Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[OH:24][C:25]([CH3:44])([CH3:43])[CH2:26][N:27]1[C:31]([CH3:32])=[C:30]([C:33](O)=[O:34])[C:29](=[O:36])[N:28]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCN(C(C)C)C(C)C>O1CCOCC1.CCOC(C)=O.O>[O:17]=[C:11]1[C:10]2[CH:18]=[CH:19][CH:20]=[CH:21][C:9]=2[C:8]2[C:13](=[N:14][CH:15]=[CH:16][C:7]=2[O:6][C:5]2[CH:22]=[CH:23][C:2]([NH:1][C:33]([C:30]3[C:29](=[O:36])[N:28]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:27]([CH2:26][C:25]([OH:24])([CH3:44])[CH3:43])[C:31]=3[CH3:32])=[O:34])=[CH:3][CH:4]=2)[NH:12]1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)c5ccccc5c34)cc2)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.4 %

Procedure:
Compound 137 (50 mg, 0.16 mmol), 1-(2-hydroxy-2-methyl-propyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (57 mg, 0.26 mmol), BOP-Cl (63 mg, 0.25 mmol), and DIEA (0.08 mL, 0.49 mmol) were suspended in dioxane (2 mL), and stirred overnight at room temperature. The reaction mixture was diluted with EtOAc/H2O, and filtered through an Extrelut column. The column was washed with EtOAc and the filtrate was concentrated. The crude material was purified via Biotage eluting with a gradient of 0 to 10% MeOH in CH2Cl2 to provide 209 (28 mg, 30% yield) as a white solid. LC-MS (M+H=576, obsd.=576).
Reaction SMILES: [CH:1]1([CH:4]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:5]2C(=O)OC(C)(C)[O:7][C:6]2=[O:14])[CH2:3][CH2:2]1.CN(C=O)C.O>CCOC(C)=O>[CH:1]1([CH:4]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:5][C:6]([OH:14])=[O:7])[CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)C(C(c2ccc(O)cc2)C2CC2)C(=O)O1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)CC(c1ccc(O)cc1)C1CC1
Temperature: 25 °C

Procedure:
A solution of 21.2 in 10:1 DMF/water (48 mL) was stirred overnight at 90° C. The mixture was cooled to room temperature, diluted with EtOAc, washed with 1 N HCl and brine, dried (MgSO4), and concentrated to afford 21.3. The crude product was used without further purification.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([OH:4])=[O:3].[C:19](ON1C(=O)CCC1=O)([O:21][CH2:22][CH:23]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20]>C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>[C:19]([NH:16][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:2]([OH:4])=[O:3])=[CH:10][CH:9]=2)=[CH:12][CH:13]=1)([O:21][CH2:22][CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30]2[C:35]1=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:20]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: NCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NCc1ccc(-c2ccc(C(=O)O)cc2)cc1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.8 %

Procedure:
4-(4-Carboxyphenyl)benzylamine hydrochloride (10 g, 0.038 mol) was taken in a mixture of 10% Na2CO3 (100 mL) and dioxane (25 mL). To this a solution of Fmoc-OSu (15.4 g, 0.045 mol) in dioxane (50 mL) was added at 10° C. and the reaction was stirred at RT for 4 h. Solvent was removed under reduced pressure and the residue was acidified with an aqueous solution of HCl (1.5 N), extracted with EtOAc and the crude was recrystallised from EtOAc to give N-Fmoc-4-(4-carboxyphenyl)benzylamine (8.5 g, 45%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([N:13]1[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]1)[CH:3]=[C:2]2[N:30]1[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]1
Reactant: CN1CCNCC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CCN(C)CC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1-methylpiperazine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 7.90 (dd, J=7.83, 1.01 Hz, 1 H), 7.79 (d, J=7.07 Hz, 1 H), 7.60-7.45 (m, 3 H), 7.34 (td, J=7.64, 1.14 Hz, 1 H), 7.28 (dd, J=8.59, 1.77 Hz, 1 H), 6.54 (s, 1 H), 5.11 (s, 2 H), 3.61-3.50 (m, 2 H), 3.37 (s, 2 H), 3.17 (brs, 4 H), 2.80 (brs, 4 H), 2.46 (s, 3 H), 2.39 (s, 3 H).
