Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]2[N:21]([CH2:33][CH3:34])[C:22]3[C:27]([C:28]=2[C:29]#[N:30])=[CH:26][CH:25]=[C:24]([O:31][CH3:32])[CH:23]=3)=[CH:14][CH:13]=1.C(OC=O)(=O)C>C1COCC1>[C:29]([C:28]1[C:27]2[C:22](=[CH:23][C:24]([O:31][CH3:32])=[CH:25][CH:26]=2)[N:21]([CH2:33][CH3:34])[C:20]=1[C:19]#[C:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][CH:8]=[O:10])=[CH:13][CH:14]=1)#[N:30]
Reactant: O=CO
Reactant: CCn1c(C#Cc2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Agent: CC(=O)OC=O
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CCn1c(C#Cc2ccc(NC=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Acetic anhydride (2.5 mL) and 98% formic acid (1.0 mL) are heated at 65° C. for 1 hour. This is cooled to 0° C. 2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.32 mmol), prepared as in example 1H, is taken up in THF (1.2 mL) and added to the formic acetic anhydride mixture. This is stirred at 0° C. for 30 minutes. The reaction mixture is then partitioned between H2O and EtOAc. The EtOAc layer is washed with saturated NaHCO3, followed by saturated brine. The organic layer is dried and concentrated. Purification by silica gel chromatography (4/1, CH2Cl2/EtOAc) yields N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-formamide (105 mg, 96%) as a yellow solid.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:38]([C:41]([CH2:48][CH3:49])([CH2:45][CH:46]=[CH2:47])[C:42](Cl)=[O:43])[CH:39]=[CH2:40]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:42](=[O:43])[C:41]([CH2:45][CH:46]=[CH2:47])([CH2:48][CH3:49])[CH2:38][CH:39]=[CH2:40])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C=CCC(CC)(CC=C)C(=O)Cl
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: C=CCC(CC)(CC=C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 77.5 %

Procedure:
A procedure similar to that described in Example 6, above, was followed, but using 1.65 g (3.0 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] and 2.80 g (15.0 mmol) of 2-allyl-2-ethyl-4-pentenoyl chloride, to provide 1.63 g of the title compound.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][N:5]1[C:11](=[O:12])[C:10]2[S:13][CH:14]=[CH:15][C:9]=2[N:8]2[CH:16]=[N:17][C:18]([C:19]([O:21]CC)=O)=[C:7]2[CH2:6]1>C(O)C>[CH3:4][N:5]1[C:11](=[O:12])[C:10]2[S:13][CH:14]=[CH:15][C:9]=2[N:8]2[CH:16]=[N:17][C:18]([C:19]([NH:2][NH2:3])=[O:21])=[C:7]2[CH2:6]1
Reactant: NN
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1sccc1-2
Solvent: O
Solvent: CCO
Product: CN1Cc2c(C(=O)NN)ncn2-c2ccsc2C1=O
Yield: 97 %

Procedure:
13 ml of hydrazine hydrate were added to a suspension of 7.0 g (24 mmol) of ethyl 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylate in 70 ml of ethanol and the mixture was heated at reflux for 3 hours. After cooling to 0° the crystals obtained were filtered off and there were obtained 6.5 g (97%) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylic acid hydrazide as colourless needles of m.p. >260°.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][C:14]=1[F:15])#[N:8].ClCCl.Br[C:23]1[N:27]2[N:28]=[C:29]([N:32]3[CH2:36][CH2:35][CH2:34][CH:33]3[C:37]3[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=3[CH3:44])[CH:30]=[CH:31][C:26]2=[N:25][CH:24]=1>O1CCOCC1.O>[CH3:44][C:38]1[CH:39]=[CH:40][C:41]([CH3:43])=[CH:42][C:37]=1[CH:33]1[CH2:34][CH2:35][CH2:36][N:32]1[C:29]1[CH:30]=[CH:31][C:26]2[N:27]([C:23]([C:11]3[CH:12]=[CH:13][C:14]([F:15])=[C:9]([CH:10]=3)[C:7]#[N:8])=[CH:24][N:25]=2)[N:28]=1
Reactant: Cc1ccc(C)c(C2CCCN2c2ccc3ncc(Br)n3n2)c1
Reactant: N#Cc1cc(B(O)O)ccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C)c(C2CCCN2c2ccc3ncc(-c4ccc(F)c(C#N)c4)n3n2)c1

