Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([Cl:17])[CH:8]=2)[S:4][N:3]=1.[CH2:18]([C:20]1[C:25](/[CH:26]=[CH:27]/[O:28][CH3:29])=[CH:24][CH:23]=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1)[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:9]1[CH:8]=[C:7]([C:5]2[S:4][N:3]=[C:2]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25](/[CH:26]=[CH:27]/[O:28][CH3:29])[C:20]=3[CH2:18][CH3:19])[N:6]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH:14]([CH3:16])[CH3:15]
Reactant: CCc1c(/C=C/OC)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(/C=C/OC)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Temperature: 120 °C
Yield: 64.9 %

Procedure:
To a solution of 3-bromo-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazole (D43) (388 mg), 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (335 mg) and tripotassium phosphate (741 mg) in N,N-dimethylformamide (DMF) (10 mL) and water (1.000 mL) stirred under nitrogen was added Pd(Ph3P)4 (134 mg). The mixture was sealed and heated under microwave at 120° C. for 10 min. After cooling the reaction, the mixture was concentrated and purified by column chromatography to give 5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-3-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,2,4-thiadiazole (D51) (313 mg) as a colorless oil. MS (ES): C22H23ClN2O2S requires 414. found 415.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:10](I)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.C([Li])CCC.CCCCCC.C1(C)C=CC(S([C:32]#[N:33])(=O)=O)=CC=1>O1CCCC1>[Cl:1][C:2]1[C:10]([C:32]#[N:33])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Clc1nn2ccccc2c1I
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#Cc1c(Cl)nn2ccccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cooled −78° C. solution of the title compound from Example 1 Step A (0.20 g, 0.718 mmol) in tetrahydrofuran (3.59 ml) was added a solution of n-butyllithium in hexane (1.6 M, 0.494 ml, 0.790 mmol). After 5 minutes, p-toluenesulfonyl cyanide (0.169 g, 0.934 mmol) was added, and the resulting reaction mixture was allowed to warm to room temperature. After 18 hours, the mixture was concentrated under reduced pressure. Purification by column chromatography on silica gel (0-30% ethyl acetate in hexanes) provided the title compound: LCMS m/z 177.91 [M+H]+, 179.86 [M+2+H]+; 1H NMR (500 MHz, CDCl3) δ 8.47 (d, J=6.9 Hz, 1 H), 7.70 (d, J=9.0 Hz, 1 H), 7.52 (dd, J=8.0, 8.0 Hz, 1 H), 7.26-7.20 (m, 1 H).
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][N:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH:13]([CH3:21])[C:14](=O)[C:15]([O:17][CH2:18]C)=[O:16]>C1COCC1>[CH3:21][C:13]1[N:7]2[C:6]([C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:10]=3[CH:9]=[CH:8]2)=[N:11][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: Nc1nccc2ncccc12
Reactant: CCOC(=O)C(=O)C(C)Br
Solvent: C1CCOC1
Product: COC(=O)c1nc2c3cccnc3ccn2c1C
Yield: 63.5 %

Procedure:
A solution of 1,6-naphthyridin-5-amine (700 mg, 4.83 mmol) in THF (25 mL) was added ethyl 3-bromo-2-oxobutanoate (1.51 g, 7.24 mmol). The mixture was stirred at reflux for 36 h. Then the mixture was concentrated under reduced pressure, and purified by column chromatography to give the product as a yellow solid (740 mg, 60% yield). ESI MS: m/z 256.1 [M+H]+.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:11][C@H:10]([O:12][C:13]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]3[C:14]=2[C:15]2([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[NH:16][C:17](=[O:24])[NH:18]3)[CH2:9]1)=[O:7])(C)(C)C.Br.O>C(O)(=O)C>[C:6]([OH:7])(=[O:5])[CH3:8].[Cl:23][C:20]1[CH:21]=[CH:22][C:13]([O:12][C@H:10]2[CH2:9][C@H:8]([C:6]([OH:7])=[O:5])[CH2:11]2)=[C:14]2[C:19]=1[NH:18][C:17](=[O:24])[NH:16][C:15]12[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@H](Oc2ccc(Cl)c3c2C2(CCCCC2)NC(=O)N3)C1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C1Nc2c(Cl)ccc(O[C@H]3C[C@H](C(=O)O)C3)c2C2(CCCCC2)N1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
The product of step (a) (207 g, 0.492 mol) was slurried in acetic acid (3100 ml) and heated to 60° C. 48% Hydrobromic acid (4.93 mol) was added dropwise keeping the temperature at 60° C. The solution was stirred at 60° C. for 30 minutes. Water (700 ml) was added dropwise keeping the temperature above 55° C. The slurry was cooled to 20° C. and stirred for a further 30 minutes after which it was filtered, washed with acetic acid:water (2000 ml) and water (1000 ml) before being dried in a vacuum oven overnight at 60° C. to yield a white solid of the title compound as an acetic acid solvate (153.6 g, 73.5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:28])[N:11]([CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[OH:37][CH2:38][C:39]1([CH:43](O)[CH3:44])[CH2:42][CH2:41][CH2:40]1>CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:28])[N:11]([CH:21]2[CH2:22][CH2:23][C:24]3([O:37][CH2:38][C:39]4([CH2:42][CH2:41][CH2:40]4)[CH:43]([CH3:44])[O:27]3)[CH2:25][CH2:26]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17]
Reactant: CC(O)C1(CO)CCC1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)OCC2(CCC2)C(C)O3)c2ncnn12
Yield: 91.8 %

