Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Si]([O:20][CH2:21][C@H:22]([OH:31])[CH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)(C(C)(C)C)(C)C.[C:32](O)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:32]([O:31][C@H:22]([CH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH2:21][OH:20])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](O)CCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(O[C@@H](CO)CCc1cccnc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.8 %

Procedure:
Solid 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.01 g) was added to a stirring solution of (2R)-1-(tert-butyldimethylsilyloxy)-4-(3-pyridyl)-2-butanol (1.97 g), benzoic acid (1.28 g) and 4-dimethylaminopyridine (0.85 g) in dichloromethane (50 ml) and the resulting solution stirred at room temperature for 20 hours. The solution was then concentrated under reduced pressure and the residue dissolved in acetonitrile (30 ml). Aqueous hydrofluoric acid (40%, 3 ml) was added and the mixture stirred for 30 minutes before being poured into saturated aqueous sodium bicarbonate solution (200 ml). The mixture was extracted with ethyl acetate, the combined extracts dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with ethyl acetate to give the sub-title compound as a solid (1.8 g).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].Br[C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][N:34]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:33]3[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][N:34]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:30])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(Br)nc1
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)(C)C)C[C@H](C)N3C(C)=O)nc1

Procedure:
In a separate vial, Tert-butyl ((2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (for a preparation see Intermediate 61) (2.2 g, 5.11 mmol), methyl 6-bromonicotinate (1.325 g, 6.13 mmol), Pd(PPh3)4 (0.591 g, 0.511 mmol) and potassium carbonate (2.120 g, 15.34 mmol) were combined in methanol (10 mL) and DME (3 mL) and heated under microwave irradiation to 100° C. for 70 mins. The two reaction mixtures were combined and partitioned between water (150 mL) and DCM (3×150 mL). The aqueous layer was acidified to pH 3 via the addition of aq. HCl and extracted with DCM (3×100 mL). The combined organic layers were dried by passing through a hydrophobic frit, and concentrated in vacuo to give crude methyl 6-((2S,4R)-1-acetyl-4-((tert-butoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinate (2.2 g) which was used directly in the next step without further purification. LCMS: (Formate, 2 min), Rt=1.06 min, MH+440.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:19][CH2:18]3)[C:7]=2[CH:27]=1.[C:28](Cl)(=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([N:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][O:26][C:28](=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:21][CH2:22]3)[C:7]=2[CH:27]=1
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CSc1ccc2c(c1)C(N1CCN(CCCO)CC1)Cc1ccccc1S2
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCCC(=O)OCCCN1CCN(C2Cc3ccccc3Sc3ccc(SC)cc32)CC1

Procedure:
In accordance with the general procedure described in the foregoing Examples, 14.0 grams of 8-methylthio-10-[4-(3-hydroxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin was reacted with 15.3 grams of lauroyl chloride (dodecanoyl chloride) in a mixture of benzene and chloroform. In this manner, 8-methylthio-10-[4-(3-dodecanoyloxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin was obtained. The pure base was a viscous oil which formed a crystalline di(hydrogen maleate) that had a melting point of 121°-122°C, after recrystallization from acetone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:10](=[O:29])[CH:11]([CH2:16][C:17]3[N:22]=[C:21](S(C)(=O)=O)[C:20]([C:27]#[N:28])=[CH:19][CH:18]=3)[CH2:12][C:13]=2[O:14][CH3:15])=[C:4]([CH3:30])[CH:3]=1.[CH3:31][NH2:32]>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:10](=[O:29])[CH:11]([CH2:16][C:17]3[N:22]=[C:21]([NH:32][CH3:31])[C:20]([C:27]#[N:28])=[CH:19][CH:18]=3)[CH2:12][C:13]=2[O:14][CH3:15])=[C:4]([CH3:30])[CH:3]=1
Reactant: COC1=C(c2c(C)cc(Br)cc2C)C(=O)C(Cc2ccc(C#N)c(S(C)(=O)=O)n2)C1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nc(CC2CC(OC)=C(c3c(C)cc(Br)cc3C)C2=O)ccc1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To 6-[[3-(4-bromo-2,6-dimethyl-phenyl)-4-methoxy-2-oxo-cyclopent-3-en-1-yl]methyl]-2-methylsulfonyl-pyridine-3-carbonitrile (2.043 mmol, 1 g) was added a solution of methylamine (5.1 ml of a 2M solution in tetrahydrofuran, 10.22 mmol). The reaction was stirred at room temperature for three hours and then concentrated under reduced pressure to give a brown gum. The crude product was purified by column chromatography on SiO2 using a hexane: EtOAc gradient to yield the desired compound (890 mg, 99%) as an orange solid. 1H NMR (400 MHz, CDCl3) (diagnostic peaks) δ ppm 7.55 (d, 1H), 7.18 (d, 2H), 6.45 (d, 1H), 3.55 (s, 3H), 3.05 (d, 3H), 2.15 (s, 3H), 2.00 (s, 3H).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[C:16]1[N:30]([CH3:31])[C:19]2=[N:20][CH:21]=[C:22]([S:24]([C:26]([F:29])([F:28])[F:27])=[O:25])[CH:23]=[C:18]2[N:17]=1)(=[O:5])=[O:4])[CH3:2].[OH:32]O.C(#N)C>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+].O>[CH2:1]([S:3]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[C:16]1[N:30]([CH3:31])[C:19]2=[N:20][CH:21]=[C:22]([S:24]([C:26]([F:29])([F:27])[F:28])(=[O:32])=[O:25])[CH:23]=[C:18]2[N:17]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cc(C(F)(F)F)ccc1-c1nc2cc(S(=O)C(F)(F)F)cnc2n1C
Reactant: OO
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCS(=O)(=O)c1cc(C(F)(F)F)ccc1-c1nc2cc(S(=O)(=O)C(F)(F)F)cnc2n1C
Temperature: 25 °C

