Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:22][C:4]=1[CH2:5][NH:6][CH:7]1[CH2:12][CH2:11][CH:10]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:8]1.[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[C:42]([F:47])[C:36]=2[S:37][C:38]=1[C:39](Cl)=[O:40]>>[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[C:42]([F:47])[C:36]=2[S:37][C:38]=1[C:39]([N:6]([CH2:5][C:4]1[CH:22]=[C:23]([C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)[CH:24]=[CH:25][C:3]=1[O:2][CH3:1])[CH:7]1[CH2:8][CH2:9][CH:10]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH2:12]1)=[O:40]
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: COc1ccc(-c2ccc(C)nc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(C)nc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 68 (813 mg, 1.85 mmol) is treated with acid chloride 8 (542 mg, 2.03 mmol) using Method D to give the title compound.
Reaction SMILES: CC([O-])(C)C.[K+].[Br:7][C:8]1[C:17]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[C:16]2[C:11]([CH:12]=[N:13][C:14](Cl)=[N:15]2)=[CH:10][CH:9]=1.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=1.CC(O)=O>CC(O)C>[Br:7][C:8]1[C:17]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[C:16]2[C:11]([CH:12]=[N:13][C:14]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([S:40](=[O:42])(=[O:41])[NH2:43])=[CH:36][CH:35]=3)=[N:15]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(Br)ccc3cnc(Cl)nc23)CC1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(Br)ccc3cnc(Nc4ccc(S(N)(=O)=O)cc4)nc23)CC1
Temperature: 105 °C
Reaction time: 2.5 h
Yield: 36.9 %

Procedure:
Solid KOtBu (442 mg, 3.95 mmole) was added to a solution of tert-butyl 4-(7-bromo-2-chloroquinazolin-8-yloxy)piperidine-1-carboxylate (500 mg, 1.13 mmole) and 4-aminobenzenesulfonamide (777 mg, 4.62 mmole) in IPA (15 mL). The reaction was sealed and heated to 105° C. with stirring. After 2.5 hours, AcOH was added to the reaction to pH 4 and the reaction was evaporated to a solid. The crude product was dissolved in DMSO (15 mL) and purified by prep. HPLC to give 241 mg of product in 37% yield (417 mmole).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].N1C=CC=CC=1.[Cl:18][CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.Cl>C1C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([CH2:19][Cl:18])=[CH:21][CH:22]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(Oc1ccc2ccccc2c1)c1ccc(CCl)cc1

Procedure:
This ester was prepared by Method C by placing 72.1 g (0.5 mole) of β-naphthol, suspended in 150 ml of benzene, and 0.5 ml of pyridine in the vessel, adding all at once, at room temperature, a solution of 95 g (0.5 mole) of p-chloromethylbenzoyl chloride in 80 ml of benzene, and refluxing this reaction mixture for 6 hours, while passing a weak current of nitrogen through the apparatus. The HCl cleavage began at about 40° C., and at an internal temperature of 50° C., a clear, homogeneous solution had formed. After the end of the reaction time the benzene was substantially removed by distillation. The residue crystallized to a grayish pink crystal mass, the yield of which was quantitative (147.5 g). The raw ester melted at 90°-96° C. It was recrystallized from 2.5 liters of isopropanol with the addition of decolorizing carbon, yielding colorless, pearly, shiny flakes of a melting point of 102°-103.5° C.
Reaction SMILES: [OH-].[K+].C(O)C.C[O:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][C:18]3[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:12][CH:11]=1)=[O:9].Cl>O>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][C:18]3[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:12][CH:11]=1)([OH:9])=[O:7]
Reactant: CCCCCCCCc1ccc2nc(-c3ccc(C(=O)OC)cc3)sc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCc1ccc2nc(-c3ccc(C(=O)O)cc3)sc2c1
Temperature: 65 °C
Yield: 95.7 %

Procedure:
To 0.76 g (11.5 mM) of 85%-potassium hydroxide, 50 ml of ethanol was added, followed by stirring at 65° C. and dissolving. To the resultant solution, 1.80 g (4.72 mM) of 2-(p-methoxycarbonylphenyl)-6-octylbenzothiazole was added, followed by stirring for 20 minutes at 65° C. After the reaction, the reaction mixture was poured into water and 1.5 ml of concentrated hydrochloric acid was added thereto to precipitate a crystal. The crystal was recovered by filtration and sufficiently washed with water, followed by drying to obtain 1.66 g of 2-(p-carboxyphenyl)-6-octylbenzothiazole (Yield: 95.7%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)[CH:2]=1.O.NN>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCc1cnc2ccccc2c1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCCCc1cnc2ccccc2c1
Yield: 89.2 %

