Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:9]([NH2:11])[CH3:10])=[N:6][C:7]=1[CH3:8].Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)[C:16]([Cl:28])=[CH:15][N:14]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:28][C:16]1[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)=[N:18][C:13]([NH:11][CH:9]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:7]([CH3:8])[N:6]=2)[CH3:10])=[N:14][CH:15]=1
Reactant: Clc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Reactant: Cc1nc(C(C)N)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1nc(C(C)Nc2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)ccc1F
Temperature: 175 °C
Yield: 27.5 %

Procedure:
A microwave reaction vessel was charged with [1-(5-fluoro-6-methylpyridin-2-yl)ethyl]amine (Method 13; 159 mg, 1.03 mmol), 2,5-dichloro-4-(5-cyclopropyl-1H-pyrazole-3-ylamino)pyrimidine (Method 7; 335 mg, 1.24 mmol) and DIEA (0.35 ml, 2.0 mmol). Anhydrous n-BuOH (1.5 ml) was added, and the tube was sealed and heated in a microwave reactor at 175° C. for 10 hours. The resulting mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc, and the combined organics were washed with brine, dried, filtered, chromatography (Rf in 50:50 hexanes:EtOAc=0.25) to afford the title compound as a colourless solid (110 mg, 28%). 1H NMR (400 MHz, CDCl3) δ 0.65-0.75 (m, 2H), 0.85-0.95 (m, 2H), 1.47 (d, J=6.8 Hz, 3H), 1.82 (tt, J=8.5, 5.1 Hz, 1H), 2.46 (d, J=2.8 Hz, 3H), 4.99-5.09 (m, 1H), 6.01 (s, 1H), 6.26 (s, 1H), 7.05 (dd, J=8.3, 3.5 Hz, 1H), 7.15-7.23 (m, 1H), 7.38-7.48 (m, 1H), 7.84 (s, 1H). Calcd.: 387. Found [M+H+] 388.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:10]=1[CH3:11])[C:7]([OH:9])=[O:8].[CH2:12](O)[CH3:13].CCN=C=NCCCN(C)C.OP([O-])(O)=O.[K+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:10]=1[CH3:11])[C:7]([O:9][CH2:12][CH3:13])=[O:8]
Reactant: CCO
Reactant: Cc1c(Br)cncc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: O=P([O-])(O)O
Solvent: ClCCl
Product: CCOC(=O)c1cncc(Br)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a stirred light brown suspension of 5-bromo-4-methylnicotinic acid (10.00 g, 46.3 mmol) and ethanol (2.97 mL) in DCM (231 mL) at 0° C. under argon was added EDCI (10.9 g, 55.5 mmol) and DMAP (566 mg, 4.63 mmol); stirring was continued overnight and the reaction mixture was allowed to warm up to room temperature. The reaction mixture was then poured on aq. 10% KH2PO4 solution followed by extraction with AcOEt (3×). The organic phases were washed once with aq. 10% KH2PO4, with sat. NaHCO3 and with aq. sat. NaCl solution. The combined organic phases were dried (Na2SO4), filtered and evaporated to afford the title compound (9.49 g, 84%) as brown solid. MS: 244.0 (M+H+, 1Br).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[I-].[CH3:20][N+]1C=CC=CC=1.[BH4-].[Na+]>>[C:1]1([CH2:7][CH2:8][C:9]([C:11]2[CH2:12][N:13]([CH3:20])[CH2:14][CH2:15][CH:16]=2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CCc1ccccc1)c1cccnc1
Reactant: C[n+]1ccccc1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CI
Product: CN1CCC=C(C(=O)CCc2ccccc2)C1