Procedure:
A mixture of 2-(2-ethylsulfonyl-4-trifluoromethylphenyl)-3-methyl-6-trifluoromethylsulfinyl-3H-imidazo[4,5-b]pyridine (0.26 g), sodium tungstate dihydrate (36 mg), 30% of aqueous hydrogen peroxide solution (1 ml) and acetonitrile (5 ml) was stirred under reflux for 4.5 hours. The mixture was cooled to room temperature. Into the reaction mixture, water was poured, and extracted with ethyl acetate. The combined organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.24 g of 2-(2-ethylsulfonyl-4-trifluoromethylphenyl)-3-methyl-6-trifluoromethylsulfonyl-3H-imidazo[4,5-b]pyridine (hereinafter, Present Compound 302).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.[Br:10]Br>C(O)(=O)C>[Br:10][CH:5]1[C:6](=[O:8])[CH2:7][CH:2]([CH3:1])[CH2:3][C:4]1=[O:9]
Reactant: BrBr
Reactant: CC1CC(=O)CC(=O)C1
Solvent: CC(=O)O
Product: CC1CC(=O)C(Br)C(=O)C1
Reaction time: 0.5 h

Procedure:
To a solution of 5-methyl-1,3-cyclohexanedione (23) (45.4 g, 360 mmol) in acetic acid (540 mL) was added bromine (19.4 mL, 378 mmol) over 5 min. After 30 min of stirring (with mechanical stirrer), the reaction mixture was filtered. The solid was left under high vacuum overnight and used in the subsequent step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[C@H:10]([C:11]([C:16]3[CH:21]=[CH:20][C:19](Cl)=[CH:18][CH:17]=3)=[N:12][O:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24]C1C=CC(C(Cl)=NO)=CC=1>C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[C@H:10]([C:11]([C:16]3[CH:21]=[CH:20][C:19]([O:24][CH3:23])=[CH:18][CH:17]=3)=[N:12][O:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(Cl)=NO)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2ON=C(c3ccc(Cl)cc3)[C@@H]2C1
Solvent: CCN(CC)CC
Product: COc1ccc(C2=NO[C@H]3CN(C(=O)OC(C)(C)C)C[C@@H]23)cc1

