Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:19]=1[O:20][CH2:21][C:22]#[N:23]>CN(C=O)C.CCOCC>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH2:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:19]=1[O:20][CH2:21][C:22]#[N:23]
Reactant: OCc1cccc(O)c1
Reactant: Cc1cccc(CBr)c1OCC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cccc(COc2cccc(CO)c2)c1OCC#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-hydroxybenzyl alcohol (202 mg, 1.63 mmol) in DMF (5.4 mL) is added K2CO3 (247 mg, 1.79 mmol) and (2-bromomethyl-6-methyl-phenoxy)-acetonitrile (430 mg, 1.79 mmol, example 24). Heated resulting mixture to 60° C. and stirred for 3 hrs then cooled to room temp and diluted with ether. Washed organic layer with water, brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 30% ethyl acetate in hexanes) to give the title compound. MS (EI) 283 (M)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][C:5](=[O:7])/[C:4](=[CH:8]/[C:9]([O:11][Si](C(C)(C)C)(C)C)=[O:10])/[O:3]1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:19])[O:3][C:4](=[CH:8][C:9]([OH:11])=[O:10])[C:5](=[O:7])[O:6]1
Reactant: CC1(C)OC(=O)/C(=C/C(=O)O[Si](C)(C)C(C)(C)C)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC1(C)OC(=O)C(=CC(=O)O)O1
Reaction time: 1 h
Yield: 62 %

Procedure:
The crude (Z)-2,2-dimethyl-5-(tert-butyldimethylsilyloxycarbonylmethylene)-1,3-dioxolan-4-one (72.4 mmol) in tetrahydrofuran (50 ml) was treated at 22° C. with acetic acid (13 ml, 0.227 mmol) followed by 73 ml (73.0 mmol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. After 1 h at 22° C., the reaction mixture was diluted with ethyl acetate (500 ml), washed with water, brine and dried (anhydrous magnesium sulfate). Evaporation of the solvent under reduced pressure and trituration of the residual solid with toluene (50 ml) gave 7.70 g (62% yield for 3 steps) of the title Z-isomer as a white crystalline solid. Concentration of the mother liquors yielded another 0.2 g of a 75:25 mixture of Z and E isomers. Z-Isomer; 1H NMR (400 MHz, CDCl3) δ: 1.78 (s, 3), 5.89 (s, 1). E-Isomer: 1H NMR (400 MHz, CDCl3) δ: 1.80 (s, 3), 6.03 (s, 1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:42])[C@@H:10]([NH:22][C:23](=[O:41])[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([CH:36](OC)[O:37]C)[CH2:32][CH2:31]2)=[CH:26][CH:25]=1)[CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:42])[C@@H:10]([NH:22][C:23](=[O:41])[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:31][CH2:32][CH:33]([CH:36]=[O:37])[CH2:34][CH2:35]2)=[CH:26][CH:25]=1)[CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)C1CCN(c2ccc(C(=O)N[C@@H](CC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=CC1CCN(c2ccc(C(=O)N[C@@H](CC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (2S)-2-{[4-(4-(dimethoxymethyl)piperidin-1-yl)benzoyl]-amino}-butanedioic acid dibenzyl ester (0.21 g, 0.4 mmol) in methylene chloride (10 mL) containing trifluoroacetic acid (0.2 ml, 2.6 mmol) was stirred at ambient temperature for 1 hour. The reaction was concentrated in vacuo to give the product which was used directly in the next step.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[C:21]2[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][C:22]2=[CH:23][N:24]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]2[CH:27]=[C:26]([C:28]([NH:10][NH:9][C:1]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)=[O:8])=[O:29])[NH:25][C:22]2=[CH:23][N:24]=1
Reactant: NNC(=O)c1cccnc1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NNC(=O)c1cc2cc(Cl)ncc2[nH]1)c1cccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of nicotinic acid hydrazide (35 mg, 0.25 mmol) in DMF (5 mL) was added triethylamine (88 μL, 0.64 mmol), 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 8, 50 mg, 0.25 mmol), HOBt (34 mg, 0.25 mmol) and EDCI (50 mg, 0.28 mmol). The mixture was allowed to stir at rt for 16 h. The solvent was removed in vacuo and the residue was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to give an oil, which was purified by flash chromatography on silica gel (dichloromethane/methanol, 9/1) to give the title compound. m/z (ES+)=316 [M+H]+; RT=2.62 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.Cl[CH2:15][CH2:16][N:17]([CH3:19])[CH3:18].Cl>C(Cl)(Cl)Cl>[CH3:18][N:17]([CH3:19])[CH2:16][CH2:15][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:8][CH:9]=1
Reactant: Oc1ccc(-c2ccncc2)cc1
Reactant: CN(C)CCCl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN(C)CCOc1ccc(-c2ccncc2)cc1

