Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([SH:12])=[N:6][C:5]=2[NH:4][CH:3]=1.[OH-].[Na+].[Cl:15][C:16]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:17]=1[C:18]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)=[O:19]>CO.COCCOC>[Cl:15][C:16]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:17]=1[C:18]([C:20]1[CH:21]=[CH:22][C:23]([CH2:24][S:12][C:7]2[NH:8][C:9](=[O:11])[C:10]3[C:2]([CH3:1])=[CH:3][NH:4][C:5]=3[N:6]=2)=[CH:26][CH:27]=1)=[O:19]
Reactant: Cc1c[nH]c2nc(S)[nH]c(=O)c12
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CO
Product: Cc1c[nH]c2nc(SCc3ccc(C(=O)c4ccc(Cl)cc4Cl)cc3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.9 %

Procedure:
In methanol (18.7 ml) was suspended 5-methyl-2-mercapto-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.36 g) followed by addition of 1N-sodium hydroxide (7.88 ml) for dissolution. Then, under ice-cooling, a solution of 4-(2,4-dichlorobenzoyl)benzyl bromide (3.09 g) in DME (8 ml) was added dropwise. The mixture was stirred at room temperature for 4 hours and the resulting crystalline precipitate was collected by filtration and rinsed with water. The crystals were further rinsed with 50% ethanol/water, methanol and ether, dried, and recrystallized from DME (1,2-dimethoxyethane) to provide the title compound (2.03 g). 1H-NMR (DMSO-d6) δ: 2.23(3H,s), 4.48(2H,s), 6.65(1H,s), 7.53(1H,d,J=8.2Hz), 7.59(1H,dd,J=1.6,8.8Hz), 7.64(2H,d,J=8.4Hz), 7.69(2H,d,J=8.4Hz), 7.80(1H,d,J=1.6Hz), 11.40(1H,s), 11.96(1H,s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH3:31])=[CH:25][CH:24]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1CCc1ccc(O)cc1
Reactant: CCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCOc1ccc(CCn2c(C)ccc2-c2ccc(OCc3ccccc3)cc2)cc1
Yield: 85.7 %

Procedure:
A solution of 4-{2-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]ethyl}phenol (1.50 g, 3.91 mmol), 1-bromoundecane (1.31 ml, 5.87 mmol) and potassium carbonate (811 mg, 5.87 mmol) in DMF (15 ml) was stirred at 80° C. for 4 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate anhydride, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 1.80 g (yield: 85.7%)
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][CH:7]([CH2:11][P:12]([OH:28])([CH:14]([NH:16][C:17]([O:19][CH:20]([O:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH3:21])=[O:18])[CH3:15])=[O:13])[C:8](O)=[O:9])=[CH:4][CH:3]=1.[CH2:31]([O:38][C:39](=[O:43])[C@H:40]([CH3:42])[NH2:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([O:38][C:39](=[O:43])[CH:40]([NH:41][C:8](=[O:9])[CH:7]([CH2:6][C:5]1[CH:29]=[CH:30][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:11][P:12]([OH:28])([CH:14]([NH:16][C:17]([O:19][CH:20]([O:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH3:21])=[O:18])[CH3:15])=[O:13])[CH3:42])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(OC(=O)NC(C)P(=O)(O)CC(Cc1ccc(Br)cc1)C(=O)O)OC(=O)C(C)C
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Product: CC(OC(=O)NC(C)P(=O)(O)CC(Cc1ccc(Br)cc1)C(=O)NC(C)C(=O)OCc1ccccc1)OC(=O)C(C)C

Procedure:
Using 1 g of the compound from step 3 and 388 mg of alanine benzyl ester, the expected compound is obtained according to the protocol in step 4 of example 3. White solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12]>C1(C)C=CC=CC=1>[C:14]1([O:13][C:11](=[O:12])[NH:4][C:3]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=2[F:1])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(F)cc1F
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(F)cc1F)Oc1ccccc1
Reaction time: 0.25 h
Yield: 84.3 %

