Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[Si:19]([O:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:19]([O:26][CH:27]1[CH2:28][CH2:29][N:30]([C:2]2[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=2)[CH2:31][CH2:32]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OC1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(Br)c1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)c1Cl
Temperature: 100 °C
Yield: 43.2 %

Procedure:
(I13A): A round bottom flask was charged with tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate (Intermediate 1) (5.39 g, 16.25 mmol), 4-((tert-butyldimethylsilyl)oxy)piperidine (3.5 g, 16.25 mmol), cesium carbonate (10.5 g, 32.5 mmol), Pd2(dba)3 (1.488 g, 1.625 mmol) and BINAP (1.012 g, 1.625 mmol) in toluene (54.2 ml). The flask was evacuated and purged with nitrogen (4×) and heated at 100° C. 2 d. After cooling to rt, the reaction mixture was diluted with ethyl acetate and vacuum filtered through a pad of Celite. The filtrate was concentrated in vacuo. The crude residue was purified by column chromatography on the Isco system (330 g, 60-95% CH2Cl2/Hex) to provide tert-butyl (3-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)carbamate (I13A) (3.27 g) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20]CC3C=CC=CC=3)=[CH:16][CH:15]=2)[C:3]=1[C:28]#[N:29].[H][H]>CCO.[Pd]>[NH2:1][C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:5]=[C:4]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)[C:3]=1[C:28]#[N:29]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)n1nc(-c2ccc(OCc3ccccc3)cc2)c(C#N)c1N
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Yield: 85 %

Procedure:
A mixture of compound 31E (1.3 g, 3.33 mmol) and Pd/C (0.071 g) in EtOH (15 mL) was hydrogenated with a balloon of hydrogen at rt for 6 hours. The solvent was removed, and residue was purified by flash column chromatography on silica gel eluting with 1:1/hexanes:EtOAc to provide 0.85 g of the desired product 31F: 1H NMR (DMSO-d6): δ 9.88 (s, 1H), 7.67 (d, J=8.9 Hz, 2H), 7.64 (s, 2H), 6.87 (d, J=8.9 Hz, 2H), 1.59 (s, 9H). MS (DCI(+)): m/z 301 (M+H).
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]([OH:7])[C@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:25]1[CH:29]=[C:28](/[CH:30]=[CH:31]/[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[N:26]1)=[N:14][C:15]=2[NH:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>[Pd].CO>[OH:1][C@H:2]1[C@@H:6]([OH:7])[C@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:25]1[CH:29]=[C:28]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[N:26]1)=[N:14][C:15]=2[NH:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)/C=C/c1cnn(-c2nc(NC3CCCC3)c3ncn([C@@H]4O[C@@H](CO)[C@H](O)[C@@H]4O)c3n2)c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1cnn(-c2nc(NC3CCCC3)c3ncn([C@@H]4O[C@@H](CO)[C@H](O)[C@@H]4O)c3n2)c1

Procedure:
10 mg of the ethyl (2E)-3-(1-{9-[(3S,5S,2R,4R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazol-4-yl)prop-2-enoate prepared in the preceding step was combined in a par bottle with 3 mL of MeOH and approximately 5 mg of 10% Pd/C (Aldrich) and the solution hydrogenated at 25-30 psi at room temperature. The Pd/c was filtered off and the filtrate condensed to provide ethyl 3-(1-{9-[(3S,5S,2R,4R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazol-4-yl)propanoate.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:15]=[N:16][N:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH:18]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].C(N(C(C)C)CC)(C)C.[F:34][C:35]([F:46])([F:45])[CH2:36]OS(C(F)(F)F)(=O)=O>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:15]=[N:16][N:17]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:36][C:35]([F:46])([F:45])[F:34])[CH2:21][CH2:20]3)[CH:18]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CCc1nc(C(N)=O)c(Nc2cnn(C3CCNCC3)c2)nc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc(C(N)=O)c(Nc2cnn(C3CCN(CC(F)(F)F)CC3)c2)nc1Cl
Reaction time: 2 h

Procedure:
To a mixture of 5-chloro-6-ethyl-3-{[1-(piperidin-4-yl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide (350 mg) and diisopropylethylamine (685 μL) in N,N-dimethylformamide (3.5 mL) was added 2,2,2-trifluoroethyltrifluoromethanesulfonate (433 μL), followed by reacting at room temperature for 2 hours. The mixture was subjected to liquid separation by the addition of ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=99:1-90:10) to obtain 5-chloro-6-ethyl-3-({1-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]-1H-pyrazol-4-yl}amino)pyrazine-2-carboxamide (424 mg) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](=[O:9])[N:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]=1[S-:16])#[N:2].[Na+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].O>CCO>[CH2:23]([O:22][C:20]([C:19]1[S:16][C:4]2[N:5]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6](=[O:9])[CH:7]=[CH:8][C:3]=2[C:1]=1[NH2:2])=[O:21])[CH3:24]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1ccc(=O)n(-c2ccccc2)c1[S-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccccc2)c1N

