Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[CH3:14][C:15]([CH3:22])([CH3:21])[C:16](=O)[CH2:17][C:18]#[N:19].Cl>CCO.[OH-].[Na+].CCOC(C)=O>[C:15]([C:16]1[CH:17]=[C:18]([NH2:19])[N:12]([C:9]2[CH:8]=[CH:7][C:6]([S:3]([CH3:2])(=[O:5])=[O:4])=[CH:11][CH:10]=2)[N:13]=1)([CH3:22])([CH3:21])[CH3:14]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(N)n(-c2ccc(S(C)(=O)=O)cc2)n1
Reaction time: 0.08 h

Procedure:
4-(methylsulfonyl)phenylhydrazine hydrochloride (1.133 g, 5.09 mmol) and 4,4-dimethyl-3-oxopentanenitrile (0.697 g, 5.57 mmol) were weighed into a 100 mL RBF. 0.2 M HCl in EtOH (42 mL) was added and the suspension was heated to reflux for 27 h, during which time all solids gradually dissolved to give a yellow solution. The solution was diluted with 1 M NaOH(aq) (˜16 mL) to pH 12-13, EtOAc (70 mL) was added and the biphasic system was vigorously stirred for 5 min. The organic layer was isolated, dried (MgSO4), filtered and concentrated to give a yellow crystalline solid. Yield: 1.42 g (95%).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2=[NH:16])=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.Cl.[Br:29][CH:30]([Br:34])[C:31](O)=[O:32]>CN(C1C=CN=CC=1)C.ClCCl>[Br:29][CH:30]([Br:34])[C:31]([N:16]=[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][N:10]1[CH2:9][C:6]1[CH:7]=[N:8][C:3]([Cl:2])=[CH:4][CH:5]=1)=[O:32]
Reactant: N=c1ccccn1Cc1ccc(Cl)nc1
Reactant: O=C(O)C(Br)Br
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(N=c1ccccn1Cc1ccc(Cl)nc1)C(Br)Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
200 mg (0.78 mmol) of the 1-[(6-chloropyridin-3-yl)methyl]pyridin-2(1H)-imine hydrochloride obtained by the method described in another method of Synthetic Example P1, 238 mg (1.95 mmol) of DMAP and 224 mg (1.17 mmol) of EDC-HCl were dissolved in 10 ml of anhydrous dichloromethane, 101 μl (202 mg, 1.17 mmol) of dibromoacetic acid was added thereto, and the resulting mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was diluted with dichloromethane, washed once with water and twice with a 1% HCl aqueous solution, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the subject material. Amount obtained 50 mg (yield 15%)
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH:6]=[C:7]1[S:11]C(=S)N[C:8]1=[O:13])([OH:3])=O.[OH-:18].[Na+].Cl>O>[C:1]1([C:4]2[C:5](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[C:7]([C:8]([OH:18])=[O:13])[S:11]1)=[O:3]
Reactant: O=C1NC(=S)SC1=Cc1ccccc1C(=O)O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc2ccccc2c(=O)s1

Procedure:
A mixture of 5-(o-carboxybenzylidene) rhodanine (4.68g.) and sodium hydroxide (5.0g.) in water (40ml.) was heated under reflux for 30 minutes, cooled and poured into 5N hydrochloric acid (250ml.). Filtration and recrystallization from ethanol-water gave the product as a white solid, mp. 260.5°-261° (lit mp. 261°-3°), (Found: C, 58.10; H, 2.92; S, 15.41. C10H6SO3 requires C, 58.24; H, 2.93; S, 15.55).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([N+:20]([O-])=O)[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([NH:20][S:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=3)(=[O:34])=[O:33])[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc(Cl)c([N+](=O)[O-])c2)cc1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3cccc(Cl)c3)c2)cc1

