Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[CH2:8][S:9][CH2:10][CH2:11][NH2:12])[CH3:3].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=1)[CH2:21][C:22]1[C:23](=[O:30])[NH:24][C:25](SC)=[N:26][CH:27]=1>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[CH2:8][S:9][CH2:10][CH2:11][NH:12][C:25]1[NH:24][C:23](=[O:30])[C:22]([CH2:21][C:20]2[CH:31]=[CH:32][CH:33]=[C:18]([O:17][CH3:16])[CH:19]=2)=[CH:27][N:26]=1)[CH3:1]
Reactant: COc1cccc(Cc2cnc(SC)[nH]c2=O)c1
Reactant: CN(C)Cc1cccc(CSCCN)c1
Solvent: c1ccncc1
Product: COc1cccc(Cc2cnc(NCCSCc3cccc(CN(C)C)c3)[nH]c2=O)c1

Procedure:
Reaction of 2-(3-dimethylaminomethylbenzylthio)ethylamine by heating under reflux for 40 hours in dry pyridine with 5-(3-methoxybenzyl)-2-methylthio-4-pyrimidone gives 2-[2-(3-dimethylaminomethylbenzylthio)ethylamino]-5-(3-methoxybenzyl)-4-pyrimidone.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH:11]=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH:15](Br)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH:15]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[CH:6]=[C:7]1[CH:11]=[O:12])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1cc2ccc(Cl)cc2[nH]1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cc2ccc(Cl)cc2n1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 42 h
Yield: 40 %