Procedure:
A mixture of 3′-fluoro-4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (23 g), 1-[1-(hydroxymethyl)cyclobutyl]ethanol (7.6 g), 4-methylbenzenesulfonic acid (0.093 g) and toluene (200 mL) was heated with a Dean-Stark apparatus under reflux for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (26 g, 90%).
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][C:11](=O)[N:12]2[C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=1[CH3:26])[CH2:4][CH3:5])[CH3:2].CSC>C1COCC1>[CH2:1]([CH:3]([O:6][C:7]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][CH2:11][N:12]2[C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=1[CH3:26])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1cc(C)nc2c1CCC(=O)N2c1c(C)cc(C)cc1C
Solvent: C1CCOC1
Solvent: CSC
Product: CCC(CC)Oc1cc(C)nc2c1CCCN2c1c(C)cc(C)cc1C
Yield: 86 %

Procedure:
The title compound was prepared in a 86% yield as a clear oil by the method analogous to that described in Example 8 starting from 5-(1-ethyl-propoxy)-7-methyl-1-(2,4,6-trimethyl-phenyl)-3,4-dihydro-1H-[1,8]naphthyridin-2-one and BH3.DMS in THF.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][CH2:10][CH3:11])[N:3]=1.[NH2:12][NH2:13].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:9]([S:8][C:4]1[N:3]=[C:2]([NH:12][NH2:13])[CH:7]=[CH:6][N:5]=1)[CH2:10][CH3:11]
Reactant: NN
Reactant: CCCSc1nccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCSc1nccc(NN)n1
Temperature: 80 °C
Yield: 47.9 %

Procedure:
4-Chloro-2-propylsulfanyl-pyrimidine (15.03 g), hydrazine (10.69 g) and potassium carbonate (15.37 g) were added to ethanol (150 mL) and the mixture was heated to 80° C. for three hours. The mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed (CH2Cl2/hexanes through silica) to give 7.036 g of (2-propylsulfanyl-pyrimidin-4-yl)-hydrazine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:12])[S:9][C:10]=1[NH2:11])=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.Br[C:56]1[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:12])[S:9][C:10]=1[NH:11][C:56]1[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=1)=[O:5])[CH3:2]
Reactant: Brc1cccnc1
Reactant: CCOC(=O)c1nc(C)sc1N
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(C)sc1Nc1cccnc1
Yield: 63.3 %

