Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[N:11]=2)[CH:5]=[CH:4][C:3]=1[O:26][CH2:27][C:28]([O:30]CC)=[O:29].[OH-].[Na+].Cl.CCOC(C)=O>C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=3)[N:11]=2)[CH:5]=[CH:4][C:3]=1[O:26][CH2:27][C:28]([OH:30])=[O:29]
Reactant: CCOC(=O)COc1ccc(SCc2cccc(-c3ccc(C(F)(F)F)cc3)n2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(SCc2cccc(-c3ccc(C(F)(F)F)cc3)n2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of ethyl ({2-methyl-4-[({6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}methyl)thio]phenyl}oxy)acetate (367 mg, 0.80 mmol) in THF (5 mL) was treated with aqueous NaOH (2M, 5 mL) and the resulting solution stirred at rt for 4 hours. The mixture was poured into a mixture of aqueous HCl (2M) and EtOAc and the layers separated. The organic layer was then washed with water and brine, dried MgSO4, filtered and then reduced under vacuum. Purification by mass-directed auto-prep HPLC afforded the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]3[C:19]=2[CH3:20])=[CH:4][C:3]=1[OH:21].[CH3:22][N:23]=[C:24]=[O:25].C(OCC)(=O)C>O1CCCC1.CO>[CH3:20][C:19]1[N:13]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]2=[N:11][C:10]=1[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:24]([NH:23][CH3:22])=[O:25])=[C:3]([OH:21])[CH:4]=1
Reactant: Cc1ccn2c(C)c(CCc3ccc(N)c(O)c3)nc2c1
Reactant: CN=C=O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(CCc2nc3cc(C)ccn3c2C)cc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of 2-[2-(4-amino-3-hydroxyphenyl)ethyl]-3,7-dimethylimidazo[1,2-a]pyridine (2.5 g) and methyl isocyanate (0.6 ml) in tetrahydrofuran (25 ml) and methanol (2.5 ml) was stirred for 1 hour at ambient temperature. To the reaction mixture was added ethyl acetate (30 ml) and the precipitate was collected by filtration. The precipitate was washed with ethyl acetate and dried to give 3,7-dimethyl-2-[2-{3-hydroxy-4-(3-methylureido)phenyl}ethyl]imidazo[1,2-a]pyridine (2.92 g).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=C(Cl)N=[C:10]([NH:15][C:16]2[C:21]([C:22]#[C:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][C:19]([CH3:28])=[CH:18][N:17]=2)[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>BrC1C=CC=CC=1>[CH2:1]([N:8]1[CH:13]=[C:23]([Si:24]([CH3:26])([CH3:25])[CH3:27])[C:22]2[C:21]3[CH:20]=[C:19]([CH3:28])[CH:18]=[N:17][C:16]=3[NH:15][C:10]=2[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cnc(Nc2nc(Cl)cn(Cc3ccccc3)c2=O)c(C#C[Si](C)(C)C)c1
Solvent: Brc1ccccc1
Product: Cc1cnc2[nH]c3c(=O)n(Cc4ccccc4)cc([Si](C)(C)C)c3c2c1
Temperature: 140 °C
Reaction time: 7 h
Yield: 83.4 %