Procedure:
1 g of 4-pyridin-4-yl-phenol, 1.3 g of (2-chloro-ethyl)-dimethyl-amine.HCl and 2.42 g of K2CO2 were heated for 48 h under reflux. The mixture was diluted with chloroform, washed with brine and dried over MgSO4. After evaporation to dryness the residue was chromatographed on silicagel with CH2Cl2/MeOH/NH3conc=90:10:1 to give dimethyl-[2-(4-pyridin-4-yl-phenoxy)-ethyl]-amine as brown powder.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH2:8][CH:9]=[O:10].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH2:8][CH:9]1[O:13][CH2:12][CH2:11][O:10]1
Reactant: O=CCC1CC2C=CC1C2
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C1=CC2CC1CC2CC1OCCO1
Yield: 95 %

Procedure:
40.0 g of (5-norbornen-2-yl)acetoaldehyde, 23.0 g of ethylene glycol, 120 ml of toluene and 200 mg of p-toluenesulfonic acid were mixed and heated under reflux for one hour while the water formed was removed through an H tube. The reaction mixture was allowed to cool down and poured into 50 ml of saturated sodium bicarbonate water. The resulting mixture separated into two layers. The organic layer was washed with water and saturated sodium chloride water, dried over anhydrous sodium sulfate, and concentrated in vacuum. It was further purified by vacuum distillation, obtaining 50.3 g of 2-(5-norbornen-2-yl)methyl-1,3-dioxolane (boiling point 63° C./200 Pa, yield 95%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1>CCO>[Cl:1][C:2]1[N:7]=[C:6]([N:9]2[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CCOC(=O)C1CCCNC1
Solvent: CCO
Product: CCOC(=O)C1CCCN(c2ccnc(Cl)n2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 2,4-dichloropyrimidine (Alfa Aesar, 10 g, 65.8 mmol) and TEA (Sigma-Aldrich, 9.15 mL, 65.8 mmol) in EtOH (68.5 mL) at 0° C. was added ethyl piperidine-3-carboxylate (Sigma-Aldrich, 10.64 mL, 65.8 mmol) in EtOH (13.70 mL). The reaction was then allowed to warm to room temperature while stirring. After 1 hour, the reaction was concentrated and the residue was purified by chromatography through a 340 g silica gel column, eluting with 10% to 80% EtOAc/hexanes, to provide ethyl 1-(2-chloropyrimidin-4-yl)piperidine-3-carboxylate as a colorless oil in 80% yield. 1H NMR (300 MHz, CDCl3) δ ppm 0.94 (t, J=6.94 Hz, 3H) 1.26 (d, J=9.35 Hz, 1H) 1.38-1.62 (m, 2H) 1.66-1.85 (m, 1H) 2.26 (m, 1H) 2.90-3.20 (m, 2H) 3.64 (m, 1H) 3.69-4.09 (m, 3H) 6.23 (d, J=5.85 Hz, 1H) 7.68 (d, J=5.99 Hz, 1H); ESI-MS M+H 270.0.
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=O.[CH3:31][NH2:32]>>[CH3:31][N:32]1[CH:2]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][N:21]([C:24]4[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=4)[CH2:22][CH2:23]3)=[CH:10][CH:9]=2)[CH2:3][CH2:4][C:5]1=[O:7]
Reactant: Cc1ccc(N2CCN(CCCCc3ccc(C(=O)CCC(=O)O)cc3)CC2)cc1
Reactant: CN
Product: Cc1ccc(N2CCN(CCCCc3ccc(C4CCC(=O)N4C)cc3)CC2)cc1

