Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCN2C(=NCCC2)CC1.C(O[CH2:16][CH:17]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34])[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])(=O)C>C1COCC1>[Cl:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[C:17]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[CH2:16]
Reactant: CC(=O)OCC(c1ccc(Cl)cc1Cl)S(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: C=C(c1ccc(Cl)cc1Cl)S(=O)(=O)c1ccccc1
Reaction time: 0.67 h
Yield: 97 %

Procedure:
DBU (1.5 eq) in THF was added to a solution of 2-(2,4-dichlorophenyl)-2-(phenylsulfonyl)ethyl acetate (3) (1 eq) in THF at rt. After stirring for 40 min., the reaction was quenched with sat. aq. NH4Cl. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to give the {[1-(2,4-dichlorophenyl)vinyl]sulfonyl}benzene (4) (97% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[OH:12].[C:13](Cl)(=O)[CH3:14]>C(O)C>[CH2:13]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([OH:12])[CH:4]=1)[CH3:14]
Reactant: O=C(O)Cc1ccc(Cl)c(O)c1
Reactant: CC(=O)Cl
Solvent: CCO
Product: CCOC(=O)Cc1ccc(Cl)c(O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of step (iii) (4 g) was added to a solution of acetyl chloride (10 ml) in ethanol (40 ml). The mixture was stirred for 1 h at RT then evaporated under reduced pressure. The residue was purified by flash column chromatography (eluent 2:1 isohexane/EtOAc) to give the subtitle compound (4.4 g).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[O:24][CH:25]=[CH:26][CH:27]=4)=[CH:19][CH:18]=3)=[CH:15][C:14]([C:28]([O:30]CC)=[O:29])=[N:13]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[OH-].[Na+].O.Cl.[CH2:37]([OH:39])[CH3:38]>>[CH2:37]([O:39][C:6]1[CH:5]=[C:4]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[O:24][CH:25]=[CH:26][CH:27]=4)=[CH:19][CH:18]=3)=[CH:15][C:14]([C:28]([OH:30])=[O:29])=[N:13]2)[CH:3]=[CH:2][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10])[CH3:38]
Reactant: CCOC(=O)c1cc(-c2ccc(-c3ccco3)cc2)n(-c2ccc(S(C)(=O)=O)c(F)c2)n1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1cc(-n2nc(C(=O)O)cc2-c2ccc(-c3ccco3)cc2)ccc1S(C)(=O)=O
Yield: 73 %

Procedure:
To a stirred solution of ethyl 1-[3-fluoro-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-1H-pyrazole-3-carboxylate (0.57 g, 1.25 mmol) in ethanol (15 mL) was added 2N-NaOH solution in water (1.6 mL, 3.14 mmol), and the mixture was heated at reflux temperature for 30 minutes. After cooling, 2N-HCl solution (4 mL) and water (30 mL) were added to the mixture. The whole was extracted with ethyl acetate (20 mL×3), the organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting solid was washed with methylene chloride to give the title compound (0.413 g, 73.0%, yield).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9])=[N+:2]=[N-:3].CN(C)C=O.[OH-].[Li+].Cl>O>[N:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[N+:2]=[N-:3]
Reactant: CCOC(=O)CCCCN=[N+]=[N-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
To ethyl 5-azidovalerate (1.6 g; 10 mmol; Example 2.1) in 5 ml-dimethylformamide, was added lithium hydroxide (1.0 g; 20 mmol; Fisher) in 5 ml water, and the reaction mixture was stirred 12 h at 25° C. The reaction mixture was adjusted to pH ˜4 by addition of 1 N HCl and was extracted with 100 ml diethyl ether. The resulting organic layer was washed with water (100 ml) and brine (100 ml), dried over sodium sulfate, and dried in vacuo. Yield: 1.4 g (9.8 mmol, 99% yield).
Reaction SMILES: C(OC([NH:8][CH:9]([C:11]1[S:12][C:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[CH:14][N:15]=1)[CH3:10])=O)(C)(C)C.[ClH:26]>C1COCC1.O1CCOCC1>[ClH:26].[NH2:8][CH:9]([C:11]1[S:12][C:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[CH:14][N:15]=1)[CH3:10]
Reactant: CC(NC(=O)OC(C)(C)C)c1ncc(C(=O)OCc2ccccc2)s1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(N)c1ncc(C(=O)OCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of benzyl 2-(1-(tert-butoxycarbonylamino)ethyl)thiazole-5-carboxylate (0.55 g, 0.55 mmol) in THF (2 mL) was added 4M HCl in dioxane (0.5 ml). The reaction solution was stirred at room temperature overnight. The solution was concentrated to dryness to afford a colorless oil (0.45 g, 100%). LC-MS: (FA) ES+ 263.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[C:15]([C:19]#[C:20][CH2:21][OH:22])[CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[CH:4][CH:3]=1>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[C:15](/[CH:19]=[CH:20]\[CH2:21][OH:22])[CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[CH:6][CH:7]=1
Reactant: OCC#Cc1cccc(C2=NOC(c3ccc(F)cc3)C2)c1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: OC/C=C\c1cccc(C2=NOC(c3ccc(F)cc3)C2)c1
Yield: 95 %

