Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.P(O)(O)O>C1C=CC=CC=1.O>[CH2:8]([NH:15][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCCCC1
Agent: OP(O)O
Solvent: O
Solvent: c1ccccc1
Product: c1ccc(CNC2CCCCC2)cc1
Reaction time: 0.5 h

Procedure:
The imine from cyclohexanone and benzylamine was prepared in benzene in the normal way. To this imine (37.4 g; 0.2 mole) was added phosphorous acid (16.4 g; 0.2 mole) and the mixture stirred while heating. The reaction mixture became a homogeneous liquid at 70° and at 95°-100° a vigorous reaction took place. After keeping at 110°-130° for 30 minutes the mixture was cooled and diluted with water. Basification with NaOH and extraction with benzene gave after evaporation of the solvent N-benzylcyclohexylamine (80%). Distillation gave pure N-benzylcyclohexylamine bp 120°-125°/3 mm.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([NH2:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)[C:2]#[CH:3].Br[C:16]1[C:17]([NH:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=1.C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:22]([C:19]1[N:20]=[CH:21][C:16]2[CH:3]=[C:2]([CH2:1][C:4]3[CH:9]=[CH:8][C:7]([CH2:10][S:11]([NH2:14])(=[O:12])=[O:13])=[CH:6][CH:5]=3)[N:24]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:17]=2[N:18]=1)#[N:23]
Reactant: CC(C)(C)CNc1nc(C#N)ncc1Br
Reactant: C#CCc1ccc(CS(N)(=O)=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)Cn1c(Cc2ccc(CS(N)(=O)=O)cc2)cc2cnc(C#N)nc21
Temperature: 70 °C
Yield: 60.7 %

Procedure:
To a solution of N.-(4-prop-2-ynyl-phenyl)-methanesulfonamide (1.0 mmol) and 5-bromo-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile (0.5 mmol) in DMF (5 ml), triethylamine (1.5 mmol), dichlorobis-dichlorobis(triphenylphosphine)palladium (II) (0.05 mmol) and copper (I) iodide (0.1 mmol) is added. The reaction mixture is heated at 70° C. ca. for 2.5 h. The mixture is quenched with saturated ammonium chloride and extracted with two 50 ml portions of AcOEt. The combined extracts are washed with brine, dried over sodium sulfate and concentrated under vacuum to give crude product, which is purified by silica gel column chromatography. Yield: 60.7%. Rf=0.55 (n-hexane:AcOEt=1:1)
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][OH:16])([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:16][CH2:15][C:11]1([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: OCC1(O)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: OCC1(O)CCNCC1

Procedure:
A suspension of 26.0 g (117 mmol) 1-benzyl-4-hydroxymethyl-piperidin-4-ol and 5.0 g 10% Pd/C in 500 mL MeOH was hydrogenated at 50° C. and 3 bar hydrogen pressure until the theoretical hydrogen uptake had occurred (4 h). The catalyst was filtered off and washed with MeOH. After the solvent had been eliminated the residue was reacted further without purification.
Reaction SMILES: [CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:19]=[C:18]([O:20][CH:21]3[CH2:39][CH:38]4[N:23]([C:24](=[O:44])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][CH:33]5[C:35]([C:41](O)=[O:42])([NH:36][C:37]4=[O:40])[CH2:34]5)[CH2:22]3)[C:17]3[C:12](=[CH:13][C:14]([O:45][CH3:46])=[CH:15][CH:16]=3)[N:11]=2)[N:9]=1)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:59]1([S:62]([NH2:65])(=[O:64])=[O:63])[CH2:61][CH2:60]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:19]=[C:18]([O:20][CH:21]3[CH2:39][CH:38]4[N:23]([C:24](=[O:44])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][CH:33]5[C:35]([C:41]([NH:65][S:62]([CH:59]6[CH2:61][CH2:60]6)(=[O:64])=[O:63])=[O:42])([NH:36][C:37]4=[O:40])[CH2:34]5)[CH2:22]3)[C:17]3[C:12](=[CH:13][C:14]([O:45][CH3:46])=[CH:15][CH:16]=3)[N:11]=2)[N:9]=1)([CH3:3])[CH3:2]
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3csc(NC(C)C)n3)nc2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3csc(NC(C)C)n3)nc2c1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
A solution of 18-[2-[2-(isopropylamino)thiazol-4-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (12, 54 mg, 0.083 mmol) and carbonyldiimidazole (20 mg, 0.125 mmol, 1.5 eq) in dry THF (4 mL) was stirred at reflux under nitrogen for 2 h. Optionally, the azalactone derivative, if desired, can be isolated. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (15 mg, 0.125 mmol) and DBU (19 mg, 0.125 mmol) were added. This solution was heated at 50° C. for 16 h. Then, the reaction mixture was cooled down at room temperature and concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and HCl 1N, the organic layer was washed with brine, dried (MgSO4) and concentrated. Purification by flash chromatography (gradient of EtOAc (0 to 50%) in DCM) afforded 45 mg (72%) of the title product which was recrystallized from water to give 12 mg of the desired product as a slightly yellow powder. m/z=751 (M+H)+. 1H NMR (CDCl3): 0.8-1.9 (m, 21H), 2.17 (m, 1H), 2.28-2.56 (m, 4H), 2.65 (m, 1H), 2.86, (m, 1H), 3.55 (m, 1H), 3.87 (m, 4H), 4.10 (m, 1H), 4.57 (m, 1H), 4.94 (t, J=9.5 Hz, 1H), 5.43 (m, 2H), 5.64 (m, 1H), 6.92 (broad s, 1H), 6.98 (dd, J=9.0 Hz, 3.0 Hz, 1H), 7.28 (m, 2H), 7.37 (s, 1H), 7.80 (d, J=9.0 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:17][C:11]=2[N:10]=1)[C:3]([O:5]CC)=[O:4].Cl[CH2:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][C:2]([CH3:30])([CH2:8][C:9]1[N:13]([CH2:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=2)[C:12]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:17][C:11]=2[N:10]=1)[C:3]([OH:5])=[O:4]
Reactant: ClCc1ccc2ccccc2c1
Reactant: CCOC(=O)C(C)(C)Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc2ccccc2c1)C(=O)O
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a 100 mL round-bottomed flask were added a stirbar, ethyl 2,2-dimethyl-3-(5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)propanoate (300 mg, 0.75 mmol), 2-(chloromethyl)naphthalene (168 mg, 0.75 mmol), potassium carbonate (310 mg, 2.25 mmol), and DMF (20 mL). The mixture was heated to 70° C. After 18 h, the flask was cooled to RT and concentrated to dryness. The resulting residue was dissolved in MeOH (9 mL) and THF (9 mL). To the solution was added 5% aqueous NaOH (2 mL) and the mixture was stirred at 40° C. overnight. The mixture was cooled and acidified to ˜pH=4-5 with 6 N HCl, then extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated to dryness and purified by reverse phase HPLC to give the title compound. MS (ESI): mass calcd. for C33H29N3O3, 515.22; m/z found, 516.2 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.34 (d, J=8.5, 1H), 8.04 (d, J=8.4, 1H), 7.92 (d, J=8.2, 1H), 7.84-7.66 (m, 5H), 7.59 (t, J=7.5, 1H), 7.48-7.40 (m, 3H), 7.31-7.21 (m, 2H), 7.19 (dd, J=8.5, 1.7, 1H), 7.01 (dd, J=8.8, 2.4, 1H), 5.67 (s, 2H), 5.40 (s, 2H), 3.17 (s, 2H), 1.30 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CN=CC=1.[O:21]=[S:22](=[O:24])=[O:23]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[O:11][C:12]([S:22]([OH:24])(=[O:23])=[O:21])=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)=O
Reactant: CC(C)(C)OC(=O)NCc1ccco1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCc1ccc(S(=O)(=O)O)o1
Temperature: 0 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
A solution of 2-(tert-butoxycarbonylaminomethyl)-furan (9.8 g, 50 mmol) in 150 mL of dichloromethane was added into a flask, and the reaction mixture was cooled to 0° C. in an ice bath. A solution of pyridine-sulfur trioxide adduct (15.9 g, 100 mmol) in 100 mL of dichloromethane were added dropwise. Upon completion of the addition, the reaction mixture was allowed to warm to room temperature. The mixture was stirred at room temperature for additional 8 h. After the completion of the reaction, the reaction mixture was then extracted with water (400 mL×2). Aqueous hydrochloric acid (10%) was slowly added dropwise to the aqueous layer. The aqueous layer was adjusted to pH 6.5-7, and extracted with dichloromethane (500 mL×2). The organic layer was washed by saturated brine, and concentrated under reduced pressure to give 5.5 g (40.0% yield) of 5-(tert-butoxycarbonylaminomethyl)furan-2-sulfonic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]2[O:19][C:18](=[O:20])[C:17]3[CH:21]=[C:22]([Cl:26])[CH:23]=[C:24]([CH3:25])[C:16]=3[N:15]=2)[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1.[CH3:27][NH:28][NH2:29].O1CCCC1>O>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:15][C:16]2[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:17]=2[C:18]([N:28]([CH3:27])[NH2:29])=[O:20])=[O:19])[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)cn3-c3ncccc3Cl)nc12
Reactant: CNN
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=O)N(C)N)c1NC(=O)c1cc(Br)cn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.9 %

Procedure:
A mixture of 0.86 g of 2-[4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrol-2-yl]-6-chloro-8-methyl-4H-3,1-benzoxazine-4-one, 0.11 g of methylhydrazine and 15 ml of tetrahydrofuran was stirred at room temperature for 2 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 0.17 g of 4-bromo-N-[4-chloro-2-(N-methylhydrazinocarbonyl)-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxamide of the formula:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][OH:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Br:23]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][OH:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:23])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1nc(OCCCO)nc2c1ncn2Cc1ccccc1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Nc1nc(OCCCO)nc2c1nc(Br)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
6-Amino-9-benzyl-2-(3-hydroxypropoxy)purine (210 mg, 0.7 mmol) and bromine (0.5 ml) were dissolved in methylene chloride (200 ml). The solution was stirred at room temperature for 4 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on magnesium sulfate and concentrated in vacuo to dryness. The residue was purified with silica gel chromatography (5% methanol/chloroform) to give the subject compound (143 mg, yield 54%).
Reaction SMILES: C(OO)(=[O:3])C.[C:6]1([CH:12]=[CH:13][C:14]2[S:15][C:16]3[C:25]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[N:19]=[CH:18][C:17]=3[N:26]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O)C>C(OC)(=O)C>[C:6]1([CH:12]=[CH:13][C:14]2[S:15][C:16]3[C:25]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[N+:19]([O-:3])=[CH:18][C:17]=3[N:26]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)OO
Reactant: C(=Cc1nc2cnc3ccccc3c2s1)c1ccccc1
Solvent: CCO
Solvent: COC(C)=O
Product: [O-][n+]1cc2nc(C=Cc3ccccc3)sc2c2ccccc21
Temperature: 25 °C

Procedure:
Peracetic acid (1.32 mL of 32% in acetic acid) was added to a suspension of 2-(2-phenyl-1-ethenyl)thiazolo[4,5-c]quinoline (1.20 g) in methyl acetate (50 mL). A precipitate formed. Ethanol was added to the reaction mixture until all of the precipitate was dissolved. The reaction mixture was heated at reflux overnight and then cooled to ambient temperature. The resulting precipitate was isolated by filtration, dried and then recrystallized from methanol/dichloromethane to provide 2-(2-phenyl-1-ethenyl)thiazolo[4,5-c]quinoline-5-oxide as a yellow solid, m.p. 268-270° C. Analysis: Calculated for: C18H12N2OS: % C, 71.03; % H, 3.97; % N, 9.20; Found: % C, 69.94; % H, 3.87; % N, 9.05.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.F[C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[N+:32]([O-:34])=[O:33]>C(#N)C>[F:31][C:29]1[CH:28]=[CH:27][C:26]([N+:32]([O-:34])=[O:33])=[C:25]([NH:2][C@@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]2)[CH:30]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](N)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(F)ccc2[N+](=O)[O-])CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of cis-4-amino-N-isopropylcyclohexanecarboxamide hydrochloride (0.1 g, 0.453 mmol) and DIPEA (0.237 mL, 1.359 mmol) in ACN (3 mL) was added 2,4-difluoro-1-nitrobenzene (0.072 g, 0.453 mmol). The reaction was stirred overnight at 80° C. The reaction mixture was concentrated, adsorbed onto a plug of silica gel, and purified by column chromatography, eluting with 0-100% EtOAc in DCM, to provide cis-4-(5-fluoro-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamide as a yellow powder (0.123 g, 84% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:13])[CH:8]=2)[N:3]=1.P(Br)(Br)([Br:16])=O.[OH-].[Na+]>P(Br)(Br)Br>[NH2:1][C:2]1[CH:11]=[C:10]([Br:16])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:13])[CH:8]=2)[N:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: Nc1cc(O)c2cc(F)ccc2n1
Agent: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(Br)c2cc(F)ccc2n1
Yield: 56.5 %

Procedure:
1 (7.2 g) was heated with POBr3 (22.0 g) in PBr3 (20 ml) at 140-160° C. under N2 for 19 hours. The reaction was cooled, carefully basified with 2 M NaOH (250 mL) and thrice extracted with CHCl3 (30 mL). The organic layer was concentrated, and the residue purified by silica gel chromatography using CHCl3/acetone/Et3N (75:25:1) to afford the product that was re-crystallized from benzene/CH2Cl2/hexane to furnish off-white crystals (5.5 g, 57% yield): 1H NMR (CDCl3) δ 4.70 (bs, 2 H, NH2), 7.10 (s, 1 H), 7.37 (m, 1 H), 7.66 (m, 2 H); HRMS-FAB (M+) calculated for 239.9698, found 239.9707.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](Cl)=[O:18])=[CH:13][C:12]=1[C:20](Cl)=[O:21]>>[CH2:1]([NH:8][C:17](=[O:18])[C:14]1[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[C:12]([C:20]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:21])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Cl)cc1C(=O)Cl
Reactant: NCc1ccccc1
Product: COc1ccc(C(=O)NCc2ccccc2)cc1C(=O)NCc1ccccc1

Procedure:
By following the general method of Example 1, benzyl amine was reacted with 4-methoxy-1,3-benzenedicarbonyl dichloride to give the titled compound. MS: M+1=375.2.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:12][S:13]([NH:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)(=[O:15])=[O:14]>>[NH2:11][C:9]1[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:21]3[CH:22]=[C:17]([NH:16][S:13]([CH3:12])(=[O:14])=[O:15])[CH:18]=[CH:19][CH:20]=3)[N:7]2[N:8]=1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: Nc1nc2cccc(Br)n2n1
Product: CS(=O)(=O)Nc1cccc(-c2cccc3nc(N)nn23)c1
Yield: 18 %

Procedure:
N-[3-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-phenyl]-methanesulfonamide was prepared from 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (1.80 g, 8.45 mmol) and 3-methylsulfonylaminophenyl boronic acid (2.0 g, 9.30 mmol), in a manner analogous to Step 73c. The residue was purified on an 80 g Isco silica gel column using a gradient of 0-7% methanol in dichloromethane as an eluent. N-[3-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-phenyl]-methanesulfonamide (461 mg, 18%) was isolated as a beige powder. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.94 (s, 1H), 7.72 (s, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.51 (m, 2H), 7.38 (d, J=8.6 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 6.97 (d, J=7.5 Hz, 1H), 6.03 (br s, 2H), 3.08 (s, 3H). MS=304 (MH)+. 83b) 5 N-[3-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-phenyl]-methanesulfonamide (162 mg, 0.534 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (150 mg, 0.587 mmol) were combined in a manner analogous to Example 77 to yield N-(3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-phenyl)-methanesulfonamide TFA salt (13.75 mg, 5%) as a yellow powder following purification via preparative HPLC on a Phenomenex Luna column using 0.1% TFA in MeCN and 0.1% TFA in Water as eluent. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.99 (s, 1H), 9.41 (s, 1H), 7.81 (s, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.64 (t, J=8.3 Hz, 1H), 7.50-7.61 (m, 3H), 7.08-7.42 (m, 3H), 6.93 (d, J=7.2 Hz, 2H), 3.67 (m, 2H), 3.18 (m, 4H), 3.07 (s, 3H), 2.86 (br s, 5H). MS=478 (MH)+.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([O:31][CH3:32])=[CH:23][C:16]=2[CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:13][CH:12]=[C:11]([CH3:33])[N:10]=1)C1C=CC=CC=1>CO.CCOC(C)=O.[Pd]>[C:27]([C:25]1[C:24]([O:31][CH3:32])=[CH:23][C:16]([CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([C:14]2[C:9](=[O:8])[NH:10][C:11]([CH3:33])=[CH:12][CH:13]=2)[CH:26]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: COc1cc(CNS(C)(=O)=O)c(-c2ccc(C)nc2OCc2ccccc2)cc1C(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(CNS(C)(=O)=O)c(-c2ccc(C)[nH]c2=O)cc1C(C)(C)C
Reaction time: 1 h

Procedure:
step 3—A mixture of 74 and 10% Pd/C (5 mg) in a mixture of MeOH (8 mL) and EtOAc (4 mL) under 1 atmosphere of H2 at RT was stirred for 1 h. The catalyst was filtered off and the filtrate was concentrated. The crude residue was purified on a preparative SiO2 TLC plate developed with 4% MeOH/DCM to afford 7.3 mg (53%) of I-37.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C:5]=12.C1C(=O)N([Cl:24])C(=O)C1>C1(C)C=CC=CC=1>[Cl:24][C:3]1[N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C:5]2=[N:1][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCn2ccnc2C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCn2c(Cl)cnc2C1

Procedure:
1,1-Dimethylethyl 5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (I18) (1.563 g, 7 mmol) and NCS (0.935 g, 7.00 mmol) were heated at 80° C. for 2 h in toluene (30 mL). The solvents were removed in vacuo and the residue was purified by flash chromatography (Isolera, 50 g, 0-100% ethyl acetate/iso-hexane) to afford product in 1.55 g.
Reaction SMILES: [CH2:1]1[N:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[NH:9][C:10](=[O:12])[CH2:11][CH:5]2[CH2:4][NH:3][CH2:2]1.[Br:17]N1C(=O)CCC1=O>C(O)(=O)C.O>[Br:17][C:14]1[CH:15]=[CH:16][C:7]2[N:6]3[CH2:1][CH2:2][NH:3][CH2:4][CH:5]3[CH2:11][C:10](=[O:12])[NH:9][C:8]=2[CH:13]=1
Reactant: O=C1CC2CNCCN2c2ccccc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC(=O)O
Product: O=C1CC2CNCCN2c2ccc(Br)cc2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 1D (1.54 g, 6.07 mmol) in acetic acid/water (1:1, 20 mL) was added N-bromosuccinimide (1.08 g, 6.07 mmol). The reaction mixture was stirred at room temperature for 2 hours. Product precipitated. The precipitate was collected to afford the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 7.36 (d, J=8.54 Hz, 1H), 7.16 (s, 1H), 7.11 (d, J=8.85 Hz, 1H), 3.54-3.63 (m, 1H), 3.22-3.40 (m, 4H), 2.93-3.07 (m, 2H), 2.65-2.72 (m, 1H), 2.08 (d, J=13.73 Hz, 1H); MS (ESI) m/z 297.8 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[CH3:11][S:12]([C:15]1([CH2:18]O)[CH2:17][CH2:16]1)(=[O:14])=[O:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>O1CCCC1>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:18][C:15]2([S:12]([CH3:11])(=[O:14])=[O:13])[CH2:17][CH2:16]2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CS(=O)(=O)C1(CO)CC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCC2(S(C)(=O)=O)CC2)cc(C)c1Br
Temperature: 0 °C
Reaction time: 48 h

Procedure:
4-bromo-3,5-dimethylphenol, (306 mg, 1.52 mmol), (1-Methanesulfonyl-cyclopropyl)-methanol (228 mg, 1.52 mmol), and triphenylphosphine (399 mg, 1.52 mmol) are suspended in dry tetrahydrofuran (10 mL) and cooled to 0° C. Di-tert-butylazodicarboxylate (350 mg, 1.52 mmol) is added and the mixture stirred at 50° C. for 48 hours then at room temperature for a further 48 hours. The mixture is concentrated under vacuum then partitioned between water and dichloromethane, The organic phase is dried and the solvent removed under vacuum. The residue is purified by flash chromatography (0-20% ethyl acetate in cyclohexane) to give the title compound as a crude material which was used without further purification (Yield 664 mg).
Reaction SMILES: Cl.O1CCOCC1.C(OC([NH:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C@@H:22]1[CH2:27][C@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@H:25]([N:36]=[N+:37]=[N-:38])[C@H:24]([CH3:39])[CH2:23]1)=O)(C)(C)C.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[NH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C@@H:22]1[CH2:27][C@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@H:25]([N:36]=[N+:37]=[N-:38])[C@H:24]([CH3:39])[CH2:23]1
Reactant: C[C@@H]1C[C@H](c2ccncc2NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1N=[N+]=[N-]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H]1C[C@H](c2ccncc2N)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution of 4 M HCl in dioxane (30.0 equiv.) was added to tert-butyl ((1S,2R,3R,5S)-5-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-2-azido-3-methylcyclohexyl)carbamate (1.0 equiv.). The solution started to go homogeneous for a few minutes, but then a ppt formed and the solution went very thick. After sitting at rt for 1 hour, the volatiles were removed in vacuo and the solid was pumped on for 5 minutes on the high vac. To the residue was added CH2Cl2 (0.15 M), TEA (5.0 equiv.) and Boc2O (1.0 equiv.). The solution was left stirring at rt for 1 hr. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was washed with Na2CO3(sat), NaCl(sat), dried over MgSO4, filtered, concentrated to yield tert-butyl (1S,2R,3R,5S)-5-(3-aminopyridin-4-yl)-2-azido-3-methylcyclohexylcarbamate in 98% yield. LC/MS (m/z)=347.3 (MH+), Rt=0.71 min.
Reaction SMILES: [C:1]1([C:7]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:10][CH2:9]O2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.[C:25]([OH:28])(=[O:27])[CH3:26]>>[C:25]([O:28][CH2:9][CH2:10][C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)O
Reactant: c1ccc(C2CCOC2(c2ccccc2)c2ccccc2)cc1
Agent: Br
Product: CC(=O)OCCC(=C(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
30.0 g of 2,2,3-triphenyltetrahydrofuran are dissolved in 125 ml of acetic acid, after which 25 ml of 40% hydrogen-bromide in acetic acid are added. The mixture is stirred for 1 h at 75° C. The solvent is evaporated, and 1 M sodium carbonate solution is added in excess. The product is extracted in toluene. The toluene solution is dried over sodium sulfate and the solvent is evaporated. The product is recrystallized from aqueous methanol and then has m.p. 81°-3° C. The yield is 28.7 g (84%).