Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:9][C:10]1[N:14]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[Cl:26])[N:13]=[C:12]([CH:27]=[N:28][OH:29])[C:11]=1[S:30]([CH3:32])=[O:31].N1C=CN=C1.O>CN(C)C=O>[Si:1]([O:29][N:28]=[CH:27][C:12]1[C:11]([S:30]([CH3:32])=[O:31])=[C:10]([NH2:9])[N:14]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:23])[F:24])=[CH:17][C:16]=2[Cl:26])[N:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)c1c(C=NO[Si](C)(C)C(C)(C)C)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 50 °C
Reaction time: 18 h
Yield: 29.6 %

Procedure:
A solution of tert-butyldimethylsilyl chloride (0.8 g) in N,N-dimethylformamide (DMF) was added to a stirred solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (2.0 g) in (DMF), followed by dropwise addition of a solution of imidazole (0.72 g) in DMF during 7-minutes. The mixture was heated at 50° C. for 3.5-hours and then held at 20° C. for 18 hours. The mixture was diluted (water), extracted (methyl tert-butyl ether) and the organic phase washed in turn with NaHCO3 solution, 5% HCl solution and with NaHCO3 solution, dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde O-(tert-butyldimethylsilyl)oxime (0.76 g)as a light yellow solid m.p.150-154° C. Compound 21.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][C:10](=[O:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:21]([CH2:24]C)CC)C.[CH3:26][Si:27](C#N)([CH3:29])[CH3:28]>ClCCl>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][C:10]([O:12][Si:27]([CH3:29])([CH3:28])[CH3:26])([C:24]#[N:21])[CH2:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCN(CC)CC
Reactant: C[Si](C)(C)C#N
Solvent: ClCCl
Product: C[Si](C)(C)OC1(C#N)CN(C(c2ccccc2)c2ccccc2)C1
Yield: 90.9 %

Procedure:
1-(Diphenylmethyl)azetidin-3-one (600 mg, 2.53 mmol), was dissolved in dichloromethane (1 mL) and treated with triethylamine (0.5 mL, 3.59 mmol) and trimethylsilylcyanide (0.8 mL, 6.01 mmol) at ambient for 2 h and then the mixture was concentrated in vacuo to afford 1-(diphenylmethyl)-3-[(trimethylsilyl)oxy]azetidine-3-carbonitrile (774 mg, 2.30 mmol, 91% yield) as a yellow solid. 1-(diphenylmethyl)-3[(trimethylsilyl)oxy]azetidine-3-carbonitrile (250 mg, 0.744 mmol) was dissolved in dichloromethane (2 mL) at 0° C. and concentrated sulfuric acid (0.2 mL) was added dropwise. The mixture was stirred at ambient for 2 h and then was cooled to 0° C. and 25% ammonium hydroxide solution was added carefully dropwise to pH ˜10-11. The mixture was extracted twice with dichloromethane. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a residue which was triturated with hexanes/ether to afford 1-(diphenylmethyl)-3-hydroxyazetidine-3-carboxamide (160 mg, 0.567 mmol, 76% yield) as an off-white solid: 1H NMR (400 MHz, CDCl3): 7.92 (br s, 1H), 7.39-7.34 (m, 4H), 7.33-7.27 (m, 4H), 7.27-7.19 (m, 2H), 5.61 (br s, 1H), 4.45 (s, 1H), 4.34 (s, 1H), 3.50 (dd, 2H), 3.20 (dd, 2H); MS (EI) for C17H18N2O2: 283 (MH+).
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.N1C=CC=CC=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH:1]1([NH:5][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: NC1CCC1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NC1CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
To a stirred solution of cyclobutylamine (0.400 g, 5.6 mmol), N,N-diisopropylethylamine (0.930 mL, 5.6 mmol) and pyridine (0.455 mL, 5.6 mmol) in methylene chloride (10 mL) at 0° C. was slowly added methanesulfonyl chloride (0.435 mL, 5.6 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 16 hrs. The mixture was concentrated and the residue purified by silica gel chromatography (0-80% ethyl acetate/hexane) to afford the product as a low melting solid (0.82 g, 98%). 1H NMR (300 MHz, CDCl3) δ 4.62 (br s, 1H), 3.94 (m, 1H), 2.94 (s, 3H), 2.50-2.30 (m, 2H), 2.10-1.85 (m, 2H), 1.85-1.60 (m, 2H).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH:4]([OH:20])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH3:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[CH3:27]N(C)C=O>>[CH2:27]([O:20][CH:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][CH:2]=[CH2:1])[C:23]1[CH:22]=[CH:21][CH:26]=[CH:25][CH:24]=1
Reactant: CCCCCC
Reactant: C=CCC(O)CCCCCCCCCCCCCCC
Reactant: CN(C)C=O
Product: C=CCC(CCCCCCCCCCCCCCC)OCc1ccccc1
Temperature: 25 °C
Yield: 72 %

