Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:7])([O-])=O.Cl.[OH-].[Na+]>O>[NH2:1][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: O=C(c1ccncc1)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccccc1C(=O)c1ccncc1
Temperature: 23 °C

Procedure:
Alternatively, to a solution of 1-iodo-2-nitrobenzene (3.76 g, 15.1 mmol) in dry THF (80 mL) at −78° C. was added n-butyl lithium (7.54 mL, 18.9 mmol) over 5 min. After 40 min at −78° C., ethyl isonicotinate was added in one portion in dry THF (70 mL). After 10 min, the reaction was allowed to warm to 0° C. for 10 min then quenched with 20 mL of glacial acetic acid: 30 mL of water. After adjusting the pH to 8 with saturated bicarbonate solution, the mixture was extracted with ethyl acetate (1×500 mL), washed with brine (2×500 mL), dried (Na2SO4). After concentration in vacuo, the reaction mixture was treated with 120 mL of 5 N NaOH:methanol:water (1:1:1). After removal of methanol in vacuo, the reaction mixture was extracted with ethyl acetate (1×500 mL), then dried (Na2SO4). After concentration in vacuo, the residue was purified by applying flash chromatography (step gradient methylene chloride 100%; the 20% ethyl acetate:methylene chloride: then 40% ethyl acetate:methylene chloride) to afford 4-(2-nitobenzoyl)pyridine. 4-(2-Nitrobenzoyl)pyridine (100 mg, 0.44 mmol), stannous chloride dihydrate (297 mg, 1.32 mmol), and 1.1 mL of concentrated hydrochloric acid were warmed to 100° C. for 10 minutes. After cooling to 23° C., the reaction was poured into water (10 mL) and 5 N sodium hydroxide (14 mL) followed by extraction with ethyl acetate (2×50 mL). The ethyl acetate layer was washed with brine (1×20 mL), dried (Na2SO4), and concentrated in vacuo to afford 4-(2-aminobenzoyl)pyridine (12).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:7]=[N:6][CH:5]=1.Br[C:24]1[CH:25]=[N:26][N:27]([CH:29]([CH3:31])[CH3:30])[CH:28]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:25]=[N:26][N:27]([CH:29]([CH3:31])[CH3:30])[CH:28]=3)[C:12]=2[CH3:21])[CH:7]=[N:6][CH:5]=1
Reactant: CC(C)n1cc(Br)cn1
Reactant: COC(=O)c1cncc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: COC(=O)c1cncc(Sc2c(C)n(-c3cnn(C(C)C)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 1, using the following starting materials: 5-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-nicotinic acid methyl ester and 4-bromo-1-isopropyl-1H-pyrazole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](OS(C(F)(F)F)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(COC)OC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:33]2[CH:32]=[C:31]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:36]=[CH:35][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(-c3ccccc3)c2)CC1
Temperature: 25 °C

Procedure:
A stirred mixture of 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.98 g, 12 mmol), 3-biphenylboronic acid (2.77 g, 14 mmol), LiCl (1.53 g, 36 mmol), dimethoxyethane (35 mL), tetrakis-(triphenylphosphin)-palladium (0.81 g, 0.7 mmol) and Na2CO3 (2M solution, 14 mL, 28 mmol) is heated at reflux under argon for 14 h. The mixture is cooled to RT, dimethoxyethane is removed in vacuo and the residue is diluted with aqueous 2N Na2CO3 solution containing a few mL of concentrated NH4OH. The aqueous layer is extracted three times with CH2Cl2. The combined organic extracts are dried (Na2SO4) and evaporated in vacuo. Flash chromatography of the dark residue (SiO2, hexane/ethyl acetate) affords 4-biphenyl-3-yl-3,6,dihydro-2H-pyridine-1-carboxylic acid t-butyl ester as a colourless oil: MS (after treatment with trifluoroacetic acid) 236.3 [M+H−C5H8O2]+; Rf 0.40 (hexane/ethyl acetate 8:2).
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][C:8]=1[C:9](O)=[O:10])=[O:5])[CH3:2].S(Cl)([Cl:27])=O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH2:1]([O:3][C:4]([O:6][C:7]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][C:8]=1[C:9]([Cl:27])=[O:10])=[O:5])[CH3:2]
Reactant: CCCCCCCC(=O)c1ccc(OC(=O)OCC)c(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCC(=O)c1ccc(OC(=O)OCC)c(C(=O)Cl)c1
Temperature: 55 °C
Reaction time: 14 h
Yield: 98.3 %

