Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][N:11]1[O:15][CH2:16][C:17]1[CH:22]=[N:21][C:20]([CH3:23])=[C:19]2[O:24]C(C)(C)[O:26][CH2:27][C:18]=12.[ClH:30]>C(O)C>[ClH:1].[ClH:30].[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][N:11]1[O:15][CH2:16][C:17]1[C:18]([CH2:27][OH:26])=[C:19]([OH:24])[C:20]([CH3:23])=[N:21][CH:22]=1
Reactant: Cc1ncc(CON2CCNC2=Nc2c(Cl)cccc2Cl)c2c1OC(C)(C)OC2
Agent: Cl
Solvent: CCO
Product: Cc1ncc(CON2CCNC2=Nc2c(Cl)cccc2Cl)c(CO)c1O
Reaction time: 48 h

Procedure:
3.7 g. of 5-[{[2-[(2,6-dichlorophenyl)imino]-1-imidazolidinyl]oxy}methyl]-2,2,8-trimethyl-4H-m-dioxino[4,5-c]pyridine are dissolved in 50 ml. of ethanol, 50 ml. of 3N hydrochloric acid are added at room temperature and the mixture is left to stand for two days. The solution is evaporated and the residue is recrystallized from methanol/acetonitrile, whereupon 5-[{[2-[(2,6-dichlorophenyl)imino]-1-imidazolidinyl]oxy}methyl]-3-hydroxy-2-methyl-4-pyridinemethanol dihydrochloride, m.p. 216°-218°, is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[BH3-]C#N.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
To 5-Bromo-1H-indole (2.5 g, 12.82 mmol) in acetic acid (10.0 mL), NaCNBH3 (2.38 g, 38.46 mmol) was added portion wise at 10° C. over the period of 20 min After that the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with saturated NaHCO3, water and brine solution. The combined ether layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford title compound as a pale yellow semi-solid (1.8 g, 71%).
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:21])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:3][CH2:4][OH:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:33]1[CH:38]=[CH:37][CH2:36][CH2:35][CH2:34]1>C(Cl)Cl>[O:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1[O:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:21])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCOC1CCCCO1
Yield: 67.2 %

Procedure:
In methylene chloride were dissolved 15 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraen-1-ol and 1.5 g of p-toluenesulfonic acid, and to the solution was dropwise added, under stirring, 8.7 g of 2,3-dihydropyran, at 0°-5° C. and over a period of 30 min. The resulting solution was further stirred at 0°-5° C. for 30 min., and then washed with an aqueous sodium carbonate solution in a separatory funnel. The solution was concentrated after the washing, and the concentrated solution was purified over a silica gel column to give 13 g of 1-(2-tetrahydropyranyl)oxy-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraene (yield 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]([C:15]23[CH2:24][CH:19]4[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]4)[CH2:16]2)[CH2:22]3)[CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])=[O:7])=[CH:4][CH:3]=1.[NH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([C:15]23[CH2:24][CH:19]4[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]4)[CH2:16]2)[CH2:22]3)[CH2:9][CH2:10][CH2:11][C:12]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:13])=[O:7])=[CH:25][CH:26]=1
Reactant: CCOC(=O)CCN
Reactant: O=C(O)CCCN(C(=O)c1ccc(Cl)cc1)C12CC3CC(CC(C3)C1)C2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCNC(=O)CCCN(C(=O)c1ccc(Cl)cc1)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-(1-adamantylamino)butyric acid and ethyl 3-aminopropionate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-(p-chlorobenzoyl)-4-(1-adamantylamino)butyryl]-3-aminopropionic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=3[F:24])=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:25][CH3:26].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][S:35]([CH3:34])(=[O:37])=[O:36])=[C:7]([O:25][CH3:26])[CH:8]=3)[N:13]=[CH:12][N:11]=2)=[C:18]([F:24])[CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc2c(Oc3ccc(Br)cc3F)ncnc2cc1OCCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(Oc3ccc(Br)cc3F)ncnc2cc1OCCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.1 %