Procedure:
3-Quinolinehexanamine was prepared in the same manner as described in Example 110, starting from 4.4 g of 2-[6-(3-quinolinyl)hexyl]-1H-isoindole-1,3(2H)-dione and 2.5 g of hydrazine hydrate in 60 ml of ethanol. The crude product was evaporatively distilled to give 2.5 g (89%) of 3-quinolinehexanamine, bp 144°-155° C./0.1 mm. Bis picrate mp 225°-226° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]=O)[CH:11]=2)[N:6]=[CH:5][N:4]=1.[S:15]1[CH2:19][C:18](=[O:20])[NH:17][C:16]1=[O:21]>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]=[C:19]3[S:15][C:16](=[O:21])[NH:17][C:18]3=[O:20])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: O=C1CSC(=O)N1
Reactant: COc1ncnc2ccc(C=O)cc12
Product: COc1ncnc2ccc(C=C3SC(=O)NC3=O)cc12

Procedure:
Following the general method as outlined in Example. 1, starting from 4-methoxy-quinazoline-6-carbaldehyde (intermediate 10) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5]([CH3:45])([CH3:44])[CH2:6][C:7]1[N:8]=[C:9]([C:18](=[O:43])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][CH2:29][C:28]4[CH:32]=[N:33][N:34]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:27]3=4)=[CH:22][CH:21]=2)[N:10]([S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH:11]=1>O1CCCC1>[CH3:4][C:5]([CH3:45])([CH3:44])[CH2:6][C:7]1[N:8]=[C:9]([C:18]([OH:43])([CH3:1])[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:31][CH2:30][CH2:29][C:28]4[CH:32]=[N:33][N:34]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:41])([CH3:42])[CH3:40])[C:27]3=4)=[CH:24][CH:25]=2)[N:10]([S:12]([N:15]([CH3:16])[CH3:17])(=[O:13])=[O:14])[CH:11]=1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)Cc1ccc(N2CCCc3cnn(COCC[Si](C)(C)C)c32)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(C)(O)Cc1ccc(N2CCCc3cnn(COCC[Si](C)(C)C)c32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methylmagnesium bromide (3 M in diethyl ether) (2 eq) was added to a 0° C. solution of 4-(2,2-dimethylpropyl)-N,N-dimethyl-2-{[4-(1-{[2-(trimethylsilyl)-ethoxy]methyl}-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridin-7-yl)phenyl]acetyl}-1H-imidazole-1-sulfonamide (1 eq) in tetrahydrofuran (3 mL). After stirring at 0° C. for 30 min, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to afford 4-(2,2-dimethylpropyl)-2-{1-hydroxy-1-methyl-2-[4-(1-{[2-(trimethylsilyl)-ethoxy]methyl}-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridin-7-yl)phenyl]ethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide which was used in the subsequent step without further purification.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:10]=[C:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1>C1COCC1>[CH2:1]([C:11]1([OH:10])[CH2:12][CH2:13][N:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[CH2:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N2CCC(=O)CC2)cc1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1ccc(N2CCC(O)(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Yield: 20 %

Procedure:
A solution of benzylmagnesium chloride (1.90 mL of a 2M solution in THF, 3.80 mmol) at −78° C. was treated with 4-(4-oxo-1-piperidinyl)benzonitrile (prepared according to the procedure described in Synthesis 1981, 606-608, 0.30 g, 1.51 mmol), and was allowed to warm to room temperature overnight. The reaction mixture was partitioned between ethyl acetate and saturated aqueous NH4Cl and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were dried (MgSO4), filtered, and concentrated. The resulting residue was purified by silica gel chromatography eluting with 20% ethyl acetate in hexanes to give the desired product (0.087 g, 20%). MS (ESI) m/e 293 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([CH2:8][C:9]([OH:11])=O)[S:6](=[O:13])(=[O:12])[C:5]2[S:14][C:15]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:16][C:4]=2[NH:3]1.O.OC1C2N=NNC=2C=CC=1.[CH3:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][NH:39][CH2:40][CH2:41][O:42][CH3:43].Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.O>[CH3:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][N:39]([CH2:40][CH2:41][O:42][CH3:43])[C:9](=[O:11])[CH2:8][CH:7]1[S:6](=[O:13])(=[O:12])[C:5]2[S:14][C:15]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:16][C:4]=2[NH:3][C:2]1=[O:1]
Reactant: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)C(CC(=O)O)C(=O)N2
Reactant: COCCNCCOCCOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCCN(CCOC)C(=O)CC1C(=O)Nc2cc(S(N)(=O)=O)sc2S1(=O)=O
Reaction time: 8 h