Procedure:
Compound 27 (3.5 g, 8.29 mmol) was dissolved in bromobenzene (150 mL). The solution was heated at 140° C. under N2 and monitored by LC every hour. The reaction was complete after 7 hours. The solution was evaporated and purified by flash chromatography (3% MeOH/CH2Cl2) to give 2.5 g (83%) of intended product as a tan solid. 1H NMR (400 MHz, CDCl3): δ 8.22 (s, 1H), 7.27-7.39 (m, 6H), 5.40 (s, 2H), 2.57 (s, 3H). MS (ES) [m+H] calc'd for C21H23N3OSi, 362; found 362.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:23]O)=[N:20][C:21]=3[CH3:22])[N:12]=2)=[CH:7][C:6]=1[CH3:25])[CH:2]([CH3:4])[CH3:3].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:51]1[CH2:54][CH:53]([C:55]([O:57][CH3:58])=[O:56])[CH2:52]1.C(N(CC)C(C)C)(C)C>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:23][N:51]4[CH2:54][CH:53]([C:55]([O:57][CH3:58])=[O:56])[CH2:52]4)=[N:20][C:21]=3[CH3:22])[N:12]=2)=[CH:7][C:6]=1[CH3:25])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1cc(-c2nc(-c3ccc(CO)nc3C)no2)ccc1CC(C)C
Reactant: COC(=O)C1CNC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(Cc2ccc(-c3noc(-c4ccc(CC(C)C)c(C)c4)n3)c(C)n2)C1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 23 (23g) using {5-[5-(4-isobutyl-3-methylphenyl)-1,2,4-oxadiazol-3-yl]-6-methylpyridin-2-yl}methanol (0.14 g, 0.43 mmol) that was obtained in Example 27 (27e), carbon tetrabromide (0.29 g, 0.86 mmol), triphenylphosphine (0.23 g, 0.86 mmol), methyl 3-azetidinecarboxylate hydrochloride (98 mg, 0.65 mmol), and N,N-diisopropylethylamine (0.22 ml, 1.3 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (2:1 to 3:1) as the eluent to afford the title compound (0.12 g) in a yield of 66% as a colourless oily product.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=1[OH:19])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[CH3:27]>C(#N)C>[CH2:26]([O:19][C:10]1[CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:14][C:9]=1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2])[CH3:27]
Reactant: CCBr
Reactant: CCc1ccccc1-c1ccc(C(=O)OC)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1cc(C(=O)OC)ccc1-c1ccccc1CC
Temperature: 50 °C

Procedure:
To a stirred solution of methyl 2′-ethyl-2-hydroxybiphenyl-4-carboxylate (3.13 g, 12.2 mmol) in anhydrous ACN (45 mL) was added anhydrous potassium carbonate (5.05 g, 36.6 mmol) followed by ethyl bromide (4.5 mL, 61 mmol). The reaction mixture was heated at 50° C. for 15 hours, and then cooled to RT and filtered. The filtrate was concentrated under vacuum. The oil was taken up with MTBE, treated with activated charcoal, filtered through a Celite pad and concentrated. After purification by flash chromatography (silica, heptane/EtOAc), the title compound was obtained as a colorless oil (2.73 g, 79%). HPLC (Method A) Rt 5.4 min (Purity: 99.7%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:14][CH2:15][N:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH2:17][CH2:18]Cl.O>CS(C)=O>[Cl:1][C:2]1[C:3]([C:8]2([C:9]#[N:10])[CH2:18][CH2:17][N:16]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[CH2:15][CH2:14]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1ncccc1Cl
Reactant: COc1ccc(CN(CCCl)CCCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CN2CCC(C#N)(c3ncccc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A solution of 3-chloro-2-pyridylacetonitrile [prepared by the method described in JP08295663] (1.46 g, 9.57 mmol) in DMSO (19 mL) was slowly added to NaH (60% oil dispersion, 1.01 g, 25.3 mmol), and the mixture was stirred at room temperature for 1 h. A solution of N,N-bis(2-chloroethyl)-p-methoxybenzylamine (2.21 g, 8.43 mmol) in DMSO (19 ml,) was added, and the resulting mixture was stirred at 75° C. for 4 h. After cooling, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried (Na2SO4), and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/2) to give 4-(3-chloro-2-pyridyl)-4-cyano-1-(4-methoxyphenyl)methylpiperidine 1 (1.91 g, 60%) as an orange oil.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:14]1(C)C=CC=CC=1>>[ClH:1].[CH3:14][O:12][C:11](=[O:13])[C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:2]
Reactant: Cc1ccccc1
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](N)Cc1ccccc1
Temperature: 27.5 °C
Reaction time: 49 h

Procedure:
To a 20% solution of ethanolic HCl (75 ml), was charged D-Phenyl alanine (15 grams, 0.090 moles). The reaction mass was further stirred for 48 to 50 hours at 25-30° C. (the reaction does not go to completion, shows 10-12% of unreacted D-Phenyl alanine) and concentrated at 50° C. under reduced pressure to form the residue. The residue was stirred in toluene (100 ml). The solid was isolated by filtration, washed with toluene (2×25 ml) and dried at 50-55° C. under vacuum to yield the desired product.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH3:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[CH3:35].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:31]2[CH:32]=[CH:33][C:34]([CH3:35])=[C:29]([CH3:28])[CH:30]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(B(O)O)cc1C
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1nc(C)n(-c2ccc(C)c(C)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 3,4-dimethylphenylboronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.27 g, 98%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[NH2:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][OH:45]>CCO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][OH:45])=[O:34])[C:15]1=[O:38]
Reactant: NCCOCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Solvent: CCO
Product: O=C(NCCOCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Temperature: 25 °C