Procedure:
A solution of 7-(3-aminopropoxy)-4-(4-bromo-2-fluorophenoxy)-6-methoxyquinazoline (2.71 g, 6.4 mmol) and triethylamine (1.1 ml, 0.80 g, 7.9 mmol) in dichloromethane (15 ml) was treated with a solution of methanesulphonyl chloride (0.53 ml, 0.79 g, 6.9 mmol) in dichloromethane (10 ml) and stirred at ambient temperature, under nitrogen for 18 hours. The dichloromethane was then removed by evaporation and THF (4 ml) added. The resulting solution was treated with saturated aqueous sodium hydrogen carbonate solution (to pH 8), stirred vigorously for 30 minutes and the precipitate filtered, washed with water and dried to give 4-(4-bromo-2-fluorophenoxy)-6-methoxy-7-(3-(N-methylsulphonylamino)propoxy)quinazoline (2.98 g, 93%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH3:22])=[O:9])[CH2:2]1.[CH:23]([C:25]1[CH:26]=[C:27](OB(O)O)[CH:28]=[CH:29][C:30]=1[F:31])=[O:24]>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[S:14][C:10]([C:8]([NH:7][CH:3]3[CH2:4][CH2:5][CH2:6][N:1]([C:27]4[CH:28]=[CH:29][C:30]([F:31])=[C:25]([CH:26]=4)[CH:23]=[O:24])[CH2:2]3)=[O:9])=[C:11]([CH3:22])[N:12]=2)=[CH:20][CH:19]=1
Reactant: O=Cc1cc(OB(O)O)ccc1F
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NC1CCCNC1
Product: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NC1CCCN(c2ccc(F)c(C=O)c2)C1
Yield: 16.9 %

Procedure:
Using N-(piperidin-3-yl)-2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (238 mg, 0.709 mmol) and 3-formyl-4-fluorophenylboric acid (238 mg, 1.42 mmol), the same procedure was followed as in Example 2 to give 55.0 mg (17%) of the desired compound as a pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[C:4]([CH3:11])[CH:3]=1.N1C=CC=CC=1.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl>[C:18]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[C:4]([CH3:11])[CH:3]=1)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1c(C)cc(N)cc1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(C)cc(NC(=O)C(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.1 %

Procedure:
Into an ice-cold solution of aniline 4 (15.1 g, 100 mmol) dissolved in methylene chloride (100 mL) were added sequentially pyridine (17.5 mL) and pivaloyl chloride (12.3 mL, 100 mmol) dropwise, and the resulting mixture was stirred at room temperature for 15 h. The mixture was diluted with methylene chloride and washed sequentially with 10% aq. hydrochloric acid, saturated aq. sodium bicarbonate and brine. Removal of solvents after drying (MgSO4) gave the pivalamide (19.8 g, 86% yield) as a pale brown solid, mp 126°-128° C. Spectral data: 1H NMR: δ 1.30 (s, 9H), 2.23 (s, 6H), 3.68 (s, 3H), 7.18 (s, 2H).
Reaction SMILES: ClCC([O:5][C:6]1[CH:14]=[CH:13][C:12]2[N:11]([CH3:15])[C:10]3[C:16](=O)[CH2:17][CH2:18][C:9]=3[C:8]=2[CH:7]=1)=O.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH3:15][N:11]1[C:12]2[CH:13]=[CH:14][C:6]([OH:5])=[CH:7][C:8]=2[C:9]2[CH2:18][CH2:17][C:16](=[N:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]1=2
Reactant: NCc1ccccc1
Reactant: Cn1c2c(c3cc(OC(=O)CCl)ccc31)CCC2=O
Solvent: Cc1ccccc1
Product: Cn1c2c(c3cc(O)ccc31)CCC2=NCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 17.5 %

Procedure:
To a stirred suspension of 7-chloroacetyloxy-1,4-dihydro-4-methylcyclopent[b]-indol-3(2H)-one (6.0 g) in toluene (50 ml) was added benzylamine (9.2 g) and the mixture was heated at reflux temperature with azeotropic removal of water using a Dean Stark trap. After 4 hours, TLC analysis indicated complete conversion to product. The mixture was allowed to cool to room temperature and filtered, and the solid material was washed with acetonitrile. The filtrate and washings were combined, concentrated and purified by flash chromatography on silica gel (2:1 hexane/acetone as eluent). The crystals which formed in the product-containing fractions were collected via filtration to give 4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol (1.1 grams) and the filtrate was concentrated to give an oil (3.0 grams) which crystallized upon standing.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]([CH3:15])[CH3:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.C([Li])(C)(C)C.CCCCC.[B:26](OC)([O:29]C)[O:27]C>O1CCCC1>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[C:2]([B:26]([OH:29])[OH:27])[CH:3]=[C:4]([CH:13]([CH3:15])[CH3:14])[C:5]=2[O:9][CH2:8]1
Reactant: CC(C)c1cc(Br)cc2c1OCC2(C)C
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)c1cc(B(O)O)cc2c1OCC2(C)C

