Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13](Cl)(=O)[CH3:14].C(N(CC)CC)C.N1C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1.O>[CH3:13][C:14]1[O:12][C:11]2[C:2](=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=[CH:9][CH:10]=2)[N:1]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cccc(O)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1cccc2oc(C)nc12
Temperature: 25 °C
Yield: 79 %

Procedure:
A solution of methyl 2-amino-3-hydroxybenzoate (167 mg, 1.0 mmol), acetyl chloride (86 mg, 1.1 mmol) and triethylamine (101 mg, 1.1 mmol) in xylene (10 mL) was stirred at 0° C. for 2 h. Pyridine (20 mg, 0.25 mmol) and TsOH (43 mg, 0.25 mmol) were then added and the mixture was heated at reflux overnight. The mixture was then cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, then dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography using petroleum ether/ethyl acetate 5:1 (v:v) as eluent to give methyl 2-methylbenzo[d]oxazole-4-carboxylate (151 mg, 79%). LC-MS (ES-API); rt 8.08 min; m/z calculated for C10H9NO3 [M+H]+ 192.1, found 192.1.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:8](=[O:15])[C:9]1C=CC=C[CH:10]=1.C(N(CC)CC)C.C(Cl)(=O)CC>C1(C)C=CC=CC=1.O>[NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:15])[CH2:9][CH3:10])[CH2:4][CH2:3]1
Reactant: NC1CCNCC1
Reactant: O=Cc1ccccc1
Agent: CCC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCC(=O)N1CCC(N)CC1
Reaction time: 1.5 h
Yield: 75.9 %

Procedure:
4-Aminopiperidine (4.01 g, 40 mmol) and benzaldehyde (4.251 g, 40 mmol) were dissolved in toluene (70 mL) and refluxed on a Dean-Stark trap until water ceased to evolve. The solvent was evaporated and the residue was reconstituted in dry THF (75 mL). Triethylamine (4.04 g, 40 mmol) was added and the reaction was cooled in an ice bath. With vigorous stirring, propionyl chloride (3.70 g, 40 mmol) was added and the reaction continued for 1.5 hours at rt. The reaction was filtered, and the filtrate was evaporated and treated with 1N HCl (50 mL) for 1 hour. The aqueous phase was washed with Et2O (3×50 mL), basified to pH>10 with NaOH, saturated with sodium chloride and extracted with DCM (5×75 mL). The combined DCM extract was evaporated and azeotropically dried with toluene to give intermediate 1 (4.74 g, 64%) as a light brown oil: 1H NMR (500 MHz, DMSO-d6) δ 4.18 (d, J=11.8 Hz, 1H), 3.74 (d, J=11.8 Hz, 1H), 3.00 (dd, J=11.8, 11.8 Hz, 1H), 2.89 (brs, 2H), 2.82-2.15 (m, 1H), 2.67 (dd, J=11.8 Hz, 11.8 Hz, 1H), 2.28 (q, J=7.1 Hz, 2H), 1.72 (d, J=11.8 Hz, 1H), 1.67 (d, J=11.8 Hz, 1H), 1.14 (q, J=10.2 Hz, 1H), 1.04 (q, J=10.2 Hz, 1H), 0.98 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40]([C:43]2([S:46]([CH3:49])(=[O:48])=[O:47])[CH2:45][CH2:44]2)=[N:41][CH:42]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[N:41][C:40]([C:43]4([S:46]([CH3:49])(=[O:48])=[O:47])[CH2:45][CH2:44]4)=[CH:39][CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: CS(=O)(=O)C1(c2ccc(Br)cn2)CC1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(C3(S(C)(=O)=O)CC3)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 58 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 5-bromo-2-(1-methanesulfonyl-cyclopropyl)-pyridine following a procedure analogous to that described in Example 1. Yield: 58% of theory; LC (method 1): tR=1.86 min; Mass spectrum (ESI+): m/z=549 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([F:18])=[C:4](F)[C:3]=1F.[C:21]([C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)#[N:22]>>[C:21]([C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:4]2[C:3]([NH:27][C:26]3[CH:28]=[CH:29][C:23]([C:21]#[N:22])=[CH:24][CH:25]=3)=[C:2]([F:1])[C:15]3[C:14](=[O:16])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7](=[O:17])[C:6]=3[C:5]=2[F:18])=[CH:25][CH:24]=1)#[N:22]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C1c2ccccc2C(=O)c2c(F)c(F)c(F)c(F)c21
Product: N#Cc1ccc(Nc2c(F)c3c(c(F)c2Nc2ccc(C#N)cc2)C(=O)c2ccccc2C3=O)cc1
Reaction time: 3 h