Procedure:
A mixture of the product of Step 2, above (14, 2.0 g, 6.8 mmol) and 5% Pd/BaSO4 (200 mg) in methanol was subjected to hydrogenation at atmospheric pressure. After the absorption of the required amount of hydrogen, the suspension was filtered and washed with methanol. Methanol was evaporated from the filtrate. The residue was purified by column chromatography on silica gel (eluent=ethyl acetate:n-hexane, 1:4) to give 1.8 g (95% yield) of the title compound as pale yellow solids.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][N:7]=1.[CH3:13][S:14][C:15](=[N:18][C:19]#[N:20])SC>C(O)C>[C:19]([NH:18][C:15](=[N:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][N:7]=1)[S:14][CH3:13])#[N:20]
Reactant: CSC(=NC#N)SC
Reactant: NCCSCc1ncccc1O
Solvent: CCO
Product: CSC(=NCCSCc1ncccc1O)NC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
A solution of 2-((2-aminoethyl)thiomethyl)-3-hydroxypyridine (7.5 g) in ethanol was added slowly to a solution of dimethylcyanodithioimidocarbonate (6.0 g) in ethanol, with stirring at room temperature. The mixture was set aside overnight at room temperature. Filtration afforded N-cyano-N'-[2-((3-hydroxy-2-pyridyl)methylthio)-ethyl]-S-methylisothiourea (4.85 g), m.p. 192°-194°. Recrystallisation from aqueous ethanol gave fine needles, m.p. 196°-198°.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].[CH3:16]I>O1CCCC1.O>[CH3:16][O:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C

Procedure:
tert-Butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (12.5 g, 66.70 mmol) was dissolved in tetrahydrofuran (334 mL) and the reaction mixture cooled to 0° C. in an ice bath. The reaction mixture was treated with 80% sodium hydride in mineral oil (2.20 g, 73.3 mmol) and stirred until back at room temperature. The reaction mixture was then treated with methyl iodide (14.5 g, 100.0 mmol) and stirred at room temperature for 18 hours. The reaction mixture was diluted with water (100 mL) and concentrated in vacuo until just the aqueous remained. The aqueous solution was treated with ethyl acetate (750 mL), the organic layer separated, dried over magnesium sulphate and concentrated in vacuo to yield the title product as a brown oil, 12.48 g. 1H NMR (CDCl3, 400 MHz) δ: 1:41 (s, 9H), 1.95 (m, 2H), 3.30 (s, 3H), 3.40 (m, 4H), 3.86 (m, 1H)
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][C:12]1[CH:26]=[CH:25][C:15]([O:16][C:17]2[N:24]=[CH:23][CH:22]=[CH:21][C:18]=2[CH:19]=O)=[CH:14][CH:13]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[C:18]([CH2:19][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:21][CH:22]=[CH:23][N:24]=2)=[CH:25][CH:26]=1
Reactant: Cn1c(Nc2ccc(Oc3ncccc3C=O)cc2)nc2ccccc21
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c(Nc2ccc(Oc3ncccc3CN3CCOCC3)cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 2-(4-(1-methyl-1H-benzo[d]imidazol-2-ylamino)phenoxy)nicotinaldehyde (0.2 g, 0.6 mmol) in DCM (2 mL) was added morpholine (0.05 mL, 0.6 mmol). Sodium triacetoxyborohydride (0.1 g, 0.6 mmol) was added and the resulting mixture was stirred for 3 h at RT. LC/MS showed complete conversion. The reaction mixture was purified by silica gel chromatography (0-10% MeOH/DCM) to afford product 1-methyl-N-(4-(3-(morpholinomethyl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine as solid. MS (ESI, pos. ion) m/z: 416.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:24]=[CH:25]/[C:26](OCC)=[O:27])=[CH:4][N:3]=1.CC(C[AlH]CC(C)C)C.CO>C1COCC1>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:24]=[CH:25]/[CH2:26][OH:27])=[CH:4][N:3]=1
Reactant: CCOC(=O)/C=C/c1cnc(N)c2c(-c3ccc(Oc4ccccc4)cc3)csc12
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ncc(/C=C/CO)c2scc(-c3ccc(Oc4ccccc4)cc3)c12
Temperature: 25 °C
Yield: 4.9 %