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.025 g, 0.049 mmol) in EtOH (1 mL) under nitrogen was treated with 2-[(2-aminoethyl)oxy]ethanol (0.0042 mL, 0.058 mmol) for 10 min.@150° C. in a microwave vessel. An additional 0.001 mL of the amine was added to the reaction and it was further microwaved for 20 min.@150° C. The reaction was then cooled to ambient temperature and the resulting suspension was filtered, washed with 1:1 water:EtOH and then thoroughly dried under high vacuum to provide the title compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 3.35-3.44 (m, 6 H), 3.44-3.51 (m, 2 H), 3.90 (t, J=5.05 Hz, 2 H), 4.11 (s, 2 H), 4.50-4.62 (m, 3 H), 7.08-7.17 (m, 2 H), 7.30-7.38 (m, 2 H), 7.82 (s, 4 H), 8.14 (s, 1 H), 8.52 (s, 1 H), 10.02 (m, 1 H), 17.11 (s, 1 H); ES+ MS: 575 (M+H+).
Reaction SMILES: [CH:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1NCC(C2CCCCC2)c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1[nH]cc(C2CCCCC2)c2ccccc12
Reaction time: 1.25 h

Procedure:
50 g of 4-cyclohexyl-3,4-dihydro-2H-isoquinoline-1-one and 20 l g of methanol-wet 30% Pd/C were heated while to 220° C in a stream of argon. Thin-layer chromatographic analysis revealed that the reaction was practically completed after 75 minutes. The product was dissolved in chloroform, the catalyst was separated and the organic phase was evaporated. After recrystallization from acetone, colorless crystals were obtained. M.p. 111° to 112° C
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[NH2:33][C:34]1[CH:35]=[CH:36][C:37]([F:48])=[C:38]([C:40]2([CH3:47])[CH2:45][O:44][CH2:43][C:42]([NH2:46])=[N:41]2)[CH:39]=1.[OH-].[Na+]>CO>[NH2:46][C:42]1[CH2:43][O:44][CH2:45][C:40]([C:38]2[CH:39]=[C:34]([NH:33][C:11]([C:8]3[CH:7]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[O:10][N:9]=3)=[O:13])[CH:35]=[CH:36][C:37]=2[F:48])([CH3:47])[N:41]=1
Reactant: O=C(O)c1cc(-c2ccco2)on1
Reactant: CC1(c2cc(N)ccc2F)COCC(N)=N1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(c2cc(NC(=O)c3cc(-c4ccco4)on3)ccc2F)COCC(N)=N1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-furan-2-yl-isoxazole-3-carboxylic acid (CAS 98434-06-1) (77.3 mg, 0.42 mmol) in methanol (2 ml) was cooled to 0° C. 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMTMM) (135 mg, 0.46 mmol) was added and the mixture stirred at 0° C. for 10 minutes. Thereafter, a solution of (RS)-5-(5-amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine (85 mg, 0.38 mmol) in methanol (1 ml) was added and the reaction mixture stirred at 0° C. for 2 hours, then kept at 4° C. for 16 hours. For the workup, the reaction mixture was treated at 0° C. with sodium hydroxide (1 N, 6 ml). The yellow suspension was extracted with ethyl acetate (15 ml), then the aqueous layer re-extracted with ethyl acetate (10 ml). The combined organic layers were dried over sodium sulfate and evaporated at reduced pressure. After chromatography on a Silicycle-Si-amine phase using a gradient of dichloromethane and methanol=100/0 to 90/10 the 5-furan-2-yl-isoxazole-3-carboxylic acid [3-((RS)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide was obtained as a white sold (16 mg, 11% of theory). Mass (calculated) C19H17FN4O4 [384.365]; (found) [M+H]+=385.
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.CC(N=NC(C#N)(C)C)(C#N)C>C1(C(F)(F)F)C=CC=CC=1>[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: BrC12CC3CC(CC(C3)C1)C2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: FC(F)(F)c1ccccc1
Product: C1C2CC3CC1CC(C2)C3