Procedure:
1,2,3,4-Tetrafluoroanthraquinone and 25 g of p-cyanoaniline were charged in a 50 cc, four necked flask and then the reaction was carried out at 150° C. for about 3 hours. After completion of reaction, p-cyanoaniline was distilled out from the reaction solution and then a column purification using a column with a silica gel was effected to give rise to 2.46 g of 2,3-bis(p-cyanoanilino)-1,4-difluoroanthraquinone (Dye 18') (yield 72,3 mol %). The physical properties of Dye 18' and analytical values defining the compound are tabulated in table 23.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][NH2:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:13][C:14](C)(C)C([O-])([O-])[O-]>CC(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][C:9]1[O:10][C:13]([CH3:14])=[N:12][N:11]=1
Reactant: NNC(=O)Cc1cccc(Br)c1
Reactant: CC(C)(C)C([O-])([O-])[O-]
Solvent: CC(=O)O
Product: Cc1nnc(Cc2cccc(Br)c2)o1
Temperature: 115 °C
Yield: 53.3 %

Procedure:
To a solution of 2-(3-bromophenyl)acetohydrazide 1104 (1.0 g, 4.37 mmol) in AcOH (10 mL) was added trimethylorthoacetate (2.62 g, 21.83 mmol) and the mixture heated to 115° C. for 18 hours. The volatiles were removed under reduced pressure and the residue purified by reverse phase chromatography to give 0.59 g of 2-(3-bromobenzyl)-5-methyl-1,3,4-oxadiazole 1105. 1H NMR 300 MHz CDCl3: δ 7.45 (m, 2H), 7.23 (m, 2H), 4.12 (s, 2H), 2.49 (s, 3H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH:25]([C:28]([O:30]CC)=[O:29])[CH2:24][CH2:23]4)=[O:21])=[CH:14][C:13]=3[C:33]([F:36])([F:35])[F:34])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+].CCO>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:23][CH2:24][CH:25]([C:28]([OH:30])=[O:29])[CH2:26][CH2:27]4)=[O:21])=[CH:14][C:13]=3[C:33]([F:35])([F:34])[F:36])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c(C(F)(F)F)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c(C(F)(F)F)c2)CC1

Procedure:
The title compound was prepared by hydrolysis of the compound of Example 252 under basic conditions (aq. NaOH/EtOH), giving a white solid, mp 88° C. (dec.). 1H NMR (DMSO-d6, 300 MHz) δ 1.40 (m, 2H), 1.98 (m, 2H), 2.95 (m, 1H), 3.15 (m, 1H), 3.45 (m, 1H), 4.20 (m, 2H), 4.35 (m, 4H), 7.00 (m, 4H), 7.20 (m, 2H), 7.90 (m, 1H), 8.20 (m, 1H), 12.30 (s, 1H). MS (APCI) m/z 494 (M+H)+. Anal. calcd. for C24H22F3NO5S.0.1H2O: C, 58.20; H, 4.52; N, 2.83. Found: C, 58.14; H, 4.69; N, 2.76.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]([F:44])([F:43])[C:6]1[CH:7]=[C:8]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:9][N:10]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]1[CH:31]=[C:30]([CH:32]=[O:33])[CH:29]=[CH:28][C:27]=1[O:34][CH3:35])[C:11](=[O:14])[O:12][CH3:13].[Cl-].[NH4+]>O1CCCC1>[F:4][C:5]([F:43])([F:44])[C:6]1[CH:7]=[C:8]([CH:36]=[C:37]([C:39]([F:40])([F:42])[F:41])[CH:38]=1)[CH2:9][N:10]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]1[CH:31]=[C:30]([CH:32]([OH:33])[CH3:1])[CH:29]=[CH:28][C:27]=1[O:34][CH3:35])[C:11](=[O:14])[O:12][CH3:13]
Reactant: C[Mg]Br
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C=O)ccc1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)O)ccc1OC
Temperature: 25 °C

