Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[C:7]([O:9][CH2:10][C@@H:11]1[CH2:15][O:14]C2(CCCCC2)[O:12]1)=[O:8])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[C:7]([O:9][CH2:10][C@@H:11]([OH:12])[CH2:15][OH:14])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)OC[C@@H]1COC2(CCCCC2)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Oc1ccccc1C(=O)OC[C@@H](O)CO
Reaction time: 2 h

Procedure:
The solution from [2S]-1,4-dioxa-spiro[4,5]dec-2-yl-methyl 2-acetoxybenzoate (527 mg, 1.58 mmol) in dichloromethane (10 ml) is treated with trifluoroacetic acid (2 ml). After 2 h at room temperature, the mixture is concentrated, the residue is taken up in toluene (10 ml) and the solution is concentrated. The residue is purified by column chromatography (dichloromethane/methanol=30/1). Yield: 161 mg.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1.[O:36]1[CH2:40][CH:39](O)[CH:38]([OH:42])[CH2:37]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:30][CH2:31][C:32]2([O:42][C@H:38]3[CH2:37][O:36][CH2:40][C@H:39]3[O:35]2)[CH2:33][CH2:34]1
Reactant: OC1COCC1O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)O[C@H]2COC[C@H]2O3)c2ncnn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 86.6 %

Procedure:
A mixture of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.75 g), tetrahydrofuran-3,4-diol (0.48 g), p-toluenesulfonic acid monohydrate (0.028 g) and toluene (25 mL) was subjected to an azeotropic dehydration reaction by stirring at 110° C. for 16 hr in a reaction vessel equipped with a Dean-stark trap. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.77 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N+:18]([O-])=O.CO>C(OCC)(=O)C.[Pd].[C]>[NH2:18][C:3]1[CH:4]=[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([OH:17])[CH3:16])=[CH:11][CH:10]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: CC(=O)c1ccc(Oc2ccc(N)c([N+](=O)[O-])c2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(O)c1ccc(Oc2ccc(N)c(N)c2)cc1
Reaction time: 24 h

Procedure:
1-{4-[(4-amino-3-nitrophenyl)oxy]phenyl}ethanone (437 mg) was dissolved in 1:1 ethyl acetate: methanol and hydrogenated over 500 mg of 10% Pd/carbon (wet, Degussa type) under an atmosphere of H2 gas. After 24 hours, the reaction was filtered through Celite and concentrated to give crude 1-{4-[(3,4-diaminophenyl)oxy]phenyl}ethanol which was used without further purification. (M+1) 245.2, 1.05 min (LC/MS method A)
Reaction SMILES: [OH:1][CH:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12].[CH:27]1([S:32][CH2:33][CH2:34]Cl)[CH2:31][CH2:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.CO>[OH:1][CH:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:34][CH2:33][S:32][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@H]1CNCC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Reactant: ClCCSC1CCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: COC(=O)[C@H]1CN(CCSC2CCCC2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Temperature: 20 °C
Yield: 49.3 %

Procedure:
0.717 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate in 15 cm3 of acetonitrile and 15 cm3 of methanol was heated for 3½ h at a temperature in the region of the reflux temperature, with stirring and under an inert atmosphere, with 0.439 g of 90% 2-chloroethyl cyclopentyl sulfide in the presence of 0.332 g of potassium carbonate and 0.4 g of potassium iodide. After cooling the reaction mixture to a temperature in the region of 20° C., the insoluble material was filtered off and then washed with acetonitrile. The filtrate was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under a nitrogen pressure of 100 kPa on a column of silica gel (particle size 40-63 μm; diameter 3.5 cm; height 45 cm), elution was carried out with a dichloromethane/methanol (95/5 by volume) mixture, and 35-cm3 fractions were collected. Fractions 25 to 45 were combined and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.48 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)-ethyl]piperidine-3-carboxylate was obtained in the form of a lacquer with a dark-green color.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C@@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:13][CH2:12][C@H:11]([CH3:14])[CH2:10][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: C[C@@H](CCl)CBr
Reactant: Oc1cccc(F)c1
Product: C[C@@H](CCl)COc1cccc(F)c1