Procedure:
To a solution of 1.94 g of 2,4-difluoroaniline in 20 ml of toluene was added dropwise 1.29 g of phenyl chloroformate. The mixture was stirred for 15 minutes, washed with three 10 ml portions of water, dried over anhydrous sodium sulfate, and filtered through a pad of diatomaceous earth. The filtrate was evaporated in vacuo to give an oil which solidified on cooling. The solid was crystallized from hexane to give 1.73 g of the desired product as pale tan crystals in 93% yield, mp 82°-84° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:23]([CH:24]=[O:25])[CH2:22][CH2:21][C:20]([C:26]([O:28]C)=[O:27])=[CH:19][C:18]=3[CH:30]=2)=[CH:10][CH:9]=1)[CH3:7])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:3][CH2:4][CH2:5][N:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:23]([CH:24]=[O:25])[CH2:22][CH2:21][C:20]([C:26]([OH:28])=[O:27])=[CH:19][C:18]=3[CH:30]=2)=[CH:12][CH:13]=1)[CH3:7])[CH3:2]
Reactant: CCOCCN(C)c1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOCCN(C)c1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
In methanol (6.6 ml) and THF (4.4 ml) was dissolved methyl 7-[4-[N-(2-ethoxyethyl)-N-methylamino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.22 g). To the solution was added 1N sodium hydroxide solution (2.2 ml), and the mixture was stirred at room temperature overnight and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-[4-[N-(2-ethoxyethyl)-N-methylamino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.18 g) as colorless amorphous.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=3)=[CH:13][C:12]([C:23]([OH:25])=O)=[N:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C(N(CC)C(C)C)(C)C.ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:59]3[CH2:63][C:62](=[O:64])[NH:61][CH2:60]3)=O)=N2)C=CC=1>C(O)=O>[C:21]([C:17]1[CH:16]=[C:15]([C:14]2[N:10]([C:5]3[CH:6]=[CH:7][C:8]([F:9])=[C:3]([C:1]#[N:2])[CH:4]=3)[N:11]=[C:12]([C:23]([N:59]3[CH2:63][C:62](=[O:64])[NH:61][CH2:60]3)=[O:25])[CH:13]=2)[CH:20]=[CH:19][CH:18]=1)#[N:22]
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Reactant: N#Cc1cccc(-c2cc(C(=O)O)nn2-c2ccc(F)c(C#N)c2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=CO
Product: N#Cc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2ccc(F)c(C#N)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 112A using 3.2 equivalents of N,N-diisopropylethylamine and with the addition of 0.1% formic acid in the preparative HPLC in analogy to the synthesis of the compound of Example 23. In order to remove the 1,1′,1″-phosphoryltripyrrolidine the product is taken up in a little tetrahydrofuran, water is added to the mixture until a precipitate forms, the tetrahydrofuran is removed in vacuo, and the precipitate is collected by suction filtration, and dried under high vacuum. 25 mg (48% of theory) of the title compound are obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][N:4]=1.[SH:14][C:15]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:17]=2[N:16]=1.[OH-].[Na+]>C(O)C>[OH:13][CH2:12][CH2:11][O:10][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:17]=3[N:16]=2)[C:8]=1[CH3:9]
Reactant: Cc1c(OCCO)ccnc1CCl
Reactant: COc1ccc2[nH]c(S)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2[nH]c(SCc3nccc(OCCO)c3C)nc2c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
60 ml of ethanol was added to a mixture comprising 0.7 g of 2-chloromethyl-4-(2-hydroxyethoxy)-3-methylpyridine, 0.63 g of 2-mercapto-5-methoxy-1H-benzimidazole and 0.16 g of sodium hydroxide to obtain a mixture. This mixture was stirred at 60° C. for one hour, concentrated and purified by silica gel column chromatography to obtain 1.08 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][N:6](C2CCCCO2)[C:5](=[O:15])[CH:4]=1.Cl.[OH-].[Na+]>CO>[OH:15][C:5]1[N:6]=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cnn(C2CCCCO2)c(=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cnnc(O)c1
Temperature: 35 °C
Yield: 65.3 %

