Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:16]2[C:15]3[CH:14]=[C:13]([OH:17])[CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH3:18].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(O)C>CN(C=O)C>[CH3:3][N:4]1[C:16]2[C:15]3[CH:14]=[C:13]([O:17][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: Cc1nc2cnc3ccc(O)cc3c2n1C
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2ncc3nc(C)n(C)c3c2c1
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
Sodium hydride (0.61 g, 15 mmol, available as a 60% dispersion in mineral oil) was added to a solution of 1,2-dimethyl-1H-imidazo[4,5-c]quinolin-8-ol (2.5 g, 12 mmol) in DMF. The reaction mixture was stirred for 30 minutes, and ethyl bromoacetate (1.96 g, 11.7 mmol) was added. The stirring was continued for five hours, and a small volume of ethanol was added. The volatiles were removed under reduced pressure, and the residue was dissolved in dichloromethane. The resulting solution was washed three times with deionized water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting yellow solid was recrystallized from ethyl acetate to provide 1.65 g of ethyl 2-[(1,2-dimethyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]acetate as a white solid.
Reaction SMILES: CN(C=O)C.Br[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[N:24]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:23]=[N:22][N:21]=2)=[CH:10][CH:9]=1.[CH2:44]([C:48]1[NH:52][C:51]([CH:53]=[O:54])=[C:50]([Cl:55])[N:49]=1)[CH2:45][CH2:46][CH3:47].C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[CH2:44]([C:48]1[N:52]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[N:24]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:23]=[N:22][N:21]=3)=[CH:10][CH:9]=2)[C:51]([CH:53]=[O:54])=[C:50]([Cl:55])[N:49]=1)[CH2:45][CH2:46][CH3:47]
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a DMF (150 mL) solution of 5-(4′-bromomethyl-biphenyl-2-yl)-1-trityl-1H-tetrazole (30 g, 53.8 mmol) was added 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (10 g, 53.8 mmol) and K2CO3 (7.4 g, 53.8 mmol). The mixture was stirred at room temperature overnight. EtOAc (500 mL) was added and the organic was washed three times with a NaHCO3 solution (200 mL) followed by saturated aqueous NaCl (200 mL). Solvent was removed and purification was achieved by silica gel chromatography (50:50 EtOAc:hexanes) using an isocratic gradient to provide intermediate (11a) a white solid (41 g). MS m/z: [M+H+] calcd for C41H35ClN6O, 663.26; found 663.4. 1H-NMR (d4-MeOH): 0.83 (m, 3H), 1.26 (m, 2H), 1.53 (m, 2H), 2.53 (m, 2H), 5.56 (s, 2H), 6.87-6.96 (m, 8H), 7.05 (m, 2H), 7.25-7.43 (m, 1OH), 7.53-7.58 (m, 2H), 7.84 (d, 1H), 9.73 (s, 1H).
Reaction SMILES: Br[C:2]1[C:3]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[N:4][N:5]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[Cu][C:29]#[N:30].[OH-].[NH4+]>CN(C)C=O.C(OCC)(=O)C.O>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][N:5]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[C:2]([C:29]#[N:30])[C:3]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[N:4]1
Reactant: Cc1ccc(-c2c(Br)c(-c3ncccn3)nn2Cc2ccccc2F)cc1
Reactant: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(-c2c(C#N)c(-c3ncccn3)nn2Cc2ccccc2F)cc1
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 90.1 %

