Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=[CH:20][CH:19]=3)=[C:10]3[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[N:11]3[N:12]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.C(OCC)(=O)C>[N:7]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[C:8]1[C:9]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)=[C:10]2[CH2:15][CH2:14][CH:13]([CH2:16][O:17][S:29]([CH3:28])(=[O:31])=[O:30])[N:11]2[N:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(-c2nn3c(c2-c2ccnc4ccccc24)CCC3CO)n1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCC1CCc2c(-c3ccnc4ccccc34)c(-c3ccccn3)nn21
Reaction time: 0.5 h

Procedure:
A solution of [2-(6-methyl-pyridin-2-yl)-3-quinolin-4-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-yl]-methanol (30 mg, 0.07 mmol) and 4-dimethylaminopyridine (catalytic) in pyridine (0.2 mL) is cooled to 0° C. and treated with methanesulfonyl chloride (8 mL, 0.105 mmol) and stirred for 30 min. The mixture is stirred at room temperature for 30 min, diluted with ethyl acetate (20 mL), washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to yield the title compound, 30 mg (86%,) as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[N:4][CH:3]=1.O.[CH3:11][C:12]([C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)([CH3:16])[C:13]([OH:15])=[O:14].C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[C:8]([C:6]1[N:7]=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([C:12]([CH3:16])([CH3:11])[C:13]([OH:15])=[O:14])=[CH:18][CH:19]=2)[CH:3]=[N:4][CH:5]=1)#[N:9]
Reactant: N#Cc1cncc(Cl)n1
Reactant: CC(C)(C(=O)O)c1ccc(B2OC(C)(C)C(C)(C)O2)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: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C(=O)O)c1ccc(-c2cncc(C#N)n2)cc1
Temperature: 80 °C
Yield: 70.2 %

Procedure:
6-Chloropyrazine-2-carbonitrile (example 20b) (890 mg, 6.4 mmol) was dissolved in DME (24 mL) and water (6 mL) followed by 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoic acid (example 20d) (1.86 g, 6.4 mmol) and K2CO3 (1.76 g, 12.7 mmol). The mixture was degassed using an argon stream, Pd(PPh3)4 (369 mg, 0.32 mmol) was added and the mixture was heated (80° C.) overnight. The solvents were removed under reduced pressure and a residue was suspended in 1M aq. NaOH (10 mL) and washed with EtOAc. The aqueous phase was then acidified to pH 4-5 using 6N aq. HCl and extracted with EtOAc (3×60 mL). The organic extracts were combined, washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was purified on silica gel (5% MeOH in DCM) to give 1.2 g (70%) of the pure intermediate 2-(4-(6-cyanopyrazin-2-yl)phenyl)-2-methylpropanoic acid. 1H NMR (400 MHz, dMSO): δ 1.50 (s, 6H), 1.69 (m, 1H), 7.54-7.56 (d, 2H), 8.13-8.15 (d, 2H), 9.17 (s, 1H), 9.56 (s, 1H), 12.50 (s, 1H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[CH2:19][NH:20][C:21]([NH:23][C:24]1[S:25][CH:26]=[C:27]([CH:29]=O)[N:28]=1)=[O:22].[NH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41]>C(Cl)Cl>[F:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[CH2:19][NH:20][C:21](=[O:22])[NH:23][C:24]1[S:25][CH:26]=[C:27]([CH2:29][NH:34][CH2:35][CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43])[N:28]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=Cc1csc(NC(=O)NCc2cccc(F)c2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNCc1csc(NC(=O)NCc2cccc(F)c2)n1

