Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[C:16]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:19]([O:22][CH2:23]C=O)=[CH:18][CH:17]=1>CCCCCC.O1CCCC1>[C:16]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH:8]2[O:7][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)=[CH:20][CH:21]=1
Reactant: O=CCOc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(COc2ccc(-c3ccccc3)cc2)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The title compound was prepared as described in General Method 1 using 4.76 g of methyl acetoacetate, 1.97 g of NaH 50% dispersion in oil, 19.5 mL of 2.1M n-butyl lithium in hexane, 8.7 g of [[1,1'-biphenyl]-4-yloxy]-acetaldehyde and 200 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 60 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 152°-154° C.). 'H NMR (CDCl3) δ2.83 (dd, 1H), 2.95 (dd, 1H) 3.61 (dd, 2H), 4.23 (dd, 1H), 4.38 (dd, 1H), 5.03-5.07 (m, 1H), 6.94-6.98 (m, 2H), 7.30-7.57 (m, 7H).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH:9]=O)=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[NH2:12][C@H:13]([CH3:16])[CH2:14][OH:15]>>[Cl:11][C:6]1[C:7]2[CH:8]=[CH:9][N:12]([C@H:13]([CH3:16])[CH2:14][OH:15])[C:2]=2[N:3]=[CH:4][N:5]=1
Reactant: O=CCc1c(Cl)ncnc1Cl
Reactant: C[C@@H](N)CO
Product: C[C@H](CO)n1ccc2c(Cl)ncnc21

Procedure:
The title compound was prepared according to the method described for Preparation 1 using (4,6-dichloropyrimidin-5-yl)acetaldehyde and (R)-2-amino-1-propanol to afford the title compound as a yellow solid in 100% yield, 11.12 g.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([NH:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[C:22]([F:35])[N:21]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:19][C:20]1[CH:25]=[C:24]([C:2]2[N:6]3[CH:7]=[C:8]([NH:11][CH:12]4[CH2:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13]4)[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:23]=[C:22]([F:35])[N:21]=1
Reactant: OC1CCCC(Nc2ccc3ncc(Br)n3c2)C1
Reactant: CC1(C)OB(c2cc(F)nc(Cl)c2)OC1(C)C
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC1CCCC(Nc2ccc3ncc(-c4cc(F)nc(Cl)c4)n3c2)C1
Temperature: 95 °C

Procedure:
To a solution of 3-trans-RS/RS (3-bromo-imidazo[1,2-a]pyridin-6-ylamino)-cyclohexanol [intermediate J step 2] (1 eq, 0.1 g), 2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (1.05 eq,82 mg), Na2CO3 (2 eq, 68 mg) in ethanol (2 ml) and water (0.2 ml), under an inert atmosphere of argon is added bis(triphenylphosphine)palladium II chloride (0.1 eq, 0.96 mmol, 22 mg). The reaction mixture is heated at 95° C. for 16 hours. The mixture is diluted with H2O (50 ml) and extracted with EtOAc. The combined organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by chromatography on silica eluting with 0-10% MeOH in EtOAc to afford the title compound; [M+H]+=360.
