Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH:25]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=6)[CH2:24][O:23][C:22]5=[O:32])=[N:17][C:16]=34)=[CH:8][CH:7]=2)=[N:2]1>C(O)C>[NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][C:18]([N:21]5[C@@H:25]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=6)[CH2:24][O:23][C:22]5=[O:32])=[N:17][C:16]=34)=[CH:10][CH:11]=2)=[N:2]1
Reactant: O=C1OCC(c2ccccn2)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)cc3)c2n1
Solvent: CCO
Product: O=C1OC[C@H](c2ccccn2)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)cc3)c2n1

Procedure:
Racemic 3-(3-(4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(pyridin-2-yl)oxazolidin-2-one (Example 69) was dissolved in hot ethanol (10 mg/3 mL) and 1.5 ml, of the solution injected (8 injections total) onto a 2.2 cm×250 mm Chiral Tech OD-H column using 35% ethanol/65% hexanes as eluent with a 21 mL/minute flow rate. Peak 1 was isolated to provide (S)-3-(3-(4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(pyridin-2-yl)oxazolidin-2-one (19.2 mg). LCMS (APCI+) m/z 425 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][N:3]=1.[C:13]([O:17][C:18](=[O:21])[CH2:19][NH2:20])([CH3:16])([CH3:15])[CH3:14].C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:20][CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:21])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: COC(=O)c1cnc(Cl)nc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(Cl)nc1NCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of the product of step (i) (1.73 g), glycine tert-butyl ester (1.4 g) and N,N-diisopropylethylamine (2.6 ml) in dimethylformamide (20 ml) was stirred at room temperature. After 4 hours, the reaction mixture was partitioned between 2M HCl and ethyl acetate. The organic phase was washed with water, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 5% ethyl acetate in toluene. Yield 1.5 g.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[O:9]=[C:10]([CH3:26])[CH2:11][N:12]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]1>CS(C)=O>[CH3:26][C:10]1([CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]2)[CH2:2][O:9]1
Reactant: CC(=O)CN1CCCN(C(=O)OC(C)(C)C)CC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(CC2(C)CO2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
Trimethylsulfoxonium iodide (22.95 g, 104 mmol) was gradually added to a suspension of sodium hydride (4.3 g, 109 mmol) in DMSO (200 ml), and the mixture was stirred at room temperature for 2 hours. To which a solution tert-butyl 4-(2-oxopropyl)homopiperazine-1-carboxylate (24.3 g, 94.8 mmol) prepared in Reference Example 10 in DMSO (25 ml) was gradually added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, and extracted with diethyl ether. The extract was washed with water, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford tert-butyl 4-(2-methyl-2-oxiranylmethyl)homopiperazine-1-carboxylate (15.38 g, yield 60%) as a pale yellow oil.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH2:23][CH2:22][C@@H:21]4[C:25]4[C:26]([O:32][CH3:33])=[N:27][CH:28]=[C:29]([F:31])[CH:30]=4)=[N:16][C:15]=23)=[O:10])[CH2:4][O:3]1.Cl>C1COCC1.CCOC(C)=O>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[N:13][N:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][CH2:23][CH2:22][C@@H:21]3[C:25]3[C:26]([O:32][CH3:33])=[N:27][CH:28]=[C:29]([F:31])[CH:30]=3)=[N:16][C:15]=12)=[O:10]
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NC[C@H]3COC(C)(C)O3)c2n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NC[C@H](O)CO)c2n1
Reaction time: 5 h
Yield: 90.5 %

Procedure:
To a solution of N—(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (36 mg, 0.077 mmol) in THF (2 mL) was added HCl (3 N aq.) at ambient temperature. The resulting mixture was stirred for 5 hours. The reaction was diluted with EtOAc, washed with saturated NH4Cl and brine, then dried (MgSO4), filtered and concentrated. The crude material was rinsed with ether to yield the final product as white solid (30 mg, 91%). LCMS (apci) m/z=431.1 (M+H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([O:23][CH3:24])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[C:35]1[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=1>CS(C)=O.C(OCC)(=O)C>[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[C:35]1[CH2:36][CH2:37][N:38]([CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([O:23][CH3:24])[CH:17]=[CH:18][CH:19]=3)[O:14]2)[CH2:39][CH:40]=1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: COc1cccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)C=C2
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cccc2c1O[C@@H](CN1CC=C(c3c[nH]c4ccc(F)cc34)CC1)C=C2
Temperature: 80 °C
Yield: 60.9 %