Procedure:
The title compound was prepared in an analogous manner as the 4-chlorophenyl cycloadduct 3a using chloro oxime 2b. However, two additional portions of chloro oxime and triethyl amine were used. 3b was isolated as a white solid.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])[O:7][C:8]=1[C:9]1[CH:23]=[CH:22][C:12]([CH2:13][NH:14]C(=O)OC(C)(C)C)=[CH:11][CH:10]=1)(=[O:3])[NH2:2].Cl.O1CCOCC1.C([O-])=O>C(Cl)Cl>[NH2:14][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([C:8]2[O:7][C:6]([C:24]3[C:25]([F:31])=[CH:26][CH:27]=[CH:28][C:29]=3[F:30])=[N:5][C:4]=2[C:1]([NH2:2])=[O:3])=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2oc(-c3c(F)cccc3F)nc2C(N)=O)cc1
Agent: Cl
Agent: O=C[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCc1ccc(-c2oc(-c3c(F)cccc3F)nc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
To a solution of tert-butyl 4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-yl)benzylcarbamate (0.110 g, 0.26 mmol) in DCM (10 mL) was added 4M HCl in dioxane (1.5 mL, 6.0 mmol) and the resulting mixture stirred at room temperature overnight. The solvent was then removed in vacuo. The residue was purified by preparative HPLC to afford 5-(4-(aminomethyl)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide (0.0366 g, 0.11 mmol, 43%) as a white solid as the formate salt. 1H NMR (DMSO) 3.95 (2H, s), 7.40 (2H, t), 7.55 (2H, d), 7.74 (3H, m), 8.21 (2H, d), 8.33 (1H, s). LCMS (2) Rt: 2.30 min; m/z (ES+) 330.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.[CH3:11][O-:12].[Na+]>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[O:12][CH3:11])=[C:4]([F:10])[CH:3]=1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1ccc(Br)cc1F

Procedure:
Reaction of 4-bromo-2-fluorobenzonitrile 11 with sodium methoxide in methanol gives 35.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]2[N:29]=[N:30][NH:31][C:26]2=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[N:28]=[C:27]3[N:29]=[N:30][NH:31][C:26]3=[CH:25][CH:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: Clc1ccc2[nH]nnc2n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc4[nH]nnc4n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1, Step 5 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (70 mg, 0.22 mmol) and 5-chloro-1H-[1,2,3]triazolo[4,5-b]pyridine (35 mg, 0.22 mmol) as starting materials.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH:11]=O.[C:13](/[CH:15]=[C:16](\[O-:18])/[CH3:17])#[N:14].[Na+]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1/[CH:11]=[C:15](/[C:16](=[O:18])[CH3:17])\[C:13]#[N:14]
Reactant: C/C([O-])=C/C#N
Reactant: O=Cc1cc2cn[nH]c2cc1F
Agent: [Na+]
Product: CC(=O)/C(C#N)=C/c1cc2cn[nH]c2cc1F

