Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:14]1[NH:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.CO.C(=O)(O)[O-].[Na+]>CO.ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CCOC(=O)N1CCCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
Combine 1-ethoxycarbonyl[1,4]diazepane (18.0 g, 104 mmol) and 2-chlorobenzimidazole (7.93 g, 52 mmol). Heat to 130° C. After 4 hours, cool to ambient temperature and add hot methanol to dissolve the reaction mixture. Add a saturated aqueous solution of sodium bicarbonate (150 mL) and concentrate in vacuo to remove most of the methanol. Combine the aqueous reaction mixture and 95/5 diethyl ether/ethyl acetate. Separate the aqueous layer and extract three times with dichloromethane. Combine the dichloromethane layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Triturate the residue with ethyl acetate (100 mL) to give a solid. Chromatograph on silica gel eluting with 10% methanol/dichloromethane/0.1% concentrated aqueous ammonia to give a residue. Triturate that residue with 9/1 diethyl ether/ethyl acetate to give a solid. Collect solid by filtration and dry in vacuo to give 1-ethoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane: mp; 161-162° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[C@@H:10]([CH3:12])O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](=[N:29][NH2:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)C.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:17]1([C:16](=[N:29][N:30]2[C:13](=[O:15])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C@@H:10]2[CH3:12])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1N=C(c1ccccc1)c1ccccc1

Procedure:
Also in accordance with Scheme 1 and starting with the reaction of t-butyloxycarbonyl-L-threonine (1b) with benzophenone hydrazone (2) in the presence of 2-ethoxy-1(2H)-quinolinecarboxylic acid ethyl ester the hydrazide derivative N-(t-butyloxycarbonyl)-L-threonine-2-(2-diphenylmethylene)hydrazide (3b) was obtained. Ring closure of (3b) as described above with diethyl azodicarboxylate and triphenylphosphine gave the β-lactam, t-butyl (S)-[1-[(diphenylmethylene)amino]-2-(S)-methyl-4-oxo-3-azetidinyl)-carbamate (4b). Catalytic hydrogenation of (4b) gave the N-amino compound t-butyl 1-amino-2-(S)-methyl-4-oxo-3-(S)-azetidinylcarbamate (5b) which was reacted with benzyl glyoxylate (6) to give the imino derivative benzyl [[4(S)-methyl-3(S)-[(t-butoxycarbonyl)amino]-2-oxo]imino]acetate (7b). Catalytic reduction of (7b) gave the amino derivative 4(S)-methyl-[[3(S)-[[(t-butyloxycarbonyl]amino]-2-oxo-1-azetidinyl]imino]acetic acid (8b) which was treated with trifluoroacetic acid to give the amino acid, [[(S)-3-amino-4-oxo-2-(S)-methyl-1-azetidinyl]iminoacetic acid trifluoroacetate (9b). Then condensation of the trimethylsilyl derivative (10b) with the activated ester of 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetic acid (11) gave the desired monobactam derivative (S)-3-[2-(2-amino-4-thiazolyl)]-(Z)-2-methoxyiminoacetylamino-2-(S)-methyl-4-oxo-1-azetidinyliminoacetic acid (12b). ##STR3##
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[C:16]([CH:20]=O)[NH:17]2)=[CH:13][CH:12]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N:22]1([CH2:20][C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[C:11]([O:10][C:2]2[S:1][C:9]4[C:4]([N:3]=2)=[N:5][CH:6]=[CH:7][CH:8]=4)[CH:19]=3)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNCC1
Reactant: O=Cc1cc2ccc(Oc3nc4ncccc4s3)cc2[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1cnc2nc(Oc3ccc4cc(CN5CCCCC5)[nH]c4c3)sc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 12.7 %