Procedure:
4-[4-Chloro-3-(3-chloro-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=463.1 (M+H+), was prepared in analogy to example 1, steps A to D. Step A was performed using 4-chloro-3-nitro-benzoyl chloride and yielded 4-(4-chloro-3-nitro-benzoylamino)-benzoic acid ethyl ester. This was reduced to 4-(4-Chloro-3-nitro-benzoylamino)-benzoic acid ethyl ester in step B. This was coupled with 3-chloro-benzenesulfonyl chloride in step C, yielding 4-[4-chloro-3-(3-chloro-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]2=[C:11]([Br:20])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:22](O)([CH3:24])[CH3:23]>>[C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([O:19][CH:22]([CH3:24])[CH3:23])=[O:18])[C:12]2=[C:11]([Br:20])[CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)O
Reactant: O=C(c1ccccc1)c1cc(Br)c2n1CCC2C(=O)O
Agent: Cl
Product: CC(C)OC(=O)C1CCn2c(C(=O)c3ccccc3)cc(Br)c21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 1.34 g. of 5-benzoyl-7-bromo-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in 50 ml. of isopropanol, cooled in an ice bath is saturated with gaseous hydrogen chloride, maintaining the temperature of the reaction mixture below 50° C. The ice bath is then removed and the reaction mixture is stirred for 1.5 hours at room temperature, and evaporated to dryness under reduced pressure; 10 ml. of benzene is added to the residue and the solution is evaporated under vacuum once again, repeating this process a total of three times to completely remove the excess hydrogen chloride, thus obtaining of isopropyl 5-benzoyl-7-bromo-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate. The product is recrystallized from methanol-ethyl acetate.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)(=[O:4])=[O:3].[Cl:18][C:19]1[N:24]=[C:23](Cl)[CH:22]=[CH:21][N:20]=1.C1C=CC2N(O)N=NC=2C=1.C([O-])([O-])=O.[K+].[K+]>CC(O)C.CC(N(C)C)=O>[Cl:18][C:19]1[N:24]=[C:23]([N:13]2[C:14]3[C:10](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12]2)[CH:22]=[CH:21][N:20]=1
Reactant: CS(=O)(=O)CCCOc1cccc2[nH]ccc12
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Agent: [K+]
Solvent: CC(C)O
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)CCCOc1cccc2c1ccn2-c1ccnc(Cl)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
4-(3-Methanesulfonyl-propoxy)-1H-indole (188.1 g), 2,4-dichloropyrimidine (221.25 g), HOBT (20.08 g), K2CO3 (143.68 g) and DMA (1.6 L) were heated to 85° C. for 20 h. IPA (5 was then added and the mixture was stirred for 20 min, then cooled to 0° C. for 3 h and filtered. The collected solid was rinsed with IPA and water, and the solid was dried in vacuo at 55° C. for 4 days to yield 1-(2-chloro-pyrimidin-4-yl)-4-(3-methanesulfonyl-propoxy)-1H-indole (94%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:13]Br>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([Br:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1cccc(C(=O)O)c1N
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COc1cc(Br)cc(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
To a 0.24 M chloroform solution of 2-amino-3-methoxybenzoic acid (4, 11.87 g, 71.7 mmol) at 0° C. was added bromine (1.08 eq. 0.31 M) in chloroform dropwise. The mixture was warmed to room temperature and stirred under argon for 16 hours. The resulting precipitate was collected by filtration and washed thoroughly with chloroform. The crude material was dried in vacuo to give the title as an HBr salt in 99% yield. ES/MS m/z 248/250 (MH+).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.[NH2:26][CH2:27][CH2:28][CH2:29][OH:30]>C1COCC1>[NH:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C@H:9]([C:11]([NH:13][C@H:14]([C:16]([NH:26][CH2:27][CH2:28][CH2:29][OH:30])=[O:18])[CH3:15])=[O:12])[CH3:10]
Reactant: NCCCO
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)NCCCO
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 84 %

