Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:8][C:9]=1[CH2:10][C:11](O)=[O:12])([O-])=O>C(O)(=O)C.[Fe]>[C:14]1([C:6]2[CH:5]=[C:4]3[C:9]([CH2:10][C:11](=[O:12])[NH:1]3)=[CH:8][CH:7]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Cc2ccc(-c3ccccc3)cc2N1
Yield: 92.9 %

Procedure:
Iron powder (2.6 g) was added all at once to 4.5 g of 3-nitrobiphenyl-4-acetic acid in 40 mL of acetic acid. The mixture was refluxed for 2 hours, concentrated to dryness and taken up in ethyl acetate. The solids were removed by filtration and the filtrate washed twice with 1N hydrochloric acid and brine and dried over anhydrous sodium sulfate. The filtrate was concentrated to give 3.4 g (93% yield) of 6-phenyl-2-oxindole as a light brown solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][C:21]2=[O:26])=[CH:16][CH:15]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCN(CC)CC>C(Cl)Cl.O>[O:26]=[C:21]1[CH2:22][O:23][CH2:24][CH2:25][N:20]1[C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:10]([C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[O:12])=[CH:19][CH:18]=1
Reactant: O=C(O)c1nc2ccccc2[nH]1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 100 mg 1H-Benzoimidazole-2-carboxylic acid and 118 mg 4-(4-Amino-phenyl)-morpholin-3-one in 2 mL DCM, 157 mg BOP-Cl and 0.3 mL NEt3 were added and the mixture was stirred for 16 h at RT. Then, after the reaction mixture was diluted with 20 mL water, the precipitated product was collected by filtration. The crude product was subjected to the next reaction step without further purification. Yield: 122 mg.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32]Br>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[F:29])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccccc1CBr
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2F)CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Ethyl 1-benzylpiperidine-4-carboxylate (2.47 g, 10 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to −78° C. Lithium bis(trimethylsilyl)amide (11 mL, 1.0 M in tetrahydrofuran) was added slowly, and stirred for 30 minutes. 2-fluoro-benzylbromide (1.34 mL, 11 mmol) in 5 mL tetrahydrofuran was added slowly. The resulting solution was allowed to reach room temperature and stirred over night. The reaction was quenched with ammonium chloride (aq, sat) and partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over magnesium sulphate, filtrated and concentrated. The crude material was purified on silica (heptane/ethyl acetate), to give 2.7 g (77%) the subtitle compound as a colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([NH2:12])[N:8]=[C:9]([CH3:11])[CH:10]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[Br:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]([NH:12][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([Br:20])=[CH:22][CH:23]=2)[N:8]=[C:9]([CH3:11])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)nn1N
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)nn1NC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-amino-5-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (310 mg, 1.83 mmol) in dichloromethane (4 ml) is added triethylamine (887 μl, 6.40 mmol). Then a solution of 4-bromobenzoyl chloride (803 mg, 3.66 mmol) in dichloromethane (2 ml) is added slowly. The reaction mixture is stirred for 18 hours at room temperature. The reaction mixture is partitioned between water and dichloromethane. The organic layer is washed with 1 N HCl, dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 2-(4-bromo-benzoylamino)-5-methyl-2H-pyrazole-3-carboxylic acid ethyl ester as brown oil; HPLC/MS 2.10 min (A), [M+H] 352/354.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][N:29]([CH3:37])[C:30](=[O:36])[CH2:31][CH2:32][C:33](O)=[O:34]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[CH2:32][CH2:31][C:30]([N:29]([CH3:37])[CH3:28])=[O:36])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: CN(C)C(=O)CCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: CN(C)C(=O)CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (103 mg, 90%), MS (ISP) m/z=458.6 [(M+H)+], mp 177.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-(dimethylamino)-4-oxobutanoic acid.
Reaction SMILES: O.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C@@H:12]1[O:17][C@H:16]([C:18]([OH:20])=[O:19])[C@@H:15]([NH2:21])[C@H:13]1[OH:14].[C:22]([O:26][C:27]([NH:29][C@H:30]([C:48](O)=[O:49])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]2[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:47])=[CH:34][CH:33]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C@@H:12]1[O:17][C@H:16]([C:18]([OH:20])=[O:19])[C@@H:15]([NH:21][C:48](=[O:49])[C@H:30]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]3[C:41]([Cl:47])=[CH:42][CH:43]=[CH:44][C:45]=3[Cl:46])=[CH:34][CH:33]=2)[NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:28])[C@H:13]1[OH:14]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(=O)O)[C@@H](N)[C@H]1O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)C(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)C(=O)N[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1C(=O)O
Yield: 49.4 %