Procedure:
A mixture of Example 1 (0.34 g at 100%) and ethyl bromoacetate (0.197 mL) in EtOH (6 mL) was stirred at room temperature for 1 h. H2O (10 mL) was then added. The solid was filtered and washed with more H2O (2 mL). The product was dried under vacuum at 40° C. to constant weight to give the title compound as a pale pink solid (0.35 g). δH (DMSO-d6) 8.20 (1H, d, J 9.6 Hz), 7.60 (3H, m), 7.45 (2H, m), 7.15 (2H, br s), 6.55 (1H, d, J 9.6 Hz), 4.15 (2H, q, J 7.1 Hz), 1.20 (3H, t, J 7.1 Hz). LCMS (ES+) RT 3.29 minutes, 315 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:18])(=[O:11])=[O:10])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1.[N:22]1([CH2:31][C:32](O)=[O:33])[CH:30]=[C:28]([CH3:29])[C:26](=[O:27])[NH:25][C:23]1=[O:24]>>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:32](=[O:33])[CH2:31][N:22]3[CH:30]=[C:28]([CH3:29])[C:26](=[O:27])[NH:25][C:23]3=[O:24])[CH2:14][C:13]2=[O:18])(=[O:11])=[O:10])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1
Reactant: O=C1CNCCN1S(=O)(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Agent: Cl
Product: Cc1cn(CC(=O)N2CCN(S(=O)(=O)c3ccc(Cl)cc3[N+](=O)[O-])C(=O)C2)c(=O)[nH]c1=O
Yield: 94.1 %

Procedure:
The title compound (1.60 g, 94%) was synthesized by reaction of 1-(4-chloro-2-nitro-benzenesulfonyl)-piperazin-2-one HCl salt (1.25 g, 3.5 mmol) with (thymin-1-yl)-acetic acid (0.64 g, 3.5 mmol) as per the procedure of example 64.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH2:19]([NH2:22])[C:20]#[CH:21].C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16]([NH:22][CH2:19][C:20]#[CH:21])=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Reactant: C#CCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCNC(=O)c1nc(-c2sc(NC(C)=O)nc2C)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above (160 mg, 0.53 mmol, 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). Propargylamine (Fluka) (35.0 mg; 0.64 mmol; 1.20 eq.) and triethylamine (0.22 ml; 1.59 mmol; 3 eq.) are added and the mixture is stirred overnight at rt. Solvents are evaporated and the crude product is purified by preparative HPLC, affording Compound (44) as a pale yellow powder (83.3 mg; 49%). 1H NMR (DMSO-d6, 300 MHz) δ 2.14 (s, 3H), 2.49 (s, 3H), 3.14 (s, 1H, C—CH), 4.04 (m, 2H), 8.01 (s, 1H), 9.20 (t, J=4.5 Hz, 1H), 12.15 (s, 1H). M− (ESI): 319.05; M+ (ESI): 321.05. HPLC (method A), Rt: 2.71 min (purity: 100%).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26](OCC)=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:34][O:35][CH2:36][CH2:37][NH2:38]>C(O)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26]([NH:38][CH2:37][CH2:36][O:35][CH3:34])=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:32][CH:33]=1
Reactant: COCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Solvent: CC(C)O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
A mixture of ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate (1.13 g, 2.50 mmol) and 2-methoxyethylamine (1.1 mL, 12.5 mmol) in isopropanol (20 mL) was heated at reflux for 3 hrs. After cooling, the resulting slurry was diluted with isopropanol (10 mL) and filtered. The precipitate was partitioned between CH2Cl2 and 1N NaHSO4. After separating the layers, the aqueous phase was back-extracted with CH2Cl2 and the combined organics were dried over Na2SO4, filtered and evaporated in vacuo to provide the product as a white solid. The isopropanol was evaporated in vacuo and the residue was partitioned between CH2Cl2 and 1N NaHSO4. After separating the layers, the aqueous phase was back-extracted with CH2Cl2 and the combined organics were dried over Na2SO4, filtered and evaporated in vacuo to provide an additional crop of the product as a white solid: 1H NMR (CDCl3) δ 10.27 (1H, br m), 8.55 (1H, s), 8.06 (1H, s), 7.24 (2H, m), 6.99 (2H, t, J=8.6 Hz), 4.35 (2H, t, J=7 Hz), 4.14 (2H, s), 3.65 (2H, m), 3.59 (2H, m), 3.50 (2H, t, J=7 Hz), 3.44 (2H, m), 3.42 (3H, s), 2.31 (2H, t, J=8 Hz), 1.97 (2H, m); ES+ MS: 483 (M+H+).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[C:8]([NH:10][C:11]1[S:12][C:13]2[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=2[C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)=[O:17])=[O:9])(=[O:4])=[O:3].[CH3:44][NH:45][CH2:46][C@@H:47]([C@H:49]([C@@H:51]([C@@H:53]([CH2:55][OH:56])[OH:54])[OH:52])[OH:50])[OH:48]>ClCCl>[CH3:34][O:33][C:31]([C:30]1[CH:35]=[CH:36][C:27]([CH2:26][CH2:25][C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:16]([C:15]3[C:14]4[CH2:37][CH2:38][CH2:39][CH2:40][C:13]=4[S:12][C:11]=3[NH:10][C:8]([C:7]3[CH:6]=[C:5]([S:2]([N:45]([CH3:44])[CH2:46][C@@H:47]([C@H:49]([C@@H:51]([C@@H:53]([CH2:55][OH:56])[OH:54])[OH:52])[OH:50])[OH:48])(=[O:4])=[O:3])[CH:43]=[CH:42][CH:41]=3)=[O:9])=[O:17])=[CH:20][CH:21]=2)=[CH:28][CH:29]=1)=[O:32]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)Cl)c4)sc4c3CCCC4)cc2)cc1
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: ClCCl
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)c4)sc4c3CCCC4)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A mixture of 250 mg of methyl 4-[2-(4-{[(2-{[3-(chlorosulfonyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 153 mg of N-methyl-D-glucamine, and 2.5 mL of dichloromethane was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was washed with water to obtain 256 mg of 1-deoxy-1-[{[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)phenyl]sulfonyl}(methyl)amino]-D-glucitol as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)([CH3:12])[C:7](=[O:20])[C:6]([C:21]([NH:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[O:22])=[C:5]2[OH:32].C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)([CH3:12])[C:7](=[O:20])[C:6]([C:21]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:22])=[C:5]2[OH:32]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(c2ccc(Cl)cc2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(c2ccc(Cl)cc2)C(=O)C(C(=O)NCC(=O)O)=C(O)c2cc(Cl)ccc21
Yield: 97.2 %

