Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:13](OCCCC)(=O)[C:14](C)=[CH2:15].[C:23](OCC(C)C)(=O)C(C)=C.[CH3:33][CH:34]([OH:42])[CH2:35][O:36][C:37]([C:39]([CH3:41])=[CH2:40])=[O:38]>>[CH3:3][C:2]([C:1]([O:6][CH:7]1[C@@:12]2([CH3:23])[C:14]([CH3:15])([CH3:13])[C@H:9]([CH2:10][CH2:11]2)[CH2:8]1)=[O:5])=[CH2:4].[CH3:33][CH:34]([OH:42])[CH2:35][O:36][C:37]([C:39]([CH3:41])=[CH2:40])=[O:38]
Reactant: C=C(C)C(=O)OC1CCCCC1
Reactant: C=C(C)C(=O)OCCCC
Reactant: C=C(C)C(=O)OCC(C)C
Agent: C=C(C)C(=O)OCC(C)O
Product: C=C(C)C(=O)OC1C[C@H]2CC[C@]1(C)C2(C)C

Procedure:
Cyclohexyl methacrylate (CHMA), butyl methacrylate (BMA), isobutyl methacrylate (IBMA) and HPMA were copolymerized using a CPO initiator according to the following:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18]([CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[N:17][C:9]2[C@H:10]3[N:14]([C:15](=[O:16])[C:8]=2[C:7]=1[C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][CH:26]=1)[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:55][C@H:56]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH2:58][CH2:57]1>ClCCl>[C@H:56]1([NH:55][C:29]([C:28]2[CH:32]=[CH:33][C:25]([C:7]3[C:8]4[C:15](=[O:16])[N:14]5[C@H:10]([C:9]=4[N:17]=[C:18]([CH2:19][CH2:20][C:21]([F:23])([F:22])[F:24])[C:6]=3[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:12][CH2:13]5)=[CH:26][CH:27]=2)=[O:31])[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH2:58][CH2:57]1
Reactant: CCOC(=O)c1c(CCC(F)(F)F)nc2c(c1-c1ccc(C(=O)O)cc1)C(=O)N1CCC[C@@H]21
Reactant: N[C@@H]1CCc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)c1c(CCC(F)(F)F)nc2c(c1-c1ccc(C(=O)N[C@@H]3CCc4ccccc43)cc1)C(=O)N1CCC[C@@H]21
Reaction time: 3 h
Yield: 49.2 %

Procedure:
To a stirred solution of 4-[(9aS)-3-(ethoxycarbonyl)-5-oxo-2-(3,3,3-trifluoropropyl)-7,8,9,9a-tetrahydro-5H-pyrido[2,3-α]pyrrolizin-4-yl]benzoic acid (0.075 g, 0.162 mmol) in 1 mL of dichloromethane, EDCI (0.037 g, 0.194 mmol), HOBT (0.026 g, 0.194 mmol) and (R)-(−)-1-aminoindane (0.051 g, 0.324 mmol) were added. The reaction mixture was allowed to stir for ˜3 h. The mixture was then concentrated and redissolved in 1 mL of ethyl acetate. The organics were then washed with saturated aqueous NaHCO3 and brine. Filtration followed by concentration provided a brown oil which was purified by radial chromatography (ethyl acetate/hexanes (4:1)) to yield 0.046 g (49%) of the desired product as a white solid: 1H NMR (CDCl3, 400 MHz) δ 7.86–7.77 (d, 2H, J=8.27), 7.45–7.37 (d, 2H, J=8.28), 7.36–7.29 (d, 1H, J=6.38), 7.28–7.16 (m, 3H), 6.48–6.37 (m, 1H), 5.72–5.64 (q, 1H, J=7.59), 4.71–4.63 (dd, 1H, J=10.34, J=6.21), 4.13–3.96 (m, 2H), 3.72–3.58 (m, 1H), 3.38–3.26 (m, 1H), 3.22–3.08 (m, 2H), 3.07–2.96 (m, 1H), 2.96–2.83 (m, 1H), 2.79–2.56 (m, 3H), 2.55–2.38 (m, 1H), 2.38–2.22 (m, 2H), 1.98–1.84 (m, 1H), 1.45–1.27 (m, 1H), 1.04–0.95 (t, 3H, J=7.07); TLC (EtOAc/Hex(4:1)): Rf=0.3; RP-HPLC (BDS Hypersil C-18 25 cm×4.6 mm; 10–100% CH3CN in H2O with 0.1% TFA buffer, 30 minutes; 1 mL/min) tr=11.8 min, 94.1% purity.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][NH2:9])[S:5][CH:6]=1.[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][N:9]2[C:13](=[O:14])[C:12]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]3[C:10]2=[O:15])[S:5][CH:6]=1
