Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:20][NH:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([OH:33])=[CH:30][CH:31]=2)[N:26]([CH3:34])[C:25]=1[CH3:35])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+].O>CCOC(C)=O>[CH3:20][NH:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([O:33][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:30][CH:31]=2)[N:26]([CH3:34])[C:25]=1[CH3:35])=[O:23]
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(C(=O)N5CCC(OC)C5)sc34)ccc12

Procedure:
This material was prepared by the reaction of 7-chloro-2-[(R)-3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 4b (157 mg, 0.5 mmole) with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid methylamide 16e (150 mg, 0.7 mmole) and Cs2CO3 (673 mg, 2.1 mmole) in a manner as previously described for example 1 to give 51 mg (39%) of a crisp foam. 1H NMR (DMSO-d6) δ8.54 (1H, dd, J=5.5, 1.13 Hz), 8.05 (1H, s), 7.84 (1H, d, J=8.6 Hz), 7.61-7.55 (1H, m), 7.54 (1H, d, J=2.1 Hz), 7.03 (1H, dd, J=2.1, 8.6 Hz), 6.64 (1H, d, J=5.5 Hz), 4.12-3.51 (5H, m), 3.67 (3H, s), 3.27, 3.24 (3H, 2 s), 2.80 (3H, d, J=4.5 Hz), 2.60 (3H, s), 2.35-1.95 (2H, m). Anal. Calcd for C25H26N4O4S.0.9 H2O.0.2 EtOAc: C, 60.47; H, 5.78; N, 10.93; S, 6.26. Found: C, 60.46; H, 5.56; N, 10.81; S, 6.34.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[CH2:23]([N:26]([CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[CH2:24][CH3:25].C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:31][CH2:30][CH2:29][CH2:28][CH2:27][N:26]([CH2:32][CH2:33][CH3:34])[CH2:23][CH2:24][CH3:25])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: CCCN(CCC)CCCCN
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)CCCCNS(=O)(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.9 %

Procedure:
The compound (150 mg) obtained in Example 24-2 was dissolved in chloroform (10 ml) and then added with the compound (131 mg) obtained in Example 1-2 and triethylamine (0.224 ml), followed by stirring at room temperature for 15 minutes. The solution was added with water and subjected to extraction. The organic layer was washed with saturated saline solution and then dried and concentrated with anhydrous sodium sulfate, thereby obtaining the subject compound (160 mg) as a colorless viscous liquid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:17]([OH:19])=O)[CH:6]=[C:7]2[C:12]=1[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]2([CH3:16])[CH3:15])#[CH:2].C(N(CC)CC)C.ClC(OCC)=O.[N-:33]=[N+:34]=[N-:35].[Na+]>O1CCCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([C:17]([N:33]=[N+:34]=[N-:35])=[O:19])[CH:6]=[C:7]2[C:12]=1[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]2([CH3:16])[CH3:15])#[CH:2]
Reactant: [N-]=[N+]=[N-]
Reactant: C#Cc1cc(C(=O)O)cc2c1OC(C)(C)CC2(C)C
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cc(C(=O)N=[N+]=[N-])cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
A stirred, cooled (ice bath) solution of 8-ethynyl-2,2,4,4-tetramethyl-chroman-6-carboxylic acid (Intermediate 210, 0.52 g, 2 mmol) in anhydrous tetrahydrofuran (10 mL) under argon, was treated with triethyl amine (0.86 mL, 6 mmol) followed by ethyl chloroformate (0.25 mL, 2.6 mmol) and the resulting reaction mixture was allowed to warm to ambient temperature and stirred for 2 h. Sodium azide 0.19 g, 3 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was then diluted with water and extracted with diethyl ether. The organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated to a residue that was purified by flash column chromatography over silica gel (230-400 mesh) to afford the title compound as a yellow solid (0.32 g, 56%).
Reaction SMILES: [CH:1]([CH:3]=O)=O.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[C:8]([NH2:13])[C:7]=1[NH2:14]>CCO>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[C:8]2[C:7]=1[N:14]=[CH:1][CH:3]=[N:13]2
Reactant: O=CC=O
Reactant: Nc1c(Br)ccc(Br)c1N
Solvent: CCO
Product: Brc1ccc(Br)c2nccnc12
Temperature: 25 °C
Yield: 79.5 %