Procedure:
Methylmagnesium bromide (0.59 mL, 0.83 mmol) was added dropwise to a solution of methyl [3,5-bis(trifluoromethyl)benzyl]{[5′-formyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (Example 73, 289 mg, 0.49 mmol) in anhydrous tetrahydrofuran at 0° C. The solution was allowed to warm to room temperature. Once the reaction was complete, saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with methylene chloride, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The title compound was obtained by flash chromatography using 30% acetone/hexane. 1HNMR (CDCl3, 600 MHz) δ 7.73 (s, 1H), 7.58 (m, 1H), 7.32-7.51 (m, 5H), 7.11 (m, 1H), 6.94 (m, 1H), 4.87 (m, 1H), 4.25-4.43 (m, 4H), 3.69 (m, 6H), 1.48 (d, J=4.2 Hz, 3H). LC-MS (M+Na) 632.0 (4.18 min).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:21]([CH3:22])=[CH:20][C:19]3[C:18]([CH3:24])([CH3:23])[CH2:17][CH2:16][C:15]([CH3:26])([CH3:25])[C:14]=3[CH:13]=2)=[CH:6][CH:5]=1.[Br:28]N1C(=O)CCC1=O.S(=O)(O)[O-].[Na+]>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH:11][C:12]2[C:21]([CH2:22][Br:28])=[CH:20][C:19]3[C:18]([CH3:23])([CH3:24])[CH2:17][CH2:16][C:15]([CH3:26])([CH3:25])[C:14]=3[CH:13]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(/C=C/c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C=Cc2cc3c(cc2CBr)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
A mixture of 1.0 g (2.76 mmol) of (E)-methyl-4-[2-(3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate, 0.64 g (3.6 mmol) of N-bromosuccinimide and 0.033 g (0.13 mmol) of benzoyl peroxide in 20 mL of carbon tetrachloride was heated under reflux, under a high intensity lamp. After 2 hours, the reaction was cooled to room temperature and poured into 10% aqueous sodium bisulfite solution. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was stirred with methyl alcohol to afford 0.88 g of Methyl-4-[2-(3-bromomethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate (72%) (M+=440).
Reaction SMILES: Br[C:2]1[C:7]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[CH3:24][O:25][CH2:26][O:27][C:28]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:29]=1[C:30](OCOC)=[O:31]>C1COCC1>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:7]1[C:2]([C:30](=[O:31])[C:29]2[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:28]=2[O:27][CH2:26][O:25][CH3:24])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: COCOC(=O)c1cc(C)ccc1OCOC
Reactant: Brc1ncccc1C1OCCO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOc1ccc(C)cc1C(=O)c1ncccc1C1OCCO1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 41.1 %

