Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([OH:25])=O.[O:43]1[C:47]2([CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:46][NH:45][C:44]1=[O:53].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([N:50]1[CH2:49][CH2:48][C:47]2([O:43][C:44](=[O:53])[NH:45][CH2:46]2)[CH2:52][CH2:51]1)=[O:25]
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Reactant: O=C1NCC2(CCNCC2)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C1NCC2(CCN(C(=O)CCC(Nc3ncnc4cc(C(=O)N5CCCC5)c(Cl)cc34)c3nc4cc(Cl)ccc4[nH]3)CC2)O1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and 1-oxa-3,8-diaza-spiro[4.5]decan-2-one with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2].[CH3:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][Br:30])=[CH:27][CH:26]=1>>[Br-:30].[C:1]([C:4]1[CH:5]=[N+:6]([CH2:24][C:25]2[CH:32]=[CH:31][C:28]([CH3:29])=[CH:27][CH:26]=2)[CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)CCC(Cc1ccncc1C(C)=O)C2=O
Reactant: Cc1ccc(CBr)cc1
Product: COc1ccc2c(c1)CCC(Cc1cc[n+](Cc3ccc(C)cc3)cc1C(C)=O)C2=O
Product: [Br-]

Procedure:
The title compound 130 is prepared according to the procedure reported in Example 38.1 with compound 103 (120 mg, 0.387 mmol) and 4-methylbenzyl bromide (122 mg, 0.66 mmol) as reactants. White solid. (Yield 181.7 mg, 95%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:5]=1[OH:12])([O-])=O.[CH2:13](OC(OCC)OCC)C>[Pd].C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:11][O:10][C:6]1[C:5]2[O:12][CH:13]=[N:1][C:4]=2[CH:9]=[CH:8][CH:7]=1
Reactant: COc1cccc([N+](=O)[O-])c1O
Reactant: CCOC(OCC)OCC
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: COc1cccc2ncoc12
Reaction time: 1.25 h
Yield: 85.2 %

Procedure:
A mixture of 2-nitro-6-methoxyphenol (2.62 g, 15.5 mmol) (EP 333176) and 10% Palladium on carbon (130 mg) in ethanol (50.0 ml) was stirred under an atmosphere of H2 for 75 min. The mixture was filtered through Celite® then immediately treated with p-toluenesulphonic acid (32.0 mg) and triethylorthoformate (6.45 ml, 38.8 mmol) then heated under reflux under an atmosphere of N2. After 20 h p-toluenesulphonic acid (30.0 mg) and triethylorthoformate (6.45 ml, 38.8 mmol) were added. After a total of 44 h heating, the reaction was allowed to cool and reduced in vacuo. The resulting residue was purified by flash chromatography (25:75 ethyl acetate/hexane) to give 1.97 g (85%) of the title compound as a yellow solid: m.p. 28-31° C.; IR (film) 1629, 1497, 1434, 1285, 1097; 1H NMR (CDCl3) δ 8.09 (1H, s), 7.40 (1H, d, J=8.0), 7.28 (1H, t, J=8.0), 6.89 (1H, d, J=8.0), 4.02 (3H, s); 13C NMR (CDCl3) δ 152.84, 145.82, 142.50, 139.99, 125.75, 113.42, 108.80, 56.97. Anal. Calcd. for C8H7N1O2. 0.1H2O: C, 63.65; H, 4.81; N, 9.29. Found: C, 63.43, H, 4.88, N, 9.05. M.S. (+FAB); 150 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@@:4]([N:30]=C=O)(OC(C)(C)C)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([O:20][C:21](=[O:24])[NH:22][CH3:23])[CH:7]=1.[ClH:34].C(OCC)C>ClCCl>[Cl-:34].[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C@H:4]([NH3+:30])[C:3]([O:2][CH3:1])=[O:33])=[CH:7][C:8]=1[O:20][C:21](=[O:24])[NH:22][CH3:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CNC(=O)Oc1cc(C[C@](N=C=O)(OC(C)(C)C)C(=O)OC)ccc1OCc1ccccc1
Reactant: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CNC(=O)Oc1cc(C[C@H]([NH3+])C(=O)OC)ccc1OCc1ccccc1
Product: [Cl-]
Reaction time: 2 h