Procedure:
The title compound was prepared from 3.7 g (80% purity, 18.0 mmol) 6-fluoro-1H-indazole-5-carbaldehyde (Example 5A) and 2.08 g (19.84 mmol) sodium (1Z)-1-cyanoprop-1-en-2-olate in analogy to the procedure described in Example 2A yielding 2.5 g (61% of th.) of product which was used in subsequent steps without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+].CS(O[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29][CH2:28]1)(=O)=O>O>[C:37]([O:36][C:34](=[O:35])[NH:33][CH:30]1[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[N:11]=3)[CH:6]=[CH:7][C:8]2=[O:12])[CH2:28][CH2:29]1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Reactant: O=c1ccc2ccc(Cl)nc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(Cl)nc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A solution of 7-chloro-1,8-naphthyridin-2(1H)-one [J. Org. Chem. 1990, 55, 4744-4750] in dry DMF (20 mL) (540 mg, 3.0 mmol) at 0° C. was treated with sodium hydride (144 mg, 60% in mineral oil, 3.6 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was cooled using an ice bath. A solution of 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1yl}ethyl methanesulfonate in DMF (Intermediate 6), 0.33 mmol/mL, 10 mL, 3.3 mmol) was then added over 1 hour. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with water and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with saturated sodium chloride solution (3×10 mL), dried over sodium sulfate and evaporated. Chromatography on silica gel using methanol in dichloromethane (0-15%) gave the title compound as a brown foam (711 mg, 58%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Cl:7][C:8]1[CH:9]=[C:10]([C@H:15]2[CH2:19][CH2:18][N:17]([C@H:20]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=4)[C:21]3=[O:35])[CH2:16]2)[CH:11]=[C:12]([Cl:14])[CH:13]=1>N1C=CC=CC=1.CS(C)=O>[Cl:14][C:12]1[CH:11]=[C:10]([C@H:15]2[CH2:19][CH2:18][N:17]([C@H:20]3[CH2:24][CH2:23][N:22]([C:25]4[CH:26]=[CH:27][C:28]([S:31]([NH:1][C:2]5[S:3][CH:4]=[CH:5][N:6]=5)(=[O:32])=[O:33])=[CH:29][CH:30]=4)[C:21]3=[O:35])[CH2:16]2)[CH:9]=[C:8]([Cl:7])[CH:13]=1
Reactant: Nc1nccs1
Reactant: O=C1[C@@H](N2CC[C@H](c3cc(Cl)cc(Cl)c3)C2)CCN1c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: O=C1[C@@H](N2CC[C@H](c3cc(Cl)cc(Cl)c3)C2)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Synthesized according to General Procedure 12, Method A: To a solution of 2-aminothiazole (15.9 mg, 0.16 mmol) in pyridine (0.4 mL) was added 4-[(3R,3′S)-3-(3,5-dichlorophenyl)-2′-oxo-1,3′-bipyrrolidin-1′-yl]benzene-1-sulfonyl chloride (25 mg, 0.05 mmol) and the reaction mixture was stirred at RT for 1 hour. The reaction mixture was diluted with DMSO, filtered and purified by reverse phase HPLC using 5%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to afford the desired product.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH2:25][CH2:26][C:27]#[N:28])[CH:20]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH4+].[Cl-].[N-:35]=[N+:36]=[N-:37].[Na+]>CN(C=O)C>[N:28]1[NH:35][N:36]=[N:37][C:27]=1[CH2:26][CH2:25][N:21]1[C:22]2[C:18](=[CH:17][C:16]([NH:15][C:13]([C:10]3([C:8]4[CH:7]=[CH:6][C:5]5[O:1][CH2:2][O:3][C:4]=5[CH:9]=4)[CH2:12][CH2:11]3)=[O:14])=[CH:24][CH:23]=2)[CH:19]=[C:20]1[C:29]([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1CCC#N
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2n1CCc1nn[nH]n1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(2-cyano-ethyl)indolin-5-yl)cyclopropanecarboxamide (50 mg, 0.12 mmol) in anhydrous DMF (2.6 mL) was added NH4Cl (230 mg, 4.3 mmol) and NaN3(280 mg, 4.3 mmol). The reaction mixture was stirred for 30 min at 110° C. in the microwave, filtrated, and purified by preparative HPLC. The solid residue was dissolved in CDCl3(3 mL) and briefly (2 to 4 min) exposed to daylight, which initiated a color change (purple). After 2 h of stirring open to the atmosphere at room temperature, the solvent was removed and the residue was purified by preparative HPLC to give N-(1-(2-(2H-tetrazol-5-yl)ethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. MS (ESI) m/e (M+H+) 473.0.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][C:10]=1[Cl:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:18][C:19]1[N:24]=[C:23]2[N:25]=[C:26]([CH2:28][CH3:29])[NH:27][C:22]2=[C:21]([CH3:30])[CH:20]=1>>[Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:25]2[C:23]3=[N:24][C:19]([CH3:18])=[CH:20][C:21]([CH3:30])=[C:22]3[N:27]=[C:26]2[CH2:28][CH3:29])=[CH:11][C:10]=1[Cl:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CBr)cc1Cl
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(O[Si](C)(C)C(C)(C)C)c(Cl)c1
Yield: 15.9 %