Procedure:
To 6-chloro-1H-indole-2-carbaldehyde (1 equiv.) in DMF at 0° C. was added NaH (1.25 equiv.) portionwise followed by benzhydryl bromide (1.46 equiv.) and Bu4Nl (0.05 equiv.). The mixture was stirred at rt for 42 h before quenching with cold 0.4N HCl at 0° C. After neutralization, the aqueous layer was extracted with ether and the organic layer was washed with cold H2O and dried. Flash chromatography on silica gel gave 1-benzhydryl-6-chloro-1H-indole-2-carbaldehyde in 40% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[C:36]([C:37](Cl)=[O:38])=[C:35]([CH3:40])[O:34][N:33]=1.[OH-].[Na+]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:16][N:15]([CH3:17])[C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:13][CH2:12][CH:11]([NH:14][C:37]([C:36]2[C:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[Cl:25])=[N:33][O:34][C:35]=2[CH3:40])=[O:38])[CH2:10][CH2:9]1
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)Cl
Reactant: CN(C)C1(c2cccc(F)c2)CCC(N)CC1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)NC1CCC(c2cccc(F)c2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The non-polar diastereoisomer of 1-(3-fluorophenyl)-N,N-dimethylcyclohexane-1,4-diamine (350 mg) was placed with 220 μI triethylamine (1.05 molar equivalents) and catalytic amounts of DMAP (about 5 mg) in 3.5 ml dichloromethane, 400 mg 3-(2-chlorophenyl)-5-methylisoxazole-4-carbonylchloride (1.05 molar equivalents), dissolved in 2 ml dichloromethane, were added dropwise at −10° C. to and the mixture was stirred overnight while being heated to room temperature. For working up, the mixture was made alkaline (pH>10) with 2-molar sodium hydroxide solution, with ice cooling, the organic phase was separated, the aqueous phase extracted with dichloromethane (20 ml) and the combined organic phases dried over sodium sulphate, filtered and evaporated to dryness. The resultant crude product (690 mg) was chromatographed on silica gel (4.0×15 cm) with methanol/ethyl acetate (V:V=1:1). 530 mg of the non-polar diastereoisomer of 3-(2-chlorophenyl)-5-methylisoxazole-4-carboxylic acid [4-dimethylamino-4-(3-fluorophenyl)cyclohexyl]amide were obtained, which, dissolved in 50 ml 2-butanone were converted overnight into the corresponding hydrochloride by adding 21 μl water and 150 μl chlorotrimethylsilane, then evaporating to dryness, and stirring with 10 ml ethyl acetate (380 mg, Mp. 231-232° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:12]([O:14]CC2C=CC=CC=2)=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.O.[OH-].[Li+].Cl.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:35]([NH2:37])[CH3:36])=[CH:29][CH:28]=1.CN(C)CCCN=C=NCC>C(#N)C.O.CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][CH:34]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:35]([NH:37][C:12]([C:7]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:8][CH2:9][CH2:10][CH2:11]2)=[O:14])[CH3:36])=[CH:31][CH:32]=1
Reactant: O=C(OCc1ccccc1)C1(c2ccccn2)CCCC1
Reactant: CC(N)C(Cc1ccc(Cl)cc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(NC(=O)C1(c2ccccn2)CCCC1)C(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(2-pyridyl)cyclopentanecarboxylic acid, benzyl ester-(Step A, 0.20 g, 0.71 mmol) in acetonitrile (3 mL) and water (1.5 mL) was added lithium hydroxide monohydrate (0.24 g, 5.6 mmol). After stirring at room temperature for 5 h and 50° C. overnight, the reaction mixture was concentrated to dryness. The residue was azeotroped with toluene and was suspended in methylene chloride (6 mL) and dimethylformamide (3 mL), and was added N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-amine hydrochloride (Diastereomer α, Reference Example 2, 0.40 g, 0.14 mm), 4-dimethylaminopyridine (0.10 g, 0.71 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (38 mg, 0.19 mmol). After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate (50 mL), washed with water and brine, dried over anhydrous sodium sulfate and concentrated to dryness. N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-1-(2-pyridyl)cyclopentanecarboxamide was obtained by flash column chromatography on silica gel eluted with 15-20% ethyl acetate in hexane. 1H NMR (400 MHz, CD3OD): δ 8.52 (d, 1H), 7.77 (t, 1H), 7.48 (d, 1H), 7.35-7.08 (m, 4H), 7.00 (d, 2H), 6.94 (d, 2H), 6.68 (d, 2H), 4.20 (m, 1H), 2.80 (dd, 1H), 2.73 (m, 1H), 2.60 (m, 2H), 2.45 (m, 1H), 2.30 (m, 1H), 2.18 (m, 1H), 1.85-1.65 (m, 4H), 0.82 (d, 3H). LC-MS: m/e 433 (M+H)+ (3.2 min).
Reaction SMILES: CC(OC([N:8]1[CH2:13][C@@H:12]([C:14]([OH:16])=[O:15])[CH2:11][CH2:10][CH2:9]1)=O)(C)C.C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CO>[NH:8]1[CH2:9][CH2:10][CH2:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)O)C1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)C1CCCNC1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
(S)-Nip.(S)-CSA 1.1. (1S)-(+)-10-Camphorsulfonic acid (11.62 g, 0.05 mol) was added to a stirred solution of racemic nipecotic acid (6.46 g, 0.05 mol) in acetone (100 mL). The solution was heated to reflux, and H2O (15 mL) was added until all solids dissolved. The solution was cooled to room temperature and allowed to stir overnight. The precipitate that formed was isolated by filtration and recrystallized three times with acetone/H2O (6/1, v/v) to afford 1.99 g (11% yield) of the desired product as a white solid: m.p. 221-223° C.; {a}D+25.3° (c 1.0, MeOH). Boc-(S)-Nip-OH 1.2. (S)-Nip.(S)-CSA (1.90 g, 5.3 mmol) was dissolved in methanol (12 mL). Triethylamine (2.2 mL, 15.8 mmol) and di-tert-butyl dicarbonate (1.38 g, 6.3 mmol) were added and the solution was stirred at 50° C. for 12 h. The solution was then concentrated, and the residue was dissolved in H2O. The aqueous solution was washed with diethyl ether, and the organic layer was discarded. The aqueous layer was acidified to pH 3 with 1 M HCl and extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated to afford 1.24 g (quantitative yield) of the desired product as a white solid: m.p. 166-168° C.; FAB-MS m/z (M+Na+) calcd for C11H19NO4Na 252.3, obsd 252.5. Boc-(S)-Nip-OBn 1.3. Boc-(S)-Nip-OH (0.70 g, 3.1 mmol) was dissolved in N,N-dimethylformamide (DMF) (14 mL). Cs2CO3 (1.0 g, 3.1 mmol) and benzyl bromide (0.41 mL, 3.5 mmol) were added, and the solution was stirred at room temperature for 24 h. The solution was then concentrated, and the residue was dissolved in H2O. The aqueous solution was then extracted with CH2Cl2. The organic solution was dried over MgSO4 and concentrated to give an oil. The crude product was purified by column chromatography eluting with ethyl acetate/hexanes (1/3, v/v) to afford 0.81 g (82% yield) of the desired product as a white solid. 2. Oligomer Synthesis
Reaction SMILES: [C:1]([CH:4]([CH:10]([C:16](=O)[CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].C(O)C.[BrH:22].[NH:23]([C:25]1[NH:26][CH2:27][CH2:28][N:29]=1)[NH2:24]>C(O)(=O)C>[BrH:22].[C:11]([C:10]1[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:1]([CH3:2])[N:24]([NH:23][C:25]2[NH:29][CH2:28][CH2:27][N:26]=2)[C:16]=1[CH3:17])([O:13][CH2:14][CH3:15])=[O:12]
Reactant: NNC1=NCCN1
Reactant: CCOC(=O)C(C(C)=O)C(C(C)=O)C(=O)OCC
Agent: Br
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1c(C(=O)OCC)c(C)n(NC2=NCCN2)c1C