Procedure:
In step 4-2, sodium carbonate (30 mg, 0.30 mmol), 3-cyano-4-fluoro phenylboronic acid (30 mg, 0.24 mmol) and Pd(DPPF)-dichloride catalyst (1,1′ bis(diphenylsphosphino-ferrocene)-dichloropalladium (II) adduct with dichloromethane) (10 mg, 0.012 mmol) was added into in a microwave vessel containing a solution of 3-bromo-6-(2-(2,5-dimethylphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (50 mg, 0.13 mmol) and 2.5 mL of 1,4-dioxane/water (3:1). The reaction mixture was subjected to the following microwave conditions using a laboratory microwave instrument (conditions: 150° C., 200 W max threshold, 20 atm. Max pressure, 20 minute reaction time). The resulting solution was purified using preparatory LC/MS (reverse phase C-18 chromatography) to yield 5-(6-(2-(2,5-dimethylphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-2-fluorobenzonitrile (4-2). 1H NMR (400 MHz, D3 acetonitrile) δ ppm 8.50-8.10 (m, 2H), 7.80 (br s, 1H), 7.50 (app d, J=8.5 Hz, 1H), 7.20 (app t, J=6.5 Hz, 1H), 7.06 (d, J=6.5 Hz, 1H), 6.93 (d, J=6.6 Hz, 1H), 6.81 (br s, 1H), 6.60 (br s, 1H), 5.22 (app dd, J=6.2, 2.1 Hz, 1H), 4.05-4.00 (m, 1H), 3.76 (app q, J=6.4 Hz, 1H), 3.36 (app d, J=2.2 Hz, 1H), 2.58-2.43 (m, 1H), 2.24 (br s, 6H), 2.19-2.08 (m, 2H). LCMS observed m/z 412.2.
Reaction SMILES: [C:1](Cl)(=O)[CH3:2].[N+:5]([C:8]([CH3:38])([CH3:37])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)=[CH:13][C:12]=1[C:30]1[N:31]([CH3:36])[N:32]=[CH:33][C:34]=1[Cl:35])([O-])=O>CO.[Zn]>[Cl:35][C:34]1[CH:33]=[N:32][N:31]([CH3:36])[C:30]=1[C:12]1[CH:13]=[C:14]([NH:17][C:18](=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH:15]=[CH:16][C:11]=1[O:10][CH2:9][C:8]([NH:5][CH2:1][CH3:2])([CH3:38])[CH3:37]
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(C)(C)[N+](=O)[O-]
Reactant: CC(=O)Cl
Agent: [Zn]
Solvent: CO
Product: CCNC(C)(C)COc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1c(Cl)cnn1C
Temperature: 23 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (388 μl, 5.44 mmol) was added dropwise to a solution of N-(4-(2-nitro-2-methylpropoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)phenyl)-3-(trifluoromethyl)benzamide (270 mg, 0.544 mmol) in methanol (5.0 mL). Zinc dust (356 mg, 5.44 mmol) was added, and the mixture was stirred at 23° C. After 1 hour, the mixture was filtered and the filtrate was evaporated to dryness. The residue was taken up in ammonium hydroxide (35%), diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried with sodium sulfate, filtered, and evaporated to dryness to afford the title compound as a colorless foam which was used without further purification. LCMS m/z (%) 469.4 (M+H, 37Cl 46.9), 467.2 (M+H, 35Cl 86.1), 452.2 (51.6%), 450.1 (100.0%).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[C:13](Cl)=[N:14][C:15]([Cl:19])=[C:16]([F:18])[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:23]([N:27]=[C:28]=[O:29])[CH2:24][CH2:25][CH3:26]>CC(N(C)C)=O>[CH2:1]([O:8][N:9]1[C:10](=[O:11])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[N:14][C:13]=2[N:27]([CH2:23][CH2:24][CH2:25][CH3:26])[C:28]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCN=C=O
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(Cl)nc21
Yield: 58.4 %