Procedure:
A solution of Example 223 (0.45 g, 10.8 mmol) in THF at −78° C. was treated with 5.4 mL DIBAL-H solution (1.0M in toluene, 5.4 mmol) and methanol (1 mL), warmed to room temperature, and concentrated. The residue was dissolved in methanol (100 mL), treated with silica gel (5 g), and concentrated. The preabsorbed silica gel was subsequently transferred to a silica gel column and chromatographed (ethyl acetate/heptane 3:1) to provide 200 mg (49%) of the product.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:12][NH:13][C:14]([C:16]1[C:21]([NH2:22])=[N:20][C:19]([NH2:23])=[C:18]([Cl:24])[N:17]=1)=[O:15])[CH2:9][CH2:10][CH3:11])(C)(C)C.Cl>O1CCOCC1>[ClH:24].[NH2:7][C@@H:8]([CH2:9][CH2:10][CH3:11])[CH2:12][NH:13][C:14]([C:16]1[C:21]([NH2:22])=[N:20][C:19]([NH2:23])=[C:18]([Cl:24])[N:17]=1)=[O:15]
Reactant: CCC[C@@H](CNC(=O)c1nc(Cl)c(N)nc1N)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCC[C@H](N)CNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ((S)-1-{[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-methyl}-butyl)-carbamic acid tert-butyl ester (1.30 g, 3.49 mmol) in 1,4-dioxane (20 mL) is added HCl (50 mL of a 4 M solution in 1,4-dioxane, 200 mmol) and the reaction mixture is stirred at RT for 16 h. The reaction mixture is concentrated in vacuo and the yellow solid obtained is triturated with diethyl ether; the diethyl ether layer is decanted and the product is dissolved in a minimal volume of MeOH and is precipitated by the addition of diethyl ether. The solvent is decanted and the resulting solid is dried under vacuum to afford the title compound. [M+H]+ 233. 1H NMR (400 MHz, CDCl3) δ 8.16 (1H, t), 7.89 (2H, br), 7.07 (4H, br), 3.42-3.38 (2H, m), 3.27-3.18 (1H, m), 1.54-1.47 (2H, m), 1.44-1.35 (2H, m), 0.89 (3H, t).
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH3:47][CH:48]([CH3:52])[C:49](Cl)=[O:50].O>N1C=CC=CC=1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:49](=[O:50])[CH:48]([CH3:52])[CH3:47])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: CC(C)C(=O)Cl
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 4.4 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.190 g, 0.33 mmol) in pyridine (2 mL) was added 2-methylpropanoyl chloride (0.042 mL, 0.40 mmol). The reaction was stirred at room temperature for 15 h. Water (10 mL) was added and the solid collected by suction filtration. The solid was dried in a vacuum oven for 3 h. The residue was dissolved in 4 N hydrochloric acid in 1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. After neutralization with aqueous sodium bicarbonate, the reaction mixture was extracted with ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and evaporated. Addition of dichloromethane (10 mL) to the residue gave the title compound (0.005 g, 5% yield) which was isolated by filtration: 1H NMR (DMSO-d6) δ 10.02 (s, 1H), 8.65 (s, 1H), 8.21 (s, 1H), 8.10 (br s, 1H), 7.78 (d, 1H), 7.65 (m, 2H), 7.45 (t, 1H), 2.63 (m, 1H), 1.19 (d, 6H); ES-MS (m/z) 347 [M+1]+.
Reaction SMILES: N12CCCN=C1CCCCC2.Br[CH2:13][CH2:14][C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:17][C:16]=1[OH:28]>C(Cl)Cl>[Cl:21][C:19]1[C:18]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:17][C:16]2[O:28][CH2:13][CH2:14][C:15]=2[CH:20]=1
Reactant: Oc1cc(N2CCCCC2)c(Cl)cc1CCBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Clc1cc2c(cc1N1CCCCC1)OCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.2 ml (8.0 mmole) of 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) are added at 0° to a solution of 2.50 g (7.8 mmole) of 1-bromo-2-[5-chloro-2-hydroxy-4-(piperidin-1-yl)-phenyl]-ethane in 50 ml of absolute methylene chloride and the whole is then stirred for 3 hours at room temperature. The reaction mixture is washed with saturated sodium chloride solution and the organic phases are combined, dried over sodium sulphate and concentrated in a vacuum rotary evaporator. The residue is chromatographed over silica gel using methylene chloride as eluant. Recrystallisation from petroleum ether yields 5-chloro-6-(piperidin-1-yl)-2,3-dihydrobenzofuran having a melting point of 38°-40°.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][NH:22][C:23](=O)[CH3:24])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[CH3:24][C:23]1[C:14]2=[C:13]3[C:18](=[CH:17][CH:16]=[C:15]2[O:19][CH2:20][CH2:21][N:22]=1)[N:10]([S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[CH:11]=[CH:12]3
Reactant: CC(=O)NCCOc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC1=NCCOc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c21
Temperature: 25 °C
Yield: 104.9 %