Procedure:
5-Methoxy-2-(tetrahydro-2H-pyran-2-yl)-3(2H)-pyridazinone (2035 g, 9.69 moles) and 2 L of methanol were added to a 22 L round bottomed flask equipped with a heating mantle, reflux condenser and mechanical stirrer. The mixture was warmed to 35° C. and 8 L of 6N HCl was added and then the mixture was heated to reflux for 2 h. The reaction mixture was then cooled slightly and transferred to a glycol cooled 22 L flask where the mixture was cooled further to 30° C. The mixture was made basic (pH 13-14) by cautious addition of 50% NaOH in small portions. The basic mixture was extracted with CH2Cl2 (4×3 L). The aqueous phase was then acidified with concentrated HCl (pH 1-2) to precipitate the product. The product was collected by vacuum filtration on a Buchner funnel. The product was dried to constant weight on a fluid bed dryer at 70° C. This afforded 798 g (65% yield) of 3-hydroxy-5-methoxypyridazine as a white solid which was recrystallized from methanol, mp=253° C.-255° C.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:10]1[CH:19]=[CH:18][C:17]2[CH2:16][N:15]([CH2:20][C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH:29]4[CH2:32][CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:22])[CH2:14][CH2:13][C:12]=2[N:11]=1>CN(C=O)C>[CH:1]1([O:6][C:10]2[CH:19]=[CH:18][C:17]3[CH2:16][N:15]([CH2:20][C:21]([N:23]4[CH2:24][CH2:25][N:26]([CH:29]5[CH2:32][CH2:31][CH2:30]5)[CH2:27][CH2:28]4)=[O:22])[CH2:14][CH2:13][C:12]=3[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCC1
Reactant: O=C(CN1CCc2nc(Cl)ccc2C1)N1CCN(C2CCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CN1CCc2nc(OC3CCCC3)ccc2C1)N1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of cyclopentanol (99 mg, 1.15 mmol) in DMF (5 mL) is added NaH (60% in mineral oil, 18.4 mg, 0.46 mmol), and the mixture is stirred at rt for 30 min. 2-Chloro-6-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-5,6,7,8-tetrahydro-1,6-naphthyridine (80 mg, 0.23 mmol) is added and the mixture is heated at 100° C. for 2 hr. Solvent is removed and the residue is partitioned between water (10 mL) and DCM (10 mL). The layers are separated and the aqueous layer is extracted with DCM (10 ml). The combined extracts are dried and evaporated. The residue is purified by PTLC to give the title compound as a light yellow oil MS (M+1): 399.3; 1H NMR (δ, CDCl3): 7.17 (d, 1H), 6.46 (d, 1H), 5.28 (m, 1H), 3.64 (q, 4H), 3.58 (s, 2H), 3.36 (s, 2H), 2.80-2.88 (m, 4H), 2.63-2.73 (m, 1H), 2.28 (q, 4H), 1.58-2.08 (m, 14H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)=[O:28])=[CH:23][CH:22]=1.[CH:36]1([N:39]([CH2:41][CH:42]2[CH2:44][CH:43]2[CH2:45]O)[CH3:40])[CH2:38][CH2:37]1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:45][CH:43]3[CH2:44][CH:42]3[CH2:41][N:39]([CH:36]3[CH2:38][CH2:37]3)[CH3:40])=[CH:31][CH:30]=2)=[O:28])=[CH:23][CH:22]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Reactant: CN(CC1CC1CO)C1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(CC1CC1COc1ccc(C(=O)c2ccc(Br)cc2)cc1)C1CC1
Reaction time: 3 h
Yield: 42.2 %

Procedure:
A solution of 6.2 g of triphenylphosphine, 6.5 g of (4-bromo-phenyl)-(4-hydroxy-phenyl)-methanone and 3.64 g of (1RS,2RS)-[2-[(cyclopropyl-methyl-amino)-methyl]-cyclopropyl]-methanol (Ex. 31.1.A.d) in 190 ml of THF is treated at room temperature during 1 hr. with 4.03 ml of diethyl azodicarboxylate in 18 ml of THF. After stirring for 3 hrs. the mixture is concentrated, taken up in ether and washed with saturated sodium bicarbonate solution and 10% sodium chloride solution, dried and concentrated. The residue is dissolved in ether and precipitated with hexane. The mother liquor is concentrated and the crude (1RS,2RS)-(4-bromo-phenyl)-[4-[2-[(cyclopropyl-methyl-amino)-methyl]-cyclopropylmethoxy]-phenyl]-methanone is dissolved in ethanol, treated with 2.7 g of fumaric acid and crystallized out. There are obtained 4.1 g of (1RS,2RS)-(4-bromo-phenyl)-[4-[2-[(cyclopropyl-methyl-amino)-methyl]-cyclopropylmethoxy]-phenyl]-methanone.fumarate (1:1), m.p. 136-137° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([C:37]([NH:39][CH:40]([C:50]([OH:52])=[O:51])[CH2:41][CH2:42][C:43]([O:45]C(C)(C)C)=[O:44])=[O:38])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].FC(F)(F)C(O)=O.C(Cl)Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([CH:14]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([C:37]([NH:39][CH:40]([C:50]([OH:52])=[O:51])[CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[O:38])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(C(=O)NC(CCC(=O)OC(C)(C)C)C(=O)O)c3ccccc3n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)O)NC(=O)c2cc(C(=O)NC(CCC(=O)O)C(=O)O)c3ccccc3n2)CC1
Yield: 97.3 %

