Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:31][CH:32]([F:34])[F:33])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[OH-].[Li+]>O1CCCC1>[F:34][CH:32]([F:33])[O:31][C:8]1[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:35])=[O:2])[N:11]=[C:10]([CH2:17][CH3:18])[C:9]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(-n2cccn2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
A solution of [4-difluoromethoxy-2-ethyl-8-fluoro-3-(4-pyrazol-1-ylbenzyl)quinolin-5-yloxy]acetic acid methyl ester (0.19 g) in tetrahydrofuran (5.0 mL) was treated with 1.0 M aqueous lithium hydroxide solution (0.78 ml), and the resulting solution was stirred at room temperature for 1 hour. The tetrahydrofuran was removed under reduced pressure and the residue acidified by the addition of 0.1M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate and the combined extracts were washed with saturated aqueous sodium chloride solution, and than dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound (0.18 g).
Reaction SMILES: C(OC([NH:8][C:9]1([C@H:12]2[CH2:16][N:15]([C@H](C3C=CC=CC=3)C)[CH2:14][C@H:13]2[F:25])[CH2:11][CH2:10]1)=O)(C)(C)C.[NH2:26][C:27]1[C:40]2[C:39](=[O:41])[C:38]([C:42]([OH:44])=[O:43])=[CH:37][N:32]3[C@@H:33]([CH3:36])[CH2:34][O:35][C:30]([C:31]=23)=[C:29](F)[C:28]=1[F:46].C(N(CC)CC)C>C(O)C.[C].[Pd].CS(C)=O>[NH2:26][C:27]1[C:40]2[C:39](=[O:41])[C:38]([C:42]([OH:44])=[O:43])=[CH:37][N:32]3[C@@H:33]([CH3:36])[CH2:34][O:35][C:30]([C:31]=23)=[C:29]([N:15]2[CH2:16][C@H:12]([C:9]3([NH2:8])[CH2:11][CH2:10]3)[C@H:13]([F:25])[CH2:14]2)[C:28]=1[F:46]
Reactant: C[C@@H](c1ccccc1)N1C[C@@H](F)[C@@H](C2(NC(=O)OC(C)(C)C)CC2)C1
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCO
Product: C[C@H]1COc2c(N3C[C@@H](F)[C@@H](C4(N)CC4)C3)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Reaction time: 4 h
Yield: 76.1 %

Procedure:
4-(R)-(1-tert-Butoxycarbonylaminocyclopropyl)-3-(S)-fluoro-1-[1-(S)-phenylethyl]pyrrolidine (900 mg, 2.58 mmol) was dissolved in ethanol (20 ml). After adding a 10% palladium-carbon catalyst (moisture content: 50.2%, 900 mg), the mixture was stirred under a hydrogen atmosphere for 4 hours. After filtering off the catalyst through celite (washed with ethanol), the filtrate was concentrated under reduced pressure. The residue thus obtained was dissolved in dimethyl sulfoxide (20 ml) and 8-amino-9,10-difluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (593 mg, 2.00 mmol) and triethylamine (3 ml) were added thereto. Then the mixture was stirred in a nitrogen atmosphere in an oil bath at 100° C. for 25 hours. After allowing it to cool, dimethyl sulfoxide was evaporated under reduced pressure and the residue was dissolved in chloroform (100 ml.) and washed with a 10% aqueous solution of citric acid (80 ml). The organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. Under ice cooling, concentrated hydrochloric acid (10 ml) was dropped into the residue followed by stirring at room temperature for 30 minutes. After adding 1 N hydrochloric acid (30 ml), the liquid reaction mixture was washed with chloroform (50 ml×4) and its pH value was adjusted to 12.0 with an aqueous solution of sodium hydroxide. The pH value of this aqueous solution was adjusted to 7.4 with 1 N hydrochloric acid followed by extraction with chloroform (500 ml×3). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was recrystallized from ethanol and dried under reduced pressure to obtain 640 mg (76.0%) of the title compound as a yellow powder.
Reaction SMILES: [CH3:1][C:2]([C:4]([OH:6])=[O:5])=[CH2:3].[NH2:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:23])[C:12]=2[C:11]([OH:24])=[CH:10][CH:9]=1.B(O)(O)O.S(=O)(=O)(O)O>>[C:4]([CH:2]([CH3:1])[CH2:3][NH:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:23])[C:12]=2[C:11]([OH:24])=[CH:10][CH:9]=1)([OH:6])=[O:5]
Reactant: C=C(C)C(=O)O
Reactant: Nc1ccc(O)c2c1C(=O)c1ccccc1C2=O
Agent: O=S(=O)(O)O
Agent: OB(O)O
Product: CC(CNc1ccc(O)c2c1C(=O)c1ccccc1C2=O)C(=O)O
Reaction time: 16 h
Yield: 94 %

