Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[CH3:9][O:10][CH2:11][CH2:12][NH2:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH3:9][O:10][CH2:11][CH2:12][NH:13][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCCCC1=O
Reactant: COCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COCCNC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-methyl-piperidone (1.00 g) in 1,2-dichloroethane (20 ml) was added 2-methoxyethylamine (0.77 ml), followed by sodium triacetoxyborohydride (2.62 g) and acetic acid (0.53 g). The reaction mixture was stirred at room temperature overnight. Dichloromethane/aqueous sodium hydrogen carbonate extraction and purification on silica gave (2-methoxy-ethyl)-(1-methyl-piperidin-4-yl)-amine (1.52 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Li]CCCC.[C:17]1(=[O:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18]1.Cl>C1COCC1>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[C:17]2([OH:26])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18]2)[CH:7]=[CH:8][CH:9]=1
Reactant: Brc1cccc2cccnc12
Reactant: O=C1CCc2ccccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2cccc3cccnc23)CCc2ccccc21
Temperature: -100 °C
Reaction time: 0.25 h

Procedure:
8-Bromoquinoline (10.4 g, 50 mmol) was introduced into 100 ml of THF, and the mixture was cooled to about −100° C. 20 ml of n-BuLi (2.5 M in hexane, 50 mmol) were added dropwise, during which the internal temperature was kept below −80° C. When the addition was complete, the mixture was stirred at −80° C. for a further 15 minutes, and 6.6 g of 1-indanone (50 mmol), dissolved in 30 ml of THF, were then added dropwise. The reaction mixture was then allowed to warm slowly to room temperature, and was then refluxed for 3 hours. After the mixture had cooled to room temperature, firstly ice and then hydrochloric acid were added to about pH 1, and the mixture was stirred for 30 minutes. The aqueous and organic phases were separated, the aqueous phase was treated with ammonia solution to about pH 9 and extractetd with ether, and the combined organic phases were subsequently evaporated to dryness under reduced pressure. The viscous oil obtained in this way (1-(8-quinolyl)-indan-1-ol (8H2O)) was treated with hydrochloric acid to pH 0, refluxed for 2 hours and subsequently neutralized. After work-up and drying, 6.6 g of 1-(8-quinolyl)indene (55%) were isolated as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:9]=2)[CH:5]=[C:4]([Cl:26])[N:3]=1.[C:27]([NH2:30])(=[O:29])[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:26][C:4]1[N:3]=[C:2]([NH:30][C:27](=[O:29])[CH3:28])[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([S:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)(=[O:19])=[O:18])[CH:9]=2)[CH:5]=1
Reactant: CC(N)=O
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cc(Cl)nc(Cl)c2)c2cccnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: CC(=O)Nc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cc(Cl)n1
Temperature: 85 °C
Yield: 25.2 %

Procedure:
A mixture of Example 7a (1.44 g, 3.57 mmol), acetamide (0.295 g, 4.99 mmol), cesium carbonate (1.743 g, 5.35 mmol), palladium (II) acetate (0.024 g, 0.107 mmol), and Xantphos (0.093 g, 0.161 mmol) was degassed and heated at 85° C. in a sealed vial for 6 hours. The reaction mixture was cooled and concentrated. The residue was treated with 20% brine and extracted with EtOAc (2×). The organic layers were dried, concentrated, and purified on a 40 g column using the ISCO Companion flash system eluting with CH2Cl2/EtOAc (90:10) to give 0.384 g of the title compound.
Reaction SMILES: N12CCCN=C1CCCCC2.[SH:12][C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1.Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH2:30])(=[O:29])=[O:28]>C(#N)C.O>[S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][S:12][C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:28])(=[O:29])[NH2:30]
Reactant: Sc1ncccn1
Reactant: NS(=O)(=O)c1ccccc1CCl
Solvent: CC#N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: NS(=O)(=O)c1ccccc1CSc1ncccn1
Reaction time: 70 h
Yield: 85.2 %

