Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].F[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17]>C1COCC1>[CH:1]1([CH2:4][O:5][C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[N+:16]([O-:18])=[O:17])[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1OCC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
Cyclopropylmethanol (15 g, 207 mmol) was added to a stirred suspension of NaH (60% in mineral oil, 8.37 g) in 200 mL THF over 15 min at 0° C. under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. A solution of 2,4-difluoro-1-nitrobenzene (30 g, 187 mmol) in 200 mL THF was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 2 h and then poured into ice water. The reaction mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to give 22.0 g of product as orange oil (86%).
Reaction SMILES: Br[C:2]1[C:3]([NH2:14])=[N:4][CH:5]=[C:6]([CH2:8][CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[N:7]=1.[CH2:15]([NH:22][C:23](=[O:40])[C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][C:25]=1[F:39])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.CO>[NH2:14][C:3]1[C:2]([C:27]2[CH:28]=[CH:29][C:24]([C:23]([NH:22][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:40])=[C:25]([F:39])[CH:26]=2)=[N:7][C:6]([CH2:8][CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:5][N:4]=1
Reactant: CS(=O)(=O)CCc1cnc(N)c(Br)n1
Reactant: CC1(C)OB(c2ccc(C(=O)NCc3ccccc3)c(F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: COCCOC
Solvent: ClCCl
Product: CS(=O)(=O)CCc1cnc(N)c(-c2ccc(C(=O)NCc3ccccc3)c(F)c2)n1
Yield: 34 %

Procedure:
To 3-bromo-5-(2-(methylsulfonyl)ethyl)pyrazin-2-amine (126 mg, 0.405 mmol) was added N-benzyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (144 mg, 0.405 mmol), PdCl2(dppf)-CH2Cl2 adduct (33.1 mg, 0.040 mmol), DME (1.5 mL) and then sodium carbonate 2 M aqueous solution (0.607 mL, 1.214 mmol). The reaction was microwave at 125° C. for 12 min followed by LCMS. To the reaction was added 5 mL of DME and 5 mL of MeOH, filtered and concentrated to residue. The crude was dissolved in 2.5 mL of DMSO, filtered, purified by prep HPLC and lyophilized to TFA salt. To the TFA salt was added 200 mL of ethyl acetate, washed with saturated sodium carbonate (3×), water (3×), dried sodium sulfate, filtered and concentrated to constant mass to give 59 mg of the desired product 4-(3-amino-6-(2-(methylsulfonyl)ethyl)pyrazin-2-yl)-N-benzyl-2-fluorobenzamide as free base in 34% yield. LCMS (m/z): 429.2 (MH+), 0.65 min; 1H NMR (400 MHz, CD3OD) δ ppm 7.95 (s, 1H), 7.83 (t, J=7.6 Hz, 1H), 7.67 (dd, J=8.0, 1.4 Hz, 1H), 7.59 (dd, J=11.7, 1.2 Hz, 1H), 7.29-7.42 (m, 4H), 7.20-7.28 (m, 1H), 4.59 (s, 2H), 3.48-3.57 (m, 2H), 3.18 (dd, J=9.0, 6.7 Hz, 2H), 2.96 (s, 3H).
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:47])[C@@H:24]([NH:25][C:26](=[O:46])/[C:27](/[C:33]4[N:34]=[C:35]([NH:38]C(OC(C)(C)C)=O)[S:36][CH:37]=4)=[N:28]\[O:29][CH2:30][CH:31]=[CH2:32])[C@H:21]3[S:20][CH2:19][C:18]=2[S:48][CH2:49][S:50][C:51]2[N:52]=[N:53][NH:54][CH:55]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].C(O)C.Cl>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.O>[NH2:38][C:35]1[S:36][CH:37]=[C:33](/[C:27](=[N:28]/[O:29][CH2:30][CH:31]=[CH2:32])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:47])[N:22]3[C:17]([C:15]([OH:16])=[O:14])=[C:18]([S:48][CH2:49][S:50][C:51]4[N:52]=[N:53][NH:54][CH:55]=4)[CH2:19][S:20][C@H:21]23)=[O:46])[N:34]=1
Reactant: C=CCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCSc3c[nH]nn3)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Solvent: COc1ccccc1
Product: C=CCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(SCSc3c[nH]nn3)CS[C@H]12)c1csc(N)n1
Reaction time: 0.83 h
Yield: 49.8 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-(2-propenyloxyimino)acetamido]-3-(1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (376 mg: 0.46 mMol.) in a mixture of anisole (1.5 ml) and nitromethane (6 ml) at -30° C. is added a solution of aluminum chloride (0.37 g: 2.8 mMol.) in anisole (1.5 ml), and the mixture is stirred for 50 minutes. The reaction mixture is mixed with ethanol (2 ml) and stirred at the same temperature for 5 minutes and mixed with 1N-hydrochloric acid (5 ml) and water (200 ml). The aqueous layer is taken, washed with ethyl acetate, and concentrated under reduced pressure to remove remaining organic solvents. The resulting aqueous layer is subjected to chromatography over styrene- divinylbenzene copolymer (methanol: water=4:1). The eluting material is washed with ethyl acetate to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-propenyloxyimino)acetamido]-3-(1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid (127 mg) as white solid. Yield: 50%.
Reaction SMILES: CO[N:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[O:7][CH2:6][CH2:5]1.CON=C1C2C(=CC=C(C)C=2)OCC1>>[F:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[O:7][CH2:6][CH2:5][CH:4]2[NH2:3]
Reactant: CON=C1CCOc2ccc(F)cc21
Agent: CON=C1CCOc2ccc(C)cc21
Product: NC1CCOc2ccc(F)cc21