Procedure:
To a suspension of 2-(4-bromo-1-(2-fluorobenzyl)-5-p-tolyl-1H-pyrazol-3-yl)pyrimidine (145 mg, 0.343 mmol) in N,N-dimethylformamide was added copper(I) cyanide (178 mg, 1.884 mmol). The solution was cooled to 23° C. and 5 mL of water, 5 mL of ammonium hydroxide, and 5 mL of ethyl acetate were added. The blue heterogeneous mixture was stirred rapidly for 45 min, and then further diluted with ethyl acetate (75 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organics were combined and washed with brine (50 mL), dried over magnesium sulfate, filtered, and the solvent was removed in vacuo to give the crude product as an oil. Purification by silica gel chromatography (hexanes/ethyl acetate) gave 1-(2-fluorobenzyl)-3-(pyrimidin-2-yl)-5-p-tolyl-1H-pyrazole-4-carbonitrile (114 mg, 0.309 mmol, 90% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.92 (d, 2H), 7.34-7.23 (m, 6H), 7.09-6.98 (m, 3H), 5.52 (s, 2H), 2.42 (s, 3H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[CH:12][CH:13]=2)[CH:8]=1)(=O)=O.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:18][O:17][C:11]1[CH:12]=[CH:13][C:14]2[C:9](=[CH:8][C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1
Product: COc1ccc2ccc(-c3ccccc3)cc2c1

Procedure:
The title compound was prepared by reacting 7-methoxy-2-naphthyl trifluoromethanesulfonate (3.01 g, 9.83 mmol) with phenylboronic acid (1.4 g, 12 mmol) according to method A to yield 1.95 g (85%) of a white solid mp 62–64° C.; 1H NMR (CDCl3) δ 3.95 (3H, s), 7.15 (1H, dd, J=2.56 Hz, J=8.79 Hz), 7.20 (1H, d, J=2.56 Hz), 7.36–7.39 (1H, m), 7.46–7.50 (2H, m), 7.60 (1H, dd, J=1.83 Hz, J=8.42 Hz), 7.70–7.73 (2H, m), 7.76 (1H, d, J=8.79 Hz), 7.84 (1H, d, J=8.42 Hz), 7.94 (1H, d, J=1.46 Hz); MS (El) m/z 234 (M)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C@H:11]([N:14]2[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][O:21][CH3:22])[CH2:15]2)[CH2:12][OH:13])[CH:8]=[CH:9][CH:10]=1.[CH3:23][O:24][CH2:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]([OH:44])[CH2:34][N:35]2[CH2:39][CH2:38][C@H:37]([O:40][CH2:41][O:42][CH3:43])[CH2:36]2)[CH:30]=[CH:31][CH:32]=1.[CH3:45][NH:46][C:47]1[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=1>>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C@H:11]([N:14]2[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][O:21][CH3:22])[CH2:15]2)[CH2:12][OH:13])[CH:8]=[CH:9][CH:10]=1.[CH3:23][O:24][CH2:25][O:26][C:27]1[CH:28]=[C:29]([C@@H:33]([OH:44])[CH2:34][N:35]2[CH2:39][CH2:38][C@H:37]([O:40][CH2:41][O:42][CH3:43])[CH2:36]2)[CH:30]=[CH:31][CH:32]=1.[CH3:23][O:24][CH2:25][O:26][C:27]1[CH:28]=[C:29]([C@@H:33]([N:46]([C:47]2[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=2)[CH3:45])[CH2:34][N:35]2[CH2:39][CH2:38][C@H:37]([O:40][CH2:41][O:42][CH3:43])[CH2:36]2)[CH:30]=[CH:31][CH:32]=1
Reactant: CNc1ccc(C(=O)OC)cc1
Reactant: COCOc1cccc(C(O)CN2CC[C@H](OCOC)C2)c1
Agent: COCOc1cccc([C@@H](CO)N2CC[C@H](OCOC)C2)c1
Product: COCOc1cccc([C@@H](O)CN2CC[C@H](OCOC)C2)c1
Product: COCOc1cccc([C@H](CN2CC[C@H](OCOC)C2)N(C)c2ccc(C(=O)OC)cc2)c1

