Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:24])[C:12]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:24])[C:12]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:21])=[CH:17][N:16]=1
Reactant: Cn1nnc(-c2ccccc2F)c1COc1ccc(C(=O)O)cn1
Reactant: CC(C)N
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccccc3F)nnn2C)nc1
Yield: 85 %

Procedure:
As described for example 19b, 6-((4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methoxy)nicotinic acid (98 mg, 0.3 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (94 mg, 85%) which was obtained as a white solid. MS: m/e=370.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Oc1ccc(F)cc1Br
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1ccc(F)cc1Br

Procedure:
The sub-title compound was prepared by the method of Example 2 step a) using 2-bromo-4-fluorophenol and ethyl bromoacetate.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([C:22]3[S:26][N:25]=[C:24]([N:27]4[CH2:32][CH2:31][C:30]([CH3:38])([C:33]([O:35]CC)=[O:34])[CH2:29][CH2:28]4)[N:23]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[OH-].[Na+]>CCO>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([C:22]3[S:26][N:25]=[C:24]([N:27]4[CH2:28][CH2:29][C:30]([CH3:38])([C:33]([OH:35])=[O:34])[CH2:31][CH2:32]4)[N:23]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3nc(N4CCC(C)(C(=O)OCC)CC4)ns3)cc(-c3ccccn3)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCNC(=O)Nc1nc2cc(-c3nc(N4CCC(C)(C(=O)O)CC4)ns3)cc(-c3ccccn3)c2s1
Temperature: 90 °C
Reaction time: 18 h
Yield: 33.8 %

Procedure:
Ethyl 1-(5-{2-[(ethylcarbamoyl)amino]-7-(pyridin-2-yl)-1,3-benzothiazol-5-yl}-1,2,4-thiadiazol-3-yl)-4-methylpiperidine-4-carboxylate (100 mg, 0.13 mmol) was dissolved in EtOH (10 mL) and 2M aqueous NaOH (2.5 mL) was added and the mixture stirred at 90° C. for 18 h, cooled to rt and concentrated to ˜⅕ volume water (10 mL) and DCM (10 mL) added. The aqueous layer was separated and the organic layer discarded. The resultant aqueous layer was acidified to pH˜2 and extracted with DCM (3×10 mL), the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to give a brown solid which was purified by flash column chromatography (2× Biotage, SP4, 12 g, 2-8% MeOH, DCM) to afford Compound 233 as a cream solid (23 mg, 34%). 1H NMR (CDCl3) δ 8.70 (dd, J=4.8, 0.8 Hz, 1H), 8.62 (d, J=1.4 Hz, 1H), 8.44 (d, J=1.3 Hz, 1H), 8.09 (d, J=8.2 Hz, 1H), 7.78 (td, J=7.8, 1.8 Hz, 1H), 7.22 (ddd, J=7.4, 4.9, 0.8 Hz, 1H), 3.83 (brs, 2H), 3.39-3.29 (m, 5H), 2.22 (d, J=13.3 Hz, 2H), 1.70-1.40 (m, 4H), 1.19 (t, J=7.3 Hz, 4H), 0.86 (t, J=7.5 Hz, 3H). MS: 524.06 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=CC=CC=1C.[F-:20].[K+]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:20].[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [F-]
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: [Br-]
Solvent: Cc1ccccc1Cl
Product: O=[N+]([O-])c1ccc(F)c(Cl)c1
Temperature: 200 °C
Yield: 81 %