Procedure:
The title compound was prepared using the procedure as described in Example 7B, substituting the product of Example 10A for the product of Example 7A. 1H NMR (300 MHz, CDCl3) δ 7.03 (dd, 1H, J=9.1 and 3.1 Hz), 6.85 (m, 1H), 6.74 (m, 1H), 4.15-4.29 (m, 2H), 4.02 (m, 1H), 2.10-2.20 (m, 1H), 1.79-1.89 (m, 1H). MS (DCI) m/e 168 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:20][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[NH2:19])[CH2:11][C@@H:6]2[CH2:5][CH2:4]1.[F:21][C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:1][CH2:2][C@H:3]2[CH2:20][N:7]3[CH2:8][CH2:9][N:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=4[NH2:19])[CH2:11][C@@H:6]3[CH2:5][CH2:4]2)=[CH:24][CH:23]=1
Reactant: Oc1ccc(F)cc1
Reactant: Nc1cc(F)ccc1N1CCN2C[C@H](CO)CC[C@H]2C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1cc(F)ccc1N1CCN2C[C@H](COc3ccc(F)cc3)CC[C@H]2C1
Temperature: 25 °C
Reaction time: 96 h
Yield: 30.6 %

Procedure:
A solution of 4.12 g (14.8 mmol) of (7R,9aS)-7-hydroxymethyl-2-(2-amino-4-fluoro-phenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine, 2.48 g (22.2 mmol) of 4-fluorophenol and 4.65 g (17.7 mmol) of triphenylphosphine in 225 mL of THF was treated with 2.79 mL (17.7 mmol) of diethyl azodicarboxylate and stirred at room temperature for 4 days. The solvent was evaporated, the residue dissolved in 1:1 ethyl acetate:ethyl ether and the solution treated with HCl(g) in ether until precipitation ceased. The mixture was filtered and the solid washed repeatedly with ethyl acetate. The solid was dissolved in a mixture of chloroform and 1M sodium hydroxide, the layers separated, and the organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 60:40 ethyl acetate:hexane gave 1.69 g (30%) of the title compound. mp (.HCl) 144–149° C. HRMS calcd for C21H25F2N3O: 373.1966, found: 373.1958.
Reaction SMILES: N([O-])=O.[Na+].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[C:13]1[NH:14][NH:15][C:16]([C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])=[N:17][N:18]=1>O.C(O)(=O)C>[F:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([F:5])[C:7]=1[C:13]1[N:18]=[N:17][C:16]([C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])=[N:15][N:14]=1
Reactant: Fc1cccc(F)c1C1=NN=C(c2c(F)cccc2F)NN1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Fc1cccc(F)c1-c1nnc(-c2c(F)cccc2F)nn1
Yield: 85.6 %

Procedure:
A solution of 0.12 g of sodium nitrite in 1 ml of water is added dropwise to the suspension of 0.4 g of 3,6-bis(2,6-difluorophenyl)-1,2-dihydro-1,2,4,5-tetrazine prepared in the preceeding step c.)] in 2.5 ml of glacial acetic acid at room temperature while stirring. The progress of the reaction is followed by thin layer chromatography. After filtration the carmine crystals are washed with water until neutral to give 0.34 g of desired product. This crude product is recrystallized from a mixture of gasoline and acetone to give 0.251 g of pure title product of Example 2, m.p.: 213.5° C.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:3].[C:11](Cl)([Cl:13])=[O:12]>ClCCl.C1(C)C=CC=CC=1>[Cl:13][C:11]([O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N:2]([CH3:3])[CH3:1])[CH:5]=1)=[O:12]
Reactant: O=C(Cl)Cl
Reactant: CN(C)c1cccc(O)c1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN(C)c1cccc(OC(=O)Cl)c1