Procedure:
4-Oxo-4-[4-(4-(4-(4-methylphenyl)piperazin-1-yl)butyl)phenyl]butyric acid and methylamine are reacted together to give N-methyl-5-[4-(4-(4-(4-methylphenyl)piperazin-1-yl)butyl)phenyl]pyrrolidin-2-one.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22]([O:24]CC)=[O:23])=[CH:14][C:13]=2[CH:27]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.C(O)C>[C:1]([C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22]([OH:24])=[O:23])=[CH:14][C:13]=2[CH:27]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=Cc2cc(C(=O)c3ccccc3)ccc2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1=Cc2cc(C(=O)c3ccccc3)ccc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 4.3 h
Yield: 62.8 %

Procedure:
The ester from Step 1 (0.24 g, 0.64 mmol) was dissolved in THF (2 mL) and ethanol (2 mL), treated with 2.5 N sodium hydroxide (1.5 mL, 3.8 mmol), and stirred at room temperature for 4.3 hours. The reaction mixture was concentrated in vacuo, acidified with 3N HCl yielding a solid. The solid was collected by filtration and was recrystallized from ethanol-water to yield a white solid (0.14 g, 64%): mp 269.8–270.8° C. 1H NMR (acetone-d6/300 MHz) 8.04 (s, 1H), 7.99 (d, 1H, J=2.0 Hz), 7.88 (dd, 1H, J=8.5 Hz 2.0 Hz), 7.79 (m, 2H), 7.68 (m, 1H), 7.57 (m, 1H), 7.23 (d, 1H, J=8.6 Hz), 5.98 (q, 1H, J=7.0 Hz). FABLRMS m/z 347 (M−H). ESHRMS m/z 347.0560 (M−H, Calc'd 347.0531). Anal. Calc'd for Cl18H11F3O4: C, 62.08; H, 3.18. Found: C, 61.48; H, 3.22.
Reaction SMILES: FC1C=C(N)C=CC=1OC1C=CN=C2C=C(C3N(C)C=CN=3)SC=12.[F:25][C:26]1[CH:47]=[C:46]([N+:48]([O-])=O)[CH:45]=[CH:44][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]2[CH:35]=[C:36]([C:38]3[N:39]=[CH:40][N:41]([CH3:43])[CH:42]=3)[S:37][C:30]=12>>[F:25][C:26]1[CH:47]=[C:46]([NH2:48])[CH:45]=[CH:44][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]2[CH:35]=[C:36]([C:38]3[N:39]=[CH:40][N:41]([CH3:43])[CH:42]=3)[S:37][C:30]=12
Reactant: Cn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Agent: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Product: Cn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1

Procedure:
Following the procedure described for the amine 9 (example 2, step 5) but substituting nitro-compound 8 for compound 11, title compound 12 was obtained as a red solid (82% yield). MS (m/z): 341.1 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[C:17]([C:40]([O:42]C)=[O:41])=[N:18][N:19]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=3)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1.[OH-].[Na+].CO.[Cl-].[NH4+]>O.C(OCC)(=O)C.O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[C:17]([C:40]([OH:42])=[O:41])=[N:18][N:19]([C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:20]=3)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1
Reactant: COC(=O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2ncc(-c3ccccn3)n2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: O=C(O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2ncc(-c3ccccn3)n2c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 77.4 %

