Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=[O:14]>N1C=CC=CC=1>[Cl:8][C:4]1[N:3]=[C:2]([NH:1][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([CH3:9])[CH:11]=2)[CH:7]=[N:6][CH:5]=1
Reactant: Nc1cncc(Cl)n1
Reactant: Cc1cccc(C(=O)Cl)c1
Solvent: c1ccncc1
Product: Cc1cccc(C(=O)Nc2cncc(Cl)n2)c1
Temperature: 100 °C
Yield: 96.9 %

Procedure:
2-Amino-6-chloropyrazine (496.0 mg, 3.83 mmol) was dissolved in pyridine (15 mL). 3-Methylbenzoyl chloride (760 μL, 5.77 mmol) was added to the reaction mixture. The reaction was heated to 100° C. for 16 h then concentrated under vacuum. The residue was partitioned between 1M K2CO3 (50 mL) and CH2Cl2 (4×50 mL). The organic extracts were combined, washed with and brine (50 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (5% EtOAc in CH2Cl2, Rf=0.39) to afford the title compound as a white solid (919.0 mg, 97%). MS m/z 248 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.[NH2:14][CH2:15][C:16]1([OH:22])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:14][CH2:15][C:16]2([OH:22])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1
Reactant: NCC1(O)CCOCC1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCC2(O)CCOCC2)c1C
Temperature: 25 °C
Yield: 17.9 %

Procedure:
Under a nitrogen atmosphere 2,4-dichloro-5,6-dimethyl-3-nitropyridine (25 g, 113 mmol) was added to a solution of 4-(aminomethyl)tetrahydro-2H-pyran-4-ol (17 g, 130 mmol) in DMF (375 mL). Triethylamine (18 mL, 130 mmol) was added slowly and the reaction mixture was stirred at ambient temperature over the weekend. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (700 mL) and saturated aqueous sodium bicarbonate (100 mL). The organic layer was washed with water (3×100 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide an orange solid. This material was triturated with ethyl acetate to provide 6.38 g of 4-{[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]methyl}tetrahydro-2H-pyran-4-ol as a yellow solid. An additional 4.36 g of product was recovered from the mother liquor.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][O:19][C:20]2[C:28]([CH:29]3[CH2:31][CH2:30]3)=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([F:32])[CH:21]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:33]1([S:37]([NH2:40])(=[O:39])=[O:38])[CH2:36][CH2:35][CH2:34]1>>[N:33]1([S:37]([NH:40][C:24](=[O:26])[C:23]2[CH:27]=[C:28]([CH:29]3[CH2:30][CH2:31]3)[C:20]([O:19][CH2:18][CH:16]3[CH2:15][N:14]([CH:1]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:17]3)=[CH:21][C:22]=2[F:32])(=[O:39])=[O:38])[CH2:36][CH2:35][CH2:34]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F

Procedure:
The compound was prepared in a similar manner to Example 408 from 4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid and azetidine-1-sulfonamide. LCMS (Method D): RT=4.74 min, m/z: 550.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 7.46-7.38 (m, 4H), 7.28 (dd, J=8.3, 6.8 Hz, 4H), 7.22-7.13 (m, 3H), 6.99-6.87 (m, 1H), 4.46 (s, 1H), 4.21 (d, J=6.1 Hz, 2H), 3.97 (s, 3H), 3.28-3.21 (m, 2H), 3.07-2.94 (m, 2H), 2.91-2.81 (m, 1H), 2.20-1.99 (m, 3H), 1.25 (d, J=6.9 Hz, 1H), 0.93-0.85 (m, 2H), 0.70-0.62 (m, 2H).
Reaction SMILES: [NH2:1][CH:2](/[CH:6]=[CH:7]/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[C:3]([OH:5])=[O:4].Cl>C(O)CCC>[CH2:3]([O:4][C:3](=[O:5])[CH:2]([NH2:1])/[CH:6]=[CH:7]/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[CH2:2][CH2:6][CH3:7]
Reactant: NC(/C=C/CP(=O)(O)O)C(=O)O
Agent: Cl
Solvent: CCCCO
Product: CCCCOC(=O)C(N)/C=C/CP(=O)(O)O

Procedure:
2.0 g of E-2-amino-5-phosphono-3-pentenoic acid are suspended in 40 ml of n-butanol and the suspension is saturated with hydrogen chloride gas for 3 hours at 40°. After concentration, the residue is dissolved in 30 ml of n-butanol, 15 ml of propylene oxide are added and the precipitate is filtered off. Recrystallisation from water/acetone 1:1 yields E-2-amino-5-phosphono-3-pentenoic acid butyl ester, m.p. 160°-161°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](N)[CH:7]=[CH:6][C:5]=1[Cl:11].[C:13]([Cu])#[N:14].[C-]#N.[K+]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([C:13]#[N:14])[CH:7]=[CH:6][C:5]=1[Cl:11]
Reactant: COC(=O)c1cc(N)ccc1Cl
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [K+]
Product: COC(=O)c1cc(C#N)ccc1Cl

Procedure:
5-Amino-2-chloro-benzoic acid methyl ester (10 g, 54 mmol) was diazotized followed by treatment with CuCN and KCN using the procedure described in example 165 to get the title compound.
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][C:2]2=O.Cl.[CH3:11][C:12]1[C:24]2[N:23]3[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]3)=[CH:17][C:16]=2[C:15]([NH:25][CH2:26][CH2:27][NH2:28])=[N:14][N:13]=1>CO.CO.CS(C)=O>[CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH:2]2[NH:28][CH2:27][CH2:26][NH:25][C:15]1[C:16]2[CH:17]=[C:18]3[N:23]([C:24]=2[C:12]([CH3:11])=[N:13][N:14]=1)[CH:22]=[CH:21][CH:20]=[CH:19]3
Reactant: O=C1CCC2CCC1C2
Reactant: Cc1nnc(NCCN)c2cc3ccccn3c12
Agent: Cl
Solvent: CO
Solvent: CS(C)=O
Product: Cc1nnc(NCCNC2CCC3CCC2C3)c2cc3ccccn3c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following the procedure of Example 12, bicyclo[3.2.1]octan-2-one in methanol (3 to 4 mL) was added to a solution of N-(4-methylpyridazino[4,5-b]indolizin-1-yl)-1,2-ethanediamine hydrochloride in methanol/DMSO (90 mL:30 mL) which had been heated to boiling and then allowed to cool. After stirring at room temperature overnight, the title compound was obtained as the free base after column chromatography (silica gel, 4:1 methylene chloride:methanol to 100% methanol containing ammonium hydroxide) and recrystallized from isopropyl ether. The compound was converted to the dihydrochloride salt by ethanolic HCl, mp 339°-344° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:17]3[N:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)[C:11](=[O:18])[S:10]2)=[CH:4][C:3]=1[NH2:19].Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:17]3[N:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)[C:11](=[O:18])[S:10]2)=[CH:4][C:3]=1[NH:19][CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:27]
Reactant: Nc1cc(N=c2sc(=O)n3n2CCCC3)ccc1Cl
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C(C)Nc1cc(N=c2sc(=O)n3n2CCCC3)ccc1Cl
Yield: 52 %

Procedure:
Into a reaction flask equipped with a Dimroth condenser, 2.2 g (7.4 mmol) of 9-(4-chloro-3-aminophenylimino)-8-thia-1,6-diazabicyclo[4.3.0]nonane-7-one, 15 ml of ethyl 2-bromopropionate and 2.0 g (24 mmol) of sodium hydrogen carbonate, were charged, and refluxed under heating for 4 hours to complete the reaction. The reaction solution was filtered, concentrated and extracted with ethyl acetate, and then washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a crude product, which was purified by column chromatography to obtain 1.5 g (yield: 52%) of colorless oily substance. Refractive index: nD20 1.5755
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:11]=[C:7]([C:8]([OH:10])=O)[C:6]([OH:12])=[CH:5][CH:4]=1.[F:14][C:15]([F:28])([F:27])[C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[NH2:19]>>[F:14][C:15]([F:27])([F:28])[C:16]1[CH:17]=[C:18]([NH:19][C:8](=[O:10])[C:7]2[CH:11]=[C:3]([N:2]([CH3:1])[CH3:13])[CH:4]=[CH:5][C:6]=2[OH:12])[CH:20]=[C:21]([C:23]([F:24])([F:26])[F:25])[CH:22]=1
Reactant: CN(C)c1ccc(O)c(C(=O)O)c1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CN(C)c1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 28.8 %

Procedure:
Using 5-dimethylaminosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@@H:13]3[CH2:15][C@H:14]3[CH2:16][CH2:17]O)=[CH:10][CH:11]=2)[N:6]([CH3:19])[C:5]1=[O:20].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@@H:13]3[CH2:15][C@H:14]3[CH2:16][CH2:17][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:10][CH:11]=2)[N:6]([CH3:19])[C:5]1=[O:20]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc([C@@H]3C[C@H]3CCO)nc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc([C@@H]3C[C@H]3CCS(C)(=O)=O)nc21
Temperature: -10 °C
Reaction time: 0.02 h

Procedure:
1-(2,2-Dimethylpropyl)-5-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (32-4, 46.4 mg, 0.15 mmol, 1.0 equiv) was added to anhydrous DCM (1.5 mL) and cooled to −10° C. Triethylamine (90 μL, 0.64 mmol, 4.2 equiv) and methanesulfonyl chloride (26 μL, 0.33 mmol, 2.2 equiv) were added sequentially and the resulting reaction mixture was stirred for 1 min. Following this duration, TLC showed complete consumption of 32-4. The reaction mixture was partitioned between ethyl acetate (5 mL) and saturated NaHCO3 (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give 32-5 as a clear, yellow oil. The crude product was carried forward without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Br:33]Br.C(OCC)(=O)C>CN(C=O)C>[Br:33][C:14]1[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=[C:12]([C:10](=[O:11])[CH2:9][C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH:13]=1
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Reactant: BrBr
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccccc1[C@H](CC(=O)c1cc(Br)c(=O)n(C)c1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 78 %

Procedure:
To a solution of (R)-5-(3-(4-bromophenyl)-3-o-tolylpropanoyl)-1-methylpyridin-2(1H)-one (0.1 g, example 223) in DMF (1 mL) were added pyridine (217 μL) and then bromine (12.6 μL) dropwise. The resulting solution was stirred at rt for 2.25 h. The reaction mixture was poured on water and ethyl acetate and the layers were separated. The aqueous layer was extracted with 2× ethyl acetate. The organic layers were washed with water and once with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by chromatography (SiO2, n-heptane/ethyl acetate 100:0 to 50:50) to give the title compound as a light brown solid (0.093 g; 78%), MS (ESI+): m/z=489.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([OH:13])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([C:11]([OH:13])=[O:12])=[C:2]1[CH3:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1[nH]c2ccccc2c1C(=O)O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)O)c2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 0.50 g (3.10 mmol) 2-methyl-1H-indole-3-carboxylic acid (described in J. Heterocyclic Chem. 1977, 14, 1123) in 5 ml DMF was added 0.27 g (6.75 mmol) of NaH (60% in oil). The mixture was stirred at RT for 30 min. and then 0.39 ml (3.28 mmol) of benzyl bromid was added. The mixture was stirred an additional hour and then poured onto water and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Crystallization in Et2O afforded 1-Benzyl-2-methyl-1H-indole-3-carboxylic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[S:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1)=O)(C)(C)C.[ClH:32]>C(Cl)Cl>[ClH:32].[C@H:12]12[CH2:14][C@H:9]([NH:8][CH2:13]1)[CH2:10][N:11]2[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][C:23]2[S:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc(Oc2nc3ccccc3s2)cc1
Agent: Cl
Solvent: ClCCl
Product: c1ccc2sc(Oc3ccc(CN4C[C@@H]5C[C@H]4CN5)cc3)nc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.2 %

Procedure:
To a stirred solution of (S,S)-5-[4-(benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (8.2 g, 18.7 mmol) in CH2Cl2 (200 mL) was added HCl (4.0 N in 1,4-dioxane, 46 mL, 187 mmol). The resulting white suspension was stirred at rt for 4 h and then concentrated affording the title compound as a white solid (5.4 g, 70%). MS (ESI): mass calcd. for C19H19N3OS, 337.12; m/z found, 338.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.84 (m, 3H), 7.64 (d, J=8.3 Hz, 1H), 7.55 (m, 2H), 7.44 (m, 1H), 7.34 (m, 1H), 4.67 (br m, 3H), 4.55 (br m, 1H), 4.05 (br m, 1H), 3.84 (br d, J=13.2 Hz, 1H), 3.60 (dd, J=13.7, 2.7 Hz, 3H), 2.79 (br m, 1H), 2.34 (br d, J=12.7 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[C:15]1([CH:21]=[CH:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([CH3:14])([OH:12])[CH2:13][N:28]2[CH2:27][CH2:26][CH:25]([O:24][CH2:23][CH:22]=[CH:21][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:30][CH2:29]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: C(=Cc1ccccc1)COC1CCNCC1
Product: C[C@](O)(CN1CCC(OCC=Cc2ccccc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 48.5 %

Procedure:
Using (R)-2-chloro-1-(2-methyloxiran-2-yl-methyl)-4-nitroimidazole prepared in Example 12 (0.198 g, 0.910 mmol) and 4-(3-phenyl-2-propenyloxy)piperidine (0.198 g, 0.910 mmol) gave (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(3-phenyl-2-propenyloxy)piperidin-1-yl]propan-2-ol (0.192 g, yield 49%) as a brown oil in the same manner as in Example 254.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:24]([O:26][CH3:27])=[O:25])=[CH:11][C:12](Br)=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]1(B(O)O)[CH2:30][CH2:29]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]([C:24]([O:26][CH3:27])=[O:25])=[CH:11][C:12]([CH:28]2[CH2:30][CH2:29]2)=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1cc(Br)c(-c2ccc(F)cc2F)cc1OCc1ccccc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc(C2CC2)c(-c2ccc(F)cc2F)cc1OCc1ccccc1
Yield: 65 %

Procedure:
A mixture of methyl 5-(benzyloxy)-2-bromo-2′,4′-difluorobiphenyl-4-carboxylate (34.3 g), cyclopropylboronic acid (17.0 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (4.87 g), a 2 M aqueous sodium carbonate solution (119 mL), tris(dibenzylideneacetone)dipalladium(0) (5.07 g), and toluene (150 mL) was stirred overnight at 100° C. The reaction mixture was poured to water at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and passed through a short silica gel (NH) column, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (20.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH:5]=O.[N+:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([O-:19])=[O:18].C(N)CCC>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4](/[CH:5]=[C:20](/[N+:17]([O-:19])=[O:18])\[CH2:21][CH2:22][CH2:23][CH3:24])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=Cc1ccc(OC2CCCCC2)c(Br)c1
Reactant: CCCCC[N+](=O)[O-]
Solvent: CCCCN
Solvent: Cc1ccccc1
Product: CCCC/C(=C\c1ccc(OC2CCCCC2)c(Br)c1)[N+](=O)[O-]
Yield: 70.4 %

Procedure:
3-bromo-4-cyclohexyloxy-benzaldehyde (13 mmol, 3.7 g), 1-nitro-pentane (19.6 mmol, 2.3 g) and n-butyl amine (2.6 mmol, 0.19 g) were dissolved in toluene (5 mL) and refluxed for 48 h. The reaction mixture was cooled, filtered and evaporated the solvent and purified by column chromatography using 2% ethyl acetate in hexane as an eluents to provide 2-bromo-1-cyclohexyloxy-4-((E)-2-nitro-hex-1-enyl)-benzene (3.5 g).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([NH:11][C:12]([C:14]2[N:15]=[C:16]([CH3:19])[S:17][CH:18]=2)=[O:13])[CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31]([OH:33])=[O:32])O1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O1CCOCC1.O.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]>[CH3:19][C:16]1[S:17][CH:18]=[C:14]([C:12]([NH:11][C:4]2[CH:3]=[C:2]([C:28]3[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=3)[C:31]([OH:33])=[O:32])[CH:10]=[C:9]3[C:5]=2[CH:6]=[N:7][NH:8]3)=[O:13])[N:15]=1
Reactant: CC1(C)OB(c2cccc(C(=O)O)c2)OC1(C)C
Reactant: Cc1nc(C(=O)Nc2cc(Br)cc3[nH]ncc23)cs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(C(=O)Nc2cc(-c3cccc(C(=O)O)c3)cc3[nH]ncc23)cs1
Temperature: 150 °C

Procedure:
N-(6-Bromo-1H-indazol-4-yl)-2-methyl-1,3-thiazole-4-carboxamide (80 mg, 0.237 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (71 mg, 0.285 mmol), Pd(dppf)Cl2 (19 mg, 0.024 mmol) and 2 M sodium carbonate (aq) (0.356 ml, 0.712 mmol) were combined in 1,4-dioxane (1 ml) and water (1 ml). The reaction was heated in a Biotage microwave at 150° C. for 15 mins. The pH was adjusted to ˜2 with 2 M HCl (aq) and the solid formed was separated. The solid was extracted with 80% DCM in MeOH (3×25 ml) and the combined organic solvent was evaporated. The residue was dissolved in MeOH:DMSO (1 ml, 1:1, v/v) and purified by MDAP (Method B). The solvent of product-containing fractions was dried under a stream of nitrogen.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]1.C(=O)([O-])[O-].[K+].[K+].[CH2:23]([NH2:26])[C:24]#[CH:25]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11]([NH:26][CH2:23][C:24]#[CH:25])=[O:12])[CH2:8]1
Reactant: C#CCN
Reactant: COc1cccc(OC2CN(C(=O)Cl)C2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCNC(=O)N1CC(Oc2cccc(OC)c2)C1
Reaction time: 0.5 h
Yield: 34.6 %

Procedure:
A mixture of 4.85 g (0.02 mole) of 3-(3-methoxyphenoxy)-1-azetidinecarbonyl chloride and 2.8 g (0.02 mole) of anhydrous potassium carbonate in 20 ml of tetrahydrofuran was stirred while 1.1 g (0.02 mole) of 2-propynylamine was added dropwise from a needle and syringe. After stirring for 30 min, a small piece of ice was added and stirring continued for 17 hr. The reaction mixture was diluted with 200 ml of water then extracted with 3×50 ml of methylene chloride. The combined extracts were dried by passing through Whatman phase separating paper then concentrated in vacuo to an oily residue (3.73 g). This residue was dissolved in 30 ml of methylene chloride and chromatographed in three portions (3 runs) on a spinning TLC plate (chromatotron) with an ethyl acetate-methylene chloride gradient from 10%-100% ethyl acetate. A white solid (1.8 g) was obtained on concentration of the product fractions. Recrystallization from isopropyl ether yielded 0.93 g (17.9%) of white crystalline product, m.p. 121°-123° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:26]=[CH:25][C:14]([CH2:15][N:16]2[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH2:18][C:17]2=[O:24])=[CH:13][CH:12]=1.OS([O-])(=O)=O.[Na+].O>C1COCC1>[Br:1][CH:18]1[C:19](=[O:23])[CH2:20][CH2:21][CH2:22][N:16]([CH2:15][C:14]2[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:26][CH:25]=2)[C:17]1=[O:24]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(CN2CCCC(=O)CC2=O)cc1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2CCCC(=O)C(Br)C2=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 151.7 %

Procedure:
N-Bromosuccinimide (2.88 g, 16.17 mmol) was added portionwise to a stirred solution of 1-(4-methoxy-benzyl)-azepane-2,4-dione (4.0 g, 16.17 mmol) and NaHSO4.H2O (0.67 g, 4.85 mmol) in THF anhydrous (80 mL) at 0° C. The reaction mixture was stirred at room temperature for 2.5 hours and the solvent evaporated in vacuo to yield 3-bromodihydro-1-[(4-methoxyphenyl)methyl]-1H-azepine-2,4(3H,5H)-dione (8 g, 91% yield, 60% pure) as a viscous orange oil which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]2[O:24][C:23]([NH:25][C:26]([C@@H:28]3[CH2:33][CH2:32][CH2:31][CH2:30][N:29]3C(OCC3C=CC=CC=3)=O)=[O:27])=[N:22][N:21]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.CCOC(C)=O>CO.[Pd]>[NH2:1][C:2]1[C:3]([C:20]2[O:24][C:23]([NH:25][C:26]([C@@H:28]3[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]3)=[O:27])=[N:22][N:21]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:18])[CH3:19])(=[O:15])=[O:16])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(NC(=O)[C@@H]4CCCCN4C(=O)OCc4ccccc4)o3)n2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(NC(=O)[C@@H]4CCCCN4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 47.8 %

Procedure:
Pd on C, wet, degussa (50 mg,) was added to a stirred solution of (S)-benzyl 2-(5-(3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)-1,3,4-oxadiazol-2-ylcarbamoyl)piperidine-1-carboxylate (251 mg, 0.25 mmol) in MeOH (5 mL)/ EtOAc (5 mL) and the reaction mixture was placed under an atmosphere of H2. The reaction was stirred at ambient temperature for 17 hours. Once the reaction had gone to completion, the Pd was removed by filtration and the solvent was removed in vacuo. The material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the product as a yellow solid (56.4 mg, 39%); 1H NMR (400.0 MHz, DMSO) d 1.19 (d, 6H), 1.38-1.49 (m, 2H), 1.51-1.61 (m, 1H), 1.80-1.83 (m, 1H), 1.89-1.92 (m, 1H), 2.09-2.11 (m, 1H), 3.01 (br s, 2H), 3.19-3.23 (m, 1H), 3.47-3.51 (m, 1H), 4.13 (d, 1H), 4.31 (br s, 1H), 7.81 (s, 2H), 7.91 (d, 2H), 8.52 (d, 2H), 9.06 (s, 1H) and 11.04 (br s, 1H) ppm; MS (ES+) 472.3