Procedure:
To a solution of [(2R)-8-methoxy-2H-chromen-2-yl]methyl 4-methyl-benzenesulfonate (0.350 g, 1.01 mmol) in methyl sulfoxide (20 mL) was added 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.655 g, 3.03 mmol) and the reaction mixture was heated to 80° C. for 12 h. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (200 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, methanol:ethyl acetate 1:9) followed by recrystallization from ethanol provided 0.240 g (61%, >97% ee) of 5-fluoro-3-(1-{[(2R)-8-methoxy-2H-chromen-2-yl]methyl}-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole as a yellow solid. [α]D25=−2.14 (c 10.27 in chloroform, >97% ee); Rf=0.49 (silica, methanol:ethyl acetate 1:9); mp 189-191° C. dec; Anal. Calcd. for C24H23FN2O2.0.3 H2O: C, 73.15; H, 5.99; N, 7.11. Found: C, 73.19; H, 6.03; N, 7.08.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[O:32][CH3:33])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH2:18]OC(=O)CC(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[N:34]1[CH:35]=[N:36][N:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=12>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[O:32][CH3:33])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][N+:34]4[CH:35]=[N:36][N:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=45)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)CC(C)=O)CS[C@H]12)c1csc(N)n1
Reactant: c1ccn2ncnc2c1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3cnn4ccccc43)CS[C@H]12)c1csc(N)n1

Procedure:
7β(2-(2-Aminothiazole-4-yl)-2(Z)-methoxyiminoacetamido]-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid and [1,2,4]triazolo[1,5-a]pyridine are treated in a way analogous to that in Example 1 to yield the desired compound.
Reaction SMILES: C[O:2]C(=O)COC1C=C(OC)C(S)=CC=1C.Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)=[CH:21][CH:20]=1>>[F:32][C:31]([F:34])([F:33])[C:28]1[CH:29]=[CH:30][C:25]([C:22]2[CH:23]=[CH:24][C:19]([CH2:18][OH:2])=[CH:20][CH:21]=2)=[N:26][CH:27]=1
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)cc2)nc1
Reactant: COC(=O)COc1cc(OC)c(S)cc1C
Product: OCc1ccc(-c2ccc(C(F)(F)F)cn2)cc1

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 1D and 18B. MS m/z 478 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:17][CH:18]=2)[N:3]=1.[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH:40]([CH3:44])[C:41]([NH2:43])=[O:42])#[CH:33].F[B-](F)(F)F.CCN(C(C)C)C(C)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[NH2:43][C:41](=[O:42])[CH:40]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[C:32]#[C:33][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:17][CH:18]=2)[N:3]=1)[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cn2)CC1
Reactant: C#Cc1ccccc1C(C)C(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C(N)=O)c1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a mixture of tert-butyl 4-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate A70 (0.397 g, 0.867 mmol), 2-(2-ethynylphenyl)propanamide K7 (0.195 g, 1.13 mmol), CuI (0.011 g, 0.057 mmol), PdCl2(PPh3)2 (0.039 g, 0.056 mmol) and t-Bu3PH.BF4 (0.017 g, 0.058 mmol) under a nitrogen atmosphere was added dioxane (12 mL) and DIPEA (0.60 mL, 3.4 mmol). The mixture was stirred at room temperature for 96 hours before being concentrated under reduced pressure and purifying by silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. and 0-20% MeOH in EtOAc) to give the title compound A71 (0.139 g, 27%). LCMS-D: rt 3.626 min; m/z 595.3 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(O)=[O:2].C[CH2:21][N:22]=C=NCCCN(C)C.Cl.CN1CCOCC1.CN>C(Cl)Cl>[CH3:21][NH:22][C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:2]
Reactant: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CNC(=O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Reaction time: 72 h
Yield: 48.2 %