Procedure:
A mixture of 228 mg methyl 4-[3-(pyridin-2-yl)imidazo-[1,2-a]pyridin-6-yl]-1-trityl-1H-pyrazole-3-carboxylate (compound in Example 366), 0.8 mL of 1 N aqueous sodium hydroxide, 5 mL methanol and 3 mL tetrahydrofuran was stirred at 50° C. for 4 hours. Saturated ammonium chloride, ethyl acetate and water were added to the reaction solution, and then the organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was evaporated. The resulting residue was crystallized from diisopropyl ether, triturated and dried under reduced pressure with a vacuum pump, to give 172 mg 4-[3-(pyridin-2-yl)imidazo-[1,2-a]pyridin-6-yl]-1-trityl-1H-pyrazole-3-carboxylic acid as pale brown crystals. From this carboxylic acid derivative, 78 mg of the title compound was obtained as a pale yellow amorphous under the same conditions as in Example 361.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[C:14]2[C:9]=1[CH2:10][N:11]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[C:12](=[O:29])[N:13]2[C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:28]>C(OCC)(=O)C.[Pd]>[NH2:18][C:16]1[CH:15]=[C:14]2[C:9]([CH2:10][N:11]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[C:12](=[O:29])[N:13]2[C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:17]=1
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc([N+](=O)[O-])cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(N)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-7-nitro-3,4-dihydroquinazolin-2(1H)-one (20.0 mg, 0.035 mmol) in ethyl acetate (2 mL) was added 10% Pd/C (14.5 mg) under argon. Hydrogen was bubbled through and the reaction mixture was stirred under hydrogen for 1.5 h. The reaction flask was purged with argon. The catalyst was filtered off washing with methanol. The filtrate was concentrated under reduced pressure to yield 7-amino-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one. Mass spectrum (ESI) 538.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:35]=[CH:34][C:6]2[N:7]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][C:24]=3[CH3:33])[C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2].N1C=CC=CC=1.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[C:42]([N:11]1[C@@H:10]([CH3:12])[C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:8](=[O:21])[N:7]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][C:24]=2[CH3:33])[C:6]2[CH:34]=[CH:35][C:3]([C:1]#[N:2])=[CH:4][C:5]1=2)(=[O:44])[CH3:43]
Reactant: CC(=O)Cl
Reactant: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)Nc2cc(C#N)ccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1c2cc(C#N)ccc2N(Cc2c(C)ccc3ccccc23)C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To a 0° C. solution of tert-butyl(3S,4S)-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (364 mg, 774 μmol) in CH2Cl2 (7.74 ml) was added pyridine (306 mg, 315 μl, 3.87 mmol), followed by acetyl chloride (71.8 μl, 1.01 mmol), dropwise. The reaction was stirred at 0° C. for 1 h, then allowed to warm to rt and stirred for an additional 15 h, then quenched by the addition of H2O and extracted with CH2Cl2. The combined organic layers were washed with sat. aq. NaHCO3 and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(3S,4S)-5-acetyl-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (235 mg, 59%) as a white solid. MS m/z 535 (MNa)+.
Reaction SMILES: [C:1]([N:4]([CH3:6])[NH2:5])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)(Cl)Cl.[CH2:18]([O:20][P:21]([O-:25])[O:22][CH2:23][CH3:24])[CH3:19]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.ClCCl>[C:1]([N:4]([CH3:6])[NH:5][P:21]([O:22][CH2:23][CH3:24])([O:20][CH2:18][CH3:19])=[O:25])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C)N
Reactant: CCOP([O-])OCC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOP(=O)(NN(C)C(C)=O)OCC

Procedure:
A mixture of 1-acetyl-1-methyl hydrazine (7.84 g., 0.09 mole), potassium carbonate (18.44 g., 0.13 mole) and triethylbenzyl ammonium chloride (0.2 g,) was stirred vigorously at reflux with dichloromethane (90 ml) and carbon tetrachloride (55 ml) for 30 minutes. A solution of diethylphosphite (12.29 g, 0.09 mole) in dichloromethane (18 ml) was then added dropwise to this refluxing mixture and the mixture stirred and refluxed for an additional 20 hours. The mixture was then filtered and the filtrate dried over anhydrous magnesium sulfate. The dried filtrate, then was evaporated down to an oil which was subjected to high vacuum for 2 or 3 hours to yield a liquid product, characterized by proton NMR, infra-red and mass spectroscopy as the subject compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([S:7]([NH2:10])(=[O:9])=[O:8])[N:4]=[CH:3]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:51]([O:53][C:54](=[O:75])[C@H:55]([O:57][C:58]1[CH:63]=[C:62](Cl)[N:61]=[C:60]([S:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[C:69]([F:73])[C:68]=2[F:74])[N:59]=1)[CH3:56])[CH3:52]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:51]([O:53][C:54](=[O:75])[C@H:55]([O:57][C:58]1[CH:63]=[C:62]([NH:10][S:7]([C:5]2[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=2)(=[O:9])=[O:8])[N:61]=[C:60]([S:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[C:69]([F:73])[C:68]=2[F:74])[N:59]=1)[CH3:56])[CH3:52]
Reactant: Cn1cnc(S(N)(=O)=O)c1
Reactant: CCOC(=O)[C@@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)c2cn(C)cn2)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1, step iv) using a mixture of 1-methyl-1H-imidazole-4-sulfonamide (0.19 g), tris(dibenzylideneacetone)dipalladium (0) (71 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (52 mg), cesium carbonate (0.38 g), 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester (the product of Example 23 step i) (0.30 g) and dioxane (10 mL). Purification was by column chromatography on silica gel using EtOAc/isohexane (1:1) as eluent to give the subtitle compound as an oil. Yield: 0.28 g
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]#[N:10])[N:3]=1.[CH2:11]([Mg]Br)[CH3:12].B(F)(F)F.CCOCC.O>C1COCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2([NH2:10])[CH2:12][CH2:11]2)[N:3]=1
Reactant: Cc1cc(C)nc(C#N)n1
Reactant: CC[Mg]Br
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: CC[Mg+]
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)nc(C2(N)CC2)n1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 4,6-dimethylpyrimidine-2-carbonitrile (0.2 g, 1.5 mmol) in anhydrous THF was added Ti(OiPr)4 (0.43 ml, 1.8 mmol, 1.2 eq.). After stirring for 15 min., Ethyl magnesium bromide (3.8 ml, 3.8 mmol, 2.5 eq.) in THF was added dropwise to the mixture at −78° C. (during the addition of EtMgBr the reaction mixture turned black). The reaction mixture was then stirred for an hour at room temperature, and then BF3.Et2O (0.320 ml, 2.2 mmol, 1.5 eq.) was added slowly to the mixture at 0° C. After the addition completed, the reaction was stirred at room temperature for one hour. 50 ml of water was added to the reaction mixture which was then filtered through Celite. The filtrate was basified with 10% NaOH solution (pH=9) and then extracted with DCM (25 ml×2) and washed with brine. The organic layer was concentrated to yield crude product was taken for the next step without purification.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[NH:11])[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:20])=O>O1CCCC1>[Cl:20][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[NH:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: N=C(NCC(F)(F)F)Nc1cccc(CO)c1
Solvent: C1CCOC1
Product: N=C(NCC(F)(F)F)Nc1cccc(CCl)c1