Procedure:
Sodium triacetoxyborohydride (937 mg, 4.42 mmol) was added to a CH2Cl2 (50 mL) solution of 1-(3-fluorobenzyl)-3-(4-formylthiazol-2-yl)urea (620 mg, 2.21 mmol) and tert-butyl 2-aminoethylcarbamate (532 mg, 3.32 mmol) at 0 C. Upon completion of the reaction, it was quenched with dilute NaHCO3. The organics were dried and evaporated. Flash chromatography afforded tert-butyl 2-((2-(3-(3-fluorobenzyl)ureido)thiazol-4-yl)methylamino)ethylcarbamate. 1H NMR (400 MHz, CDCl3): δ 8.05 (1H, br), 7.28 (m, 1H), 7.00 (m, 3H), 6.61 (s, 1H), 4.80 (s, 1H), 4.49 (d, 2H), 3.73 (s, 2H), 3.17 (m, 2H), 2.63 (t, 2H), 1.41 (s, 9H). MS (ES+): M/Z 424 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:34]([CH2:36][NH:37][C:38]([CH:40]1[CH:45]([CH2:46]O)[CH:44]2[CH2:48][CH:41]1[CH:42]=[CH:43]2)=[O:39])#[N:35].[F:49][C:50]1[CH:55]=[CH:54][C:53]([SH:56])=[CH:52][CH:51]=1>CN(C)C=O>[C:34]([CH2:36][NH:37][C:38]([CH:40]1[CH:45]([CH2:46][S:56][C:53]2[CH:54]=[CH:55][C:50]([F:49])=[CH:51][CH:52]=2)[CH:44]2[CH2:48][CH:41]1[CH2:42][CH2:43]2)=[O:39])#[N:35]
Reactant: N#CCNC(=O)C1C2C=CC(C2)C1CO
Reactant: Fc1ccc(S)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: N#CCNC(=O)C1C2CCC(C2)C1CSc1ccc(F)cc1
Reaction time: 19 h

Procedure:
A solution of triphenylphosphine (140 mg, 540 mmol) in dimethylformamide (1.0 mL) was cooled to 0° C. Diisopropyl azodicarboxylate (98 μL, 500 μmol) was added and the reaction mixture was stirred for 2 min. (1R/S,2R/S,3R/S,4S/R)-N-(Cyanomethyl)-3-(hydroxymethyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide (94 mg, 450 μmol) and 4-fluorothiophenol (53 μL, 500 μmol) were added. After stirring the reaction mixture for 19 h, it was partitioned between ethyl acetate (20 mL) and 1:1 water:saturated aqueous sodium chloride (20 mL). The product was extracted into ethyl acetate and the combined organics were washed with 1 mL saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated using a rotary evaporator. Chromatography of the residue on silica gel eluting with 1:2 ethyl acetate:hexanes provided (1S/R,2R/S,3R/S,4R/S)-N-(cyanomethyl)-3-{[(4-fluorophenyl)sulfanyl]methyl}bicyclo[2.2.1]heptane-2-carboxamide as a colorless syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:24][C:25](=[O:40])[CH2:26][CH2:27][NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:10]([N:12]([CH2:16][CH:17](OCC)OCC)[CH:13]([CH3:15])[CH3:14])=[O:11])=[CH:4][CH:3]=1>C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]2[N:24]3[C:25](=[O:40])[CH2:26][CH2:27][N:28]([S:29]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)(=[O:31])=[O:30])[CH:17]3[CH2:16][N:12]([CH:13]([CH3:14])[CH3:15])[C:10]2=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(CN(C(=O)C(Cc1ccc(Cl)cc1)NC(=O)CCNS(=O)(=O)c1ccc(OC)cc1)C(C)C)OCC
Solvent: O=CO
Product: COc1ccc(S(=O)(=O)N2CCC(=O)N3C(Cc4ccc(Cl)cc4)C(=O)N(C(C)C)CC32)cc1

