Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([S@@:5](/[N:7]=[CH:8]/[C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:6])([CH3:4])[CH3:3].[Cl:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[CH:24][C:25]=1[Cl:26].[NH4+].[Cl-].O>C1COCC1.CCOC(C)=O>[Cl:19][C:20]1[CH:21]=[C:22]([C@@H:8]([C:9]2[C:14]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:12]=[CH:11][N:10]=2)[NH:7][S@:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[O:6])[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: CC(C)(C)[S@](=O)/N=C/c1ncccc1C(F)(F)F
Reactant: Clc1ccc([Mg]Br)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[S@](=O)N[C@@H](c1ccc(Cl)c(Cl)c1)c1ncccc1C(F)(F)F
Reaction time: 0.08 h

Procedure:
(S,E)-2-Methyl-N-((3-(trifluoromethyl)pyridin-2-yl)methylene)propane-2-sulfinamide (0.493 g, 1.772 mmol) was dissolved in dry THF (10 mL) and cooled in an ice bath. 3,4-Dichlorophenylmagnesium bromide (Aldrich, 0.5 M solution in THF, 4.0 mL, 2.0 mmol) was added, and the reaction mixture was stirred for 5 minutes. Saturated aqueous NH4Cl (10 mL), H2O (100 mL) and EtOAc (100 mL) were added, and the phases were mixed and separated. The organic layer was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to EtOAc gradient) gave (S)—N—((S)-(3,4-dichlorophenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[CH2:16][C:11]3[C:12]4=[C:13]2[C:4](=[CH:5][CH:6]=[C:7]4[CH:8]=[CH:9][CH:10]=3)[CH:3]=1.CC(O)(C)C.CS(C)=O.CI>C(Cl)Cl.O.CN(P(N(C)C)(N(C)C)=O)C>[Br:1][C:2]1[CH:15]=[C:14]2[CH2:16][C:11]3[C:12]4[C:13]2=[C:4]([CH2:5][CH2:6][C:7]=4[CH:8]=[CH:9][CH:10]=3)[CH:3]=1
Reactant: Brc1cc2c3c(ccc4cccc(c43)C2)c1
Solvent: O
Solvent: ClCCl
Solvent: CI
Product: Brc1cc2c3c(c1)Cc1cccc(c1-3)CC2
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 172.4 %

Procedure:
2-bromo-4H-cyclopenta[def]phenanthrene (2.6 g, 7.7 mmol), t-BuOH (20.8 g, 61.6 mmol), DMSO (20 ml), and HMPA (20 ml) were put into a 50 ml round bottom flask using a syringe. The reaction mixture was stirred at room temperature for 50 minutes and cooled to 0° C. Then, CH3I (3.75 ml, 61.6 mmol) was dropwise added to the flask using a syringe at 0° C. and the reaction mixture was stirred at 0° C. for 30 minutes. Then, water (50 ml) and methylene chloride (50 ml) were added to the flask to separate an organic phase. The organic phase was purified by silica gel column chromatography to give a compound 2 (3.6 g, 80%). 1H NMR (300 MHz, CDCl3, δ): 7.98 (2H, s), 7.79 (2H, s), 7.73 (2H, s), 6.94 (dd, 1H), 1.93 (m, 6H).
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:42]=[CH:43][CH:44]=1)[C:9]([NH:11][C:12]1[S:13][C:14]2[CH2:41][CH2:40][CH2:39][CH2:38][C:15]=2[C:16]=1[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)=[O:18])=[O:10])([CH3:3])[CH3:2].[CH2:45]([O:47][P:48]([CH2:53][CH2:54][CH2:55][C:56](O)=[O:57])([O:50][CH2:51][CH3:52])=[O:49])[CH3:46]>>[CH2:51]([O:50][P:48]([CH2:53][CH2:54][CH2:55][C:56]([N:4]([CH2:5][C:6]1[CH:7]=[C:8]([CH:42]=[CH:43][CH:44]=1)[C:9]([NH:11][C:12]1[S:13][C:14]2[CH2:41][CH2:40][CH2:39][CH2:38][C:15]=2[C:16]=1[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][CH:37]=2)=[CH:22][CH:21]=1)=[O:18])=[O:10])[CH:1]([CH3:3])[CH3:2])=[O:57])([O:47][CH2:45][CH3:46])=[O:49])[CH3:52]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CNC(C)C)c4)sc4c3CCCC4)cc2)cc1
Reactant: CCOP(=O)(CCCC(=O)O)OCC
Product: CCOP(=O)(CCCC(=O)N(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1)C(C)C)OCC
Yield: 82.4 %