Procedure:
The product of Step C (1.79 g, 5.15 mmol) was used to alkylate 0.750 g (4.29 mmol) of 5,7-dimethyl-2-ethylimidazo[4,5-b]-pyridine (prepared as described in EP 400,974 published Dec. 5, 1990) according to the procedure described for Step B of Example 2, which after purification afforded 0.294 g (15%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[NH:4][N:3]=1.C(O)(=O)C.[Br:12][CH:13]([C:19](=O)[CH3:20])[C:14](OCC)=[O:15]>C(OCC)C>[Br:12][C:13]1[C:19]([CH3:20])=[N:7][C:5]2[N:4]([N:3]=[C:2]([CH3:1])[CH:6]=2)[C:14]=1[OH:15]
Reactant: CCOC(=O)C(Br)C(C)=O
Reactant: Cc1cc(N)[nH]n1
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1cc2nc(C)c(Br)c(O)n2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
A mixture of 3-methyl-1H-pyrazol-5-amine (0.186 g, 1.92 mmol) and acetic acid (3.71 mL, 65.2 mmol) was slightly heated until complete dissolution and the resultant solution was cooled to RT and mixed with ethyl 2-bromo-3-oxobutanoate (1.20 g, 5.74 mmol). The resultant reaction mixture was stirred at RT for 16 h, after which time the reaction mixture was diluted with diethyl ether, cooled to 0° C. and stirred at that temperature for 30 min. The white solid precipitate was separated by filtration and washed with cold diethyl ether and dried to give the desired product (363 mg, 78%) as a white solid. LCMS calculated for C8H9BrN3O (M+H)+: m/z=242.0, 244.0. found: 241.9, 244.0.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C(F)=NC(F)=NC=1[F:16].N1C=CC=CC=1>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([C:11]([F:16])=[O:13])[CH3:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)F
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
To an oven-dried, septaed 10 mL round-bottom flask, cooled under an argon atmosphere, and charged with (S)-N-BOC-alanine, 24c, (189.2 mg, 1.00 mmol) was added 2.5 mL freshly distilled CH2Cl2 under argon. The reaction was cooled to −15° C. and to the flask was added cyanuric fluoride (450 μL, 5 mmol). The reaction was stirred at −15° C. for 15 minutes then anhydrous pyridine (81 μL, 1.0 mmol) was added. Stirring was maintained at −15° C. for 90 minutes, with reaction progress indicated by the gradual formation of a precipitate. Without warming, the crude reaction was poured over ice, and immediately extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed once with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting colorless oil was dissolved in CH2Cl2, and precipitated with hexane to afford 163.5 mg of a mixture of 24c and 25c as white crystals. FTIR (film) 1842 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:26][CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: NCCc1ccccn1
Product: O=C(NCCc1ccccn1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-(2-aminoethyl)pyridine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (CF3CO2D) δ 8.84 (1H, d, J=6 Hz), 8.79 (1H, s), 8.71 (1H, t, J=8 Hz), 8.55 (1H s), 8.20 (1H, d, J=8 Hz), 8.11 (1H, t, J=7 Hz), 7.35 (2H, dd, J=8.6, 5.3 Hz), 7.20 (2H, t, J=8.6 Hz), 4.48 (2H, s), 4.26 (2H, t, J=7 Hz), 3.75 (2H, t, J=7 Hz); ES+ MS: 4419 (M+H+, 100).
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[C:31]1(CCN)[CH2:36][CH2:35]C[CH2:33][CH:32]=1>>[C:12]1([CH2:11][CH2:10][NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:35][CH2:36][CH2:31][CH2:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: NCCC1=CCCCC1
Product: O=C(NCCC1=CCCCC1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-(1-cyclohexenyl)ethylamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 367 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (1H, br. s.) 10.20 (1H, s) 7.94-8.06 (2H, m) 7.76 (1H, d, J=5.37 Hz) 7.44 (1H, d, J=5.37 Hz) 7.30 (1H, dd, J=3.37, 2.49 Hz) 6.77 (1H, d, J=5.37 Hz) 6.43 (1H, dd, J=3.47, 1.90 Hz) 5.37 (1H, br. s.) 3.25-3.37 (2H, m) 2.11 (2H, t, J=7.96 Hz) 1.91 (2H, t, J=5.81 Hz) 1.84 (2H, br. s.) 1.49-1.60 (2H, m) 1.36-1.47 (2H, m)
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[C:12]([Br:13])=[CH:11][S:10][C:9]=1[C:14]([O:16]C)=O)[CH3:5].O>C1COCC1>[CH3:3][N:4]([N:6]=[N:7][C:8]1[C:12]([Br:13])=[CH:11][S:10][C:9]=1[C:14]([NH2:2])=[O:16])[CH3:5]
Reactant: COC(=O)c1scc(Br)c1N=NN(C)C
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)N=Nc1c(Br)csc1C(N)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 53 %

Procedure:
To an ice cold (0-5° C.) solution of ammonium hydroxide (10 mL) was added a solution of methyl 3-[(dimethylamino)diazenyl]-4-bromothiophene-2-carboxylate (500 mg) in THF (5 mL) for 5 min and stirred at rt for 20 h. The solution was poured into ice cooled water and extracted with ethyl acetate (3×50 mL). The combined EtOAc layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (98:2) as eluents to give the product as an off-white solid (250 mg, 53%), mp 194-196° C. 1H NMR (400 MHz, DMSO-d6): δ 7.85 (1H, s), 7.75 (1H, br s), 7.56 (1H, br s), 3.56 (3H, br s), 3.21 (3H, br s); LC-MS (positive ion mode): m/z 277, 279 (M+H)+.