Reactant: NCCc1cc(Br)cs1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1CCc1cc(Br)cs1

Procedure:
A mixture of 2(4-bromo-2-thienyl)-ethylamine (37 g) and phthalic anhydride (26.7 g) in glacial acetic acid (500 ml) is heated at reflux over 15 hours. It is concentrated at reduced pressure, the residue is triturated with ethanol and collected. The solid is recrystallized from ethanol to afford N-[2-(4-bromo-2-thienyl)ethyl]-phthalimide, m.p. 115°-117°.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[Cl:13][C:14]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][OH:37])=[CH:30][C:15]=1[C:16]([NH:18][CH2:19][C:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2)=[O:17]>ClCCl.C(OCC)(=O)C>[Cl:13][C:14]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][O:37][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:30][C:15]=1[C:16]([NH:18][CH2:19][C:20]12[CH2:29][CH:24]3[CH2:23][CH:22]([CH2:28][CH:26]([CH2:25]3)[CH2:27]1)[CH2:21]2)=[O:17]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCO)ccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)OCCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
Methanesulfonyl chloride (1.1 ml) and triethylamine (2 ml) were added to a solution of 2-chloro-5-(3-hydroxypropyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 6d, 2.65 g) in dichloromethane at 0° C. After 1 h the reaction mixture was diluted with ethyl acetate and extracted once with water, twice with saturated sodium hydrogencarbonate solution and once with brine, dried over magnesium sulfate and concentrated under reduced pressure to give the subtitled compound as an oil which slowly solidified (3.2 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:16]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:52]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:16][Br:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCC(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Reaction time: 1 h
Yield: 69.5 %

Procedure:
First, 13.8 g of 2,2-bis(6-benzyloxyhexyl)ethanol, 10.2 g of triphenylphosphine, and 50 ml of methylene chloride were placed in a 200 ml flask. Then, 50 ml of a methylene chloride solution containing 16.1 g of carbon tetrabromide was added dropwise to the reaction mixture at room temperature, and the reaction mixture was stirred for 1 hour. The reaction mixture was washed with an aqueous solution of sodium bicarbonate and water in this order. The resultant reaction mixture was dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene) to obtain 11 g of 2,2-bis(6-benzyloxyhexyl)ethyl bromide (Y: 69%). The compound thus obtained had a purity of 97.5% by GC.