Reaction SMILES: [CH:1]12[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH:5]1[CH2:4][CH2:3][NH:2]2.[OH-].[Na+].Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1(C)C=CC=CC=1.O>[CH:1]12[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH:5]1[CH2:4][CH2:3][N:2]2[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC2CCNC2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC2CN(C(=O)OC(C)(C)C)CC21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
13 g (61.2 mmol) of tert.-butyl 2,7-diazabicyclo[3.3.0]octane-7-carboxylate are dissolved in 100 ml of toluene, a solution of 3 g of sodium hydroxide in 20 ml of water is added, and 7 g (64.5 mmol) of ethyl chloroformate are added dropwise at room temperature. The mixture is stirred for 3 hours at room temperature, and the aqueous phase is separated off and extracted twice using 100 ml portions of methylene chloride. The organic solutions are dried over magnesium sulphate, concentrated and distilled.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[N:15]([CH2:16][CH2:17][CH2:18]O)[C:14]2[C:20]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:21][CH:22]=[CH:23][C:13]=2[N:12]=1)=[O:10].[Br:29]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[Br:29][CH2:18][CH2:17][CH2:16][N:15]1[C:14]2[C:20]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:21][CH:22]=[CH:23][C:13]=2[N:12]=[C:11]1[C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:10]
Reactant: CCN(CC)c1cccc2nc(C(=O)c3ccc(Cl)cc3Cl)n(CCCO)c12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCN(CC)c1cccc2nc(C(=O)c3ccc(Cl)cc3Cl)n(CCCBr)c12
Reaction time: 0.25 h
Yield: 87.6 %

Procedure:
To a stirred suspension of (2,4-dichlorophenyl)[7-(diethylamino)-1-(3-hydroxypropyl)-1H-benzimidazol-2-yl]methanone (404 mg, 0.961 mmol) and tetrabromomethane (637 mg, 1.92 mmol) in acetonitrile was added triphenylphosphine (504 mg, 1.92 mmol). After 15 min, the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to afford the desired product as yellow solid (407 mg, 0.842 mmol), 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].C(N(CC)CC)C.[C:19]([C:23](Cl)=[O:24])([Cl:22])([Cl:21])[Cl:20]>C1COCC1>[Cl:20][C:19]([Cl:22])([Cl:21])[C:23]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5])=[O:24]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: COc1cccc(N)c1C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(NC(=O)C(Cl)(Cl)Cl)c1C=O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 2-Amino-6-methoxy-benzaldehyde (6.00 g, 0.04 mol) and triethylamine (4.4 g, 0.044 mol) is dissolved in THF (20 mL) and cooled to 0° C., then CCl3COCl (7.95 g, 0.044 mol) is added and stirred at 25° C. for 24 h. The mixture is extracted from water with ethylacetate to give the desired product.
Reaction SMILES: [Si]([O:8][C@H:9]([C:39](=[O:41])[NH2:40])[CH2:10][C@H:11]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[N:17]=[CH:16][N:15]=[C:14]([O:23][CH:24]4[CH2:29][CH2:28][CH:27]([N:30](C)[C:31](=O)OC(C)(C)C)[CH2:26][CH2:25]4)[C:13]=3[C:12]1=2)(C(C)(C)C)(C)C.Cl.[NH4+].[OH-]>ClCCl>[OH:8][C@@H:9]([CH2:10][C@H:11]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[N:17]=[CH:16][N:15]=[C:14]([O:23][CH:24]4[CH2:25][CH2:26][CH:27]([NH:30][CH3:31])[CH2:28][CH2:29]4)[C:13]=3[C:12]1=2)[C:39]([NH2:40])=[O:41]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](O[Si](C)(C)C(C)(C)C)C(N)=O)CC4)CC1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](O)C(N)=O)CC4)CC1
Reaction time: 0.25 h
Yield: 47.6 %

Procedure:
A solution of tert-butyl N-(4-[[(3R)-3-[(2S)-2-[(tert-butyldimethylsilyl)oxy]-2-carbamoylethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (160 mg, 0.26 mmol, 1.00 equiv) and hydrogen chloride (conc.) (0.3 mL) in dichloromethane (10 mL) was stirred for 2 h at 0° C. in a water/ice bath. The pH value of the solution was adjusted to 8 with NH4OH. The resulting mixture was concentrated under vacuum. The crude product (150 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-015(Waters)): Column, Xbridge C18, 19*150 mm, 5 μm; mobile phase: water (50 mM NH4HCO3) and CH3CN (10% CH3CN up to 21% in 15 min, up to 95% in 1.5 min, down to 10% in 1.5 min); UV detection at 254/220 nm. The product was freeze-dried to afford (2S)-2-hydroxy-3-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanamide (48.3 mg, 47%) as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.46 (s, 1H), 5.30 (m, 1H), 4.16 (m, 1H), 3.59 (m, 1H), 3.16-2.94 (m, 2H), 2.77-2.68 (m, 1H), 2.58-2.52 (m, 6H), 2.48-2.10 (m, 4H), 1.75-1.72 (m, 3H), 1.66-1.34 (m, 2H). MS: m/z=391 (M+H)+.
