Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH:15]([CH2:21][CH2:22][CH3:23])[C:16]([O:18]CC)=[O:17])=[C:13]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[C:12]2[C:11]3[CH2:10][CH2:9][N:8]([CH3:31])[CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1.[OH-].[Na+]>CO.C(O)C>[CH3:1][C:2]1[C:14]([CH:15]([CH2:21][CH2:22][CH3:23])[C:16]([OH:18])=[O:17])=[C:13]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[C:12]2[C:11]3[CH2:10][CH2:9][N:8]([CH3:31])[CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1
Reactant: CCCC(C(=O)OCC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCN(C)C3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCN(C)C3
Yield: 5.9 %

Procedure:
To a suspension of ethyl [2,7-dimethyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]pentanoate (0.438 g; 1 mmol) in a mixture methanol-ethanol (2:1) (15 mL) was added a 5% sodium hydroxide solution (15 mmol; 12 mL) and the reaction mixture was heated at reflux for 18 h. After cooling, the organic volatiles were removed under reduced pressure and the remaining basic solution was acidified with HCl (1N) until pH 2 and the aqueous layer was extracted with ethyl acetate. The organics were combined, dried over magnesium sulphate and concentrated under reduced pressure. Purification by preparative HPLC (HPLC method 2) furnished 0.024 g (5.8%) of the title compound as a yellow oil.
Reaction SMILES: C[Al](C)C.[NH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:11]([C:13]1[C:18]2[N:19]=[C:20]([C:22](OCC)=[O:23])[O:21][C:17]=2[C:16]([F:27])=[C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:14]=1[CH3:34])#[N:12].Cl>ClCCl>[F:27][C:16]1[C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:14]([CH3:34])[C:13]([C:11]#[N:12])=[C:18]2[C:17]=1[O:21][C:20]([C:22]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:23])=[N:19]2
Reactant: CCOC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reactant: C1CCNCC1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N3CCCCC3)nc2c1C#N
Reaction time: 0.25 h
Yield: 36.9 %

Procedure:
Under nitrogen atmosphere, trimethylaluminium (1.03 M n-hexane solution, 898 μl, 925 μmol) was dropwise added to a dichloromethane (1 ml) solution of piperidine (92 μl, 925 μmol) at room temperature, and stirred for 15 minutes. Subsequently, a dichloromethane (2 ml) solution of ethyl 4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carboxylate (I-111) (150 mg, 463 μl) was dropwise added and stirred for 63 hours. After the reaction, aqueous 1 N hydrochloric acid solution was added to the reaction liquid with cooling with ice, followed by stirring at room temperature. The reaction liquid was extracted with chloroform. Next, the obtained organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with n-hexane/ethyl acetate (4:1, v/v) gave the entitled compound (62 mg, 37%) as a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=3[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:2][CH3:3].I[CH2:26]CC>>[CH:2]1([CH2:1][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[C:12]3[C:13]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=4[NH:15][C:16]=3[CH:17]=[CH:18][CH:19]=2)[CH2:26][CH2:3]1
Reactant: CCCOc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3
Reactant: CCCI
Product: c1ccc(-c2cccc3[nH]c4c(c23)CCNCC4)c(OCC2CC2)c1

