Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([N:11]1[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+].O.Cl>CO>[CH:6]1([CH2:5][CH:4]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:3]([OH:25])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)n1ncc(Oc2ccccc2)cc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2)cc1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
A solution of 3-cyclopentyl-2-(6-oxo-4-phenoxy-6H-pyridazin-1-yl)-propionic acid methyl ester (1.70 g, 4.96 mmol) in methanol (8.3 mL, 0.6M) was treated with a 4N aqueous sodium hydroxide solution (1.37 mL, 5.46 mmol) and was stirred at 25° C. for 4 h. After this time, the reaction was poured into water (150 mL) which was acidified with a 3N aqueous hydrochloric acid solution and then was extracted into 90/10 methylene chloride/methanol (3×100 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford 3-cyclopentyl-2-(6-oxo-4-phenoxy-6H-pyridazin-1-yl)-propionic acid (1.60 g, 98%) as a white solid; ES+-HRMS m/e calcd for C18H20N2O4 [M+H+] 329.1496, found 329.2496. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.11 (br s, 2H), 1.35-1.78 (m, 7H), 1.86-2.05 (m, 1H), 2.10-2.25 (m, 1H), 5.31 (dd, J=10.9, 4.2 Hz, 1H), 5.73 (d, J=2.7 Hz, 1H), 7.30 (d, J=7.5 Hz, 2H), 7.37 (t, J=7.5 Hz, 1H), 7.53 (t, J=7.5 Hz, 2H), 8.10 (d, J=2.7 Hz, 1H), 13.02 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:14][C:15]([NH2:17])=[S:16])[S:5][C:6]=1[C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=1.[ClH:18].[C:19](OCC)(=O)[CH3:20]>CN(C)C=O.O1CCOCC1.ICC>[ClH:18].[ClH:18].[CH3:1][C:2]1[N:3]=[C:4]([NH:14][C:15](=[NH:17])[S:16][CH2:19][CH3:20])[S:5][C:6]=1[C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=1
Reactant: Cc1ccnc(-c2sc(NC(N)=S)nc2C)c1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCI
Solvent: C1COCCO1
Product: CCSC(=N)Nc1nc(C)c(-c2cc(C)ccn2)s1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a suspension of N-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-yl)thiourea (529 mg) in N,N-dimethylformamide (10 ml) were added a solution of hydrogen chloride in 1,4-dioxane (4N, 1 ml) and iodoethane (0.8 ml), and the mixture was stirred at 70° C. for 4 hours. Ethyl acetate (100 ml) was added to the mixture, and the mixture was cooled. The precipitate was collected by filtration and purified by column chromatography (silica gel, triethylamine:methanol:dichloromethane=1:2:100). The combined fractions were evaporated under reduced pressure, and the residue was dissolved in ethyl acetate (5 ml). To the solution was added a solution of hydrogen chloride in 1,4-dioxane (4N, 1.25 ml). The precipitate was collected by filtration and dried under reduced pressure to give N-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-yl)-S-ethylisothiourea dihydrochloride (0.69 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:15])([CH3:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:5]=[C:4]([NH:16][C:17]([CH3:23])([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[N:3]=1.[CH:24]12[CH2:32][CH2:31][CH:28]([CH2:29][CH2:30]1)[CH2:27][NH:26][CH2:25]2>COCCOCCOC>[CH3:22][C:17]([NH:16][C:4]1[N:5]=[C:6]([NH:8][C:9]([CH3:15])([CH3:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=[C:2]([N:26]2[CH2:27][CH:28]3[CH2:31][CH2:32][CH:24]([CH2:30][CH2:29]3)[CH2:25]2)[N:3]=1)([CH3:23])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)C(C)(C)Nc1nc(Cl)nc(NC(C)(C)C(C)(C)C)n1
Reactant: C1CC2CCC1CNC2
Solvent: COCCOCCOC
Product: CC(C)(C)C(C)(C)Nc1nc(NC(C)(C)C(C)(C)C)nc(N2CC3CCC(CC3)C2)n1

Procedure:
A 10.25 g. portion of 2-chloro-4,6-bis[(1,1,2,2-tetramethylpropyl)amino]-s-triazine and 7.65 g. of 3-azabicyclo[3.2.2]nonane in 50 ml. of diglyme is heated at reflux for 3 hours and then cooled, giving a pink solid. This solid is collected, washed with diglyme, suspended in 500 ml. of water, stirred, filtered and washed with water giving a pink solid. This solid is recrystallized from ethanol (charcoal being employed in decolorization) to give the desired product m.p. 282°-284° C.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:30])[C:13]([O:21][CH2:22]/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:14][N:15]3[CH:18]([CH3:20])[CH3:19])=[CH:10][C:9]=2[F:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[C].[Rh].C(O)C>[CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:30])[C:13]([O:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:14][N:15]3[CH:18]([CH3:19])[CH3:20])=[CH:10][C:9]=2[F:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/COc1cn(C(C)C)c2cc(NC3CCCCC3)c(F)cc2c1=O
