Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([O-])([O-])=[O:2].[Tl+].[CH2:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][CH2:8]1>CO.C(Cl)(Cl)Cl>[CH3:18][O:17][CH:14]1[CH2:13][CH2:12][C:11]2=[CH:10][CH:9]=[CH:8][C:6](=[O:2])[CH2:7][CH:16]2[CH2:15]1
Reactant: C=C1CCCc2ccc(OC)cc21
Reactant: O=[N+]([O-])[O-]
Agent: [Tl+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC1CCC2=CC=CC(=O)CC2C1
Reaction time: 0.02 h
Yield: 70.7 %

Procedure:
To a solution of thallium nitrate (2.4 g) in methanol (24 ml) was added 1-methylene-7-methoxy-1,2,3,4-tetrahydronaphthalene (1.0 g) in methanol (7 ml) in one portion. The mixture was stirred for 1 minute and diluted with chloroform (24 ml). The resulting precipitate was filtered off and the filtrate was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution; 8:1, n-hexane-ethyl acetate) to give 3-methoxy-1,2,3,4-tetrahydro-5H-benzocyclohepten-6-one (0.78 g).
Reaction SMILES: C([NH:8][C@@H:9]1[C@@H:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH2:8][C@@H:9]1[C@@H:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NCc2ccccc2)[C@@H](O)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](N)[C@@H](O)C1
Yield: 98.9 %

Procedure:
A solution of the intermediate (5.4 g, 18.5 mmol) of step B, Pd(OH)2/C (0.3 g) in MeOH (200 mL) was stirred under hydrogen at 55 psi overnight. The catalyst was filtered off and the filtrate was concentrated to give 3.7 g of the desired product as a solid. MS calculated (M+H)+ 203, found 203.
Reaction SMILES: [CH:1]([C:4]1[S:5][C:6]2[CH2:12][CH2:11][CH:10]([C:13](OCC)=[O:14])[CH2:9][C:7]=2[N:8]=1)([CH3:3])[CH3:2]>CCOCC>[CH:1]([C:4]1[S:5][C:6]2[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][C:7]=2[N:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CCc2sc(C(C)C)nc2C1
Solvent: CCOCC
Product: CC(C)c1nc2c(s1)CCC(CO)C2
Yield: 83 %

Procedure:
The compound is prepared by reduction of the above derivative (III) with AlLiH4 in ether at room temperature. B.p.0.1 =122°-126° C. Yield: 83%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:17][NH:18][C:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[C:23]([N+:31]([O-:33])=[O:32])[CH:22]=3)=[O:20])[CH3:16])[C:10]=2[OH:34])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:17][NH:18][C:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[C:23]([N+:31]([O-:33])=[O:32])[CH:22]=3)=[O:20])[CH3:16])[C:10]=2[OH:34])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(Cl)c(Cl)c3)c2O)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: CC(=NNC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1)c1nn(C)c(-c2ccc(Cl)c(Cl)c2)c1O
Yield: 66.3 %

Procedure:
From methyl 4-[(2-{1-[5-(3,4-dichlorophenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]-2-nitrobenzoate (0.40 mmol, 200 mg) and 1 M sodium hydroxide aqueous solution (1.98 mL, 1.98 mmol), 130.5 mg of the desired product was obtained in the same manner as in Synthetic Example 58 as a yellow solid (yield 67%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:23][C:24]1[O:25][CH:26]=[CH:27][CH:28]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[N:14]([CH2:23][C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3cc(F)ccc23)CC1
Reactant: BrCc1ccco1
Product: CCOC(=O)N1CCC(c2cn(Cc3ccco3)c3cc(F)ccc23)CC1
Reaction time: 5 h
Yield: 100.5 %