Reaction SMILES: [N:1]12[CH2:8][C:5]([CH2:9][OH:10])([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.C([Li])CCC.CCCCCC.N1([C:27]([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH3:38])[N:30]=2)=[O:28])C=CNC1>O1CCCC1>[N:1]12[CH2:8][C:5]([CH2:9][O:10][C:27]([C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]([CH3:38])[N:30]=3)=[O:28])([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2
Reactant: OCC12CCCN(CC1)C2
Reactant: Cn1nc(C(=O)N2C=CNC2)c2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1nc(C(=O)OCC23CCCN(CC2)C3)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
A cooled (0° C.) solution of 1-azabicyclo[3.2.1]oct-5-ylmethanol (1.70 g, 12 mmol) in anhydrous tetrahydrofuran (15 mL) under nitrogen was treated (via syringe) with 2.45N n-butyllithium/hexane (12 mmol), then stirred at room temperature for thirty minutes and concentrated in vacuo to remove all hexane. Anhydrous tetrahydrofuran (15 mL) was added, followed by 3-(3H-imidazol-1-ylcarbonyl)-1-methyl-1H-indazole (2.49 g, 11 mmol), and the mixture was stirred under nitrogen at room temperature for 18 hours, then at 60° C. for three hours, and concentrated in vacuo. The residue was partitioned between 1.0N sodium carbonate (75 mL) and toluene (125 mL) containing some 2-propanol, and the organic layer was set aside. The aqueous solution was extracted with toluene (2×50 mL) containing some 2-propanol, and the combined organic solution was rinsed with water to remove imidazole, then dried azeotropically with toluene. The residue was filtered through alumina (eluted with 15% methanol/tetrahydrofuran), concentrated in vacuo, and triturated from ether/petroleum ethers (30°-60°), then recrystallized from ether/petroleum ethers (30°-60°) to afford 1.75 g (53%) of the product as a colorless solid; mp. 93°-95° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3]C1C=C2C(C=CN2)=CC=1.[C:15]([C:18]1[C:26]2[C:21](=[CH:22][C:23](F)=[C:24](F)[CH:25]=2)[N:20]([CH2:29][C:30]([OH:32])=[O:31])[CH:19]=1)(=[O:17])[NH2:16]>>[C:15]([C:18]1[C:26]2[C:21](=[CH:22][C:23]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:24][CH:25]=2)[N:20]([CH2:29][C:30]([OH:32])=[O:31])[CH:19]=1)(=[O:17])[NH2:16]
Reactant: NC(=O)c1cn(CC(=O)O)c2cc(F)c(F)cc12
Reactant: FC(F)(F)Oc1ccc2cc[nH]c2c1
Product: NC(=O)c1cn(CC(=O)O)c2cc(OC(F)(F)F)ccc12

Procedure:
was prepared from 6-trifluoromethoxy-1H-indole [467451-91-8] in a similar manner as described for the preparation of (3-carbamoyl-5,6-difluoro-indol-1-yl)-acetic acid. White solid. MS (LC/MS): 303.0 [M+H]+, 605.0 [2M+H]+; tR (HPLC conditions k): 2.75 min.
Reaction SMILES: [CH:1]1([C:6]2[CH:10]=[C:9]([NH:11][C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=3[Cl:22])=[O:13])[N:8]([C:23]3[CH:31]=[C:30]4[C:26]([CH2:27][CH2:28][CH:29]4[C:32](O)=[O:33])=[CH:25][CH:24]=3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=[N:41]C=2C=1.CCN=C=NCCCN(C)C.N.O1CCOCC1>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C>[C:32]([CH:29]1[C:30]2[C:26](=[CH:25][CH:24]=[C:23]([N:8]3[C:9]([NH:11][C:12]([NH:14][C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=4[Cl:22])=[O:13])=[CH:10][C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[N:7]3)[CH:31]=2)[CH2:27][CH2:28]1)(=[O:33])[NH2:41]
Reactant: On1nnc2ccccc21
Reactant: O=C(Nc1cccc(Cl)c1Cl)Nc1cc(C2CCCC2)nn1-c1ccc2c(c1)C(C(=O)O)CC2
Agent: CCN=C=NCCCN(C)C