Agent: [Rh]
Solvent: CCO
Product: CCOC(=O)CCCOc1cn(C(C)C)c2cc(NC3CCCCC3)c(F)cc2c1=O
Yield: 71.8 %

Procedure:
To an 8.0 ml ethanol solution of 280 mg of ethyl (2E)-4-{[7-(cyclohexylamino)-6-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinolin-3-yl]oxy}but-2-enoate was added 28 mg of rhodium-carbon (10%) at room temperature, followed by stirring for 2 hours in an atmosphere of hydrogen. After filtration using celite, the filtrate was evaporated under a reduced pressure, and the residue was purified by silica gel column chromatography to obtain 202 mg of ethyl 4-{[7-(cyclohexylamino)-6-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinolin-3-yl]oxy}butanoate.
Reaction SMILES: [C:1]([N:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].CS(C)=O.C(N(CC)CC)C.N1C(=O)CC[C@H]1C(O)=O>ClCCl.CCCCCCC.C(OCC)(=O)C>[C:1]([N:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[O:19])[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C(=O)N(CCCCCCO)C(C)(C)C
Agent: O=C1CC[C@@H](C(=O)O)N1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CS(C)=O
Product: CCOC(=O)C(=O)N(CCCCCC=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
A solution of 1.1 g of 16f, in a mixture of 30 ml of dichloromethane, 15 ml of DMSO and 3 ml of triethyl amine, was treated with 1 g of Pyr.SO3 at 0° C. The reaction mixture was then stirred at RT for 2 hr. The mixture was partially concentrated and poured into water and the product was extracted with diethyl ether. The organic extract was washed with water, dried, concentrated and the crude material was purified by passing through a short silica column, to give 1.1 g of crude product, which was passed through silica gel, using a gradient of heptane/ethyl acetate as eluent, to provide 0.85 g of 16g as a colorless oil.
Reaction SMILES: C(OC1N=C2C(N=C(OC)N2CCCC2CCCCN2)=C(N)N=1)CCC.[NH2:27][C:28]1[N:36]=[C:35]([O:37][C@@H:38]([CH3:42])[CH2:39][CH2:40][CH3:41])[N:34]=[C:33]2[C:29]=1[N:30]=[C:31]([O:62][CH3:63])[N:32]2[CH2:43][CH2:44][CH2:45][CH:46]1[CH2:51][CH2:50][N:49](C(OCC2C=CC=CC=2)=O)[CH2:48][CH2:47]1>>[CH3:42][C@H:38]([O:37][C:35]1[N:34]=[C:33]2[C:29]([N:30]=[C:31]([O:62][CH3:63])[N:32]2[CH2:43][CH2:44][CH2:45][CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[C:28]([NH2:27])[N:36]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCNCC3)c2n1

Procedure:
Prepared similarly to Intermediate 32 from phenylmethyl 4-{3-[6-amino-2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-9-yl]propyl}-1-piperidinecarboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9].[Br:10]Br.[Cl-].[Al+3].[Cl-].[Cl-].S([O-])([O-])=O.[Na+].[Na+]>ClCCl.[Fe]>[Br:10][C:6]1[CH:5]=[CH:4][C:3]([S:8][CH3:9])=[C:2]([F:1])[CH:7]=1
Reactant: BrBr
Reactant: CSc1ccccc1F
Agent: [Fe]
Agent: O=S([O-])[O-]
Agent: [Al+3]
Solvent: ClCCl
Product: CSc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-fluorothioanisole (1.42 g, 10 mmol) and iron powder (0.03 g, 0.5 mmol) in dichloromethane (20 mL) was chilled to ° C. and treated dropwise with Bromine (0.5 mL, 10 mmol). Upon completion of the Bromine treatment, the reaction was sampled for TLC (100% hexanes). A new, higher Rf material was present but the reaction had not gone to completion so another equivalent of bromine was added along with a catalytic amount of aluminum chloride. The reaction mixture was stirred overnight at room temperature. Aqueous sodium sulfite was added to the reaction mixture and the organic layer was isolated, dried over MgSO4, and filtered. The filtrate was filtered through a pad of silica gel to remove color then concentrated under reduced pressure to provide the product as a clear, colorless oil (yield: 1.3 g; 60%). 1H NMR (300 MHz, DMSO-d6) δ 2.48 (s, 3H), 7.31 (t, J=9 Hz, 1H), 7.43 (dd, J=9 Hz, 3 Hz, 1H) 7.54 (dd, J=9 Hz, 3 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][N:5]=2.[Li][CH2:12]CCC.CC([O-])(C)C.[K+].CI>C(OCC)C>[CH2:1]([C:2]1[NH:3][C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[CH:10]=1)[CH3:12]
