Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([C:19]4[CH:20]=[C:21]([CH:25]=[C:26]([N:28]5[CH2:32][CH2:31][O:30][C:29]5=[O:33])[CH:27]=4)[C:22]([O-:24])=[O:23])[C:11]3=[O:34])[CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Li+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([C:19]4[CH:20]=[C:21]([CH:25]=[C:26]([N:28]5[CH2:32][CH2:31][O:30][C:29]5=[O:33])[CH:27]=4)[C:22]([OH:24])=[O:23])[C:11]3=[O:34])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])c1cc(N2CCOC2=O)cc(N2C(=O)[C@@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(N2CCOC2=O)cc(N2C(=O)[C@@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
To a solution of (1S,2S) and (1R,2R)-3-(2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-5-(2-oxooxazolidin-3-yl)benzoate (43 mg, 0.088 mmol) in MeOH (2 mL) and H2O (0.2 mL) was added lithium hydroxide (18 mg, 0.44 mmol). The reaction mixture was stirred at room temperature until TLC indicated no further reaction. The methanol was removed under reduced pressure. After quenching with concentrated HCl (3.0 N), the mixture was extracted with ethyl acetate for three times. The organic layers were dried over anhydrous Na2SO4 and concentrated to give the crude product. Purification by preparative HPLC gave desired product as white solid (29 mg, 70%). LC/MS m/e calcd. for C26H19ClN2O5: 474, observed (M+H)+: 475.1 1H NMR (400 MHz, MeOD-d4) δppm 2.22-2.33 (m, 2 H) 3.35-3.39 (m, 1 H) 4.22 (t, J=8.08 Hz, 2H) 4.56 (t, J=7.96 Hz, 2 H) 6.15 (d, J=7.07 Hz, 1 H) 6.81 (t, J=7.20 Hz, 1 H) 6.96 (d, J=7.83 Hz, 1 H) 7.15 (t, J=7.33 Hz, 1 H) 7.33 (q, J=8.51 Hz, 4 H) 7.91 (s, 1 H) 8.11 (t, J=2.02 Hz, 1 H) 8.26 (s, 1 H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2.[C:20]([O:23]C1C=CC=C2C=1C=CN2)(=[O:22])[CH3:21]>>[C:20]([O:23][C:5]1[CH:4]=[CH:3][CH:2]=[C:10]2[C:6]=1[CH:7]=[C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)[NH:9]2)(=[O:22])[CH3:21]
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Reactant: CC(=O)Oc1cccc2[nH]ccc12
Product: CC(=O)Oc1cccc2[nH]c(B3OC(C)(C)C(C)(C)O3)cc12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 1H-indol-4-yl acetate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:16][C:17]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:18]=1[CH2:19][N:20]1[CH:24]=[CH:23][C:22]([NH2:25])=[N:21]1>>[Cl:16][C:17]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:18]=1[CH2:19][N:20]1[CH:24]=[CH:23][C:22]([NH:25][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])=[N:21]1
Reactant: Nc1ccn(Cc2ccc(Cl)cc2Cl)n1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3ccn(Cc4ccc(Cl)cc4Cl)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(2,4-dichloro-benzyl)-1H-pyrazol-3-ylamine. The title compound was obtained as a light yellow solid (Yield=72%). MS ISP (m/e): 423.1 (100) [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]2[CH:45]=[CH:44][C:17]3[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][N:24]([C:27](=[O:43])[C@@H:28]([NH:35]C(=O)OC(C)(C)C)[CH2:29][C:30]5[S:31][CH:32]=[CH:33][CH:34]=5)[CH2:23][CH2:22]4)[S:20][C:16]=3[CH:15]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[ClH:46]>O1CCOCC1>[ClH:46].[NH2:35][C@@H:28]([CH2:29][C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)[C:27]([N:24]1[CH2:25][CH2:26][N:21]([C:19]2[S:20][C:16]3[CH:15]=[C:14]([C:12]([NH:11][C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)=[O:13])[CH:45]=[CH:44][C:17]=3[N:18]=2)[CH2:22][CH2:23]1)=[O:43]
Reactant: COc1ccc(NC(=O)c2ccc3nc(N4CCN(C(=O)[C@H](Cc5cccs5)NC(=O)OC(C)(C)C)CC4)sc3c2)cc1OC
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(NC(=O)c2ccc3nc(N4CCN(C(=O)[C@@H](N)Cc5cccs5)CC4)sc3c2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-tert-butyl 1-(4-(6-(3,4-dimethoxyphenylcarbamoyl)benzo[d]thiazol-2-yl)piperazin-1-yl)-1-oxo-3-(thiophen-2-yl)propan-2-ylcarbamate (0.95 g, 1.45 mmol) was dissolved in 1,4-dioxane (2 ml) and treated with 4M HCl in 1,4-dioxane (2 ml). The resulting mixture was stirred at room temperature overnight. The resulting solid was filtered and treated with 4M HCl in 1,4-dioxane (2 ml), again stirring overnight. The solid was filtered, dissolved in dichloromethane and washed with saturated NaHCO3 to yield the title compound as its corresponding free base. The free base was chromatographed eluting with dichloromethane/methanol/ammonium hydroxide to yield the free base as a residue. The free base residue (0.50 g, 0.91 mmol) was dissolved in dichloromethane (2 ml) and treated with 1M HCl in diethyl ether (0.91 ml, 0.91 mmol) and the resulting mixture stirred at room temperature for 2 h. The resulting solid was filtered, washed with diethyl ether (2×) and dried to yield (S)-2-(4-(2-amino-3-(thiophen-2-yl)propanoyl)piperazin-1-yl)-N-(3,4-dimethoxyphenyl)benzo[d]thiazole-6-carboxamide, as its corresponding hydrochloride salt.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].C1(C)C(S(O[CH2:31][CH:32]2[CH2:36][CH:35]=[CH:34][CH2:33]2)(=O)=O)=CC=CC=1>>[CH:32]1([CH2:31][N:8]2[C:9]([S:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])[CH2:36][CH:35]=[CH:34][CH2:33]1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: Cc1ccccc1S(=O)(=O)OCC1CC=CC1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2CC2CC=CC2)c1
Yield: 62.8 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and (cyclopent-3-en-1-yl)methyl toluenesulfonate were reacted by the same way with example 1 to obtain the titled compound.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:16])=[C:6]2[C:11](=[C:12]([Cl:14])[CH:13]=1)[S:10][CH2:9][CH2:8][C:7]2=[O:15])([OH:3])=[O:2].S(Cl)(Cl)=O.[CH2:21]([N:23]1[C:27](O)=[CH:26][CH:25]=[N:24]1)[CH3:22].C(N(CC)CC)C>C(Cl)Cl>[Cl:14][C:12]1[CH:13]=[C:4]([C:1]([O:3][C:27]2[N:23]([CH2:21][CH3:22])[N:24]=[CH:25][CH:26]=2)=[O:2])[C:5]([CH3:16])=[C:6]2[C:11]=1[S:10][CH2:9][CH2:8][C:7]2=[O:15]
Reactant: CCn1nccc1O
Reactant: Cc1c(C(=O)O)cc(Cl)c2c1C(=O)CCS2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCn1nccc1OC(=O)c1cc(Cl)c2c(c1C)C(=O)CCS2
Temperature: 40 °C
Yield: 83.7 %