Agent: N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)C1CCc2ccc(-n3nc(C4CCCC4)cc3NC(=O)Nc3cccc(Cl)c3Cl)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 1:1:1 mix of EtOH:H2O:dioxane (6 mL) was placed ethyl 6-(3-cyclopentyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-2,3-dihydro-1H-indene-1-carboxylate (520 mg, 0.986 mmol) and lithium hydroxide (71 mg, 2.96 mmol). The solution warmed to 40 C and stirred, ON. LC shows complete reaction. The solution cooled to RT and diluted with 5% citric acid (20 mL) and Ethyl acetate (20 mL). The organic phase separated, washed with brine and dried over sodium sulfate. The solvents were evaporated at reduced pressure to give 6-(3-cyclopentyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-2,3-dihydro-1H-indene-1-carboxylic acid as a foam, 474 mg (96%), used as is. In DMF (5 mL) was placed 6-(3-cyclopentyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-2,3-dihydro-1H-indene-1-carboxylic acid (474 mg, 0.949 mmol), HOBt (196 mg, 1.09 mmol) and EDAC (218 mg, 1.42 mmol). The mixture was stirred at RT for 1 hr and then treated with a solution of 0.5N ammonia in dioxane (7.59 mL, 3.80 mmol). The mixture was stirred at RT, ON. LC shows complete reaction. The mixture was diluted with 5% citric acid (20 mL) and Ethyl acetate (20 mL). The organic phase separated, washed with saturated sodium bicarbonate (20 mL), brine (20 mL) and dried over sodium sulfate. The solvents evaporated at reduced pressure to give a foam, dried on high vacuum line at RT for 2 hrs. The foam was then purified by Biotage chromatography (S1-25 column, 65-95% Ethyl acetate/Hex). Fractions 10-19 were combined and evaporated at reduced pressure to give 1-(1-(3-carbamoyl-2,3-dihydro-1H-inden-5-yl)-3-cyclopentyl-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea as a white solid. The solid was dried on the high vacuum line at 65 C in the abderhalden for 3 hrs, 210 mg (44%). 1H NMR (DMSO-d6) 1.59-1.73 (m, 6H), 1.95-1.99 (m, 2H), 2.23-2.33 (m, 2H), 2.88-3.06 (m, 3H), 3.90-4.04 (m, 1H), 6.31 (s, 1H), 6.98 (s, 1H), 7.26-7.42 (m, 5H), 7.63 (br s, 1H), 8.07-8.09 (m, 1H), 8.77 (s, 1H), 9.21 (s, 1H). LC-MS (EI) m/z: 500.0 (M+H+).
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:28][C:29]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:30]=1[CH2:31]Br>>[Br:28][C:29]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:30]=1[CH2:31][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:8]2[N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:11]3[CH:12]=[CH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][C:10]=3[N:9]=2)=[CH:22][CH:23]=1
Reactant: COc1ccc(Br)c(CBr)c1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(O)cc1)n2C1CCCCC1
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc(OC)ccc3Br)cc1)n2C1CCCCC1

Procedure:
Ethyl 1-cyclohexyl-2-(4-hydroxyphenyl)benzimidazole-5-carboxylate obtained in Example 3 and 2-bromo-5-methoxybenzyl bromide were treated in the same manner as in Example 4 to give the title compound (59 g).
Reaction SMILES: [N+:1]([CH:3](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:4])#[C-:2].[F:15][C:16]1[C:23]([F:24])=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:17]=1[CH:18]=[O:19].C([O-])([O-])=O.[K+].[K+].O>CO>[F:15][C:16]1[C:23]([F:24])=[C:22]([C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:17]=1[C:18]1[O:19][CH:2]=[N:1][C:3]=1[CH3:4]
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ncoc1-c1ccc(C(F)(F)F)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
A mixture of 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (1 0.0 g, 47.8 mmol), 2,3-difluoro-4-(trifluoromethyl)benzaldehyde (9.68 g, 46.1 mmol), and K2CO3 (13.1 g, 95.0 mmol) in MeOH (240 mL) was heated to reflux. After 2 hr, the reaction mixture was cooled to ambient temperature, water (700 mL) was added, and the product was extracted with EtOAc (700 mL). The organic layer was washed with brine and dried over Na2SO4, filtered, and concentrated to an orange oil. The crude product was purified by chromatography on silica gel in five batches (Analogix® SF40-240G column, 100% CH2Cl2, 65 mL/min) to afford 7.22 g (60%) of the title compound as a light yellow liquid. 1H NMR (300 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.78-7.69 (m, 1H), 7.68-7.59 (m, 1H), 2.30 (d, J=2.5, 3H). MS (DCI+) m/z 264 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[C:15]([OH:17])=[O:16])[CH2:3][CH2:2]1.C[O-].[Na+].[CH3:21][O:22]C(OC)N(C)C>CO>[C:15]([C:11]1[N:10]([CH2:9][CH2:8][CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([CH:21]=[O:22])[CH2:2][CH2:3]2)[CH:14]=[CH:13][N:12]=1)([OH:17])=[O:16]