Procedure:
25 g of hexadecyltributylphosphonium bromide are dissolved at 60° C. in 1010 g (5.25 mol) of 3,4-dichloronitrobenzene. 100 g of 2-chlorotoluene are added to the solution. After addition of 290 g (5.0 mol) of potassium fluoride, the resulting suspension is heated for 16 h at 200° C. During this time, some of the 2-chlorotoluene is continuously distilled off. The reaction suspension is then quickly filtered off using suction, the filter cake is washed with 2-chlorotoluene and the combined filtrates are fractionated in vacuo. In this manner, 711 g (81% of theory) of 3-chloro-4-fluoronitrobenzene and 115 g of unreacted 3,4-dichloronitrobenzene are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17].O>O1CCCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:16](=[O:17])[O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)nc1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a solution of 6-chloropyridine-3-amine (1.00 g, 7.78 mmol) and pyridine (0.761 ml, 9.33 mmol) in tetrahydrofuran (25 ml) was added 2,2,2-trichloroethyl chloroformate (1.29 ml, 9.33 mmol) with ice-cooling and the mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. Hexane was poured to the residue and a solid was collected by filtration to obtain the desired product (2.17 g, 92.0%).
Reaction SMILES: [BH4-].[Na+].[O:3]([C:21]1[CH:28]=[C:27]([O:29][CH3:30])[C:24]([CH:25]=[O:26])=[C:23]([O:31][CH3:32])[CH:22]=1)[Si:4]([C:17]([CH3:20])([CH3:19])[CH3:18])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>O1CCCC1>[O:3]([C:21]1[CH:22]=[C:23]([O:31][CH3:32])[C:24]([CH2:25][OH:26])=[C:27]([O:29][CH3:30])[CH:28]=1)[Si:4]([C:17]([CH3:20])([CH3:19])[CH3:18])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COc1cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc(OC)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc(OC)c1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.7 %

Procedure:
Sodium borohydride (519.0 mg, 13.73 mmol) was added to an ice-cold solution of 4-t-butyldiphenylsiloxy-2,6-dimethoxybenzaldehyde (3.85 g, 9.15 mmol) in tetrahydrofuran (40 mL), and the mixture was stirred at room temperature for 2 hours and 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford crude 4-t-butyldiphenylsiloxy-2,6-dimethoxybenzyl alcohol as a colorless crystalline powder (melting point: 127.5-129.0° C.) (4.01 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:14][O:13][C:12]3=[O:22])=[N:7][C:6]=12.[F:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][C:25]=1[C:39]1[N:43]=[CH:42][N:41]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[N:40]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:23][C:24]1[CH:29]=[C:28]([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[CH:9][C:8]([N:11]4[C@@H:15]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=5)[CH2:14][O:13][C:12]4=[O:22])=[N:7][C:6]=23)[CH:27]=[CH:26][C:25]=1[C:39]1[N:43]=[CH:42][N:41]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[N:40]=1
Reactant: O=C1OC[C@H](c2ccccn2)N1c1ccn2ncc(Br)c2n1
Reactant: CC1(C)OB(c2ccc(-c3ncn(COCC[Si](C)(C)C)n3)c(F)c2)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cnc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@@H]5c5ccccn5)nc34)cc2F)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 22.8 %