Procedure:
1-(6-Amino-9H-purin-9-yl)-1,3-dideoxy-3-[N-tert-butoxycarbonyl-O-(2,6-dichlorobenzyl)-L-tyrosylamino]-β-D-ribofuranuronic acid (260 mg) was prepared by reacting 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronic acid monohydrate (223.5 mg) prepared in Example 99 with N-hydroxysuccinimide ester of N-tert-butoxycarbonyl-O-(2,6-dichlorobenzyl)-L-tyrosine (388 mg) according to a similar manner to that of Example 5, mp. 166°-176° C. (dec.).
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7]#[C:8][C:9](Cl)=[O:10])=[CH:3][CH:2]=1.[Cl:18][C:19]1[CH:32]=[C:31]([NH2:33])[CH:30]=[CH:29][C:20]=1[O:21][CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH3:26]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:18][C:19]1[CH:32]=[C:31]([NH:33][C:9](=[O:10])[C:8]#[C:7][C:4]2[CH:5]=[CH:6][C:1]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:2][CH:3]=2)[CH:30]=[CH:29][C:20]=1[O:21][CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH3:26]
Reactant: O=C(Cl)C#Cc1ccc(-c2ccccc2)cc1
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCN(CC)CCOc1ccc(NC(=O)C#Cc2ccc(-c3ccccc3)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.48 g (2.0 mmol) of biphenyl-4-ylpropynoic acid chloride (for preparation method see Bioorg. Med. Chem. 1996, 4, 851) is dissolved in 15 mL of toluene and 0.58 g (2.4 mmol) of [2-(2-chloro-4-aminophenoxy)ethyl]diethylamine (educt IV.1) in 10 mL of toluene at ambient temperature is added dropwise. The mixture is stirred for 8 hours at ambient temperature, the solvent is eliminated, and the residue is taken up in ethyl acetate and washed with water. The organic phase is dried over sodium sulfate, the solvent is eliminated and the residue is purified through a silica gel column with dichloromethane/methanol/ammonia (9:1:0.01) as eluant. Yield: 0.28 g (31% of theory); m.p.: 105-108° C.; Rf value: 0.50 (silica gel, dichloromethane/methanol/ammonia=9:1:0.1); C27H27ClN2O2; EII mass spectrum: m/z=447/449 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([O:11][CH3:12])[C:5]=1[N:13]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:14]([CH2:16][NH2:17])=[O:15].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.O.[CH3:58][O:59][C:60]([CH2:62][N:63]1[C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:65]=[C:64]1[C:72](O)=[O:73])=[O:61]>CN(C)C=O>[CH3:58][O:59][C:60](=[O:61])[CH2:62][N:63]1[C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:65]=[C:64]1[C:72](=[O:73])[NH:17][CH2:16][C:14](=[O:15])[N:13]([C:5]1[C:6]([O:11][CH3:12])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=1[O:3][CH3:2])[CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: COC(=O)Cn1c(C(=O)O)cc2ccccc21
Reactant: COc1cc(C)cc(OC)c1N(CCC(C)C)C(=O)CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)Cn1c(C(=O)NCC(=O)N(CCC(C)C)c2c(OC)cc(C)cc2OC)cc2ccccc21
Reaction time: 20 h
Yield: 91 %