Procedure:
A 40% aqueous solution of glyoxal (8.8 M, 6.3 mL, 55.1 mmol, 1.3 equiv) was added to a suspension of 3,6-dibromo-benzene-1,2-diamine (Step 179.6) (11.3 g, 42.4 mmol) in EtOH (280 mL). The reaction mixture was heated to reflux for 3 h and allowed to cool to rt overnight. Vacuum filtration of the reaction mixture afforded 9.7 g of the title compound as a yellow solid: APCI-MS: 286/288/291 [M−1]−; tR=4.40 min (System 1).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:18])([CH3:17])[C:9](=[O:16])[N:10]([CH3:15])[C:11]2=[O:14])=[CH:6][CH:5]=1)([O-])=O>CO.ClCCl.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:18])([CH3:17])[C:9](=[O:16])[N:10]([CH3:15])[C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: CN1C(=O)c2cc([N+](=O)[O-])ccc2C(C)(C)C1=O
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CN1C(=O)c2cc(N)ccc2C(C)(C)C1=O
Yield: 100.8 %

Procedure:
7-Nitro-2,4,4-trimethyl-4H-isoquinoline-1,3-dione (45 g, 20 mmol) was dissolved in a methanol (500 ml)/dichloromethane (100 ml) mixture and treated with 10% Pd/C (0.5 g). The reaction mixture was hydrogenated for 2 h before removal of the palladium catalyst by filtration through Celite. The filtrate was evaporated to dryness in vacuo to give the title compound (4.4 g, quant).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[N:6]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:13][C:9]1[CH:8]=[C:7]([C:5]2[N:6]=[C:2]([N:17]3[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]3)[S:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Fc1cccc(-c2csc(Br)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(F)c3)cs2)CC1
Yield: 69.3 %

Procedure:
A solution of 2-bromo-4-(3-fluorophenyl)-1,3-thiazole (800 mg, 3.10 mmol), tert-butyl piperazine-1-carboxylate (1.15 g, 6.20 mmol) and potassium carbonate (428 mg, 3.10 mmol) in dimethylformamide (10 ml) was stirred at 120° C. for 12 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 781 mg (69.4%) of the desired product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[CH:10][C:11]([CH:12]([CH3:14])[CH3:13])=[C:4]2[N:3]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCO>[CH2:15]([NH:22][C:6]1[N:5]2[N:9]=[CH:10][C:11]([CH:12]([CH3:14])[CH3:13])=[C:4]2[N:3]=[C:2]([Cl:1])[CH:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: CC(C)c1cnn2c(Cl)cc(Cl)nc12
Solvent: CCO
Product: CC(C)c1cnn2c(NCc3ccccc3)cc(Cl)nc12
Temperature: 25 °C

Procedure:
5,7-dichloro-3-isopropylpyrazolo[1,5-α]pyrimidine (500 mg, 2.17 mmol) and benzyl amine (0.52 mL, 4.78 mmol) in EtOH (20 mL) were refluxed for about 3 hours. The reaction mixture was then cooled to ambient temperature and concentrated in vacuo. The remaining residue was purified by flash chromatography on silica (methanol/ethyl acetate) to yield N-benzyl-5-chloro-3-isopropylpyrazolo[1,5-α]pyrimidin-7-amine as a white solid in analytically pure form (630 mg, 97%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([CH3:15])[C:12](=[O:16])[N:11]([CH3:17])[C:10]2[CH:18]=[N:19][C:20](Cl)=[N:21][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[O:29])=[CH:26][C:25]=1[O:40][CH3:41].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH2:1]([N:8]1[CH2:14][CH:13]([CH3:15])[C:12](=[O:16])[N:11]([CH3:17])[C:10]2[CH:18]=[N:19][C:20]([NH:23][C:24]3[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]4[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]4)=[O:29])=[CH:26][C:25]=3[O:40][CH3:41])=[N:21][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: CC1CN(Cc2ccccc2)c2nc(Cl)ncc2N(C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(Cc1ccccc1)CC(C)C(=O)N2C
Yield: 51.8 %