Reaction SMILES: C([O-])(=[O:3])C.[Li+].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[C:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8]=1[C:20]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(O)(C(F)(F)F)=O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](/[C:13](/[OH:3])=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8]=1[C:20]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)C#Cc1cccc(Cl)c1C1(C(=O)OCC)CCOCC1
Agent: [Pd+2]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)/C=C(\O)c1cccc(Cl)c1C1(C(=O)OCC)CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
A mixture of lithium acetate (0.21 g, 3.2 mmol) in 5 mL TFA at room temperature was treated with ethyl 4-(2-chloro-6-(3-ethoxy-3-oxoprop-1-ynyl)phenyl)-tetrahydro-2H-pyran-4-carboxylate (1.18 g, 3.2 mmol), and palladium(II) acetate (0.036 g, 0.16 mmol). The reaction was stirred at room temperature for 2 hours. The residue was diluted with 100 mL EtOAc, washed with water (3×20 mL), saturated NaCl (20 mL), dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (10-20% EtOAc/hexane) to give 0.38 g yellow oil. MS m/e: (M+H)+ 383.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[C:31]([C:33]1[CH:34]=[CH:35][C:36]([NH:39][CH3:40])=[N:37][CH:38]=1)#[CH:32]>>[C:16]([C:14]1[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([O:25][CH3:26])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:4]([N:1]3[CH:32]=[C:31]([C:33]4[CH:38]=[N:37][C:36]([NH:39][CH3:40])=[CH:35][CH:34]=4)[N:3]=[N:2]3)[CH:5]=2)[CH:15]=1)([CH3:18])([CH3:19])[CH3:17]
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: C#Cc1ccc(NC)nc1
Product: CNc1ccc(-c2cn(-c3cc(C(=O)Nc4cc(C(C)(C)C)cc(NS(C)(=O)=O)c4OC)ccc3C)nn2)cn1

Procedure:
Example 19 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide and (5-ethynyl-pyridin-2-yl)-methyl-amine in the same manner as Example 15. ESI MS m/z 564 [C28H33N7O4S+H]+.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15]([OH:17])=O)=[C:10]2[CH:9]=[C:8]([CH3:19])[CH:7]=1.[NH2:25][CH:26]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:27]#[N:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([CH:26]([C:27]#[N:28])[NH:25][C:15]([C:14]2[C:13]([CH3:18])=[N:12][N:11]3[C:6]([O:5][CH2:4][C:3]4[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:2]=4[F:1])=[CH:7][C:8]([CH3:19])=[CH:9][C:10]=23)=[O:17])=[CH:34][CH:33]=1
Reactant: N#CC(N)c1ccc(Cl)cc1
Reactant: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)NC(C#N)c3ccc(Cl)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
33 mg (0.10 mmol) of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 4A were initially charged in a 96-well deep well multititre plate. A solution of 17 mg (0.10 mmol) of rac-amino(4-chlorophenyl)acetonitrile in 0.4 ml of DMF and a solution of 45.6 mg (0.12 mol) of HATU in 0.4 ml of DMF were added successively. After adding 20.2 mg (0.20 mmol) of 4-methylmorpholine, the mixture was shaken at RT overnight. Then the mixture was filtered and the target compound was isolated from the filtrate by preparative LC-MS (Method 9). The product-containing fractions were concentrated under reduced pressure using a centrifugal dryer. The residue of each product fraction was dissolved in 0.6 ml of DMSO. These were combined and finally freed of the solvent in a centrifugal dryer. 0.7 mg (1.5% of theory) were obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=O)[NH:11][N:10]=2)[CH:2]=1.P(Cl)(Cl)([Cl:22])=O.Cl>C(#N)C.O1CCOCC1>[Cl:22][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([CH2:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:10][N:11]=1
Reactant: O=c1[nH]nc(CCc2cccnc2)c2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: Clc1nnc(CCc2cccnc2)c2ccccc12
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
Under exclusion of air, 2.4 g (9.55 mmol) 4-[2-(pyridin-3-yl)ethyl]phthalazin-1(2H)-one in 36 ml acetonitrile is mixed with 2.18 ml (23.8 mmol) phosphoryl chloride and 4.75 ml 4 N HCl in dioxane and stirred for 3.5 h at 60° C. After cooling to RT, the product is filtered off as hydrochloride and washed with CH3CN. The crystals are dissolved in about 10 ml H2O, mixed with 15 ml H2O and 1.5 ml sat. NH3 solution and extracted immediately 3 times with EtOAc. Drying (Na2SO4) of the organic phases and evaporation yield the title compound; FAB-MS (M+H)+=270.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:30])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[CH3:31][C:32]([OH:36])([C:34]#[CH:35])[CH3:33].ClCCl>C1COCC1.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:30])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10]([C:35]#[C:34][C:32]([OH:36])([CH3:33])[CH3:31])[C:3]=12