Procedure:
Following the procedure for the preparation of 10-(2-propoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole and substituting (bromomethyl)cyclopropane for 1-iodopropane while making non-critical variations the title compound was obtained as 74 mg (14%) of a brown oil: 1H NMR (400 MHz, CDCl3) δ 7.92 (br s, 1H), 7.29-7.21 (m, 2H), 7.12 (d, J=8.0 Hz, 1H), 7.07-7.03 (m, 1H), 6.98-6.94 (m, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.86 (d, J=7.1 Hz, 1H), 3.70 (d, J=6.3 Hz, 2H), 3.01-2.95 (m, 2H), 2.85-2.73 (m, 4 H), 2.37-2.31 (m, 2H), 0.95-0.93 (m, 1H), 0.30-0.25 (m, 2H), 0.00-(−0.03) (m, 2H); HRMS (FAB) calcd for C22H24N2O+H1: 333.1967 found 333.1955.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:10](OC(=O)C)(=[O:12])[CH3:11].N1C=CC=CC=1>CCOCC>[C:10]([O:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(O)cc1Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)Oc1ccc(C)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a solution of 3-chloro-4-methylphenol (500 mg) in ether (5.0 ml) were added acetic anhydride (430 mg) and pyridine (416 mg), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was washed with 1N hydrochloric acid (once) and saturated brine (twice), dried over magnesium sulfate and concentrated to dryness under reduced pressure to give the objective compound (645 mg) as a pale-yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[C:3]=1[I:9].[NH2:10][NH2:11].C(#N)C.O.C(O)(C(F)(F)F)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:10][NH2:11])[C:3]=1[I:9]
Reactant: NN
Reactant: Fc1nccc(Br)c1I
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Product: NNc1nccc(Br)c1I
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of 4-bromo-2-fluoro-3-iodopyridine (29 g, 96 mmol) in THF (300 mL) was added hydrazine (anhydrous, 30 mL, 960 mmol) at 20° C. The reaction mixture was stirred at 20° C. for 2 h. The reaction was monitored by HPLC (acetonitrile-water-TFA) and completed in 2 h. The reaction mixture was concentrated in vacuo to reduce volume by 70% and H2O (300 mL) was then added. The resulting mixture was filtered and the collected solid (1st crop) was washed with H2O. The filtrate was concentrated in vacuo to remove most of the THF. Newly formed solid was then filtered. This 2nd crop was washed with H2O. The two crops were combined and dried under high vacuum to obtain the title compound as an off-white, fluffy solid (28.6 g, 91 mmol). MS: [M+H]+=313.9. 1H NMR (400 MHz, CDCl3) δ 6.97 (d, J=5.50 Hz, 1H), 7.92 (d, J=4.95 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH2:23])=[O:22])=[CH:16][CH:15]=1>>[C:9]1([C@H:20]2[C@H:20]([C:17]3[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][CH:18]=3)[C:21](=[O:22])[NH:23][C:21]2=[O:22])[C:3]2=[C:4]3[C:5](=[CH:6][CH:7]=[CH:2]2)[CH2:19][CH2:14][CH2:15][N:12]3[CH:10]=1
Reactant: NC(=O)Cc1ccc(F)cc1Cl
Reactant: NC(=O)Cc1ccc(Cl)cc1
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1ccc(Cl)cc1

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(4-chlorophenyl)pyrrolidine-2,5-dione was prepared according to Example 40 replacing 2-chloro-4-fluorophenylacetamide with 4-chlorophenylacetamide. Yield 32.7 mg, 9.0%. 1H NMR (DMSO-d6) 400 MHz δ: 11.54 (s, 1H), 7.40 (m, 4H), 7.33 (s, 1H), 7.15 (dd, 1H, J=6.8 0.8 Hz), 6.86 (m, 2H), 4.54 (d, 1H, J=8.0 Hz), 7.38 (d, 1H, J=7.6 Hz), 4.10 (t, 2H, J=5.6 Hz), 2.90 (t, 2H, J=6.0 Hz), 2.11 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:56][CH3:57])=[C:21]([CH:55]=1)[CH2:22][C@H:23]1[C:29](=[O:30])[N:28]([C:31](OC2C=CC=CC=2Cl)=[O:32])[CH2:27][C:26](=[O:41])[N:25](CC2C(OC)=CC(OC)=CC=2OC)[CH2:24]1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:56][CH3:57])=[C:21]([CH:55]=1)[CH2:22][C@H:23]1[C:29](=[O:30])[N:28]([C:31]([NH:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])=[CH:14][CH:15]=2)=[O:32])[CH2:27][C:26](=[O:41])[NH:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)c1ccc(CN)cc1
Reactant: COc1cc(OC)c(CN2C[C@@H](Cc3cc(Cl)ccc3OC)C(=O)N(C(=O)Oc3ccccc3Cl)CC2=O)c(OC)c1
Product: COc1ccc(Cl)cc1C[C@@H]1CNC(=O)CN(C(=O)NCc2ccc(C(=O)OC(C)(C)C)cc2)C1=O

Procedure:
Instead of the starting material, that is, the compound S11, of Reference Example 43, tert-butyl 4-(aminomethyl)benzoate was used, and instead of (6R)-2-chlorophenyl 6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepan-1-carboxylate, the compound S45 was used for a similar reaction as in Reference Example 43 to obtain tert-butyl 4-{[({(6R)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-1,4-diazepan-1-yl}carbonyl)amino]methyl}benzoate (compound S47a).
Reaction SMILES: [N:1]1([CH:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=O)[CH3:15])=[C:9]([N+:17]([O-:19])=O)[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.CC(O)C.Cl.[H][H]>CO>[N:1]1([CH:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]2[CH:12]=[CH:11][C:10]3[N:13]=[C:14]([CH3:15])[N:17]([OH:19])[C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: [H][H]
Reactant: CC(=O)Nc1ccc(C(c2ccccc2)n2ccnc2)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: Cc1nc2ccc(C(c3ccccc3)n3ccnc3)cc2n1O
Yield: 40.6 %