Procedure:
5.59 g (16.6 mmol) of 2-ethoxycarbonyloxy-5-octanoylbenzoic acid are dissolved in 56 ml of toluene with a few drops of pyridine. 1.45 ml (20 mmol) of thionyl chloride are added dropwise and the mixture is stirred at 55° C. for 14 hours and then concentrated to dryness. 5.79 g of 2-ethoxycarbonyloxy-5-octanoylbenzoyl chloride are obtained in a yield of 98%.
Reaction SMILES: [CH:1]1[C:11]2[N:10]3[CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][C:7](=O)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.B#B.CSC.O.[OH-].[Na+]>O1CCCC1>[CH:1]1[C:11]2[N:10]3[CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1Cc2cccn2-c2ccccc2N1
Agent: B#B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CSC
Product: c1ccc2c(c1)NCCc1cccn1-2
Yield: 99.9 %

Procedure:
To a solution of 0.070 g of 6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-6-one in 2 ml of tetrahydrofuran is added 0.45 ml of a 2.0M solution of diborane-dimethylsulfide in tetrahydrofuran. The mixture is refluxed for 3 hours, poured into water and make basic with 2N NaOH. The tetrahydrofuran is removed under vacuum and the residual aqueous mixture extracted with diethyl ether. The extract is washed with brine, dried (Na2SO4) and the solvent removed to give 0.065 g of a colorless oil; one spot by thin layer chromatography (silica gel) with ethyl acetate-hexane (1:2) as solvent (Rf 0.81).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][N:6]1[C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][C:9](=[O:17])[C:8]2[CH:18]=[C:19]([O:24][CH2:25][C:26]([O:28]CC)=[O:27])[C:20](=[O:23])[CH:21]=[CH:22][C:7]1=2)C.[OH-].[K+].Cl>>[C:12]([C:11]1[N:6]([CH2:5][C:4]([OH:31])=[O:3])[C:7]2[CH:22]=[CH:21][C:20](=[O:23])[C:19]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:18][C:8]=2[C:9](=[O:17])[CH:10]=1)([OH:14])=[O:13]
Reactant: CCOC(=O)COc1cc2c(=O)cc(C(=O)OCC)n(CC(=O)OCC)c2ccc1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)COc1cc2c(=O)cc(C(=O)O)n(CC(=O)O)c2ccc1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 4,7-dihydro-4,7-dioxo-2-ethoxycarbonyl-6-[(2-ethoxy-2-oxoethyl)oxy]-1H-cyclohepta[b]pyridine-1-acetic acid ethyl ester (1.72 g, described in Example 15) and 2N potassium hydroxide (12 ml) is stirred at room temperature for 2.5 hr and 19% hydrochloric acid is added until the mixture is acidic. The precipitate is collected and washed with water, acetone and ether to obtain the title compound. The precipitate is dissolved in aqueous aminoethanol (1M, 4 ml) and acetone (50 ml is added). The precipitate is collected, washed with acetone and crystallized from water-acetone to give crystals of the aminoethanol salt of the title compound, mp 236°-237° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][N:11]([CH2:15][CH:16]=[CH2:17])[CH2:12][CH:13]=[CH2:14])=[CH:8][CH:9]=1)=[O:4].[OH-].[K+]>CO>[CH2:12]([N:11]([CH2:10][C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=1)[CH2:15][CH:16]=[CH2:17])[CH:13]=[CH2:14]
Reactant: C=CCN(CC=C)Cc1ccc(C(=O)OC)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=CCN(CC=C)Cc1ccc(C(=O)O)s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a solution of 4.5 g (17.9 mmol) 5-diallylaminomethyl-thiophene-2-carboxylic acid methyl ester in 45 ml methanol were added to 17.9 ml of a 1 N aqueous solution of KOH (17.9 mmol). The reaction mixture was stirred at 50° C. for 16 h and 1 h at reflux. The solvent was evaporated, 20 ml water was added to the residue and 9 ml of a 2 N aqueous solution of HCl. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over Na2SO4. The solvent was evaporated and the residue was subjected to silica gel chromatography (ethyl acetate) to yield 4.05 g (17.06 mmol) 5-diallylaminomethyl-thiophene-2-carboxylic acid; exact MW [M+H] calc'd: 238.09; MW found [M+H]: 238.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][C:6]1[C:7](=[O:14])[NH:8][C:9](SC)=[N:10][CH:11]=1.[CH3:19][C:20]1[NH:24][CH:23]=[N:22][C:21]=1[CH2:25][S:26][CH2:27][CH2:28][NH2:29]>C(O)C>[CH3:19][C:20]1[NH:24][CH:23]=[N:22][C:21]=1[CH2:25][S:26][CH2:27][CH2:28][NH:29][C:9]1[NH:8][C:7](=[O:14])[C:6]([CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=2[O:2][CH3:1])=[CH:11][N:10]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: COc1ccccc1Cc1cnc(SC)[nH]c1=O
Solvent: CCO
Product: COc1ccccc1Cc1cnc(NCCSCc2nc[nH]c2C)[nH]c1=O