Procedure:
A solution of 0.050 g (0.00016 mole) of (rac)-9-benzyl-2-chloro-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-42), 0.042 g (0.00016 mole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.046 g (0.00024 mole) of p-toluenesulfonic acid monohydrate in 4.0 mL of 2-propanol was heated at 180 degrees for 2 hours in a microwave reactor. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane and the combined organic phases washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane-methanol (100:0-75:25) to give 0.0451 g of (rac)-4-(9-benzyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-42) as white powder. HRMS (ES+) m/z Calcd for C30H37N7O3+H [(M+H)+]: 544.3031. Found: 544.3031.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([C:15](=O)[C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=[C:6]([CH2:10][C:11](OC)=[O:12])[CH:7]=2)[O:2]1.O.[NH2:25][NH2:26].C(O)(=O)C>C(O)C>[CH2:1]1[O:2][C:3]2=[CH:4][C:5]3[C:15]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=4)=[N:26][NH:25][C:11](=[O:12])[CH2:10][C:6]=3[CH:7]=[C:8]2[O:9]1
Reactant: COC(=O)Cc1cc2c(cc1C(=O)c1ccc(C)cc1)OCO2
Reactant: NN
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)cc1

Procedure:
The title compound was prepared from methyl 4,5-methylenedioxy-2-(4-methylbenzoyl)phenylacetate (90 mg, 0.29 mmol), hydrazine hydrate (50 μL, 0.88 mmol) and acetic acid (40 μL) in ethanol (10 mL), mp: 222°-224° C. 1H NMR (CDCl3) 8.36 (s, 1H), 7.48 (d, 2H, J=8.0), 7.23 (d, 2H, J=8.0), 6.82 (s, 1H), 6.64 (s, 1H), 6.02 (s, 2H), 3.45 (s, 2H), 2.41 (s, 3H). Anal. Calcd. for C17H14N2O3 : C, 69.38; H, 4.79; N, 9.52. Found: C, 69.14; H, 4.80; N, 9.30.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14]C)=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.O>C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[CH2:12][CH2:11][C:10](=[O:14])[CH2:9]2
Reactant: COc1ccc2c(OC)cccc2c1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: COc1cccc2c1CCC(=O)C2
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
1.6-Dihydroxynapthalene (44 g (0.247 mole)) was mixed with 245 mL of 2N NaOH and 55 mL of methyl sulfate. The mixture was stirred at room temperature. When the pH of the mixture was 6, 124 mL of 2N NaOH and 26.4 mL of methyl sulfate were added and stirred until 1,6-dihyroxynapthalene was disappeared. Excess of methyl sulfate was destroyed by heating for 30 minutes at 100° C. The warm liquid was acidified and extracted with CH2Cl2. The CH2Cl2 layer was washed twice with 2N NaOH and evaporated. A yield of 47.73 g(92%) of 1,6-dimethoxynaphthanene was obtained. Sodium (19 g) was added to a solution of 22.5 of crude 1,6-dimethoxynaphthalene in 190 mL of boiling ethanol. Ethanol (40 mL) was then added and heating continued under reflux until the Na had disappeared (about 40 minutes). Water (60 mL) was added cautiously and then most of the ethanol was removed under reduced pressure. The residue was mixed with 30 mL of water and the lower aqueous layer was separated and extracted twice with dioxane, which was then combined with the oily upper layer. Water (25 mL) and then hydrochloric acid (density of 1.18 g/mL) until the mixture was acidic (pH 2-3). Then, 3 mL more of HCl was added and the liquid was stirred at about 70° C. for 30 minutes. The lower oily layer was separated, the aqueous layer was diluted with 100 mL of water, separated from more oil, and extracted thrice with methylene chloride. The combined oil and methylene chloride extracts were stirred with 50 mL of saturated aqueous sodium bisulfite until crystallization began. The solid was triturated with ether, then washed with ether and dried. Free 5-methoxy-2-tetralone was obtained by treating the bisulfite addition compound with excess 10% Na2CO3 and extracting the resulting mixture with methylene chloride. The extract was washed with 10% HCl and then with water and dried with Na2SO4. Volatiles were removed under reduced pressure to leave 17 g (81% yield) of liquid. On keeping, the 3,4-Dihydro-5-methoxy-2-(1H)-naphthalenone (hereinafter, “Compound 20”) solidified in massive prisms with a melting point of 25-36° C.
Reaction SMILES: C1(C(N)C)CCCCC1.O[CH2:11][CH2:12][NH:13][CH:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH3:15].O=S(Cl)[Cl:24]>>[Cl-:24].[Cl:24][CH2:11][CH2:12][NH2+:13][CH:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH3:15]
Reactant: CC(NCCO)C1CCCCC1
Reactant: O=S(Cl)Cl
Agent: CC(N)C1CCCCC1
Product: CC([NH2+]CCCl)C1CCCCC1
Product: [Cl-]