Procedure:
This compound was obtained following procedure described in example 13 (part B) at room temperature for 5 hours, starting with 5 g (17.2 mmol) of 4-(6-fluoro-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were and 3.2 g (20 mmol) of 2-bromomethyl-furan. After standard work-up, 6.4 g (99% of yield) of 4-(6-fluoro-1-furan-2-ylmethyl-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1([C:17]([OH:19])=O)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Br-:52].[Br-].[NH3+:54][CH2:55][CH2:56][CH2:57][P+:58]([C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>CN(C)C=O.C(Cl)Cl>[Br-:52].[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1([C:17]([NH:54][CH2:55][CH2:56][CH2:57][P+:58]([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)([C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)[C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)=[O:19])[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)[CH3:9])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [NH3+]CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(CC1(C(=O)O)CCOCC1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(CC1(C(=O)NCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CCOCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-{[(tert-Butoxycarbonyl)(methyl)amino]methyl}tetrahydro-2H-pyran-4-carboxylic acid (549 mg, 2.01 mmol) was dissolved in N,N-dimethylformamide (5.5 mL). To this solution were added N,N-diisopropylethylamine (385 μL, 2.21 mmol), 1-hydroxybenzotriazole hydrate (323 mg, 2.11 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (578 mg, 3.01 mmol), and (3-ammoniopropyl)(triphenyl)phosphonium dibromide (1.16 g, 2.41 mmol). The reaction mixture was stirred overnight at room temperature, then diluted with methylene chloride and washed with 5% aqueous lithium chloride (3 times), 1N aqueous hydrogen chloride, and saturated sodium bicarbonate. The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude the title compound. The crude product was purified on a silica gel column eluting with 10% methanol with methylene chloride to isolate the title compound (729 mg, 55.4% yield).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:40])[C@:7]1([O:35][C:36](=[O:39])[CH2:37][CH3:38])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([O:26]C(=O)C(F)(F)F)[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:33])[CH:17]=[CH:18]2)[C@@H:13]([CH3:34])[CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].C(N(CC)CC)C>CO>[C:1]([O:4][CH2:5][C:6](=[O:40])[C@:7]1([O:35][C:36](=[O:39])[CH2:37][CH3:38])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([OH:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:33])[CH:17]=[CH:18]2)[C@@H:13]([CH3:34])[CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: CCC(=O)O[C@]1(C(=O)COC(C)=O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](OC(=O)C(F)(F)F)C[C@@]21C
Solvent: CCN(CC)CC
Solvent: CO
Product: CCC(=O)O[C@]1(C(=O)COC(C)=O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Yield: 79.1 %

Procedure:
3.5 g of 21-acetoxy-6α-methyl-17-propionyloxy-11β-trifluoroacetoxy-1,4-pregnadiene-3,20-dione is stirred in 80 ml of methanol and 4.2 ml of triethylamine for 4 hours at room temperature. The crude product is purified on 600 g of silica gel with a methylene chloride-acetone gradient (0-15% acetone), thus isolating 2.3 g of 21-acetoxy-11β-hydroxy-6α-methyl-17-propionyloxy-1,4-pregnadiene-3,20-dione.
Reaction SMILES: [OH:1][N:2]1[C:6](=O)[CH2:5][CH2:4][C:3]1=O.C(N(CC)CC)C.[Br:16][C:17]([CH3:22])([CH3:21])[C:18](Br)=[O:19]>C(Cl)Cl>[N:2]1([O:1][C:18](=[O:19])[C:17]([Br:16])([CH3:22])[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)(Br)C(=O)Br
Reactant: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(Br)C(=O)ON1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
A solution of N-hydroxysuccinimide (NHS) (3.0 g, 26 mmol) in dry methylene chloride (300 mL) was stirred under an inert (argon or nitrogen) atmosphere. Triethylamine (7.3 mL, 52 mmol) was added, the mixture was cooled to 0° C., and 2-bromo-2-methylpropionyl bromide (3.9 mL, 31 mmol) was added dropwise over a period of 15 minutes. The mixture was stirred for 1 hour at 0° C., then warmed to room temperature and stirred overnight. Most of the solvent was removed by evaporation, and the remaining mixture was diluted with cold water (400 mL), and extracted with diethyl ether (3×30 mL), then washed with aqueous potassium carbonate (3×30 mL) and 1M HCl(aq) (3×30 mL). The organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated to give a brown solid. Crystallization from ethyl acetate gave the desired product as a white powder (2.62 g, 39%). 1H NMR (CDCl3) δ (ppm) 2.09 (s, 6H, CH3)2Br), 2.88 (s, 4H, HNHS); 13C NMR (CDCl3) δ (ppm) 25.7 (CNHS), 30.8 (C(CH3)2Br), 51.3 (C(CH3)2Br), 167.6 (C═O), 168.7 (CNHS═O).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH2:19]([N:21]([CH2:35][CH3:36])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][CH:28]=1)=[O:26])[CH3:20]>C(O)C.N1CCCCC1>[CH2:35]([N:21]([CH2:19][CH3:20])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:13][C:12]2=[O:18])[NH:29][CH:28]=1)=[O:26])[CH3:36]
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Reactant: CCN(CC)CCNC(=O)c1c[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(OC)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.1 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The solvent was evaporated and the solid was washed by ether for three times to provide pure product 5-[4-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (67.5 mg, 57%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)[O:3]1.[CH2:20]([N:22]([CH2:37][CH3:38])[CH2:23][CH2:24][NH:25][C:26]([C:28]1[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=1[CH3:36])=[O:27])[CH3:21].N1CCCCC1>CCO>[CH2:37]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][NH:25][C:26]([C:28]1[C:32]([CH3:33])=[C:31](/[CH:34]=[C:12]2\[C:13](=[O:18])[NH:14][C:15]3[C:11]\2=[CH:10][C:9]([B:4]2[O:3][C:2]([CH3:19])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:17][CH:16]=3)[NH:30][C:29]=1[CH3:36])=[O:27])[CH3:38]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: CC1(C)OB(c2ccc3c(c2)CC(=O)N3)OC1(C)C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc32)c1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
To a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (195 mg, 0.75 mmol) in EtOH (3 ml) was added N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (200 mg, 0.76 mmol) and piperidine (82 μL, 0.83 mmol). The mixture was stirred at 80° C. for 1 hour. After cooled down to room temperature, the reaction mixture was concentrated, filtrated, and washed with EtOH to give (Z)—N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-3-ylidene)methyl)-1H-pyrrole-3-carboxamide (218 mg) as yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:13][CH:14]([NH2:16])[CH3:15]>>[CH:14]([NH:16][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12])([CH3:15])[CH3:13]
Reactant: CC(C)N
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Product: CC(C)NC(=O)c1ccc2[nH]ccc2c1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-10, using 1H-indole-5-carboxylic acid and propan-2-amine (0.420 g, 67%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].C([Li])CCC.CN([CH:18]=[O:19])C.Cl>C1COCC1.CCOCC>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH:18]=[O:19])=[C:3]([CH3:9])[CH:4]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(F)ccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(F)ccc1C=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 71.1 %