Procedure:
A mixture containing 2.0 g (7.8 mmol) of 6-carboxy-8-chloro-5-methylthiochroman-4-one and 2.8 g (3.0 eq., 24 mmol) of thionyl chloride was stirred under heat at 40° C. for 2 hours. After the completion of the reaction, excess thionyl chloride was removed under reduced pressure. Then, the resultant acid chloride was dissolved in 10 ml of methylene chloride, and 0.96 g (1.1 eq., 8.6 mmol) of 1-ethyl-5-hydroxypyrazole and 0.95 ml (9.41 mmol) of triethylamine were added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with methylene chloride, washed with diluted hydrochloric acid and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off to give 2.29 g (yield 84%) of 8-chloro-6-(1-ethylpyrazol-5-yl)oxycarbonyl-5-methylthiochroman-4-one.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:20][CH2:21][CH3:22])[C:5]1([C@H:8]([NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[C:9]#[N:10])[CH2:7][CH2:6]1)[CH3:2].[OH-].[Na+].[H][H]>C(O)C.[Ni]>[NH2:10][CH2:9][C@@H:8]([NH:11][C@H:12]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:13])[C:5]1([CH:4]([O:3][CH2:1][CH3:2])[O:20][CH2:21][CH3:22])[CH2:7][CH2:6]1
Reactant: [H][H]
Reactant: CCOC(OCC)C1([C@@H](C#N)N[C@@H](C)c2ccccc2)CC1
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(OCC)C1([C@@H](CN)N[C@@H](C)c2ccccc2)CC1