Procedure:
To a stirred solution of 1-bromoadamantane (100 mg, 0.46 mmol) and tris (2-perfluorohexyl)ethyltin hydride (640 mg, 0.55 mmol) in benzotrifluoride (9.2 mL) was added a catalytic amount of AIBN. The reaction mixture was heated at reflux temperature for 3 h. The solvent was evaporated and the crude residue was partitioned between dichloromethane (20 mL) and perfluoromethylcyclohexane (10 mL). The two layers were separated and the dichloromethane phase was concentrated yielding adamantane as a pure compound (56 mg, 90%).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[C:7]([Cl:11])=[CH:6][C:3]=1[C:4]#[N:5].CCN(C(C)C)C(C)C.[CH:21]1([C:24]2[NH:28][N:27]=[C:26]([NH2:29])[CH:25]=2)[CH2:23][CH2:22]1>CCCCO>[Cl:1][C:2]1[N:9]=[C:8]([NH:29][C:26]2[CH:25]=[C:24]([CH:21]3[CH2:23][CH2:22]3)[NH:28][N:27]=2)[C:7]([Cl:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: N#Cc1cc(Cl)c(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: N#Cc1cc(Cl)c(Nc2cc(C3CC3)[nH]n2)nc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
To a solution of 2,5,6-trichloronicotinonitrile (Method 44, 1.0 g, 4.8 mmol) and DIEA (0.81 g, 6.2 mmol) in n-BuOH (5 ml) was added 5-cyclopropyl-1H-pyrazol-3-amine (2.3 g, 19.3 mmol). The reaction was heated to 60° C. for 2 hours, at which point the reaction was cooled to room temperature and concentrated. The resulting residue was diluted with 10 ml ACN, and stored at 0° C. for 1 hour. The solids that formed were then filtered, washed with cold ACN, dried and collected to give the title compound (0.62 g, 43%). MS: Calcd.: 294. Found: [M+H]+ 295.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13]C)[CH:8]=2)[CH2:4][N:3]1[CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>Br>[CH3:1][C@H:2]1[CH2:6][C@@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=2)[CH2:4][N:3]1[CH2:15][CH2:16][CH3:17]
Reactant: CCCN1CC(c2cccc(OC)c2)CC1C
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCN1C[C@H](c2cccc(O)c2)C[C@@H]1C
Yield: 69.4 %

Procedure:
2-Methyl-4-(3-methoxyphenyl)-N-n-propylpyrrolidine (cis and trans mixture 85: 15, 920 mg, 3.95 mmol) was dissolved in 47% hydrobromic acid (20 mL) and heated at reflux temperature for 1.5 hours. The mixture was made alkaline by the addition of 10% sodium carbonate (75 mL) and the product extracted with diethyl ether and ethyl acetate (1:1,3×20 mL). Drying (MgSO4) afforded 840 mg of the crude product as a white solid. Chromatography on a SiO2HPLC column yielded 601 mg of the title compound.: m.p. 123°-24° C.; MS (EI) m/e calc'd for C14H21NO: 219.162, found 219.163; 219.15 (10, M+), 204.05 (47), 191.05 (14), 190.05 (100), 161.05 (6), 133.05 (6), 106.95 (8), 90.95 (6), 84.05 (12).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8].[CH:12](OCC)=[O:13]>C1(C)C=CC=CC=1>[CH:12]([NH:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:13]
Reactant: COc1cccc(CCN)c1
Reactant: CCOC=O
Solvent: Cc1ccccc1
Product: COc1cccc(CCNC=O)c1
Yield: 99.9 %