Procedure:
A solution of 1,1-dimethylethyl N-((6-chloro-1-(4-chlorophenyl)-4-hydroxy-1-methyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (0.675 g, 1.42 mmol) in TFA (10.0 mL, 127 mmol) was stirred at 25° C. for 10 minutes. The solution was concentrated, azeotroped in DCM (2×300 mL), and dried in a vacuum oven at 60° C. to give the title compound (0.580 g). MS m/e=420 (M+H)+. Calculated for C20H15Cl2NO5 419.03.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2>>[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3ccc(Br)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 75.2 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-bromo-1,3-dihydro-indol-2-one as starting materials to give 2-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (62 mg, 75.2%) as an orange solid.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH3:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>CC(N(C)C)=O.O>[C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH3:29])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: C1COCCN1
Reactant: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(N3CCOCC3)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
A solution of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (50 mg, 0.1009 mmol, example 58), morpholine (22 μl, 0.252 mmol) and 2,6-di-tert-butylpyridine (45.4 μl, 0.202 mmol) in DMA (1 ml) was heated in a sealed tube at 100° C. overnight. Then additional morpholine (8.8 μl, 0.1009 mmol) was added and the solution was stirred another 2 h at 100° C. The mixture was then cooled to room temperature and diluted with water. The pH was adjusted to 10 by addition of saturated Na2CO3 solution and the mixture was extracted 3 times with EtOAc. The combined organic layers were washed two times with Na2CO3 solution (pH 10) and with brine, dried over Na2SO4 and evaporated. The remaining light brown solid was purified by silica gel chromatography (DCM/EtOAc 4:1-1:1) to obtain the title compound (33 mg, 65%) as white foam. MS (EI): 502.2 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([N:24]1[C:30](=[O:31])[C:29]([CH3:33])([CH3:32])[C:28](=[O:34])[N:27]([CH3:35])[C:26]2[CH:36]=[C:37]([O:40][CH2:41][CH2:42][CH2:43]I)[CH:38]=[CH:39][C:25]1=2)[CH3:23].C(O)C.[ClH:48]>C(O)(C)C.CN(C=O)C>[ClH:48].[CH2:22]([N:24]1[C:30](=[O:31])[C:29]([CH3:32])([CH3:33])[C:28](=[O:34])[N:27]([CH3:35])[C:26]2[CH:36]=[C:37]([O:40][CH2:41][CH2:42][CH2:43][N:11]3[C:10]4[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=4[N:8]=[C:7]3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:38]=[CH:39][C:25]1=2)[CH3:23]
Reactant: c1ccc(-c2nc3ccccc3[nH]2)cc1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCI)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CC(C)O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCn3c(-c4ccccc4)nc4ccccc43)ccc21
Temperature: 60 °C
Reaction time: 7 h

