Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([NH:9][CH2:10][C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:12]=2)=[O:8])=[CH:5][N:6]=1.Cl.[CH3:30][S:31]([CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[Cl:22][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:21])[C:11]([CH2:10][NH:9][C:7]([C:4]3[S:3][C:2]([N:37]4[CH2:38][CH2:39][CH:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:35][CH2:36]4)=[N:6][CH:5]=3)=[O:8])=[CH:12][N:13]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnc(Br)s1
Reactant: CS(=O)(=O)C1CCNCC1
Agent: Cl
Product: CS(=O)(=O)C1CCN(c2ncc(C(=O)NCc3cn(-c4ccccc4)c4cc(Cl)ccc4c3=O)s2)CC1

Procedure:
2-(4-Methanesulfonyl-piperidin-1-yl)-thiazole-5-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate F and 4-methanesulfonyl piperidine hydrochloride. MS calcd. for C26H25ClN4O4S2 [(M+H)+] 557.1, obsd. 557.
Reaction SMILES: [CH2:1]([S:7][C:8]1[S:18][C:11]2=[N:12][C:13](O)=[CH:14][C:15](=[O:16])[N:10]2[N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].P(Cl)(Cl)(Cl)(Cl)[Cl:20].P(Cl)(Cl)(Cl)=O>>[Cl:20][C:13]1[N:12]=[C:11]2[S:18][C:8]([S:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:9][N:10]2[C:15](=[O:16])[CH:14]=1
Reactant: CCCCCCSc1nn2c(=O)cc(O)nc2s1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCSc1nn2c(=O)cc(Cl)nc2s1
Reaction time: 2 h
Yield: 41 %

Procedure:
A mixture of 23.5 g of the thus obtained 2-hexylthio-7-hydroxy-5H-1,3,4-thiadiazolo[3,2-a]-pyrimidin-5-one, 17.8 g of phosphorus pentachloride and 50.4 g of phosphorus oxychloride was heated to 65°~90° C. and was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in toluene. The solution was washed with a potassium carbonate aqueous solution and water respectively, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was separated by silica gel column chromatography using an ethyl acetate/toluene mixture as an eluent, and 10.2 g of 7-chloro-2-hexylthio-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. m.p. 95°~96° C. Yield 41%.
Reaction SMILES: C(OC[N:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])=[CH:16][N:15]=2)[N:11]=[N:10]1)(=O)C(C)(C)C.[OH-].[Na+].Cl.O>CO>[CH2:25]([O:24][CH:20]([O:21][CH2:22][CH3:23])[C:17]1[CH:18]=[CH:19][C:14]([C:12]2[N:11]=[N:10][NH:9][CH:13]=2)=[N:15][CH:16]=1)[CH3:26]
Reactant: CCOC(OCC)c1ccc(-c2cn(COC(=O)C(C)(C)C)nn2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC(OCC)c1ccc(-c2c[nH]nn2)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
In methanol (12 mL) was dissolved (4-(5-(diethoxymethyl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (1.96 g, 5.41 mmol) obtained in Step 3. To the solution was added a 1 mol/L aqueous sodium hydroxide solution (11.9 mL, 11.9 mmol) and the mixture was stirred at room temperature for 5 minutes. To the reaction mixture were added 1 mol/L hydrochloric acid (11.9 mL) and water. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure to give 5-(diethoxymethyl)-2-(1H-1,2,3-triazol-4-yl) pyridine (1.34 g, 100% yield).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[NH:9][C:10](=[O:30])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[N:12]=1)C1C=CC=CC=1.C(OCC)(=O)C.[H][H]>[Pd].CO>[CH3:18][O:17][C:15]1[CH:14]=[C:13]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=2)[N:12]=[C:11]([C:10]([NH:9][NH2:8])=[O:30])[CH:16]=1
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN(Cc2ccccc2)Cc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN)c1