Procedure:
22 Parts of α-methacrylic acid are gradually added to a mixture of 23.9 parts of 1-amino-4-hydroxyanthraquinone, 6.2 parts of boric acid and 150 parts of 90% sulphuric acid at 35°-40° C, and the mixture is then stirred for 16 hours at 85°-90° C. The reaction mixture is processed as previously described to give 31 parts (94%) of 1-(β-carboxypropylamino)-4-hydroxyanthraquinone.
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-])=O.[SH:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].C(N(CC)CC)C>CS(C)=O>[N+:12]([C:10]1[CH:9]=[CH:8][C:5]2[CH:6]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[S:15][C:4]=2[CH:11]=1)([O-:14])=[O:13]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: COC(=O)CS
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2ccc([N+](=O)[O-])cc2s1
Temperature: 80 °C

Procedure:
2 g (10.2 mmol) of 2,4-dinitrobenzaldehyde, 1.08 g (10.2 mmol) of methyl mercaptoacetate and 2.84 ml (20.4 mmol) of triethylamine are successively dissolved in 6 ml of DMSO. The reaction solution is heated at 80° C. for 1 h and then poured into 200 ml of ice-water. Several dichloromethane extractions are carried out. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. Chromatography (mobile phase: dichloromethane) on silica gel affords 1.12 g (46.1% of theory) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([O:18]CC1C=CC=CC=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([OH:18])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccccc1OCc1ccccc1)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1ccccc1OCc1ccccc1
Reaction time: 16 h
Yield: 38.4 %

Procedure:
To a suspension of benzyl (2-benzyloxyphenyl)acetate (100 g) in ethanol (500 ml) was added a solution of sodium hydroxide (36 g) in water (300 ml). After being stirred for 16 hours, the mixture was concentrated under reduced pressure. Water was added to the residue and the mixture was washed with diethyl ether. The aqueous layer was acidified by concentrated-hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried and evaporated in vacuo. The residual oil was crystallized from diisopropyl ether to afford (2-benzyloxyphenyl)acetic acid (28 g).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[OH:7][CH2:8][C:9]([S:12]([CH2:15][CH:16]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])(=[O:14])=[O:13])([CH3:11])[CH3:10]>N1C=CC=CC=1>[CH:1]1([C:4]([O:7][CH2:8][C:9]([S:12]([CH2:15][CH:16]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])(=[O:14])=[O:13])([CH3:11])[CH3:10])=[O:5])[CH2:3][CH2:2]1
Reactant: CC(C)(CO)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Product: CC(C)(COC(=O)C1CC1)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
In an analogous manner to that described in paragraph (d) above, by reacting cyclopropanecarbonyl chloride and benzyl rac-α-[[(2-hydroxy-1,1-dimethylethyl)sulfonyl]methyl]hydrocinnamate in pyridine there was obtained benzyl rac-[[[2-[(cyclopropylcarbonyl)oxy]-1,1-dimethylethyl]sulfonyl]methyl]hydrocinnamate as a colourless oil, MS: 367 (M-benzyl)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:5]2[O:6][CH2:7][O:8][CH2:9][C:4]=2[CH:3]=1.[C:15](Cl)(Cl)=[O:16].C(N(CC)CC)C.[F:26][CH2:27][CH2:28][OH:29]>C1(C)C=CC=CC=1>[CH2:13]([O:12][C:10]1[C:5]2[O:6][CH2:7][O:8][CH2:9][C:4]=2[CH:3]=[C:2]([NH:1][C:15](=[O:16])[O:29][CH2:28][CH2:27][F:26])[CH:11]=1)[CH3:14]
Reactant: O=C(Cl)Cl
Reactant: OCCF
Reactant: CCOc1cc(N)cc2c1OCOC2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOc1cc(NC(=O)OCCF)cc2c1OCOC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.9 %