Procedure:
By using 550 mg of methyl 4-{2-[4-({[2-({3-[(isopropylamino)methyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate and 200 mg of 4-(diethoxyphosphoryl)butanoic acid as starting materials, the reaction similar to Preparation Example 27 was performed, thereby obtaining 600 mg of methyl 4-[2-(4-{[(2-{[3-({[4-(diethoxyphosphoryl)butanoyl](isopropyl)amino}methyl)benzoyl}amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:36])[C:18](=[O:35])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[NH:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:36])[C:18](=[O:35])[NH:19][N:20]=2)[CH2:9]1
Reactant: CC1C(=O)NN=C2COc3cc(OCc4ccccc4)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1C(=O)NN=C2COc3cc(OCc4ccccc4)c(NC4CNC4)cc3N21
Yield: 58 %

Procedure:
A solution of 3-(7-benzyloxy-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.028 g, 0.057 mmol) in TFA (0.5 mL) and DCM (3 mL) was stirred at rt for 2 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC (Table 3, Method 18) to give 6-(azetidin-3-ylamino)-7-benzyloxy-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (0.013 g, 58%). LC/MS (Table 1, Method 5) Rt=2.201 min; MS m/z: 394 [M+H]+
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16]Br)[CH:11]=1>C1COCC1>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[CH2:16][O:1][CH2:2][C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)CO
Reactant: BrCc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COCc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Methyl hydroxyacetate (0.80 g, 8.8 mmol) was dissolved in THF (10 mL) and allowed to stir at 0° C. under a nitrogen atmosphere. NaH (0.40 g, 9.6 mmol, 60% dispersion in oil) was added portionwise over approximately 5 minutes. The cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature. 1-Bromo-3-(bromomethyl)benzene (2.0 g, 8.0 mmol) was added in a single portion and the resulting mixture was heated to 40° C. After 4 hours, the reaction mixture was allowed to cool to ambient temperature and partitioned between water and EtOAc. The layers were separated, and the organic layer was washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the title compound, which was carried forward without further purification. 1H NMR (600 MHz, CDCl3): δ 7.53-7.50 (m, 1H), 7.42-7.38 (m, 1H), 7.30-7.17 (m, 2H), 4.57 (s, 2H), 4.09 (s, 2H), 3.74 (s, 3H).
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:32][CH2:31][CH:30]([CH2:33][C:34](O)=[O:35])[CH2:29][CH2:28]2)[C:9]=1[Br:37].[CH3:48][S:49]([NH2:52])(=[O:51])=[O:50].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:32][CH2:31][CH:30]([CH2:33][C:34]([NH:52][S:49]([CH3:48])(=[O:51])=[O:50])=[O:35])[CH2:29][CH2:28]2)[C:9]=1[Br:37]
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(Br)c(C2CCC(CC(=O)O)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)CC1CCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N)c2Br)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetic acid (60 mg, 0.081 mmol), methanesulfonamide (12 mg, 0.122 mmol), 4-dimethylaminopyridine (20 mg, 0.163 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (32 mg, 0.163 mmol) in dichloromethane (2.0 ml) was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The crude mixture was dissolved in methanol (2 ml) and treated with 1N hydrochloride solution (2 ml) at 65° C. for 2 h. The reaction solution was concentrated and purified by prep-LC to afford the title compound (two isomers, cis and trans). Isomer 1: LC/MS RT=3.63 min. Mass calculated for, M+H 557.09, observed 557.09. Isomer 2: LC/MS RT=3.88 min. Mass calculated for, M+H 557.09, observed 557.09.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[CH2:10][S:9][N:8]=[C:7]([N:12]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]3=[N:27][N:28]([CH2:30][C:31]4[C:36]([CH3:37])=[C:35]([O:38][CH3:39])[C:34]([CH3:40])=[CH:33][N:32]=4)[N:29]=[C:4]([C:5]=23)[CH2:3]1.CS(C)=O.[C:45](OC(=O)C)(=[O:47])[CH3:46]>C(OCC)(=O)C>[C:45]([O:1][C:2]1[C:11]2[CH2:10][S:9][N:8]=[C:7]([N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]3=[N:27][N:28]([CH2:30][C:31]4[C:36]([CH3:37])=[C:35]([O:38][CH3:39])[C:34]([CH3:40])=[CH:33][N:32]=4)[N:29]=[C:4]([C:5]=23)[CH:3]=1)(=[O:47])[CH3:46]
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(C)cnc(CN2N=C3CC(O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1c(C)cnc(Cn2nc3cc(OC(C)=O)c4c-3c(n2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
A mixture composed of di-tert-butyl {8-hydroxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 32 (778 mg), dimethyl sulfoxide (10 mL) and acetic anhydride (1 mL) was stirred in a nitrogen atmosphere at room temperature for 12 hours. After confirming that the raw material disappeared, the reaction mixture was diluted with ethyl acetate and sequentially washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (507 mg, 61%) as an oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:5][CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 6.87 g (0.043 mol) of 4-trifluoromethylaniline in 110 ml of dichloromethane was added 5.25 ml (0.043 mol) of pivaloylchloride. After stirring for 1.5 hours, 190 ml of a saturated solution of aqueous sodium bicarbonate was added. The reaction proceeded an additional 2 hours and the organic layer was separated and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed to give the title compound, yield 9.16 g (88%), m.p. 154°-158° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: Fc1cccc(Cc2cc(Cl)ncn2)c1F
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(Cc2cccc(F)c2F)ncn1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
In 2 ml of tetrahydrofuran was suspended 0.05 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.07 g of 2-butyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, to which 0.6 ml of a tetrahydrofuran solution containing 0.2 g of 4-chloro-6-(2,3-difluorobenzyl)pyrimidine was slowly added dropwise at room temperature, followed by stirring for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.22 g of 4-(2-butynyloxy)-6-(2,3-difluorobenzyl)pyrimidine (the present compound (96)).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][NH:11]1.Cl[CH2:16][C:17](=O)[CH3:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[N:9]1[C:10]2=[N:11][CH2:12][CH2:13][N:14]2[C:17]([CH3:18])=[CH:16]1
Reactant: CC(=O)CCl
Reactant: Brc1cccc(Br)c1N=C1NCCN1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1=CN(c2c(Br)cccc2Br)C2=NCCN12
Temperature: 150 °C