Procedure:
To a suspension of 6-(thiazolo[4,5-b]pyridin-2-yloxy)-1H-indole-2-carbaldehyde (76 mg, 0.26 mmol) in DCM (3 mL) was added piperidine (0.05 mL, 43 mg, 0.51 mmol), Na(OAc)3BH (65 mg, 0.31 mmol) and the reaction mixture was stirred (rt, 12 h). The reaction mixture was partitioned between saturated NaHCO3 (10 ml) and DCM (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2×25 mL). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC to provide the title compound as a colorless solid (12 mg, 13%). MS (ESI): mass calcd. for C20H20N4OS, 364.1; m/z found, 365.1 [M+H]+. 1H NMR (500 MHz, CDCl3/CD3OD, 10/1): 8.51 (d, J=4.8, 1H), 7.97 (d, J=7.9, 1H), 7.54 (d, J=8.5, 1H), 7.40 (s, 1H), 7.18 (dd, J=7.9, 4.9, 1H), 7.02 (d, J=8.5, 1H), 6.36 (s, 1H), 3.63 (s, 2H), 2.53-2.47 (m, 2H), 2.47-2.36 (m, 2H), 1.76-1.44 (m, 6H).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[C:32]([CH3:31])[CH:33]=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Reactant: Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(-n2c(C(=O)N3CCS(=O)(=O)CC3)cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc32)c1
Yield: 94 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 3-methylphenylboronic acid, copper(II) acetate, pyridine and using chloroforme instead of dichloromethane as solvent, to give the desired product as a colorless foam (94%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:13][CH:12]2[N:14]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:8]([CH2:9][C:10](=[O:25])[CH2:11]2)[CH2:7]1)=[O:5])[CH3:2].[CH2:26](O)[CH2:27][OH:28]>C(Cl)Cl>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:14]2[CH:12]3[CH2:13][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH:8]2[CH2:9][C:10]2([CH2:11]3)[O:28][CH2:27][CH2:26][O:25]2)(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: CCOC(=O)C1CC2CC(=O)CC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: OCCO
Solvent: ClCCl
Product: CCOC(=O)C1CC2CC3(CC(C1)N2S(=O)(=O)c1ccc(Cl)cc1)OCCO3
Yield: 89.9 %

Procedure:
To a solution of 9-(4-chloro-benzenesulfonyl)-7-oxo-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid ethyl ester (6) (1.62 g, 4.19 mmol) in CH2Cl2 (14 mL) was added ethylene glycol (0.94 mL, 16.7 mmol) and TMSC1 (1.06 mL, 8.39 mmol). The resulting solution was heated to reflux for 48 h and was subsequently washed with saturated aqueous NaHCO3 (10 mL). The organic phase was dried (Na2SO4), filtered and concentrated under vacuum to yield 1.62 g (90%) of compound 50. MS (ESI) 430.1 (M+H).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:29])[CH:7]([CH2:13][C:14]1[C:15]([CH3:28])=[N:16][C:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:18][CH:19]=1)[C:8]([O:10]CC)=[O:9])[CH3:4].CCOC(C)=O>CCO.CCO.C(Cl)Cl>[CH2:3]([O:5][C:6](=[O:29])[CH:7]([CH2:13][C:14]1[C:15]([CH3:28])=[N:16][C:17]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])=[CH:18][CH:19]=1)[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1C)C(=O)O
Temperature: 25 °C
Reaction time: 40 h
Yield: 84.7 %

Procedure:
A solution of KOH (300 mg, 5.35 mmol) in EtOH (4 mL) was added to a solution of 2-(6-tert-butoxycarbonylamino-2-methyl-pyridin-3-ylmethyl)-malonic acid diethyl ester (1.85 g, 4.86 mmol) in EtOH/methylene chloride (2:1, 21 mL) at 0° C. The mixture was stirred for 40 h at room temperature and EtOAc was added. The mixture was washed with 0.5 M HCl and brine, dried and concentrated under reduced pressure to give crude 2-(6-tert-butoxycarbonylamino-2-methyl-pyridin-3-ylmethyl)-malonic acid monoethyl ester (1.45 g).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH:11]=[N:10][CH:9]=[N:8]2)=[CH:4][CH:3]=1.C([Li])CCC.[CH2:19]([CH:21]([CH2:24][CH3:25])[CH:22]=[O:23])[CH3:20]>C1COCC1>[CH2:19]([CH:21]([CH2:24][CH3:25])[CH:22]([C:11]1[N:7]([CH2:6][C:5]2[CH:12]=[CH:13][C:2]([F:1])=[CH:3][CH:4]=2)[N:8]=[CH:9][N:10]=1)[OH:23])[CH3:20]
Reactant: CCC(C=O)CC
Reactant: Fc1ccc(Cn2cncn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)C(O)c1ncnn1Cc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 47 %