Procedure:
Using the General Method 5, the reaction of N-benzyloxy-2,6-dichloro-5-fluoro-3-pyridinecarboxamide (Example M-2, 2.00 g, 6.34 mmol) and 60% NaH in oil (300 mg, 7.52 mmol) with n-butyl isocyanate (2.14 mL, 19.02 mmol) in DMA afforded crude product. Recrystallization from chloroform provided 1.40 g of the title compound as a solid, mp 147-148° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([O:30][P:31]([O:36][CH2:37][CH3:38])([O:33][CH2:34][CH3:35])=[O:32])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[O:39]1[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][C@@H:47]([NH:56][C:57]2[CH:62]=[CH:61][C:60]([S:63]([NH2:66])(=[O:65])=[O:64])=[CH:59][C:58]=2[S:67]([C:70]([F:73])([F:72])[F:71])(=[O:69])=[O:68])[CH2:48][S:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:41][CH2:40]1.C(Cl)CCl>C(Cl)Cl>[ClH:1].[P:31]([O:36][CH2:37][CH3:38])([O:33][CH2:34][CH3:35])([O:30][C@@H:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:29]=[CH:28][C:24]([C:25](=[O:26])[NH:66][S:63]([C:60]3[CH:61]=[CH:62][C:57]([NH:56][C@H:47]([CH2:46][CH2:45][N:42]4[CH2:43][CH2:44][O:39][CH2:40][CH2:41]4)[CH2:48][S:49][C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)=[C:58]([S:67]([C:70]([F:72])([F:73])[F:71])(=[O:69])=[O:68])[CH:59]=3)(=[O:64])=[O:65])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=[O:32]
Reactant: CCOP(=O)(OCC)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: NS(=O)(=O)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOP(=O)(OCC)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@H](CCN4CCOCC4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)cc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (R)-4-(4-((4′-chlorobiphenyl-2-yl)(diethoxyphosphoryloxy)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 120, 371 mg, 0.66 mmol), (R)-4-(4-morpholino-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 69, 368 mg, 0.66 mmol), EDC (255 mg, 1.33 mmol), TEA (0.185 ml, 1.33 mmol), and DCE (5 ml) were stirred at r.t. for 2 hours. The mixture was diluted with DCM (15 ml) and adsorbed onto silica gel. Purification by column chromatography (ISCO, eluting with 0→10% MeOH/DCM over 19 minutes followed by elution with 0→10% 2M NH3/MeOH/DCM over 24 minutes) gave a residue which was further purified by reverse phase HPLC, according to the conditions:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[NH:11][CH2:10][CH2:9][NH:8][C:7]1=[O:12])=[O:5])[CH3:2].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][C:4]([CH:6]1[N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH2:9][NH:8][C:7]1=[O:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1NCCNC1=O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1C(=O)NCCN1C(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
To a cold (-20° C.) solution of above 2-oxopiperazine-3-carboxylic acid ethyl ester (0.34 g) in tetrahydrofuran are dropwise added benzyl chloroformate (340 mg) and triethylamine (202 mg). After standing for 30 minutes the reaction mixture is concentrated in vacuum, diluted with ethyl acetate, and chromatographed to give oily 2-oxo-4-benzyloxycarbonylpiperazine-3-carboxylic acid ethyl ester (320 mg) as oil.
Reaction SMILES: [C:1]1([CH2:11][C:12]#[N:13])([CH2:8][C:9]#[N:10])[CH2:4][C:3](=[CH:5][C:6]#[N:7])[CH2:2]1.[NH:14]1[CH:18]=[C:17]([C:19]2[C:20]3[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:21]=3[N:22]=[CH:23][N:24]=2)[CH:16]=[N:15]1.N12CCCN=C1CCCCC2>C(#N)C>[CH3:33][Si:32]([CH3:35])([CH3:34])[CH2:31][CH2:30][O:29][CH2:28][N:25]1[C:21]2[N:22]=[CH:23][N:24]=[C:19]([C:17]3[CH:16]=[N:15][N:14]([C:3]4([CH2:5][C:6]#[N:7])[CH2:2][C:1]([CH2:8][C:9]#[N:10])([CH2:11][C:12]#[N:13])[CH2:4]4)[CH:18]=3)[C:20]=2[CH:27]=[CH:26]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: N#CC=C1CC(CC#N)(CC#N)C1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(CC#N)(CC#N)C4)c3)ncnc21
Temperature: 50 °C