Procedure:
In ethanol (9.0 ml) was dissolved (2S)-2-[1-(diethoxymethyl)cyclopropyl]-2-{[(1S)-1-phenylethyl]amino}acetonitrile (150 mg, 0.496 mmol). To the resulting solution were added a 5 mol/l aqueous solution of sodium hydroxide (0.5 ml, 2.5 mmol) and Raney-nickel (R-100, 1.5 g) were added and the mixture was stirred at room temperature for 5 hours in a hydrogen gas stream. The catalyst was filtered off and the residue was washed with ethanol. The filtrate was concentrated under reduced pressure. Water and chloroform were added to the residue for separation. The organic layer was dried over sodium sulfate, filtered, and then evaporated under reduced pressure, whereby the title compound (150 mg, 98.4%) was obtained as a slightly yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[F:11][CH2:12][CH2:13][OH:14]>>[NH2:1][C:2]1[CH:9]=[C:8]([O:14][CH2:13][CH2:12][F:11])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: OCCF
Product: N#Cc1cnc(N)cc1OCCF

Procedure:
From intermediate 21 and 2-fluoroethanol, reacted in an analogous manner to the preparation of intermediate 89. (UPLC-MS 6) tR 0.50; ESI-MS 182.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:33]2[CH:38]=[CH:37][C:36]([C:39](O)=[O:40])=[CH:35][CH:34]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@@H:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31].[F:42][CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>ClCCl.C(=O)(O)[O-].[Na+]>[Cl:32][C:6]1[CH:5]=[C:4]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([N:48]3[CH2:49][CH2:50][N:45]([CH2:44][CH2:43][F:42])[CH2:46][CH2:47]3)=[O:40])=[CH:35][CH:34]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@@H:17]([O:20][Si:21]([CH:22]([CH3:24])[CH3:23])([CH:28]([CH3:29])[CH3:30])[CH:25]([CH3:26])[CH3:27])[CH2:16][CH2:15]2)[C:10]1=[O:31]
Reactant: CC(C)[Si](O[C@H]1CC[C@@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Reactant: FCCN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[Si](O[C@H]1CC[C@@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCN(CCF)CC5)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Treat a mixture of 3′,5′-dichloro-4′-[(R)-2-oxo-cis-1-(4-triisopropylsilanyloxy-cyclohexyl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid (4 g, 5.46 mmol), 1-(2-fluoro-ethyl)-piperazine (2.97 g, 12.12 mmol) and diisopropylethylamine (3.13 g, 24.24 mmol) in 125 mL dichloromethane with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.1 g, 16.16 mmol) and stir at room temperature overnight. Dilute with 150 mL saturated sodium bicarbonate and separate layers. Wash the organic layer with 150 mL water then 100 mL brine. Extract the combined aqueous layers with 100 mL dichloromethane and combine with original organic layer. Dry over sodium sulfate, filter, concentrate, and purify via silica chromatography to give 4 g (67%) product as a foam: MS (m/z): 732 (M+).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:8](=O)[CH2:7][O:6][CH2:5][C:4]1=[O:10].F[B-](F)(F)F.[C:16]([C:21]1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:23][CH2:22]1)([O:18][CH2:19][CH3:20])=[O:17]>C1COCC1>[CH2:19]([O:18][C:16]([C:21]1[CH2:22][CH2:23][N:3]2[C:4](=[O:10])[CH2:5][O:6][CH2:7][C:8]=12)=[O:17])[CH3:20]
Reactant: CCOC(=O)C1([P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: O=C1COCC(=O)N1
Agent: F[B-](F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C2COCC(=O)N2CC1
Reaction time: 0.17 h

Procedure:
To a suspension of sodium hydride (480 mg, 60% in mineral oil, 12 mmol) in 10 ml of anhydrous THF is added morpholine-3,5-dione (1.2 g, 10 mmol) in 20 ml of THF under an argon athmosphere. After 10 min., 1-carbethoxycyclopropyltriphenylphosphonium tetrafluoroborate (Fuchs' reagent, 6.8 g, 11 mmol)) in 20 ml of THF are added and the mixture is refluxed for 21 hours. After cooling, the suspension is concentrated on a rotary evaporator, poured onto ice/sat. sodium bicarbonate solution, and extracted three times with ether. The combined organic phases are washed with brine, dried over anhydrous sodium sulphate, and evaporated. The residual yellow oil (3.04 g) is purified by chromatography (Silica gel 60, 0.063-0.2 mesh, cyclohexane/ethyl acetate 1:1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH2:12]1[O:20][C:19]2[CH:18]=[CH:17][C:16]([N:21]=[C:22]=[O:23])=[CH:15][C:14]=2[O:13]1>>[O:20]1[C:19]2[CH:18]=[CH:17][C:16]([NH:21][C:22]([NH:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]=[CH:7][CH:6]=[CH:5]4)=[O:23])=[CH:15][C:14]=2[O:13][CH2:12]1
Reactant: Nc1ccc2ncccc2c1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Product: O=C(Nc1ccc2c(c1)OCO2)Nc1ccc2ncccc2c1