Procedure:
Alternatively, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-[(1-carboxy-3-(1,1-dimethylethoxycarbonyl)propyl)aminocarbonyl]quinoline (136 mg, 0.187 mmol) was treated with trifluoroacetic acid:methylene chloride (1:1, 1.2 mL) at ambient temperature for 1 hour. The solvents were evaporate and resulting residue diluted with methylene chloride, followed by evaporation of the solvent gave 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-[(1,3-dicarboxypropyl)aminocarbonyl]quinoline (112 mg); NMR (CD3OD) 1.20 (m, 3), 1.90 (m, 1), 2.10 (m, 2), 2.30–2.50 (m, 5), 3.40–3.80 (m, 8), 4.10 (m, 2), 4.70 (m, 1), 5.18 (m, 1), 7.60 (m, 1), 7.80 (m, 1), 8.20 (m, 3) ppm.
Reaction SMILES: [Cl:1][C:2]1=[C:3]([Cl:9])[C:4]([O:6][C:7]1=[O:8])=[O:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][NH2:20])=[CH:13][CH:12]=1.O>C(O)(=O)C>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][N:20]=[C:4]([OH:5])/[C:3](/[Cl:9])=[C:2](/[Cl:1])\[C:7]([OH:6])=[O:8])=[CH:15][CH:16]=1
Reactant: NCCCc1ccc(Cl)cc1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)/C(Cl)=C(/Cl)C(O)=NCCCc1ccc(Cl)cc1
Temperature: 20 °C
Yield: 77.5 %

Procedure:
16.7 g (0.1 mol) of dichloromaleic anhydride and 17.0 g (0.1 mol) of 3-(4-chlorophenyl)-propylamine are stirred in 100 ml of glacial acetic acid under reflux for 4 hours. 50 ml of water are added and the mixture is cooled to 20° C. The product is filtered off with suction and dried. 26.1 g (82% of theory) of dichloromaleic acid N-[3-(4-chlorophenyl)-propyl]-imide of melting point 72°-73° C. are obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[NH:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:2]1.[CH3:18][CH2:19][O-:20].[Na+]>C(O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[NH:15][C:14](=[O:16])[N:13]([CH2:4][CH2:3][CH2:2][N:1]3[CH2:9][CH2:8][O:20][CH2:19][CH2:18]3)[C:12]2=[O:17])=[CH:2]1
Reactant: CC[O-]
Reactant: O=C1NC(=O)C(Cc2c[nH]c3ccccc23)N1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1NC(Cc2c[nH]c3ccccc23)C(=O)N1CCCN1CCOCC1

Procedure:
5-[(Indol-3-yl)methyl]hydantoin (5 g; 0.022 mole) was added to NaOC2H5 (0.022 mole) in 300 ml of anhydrous C2H5OH. The first mixture was heated to reflux, and 1-(3-chloropropyl)-morpholine (3.5 g, 0.022 mole) was added. The mixture was heated for 6 hours and then diluted with H2O. The solid was collected and recrystallized from 2-propanol-petroleum ether, yield 3 g, mp 158°-60°.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([C:12]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][O:14][CH:13]=1)=O)C>O1CCCC1>[C:17]1([C:16]2[C:12]([CH2:10][OH:9])=[CH:13][O:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1cocc1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cocc1-c1ccccc1
Temperature: 25 °C

Procedure:
LiAlH4 (1.0M solution in hexane 1.14 ml, 1.14 mmol) was added dropwise to a solution of ethyl-4-phenyl-3-furoate (246 mg, assumed 1.28 mmol) in tetrahydrofuran (20 ml) at 0 degrees under argon. The solution was stirred and was allowed to warm to room temperature gradually over 1/2 hour. The mixture was quenched with saturated ammonium chloride and the organics were extracted into ethyl ether, and washed with H2O. Evaporation of the dried (magnesium sulfate) extracts gave an oil, which was purified by flash chromatography on silica using 20% ethyl acetate/hexanes. This was further purified by recrystallation (hexane/ethyl ether) to give the title compound as pale yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:37][CH:38]([CH3:40])[CH3:39])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.[OH-].[Na+].Cl>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:37][CH:38]([CH3:40])[CH3:39])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1)=[CH:17][C:16]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:15][CH:14]=2)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)CCCCOc1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCCCCC(=O)O)cc23)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.1 %