Procedure:
A solution of 3-(N,N-dimethylamino)phenol (1.0 g)in dichloromethane (20 ml) was added, dropwise, to a solution of phosgene in toluene (1.93M, 30 ml) previously cooled to -5°. The resulting mixture was stirred at a temperature between -5 to 0° to 30', then decanted and concentrated in vacuo to a brown oil (0.63 g). IR: 1784 (C=O), 1616 and 1572 (C=C) cm-1; 1H-NMR: 7.23 (m); 6.65 (dd); 6.53 (dd); 6.50 (m); 2.96 (s).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(OC(C)C)=CC=2)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:17]1([CH2:16][N:15]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:26][CH:27]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:32])=[O:3])=[CH:8][N:9]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(OC(C)C)cc2)s1
Agent: CC(C)Oc1ccc(NCC2CCCC2)cc1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: CC(C)Oc1ccc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)cc1

Procedure:
The title compound was prepared via {2-[3-(4-isopropoxy-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-isopropoxy-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]#[C:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][CH2:26][OH:27])=[CH:19][CH:18]=2)[CH:6]=1)=[O:4].CC1(C)C2CC1CCC2NS(C1C=CC(C#CCCO)=CC=1)(=O)=O>>[F:29][C:2]([F:1])([F:28])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][OH:27])=[CH:21][CH:22]=2)[CH:6]=1)=[O:4]
Reactant: O=C(c1cn(CC#Cc2ccc(C#CCCO)cc2)c2ccccc12)C(F)(F)F
Agent: CC1(C)C2CCC(NS(=O)(=O)c3ccc(C#CCCO)cc3)C1C2
Product: O=C(c1cn(CCCc2ccc(CCCCO)cc2)c2ccccc12)C(F)(F)F
Yield: 92 %

Procedure:
When the product of Step D was substituted for N-(6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-4-(4-hydroxybut-1-ynyl)benzene sulphonamide in Example 18, Step C, the identical process afforded the title compound in 92% yield, as pale paste. 1H-NMR (CDCl3) 8.40 (broad s, 1H); 7.86 (s, 1H); 7.37-7.32 (m, 3H); 7.11 (d, 2H, J=8.07 Hz); 7.05 (d, 2H, J=8.07 Hz); 4.19 (t, 2H, J=7.17 Hz); 3.72-3.63 (m, 4H); 2.66-2.59 (m, 4H); 1.68-1.60 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]3[N:23]([CH2:24][CH2:25][CH2:26][O:27][CH3:28])[C:22]4[C:29]([Cl:33])=[CH:30][CH:31]=[CH:32][C:21]=4[N:20]=3)[CH2:14]2)=[O:12])=[CH:4][CH:3]=1.[C:42]1(B(O)O)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:2]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]3[N:23]([CH2:24][CH2:25][CH2:26][O:27][CH3:28])[C:22]4[C:29]([Cl:33])=[CH:30][CH:31]=[CH:32][C:21]=4[N:20]=3)[CH2:14]2)=[O:12])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(Br)cc3)NC(=O)OC(C)(C)C)C2)nc2cccc(Cl)c21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(-c4ccccc4)cc3)NC(=O)OC(C)(C)C)C2)nc2cccc(Cl)c21
Temperature: 120 °C