Procedure:
To a solution of 2-bromo-3-(1,3-dioxolan-2-yl)pyridine (3.50 g) in THF (50 ml) was added, at -78° C. under argon atmosphere, a 1.6M n-butyl lithium hexane solution (10.5 ml), which was stirred for 20 minutes. This reaction mixture was added, at the same temperature under argon atmosphere, to a solution of methoxymethyl 2-methoxymethoxy-5-methylbenzoate (3.66 g) in THF (50 ml). The mixture was stirred for 40 minutes, then for further one hour while warming up to room temperature. The reaction mixture was poured into a saturated aqueous saline solution, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate) and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give 3-(1,3-dioxolan-2-yl)-2-(2-methoxymethoxy-5-methylbenzoyl)pyridine (2.06 g) (Compound E-14). The physical properties and spectrum data are shown in Table 16 and Table 19.
Reaction SMILES: [Br:1][CH:2]1[C:7]([CH2:8][Br:9])=[C:6]([C:10]([O:12]C(C)(C)C)=[O:11])[N:5]2[C:17](=[O:29])[CH:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:4]2[S:3]1=[O:30]>FC(F)(F)C(O)=O>[Br:1][CH:2]1[C:7]([CH2:8][Br:9])=[C:6]([C:10]([OH:12])=[O:11])[N:5]2[C:17](=[O:29])[CH:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C@H:4]2[S:3]1=[O:30]
Reactant: CC(C)(C)OC(=O)C1=C(CBr)C(Br)S(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)=C(CBr)C(Br)S(=O)[C@H]12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.6 %

Procedure:
5.6 g of t-butyl 2-bromo-3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate 1-oxide, prepared by the procedure of Step C of Example II, were dissolved in 40 ml of trifluoroacetic acid and the solution was stirred for 15 minutes at room temperature. The solvent was then evaporated, diethyl ether was added and the solvent was evaporated again. Diethyl ether was added again and the solid was filtered and dried under vacuum at room temperature to obtain 4.72 g (93.6% yield) of 2-bromo-3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylic acid 1-oxide as a pale yellow solid.
Reaction SMILES: [ClH:1].[CH:2]1([C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([C:19]([O:21][CH3:22])=[O:20])[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3]1>C(O)C.C1(C)C=CC=CC=1>[Cl:1][CH2:4][CH2:3][CH2:2][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([C:19]([O:21][CH3:22])=[O:20])[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=1)=[O:6]
Reactant: COC(=O)C(Cc1ccc(C(=O)C2CC2)cc1)C(=O)OC
Reactant: Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)C(Cc1ccc(C(=O)CCCCl)cc1)C(=O)OC
Temperature: 68 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
Bubble hydrogen chloride gas through a solution of [4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, dimethyl ester (315 mg, 1.1 mmol) in ethanol (3 mL) and toluene (9 mL) for 10 minutes. Heat the solution to 68° C. After 4 hours, cool the solution to room temperature and bubble nitrogen through the solution for 1 hour. Add ethyl acetate and water to the residue. Dry the organic phase over anhydrous magnesium sulfate and concentrate to give the title compound (321 mg, 91%).
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[C:12]([NH:15][C:16]([NH2:18])=[NH:17])(=[O:14])[CH3:13]>CN(C=O)C>[C:12]([NH:15][C:16]1[NH:17][C:2]([CH3:11])=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:18]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)NC(=N)N
Reactant: CC(Br)C(=O)c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(-c2ccccc2)c(C)[nH]1

Procedure:
Prepared by reacting 2-bromo-propiophenone with 3 equivalents of 1-acetyl-guanidine in DMF (ambient temperature, 3 days).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH2:12][NH:13][N:14](COCC[Si](C)(C)C)[C:10]=2[C:9]2[CH:8]=[C:7]([C:23]#[N:24])[C:6]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[CH:5][C:4]=2[N:3]1[CH2:31][C:32]([F:35])([F:34])[F:33].O=C1C2=CN(COCC[Si](C)(C)C)N=C2C2C=C(C#N)C(C3C=CN=CC=3)=CC=2N1CC(F)(F)F.[ClH:71]>>[ClH:71].[O:1]=[C:2]1[C:11]2=[CH:12][NH:13][N:14]=[C:10]2[C:9]2[CH:8]=[C:7]([C:23]#[N:24])[C:6]([C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)=[CH:5][C:4]=2[N:3]1[CH2:31][C:32]([F:34])([F:35])[F:33]
Reactant: C[Si](C)(C)CCOCN1NCc2c1c1cc(C#N)c(-c3ccncc3)cc1n(CC(F)(F)F)c2=O
Agent: C[Si](C)(C)CCOCn1cc2c(=O)n(CC(F)(F)F)c3cc(-c4ccncc4)c(C#N)cc3c2n1
Agent: Cl
Product: N#Cc1cc2c3n[nH]cc3c(=O)n(CC(F)(F)F)c2cc1-c1ccncc1
Yield: 15 %