Procedure:
Prepared by Procedure U and Scheme AK using 3-fluorophenol and (2S)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:31])[C:5]([C:3]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ncc2c(cc(-c3ccc(OC)cc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(-c2cc3c(O)c(C(=O)NCCC(=O)O)ncc3n(Cc3ccccc3)c2=O)cc1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.072 mmol), β-alanine (854 mg, 9.6 mmol) and NaOMe solution (14.4 mL, 7.2 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 25 mg of the title compound. MS: (+) m/z 474.30 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[H-].[Na+].[F:13][C:14]([F:44])([F:43])[C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23][N:22]2[C:31](OC2C=CC([N+]([O-])=O)=CC=2)=[O:32])=[CH:17][CH:16]=1.O>C1COCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:31]([N:22]2[CH2:23][CH2:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:21]2[C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:43])([F:13])[F:44])=[CH:16][CH:17]=2)=[O:32])=[C:3]([CH3:10])[CH:4]=1)#[N:7]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(C#N)ccc1N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C#N)ccc1NC(=O)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a solution of 4-amino-3-methylbenzonitrile (30 mg, 226 μmol) in THF (2 mL) was added sodium hydride, 60% dispersion in mineral oil (15 μL, 339 pimp. The resulting mixture was then stirred at RT for 2 min. Then, (R)-4-nitrophenyl 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 226 μmol, example 88) was added and the mixture was stirred at RT for overnight. Then, 26 mg of NaH (60% dispersion in mineral oil) was added and the mixture was stirred at RT for overnight. Then, H2O (0.2 mL) was added and the solvents were removed. The residue was then dissolved in a solution of DMSO and MeOH (1:1, 1.0 mL). The solution was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the desired product, which was dissolved in MeOH (1.0 mL). The solution was then washed through PL-HCO3 MP resin (polymerlabs, 200 mg/6 mL tube) and the resin was then washed with MeOH (2×0.5 mL). The combined washings were then concentrated and dried under vacuum to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 436 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:13][CH:12]=3)=[CH:10][C:3]=12.Br[C:34]1[C:35]([C:41]2[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:52])[N:49]([CH3:51])[CH3:50])=[CH:43][CH:42]=2)=[N:36][N:37]([CH2:39][CH3:40])[CH:38]=1>>[CH2:39]([N:37]1[CH:38]=[C:34]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:25])=[O:26])[C:9]([C:11]4[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][N:19]5[CH2:23][CH2:22][CH2:21][CH2:20]5)=[CH:13][CH:12]=4)=[CH:10][C:3]=23)[C:35]([C:41]2[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:52])[N:49]([CH3:51])[CH3:50])=[CH:43][CH:42]=2)=[N:36]1)[CH3:40]
Reactant: CCn1cc(Br)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Reactant: O=S(=O)(c1ccccc1)n1c(-c2ccc(CCN3CCCC3)cc2)cc2c(Br)ccnc21
Product: CCn1cc(-c2ccnc3c2cc(-c2ccc(CCN4CCCC4)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Reaction time: 4.5 h

Procedure:
Following the procedure described for Intermediate 32 using 4-bromo-1-(phenylsulfonyl)-2-{4-[2-(1-pyrrolidinyl)ethyl]phenyl}-1H-pyrrolo[2,3-b]pyridine and then following the procedure described for Intermediate 100 using N′-[4-(4-bromo-1-ethyl-1H-pyrazol-3-yl)phenyl]-N,N-dimethylurea and stirring for 4.5 hours provided the title compound. ESMS [M+H]+: 688.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][C:7]([N+:15]([O-])=O)=[C:6]2[CH3:18].[H][H]>O1CCCC1.[Pd]>[NH2:15][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[CH3:18])=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2
Reactant: COc1cc2ncc([N+](=O)[O-])c(C)c2cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc2ncc(N)c(C)c2cc1OC
Yield: 79.5 %