Procedure:
A solution of 167 mg of 3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropyl-2-[3-(4-methoxybenzenesulfonylamino)propionylamino]propionamide in 3 ml of formic acid is stirred at room temperature for 12 h. The reaction solution is concentrated under reduced pressure, and the residue is separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). The desired product is obtained with MW=506.02 (calculated); measured value (M+H)+: 506.34
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:24][CH:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:14](=[O:34])[N:13]1[CH:9]([CH2:10][CH:11]([O:35][C:36]3[C:45]4[C:40](=[C:41]([CH3:48])[C:42]([O:46][CH3:47])=[CH:43][CH:44]=4)[N:39]=[C:38]([C:49]4[S:50][CH:51]=[C:52]([CH:54]([CH3:56])[CH3:55])[N:53]=4)[CH:37]=3)[CH2:12]1)[C:8](=[O:57])[NH:7]2)=[O:5])C.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.O>[CH:54]([C:52]1[N:53]=[C:49]([C:38]2[CH:37]=[C:36]([O:35][CH:11]3[CH2:10][CH:9]4[N:13]([C:14](=[O:34])[N:15]([CH2:25][C:26]5[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=5)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH:23]5[C:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]4=[O:57])[CH2:24]5)[CH2:12]3)[C:45]3[C:40](=[C:41]([CH3:48])[C:42]([O:46][CH3:47])=[CH:43][CH:44]=3)[N:39]=2)[S:50][CH:51]=1)([CH3:56])[CH3:55]
Reactant: CCOC(=O)C12CC1C=CCCCCCN(Cc1ccc(OC)cc1)C(=O)N1CC(Oc3cc(-c4nc(C(C)C)cs4)nc4c(C)c(OC)ccc34)CC1C(=O)N2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)O)NC(=O)C3CC(Oc4cc(-c5nc(C(C)C)cs5)nc5c(C)c(OC)ccc45)CN3C2=O)cc1
Reaction time: 8 h
Yield: 60 %

Procedure:
Ethyl ester 137 (366 mg, 0.460 mmol) was dissolved in THF/MeOH/H2O 2:1:1 (30 mL) and 1M LiOH (4.6 mL, 4.40 mmol) was added dropwise at room temperature during 5 minutes after which the solution was stirred overnight. The mixture was acidified to pH 3-4 by addition of solid citric acid and the organic solvents were evaporated. The water phase was diluted with brine (50 mL) and was then extracted trice with DCM. The combined organic phase was washed twice with brine and was thereafter dried, filtered and concentrated. The crude was then purified by flash column chromatography (ethyl actetate/methanol 7:1) to give the title compound (212 mg, 60%). (M+H)+ calcd: 768.3. found: 768.7.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:6]([F:15])=[C:7]([F:14])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])(=[O:3])[CH3:2].O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3].[CH:34](OC)(OC)[O:35]C.[CH2:41](Cl)Cl>>[F:14][C:7]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:5]([CH2:4][C:1]([O:35][CH3:34])([O:3][CH3:41])[CH3:2])[C:6]=1[F:15]
Reactant: COC(OC)OC
Reactant: ClCCl
Reactant: CC(=O)Cc1c([N+](=O)[O-])ccc(F)c1F
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Product: COC(C)(Cc1c([N+](=O)[O-])ccc(F)c1F)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
A solution of 3-acetylmethyl-1,2-difluoro-4-nitrobenzene (500 mg, 2.3 mmol) in methylene chloride (5 ml) containing montmorillonite K10 (1 g) and trimethyl orthoformate (5 ml) was stirred for 24 hours at ambient temperature. The solid was filtered, washed with methylene chloride and the filtrate was evaporated to give 1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene (534 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23]([O:25]C)=O)[CH:5]=[CH:6][CH:7]=1.Cl.[OH-].[NH4+:29]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(Cl)c1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(Cl)c1
Yield: 47 %