Procedure:
Following General Procedure A and using 5-bromo-3,3-dimethyl-7-iso-propyl-2,3-dihydro-benzofuran (0.8 g, 3 mmol), 15 mL of anhydrous tetrahydrofuran, 1.7M solution of t-butyllithium in n-pentane (3.53 mL, 6 mmol) and trimethyl borate (0.75 mL, 6 mmol), the title compound was obtained as a foam that was used as such for the next step without purification and characterization. 5-Bromo-3,3-dimethyl-7-iso-propyl-2,3-dihydro-benzofuran can be prepared as described in U.S. Pat. No. 6,093,838.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].C(N(CC)CC)C.[C:18]([CH2:22][CH2:23][C:24](Cl)=[O:25])([O:20][CH3:21])=[O:19]>C(Cl)Cl>[CH3:21][O:20][C:18](=[O:19])[CH2:22][CH2:23][C:24](=[O:25])[NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10]
Reactant: NCCCN1CCCC1=O
Reactant: COC(=O)CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCC(=O)NCCCN1CCCC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To a solution of 1-(3-aminopropyl)-2-oxopyrrolidine (570 mg) in methylene chloride (10 ml) were added triethylamine (0.67 ml) and 3-carbomethoxy propionylchloride (600 mg) in sequence under ice-cooling and the mixture was stirred for 0.5 hour. After 3.5 hours' stirring at room temperature, the reaction mixture was poured into ice water and extracted with chloroform. The organic layer was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and saturated brine in sequence, and dried over magnesium sulfate, followed by concentration. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 902 mg of 4-oxo-4-[3-(2-oxo-1-pyrrolidinyl)propylamino]butyric acid methyl ester.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[C:17](#[N:19])[CH3:18]>>[C:2]1([C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:18][C:17]#[N:19])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: CC#N
Agent: [K+]
Agent: [OH-]
Product: N#CC=C(c1ccccc1)c1ccccc1
Yield: 73.3 %

Procedure:
To a solution of benzophenone (9.1 g, 50 mmol) in acetonitrile (20 mL) was added potassium hydroxide (3.3 g, 50 mmol) in acetonitrile (25 mL). The solution was refluxed for 8 hours. The hot reaction mixture was poured into 100 g crushed ice and then extracted with dichloromethane. The organic extract was washed with water, dried over sodium sulfate, and concentrated in vacuo. The crude material was purified by flash column chromatography (diethyl ether/hexanes) to give 3,3-diphenylacrylonitrile (7.7 g, 73.3%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13]2)[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:8][C:3]=1[C:4](OC)=[O:5].[NH2:23][C:24]([NH2:26])=[NH:25].O>CO>[NH2:25][C:24]([NH2:26])=[N:23][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13]2)=[CH:11][C:2]=1[CH3:1]
Reactant: N=C(N)N
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(N2CCCC(O)C2)cc1C
Solvent: CO
Solvent: O
Product: Cc1cc(N2CCCC(O)C2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Reaction time: 1 h

Procedure:
A solution of 4.2 g of methyl 2-methyl-4-(3-hydroxy-1-piperidyl)-5-methylsulfonylbenzoate [obtainable by reacting 3-hydroxypiperidine with 2-methyl-4-chloro-5-methylsulfonylbenzoic acid followed by esterification] and 3.89 g of guanidine in 20 ml of methanol is stirred at 50° over a period of three hours. The solution is cooled, water is added, the mixture is stirred for 1 hour and the precipitate which is formed is separated off. After recrystallization from acetone/methanol, N-diaminomethylene-2-methyl-4-(3-hydroxy-1-piperidyl)-5-methylsulfonylbenzamide is obtained, m.p. 194-196°.
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C@H:8]([C:24]([N:26]2[CH2:30][CH2:29][NH:28][C:27]2=[O:31])=[O:25])[CH2:7]1)(=[O:4])=[O:3].CO.[H][H]>[Pd].O1CCCC1>[CH3:1][S:2]([O:5][C@H:6]1[CH2:10][NH:9][C@H:8]([C:24]([N:26]2[CH2:30][CH2:29][NH:28][C:27]2=[O:31])=[O:25])[CH2:7]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCNC2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)O[C@H]1CN[C@H](C(=O)N2CCNC2=O)C1
Yield: 81.9 %