Procedure:
To a solution of 15 g. (0.0581 mole) of diethyl 2,3-diacetylsuccinate in 150 ml. of absolute ethanol, 1.2 ml. of glacial acetic acid is added. The mixture is gently refluxed for 5 minutes then 8.13 g. (0.0467 mole) of 2-hydrazino-4,5-dihydro-1H-imidazole hydrobromide is added. The mixture is refluxed for 20 hours, then the solvent is evaporated off. The obtained residue is recrystallized several times from isopropanol, and 6.3 g. of the title compound are recovered. M.p. 172°-4°C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([CH3:21])=[CH:4][N:3]=1.[CH3:22][P:23]([C:26]1[N:31]=[C:30]([O:32][CH3:33])[C:29]([NH2:34])=[CH:28][CH:27]=1)([CH3:25])=[O:24]>>[CH3:25][P:23]([C:26]1[N:31]=[C:30]([O:32][CH3:33])[C:29]([NH:34][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([CH3:21])=[CH:4][N:3]=2)=[CH:28][CH:27]=1)([CH3:22])=[O:24]
Reactant: COc1nc(P(C)(C)=O)ccc1N
Reactant: Cc1cnc(Cl)nc1Nc1ccccc1S(=O)(=O)C(C)C
Product: COc1nc(P(C)(C)=O)ccc1Nc1ncc(C)c(Nc2ccccc2S(=O)(=O)C(C)C)n1

Procedure:
This compound can be prepared as in Example 32 by reacting 2-Chloro-5-methyl-N-[2-(propan-2-ylsulfonyl)phenyl]-pyrimidin-4-amine with 6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (prepared in Example 32).
Reaction SMILES: ClCl.[CH:3](=[N:10][OH:11])[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][O:5]1.[C-:12]#[N:13].[K+]>CCOCC.C(Cl)Cl.CO>[N:10](=[C:3]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][O:5]1)[C:12]#[N:13])[OH:11]
Reactant: [C-]#N
Reactant: ON=CC1CCCCO1
Agent: ClCl
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: N#CC(=NO)C1CCCCO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.4 %