Procedure:
The product is obtained according to the procedure described in Step 4.3. starting with 4-oxo-7-(pyrid-4-yl)-5-(2,2,2-trifluoroethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-8-carbonitrile and 4-oxo-7-(pyrid-4-yl)-5-(2,2,2-trifluoroethyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-8-carbonitrile, in the form of a white powder (1.8 hydrochloride; yield 15%).
Reaction SMILES: [K+].[NH:2]1[CH2:6][CH2:5][C@H:4]([S:7][C:8]2[C@H:9]([CH3:22])[C@@H:10]3[C@@H:17]([C@H:18]([OH:20])[CH3:19])[C:16](=[O:21])[N:11]3[C:12]=2[C:13]([O-:15])=[O:14])[C:3]1=[S:23].[C:24]([O:29][CH2:30]I)(=[O:28])[CH:25]([CH3:27])[CH3:26]>>[C:24]([O:29][CH2:30][O:14][C:13]([C:12]1[N:11]2[C:16](=[O:21])[C@H:17]([C@H:18]([OH:20])[CH3:19])[C@H:10]2[C@@H:9]([CH3:22])[C:8]=1[S:7][C@H:4]1[CH2:5][CH2:6][NH:2][C:3]1=[S:23])=[O:15])(=[O:28])[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)C(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S[C@H]3CCNC3=S)[C@H](C)[C@H]12
Agent: [K+]
Product: CC(C)C(=O)OCOC(=O)C1=C(S[C@H]2CCNC2=S)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12

Procedure:
In the same manner as described in Example 48, (1R, 5S, 6S)-2-[(3S)-pyrrolidine-2-thion-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid potassium salt is treated with isobutyryloxymethyl iodide to give (1R, 5S, 6S)-2-[(3S)-pyrrolidine-2-thion-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid isobutyryloxymethyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]([C:14]1([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:16][CH2:15]1)=[O:13])[CH2:6][CH2:5]2.[CH3:24][O:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O)=[O:27].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd](Cl)Cl>[CH3:24][O:25][C:26](=[O:27])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]([C:14]1([NH:17][C:18](=[O:23])[C:19]([F:20])([F:21])[F:22])[CH2:15][CH2:16]1)=[O:13])[CH2:6][CH2:5]2
Reactant: O=C(NC1(C(=O)NC2CCc3cc(Br)ccc32)CC1)C(F)(F)F
Reactant: COC(=O)c1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1-c1ccc2c(c1)CCC2NC(=O)C1(NC(=O)C(F)(F)F)CC1
Temperature: 50 °C
Yield: 92.1 %