Procedure:
A −78° C. solution of 2-bromo-5-fluorotoluene (12.0 g, 63.5 mmol) in dry THF (60 mL) is treated with a 1.6 M hexanes solution of n-butyl lithium (59.5 mL, 95.3 mmol) and then stirred for 15 minutes at −78° C. under N2. The mixture is then treated with DMF (27.8 g, 0.381 mol) and warmed to rt. The reaction is acidified with 1 N HCl, diluted with Et2O and extracted with water. The organic layer is dried (Na2SO4), and the solvent removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using a gradient of 5/1 to 3/1 to hexanes/ethyl acetate to afford 6.24 g (71%) of the title compound. Rf=0.49 (2/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[O:9][CH2:10][CH2:11][CH2:12][NH2:13].CS[C:19]([N:23]([CH3:32])[N:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[N:20][C:21]#[N:22]>>[C:21]([N:20]=[C:19]([N:23]([CH3:32])[N:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:13][CH2:12][CH2:11][CH2:10][O:9][C:8]1[CH:14]=[CH:15][CH:16]=[C:6]([CH:2]2[O:3][CH2:4][CH2:5][O:1]2)[CH:7]=1)#[N:22]
Reactant: NCCCOc1cccc(C2OCCO2)c1
Reactant: CSC(=NC#N)N(C)N=Cc1ccccc1
Product: CN(N=Cc1ccccc1)C(=NC#N)NCCCOc1cccc(C2OCCO2)c1

Procedure:
3-[3-(1,3,-Dioxolan-2-yl)phenoxy]propanamine (8.92 g) and N-cyano-1-methyl-2-(phenylmethylene)hydrazinecarboximidothioic acid methyl ester (9.28 g) were heated under water-pump vacuum at 80° for 4 h to yield the title compound, a pale yellow glass (16.03 g). TLC silica; ethyl acetate:cyclohexane 1:1; Rf 0.2 NMR (CDCl3) 2.3-2.2 m (10H); 4.36 s (1H), 5.8-6.1 m (8H); 6.55 s (3H); 7.83 m (2H).
Reaction SMILES: [OH:1][O:2][S:3]([OH:6])(=[O:5])=[O:4].[S:7](=O)(=[O:10])([OH:9])[OH:8]>>[S:3](=[O:4])(=[O:2])([OH:6])[OH:5].[OH:4][S:3]([O:2][O:1][S:7]([OH:10])(=[O:9])=[O:8])(=[O:6])=[O:5]
Reactant: O=S(=O)(O)OO
Agent: O=S(=O)(O)O
Product: O=S(=O)(O)OOS(=O)(=O)O

