Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.C(N(CC)CC)C.[CH2:29]([N:35]=[C:36]=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>O1CCCC1>[ClH:21].[ClH:1].[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][NH:4][C:36]([NH:35][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:37])[CH2:9][CH2:10]2)=[CH:20][CH:19]=1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CCCCCCN=C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCNC(=O)NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 171 %

Procedure:
The procedure described in Example 3 was followed, using 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (3.77 g; 10 mmole), tetrahydrofuran (50 ml), triethylamine (4.2 ml; 30 mmole) and n-hexyl isocyanate (1.41 g; 10 mmole). Recrystallization from ethanol provided the title compound (4.00 g; 83% yield) as colorless crystals, m.p. 214°-215° C.
Reaction SMILES: [CH3:1][C:2]1([C:8]#[N:9])[CH2:6][CH2:5][CH2:4][C:3]1=O.C([O-])(=O)C.[NH4+].C([BH3-])#[N:16].[Na+]>CO>[NH2:16][CH:3]1[CH2:4][CH2:5][CH2:6][C:2]1([CH3:1])[C:8]#[N:9]
Reactant: CC1(C#N)CCCC1=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC1(C#N)CCCC1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 177.7 %

Procedure:
A mixture of 1-methyl-2-oxocyclopentanecarbonitrile (272 mg, 2.209 mmol, from Step 1) and ammonium acetate (917 mg, 11.90 mmol) in methanol (2 mL) was stirred at room temperature for 2 h. Sodium cyanoborohydride (69.4 mg, 1.104 mmol) was added. After 17 h at room temperature, the mixture was concentrated. The residue was dissolved in water and ethyl acetate and stirred vigorously. The ethyl acetate phase was separated, dried (MgSO4), filtered and concentrated to give crude 2-amino-1-methylcyclopentanecarbonitrile (0.2436 g), which was taken to the next reaction without purification.
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[C:9]([CH3:15])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20](=[O:30])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][C:22]=1[CH3:29].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:18][O:19][C:20](=[O:30])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:17])[CH3:16])=[CH:8][C:9]=2[CH3:15])[CH3:14])=[CH:23][C:22]=1[CH3:29]
Reactant: COC(=O)c1ccc(C=O)cc1C
Reactant: CNc1ccc(O[Si](C)(C)C(C)(C)C)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)c1ccc(CN(C)c2ccc(O[Si](C)(C)C(C)(C)C)cc2C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.1 %

Procedure:
A mixture of [4-(tert-butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-methyl-amine (643 mg, 2.6 mmol, 1.2 eq) and 4-formyl-2-methyl-benzoic acid methyl ester (380 mg, 2.1 mmol), acetic acid (252 mg, 4.2 mmol, 2.0 eq.), sodium triacetoxyborohydride (890 mg, 4.2 mmol, 2.0 eq.) in 1,2-dichloroethane is stirred at room temperature overnight. The mixture is concentrated under reduced pressure and the resulting residue is partitioned between EtOAc (50 mL) and 5% NaHCO3 (40 mL). The organic. phase is washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography eluting with a gradient of EtOAc/Hexane to afford the title compound as a syrup (1.0 g, 95%). LC-ES/MS m/e 414.3 (M+1).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([NH2:13])=[N:7][NH:8]2.[C:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br)#[N:15].O>CS(C)=O>[NH2:13][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[Cl:3])[N:8]([CH2:19][C:18]2[CH:17]=[C:16]([CH:23]=[CH:22][CH:21]=2)[C:14]#[N:15])[N:7]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: Nc1n[nH]c2cccc(Cl)c12
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cccc(Cn2nc(N)c3c(Cl)cccc32)c1
Reaction time: 2 h