Procedure:
A Schlenck flask was charged with 5-amino-2-methyl-thiazole-4-carboxylic acid ethyl ester (0.33 g, 1.80 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.15 g, 0.26 mmol) and palladium dibenzylideneacetone (Pd2dba3)-chloroform complex (0.08 g, 0.08 mmol). Degassed dioxane (6.00 ml) was added, followed by 3-bromopyridine (0.23 g, 1.50 mmol). The flask was subjected to 5 cycles of evacuation and backfiring with argon. The reaction mixture was then transferred under argon to a microwave vial containing cesium carbonate (0.84 g, 2.60 mmol). The vial was then irradiated in a microwave oven at 150° C. for 10 min. The mixture was diluted with THF and the solids filtered, washing with THF. The filtrate was evaporated and the residue purified by flash chromatography (ethyl acetate/methanol) to yield 2-methyl-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid ethyl ester (0.25 g, 65%) as a light yellow solid, MS (ISP): m/e=264.1 (M+H+).
Reaction SMILES: NC1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].CI.C(=O)([O-])[O-].[K+].[K+].O.[CH3:31][N:32]([CH3:35])[CH:33]=O>>[CH3:31][N:32]([CH3:35])[C:33]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2Cl)c1N
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: CCOC(=O)Cc1cccc(Oc2ccccc2Cl)c1N(C)C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of ethyl 2-[2-amino-3-(2-chlorophenoxy)phenyl]acetate (11.8 g), methyl iodide (11.9 g) and potassium carbonate (10.7 g) in dried dimethylformamide (100 ml) was stirred at room temperature for 17 hrs. The reaction mixture was poured into water (400 ml) and extracted with diethyl ether (150 ml×2). The extract was washed with saline, dried over magnesium sulfate and evaporated in vacuo. The oily residue (12.7 g) was subjected to column chromatography on silica gel and eluted with a mixture of benzene and n-hexane (1:1) to give oily ethyl 2-[2-dimethylamino-3-(2-chlorophenoxy)phenyl]acetate (7.4 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@@H:15]([C:19]([NH2:21])=O)[CH2:14]2)=[CH:9][CH:8]=1.S(Cl)(Cl)=O>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@@H:15]([C:19]#[N:21])[CH2:14]2)=[CH:9][CH:8]=1
Reactant: NC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: N#C[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 25 °C

Procedure:
A mixture of (R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid amide (0.400 g, 0.001 mol) and thionyl chloride (2.3 ml, 0.032 mol) was refluxed under argon for 3 hours. The mixture was cooled to room temperature, diluted with 5 ml tetrahydrofuran, concentrated under vacuum and purified by column chromatography on silica gel using a 2:3-mixture of ethyl acetate and hexane as the eluent. The product fractions were concentrated to dryness to yield (0.106 g, 28% of theory) of a light brown oil. MS (m/e)=311.1 (M+H)+.
Reaction SMILES: CO[CH:3]=[CH:4][C:5](=[O:7])[CH3:6].[CH3:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=1>>[C:9]1([CH3:8])[CH:16]=[CH:15][C:12]([CH2:13][NH:14][CH:3]=[CH:4][C:5](=[O:7])[CH3:6])=[CH:11][CH:10]=1
Reactant: COC=CC(C)=O
Reactant: Cc1ccc(CN)cc1
Product: CC(=O)C=CNCc1ccc(C)cc1

Procedure:
The title compound 58 is prepared according to the procedure reported in step A of Example 18 with 4-methoxy-3-buten-2-one (0.103 g, 1 mmol) and 4-methylbenzylamine (0.125 g, 1 mmol) as reactants. Yellow oil. (Yield 0.19 g, 98%).
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([OH:23])[CH:20]=[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[C:18]=2[F:31])=[C:13]([F:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+].Cl>C1COCC1.O>[F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([OH:23])[CH:20]=[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[C:18]=2[F:31])=[C:13]([F:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(O)cc(-c3cccc(F)c3)c2F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1ccc(F)c(NCc2cc(O)cc(-c3cccc(F)c3)c2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a stirred solution of ethyl 2-[2,4-difluoro-3-[[2-fluoro-3-(3-fluorophenyl)-5-hydroxy-phenyl]methylamino]phenoxy]acetate (120 mg, 0.27 mmol, 1.0 eq) in THF (6 mL) at room temperature was added NaOH (1M aqueous solution, 3 mL, 3.0 mmol, 11.1 eq). The reaction was stirred at room temperature for 2 h. The solvent was then removed in vacuo and the solid obtained taken up in water and the aqueous layer acidified to pH 3-6 by addition of 1M HCl. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated in vacuo to give the title compound (I(f)) as a gummy solid (105 mg, 94%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9](I)[CH:8]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.[CH3:19][O:20][CH2:21][C:22]1[CH:26]=[CH:25][O:24][C:23]=1[Sn](C)(C)C>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([C:23]3[O:24][CH:25]=[CH:26][C:22]=3[CH2:21][O:20][CH3:19])[CH:8]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1
Reactant: COCc1ccoc1[Sn](C)(C)C
Reactant: Cc1ccc(-n2c(N)nc3ccccc32)cc1I
Product: COCc1ccoc1-c1cc(-n2c(N)nc3ccccc32)ccc1C