Procedure:
tert-Butyl (R)-1-(4-bromophenyl)-4-((R)-3-(7-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (31A) (0.111 mmol max, crude oil) and phenylboronic acid (0.144 mmol, 0.018 g) were added to a 5 mL microwave vessel equipped with a magnetic stir bar. Dioxane (2 mL) and Na2CO3 (1 mL of a 2 M in aqueous solution) were then added and the reaction vessel was flushed with nitrogen gas. PdCl2(dppf) (0.006 mmol, 0.004 g) was added, the reaction vessel was sealed and placed in a microwave reactor and heated to 120° C. for 15 minutes. The reaction solution was then poured into water, extracted with ethyl acetate, and washed once with saturated aqueous sodium chloride. The organic layer was collected and subsequently dried with anhydrous Na2SO4 and filtered. This filtrate was collected, concentrated, and dried in-vacuo. This crude material was directly purified by preparative LC/MS (gradient 25-85% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-butyl (R)-1-(biphenyl-4-yl)-4-((R)-3-(7-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (31B) as a clear oil. ESI-MS: m/z 645.5 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@H:13]([C:22]([O:24][CH3:25])=[O:23])[CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]O)=[C:29]([N+:35]([O-:37])=[O:36])[CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[O:15][CH2:14][CH:13]([N:12]([S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:10])=[O:11])[CH2:31][C:30]1[CH:33]=[CH:34][C:27]([Cl:26])=[CH:28][C:29]=1[N+:35]([O-:37])=[O:36])[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)[C@H](COC1CCCCO1)NS(=O)(=O)c1ccc(OC)cc1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(COC1CCCCO1)N(Cc1ccc(Cl)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1.67 g (4.4 mmol) of (D,L) N-(4-methoxybenzenesulfonyl)-O-(2-tetrahydropyranyl) serine, methyl ester, 0.825 g (4.4 mol) of 4-chloro-2-nitrobenzyl alcohol and 1.16 g (4.4 mmol) of triphenylphosphine in 4.5 ml of tetrahydrofuran was added dropwise a solution of 0.766 g (4.4 mmol) of diethyl azodicarboxylate in 1 ml of tetrahydrofuran. The mixture was stirred at room temperature overnight and the solvent removed under vacuum. The residue was triturated with diethyl ether, filtered and the filtrate passed through a thin pad of hydrous magnesium silicate. The pad was washed with ethyl acetate and the total filtrate concentrated to dryness under vacuum to give 4.54 g of solid. The solid was chromatographed on silica gel with hexane-ethyl acetate (55:45) as solvent. The fractions containing product were combined and the solvent removed to give 0.55 g of oily solid; Mass spectrum (ES) 543.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])[O:8][CH:7]([C:17]([F:20])([F:19])[F:18])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2.[H-].[Na+].I[CH3:29].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([CH3:15])([CH3:16])[CH2:13][O:14][CH3:29])[O:8][CH:7]([C:17]([F:20])([F:19])[F:18])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2
Reactant: CI
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(C(C)(C)CO)cc2OC1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(C(C)(C)COC)cc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 6-chloro-7-(2-hydroxy-1,1-dimethylethyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylate (205 mg, 0.584 mmole) in 8 mL of dry DMF was added 86 mg of 60% NaH, and 0.5 mL of iodomethane. The mixture was stirred overnight at room temperature. Water was added, the mixture extracted with DCM, the combined organic extracts dried over Na2SO4, filtered, and evaporated. Chromatography of the residue over silica gel using DCM as eluent gave the title compound, 49 mg, as an oil.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[C:5]2[CH2:6][C:7]3([O:12][C:4]=2[C:3]=1[O:23][CH3:24])[CH2:11][CH2:10][CH2:9][CH2:8]3.C([Li])CCC.Cl.O>C1COCC1.CCCCCC>[CH3:24][O:23][C:3]1[C:4]2[O:12][C:7]3([CH2:11][CH2:10][CH2:9][CH2:8]3)[CH2:6][C:5]=2[C:13]([C:15]#[C:16][C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)=[CH:14][CH:2]=1
Reactant: COc1c(Br)cc(C#Cc2ccncc2)c2c1OC1(CCCC1)C2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C#Cc2ccncc2)c2c1OC1(CCCC1)C2
Reaction time: 1 h
Yield: 17.6 %

Procedure:
Under an argon atmosphere, a solution (2.6 ml) of Compound 142b (0.1 g) obtained in Step B in THF was cooled to −78° C., and then a 1.7M solution (0.2 ml) of n-butyl lithium in hexane was dropwise added thereto, followed by stirring at the same temperature for one hour. The reaction solution was adjusted to pH 7 by adding dropwise 1N hydrochloric acid, followed by stirring at room temperature for one hour. A small amount of water was added to the reaction solution and the mixture was extracted with ether. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/2) to give Compound 142 (0.014 g, 17.4%) as pale-yellow crystals.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[C:7]([O:12][CH3:13])(=[O:11])[C:8]([CH3:10])=[CH2:9]>CO>[CH3:13][O:12][C:7](=[O:11])[CH:8]([CH3:10])[CH2:9][NH:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCN
Reactant: C=C(C)C(=O)OC
Solvent: CO
Product: COC(=O)C(C)CNCCC(C)C
Yield: 76.4 %

Procedure:
A solution of 8.72 g (0.10 mole) of isoamylamine, 12.01 g (0.12 mole) of methyl methacrylate and 50 mL of methanol was heated at reflux under an argon atmosphere for 22 hours. After cooling the mixture was concentrated, then distilled under vacuum to give 14.31 g of (rac)-2-methyl-3-(3-methyl-butylamino)-propanoic acid methyl ester as colorless oil. b.p. 73-75 degrees, 2 mm Hg.
Reaction SMILES: [CH2:1]([NH:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[S:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:25]([C:30](O)=[O:31])#[C:26][C:27]([OH:29])=[O:28]>>[CH2:15]([N:14]1[C:30](=[O:31])[C:25](=[CH:26][C:27]([OH:29])=[O:28])[S:13][C:12]1=[N:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCNC(=S)NCCCCCCCCCC
Reactant: O=C(O)C#CC(=O)O
Product: CCCCCCCCCCN=C1SC(=CC(=O)O)C(=O)N1CCCCCCCCCC
Yield: 93.1 %