Procedure:
5-(2-Methoxybenzyl)-2-methylthio-4-pyrimidone (2.00 g) was reacted with 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (1.37 g) by the procedure of Example 1(ii) to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-methoxybenzyl)-4-pyrimidone, m.p. 163°-167° C. (ex ethanol).
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.[C:13]([O:17][C:18]([CH:20]1[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(Br)C=C.[Cl-].[NH4+]>O1CCCC1.CCCCCC.O>[C:13]([O:17][C:18]([C:20]1([CH2:7][CH:5]=[CH2:6])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)NC(C)C
Reactant: CC(C)(C)OC(=O)C1CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: C=CCC1(C(=O)OC(C)(C)C)CC1
Temperature: -75 °C
Reaction time: 0.83 h
Yield: 65 %

Procedure:
15.9 ml (1.15 eq.) diisopropylamine were dissolved in 65 ml tetrahydrofuran and cooled to ca −10° C. 65 ml (1.08 eq.) 1.6 M butyllithium solution in hexane were added over 25 min, maintaining the temperature between −10° C. and 0° C. After 50 min at ca. −5° C., the reaction mixture was cooled to −75° C. A solution of 15 g (96.7 mmol, 1 eq., 92% w/w purity) cyclopropanecarboxylic acid tert-butyl ester in 20 ml tetrahydrofuran was added over 15 min keeping the temperature between −75° C. and −70° C. The reaction mixture was stirred 5 h at −75° C. (milky reaction mixture obtained after 2.5 h). A solution of 12.87 g (1.10 eq.) allyl bromide was added over 20 min keeping the temperature between −75° C. and −60° C. The reaction mixture was stirred at −78° C. for 1 h, warmed to room temperature and stirred overnight. The reaction mixture was cooled to 0° C. 100 ml sat. aq. ammonium chloride solution were added followed by 30 ml water providing a clear biphasic mixture. The mixture was extracted 3 times with 50 ml tert-butyl methyl ether. The organic phases were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure (40° C./20 mbar) to afford 16.44 g of crude product. The crude product was distilled (2 mbar; ca 40° C. distillation head temperature) to provide the titled compound in ca 65% yield.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.Br[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1.[Mg]>C1COCC1>[F:19][C:16]1[CH:17]=[C:18]([C:7]2([OH:10])[CH2:6][CH2:5][C:4]3([O:3][CH2:2][CH2:1][O:11]3)[CH2:9][CH2:8]2)[CH:13]=[CH:14][C:15]=1[F:20]
Reactant: Fc1ccc(Br)cc1F
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2ccc(F)c(F)c2)CCC2(CC1)OCCO2
Yield: 38 %