Procedure:
1-Cyclohexyl-1-ethylamine was converted to N-(2-hydroxyethyl)-N-(1-cyclohexyl-1-ethyl)amine according to Method B5a. The alcohol was reacted with SOCl2 according to Method B7a to give N-(2-chloroethyl)-N-(1-cyclohexyl -1-ethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2-(2-methyl-4-nitrophenylimino)-3-(1-cyclohexyl-1-ethyl)-1,3-thiazolidine.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][S:8][C:9]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:10]=2[NH2:11])[CH:3]=[N:2]1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1>[Cl:16][C:13]1[CH:14]=[CH:15][C:9]([S:8][CH2:7][CH2:6][C:4]2[CH:5]=[N:1][NH:2][CH:3]=2)=[C:10]([NH:11][S:26]([C:18]2[O:17][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH:19]=2)(=[O:27])=[O:28])[CH:12]=1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: Nc1cc(Cl)ccc1SCCc1cn[nH]c1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)ccc1SCCc1cn[nH]c1)c1cc2ccccc2o1
Yield: 45.9 %

Procedure:
Following General Procedure B, the title compound (123 mg) was prepared from 2-((2-(1H-pyrazol-4-yl)ethyl)thio)-5-chloroaniline (157 mg, 0.618 mmol) and benzofuran-2-sulfonyl chloride (133 mg, 0.618 mmol) in pyridine (3 ml).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[CH2:16]([N:18]1[C:27]2[C:22](=[CH:23][C:24]([CH:32]([CH3:34])[CH3:33])=[CH:25][C:26]=2[C:28](=O)[CH2:29][CH3:30])[C:21]([CH3:36])([CH3:35])[CH2:20][CH2:19]1)[CH3:17]>>[CH2:2]([O:3][C:4](=[O:5])/[C:6](/[F:7])=[C:28](\[C:26]1[CH:25]=[C:24]([CH:32]([CH3:34])[CH3:33])[CH:23]=[C:22]2[C:27]=1[N:18]([CH2:16][CH3:17])[CH2:19][CH2:20][C:21]2([CH3:35])[CH3:36])/[CH2:29][CH3:30])[CH3:1]
Reactant: CCC(=O)c1cc(C(C)C)cc2c1N(CC)CCC2(C)C
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Product: CCOC(=O)/C(F)=C(/CC)c1cc(C(C)C)cc2c1N(CC)CCC2(C)C