Procedure:
A mixture of 4.9 parts of N-[4-[(1H-imidazol-1-yl)phenylmethyl]-2-nitrophenyl]acetamide, 12 parts of 2-propanol, saturated with hydrogen chloride and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of platinium-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in dichloromethane and water and then the solution was neutralized with an ammonium hydroxide solution. The dichloromethane layer was separated, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (85:15 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 2.2 parts (40.6%) of 6-[(1H-imidazol-1-yl)phenylmethyl]-2-methyl-1H-benzimidazol-1-ol as a residue (compound 219).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3]1.[N:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])=[C:13]=[S:14]>O1CCCC1>[N+:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:12][C:13]([NH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3]1)=[S:14])([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccccc1N=C=S
Reactant: CCOC(=O)N1CCC(N)C1
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(NC(=S)Nc2ccccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 15.8 parts of ethyl 3-amino-1-pyrrolidinecarboxylate, 18 parts of 1-isothiocyanato-2-nitrobenzene and 180 parts of tetrahydrofuran was stirred for 1 hour at room temperature. The reaction mixture was evaporated, yielding 34 parts (100%) of ethyl 3[[[(2-nitrophenyl)amino]thioxomethyl]amino]-1-pyrrolidinecarboxylate as a residue (int. 22).
Reaction SMILES: [OH:1][C:2]1[CH:41]=[CH:40][C:5]2[CH:6]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][S:29][CH2:30][CH2:31][CH2:32][C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])[CH:18]=3)[CH:7]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[CH2:8][O:9][C:4]=2[CH:3]=1.C[OH:43].O>O1CCOCC1>[OH:1][C:2]1[CH:41]=[CH:40][C:5]2[CH:6]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][S:29]([CH2:30][CH2:31][CH2:32][C:33]([F:39])([F:38])[C:34]([F:35])([F:36])[F:37])=[O:43])[CH:18]=3)[CH:7]([C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CO
Reactant: Oc1ccc(C2COc3cc(O)ccc3C2c2cccc(OCCCCCSCCCC(F)(F)C(F)(F)F)c2)cc1
Solvent: O
Solvent: C1COCCO1
Product: O=S(CCCCCOc1cccc(C2c3ccc(O)cc3OCC2c2ccc(O)cc2)c1)CCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
7-Hydroxy-3-(4-hydroxyphenyl)-4-[3-(5-(4,4,5,5,5-pentafluoropentylthio)pentyloxy)phenyl]-2,3-dihydro-4H-benzopyran (90 mg, 0.15 mmol) was dissolved in 1,4-dioxane (1.5 ml), methanol (1.5 ml) and water (0.38 ml), and NaIO4 (35.5 mg, 0.16 mmol) was added dropwise thereto. The reaction solution was stirred for 8 hours at room temperature and then filtered. The filtrate was concentrated and the residue was separated by column chromatography (n-hexane:ethyl acetate=1:1) to obtain 58 mg (yield: 63%, 3RS,4RS/3RS,4SR=1:1) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([CH3:21])[CH:9]=2)=[O:5])[CH3:2].[Br:23]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.[W]>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([CH2:21][Br:23])[CH:9]=2)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(C)cc2C1=O
Agent: [W]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(CBr)cc2C1=O
Yield: 36.6 %