Procedure:
7.8 g of chlorine were passed into a cooled solution of 12.9 g of 2-formyltetrahydropyran oxime in 140 ml of ether at below 0° C. Thereafter, the volatile constituents of the reaction mixture were stripped off, the residue was taken up in 200 ml of methylene chloride, and the mixture was kept at room temperature for 24 hours. This liquid was then added dropwise to a suspension, cooled to 10°-15° C., of 6.8 g of potassium cyanide in 75 ml of methanol, and the mixture was stirred for a further 3 hours at room temperature. The precipitated potassium chloride was filtered off under suction, the filtrate was evaporated down, the residue was taken up in ether, the solution was washed three times with water and dried over magnesium sulfate, and the solvent was stripped off under 0.005 mbar and at 30° C. to give 11.3 g of α-oximino(tetrahydropyran-2-yl)-acetonitrile as a yellowish solid which melted from 45° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([O:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:5]=[CH:4][CH:3]=1.[C:17]([NH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1)(=[O:19])[CH3:18].[OH-].[K+].Cl>C(O)C.O>[C:17]([NH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[CH:9][C:8]([C:7]2[C:2]([OH:1])=[CH:3][CH:4]=[CH:5][C:6]=2[O:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])=[CH:23][CH:22]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: COC(=O)COc1cccc(O)c1C(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc(C=CC(=O)c2c(O)cccc2OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
To a mixture of 6′-hydroxy-2′-(methoxycarbonylmethoxy)acetophenone (2.24 g) and 4-acetylaminobenzaldehyde (2.45 g) in ethanol (30 mL) were added water (10 mL) and potassium hydroxide (6.73 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 2 mol/L hydrochloric acid (70 mL), and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give 4-acetylamino-2′-(carboxymethoxy)-6′-hydroxychalcone (3.35 g). A mixture of the obtained 4-acetylamino-2′-(carboxymethoxy)-6′-hydroxychalcone (3.3 g) and 10% palladium-carbon powder (1 g) in methanol (50 mL) was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration. The solvent of the filtrate was removed under reduced pressure, and the residue was dissolved in acetic acid (13.2 mL). To the solution were added sodium acetate (4.77 g) and acetic anhydride (4.8 mL), and the mixture was stirred at 115° C. for 20 hours. The reaction mixture was poured in to water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (10 mL). To the solution was added sodium methoxide (28% methanol solution, 5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. To the residue were added 1 mol/L hydrochloric acid (30 mL) and ethyl acetate, and the mixture was stirred for 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was treated with dichloromethane-methanol. The precipitated crystals were collected by filtration. The crystals were washed with dichloromethane and dried under reduced pressure to give the title compound (0.86 g).
Reaction SMILES: BrN1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.BrC[C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[C:39](=[O:42])([O-:41])[O-:40].[Ca+2].Cl>C(Cl)(Cl)(Cl)Cl.O1CCOCC1.O>[C:33]1([C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:31]=[CH:32][C:23]=2[C:39]([OH:40])=[O:42])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[C:39](=[O:40])([O-:42])[O-:41]
Reactant: BrCc1ccc2ccccc2c1-c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc2ccccc2c1-c1ccccc1