Procedure:
A mixture of 4-(3-carboxyphenoxy)-1-nitrobenzene (3.72 g, 14.4 mmol), EDCI.HCl (3.63, 18.6 mmol), N-methylmorpholine (1.6 mL, 14.5 mmol) and methylamine (2.0 M in THF; 8 mL, 16 mmol) in CH2Cl2 (45 mL) was stirred at room temp. for 3 d, then concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and the resulting mixture was extracted with a 1M HCl solution (50 mL). The aqueous layer was back-extracted with EtOAc (2×50 mL). The combined organic phases were washed with a saturated NaCl solution (50 mL), dried (Na2SO4), and concentrated under reduced pressure to give 4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene as an oil (1.89 g).
Reaction SMILES: [CH:1](=[O:10])[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:11]([C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1)[CH3:12].[NH4+].[Cl-]>C1COCC1>[CH2:11]([C:13]1[CH:18]=[CH:17][C:16]([CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])[OH:10])=[CH:15][CH:14]=1)[CH3:12]
Reactant: CCc1ccc([Mg]Br)cc1
Reactant: COc1ccccc1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1ccc(C(O)c2ccccc2OC)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1.01 g of o-anisaldehyde are dissolved in THF and cooled to 0° C. 16.29 ml of 4-ethylphenylmagnesium bromide (0.5 M in THF) are added to the mixture. The reaction solution is stirred at room temperature overnight and then poured into 20% NH4Cl solution and extracted with ethyl acetate. 1.92 g of the product are obtained, and this can be employed without further purification. C16H18O2 (242.32) MS (ESI+) 225.15 (M−OH)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](=[O:29])[N:24]([CH3:30])[CH:23]=2)[C:9]2[C:10]([C:18]([OH:20])=O)=[N:11][N:12]([CH:15]3[CH2:17][CH2:16]3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([CH:15]4[CH2:17][CH2:16]4)[C:13]=3[CH3:14])[C:18](=[O:20])[N:21]2[C:22]2[CH:27]=[C:26]([CH3:28])[C:25](=[O:29])[N:24]([CH3:30])[CH:23]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(NC(c2ccc(Cl)cc2)c2c(C(=O)O)nn(C3CC3)c2C)cn(C)c1=O
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(N2C(=O)c3nn(C4CC4)c(C)c3C2c2ccc(Cl)cc2)cn(C)c1=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)((1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)amino)methyl)-1-cyclopropyl-5-methyl-1H-pyrazole-3-carboxylic acid (Step 20.4). tR: 4.06 min (HPLC 1); tR: 0.92 min (LC-MS 2); ESI-MS: 409.2 [M+H]+ (LC-MS 2); Rf=0.39 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.94-1.17 (m, 4H) 1.91 (s, 3H) 2.13 (s, 3H) 3.34 (s, 3H) 3.60-3.67 (m, 1H) 6.09 (s, 1H) 7.20-7.26 (m, 2H) 7.32-7.43 (m, 3H) 7.70 (d, J=2.7 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[C:7]([O:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:6][C:3]=1[CH:4]=[CH2:5].ClC1C=CC=C(C(OO)=[O:33])C=1>C(OC(=O)C)C.C1CCCCC1>[Cl:1][C:2]12[O:33][C:3]1([CH:6]=[C:7]([O:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[C:8]([O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:9]2[Cl:10])[CH:4]=[CH2:5]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1cc(OCOCCOC)c(OCOCCOC)c(Cl)c1Cl
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: C=CC12C=C(OCOCCOC)C(OCOCCOC)=C(Cl)C1(Cl)O2
Yield: 99.6 %

Procedure:
Using the procedure of Stage D of Example 40, 13.2 g of thee allylic alcohol of Step C and 10.3 g of m-chloro perbenzoic acid were reacted to obtain 13.7 g of the expected product with a Rf=0.25 (AcOEt-cyclohexane 6-4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][C:19]2([CH3:32])[CH3:31])[C:14]1=[O:33].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:31][C:19]1([CH3:32])[CH:18]([N:15]2[CH2:16][CH2:17][C@H:13]([NH:12][C:3]3[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:7][C:2]=3[F:1])[C:14]2=[O:33])[CH2:23][CH2:22][NH:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](Nc3ccc(S(C)(=O)=O)cc3F)C2=O)C(C)(C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CNCCC1N1CC[C@H](Nc2ccc(S(C)(=O)=O)cc2F)C1=O
Reaction time: 1 h
Yield: 24.8 %

Procedure:
tert-Butyl 4-((S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)-3,3-dimethylpiperidine-1-carboxylate (0.10 g, 0.21 mmol) was dissolved in DCM (5 mL). TFA (5 mL) was added and the reaction was stirred for 1 hour. The solution was concentrated, neutralized with saturated NaHCO3 solution, and extracted with dichloromethane (3 times). The organic layers were combined, dried, filtered and concentrated to give (3S)-1-(3,3-dimethylpiperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (0.020 g, 0.052 mmol, 25% yield) as a white solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[C:11]=1[CH2:12][CH2:13][CH2:14][NH2:15].C(N(CC)CC)C.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>ClCCl>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[C:11]=1[CH2:12][CH2:13][CH2:14][NH:15][C:26]([CH:23]1[CH2:25][CH2:24]1)=[O:27]
Reactant: NCCCc1c(F)ccc2c1CCO2
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCc1c(F)ccc2c1CCO2)C1CC1
Reaction time: 16 h