Procedure:
The crude 2,2′,2″-cyclobutane-1,1-diyl-3-ylidenetriacetonitrile (1 g, 0.006 mol) was combined with 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.2 g, 0.0006 mol) in acetonitrile (10 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 mL, 0.001 mol) was added under nitrogen. The mixture was heated at 50° C. over night. The reaction was concentrated and purified with Combiflash (silica gel, 0-100% EtOAc/Hex) to give the desired product as light brown oil. LCMS calculated for C25H31N8OSi(M+H)+: 487.2; Found: 487.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.[C:12](Cl)(=[O:14])[CH3:13]>>[C:12]([C:11]1[C:3]([O:2][CH3:1])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12)(=[O:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: COc1cc2ccccn2n1
Product: COc1nn2ccccc2c1C(C)=O

Procedure:
A mixture of 2-methoxypyrazolo[1,5-a]pyridine (280 mg) acetic anhydride (3 ml) and acetyl chloride (1 ml) was refluxed for 1 hr and the reaction mixture was concentrated under reduced pressure. Water was added to the residue and the solution was made basic with potassium carbonate. The precipitated crystals were collected and washed with water. Recrystallization from n-hexane-ethyl acetate gave colorless needles, mp 158.0°-158.5°. Yield 160 mg.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]([CH2:21][C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=2)S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)=[C:5]([CH2:32][OH:33])[CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].C1(S)C=CC=CC=1>CN(C=O)C>[CH3:28][C:27]1[C:22]([CH2:21][NH:8][CH2:7][C:6]2[CH:30]=[CH:31][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[CH2:32][OH:33])=[N:23][CH:24]=[C:25]([CH3:29])[CH:26]=1
Reactant: Cc1cnc(CN(Cc2ccc(C#N)cc2CO)S(=O)(=O)c2ccccc2[N+](=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cnc(CNCc2ccc(C#N)cc2CO)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.5 %

Procedure:
To a solution of N-(4-cyano-2-hydroxymethyl-benzyl)-N-(3,5-dimethyl-pyridin-2-ylmethyl)-2-nitro-benzene-sulfonamide (0.82 g, 1.76 mmol) dissolved in DMF (35 mL) was added K2CO3 (1.21 g, 8.75 mmol) and thiophenol (0.54 mL, 5.28 mmol). The mixture was stirred at room temperature for 3 hours then concentrated in vacuo and redissolved in CH2Cl2 (50 mL). The mixture was filtered through a celite plug and the filtrate was concentrated in vacuo to afford a yellow solid. Purification by column chromatography on silica gel (hexane:EtOAc, 4:1, v/v →EtOAc) afforded 4-{[(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-methyl}-3-hydroxymethyl-benzonitrile (0.176 g, 35%) as a yellow solid. 1H NMR (CDCl3) δ 2.20 (s, 3H), 2.28 (s, 3H), 3.82 (s, 2H), 3.99 (s, 2H), 4.65 (s, 2H), 7.26 (s, 1H), 7.36 (d, 1H, J=6.0 Hz), 7.55 (d, 1H, J=6.0 Hz), 7.64 (s, 1H), 8.20 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=2)[C:5]([C:16]#[N:17])=[C:4](F)[CH:3]=1.CC([O-])(C)C.[K+].[CH:25]1([OH:29])[CH2:28][CH2:27][CH2:26]1.Cl>>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=2)[C:5]([C:16]#[N:17])=[C:4]([O:29][CH:25]2[CH2:28][CH2:27][CH2:26]2)[CH:3]=1
Reactant: OC1CCC1
Reactant: CCc1ccc(-c2cc(Br)cc(F)c2C#N)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: CCc1ccc(-c2cc(Br)cc(OC3CCC3)c2C#N)cc1
Reaction time: 5 h