Procedure:
Then 97.8 g of that product was combined with 81.9 g of N-bromosuccinimide and 4.2 g of α,α-azo bis isobutyronitrile in 300 ml of carbon tetrachloride and then heated under reflux for 8 hours. The resulting product is filtered off from the succinimide. Then after the solvent is removed in a vacuum, a pale yellow solid was obtained which was determined to be 2-bromomethyl-1-phenylnapthalene was heated with 23 g of calcium carbonate in a mixture consisting of 250 ml of an equal volume mixture of water and dioxane for 10 hours under reflux. The reaction mixture was carefully poured into diluted hydrochloric acid and then extracted with ether and dried and freed of solvent. The resulting product, 2-hydroxymethyl-1-phenylnaphthalene, in an amount of about 0.45 mol was dissolved in 200 ml of acetone and added dropwise to a hot suspension of 207g of KMnO4, 280 ml of water, and 1000 ml of acetone. The suspension was poured into a large glass beaker containing 1000 ml of water to dissolve the magnesium dioxide by the portion-wise addition of dilute HCl and Na2SO3. The product 1-phenylnaphthalene-2-carboxylic acid was isolated by extraction with ether together with extraction of the organic phase with aqueous carbonate solution. This carboxylic acid product was then reacted with polyphosphoric acid. Specifically, 250 g of polyphorphoric acid was heated to 100°-120° C. in a 1000 ml flask. Then 23.9 g of the 1-phenylnaphthalene-2-carboxylic acid was added in portions and the mixture allowed to stand for 1 hour at that temperature. The mixture was then allowed to cool and diluted to 750 ml by the careful addition of ice water. The sticky crude product was extracted with hot toluene and washed with warm aqueous sodium bicarbonate solution. The organic phase was dried and filtered over silica gel. In a cooling cabinet, dark red crystals of the benzo(c) fluorenone separated from the deep red solution.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:30]=[CH:31][C:32]=2[O:33][CH3:34])[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:35][C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])[CH:30]=[CH:31][C:32]=3[O:33][CH3:34])[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Product: COc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(c2ccccc2)c2ccccc2)CC1

Procedure:
Example 20 was prepared from diphenyl acetyl chloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methoxyphenyl}-2-methylpropanamide according to the procedures described in Scheme 8: ESMS m/e: 528.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4](O)=[O:5].Cl.[N:15]([O-])=O.[Na+].S(=O)=O>O>[N+:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:15][NH:1]2)([O-:13])=[O:12]
Reactant: O=N[O-]
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)O
Agent: Cl
Agent: O=S=O
Agent: [Na+]
Solvent: O
Product: O=c1[nH][nH]c2cccc([N+](=O)[O-])c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5 g (27.5 mmol) 2-amino-6-nitro-benzoic acid are combined with 22.2 ml (225.3 mmol) concentrated HCl and 45 ml (30.0 mmol) 5% aqueous sodium nitrite solution and stirred for 1 h at ambient temperature. Then the suspension is diluted with 150 ml dist. H2O and added dropwise to 350 ml destilliertes water which has been saturated with sulphur dioxide. Sulphur dioxide is piped through the reaction mixture for a further 30 min. Then the reaction mixture is refluxed for 30 min and then left to cool slowly to 20° C. The resulting precipitate is filtered off.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32](=[O:34])[NH2:33])=[CH:28][N:27]=2)[CH2:16]1)=O)(C)(C)C>ClCCl>[CH2:16]1[C:17]2[C:22](=[C:21]([O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([NH2:33])=[O:34])=[CH:28][N:27]=3)[CH:20]=[CH:19][CH:18]=2)[CH2:23][CH2:24][NH:15]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2Oc2ccc(C(N)=O)cn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1ccc(Oc2cccc3c2CCNC3)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.2 %