Procedure:
With cooling, 7.9 g of 97% 1,8-diazabicyclo[5.4.0]undec-7-ene are added to a suspension of 5.7 g of 98% 2-mercaptopyrimidine in 50 ml of acetonitrile. To the yellowish solution so obtained are added 10.3 g of 2-chloromethylbenzenesulfonamide. The reaction solution is stirred for 70 hours at 20°-22° C. and then diluted with 1 liter of water. The precipitate is isolated by filtration and dried, affording 12.0 g (85% of theory) of 2-(2-sulfamoylphenylmethylthio)pyrimidine of m.p. 128°-130° C.
Reaction SMILES: ClC1C=C(Cl)C2N(C(C(O)=O)=CN=2)N=1.[Br:15][C:16]1[C:17]2[N:18]([C:23]([C:26]([OH:28])=O)=[CH:24][N:25]=2)[N:19]=[C:20]([Cl:22])[CH:21]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[Cl:40][C:41]1[CH:46]=[C:45]([NH2:47])[CH:44]=[CH:43][N:42]=1.C(N(CC)C(C)C)(C)C.ClC1C=C(Cl)C2N(C(C(NC3C=CN=C(Cl)C=3)=O)=CN=2)N=1>ClCCCl>[Br:15][C:16]1[C:17]2[N:18]([C:23]([C:26]([NH:47][C:45]3[CH:44]=[CH:43][N:42]=[C:41]([Cl:40])[CH:46]=3)=[O:28])=[CH:24][N:25]=2)[N:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: O=C(O)c1cnc2c(Br)cc(Cl)nn12
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Nc1ccnc(Cl)c1)c1cnc2c(Cl)cc(Cl)nn12
Agent: O=C(O)c1cnc2c(Cl)cc(Cl)nn12
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccnc(Cl)c1)c1cnc2c(Br)cc(Cl)nn12
Temperature: 65 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
A ˜1:1 mixture 6,8-dichloroimidazo[1,2-b]pyridazine-3-carboxylic acid and 8-bromo-6-chloroimidazo[1,2-b]pyridazine-3-carboxylic acid (6.57 g, 28.3) was suspended in DCE (140 mL), and treated with neat oxalyl chloride (5.52 g, 42.5 mmol) followed by N,N-dimethylformamide (0.207 g, 2.83 mmol). The reaction mixture was heated at 65° C. for 5 hours, concentrated and dried under high vacuum for 1 hr and taken into the next step without further purification. The crude mixture of acid chloride was suspended in DCE (100 mL) and treated with 2-chloropyridin-4-amine (4.37 g, 34.0 mmol) and N,N-diisopropylethylamine (5.49 g, 42.5 mmol) and stirred at room temperature for 2 hours. The reaction mixture was filtered through a Buchner funnel, and washed with DCE (2×25 mL) to isolate a 1:1 mixture of 6,8-dichloro-N-(2-chloropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide and 8-bromo-6-chloro-N-(2-chloropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (7.7 g, 22.5 mmol, 79% yield) as a light brown solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=1.51 minutes. [M+H[=343.84, and [M+H[=387.8.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[C:8]3[N:22]=[CH:21][CH:20]=[CH:19][C:9]=3[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)=[C:6]2[CH:5]=[CH:4][N:3]=1.C(Cl)Cl.C([O-])([O-])=[O:27].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]2[C:8]3[N:22]=[CH:21][CH:20]=[CH:19][C:9]=3[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17]([CH3:18])=[O:27])[N:12]=3)=[C:6]2[CH:5]=[CH:4][N:3]=1
Reactant: CSc1nccc(-c2c3cccnc3n3c(N)nccc23)n1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nccc(-c2c3cccnc3n3c(N)nccc23)n1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a cooled (0° C.) solution of 21 (20 mg, 0.07 mmol) in CH2Cl2 (5 ml) mCPBA (32 mg, 0.13 mmol) was added. The mixture was stirred for 30 min. A saturated aq. Na2S203 solution was added (1 ml) and was basified with saturated aq. Na2CO3. The organic layer was separated and the aqueous layer extracted with CH2Cl2. The organic solutions were dried and evaporated together to give 9-amino-5-(2-methanesulfinylpyrimidin-4-yl)pyrido[3′,2′:4,5]-pyrrolo[1,2-c]pyrimidine (20 mg, 90%).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])C1C=CC=CC=1.N1C=CC=CC=1.[CH2:26]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)[CH3:27]>ClCCl.CN(C1C=CC=CN=1)C>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[NH:10][S:34]([C:31]1[CH:32]=[CH:33][C:28]([CH2:26][CH3:27])=[CH:29][CH:30]=1)(=[O:36])=[O:35]
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(Nc1ccc(F)cc1F)OCc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1ccc(S(=O)(=O)Nc2ccc(F)cc2F)cc1
Yield: 94.3 %