Procedure:
To a solution of 6-amino-8-ethoxy-1,3-benzodioxane (1.95 g) in toluene (20 ml), a toluene solution containing phosgene (10 g) was dropwise added at 10° to 20° C. The resultant mixture was heated gradually and, after being refluxed for 30 minutes, cooled to room temperature. The solvent was removed in vacuo, whereby crude 8-ethoxy-1,3-benzodioxan-6-ylisocyanate was obtained. This crude substance was dropwise added to a toluene solution (50 ml) containing triethylamine (1.0 g) and 2-fluoroethanol (0.70 g) at room temperature. The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give 2-fluoroethyl N-(8-ethoxy-1,3-benzodioxan-6-yl)carbamate (Compound No. 10) (2.31 g) in a yield of 80.9%. M.P., 154° -154.5° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2.[CH3:23]N(C=O)C>>[F:22][C:2]([F:1])([F:21])[C:3]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[CH3:23]
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1nc(NCCc2ccccc2)nc2nc[nH]c12
Product: Cn1cnc2c(C(F)(F)F)nc(NCCc3ccccc3)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
To a solution of 6-Trifluoromethyl-2-phenethylaminopurine (compound 9, 0.600 g, 1.95 mmol) in DMF (14 ml) K2CO3 (0.351 g, 2.54 mmol) and Mel (0.158 ml, 2.54 mmol) were added. The mixture was stirred at room temperature and after 0.5 h the reaction was complete (HPLC: Rt,product=4.1). Crystallization occurred after the slow addition of water (17 ml). After stirring for 0.5 h the mixture was filtrated and the residue was washed with four 10-ml portions of water. The filtrate was again filtrated after 1 h and the residue was washed with three 5-ml portions of water. The residue was dried in vacuo at 60° C. obtaining the product as a white solid (503 mg, 80%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][CH2:21][OH:22])[CH:15]=[CH:14]2)#[CH:10].C(NC(C)C)(C)C>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]#[C:9][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][CH2:21][OH:22])[CH:15]=[CH:14]3)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C#Cc1ccc2c(ccn2CCO)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OCCn1ccc2cc(C#Cc3ccc(Br)cn3)ccc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Under an N2 atmosphere 29.4 g (124 mmol) 2,5-dibromo-pyridine, 241 mg (1.3 mmol) CuI and 888 mg (1.3 mmol) Pd(PPh3)2Cl2 are added to a solution of 23.0 g (124 mmol) 2-(5-ethynyl-indol-1-yl)-ethanol and 35 mL (248 mmol) diisopropylamine in 1150 mL THF and the reaction mixture is heated to 50° C. for 3.5 h. Another 241 mg CuI and 888 mg Pd(PPh3)2Cl2 and 9 g (38 mmol) 2,5-dibromo-pyridine are added, the mixture is stirred for a further 2.5 h at 50° C., 64 h at RT and a further 8 h at 60° C. The mixture is evaporated down i. vac., the residue is combined with 500 mL 3% NH3 solution and 800 mL EtOAc. The precipitate formed is filtered off, washed with water and dried at 50° C. The two phases of the filtrate are separated and the organic phase is evaporated down i.vac. The residue is stirred vigorously with 500 mL PE/diisopropylether (1:1) and suction filtered. The two product fractions are then combined.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[S:16])[N:6]([CH2:9][C:10]2[C:14]([CH3:15])=[N:13][O:12][N:11]=2)[C:7]=1[NH2:8].[C:18](O)(=O)C.C(N)=N>O>[CH3:15][C:14]1[C:10]([CH2:9][N:6]2[C:7]3[N:8]=[CH:18][NH:1][C:2]=3[C:3](=[O:17])[NH:4][C:5]2=[S:16])=[N:11][O:12][N:13]=1
Reactant: Cc1nonc1Cn1c(N)c(N)c(=O)[nH]c1=S
Reactant: CC(=O)O
Agent: N=CN
Solvent: O
Product: Cc1nonc1Cn1c(=S)[nH]c(=O)c2[nH]cnc21
Temperature: 25 °C
Yield: 14166.7 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 12(d) by using 5,6-diamino-1-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.41 g, 1.6 mmol, obtained from Example 16(c)) and formamidine acetate (0.25 g, 2.4 mmol) with the exception that after the reaction mixture had cooled to r.t., water (20 mL) was added. The cloudy solution was maintained at 5° C. o.n. and the precipitate that formed was collected by filtration, washed with water and methanol and dried. The material was further purified by recrystallization from DMSO/water to give the title compound (59.9 g, 14% yield).
Reaction SMILES: BrBr.C(Cl)(Cl)(Cl)Cl.N1C2C(=CC=CC=2)C=CC=1.[CH3:18][S:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:22][CH:21]=1.[OH2:37]>C(O)(=O)C>[CH3:18][S:19]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:22][CH:21]=1)=[O:37]
Reactant: CSc1ccc(NC(=O)OCc2cccnc2)cc1
Reactant: O
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Solvent: c1ccc2ncccc2c1
Product: CS(=O)c1ccc(NC(=O)OCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34 %