Procedure:
To N-(2-{[1-(phenylsulfonyl)-1H-indol-5-yl]oxy}ethyl)acetamide (Intermediate 25, 5.0 g, 14 mmol) in acetonitrile (7.5 L) was phosphoryl chloride (100 mL) added and the reaction mixture was heated at reflux overnight. The reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure to give the crude material of the title compound (5.0 g). A small amount of the crude material was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (12 mg). MS m/z 341 [M+H]+.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[N:17]([CH3:18])[C:16]2[C:19]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:20][CH:21]=[CH:22][C:15]=2[N:14]=1.[C:28]1([CH3:38])[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[C:29]=1[CH:36]=[O:37]>C(OCC)C>[CH2:24]([CH:23]([C:19]1[C:16]2[N:17]([CH3:18])[C:13]([CH:36]([C:29]3[C:28]([CH3:38])=[CH:33][C:32]([CH3:34])=[CH:31][C:30]=3[CH3:35])[OH:37])=[N:14][C:15]=2[CH:22]=[CH:21][CH:20]=1)[CH2:26][CH3:27])[CH3:25]
Reactant: CCC(CC)c1cccc2nc(Br)n(C)c12
Reactant: Cc1cc(C)c(C=O)c(C)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCC(CC)c1cccc2nc(C(O)c3c(C)cc(C)cc3C)n(C)c12
Reaction time: 0.5 h
Yield: 15.8 %

Procedure:
A solution of n-butyllithium in n-hexane (1.6M solution, 0.25 mL, 0.40 mmol) was added dropwise to a solution of 2-bromo-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole (100 mg, 0.36 mmol) in diethyl ether (4 mL) at 0° C. To the reaction mixture was added a solution of mesitaldehyde (74 mg, 0.50 mmol) in diethyl ether (1 mL) at 0° C. The reaction mixture was stirred for 0.5 hr, and the reaction was quenched by the addition of 1N hydrochloric acid to the mixture, and the mixture was extracted with ethyl acetate. The organics were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC eluting with a 10-100% water/acetonitrile gradient mixture containing 0.1% trifluoroacetic acid. The fractions containing the title compound were concentrated in vacuo, and the residue was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The organics were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was recrystallized from ethanol/water to give the title compound (20 mg, 0.057 mmol, 16%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:11][C@H:10]2[NH2:12])=[CH:5][CH:4]=1.[OH:13][CH:14](C(O)C([O-])=O)[C:15]([O-])=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[CH2:11][C@H:10]2[NH:12][C:14](=[O:13])[CH3:15])=[CH:7][CH:8]=1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Reactant: COc1ccc([C@@H]2C[C@H]2N)cc1
Product: COc1ccc([C@@H]2C[C@H]2NC(C)=O)cc1