Procedure:
To 2,4-difluoro-phenylamine (30, 2.0 g, 15.5 mmol) in 20 mL of dichloromethane, pyridine (1.326 mL, 16.4 mmol) and dimethylaminopyridine (0.076 g, 0.62 mmol) are added followed by the dropwise addition of 4-ethyl-benzenesulfonyl chloride (59, 3.357 g, 16.4 mmol) and the reaction is heated to reflux overnight. The reaction is concentrated under vacuum to dryness, then brought up in ethyl acetate and water for extraction. The organic layer is isolated and concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with a gradient of 10-20% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (60, 4.344 g).
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5].[O:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Li])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[C:15]([O:14][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4](=[O:5])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:7]1)=[O:13])([CH3:16])([CH3:17])[CH3:18]
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: [Li]c1ccccc1Oc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2ccccc2Oc2ccccc2)C1
Temperature: 25 °C
Yield: 120.4 %

Procedure:
To a solution of (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (4.40 g, 16.2 mmol) in anhydrous THF (18 mL) at −10° C., was added dropwise the solution of 2-phenoxyphenyllithium prepared in Step 1 (80 mL, 32 mmol). The mixture was then warmed to rt, and stirred until no starting material remained (˜30 min). The reaction was quenched with 1 N HCl (˜30 mL) and extracted with Et2O (4×10 mL). The combined organic layers were washed with sat'd aq NaHCO3 and brine, and dried over Na2SO4. The solvent was removed to give (3R)-1-(tert-butoxycarbonyl)-3-(2-phenoxybenzoyl)piperidine (7.44 g, quantitative).
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:1][C@@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4]
Reactant: CC(C)C[C@H](O)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C[C@H](O)C(=O)OCc1ccccc1
Reaction time: 12 h

Procedure:
To a stirring solution of (2S)-2-hydroxy-4-methylvaleric acid (5.0 g) and benzyl bromide (4.95 ml) in DMF (50 ml) was added potassium carbonate (3.13 g) at room temperature. After being stirred for 12 hours, the solvent was removed by evaporation in vacuo. The residue was dissolved in ethyl acetate (100 ml) and washed with water, 1N HCl and brine successively. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residual oil was purified with silica gel column chromatography (hexane-ethyl acetate as an eluent) to give benzyl (2S)-2-hydroxy-4-methylvalerate (8.2 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([N+:13]([O-])=O)[C:5]=1[S:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1.[Ni]>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[C:6]([NH2:13])[C:5]=1[S:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1SCc1ccccc1
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)cc(N)c1SCc1ccccc1

Procedure:
The 2-benzylthio-3,5-dinitrobenzoic acid methyl ester obtained in the previous stage (see Example 1.14), which is still damp, is dissolved in 2 l of tetrahydrofuran and hydrogenated at from 30° to 35° C. with the addition of 3×40 g of Raney nickel. The catalyst is then removed by filtration, the filtrate is concentrated and the residue is taken up in ethyl acetate. After drying over magnesium sulfate and treating with activated carbon and fuller's earth, the filtrate is concentrated and the product is caused to crystallise by the addition of diethyl ether.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1.[CH3:20][CH:21]([CH3:25])[CH2:22][CH2:23][NH2:24]>>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:24][CH2:23][CH2:22][CH:21]([CH3:25])[CH3:20])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1
Reactant: CC(C)CCN
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)nc1
Product: CC(C)CCNCc1ccc(Oc2ccc(C(N)=O)cn2)c(F)c1
Yield: 99 %

Procedure:
Using the compound of Example 223, step 1, and using 3-methylbutylamine, the title compound was prepared by reductive amination as described previously.
Reaction SMILES: [C:1]1([CH2:13][C:14]([NH2:16])=[O:15])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.C[O:18][C:19](=O)[C:20]([C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]([CH2:31][CH2:32][CH2:33][OH:34])[CH:23]=1)=O>>[C:1]1([C:13]2[C:14](=[O:15])[NH:16][C:19](=[O:18])[C:20]=2[C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH2:31][CH2:32][CH2:33][OH:34])[CH:23]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: COC(=O)C(=O)c1cn(CCCO)c2ccccc12
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1cn(CCCO)c2ccccc12

Procedure:
Beginning with 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetamide and 1-(3-hydroxypropyl)indole-3-glyoxylic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=2[CH3:21])=[O:11])[CH2:3]1.[C:22]([C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1)#[N:23]>>[C:22]([C:24]1[CH:25]=[C:26]([S:30]([N:7]2[C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=3[CH3:21])=[O:11])[CH2:3][C@H:2]2[CH3:1])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1)#[N:23]
Reactant: COc1cccc(NC(=O)CN2C[C@@H](C)N[C@@H](C)C2)c1C
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Product: COc1cccc(NC(=O)CN2C[C@@H](C)N(S(=O)(=O)c3cccc(C#N)c3)[C@@H](C)C2)c1C