Procedure:
2-(S)-(3-Methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol and 1-(R)-(3-methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol were prepared from (R)-1-(3-methoxymethoxyphenyl)-1,2-ethanediol-2-tosylate in 58% yield as a mixture according to the procedures similar to those described in Preparation 3. Title compound was prepared by reacting the mixture of 2-(S)-(3-methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrroldin-1-yl)ethanol and (3-methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol with methyl 4-methylaminobenzoate in 54% yield according to the procedures similar to those described in Example 1 (i).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:31](=O)[N:30]([CH3:33])[C:12]2[N:13]([CH3:29])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20](=O)[CH2:21][C:22](=O)[CH2:23][N:24]([CH3:26])[CH3:25])=[CH:16][CH:15]=3.[OH2:34].[NH2:35][NH2:36]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:31](=[O:34])[N:30]([CH3:33])[C:12]2[N:13]([CH3:29])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:35][N:36]=[C:22]([CH2:23][N:24]([CH3:26])[CH3:25])[CH:21]=1)=[CH:16][CH:15]=3
Reactant: O
Reactant: CN(C)CC(=O)CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Reactant: NN
Product: CN(C)Cc1cc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)[nH]n1

Procedure:
The process is carried out as in Example 43 above, with compound A 1-[3-(2,4-dichlorophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-4-dimethylaminobutane-1,3-dione and hydrazine monohydrate.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[N:8][C:9]([NH2:10])=[C:4]2[CH:3]=[N:2]1.C1C(=O)N([I:18])C(=O)C1>CN(C=O)C>[I:18][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:10])[NH:1][N:2]=1
Reactant: Nc1ncnc2[nH]ncc12
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Nc1ncnc2[nH]nc(I)c12
Temperature: 70 °C
Reaction time: 8 h
Yield: 42.5 %

Procedure:
A mixture of 1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (5.0 g, 37 mmol) and NIS (10.7 g, 45 mmol) in DMF (100 mL) was stirred at 70° C. overnight. Then the mixture was cooled to room temperature and filtered to give 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (4.1 g) as a white solid. The filtrate was concentrated and the residue was treated with 10% Na2SO3 and filtered to give another batch. (5.1 g, 96% of total yield)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]3[C:16]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)=[C:15]([C@H:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:25]([OH:27])=[O:26])[C:14]([CH3:33])=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:40](I)[CH3:41]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]3[C:16]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)=[C:15]([C@H:24]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[C:25]([O:27][CH2:40][CH3:41])=[O:26])[C:14]([CH3:33])=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2nc(-c3cccc(Br)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cccc(Br)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of (S)-2-(2-(3-bromophenyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetic acid (104 mg, 0.191 mmol) in DMF, was added Cs2CO3 (152 mg, 0.467 mmol), ethyl iodide (30 μL, 0.343 mmol). The reaction was stirred at room temperature for 2 hs. The reaction mixture was washed by sat. NaHCO3, extracted by EtOAc, dry over MgSO4, filtered, purified by silica gel column, eluting by 0-50% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C28H27BrClNO3S: 572.1 (M+H+); Found: 572.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].Cl[CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]2[CH2:33][O:34][CH2:35][CH:29]2[CH2:28]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH:30]5[CH2:33][O:34][CH2:35][CH:29]5[CH2:28]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: ClCCCN1CCC2COCC2C1
Reactant: C#Cc1cccc(Nc2ncnc3cc(OC)c(O)cc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C#Cc1cccc(Nc2ncnc3cc(OC)c(OCCCN4CCC5COCC5C4)cc23)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
A mixture of 4-((3-ethynylphenyl)amino)-7-methoxyquinazolin-6-ol (250 mg, 0.68 mmol, 1 eq), 5-(3-chloropropyl)octahydrofuro[3,4-c]pyridine (280 mg, 0.82 mmol, 1.2 eq) and K2CO3 (188 mg, 1.36 mmol, 2 eq) in DMF (10 mL) was stirred at 80° C. overnight and cooled to room temperature. To this, CH2Cl2 (50 mL) was added. The mixture was washed with brine (20 mL×3) and water (20 mL×2), then dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the title compound as a yellow solid (140 mg, 45.50%), HPLC: 98.47%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 459.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.73-1.75 (2H, m), 2.35-2.46 (3H, m), 2.54-2.68 (2H, m), 2.65-2.70 (3H, m), 2.72-2.76 (2H, m), 2.96-3.03 (3H, m), 3.05-3.10 (2H, m), 3.71-3.90 (2H, m), 4.03 (1H, s), 4.22-4.27 (2H, m), 7.06-7.12 (1H, m), 7.13 (1H, s), 7.76-7.82 (2H, m), 7.85 (1H, s), 8.06-8.11 (1H, m), 8.55 (1H, s) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[OH:26])[C:6]([C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][C:9]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7].[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32]Cl)[CH3:28]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH2:32][CH2:31][CH2:30][N:29]([CH2:34][CH3:35])[CH2:27][CH3:28])[C:6]([C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][C:9]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7]
Reactant: COc1cc(C(=O)c2c(-c3ccccc3)oc3ccccc23)ccc1O
Reactant: CCN(CC)CCCCl
Product: CCN(CC)CCCOc1ccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1OC