Procedure:
To a solution of (S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-(pyridin-2-yl)oxazolidin-2-one (0.25 g, 0.69 mmol) in dioxanes (70 mL) purged continuously with nitrogen gas was added 3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole (0.44 g, 1.0 mmol) and sodium carbonate (1.7 mL, 3.5 mmol) (2M in water). Pd2 dba3 (70 mg) and X-Phos (70 mg) were added, and the reaction mixture was stirred at 80° C. for 3 hours, then diluted with EtOAc (200 mL). The organic layer was washed with water and brine, dried over MgSO4, filtered concentrated in vacuo. The crude material was chromatographed using 50% EtOAc/hexane as eluent to yield (S)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(pyridin-2-yl)oxazolidin-2-one (0.090 g, 22.5%).
Reaction SMILES: [CH:1]1([C:4]#[CH:5])[CH2:3][CH2:2]1.C([Mg]Cl)CCC.[H-].[Na+].FC(F)(F)CO.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[C:23]([C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[CH:22]=1>O1CCCC1.[Br-].[Zn+2].[Br-]>[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[C:23]([C@@:28]([C:5]#[C:4][CH:1]2[CH2:3][CH2:2]2)([C:29]([F:31])([F:32])[F:30])[OH:33])[CH:22]=1
Reactant: C#CC1CC1
Reactant: Nc1ccc(Cl)cc1C(=O)C(F)(F)F
Agent: CCCC[Mg]Cl
Agent: [Br-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: OCC(F)(F)F
Product: Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
A solution of chloromagnesium-cyclopropylacetylide (CPA-MgCl) was prepared by adding neat cyclopropyl acetylene (3.62 gms) to a stirred solution of n-butyl magnesium chloride (2M solution in tetrahydrofuran, 26.8 ml) at 0-5° C. The solution was stirred for another 2 hours at 0-5° C. Step B: In another dry flask, to anhydrous tetrahydrofuran (80 ml) at 0-5° C., sodium hydride (57% dispersion in mineral oil, 4.71 gms) was added slowly. The mixture was stirred for 30 minutes at 25° C. to 30° C. and again cooled to 0° C. to 5° C. (1R,2S)-Pyrrolidinyl norephidrine (13.5 gms) and 2,2,2-trifluoroethanol (4.3 gm) were added and stirred for 60 minutes at 25° C. to 30° C. To the reaction mixture, was added a solution of zinc bromide (12 gms) in tetrahydrofuran (40 ml) and stirred for 60 minutes at 25° C. to 30° C., to obtain ephedrine zincate complex. The solution of chloromagnesium-cyclopropylacetylide of Step A was then added to the ephedrine zincate complex at 25° C. to 30° C. and stirred for 2 hours at the same temperature. To the resultant reaction mass was added 4-chloro-2-trifluoroacetyl aniline (10 gms) at 25° C. to 30° C. and the mixture was stirred 15 hours at same temperature. After completion of the reaction, the reaction mixture was quenched with 30% aqueous potassium carbonate (5.5 ml) and the solid precipitate was filtered. The filtrate was taken and partially concentrated and then toluene (100 ml) added followed by washed with 30% citric acid solution in water (50 ml). The organic layer was partially concentrated and hexane (50 ml) was added. The mixture was cooled to 0° C., filtered and the solid precipitate was washed with chilled hexane (10 ml). The wet product was dried at 50° C. to 55° C. under reduced pressure to afford the title compound. Yield: 10 gms.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:4][C:3]1=2.[CH3:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[CH3:20][C:21]1[CH:26]=[C:25]([C:6]2[CH:7]=[C:8]3[C:3](=[CH:4][CH:5]=2)[C:2](=[O:1])[CH2:11][CH2:10][CH2:9]3)[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Product: Cc1cccc(-c2ccc3c(c2)CCCC3=O)c1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and 3-methylphenyl boronic acid according to the coupling procedure as described in example 6. MS (ESI) m/z 237.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Br[C:34]1[CH:42]=[C:41]2[C:37]([CH2:38][CH2:39][C:40]2=[O:43])=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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.[Pd]>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18]([C:34]4[CH:42]=[C:41]5[C:37](=[CH:36][CH:35]=4)[CH2:38][CH2:39][C:40]5=[O:43])[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:4])=[O:5])[CH3:2]
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc5c(c4)C(=O)CC5)cc23)CC1
Temperature: 160 °C

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (200 mg, 0.434 mmol) in dioxane (3.0 mL) and H2O (1.0 mL) was added 6-bromo-2,3-dihydro-1H-inden-1-one (274 mg, 1.30 mmol), and potassium carbonate (360 mg, 2.60 mmol) in a microwave tube. The reaction mixture was degassed for 5 min before the addition of tetrakis (triphenylphosphosphine) palladium (0) (50 mg, 0.043 mmol). The reaction was then heated in the microwave for 30 min at 160° C. The reaction was then filtered and the solid was dissolved in EtOAc and H2O. The organic layer was separated and concentrated. The crude residue was purified by Gilson Preparatory HPLC to yield 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-oxo-2,3-dihydro-1H-inden-5-yl)-1H-indole-7-carboxamide.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH2:5](Cl)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(O)C>[CH2:5]([NH:3][CH2:2][CH2:1][NH2:4])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCl
Reactant: NCCN
Solvent: CCO
Product: CCCCCCCCNCCN