Procedure:
2-Amino-1-[3-(3-methoxymetyl-2-furyl)-4-methylphenyl]benzimidazole was prepared from 4-(2-amino-1-benzimidazolyl)-2-iodotoluene and 3-methoxymethyl-2-trimethylstannylfuran according to method C. mp 174°-176° C.
Reaction SMILES: [H-].[Na+].[S:3]([N:13]1[C:17]2=[N:18][CH:19]=[C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:21]=[C:16]2[CH:15]=[CH:14]1)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].Br[CH2:31][C:32]([CH:34]1[CH:39]([CH3:40])[CH2:38][CH2:37][N:36]([C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])[CH2:35]1)=[O:33]>CN(C=O)C>[C:25]([O:24][C:23]([N:22]([C:20]1[N:21]=[C:16]2[CH:15]=[CH:14][N:13]([S:3]([C:6]3[CH:7]=[CH:8][C:9]([CH3:10])=[CH:11][CH:12]=3)(=[O:5])=[O:4])[C:17]2=[N:18][CH:19]=1)[CH2:31][C:32]([CH:34]1[CH:39]([CH3:40])[CH2:38][CH2:37][N:36]([C:41]([O:43][CH2:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:42])[CH2:35]1)=[O:33])=[O:29])([CH3:26])([CH3:28])[CH3:27]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NC(=O)OC(C)(C)C)cnc32)cc1
Reactant: CC1CCN(C(=O)OCc2ccccc2)CC1C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(N(CC(=O)C4CN(C(=O)OCc5ccccc5)CCC4C)C(=O)OC(C)(C)C)cnc32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 0.088 g, 2.2 mmol) in DMF at about 0° C. (10 mL) was added a solution of tert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (0.86 g, 2.2 mmol, Step F) in DMF (10 mL) and the mixture was stirred at about 0° C. for about 1 h. A solution of benzyl 3-(2-bromoacetyl)-4-methylpiperidine-1-carboxylate (0.78 g, 2.2 mmol, Step B) in DMF (5 mL) was added drop-wise and the resulting mixture was stirred at ambient temperature for about 16 h. The solvent was removed and the residue was partitioned between EtOAc and water (40 mL each). The organic phase was washed with brine (20 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give benzyl 3-(2-(tert-butoxycarbonyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)-4-methylpiperidine-1-carboxylate (1.45 g, 100%): LC/MS (Table 2, Method a) Rt=3.14 min; MS m/z: 662 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][N:16]([CH2:24][CH:25]([CH3:27])[CH3:26])C(=O)OC(C)(C)C)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([O:15][NH:16][CH2:24][CH:25]([CH3:27])[CH3:26])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)CN(OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CNOCc1ccccc1
Yield: 101.2 %

Procedure:
Trifluoroacetic acid (21 mL, 270 mmol) was added in a single portion to a solution of tert-butyl N-benzyloxy-N-(2-methylpropyl)carbamate (7.6 g, 27 mmol) in methylene chloride (21 mL). A spontaneous reflux occurred. The reaction mixture was stirred without external heating for 20 minutes and then concentrated under vacuum at 45° C. Saturated aqueous sodium bicarbonate was added to the residue followed by a quantity of solid sodium bicarbonate sufficient to bring the pH of the reaction mixture up to a value of 9. The mixture was extracted twice with methylene chloride. The extracts were combined, dried over magnesium sulfate then concentrated under vacuum to provide 4.9 g of N-benzyloxy-N-(2-methylpropyl)amine as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].[NH:27]1[CH:31]=[CH:30][CH:29]=[N:28]1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:7]2[N:6]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:5]([CH2:4][CH2:3][CH2:2][N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: c1cn[nH]c1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCl)CCC2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2C(CCCn3cccn3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=428.5 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-pyrazole.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:23]C1N=C(F)N=C(F)N=1.N1C=CC=CC=1>ClCCl>[CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([F:23])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (as prepared in Scheme 1; also described in WO 2009061879) (5.2 g, 17.03 mmol) dissolved in dichloromethane (DCM) (75 mL) was added 2,4,6-trifluoro-1,3,5-triazine (1.5 mL, 17.9 mmol) followed by pyridine (1.51 mL, 18.7 mmol). The reaction mixture was stirred at 25° C. for 2 h, and then the reaction mixture was diluted with DCM (100 mL) and washed (1×50 mL) with 5% citric acid followed by 50 mL of sat. NaHCO3. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl fluoride as a pale yellow oil. LC-MS (ES) m/e 306.8 (M+H)+.
Reaction SMILES: [C:1]([C:3]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=[CH:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:5](=[O:17])[CH2:4]1)#[N:2].[H][H]>CO.[Pd]>[C:1]([C:3]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:5](=[O:17])[CH2:4]1)#[N:2]
Reactant: [H][H]
Reactant: N#CC1(c2ccccc2)C=CN(Cc2ccc(F)cc2)C(=O)C1
Agent: [Pd]
Solvent: CO
Product: N#CC1(c2ccccc2)CCN(Cc2ccc(F)cc2)C(=O)C1