Procedure:
A mixture consisting of 9.6 gm (0.03 mol) of 2-(2,6-dibromophenyl-imino)-imidazoline, 2.6 ml (110% of the stoichiometrically required amount) of chloroacetone, 3 ml of triethylamine and 30 ml of absolute toluene was heated in a closed tube at 150° C. for 17 hours. Thereafter, the toluene phase was decanted, and the residue was dissolved in dilute hydrochloric acid. The resulting solution was fractionally extracted with ether at stepwisely increasing pH values (addition of 2 N sodium hydroxide). The thin-layer chromatographically pure ethereal fractions were combined, dried over anhydrous calcium sulfate and evaporated in vacuo, leaving 1.65 gm (15.4% of theory) of the compound of the formula ##STR9## which had a melting point of 144°-147° C.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][NH:11]1>O>[CH3:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(F)n1
Reactant: CC1CCCCN1
Solvent: O
Product: CC1CCCCN1c1cccc(N)n1
Temperature: 205 °C
Yield: 49.1 %

Procedure:
A suspension of 6-fluoropyridin-2-amine (448 mg, 4 mmol) and 2-methylpiperidine (596 mg, 6 mmol) in water (0.5 mL) was heated to 205° C. in a microwave oven for 30 minutes. The reaction mixture was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=10:1) to give 6-(2-methylpiperidin-1-yl)pyridin-2-amine (376 mg, 49%) as a brown oil. LC-MS: [M+H]+, 192.2, tR=1.266 min.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([C:13](Cl)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:16][C:17]1[N:21]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[N:20]=[CH:19][C:18]=1[C:32]([NH:34][C:35]1[CH:36]=[N:37][C:38]([C:42]2[CH2:43][CH2:44][NH:45][CH2:46][CH:47]=2)=[C:39]([CH3:41])[CH:40]=1)=[O:33]>ClCCl.O>[CH3:16][C:17]1[N:21]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[N:20]=[CH:19][C:18]=1[C:32]([NH:34][C:35]1[CH2:36][N:37]([C:13]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:14])[C:38]([C:42]2[CH2:43][CH2:44][NH:45][CH2:46][CH:47]=2)=[C:39]([CH3:41])[CH:40]=1)=[O:33]
Reactant: O=C(Cl)N1CCCC1
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1=C(C2=CCNCC2)N(C(=O)N2CCCC2)CC(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)=C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Triethylamine (38 μl) and 1-pyrrolidinecarbonyl chloride (30 μl) were added to a mixture of 5-methyl-N-[5-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (100 mg) described in Reference Example 170 and dichloromethane (4.6 ml), and stirred at room temperature for six hours. Then, triethylamine (380 μl) and 1-pyrrolidinecarbonyl chloride (300 μl) were added and stirred at room temperature all night and all day. Triethylamine (95 μl) and water was added to the reaction solution, dichloromethane was evaporated in vacuo, and the precipitated solid was washed with ethanol to give the titled compound (99 mg) as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:20]=[CH:19][C:18]3[C:13](=[CH:14][C:15]([C:21]([O:23]C)=[O:22])=[CH:16][CH:17]=3)[N:12]=2)=[CH:5][CH:4]=1)#[N:2].O1CCCC1.Cl>[OH-].[Li+]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:20]=[CH:19][C:18]3[C:13](=[CH:14][C:15]([C:21]([OH:23])=[O:22])=[CH:16][CH:17]=3)[N:12]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc2cnc(CCc3ccc(C#N)cc3)nc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1ccc(CCc2ncc3ccc(C(=O)O)cc3n2)cc1
Reaction time: 0.5 h