Reactant: CC(c1oc2ccccc2c(=O)c1-c1ccccc1)n1nc(I)c2c(N)ncnc21
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1ccccc1)n1nc(C#CC(C)(C)O)c2c(N)ncnc21
Yield: 68.1 %

Procedure:
To a solution of Example 57b (0.500 g, 0.981 mmoles) in THF (14 ml), 2-Methyl-3-butyn-2-ol (0.1 ml, 1.178 mmoles) diisopropylamine (0.70 ml, 4.90 mmoles), copper(I) iodide (18.6 mg, 0.098 mmoles) and) Tetrakistriphenylphosphine Palladium (0.113 g, 0.098 mmoles) were added and the system is degassed for 30 min. and heated to reflux for 4 h. The reaction mixture filtered through celite pad and washed with ethyl acetate. The filtrate was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as brown solid (0.311 g, 68% yield). MP: 109-113° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.05 (m, 3H), 7.83 (dt, J=8.6, 1.5 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.52 (t, J=7.2 Hz, 1H), 7.30-7.11 (m, 4H), 5.84 (q, J=7.1 z, 1H) 5.74 (s, 1H), 1.82 (d, J=7.0 Hz, 3H), 1.46 (s, 6H). Mass: 466.09 (M++1).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[CH3:27][C:28]1[N:33]=[CH:32][C:31]([C:34]([C:36]2[N:37]=[CH:38][N:39]3[CH:43]=[C:42]([Sn](CCCC)(CCCC)CCCC)[S:41][C:40]=23)=[O:35])=[CH:30][CH:29]=1>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[C:8]([C:42]3[S:41][C:40]4=[C:36]([C:34]([C:31]5[CH:32]=[N:33][C:28]([CH3:27])=[CH:29][CH:30]=5)=[O:35])[N:37]=[CH:38][N:39]4[CH:43]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3ccc(C)nc3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: Cc1ccc(C(=O)c2ncn3cc(C4=C(C(=O)OCc5ccc([N+](=O)[O-])cc5)N5C(=O)[C@H]([C@@H](C)O)[C@H]5[C@H]4C)sc23)cn1
Yield: 77.3 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(6-methylpyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (499 mg) was prepared in the same manner as in step a) of Example 1, except that 398 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 923 mg of 7-(6-methylpyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[N:37](S(C2C=CC(C)=CC=2)(=O)=O)[C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][NH:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:27][CH:26]=3)=[C:17]2[CH:16]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[NH:37][C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][NH:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]4)=[CH:27][CH:26]=3)=[C:17]2[CH:16]=1
Reactant: COc1cc2c(-c3cc4c(CNc5ccc(N6CCCCC6)cc5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4c(CNc5ccc(N6CCCCC6)cc5)ccnc4[nH]3)cn(C)c2cc1OC
Yield: 23.3 %

Procedure:
[2-(5,6-Dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,33-b]pyrid-4-ylmethyl](4-piperid-1-ylphenyl)amine is prepared as described in Example 179a starting with 0.09 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-piperid-1-ylphenyl)amine instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl] (4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 0.55 cm3 of 5N potassium hydroxide. 0.016 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-piperid-1-ylphenyl)amine is obtained, the characteristics of which are as follows:
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+:20]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([O:15][C:14](=[O:16])[C@@H:13]2[CH2:17][CH2:18][CH2:19][N:12]2[C:10](=[O:11])[CH2:9][NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
A solution of 3.0 g (11.6 mmol) of N-BOC-glycylproline and 1.93 g (13.9 mmol) of 4-nitrophenol in 82 mL of dry THF was cooled to 0° C. and 3.34 g (16.2 mmol) of DCC was added. The mixture was stirred at 0° C. for 1 hour, the ice bath was removed, and the mixture was stirred for 16 hours at room temperature. HOAc (579 μL) was added to the mixture and it was allowed to stir for 30 minutes. The mixture was kept in the freezer for 30 minutes and filtered under vacuum. The filtrate was concentrated and purified by silica gel chromatography (18×150 mm bed, 2.5% EtOAc/97.5% CH2Cl2/1% HOAc). Traces of acetic acid were removed by concentrating from dioxane several times on the rotary evaporator. The concentrate was triturated with 3/1 hexane Et2O and the resulting white solid was collected by filtration to give 4.1 g (90%) of compound 15 as a white solid; TLC Rf 0.09, 40/60/1 EtOAc/hexane/HOAc; 1H NMR(CDCl3) δ 1.09-2.55 (m, 4H), 1.48 (s, 9H), 3.47-3.77 (m, 2H), 4.05 (m, 2H), 4.74 (m, 1H), 5.45 (bd s, 1H), 7.35 (d, 2H), 8.30 (d, 2H).