Procedure:
A mixture of (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-(2-oxoimidazolidin-1-yl)carbonylpyrrolidine (30 g), 10% palladium on carbon (10 g), methanol (300 ml) and tetrahydrofuran (150 ml) was stirred for 5 hours under atmospheric pressure of hydrogen at ambient temperature. After the catalyst was filtered off, the filtrate was evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (250 g) eluting with a mixture of chloroform and methanol (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-methanesulfonyloxy-2-(2-oxoimidazolidin-1-yl)carbonylpyrrolidine (14.92 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].B.CO>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1Br
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(CO)ccc1Br

Procedure:
4-Bromo-3-methoxybenzoic acid (23.1 g, 0.1 m) dissolved in tetrahydrofuran (200 ml) is added to 1M borane in tetrahydrofuran (150 ml) stirred at 5°. The mixture is refluxed, cooled, treated with methanol, refluxed and concentrated in vacuo to give 4-bromo-3-methoxybenzyl alcohol.
Reaction SMILES: C(OC([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:13]=2[CH2:12]1)=O)C1C=CC=CC=1.[ClH:32]>CO.O1CCOCC1.[Pd]>[ClH:32].[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]3[CH2:22][CH2:23][NH:11][CH2:12][C:13]2=3)=[CH:26][CH:27]=1
Reactant: O=C(OCc1ccccc1)N1CCc2c(n(Cc3ccc(F)cc3)c3ccccc23)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Fc1ccc(Cn2c3c(c4ccccc42)CCNC3)cc1
Reaction time: 6 h
Yield: 90 %

Procedure:
To a solution of 2-benzyloxycarbonyl-9-{[4-(fluoro)phenyl]methyl}-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole (5.28 g, 12.7 mmole) in methanol (50 mL), dioxane (50 mL) and HCl (19 mL, 1M in dioxane) at RT in a Parr hydrogenation flask was added 10% Pd/C (0.5 g). The reaction mixture was shaken under 45 psi of H2 for 6 hr. The suspension was filtered through celite®, and the filter pad was washed with methanol. The filtrate was concentrated on the rotavap, and the residue was dried under high vacuum to afford the titled compound (3.61 g, 90%) as a white solid: MS (ES) m/e 281 (M+H−HCl)+.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH:20]C(=O)C(Cl)(Cl)[Cl:23])[C:11]=2[N:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].Cl>CO.C(O)(C)C>[ClH:23].[CH2:1]([C:8]1[S:9][C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:20])[C:11]=2[N:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1nc2ccccc2c2sc(Cc3ccccc3)nc12)C(Cl)(Cl)Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Product: Nc1nc2ccccc2c2sc(Cc3ccccc3)nc12
Temperature: 25 °C