Procedure:
Solutions containing Caro's acid and sulfuric acid can be used in the method of DE 10 80 083 which were obtained either by means of electrolysis of a sulfuric acid with a content of preferably 35% to 50% by weight, with subsequent hydrolysis of the peroxodisulfuric acid formed or by means of the reaction of 50% to 88% by weight aqueous hydrogen peroxide with concentrated or fuming sulfuric acid (oleum). In order to prepare sodium peroxymonosulfate, such H2SO5 /H2SO4 solutions are neutralized with a soda solution up to pH 2.9, freed of the precipitated Glauber salt and subsequently dried.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][CH:19]=[O:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.Br[C:22]1[CH:26]=[CH:25][S:24][CH:23]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][C:19]([C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)=[O:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CC=O)cc1
Reactant: Brc1ccsc1
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)c2ccsc2)cc1

Procedure:
Prepared from (6-methyl-2-p-tolyl-imidazo[1,2-a]pyridine-3-yl)-acetaldehyde 6b and 3-bromo-thiophene using the procedure of Method B described above. 1H NMR (400 MHz, CDCl3) 2.33 (s, 3H), 2.41 (s, 3H), 4.60 (s, 2H), 7.05 (dd, J=1.4 Hz, 9.1 Hz, 1H), 7.30 (m, 4H), 7.53 (d, J=1.4 Hz, 1H), 7.55 (d, J=8.0 Hz, 2H), 7.59 (s, 1H), 7.99 (d, J=1.1, 2.5 Hz, 1H). Mass spectrum (m/e) 347 (M+).
Reaction SMILES: [CH:1]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3][CH2:2]1.[Li+].[CH3:11]C([N-]C(C)C)C.IC>C1COCC1>[CH3:11][C:1]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of ethyl cyclobutanecarboxylate (20.0 g, 156.0 mmol) in THF (160 mL) was added dropwise to a cold (−78° C.) solution of LDA (164 mmol of 2M solution) in THF (40 mL). The solution was warmed to 0° C. and then cooled again to −40° C. before the addition of iodomethane (10.2 mL, 163.8 mmol). The solution was slowly warmed to room temperature and stirred overnight. The reaction was quenched with an aqueous saturated solution of ammonium chloride and ether was added. The layers were separated and the aqueous layer was washed with ether. The combined organic layers were washed with 1N HCl then dried over MgSO4. The product was purified by distillation: 1H NMR (400 MHz, MeOD) δ 4.20-4.05 (m, 2H), 2.57-2.33 (m, 2H), 2.08-1.94 (m, 1H), 1.94-1.77 (m, 3H), 1.40 (s, 3H), 1.27 (tt, J=7.1, 1.5 Hz, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:5][N:4]([C:6]([NH:8][S:9]([NH2:12])(=[O:11])=[O:10])=[O:7])[C:3]1=[O:13].C1(N=C=NC2CCCCC2)CCCCC1.OC1C2N=NNC=2C=CC=1.[C:39]1([CH2:45][C:46](O)=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[NH2:12][S:9]([NH:8][C:6]([N:4]1[CH2:5][C@H:2]([NH:1][C:46]([CH2:45][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:47])[C:3]1=[O:13])=[O:7])(=[O:10])=[O:11]
Reactant: N[C@H]1CN(C(=O)NS(N)(=O)=O)C1=O
Reactant: O=C(O)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Product: NS(=O)(=O)NC(=O)N1C[C@H](NC(=O)Cc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 6 h
Yield: 34.1 %

Procedure:
(S)-3-Amino-N-(aminosulfonyl)-2-oxo-1-azetidinecarboxamide (see example 22, or prepared by hydrogenating 140 mg of (S)-N-(aminosulfonyl)-3-[[(phenylmethoxy)carbonyl]amino]-2-oxo-1-azetidinecarboxamide in dimethylformamide used 50 mg of 5% palladium on charcoal catalyst) was acylated with 100 mg of dicyclohexylcarbodiimide, 20 mg of hydroxybenzotriazole and 55 mg of benzeneacetic acid. The mixture was stirred at 0° C. for 6 hours and dicyclohexylurea was filtered off. Dimethylformamide was distilled off, the residue was dissolved in 5 ml of acetone and the solution was, after standing for about 16 hours, filtered and then evaporated. The crude material was chromatographed on an HP-20 column eluting with water/acetone (6:4) to give 45 mg of the title compound, melting point 137° C.
Reaction SMILES: ON1[C:6]2[CH:7]=[CH:8][CH:9]=C[C:5]=2[N:4]=N1.C(N(CC)CC)C.[C:18]([O:22][C:23]([NH:25][C@H:26]([C:33]([OH:35])=O)[CH2:27][C:28]1[N:29]=[CH:30][S:31][CH:32]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1>[C:18]([O:22][C:23]([NH:25][C@H:26]([C:33]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:8]1[CH3:9])=[O:35])[CH2:27][C:28]1[N:29]=[CH:30][S:31][CH:32]=1)=[O:24])([CH3:19])([CH3:20])[CH3:21]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1CCCN1C(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 323.1 %