Procedure:
Prepared from 6-aminoquinoline and 3,4-(methylenedioxy)phenyl isocyanate. m/z (ES+) 308 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:16][CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3([CH2:16][CH3:17])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]3=[O:15])[CH2:27][CH2:26]2)=[CH:23][CH:24]=1
Reactant: CCC1(CCCCCl)C(=O)Nc2ccccc21
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: CCC1(CCCCN2CCN(c3ccc(Cl)cc3)CC2)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(4-chlorophenyl)-piperazine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)(=[O:32])=[O:33])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: O=S(=O)(c1ccccc1Br)N1CCNCC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCNCC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)piperazine. MS (ESI): mass calcd. for C20H20FN5O2S, 413.13; m/z found, 414.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.39 (m, 1H), 8.21-8.13 (m, 2H), 8.01-7.95 (m, 1H), 7.79-7.74 (m, 1H), 7.69-7.63 (m, 1H), 7.50-7.46 (m, 1H), 7.37-7.30 (m, 2H), 3.14-3.08 (m, 4H), 3.06-2.99 (m, 4H).
Reaction SMILES: [NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[C:5]([C:12]([OH:14])=[O:13])=[C:6]([CH2:9][O:10][CH3:11])[CH2:7][S:8][C@H:3]12.[F:17][C:18]([F:26])([F:25])[CH2:19][S:20][CH2:21][C:22](Cl)=[O:23]>>[F:17][C:18]([F:26])([F:25])[CH2:19][S:20][CH2:21][C:22]([NH:1][CH:2]1[C:15](=[O:16])[N:4]2[C:5]([C:12]([OH:14])=[O:13])=[C:6]([CH2:9][O:10][CH3:11])[CH2:7][S:8][C@H:3]12)=[O:23]
Reactant: O=C(Cl)CSCC(F)(F)F
Reactant: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)CSCC(F)(F)F)[C@H]2SC1

Procedure:
Using the procedure of Example 1, 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid is acylated with trifluoroethylmercaptoacetyl chloride to give 7-trifluoroethylmercaptoacetamido-3-methoxymethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: FC(F)(F)C([O-])=O.[Cl:8][C:9]1[C:13]([Cl:14])=[C:12]([CH3:15])[NH:11][C:10]=1[C:16]([NH:18][CH:19]1[CH2:24][CH2:23][NH2+:22][CH2:21][CH2:20]1)=[O:17].C(Cl)(Cl)Cl.C(O)(C)C.C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:8][C:9]1[C:13]([Cl:14])=[C:12]([CH3:15])[NH:11][C:10]=1[C:16]([NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:17]
Reactant: Cc1[nH]c(C(=O)NC2CC[NH2+]CC2)c(Cl)c1Cl
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl

Procedure:
4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidinium trifluoroacetate (Intermediate 86, 6.07 g) was suspended in water (100 ml). To this was added 100 ml of CHCl3:isopropanol (3:1) and sat. Na2CO3 (50 ml). The organic portion was separated and the aqueous portion was washed with 100 ml portions of CHCl3:isopropanol (3:1) five times. The organic portions were combined, dried with MgSO4 and concentrated to a yellow solid (2.73 g, 64%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].[H-].[Na+].Cl[C:16]1[N:17]=[C:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:20][CH:21]=1>O1CCCC1>[C:28]1([C:18]2[N:17]=[CH:16][C:21]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[N:20][C:19]=2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Clc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: OCCCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(-c2ncc(OCCCCOC3CCCCO3)nc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.8 %