Procedure:
0.8 9 of [(2,6-dimethoxy-4-methylphenyl)(isopentyl)carbamoyl]methylamine hydrochloride (compound 100) is dissolved in 10 ml of dimethylformamide and 0.58 g of 1-(methoxycarbonylmethyl)-2-indolecarboxylic acid, 1.12 g of BOP and then, dropwise, 0.75 g of triethylamine are successively added to the reaction mixture at room temperature. The reaction mixture is left at room temperature for 20 hours, is then poured into cold water and the aqueous phase is extracted with ethyl acetate. The organic extracts are washed with water and then dried over anhydrous sodium sulphate. Evaporation of the solvent leaves a yellow oil which is purified by flash chromatography on a column of silica gel, eluent: dichloromethane/methanol 98/2 (v/v) in order to obtain white crystals of methyl{2-[[(2,6-dimethoxy-4-methylphenyl)(isopentyl)carbamoyl]methylcarbamoyl]-1-indolyl}acetate; M.p.=141° C.; Yield: 91%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:18][C@@H:19]1[C@@H:24]([O:25][CH3:26])[C@@H:23]([CH3:27])[CH2:22][O:21][C@H:20]1[CH2:28][OH:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCl.C(Cl)Cl>[Si:11]([O:18][C@@H:19]1[C@@H:24]([O:25][CH3:26])[C@@H:23]([CH3:27])[CH2:22][O:21][C@H:20]1[CH:28]=[O:29])([C:14]([CH3:16])([CH3:17])[CH3:15])([CH3:13])[CH3:12]
Reactant: CO[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO)OC[C@@H]1C
Agent: ClCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](C=O)OC[C@@H]1C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 85.4 %

Procedure:
To a solution of oxalyl chloride (0.036 ml, 0.42 mmole) in dry CH2 Cl2 (0.5 ml) there was added dropwise a solution of dry DMSO (0.049 ml, 0.69 mmole) in dry CH2Cl2 (0.1 ml) at -78° C. over 5 min. After stirring for 10 min at -78° C., a solution of (2S,3R,4S,5S)-[3-(tert-butyldimethylsilyloxy)-4-methoxy-5-methyltetrahydro-2H-pyran-2-yl]methanol (0.1 g, 0.345 mmole) in dry CH2Cl2 (0.1 ml) was added dropwise to the resulting milky suspension over 5 min at -78° C. After stirring for 15 min at -78° C., triethylamine (0.24 ml, 1.73 mmole) was added dropwise to the reaction mixture over 3 min, and stirring was continued for 30 min at -78° C. The reaction mixture was then warmed up to room temperature gradually and partitioned between CH2Cl2 (10 ml) and water (10 ml). The methylene chloride layer was washed with brine (5 ml×2), dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel using AcOEt/n-hexane (1:9) as an eluent to give (2R,3R,4S,5S)-3-(tert-butyldimethylsilyloxy)-4-methoxy-5-methyltetrahydro-2H-pyran-2-carbaldehyde (0.085 g, 86% yield) as a colorless oil; EI-MS: m/z 288 (M+); 1H-NMR (CDCl3)d: 0.85 (3H,d,J=7 Hz), 0.87 (9H,s), 2.28 (1H,m), 3.12 (1H,dd,J=4 & 5 Hz), 3.28 (3H,s), 3.59 (1H,dd,J=5 & 11.5 Hz), 3.81 (1H,d,J=4. Hz), 3.81 (1H,dd,J=9 & 11.5 Hz), 4.08 (1H,dd,J=4 & 5 Hz), 9.80 (1H,s).
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].[CH:5]1([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6]1.O>CCOC(C)=O>[CH:5]1([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([N+:1]([O-:3])=[O:2])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1
Reactant: c1ccc2c(C3CC3)cccc2c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(C2CC2)c2ccccc12
Temperature: 0 °C
Yield: 64 %

Procedure:
Sodium nitrite (30 mL) was slowly added (over 2 hours) to 1-cyclopropyl-naphthalene (6.4 g, 38 mmol) stirred at 0° C. The reaction mixture was stirred at 0° C. for an extra 30 min and then was slowly poured into ice. Water was added, followed by EtOAc. After extraction, the organic layer was washed with a 1% aqueous solution of NaOH, then washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to yield 1-cyclopropyl-4-nitro-naphthalene (5.2 g, 64%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[C:4]([Cl:17])=[C:5]([C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[C:6](=[N:8][OH:9])[NH2:7].[CH:20]1([CH2:23]Br)[CH2:22][CH2:21]1>C(Cl)(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:20]1([CH2:23][O:9][N:8]=[C:6]([NH2:7])[C:5]2[C:10]([C:13]([F:15])([F:14])[F:16])=[CH:11][CH:12]=[C:3]([C:2]([F:18])([F:1])[F:19])[C:4]=2[Cl:17])[CH2:22][CH2:21]1
Reactant: BrCC1CC1
Reactant: NC(=NO)c1c(C(F)(F)F)ccc(C(F)(F)F)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClC(Cl)Cl
Product: NC(=NOCC1CC1)c1c(C(F)(F)F)ccc(C(F)(F)F)c1Cl
Yield: 56.7 %