Procedure:
To a solution of 11.0 g of 1-nonadecen-4-ol in 60 ml of dimethylformamide was added hexane-washed sodium hydride (from 2.34 g of a 50% oil dispersion). The reaction mixture was heated to 50° and 4.6 ml of benzyl bromide was added. The mixture was cooled to room temperature, quenched by the addition of water, and concentrated. The concentrate was diluted with water and then extracted with diethyl ether. The combined extracts were washed with water, dried over anhydrous sodium sulfate and concentrated to an oil. Purification of the oil by high pressure liquid chromatography utilizing diethyl ether/hexane (1:99) yielded 10.5 g (72%) of 4-benzyloxy-1-nonadecene as a liquid.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([C:13]3[O:14][C:15]4[C:21]([C:22]([O:24]C)=O)=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH4+:27]>C(O)C>[N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:27])=[O:24])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2nc(-c3cccc(CN4CCCC4)c3)oc12
Solvent: O
Solvent: CCO
Product: NC(=O)c1cccc2nc(-c3cccc(CN4CCCC4)c3)oc12
Temperature: 30 °C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
Methyl 2-(3-(pyrrolidin-1-ylmethyl)phenyl)benzo[d]oxazole-7-carboxylate (56 mg, 0.18 mmol) and ammonium water (50.4 mg, 1.44 mmol) were added to ethanol (30 mL) and the mixture was stirred at 30° C. for 1 hr. The resulting mixture was evaporated under reduced pressure and purified with Pre-HPLC to obtain 2-(3-(pyrrolidin-1-ylmethyl)phenyl)benzo[d]oxazole-7-carboxamide (14 mg, yield 22%). 1H-NMR (400 MHz, DMSO-d6) δ 1.92 (s, 4H), 3.19 (s, 4H), 4.42 (s, 2H), 7.49 (s, 1H), 7.70-7.94 (m, 6H), 8.35-8.43 (d, J=32 Hz, 2H); LC-MS (ESI) m/z 322 [M+1]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:37])([F:36])[C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[C:13]([C:32]([O:34][CH3:35])=[O:33])[C:14]3[NH:15][C:16]4[CH:17]=[C:18]([O:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[CH:19]=[CH:20][C:21]=4[C:22]=3[N:23]=2)[CH:8]=[CH:9][CH:10]=1.Br[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=1>CN(C=O)C>[CH3:47][O:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][N:15]2[C:16]3[CH:17]=[C:18]([O:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[CH:19]=[CH:20][C:21]=3[C:22]3[N:23]=[C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([F:3])([F:36])[F:37])[CH:6]=4)[CH:12]=[C:13]([C:32]([O:34][CH3:35])=[O:33])[C:14]2=3)=[CH:41][CH:42]=1
Reactant: COc1ccc(CBr)cc1
Reactant: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc(OS(=O)(=O)C(F)(F)F)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c3ccc(OS(=O)(=O)C(F)(F)F)cc3n(Cc3ccc(OC)cc3)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 36.3 %