Procedure:
1-Bromo-4-cyano-3-fluoro-5-(4-ethyl-phenyl)-benzene (1.2 g) is added to a flask charged with a stir bar, KOtBu (0.5 g) and cyclobutanol (3.0 g). The solution is stirred at room temperature overnight, before another portion of KOtBu (0.2 g) is added. The solution is stirred for another 5 h and then neutralized with 1 M aqueous HCl solution. The resulting mixture is extracted with ethyl acetate, the combined organic phases are dried (sodium sulphate) and the solvent is removed to give the title compound.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=2[O:2]1.C(=O)([O-])[O-].[Na+].[Na+].[C:19]([NH:27][C:28]1[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:29]=1[C:30]([O:32]C)=[O:31])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C(=O)C>[C:19]([NH:27][C:28]1[CH:37]=[C:36]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)[CH:35]=[CH:34][C:29]=1[C:30]([OH:32])=[O:31])(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: COC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cc(-c2ccc3c(c2)OCO3)ccc1C(=O)O)c1ccccc1
Temperature: 90 °C
Reaction time: 22 h
Yield: 56.8 %

Procedure:
52 mg of 3,4-methylenedioxyphenylboronic acid, 55 mg of sodium carbonate and 30 mg of polymer supported bis(acetato)triphenylphosphine palladium(II) were added to 2.5 mL of N,N-dimethylacetamide solution containing 70 mg of methyl 2-(benzamido)-4-bromobenzoate, and stirred at 90° C. for 22 hours. After the reaction mixture was cooled to room temperature, insoluble were removed by filtration and ethyl acetate and 1.2 mol/L hydrochloric acid were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 1.0 mol/L hydrochloric acid and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. 1.0 mL of 1.0 mol/L aqueous sodium hydroxide and 2.0 mL of ethanol were added to the obtained residue and stirred at room temperature for 1 hour. 0.6 mol/L hydrochloric acid was added to the reaction mixture and a solid substance was separated by filtration to obtain 43 mg of 2-(benzamido)-4-(benzo[1,3]dioxol-5-yl)benzoic acid as white solid.
Reaction SMILES: CC(C)([O-])C.[K+].CO[C:9](=[O:32])[C:10]1[CH:15]=[C:14]([Br:16])[C:13]([Cl:17])=[CH:12][C:11]=1[N:18]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:25][O:24][C:22]([CH:21]1[CH2:20][CH2:19][N:18]([C:26]([O:28][CH:29]([CH3:30])[CH3:31])=[O:27])[C:11]2[CH:12]=[C:13]([Cl:17])[C:14]([Br:16])=[CH:15][C:10]=2[C:9]1=[O:32])=[O:23]
Reactant: COC(=O)CCCN(C(=O)OC(C)C)c1cc(Cl)c(Br)cc1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)C1CCN(C(=O)OC(C)C)c2cc(Cl)c(Br)cc2C1=O
Temperature: 25 °C
Yield: 61.6 %

Procedure:
To a heated mixture of potassium t-butoxide (1.27 g, 11.3 mmol) in toluene (50 ml) at 70° C. was added a solution of 5-Bromo-4-chloro-2-[isopropoxycarbonyl-(3-methoxycarbonyl-propyl)-amino]-benzoic acid methyl ester (2.55 g, 5.66 mmol) in toluene (50.0 ml) over 30 minutes. After the addition was completed, the mixture was cooled to room temperature and diluted with ethyl acetate (100 ml), and then washed with 1.00N HCl(aq) (120 ml) and brine (3×120 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purification by silica gel chromatography (gradient eluent, 0-15% ethyl acetate in hexane) provided 7-Bromo-8-chloro-5-oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1,4-dicarboxylic acid 1-isopropyl ester 4-methyl ester (1.46 g, 62%) as oil. MS (ES+): 418, 420 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[N+:18]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])([O-:20])=[O:19].CO.C([O-])(O)=O.[Na+]>COCCO>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:24][C:23]1[CH:25]=[CH:26][CH:27]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: COCCO
Product: COc1cc2ncc(C#N)c(Nc3cccc([N+](=O)[O-])c3)c2cc1OC
Yield: 68.5 %