Procedure:
The title compound was prepared from the product of Example 65 step (i) (0.503 mmol) and 3-cyanobenzenesulphonyl chloride (0.503 mmol) by the method of Example 58 step (ii) as a white solid. Yield: 21 mg
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]1[C@@H:13]([CH2:14][OH:15])[NH:12][C:10](=[O:11])[CH2:9]1.C(=O)C1C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:1]1([C@@H:7]2[N:12]3[C:10](=[O:11])[CH2:9][CH2:8][C@H:13]3[CH2:14][O:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CC[C@@H](CO)N1
Reactant: Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O=Cc1ccccc1
Solvent: O
Product: O=C1CC[C@H]2CO[C@H](c3ccccc3)N12
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
Toluene (36 L, 6 vol), L-pyroglutaminol (6.0 Kg, 1.0 eq), benzaldehyde (8.3 Kg, 1.5 eq) and p-toluenesulfonic acid (134 g, 1.5% mol) were charged to a reactor. The resulting mixture was heated to reflux and the water formed during the reaction was separated out by using Dean-Stark condenser. The completion of the reaction was monitored by HPLC until L-pyroglutaminol was ≦0.1%. It was cooled to 15˜20° C., added aqueous 5% NaHCO3 (3 vol), agitated for 15 min and separated the layers. 20% aqueous NaHSO3 (6 vol) was charged to the organic phase, upon stirring for 30 min, filtered through Celite and washed the cake with toluene. Separated the organic phase (this step could be skipped if there was no solid), and filtered the organic phase through a thin pad of silica gel (1.0 wt/wt) and washed the silica gel with toluene three times. Combined the organic phase and monitored by HPLC. If impurity (RRT=1.5)>1.5%, repeated the silica gel filtration procedures until the impurity (RRT=1.5)≦1.5%. Dried the filtrate with anhydrous Na2SO4 for at least 2 hrs, filtered and washed the cake with toluene for twice. Concentrated below 55° C. (bath temp) under vacuum to afford 8.30 kg (78.6% yield) of the title compound with 94.6% HPLC purity. ESI MS m/z (M+H)+ 204.11.
Reaction SMILES: [CH3:1]I.[Cl:3][C:4]1[N:9]=[C:8]([OH:10])[C:7]([F:11])=[CH:6][CH:5]=1>C(=O)([O-])[O-].[Ag+2].C(Cl)(Cl)Cl>[Cl:3][C:4]1[N:9]=[C:8]([O:10][CH3:1])[C:7]([F:11])=[CH:6][CH:5]=1
Reactant: CI
Reactant: Oc1nc(Cl)ccc1F
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1nc(Cl)ccc1F
Temperature: 40 °C
Reaction time: 5 h

Procedure:
Methyl iodide (262 ul) and silver carbonate (1.12 g) were added to a chloroform (3 ml) solution of the compound 325-1 (300 mg), and the obtained mixture was stirred at 40° C. for 5 hours. The temperature of the reaction solution was cooled to room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=1:0 to 1:1), so as to obtain the title compound (86 mg).
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[C:5]([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH:4]=1)#[N:2].Cl.[NH2:24][OH:25].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[O:14][C:5]1[CH:4]=[C:3]([CH:13]=[CH:12][C:6]=1[NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:1](=[N:24][OH:25])[NH2:2]
Reactant: CS(=O)(=O)Nc1ccc(C#N)cc1Oc1ccc(F)cc1F
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)Nc1ccc(C(N)=NO)cc1Oc1ccc(F)cc1F
Yield: 60.5 %

Procedure:
A mixture of 4'-cyano-2'-(2,4-difluorophenoxy)methanesulfonanilide (1.5 g), hydroxylamine hydrochloride (0.8 g), and sodium carbonate (1.2 g) in ethanol (21 ml) and water (32 ml) was refluxed for 13 hours. The mixture was concentrated and the residue was dissolved in water, acidified with diluted hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by column chromatography on silica gel (40 g) eluting with a mixture of toluene and ethyl acetate (1:1) to give colorless crystals of 3-(2,4-difluorophenoxy)-4-(methanesulfonamido)benzamidoxime (1.0 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11](=O)[CH2:12]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26](C(C)(C)C)[N:25]=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]1[N:23]=[C:24]2[CH:29]=[CH:28][C:27]([C:2]([CH3:7])([CH3:3])[CH3:1])=[CH:26][N:25]2[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)CBr
Reactant: CC(C)(C)c1cccc(N)n1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)c1cn2cc(C(C)(C)C)ccc2n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 1 %