Procedure:
A solution of 1,4-cyclohexanedione monoethylene ketal (15.6 g, 100 mmole) in dry THF (250 ml) was reacted with a solution of the Grignard reagent prepared from 1-bromo-3,4-difluorobenzene (19 g, 100 mmole) and magnesium (2.4 g, 100 mmole) in dry THF at -60° C. as described in example 3 to give the product (38%, mp: 118-120° C.). Calc'd for C14H16F2O3 : C, 62.22%; H,5.97%. Found: C, 61.97%; H, 6.35%.
Reaction SMILES: [C:1]([CH2:9][S:10]([C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][NH:19][CH2:20]2)=[CH:15][CH:14]=1)(=O)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](N1CCC2C(=CC(S(Cl)(=O)=O)=CC=2)C1)(=[O:25])[CH3:24].C1C2C(=CC=CC=2)CCN1.C(N1CCC2C(=CC(S)=CC=2)C1)(=O)C>C(O)(=O)C.Cl>[C:23]([N:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][C:13]([S:10][CH2:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:15]=2)[CH2:20]1)(=[O:25])[CH3:24]
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Reactant: O=C(CS(=O)(=O)c1ccc2c(c1)CNCC2)c1ccccc1
Agent: CC(=O)N1CCc2ccc(S)cc2C1
Agent: Cl
Agent: c1ccc2c(c1)CCNC2
Solvent: CC(=O)O
Product: CC(=O)N1CCc2ccc(SCC(=O)c3ccccc3)cc2C1

Procedure:
The starting appropriately substituted tetrahydroisoquinolines of the formula (A) are conveniently prepared by standard reactions well known in the chemical arts as shown below: ##STR3## 2-Acetyl-7-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline, which is prepared by acylating and then chlorosulfonating 1,2,3,4-tetrahydroisoquinoline, is reduced to 2-acetal-7-mercapto-1,2,3,4-tetrahydroisoquinoline employing stannous chloride in acetic acid-hydrochloric acid mixture. The 2-acetyl-7-mercapto-1,2,3,4-tetrahydroisoquinoline is then condensed with the appropriately substituted α-bromo acetophenone to afford 2-acetyl-7-benzoylmethylthio-1,2,3,4-tetrahydroisoquinoline (B) which is then oxidized with m-chloroperbenzoic acid and hydrolyzed to yield the desired 7-benzoylmethylsulfonyl-1,2,3,4-tetrahydroisoquinoline (A). Bis(chlorosulfonyl)imide is prepared from chlorosulfonic acid and chlorosulfonylisocyanate.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]([OH:11])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH2:60])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1>C1COCC1.C(Cl)(Cl)Cl>[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH:60][C:9](=[O:11])[CH2:8][CH2:7][N:3]3[CH2:4][CH2:5][CH2:6][C:2]3=[O:1])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1
Reactant: O=C(O)CCN1CCCC1=O
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)CCN3CCCC3=O)nc12

Procedure:
From 2-oxo-1-pyrrolidinepropionic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+21.5° (c=1.05, CHCl3), ES-MS m/e (%): 406 (M+H+, 100).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: NCCCCCCCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NCCCCCCCNS(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 8 h