Procedure:
To a solution of (2,3-dihydro-2,4,4-trioxo-6-sulfamoyl-1H-thieno[2,3-b][1,4]thiazin-3-yl)acetic acid (3 g, 9 mmol) in dry DMF (25 ml) was added hydroxybenzotriazole hydrate (1.22 g, 9 mmol), N-methoxyethoxyethyl-N-methoxyethylamine (3.19 g, 18 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.59 g, 14 mmol), and the resulting reaction mixture was stirred overnight. Water (10 ml) was added, the mixture stirred an additional 2 hours and concentrated to dryness under reduced pressure. The residue was treated with 0.5N HCl and the pH adjusted to 6.5-6.9 by the additon of dilute NH4OH. The aqueous mixture was extracted with ethyl acetate and the combined extracts were washed with brine and dried over sodium sulfate. After filtration and removal of the solvent, the residue was recrystallized from water to give N-methoxyethoxyethyl-N-methoxyethyl-(2,3-dihydro-2,4,4-trioxo-6-sulfamoyl-1H-thieno-[2,3-b][1,4]thiazin-3-yl)acetamide, mp 156°-158° C.
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[NH:8][CH2:7][C:6](=[O:9])[N:5]1[CH2:10][C:11]([O:13]CC)=O)[CH3:3].[NH3:16]>CO>[CH3:3][CH:2]([CH:4]1[NH:8][CH2:7][C:6](=[O:9])[N:5]1[CH2:10][C:11]([NH2:16])=[O:13])[CH3:1]
Reactant: N
Reactant: CCOC(=O)CN1C(=O)CNC1C(C)C
Solvent: CO
Product: CC(C)C1NCC(=O)N1CC(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An ice cold solution of 3.8 g (0.018 mol) of ethyl 2-(1-methylethyl)-5-oxo-1-imidazolidineacetate in 100 ml of methanol was saturated with gaseous ammonia. The solution was stirred at room temperature overnight and the solvent was evaporated under reduced pressure, to give 2-(1-methylethyl)-5-oxo-1-imidazolidineacetamide (3.4 g) as a viscous oil (Rf 0.33; ethyl acetate/methanol 6:4; silica gel plates). Monohydrate of sulphate salt m.p. 64° C. resolidifying with final decomposition at 114°-118° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[C:12]([NH:19][C:20]([O:22]CC)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+:26]>N1CCOCC1>[CH2:1]([O:8][C:9]1[C:18]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[C:12]([NH:19][C:20]([N:26]2[CH2:10][CH2:9][O:8][CH2:1][CH2:2]2)=[O:22])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: CCOC(=O)Nc1ccc(OCc2ccccc2)c2c1OCCO2
Agent: [Cl-]
Solvent: C1COCCN1
Product: O=C(Nc1ccc(OCc2ccccc2)c2c1OCCO2)N1CCOCC1

Procedure:
A mixture of 38 g of 5-benzyloxy-8-ethoxycarbonylamino-1,4-benzodioxane (XIg), code number 770 522, and 300 ml of morpholine was brought to reflux for 16 hours, in the presence of a pinch of ammonium chloride. Then the morpholine in excess was evaporated and the residue was recrystallized in 96° ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10](#[N:14])[CH2:11][C:12]#[N:13].N1CCCCC1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:11]([C:10]#[N:14])[C:12]#[N:13])[CH:7]=[CH:8][CH:9]=1
Reactant: N#CCC#N
Reactant: O=Cc1cccc(Br)c1
Solvent: C1COCCO1
Solvent: C1CCNCC1
Product: N#CC(C#N)=Cc1cccc(Br)c1

Procedure:
In this situation the aldehyde, such as 3-bromobenzaldehyde as a representative example, is reacted with malononitrile in the presence of catalytic piperidine in a solvent such as dioxane to afford the 2-[(3-bromophenyl)methylene]malononitrile. Epoxide formation proceeds readily with commercial bleach at a pH of 5 to 6. Treatment with hydrobromic acid in methanol then affords the required methyl 2-bromo-2-(3-bromophenyl)acetate. Similarly prepared was methyl 2-bromo-2-(3-cyanophenyl)acetate
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][CH3:6])[CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=1>C(OCC)(=O)C>[CH:1]1([C:4]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]3[C:5]=2[CH3:6])[CH2:3][CH2:2]1
Reactant: CCC(=O)C1CC1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Solvent: CCOC(C)=O
Product: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12