Reactant: Cc1cc2cccnc2[nH]1
Reactant: [Li]CCCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CI
Product: CCc1cc2cccnc2[nH]1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-methyl-7-azaindole (1.32 g, 10 mmol) in dry diethyl ether (60 ml) at room temperature under an inert atmosphere is added n-BuLi (18.8 ml of a 1.6 M solution in hexanes, 30 mmol) followed by t-BuOK (2.24 g, 20 mmol). The reaction mixture is stirred at room temperature for 40 minutes and then cooled to −70° C. whereupon methyl iodide (1.25 ml, 20 mmol) is added dropwise. Stirring continues for a further 2 hours after which time, the reaction mixture is quenched with water (2 ml) and is allowed to slowly warm to room temperature. The cooled solution is poured onto water (200 ml), neutralized with 1N HCl and then extracted with diethyl ether (80 ml). The organic portion is washed with water (2×60 ml), dried (Na2SO4) and concentrated in vacuo to yield the titled compound as orange crystals. [MH+CH3CN]+=188)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH3:14][C:15](=[CH:17][CH2:18][CH2:19][C:20](=[CH:22][CH:23]=[O:24])C)C.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([N:6]2[CH:10]=[CH:9][N:8]=[CH:7]2)[CH:23]([OH:24])[CH:22]=[CH:20][CH2:19][CH2:18][CH:17]=[CH:15][CH3:14])[CH:11]=[CH:12][CH:13]=1
Reactant: Clc1cccc(Cn2ccnc2)c1
Reactant: CC(C)=CCCC(C)=CC=O
Solvent: O
Solvent: C1CCOC1
Product: CC=CCCC=CC(O)C(c1cccc(Cl)c1)n1ccnc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
26 ml (40 mmol) of 1.55 molar n-butyllithium-hexane solution were added dropwise to a solution of 7.70 g (40 mmol) of N-(3-chlorobenzyl)-imidazole in 100 ml of absolute THF at -70° C. in the course of 15 minutes. The mixture was stirred for 30 minutes at -70° C., after which a solution of 6.10 g (40 mmol) of citral (cis/trans mixture) in 50 ml of absolute THF was added dropwise at -70° C., stirring was continued for 45 minutes at about -70° C., the mixture was allowed to warm up to room temperature in the course of about 2 hours, 300 ml of water were added, while cooling, and the mixture was extracted with CH2Cl2. The combined CH2Cl2 extracts were dried, filtered and evaporated down in vacuo. The residue (13.2 g) from the extract was chromatographed over a silica gel S/n-hexane column (diameter 2.5 cm, height 56 cm), with elution with hexane/ethanol mixtures having an increasing ethanol content (up to a maximum of 20% of ethanol). The course of the elution was monitored by means of thin layer chromatography. This showed that the desired compound was present in the form of 4 stereoisomers in similar amounts. Fractions which were shown to be pure by thin layer chromatography were combined and evaporated down in vacuo until the weight remained constant. In this way, 1.2 g of virtually pure stereoisomer (a), having the highest Rf value, were obtained. In addition, 8.2 g of a mixture of the stereoisomers (b), (c)≥(a), (d) were obtained. Finally, 2.6 g were eluted, which were found by thin layer chromatography to contain a high concentration of the stereoisomer (d) (lowest Rf value). This product was subjected to a second chromatography by the same procedure, over a silica S/hexane column (diameter 2 cm, height 22 cm). 1.2 g of a steroisomer (d) which was shown to be virtually completely pure by thin layer chromatography was obtained.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@H:8]([OH:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1.O[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:17]([CH3:28])[CH:16]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.CCCCP(CCCC)CCCC>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([C@@H:8]([O:13][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:17]([CH3:28])[CH:16]=2)[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[C@@H](O)c1cccc(Br)n1
Reactant: CCOC(=O)CCc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCC[C@H](Oc1ccc(CCC(=O)OCC)c(C)c1)c1cccc(Br)n1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