Procedure:
Dissolve 1,9-diazanonane (13g, 0.1 mol) in pyridine (50 mL) and cool to ° C. Add, in portions, p-toluenesulfonyl chloride (41.9 g, 0.22 mol) and stir overnight. Extract into chloroform, wash with water, 5% hydrochloric acid, water and dry (MgSO4). Evaporate the solvent in vacuo and purify by silica gel chromatography to give 1,9-bis[(4-methylphenyl)sulfonyl]-1,9-diazanonane.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]([CH:19]([CH3:21])[CH3:20])[C:16](=[O:18])[CH3:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)=O.[NH2:22][C:23]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[C:24]=1[C:25]([NH2:27])=[O:26].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.O>[CH3:35][O:34][C:28]1[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=[C:23]2[C:24]=1[C:25](=[O:26])[NH:27][C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]3[CH2:14][CH2:13][CH:12]([N:15]([CH:19]([CH3:21])[CH3:20])[C:16](=[O:18])[CH3:17])[CH2:11][CH2:10]3)=[CH:5][CH:4]=1)=[N:22]2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CC(=O)N(C(C)C)C1CCN(c2ccc(C=O)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(N(C(C)=O)C(C)C)CC4)cc3)nc2c1
Temperature: 155 °C
Yield: 20.7 %

Procedure:
To a solution of N-(1-(4-formylphenyl)piperidin-4-yl)-N-isopropylacetamide (0.300 g, 1.04 mmol) in DMA (10 mL) was added 2-amino-4,6-dimethoxybenzamide (0.204 g, 1.04 mmol), NaHSO3 (0.129 g, 1.24 mmol) and p-TsOH (0.019 g, 0.10 mmol). The resulting solution was heated to 155° C. overnight and then cooled to room temperature. The solution was diluted with water, extracted with CH2Cl2, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was purified by flash chromatography on silica gel eluting, with 30% to 100% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2, to afford the title compound (0.100 g, 20%). 1H NMR (300 MHz, DMSO-d6): mixture of rotamers δ 11.66 (s, 1H), 8.07 (d, J=8.3 Hz, 2H), 6.89-7.15 (m, 2H), 6.67 (s, 1H), 6.46 (s, 1H), 3.90-4.11 (m, 3H), 3.88 (s, 3H), 3.83 (s, 3H), 2.80-3.02 (m, 2H), 2.39-2.66 (m, 1H), 1.92-2.06 (m, 3H), 1.63-1.82 (m, 2H), 1.32-1.47 (m, 1H), 1.21-1.32 (m, 3H), 1.08-1.21 (m, 4H). ESI MS m/z 463 [M−H]−.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:21][C:22](O)=[O:23])=[CH:11][CH:12]=2)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:67]1([C:73]2[CH:78]=[CH:77][C:76]([NH2:79])=[CH:75][CH:74]=2)[CH2:72][CH2:71][O:70][CH2:69][CH2:68]1.C(O)C(N)(CO)CO>C(Cl)(Cl)Cl>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:21][C:22]([NH:79][C:76]3[CH:75]=[CH:74][C:73]([N:67]4[CH2:68][CH2:69][O:70][CH2:71][CH2:72]4)=[CH:78][CH:77]=3)=[O:23])=[CH:11][CH:12]=2)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1ncc2cc(Oc3ccccc3CC(=O)O)ccc21
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC(CO)(CO)CO
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)Cn1ncc2cc(Oc3ccccc3CC(=O)Nc3ccc(N4CCOCC4)cc3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.3 %