Procedure:
N,N-dicyclohexylcarbodiimide (10.83 g, 52.5 mmol), N-hydroxybenzotriazole (2.03 g, 15 mmol) and triethylamine (7.7 ml, 55.2 mmol) were added to a solution (130 ml) of N-(tert-butoxycarbonyl)-3-(thiazol-4-yl)-L-alanine (1) (13.62 g, 50 mmol) obtained by the method described in literatures (J. Am. Chem. Soc. 73, 2935 (1951) and Chem. Pharm. Bull. 38, 103 (1950)) and 2(R)-2-methylpyrrolidine p-toluenesulfonic acid (2) (12.79 g, 50 mmol) obtained by the method described in a literature (Helv. Chim. Acta, 34, 2202 (1951)) in tetrahydrofuran. The mixture was stirred for 20 hours at room temperature. After the precipitates are filtered off, the obtained filtrate was concentrated under reduced pressure. Thus-obtained residue was dissolved in ethyl acetate (200 ml) and the solution were washed with an aqueous solution of sodium hydrogencarbonate and water, successively. The organic layers were dried over magnesium sulfate and concentrated under reduced pressure to give a title compound (3) (16.45 g, 100%) as oil.
Reaction SMILES: O=S(Cl)Cl.[N+:5]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[C:13]2[C:18]([OH:20])=[O:19])([O-:7])=[O:6].[CH3:21]O>>[CH3:21][O:19][C:18]([C:13]1[C:12]2[C:17](=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=[CH:10][CH:11]=2)[N:16]=[CH:15][CH:14]=1)=[O:20]
Reactant: CO
Reactant: O=C(O)c1ccnc2c([N+](=O)[O-])cccc12
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccnc2c([N+](=O)[O-])cccc12
Temperature: 70 °C
Yield: 22 %

Procedure:
SOCl2 (10 ml, 137 mmol) was added slowly to 8-nitro-quinoline-4-carboxylic acid 473 (3.0 g, 13.8 mmol) in MeOH (40 ml) and the mixture was heated at 70° C. for 7 h. After cooling, the solvent was removed in vacuo and the residue was diluted with EtOAc. The organic phase was washed with sat. NaHCO3 solution and brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with n-hexane/EtOAc (95:5) as the eluent to give the title compound (0.70 g, 22%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]3[N:26]4[C:21]([C:22]([NH2:27])=[N:23][CH:24]=[N:25]4)=[C:20](Br)[CH:19]=3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]3[C:44]([CH:45]=2)=[N:43][NH:42][CH:41]=3)O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]3[N:26]4[C:21]([C:22]([NH2:27])=[N:23][CH:24]=[N:25]4)=[C:20]([C:37]4[CH:38]=[CH:39][C:40]5[C:44]([CH:45]=4)=[N:43][N:42]([CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:41]=5)[CH:19]=3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc3c[nH]nc3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(-c3cc(Br)c4c(N)ncnn34)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cc2C1

Procedure:
To a solution of 7-(4-amino-5-bromo-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.2 g, 2.7 mmol) in DMF (20 mL), 2-benzyl- was added 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazole (1.4 g, 4.3 mmol), Pd(dppf)Cl2 (311 mg, 0.27 mmol) and 2 N Na2CO3 solution (12 mL). The mixture was degassed with N2 for 20 min. The reaction was irradiated in a microwave reactor at 150° C. for 10 min. After cooling, the mixture was partitioned between EtOAc and H2O, The organic layer was separated and dried over Na2SO4. Biotage® chromatography (50-100% EtOAc/hexane) provided the title product as off white solid, 1.1 g (71%). 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 4.6 (m, 2 H), 3.6 (m, 2 H), 2.80 (m, 2 H), 1.4 (m, 9 H); ES-MS m/z 572.24 [M+H]+, HPLC RT (min) 3.44.