Procedure:
4-methoxy-6-[3-(trifluoromethyl)phenoxy] picolinic acid, N',N'-dibenzyl hydrazide (7.38 g, 0.0145 mol) was mixed with a mixed solution of ethyl acetate (about 50 ml) and methanol (about 50 ml), and further with 10% palladium/carbon (1.0 g, 0.0145×0.065 mol) in a hydrogen atmosphere. The resultant mixture was stirred at a temperature of 50 to 60° C. for about 5 hours. The obtained reaction solution was filtered and concentrated, thereby obtaining an aimed product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][C:14]#[N:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:13][C:14]#[N:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: [H][H]
Reactant: CCOc1cc(C(=CC#N)c2ccccc2)ccc1OC
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1cc(C(CC#N)c2ccccc2)ccc1OC
Yield: 16.7 %

Procedure:
To a solution of 3-(3-ethoxy-4-methoxyphenyl)-3-phenylacrylonitrile (0.9 g, 3.2 mmol) in a mixture of ethanol and ethyl acetate (20 mL/30 mL) was added 0.5 g of 10% palladium on carbon catalyst in portions. The mixture was hydrogenated in a Parr-Shaker apparatus at 55-60 psi of hydrogen for 12 days. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford the crude product. The crude product was purified by flash column chromatography (silica gel, 4% hexane/methylene chloride) to afford 0.15 g (15%) of the product as an oil: 1H NMR (CDCl3) δ7.40-7.16 (m, 5 H); 6.88-6.78 (m, 3 H), 4.32 (t, J=7.5 Hz, 1 H), 4.03 (q, J=7 Hz, 2 H), 3.85 (s, 3 H), 3.00 (d, J=7.5 Hz, 2 H), 1.42 (t, J=7 Hz, 3 H); 13C NMR (CDCl3) δ148.7, 148.5, 141.5, 133.7, 128.8, 127.4, 127.3, 119.5, 118.5, 112.7, 111.6, 64.4, 55.9, 46.7, 24.5, 14.7; Anal. Calcd for C18H17NO2. Theoretical: C, 76.84; H, 6.81; N, 4.98. Found: C, 76.53; H, 6.92; N, 4.95.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[CH3:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][N:35]=1.ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:30]=[C:29]([C:28]2[CH:31]=[CH:32][C:25]([CH3:24])=[C:26]([O:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:42])([F:43])[F:41])=[CH:36][N:35]=3)[CH:27]=2)[N:2]([CH3:1])[N:3]=1
Reactant: Cc1ccc(C#N)cc1Oc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Agent: Cl[Fe](Cl)Cl
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2nc(-c3c(F)cccc3Cl)nn2C)cc1Oc1ccc(C(F)(F)F)cn1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.10 g), 4-methyl-3-(5-trifluoromethylpyridine-2-yloxy)benzonitrile (0.90 g), anhydrous iron (III) chloride (0.60 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.60 g of desired compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:16])[C@H:13]([CH3:15])[NH2:14])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([O:20][C:21](=[O:32])/[CH:22]=[CH:23]/[C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:19].[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]\[C:36]([OH:38])=[O:37]>C1C=CC=CC=1>[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]\[C:36]([OH:38])=[O:37].[C:1]([O:5][C:6](=[O:17])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:16])[C@H:13]([CH3:15])[NH:14][C@H:22]([C:21]([O:20][CH2:18][CH3:19])=[O:32])[CH2:23][C:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:31])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: CCOC(=O)/C=C/C(=O)c1ccccc1
Agent: O=C(O)/C=C\C(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)[C@H](CC(=O)c1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Yield: 59.5 %

Procedure:
4.84 g (20 mmoles) of (S)-alanyl-(S)-proline-t-butylester are dissolved in 40 ml of dry benzene and 4.08 g (20 mmoles) of E-ethyl-3-benzoyl-acrylate are added at room temperature under stirring. After one hour stirring at room temperature the solvent is evaporated off under reduced pressure, the residue is dissolved in 20 ml of ethyl acetate and 2.32 g (20 mmoles) of maleinic acid are added. The precipitated crystals are filtered off after one hour standing and washed with 20 ml of ethyl acetate. 6.7 g (60%) of product are obtained with a melting point of 109°-110° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH:13]([CH2:14][O:15][CH3:16])[CH:12]2[CH2:11][N:10]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:9]3)=[CH:4][CH:3]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][C:25]1=[O:29].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Cu]I>[CH3:16][O:15][CH2:14][CH:13]1[C:8]2([C:5]3[CH:6]=[CH:7][C:2]([N:24]4[CH2:28][CH2:27][CH2:26][C:25]4=[O:29])=[CH:3][CH:4]=3)[CH:12]1[CH2:11][N:10]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:9]2
Reactant: O=C1CCCN1
Reactant: COCC1C2CN(C(=O)OC(C)(C)C)CC12c1ccc(Br)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COCC1C2CN(C(=O)OC(C)(C)C)CC12c1ccc(N2CCCC2=O)cc1
Temperature: 120 °C
Yield: 66.6 %