Procedure:
6,7-Dimethoxy-4-methyl-3-nitroquinoline (5.80 g, 23.36 mmol) is dissolved in tetrahydrofuran (60 ml). Palladium on carbon (5%, 2.90 g, water-moist) is subsequently added, and the suspension is stirred turbulently in a hydrogen atmosphere at room temperature for 16 h. When the reaction is complete, the solid material is filtered off with suction through kieselguhr and rinsed with tetrahydrofuran. The filtrate is evaporated to dryness in vacuo, giving 3-amino-6,7-dimethoxy-4-methylquinoline (4.05 g, 18.56 mmol) as a solid. MS: 219.0 (M+H+), TLC (HPTLC): Rf=0.35 (ethyl acetate/ethanol 8:1, parts by volume).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][N:5]=1.[OH-].[Na+:15]>CO>[Na+:15].[CH3:1][O:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O-:10])=[O:9])=[CH:6][N:5]=1
Reactant: COCc1ccc(C(=O)OC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCc1ccc(C(=O)[O-])cn1

Procedure:
A mixture of methyl 6-methoxymethylnicotinate (737 mg) in a 2N aqueous sodium hydroxide solution (2 ml) and methanol (15 ml) was refluxed overnight. After cooling, the reaction mixture was concentrated under reduced pressure, and the resulting residue was triturated with diethyl ether to obtain 6-methoxymethylnicotinic acid sodium salt (754 mg) as colorless powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:15](=[O:54])[NH:16][C:17]2[CH:25]=[C:24]3[C:20]([C:21]([C:45]4[CH:50]=[CH:49][N:48]=[C:47]([CH:51]5[CH2:53][CH2:52]5)[CH:46]=4)=[N:22][N:23]3[C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:19][CH:18]=2)([O:13][CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:57]I>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:15](=[O:54])[N:16]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]([C:45]4[CH:50]=[CH:49][N:48]=[C:47]([CH:51]5[CH2:52][CH2:53]5)[CH:46]=4)=[N:22][N:23]3[C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:19][CH:18]=2)[CH3:57])([O:13][CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: COC1(C(=O)Nc2ccc3c(-c4ccnc(C5CC5)c4)nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3c2)CCN(C(=O)OC(C)(C)C)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(C(=O)N(C)c2ccc3c(-c4ccnc(C5CC5)c4)nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3c2)CCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.17 h

Procedure:
3-[3-(2-Cyclopropyl-pyridin-4-yl)-1-trityl-1H-indazol-6-ylcarbamoyl]-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester 3M (216 mg, 0.3 mmol) was dissolved in THF (10 mL) at r.t. To this solution was added NaH (40 mg, 60% suspension in mineral oil, 1 mmol). After stirring for 10 min, CH3I (0.6 mL, 9.6 mmol) was added. The reaction was worked up after 4 hrs by quenching with sat. NH4Cl solution. After extraction with ethyl acetate, the combined organic layers was dried and concentrated in vacuo to obtain 4M. 4M is used as the resulting crude.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:19][CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:28](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:19][CH2:20][CH2:21][C:22]([F:25])([F:23])[F:24])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:28])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(CC(CCCC(F)(F)F)c1ccc(Br)cc1)c1ccc(=O)[nH]c1
Agent: [K+]
Solvent: CI
Product: Cn1cc(C(=O)CC(CCCC(F)(F)F)c2ccc(Br)cc2)ccc1=O

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-7,7,7-trifluoro-heptanoyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a light yellow oil, MS (ESI+): m/z=430.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([O-])([OH:21])=[O:20].[OH-].[K+]>C(O)(=O)C>[N+:19]([C:15]1[CH:16]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]([O:17][CH3:18])=[CH:11][C:12]=1[C:13]#[N:14])([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C#N)ccc1OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cc(C#N)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-benzyloxy-3-methoxybenzonitrile (4.78 g, 20 mmol) in acetic acid (10 ml) was slowly added to nitric acid (25 ml) at 20° C. to 30° C. The mixture was stirred at room temperature for 6 hours, basified (pH 10-11) with cooling (KOH 10N), extracted with methylene chloride, dried over MgSO4 evaporated. The solid was recristallysed in hot EtOAc, a yellow solid of title compound was obtained (3.62 g, 64%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])#[N:2].S(Cl)([Cl:14])=O.CN(C)C=O>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:14])=[O:7])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cccc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: N#Cc1cccc(C(=O)Cl)c1
Temperature: 80 °C