Procedure:
To a suspension of ground potassium hydroxide (421 mg, 7.50 mmol) in anhydrous dimethyl sulfoxide (5 mL) at room temperature under nitrogen was added a solution of 4-chloro-1H-indazol-3-amine (for a preparation see Intermediate 40) (503 mg, 3.0 mmol) in anhydrous dimethyl sulfoxide (15 mL). After 30 minutes 3-cyanobenzyl bromide (Aldrich) (735 mg, 3.75 mmol) was added in one portion. The reaction mixture was stirred for 2 hours. The reaction mixture was poured into water (200 mL), forming a yellow/brown emulsion. This was extracted using chloroform (2×200 mL). The combined organic solutions were washed with water:brine (1:1) (200 mL), passed through a hydrophobic frit, and evaporated in-vacuo to yield a brown oil. The oil was applied to a 100 g silica SPE cartridge and purified by chromatography on Flashmaster II using a 0-100% ethyl acetate in cyclohexane gradient over 80 min. Fractions 32-34 were combined and the solvent was evaporated in-vacuo to yield the title compound as an off white solid (216 mg, 25%). LCMS (System B) RT=2.51 min, ES+ve m/z 283 (M+H)+.
Reaction SMILES: O=C1NC=C([C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)C=C1C(O)=O.[NH:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]1=[O:23]>N1C2C(=CC=CC=2)C=CC=1>[N:12]1[CH:11]=[CH:16][N:15]([C:21]2[CH:20]=[CH:19][C:18](=[O:23])[NH:17][CH:22]=2)[CH2:14][CH:13]=1
Reactant: O=C(O)c1cc(-c2cnccn2)c[nH]c1=O
Reactant: O=c1cccc[nH]1
Solvent: c1ccc2ncccc2c1
Product: O=c1ccc(N2C=CN=CC2)c[nH]1
Temperature: 25 °C

Procedure:
1,2-Dihydro-2-oxo-5-(2-pyrazinyl)nicotinic acid (72.5 g) is added as a fine powder to 800 ml of stirred quinoline heated to just below boiling. The reaction mixture is refluxed for 24 hours, allowed to cool to RT and then placed in an ice bath, and the solid crystallized out. The solid is filtered, washed with ether, dried and recrystallized from isopropanol (first treating with charcoal and filtering while hot) yielding the desired decarboxylated pyridone.
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH2:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:13](Cl)(Cl)=[O:14]>C1(C)C=CC=CC=1>[O:14]=[C:13]1[NH:8][C:7]2[C:6](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:1]2[CH:2]=[CH:3][CH:4]=[C:5]12
Reactant: O=C(Cl)Cl
Reactant: Nc1ccccc1-n1cccc1
Solvent: Cc1ccccc1
Product: O=c1[nH]c2ccccc2n2cccc12

Procedure:
15 g (0.095 mol) of 2-(1-pyrrolyl)aniline is brought to reflux for 1 h 30 min, in 200 cm3 of toluene, in the presence of 50 cm3 of a 20% solution of phosgene in toluene. After cooling, the precipitate formed is filtered off, washed with ethyl ether, dried and recrystallized from acetonitrile (white powder sublimed at 270° C.).
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH:17][CH:18]([CH2:22][CH2:23][CH2:24][CH3:25])[C:19]([OH:21])=[O:20]>C(OCC)(=O)C>[OH:17][CH:18]([CH2:22][CH2:23][CH2:24][CH3:25])[C:19]([O:21][CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:20]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CCCCC(O)C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCC(O)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 90 ml of ethyl acetate, the 2-hydroxy-L-hexanoic acid (H-L-norLEUA-OH) was dissolved. A solution (15.1 g/30 ml) of diphenyldiazomethane in ethyl acetate was added dropwise to the resulting solution, followed by stirring overnight at room temperature. The reaction mixture was adjusted to pH 2 with 2N--HCl, followed by washing thrice with 200 ml portions of a saturated aqueous solution of sodium bicarbonate. The organic layer so obtained was dried over anhydrous magnesium sulfate and then filtered. The filtrate was thereafter concentrated under reduced pressure. The residue obtained was then purified by subjecting to chromatography on a silica gel column (toluene:ethyl acetate=20:1), whereby 11.35 g of the title compound were obtained as pale yellow crystals (yield: 54.7%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([CH3:10])[CH3:9])[CH:3]=1.[C:11]([N:14]1[CH2:18][CH2:17][NH:16][C:15]1=O)(=[O:13])[CH3:12]>P(Cl)(Cl)(Cl)=O>[C:11]([N:14]1[CH2:18][CH2:17][N:16]=[C:15]1[NH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([CH3:10])[CH3:9])[CH:3]=1)(=[O:13])[CH3:12]
Reactant: CC(C)c1cc(N)n(C)n1
Reactant: CC(=O)N1CCNC1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)N1CCN=C1Nc1cc(C(C)C)nn1C
Reaction time: 40 h