Procedure:
To a solution of (15p) (0.04 g, 0.123 mmol), PyBOP (0.135 g, 0.26 mmol) and DIEA (0.02 mL, 0.12 mmol) in CHCl3 (2 ml), 4-morpholin-4-yl-phenylamine (0.044 g, 0.247 mmol) were added. The mixture was stirred at room temperature for 16 hours, treated with AP-trisamine resin (0.25 g, 2.49 mmol/g), and finally the solvent was removed under reduced pressure after filtration from the resin. The resulting residual was purified by chromatography (Sep-Pak, 10 g) with ether to provide the desired product (16p) (0.024 g, 40%). 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.50 (br s, 1H), 7.45 (dd, J=7.83, 1.57 Hz, 1H), 7.39 (d, J=9.39 Hz, 2H), 7.31-7.26 (m, 3H), 7.23 (dd, J=7.83, 1.57 Hz, 1H), 7.15-7.09 (m, 2H), 6.86-6.79 (m, 3H), 4.17 (d, J=7.04 Hz, 2H), 3.86-3.82 (m, 4H), 3.80 (s, 2H), 3.11-3.06 (m, 4H), 2.41-2.29 (m, 1H), 0.95 (s, CH3), 0.94 (s, CH3); MS (APCI+) m/z 485.2 (M+H) was detected.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]#[C:10][C:11]2([CH3:14])[CH2:13][CH2:12]2)[CH:3]=1.CC([O-])(C)C.[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:9]=[C:10]([C:11]3([CH3:14])[CH2:13][CH2:12]3)[NH:8][C:5]2=[CH:6][N:7]=1
Reactant: CC1(C#Cc2cc(Cl)ncc2N)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(c2cc3cc(Cl)ncc3[nH]2)CC1
Temperature: 80 °C
Yield: 71 %

Procedure:
To a solution of 6-chloro-4-((1-methylcyclopropyl)ethynyl)pyridin-3-amine (3.0 g, 15 mmol) in DMF (50 mL) was added t-BuOK (3.3 g, 29 mmol) under N2 atmosphere. The mixture was heated at 80° C. overnight and quenched with H2O (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and purified by chromatography on silica gel (3% EtOAc in petroleum ether) to afford 5-chloro-2-(1-methylcyclopropyl)-1H-pyrrolo[2,3-c]pyridine (2.2 g, 73%). 1H-NMR (CDCl3, 300 MHz) δ 9.79 (br s, 1H), 8.37 (s, 1H), 7.36 (s, 1H), 6.16 (s, 1H), 1.51 (s, 3H), 1.09 (m, 2H), 0.89 (m, 2H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11](=[O:33])[CH2:12][C@@H:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:18]=1[F:32])[CH3:14])(C)(C)C.Cl>C(OCC)(=O)C>[NH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:33])[CH2:12][C@@H:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:18]=1[F:32])[CH3:14]
Reactant: C[C@@H](CC(=O)NCCNC(=O)OC(C)(C)C)NCc1ccc(Cl)c(C(=O)c2ccccc2)c1F
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](CC(=O)NCCN)NCc1ccc(Cl)c(C(=O)c2ccccc2)c1F
Reaction time: 1 h
Yield: 76.6 %

Procedure:
Step 4 A mixture of {2-[(S)-3-(3-benzoyl-4-chloro-2-fluoro-benzylamino)-butyrylamino]-ethyl}-carbamic acid tert-butyl ester (92 mg) and 2N hydrogen chloride in ethyl acetate (2 ml) was allowed to stand at room temperature for 60 minutes. The mixture was concentrated and re-concentrated from methanol (×2). Ethyl acetate was added to the residue and a solid produced by scratching. The material was obtained by filtration and was dried in a vacuum oven furnishing the desired compound as a white solid (56.1 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[CH:12]=O.[S:14]1[CH2:20][C:18](=[O:19])[NH:17][C:15]1=[S:16].C(O)(=O)C.C([O-])(=O)C.[Na+]>O>[C:6]([C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[C:4]=1[CH:12]=[C:20]1[S:14][C:15](=[S:16])[NH:17][C:18]1=[O:19])([OH:8])=[O:7]
Reactant: COc1cccc(C(=O)O)c1C=O
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(C(=O)O)c1C=C1SC(=S)NC1=O

Procedure:
To a stirred hot solution of 0.45 g. (2.50 mM) of 3-methoxyphthalaldehydic acid and 0.34 g. (2.50 mM) rhodanine in 3 ml. of acetic acid is added 0.68 g. (8.2 mM) of anhydrous sodium acetate. The resulting solution is refluxed 1.5 hours, cooled, and poured into 40 ml. of water to give a yellow gum which slowly solidifies to a yellow solid. The solid is collected, washed with water, and air-dried to give 5-(2-carboxy-6-methoxybenzylidene)rhodanine.