Procedure:
1-(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid ((rac)-5-bromo-indan-1-yl)-amide (intermediate A-1 [B]) (0.20 g, 511 μmol) and 2-(methoxycarbonyl)phenylboronic acid (184 mg, 1.02 mmol) were dissolved in dioxane (9.0 ml); then, sodium carbonate (163 mg, 1.53 mmol), dissolved in water, was added while stirring. Subsequently, (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) (18.7 mg, 25.6 μmol, eq: 0.05) was added and the reaction mixture was heated up to 50° C. for 5 hours. It was then poured into H2O (50 ml) and extracted with EtOAc (2×25 mL). The organic layers were dried over MgSO4, filtered and concentrated in vacuo to give a crude product (0.296 g) which was purified by flash chromatography (silica gel, 20 g, 0% to 2% MeOH in CH2Cl2) to yield the title compound (0.21 g, 91%) as light brown oil. MS: 445.1 (M−H−).
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCC[CH2:12]1.IC.C(N(CC)CC)C>C(OCC)(=O)C.O>[CH:1]1([N:7]([CH3:12])[CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCNC1CCCCC1
Reactant: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CI
Product: CN(CCO)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a mixture of N-cyclohexylethanolamine (2.1 g, 14.7 mmol) and tetrahydrofuran (70 ml) were added iodomethane (1.1 ml, 17.6 mmol) and triethylamine (2.26 ml, 16.2 mmol) at room temperature, and the reaction mixture was stirred for 1 hour under heating refluxing. The reaction mixture was cooled at room temperature (external temperature). To the mixture was added water to stop the reaction. To the reaction mixture was added ethyl acetate, and the organic layer was separated. The organic layer was washed with water and an aqueous saturated sodium chloride solution, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate, NH silica gel) to obtain the title compound (790.7 mg, 5.0 mmol, 34%).
Reaction SMILES: [CH:1]1([CH:4]([NH:12]C(=O)OC(C)(C)C)[CH2:5][C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[O:7])[CH2:3][CH2:2]1.[ClH:20].C(OCC)C>ClCCl.CO>[ClH:20].[NH2:12][CH:4]([CH:1]1[CH2:3][CH2:2]1)[CH2:5][C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)=[O:7]
Reactant: CC(C)(C)OC(=O)NC(CC(=O)NC1CC1)C1CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: NC(CC(=O)NC1CC1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To the solution of tert-butyl 1-cyclopropyl-3-(cyclopropylamino)-3-oxopropylcarbamate (38.10 g, 150 mmol) in dichloromethane (600 mL) and methyl alcohol (40 mL) was added 2 M solution of hydrochloric acid in diethyl ether (300 mL, 600 mmol) with an addition funnel at such a rate that the temperature of the reaction remained below 30° C. The reaction was allowed to stir at room temperature overnight. After 18 h, the reaction was complete as indicated by ELSD/MS. The reaction mixture was evaporated under reduced pressure. Diethyl ether (2×200 mL) was added to the residue, and the mixture was stirred for 15 min, and then decanted. This process was repeated to remove excess of hydrochloric acid. It was further dried in a vacuum oven overnight to afford 3-amino-N,3-dicyclopropylpropanamide hydrochloride (30 g, >100% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1)C1C=CC=CC=1>>[CH2:11]([O:10][C:6]1[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][NH:1][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[O:4][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCc1cc(=O)c(OCc2ccccc2)co1
Agent: O=c1cc(CNS(=O)(=O)c2ccccc2)occ1OCc1ccccc1
Product: Cc1ccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)co2)cc1
Yield: 57.1 %

Procedure:
N-(5-Benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-4-methyl-benzenesulfonamide (7-06) (20.0 g, 57.08%) was synthesized as a light brown solid from 2-aminomethyl-5-benzyloxy-pyran-4-one (5) (21.0 g, 90.90 mmol) and 4-methyl-benzenesulfonyl chloride (6-06) (20.7 g, 109.09 mmol) following the procedure described for N-(5-benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (7-01).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][NH2:16])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[C:27]1([S:37](Cl)(=[O:39])=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][NH:16][S:37]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)(=[O:39])=[O:38])[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CN)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CNS(=O)(=O)c2cccc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of trans-(4-aminomethyl-cyclohexylmethyl) carbamic acid tert-butyl ester (17 g) and ethyldiisopropylamine (14.41 ml) in N,N-dimethylformamide (350 ml) is cooled to 0° C. and treated with a solution of naphthalene-1-sulfonylchloride (15.9 g) in N,N-dimethylformamide (100 ml). The reaction is stirred at ambient temperature for 2 h, concentrated in vacuo. The residue is taken up in dichloromethane, washed with a 0.5 N HCl solution, a saturated aqueous sodium carbonate solution and water, dried and concentrated. Crystallization from hexanes-ethyl acetate gives trans-{4-[(naphthalene-1-sulfonylamino)-methyl]cyclohexylmethyl}-carbamic acid tert-butyl ester as a white powder, melting at 199-200° C. Rf (A1) 0.42.