Procedure:
Employing the general methods of Examples 4 and 6 above, 10 g (47.3 mmol) of 3-phenyl-1-(3-pyridinyl)-1-propanone was first converted by the action of methyl iodide to the N-methylpyridinium iodide and then reduced by the action of sodium borohydride to produce 3-phenyl-1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)-1-propanone which was isolated as the hydrochloride salt (5.2 g, 58%), mp 195°-197° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:12])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:13][C:14](OC(C)=O)=[O:15].O>CC(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:12][C:14](=[O:15])[CH3:13])[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Bromo-5-(trifluoromethyl)phenylamine (5 g, Alfa-Aesar) was dissolved in AcOH (140 ml) and Ac2O (5.9 ml, Aldrich) was added. The reaction was stirred at RT overnight. The mixture was added slowly to H2O (˜700 ml) forming a white precipitate. The solid was isolated by filtration, washed with H2O and dried under vacuum to yield N-(3-bromo-5-trifluoromethyl-phenyl)-acetamide.
Reaction SMILES: Cl.C([NH:4][C:5]1[N:10]=[C:9]([C:11](=[N:35][O:36][CH2:37][C:38]#[CH:39])[C:12]([NH:14][CH:15]2[C:33](=[O:34])[N:17]3[C:18]([C:30]([OH:32])=[O:31])=[C:19]([CH:22]([S:24][C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH3:23])[CH2:20][S:21][C@H:16]23)=[O:13])[CH:8]=[CH:7][CH:6]=1)=O>CO>[NH2:4][C:5]1[N:10]=[C:9]([C:11](=[N:35][O:36][CH2:37][C:38]#[CH:39])[C:12]([NH:14][CH:15]2[C:33](=[O:34])[N:17]3[C:18]([C:30]([OH:32])=[O:31])=[C:19]([CH:22]([S:24][C:25]4[NH:26][N:27]=[N:28][N:29]=4)[CH3:23])[CH2:20][S:21][C@H:16]23)=[O:13])[CH:8]=[CH:7][CH:6]=1
Reactant: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1cccc(NC=O)n1
Agent: Cl
Solvent: CO
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1cccc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
Conc. Hydrochloric acid (0.43 ml.) was added to a solution of 7-[2-(6-formamidopyridin-2-yl)-2-propargyloxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer) (2.35 g.) in methanol (15 ml.), and the mixture was stirred at ambient temperature for 30 minutes. The methanol was removed by distillation under reduced pressure from the reaction mixture, and the remaining aqueous solution was diluted with water (100 ml.) and then adjusted to pH 2 with an aqueous solution of sodium bicarbonate. The precipitating crystals were collected by filtration, washed with water and then dried to give 7-[2-(6-aminopyridin-2-yl)-2-propargyloxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer) (1.05 g.), mp. 163°-165° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[CH2:27]([O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)[CH:28]([CH3:30])[CH3:29].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>[CH2:27]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N:3]2[C:4](=[O:26])[C:5]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=[C:2]2[CH3:1])=[CH:34][CH:33]=1)[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)COc1ccc(B(O)O)cc1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1nc(C)n(-c2ccc(OCC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), (4-isobutoxyphenyl)boronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (3.0 g) in methylene chloride (10 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred at room temperature 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 (1.30 g, 91%).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.CCO.C(OCC)(=O)C>[Pd].C(O)(=O)C>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(Nc1nccs1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccc(C(=O)Nc2nccs2)cc1
Reaction time: 72 h

Procedure:
4-Nitro-N-thiazol-2-yl-benzamide (28 mmol) was suspended in abs. EtOH (400 mL) and ethyl acetate (200 mL) and glacial acetic acid (50 mL) was added followed by 10% Pd/C (0.5 g). The mixture was hydrogenated for 72 h at 3 bar H2. The hydrogenation mixture was filtered, and the solvent was removed under reduced pressure. The crude product was added NaHCO3 (sat.) and ethyl acetate, the remaining solid fraction was removed by filtration and dried in vacuo. The liquid phases were separated, the organics were washed with brine, dried over MgSO4, filtered and evaporated to yield a solid. The solid fractions were combined.
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1([C:16](O)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+].Cl.C(N=C=NCCCN(C)C)C>C(OCC)(=O)C.O>[CH:1]1([C:6]2[O:7][C:16](=[O:17])[C:10]3([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1(C(=O)O)CCCCC1
Reactant: O=C(Cl)C1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1OC(C2CCCC2)=NC12CCCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.5 %