Procedure:
6-Methyl-1-oxo-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (3 g, 10.3 mmol) obtained in Step 4 was dissolved in carbon tetrachloride, and N-bromosuccinimide (2 g, 11.4 mmol) and 2,2′-azobisisobutyronitrile (500 mg, 3.09 mmol) were added thereto. The mixture was refluxed for 3 hrs under the irradiation of a 375 W tungsten lamp. Upon the completion of the reaction, the resulting mixture washed with saturated saline and extracted with dichloromethane. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 1.4 g of the titled compound (yield: 36.7%) in oil state.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:31]1CCOCC1)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N>CN(C=O)C>[NH2:31][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:21])=[O:22])=[CH:16][CH:15]=1
Reactant: CCN1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(S(=O)(=O)c2ccccc2)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(S(=O)(=O)c2ccccc2)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-3-(4-(phenylsulfonyl)phenyl)propanoic acid (675 mg) was dissolved in DMF (8 mL) and to the solution was added N-ethylmorpholine (0.316 mL) followed by TBTU (802 mg). The reaction mixture was stirred at room temperature for 20 min then it was cooled to 0° C. Aqueous ammonia (0.379 mL) was added and the mixture was allowed to reach room temperature over 1 h. The reaction mixture was left to stir for a further 2 h. LCMS showed little change so further TBTU (400 mg) and ammonia (0.3 mL) were added, and the mixture stirred for a further 2 h. The reaction mixture was partitioned between ethyl acetate and diluted brine, and the aqueous phase was extracted into ethyl acetate twice more. The combined organic phases were dried over sodium sulphate, filtered and concentrated in vacuo to yield a pale gum. This was purified by flash silica chromatography, eluting with ethyl acetate to give the subtitle compound (450 mg) as a colourless gum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.S(Cl)(Cl)=O.[NH2:17][C:18]([CH3:22])([CH3:21])[CH2:19]O.[OH-].[Na+]>CN(C=O)C.O.C(Cl)Cl.C(OCC)(=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][CH2:19][C:18]([CH3:22])([CH3:21])[N:17]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C(=O)O)cc1Br
Reactant: CC(C)(N)CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C2=NC(C)(C)CO2)cc1Br
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
3-Bromo-4-methoxybenzoic acid (8.75 g, 37.9 mmol), toluene (80 ml), ethyl acetate (20 m1l), methylene chloride (20 ml) and DMF (1 drop) were mixed, and to this solution was added thionyl chloride (6.5 ml, 90 mmol). The mixture was stirred at 70° C. for 0.5 hour. The reaction mixture was concentrated under reduced pressure, and toluene was added. The mixture was further concentrated under reduced pressure. Methylene chloride (160 ml) was added to the obtained residue, and this solution was cooled to 0° C. 2-Amino-2-methyl-1-propanol (7.64 nil, 80 mmol) was added dropwise, and the mixture was stirred at room temperature for 14 hours. The precipitated crystals were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (200 ml), and this solution was washed with 1N hydrochloric acid (50 ml). This solution was dried over anhydrous magnesium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure. The obtained residue and methylene chloride (150 ml) were mixed, and thionyl chloride (10.9 ml, 150 mmol) was added under ice-cooling. The mixture was stirred at room temperature for 2 hours. To this reaction mixture were successively added water (13 ml) and a 50% aqueous sodium hydroxide solution (40 ml) under ice-cooling. The aqueous layer was extracted 3 times with ethyl acetate (100 ml). The organic layers were combined, washed twice with saturated brine (100 ml). This solution was dried over anhydrous magnesium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (hexane/ethyl acetate=2/1-1/2) to give 2-(3-bromo-4-methoxyphenyl)4,4-dimethyl-4,5-dihydrooxazole (7.10 g, 66%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][N:4]=[C:5]([NH2:25])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH:16][C:17](=[N:20][S:21]([CH3:24])(=[O:23])=[O:22])SC)[N:11]=1.[CH3:28][NH2:29]>>[F:27][C:2]([F:1])([F:26])[CH2:3][N:4]=[C:5]([NH2:25])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH:16][C:17]([NH:29][CH3:28])=[N:20][S:21]([CH3:24])(=[O:22])=[O:23])[N:11]=1
Reactant: CN
Reactant: CSC(=NS(C)(=O)=O)NCCSCc1csc(NC(N)=NCC(F)(F)F)n1
Product: CNC(=NS(C)(=O)=O)NCCSCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 64 h

Procedure:
2-[2-(2,2,2-Trifluoroethyl)guanidino]-4-[2-(3-methylsulphonyl-2-methylisothioureido)ethylthiomethyl]-thiazole (0.4 g.) was dissolved in ethanolic methylamine (33% w/v 15 ml.) and allowed to stand at room temperature for 64 hours. The solvent was evaporated and the residual gum was purified by preparative thin layer chromatography using chloroform/methanol/ammonia 8:2:0.2 v/v/v as developing solvent. The appropriate zone of the chromatogram was isolated and extracted with methanol/ammonia 10:1 v/v (50 ml.). The solvent was evaporated and the residual gum was dissolved in acetonitrile, filtered and the filtrate evaporated. The residual gum was dissolved in methanol and treated with a solution of excess fumaric acid in methanol. The solvent was evaporated and the residue triturated with acetonitrile to give 2-[2-(2,2,2-trifluoroethyl)-guanidino]-4-[2-(2-methylsulphonyl-3-methylguanidino)ethylthiomethyl]thiazole as a cream solid (0.29 g.), m.p. 118°-123° (decomp.), containing 1.5 molar equivalents of fumaric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[C:12]1([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)[CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)=[O:6]
Reactant: O=C(O)c1c(F)cccc1Cl
Reactant: NCC(c1ccccc1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(c1ccccc1)c1ccc(C(F)(F)F)nc1)c1c(F)cccc1Cl