Procedure:
To a solution of (S)-3-(4-Benzyloxy-3-methylcarbamoyloxy-phenyl)-2-tert-butoxy-carbonylamino-propionic acid methyl ester (0.80 g) in dichloromethane (10 ml) was added HCl solution (4M in dioxane, 4 ml) at 0° C. The mixture was stirred at this temperature for 2 h. Diethyl ether was added and a white solid precipitated. (S)-2-(4-Benzyloxy-3-methylcarbamoyloxy-phenyl)-1-methoxycarbonyl-ethyl-ammonium chloride was obtained by filtration as a white solid, 0.654 g. 1H NMR (400 MHz, d6-DMSO) 2.65 (d, 3H), 3.01-3.14 (m, 2H), 3.67 (s, 3H), 4.24 (m, 1H), 5.10 (s, 2H), 7.01-7.11 (m, 3H), 7.30-7.44 (m, 5H), 7.61 (m, 1H), 8.64 (br, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[C:4]([CH3:11])[C:3]=1[C:12]([OH:14])=[O:13].[C:15]1([S:21]([NH2:24])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[C:15]1([S:21]([NH:24][C:8]([C:6]2[CH:5]=[C:4]([CH3:11])[C:3]([C:12]([OH:14])=[O:13])=[C:2]([CH3:1])[CH:7]=2)=[O:10])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: Cc1cc(C(=O)O)cc(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NS(=O)(=O)c2ccccc2)cc(C)c1C(=O)O
Temperature: 0 °C

Procedure:
2,6-Dimethyl-1,4-benzenedicarboxylic acid (from Preparation 7) (500 mg, 2.6 mmol) and benzene sulfonamide (486 mg, 3.1 mmol) were combined in dry DMF (25 mL), and EDCI (494 mg, 2.6 mmol) was then added with stirring at 0° C. The mixture was stirred for 2 hours at 0° C. and 2 days at room temperature, then 1N HCl (10 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with 1N HCl (1×), water (5×), and brine (3×); dried (Na2SO4); and rotary evaporated to give the crude product (used as such in the next step) as a white solid; NMR (acetone-d6) showed 8.0-7.4 ppm (multiplet with a singlet at 7.7 ppm, 7H) and 2.4 ppm (singlet, 6H).
Reaction SMILES: CN(C)C=O.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=2)=[C:9]([F:30])[CH:8]=1.[CH3:31][C:32]([CH3:55])([CH2:37][O:38][C:39]1[CH:44]=[C:43]([CH3:45])[C:42](B2OC(C)(C)C(C)(C)O2)=[CH:41][N:40]=1)[C:33]([O:35][CH3:36])=[O:34].C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C>[F:30][C:9]1[CH:8]=[C:7]([C:42]2[C:43]([CH3:45])=[CH:44][C:39]([O:38][CH2:37][C:32]([CH3:31])([CH3:55])[C:33]([O:35][CH3:36])=[O:34])=[N:40][CH:41]=2)[CH:12]=[CH:11][C:10]=1[C:13]1[N:14]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1
Reactant: COC(=O)C(C)(C)COc1cc(C)c(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)COc1cc(C)c(-c2ccc(-c3nc(C(F)(F)F)cn3COCC[Si](C)(C)C)c(F)c2)cn1
Temperature: 60 °C
Reaction time: 5 h
Yield: 102.3 %

Procedure:
N,N-dimethylformamide (4 mL) was added to 2-(4-bromo-2-fluorophenyl)-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (500 mg), methyl 2,2-dimethyl-3-{[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}propanoate (477 mg) and palladium chloride (dppf) methylene chloride complex (46 mg), and after adding 2N aqueous sodium carbonate solution (1.71 mL) to the mixture, the atmosphere was replaced with nitrogen and the resulting mixture was stirred at 60° C. for 5 hours. To the reaction mixture were added ethyl acetate and water, and the liquids were separated. The organic layer was separated, washed with a saturated brine, and the residue obtained by concentrating the mixture under reduced pressure was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5 to 82:18) to obtain methyl 3-[(5-{3-fluoro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate (677 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([OH:19])=[CH:16]2)=[CH:11][C:10]=1[C:20]1[N:21]=[N:22][C:23]([N:26]([CH3:37])[CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)=[CH:24][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:38]N1C(=O)CCC1=O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([OH:19])=[C:16]2[Br:38])=[CH:11][C:10]=1[C:20]1[N:21]=[N:22][C:23]([N:26]([CH3:37])[CH:27]2[CH2:32][C:31]([CH3:33])([CH3:34])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)=[CH:24][CH:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(c1ccc(-c2cc3ccc(O)cc3cc2OCc2ccccc2)nn1)C1CC(C)(C)NC(C)(C)C1
Solvent: CN(C)C=O
Product: CN(c1ccc(-c2cc3ccc(O)c(Br)c3cc2OCc2ccccc2)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29 %