Procedure:
Quinoline-bromine complex was prepared by adding 3.2 g. (0.02 mole) of bromine in 50 ml. of CCl4 to a solution of 2.6 g. (0.02 mole) of quinoline in 50 ml. of CCl4. A yellow solid separated which was filtered off and air-dried. The yield was 3.5 g. (60%). To a solution of 2.7 g. (0.01 mole) of 3-pyridylmethyl N-(4'-methylthiophenyl)carbamate in 100 ml. of 70% aqueous acetic acid was added, portionwise, 2.7 g. (0.01 mole) of the quinoline-bromine complex. The mixture was stirred at ambient temperature for 15 min. and poured into 100 ml. of water. A negligible amount of solid formed and was removed by filtration. The filtrate was made alkaline with 25% aqueous NaOH, and a white precipitate formed which was filtered off and recrystallized from aqueous ethanol. There was obtained 0.5 g. of recrystallized product, melting at 118° - 121°C., which proved to be a mixture of two components by thin layer chromatography. The filtrate was concentrated to near-dryness, and yielded after oven drying in vacuo 1 g. of a white solid melting at 139° - 143° C. This was a 34% yield of 3-pyridylmethyl N-(4'-methylsulfinylphenyl)-carbamate.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=3)C(=O)[O:19][N:18]=2)=[N:14][O:15][N:16]=1.[S:31](N)([NH2:34])(=[O:33])=[O:32].[OH-].[Na+]>N1C=CC=CC=1.O>[NH2:34][S:31]([NH:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13]([C:17](=[N:18][OH:19])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=2)=[N:14][O:15][N:16]=1)(=[O:33])=[O:32]
Reactant: NCCCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Reactant: NS(N)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: NS(=O)(=O)NCCCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 85.4 %