Procedure:
The above guanidine (1.121 g.) was dissolved in dry tetrahydrofuran (40 ml.) and thionyl chloride (0.7 ml.) was added. After 45 minutes at 30°-40° volatile material was evaporated in vacuo to give 1-(3-chloromethylphenyl)-3-(2,2,2-trifluoroethyl)guanidine as a syrup.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[CH3:29][NH2:30]>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:26])([CH3:25])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([NH:30][CH3:29])=[O:20])[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)O)C1(C)C
Reactant: CN
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)NC)C1(C)C

Procedure:
The product from Example 173 and methylamine hydrochloride (Aldrich) were processed using the method described in Example 178 to afford the title compound. 1H NMR (DMSO-d6) δ 0.47 (s, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.19 (s, 3H), 1.22 (s, 3H), 1.26-1.33 (m, 2H), 1.36-1.45 (m, 1H), 1.57 (s, 9H), 1.57-1.68 (m, 3H), 1.96-2.08 (m, 1H), 2.57 (d, J=4.7 Hz, 3H), 2.60-2.67 (m, 3H), 2.72-2.83 (m, 1H), 4.78 (q, J=4.5 Hz, 1H), 8.50 (s, 1H). MS (ESI+) m/z 408 (M+H)+. Anal. calcd. for C22H37N3O2S: C, 64.83; H, 9.15; N, 10.31. Found: C, 64.20; H, 9.03; N, 10.25.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][C:4]1=[O:13].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1COCC1>[CH2:26]([N:3]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][C:4]1=[O:13])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15]
Reactant: CCCCCCCCCCCCBr
Reactant: CCOC(=O)C1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCN1C(=O)CCC1C(=O)OCC
Temperature: 25 °C

Procedure:
To a stirred solution of 1.92 g NaH (60%, washed with pet ether) in dry THF at room temperature under N2 was added dropwise a solution of 7.06 g of ethyl 2-pyrrolidone-5-carboxylate in 20 mL of THF. The mixture was refluxed for 1 h, cooled to room temperature, followed by dropwise addition of 1.3 equivalents of 1-bromododecane. After additional reflux overnight and workup, the crude oil was subjected to flash chromatography (silica, 8:2 pet ether/EtOAc) to give 3.14 g of ethyl 1--N-dodecyl-2-pyrrolidone-5-carboxylate as a clear oil: NMR (CDCl3) δ 4.2(m), 3.68(m), 2.9(m), 2.6-2.2(m), 2.1(m), 1.6-1.0(m), 0.9(t).