Procedure:
0.3 g (0.94 mmol) of methyl 2-[2-(4-cyanophenyl)-ethyl]-quinazoline-7-carboxylate were dissolved in 4.7 ml of 1N lithium hydroxide solution and 4 ml of tetrahydrofuran and stirred for 3 hours at ambient temperature. Then 4.7 ml of 1N hydrochloric acid were added and the mixture was stirred for 30 minutes. The product precipitated was suction filtered, washed with water and dried. Yield: 0.30 g (100% of theory), Rf value: 0.1 (silica gel, ethyl acetate/cyclohexane=1:1)
Reaction SMILES: C(O)C.[OH-].[K+].[Cl-].[Na+].[CH2:8]([C:10]([CH3:21])([CH2:19][CH3:20])[C:11](=[O:18])[CH2:12][CH:13](O)[C:14]([OH:16])=[O:15])[CH3:9]>O>[CH2:19]([C:10]([CH3:21])([CH2:8][CH3:9])[C:11](=[O:18])[CH:12]=[CH:13][C:14]([OH:16])=[O:15])[CH3:20]
Reactant: CCC(C)(CC)C(=O)CC(O)C(=O)O
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC(C)(CC)C(=O)C=CC(=O)O
Temperature: 0 °C

Procedure:
The product of the preparation immediately above was dissolved in 400 ml. of ethanol and brought to a boil. To it was quickly added 40 g. of potassium hydroxide in 360 ml. of water, and the temperature was held at 72° for 2 minutes. The mixture was then poured immediately into 1 liter of ice-water, and 50 g. of sodium chloride was added. The aqueous mixture was extracted with 1000 ml. of diethyl ether, and the aqueous layer was made acid with concentrated hydrochloric acid. It was then extracted 4 times with 500 ml. portions of dichloromethane, and the organic layers were combined, dried over magnesium sulfate and evaporated under vacuum to obtain 20 g. of the desired acid, as a mixture with 5-ethyl-2-hydroxy-5-methyl-4-oxoheptanoic acid, the presence of which was indicated by nuclear magnetic resonance signals, δ 4.35 (q, 1H); 2.6-3.8 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:17])([CH3:16])[CH2:4][NH:5][C:6]1[C:7]2[CH:15]=[CH:14][NH:13][C:8]=2[N:9]=[C:10](Cl)[N:11]=1.[NH2:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[N:24][NH:25]2)=[CH:21][CH:20]=1.C[Si](Cl)(C)C>C(O)CCC>[NH2:1][CH2:2][C:3]([CH3:17])([CH3:16])[CH2:4][NH:5][C:6]1[C:7]2[CH:15]=[CH:14][NH:13][C:8]=2[N:9]=[C:10]([NH:18][C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][NH:25]3)=[CH:21][CH:20]=2)[N:11]=1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: CC(C)(CN)CNc1nc(Cl)nc2[nH]ccc12
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(C)(CN)CNc1nc(Nc2ccc3cn[nH]c3c2)nc2[nH]ccc12
Temperature: 116 °C
Yield: 15.3 %

Procedure:
A mixture of N-(3-amino-2,2-dimethylpropyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine (70 mg, 0.28 mmol), 6-aminoindazole (93 mg, 0.70 mmol) and trimethylsilyl chloride (0.100 mL, 0.72 mmol) in nBuOH (2 mL) was heated at 116° C. overnight. It was then purified by HPLC to give the titled compound (15 mg). MS 351.4 (M+H); UV 206.1, 242.6, 304.3 nm.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=2)=[CH:2]1.[OH-].[Na+]>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)=[CH:2]1
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(Cc2c[nH]c3ccccc23)cc1