Procedure:
In 1 liter of toluene, 200 g of 3-cyanobenzoic acid were suspended, followed by the addition of 128 ml of thionyl chloride and 1 ml of N,N-dimethylformamide. The resulting mixture was stirred under heating at 80° C. for 5 hours. After cooling of the reaction mixture, the solvent was distilled off under reduced pressure. To the residue, n-hexane was added. By distilling off the solvent under reduced pressure, 3-cyanobenzoyl chloride was obtained. The resulting 3-cyanobenzoyl chloride was dissolved in 3 liters of dried 1,2-dichloroethane, followed by the addition of 200 g of 2-amino-4-methoxycarbonyl-1,3-thiazole. The resulting mixture was heated under reflux for 5 hours. The reaction mixture was cooled. Crystals so precipitated were collected by filtration and then washed with water, whereby 289 g of 2-[N-(3-cyanobenzoyl)amino]-4-methoxycarbonyl-1,3-thiazole.hydrochloride were obtained. Yield: 80%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:22][CH2:21][C:14]2([C:19](=[O:20])[NH:18][CH2:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].[CH2:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1)[CH3:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:22][CH2:21][C:14]2([C:19](=[O:20])[N:18]([C:30]3[CH:31]=[CH:32][C:27]([CH2:26][O:25][CH2:23][CH3:24])=[CH:28][CH:29]=3)[CH2:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: CCOCc1ccc(I)cc1
Reactant: O=C1NCCCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Product: CCOCc1ccc(N2CCCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1

Procedure:
This material was prepared in analogy to example 158) from 9-(2-chloro-benzenesulfonyl)-2,9-diaza-spiro[5.5]undecan-1-one and 1-ethoxymethyl-4-iodo-benzene. White solid. MS (ESI): 477.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[N+]([O-])(O)=O.[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([NH:32][C:33]([NH2:35])=[NH:34])=[CH:31][C:26]=2[O:25][CH2:24]1>>[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([NH:32][C:33]3[N:35]=[CH:13][C:10]4[CH2:9][C:8](=[O:17])[NH:7][C:6]5[CH:18]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:11]=4[N:34]=3)=[CH:31][C:26]=2[O:25][CH2:24]1
Reactant: N=C(N)Nc1ccc2c(c1)OCO2
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Solvent: O=[N+]([O-])O
Product: O=C1Cc2cnc(Nc3ccc4c(c3)OCO4)nc2-c2ccc(Cl)cc2N1

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and N-benzo[1,3]dioxol-5-yl-guanidine nitrate were converted to I-34 (32%): HRMS Calcd. for C19H13ClN4O3: 381.0754, Found 381.0759.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[C:4]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[N:3]=1
Reactant: NCCc1ccc(O)cc1
Reactant: Clc1nc(Cl)c2ncn([C@@H]3CCOC3)c2n1
Product: Oc1ccc(CCNc2nc(Cl)nc3c2ncn3[C@@H]2CCOC2)cc1

Procedure:
Following the procedure of Example 128b, (R)-2,6-dichloro-9-(tetrahydrofuran-3-yl)-9H-purine (b) was reacted with tyramine. The crude reaction mixture was purified by reverse-phase preparative HPLC. MS m/z 360.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10](O)(=O)CC(O)=O>C(O)(=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1)=[CH2:10]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(O)cc1
Solvent: CC(=O)O
Product: C=Cc1ccc(O)cc1
Yield: 40 %