Procedure:
A solution of the 9-[(3-chlorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (156.2 mg, 0.43 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was sonicated for 5 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 69.7 mg (47%) of the 9-[(3-chlorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (dd, 1H, J=1 and 8 Hz), 7.45 (m, 2H), 7.3 (m, 3H), 7.2 (s, 1H), 7.1 (d, 1H, J=8 Hz), 6.95 (s, 1H), 6.6 (d, 1H, J=8 Hz), and 5.7 (s, 2H). IR (CHCl3, cm−1) 3433, 3202 (br), 1630, 1600, 1580, 1564, 1433, 1330, 1261, and 776. MS (ES) m/e 349, 351, 353.
Reaction SMILES: Cl.O.[Br:3][C:4]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:5]=1[N:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CCN(CC)CC>CO.[Fe]>[Br:3][C:4]1[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:5]=1[N:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCN(CCCCCC)c1ccc([N+](=O)[O-])cc1Br
Agent: [Fe]
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCN(CCCCCC)c1ccc(N)cc1Br
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 51.4 %

Procedure:
A mixture of concentrated hydrochloric acid (4.0 mL), water (100 mL) and iron powder (13.44 g, 241 mmol) was stirred at 65° C. for 15 min. The aqueous layer of the mixture was poured out, and a solution of 2-bromo-N,N-dihexyl-4-nitroaniline (9.28 g, 24.1 mmol) in MeOH (150 mL) was added to the above processed iron powder. The mixture was acidified to pH 3 with hydrochloric acid and stirred at 65° C. for 30 min. The mixture was then cooled to rt, adjusted to pH 10 with Et3N and filtered and the filtrate was concentrated. The residue was dissolved in 150 mL of DCM and the solution was washed with water (100 mL×3) and brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=20:1) to give the title compound as colorless oil (4.40 g, 51%).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>N1C=CC=CC=1>[Si:1]([O:8][CH:9]1[CH2:13][CH2:12][CH:11]([O:14][S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(O)C1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCC(O[Si](C)(C)C(C)(C)C)C2)cc1
Yield: 98.1 %

Procedure:
3-(tert-Butyldimethylsilyloxy)cyclopentanol (4.8 g, 0.022 mol) and 4.22 g (0.022 mol) of tosyl chloride were mixed with 45 mL of pyridine and stinted at room temperature over night. TLC revealed the completion of the reaction. The pyridine was removed in vacuo and the residue was dissolved in ethyl acetate, washed with 1 N HCl and brine, and dried over Na2SO4. The filtrate was concentrated under vacuum to dryness to obtain 8.0 g of crude desired product as a light pink residue. The crude product was purified over SiO2 using 3% EtOAc in hexanes as eluant to give two lots material. The first lot contained 2.50 g of product approximately 90% pure. The second lot contained 2.66 g of desired product with greater than 98% purity. The combined yield was approximately 60%.
Reaction SMILES: [Cl-].[NH4+].O.[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([N+:20]([O-])=O)[C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C.[Zn]>[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[NH2:20])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: COc1ccc(OCc2ccccc2)cc1N
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
1.38 kg of zinc powder and 15 g of ammonium chloride in 3.25 liters of ethanol to which have been added 600 ml of water are heated to 80° C. 2.5 mole (648 g) of 3-benzyloxy-6-methoxynitrobenzene is added little by little. Stirring is continued for 15 minutes after the end of the addition. The zinc is removed by filtering the reaction medium hot. The product crystallizes from the filtrate by cooling. After centrifuging and then washing with petrol ether, the product is dried. It melts at 81° C.
Reaction SMILES: [CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[CH:19]=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[N:26]5[CH2:27][CH2:28][NH:29][CH2:30][C:25]5=[N:24][CH:23]=4)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[CH:19]=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[N:26]5[CH2:27][CH2:28][N:29]([CH3:33])[CH2:30][C:25]5=[N:24][CH:23]=4)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1
Reactant: N#CCC(C1CC1)n1cc(-c2nc(-c3cnc4n3CCNC4)cc3nccn23)cn1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCn2c(-c3cc4nccn4c(-c4cnn(C(CC#N)C5CC5)c4)n3)cnc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
To 3-cyclopropyl-3-(4-(7-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (Example 56; 10 mg, 0.025 mmol) in DCM/MeOH (1 mL/1 mL) was added formaldehyde (50 mg, 0.50 mmol) and sodium triacetoxyborohydride (16 mg, 0.075 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1) to give the final product (5.0 mg, 48% yield). MS (apci) m/z=414.4 (M+H).
Reaction SMILES: C12C(C=O)C(CC1)=CC=2.[CH:10]1([CH:16]=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[C:18]12([O:28][CH2:29][C:30]3[NH:34][C:33]([CH:35]4[CH:39]5[CH:40]=[CH:41][CH:36]4[CH:37]=[CH:38]5)=[N:32][C:31]=3[C:42]([OH:44])=[O:43])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2.[CH2:45]([O:52][C:53](=[O:61])[C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([NH2:60])[CH:55]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH2:16]([O:17][C:42]([C:31]1[N:32]=[C:33]([CH:35]2[CH:36]3[CH:37]=[CH:38][CH:39]2[CH:40]=[CH:41]3)[NH:34][C:30]=1[CH2:29][O:28][C:18]12[CH2:25][CH:24]3[CH2:26][CH:20]([CH2:21][CH:22]([CH2:23]3)[CH2:27]1)[CH2:19]2)=[O:43])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:45]([O:52][C:53](=[O:61])[C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([NH:60][C:42]([C:31]2[N:32]=[C:33]([CH:35]3[CH:39]4[CH:40]=[CH:41][CH:36]3[CH:37]=[CH:38]4)[NH:34][C:30]=2[CH2:29][O:28][C:18]23[CH2:27][CH:22]4[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]4)[CH2:19]2)[CH2:25]3)=[O:44])[CH:55]=1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: Nc1cccc(C(=O)OCc2ccccc2)c1
Reactant: O=C(O)c1nc(C2C3C=CC2C=C3)[nH]c1COC12CC3CC(CC(C3)C1)C2
Reactant: O=CC1CCCCC1
Agent: O=CC1C2=CC=C1CC2
Product: O=C(OCc1ccccc1)c1cccc(NC(=O)c2nc(C3C4C=CC3C=C4)[nH]c2COC23CC4CC(CC(C4)C2)C3)c1
Product: O=C(OCc1ccccc1)c1nc(C2C3C=CC2C=C3)[nH]c1COC12CC3CC(CC(C3)C1)C2