Procedure:
Following General Procedure E, triethyl-2-fluoro-2-phosphonoacetate (15.1 g, 62.3 mmol) and 1-(1-ethyl-6-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-8-yl)-1-propanone (Intermediate 13, 4.48 g, 15.6 mmol) were reacted to give the title compound as bright yellow oil after purification by flash chromatography (SiO2, 2:98 ethyl acetate:hexane).
Reaction SMILES: [I-].C(OC([N:8]1[C@H:12]([CH2:13][C:14]2[S:18][C:17]3=[CH:19][N:20]([CH2:23][O:24][CH3:25])[C:21]([CH3:22])=[N+:16]3[CH:15]=2)[CH2:11][C@H:10]([S:26][C:27]2[C@H:28]([CH3:44])[C@@H:29]3[C@@H:39]([C@H:40]([OH:42])[CH3:41])[C:38](=[O:43])[N:30]3[C:31]=2[C:32]([O:34]CC=C)=[O:33])[CH2:9]1)=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1.C(O)C>[OH:42][C@@H:40]([C@H:39]1[C:38](=[O:43])[N:30]2[C:31]([C:32]([O-:34])=[O:33])=[C:27]([S:26][C@H:10]3[CH2:11][C@@H:12]([CH2:13][C:14]4[S:18][C:17]5=[CH:19][N:20]([CH2:23][O:24][CH3:25])[C:21]([CH3:22])=[N+:16]5[CH:15]=4)[NH:8][CH2:9]3)[C@H:28]([CH3:44])[C@H:29]12)[CH3:41]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3c[n+]4c(C)n(COC)cc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Solvent: CCO
Product: COCn1cc2sc(C[C@@H]3C[C@H](SC4=C(C(=O)[O-])N5C(=O)[C@H]([C@@H](C)O)[C@H]5[C@H]4C)CN3)c[n+]2c1C
Yield: 6.9 %

Procedure:
Anhydrous THF (0.5 ml) and 0.5 ml of dry ethanol are added to 47.9 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[6-methoxymethyl-5-methylimidazo[5,1-b]thiazolium-2-yl]methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate iodide. Triphenylphosphine (5.8 mg), 0.012 ml of morpholine, and 3.2 mg of tetrakis(triphenylphosphine)palladium(0) are successively added in an argon atmosphere at room temperature for 75 min. THF (10 ml) is added thereto, and the resultant precipitate is further washed twice with 3 ml of THF and dried in vacuo to give a yellow powder which is then purified by column chromatography on Cosmosil 40C18-PREP (water-methanol) to give 2.2 mg of the title compound as a colorless flocculent material.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH2:15][CH:14]([CH2:16][C:17]#[N:18])[O:13][N:12]=2)=[C:9]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C([NH:27][C:28]1[N:32]([CH3:33])[N:31]=[N:30][N:29]=1)C=C.C(Cl)(=O)C(Cl)=O.O>N1C=CC=CC=1.ClC(Cl)C>[Cl:1][C:2]1[C:10]([C:11]2[CH2:15][CH:14]([CH2:16][C:17]#[N:18])[O:13][N:12]=2)=[C:9]([S:19]([CH2:22][CH3:23])(=[O:20])=[O:21])[CH:8]=[CH:7][C:3]=1[C:4]([NH:27][C:28]1[N:32]([CH3:33])[N:31]=[N:30][N:29]=1)=[O:5]
Reactant: C=CCNc1nnnn1C
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1C1=NOC(CC#N)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCS(=O)(=O)c1ccc(C(=O)Nc2nnnn2C)c(Cl)c1C1=NOC(CC#N)C1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
178 mg (0.5 mmol) of 2-chloro-3-[5-(cyanomethyl)-4,5-dihydro-1,2-oxazol-3-yl]-4-(ethylsulfonyl)benzoic acid and 90 mg (0.65 mmol) of N-allyl-1-methyl-1H-tetrazol-5-amine are stirred in 3 ml of pyridine at room temperature (RT) for 1 h, and then a solution of 86 mg (0.675 mmol) of oxalyl chloride in 2 ml of dichloroethane is added. Subsequently, the mixture is stirred at 75° C. for 4 h. After cooling to RT, 0.5 ml of water is added. Then the mixture is stirred at RT for 30 min. The reaction solution is filtered and concentrated. The residue is purified by means of preparative HPLC (acetonitrile/water). Yield: 19 mg (8%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[CH:9]1[CH2:13][CH2:14][CH:5]2[CH2:6][N:7]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:8]1.C1C(=O)N([Br:28])C(=O)C1>C(Cl)Cl.C(O)(=O)C>[NH2:1][C:2]1[C:3]([Br:28])=[C:4]2[C:10](=[CH:11][CH:12]=1)[CH:9]1[CH2:13][CH2:14][CH:5]2[CH2:6][N:7]([C:15](=[O:20])[C:16]([F:19])([F:17])[F:18])[CH2:8]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc2c(c1)C1CCC2CN(C(=O)C(F)(F)F)C1
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1ccc2c(c1Br)C1CCC2CN(C(=O)C(F)(F)F)C1
Reaction time: 0.5 h