Procedure:
A solution of 25 Kg of 3-methoxyphenethylamine, 9 Kg of toluene and 23 Kg of ethyl formate was heated to reflux (62°-76° C.) for 6 hours. The volatile components were removed under vacuum, the residue treated with a further 9 Kg of toluene and the solvent removed under vacuum, leaving 29.6 Kg of N-formyl-3-methoxy-phenethylamine as a pale yellow oil.
Reaction SMILES: Cl.[Cl:2]C1C=C([C:9]2([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[OH:15])C=CC=1.[Cl:26][C:27]1[CH:28]=[C:29](C2(CN(C)C)CCCCC2=O)[CH:30]=[CH:31][CH:32]=1.N.C1([Mg]Cl)C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1.O>[ClH:2].[Cl:26][C:27]1[CH:32]=[C:31]([CH:22]([N:23]([CH3:24])[CH3:25])[CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[OH:15])[CH:30]=[CH:29][CH:28]=1
Reactant: CN(C)CC1(c2cccc(Cl)c2)CCCCC1=O
Reactant: CN(C)CC1(c2cccc(Cl)c2)CCCCC1(O)c1ccccc1
Agent: Cl
Agent: Cl[Mg]c1ccccc1
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(c1cccc(Cl)c1)C1CCCCC1(O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.2 %

Procedure:
The base was freed from 2.5 g (8.27 mmole) of the hydrochloride of 2-[(3-chlorophenyl)(dimethylaminomethyl]cyclohexanone obtained according to stage 1 with 30 ml of water and 5 ml of ammonia solution (25 vol. %), extracted three times with 30 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to 10 mbar). 2.0 g (7.5 mmole) of this base were dissolved in 5 ml of tetrahydrofuran, added dropwise while cooling in an ice bath to 4.5 ml (9.0 mmole) of phenylmagnesium chloride (2 M solution in tetrahydro-furan), and the whole was stirred for 15 hours at RT. The reaction mixture was worked up by adding 10 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 15 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 2.30 g of crude base (88.8% of theory) were obtained, from which 2.18 g of 2-[(3-chlorophenyl)dimethylaminomethyl]-1-phenylcyclohexanol, hydrochloride (76.2% of theory) were obtained according to the procedure described in Example 1 (3rd stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 139° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([O:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])=[O:4].[H][H]>[Pd]>[F:1][C:2]([F:14])([F:15])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:4]
Reactant: [H][H]
Reactant: C=CCCCCC=COC(=O)C(F)(F)F
Agent: [Pd]
Product: CCCCCCCCOC(=O)C(F)(F)F

Procedure:
The resultant 1,7-octadienyl trifluoroacetate was hydrogenated at 150 psig of hydrogen at ambient temperature using 5% palladium on BaSO4 to produce trifluoroacetoxyoctane.
Reaction SMILES: [CH3:1][C:2]1[S:13][C:5]2[N:6]=[C:7]([O:11][CH3:12])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:32][C:33]1[CH:34]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1>C1COCC1>[Cl:32][C:33]1[CH:34]=[C:35]([S:39]([NH:10][C:9]2[CH:8]=[C:7]([O:11][CH3:12])[N:6]=[C:5]3[S:13][C:2]([CH3:1])=[C:3]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=4)[C:4]=23)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: COc1cccc(-c2c(C)sc3nc(OC)cc(N)c23)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(-c2c(C)sc3nc(OC)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 25 °C
Yield: 42.1 %

Procedure:
To a solution of 2-methyl-6-(methyloxy)-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (Description 37) (16.5 mg, 0.055 mmol) in THF (0.5 mL) at −78° C. under a nitrogen atmosphere was added LiHMDS (1M solution in THF) (0.055 mL, 0.055 mmol). The solution was stirred at −78° C. for ca. 10 min before the addition of 3-chlorobenzenesulfonyl chloride (7.73 μL, 0.055 mmol). The reaction mixture was then warmed to RT under a nitrogen atmosphere overnight and was then partitioned between water and ethyl acetate (ca. 10 mL each). The aqueous layer was separated and re-extracted with ethyl acetate (ca. 10 mL). The combined organic layer was passed through phase separator and the solvent concentrated in vacuo. The residue was purified by MDAP (acidic conditions), to give the title compound (11 mg). LCMS (A) m/z: 475 [M+1]+, Rt 1.63 min (acidic).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH:28]1([CH2:31][C:32](O)=[O:33])[CH2:30][CH2:29]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][CH:28]5[CH2:30][CH2:29]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: O=C(O)CC1CC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(CC1CC1)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (11.5 mg, 51%), MS (ISP) m/z=414.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (20 mg, 0.0543 mmol) and 2-cyclopropylacetic acid.