Procedure:
To a solution of tert-butyl 1-(4-bromophenyl)-6-(methoxymethyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylate (Intermediate IX, 890 mg, 2.33 mmol) in 1,4-dioxane (15 mL), was added 2-pyrrolidinone (0.177 mL, 2.33 mmol), (±)-trans-1,2-diamine (0.139 mL, 1.16 mmol), CuI (221.3 mg, 1.16 mmol) and potassium carbonate (643 mg, 4.66 mmol) under nitrogen atmosphere. The reaction mixture was heated at 120° C. for 36 h. After completion of the reaction as confirmed by TLC, the solvent was removed in vacuo to afford the crude compound, which was purified by column chromatography (silica gel, 2:8 EtOAc:Pet. ether) to afford pure tert-butyl 6-(methoxymethyl)-1-(4-(2-oxopyrrolidin-1-yl)phenyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylate (600 mg, 66%) as a viscous oil.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1)[NH2:3].[C:13]1([CH:19]([C:22](=O)[C:23]([F:26])([F:25])[F:24])[C:20]#[N:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH2:21][C:20]1[N:2]([C:4]2[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][OH:12])=[CH:8][CH:9]=2)[N:3]=[C:22]([C:23]([F:24])([F:25])[F:26])[C:19]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NNc1ccc(CCO)cc1
Reactant: N#CC(C(=O)C(F)(F)F)c1ccccc1
Agent: Cl
Product: Nc1c(-c2ccccc2)c(C(F)(F)F)nn1-c1ccc(CCO)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from 2-(4-hydrazinophenyl)ethanol hydrochloride and 2-phenyl-2-(trifluoroacetyl)acetonitrile: MS (ESI) m/z 348 [M+H]+, 346 [M−H]−, 1H-NMR (CDCl3) δ 7.58 (2H, J=8.4 Hz), 7.46-7.36 (7H, m), 3.94-3.88 (2H, m), 2.94 (2H, t, J=6.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][N:31]=1>C(Cl)Cl>[Cl:29][C:30]1[N:31]=[CH:32][C:33]([NH:36][C:37]([N:9]2[CH2:10][CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:38])=[CH:34][CH:35]=1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: O=C=Nc1ccc(Cl)nc1
Solvent: ClCCl
Product: CC(C)(C)CC1CN(C(=O)Nc2ccc(Cl)nc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (60.8 mg, 0.144 mmol) and 2-chloro-5-isocyanatopyridine (109.1 mg, 0.144 mmol, Maybridge) in CH2Cl2 (6 mL) was stirred at rt for 16 hrs. The reaction mixture was then purified by flash column to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid (6-chloro-pyridin-3-yl)-amide (59.1 mg, 71.1%). HRMS (ES+) m/z Calcd for C28H25Cl3F2N4O+H [(M+H)+]: 577.1135; Found: 577.1135.
Reaction SMILES: I[C:2]1[C:11]([NH:12][C:13](=[O:15])[CH3:14])=[C:10]([Cl:16])[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[OH:17].[C:18]1([C:24]#[CH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:13]([NH:12][C:11]1[C:2]2[CH:25]=[C:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:17][C:3]=2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][C:10]=1[Cl:16])(=[O:15])[CH3:14]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)c(I)c1O
Reactant: C#Cc1ccccc1
Product: COC(=O)c1cc(Cl)c(NC(C)=O)c2cc(-c3ccccc3)oc12