Procedure:
The sub-title compound was prepared according to the method of Example 4, step a) from (1R-trans)-2-(4-methoxyphenyl)cyclopropanamine, [R-(R*,R*)]-2,3-dihydroxybutanedioate (1:1) (prepared as described in W09905143) to give a white solid (655 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:10][CH3:11])=[C:6]([CH2:8]O)[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:10][CH3:11])=[C:6]([CH2:8][Br:32])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1c(C)cc(Br)cc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1c(C)cc(Br)cc1CBr
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(5-Bromo-2-methoxy-3-methylphenyl)methanol (2.0 g, 8.7 mmol) and triphenylphosphine (4.5 g, 17.4 mmol) were combined in tetrahydrofuran (30 mL) and cooled to 0° C. N-Bromosuccinimide (3.2 g, 17.4 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with ethyl acetate, washed with concentrated sodium bicarbonate (2×), then brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (hexanes) gave 1.87 g (73%) as a white powder. 1H-NMR (CDCl3, 300 MHz) δ 7.32-7.33 (m, 1H), 7.23-7.24 (m, 1H), 4.46 (s, 2H), 3.82 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[NH:7]1)=[O:5])C.O.[OH-].[Li+].O>O1CCCC1>[O:11]=[S:8]1(=[O:12])[CH2:9][CH2:10][CH:6]([C:4]([OH:5])=[O:3])[NH:7]1
Reactant: CCOC(=O)C1CCS(=O)(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCS(=O)(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of crude 2-{3-[((S)-3-chloro-phenyl)-1-dimethylaminomethyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid ethyl ester (430 mg, approx. 0.96 mmol) in tetrahydrofuran (4 mL) was added lithium hydroxide hydrate (71 mg, 1.7 mmol) followed by water (1 mL). The reaction mixture was stirred at room temperature for 2 h, and then the mixture was concentrated under reduced pressure to remove tetrahydrofuran. The remaining solution was stirred and approximately 25 drops of 1 M hydrochloric acid were added to bring the pH to 4.5. The sample was stirred for 10 min and the aqueous solution was decanted away from the yellow gum. The gum was washed with water (2 mL). The combined aqueous layers were evaporated to dryness, and dried overnight to give 2-{3-[((S)-3-chloro-phenyl)-1-dimethylaminomethyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid as a white residue (200 mg).
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:9]([NH2:10])=[CH:8][C:7]([CH3:11])=[N:6]1)([CH3:4])[CH3:3].[CH:12]1(/[C:15](/O)=[CH:16]/[C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1>C(O)(=O)C>[CH:12]1([C:15]2[CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]3[C:7]([CH3:11])=[N:6][N:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:9]=3[N:10]=2)[CH2:13][CH2:14]1
Reactant: Cc1cc(N)n(C(C)(C)C)n1
Reactant: CCOC(=O)C(=O)/C=C(\O)C1CC1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C(C)(C)C

Procedure:
1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-amine (166 mg, 1.086 mmol), ethyl (3Z)-4-cyclopropyl-4-hydroxy-2-oxo-3-butenoate (200 mg, 1.086 mmol) and acetic acid (10 mL) were heated to reflux for 2 hours. The solvent was removed in vacuo and the residue purified by silica gel chromatography (eluent: 0% to 7% EtOAc:Hex). The product was collected as 278 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.07 (dt, 2 H), 1.13-1.20 (m, 2 H), 1.46 (t, J=7.20 Hz, 3 H), 1.78 (s, 9 H), 2.18 (m, J=7.99, 7.99, 4.74, 4.55 Hz, 1 H), 2.65 (s, 3 H), 4.47 (q, J=7.07 Hz, 2 H), 7.43 (s, 1 H). LCMS(ES) [M+H]+ 302.2
Reaction SMILES: N[C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.N([O-])=[O:12].[Na+]>O.S(=O)(=O)(O)O>[OH:12][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=N[O-]
Reactant: Nc1nccnc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1nccnc1O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 58530.9 %

Procedure:
The 3-amino-pyrazine-2-carboxylic acid (6.95 g, 0.05 mmol) was dissolved in a mixture of water (55 mL) and sulfuric acid (55 mL, 3.75M) and heated to 50° C. A solution of sodium nitrite (18.5 mL, 0.06 mmol) was added to the above solution which was cooled to 12° C. The temperature was maintained at 10-16° C. over 30 mins during addition period and then the mixture was heated to boiling over a period of 30 mins. After cooling to RT, the yellow solid was collected by filtration. The solid was dissolved in a dilute sodium bicarbonate solution, the carboxylic acid product precipitated by treatment with hydrochloric acid (10%) and collected by filtration, the crude carboxylic acid product was recrystallized from water to give a yellow-orange crystalline solid (4.1 g, yield 58%).