Procedure:
To a stirred solution of 1-(4-fluorobenzyl)-1H-1,2,4-triazole (0.500 g, 2.82 mmol) in THF (30 mL) at −78° C. was added a solution of n-butyllithium (2.5M in hexanes, 1.1 mL, 2.9 mmol) dropwise. The mixture was stirred at −78° C. for 1.5 h, then 2-ethylbutyraldehyde (0.42 mL, 3.4 mmol) was added. The solution was slowly warmed to room temperature and stirred i 8 h. It was then quenched with saturated aqueous NH4Cl and extracted twice with EtOAc. The organic extracts were dried (MgSO4), filtered, concentrated in vacuo and purified by column chromatography (SiO2, EtOAc/hexane, 1:1) to yield an oil in 47% yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([CH:21]([OH:31])[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:51][C:52]1[CH:53]=[CH:54][C:55](O)=[N:56][CH:57]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1COCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([CH:21]([O:31][C:55]2[CH:54]=[CH:53][C:52]([Cl:51])=[CH:57][N:56]=2)[CH2:22][O:23][Si:24]([C:27]([CH3:28])([CH3:30])[CH3:29])([CH3:26])[CH3:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Reactant: Oc1ccc(Cl)cn1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCC(Oc1ccc(Cl)cn1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 45 °C
Yield: 71.3 %

Procedure:
(RS)-1-[(3SR,4RS)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(tert-butyl-dimethyl-silanyloxy)-ethanol (123 mg. 0.256 mmol) and PPh3 (PPh3 polymer bound, 3 mmol PPh3/g resin) (125 mg, 0.38 mmol) were suspended in THF (3 mL). To the mixture were added 5-chloro-pyridin-2-ol (50 mg, 0.384 mmol) and then DBAD (0.088 g, 0.384 mmol). The reaction mixture was stirred at 45° C. over night. The mixture was diluted with ethyl acetate and filtered on celite and concentrated under vacuo. The residue was purified by column chromatography (SiO2, EtOAc/H, 1:15) yielded 108 mg (72%) of the title compound as a colorless oil. ES-MS m/e: 593.3 (M+H+).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.Br.[N+:21]([C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][NH:27][CH2:28]2)([O-:23])=[O:22].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[N+:21]([C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][N:27]([C:11]1[CH:12]=[C:13]3[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=1[F:15])[CH2:28]2)([O-:23])=[O:22]
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: O=[N+]([O-])c1cccc2c1CNC2
Agent: Br
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2cc(N3Cc4cccc([N+](=O)[O-])c4C3)c(F)cc2c1=O
Yield: 33.4 %

Procedure:
159 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 176 mg of 4-nitroisoindoline hydrobromide, 164 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 82 mg of the target compound.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:13]([CH2:27][CH2:28][CH3:29])=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:30]Br.O>C(O)(=O)C>[Br:30][C:10]1[C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[C:13]([CH2:27][CH2:28][CH3:29])[N:14]2[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: BrBr
Reactant: CCCc1cc2cc(OCc3ccccc3)ccc2n1S(=O)(=O)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCCc1cc2c(Br)c(OCc3ccccc3)ccc2n1S(=O)(=O)c1ccccc1
Reaction time: 0.17 h