Procedure:
1.98 g (15 mmol) of cyclopentanecarbonyl chloride was added to a solution of 2.16 g (15 mmol) of 1-aminocyclohexanecarboxylic acid and 4.8 g (45 mmol) of sodium carbonate in 50 ml of ethyl acetate-50 ml of water under ice-cooling. After the mixture was stirred at room temperature overnight, ethyl acetate was added thereto, and the mixture was washed with a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium bicarbonate solution and then saturated brine. After the obtained organic layer was washed with saturated brine, it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, methylene chloride was added thereto, and 1.59 g (8.3 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added under ice-cooling. After the mixture was stirred at room temperature overnight, the reaction solution was concentrated under reduced pressure, ethyl acetate was added thereto, and the mixture was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.41 g (42%) of the title compound.
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:20])[C@:6]1([CH3:19])[CH2:10][C@@H:9]([OH:11])[CH2:8][N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>C1COCC1.O>[C:12]([N:7]1[CH2:8][C@H:9]([O:11][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([Br:21])=[CH:23][CH:24]=2)[CH2:10][C@@:6]1([CH3:19])[C:5]([OH:4])=[O:20])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: BrCc1ccc(Br)cc1
Reactant: COC(=O)[C@]1(C)C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccc(Br)cc2)C[C@@]1(C)C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 28.4 %

Procedure:
To a suspension of sodium hydride (60% in oil) (0.12 g) (1.5 eq.) in 5 mL of dry THF was added (2S,4R)-N-Boc-4-hydroxy-2-methyl-proline methyl ester (0.55 g) in 5 mL of dry THF. The reaction mixture was stirred for 45 min., and a solution of 4-bromobenzyl bromide (0.75 g) (1.5 eq.) in 5 mL of dry THF was added. The reaction mixture was refluxed for 3 h. After cooling to RT, the reaction mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified and extracted with DCM. The combined organic extracts were washed with water, dried over MgSO4 and evaporated under reduced pressure to afford (2S,4R)-N-Boc-4-(4-bromo-benzyloxy)-2-methyl-proline (0.25 g).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:23]#[N:24])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([OH:22])[CH2:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[CH:10]=2)[NH:5][CH:4]=1)=[O:2].CC(=CC)C.Cl([O-])=[O:31].[Na+].O.OP([O-])(O)=O.[Na+].[Cl-].[NH4+]>O1CCCC1.C(O)(C)(C)C>[C:23]([C:8]1[CH:7]=[C:6]2[C:11]([C:3]([C:1]([OH:31])=[O:2])=[CH:4][NH:5]2)=[CH:10][C:9]=1[C:12]1[CH:13]=[CH:14][C:15]([C:18]2([OH:22])[CH2:21][CH2:20][CH2:19]2)=[CH:16][CH:17]=1)#[N:24]
Reactant: [O-][Cl+][O-]
Reactant: N#Cc1cc2[nH]cc(C=O)c2cc1-c1ccc(C2(O)CCC2)cc1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: N#Cc1cc2[nH]cc(C(=O)O)c2cc1-c1ccc(C2(O)CCC2)cc1
Temperature: 0 °C
Reaction time: 7 h
Yield: 67 %