Procedure:
Reaction of 3-(3-methoxy-4-hydroxybenzoyl)-2-phenylbenzofuran with 3-diethylaminopropyl chloride according to the procedure of Example 1 gives the title compound.
Reaction SMILES: [S:1](=[C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH2:5]1)(=[O:3])=[O:2].[CH2:14]([NH2:18])[CH2:15][CH2:16][CH3:17].C(#[N:21])C>>[CH2:14]([NH:18][S:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:21])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])=[O:2])[CH2:15][CH2:16][CH3:17]
Reactant: CC#N
Reactant: CCCCN
Reactant: O=S(=O)=C1C=CC(S(=O)(=O)Cl)=CC1
Product: CCCCNS(=O)(=O)c1ccc(S(N)(=O)=O)cc1
Reaction time: 3 h
Yield: 70 %

Procedure:
The reaction flask was charged with 10 g (0.039 mole) of 4-(sulfonyl)benzenesulfonyl chloride prepared by a procedure described in J. Med. Chem., 6 pp. 307-11 (1963) in 7 ml acetonitrile. A dropping funnel was charged with 8.8 g (0.12 mole) of butylamine and the amine was added dropwise, allowing the temperature to rise. The mixture was stirred for three hours and then concentrated to a thick residue. The residue was slurried with 100 ml water and the mixture filtered to collect a white solid. After drying, the weight of solid was 8.0 g (70% yield), mp 164°-167° C. A recrystallization from 190 proof ethanol (4 ml/g) and water (4 ml/g) gave 6.6 g of title compound, mp 170°-172° C.
Reaction SMILES: [CH:1]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15](O)=[O:16])=[C:11]([C:18]([OH:20])=[O:19])[CH:10]=2)=[O:8])=[CH:5][C:4]([C:21]([OH:23])=[O:22])=[C:3]([C:24]([OH:26])=O)[CH:2]=1.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[CH:1]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]3[C:15]([O:20][C:18](=[O:19])[C:11]=3[CH:10]=2)=[O:16])=[O:8])=[CH:5][C:4]2[C:21]([O:22][C:24](=[O:26])[C:3]=2[CH:2]=1)=[O:23]
Reactant: O=C(c1ccc(C(=O)O)c(C(=O)O)c1)c1ccc(C(=O)O)c(C(=O)O)c1
Agent: O=C(c1ccccc1)c1ccccc1
Product: O=C(c1ccc2c(c1)C(=O)OC2=O)c1ccc2c(c1)C(=O)OC2=O

Procedure:
A process for producing benzophenone tetracarboxylic dianhydride, which comprises adding benzophenone tetracarboxylic acid to a solvent comprising, as the main constituent, an organic compound having a boiling point of more than 100° C. and being inert to benzophenone tetracarboxylic acid and benzophenone tetracarboxylic anhydrides, and heating the resulting mixture. This process enables one to produce benzophenone tetracarboxylic dianhydride having a very low moisture absorbency.
Reaction SMILES: C=O.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24](OC(C)(C)C)=O)[CH2:20][CH2:19]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl.C(OCC)C>O.C(O)=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH:18]1[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1ccc(OCC2CCN(C(=O)OC(C)(C)C)CC2)c(OC)c1
Agent: C=O
Agent: Cl
Solvent: O=CO
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1ccc(OCC2CCN(C)CC2)c(OC)c1
Temperature: 95 °C
Yield: 111.9 %