Procedure:
Sodium hydride (22 mg, 0.54 mmol, 60% dispersion in oil) was added to an ice-cooled stirred solution of methyl 2-(3-(trifluoromethyl)phenyl)-7-(trifluoromethylsulfonyloxy)-5H-pyrido[3,2-b]indole-4-carboxylate (200 mg, 0.386 mmol) in DMF (4 ml). This was left stirring until gas evolution stopped. 1-(bromomethyl)-4-methoxybenzene (0.072 ml, 0.502 mmol) was added and the reaction was kept in the ice bath for 2 hr. After an additional 1 hr at RT, the reaction was quenched with a saturated aqueous solution of NH4Cl solution and extracted with EtOAc. The organic extracts were washed with water (5×), brine, and dried with sodium sulfate. Removal of the solvent, followed by radial chromatography (step gradient elution with hexane containing 0 to 5% DCM) afforded methyl 5-(4-methoxybenzyl)-2-(3-(trifluoromethyl)phenyl)-7-(trifluoromethylsulfonyloxy)-5H-pyrido[3,2-b]indole-4-carboxylate (91 mg, 0.14 mmol, 37% yield). MS (ESI) m/z 639.1 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 8.55 (1H, d, J=8.55 Hz), 8.42 (1H, s), 8.33 (1H, d, J=7.63 Hz), 8.08 (1H, s), 7.59-7.71 (2H, m), 7.40 (1H, d, J=2.14 Hz), 7.29 (1H, dd, J=8.55, 2.14 Hz), 6.88 (2H, d, J=8.85 Hz), 6.76 (2H, d, J=8.85 Hz), 5.71 (2H, s), 3.86 (3H, s), 3.73 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:24]1[C:25](=[O:39])[N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:27]=[C:28]([NH2:30])[CH:29]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:40][C:41]1[CH:55]=[CH:54][C:44]([CH2:45][N:46]2[CH:50]=[C:49]([C:51](Cl)=[O:52])[CH:48]=[N:47]2)=[CH:43][CH:42]=1>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:24]1[C:25](=[O:39])[N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:38])[CH3:37])[CH:27]=[C:28]([NH:30][C:51]([C:49]2[CH:48]=[N:47][N:46]([CH2:45][C:44]3[CH:54]=[CH:55][C:41]([CH3:40])=[CH:42][CH:43]=3)[CH:50]=2)=[O:52])[CH:29]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN1CCN(c2ccc3c(c2)cc(-c2cc(N)cn(COCC[Si](C)(C)C)c2=O)n3C(=O)OC(C)(C)C)CC1
Reactant: Cc1ccc(Cn2cc(C(=O)Cl)cn2)cc1
Product: Cc1ccc(Cn2cc(C(=O)Nc3cc(-c4cc5cc(N6CCN(C)CC6)ccc5n4C(=O)OC(C)(C)C)c(=O)n(COCC[Si](C)(C)C)c3)cn2)cc1

Procedure:
The title compound was prepared by the route outlined in Scheme 10 and using the experimental from Example 115, Step 4, with intermediate (10e), 2-[5-amino-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(4-methyl-piperazin-1-yl)-indole-1-carboxylic acid tert-butyl ester (0.1 g, 0.18 mmol) and 1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl chloride (0.047 g, 0.2 mmol). The resultant crude product was purified by flash chromatography on SiO2 eluting with dichloromethane—8% methanol/dichloromethane (gradient) to afford the desired title compound as a pale brown solid, 0.107 g, 79%.
Reaction SMILES: [H-].[Na+].[CH:3]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:4]=1[CH2:5][C@@H:6]1[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C@@H:7]12.I[CH3:20].O>O1CCCC1>[CH3:20][N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C@H:6]2[CH2:5][C:4]3[C:15]([C@@H:7]12)=[CH:16][CH:17]=[CH:18][CH:3]=3
Reactant: CI
Reactant: c1ccc2c(c1)C[C@@H]1c3ccccc3N[C@H]21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN1c2ccccc2[C@H]2Cc3ccccc3[C@H]21
Reaction time: 1 h