Procedure:
3-(2,3-Dihydro-5-fluorobenzofuran-4-yl)propylamine hydrochloride (0.27 g) in dichloromethane (5 ml) containing triethylamine (0.5 ml) was cooled in ice. Cyclopropanecarbonyl chloride (0.12 ml) was added and stirring continued at 5° for 2 h and at room temperature for 16 h. The mixture was washed with water and passed through a solid phase extraction cartridge using ethyl acetate/hexane (1:1) to give the title compound as a white solid (0.21 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.[NH2:21][C:22]1[CH:32]=[CH:31][C:25]2[NH:26][C:27](=[O:30])[CH2:28][S:29][C:24]=2[CH:23]=1>CCO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[N:21][C:22]1[CH:32]=[CH:31][C:25]2[NH:26][C:27](=[O:30])[CH2:28][S:29][C:24]=2[CH:23]=1
Reactant: O=Cc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: Nc1ccc2c(c1)SCC(=O)N2
Solvent: CCO
Product: O=C1CSc2cc(N=Cc3cccc(OCc4ccc5ccccc5n4)c3)ccc2N1
Reaction time: 24 h
Yield: 92.5 %

Procedure:
A liquid mixture of 1.316 g (5 mmol) of 3-(2-quinolinylmethoxy)benzaldehyde, 0.901 g (5 mmol) of 7-amino-3,4-dihydro-2H-1,4-benzothiazin-3-one and 70 ml of EtOH was heated under reflux and stirring for 24 hours. The mixture was then allowed to cool down. The precipitate was collected by filtration, whereby 1.969 g of the title compound were obtained as pale yellow powder (yield: 92.3%).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1[C:27]2[C:22]3[C:23](=[CH:28][CH:29]=[CH:30][C:21]=3[C:20]1=[O:31])[CH:24]=[CH:25][CH:26]=2.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:8][NH:9][C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:19]1[C:27]2[C:22]3[C:23](=[CH:28][CH:29]=[CH:30][C:21]=3[C:20]1=[O:31])[CH:24]=[CH:25][CH:26]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2cccc3cccc1c23
Reactant: O=C(CCCCCCBr)NOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(CCCCCCN1C(=O)c2cccc3cccc1c23)NOCc1ccccc1

Procedure:
In a manner analogous to that of example 2(b), 7-bromo-heptanoic acid benzyloxy-amide 0.46 g, 1.5 mmol) was reacted with benzo[cd]indol-2(1H)-one (0.25 g, 1.5 mmol) in the presence of potassium carbonate (0.2 g, 1.4 mmol) to give 7-(2-oxo-2H-benzo[cd]indol-1-yl)-heptanoic acid benzyloxyamide as an amorphous solid (yield 0.08 g, 13%; purified by column chromatography using silica gel and ethyl acetate:heptane=1:1 as an eluent). MS (M+H+)=403.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([NH:11][C:12](=[O:16])[C:13]([OH:15])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:17]1([CH3:30])[CH:22]=[CH:21][C:20]([O:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:19][CH:18]=1>C(OCC)C>[SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([NH:11][C:12](=[O:16])[C:13]([N:27]3[CH2:28][CH2:29][CH:24]([O:23][C:20]4[CH:21]=[CH:22][C:17]([CH3:30])=[CH:18][CH:19]=4)[CH2:25][CH2:26]3)=[O:15])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=C(O)C(=O)Nc1ccc2nc(S)[nH]c2c1
Reactant: Cc1ccc(OC2CCNCC2)cc1
Solvent: CCOCC
Product: Cc1ccc(OC2CCN(C(=O)C(=O)Nc3ccc4nc(S)[nH]c4c3)CC2)cc1