Procedure:
A solution of 3-formyl-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-6-carbonitrile (223 mg, 0.705 mmol) in tetrahydrofuran (6 mL) and tert-butanol (6 mL) was treated with 2-methyl-2-butene (2.25 mL, 21.2 mmol) and cooled to 0° C. The reaction mixture was then treated with a solution of sodium chlorite (594 mg, 7.0 mmol) and sodium phosphate monobasic hydrate (1.0 g, 7.2 mmol) and warmed to room temperature. The reaction mixture was stirred vigorously at room temperature for 7 hours, and was then poured into saturated aqueous ammonium chloride (40 mL). The product was extracted with ethyl acetate (4×25 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified using flash chromatography eluting with heptanes/ethyl acetate (with 0.2% formic acid) (85:15 to 0:100). The fractions containing product were combined, concentrated in vacuo, diluted with toluene (40 mL) and concentrated in vacuo to give the title compound (157 mg, 67%) as a white solid. This material was dissolved in ethanol (3.5 mL) with heating at 80° C., and treated with water (ca. 3 mL) dropwise with heating at 80° C. The resulting solution was stored at room temperature for two hours, then at 8° C. for 2 hours. The resulting crystals were collected by filtration, washed with water (2 mL) and dried in vacuo at 60° C. for 14 hours to give the title compound (100 mg, 42.7%) as an off-white crystalline solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC([O-])(C)C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.Br[C:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][C:54]=2[Cl:56])[CH:49]=[CH:48][CH:47]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:46]2[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][C:54]=3[Cl:56])[CH:49]=[CH:48][CH:47]=2)[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Clc1cccc2cccc(Br)c12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3cccc(Cl)c23)CC1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
A third intermediate compound, 1-(8-Chloro-naphthalen-1-yl)-piperazine, was produced as follows: To an oven dried flask, 1-boc-piperazine (1.2 g, 6.47 mmol), NaOtBu (0.724 g, 7.54 mmol), Pd(OAc)2 (0.12 g, 0.539 mmol), 2-(di-cyclohexylphosphino)biphenyl (0.12 g, 0.539 mmol), toluene (15 mL) and 1-bromo-8-chloro-naphthalene (1.3 g, 5.39 mmol) were added. While stirring the reaction mixture at room temperature, the air in the flask was removed and refilled with N2. This process was repeated three times. The reaction mixture was stirred for 3 h at 80–90° C. Diethyl ether was added at room temperature and the mixture was filtered through a pad of silica gel. The brown oily material was purified by chromatography on silica, eluting with hexanes:chloroform (1:1) and then changing to 100% chloroform, to give 4-(8-chloro-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butyl ester as an oil (1.35 g, 72%). 1H-NMR (400 MHz, CDCl3) δ 7.73 (dd, 1H), 7.56 (dd, 1H), 7.52 (dd, 1H), 7.42 (t, 1H), 7.34 (t, 1H), 7.18 (dd, 1H), 4.16 (s, 2H), 3.38 (s, 2H), 3.22 (m, 2H), 2.76 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=1.O>ClCCl>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[C:15]([C:5](=[O:8])[CH2:6][CH3:7])[CH:16]=1
Reactant: COc1ccc(Br)cc1
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCC(=O)c1cc(Br)ccc1O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 91.1 %

Procedure:
Aluminium chloride (3.747 kg) was added to dichloromethane (7.0 l) at room temperature and propionyl chloride (1.297 kg) was then added over a 10 minute period. The mixture was stirred for 45 minutes and then a solution of 4-bromoanisole (1.312 kg) in dichloromethane (0.87 l) was added over a 15 minute period. The mixture was heated under reflux for 6.5 hours and then kept overnight at room temperature. The ice-cooled reaction mixture was quenched by the slow addition of ice (15 kg) over 1.5 hours. The mixture obtained was stirred for 15 minutes, the layers were separated and the aqueous layer extracted with dichloromethane (2×1.0 l). The organic layers were combined and washed with water (2×2.0 l), then two-thirds of the solvent removed by distillation at atmospheric pressure. Methanol (5.63 l) was then added slowly and the distillation continued until a pot temperature of 64° C. and a head temperature of 62° C. was achieved. Water (0.4 l) was added slowly and the mixture was cooled resulting in the precipitation of an off-white solid. Further water (0.4 l) was then added slowly and the precipitated solid granulated at about 10° C. for 2 hours. The solid was then filtered off, washed sparingly with a 6:1 methanol/water mixture and dried under reduced pressure at 50° C. to provide the title compound (1.464 kg).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[C:7]([CH:8]=O)[C:6]([OH:11])=[CH:5][CH:4]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]([F:33])([F:32])/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28]>O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:25]([C:24]([F:23])([F:33])[F:32])[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:8][C:7]=2[CH:10]=1
Reactant: CSc1ccc(O)c(C=O)c1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(SC)ccc2OC1C(F)(F)F
Temperature: 65 °C

Procedure:
5-Methylthiosalicylaldehyde (Step 1) (2.516 g, 14.96 mmole) was added to dimethylformamide (3.5 mL), potassium carbonate (2.27 g, 16.45 mmole) and ethyl 4,4,4-trifluorocrotonate (3.3 mL, 3.8 g, 22.4 mmole). The mixture was heated to 65° C. for 3 h. The reaction was cooled to room temperature, poured into H2O (50 mL), and extracted with diethyl ether (2×75 mL). The combined ethereal phases were washed with aqueous NaHCO3 solution (3×50 mL), aqueous 2 N HCl solution (3×50 mL), and brine (3×50 mL), dried over MgSO4, filtered, diluted with isooctane and partially concentrated in vacuo causing the precipitation of the ethyl ester (2.863 g, 60%) as a yellow powder: mp 87.8–89.6° C. This ester was of suitable purity to use without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](/[CH:10]=[CH:11]/[CH2:12][OH:13])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[OH-].[K+].Cl.Cl[CH2:18][CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C([O-])(=O)C([O-])=O>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8](/[CH:10]=[CH:11]/[CH2:12][O:13][CH2:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: OC/C=C/c1ccc2occc2c1
Reactant: ClCCCN1CCCC1
Agent: Cl
Agent: O=C([O-])C(=O)[O-]
Agent: [K+]
Product: C(=C/c1ccc2occc2c1)\COCCCN1CCCC1
Yield: 12.2 %