Procedure:
A flame dried flask was charged with sodium hydride (60 mg, 2.5 mmol), and tetrahydrofuran (THF) (5 cm3) protected under an atmosphere of nitrogen. To the stirring suspension was added cis-4b,5,9b,10-tetrahydroindeno[1,2-b]indole (500 mg, 2.4 mmol) in THF (5 cm3) dropwise. The reaction was stirred for 1 hour, a pink colour developing. Iodomethane (0.2 cm3) was added, and the solution was stirred overnight. Water (5 cm3) was added, and the THF removed in vacuo. The colourless solid thus obtained was filtered, and dried in a vacuum desiccator. The product was dissolved in 5% ethyl acetate petrol (60°-80° C.) and filtered through a pad of flash silica. After evaporation of the solvent in vacuo, the title compound was obtained as a colourless solid. Yield: 450 mg (85%). M.p. 76°-77° C. 1H NMR (CDCl3) δ: 3.0 (3H, s,), 3.1 (1H, dd,), 3.4 (1H, dd,), 4.1 (1H, ddd,), 4.9 (1H, d,), 6.4 (1H, d,), 6.7 (1H, dd,), 7.1-7.5 (6H, m,).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([N+:8]([O-])=O)=[CH:6][CH:7]=1>[Pd]>[OH:11][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[NH2:8]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: [Pd]
Product: Nc1ccc(F)cc1O
Reaction time: 12 h
Yield: 100.1 %

Procedure:
3-fluoro 6-nitrophenol (2 g, 11 mmol) was treated with 10% Pd/C(1 g) at 23° C. The reaction mixture was flushed with hydrogen gas and the reaction was allowed to stir 12 h before it was filtered through celite. The filtrate was concentrated in vacuo to afford the title compound (1.4 g, 77%). EI-MS m/z 169(M+H)+.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].Cl[C:8]1[N:13]=[C:12]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH3:25])=[O:23])[CH:17]=2)[C:11]([C:26]#[N:27])=[C:10]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]=1[C:34]#[N:35]>CN(C=O)C>[C:26]([C:11]1[C:12]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH3:25])=[O:23])[CH:17]=2)=[N:13][C:8]([O:3][CH2:2][CH2:1][OH:4])=[C:9]([C:34]#[N:35])[C:10]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)#[N:27]
Reactant: CNC(=O)c1cc(CSc2nc(Cl)c(C#N)c(-c3ccccc3)c2C#N)ccn1
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(CSc2nc(OCCO)c(C#N)c(-c3ccccc3)c2C#N)ccn1
Temperature: 115 °C
Reaction time: 0.25 h

Procedure:
22 mg (0.357 mmol) of 1,2-ethanediol are initially charged in 0.5 ml of DMF, and 4.8 mg (0.179 mmol) of sodium hydride are added. After 15 min at RT, 50 mg (0.119 mmol) of the compound from Example 25A are added and the reaction mixture is stirred at 115° C. overnight. After cooling, the reaction solution is purified by prep. HPLC.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[S:13])[S-:12].C([NH+](CC)CC)C.C([O:24][CH2:25][C:26]([CH2:28]Cl)=O)(=O)C.Cl>C(O)C>[OH:24][CH2:25][C:26]1[N:10]([C:3]2[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=2[F:1])[C:11](=[S:12])[S:13][CH:28]=1
Reactant: Fc1ccc(NC(=S)[S-])c(F)c1F
Reactant: CC(=O)OCC(=O)CCl
Agent: CC[NH+](CC)CC
Agent: Cl
Solvent: CCO
Product: OCc1csc(=S)n1-c1ccc(F)c(F)c1F
Reaction time: 0.33 h
Yield: 85 %

Procedure:
Triethylammonium N-(2,3,4-trifluorophenyl)dithiocarbamate (81.2 g) prepared in the same manner as in Reference Example 1 was added to ethanol (800 ml) and thereto 1-acetoxy-3-chloroacetone (37.7 g) was added dropwise at 5° to 7° C. with stirring over a period of 20 minutes. After stirring the mixture for 50 minutes, 10% solution of hydrogen chloride in ethanol (240 ml) was added and the mixture was refluxed for 3 hours. After the solvent was distilled off under the reduced pressure, cooled water was added to the residue and resultant was extracted with chloroform. The extract was washed with a NaCl solution and dried over anhydrous sodium sulfate, followed by distilling off the solvent under reduced pressure. The residue was recrystallized from a mixed solvent of hexane-ethyl acetate to give the title compound (59 g) as pale yellow crystals. The compound had physical properties identical to those of 4-hydroxymethyl-3-(2,3,4-trifluorophenyl)-2(3H)-thiazolethione prepared in the above Reference Example 18.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C[N:7]1CC[O:10]CC1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>ClCCl>[N:13]1([C:3]([NH2:7])=[O:4])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Cl:1][CH2:2][C:3]([OH:4])=[O:10]
Reactant: CN1CCOCC1
Reactant: O=C(Cl)CCl
Reactant: C1COCCN1
Solvent: ClCCl
Product: NC(=O)N1CCOCC1
Product: O=C(O)CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine chloroacetyl chloride (2.00 mL, 25.0 mmol) and N-methylmorpholine (2.76 mL, 25.0 mmol) in dichloromethane (100 mL). Cool in an ice-bath. Add morpholine (2.19 mL, 25.0 mmol) and stir in the ice-bath for 1 hour. Warm to ambient temperature and stir for 1 hour. Extract with cold aqueous 5% sulfuric acid solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to obtain chloroacetic acid morpholine carboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[NH:12][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:14][N:15]=1.[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1>[C:19]([O:18][C:17](=[O:23])[NH:16][C:13]1[NH:12][C:11]([CH2:10][S:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[NH:1][S:33]([C:25]2[O:24][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH:26]=2)(=[O:34])=[O:35])=[N:15][N:14]=1)([CH3:20])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)Nc1nnc(CSc2ccc(Cl)cc2N)[nH]1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1nnc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)[nH]1