Procedure:
Formaldehyde (35 ml of a 37% solution in water, 420 mmol) was added to a solution of ethyl 3-methoxy-4-(1-tert-butyloxycarbonylpiperidin-4-ylmethoxy)benzoate (35 g, 89 mmol) in formic acid (35 ml) and the reaction was heated at 95° C. for 3 hours. The reaction was cooled, the volatiles we removed in vacuo and the residue was dissolved in dichloromethane. 3.0 N Hydrogen chloride in diethyl ether (40 ml, 120 mmol) was added, together with a little diethyl ether and a solid was precipitated. Collection of the solid by suction filtration followed by drying in vacuo yielded ethyl 3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (30.6 g, 100% yield) as a white solid:
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][N:9]1[CH2:18][C@@H:19]([OH:30])[C@@H:20]([NH2:29])[CH2:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+].O.[C:37]([O:40][C:41]1[C:42]([CH3:50])=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44](Cl)=[O:45])(=[O:39])[CH3:38]>C(OCC)(=O)C>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][N:9]1[CH2:18][C@@H:19]([OH:30])[C@@H:20]([NH:29][C:44](=[O:45])[C:43]1[CH:47]=[CH:48][CH:49]=[C:41]([O:40][C:37](=[O:39])[CH3:38])[C:42]=1[CH3:50])[CH2:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1C
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@@H](N)CSc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cccc(C(=O)N[C@@H](CSc2ccccc2)[C@H](O)CN2C[C@H]3CCCC[C@H]3C[C@H]2C(=O)NC(C)(C)C)c1C
Yield: 101.1 %

Procedure:
(3S,4aS,8aS)-2-((2R, 3R)-3-Amino-2-hydroxy-4-phenylthiobutyl)-decahydroisoquinoline-3-carboxylic acid t-butylamide (compound [14], 9.39 g) and sodium hydrogencarbonate (4.55 g, 54.2 mmol) were added to a suspension of water (40 ml) and ethyl acetate (40 ml). A solution of 3-acetoxy-2-methylbenzoyl chloride (4.37 g, 20.6 mmol) in ethyl acetate (40 ml) was dropwise added to the suspension with stirring under ice-cooling. The mixture was further stirred for one hour under ice-cooling and water (20 ml) was added. The organic layer was separated and washed with a saturated aqueous solution (20 ml) of sodium hydrogencarbonate. After drying over magnesium sulfate, the solvent was distilled away under reduced pressure to give (3S,4aS,8aS)-2-[(2R,3R)-3-(3-acetoxy-2-methylbenzoylamino)-2-hydroxy-4-phenylthiobutyl]decahydroisoquinoline-3-carboxylic acid t-butylamide (12.7 g, yield 96%) as colorless amorphous.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[N:15][CH:14]=[CH:13][C:9]=3[CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>O1CCCC1>[CH3:19][N:20](/[CH:22]=[C:10]1/[C:11](=[O:12])[C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:6]=2[NH:7][C:8]2[CH:16]=[N:15][CH:14]=[CH:13][C:9]/1=2)[CH3:21]
Reactant: O=C1Cc2ccncc2Nc2ncccc21
Reactant: COC(OC)N(C)C
Solvent: C1CCOC1
Product: CN(C)/C=C1/C(=O)c2cccnc2Nc2cnccc21
Temperature: 60 °C