Procedure:
50 g (0.83 mol) of anhydrous ethylenediamine, 31.2 g (0.21 mol) of octyl chloride and 400 ml of ethanol were mixed and refluxed 6 hours under heating. After evaporation of ethanol under reduced pressure, the lower layer was removed and 200 ml of benzene and 100 ml of water were added to the upper layer for full rinsing. The benzene fraction was dried over anhydrous sodium sulfate, concentrated and then cooled to precipitate crystals. After filtering, crystals were redissolved into 200 ml of benzene and the solution was fully rinsed with water. After being dried over anhydrous sodium sulfate, the benzene solution was concentrated and cooled to precipitate crystals. After filtration, crystals were washed with a small volume of methanol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])[CH:13]=1)[C:8](O)=[O:9])=[O:4].O1CCCC1.O1CCCC1.CO>O1CCCC1>[OH:9][CH2:8][C:7]1[CH:6]=[C:5]([CH:13]=[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1cc(C(=O)O)cc(N(C)S(C)(=O)=O)c1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(CO)cc(N(C)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
To a solution of 3-(methoxycarbonyl)-5-[methyl(methylsulfonyl)amino]benzoic acid obtained in Reference Example 62.07 g (7.2 mmol) in tetrahydrofuran (10 mL) was added 1.0 M BH3.tetrahydrofuran/tetrahydrofuran solution 9 mL dropwise under ice-cooling and the mixture was stirred at room temperature for 16 hours. To the reaction solution was added methanol (3 mL) under ice-cooling, and the solvent was evaporated. To the residue was added water and the mixture was extracted with ethyl acetate. After drying of the mixture on magnesium sulfate, the solvent was evaporated and the resulting solid was recrystallized from chloroform/hexane to give 1.64 g (6.0 mmol) of the title compound (yield: 83%).
Reaction SMILES: C([O:8][C:9]1[N:10]=[N:11][C:12](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1.B(Br)(Br)Br.CO>ClCCl>[Cl:31][C:28]1[CH:29]=[CH:30][C:25](/[CH:24]=[CH:23]/[C:12]2[CH:13]=[C:14]([OH:15])[C:9](=[O:8])[NH:10][N:11]=2)=[CH:26][CH:27]=1
Reactant: Clc1ccc(/C=C/c2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=c1[nH]nc(/C=C/c2ccc(Cl)cc2)cc1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
To a solution (5 mL) of 3,4-bis(benzyloxy)-6-[(E)-2-(4-chlorophenyl)vinyl]pyridazine (150 mg) in dichloromethane was added a solution (770 μL) of 1M boron tribromide in dichloromethane at −78° C. and the mixture was stirred at 0° C. for 3 hr. Methanol was added to terminate the reaction, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) and the obtained solid was washed with ethanol-water, collected by filtration and dried under reduced pressure to give 6-[(E)-2-(4-chlorophenyl)vinyl]-4-hydroxypyridazin-3(2H)-one (58 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1>>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl
Product: COC(=O)c1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 73 %

Procedure:
Following general procedure B1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.100 g, 0.33 mmol) was reacted with methyl 4-aminobenzoate (0.055 g, 0.36 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.100 g, 80%) as a white solid. MW=415.31. 1H NMR (DMSO-d6, 500 MHz) δ 9.94 (s, 1H), 8.05 (d, J=8.5 Hz, 2H), 7.98-7.96 (m, 1H), 7.81-7.77 (m, 1H), 7.68-7.64 (m, 1H), 7.60 (t, J=7.5 Hz, 1H), 7.55 (d, J=8.5 Hz, 2H), 7.33 (s, 1H), 3.86 (s, 3H), 3.18 (t, J=7.5 Hz, 2H), 2.97 (t, J=7.5 Hz, 2H), 2.24 (quin, J=7.5 Hz, 2H); APCI MS m/z 379 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1.C([BH3-])#N.[Na+].Cl>CO>[OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[CH:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:12][CH:13]=1
Reactant: CC(C(=O)O)c1ccc(C=C2CCCC2=O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C(=O)O)c1ccc(C=C2CCCC2O)cc1
Temperature: 0 °C
Yield: 64.5 %