Reaction SMILES: [F:1][C:2]([CH3:33])([CH3:32])[CH2:3][CH2:4][CH:5]1[C:9](=[O:10])[O:8][CH:7]([CH:11]([NH:19][C:20]([C:22]2[CH:31]=[N:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[O:21])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1.[NH2:34][NH2:35]>CO>[CH2:12]([CH:11]([NH:19][C:20]([C:22]1[CH:31]=[N:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1)=[O:21])[CH:7]([OH:8])[CH2:6][CH:5]([C:9]([NH:34][NH2:35])=[O:10])[CH2:4][CH2:3][C:2]([F:1])([CH3:33])[CH3:32])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NN
Reactant: CC(C)(F)CCC1CC(C(Cc2ccccc2)NC(=O)c2cnc3ccccc3n2)OC1=O
Solvent: CO
Product: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=O)NN
Reaction time: 18 h
Yield: 94 %

Procedure:
To a solution of quinoxaline-2-carboxylic acid {1-[4-(3-fluoro-3-methyl-butyl)-5-oxo-tetrahydro-furan-2-yl]-2-phenyl-ethyl}-amide (220 mg, 0.489 mmol) in methanol (5 mL) was added excess hydrazine (0.500 mL) and stirred for 18 hours. The reaction was concentrated to give the title compound (222 mg, 94%).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]#[N:7].C1(P([N:29]=[N+:30]=[N-:31])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:29]([CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]#[N:7])=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: N#Cc1cc(CO)cc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: N#Cc1cc(CN=[N+]=[N-])cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
A solution of 3-hydroxymethyl-5-trifluoromethyl-benzonitrile (200 mg, 0.994 mmol) in toluene (1 ml) at 0° C. was treated with diphenyl phosphoryl azide (328 mg, 1.19 mmol), followed by DBU (182 mg, 1.19 mmol) and stirred at 0° C. for 2 hours. The ice bath was removed and the reaction was stirred at room temperature for overnight. Reaction was diluted with ethyl acetate and washed with 10% HCl solution, dried over anhydrous magnesium sulphate and concentrated in vacuo. The residue was purified by silica gel chromatography over 12+S Biotage silica column (eluted with 0-30% ethyl acetate in hexanes) to yield the title compound (150 mg, 67%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.54 (s, 2H) 7.82 (s, 2H) 7.88 (s, 1H).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:18][O:19][CH:20]([O:39][CH3:40])[C:21]1[C:30]([CH2:31][N:32]2[CH2:36][CH2:35][C@H:34]([OH:37])[C:33]2=[O:38])=[CH:29][C:28]2[CH2:27][CH2:26][CH2:25][NH:24][C:23]=2[N:22]=1>CN(C1C=CN=CC=1)C.CN(C=O)C.C(Cl)Cl>[Si:1]([O:37][C@H:34]1[CH2:35][CH2:36][N:32]([CH2:31][C:30]2[C:21]([CH:20]([O:39][CH3:40])[O:19][CH3:18])=[N:22][C:23]3[NH:24][CH2:25][CH2:26][CH2:27][C:28]=3[CH:29]=2)[C:33]1=[O:38])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(OC)c1nc2c(cc1CN1CC[C@H](O)C1=O)CCCN2
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(OC)c1nc2c(cc1CN1CC[C@H](O[Si](C)(C)C(C)(C)C)C1=O)CCCN2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
tert-Butyldimethylsilyl chloride (3.77 g, 25.02 mmol), DIPEA (4.84 ml, 27.7 mmol) and DMAP (51 mg, 0.42 mmol) were added to a solution of (S)-1-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-3-hydroxypyrrolidin-2-one (intermediate 103A, 6.7 g, 20.85 mmol) in DMF (15 ml) and DCM (60 ml) at 0° C. The reaction mixture was stirred for 2 days at room temperature, partitioned between water and DCM, the organic layers washed with saturated aqueous NaHCO3, dried over Na2SO4 and evaporated to give the title compound as a brown glass. (UPLC-MS 6) tR 0.94; ESI-MS 436.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([CH3:15])[CH:8]=[C:7]2[C:16]1[N:24]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[CH:17]=1.[CH2:35]([O:37][C:38]([C:40]1(Br)[CH2:43][CH2:42][CH2:41]1)=[O:39])[CH3:36]>CN(C)C=O>[CH2:35]([O:37][C:38]([C:40]1([O:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][C:12]=2[O:13][CH3:14])[N:9]([CH3:15])[CH:8]=[C:7]3[C:16]2[N:24]([S:25]([C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=3)(=[O:27])=[O:26])[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[CH:17]=2)[CH2:43][CH2:42][CH2:41]1)=[O:39])[CH3:36]