Procedure:
To a rt solution of 5-[(phenylmethyl)oxy]-1-(phenylsulfonyl)-2-propyl-1H-indole (1.16 g, 0.0024) in acetic acid (20 mL, glacial) was added Br2 (1.2 g, 0.008 mol in acetic acid) dropwise. The mixture was stirred for an additional 10 min and water (10 mL) was added. The mixture was extracted with EtOAc (100 mL). The organic layer was separated and dried (MgSO4) and concentrated. Purification via ISCO normal phase chromatography (SiO2, 5-15% ethyl acetate/hexanes) to provide 4-bromo-5-[(phenylmethyl)oxy]-1-(phenylsulfonyl)-2-propyl-1H-indole as the regioselective bromination product: MS (ES) m/z 485 (M+1).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])[N:8]=1)=O.[Cl:23][C:24]1[CH:25]=[C:26]([NH:30]N)[CH:27]=[CH:28][CH:29]=1>>[Cl:23][C:24]1[CH:25]=[C:26]([N:30]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=4)[C:17]#[N:18])[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:27]=[CH:28][CH:29]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C#N)c2)ccc1=O
Reactant: NNc1cccc(Cl)c1
Product: N#Cc1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc(Cl)c3)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-benzonitrile (A-19) and 3-chloro-phenylhydrazine according to the method described for example 1. MS: M=374.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C@:10]3([C@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH2:26]Cl)[C@@H:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1.[CH3:32]OC([Si](C)(C)C)C.[NH:40]1[CH2:45][CH2:44][CH:43]([NH:46][C:47](=[O:49])[CH3:48])[CH2:42][CH2:41]1.FC(F)(F)C(O)=O>>[CH3:25][CH2:24][N:12]([CH:11]([CH3:10])[CH3:28])[CH:13]([CH3:14])[CH3:32].[C:47]([NH:46][CH:43]1[CH2:44][CH2:45][N:40]([CH2:26][CH2:25][CH2:24][N:12]2[C:13](=[O:23])[CH2:14][CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[C:10]3([C:5]4[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:31])[CH:11]2[C:28]([CH3:30])=[CH2:29])[CH2:41][CH2:42]1)(=[O:49])[CH3:48]
Reactant: C=C(C)[C@H]1N(CCCCl)C(=O)C[C@@H](c2cccc(Cl)c2)[C@]12C(=O)Nc1cc(Cl)ccc12
Reactant: CC(=O)NC1CCNCC1
Reactant: COC(C)[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)C1N(CCCN2CCC(NC(C)=O)CC2)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Product: CCN(C(C)C)C(C)C
Yield: 80.5 %

Procedure:
In a manner similar to the method described in example 60b, (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-1′-(3-chloro-propyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane prepared in example 123a (0.12 g, 0.20 mmol) was reacted with N-piperidin-4-yl-acetamide (0.56 g, 4 mmol), trifluoroacetic acid (2 mL) and then N,N′-diisopropylethylamine (2 mL) to give racemic (2′R,3R,4′S)-1′-[3-(4-acetylamino-piperidin-1-yl)-propyl]-6-chloro-4′-(3-chlorophenyl)-2′-isopropenylspiro[3H-indole-3,3′ piperidine]-2,6′(1H)-dione as a brown solid (Yield: 47 mg, 40.8%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[C@@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:9][C:8]1=[O:17])[CH3:5])[CH3:2].C([Li])CCC.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.CCCCCC.C(=O)(O)[O-].[Na+]>[C:23]([N:9]1[C@H:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])[C:8]1=[O:17])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(C)O[C@@H]1C(=O)N[C@@H]1c1ccccc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(C)O[C@@H]1C(=O)N(C(=O)c2ccccc2)[C@@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 101.7 %

Procedure:
To a solution of 2.35 g (10 mmol) of cis-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one in 40 mL of THF at -78° C. was added 6.1 mL (10.07 mmol) of a 1.65 M solution of n-butyllithium in hexane. The mixture was stirred for 10 min at -78° C. and a solution of 1.42 g (10.1 mmol) of benzoyl chloride in 10 mL of THF was added. The mixture was stirred at -78° C. for 1 h and diluted with 70 mL of saturated aqueous sodium bicarbonate and extracted with three 50 mL portions of ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulfate and concentrated to give 3.45 g of an oil. Chromatography of the oil on silica gel eluted with ethyl acetate/hexane gave 3.22 g (95%) of cis-1-benzoyl-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one (2) as a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[CH:15]=2)[C:12](=[O:29])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:30])[N:5]=1)[CH3:3].Cl[C:32]1[C:33]2[CH:40]=[CH:39][NH:38][C:34]=2[N:35]=[CH:36][N:37]=1.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:35]1[C:34]2[NH:38][CH:39]=[CH:40][C:33]=2[C:32]([NH:1][C@H:2]([C:4]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:28])([F:27])[C:23]([F:24])([F:25])[F:26])[CH:15]=3)[C:12](=[O:29])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[F:30])[N:5]=2)[CH3:3])=[N:37][CH:36]=1
Reactant: C[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)C(F)(F)F)c1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: C[C@H](Nc1ncnc2[nH]ccc12)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 36 h
Yield: 10.9 %