Procedure:
3-[4-(3-Aminopropyl)-1,2,5-oxadiazol-3-yl]-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one trifluoroacetate (7.8 mg, 0.017 mmol) and sulfamide (9.4 mg, 0.98 mol) was dissolved in pyridine (1.0 mL). The solution was heated at 120° C. for 3 minutes in a microwave. A solution of sodium hydroxide in water (0.5 mL, 1.0; N) was added and the mixture stirred at room temperature for 16 hrs. Acidification with acetic acid and purification by preparative LCMS gave the desired product (5.7 mg, 84%). 1H NMR (400 MHz, CD3OD): δ 7.02 (t, 1H), 6.95 (m, 1H), 6.7 (m, 1H), 3.1 (m, 2H), 2.9 (m, 2H), 2.0 (m, 2H). MF=C12H14ClFN6O4S. LCMS calculated for C12H15ClFN6O4S (M+H)+: m/z=393.0.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:29]=[CH:30][C:31]=3[O:32][CH3:33])[C:14]([CH2:16][O:17][C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:21]([O:23][CH3:24])=[O:22])=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:52]N1C(=O)CCC1=O.O>C(Cl)(Cl)(Cl)Cl.ClCCl>[C:1]12([C:11]3[CH:12]=[C:13]([CH:29]=[CH:30][C:31]=3[O:32][CH3:33])[C:14]([CH2:16][O:17][C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=3[CH2:28][Br:52])[C:21]([O:23][CH3:24])=[O:22])=[O:15])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(OCC(=O)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(CBr)c(OCC(=O)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)c1
Yield: 34 %

Procedure:
A solution of methyl 3[(3-(1-adamantyl)-4-methoxybenzoyl)methyloxy]-4-methylbenzoate (2.36 g, 5.26 mmol) and benzoyl peroxide (0.02 g) in carbon tetrachloride (50 ml) was heated to reflux. Benzoyl peroxide (0.03 g) and N-bromosuccinimide (1.05 g, 5.9 mmol) were added. The mixture was heated for four hours at reflux. 50 ml of water and 50 ml of dichloromethane were added. After separation of the phases once settling had taken place, the organic phase was washed twice with 50 ml of water and dried over magnesium sulfate. After concentration on a rotary evaporator at 40° C. under vacuum, the desired product was isolated by flash chromatography (CH2Cl2). Its properties were as follows:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.N1C=CC=CC=1.[CH3:17][N:18]=[C:19]=[O:20].CN(C=O)C>CO>[CH3:17][NH:18][C:19](=[O:20])[NH:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1
Reactant: Nc1nc2cnccc2s1
Reactant: CN=C=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CO
Product: CNC(=O)Nc1nc2cnccc2s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79 %

Procedure:
A mixture of 2-aminothiazolo[4,5-c]pyridine (151 mg, 1 mmole), pyridine (1.8 ml), CH3NCO (1.2 ml) and 3 ml DMF was stirred at room temperature for 2 days. To the reaction mixture was added CH3OH, and the mixture was evaporated in vacuo. The residue was treated with CH3OH and ether to give 165 mg (79%) of crystalline solid. Mp. 178°~187° C. (dec.).
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH3:12][O:13][C:14](=[O:20])[CH2:15][C:16](=[O:19])[CH2:17][CH3:18].[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH2:29]Cl>O1CCCC1.O>[CH3:12][O:13][C:14](=[O:20])[CH:15]([CH2:29][C:23]1[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=1[Cl:21])[C:16](=[O:19])[CH2:17][CH3:18]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: CCC(=O)CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: CCC(=O)C(Cc1ccc(Cl)cc1Cl)C(=O)OC
Temperature: 25 °C
Reaction time: 144 h