Procedure:
5-amino-3-isopropyl-1-methyl pyrazole (described in British Patent 1,057,740) (19.3 g) was dissolved in 180 ml phosphorus oxychloride (POCl3). 1-Acetyl-2-imidazolidinone (J. Chem Soc 1964, 178) (20.1 g) was added. This reaction mixture was stirred at 55° for 40 hr. The solvents were concentrated in vacuum, ice and methylene chloride were added and the mixture neutralized with 25% sodium hydroxide in water. The methylene chloride layer was dried over MgSO4 and then concentrated and the residue crystallized from isopropyl alcohol and ether to give 12.73 g. of product, mp 145°-147° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23]([NH:26][CH3:27])=[C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH:21]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23]([N:26]([CH3:27])[C:6](=[O:7])[C:5]2[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=2)=[C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH:21]=1
Reactant: CNc1cnc(OC)cc1-c1ccccc1C
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(-c2ccccc2C)c(N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reaction time: 2 h
Yield: 74.7 %

Procedure:
3,5-Bis-trifluoromethylbenzoyl chloride (126 μL, 0.69 mmol, CAS RN 1271-19-8) was added to a solution of 6-methoxy-N-methyl-4-o-tolylpyridin-3-amine (105 mg, 0.46 mmol) and DIPEA (240 μL, 1.38 mmol) in CH2Cl2 and stirred for 2 h. The reaction mixture was then loaded directly onto a silica gel column Elution with 20% EtOAc in n-hexane gave the title product as a colorless foam (161 mg, 76%). MS (ESI): m/z=469.0 [M+H]+.
Reaction SMILES: [N:1]([CH:4]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][CH:22]=1)[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1)=[N+:2]=[N-:3].[OH-].[Na+].O1CCCC1.Cl>CO>[N:1]([CH:4]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][CH:22]=1)[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)=[N+:2]=[N-:3]
Reactant: COC(=O)c1ccc(COc2cccc(C(N=[N+]=[N-])c3ccccc3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: [N-]=[N+]=NC(c1ccccc1)c1cccc(OCc2ccc(C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.7 %

Procedure:
To a stirred suspension of methyl 4-((3-(azido(phenyl)methyl)phenoxy)-methyl)benzoate (1 g, 2.79 mmol) in methanol (25 mL), was added 2M sodium hydroxide (25 mL). The reaction was allowed to stir at room temperature for 3 days. Tetrahydrofuran (10 mL) was added to the reaction mixture, and the mixture was stirred at 50° C. for 4 hours followed by 16 hours at room temperature. The reaction mixture was acidified with 10% hydrochloric acid, extracted with dichloromethane, dried (sodium sulphate), filtered, and concentrated under reduced pressure to give the title compound (1 g, quantitative).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35].C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH2:15]([C:12]1[C:13](=[O:14])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH:3]=2)[C:9]2[N:25]=[CH:24][CH:23]=[CH:22][C:10]=2[N:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Reactant: CC(C)OC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)OC(=O)Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-(3-aminophenyl)-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (192 mg) and triethylamine (0.12 ml) in 1,4-dioxane (4 ml) was added isopropyl chloroformate (0.10 ml). The mixture was stirred at room temperature for 30 minutes, then poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with methanol to give 2-benzyl-4-(3-isopropoxycarbonylaminophenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (167 mg).
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[O:48]1[CH2:53][CH2:52][CH:51]([NH2:54])[CH2:50][CH2:49]1>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([NH:54][CH:51]4[CH2:52][CH2:53][O:48][CH2:49][CH2:50]4)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:4])([CH3:3])[CH3:5]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: NC1CCOCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NC2CCOCC2)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with tetrahydro-pyran-4-ylamine (Matrix Scientific) to give the title compound. HR-MS (ES, m/z) calculated for C40H51Cl2N6O4 [(M+H)+] 749.3344, observed 749.3343.
Reaction SMILES: C(N=C=NCCCN(C)C)C.[CH:12]([NH:15][CH:16]([CH3:18])[CH3:17])([CH3:14])[CH3:13].[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1>ClCCl>[CH:12]([N:15]([CH:16]([CH3:18])[CH3:17])[C:27](=[O:28])[CH2:26][C:23]1[CH:24]=[CH:25][C:20]([Br:19])=[CH:21][CH:22]=1)([CH3:14])[CH3:13]
Reactant: CC(C)NC(C)C
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)N(C(=O)Cc1ccc(Br)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4.21 g of 1-ethyl 3-(3-dimethylamino-propyl)-carbodiimide (EDAC) and 3.08 ml of diisopropylamine were added to a solution of 4.3 g of 4-bromo-benzeneacetic acid (BrPhCH2COOH) in 15 ml of dichloromethane and the mixture was stirred for 10 minutes at ambient temperature. After evaporation under reduced pressure, the crude product was chromatographed on silica, eluting with an ethyl acetate/cyclohexane mixture (2/8) to obtain 3.7 g of product in the form of an oil with a Rf=0.21 ethyl acetate/cyclohexane 2/8).
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[NH:34]1[CH2:38][CH2:37][C@@H:36]([CH2:39][OH:40])[CH2:35]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:34]4[CH2:38][CH2:37][C@@H:36]([CH2:39][OH:40])[CH2:35]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: OC[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CC[C@@H](CO)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, DIPEA and (R)-pyrrolidin-3-ylmethanol. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 4.72 (1H), 3.66 (m, 2H), 3.49 (m, 2H), 3.32 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.30 (m, 2H). m/z: 438 [M+H]
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[S:8]1(=[O:24])=[O:23].[CH3:25][NH2:26]>>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:26][CH3:25])[S:8]1(=[O:24])=[O:23]
Reactant: CN
Reactant: O=S1(=O)N(CCOCCBr)c2ccccc2N1c1ccccc1F
Product: CNCCOCCN1c2ccccc2N(c2ccccc2F)S1(=O)=O
Yield: 95 %