Procedure:
To a mixture of 7-(benzyloxy)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol (100 mg, 0.201 mmol) in DMF (1 mL) was added N-bromosuccinimide (39.4 mg, 0.221 mmol) at 0° C. The reaction mixture was stirred at RT for 1.5 h, then loaded onto a 2 g SCX column, washed with MeOH, and eluted with 2M NH3 in MeOH. The product-containing fractions were concentrated and the crude material was purified via silica gel flash column chromatography to give the desired product as a brown solid (33.6 mg, 29% yield). MS (M+1)=577.3.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15](CC(F)(F)F)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.BrC1C=CC2C3N=C(C(N)=O)SC=3[CH2:36][CH2:37][O:38]C=2C=1.N([CH:46]([OH:49])[CH2:47][CH3:48])N>>[Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:47]([CH3:48])[CH2:46][O:49][C:37](=[O:38])[CH3:36])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CCC(O)NN
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(=O)OCC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2

Procedure:
Following the procedure for 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene, 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide 25 was reacted with 1-hydrazino-propan-1-ol to give Acetic acid 2-[5-(8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-[1,2,4]triazol-1-yl]-propyl ester. MS(ESI+) 449.0/451.0.
Reaction SMILES: C(O[C:4](=[O:20])[NH:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[N:9]=[CH:8][N:7]=1)C.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1(C)C=CC=CC=1>O>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:4]([NH:5][C:6]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])[N:9]=[CH:8][N:7]=2)=[O:20])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCOC(=O)Nc1cc(-c2ccccc2OC)ncn1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccccc1-c1cc(NC(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ncn1
Reaction time: 0.17 h
Yield: 53.2 %