Procedure:
Under nitrogen, to (S)-2-(1-aminoethyl)-5-fluoro-3-(3-(2,2,3,3,3-pentafluoropropoxy)phenyl)quinazolin-4(3H)-one (86 mg, 0.20 mmol, 1.0 equiv) in t-BuOH (0.2 mL) at 23° C. was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (34 mg, 0.22 mmol, 1.1 equiv) and diisopropylethylamine (70 μL, 0.40 mmol, 2.0 equiv). After stirring for 36 hr at 120° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 12 mg of the title compound (11% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Cl.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[N:8]1
Reactant: Fc1cccc(CCl)c1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2cccc(F)c2)c1
Temperature: 70 °C
Yield: 33 %

Procedure:
A mixture of 5-nitro-1H-indazole (8.15 gm, 50 mmole), m-fluoro-benzyl chloride (7.95 gm, 1.1 equiv), K2CO3 (7.59 gm, 1.1 equiv), and KI (8.47 gm, 1.02 equiv) in dry DMF (75 mL) was heated at 70° C. overnight. After cooling to RT, water (75 mL) was slowly added to give a precipitate that consisted of about a one to one mixture of isomers [HPLC Ret Time: 1.92 (1-substitued isomer vs. 2.03 (2-substituted isomer) YMC C18 S5 4.6×50 mm, 3 min gradient, 4 mL/min]. This was collected by filtration and washed with water. The solid was crystallized twice from acetone/water to afford the desired 1-(3-fluoro-benzyl)-5-nitro-1H-indazole (4.47 gm, 33%). A suspension of this material (3.00 gm, 11.1) and 10% Pd/C (3.00 gm) in EtOH (21 mL) was kept under an H2 atmosphere (balloon) for 24 hr. The catalyst was removed by filtration and the solvent was evaporated to leave the product as a solid (2.4 gm, 90%). 1H NMR (CDCl3): δ 3.61 (br s, 2H), 5.52 (s, 2H), 6.81-7.85 (m, 7H), 7.85 (s, 1H); MS: 242 (M+H)+; HPLC Ret Time: 1.03 min (YMC Xterra ODS S7, 3.0×50 mm column, 2 min gradient, 5 mL/min).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.C1(C)C=CC(S([CH2:28][N+:29]#[C-:30])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15]4[O:16][CH:30]=[N:29][CH:28]=4)=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(-c2cn3cc(I)ccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Ic1ccc2nc(-c3ccc(-c4cnco4)cc3)cn2c1
Yield: 45.9 %

Procedure:
4-(6-Iodoimidazo[1,2-a]pyridin-2-yl)benzaldehyde (647 mg) and p-toluenesulfonylmethyl isocyanide (454 mg) were dissolved in methanol (10 mL), and potassium carbonate (321 mg) was added to the solution at room temperature, followed by refluxing for 13 hours. The precipitated product was recovered through filtration and dried, to thereby yield the title compound (330 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].[C:12]([NH:16][C:17](=[O:31])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:19]=1)([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:28]2[CH2:27][CH2:26][N:25]([CH2:24][C:20]3[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=3)[C:17]([NH:16][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:31])[CH2:30][CH2:29]2)=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Reactant: Cc1cc(C(=O)O)ccc1N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N2CCN(Cc3cccc(C(=O)NC(C)(C)C)c3)CC2)ccc1N
Reaction time: 1 h
Yield: 44.4 %

Procedure:
To a stirred solution, of. 4-amino-3-methylbenzoic acid (3.31 mmol, 0.50 g), N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (3.45 mmol, 0.95 g) and triethylamine (14.35 mmol, 2.00 mL, 1.452 g) in dichloromethane (10 mL) was added 1-propanephosphonic acid cyclic anhydride (6.75 mmol, 4 mL, 4.30 g, 50% in ethyl acetate) dropwise. The mixture was allowed to stir for 1 hour. After this time ethyl acetate was added and the organic mixture was washed with saturated sodium hydrogen carbonate (×2), water (×2) and finally brine. The organic layer was dried with sodium sulfate and concentrated under vacuum to yield the title compound (0.60 g).