To a stirring solution of (1R)-1-(6-bromo-2-pyridinyl)-1-pentanol (261 mg, 1.07 mmol) and ethyl 3-(4-hydroxy-2-methylphenyl)propanoate (329 mg, 1.58 mmol) in THF (13 mL) at 0° C. under nitrogen was added ADDP (531 mg, 2.10 mmol) followed by tri-N-butylphosphine (0.525 mL, 2.10 mmol) drop-wise. The resulting mixture was then stirred with slow warming to ambient temperature over 15 h. The reaction mixture was then concentrated under vaccum and the solid residue purified directly by SPE (silica, 10 g cartridge) with a pad of celite on the top, eluting with cyclohexane:EtOAc (gradient 100:1 to 20:1) to afford the title compound (350 mg).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[CH2:16](Br)[C:17]#[CH:18]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.C(OCC)C>[C:8]1([N:7]([CH2:18][C:17]#[CH:16])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: C#CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CCN(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.7 %

Procedure:
To a well-stirred mixture of diphenylamine (50 g, 0.3 mol), powdered potassium hydroxide (43 g, 0.65 mol) and tetrabutylammonium bromide (4.7 g, 0.015 mol) in 500 ml of tetrahydrofuran is added dropwise with cooling propargyl bromide (42 g, 0.35 mol). The resulting mixture is stirred at room temperature for one hour and then at 60° C. for ten hours. The mixture is cooled, diluted with diethyl ether and then filtered. The solvent is removed from the filtrate in vacuo to give a black oil. Distillation of said oil gives a fraction boiling at 105-107 at 0.4 torr. Said fraction is then chromatographed (silica gel, hexane) to give 16 g (27% yield) of the title compound as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH2:30]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:30][CH2:29][CH2:28][N:27]([CH3:31])[CH3:26])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: CN(C)CCN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCN(C)C)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and N,N-dimethylethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CD3OD) δ ppm 8.05-8.01 (m, 3 H), 7.88-7.86 (d, J=8.8 Hz, 1 H), 7.70-7.68 (d, J=1.2 Hz, 1 H), 7.56-7.52 (m, 2 H), 6.05 (s, 1 H), 5.41 (s, 2 H), 4.56 (s, 2 H), 3.96-3.93 (dd, J=6.0, 6.4 Hz, 2 H), 3.75-3.73 (q, J=4.4 Hz, 2 H), 3.43-3.40 (q, J=6.0 Hz, 2 H), 3.01 (s, 3 H), 2.45 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]([C:13](=[O:15])[CH3:14])[C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[CH3:16].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]([C:13](=[O:15])[CH3:14])[C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[CH2:16][Br:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)N(C(C)=O)c1cc(C)c(Cl)cc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)N(C(C)=O)c1cc(CBr)c(Cl)cc1F
Yield: 7.9 %

Procedure:
A mixture of 7.8 g (0.032 mole) of 2-chloro-4-fluoro-5-diacetylaminotoluene, 6.2 g (0.035 mole) of N-bromosuccinimide, 0.5 g of benzoyl peroxide, and 200 ml of carbon tetrachloride was heated at reflux for two days. This mixture was filtered, and the filtrate was washed with water. The filtrate was dried, and the solvent was evaporated under reduced pressure. The residue was passed through a column of silica gel, eluting with ethyl acetate/heptane (1/4). Appropriate fractions were combined, and the solvent was evaporated under reduced pressure, yielding 0.82 g of 2-chloro-4-fluoro-5-diacetylaminobenzyl bromide. The nmr was consistent with the proposed structure.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@H:8]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[O:24])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](Cc1ccccc1)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
A solution of {(R)-1-benzyl-2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-ethyl}-carbamic acid tert-butyl ester (1.12 g, 2.54 mmol) and trifluoroacetic acid (3 ml) in dichloromethane (6 ml) is stirred at ambient temperature for 3 hours. The solvent is evaporated and the residue takenup in hydrochloric acid (2M), washed with ethylacetate and basified with sodium hydroxide solution (4M) to pH8-9. The suspension is extracted with dichloromethane, the dichloromethane dried over magnesium sulphate and the solvent evaporated to afford [1-((R)-2-amino-3-phenyl-propyl)-piperidin-4-yl]-(4-fluoro-phenyl)-methanone. [MH]+341.7.