Procedure:
Add drop wise via an addition funnel a solution of trifluoroacetic acid (5.7 mL) in dichloromethane (25 mL) to a stirred solution of 5-(5-carbamoyl-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (2.1 g, 5.7 mmol) in dichloromethane (75 mL) at 0° C. Warm to room temperature and stir for 18 hours. Evaporate on a rotary evaporator, dissolve the residue in methanol (50 mL) and dichloromethane (50 mL), and then add MP-carbonate resin (7.9 g A 2.87 eq/g). Agitate for 2 hours, filter, concentrate on a rotary evaporator, and dry under vacuum to yield 6-(1,2,3,4-tetrahydro-isoquinolin-5-yloxy)-nicotinamide (1.5 g, 5.6 mmol): HPLC=85% (50/50 to 90/10 ACN/(0.1% TFA in water), Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nm). 1H NMR (DMSO-d6, 300.00 MHz): 8.55 (d, 1H), 8.23 (dd, 1H), 8.01 (s, 1H), 7.46 (s, 1H), 6.95 (m, 5H), 3.90 (s, 2H), 2.85 (m, 2H), 2.38 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][NH:10][C:11](=[O:22])[CH:12]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([NH2:21])[CH:15]=2)[CH3:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:25](OCC)(OCC)OCC>>[NH:20]1[C:17]2[CH:18]=[CH:19][C:14]([CH:12]([CH3:13])[C:11]([NH:10][CH2:9][C:8]3[CH:23]=[CH:24][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=3)=[O:22])=[CH:15][C:16]=2[N:21]=[CH:25]1
Reactant: CCOC(OCC)OCC
Reactant: CC(C(=O)NCc1ccc(C(C)(C)C)cc1)c1ccc(N)c(N)c1
Product: CC(C(=O)NCc1ccc(C(C)(C)C)cc1)c1ccc2[nH]cnc2c1

Procedure:
The compound was obtained by reacting N-(4-tert.-butylbenzyl)-2-(3,4-diaminophenyl)propanamide with triethyl orthoformate in a similar manner to example compound 13.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:15]=3[C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)[C:20](O)=[O:21])=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:15]=3[C:16]([NH:18][C@H:19]([C:20](=[O:21])[NH:44][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: NCc1ccccc1
Reactant: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)NCc1ccccc1)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Yield: 33 %

Procedure:
The title compound (19 mg, 33%) was obtained from (S)-2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionic acid and benzyl amine as in Example 1, Part C. HPLC: RT=10.73 min. MS (ESI−): mass calcd. for C29H22Cl3N5O4S2, 675.01; m/z found, 672/674 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.59 (s, 1H), 8.38 (dd, J=7.1, 0.7, 1H), 8.20 (d, J=8.8, 1H), 7.74-7.71 (m, 2H), 7.37-7.25 (m, 5H), 7.13-7.11 (m, 2H), 7.03-6.98 (m, 1H), 6.96-6.87 (m, 2H), 5.79-5.71 (m, 1H), 4.66-4.61 (m, 1H), 4.50-4.45 (m, 1H), 4.33-4.29 (m, 1H), 3.14-3.10 (m, 1H), 3.00-2.96 (m, 1H),
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[S:11]([OH:14])(=[O:13])=[O:12].COC1C(N)=CC=CC=1.[ClH:24].N([O-])=O.[I-].[K+]>O>[NH2:3][C:4]1[CH:9]=[C:8]([Cl:24])[C:7]([CH3:10])=[CH:6][C:5]=1[S:11]([OH:14])(=[O:12])=[O:13]
Reactant: Cc1ccc(N)c(S(=O)(=O)O)c1
Reactant: Cl
Agent: O=N[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: COc1ccccc1N
Product: Cc1cc(S(=O)(=O)O)c(N)cc1Cl
Yield: 84.5 %

Procedure:
A mixture of 11.2 grams of 50% sodium hydroxide solution, 13.4 grams of 2-amino-5-methyl-benzene sulfonic acid .[.(o-anisidine).]. and 13.4 grams of 2-amino-4-chloro-5-methyl benzene sulfonic acid is prepared, and 300 ml. of water is added with stirring until clear. Ice is added to a volume of 488 ml. and the temperature is 0°±2° C., Concentrated hydrochloric acid (36.2 grams) is added with stirring over a period of 4 to 6 minutes. A solution of 10 grams of sodium nitride and 20 ml. of water is added, and the resulting mixture is stirred for 15 minutes at 10°-12° C. while testing for excess acid with Congo Red and for nitrite with potassium iodide paper.