Procedure:
Methyl 3-iodo-4-acetamido-5-chloro-salicylate was reacted with phenylacetylene in analogy to what described in Example 1, Method A and B, except that no SiO2 was added. After column chromatography the title product was obtained.
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][C:7]2[C:3](=[N:4][O:5][N+:6]=2[O-:10])[CH:2]=1.[N:11]#[C:12][NH2:13]>>[CH:1]1[CH:9]=[CH:8][C:7]2[N+:6]([O-:10])=[N:11][C:12]([NH2:13])=[N+:4]([O-:5])[C:3]=2[CH:2]=1
Reactant: [O-][n+]1onc2ccccc21
Reactant: N#CN
Product: Nc1n[n+]([O-])c2ccccc2[n+]1[O-]

Procedure:
More particularly, benzofuroxan is reacted with a stoichiometric excess of cyanamide in the presence of an organic base in a non-aqueous medium at about room temperature. When the reaction is complete the reaction mixture is treated with an organic acid to give tirapazamine.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[N:16]=[CH:15][C:14]([F:17])=[CH:13][C:9]=2[C:10]([OH:12])=O)=[CH:4][CH:3]=1.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[C:9]([C:10]([NH:21][C@H:22]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=3)[CH3:23])=[O:12])=[CH:13][C:14]([F:17])=[CH:15][N:16]=2)=[CH:18][CH:19]=1
Reactant: O=C(O)c1cc(F)cnc1COc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(F)cnc2COc2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 2-[(4-chlorophenoxy)methyl]-5-fluoronicotinic acid (step 5) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [O:1]1CCC[CH2:2]1.[Br:6][C:7]1[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:10]2[CH:11]=[N:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:14](=[O:15])[C:9]=2[C:8]=1[CH2:33]Br.CO.C[O-].[Na+]>O>[Br:6][C:7]1[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:30])[CH3:31])[C:10]2[CH:11]=[N:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:14](=[O:15])[C:9]=2[C:8]=1[CH2:33][O:1][CH3:2]
Reactant: C1CCOC1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CBr)c(Br)n2COCC[Si](C)(C)C)c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCc1c(Br)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To 4 ml of tetrahydrofuran solution containing 459 mg (0.81 mmol) of 2-bromo-3-bromomethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 25-(a) was added 4 ml of 28% sodium methoxide methanol solution, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=4:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 359 mg of the title compound as a colorless oil. (Yield: 86%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[S:21][C:20]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[O:23])=[C:19]([CH3:33])[CH:18]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:17]2[S:21][C:20]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])=[C:19]([CH3:33])[CH:18]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Br)sc1C(=O)NCc1ccc(F)cc1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Product: Cc1cc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 28 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 4-(benzyloxy)pyridin-2(1H)-one in place of 4-aminopyridin-2(1H)-one to react with 5-bromo-N-(4-fluorobenzyl)-3-methylthiophene-2-carboxamide in place of N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 28% yield: mp 175-177° C.; 1H NMR (300 MHz, CDCl3) δ 7.55 (d, J=7.8 Hz, 1H), 7.43-7.36 (m, 5H), 7.31 (dd, J=8.5, 5.6 Hz, 2H), 7.02 (dd, J=8.5, 8.5 Hz, 2H), 6.84 (s, 1H), 6.20 (t, J=5.4 Hz, 1H), 6.14 (dd, J=7.8, 2.4 Hz, 1H), 6.05 (d, J=2.4 Hz, 1H), 5.03 (s, 2H), 4.54 (d, J=5.4 Hz, 2H), 2.53 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.8, 162.9, 162.2, 139.8, 139.7, 134.7, 134.4, 133.8 (JC-F=3.3 Hz), 129.5 (JC-F=8.1 Hz), 128.8, 127.8, 126.8, 121.9, 115.6 (JC-F=21.4 Hz), 103.4, 98.1, 70.6, 43.2, 15.9; MS (ES+) m/z 449.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:29]=[N:28][C:13]3[N:14]([CH2:26][CH3:27])[C:15]4[N:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:16]=4[N:17]([CH3:20])[C:18](=[O:19])[C:12]=3[CH:11]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[Cl:25][C:23]1[CH:22]=[CH:21][C:16]2[N:17]([CH3:20])[C:18](=[O:19])[C:12]3[CH:11]=[C:10]([CH2:9][CH2:8][C:5]4[CH:6]=[CH:7][C:2]([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:3][CH:4]=4)[CH:29]=[N:28][C:13]=3[N:14]([CH2:26][CH3:27])[C:15]=2[N:24]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCN1c2ncc(CCc3ccc(N)cc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN1c2ncc(CCc3ccc(NS(C)(=O)=O)cc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 8-[2-(4-aminophenyl)ethyl]-2-chloro-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (16 mg, 0.04 mmol) and 6 μL of pyridine in dichloromethane at 0° C. was added 5 μL of methanesulfonyl chloride. The reaction mixture was allowed to stir at room temperature overnight. The orange reaction mixture was then concentrated to dryness and the product was purified by flash chromatography, eluting with methanol/dichloromethane, and recrystallization from ethanol/hexanes to give 6 mg of the title compound, m.p. 199°-204° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][N:9]([CH3:27])[CH2:10][CH2:11][CH:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>C1C=CC=CC=1>[CH3:27][N:9]([CH3:8])[CH2:10][CH2:11][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:1](=[O:3])[CH3:2])=[CH:22][CH:21]=1
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)CCC(Oc1ccc(N)cc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CC(=O)Nc1ccc(OC(CCN(C)C)c2ccccc2)cc1
Reaction time: 0.75 h