Procedure:
A Following the procedure described in example 2, but starting from trans-3-(benzofuran-5-yl)prop-2-en-1-ol (600 mg), potassium hydroxide (477 mg 85% wt) and 1-(3-chloropropyl)pyrrolidine, hydrochloride (647 mg) in dimethylsufoxide (5 mL) affords 120 mg of trans-1-{3-[3-(benzofuran-5-yl)allyloxy]propyl}pyrrolidine, oxalate as a white solid.
Reaction SMILES: [CH3:1][C:2]1([C:20]2[CH:21]=[C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([C:8](=O)[CH2:9][C:10]([CH3:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[CH2:6]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1([C:20]2[CH:21]=[C:22]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:23]=[CH:24][CH:25]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:8][CH2:9][C:10]([CH3:11])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:18])[CH2:6]2
Reactant: CC(C)(CC(=O)N1CC2C(C1)C2(C)c1cccc(NS(C)(=O)=O)c1)c1ccccc1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(CCN1CC2C(C1)C2(C)c1cccc(NS(C)(=O)=O)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
To a solution of N-{3-[6-methyl-3-(3-methyl-3-phenylbutanoyl)-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide (Preparation 122, 59 mg, 0.138 mmol) in anhydrous tetrahydrofuran (1 ml) under a nitrogen atmosphere at 0° C. was added dropwise lithium aluminium hydride (1.0M solution in tetrahydrofuran, 0.28 ml, 0.28 mmol) and the mixture was stirred at room temperature for 3 h. The rapidly stirred reaction mixture was treated sequentially with water (0.28 ml), sodium hydrogen carbonate (200 mg) and ethyl acetate (10 ml). After 30 min the reaction mixture was filtered and concentrated in vacuo to afford a pale yellow oil. This was purified by preparative HPLC (condition 8) to give a light brown oil which was partitioned between dichloromethane (15 ml) and aqueous potassium carbonate solution (7% w:v, 5 ml). The layers were separated and the organic layer was washed with water (5 ml), dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a colourless oil (38 mg, 66%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=[O:26])[C:16]2=[C:27]([Cl:30])[CH:28]=[CH:29][N:15]2[N:14]=1)(C)(C)C.CCN(CC)CC.[Cl:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1.Cl>C(Cl)Cl.O1CCOCC1.C(#N)C.O>[ClH:30].[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=[O:26])[C:16]2=[C:27]([Cl:30])[CH:28]=[CH:29][N:15]2[N:14]=1)[C:44](=[O:45])[C:43]1[CH:47]=[CH:48][C:40]([Cl:39])=[CH:41][CH:42]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCCNCc1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1COCCO1
Product: NCCCN(Cc1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1)C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 102.4 %

Procedure:
To a solution of (±)-{3-[(3-benzyl-5-chloro-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-ylmethyl)-amino]-propyl}-carbamic acid tert-butyl ester (12 mg, 0.027 mmole) in methylene chloride (0.5 mL) at 0° C. was added Et3N (11 μL, 0.081 mmole) followed by 4-chlorobenzoyl chloride (10 mL, 0.081 mmol). After stirring at 0° C. for 1.5 h, the reaction was quenched with 10 mL of saturated NaHCO3 solution and extracted with EtOAc (3×20 mL). The pooled organic extracts were dried over anhydrous MgSO4 and concentrated in vacuo. Purification of the residue by flash column chromatography (SiO2, 2% MeOH/CHCl3) gave a residue which was immediately treated with 4 N HCl in dioxane (1 mL). The crude product was lyophilized with acetonitrile/water to give the title compound as a white powder (7.2 mg, 51%): MS (ESI+) 484 (M++H).