaction SMILES: [CH2:1]([O:8][CH:9]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:10][CH2:11][CH2:12][C:13](N1CCOCC1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:28].[K+]>C(O)(C)C>[CH2:1]([O:8][CH:9]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:10][CH2:11][CH2:12][C:13]([OH:14])=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: O=C(CCCC(OCc1ccccc1)c1ccc(F)cc1)N1CCOCC1
Agent: [K+]
Solvent: CC(C)O
Product: O=C(O)CCCC(OCc1ccccc1)c1ccc(F)cc1
Yield: 79.9 %

Procedure:
10 gms of 5-Benzyloxy-5-(4-fluoro-phenyl)-1-morpholin-4-yl-pentan-1-one was added to 100 ml of isopropyl alcohol and 7.5 gms of potassium hydroxide. Heated the reaction mass at reflux temperature and maintain for about 36 hours and distilled off solvent completely. To the obtained oily mass 60 ml of water was added and washed with dichloromethane. Layers were separated and acidify the aqueous layer with hydrochloric acid and adjusted the pH to 2.0. The obtained aqueous layer was extracted with dichloromethane and dried the organic layer over sodium sulphate followed by concentration. 6.5 gms of 5-Benzyloxy-5-(4-fluoro-phenyl)-pentanoic acid was isolated in heptane.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:12]=[C:11]([Cl:21])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=O.Cl.[NH2:23][OH:24].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:14]=[C:13]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:12]=[C:11]([Cl:21])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[N:23][OH:24]
Reactant: NO
Reactant: O=CCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: ON=CCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 42 %

Procedure:
To a mixture of 5.58 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentanal and 50 ml of pyridine was added 1.25 g of hydroxylamine hydrochloride. After stirring at room temperature for 24 hours, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 2.44 g (yield, 41%) of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentanal oxime, nD23.4 1.5600.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2([O:16][CH2:17][CH3:18])[CH2:15][CH2:14]2)=[C:9]([CH:19]([CH3:21])[CH3:20])[CH:8]=1)(=O)=O.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>C(N(CC)CC)C.CN(C=O)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>[CH2:17]([O:16][C:13]1([C:10]2[CH:11]=[CH:12][C:7]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[CH:8][C:9]=2[CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]1)[CH3:18]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC1(c2ccc(OS(=O)(=O)C(F)(F)F)cc2C(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC1(c2ccc(C#C[Si](C)(C)C)cc2C(C)C)CC1
Temperature: 95 °C

Procedure:
Using General Procedure D; 4-(1-ethoxycyclopropyl)-3-isopropyl-phenyl 1,1,1-trifluoromethansulfonate (Intermediate 101, 240.0 mg, 0.68 mmol) in triethylamine (2 mL) and DMF (6 mL) was sparged with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (38.0 mg, 0.05 mmol). The resulting reaction mixture was heated to 95° C. for 5 d. The title compound, 200.0 mg (99%), was isolated by chromatography (0-2% EtOAc-hexanes) as an orange oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:20]=[CH:19][C:18]2[N:17]3[CH2:21][CH2:22][CH2:23][N:24]=[C:16]3[C:15]3(OCCC[O:25]3)[C:14]=2[CH:13]=1)(=[O:11])=[O:10].OS(O)(=O)=O.[NH4+].[OH-]>>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:20]=[CH:19][C:18]2[N:17]3[CH2:21][CH2:22][CH2:23][N:24]=[C:16]3[C:15](=[O:25])[C:14]=2[CH:13]=1)(=[O:11])=[O:10]
Reactant: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C1=NCCCN12
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C(=O)C1=NCCCN12
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 78.7 %

Procedure:
8′-{[(2S)-2-(Methoxymethyl)pyrrolidinyl]sulfonyl}-3′,4′-dihydrospiro(1,3-dioxane-2,10′ (2′H)-pyrimido(1,2-a)indole) (1.30 g, 3.32 mmol) was added portion-wise to concentrated H2SO4 (13 mL) over a period of 15 minutes with cooling in an ice bath. The mixture was allowed to warm to room temperature, stirred for 1.25 hours, poured into ice and basified to pH 10.5 by the careful addition of concentrated NH4OH maintaining internal ice with an external ice bath. The resulting bright yellow-orange solid was filtered, dried, and dissolved in CH2Cl2. After stirring for 1 hour the solution was filtered and the solid was dried in vacuo at 52° C. to give the title compound as a bright yellow solid (0.95 g, 79% yield). Anal: Calc'd. for C17H21N3O4S : C, 56.18; H, 5.82; N, 11.56; Found: C, 56.38; H, 5.90; N, 11.43. NMR: consistent. MS: (ES−) m/z 362 [M−H]. IR: consistent. m.p.: 171-172° C. Opt. Rotation: −109.70 (calculated) at 25° C. in CHCl3 (1%concentration), wavelength 589.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][N:8]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=2)[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[N-:33]=[N+:34]=[N-:35].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH:33]1[C:29]([C:25]2[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=2)[CH2:22][N:8]([CH2:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:32][CH:31]=2)[CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)=[N:30][N:35]=[N:34]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(N(CCc2ccc(Cl)cc2)Cc2cccc(C#N)c2)CC1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(N(CCc2ccc(Cl)cc2)Cc2cccc(-c3nnn[nH]3)c2)CC1
Temperature: 25 °C
Yield: 60 %

Procedure:
tert-Butyl 4-((4-chlorophenethyl)(3-cyanobenzyl)amino)piperidine-1-carboxylate obtained in Step 1 was dissolved in toluene (5 mL/mmol) and sodium azide (3 equiv) and triethylamine hydrochloride (0.1 equiv) were added to this solution. The heterogeneous mixture was refluxed for 3 days after which time the starting material could no longer be detected. After cooling down to ambient temperature the solids were filtered off and the solvent was stripped off in vacuo. The crude product was purified by silica gel chromatography (yield 60%).