Procedure:
A mixture of 4-hydroxybenzaldehyde (1.0 g, 0.0082 mol), malonic acid (1.69 g, 0.0163 mol), triethylamine(2–4 mL) and acetic acid (10–15 mL) were taken in a 100 ml Erlenmeyer flask fitted with a loose funnel at the top. The flask was shaken well and placed inside the microwave oven and irradiated for 2–8 minutes in parts. The cooled mixture was poured into ice cold water and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate, dil HCl., saturated sodium chloride and then organic layer dried over sodium sulphate. The solvent was evaporated under reduced pressure to obtain liquid which was purified on silica gel column chromatography using mixture of hexane and ethyl acetate (9:1 to 6:4), provided sweet and pleasant smelling liquid in 40% yield; 1H NMR (CDCl3) δ 7.31 (2H, d, J=8.5 Hz, H-2 and H-6), 6.81 (2H, d, J=8.8 Hz, H-3 and H-5), 6.67 (1H, dd, J=17.8 Hz, 11.3 Hz, (CH═CH2), 5.51 (1H, s, OH), 5.2 (1H, d, J=17.8, cis-CH═CH2), 5.14 (1H, d,J=11.3 Hz, trans-CH═CH2); 13C NMR (CDCl3) δ 155.5 (C-1), 136.5 (CH═CH2), 130.9 (C-4), 128.0 (C-3 and C-5), 115.8 (C-2 and C-6), 112.0 (CH═CH2).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[F:11])=[O:3].C([O-])([O-])=O.[K+].[K+].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25]>CS(C)=O>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[C:5]([F:11])[CH:6]=1
Reactant: Oc1ccccc1Cl
Reactant: CC(=O)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)c1ccc(Oc2ccccc2Cl)cc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
156 mg (1 mmol) of 2,4-difluoracetophenone were dissolved in 5 ml DMSO, taken and combined with 200 mg (1.45 mmol) of K2CO3. 128 mg (1 mmol) of 2-chlorophenol were dissolved in 5 ml DMSO and added thereto and the mixture was stirred for 2 days at ambient temperature. The reaction mixture was filtered through basic Alox, washed with DMF and concentrated by rotary evaporation. The substance was purified by reversed-phase chromatography.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[CH2:3][C@H:4]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:20]3[C:15](=[CH:16][N:17]=[CH:18][CH:19]=3)[CH:14]([CH3:21])[O:13][C:11]=2[CH:12]=1.C1C(=O)N([I:38])C(=O)C1>C(#N)C>[I:38][C:8]1[C:7]([O:6][CH2:5][C@@H:4]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:3][CH:2]([CH3:30])[CH3:1])=[CH:12][C:11]2[O:13][CH:14]([CH3:21])[C:15]3[C:20]([C:10]=2[CH:9]=1)=[CH:19][CH:18]=[N:17][CH:16]=3
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)C[C@@H](COc1ccc2c(c1)OC(C)c1cnccc1-2)NC(=O)OC(C)(C)C
Solvent: CC#N
Product: CC(C)C[C@@H](COc1cc2c(cc1I)-c1ccncc1C(C)O2)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 48.9 %

Procedure:
To a solution of tert-butyl ((2S)-4-methyl-1-((5-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)pentan-2-yl)carbamate (200 mg, 0.485 mmol) in acetonitrile (4 mL) was added NIS (654 mg, 2.91 mmol) and the mixture refluxed at 80° C. for 12 h. The volatiles were removed under reduced pressure. The residue was dissolved in water (10 mL) and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (15 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (pet ether: ethyl acetate) to afford tert-butyl ((2S)-1-((9-iodo-5-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (150 mg, 0.237 mmol, 49% yield) as a dark brown oil. LCMS (ESI) m/e 539.0 [(M+H)+, calcd for C24H321N2O4539.1]; LC/MS retention time (method D): tR=1.84 min.
Reaction SMILES: [CH2:1]([CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O)[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26]>C(O)C.Cl.Cl.NNC(N)=N>[ClH:26].[ClH:26].[C:21]([NH:24][N:25]=[CH:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH2:1][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=[N:25][NH:24][C:21](=[NH:22])[NH2:23])[CH:4]=1)(=[NH:23])[NH2:22]
Reactant: N=C(N)NN
Reactant: O=Cc1cccc(OCCOc2cccc(C=O)c2)c1
Agent: Cl
Solvent: CCO
Product: N=C(N)NN=Cc1cccc(OCCOc2cccc(C=NNC(=N)N)c2)c1
Yield: 78.5 %

Procedure:
3,3'-(ethylenedioxy)dibenzaldehyde (1.08 g), aminoguanidine hydrochloride (1.105 g), and aminoguanidine dihydrochloride (0.005 g) were heated in 96% ethanol (6.25 mL) for 18 hr under nitrogen. Cooling and filtration gave 1.428 g of 3,3'-(ethylenedioxy)dibenzaldehyde bis(amidinohydrazone) dihydrochloride, mp 264-6° C.