Reactant: O=C(O)c1nccn1CCCC1CCNCC1
Reactant: COC(OC)N(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=CN1CCC(CCCn2ccnc2C(=O)O)CC1
Temperature: 80 °C

Procedure:
A mixture of 1-[3-(4-piperidinyl)propyl]-1H-imidazole-2-carboxylic acid 1.75 molar hydrochloride 0.65 molar hydrate (1.3 g, 0.0047M) and sodium methoxide (0.005M) in methanol (23 ml) was added to dimethylformamide dimethylacetal (15 ml) and heated at 80° C. for 8 hrs. The reaction mixture was filtered and stripped to dryness to give 4-[3-(2-carboxy-1H-imidazol-1-yl)propyl]-1-piperidine carboxaldehyde. The solution of the above piperidine carboxaldehyde dimethylacetal in methanol (5 ml) was then added to a mixture of 6-aminopenicillanic acid (0.81 g, 0.0037M) and diisopropylethylamine (0.4 ml) in chloroform (30 ml) at 0° C. The reaction was stirred at 0° C. 2 hrs and room temperature for 2 hrs. The solvent was removed and water (15 ml) was added. After being washed with ether, the aqueous solution, acidified to pH 3 to about 3.5, was purified on Sephadex LH 20 columns to give [2S-(2alpha,5alpha,6beta]-6-[[[1-(3-(2-carboxy-1H-imidazol-1-yl)propyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hydrate (0.38 g, 17% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[NH2:13][C:14]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:15]=1[C:16](O)=[O:17]>O1CCCC1>[NH2:13][C:14]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:15]=1[C:16]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:17]
Reactant: Brc1ccccn1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1ccc(Cl)cc1C(=O)c1ccccn1
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
To a cooled solution (−40° C.) of 2-bromopyridine (1.68 mL, 17.6 mmol) in tetrahydrofuran (THF) (30 mL) was added n-butyllithium (nBuLi) (9.7 mL, 19 mmol, 2M in pentane) in a dropwise fashion and the resulting mixture was stirred for 30 min. 2-amino-5-chlorobenzoic acid (0.7 g, 4 mmol) was added and stirring was continued at 0° C. After 2 h, the mixture was quenched with trimethylchlorosilane (TMSCl) (10 mL), and hydrolyzed with 1N HCl (30 mL). The aqueous layer was separated from the organic phase, neutralized with 3N aq. sodium hydroxide, and extracted with ether (3×100 mL). The combined ether extracts were dried (Na2SO4), filtered, concentrated and purified by flash chromatography on silica gel [hexanes:ethyl acetate (7:3)] to give (2-amino-5-chlorophenyl)-pyridin-2-yl-methanone (0.71 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:28]2[CH:29]=[CH:30][C:25]([C:23]#[N:24])=[CH:26][CH:27]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccc(-c2ccccc2C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1
Yield: 45.5 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 4-cyanophenylboronic acid (0.027 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.032 g (46%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-2-carboxamide as a white solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:2]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(I)cc1
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(-c2ccccc2)cc1
Yield: 52.1 %

Procedure:
The Suzuki coupling of (+,−) Cis propane-2-sulfonic acid [2-(4-iodo-phenyl)-cyclopentyl]-amide (167 mg, 0.43 mmol, prepared in example 17) and phenylboronic acid (62 mg, 0.51 mmol) was accomplished in a manner analogous to the procedure described in example 27. The reaction was worked up in a manner analogous to example 3. Purification by silica chromatography using a Chromatotron® was achieved eluting with methylene chloride. Further purification was achieved by reverse phase C18 chromatography to afford 77 mg (53%) of the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.ClC(OCC)=O.Cl.[NH2:37][CH:38]1[CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39]1>ClCCl>[CH2:39]1[C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:46][CH:38]1[NH:37][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][C:14]([NH:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:22]
Reactant: NC1Cc2ccccc2C1
Reactant: COc1ccc(CCNC(=O)CCCCC(=O)O)cc1OC
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCNC(=O)CCCCC(=O)NC2Cc3ccccc3C2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
6-[2-(3,4-Dimethoxyphenyl)ethylamino]-6-oxohexanoic acid (6.0 g, 0.019 mole) was dissolved in dry dichloromethane (200 ml) and triethylamine (2.28 g, 0.021 mole) added followed by ethyl chloroformate (1.86 ml, 0.019 mole) at 0°. The solution was stirred at 0° for 30 min and a solution of 2-aminoindane hydrochloride (3.3 g, 0.019 mole) and triethylamine (2.52 ml 0.019) in dry dichloromethane (200 ml) added, allowed to warm to room temperature and stirred for a further 18 hr. The reaction mixture was washed with water, dried (MgSO4) and evaporated and the residue recrystallised from methanol to give the sub-title compound as a white solid (6.4 g), mp 162°-4°.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([C:12](Cl)=[O:13])=[CH:9][CH:8]=2)=[CH:5][C:4]([C:15]([F:18])([F:17])[F:16])=[N:3]1.C1COCC1.Cl.[NH2:25][C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:31][N:27]1[CH:28]=[CH:29][CH:30]=[C:26]1[NH:25][C:12]([C:10]1[S:11][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:5]=2)=[CH:8][CH:9]=1)=[O:13]
Reactant: Cn1cccc1N
Reactant: Cn1nc(C(F)(F)F)cc1-c1ccc(C(=O)Cl)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cccc1NC(=O)c1ccc(-c2cc(C(F)(F)F)nn2C)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
5-(1-Methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carbonyl chloride (295 mg) and THF (3 ml) were added to a mixture of 2-amino-1-methylpyrrole hydrochloride (202 mg), potassium carbonate (553 mg), THF (2 ml) and water (4 ml), followed by stirring at room temperature for 30 minutes. Water was added to the reaction solution, the thus formed product was extracted with ethyl acetate and then the extract was washed with 1 N hydrochloric acid, saturated sodium bicarbonate aqueous solution and water in that order. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=2:1-3:2) and then recrystallized from a mixed solvent of ethyl acetate and n-hexane to give N-(1-methyl-2-pyrrolyl)-5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carboxamide (126 mg) as light yellow powder crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:11]2[O:12][CH:10]2[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:8]=2)[O:3]1.[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1>[O:20]=[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]1[C@@H:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:8]=2)[O:3][C:2]([CH3:19])([CH3:1])[C@H:11]1[OH:12]
Reactant: CC1(C)Oc2ccc(C(=O)C(F)(F)F)cc2C2OC21
Reactant: Oc1ccccn1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: CC1(C)Oc2ccc(C(=O)C(F)(F)F)cc2[C@@H](n2ccccc2=O)[C@@H]1O

Procedure:
A mixture containing 1.9 g of 2,2-dimethyl-3,4-epoxy-6-trifluoroacetylchromane (PREPARATION II), 1.4 g of 2-hydroxypyridine, 5 ml of dioxane and 0.2 ml of a methanolic solution containing 35% of benzyltrimethylammonium hydroxide is refluxed for 20 hours. The residue obtained after concentration under vacuum is taken up with 20 ml of water and the insoluble material is then filtered off and washed with water and boiling isopropyl ether. It is chromatographed on a column of 50 g of silica using a methylene chloride/ethyl acetate mixture (7/3) as the eluent. This gives 0.3 g of dry product.