Procedure:
5-(Adamantan-1-yloxymethyl)-2-bicyclo[2.2.1]hepta-2,5-dien-7-yl-1H-imidazole4-carboxylic acid benzyl ester was prepared according to the procedure of Example 216, steps a, b, c and d with the modification that norbornadiene-7-carboxaldehyde (J. Stapersma and G. W. Klumpp Tetrahedron, 1981, 37, 187) was used in step d instead of cyclohexanecarboxaldehyde. The benzyl ester was hydrolysed according to the procedure of Example 211, step b and the resulting 5-(adamantan-1-yloxymethyl)-2-bicyclo[2.2.1]hepta-2,5-dien-7-yl-1H-imidazole-4-carboxylic acid was reacted with 3-amino-benzoic acid benzyl ester according to the procedure of Example 20, step d to afford 3-{[5-(adamantan-1-yloxymethyl)-2-bicyclo[2.2.1]hepta-2,5-dien-7-yl-1H-imidazole-4-carbonyl]-amino}-benzoic acid benzyl ester. The benzyl ester was hydrolysed according to the procedure of Example 211, step b and the crude product was purified by flash column chromatography (silica, DCM/methanol 95:5 ) to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 12.10 (1H, br s), 9.65 (1H, br s), 8.42 (1H, br s), 7.92 (1H, d), 7.62 (1H, d), 7.41 (1H, t), 6.90 (2H, s), 6.59 (2H, s), 4.75 (2H, s), 4.06 (2H, s), 3.47 (1H, s), 2.10 (3H, br s), 1.75 (6H, s), 1.58 (6H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 58.71; H, 7.44; N, 7.50%. C36H48N4O9.3.0 mols H2O requires: C, 58.84; H, 7.41; N, 7.62%.
Reaction SMILES: C1(N2C(=O)C3S[CH:15]=[C:16]([C:17]4C=CC=CC=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])=[CH:27][S:26][C:25]=1[C:36]([O:38]C)=O.[CH:40](OCC)(OCC)OCC.C(N)C(C)(C)C>C(O)(=O)C>[F:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:28]1[C:24]2[N:23]=[CH:8][N:9]([CH2:10][C:16]([CH3:17])([CH3:40])[CH3:15])[C:36](=[O:38])[C:25]=2[S:26][CH:27]=1
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Reactant: CCOC(OCC)OCC
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: CC(C)(C)CN
Solvent: CC(=O)O
Product: CC(C)(C)Cn1cnc2c(-c3ccccc3F)csc2c1=O
Yield: 76.3 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (100 mg, 0.40 mmol), triethyl orthoformate (1 ml), neopentylamine (0.090 ml, 0.76 mmol), and acetic acid (0.1 ml) were used to give 96.5 mg (0.31 mmol, 76.3% yield) of the title compound.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](OC)=O)[C:3]=1[C:4]([OH:6])=O.[N+](C1C=CC=[C:20]([C:21](O)=[O:22])[C:19]=1C(O)=O)([O-])=O.C(O)(C(F)(F)F)=O>CO>[OH:6][CH2:4][C:3]1[CH:2]=[CH:10][CH:9]=[C:8]2[C:7]=1[CH:11]=[CH:19][CH:20]=[C:21]2[OH:22]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Reactant: COC(=O)c1cccc(N)c1C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: OCc1cccc2c(O)cccc12