Reaction SMILES: C([N:8]1[C@@H:13]2[C@H:14]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:15][C@@:9]1([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@@H:10]([O:25][CH2:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=1)[CH:11]=[CH:12]2)C1C=CC=CC=1>[Pd].C(O)C>[F:36][C:33]([F:34])([F:35])[C:31]1[CH:32]=[C:27]([CH2:26][O:25][C@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:15][C@H:14]3[S:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:28]=[C:29]([C:37]([F:40])([F:38])[F:39])[CH:30]=1
Reactant: O=S(=O)(c1ccccc1)[C@@H]1C[C@@]2(c3ccccc3)[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C=C[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=S(=O)(c1ccccc1)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A mixture of (1R*,2S*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]oct-3-ene (Description 6; 390 g, 0.59mol), 10% palladium on charcoal (473 mg) and ethanol (25 ml) was stirred under hydrogen atmosphere (1 atm) at +70° C. for 2 hours and at room temperature overnight. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated and purified by flash chromatography to give the title compound (250 mg, 74%). The hydrochloride salt of the title compound was prepared by treatment with ethereal HCl and recrystallized from dichloromethane-ether.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[NH:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH3:13])=[CH:6][CH:5]=1)([O-])=O.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH:10]([NH:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH3:13])[C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(C(NC(C)c2ccc(F)c(F)c2)c2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(NC(C)c2ccc(F)c(F)c2)c2ccc(N)cc2)cc1

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[(4-nitrophenyl)-(4-methoxyphenyl)methyl]-N-[1-(3,4-difluorophenyl)ethyl]amine (3.20 g) [prepared as described in step (a) above] in methanol (60 ml), nickel chloride hexahydrate (3.82 a) and sodium borohydride (1.21 g) were reacted and purified, to afford the less polar isomer A (720 mg) as a pale yellow oil and the more polar isomer B (805 mg) as a pale yellow oil of the title compound.
Reaction SMILES: O[C:2]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)([CH3:11])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>O>[CH2:11]=[C:2]([CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]1)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(C)(O)C#Cc2ccccc2)CC1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: O
Product: C=C(C#Cc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C

Procedure:
A well homogenised mixture of Compound 253a (0.3 g, 0.911 mmol) and Burgess' reagent (Methyl N-(triethylammoniumsulphonyl)carbamate) (0.35 g, 1.49 mmol) was heated at 60° C. for 2 h. Afterwards, the reaction mixture was cooled, poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with Petroleum Ether-EtOAc 95:5, affording the title products as an oily mixture.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH3:10][CH:11]1[CH2:16][C:15](=[O:17])[O:14][C:13](=[O:18])[CH2:12]1.C1(C)C=CC=CC=1.CS(C)=O>O>[C:8]([C:5]1[N:6]=[CH:7][C:2]([NH:1][C:15]([CH2:16][CH:11]([CH3:10])[CH2:12][C:13]([OH:18])=[O:14])=[O:17])=[CH:3][CH:4]=1)#[N:9]
Reactant: N#Cc1ccc(N)cn1
Reactant: CC1CC(=O)OC(=O)C1
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)nc1
Yield: 48.2 %

Procedure:
A solution of 5-aminopyridine-2-carbonitrile (300.0 mg, 2.518 mmol) and 4-methyldihydro-2H-pyran-2,6(3H)-dione (354.931 mg, 2.77 mmol) in a mixed solvent of toluene (7 mL) and DMSO (0.7 mL) was stirred at 110° C. for 16 hr. To the reaction mixture was added cold water, and the mixture was extracted with ethyl acetate (4×30 mL). The organic layer was washed with water, and dried, and the solvent was evaporated under reduced pressure. The obtained solid was washed with 50% dichloromethane/hexane solution to give 4-(6-cyanopyridin-3-ylcarbamoyl)-3-methylbutyric acid (300 mg, 48.2%) as a pale-yellow powder.