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([Si](C)(C)C)=[CH:10]2)(=[O:5])=[O:4].F>CC#N>[CH3:1][NH:2][S:3]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)Cc1ccc2[nH]c([Si](C)(C)C)cc2c1
Agent: F
Solvent: CC#N
Product: CNS(=O)(=O)Cc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
5-[[(Methylamino)sulfonyl]methyl]-2-(trimethylsilyl)-1H-indole (4) (1.0 g, 0.00356 mol) was dissolved in CH3CN (40 mL). Concentrated hydrofluoric acid (HF, 1 mL) was added and the mixture was stirred at RT for 3 h. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The organic phase was extracted sequentially with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo. Silica gel chromatography (10-100% EtOAc gradient in hexane) of the residue gave the product (5) (0.52 g, 65.2%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F-:11].[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:31]1[S:35](=[O:37])(=[O:36])[CH2:34][CH2:33][CH2:32]1>>[F:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:34]1[S:35](=[O:37])(=[O:36])[CH2:31][CH2:32][CH2:33]1
Reactant: [F-]
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1ccccc1F
Temperature: 110 °C
Yield: 80 %

Procedure:
1,300 parts of o-chloronitrobenzene, 960 parts of potassium fluoride and 82.5 parts of 18-crown-6 in 1,300 parts of tetramethylenesulfone are stirred under nitrogen for 30 hours at 180° C. The solution is cooled to 110° C. and filtered, the solid residue is rinsed with 500 parts of methylene chloride and the filtrates are combined and distilled. 932 parts (80% of theory) of o-fluoronitrobenzene of boiling point 55°-57° C./1.2 mm Hg and 1,290 parts (99.2% of theory) of tetramethylenesulfone of boiling point 105°-110° C. are obtained. About 70% of the crown ether can be recovered from the distillation residue by repeated extraction by shaking with water.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:16]3[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=3)=[N:9][N:10]3[CH2:15][CH2:14][CH2:13][S:12][C:11]=23)=[CH:3][CH:2]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][C:25]=1[C:33]([F:36])([F:35])[F:34]>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:8]3[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[C:11]4[S:12][CH2:13][CH2:14][CH2:15][N:10]4[N:9]=3)[CH:17]=2)=[O:32])=[CH:26][C:25]=1[C:33]([F:34])([F:35])[F:36]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cccc(-c2nn3c(c2-c2ccncc2)SCCC3)c1
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2nn3c(c2-c2ccncc2)SCCC3)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
3-(3-Pyridin-4-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazin-2-yl)-phenylamine (50 mg, 0.162 mmol) was dissolved in dry DCM under nitrogen atmosphere. 4-chloro-3-trifluoromethylphenylisocyanate (43 mg, 0.195 mmol, 1.2 eq) was added, the mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluant: 100% ethyl acetate) to give 64 mg (75%) of 1-(4-chloro-3-trifluoromethyl-phenyl)-3-[3-(3-pyridin-4-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazin-2-yl)-phenyl]-urea as white powder.