Procedure:
Operations similar to Production Example 1-(1) were conducted using 1-cyclopropyl-1-propanone, and successively those of Production 1-(2) were conducted using 2-amino-5-nitropyridine. The solid whereupon obtained was suspended in ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution and purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to provide the title compounds as yellow crystals.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:15][C:16]1[C:21]([CH2:22]Br)=[C:20]([F:24])[CH:19]=[CH:18][C:17]=1[F:25]>CN(C)C=O>[F:24][C:20]1[CH:19]=[CH:18][C:17]([F:25])=[C:16]2[C:21]=1[CH2:22][N:10]([S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:11])=[CH:6][CH:5]=1)(=[O:8])=[O:9])[CH2:15]2
Reactant: Fc1ccc(F)c(CBr)c1CBr
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2Cc3c(F)ccc(F)c3C2)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
A solution of 4-toluenesulphonamide (2.44 g, 14.28 mmol) in N,N-dimethylformamide (10 ml) was added dropwise to a vigourously stirred suspension of sodium hydride (1.2 g, 60 wt % in mineral oil, 30.0 mmol) in anhydrous N,N-dimethylformamide (60 ml). The mixture was stirred at room temperature for 1 hour, at 110° C. for 1 hour and was then cooled to 60° C. and a solution of 2,3-bis-bromomethyl-1,4-difluorobenzene (4.28 g, 14.28 mmol) in N,N-dimethylformamide (30 ml) was added dropwise. The mixture was stirred at 60° C. for 1 hour and then at room temperature for 16 hours. The solvent was removed in vacuo and the residue partitioned between dichloromethane and 1M hydrochloric acid. The organic layer was separated, washed with 5% aqueous potassium carbonate solution, the organics were separated and the solvent removed in vacuo. The residue was rinsed with diethyl ether, filtered and the solids sucked dry under reduced pressure to afford 4,7-difluoro-2-(toluene-4-sulfonyl)isoindoline (2.46 g, 56%) as a pale tan solid. 1H NMR (DMSO-d6) 7.82 (2H, d), 7.43 (2H, d), 7.15 (2H, dd), 4.66 (4H, s), 2.36 (3H, s). MS: [M+H]+ 310.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH2:9][CH2:8]2.[Cl:14][CH2:15][C:16](Cl)=[O:17].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[Cl:14][CH2:15][C:16]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10](=[O:13])[NH:11]2)=[O:17]
Reactant: COc1cccc2c1NC(=O)CC2
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)CCl)c2c1NC(=O)CC2
Reaction time: 15 h
Yield: 38.7 %

Procedure:
13 g of 8-hydroxy-3,4-dihydrocarbostyril (VII) and 20 g of chloroacetyl chloride were dissolved in 100 ml of nitrobenzene, and 40 g of aluminum chloride was added slowly to the mixture followed by stirring at a temperature of 70° to 75°C for 15 hours. The nitrobenzene was then steam-distilled. After allowing the mixture to cool, the precipitated crystals were filtered, washed with hot water and recrystallized from methanol to give 7.2 g of 5-chloroacetyl-8-hydroxy-3,4-dihydrocarbostyril (IV) as light yellow crystals having a melting point of 189° to 190°C.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:19])[NH:10]2.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22].[ClH:26].Cl.C(O)C>CO>[ClH:26].[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:20][NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:6]2[C:11]=1[NH:10][C:9](=[O:19])[CH2:8][CH2:7]2)[C:17]#[CH:18]
Reactant: C#CCOc1ccc(OCC2CO2)c2c1NC(=O)CC2
Reactant: CC(C)(C)N
Agent: Cl
Solvent: CO
Solvent: CCO
Product: C#CCOc1ccc(OCC(O)CNC(C)(C)C)c2c1NC(=O)CC2
Reaction time: 12 h