Procedure:
A mixture of [6-(2-methoxy-phenyl)-pyrimidin-4-yl]-carbamic acid ethyl ester (XL) (0.30 g, 1.1 mmol), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.23 g, 1.1 mmol) and toluene (4 ml) was subjected to microwave conditions at 120° C. and 100 psi pressure for 10 minutes. The reaction was monitored by TLC. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to provide 0.250 g of 4-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-ureido}-piperidine-1-carboxylic acid tert-butyl ester (XLIV).
Reaction SMILES: [NH:1]([C:3]([C:5]1[N:6]=[CH:7][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:9][CH:10]=1)=[O:4])[NH2:2].[N:16]([O-])=O.[Na+].O.Cl>ClCCl>[N:1]([C:3]([C:5]1[N:6]=[CH:7][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:9][CH:10]=1)=[O:4])=[N+:2]=[N-:16]
Reactant: O=N[O-]
Reactant: CCOC(=O)c1cnc(C(=O)NN)cn1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cnc(C(=O)N=[N+]=[N-])cn1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
A mixture of ethyl 5-(hydrazinecarbonyl)pyrazine-2-carboxylate (1.00 g, 4.76 mmol), sodium nitrite (1.76 g, 25.5 mmol), water (18 mL) and dichloromethane (18 mL) was cooled to 0to 5° C. (ice-bath) under vigorous stirring. 6M hydrochloric acid (7.4 mL) was added drop-wise over 30 minutes, keeping the temperature under 10° C. After stirring for a further 30 minutes, the organic layer was separated, dried over magnesium sulfate and concentrated under vacuum to afford the title compound (1.01 g).
Reaction SMILES: OO[S:3]([O-:5])=[O:4].[K+].[OH:7][CH:8]1[CH2:13][CH:12]([CH2:14][CH2:15][CH3:16])S[C:10]2[S:17][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:19][C:9]1=2>O.CO>[OH:7][CH:8]1[CH2:13][CH:12]([CH2:14][CH2:15][CH3:16])[S:3](=[O:5])(=[O:4])[C:10]2[S:17][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:19][C:9]1=2
Reactant: CCCC1CC(O)c2cc(S(N)(=O)=O)sc2S1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCC1CC(O)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of "oxone"® (196.7 g, 0.32 mol) in water (870 ml) was added to a stirred solution of 5 (56.6 g, 0.19 mol) in methanol (870 ml) over 45 minutes. After stirring at ambient temperature for 20 hours, the mixture was filtered and the solid washed with methanol. The combined filtrate and washings were concentrated in vacuo below 50° C. to remove methanol. The aqueous suspension was extracted with ethyl acetate (1000 ml and 2×600 ml), the combined extracts were washed twice with water, dried over sodium sulfate and evaporated in vacuo to yield 47.37 g of 6.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:30]=[CH:29][C:10](/[CH:11]=[CH:12]/[C:13]2[N:21]([CH3:22])[C:20]3[C:19](=[O:23])[N:18]([CH2:24][CH3:25])[C:17](=[O:26])[N:16]([CH2:27][CH3:28])[C:15]=3[N:14]=2)=[CH:9][CH:8]=1.[N-:31]=[N+:32]=[N-:33].[Na+].O>CN(C)C=O>[N:31]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:30]=[CH:29][C:10](/[CH:11]=[CH:12]/[C:13]2[N:21]([CH3:22])[C:20]3[C:19](=[O:23])[N:18]([CH2:24][CH3:25])[C:17](=[O:26])[N:16]([CH2:27][CH3:28])[C:15]=3[N:14]=2)=[CH:9][CH:8]=1)=[N+:32]=[N-:33]
Reactant: CCn1c(=O)c2c(nc(/C=C/c3ccc(OCCCCBr)cc3)n2C)n(CC)c1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(OCCCCN=[N+]=[N-])cc3)n2C)n(CC)c1=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Compound 177 (235 mg, 0.49 mmol) obtained in Reference Example 116 was dissolved in 10 ml of dimethylformamide. To the solution was added 161 mg (2.48 mmol) of sodium azide, and the mixture was stirred at 80° C. for 3 hours. Water was added thereto under ice cooling and the deposited crystals, were collected by filtration. The collected crude crystals were dissolved in chloroform, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent:chloroform), followed by recrystallization from hexane/ethyl acetate to give 216 mg (yield quant.) of Compound 178 as pale yellow grains.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:17]=1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:29].[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:17]=2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1cccc(CCN2CCCC2)c1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1cccc(CCN2CCCC2)c1
Yield: 94.8 %

Procedure:
Following general procedure II, 1-(6-chloro-4-{3-[2-(pyrrolidin-1-yl)ethyl]phenylamino}-1,5-naphthyridin-3-yl)ethanone (59 mg, 0.15 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (61 mg, 0.23 mmol) followed by formation of the dihydrochloride salt to afford the desired product (63 mg, 72%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.30 (s, 1H), 8.43 (d, J=9.0 Hz, 1H), 8.34 (d, J=8.9 Hz, 1H), 7.54-7.30 (m, 4H), 7.23 (br s, 1H), 7.13 (br s, 1H), 3.68-3.60 (m, 2H), 3.35-3.23 (m, 2H), 3.11-2.99 (m, 4H), 2.80 (br s, 3H), 2.19-2.07 (m, 2H), 2.05-1.96 (m, 2H); ESI MS m/z 505 [M+H]+; HPLC>99% (AUC), tR=10.17 min.
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:22]1[CH2:28][CH2:27][CH2:26][O:25][C:24]2[CH:29]=[C:30]([C:33]([C:35]3[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH3:44])[CH:36]=3)=O)[CH:31]=[CH:32][C:23]1=2>C1COCC1>[O:22]1[CH2:28][CH2:27][CH2:26][O:25][C:24]2[CH:29]=[C:30]([C:33]([C:35]3[CH:36]=[C:37]([O:43][CH3:44])[CH:38]=[C:39]([O:41][CH3:42])[CH:40]=3)=[CH:9][C:10]#[N:11])[CH:31]=[CH:32][C:23]1=2
Reactant: COc1cc(OC)cc(C(=O)c2ccc3c(c2)OCCCO3)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCCO3)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 88.9 %