Procedure:
Following General Procedure B, the title compound was prepared from tert-butyl (5-(((2-amino-4-chlorophenyl)thio)methyl)-4H-1,2,4-triazol-3-yl)carbamate (330 mg, 0.925 mmol) and benzofuran-2-sulfonyl chloride (200 mg, 0.925 mmol) in pyridine (2 ml).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@@H:15]1[CH2:19][CH2:18][N:17](C(OCC2C=CC=CC=2)=O)[CH2:16]1)[C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[C].[Pd].C(O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([C@@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)[C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(c1ccco1)[C@@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(c1ccco1)[C@@H]1CCNC1
Reaction time: 4 h
Yield: 98.1 %

Procedure:
An ethanol (10 ml) solution of 3-(R)-[1-tert-butoxycarbonylamino-1-(2-furyl)methyl]-1-benzyloxycarbonylpyrrolidine [F1] (507 mg, 1.37 mmol) was mixed with 10% palladium-carbon catalyst (53.8% moisture, 500 mg), and catalytic hydrogenation was carried out at room temperature for 4 hours under ordinary pressure. The reaction solution was filtered and the solvent of the filtrate was evaporated under a reduced pressure to obtain 358 mg of the crude title compound as colorless crystals. This was used in the subsequent reaction without purification.
Reaction SMILES: C(N1[CH2:8][CH2:7][O:6]CC1)C.CN(C(ON1N=N[C:19]2[CH:20]=C[CH:22]=[CH:23][C:18]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.O.[CH3:32]N(C=O)C>>[CH3:20][CH2:19][CH2:18][CH2:23][CH2:22][CH2:7][CH3:8].[CH:7]([O:6][CH:23]([CH3:22])[CH3:18])([CH3:8])[CH3:32]
Reactant: CN(C)C=O
Reactant: CCN1CCOCC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Product: CC(C)OC(C)C
Product: CCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of the product of example 1i (220 mg) and the product of example 23a (145 mg) in DMF (1.5 ml) was added N-ethylmorpholine (100 μl) and TBTU (200 mg). The reaction mixture was stirred at room temperature for 2 h. Water (5 ml) was added, followed by filtration and drying of the precipitate. Trituration with heptane/diisopropylether afforded the product.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Pr+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.FC(F)(F)S(O)(=O)=O.[C:34]1([O:40][CH3:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[C:42]1([CH3:51])[CH:47]=[CH:46][C:45]([C:48](O)=[O:49])=[CH:44][CH:43]=1>C1(C)C=CC=CC=1.O>[CH3:41][O:40][C:34]1[CH:39]=[CH:38][C:37]([C:48]([C:45]2[CH:46]=[CH:47][C:42]([CH3:51])=[CH:43][CH:44]=2)=[O:49])=[CH:36][CH:35]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: COc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Pr+3]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C(=O)c2ccc(C)cc2)cc1
Reaction time: 22 h
Yield: 59.7 %