Procedure:
To a solution of ethyl 5-{[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}pentanoate (1.6 g, 2.9 mmol) in tetrahydrofuran (10 ml)-ethanol (10 ml) was added 2N aqueous sodium hydroxide solution (3 ml), and the mixture was stirred at room temperature for 5 hrs. The reaction mixture was acidified with 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under-reduced pressure and the residue was crystallized from diisopropyl ether to give 5-{[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}pentanoic acid (1.3 g, yield 87%) as crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[K+]>C(O)C>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccccc1)C(=O)O
Yield: 90.9 %

Procedure:
Benzylmalonic acid diethyl ester (10 g, 40 mmol) in 25 mL of ethanol is cooled to 0° C. Potassium hydroxide (2.5 g, 40 mmol) dissolved in 25 mL of ethanol is added dropwise over 50 minutes. The cooling bath is removed and the mixture is stirred for one additional hour. The volume of solvent is reduced by evaporation in vacuo, and the residual solution is poured into aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The aqueous phase is acidified with aqueous 10% HCl and extracted twice with ethyl acetate. The organic phase is dried with a brine extraction, filtered from anhydrous sodium sulfate, and concentrated in vacuo, yielding 8.08 g of the title compound as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.[CH3:19][C@H:20]1[CH2:25][NH:24][CH2:23][C@@H:22]([CH3:26])[NH:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:18][C:7]1[N:8]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[S:11][C:3]([CH2:2][N:24]3[CH2:23][C@H:22]([CH3:26])[NH:21][C@H:20]([CH3:19])[CH2:25]3)=[CH:4][C:5]=2[N:6]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 17 h
Yield: 77.3 %

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (150 mg, 0.43 mmol) in DMF (4 mL) were added (cis)-2,6-dimethyl-piperazine (74 mg, 0.648 mmol) and potassium carbonate (117 mg, 0.847 mmol). The resulting mixture was stirred at RT for 17 h, then concentrated in vacuo. The resulting residue was triturated with water to give the title compound as an off-white solid (127 mg, 77%).
Reaction SMILES: [N:1]1([S:6]([CH:9]([S:11]([NH2:14])(=[O:13])=[O:12])[CH3:10])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([NH:25][C:26](=O)[O:27]C2C=CC=CC=2)[N:18]=1.N12CCCN=C1CCCCC2.Cl>C(#N)C>[CH3:24][O:23][C:21]1[CH:22]=[C:17]([O:16][CH3:15])[N:18]=[C:19]([NH:25][C:26](=[O:27])[NH:14][S:11]([CH:9]([S:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:8])[CH3:10])(=[O:13])=[O:12])[N:20]=1
Reactant: CC(S(N)(=O)=O)S(=O)(=O)N1CCCC1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)C(C)S(=O)(=O)N2CCCC2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 3.6 g (0.015 mol) of 1-pyrrolidinosulfonylethanesulfonamide (Example 1a) and 4.0 g (0.019 mol) of phenyl 4,6-dimethoxypyrimidin-2-ylcarbamate in 40 ml of acetonitrile there are added 2.9 g (0.019 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). After the mixture has been stirred for five hours at room temperature, it is treated with 250 ml of ice/water and acidified with HCl to pH 2. Extraction with dichloromethane, drying and evaporation give crude 3-(4,6-dimethoxypyrimidin-2-yl)-1-(1-pyrrolidinosulfonylethylsulfonyl)urea, which is purified by trituration with diisopropyl ether (yield: 4.6 g; 73% of theory; melting point 145°-146° C.).
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:14]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:18][CH:17]=1)[CH3:15]>>[CH2:14]([C:16]1[CH:17]=[CH:18][C:19]([N:22]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])=[CH:20][CH:21]=1)[CH3:15]
Reactant: CCc1ccc(NCCN2CCCCC2)cc1
Reactant: O=C(O)C1CCCc2ccccc21
Product: CCc1ccc(N(CCN2CCCCC2)C(=O)C2CCCc3ccccc32)cc1
Yield: 86.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.34 g) and (4-ethylphenyl)(2-piperidinoethyl)amine (0.47 g) as starting materials, N-(4-ethylphenyl)-N-(2-piperidinoethyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.65 g) was obtained.