Procedure:
In 10 ml of chloroform was dissolved 0.60 g of 3,6-bistrifluoromethyl-2-chlorobenzamidoxime and 0.50 g of cyclopropylmethylbromide, and to the solution was added 0.1 g of tetrabutylammonium bromide at room temperature with stirring, and then 1.2 ml of 10% aqueous solution of sodiunhydroxide, then stirred for 3 hours at 30°-40° C. The solution was washed with water, washed with saturated saline solution and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography to obtain 0.40 g of the objective compound.m.p. 75°-80° C.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:37])[C@@H:15]4[C@@H:32]([C@H:33]([OH:35])[CH3:34])[C:31](=[O:36])[N:16]4[C:17]=3[C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])[S:10][C:9]=12)=[O:4].[I-].[Na+].[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>CC(C)=O.[Cl-].[Na+].O>[OH:35][C@@H:33]([C@H:32]1[C:31](=[O:36])[N:16]2[C:17]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:13]([C:11]3[S:10][C:9]4=[C:5]([C:3](=[O:4])[CH2:2][N:40]5[CH2:44][CH2:43][CH2:42][CH2:41]5)[N:6]=[CH:7][N:8]4[CH:12]=3)[C@H:14]([CH3:37])[C@H:15]12)[CH3:34]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)CCl)c4s3)[C@H](C)[C@H]12
Reactant: C1CCNC1
Agent: [Cl-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)CN5CCCC5)c4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-(7-chloroacetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (161 mg) was dissolved in 5 ml of acetone to prepare a solution. Sodium iodide (67 mg) was added to the solution, and the mixture was stirred at room temperature for 1.5 hr. Brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation, and the residue was dissolved in 5 ml of N,N-dimethylformamide to prepare a solution. Pyrrolidine (0.03 ml) was added to the solution, and the mixture was stirred at room temperature for 2 hr. Brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation, and the residue was washed with diethyl ether to give 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyrrolidin-1-yl)acetylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C:10]1[C:11]([CH3:16])=[CH:12][CH:13]=[CH:14][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[C:11]1([CH3:16])[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:6]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[O:8]
Reactant: Cc1ccccc1N
Reactant: O=C(O)c1ncc[nH]1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1NC(=O)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
To a solution of 1H-imidazole-2-carboxylic acid (0.52 g, 4.64 mmol) in DMF (20 mL) was added o-toluidine (0.50 mL, 4.64 mmol), EDCHCl (1.35 g, 6.96 mmol) and HOBt (0.94 g, 6.96 mmol). The reaction mixture was stirred at room temperature for 16 hours. Then, it was poured into water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulphate, filtered and concentrated to dryness. The crude product was purified by flash chromatography (2% to 3% MeOH/DCM) to yield 0.93 g (99%) of the title compound as a beige solid.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13].O>C(#N)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:8][CH2:18][C:17]1[C:10]([F:9])=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C#N)c1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: O
Product: N#Cc1cccc(CBr)c1F
Temperature: 25 °C
Yield: 70.2 %

Procedure:
NBS (1.729 g, 9.71 mmol) was added to a solution of 2-fluoro-3-methylbenzonitrile (1.25 g, 9.25 mmol) in acetonitrile (25 mL). The obtained mixture was refluxed, and then benzoic peroxyanhydride (0.045 g, 0.18 mmol) was added. The reaction mixture was refluxed overnight, then cooled to r.t. and water was added. The aqueous phase was discarded and the organic phase was dried over MgSO4 and concentrated. The crude product was purified by flash chromatography using a gradient of EtOAc in heptane as eluent to give the title compound (1.39 g, 70% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 4.75 (s, 2H) 7.43 (t, 1H) 7.93 (t, 2H); MS (EI) m/z 213 M+.
Reaction SMILES: C[N:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[C:3]1=[O:10].[CH3:11][NH:12][CH3:13].N1CCC[CH2:15]1>>[CH3:11][N:12]([CH3:15])[CH2:13][C:9]#[C:8][CH2:7][N:4]1[CH2:5][CH2:6][NH:2][C:3]1=[O:10]
Reactant: CNC
Reactant: C#CCN1CCN(C)C1=O
Reactant: C1CCNC1
Product: CN(C)CC#CCN1CCNC1=O