Procedure:
2 g of 5-(2,3-epoxypropoxy)-8-(2-propynyloxy)-3,4-dihydrocarbostyril was dissolved in 15 ml of methanol, and 2.6 g of t-butylamine was added to the solution, followed by allowing the mixture to stand at 15°-20° C. for 12 hours. After completion of the reaction, the methanol and the t-butylamine were evaporated under reduced pressure, and the resulting crude oil was converted into the hydrochloride thereof using hydrochloric acid and ethanol. The solvent was evaporated under reduced pressure, and the resulting crystals were dissolved in water and washed with chloroform to remove impurities. The aqueous layer was made alkaline with sodium hydroxide and then extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The chloroform was evaporated under reduced pressure to obtain colorless crystals, which were converted into the hydrochloride thereof with hydrochloric acid-ethanol. The solvent was evaporated under reduced pressure, and the residue was recrystallized from isopropanol to obtain 1.6 g of 8-(2-propynyloxy)-5-[3-(t-butylamino)-2-hydroxypropoxy]-3,4-dihydrocarbostyril hydrochloride having a melting point of 182°-183° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.[K+].[Br-]>>[CH3:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:1]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[NH:2])=[CH:13][CH:12]=1
Reactant: N#Cc1cccnc1
Reactant: COc1ccc(N)cc1
Agent: [Br-]
Agent: [K+]
Product: COc1ccc(NC(=N)c2cccnc2)cc1
Yield: 62.82 %

Procedure:
The title compound was prepared from 3-cyanopyridine (8.5 g, 83 mmol) and 4-methoxyaniline (10 g, 83 mmol) by following the procedure described in preparation 10 (11.6 g, yield 62.82%, mp 137-139° C., purity 97.2% by HPLC). 1H-NMR (CDCl3):δ 3.81 (s, 3H), 4.94 (bs, 2H, D2O exchangeable), 6.93 (s, 4H), 7.37-7.4 (d, 1H), 8.22-8.24 (d, 1H), 8.70-8.71 (d, 1H), 9.0 (s, 1H). IR (KBr) cm−1: 3281, 3085, 3001, 2960, 2937, 1660. MS m/z:228.2 (M+).
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[CH2:6][S:5]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:27](O)=[O:28])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH2:30][N:31]2[CH2:32][CH2:33][CH2:34][CH2:35]2)[C:27]([N:16]2[CH2:17][CH2:18][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[S:5][CH2:6][C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:14][CH2:15]2)=[O:28])=[CH:22][CH:21]=1
Reactant: O=C(O)C(CN1CCCC1)c1ccc(Cl)cc1
Reactant: C[C@@H]1SCc2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1SCc2ncnc(N3CCN(C(=O)C(CN4CCCC4)c4ccc(Cl)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
To a solution of (S)-5-methyl-4-(piperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine dihydrochloride (1 g, 3.23 mmol) and 2-(4-chlorophenyl)-3-(pyrrolidin-1-yl)propanoic acid (2 g, 7.88 mmol) in DCM (40 mL) were added HBTU (1.5 g, 3.96 mmol) and triethylamine (2.75 mL, 19.8 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was removed, and the residue was dissolved in ethyl acetate (200 mL) and washed with brine (5×100 mL) and water (3×100 mL). The organic phase was dried and concentrated. The residue was purified by silica gel chromatography, eluting with ethyl acetate-DCM/MeOH (20:1) to give 2-(4-chlorophenyl)-1-(4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-3-(pyrrolidin-1-yl)propan-1-one (0.713 g, 46.7%). 1H NMR (CDCl3, 400 MHz) δ 8.47 (s, 1H), 7.38-7.28 (m, 4H), 4.75 (m, 1H), 4.54 (m, 1H), 4.17 (m, 2H), 3.88-3.25 (m, 14H), 2.12 (m, 4H), 1.43 (m, 3H). MS (APCI+) [M+H]+ 473.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:35]=[CH:34][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([CH2:28][C:29]([O:31]C)=[O:30])=[C:20]2[CH3:33])=[CH:16][CH:15]=1)=[O:12].O.[OH-].[Li+].O1CCCC1>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([CH2:28][C:29]([OH:31])=[O:30])=[C:20]2[CH3:33])=[CH:34][CH:35]=1)=[O:12]
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)c2ccccc2n1Cc1ccc(NC(=O)c2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
Into a dry reaction vessel, methyl 2-[1-[4-(2-naphthamido)benzyl]-2-methyl-1H-indol-3-yl]acetate (150 mg, 0.324 mmol), lithium hydroxide monohydrate (55 mg, 1.31 mmol), 3 mL tetrahydrofuran, 3 mL water were weighed, and stirred at room temperature for 2 h. The reaction was monitored to be complete by TLC. The solvent was rotate evaporated. It was adjusted to pH=3-4 with 2 N HCl solution. It was extracted by ethyl ester, rotate evaporated to dryness to obtain the product as a white solid 80 mg. After recrystallization by ethyl acetate, a pure product 51 mg was obtained, at a yield of 35.2%.