Procedure:
To a solution of 4-cyano-1-(4-fluorobenzyl)-4-phenyl-1,2,3,4-tetrahydropyridin-2-one (3.98 g, 13.0 mmol) in degassed methanol was added 10% Pd/C (0.8 g). The reaction shaken under an atmosphere of 33 psi of hydrogen for 18 hours. More 10% Pd/C (0.4 g) was added and the mixture was shaken under 45 psi of hydrogen for 48 hours. The mixture was filtered through a bed of celite and the filtrate was concentrated to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.55 (d, J=7.7 Hz, 2H), 7.46 (t, J=7.9 Hz, 2H), 7.38 (t, J=7.3 Hz, 1H), 7.28 (t, J=3 Hz, 2H), 7.16 (t, J=2.4 Hz, 2H), 4.58 (s, 2H), 3.44 (m, 1H), 3.25 (m, 1H), 3.07 (q, J=16 Hz, 2H), 2.41 (s, 2H) ppm. ES MS M+1=309.
Reaction SMILES: [C:1]1([O:7][CH2:8][CH:9]2[O:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:13]([NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(O)(C)C>[CH2:13]([N:20]([CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=1)[CH2:10][CH:9]([OH:11])[CH2:8][O:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Oc1ccc(CCNCc2ccccc2)cc1
Reactant: c1ccc(OCC2CO2)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Oc1ccc(CCN(Cc2ccccc2)CC(O)COc2ccccc2)cc1
Yield: 88.7 %

Procedure:
A mixture of phenylglycidyl ether (8.0 g), N-benzyltyramine hydrochloride (13.0 g) and triethylamine (7.5 ml) in isopropanol (200 ml) was heated to reflux for 3hours. The solvent was evaporated and toluene was added to the residue. Volatile material was evaporated. The residue was purified by chromatography on K60 silica (300 g) using a gradient mixture of methanol in dichloromethane (1 to 2% methanol). Thus was obtained 4-[2-(N-benzyl-N-(2-hydroxy-3-phenoxypropyl)amino)ethyl]phenol (16.5 g) as an oil which slowly crystallised, m.p. 103°-5° C.: NMR: 2.55-2.85[m,6H, CHCH2NHCH2CH2 ]; 3.65-4.05 [m,5H, PhOCH2CHOH +PhCH2 ]; 6.65-7.4[m,14H, aromatic H].
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][C:9]=3[N:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16]Br.N>CO.C(Cl)Cl>[CH:1]1([N:6]2[C:10]3[CH:11]=[CH:12][C:13]([NH2:15])=[C:14]([Br:16])[C:9]=3[N:8]=[CH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccc2c(c1)ncn2C1CCCC1
Reactant: BrBr
Agent: N
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc2c(ncn2C2CCCC2)c1Br
Yield: 35 %

Procedure:
To a solution of 1-cyclopentyl-5-aminobenzimidazole (1.1 g, 5.5 mmol) in 20 ml of ACOH was added solution of Br2 in. ACOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CH2Cl2) to provide 0.54 g (1.9 mmol, 35%) of the product.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[BrH:12].BrBr>C(O)(=O)C>[Br:12][CH:9]([CH3:10])[C:8]([C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1)=[O:11]
Reactant: CCC(=O)c1cccnc1F
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: CC(Br)C(=O)c1cccnc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 1-(2-fluoropyridin-3-yl)propan-1-one (12.9 g) and 25% solution (70 mL) of hydrogen bromide in acetic acid was added dropwise bromine (4.4 mL), and the obtained mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure to give the title compound as a red-brown oil (yield 29.6 g, quantitative).