Procedure:
123 mg of 2-[4-(2-oxocyclopentylidenemethyl)phenyl]propionic acid (which can be prepared as described in United Kingdom Patent Specification No. 2,002,762) and 75 mg of sodium cyanoborohydride were dissolved in 5 ml of methanol. The pH of the solution was adjusted to a value of 3 by the addition of 6N hydrochloric acid, whilst ice-cooling. The mixture was stirred under reflux for 40 minutes, after which it was diluted with ice-water and then extracted with diethyl ether. The extract was washed with water and then the solvent was distilled off to give crystals. These were recrystallised from a 1:1 by volume mixture of ethyl acetate and hexane, to give 80 mg of the title compound, melting at 125°-132° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:13][C:14]([C:24]1([CH3:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)([OH:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22]>CN(C)C=O>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][C:14]([C:24]1([CH3:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)([OH:23])[CH2:13][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC1(C(O)(CCl)Cc2ccccc2Cl)CCCCC1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C(O)(Cc2ccccc2Cl)Cn2cncn2)CCCCC1
Temperature: 80 °C
Yield: 46.4 %

Procedure:
12 g (174 mmol) of 1,2,4-triazole and 17 g (123 mmol) of potassium carbonate are initially introduced into 30 ml of absolute dimethylformamide under a nitrogen atmosphere and the mixture is heated to 80° C. At this temperature, a solution of 16.7 g (55.5 mmol) of 1-chloro-3-(2-chlorophenyl)-2-(1-methyl-cyclohex-1-yl)-propan-2-ol in 20 ml of absolute dimethylformamide is added dropwise with stirring. The reaction mixture is then stirred at 80° C. for a further 8 hours. The precipitate is filtered off with suction, and the filtrate is concentrated by stripping off the diluent under reduced pressure. The residue is taken up in ethyl acetate, washed with water and, after drying over sodium sulphate, the solvent is stripped off under reduced pressure. The product which remains is chromatographed through a silica gel column using dichloromethane/ethanol=99:1 as the eluent. 8.6 g (46.5% of theory) of 1-(2-chlorophenyl)-2-(1-methyl-cyclohex-1-yl)-3 -(1,2,4-triazol-1-yl)-propan-2-ol are obtained in this manner in the form of a solid substance of melting point 105° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[C:17][Si](C)(C)C)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:33])[N:7]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[CH:17])[CH:11]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCc1cccc(C#C[Si](C)(C)C)c1)Cc1ccc(C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cccc(CCN(Cc2ccc(C(C)(C)C)cc2)C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.5 %

Procedure:
To a solution of (4-tert-butyl-benzyl)-[2-(3-trimethylsilanylethynyl-phenyl)-ethyl]-carbamic acid tert-butyl ester (440 mg, 0.949 mmol) in THF (7.6 ml) was added a 1 molar solution of TBAF in THF (949 μl, 0.949 mmol) at −78° C. After 15 min at −78° C. the solution was allowed to warm to 0° C. for 30 min. Then brine was added and the mixture was extracted with ether. The combined ether layers were dried (Na2SO4) and evaporated and the remaining residue was purified by chromatography (pentane/ether 100:0 to 90:10) to obtain the title compound as a colorless oil (314 mg, 84%). MS (ISP) 392.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[CH3:17])=[O:10].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[CH3:17])=[O:10])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1cnccc1C(=O)c1cc(Cl)ccc1N
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: Cc1cnccc1C(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 123 mg of (2-Amino-5-chloro-phenyl)-(3-methyl-pyridin-4-yl)-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride.