Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]2[O:23][C:22](=[O:24])[C:21]3[C:16](=[C:17]([CH3:28])[CH:18]=[C:19]4[CH:27]=[N:26][NH:25][C:20]4=3)[N:15]=2)[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[N:6]=1.[CH:29]([NH2:32])([CH3:31])[CH3:30]>C(#N)C.O>[CH:29]([NH:32][C:22]([C:21]1[C:16]([NH:15][C:14]([C:4]2[N:5]([C:7]3[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=3)[N:6]=[C:2]([Br:1])[CH:3]=2)=[O:23])=[C:17]([CH3:28])[CH:18]=[C:19]2[C:20]=1[NH:25][N:26]=[CH:27]2)=[O:24])([CH3:31])[CH3:30]
Reactant: Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Reactant: CC(C)N
Solvent: O
Solvent: CC#N
Product: Cc1cc2cn[nH]c2c(C(=O)NC(C)C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To a suspension of 600 mg of the above 7-[5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazol-3-yl]-5-methyl-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 10 mL of acetonitrile/water (4:1, v/v) is added 1.11 mL (13.1 mmol) of isopropylamine. The reaction mixture is stirred for 9 hours at ambient temperature and then concentrated in vacuo. The residue is taken-up with brine and ethyl acetate. The phases are separated and the aqueous layer is washed with ethyl acetate. The combined organic layers are washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (SiO2, hexane/ethyl acetate 1:2) affords 110 mg (16% over two steps) of the product as a white solid; LC/MS:518/520 (M+H)+, m.p.: 163-166° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH2:15][O:16][CH3:17])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])[NH2:5].[C:18](Cl)(Cl)=[O:19]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]=[C:18]=[O:19])[CH:6]=[C:7]([CH2:15][O:16][CH3:17])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14]
Reactant: O=C(Cl)Cl
Reactant: COCc1cc(N)cc(Cl)c1OCCCC#N
Solvent: Cc1ccccc1
Product: COCc1cc(N=C=O)cc(Cl)c1OCCCC#N
Temperature: 25 °C
Yield: 99.6 %

Procedure:
3-Chloro-4-(3-cyanopropyloxy)-5-methoxymethylaniline (2.55 g) in toluene (20 ml) was dropwise added to a toluene solution containing 10 g of phosgene at 10° to 20° C. The resulting mixture was gradually heated and, after being refluxed for 30 minutes, cooled to room temperature. The solvent was removed by distillation under reduced pressure to give 3-chloro-4-(3-cyanopropyloxy)-5-methoxymethylphenyl isocyanate (2.80 g). The thus obtained crude substance was added to a toluene solution (50 ml) containing triethylamine (1.0 g) and isopropanol (1.0 g). The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-[3-chloro-4-(3-cyanopropyloxy)-5-methoxymethylphenyl]carbamate (Compound No. 6) (2.70 g) in a yield of 79.2%. nD20.0 1.5196.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([OH:53])[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2].[CH3:57]I>[Ag]=O>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([O:53][CH3:57])[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(O)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: CI
Agent: O=[Ag]
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(OC)C3)C(C)CCC1=O)C(C)CC2OC

Procedure:
A suspension of 17-ethyl-1-hydroxy-12-[2'-(4"-azido-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (20 mg, Example 42)) and silver oxide (20 mg) in 1.5 ml of methyl iodide was refluxed in a gas-tight bottle for 4 days. The yellow solid was filtered off and the excess methyl iodide was removed. Purification of crude material by preparative tlc on silica gel (1:1 hexane/ethyl acetate) gave 4 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([OH:30])[CH2:17][CH2:18][N:19]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:11][CH2:10]1.O.NN>C(O)C>[NH2:19][CH2:18][CH2:17][CH:16]([OH:30])[CH2:15][N:12]1[CH2:11][CH2:10][N:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=2[CH3:1])[CH2:14][CH2:13]1
Reactant: Cc1cccc(N2CCN(CC(O)CCN3C(=O)c4ccccc4C3=O)CC2)c1C
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cccc(N2CCN(CC(O)CCN)CC2)c1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 55.5 %

Procedure:
To a mixture of 2-(4-(4-(2,3-dimethylphenyl)piperazin-1-yl)-3-hydroxybutyl)isoindoline-1,3-dione obtained in step 4 (0.26 g, 0.65 mmol) in ethanol (1.5 ml), was added hydrazine monohydrate (0.063 ml, 2.02 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 17 hours. After the reaction complete, the reaction mixture thus obtained was sonicated and filtered. The filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate and water. The organic phase thus separated was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.1 g). The compound was used for the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:16]=[C:10]2[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH:16]=[C:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cc(-c3ccc(F)cc3)nn2CCN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc(-c2cc3n(n2)CCN(Cc2ccccc2)C3)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.2 %

Procedure:
To a solution of Intermediate 1D (23.00 g, 71.6 mmol) in THF (230 mL) under N2 at −10° C. was added LAH (59.6 mL, 2.4 M solution in THF, 143 mmol). Reaction mixture was allowed to stir at room temperature for 12 h. Reaction mixture was quenched with ice-cold water and filtered through CELITE® pad and the filtrate was extracted with chloroform (3×150 mL) The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was triturated with diethyl ether (2×150 mL) and the resulting solid was filtered, rinsed with diethyl ether and dried to afford Intermediate 1E (17 g, 77%). MS(ES): m/z=308 [M+H]+; 1H NMR (300 MHz, CDCl3) δ ppm 7.67-7.82 (m, 2H), 7.31-7.47 (m, 514), 7.01-7.14 (m, 2H), 6.19 (s, 1H), 4.22 (t, J=4.2 Hz, 2H), 3.73 (s, 2H), 3.70 (s, 2H), 2.97 (t, J=5.6 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:23])[CH:11]=2)[CH:6]=1.[F:25][C:26]([F:42])([F:41])[C:27]1[CH:28]=[C:29]([S:37](Cl)(=[O:39])=[O:38])[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:37]([C:29]3[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=[C:27]([C:26]([F:25])([F:41])[F:42])[CH:28]=3)(=[O:39])=[O:38])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:23])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(N)cc2)c1C
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(NS(=O)(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.1 %

Procedure:
To a solution of [4-(4-amino-phenyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (55 mg, 0.17 mmol) and 3,5-bis(trifluoromethyl)benzenesulfonyl chloride (54 mg, 0.17 mmol) in THF (3 mL) was added diisopropylethylamine (62 mg, 0.48 mmol) at 0° C. under nitrogen. After addition, the reaction mixture was warmed to room temperature and stirred for 3 hours. The solvent was removed under vacuum and the residue was diluted with water (10 mL). The mixture was extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (20 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum gave the crude residue which was purified using an ISCO (12 g) column, eluting with 2-25% ethyl acetate in hexanes, to afford {4-[4-(3,5-bis-trifluoromethyl-benzenesulfonylamino)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (21.5 mg, 21%) as a light brown solid. 1H NMR (300 MHz, CDCl3) δ ppm 8.23 (s, 2 H), 8.09 (s, 1 H), 7.78 (dd, J=8.8, 5.7 Hz, 1 H), 7.73 (s, 1 H), 7.11-7.24 (m, 5 H), 7.04 (s, 1 H), 6.73 (d, J=10.9 Hz, 1 H), 3.87 (s, 2 H), 3.75 (s, 3 H), 2.07 (s, 3 H). HRMS calcd. for C28H19F7NO4S [(M−H)−] 598.0928, obsd. 598.0925.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:14])=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].C([O:22][C:23]1[C:32]([CH3:33])=[CH:31][C:26]([C:27]([NH:29][NH2:30])=O)=[CH:25][C:24]=1[CH2:34][CH3:35])C1C=CC=CC=1>>[CH2:34]([C:24]1[CH:25]=[C:26]([C:27]2[O:13][C:11]([C:8]3[CH:7]=[C:6]([CH3:14])[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])=[CH:10][N:9]=3)=[N:30][N:29]=2)[CH:31]=[C:32]([CH3:33])[C:23]=1[OH:22])[CH3:35]
Reactant: Cc1cc(C(=O)O)ncc1CC(C)C
Reactant: CCc1cc(C(=O)NN)cc(C)c1OCc1ccccc1
Product: CCc1cc(-c2nnc(-c3cc(C)c(CC(C)C)cn3)o2)cc(C)c1O

Procedure:
The title compound is prepared in analogy to Example 18 starting from 5-isobutyl-4-methyl-pyridine-2-carboxylic acid and 4-benzyloxy-3-ethyl-5-methyl-benzoic acid hydrazide; LC-MS: tR=1.07 min, [M+H]+=357.18.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=[O:14].FC(F)(F)C(O[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=O>N1C=CC=CC=1>[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([O:14][C:13]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=3)=[O:15])=[CH:22][CH:23]=1)([O-:29])=[O:28]
Reactant: Cc1ccc2c(O)c(C(=O)O)cnc2n1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Solvent: c1ccncc1
Product: Cc1ccc2c(O)c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc2n1
Reaction time: 2 h

Procedure:
A mixture of 1 g of 4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylic acid and 25 ml of anhydrous pyridine was heated on an oil bath at 50° to 60° C while stirring. Then, 1.38 g of p-nitrophenyl trifluoroacetate were added thereto and, after the heating was interrupted, stirring was carried out for 2 hours. The precipitated crystals were collected by filtration and washed with ethanol to give 4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylic acid p-nitrophenyl ester as pale yellow crystalline powder melting at 311 to 313° C (decomp.). Yield, 1.2 g. IR νC=O 1700 cm-1 ; νNO2 1520 cm-1, 1345 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1/[CH:13]=[CH:14]\[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[N:31]1>CO.N1CCCCC1>[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](/[CH:39]=[C:8]2\[O:9][C:5]3[C:4](/[CH:13]=[CH:14]\[CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:31]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1/C=C\CCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1/C=C\CCN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
A solution of tert-butyl (Z)-4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)but-3-enyl]piperazine1-carboxylate (0.0562 g, 0.139 mmol) in methanol (5 mL) was added with 1H-indazole-3-carboxaldehyde (0.0203 g, 0.139 mmol) and piperidine (7 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and then the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl 4-((Z)-4-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}but-3-enyl)piperazine-1-carboxylate (0.0672 g, 91%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:27][C:28]1[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][CH:31]=[CH:30][N:29]=1.BrBr>ClC1C=CC=CC=1>[Br:1][CH2:27][C:28]1[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ncccc1[N+](=O)[O-]
Agent: BrBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Product: O=[N+]([O-])c1cccnc1CBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
51 g (290 mmol) of N-bromosuccinimide and 0.5 g of benzoyl peroxide were added, a little at a time, to a mixture of 40 g (290 mmol) of 2-methyl-3-nitropyridine (Example 3.b) and 400 ml of chlorobenzene, at the boiling point (liberation of bromine). After approximately 2 hours, the reaction mixture was cooled to room temperature (approximately 25° C.) and filtered, and the resulting solution was freed from solvent under reduced pressure. The resulting residue was chromatographed twice (cyclohexane/methylene chloride; cyclohexane/ethyl acetate). This gave 10.4 g (17%) of the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[CH3:9][S-:10].[Na+]>CN(C=O)C.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:10][CH3:9])[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CSc1cccc(Br)n1

Procedure:
To a solution of 2,6-dibromopyridine (0.50 g, 2.11 mmol) in DMF (21 mL) was added sodium thiomethoxide (0.16 g, 2.32 mmol) and the solution was allowed to react overnight. The solution was then diluted with ethyl ether, washed with water, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography to yield the title compound. 1H NMR (600 MHz, CDCl3): 7.32 (t, J=7.3 Hz, 1H), 7.15 (dd, J=9.6, 1.2 Hz, 1H), 7.12 (dd, J=9.0, 0.6 Hz, 1H), 2.55 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[CH:17]=1)=[O:14].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1>>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[CH2:12][C:7]2[C:8]3[C:3](=[C:2]([C:33]4[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=4)[CH:11]=[CH:10][CH:9]=3)[CH:4]=[CH:5][CH:6]=2)=[CH:17][C:18]=1[N:24]1[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]1
Reactant: OB(O)c1cccnc1
Reactant: COc1ccc(NC(=O)Cc2cccc3c(Br)cccc23)cc1N1CCN(C)CC1
Product: COc1ccc(NC(=O)Cc2cccc3c(-c4cccnc4)cccc23)cc1N1CCN(C)CC1

Procedure:
The title compound was prepared from 5-bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]naphth-1-ylacetamide (E20) and 3-pyridylboronic acid using a similar procedure to Example 4 (13%).
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:27])[C:24]([CH3:26])=[CH2:25])[CH:19]=[CH:20][CH:21]=3)[C:10]=2[CH:9]=[CH:8]1.C1C(=O)N([Br:37])C(=O)C1>CC#N>[Br:37][C:9]1[C:10]2[C:15]([C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:27])[C:24]([CH3:26])=[CH2:25])[CH:19]=[CH:20][CH:21]=3)=[N:14][CH:13]=[N:12][C:11]=2[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:28])[CH3:29])[CH:8]=1
Reactant: C=C(C)C(=O)Nc1cccc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: C=C(C)C(=O)Nc1cccc(-c2ncnc3c2c(Br)cn3COCC[Si](C)(C)C)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of N-(3-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)methacrylamide (5.20 g, 12.7 mmol) in CH3CN (80 mL), was added NBS (2.40 g, 13.5 mmol) in several portions at 80° C. The resulting solution was stirred for 2 hours at 80° C. before being concentrated in vacuo. The reaction was then purified by chromatography using silica gel, eluting with 0-33% EtOAc/petroleum ether. The product was collected and concentrated in vacuo to afford N-(3-(5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)methacrylamide as a yellow solid. LRMS (ESI) calc'd for C22H28N4O2SiBr [M+H]+: 487, found 487.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11](Cl)(Cl)=[O:12]>C(OC(=O)C)C.C1(C)C=CC=CC=1>[C:2]1([C:1]2[O:8][C:11](=[O:12])[NH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: NNC(=O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(-c2ccccc2)o1
Temperature: 25 °C

Procedure:
Into a stirred slurry of 25 g (0.18 mole) benzoylhydrazine in ethylacetate, 142.5 g (0.18 mole) 12.5% phosgene in toluene was dropped in. The reaction mixture was refluxed about 3 hours, and then allowed to stir over the weekend at ambient temperature. The flask was hooked to an aspirator and placed under vacuum to remove any possible peroxides. The mixture was filtered to give the above-identified product as a solid, melting point 133°-135° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]([CH2:13][CH3:14])[CH2:10][CH2:9][C:8]2=[O:15].N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].O>CN(C)C=O>[O:15]=[C:8]1[C:7]2[C:12](=[C:3]([CH2:2][O:1][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:4]=[CH:5][CH:6]=2)[N:11]([CH2:13][CH3:14])[CH2:10][CH2:9]1
Reactant: CCN1CCC(=O)c2cccc(CO)c21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCC(=O)c2cccc(CO[Si](C)(C)C(C)(C)C)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
8-Hydroxymethyl-1-ethyl-4-oxo-1,2,3,4-tetrahydroquinoline (1.44 g) was dissolved in dimethyl formamide (2 ml). Imidazole (1.57 g) and t-butyl dimethylsilyl chloride (1.16 g) were added to the solution and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate-toluene. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off. The resulting residue was purified by silica gel column chromatography [eluent: n-hexane-ethyl acetate (3: 1) ] to give 4-oxo-8-t-butyldimethylsilyloxymethyl- 1-ethyl-1,2,3,4-tetrahydroquinoline (2.18 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17](=O)[C:12]2[C:13]([CH3:16])=[CH:14][O:15][C:11]=2[CH2:10]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:18]/[C:17](=[N:24]\[NH:23][C:20]([NH2:22])=[NH:21])/[C:12]2[C:13]([CH3:16])=[CH:14][O:15][C:11]=2[CH2:10]1
Reactant: N=C(N)NN
Reactant: Cc1coc2c1C(=O)CC(c1cccc(Cl)c1Cl)C2
Agent: Cl
Solvent: CCO
Product: Cc1coc2c1/C(=N/NC(=N)N)CC(c1cccc(Cl)c1Cl)C2
Temperature: 90 °C
Reaction time: 2 h
Yield: 162.4 %

Procedure:
To a mixture of 6-(2,3-dichlorophenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.15 g) and aminoguanidine hydrochloride (56 mg) were added ethanol (10 ml) and 6N hydrochloric acid (0.044 ml), and the mixture was stirred at 90° C. for 2 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-6-(2,3-dichlorophenyl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 43) (0.16 g).
Reaction SMILES: Br[C:2]1[C:3]([OH:14])=[C:4]([CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=[O:6].[CH3:15][O:16][C:17]1[C:22](B(O)O)=[CH:21][CH:20]=[CH:19][N:18]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.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:10]([C:8]1[CH:9]=[C:2]([C:22]2[C:17]([O:16][CH3:15])=[N:18][CH:19]=[CH:20][CH:21]=2)[C:3]([OH:14])=[C:4]([CH:7]=1)[CH:5]=[O:6])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Reactant: COc1ncccc1B(O)O
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: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ncccc1-c1cc(C(C)(C)C)cc(C=O)c1O
Yield: 77.4 %

Procedure:
step 1—A sealed tube containing 3-bromo-5-tert-butyl-2-hydroxy benzaldehyde E-1b (R1═OH, R4=tert-Bu, 858 mg, 3.339 mmol), 37 (766 mg, 5.008 mmol), Pd(PPh3)4 (240 mg, 0.208 mmol), and Na2CO3 (891 mg, 8.406 mmol) in a mixture of MeOH (10 mL) and DCM (2 mL) was irradiated in a microwave reactor at 115° C. for 30 min. The organic volatiles were removed under reduced pressure and the residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (3 to 5% EtOAc) to afford 737 mg (77%) of 5-tert-butyl-2-hydroxy-3-(2-methoxy-pyridin-3-yl)-benzaldehyde (48) as a pale yellow oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]#[N:26])[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl-].[NH4+].[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[NH:31][N:30]=[N:29][N:26]=4)[CH2:21][CH2:20]3)=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C#N)CC3)cn2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(c4nnn[nH]4)CC3)cn2)cc1
Temperature: 100 °C

Procedure:
A solution of (4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarbonitrile (241 mg, 0.65 mmol) in DMF (3 mL) was treated with ammonium chloride (52 mg, 0.97 mmol) and sodium azide (63 mg, 0.97 mmol) at room temperature. The mixture was heated at 100° C. for 19 h. After cooling down, the solid was removed by filtration and washed with DMF. The filtrate was concentrated and a small amount of MeOH and CH2Cl2 was added to the residue. After sonication, the resulting precipitate was collected and washed with THF including a small amount of water. 2-[4-(Methylsulfonyl)phenyl]-5-({[1-(1H-tetrazol-5-yl)-4-piperidinyl]methyl}oxy)pyridine was obtained as a light gray solid (170 mg, 60%) after drying in vacuo. 1H NMR (400 MHz, DMSO-d6): δ 8.44 (d, 1H, J=2.9 Hz), 8.28 (d, 2H, J=8.6 Hz), 8.07 (d, 1H, J=8.8 Hz), 7.99 (d, 2H, J=8.6 Hz), 7.55 (dd, 1H, Ja=8.8 Hz, Jb=2.9 Hz), 4.03 (d, 2H, J=6.3 Hz), 3.88 (d, 2H, J=12.7 Hz), 3.25 (s, 3H), 3.13-3.00 (m, 2H), 2.13-2.01 (m, 1H), 1.93-1.84 (m, 2H), 1.47-1.31 (m, 2H); LRMS (ESI), m/z 415 (M+H).