Procedure:
2.8 ml of 98% acetic acid anhydride were added under an inert atmosphere to a solution of 7.6 g of N,N-dimethyl-γ-(4-amino-phenoxy)-benzene-propanamine in 80 ml of benzene and the mixture was stirred for 45 minutes. 50 ml of 2 N sodium hydroxide were added thereto and the decanted organic phase was washed with aqueous sodium chloride solution and was dried, treated with activated carbon and filtered. The filtrate was evaporated to dryness to obtain 9 g of N-[4-(3-dimethylamino-1-phenyl-propyloxy)-phenyl]acetamide.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C=O)C>[Si:30]([O:29][CH2:28][CH2:27][CH2:26][O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3][B:2]([OH:1])[C:6]=2[CH:7]=1)([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:32])[CH3:31]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(OCCCO[Si](C)(C)C(C)(C)C)cc(C)c21
Temperature: 60 °C

Procedure:
To a mixture of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (0.5 g, 2 mmol) and cesium carbonate (1.95 g, 6 mmol) in 10 ml DMF was added (3-bromopropoxy)(tert-butyl)dimethylsilane (1.39 ml, 6 mmol). The reaction was heated at 60° C. for six hours. It was then quenched by water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude was purified by column.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH:10]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Product: COc1ccc(Nc2cc(Cl)ccc2C(=O)O)cc1
Yield: 60 %

Procedure:
4-Chloro-2-(4-methoxyphenylamino)benzoic acid [VII; R=4--Cl, R"=H, OR°=4--OCH3 ] was prepared from 2,4-dichlorobenzoic acid and 4-methoxyaniline according to the procedure of Example 1, part (a), and was obtained in about 60% yield as a green-grey solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[F:18])=[N:5]1.[OH:20][C:21]([C:24]1[O:28][N:27]=[C:26]([C:29](O)=[O:30])[CH:25]=1)([CH3:23])[CH3:22].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[C:10]([F:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:29]([C:26]3[CH:25]=[C:24]([C:21]([OH:20])([CH3:22])[CH3:23])[O:28][N:27]=3)=[O:30])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1
Reactant: CC(C)(O)c1cc(C(=O)O)no1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1)NC(=O)c1cc(C(C)(C)O)on1

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile (0.3 g, 1.07 mmol), 5-(2-hydroxypropan-2-yl)-isoxazole-3-carboxylic acid (0.22 g, 1.29 mmol), HOBt (0.22 g, 1.61 mmol), DIPEA (0.56 mL, 3.23 mmol) and EDCI (0.31 g, 1.61 mmol) using DMF (10 mL) as solvent using the method of Example 34(d). Yield 40 mg. 1H NMR (400 MHz; CDCl3): δ 1.23 (d, 3H), 1.62 (s, 6H), 4.36 (m, 2H), 4.59 (m, 1H), 6.57 (m, 1H), 6.82 (dd, 1H), 7.54 (m, 2H), 8.00 (m, 1H), 8.20 (m, 1H).