Procedure:
Prepared by the method described in Example 16 from N,N'-didecylthiourea (15.0 g, 42 mmoles) and acetylenedicarboxylic acid (5.0 g, 42 mmoles). Recrystallization from hexane gave the product (17.7 g), mp 68°-69° C.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:11]=2[CH:12]=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21](=[O:34])[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=2)[CH:25]=[C:24]1[CH3:33]>>[CH3:19][O:20][C:21](=[O:34])[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=2)[C:25]([CH2:12][C:11]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:10]=2[S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[C:24]1[CH3:33]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1ccc(Cl)cc1S(=O)(=O)c1ccccc1
Product: COC(=O)Cn1c(C)c(Cc2ccc(Cl)cc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using 2-benzenesulfonyl-4-chlorobenzaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: [CH2:1]1[O:23][CH:4]([C:5]2[C:13]3[NH:12][C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[N:10][C:9]=3[CH:8]=[CH:7][CH:6]=2)[O:3][CH2:2]1.[H-].[Na+].[CH3:26]I.O>C1COCC1>[CH2:1]1[O:23][CH:4]([C:5]2[C:13]3[N:12]=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])[N:10]([CH3:26])[C:9]=3[CH:8]=[CH:7][CH:6]=2)[O:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccccc1-c1nc2cccc(C3OCCO3)c2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(-c2ccccc2[N+](=O)[O-])nc2c(C3OCCO3)cccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2-(2-nitrophenyl)-benzimidazole-4-carboxaldehyde ethylene acetal 5 (4.53 g, 14.6 mmol) in dry THF (20 mL) was added to a stirring suspension of NaH (0.640 g, 60% dispersion in mineral oil, 16.0 mmol) in dry THF (50 mL) at 0° C. under N2. The mixture was then allowed to warm to room temperature for 1 hour resulting in an orange solution. Methyl iodide (4.58 mL, 72.8 mmol) was syringed into the above mixture at room temperature under N2. This mixture was stirred for 24 hours under N2 to give a yellow mixture. Water was added and the aqueous layer was extracted with CHCl3. The combined extracts were washed with brine and dried over Na2SO4. After rotary evaporation, the resulting residue was purified by column chromatography on silica gel using Et2O:CH2Cl2 (3:1) as the eluent to give the title compound. (3.53 g, 74%). 1H NMR (CDCl3): δ 3.58 (s, 3H), 4.02-4.19 (m, 4H), 6.55 (s, 1H), 7.33-7.41 (m, 1H), 7.52-7.56 (m, 1H), 7.62-7.75 (m, 4H), 8.19 (d, J=1.7, 7.9 Hz, 1H); HRMS: Calcd. for C17H15N3O4 325.1062, found 325.1050.
Reaction SMILES: C[O-].[Na+].CCO.Cl.[N:8]1[CH2:12][CH2:11][CH2:10][C:9]=1[NH2:13].Br[C:15](=[CH:18]OCCC)[CH:16]=[O:17]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[N:13]1[C:15]([CH:16]=[O:17])=[CH:18][N:8]2[CH2:12][CH2:11][CH2:10][C:9]=12
Reactant: CCCOC=C(Br)C=O
Reactant: NC1=NCCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=Cc1cn2c(n1)CCC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40.9 %

Procedure:
28% Sodium methoxide (5.26 g) was added to the EtOH (250 mL) solution of 4,5-dihydro-3H-pyrrol-2-ylamine hydrochloride (3.27 g) at room temperature. After stirring for 5 min at room temperature, 2-bromo-3-propoxy-propenal (5.79 g) was added to the mixture at room temperature, then the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was taken to dryness in vacuo. The residue was dissolved in CHCl3 (300 mL) and triethylamine (3.8 mL) was added. The mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature, washed with 50% K2CO3, dried over anhydrous K2CO3, filtered, and evaporated under reduced pressure. The residue was applied with silicagel column chromatography, eluted with CHCl3-acetone (2:1), and 6,7-Dihydro-5H-pyrrolo[1,2-a]imidazole-2-carbaldehyde (41%, 1.51 g) was obtained as a pale yellow solid.