Procedure:
To a solution of 6,11-dihydro-5H-dipyrido[2,3-b:4′,3′-f]azepin-5-one (as described in WO 2007038215) (0.38 g) and dimethylformamide dimethylacetal (1.5 mL) in tetrahydrofuran (10 mL) were heated at 60° C. under nitrogen for 24 hours. Additional dimethylformamide dimethylacetal (2 mL) was then added and the mixture heated at 60° C. under nitrogen for an additional 48 hours. The reaction mixture was cooled and solvent removed under reduced pressure to give the desired product, (E)-6-((dimethylamino)methylene)-6,11-dihydro-5H-dipyrido[2,3-b:4′,3′-f]azepin-5-one (0.745 g) as a brown solid, which was used without further purification in Step 2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:16](=[O:18])[CH3:17])[CH:7]=[C:8]([S:10]([F:15])([F:14])([F:13])([F:12])[F:11])[CH:9]=1)[CH3:2].[Br-:19].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1.C(Cl)Cl>[Br:19][CH2:17][C:16]([C:6]1[CH:7]=[C:8]([S:10]([F:11])([F:12])([F:13])([F:15])[F:14])[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)=[O:18]
Reactant: CCOc1cc(C(C)=O)cc(S(F)(F)(F)(F)F)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOc1cc(C(=O)CBr)cc(S(F)(F)(F)(F)F)c1
Yield: 125.4 %

Procedure:
1-[3-Ethoxy-5-(pentafluorosulfanyl)phenyl]ethanone (2.07 g) was dissolved in THF (80 ml) and phenyltrimethylammonium tribromide (2.90 g) was added while stirring. After stirring at RT for 3 h, the mixture was diluted with DCM and washed once with 5% sodium thiosulfate solution. The DCM phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified using silica gel (120 g cartridge, n-heptane/MtB ether gradient of 0-20% within 60 min). 2.07 g of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[NH:7][N:6]=1)=[O:4].[C:13](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[N:7]([CH3:13])[N:6]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc([N+](=O)[O-])[nH]n1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])n(C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
500 mg (2.93 mM) of 5-nitro-1H-pyrazole-3-carboxylic acid methyl ester was dissolved in 5 ml of N,N-dimethylformamide, to which 810 mg (5.86 mM, eq) of potassium carbonate was added. Subsequently, 0.49 ml (3.22 mM) of iodomethane was added dropwise thereto at 0° C., and the resulting mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent was distilled off under reduced pressure, and the resultant was extracted with ethyl acetate and brine. The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane:ethyl acetate=10:1), to obtain 314 mg (56%) of the title compound.
Reaction SMILES: N([C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][C:13]([F:16])([F:15])[F:14])[CH:9]=[CH:8][C:6]=2[N:7]=1)N.S(Cl)([Cl:19])=O>>[Cl:19][C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][C:13]([F:16])([F:15])[F:14])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: NNc1nc2ccc(OC(F)(F)F)cc2s1
Product: FC(F)(F)Oc1ccc2nc(Cl)sc2c1
Temperature: 50 °C

Procedure:
49.4 g of 2-hydrazino-6-trifluoromethoxybenzothiazole are added over one hour to 97.9 g of thionyl chloride heated to 50° C. The mixture is then heated for one hour at this same temperature and then cooled to 0° C. After addition of 200 g of an ice/water mixture (1/1 by weight), the precipitate is filtered off and washed with twice 50 cm3 of water. 54.5 g of 2-chloro-6-trifluoromethoxybenzothiazole are thus obtained, melting at 50° C.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][CH2:7]OS(C)(=O)=O)(=[O:4])=[O:3].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OC(=O)C)C>[CH2:13]([NH:20][CH2:7][CH2:6][NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)NCCOS(C)(=O)=O
Reactant: NCc1ccccc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Methanesulphonamido 2-methanesulphonyloxyethane (23.3 g) was added in small portions to benzylamine (24 ml) at such a rate that the temperature did not rise above 30° C. When the addition was complete the mixture was stirred at room temperature for one hour. Ethylacetate (150 ml) was then added to the mixture and the precipitated solid was filtered off. The filtrate was evaporated and the product isolated by column chromatography of the residue using gradient elution (Kieselgel, ethylacetate going to 30% methanol in ethylacetate as eluent). The product was recrystallised from ethylacetate-petroleum ether to give 10.9 g of pale yellow crystals, mpt 71°-73° C.