Procedure:
A solution of methyl 4-((1H-indol-3-yl)methyl)benzoate (Tet. Lett. 44 (2003) 4589-4591) (0.50 g, 1.88-mmol) in methanol is treated with an aqueous solution of NaOH (4.15 mL, 1N, 4.15 mmol), heated to reflux temperature for 3 h and concentrated in vacuo. The resultant solid residue is dissolved in H2O and acidified with HCl. The resultant precipitate is removed by filtration and dried to yield 4-((1H-indol-3-yl)methyl)benzoic acid as a white solid, 0.468 g (99%). A microwave vial is charged with PS-Carbodiimide (0.275 g, 1.2 mmol/g, 0.33 mmol). To the vial is added a solution of 4-((1H-indol-3-yl)methyl)-benzoic acid (0.070 g, 0.28 mmol) in CH3CN, a solution of HOBT (0.045 g, 0.33 mmol) in CH3CN, a solution of (S)-1,3′-bipyrrolidine (0.065 g, 0.31 mmol) in CH3CN and 0.11 mL of triethylamine. The reaction mixture is irradiated in the Emry's Optimizer at 110° C. for 6 minutes and then concentrated under reduced pressure. The resultant residue is purified by flash chromatography to yield the title product as a white solid, 0.064 g, (68%), mp 141-153° C., identified by H1 NMR and mass spectral analyses. MS (ES) m/z 372.2.
Reaction SMILES: [N+:1]([C:4]1[O:5][C:6]([S:9]([CH2:11][C:12]([OH:14])=O)=[O:10])=[CH:7][CH:8]=1)([O-:3])=[O:2].[NH2:15][CH:16]1[C:34](=[O:35])[N:18]2[C:19]([C:31]([OH:33])=[O:32])=[C:20]([CH2:23][S:24][C:25]3[S:29][C:28]([CH3:30])=[N:27][N:26]=3)[CH2:21][S:22][C@H:17]12>>[N+:1]([C:4]1[O:5][C:6]([S:9]([CH2:11][C:12]([NH:15][CH:16]2[C:34](=[O:35])[N:18]3[C:19]([C:31]([OH:33])=[O:32])=[C:20]([CH2:23][S:24][C:25]4[S:29][C:28]([CH3:30])=[N:27][N:26]=4)[CH2:21][S:22][C@H:17]23)=[O:14])=[O:10])=[CH:7][CH:8]=1)([O-:3])=[O:2]
Reactant: O=C(O)CS(=O)c1ccc([N+](=O)[O-])o1
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CS(=O)c4ccc([N+](=O)[O-])o4)[C@H]3SC2)s1

Procedure:
438 mg. of 2-(2-nitrofuran-5-ylsulfinyl)acetic acid and 7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 382 mg. of 7-[2-(2-nitrofuran-5-ylsulfinyl)acetamido]-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[CH2:29][O:28][CH2:27][CH2:26][C:11]=3[N:12]([C:14]([NH:16][C@@H:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:18]([NH:20][CH3:21])=[O:19])=[O:15])[N:13]=2)[CH:5]=[CH:6][C:7]=1[F:8].N[C@@H](C(C)(C)C)[C:32](NCCO)=[O:33]>>[OH:33][CH2:32][CH2:21][NH:20][C:18](=[O:19])[C@@H:17]([NH:16][C:14]([N:12]1[C:11]2[CH2:26][CH2:27][O:28][CH2:29][C:10]=2[C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)=[N:13]1)=[O:15])[C:22]([CH3:24])([CH3:25])[CH3:23]
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(C)(C)C
Reactant: CC(C)(C)[C@H](N)C(=O)NCCO
Product: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(=O)NCCO

Procedure:
Compound 36 was prepared according to the procedure described for the synthesis of compound 28 by replacing tert-leucine methylamide with intermediate 23. 1H NMR (CDCl3) δ 7.89 (d, J=9.1 Hz, 1H), 7.46-7.51 (m, 1H), 7.21-7.30 (m, 2H), 4.82 (s, 2H), 4.20 (d, J=9.0 Hz, 1H), 3.94 (t, J=5.5 Hz, 2H), 3.74 (br, 2H), 3.44-3.49 (m, 2H), 3.17 (br, 2H), 1.11 (s, 9H). LCMS (+ESI) m/z=437 [M+H]+.