Procedure:
1-(4-Amino-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-10-yl)-2,2,2-trifluoro-ethanone (20 mg, 0.0204 mmol) was placed in CH2Cl2 (3 mL) and acetic acid (0.1 mL). NBS was added. The reaction was stirred for 30 min. and then concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-8% MeOH/CH2Cl2 as the eluting solvent to obtain 1-(4-amino-3-bromo-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-10-yl)-2,2,2-trifluoro-ethanone as a yellow film (14.82 mg, 58%). LCMS (m/e) 363 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.18 (d, 1H, J=10.6 Hz), 6.57 (d, 1H, J=8.34 Hz), 4.25-4.10 (m, 1H), 4.03 (bs, 2H), 3.90-3.78 (m, 1H), 3.50-3.40 (m, 1H), 3.40-3.26 (m, 1H), 3.12-3.00 (m, 2H), 2.30-1.90 (m, 2H), 1.80-1.65 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][NH:11][C:10]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1.N1C=CC=CC=1.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][N:11]([C:28]([CH:25]3[CH2:27][CH2:26]3)=[O:29])[C:10]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1
Reactant: Clc1ccc2c(c1)C=Cc1cc(Br)ccc1CN2
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: O=C(C1CC1)N1Cc2ccc(Br)cc2C=Cc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A solution of 9-Bromo-2-chloro-5,6-dihydro-dibenzo[b,f]azocine (30 mg, 0.09 mmol) (prepared in a manner analogous to that described for Example 1F) in dichloroethane was treated with pyridine (0.02 mL, 0.27 mmol) and cyclopropanecarbonyl chloride (0.011 mL, 0.12 mmol). The reaction mixture was stirred at room temperature for two hours then concentrated, diluted with MeOH and filtered. The crude product was purified by preparative reversed-phase HPLC to afford Example 326A (30 mg, 82%). HPLC Rt=4.05 min. m/z=388 (M+H+)
Reaction SMILES: [CH3:1]C([O-])(C)C.[Na+].[CH3:7][C:8]1[S:9][CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][OH:15].CI>C1COCC1.CC(OC)(C)C>[CH3:1][O:15][CH2:14][CH2:13][C:12]1[CH:11]=[CH:10][S:9][C:8]=1[CH3:7]
Reactant: Cc1sccc1CCO
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CI
Solvent: C1CCOC1
Product: COCCc1ccsc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of NaOtBu (3.00 g, 31.3 mmol) in THF (25 mL) was added the above prepared 2-(2-methyl-thiophen-3-yl)-ethanol (3.56 g, 25 mmol) and then methyl iodide (2.34 mL, 37.5 mmol). After stirring at rt for 1 h the reaction mixture was diluted with TBME (150 mL) and washed with 0.5M HCl (50 mL), 0.1M Na2S2O3 (50 mL) and 10% brine. The aqueous layers were extracted with TBME (50 mL) and the combined organic layers were dried (Na2SO4) and evaporated affording 3.78 g (96.7%, GC 96.0%) crude product as a yellow oil which was used without purification in the next step.