Procedure:
2-Phenyl-1H-benzimidazole(0.2 g) and potassium carbonate(0.29 g) were added to a DMF solution(5 ml) of 1-ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(0.49 g). The mixture was stirred at 60° C. for 7 hours. The reaction mixture was poured to ice water(50 ml), and the generated insoluble matter was separated. The insoluble matter was dissolved in ethyl acetate. The liquid was dried over sodium sulfate and condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:3). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride ethanol solution(1.0 ml) was added to an isopropyl alcohol solution of the residue. The mixture was condensed under reduced pressure. Ether was added to the residue. The generated insoluble matter was separated by filtration and dried to give the title compound(0.32 g) as a white powder.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5](=[N:7][C:8]2[N:13]=[C:12]([C:14](OC)=[O:15])[CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:18][O:19][CH3:20])[CH:3]=1.[BH4-].[Li+].O>O1CCCC1>[Br:1][C:2]1[S:6][C:5](=[N:7][C:8]2[N:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:18][O:19][CH3:20])[CH:3]=1
Reactant: COCn1cc(Br)sc1=Nc1cccc(C(=O)OC)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COCn1cc(Br)sc1=Nc1cccc(CO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
6.50 g (18.0 mmol) of methyl 6-(5-bromo-3-methoxymethyl-3H-thiazol-2-ylideneamino)-pyridine-2-carboxylate was dissolved in 80 ml of tetrahydrofuran, 790 mg (36.0 mmol) of lithium borohydride was added thereto and the mixture was heated under reflux. After 1 hour, 790 mg (36.0 mmol) of lithium borohydride was added thereto followed by further heating under reflux for 1 hour, the reaction mixture was cooled to room temperature and water was added thereto. After water was added until no more bubbling took place, the mixture was extracted with ethyl acetate. The resulting ethyl acetate solution was washed with 100 ml of water for two times and then washed with 100 ml of brine. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography to give 2.67 g (8.09 mmol) of the title compound as a white solid.
Reaction SMILES: C([NH:3][C@@H:4]1[C:34](=[O:35])[N:6]2[C:7]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:8]([S:11][CH2:12][C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[CH2:9][S:10][C@H:5]12)=O.Cl>CO>[NH2:3][C@@H:4]1[C:34](=[O:35])[N:6]2[C:7]([C:18]([O:20][CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:19])=[C:8]([S:11][CH2:12][C:13]3[CH:17]=[N:16][NH:15][CH:14]=3)[CH2:9][S:10][C@H:5]12
Reactant: O=CN[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3cn[nH]c3)CS[C@H]12
Agent: Cl
Solvent: CO
Product: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3cn[nH]c3)CS[C@H]12
Reaction time: 3 h
Yield: 53.6 %

Procedure:
Diphenylmethyl 7β-formamido-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (2.96 g) was dissolved in methanol (30 ml) and concentrated hydrochloric acid (2.2 ml) was added thereto at the room temperature. Stirring was continued for 3 hours, then solvent was evaporated. The residue was diluted with a mixture of water. The ethyl acetate and aqueous layer was adjusted to pH 6.5 with 30% aqueous potassium carbonate. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. Solvent was evaporated to afford diphenylmethyl 7β-amino-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (1.50 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].Br[C:15]1[CH:20]=[C:19](F)C(F)=[CH:17][C:16]=1O[C@H](CC=C)C>>[Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:5]=[CH:4][C:3]=1[O:13][C@H:20]([CH2:15][CH:16]=[CH2:17])[CH3:19]
Reactant: Oc1ccc(OC(F)(F)F)cc1Br
Reactant: C=CC[C@H](C)Oc1cc(F)c(F)cc1Br
Product: C=CC[C@H](C)Oc1ccc(OC(F)(F)F)cc1Br
Yield: 88 %

Procedure:
Prepared in 88% yield from 2-bromo-4-(trifluoromethoxy)phenol following the same procedure as (S)-1-bromo-4,5-difluoro-2-(pent-4-en-2-yloxy)benzene. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=2.3 Hz, 1H), 7.13 (dd, J=8.9, 2.1 Hz, 1H), 6.90 (d, J=9.0 Hz, 1H), 5.90 (ddt, J=17.2, 10.1, 7.1 Hz, 1H), 5.22-5.09 (m, 2H), 4.50-4.35 (m, 1H), 2.63-2.48 (m, 1H), 2.48-2.36 (m, 1H), 1.37 (d, J=6.0 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CCC(O)C1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:23][CH2:24][CH:26]([OH:25])[CH2:27]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: OC1CCNC1
Product: CC(C)(C)c1nc(N2CCC(O)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and pyrrolidin-3-ol and isolated as colorless foam. MS(m/e): 387.4 (MH+).