Procedure:
A solution of 0.500 g (2.00 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile and 0.332 g (2.41 mmol) of 3-nitroaniline in 6 mL of methyl cellosolve was refluxed under N2 for 8 hr. Methanol was added, followed by satd NaHCO3 (pH 8) and volatile material was removed. The residue was slurried with water, collected by filtration and dried. Recrystallization from ethanol gave 0.480 g of 6,7-dimethoxy-4-(3-nitrophenylamino)quinoline-3-carbonitrile as yellow crystals: mass spectrum (electrospray, m/e): M+H 351.0.
Reaction SMILES: [Cl:1][C:2]([Cl:14])([Cl:13])[CH2:3][O:4][C:5]([NH:7][C:8]1[CH:12]=[CH:11][O:10][N:9]=1)=[O:6].O[CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH2:34][CH2:33][N:32]([CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:31][CH:30]=3)=[C:25]([F:42])[CH:24]=2)[CH2:18]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[O:10]1[CH:11]=[CH:12][C:8]([N:7]([CH2:16][C@@H:17]2[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH2:34][CH2:33][N:32]([CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH2:31][CH:30]=4)=[C:25]([F:42])[CH:24]=3)[CH2:18]2)[C:5]([O:4][CH2:3][C:2]([Cl:1])([Cl:13])[Cl:14])=[O:6])=[N:9]1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(C2=CCN(Cc3ccccc3)CC2)c(F)c1
Reactant: O=C(Nc1ccon1)OCC(Cl)(Cl)Cl
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: O=C1O[C@@H](CN(C(=O)OCC(Cl)(Cl)Cl)c2ccon2)CN1c1ccc(C2=CCN(Cc3ccccc3)CC2)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-(2,2,2-trichloroethyloxycarbonylamino)isoxazole (1.30 g, 5.0 mmol), 5(R)-hydroxymethyl-3-(3-fluoro-4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)oxazolidin-2-one (WO 97/30995; 1.91 g, 5.0. mmol) and tributylphosphine (1.52 g, 7.5 mmol) in dry tetrahydrofuran (50 ml) under a nitrogen atmosphere at 0° C., was added 1,1′-(azodicarbonyl)dipiperidine (1.89 g, 7.5 mmol) in dry tetrahydrofuran (15 ml). The solution was stirred at 0° C. for 30 minutes before being allowed to come to room temperature and it was then stirred for 2 days. The mixture was filtered, concentrated by rotary evaporation and chromatographed by MPLC (30% ethyl acetate/hexane, ICN Alumina N 32-63), and triturated with ether to give the title compound as a white amorphous solid (1.62 g, 52%). NMR: 2.41 (m, 2H), 2.60 (t, 2H), 3.15 (m, 2H), 3.90 (dd, 1H), 4.18 (m, 2H), 4.37 (dd, 1H), 5.04 (dd, 3H), 5.95 (broad s, 1H), 6.88 (s, 1H), 7.32 (m, 3H), 8.89 (s, 1H); m/z ES+ (M+H)=623.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][O:12][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCC2(CC1)OCCO2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1,4-dioxa-spiro[4.5]dec-8-yl)-methanol (1.0 g, 5.8 mmol, 1.0 eq.) and ethyldiisopropylamine (17 mL, 3.0 eq.) in methylene chloride (4 mL) at 0° C. was added dropwise MsCl (0.46 mL, 1.0 eq.) and the resulting mixture was warmed to room temperature and stirred for 2 h. The reaction was quenched by addition of sat. NaHCO3 and the separated aqueous phase was extracted with 3× methylene chloride and 4×EtOAc. The combined organic phase was dried over over Na2SO4, filtered and concentrated to give a crude methanesulfonic acid 1,4-dioxa-spiro[4.5]dec-8-ylmethyl ester.