Procedure:
In an analogous manner as described in general procedure V, 1-[2-(2-bromoethoxy)ethyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.07 g, 0.16 mmol) was treated with methylamine (10 mL) to provide 0.05 g (95%) of 2-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethoxy}-N-methylethanamine. MS (ES) m/z 366.0; HRMS: calculated for C17H20FN3O3S+H+, 366.12822; found (ESI, [M+H]+), 366.1285; HPLC purity 100.0% at 210-370 nm, 8.4 minutes; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammon. Bicarb Buff. pH=9.5/ACN+MeOH) for 10 minutes hold 4 minutes.
Reaction SMILES: C([O:3][C:4]([C:6]1([N:9]([CH:51]([CH3:53])[CH3:52])[S:10]([C:13]2[CH:14]=[C:15]([CH:48]=[CH:49][CH:50]=2)[C:16]([NH:18][C:19]2[S:20][C:21]3[CH2:47][CH2:46][CH2:45][CH2:44][C:22]=3[C:23]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]3[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=3)=[CH:29][CH:28]=2)=[O:25])=[O:17])(=[O:12])=[O:11])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C>[C:4]([C:6]1([N:9]([CH:51]([CH3:53])[CH3:52])[S:10]([C:13]2[CH:14]=[C:15]([CH:48]=[CH:49][CH:50]=2)[C:16]([NH:18][C:19]2[S:20][C:21]3[CH2:47][CH2:46][CH2:45][CH2:44][C:22]=3[C:23]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]3[CH:36]=[CH:37][C:38]([C:39]([OH:41])=[O:40])=[CH:42][CH:43]=3)=[CH:29][CH:28]=2)=[O:25])=[O:17])(=[O:12])=[O:11])[CH2:7][CH2:8]1)([OH:5])=[O:3]
Reactant: CCOC(=O)C1(N(C(C)C)S(=O)(=O)c2cccc(C(=O)Nc3sc4c(c3C(=O)Nc3ccc(CCc5ccc(C(=O)O)cc5)cc3)CCCC4)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)N(C1(C(=O)O)CC1)S(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)O)cc4)cc2)CCCC3)c1
Yield: 56.1 %