Procedure:
This product was prepared according to Example 1, Part B, by substituting 1-(2-propynyl)-2-imidazolidinone for 1-methyl-3-(2-propynyl)-2-imidazolidinone and dimethylamine for pyrrolidine; m.p. 83°-87° C.
Reaction SMILES: O[CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:13]([O:22][CH2:23][CH:24]2[CH2:26][CH2:25]2)[N:12]=1)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6].[N-:27]=[N+:28]=[N-:29].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C(Cl)(Cl)(Cl)Cl>[N:27]([CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:13]([O:22][CH2:23][CH:24]2[CH2:25][CH2:26]2)[N:12]=1)=[O:10])[CH2:4][CH:5]([CH3:6])[CH3:7])=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)C[C@@H](CO)NC(=O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)C[C@@H](CN=[N+]=[N-])NC(=O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Temperature: 90 °C
Reaction time: 4 h
Yield: 44.5 %

Procedure:
To a colorless solution of 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (Example 14b; 231 mg, 639 μmol) in DMF (25.6 mL) and CCl4 (6.4 mL) was added sodium azide (49.9 mg, 767 μmol) and triphenylphosphine (352 mg, 1.34 mmol). The resulting reaction mixture was stirred at 90° C. for 4 hours. After cooling to room temperature the solvent was removed in vacuo. The residue was partitioned between water and ethyl acetate; the organic phases were washed with brine, combined, dried with Na2SO4, filtered and concentrated in vacuo. The residue, a brown waxy solid, was purified by flash chromatography (silica gel, 50 g, 0% to 60% ethyl acetate in heptane) to give the title compound (110 mg, 45%) as white solid; MS (ESI) 387.3 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:17]=[CH:16][C:10]([O:11][CH2:12][CH:13]3[CH2:15][O:14]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:18]=[N+:19]=[N-:20].[Na+].C(OC)=O.CO>O>[C:1]1([C:7]2[CH:17]=[CH:16][C:10]([O:11][CH2:12][CH:13]([OH:14])[CH2:15][N:18]=[N+:19]=[N-:20])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2ccc(OCC3CO3)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: COC=O
Solvent: CO
Solvent: O
Product: [N-]=[N+]=NCC(O)COc1ccc(-c2ccccc2)cc1
Yield: 86.5 %

Procedure:
A procedure similar to that described in Preparation 12 was repeated, except that 3.00 g of 4-phenylphenoxymethyloxirane (prepared as described in Preparation 82), 4.23 g of sodium azide, 15 ml of methyl formate and 90 ml of an 8:1 by volume mixture of methanol and water were used, to give 3.09 g of the title compound, melting at 72.2° to 73.9° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=1>>[CH3:26][C:23]1[CH:22]=[N:21][C:20]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:10])[CH2:5][CH2:4]2)=[N:25][CH:24]=1
Reactant: Cc1cnc(Cl)nc1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Product: Cc1cnc(NCC2CCN(C(=O)OCc3ccccc3)CC2)nc1

Procedure:
The title compound was prepared as described in EXAMPLE 13, except using benzyl 4-(aminomethyl)-1-piperidinecarboxylate (298 mg, 1.20 mmol), 2-chloro-5-methylpyrimidine (EXAMPLE 144, Step 1) (51 mg, 0.40 mmol) as starting materials and using no solvent and gave the title compound as a yellow oil.
Reaction SMILES: [CH:1]([CH:4]1[N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7][N:6]2[C:17]3[CH:23]=[C:22]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[CH:20][C:18]=3[N:19]=[C:5]12)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([CH:4]1[NH:9][CH2:8][CH2:7][N:6]2[C:17]3[CH:23]=[C:22]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=[CH:20][C:18]=3[N:19]=[C:5]12)([CH3:3])[CH3:2]
Reactant: CC(C)C1c2nc3ccc(S(C)(=O)=O)cc3n2CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C1NCCn2c1nc1ccc(S(C)(=O)=O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 136.3 %

Procedure:
To a solution of tert-butyl 1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate (20.mg, 0.05 mmol) in CH2Cl2 (1 mL) was added TFA (0.3 mL) under N2. The mixture was stirred at rt for 1 h. The mixture was concentrated to afford 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine (20 mg, TFA salt, 100% yield) as a yellow solid, which was used for the next step without further purification. LC-MS m/z 352.1 [M+H]+.