Procedure:
Praseodymium (III) trifluoromethanesulfonate (1.18 g as a wet solid), trifluoromethanesulfonic acid (0.30 g), anisole (2.38 g) and para-toluic acid (2.72 g) were refluxed together in 175 mL toluene with azeotropic removal of the lower water layer (Dean-Stark apparatus). After 22 hours, the mixture was cooled and extracted with 3×25 mL water, then by 2×25 mL saturated sodium bicarbonate solution. The organic layer was dried using anhydrous sodium sulfate, filtered, then concentrated down in vacuo to give crude 4-methoxy-4′-methylbenzophenone (2.7 g, 60% yield) as a cream-colored crystalline solid.
Reaction SMILES: I[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[N:10]([CH3:15])[C:9]2=[O:16])=[CH:4][CH:3]=1.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)#[CH:18].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:15][N:10]1[C:11]([CH3:14])([CH3:13])[CH2:12][N:8]([C:5]2[N:6]=[N:7][C:2]([C:18]#[C:17][C:19]3[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)=[CH:3][CH:4]=2)[C:9]1=[O:16]
Reactant: CN1C(=O)N(c2ccc(I)nn2)CC1(C)C
Reactant: C#Cc1cccc(C)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(C#Cc2ccc(N3CC(C)(C)N(C)C3=O)nn2)c1
Temperature: 60 °C
Yield: 24.9 %

Procedure:
To a solution of 1-(6-iodopyridazin-3-yl)-3,4,4-trimethylimidazolidin-2-one (Example 154, step 4) (75 mg, 226 μmol), 1-ethynyl-3-methylbenzene (44.6 mg, 49.5 μl, 384 μmol, 1.7 equiv.), triethylamine (68.5 mg, 94.4 μl, 677 μmol, 3 equiv.), bis(triphenylphosphine)palladium (II) chloride (9.51 mg, 13.5 μmol, 0.06 equiv.) and triphenylphosphine (1.78 mg, 6.77 μmol, 0.03 equiv.) in 2 ml of THF was added under an Argon atmosphere copper (I) iodide (1.29 mg, 6.77 μmol, 0.03 equiv.). The suspension was warmed to 60° C. for 2 hours, taken up in 5 ml of ethyl acetate and adsorbed on 4 g of silica. Purification by flash chromatography on silicagel using a heptane to 50% ethyl acetate/heptane gradient yielded the title compound as a crystalline light yellow solid (18 mg, 25% yield), MS: m/e=321.2 (M+H+).
Reaction SMILES: N1C=CC=C(CN)C=1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][NH2:16].FC1C=CC(CN2[C@@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1.[CH3:41][C:42]1[N:43]=[C:44]([N:50]2[CH2:54][C@@H:53]([CH3:55])[N:52]([CH2:56][C:57]3[CH:62]=[CH:61][C:60]([C:63]([F:66])([F:65])[F:64])=[CH:59][CH:58]=3)[C:51]2=[O:67])[S:45][C:46]=1[C:47](O)=[O:48]>>[CH3:41][C:42]1[N:43]=[C:44]([N:50]2[CH2:54][C@@H:53]([CH3:55])[N:52]([CH2:56][C:57]3[CH:62]=[CH:61][C:60]([C:63]([F:64])([F:66])[F:65])=[CH:59][CH:58]=3)[C:51]2=[O:67])[S:45][C:46]=1[C:47]([NH:16][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=1)=[O:48]
Reactant: NCc1ccccn1
Reactant: Cc1nc(N2C[C@@H](C)N(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(N2C[C@@H](C)N(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)NCc1ccccn1

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with pyridin-2-ylmethanamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (R)-4-methyl-2-(4-methyl-2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid, the title compound was obtained as a solid (61%): mp 136-137° C. (ethyl acetate/hexane); 1H NMR (300 MHz, DMSO-d6) δ 8.55-8.49 (m, 2H), 7.79-7.71 (m, 3H), 7.56 (d, J=8.1 Hz, 2H), 7.31-7.24 (m, 2H), 4.67 (d, J=16.1 Hz, 1H), 4.49-4.43 (m, 3H), 4.22 (dd, J=10.1, 9.1 Hz, 1H), 3.84-3.77 (m, 1H), 3.56 (dd, J=10.1, 6.8 Hz, 1H), 2.49 (s, 3H), 1.22 (d, J=6.2 Hz, 3H); MS (ES+) m/z 489.9 (M+1).