Procedure:
From 2-chloro-6-fluorobenzoic acid and 2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS (MH+): m/z=423.1, tR (minutes, Method D)=0.80
Reaction SMILES: CI.[CH3:3][N:4]1[C:8]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:7][NH:6][C:5]1=[S:15].[OH-].[Na+].[CH2:18](Cl)Cl>CCO>[CH3:3][N:4]1[C:5]([S:15][CH3:18])=[N:6][N:7]=[C:8]1[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cn1c(-c2cccnc2)n[nH]c1=S
Reactant: ClCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CI
Product: CSc1nnc(-c2cccnc2)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
MeI (2 mL, 32 mmol) in EtOH (10 mL) was added to a mixture of 4-methyl-5-pyridin-3-yl-2,4-dihydro-3H-1,2,4-triazole-3-thione in 1 M NaOH (70 mL, 70 mmol). After 1 h stirring at r.t., DCM was added and the layers were separated. The water phase was washed with DCM and the combined organic phases were dried and concentrated to give 6.5 g (98%) of the title compound. 1H NMR: 2.76 (s, 3H) 3.59 (s, 3H) 7.43 (m, 1H) 7.99 (m, 1H) 8.71 (m, 1H) 8.86 (m, 1H)
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH3:16][C:17]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH:28]2[CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:16][C:17]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][N:30]([C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])[CH2:29][CH:28]2[CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1
Reactant: O=C(O)/C=C/C(F)(F)F
Reactant: COC(=O)CC1CNCCN1c1cc(C)nc2ccccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC1CN(C(=O)/C=C/C(F)(F)F)CCN1c1cc(C)nc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (15.4 mg, 0.08 mmol) was dissolved in DCM (1 ml), oxalyl chloride was added (9.4 μl, 0.11 mmol) followed by a drop of DMF. The mixture was stirred for 10 minutes at room temperature. Methyl 2-[1-(2-methyl-4-quinolyl)piperazin-2-yl]acetate (33.6 mg, 0.1 mmol) was dissolved in DMF (1 ml) together with diisopropylethylamine (44 μl, 0.25 mmol), the solutions were combined and the resulting mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 3.9 mg (0.0093 mmol, 9%).
Reaction SMILES: C(Cl)CCl.[C:5]1([CH2:11][CH2:12][NH2:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:13][CH2:12][CH2:11][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NCCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: O=S(=O)(NCCc1ccccc1)c1ccc(Cl)cc1

Procedure:
To a mixture of 150 ml of ethylene chloride and 150 ml of water are added 30.3 g of 2-phenylethylamine, 12 g of sodium hydroxide and 0.5 g of tetrabutylammonium bromide. 65.5 g of 4-chlorobenzenesulphonic acid chloride are added to the mixture in batches with stirring. After 30 minutes the organic phase is separated off, evaporated down and the residue is recrystallised from toluene.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13]C)=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Cl>ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[CH:10][C:9]([OH:13])=[CH:8]2
Reactant: COc1ccc2c(OC)cccc2c1
Agent: Cl
Solvent: CC(Cl)Cl
Product: COc1cccc2cc(O)ccc12

Procedure:
Bromocatecholborane (4.11 g, 20.7 mmol) is added to a solution of 1,6-dimethoxynaphthalene (3.89 g, 20.7 mmol) in dichloroethane (60 mL). The resulting solution is heated to reflux for 72 hours, allowed to cool, and then poured into 1N HCl. The resulting mixture is extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4), filtered and concentrated to dryness. The product is purified by three columns (step gradient of 50–60–65%CH2Cl2 in hexanes) to give 5-methoxy-2-hydroxy naphthalene as an oil that solidifies on sitting (955 mg, 27%). 1H NMR (300 MHz, CDCl3) δ 8.17, 7.2–7.4, 7.0–7.1, 6.66, 5.08, 3.97.