Procedure:
The title compound is prepared from N-(2-mercapto-3H-benzimidazol-5-yl)-oxalamic acid (Example 60b) and 4-p-tolyloxy-piperidine according to the method described in Example 1c. Melting Point: 311-314° C. (diethylether)
Reaction SMILES: FC1C=C(F)C=CC=1[OH:9].[F:10][C:11]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:12]=1[O:13][C:14]1[C:15](=[O:31])[O:16][C:17]([CH3:30])([CH3:29])[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1>ClCCl>[CH3:29][C:17]([O:16][C:15](=[O:31])[CH2:14][O:13][C:12]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:11]=1[F:10])([CH3:30])[C:18]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)=[O:9]
Reactant: CC1(C)OC(=O)C(Oc2ccc(F)cc2F)=C1c1ccc(S(C)(=O)=O)cc1
Reactant: Oc1ccc(F)cc1F
Solvent: ClCCl
Product: CC(C)(OC(=O)COc1ccc(F)cc1F)C(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride, 60% dispersion (66 mg, 1.66 mmol), was rinsed with hexane, suspended in 7 mL of DMF and cooled to 0° C. To this suspension was added 2,4-difluorophenol (170μL, 1.79 mmol). After 5 minutes at 0° C., 2-bromoacetic acid 2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one ester (Step 1) (233 mg, 1.79 mmol) was added and the reaction mixture was stirred for 30 minutes. Dichloromethane was added and the mixture was washed with 1N HCl and the organic solvent was evaporated under vacuum. The residue was dissolved in 25%EtOAc/Et2O and washed with 1N NaOH, water (2×) brine and dried over MgSO4. After filtration and evaporation of the solvent under vacuum 470 mg of the title compound was obtained.
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][Si](C)(C)C)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO.C(Cl)Cl.C(Cl)Cl>[F:1][CH:2]([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1
Reactant: C[Si](C)(C)C#Cc1ccc(OC(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1ccc(OC(F)F)cc1
Reaction time: 1.5 h
Yield: 97 %

Procedure:
A solution of {[4-(difluoromethoxy)phenyl]ethynyl}(trimethyl)silane (10.0 g, 41.7 mmol) in MeOH/CH2Cl2 (1/1) was treated with cesium carbonate (16.3 g, 50 mmol) at room temperature, stirred for 1.5 h, diluted with CH2Cl2 and filtered through a pad of silica gel. The filtrate was concentrated to dryness to give the title compound (6.8 g, 97%) as an oil. MS (+) EI: 168.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:29][CH:28]([OH:30])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:38]([N:40]=[C:41]=[O:42])[CH3:39]>ClCCl>[CH2:38]([NH:40][C:41](=[O:42])[O:30][CH:28]1[CH2:27][N:26]([S:23]([C:21]2[CH:20]=[CH:19][C:8]3[N:9]([CH2:10][CH:11]4[CH2:16][CH2:15][C:14]([F:17])([F:18])[CH2:13][CH2:12]4)[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][C:7]=3[CH:22]=2)(=[O:25])=[O:24])[CH2:29]1)[CH3:39]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(O)C3)ccc2n1CC1CCC(F)(F)CC1
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)OC1CN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCC(F)(F)CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a solution of 1-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)azetidin-3-ol (100 mg, 0.23 mmol) in 2 mL of dry dichloromethane was added triethylamine (3 uL, 0.023 mmol) and ethyl isocyanate (0.11 mL, 1.4 mmol), respectively. The reaction mixture was stirred at room temperature for 1 hour and then concentrated. The crude product was purified by LCMS using high pH column 40-70% acetonitrile gradient to give 100 mg (85%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.00 (t, J=7.23 Hz, 3 H), 1.48-1.57 (m, 2 H), 1.59 (s, 9 H), 1.63-1.83 (m, 4 H), 2.04 (d, J=26.56 Hz, 2 H), 2.18-2.31 (m, 1 H), 3.00 (q, J=7.23 Hz, 2 H), 3.63 (dd, J=9.18, 5.08 Hz, 2H), 4.01-4.09 (m, 2 H), 4.42 (d, J=7.62 Hz, 2 H), 7.70-7.75 (m, 1 H), 7.79-7.84 (m, 1 H), 8.10 (s, 1 H); MS (APPI) (M+H)+=513.3; Anal. Calc. for C24H34F2N4O4S+1.1 TFA: C, 49.32; H, 5.54; N, 8.78. Found: C, 49.31; H, 5.42; N, 8.59.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21][N:22]3C(=O)[C:25]4=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]4[C:23]3=O)=[N:19][N:18]=[C:17]2[Cl:33])=[C:6]([CH:15]=1)C(C1C=CC=CC=1)=O.C(N)C>>[Cl:33][C:17]1[N:16]2[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:15][C:6]=3[C:23]([C:24]3[CH:25]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:22][CH2:21][C:20]2=[N:19][N:18]=1
Reactant: O=C(c1ccccc1)c1cc(F)ccc1-n1c(Cl)nnc1CN1C(=O)c2ccccc2C1=O
Agent: CCN
Product: Fc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(Cl)n1-2

Procedure:
The 5-fluoro-2-(3-chloro-5-phthalimidomethyl-4H-1,2,4-triazol-4-yl)benzophenone is reacted with ethylamine to form the titled product.