Reactant: COc1cc2c(cc1O)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Reactant: CCOC(=O)C1(Br)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Oc2cc3c(-c4cc5cccnc5n4S(=O)(=O)c4ccc(C)cc4)cn(C)c3cc2OC)CCC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Sodium hydride (43 mg, 60% dispersion in mineral oil) was added to a stirred solution of 2-(5-hydroxy-6-methoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine [400 mg, Reference Example 28(a)] in dry dimethylformamide (20 mL) under a nitrogen atmosphere at ambient temperature. The mixture was allowed to stir for 1 hour then treated with ethyl-1-bromocyclobutanecarboxylate (216 μl) and stirring was continued overnight. Additional portions of sodium hydride (43 mg, 60% dispersion in mineral oil) and ethyl 1-bromocyclobutanecarboxylate (216 μl) were then added, then the mixture was heated at 50° C. for 5 hours. The cooled reaction mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water, then with brine, then dried over magnesium sulfate and then evaporated. The yellow residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (2:3, v/v) to give the title compound (266 mg) as a yellow oil. MS: 576(MH+). HPLC (METHOD A): RT=11.07 minutes.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[OH:28][C:29]1([CH2:33][C:34](O)=[O:35])[CH2:32][CH2:31][CH2:30]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34](=[O:35])[CH2:33][C:29]5([OH:28])[CH2:32][CH2:31][CH2:30]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)CC1(O)CCC1
Agent: Cl
Product: O=C(CC1(O)CCC1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (62 mg, 56%), MS (ISP) m/z=443.5 [(M+H)+], mp 155° C., was prepared in accordance with the general method of example 5 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 2-(1-hydroxy-cyclobutyl)-acetic acid.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([NH:25][C@@H:24]([C:26]([O:28]C)=O)[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH3:43]>>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C@@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([NH:25][C@@H:24]([C:26]([NH2:43])=[O:28])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:8]=1
Reactant: N
Reactant: COC(=O)[C@H]1CC[C@@]2(CCN(C(=O)N(C)[C@@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Product: Cc1cc(F)ccc1[C@H]1C[C@]2(CC[C@H](C(N)=O)N2)CCN1C(=O)N(C)[C@@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 72.5 %

Procedure:
In a sealed tube a solution of methyl (2R,5S,7R)-8-{[{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-1,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 28, 90 mg, 0.149 mmol) in 7M methanolic ammonia (5 ml, 35.0 mmol) was shaken overnight. The solvent was evaporated and the crude was purified by flash-chromatography (Si cartridge 5 g; from 1:0 to 95:5 DCM/MeOH) to give the title compound (63.3 mg, 0.108 mmol, 72.1% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.93 (s, 1H) 7.56 (s, 2H) 7.23-7.31 (m, 1H) 7.14-7.21 (m, 1H) 6.95-7.05 (m, 1H) 6.90 (d, 1H) 6.76 (t, 1H) 5.27-5.43 (m, 1H) 4.14 (d, 1H) 3.41-3.56 (m, 1H) 3.23-3.39 (m, 1H) 2.84 (s, 3H) 2.72 (t, 1H) 2.60-2.68 (m, 1H) 2.32 (s, 3H) 2.06-2.18 (m, 1H) 1.53-1.87 (m, 6H) 1.49 (d, 3H) 1.42 (t, 1H); HPLC: peak @ Rt=4.91 mins; MS: m/z=589 [M+H]+ and 611 [M+Na]+
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22]Cl)[CH:18]=2)[NH:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][C:26]1([CH3:33])[C:30]([CH3:32])([CH3:31])[CH2:29][NH:28][CH2:27]1.Cl>C(#N)C.C(Cl)Cl>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][N:28]3[CH2:29][C:30]([CH3:32])([CH3:31])[C:26]([CH3:33])([CH3:25])[CH2:27]3)[CH:18]=2)[NH:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CNCC1(C)C
Reactant: Cc1[nH]c2ccc(OCCCl)cc2c1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: ClCCl