Procedure:
To a stirred solution of cyanomethylphosphonic acid diethyl ester (1.3 mL, 8.3 mmol) in THF (10 mL) in an ice bath was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 8.2 mL, 8.2 mmol) dropwise. The mixture was stirred at room temperature for 40 min. A solution of (3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-(3,5-dimethoxy-phenyl)-methanone (1.3 g, 4.1 mmol) in anhydrous THF (10 mL) was added to the mixture. The mixture was refluxed overnight. The solution was poured into ice water (20 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers was washed with water (50 mL), sodium hydrogen carbonate (50 mL, sat), brine (50 mL) and dried over magnesium sulfate. Removal of solvent and chromatography (Silica Gel) gave a mixture of (E/Z) 3-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile as an oil (1.23 g, 89% yield): 1H NMR (DMSO-d6) δ 2.09-2.16 (m, 4H, 2CH2), 3.73 (s, 6H, 2CH3), 4.12-4.25 (m, 8H, 4CH2), 6.24 (s, 1H, CH), 6.30 (s, 1H, CH), 6.44-6.45 (m, 4H, Ar), 6.62-6.65 (m, 2H, Ar), 6.93-7.09 (m, 6H, Ar); 13C NMR (DMSO-d6) δ 30.97, 31.13, 55.40, 70.37, 70.52, 95.05, 95.87, 100.90, 101.82, 106.72, 107.06, 118.06, 118.12, 121.09, 121.61, 121.64, 122.39, 123.41, 124.47, 131.71, 132.26, 138.98, 140.12, 150.42, 150.55, 152.09, 152.89, 160.31, 160.39, 160.43.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17].C(OCC)(=O)C>C(#N)C>[Si:20]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1

Procedure:
3-Hydroxybenzaldehyde (5.0 g, 40.9 mmol) was dissolved in acetonitrile (10.0 mL). Subsequently, potassium carbonate (11.3 g, 81.9 mmol), and then tert-butyldimethylchlorosilane (7.4 g, 49.1 mmol) were added thereto, and the resultant mixture was stirred at room temperature. After completion of reaction, ethyl acetate was added thereto, followed by washing sequentially with water and brine, and drying over anhydrous sodium sulfate. The reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (n-hexane/ethyl acetate=20/1), whereby the target compound was obtained (9.1 g, 94%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[CH2:27]([O:29][C:30]1[CH:39]=[C:38]2[C:33]([CH:34]=[CH:35][C:36]([CH:40]=O)=[N:37]2)=[CH:32][C:31]=1[F:42])[CH3:28]>C(O)C>[CH2:27]([O:29][C:30]1[CH:39]=[C:38]2[C:33]([CH:34]=[CH:35][C:36](/[CH:40]=[N:11]/[NH:10][C:7]3[N:6]=[CH:5][C:4]([C@@H:3]([N:12]4[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]4)[C:2]([F:25])([F:1])[F:26])=[CH:9][CH:8]=3)=[N:37]2)=[CH:32][C:31]=1[F:42])[CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Reactant: CCOc1cc2nc(C=O)ccc2cc1F
Solvent: CCO
Product: CCOc1cc2nc(/C=N/Nc3ccc([C@@H](N4CC[C@H](NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)ccc2cc1F

Procedure:
tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (240 mg, 0.639 mmol) and 7-ethoxy-6-fluoroquinoline-2-carbaldehyde (140 mg, 0.639 mmol) in ethanol (5 mL) were stirred at ambient temperature for 24 hours. After concentration, the residue was used in the next step without purification.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27]1[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:34]1(=[O:39])[CH2:38][CH2:37][CH2:36][CH2:35]1.[Cl-].[NH4+]>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:34]2([OH:39])[CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:29][CH:28]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCCC1
Reactant: Brc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(c2ccc(Cc3ccccc3OCc3ccccc3)cc2)CCCC1
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.59 M, 294 mL) was added dropwise to a solution of 1-benzyloxy-2-(4-bromobenzyl)benzene (1.5 g, 4.25 mmol) in THF (16.5 mL) at −78° C. and the mixture was stirred at the same temperature for 30 minutes. To this mixture, a solution of cyclopentanone (357 mg, 4.25 mmol) in THF (4 mL) was added dropwise at −78° C. The reaction mixture was stirred at the same temperature for 50 minutes and at 0° C. for one hour, and then a saturated ammonium chloride aqueous solution was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain the title compound (1.14 g, 75%) as a colorless oil.