Procedure:
A suspension of potassium tert-butoxide (8.4 g) in anhydrous tetrahydrofuran (180 mL) at 0° C. was treated with a mixture of tert-butanol (0.4 mL) and 3-oxopentanoic acid methyl ester (9.8 g). After stirring at room temperature for 30 minutes a solution of 2,4-dichloro-1-chloromethylbenzene (14.7 g) in tetrahydrofuran (20 mL) was added and the resulting mixture warmed to room temperature and then stirred at this temperature for 6 days. The mixture was diluted with water (200 mL), extracted with ethyl acetate and the combined extracts washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of pentane and dichloromethane (1:0 to 1:1 by volume) to afford title compound as a white solid, 7.0 g.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:25]=[C:26]([O:34][CH3:35])[CH:27]=[C:28]5[C:33]=4[N:32]=[CH:31][CH:30]=[CH:29]5)[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[C:8]2[C:3]=1[C:4]([O:40][CH3:41])=[CH:5][C:6]([C:36]([F:39])([F:38])[F:37])=[N:7]2.C[C:43]([CH3:45])=[O:44].C1C[O:49][CH2:48][CH2:47]1.[OH2:51]>>[C:43]([OH:44])(=[O:49])[CH2:45][CH2:25][C:26]([OH:34])=[O:51].[C:43]([OH:44])(=[O:34])[CH2:45][CH2:47][C:48]([OH:49])=[O:51].[F:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:25]=[C:26]([O:34][CH3:35])[CH:27]=[C:28]5[C:33]=4[N:32]=[CH:31][CH:30]=[CH:29]5)[CH2:20][CH2:19]3)[CH2:16][CH2:17]2)=[C:8]2[C:3]=1[C:4]([O:40][CH3:41])=[CH:5][C:6]([C:36]([F:37])([F:39])[F:38])=[N:7]2
Reactant: C1CCOC1
Reactant: CC(C)=O
Reactant: O
Agent: COc1cc(N2CCN(C3CCN(c4ccc(F)c5c(OC)cc(C(F)(F)F)nc45)CC3)CC2)c2ncccc2c1
Product: O=C(O)CCC(=O)O

Procedure:
The weight of the resulting product was 311 g, or about 91.6% yield. NMR analysis indicated that the compound was the disuccinate salt form of 5-fluoro-4-methoxy-8-(4-(4-(6-methoxy-quinolin-8-yl)-piperazin-1-yl)-piperidin-1-yl)-2-trifluoromethyl-quinoline. In addition, residual solvents were found at concentrations of 0.047% for acetone, 0.027% for THF, and 0.14% for water.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:20]([NH2:22])=[O:21]>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:18]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@H:12]([NH:22][CH:20]=[O:21])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CC[C@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: NC=O
Solvent: O=CO
Product: O=CN[C@@H]1CC[C@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Temperature: 162.5 °C

Procedure:
(R)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone (1.2 g) was added formic acid (3 mL) and formamide (3 mL). The reaction mixture was heated to 160-165° C. for 15 h under nitrogen atmosphere. The reaction mixture was cooled to rt and decanted the solvent. The residue solids was passed through flash column using EtOAc:Hexane (3:7 to 1:1) to give and (1R,4R)—Norsertralaine formamide (400 mg, first spot), and (1S,4R)—Norsertraline formamide (360 mg). 1H NMR of the first product [(1R,4R)-isomer]: (CDCl3) δ 1.80-2.10 (m, 3H), 2.10-2.20 (m, 1H), 4.00-4.10 (m, 1H), 5.22-5.30 (m, 1H), 6.10-6.20 (m, 1H), 6.80-6.90 (M, 1H), 6.90-6.96 (m, 1H), 7.10-7.40 (m, 5H), 8.22 (s, 1H). M+320. 1H NMR of the second product [(1S,4R)-isomer: δ 1.64-1.90 (m, 2H), 2.10-2.28 (m, 2H), 4.10 (m, 1H), 5.38-5.42 (m, 1H), 5.82-6.05 (m, 1H), 6.80-6.90 (m, 2H), 7.10-40 (m, 5H), 8.28 (s, 1H). Mass Spec. M+320.