Product: Cc1[nH]c2ccc(OCCN3CC(C)(C)C(C)(C)C3)cc2c1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 42 %

Procedure:
A mixture of 5-(2-chloro-ethoxy)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (Example 1, Step A, 0.300 g, 0.873 mmol), 3,3,4,4-tetramethyl-pyrrolidine; hydrochloride (0.571 g, 3.49 mmol), K2CO2 (0.724 g, 5.234 mmol), and KI (0.014 g, 0.087 mmol) in 17.5 mL of acetonitrile was heated at reflux for 24 hours. The reaction mixture was cooled to room temperature, diluted with CH2Cl2 (50 mL) and washed with water (2×20 mL). The organic layer was dried over MgSO4 and concentrated to give 0.379 g (42.0%) of a white solid: mp 181-182° C.;IR(KBr)3283, 2961, 1671, 1652, 1457, 1171, 1074 cm−1; 1HNMR (400 MHz, DMSO-d6) δ 0.85 (s, 12H, NCH2C(CH3)2), 2.46 (s, 3H, CCH3), 2.60 (s, 4H, NCH2C(CH3)2), 2.81-2.84 (m, 2H, OCH2CH2),3.83 (t, J=6.12 Hz, 2H, OCH2CH2), 5.27 (s, 2H, OCH2Ar), 6.67 (dd, J=8.31, 3.20 Hz, 1H, ArH), 7.20 (d, J=8.40 Hz, 1H, ArH), 7.23-7.40 (m, 4H, ArH), 7.46 (d, J=7.89 Hz, 2H, ArH), 11.70 (s, 1H, NH); MS(APCI+): m/z 435.3 (MH+). Anal. Calcd for C27H34N2O3: C, 74.62; H, 7.89; N, 6.45. Found: C, 74.31; H, 7.98; N, 6.19.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=O)[C:7](=[CH:18]N(C)C)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[NH2:25][C:26]([NH2:28])=[S:27].C[O-].[Na+]>CO.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:28]=[C:26]([SH:27])[N:25]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: CN(C)C=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2C1=O
Reactant: NC(N)=S
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Sc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2.8 g (7.8 mmole) of 8-chloro-1-(2-chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one, 2.8 g (37 mmole) of thiourea, and 8.0 ml (32 mmole) of a 4.0M methanol solution of sodium methoxide in 80 ml of methanol was stirred at room temperature for 18 hr. The mixture was diluted with water and extracted with ether. The aqueous layer was neutralized with acetic acid and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a yellow solid, mp 238°-239° C. Recrystallization from tetrahydrofuran gave yellow crystals, mp 232°-234° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.O1CCCCC1[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Br>CN(C)C=O>[OH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH3:3])=[C:5]1[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: BrCCCCCCCCOC1CCCCO1
Reactant: Cc1c(-n2ccnc2)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-n2ccnc2)n(CCCCCCCCO)c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3.0 g of 50% sodium hydride in mineral oil in 40 ml of dimethylformamide under nitrogen at 0°-5° is added dropwise over 20 minutes a solution of 10.0 g of 3-methyl-2-(1-imidazolyl)indole in 60 ml of dimethylformamide. The mixture is stirred for 0.5 hour at 0°-5° followed by the dropwise addition of 17.5 g of 1-tetrahydropyranyloxy-8-bromooctane in 50 ml of dimethylformamide. After stirring at 0°-10° for 1 hour and at room temperature for 0.5 hour, the reaction mixture is poured into ice-water and extracted with ether. The ether extract is washed with water, dried over MgSO4 and evaporated to dryness. The residue is dissolved in 100 ml of 3N hydrochloric acid, the resulting mixture is kept at room temperature for 0.5 hour, washed with ether, basified with aqueous 3N sodium hydroxide solution and extracted with methylene chloride. The methylene chloride solution is evaporated to dryness to give 1-(8-hydroxyoctyl)-2-(1-imidazolyl)-3-methylindole.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:34][CH3:35])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[C:31]([CH3:33])[CH:32]=3)[C:26]([O:28]C)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].O.[OH-].