Procedure:
Trichloroacetyl isocyanate (1.2 mL, 10.3 mmol) was added to a solution of 2-benzylthiazolo[4,5-c]quinoline-5N-oxide (2.0 g, 6.8 mmol) in dichloromethane (100 mL). The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated to provide crude N-(2-benzylthiazolo[4,5-c]quinolin-4-yl)trichloroacetamide. The amide was dissolved in methanol. Sodium methoxide (1 equivalent) was added. The reaction mixture was heated on a steam bath for 30 minutes and then allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration and then suspended in a mixture of methanol and isopropanol. Hydrochloric acid (1 equivalent) was added and all of the solid dissolved initially. A white solid crystallized out. This material was isolated by filtration, washed with isopropanol and then dried to provide 1.5 g of 2-benzylthiazolo[4,5-c]quinolin-4-amine hydrochloride, m.p. 152–155° C. Analysis: Calculated for: C17H13N3S.HCl: % C, 62.28; % H, 4.30; % N, 12.82; Found: % C, 62.05; % H, 4.23; % N, 12.82.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[N:32]=[C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:34][CH:35]=1.O>CN(C)C=O>[C:14]1([C:12]2[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][N:9]([CH2:8][C:7]3[CH:27]=[CH:28][C:4]([O:3][CH2:30][C:31]4[N:32]=[C:33]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[O:34][CH:35]=4)=[CH:5][CH:6]=3)[CH:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Reactant: ClCc1coc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-phenyloxazole (290 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatograpy, and ethyl 3-[4-phenyl-1-[4-(2-phenyl-4-oxazolylmethoxy)benzyl]-3-pyrrolyl]propionate (550 mg, yield: 72%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([N+:19]([O-])=O)[CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:22][P:23](=[O:27])([CH2:25]N)[CH3:24]>C1(C)C=CC=CC=1>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=2)=[CH:11][C:12]=1[NH:19][CH2:22][P:23](=[O:27])([CH3:25])[CH3:24])([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(Oc2ncc(Cl)cc2Cl)cc1[N+](=O)[O-]
Reactant: CP(C)(=O)CN
Solvent: Cc1ccccc1
Product: CP(C)(=O)CNc1cc(Oc2ncc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Yield: 83.7 %

Procedure:
A solution of 4.95 g (3,5-Dichloro-2-pyridyloxy)-3,4-dinitrobenzene in 15 ml of toluene is refluxed, and 3.21 g of melted P,P-dimethyl-aminomethylphosphine oxide are added. After the initial evolution of nitrous gases has finished, the mixture is refluxed for a further 2 hours. The brown solution is subsequently concentrated by evaporation, and the residue is recrystallised from 20 ml of ethyl acetate and 100 ml of ether. There are obtained, in the form of yellow crystals, 4.9 g (84% of theory) of N-[2-nitro-5-(3,5-dichloro-2-pyridyloxy)-phenyl]-P,P-dimethyl-aminomethylphosphine oxide, m.p. 153°-155° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.[C:12]1([CH:18]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][NH2:29])[CH2:22][CH2:21]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)C(C)C)C>C(O)CCC>[C:30]1([CH:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][NH:29][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8](=[O:11])[NH:9][N:10]=4)[N:7]=3)[CH2:22][CH2:21]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: O=c1[nH]nc2ccc(Cl)nn12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Yield: 28.1 %

Procedure:
0.512 g of 6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one was dissolved in 15 ml of n-butanol; 0.88 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 1.04 ml of N-ethyldiisopropylamine were added, followed by refluxing under heating in an oil bath for 5 hours. After cooling, the n-butanol was mostly distilled off under reduced pressure; to the residue, an aqueous solution of sodium hydrogen carbonate was added; the reaction mixture was extracted with ethyl acetate; the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (85:15:1). The desired fraction was collected and concentrated; the crystal obtained was filtered, washed with diethyl ether, and dried, to yield 0.35 g of the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].[C:14]1([CH3:26])[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23].O.Cl>[OH-].[Na+].O1CCOCC1>[C:14]1([CH3:26])[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22]([NH:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3])(=[O:23])=[O:24]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(S(=O)(=O)N[C@@H](C)C(=O)N2CCC[C@H]2C(=O)O)c(C)c1
Yield: 45.3 %

Procedure:
L-alanyl-L-proline (1.86 g, 10 mmole) was dissolved in aqueous sodium hydroxide (10 ml)-dioxane (10 ml), and dioxane (5 ml) solution of mesitylenesulfonylchloride (2.19 g, 10 mmole) was added dropwise to the solution while cooling and stirring while keeping pH value thereof to 10 to 11 with 1N aqueous sodium hydroxide. After that; the mixture was stirred further for 2 hours at room temperature. Water (20 ml) was added thereto and the mixture thus obtained was washed with diethyl ether (40 ml). The water layer was filtered and the filtrate thus obtained was adjusted to pH 2.0 with 1N hydrochloric acid while cooling and stirring to precipitate white solid material. The material was dissolved in 0.5N aqueous sodium hydroxide and the solution thus obtained was crystallized by addition of 1N aqueous hydrochloric acid to give N-mesitylenesulfonyl-L-alanyl-L-proline yield: 1.67 g, 45.3%).