Procedure:
A mixture of 137 mg of 4-(2-{4-[({2-[(3-{[1-(ethoxycarbonyl)cyclopropyl](isopropyl)sulfamoyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoic acid, 0.5 mL of a 5.0 M aqueous sodium hydroxide, and 1.4 mL of ethanol was heated and refluxed overnight. The reaction mixture was concentrated under reduced pressure, and to the residue were added water, citric acid, dichloromethane, and THF in this order. The organic layer was separated and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol). The obtained crude product was washed with diethyl ether to obtain 74 mg of 4-{2-[4-({[2-({3-[(1-carboxycyclopropyl)(isopropyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoic acid as a pale yellow crystal.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][CH2:23][C:24]2=[O:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:33][CH2:34][CH3:35])(=[O:32])[CH3:31].O>O1CCCC1>[OH:29][C:24]1([CH2:31][C:30]([O:33][CH2:34][CH3:35])=[O:32])[C:25]2[C:20](=[C:19]([O:18][Si:1]([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:22][CH2:23]1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCCC2=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC1(O)CCCc2c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cccc21
Reaction time: 1 h

Procedure:
To a solution of diisopropylamine (17 ml) in THF (tetrahydrofuran) (210 ml) was added n-butyllithium (67 ml, 1.6N in hexane) at -78° C. under N2. The solution was stirred for 30 minutes at 0° C. and then cooled to -78° C. To the solution was added ethyl acetate (12 g) and the mixture was stirred for 30 minutes at the same temperature to give Li-enolate solution. A solution of 5-t-butyldiphenylsilyloxy-1-oxo-1,2,3,4-tetrahydronaphthalene (10 g) in THF (50 ml) was cooled to -78° C., the above Li-enolate solution (35 ml) was added, and stirred for 1 hour at the same temperature. The mixture was poured into a mixture of ethyl acetate and water. The organic layer was washed with 1N--HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 1-hydroxy-1-ethoxycarbonylmethyl-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (8.0 g). 2.72 (2H, t, J=6.6 Hz), 2.90 (2H, t, J=8.0 Hz), 4.30 (2H, t, J=7.0 Hz), 5.78 (1H, t, J=4.4 Hz), 6.33 (1H d, J=8 Hz), 6.6-6.9 (2H, m), 7.1-7.8 (20H, m) MS m/z: 624 (M+ +1)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:15](OCC)(OCC)(OCC)[CH3:16].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:15]([CH3:16])[N:9]([CH:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[C:4]=2[CH:3]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: Nc1ccc(Br)cc1NC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1nc2ccc(Br)cc2n1C1CCCC1

Procedure:
Heat a mixture of 4-bromo-N2-cyclopentyl-benzene-1,2-diamine (10.6 g), triethyl orthoacetate (9.5 ml) and acetic acid (6.3 mL) at 100° C. for 2.5 h. Dilute with DCM and pour onto an aqueous saturated solution of sodium bicarbonate. Dry over sodium sulfate and remove the solvent under vacuum. Purify by silica gel column chromatography, eluting with DCM/ethanol-10% NH3 (0-3%) to afford 10.67 g of the title compound. MS (ES+): m/z=280 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:13][N:14]1[CH2:23][CH:22]([C:24]2[CH:25]=[C:26]([CH2:30][C:31](Cl)=[O:32])[CH:27]=[CH:28][CH:29]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1>ClC(Cl)C>[CH3:13][N:14]1[CH2:23][CH:22]([C:24]2[CH:25]=[C:26]([CH2:30][C:31]([NH:1][C:2]3[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=3[C:4]([O:6][CH3:7])=[O:5])=[O:32])[CH:27]=[CH:28][CH:29]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: CN1Cc2ccccc2C(c2cccc(CC(=O)Cl)c2)C1
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc(Cl)cc1NC(=O)Cc1cccc(C2CN(C)Cc3ccccc32)c1

Procedure:
2 g (10.7 mmol) of methyl 2-amino-4-chlorobenzoate are dissolved in 30 ml of dichloroethane and, after addition of 4.0 g of 3-[2-methyl-1,2,3,4-tetrahydro-4-(R,S)-isoquinolinyl]phenylacetyl chloride, dissolved in approximately 20 ml of dichloroethane, the mixture is heated under reflux for three hours. The solvent is then distilled off and the residue worked up as is customary. The residue is purified by chromatography on silica gel/dichloromethane (treated with 1-2% of methanol). Methyl 2-{3-[2-methyl-1,2,3,4-tetrahydro-4-(R,S)-isoquinolinyl]phenyl}acetami-do-4-chlorobenzoate is obtained.