Procedure:
2-Amino-6-(methoxycarbonyl) benzoic acid (1) was made from 3-nitrophthalic acid using the procedure first reported by Rogers and Averill (Rodgers, M. E. and Averill, B. A., J. Org. Chem., 1986, 51, 3308) and then used immediately to make Diels Alder cycloadduct 2 via the 3-(methoxhycarbonyl)dehydrobenzene intermediate that is generated under aprotic diazotization reaction conditions (based on modified conditions first reported by Giles, R. G. F., Sargent, M. V., and Sianipar, H., J. Chem. Soc. Perkin Trans I, 1991, 1571). Treatment of cycloadduct 2 with TFA in refluxing methanol yielded a 1:2 mixture of regioisomeric naphthols 3a and 3b which were separated by column chromatography on silica gel. The 1,5-naphthol regioisomer (3a) was then reduced with LAH to produce 5-hydroxymethyl naphthol 4, which was then coupled to carbapenem intermediate 5 (CPI 5) with catalytic palladium to produce the 1-carbon naphthol coupled CPI 6.
Reaction SMILES: C(OC([C:6]1[CH2:7][CH2:8][N:9]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:10][C:11]=1[NH:12][CH2:13]C1C=CC=CC=1)=O)C.C(OC(C1CCN(C(OC(C)(C)C)=O)CC1=O)=O)C.C(N)C1C=CC=CC=1>C1(C)C=CC=CC=1>[C:23]([O:22][C:20]([N:9]1[CH2:8][CH2:7][CH:6]2[CH:11]([NH:12][CH2:13]2)[CH2:10]1)=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: CCOC(=O)C1=C(NCc2ccccc2)CN(C(=O)OC(C)(C)C)CC1
Agent: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1=O
Solvent: Cc1ccccc1
Solvent: NCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2CNC2C1
Yield: 92.5 %

Procedure:
5-Benzylamino-3,6-dihydro-2H-pyridine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester. 3-Oxo-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (8.15 g, 30 mmol) from Step A and benzyl amine (3.43 g, 31.8 mmol) were dissolved into toluene (150 mL). The mixture was refluxed vigorously for 72 h and the generated water was collected into Dean-Stark apparatus. The residual solution was concentrated to yield the title compound (10.2 g, 92.5%). MS (ESI) mass calcd. for C20H28N2O4, 360.45, m/z found, 361.2 [M+H]+. The crude product was carried to the next step without any purification.