Procedure:
1.57 g of 4-(2-tetrahydropyranyloxy)-1-butanol was dissolved in 20 ml of tetrahydrofuran and 360 mg of 60% sodium hydride was added under ice cooling, followed by stirring at room temperature for 1.5 hours. The mixture was refluxed for 30 minutes and ice-cooled again and 2.00 g of 5-chloro-2,3-diphenylpyrazine was added. After stirring for 40 minutes, the mixture was heated to 80° C., stirred at the same temperature for 4.5 hours and then stirred at room temperature for 88 hours. The reaction solution was combined with ice water, extracted with ethyl acetate and then washed with saturated brine. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to obtain 2.39 g of the desired compound as an oily substance.
Reaction SMILES: [O:1]=[C:2]1[C@@H:6]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:5][CH2:4][N:3]1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(C(C)C)C(C)C)C.Cl[C:31]1[C:36]([Cl:37])=[CH:35][C:34]([C:38]([F:41])([F:40])[F:39])=[CH:33][N:32]=1>CN(C=O)C.CCOC(C)=O>[Cl:37][C:36]1[C:31]([N:18]2[CH2:17][CH2:16][CH:15]([N:3]3[CH2:4][CH2:5][C@H:6]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:2]3=[O:1])[CH2:20][CH2:19]2)=[N:32][CH:33]=[C:34]([C:38]([F:40])([F:39])[F:41])[CH:35]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C2CCNCC2)C1=O
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C2CCN(c3ncc(C(F)(F)F)cc3Cl)CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
To a solution of (S)-tert-butyl 2-oxo-1-(piperidin-4-yl)pyrrolidin-3-ylcarbamate (4.0 g, 14 mmol) in DMF (50 mL) was added N-ethyl-N-isopropylpropan-2-amine (5.5 g, 42 mmol) and 2,3-dichloro-5-(trifluoromethyl)pyridine (9.1 g, 42 mmol) and the reaction was stirred overnight at ambient temperature. The reaction was diluted with EtOAc (about 200 mL) and the organic layer was washed with water (100 mL), and brine (50 mL), dried over MgSO4, and concentrated under vacuum. The crude material was purified on silica using a gradient of DCM to 5% EtOAc/DCM as eluent to give (S)-tert-butyl 1-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-ylcarbamate (4.0 g, 61%).
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[CH:11][N:10]=2)=[CH:5][C:4]=1[F:30])#[N:2].[CH2:31]([C:34]1[CH:35]=[N:36]C(Br)=[N:38][CH:39]=1)[CH2:32][CH3:33]>>[C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]4[N:38]=[CH:39][C:34]([CH2:31][CH2:32][CH3:33])=[CH:35][N:36]=4)[CH2:17][CH2:16]3)=[CH:11][N:10]=2)=[CH:5][C:4]=1[F:30])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(COc3ccc(C#N)c(F)c3)nc2)CC1
Reactant: CCCc1cnc(Br)nc1
Product: CCCc1cnc(N2CCC(c3ccc(COc4ccc(C#N)c(F)c4)nc3)CC2)nc1

Procedure:
The title compound was prepared from tert-butyl 4-[2-(4-cyano-3-fluorophenoxymethyl)pyridin-5-yl]piperidine-1-carboxylate (Example 13) (50 mg, 0.12 mmol) and 5-propyl-2-bromopyrimidine (33 μL, 0.24 mmol) following a procedure analogous to that in Example 48 as a white crystal (35 mg, yield 67%).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)C[CH2:4][CH2:3][CH2:2]1.CC1[O:28][N:27]=C(N)C=1>>[CH3:13][C:12]1[C:7]([NH:6][C:1]2[CH:2]=[C:3]([CH3:4])[O:28][N:27]=2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1cc(N)no1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1cc(Nc2nc(NCc3ccccn3)nc(C)c2C)no1

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 5-methylisoxazol-3-amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.06 (s, 3H), 2.35 (s, 3H), 4.75 (d, J=2.8 Hz, 2H), 5.92 (bs, 1H), 6.54 (s, 1H), 7.18 (m, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.64 (t, J=7.5 Hz, 1H), 8.59 (d, J=4.0 Hz, 1H); MS (ESI) m/z 311.5 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:17]([OH:19])=O)[N:5]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=O)[CH:6]=1.[CH2:20]([NH2:23])[CH2:21][NH2:22]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:17](=[O:19])[N:22]3[CH2:21][CH2:20][NH:23][C:8]3([C:10]3[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=3)[CH2:7][N:5]2[CH:6]=1
Reactant: O=C(Cn1cc(Br)cc1C(=O)O)c1ccc(Cl)cc1
Reactant: NCCN
Solvent: CCO
Product: O=C1c2cc(Br)cn2CC2(c3ccc(Cl)cc3)NCCN12
Yield: 68.7 %

Procedure:
To a solution of crude 4-bromo-1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylic acid (100 mg, 0.29 mmol) dissolved in a mixture of xylenes (10 mL) and ethanol (3 mL) was added ethane-1,2-diamine (100 μL, 1.5 mmol). The reaction mixture was heated at reflux. After 90 minutes (monitored by LCMS) the mixture was concentrated in vacuo and the resultant residue purified flash chromatography (Biotage SP4, 40 g cartridge, 0-5% MeOH gradient in CH2Cl2) to give 7-bromo-10a-(4-chlorophenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one as a light yellow solid (73 mg, yield: 68%).