[Li+]>O1CCCC1>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:34][CH3:35])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[C:31]([CH3:33])[CH:32]=3)[C:26]([OH:28])=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-5-methylbenzoate (3.49 g, 7.28 mmol) was dissolved in tetrahydrofuran (THF) (90 ml) and water (30.0 ml) was added. Lithium hydroxide (0.458 g, 10.92 mmol) was added and the mixture stirred under argon at room temperature overnight. The THF was rotavaped off, and the aqueous residue was adjusted to ˜pH of 6 with 1N HCL. A white solid formed and was filtered and washed 2× with water (10 mL). This solid was dried at 50° C. in a vacuum oven for 6 h to give the title compound as a white solid. LC-MS m/z 466.0 (M+H)+, 0.73 min (ret time); mp 236-239° C.; analytical HPLC shows 97.3% purity, (ret time 10.841 min).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH3:32])[C:27]([OH:29])=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:48][CH:49]1[C:64](=[O:65])[N:51]2[C:52]([C:61]([OH:63])=[O:62])=[C:53]([CH2:56][S:57][C:58](=[O:60])[CH3:59])[CH2:54][S:55][C@H:50]12>C(N(CC)CC)C.C(Cl)Cl.O1CCCC1>[C:58]([S:57][CH2:56][C:53]1[CH2:54][S:55][C@@H:50]2[CH:49]([NH:48][C:27](=[O:29])[C:26]([C:24]3[N:25]=[C:21]([NH:20][C:1]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[S:22][CH:23]=3)=[N:30][O:31][CH3:32])[C:64](=[O:65])[N:51]2[C:52]=1[C:61]([OH:63])=[O:62])(=[O:60])[CH3:59]
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(=O)SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -20 °C

Procedure:
A mixture of 2.22 g of the anti isomer of 2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetic acid, 20 ml of dry tetrahydrofuran, 15 ml of methylene chloride and 0.55 ml of N-methyl-morpholine under argon was cooled to -20° C. and 0.65 ml of isobutyl chloroformate was added thereto. The mixture was stirred and was cooled to -35° C. and then a solution of 1.44 g of 7-amino-3-acetylthiomethyl-ceph-3-eme-4-carboxylic acid, 25 ml of methylene chloride and 1.4 ml of anhydrous triethylamine was added thereto. The mixture spontaneously heated up and the solvents were removed. The residue was taken up in methylene chloride and 7 ml of N hydrochloric acid and the mixture was vacuum filtered. The filtrate was decanted and the aqueous phase was extracted with methylene chloride. The organic phase was washed with water, dried and vacuum filtered. The filtrate was evaporated to dryness to obtain 4.58 g of raw anti isomer of 3-acetylthiomethyl-7-[{2 -(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetyl}amino]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C(C(C)=O)C.[OH-].[Na+]>O1CCCC1.C1(C)C=CC=CC=1.O>[OH:7][CH2:6][C:5]1[CH:4]=[N:3][C:2]([Br:1])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(Br)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCC(C)=O
Solvent: C1CCOC1
Product: OCc1ccc(Br)nc1
Reaction time: 0.83 h
Yield: 89.2 %

Procedure:
To a mechanically-stirred solution of 80 g of methyl 6-bromo-nicotinate in a mixture of 386 mL of tetrahydrofuran and 114 mL of toluene at 0° C. was added drop by drop a 1.5 molar toluene solution of diisobutyl aluminium hydride at a rate such that the temperature never exceeded 10° C. This addition took 50 minutes. 21.59 mL of methyl ethyl ketone was added to the reaction mixture while the temperature rose to 25° C. A solution of 2.58 g of NaOH in 40 mL of water was added to the reaction mixture drop by drop (CAUTION: EXOTHERMIC). 121 mL of water was added with vigorous stirring. After completion of the addition, a white solid appeared. The mixture was filtered through celite and 196 mL of toluene was used to wash the solid and filter. The filtrate was concentrated in vacuo and 48 mL of heptane was added. The mixture was cooled in an ice-salt bath for 1 hour. The precipitated solid was filtered and washed with heptane to give 62.09 g of 3-hydroxymethyl-6-bromopyridine as a solid.