Procedure:
A mixture of tert-butyl {(1S)-1-[(benzyloxy)methyl]-3-bromo-2-oxopropyl}carbamate (3.72 g, 10.0 mmol) and 2-amino-6-tert-butylpyridine (1.5 g, 10.0 mmol) in toluene (50 mL) was stirred at room temperature for 14 hours and then refluxed for 5 hours. The reaction mixture was cooled and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with 30% EtOAc in petroleum ether. The residue was treated with cold conc. HCl (5 mL) at 0° C. followed by stirring at room temperature for 18 hours. The reaction mixture was basified with saturated aqueous Na2CO3 solution, extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo to afford a residue which was purified further by preparative TLC eluting with 20% MeOH in EtOAc to afford the title compound (21 mg, 25%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([CH2:11][O:12][CH2:13][C:14]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:8]2[C:4](=[CH:5][N:6]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[N:7]=2)[CH:3]=1.[C:41]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)#[N:42].O1CCCC1.[OH-].[K+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)C>[C:41]([C:43]1[CH:48]=[CH:47][C:46]([C:2]2[CH:10]=[C:9]([CH2:11][O:12][CH2:13][C:14]3([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH2:18][CH2:19]3)[C:8]3[C:4](=[CH:5][N:6]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:39])([CH3:40])[CH3:38])[N:7]=3)[CH:3]=2)=[CH:45][CH:44]=1)#[N:42]
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccccc2)CC1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(-c3ccc(C#N)cc3)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccccc2)CC1
Temperature: 110 °C

Procedure:
A microwave tube was charged with tert-butyl 4-(((5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (400 mg, 0.63 mmol), 4-cyanophenylboronic acid (280 mg, 1.90 mmol), and tetrakis(triphenylphosphine)-palladium(0) (36.6 mg, 0.032 mmol). The tube was flushed with nitrogen and treated with tetrahydrofuran (12 mL) and potassium hydroxide (1 M in water) (1.90 mL, 1.90 mmol). The tube was sealed and heated at 110° C. for 1 h via microwave. The reaction was cooled, poured into diethyl ether, washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (25%→32% EtOAc/Hex) gave 391 mg (94%) as an oil. 1H-NMR (CDCl3, 500 MHz) δ 8.16 (s, 1H), 7.76 (d, J=1.2 Hz, 1H), 7.71 (d, J=8.2 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.40 (m, 2H), 7.31 (m, 3H), 7.19 (m, 1H), 5.70 (s, 2H), 4.92 (s, 2H), 3.73 (br, 2H), 3.63 (t, J=8.2 Hz, 2H), 3.59 (s, 2H), 3.06 (m, 2H), 2.22 (m, 2H), 1.94 (m, 2H), 1.40 (s, 9H), 0.94 (t, J=8.2 Hz, 2H), −0.03 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 155.1, 146.8, 146.3, 143.2, 133.4, 132.6, 129.5, 128.5, 127.8, 127.4, 126.3, 123.8, 122.7, 122.6, 119.1, 118.1, 110.5, 82.0, 79.9, 79.4, 68.9, 67.7, 41.8, 40.3 (br), 32.2, 28.6, 17.9, −1.3.
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[N:9][N:8]([CH2:11][C:12]2[O:16][C:15]([CH2:17][OH:18])=[CH:14][CH:13]=2)[N:7]=1)([O-:5])=[O:4]>C(C#N)(C)=O.O=[Mn]=O>[N+:3]([C:6]1[CH:10]=[N:9][N:8]([CH2:11][C:12]2[O:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=2)[N:7]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1cnn(Cc2ccc(CO)o2)n1
Agent: O=[Mn]=O
Agent: CC(=O)C#N
Agent: N#N
Product: O=Cc1ccc(Cn2ncc([N+](=O)[O-])n2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(4-nitro-[1,2,3]triazol-2-ylmethyl)-furan-2-yl]-methanol (248 mg, 1.11 mmol) in AcCN (11.0 mL) was treated at rt with MnO2 (644 mg, 6.67 mmol). The reaction mixture was stirred at rt overnight before being filtered through Celite and the solvent was removed under reduced pressure. Purification of the residue by FC (40:60 hept-EA) gave the title compound: TLC:rf (40:60 hept-EA)=0.26. LC-MS-conditions 02: tR=0.84 min.