Procedure:
To a vigorously stirring solution of Boc-(Ala)2-OH (1.55 gm, 5.96 mmol) and NMM (0.98 mL, 8.9 mmol) in THF (15 mL) cooled to −15° C. was added under an atmosphere of N2 ethyl chloroformate (ECF) (587 μL, 6.14 mmol). After stirring for 2 min, a solution of H2N(CH2)3OH (546 uL, 7.2 mmol) in THF (5 mL) was added to the mixture followed by NMM (1.64 mL, 14.9 mmol) and the mixture was warmed to r.t. and stirred until silica gel TLC indicated complete consumption of the starting acid (eluting solvent-MeOH:DCM—1:10, Rf—0.5) (˜8 h). The solvent was evaporated, and the residue was diluted with EtOAc and washed with brine, water, saturated solutions of citric acid and NaHCO3, and the organic layer was dried using NaHSO4, and the solvent was removed under vacuum to yield a residue which was purified using silica gel flash column chromatography—Hexanes:EtOAc—1:4; to give the desired product in 84% yield (1.59 g) as a solid, m.p.—142° C.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[O:15])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH2:18]([Sn](CC)(CC)CC)[CH3:19]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:18]([C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[O:15])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1)[CH3:19]
Reactant: CC[Sn](CC)(CC)CC
Reactant: O=C1c2ccccc2CCc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCc1ccc2c(c1)CCc1ccccc1C2=O
Temperature: 130 °C

Procedure:
A mixture of the product from step (iv) (1.52 g), tetraethyl tin (10.4 ml) and tetrakis(triphenylphosphine)palladium(0) (100 mg) in dimethylformamide (20 ml) was heated at 130° C. for 48 hours. The mixture was evaporated and the residue purified by chromatography eluting with isohexane then 50% toluene in isohexane then toluene. Yield 0.88 g.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[N:10][OH:11])[NH2:9])=[CH:4][CH:3]=1.[CH3:12][C:13]([CH3:18])([CH3:17])[C:14](Cl)=O>C1(C)C=CC=CC=1.CC(O)=O>[C:13]([C:18]1[O:11][N:10]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=2)[N:9]=1)([CH3:17])([CH3:14])[CH3:12]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NC(=NO)c1ccc(Cl)nc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)c1nc(-c2ccc(Cl)nc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
A mixture of 1.5 g (8.74 mmol) of 6-chloro-N′-hydroxypyridine-3-carboximidamide and 1.13 mL (9.18 mmol) of trimethylacetyl chloride in 15 mL of toluene is stirred for 1 hour at room temperature and then refluxed for 4 hours. The medium is filtered. The insoluble material formed is dissolved in 15 mL of AcOH and then heated at 60° C. for 5 hours. After cooling to room temperature, the medium is concentrated under reduced pressure and then purified by chromatography on silica gel, eluting with a cyclohexane/EtOAc mixture (9/1). 0.39 g of 5-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-2-chloropyridine is obtained in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]([C:18]([OH:20])=O)[CH:7]=[CH:6][C:5]2=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Br:1][C:2]1[CH:14]=[C:13]([C:15]([NH2:16])=[O:17])[C:12]2[NH:11][C:10]3[C:5]([C:4]=2[CH:3]=1)=[CH:6][CH:7]=[C:8]([C:18]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:20])[CH:9]=3
Reactant: C1COCCN1
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(C(=O)O)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Br)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
6-Bromo-8-carbamoyl-9H-carbazole-2-carboxylic acid (758 mg, 1.707 mmol, Example 58D) was mixed with morpholine (892 mg, 10.24 mmol), HATU (1947 mg, 5.12 mmol) and DMAP (625 mg, 5.12 mmol) in DMF (8 mL) and stirred for 2 hrs at r.t. The mixture was added slowly to 200 ml H2O while stirring. Resulting mixture was stirred for 10 mins. The resulting yellow precipitate was filtered and air-dried overnight with air-suction to give 546 mg of 3-bromo-7-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide which was used as such in the next step.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].Cl.[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=1)([O-:17])=[O:16].CCN(C(C)C)C(C)C.[NH4+].[Cl-]>>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:29]2[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][C:21]3[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:23][CH:22]=3)[CH2:27][CH2:28]2)=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cc1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCN(CCc2ccc([N+](=O)[O-])cc2)CC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Bromo-1-(4-nitrophenyl)ethanone (269 mg, 1.10 mmol) was added to a stirred solution of 1-[2-(4-nitrophenyl)ethyl]piperazine hydrochloride (200 mg, 0.736 mmol) followed by Hünig's base, then was stirred at RT for 1 h. The reaction mixture was poured into saturated NH4Cl solution and extracted twice with ethyl acetate. The combined organic layers were washed with water, then brine. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by preparative TLC using 5% MeOH/DCM solvent system to yield 1-(4-nitrophenyl)-2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethanone.
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)=[O:9])([CH3:6])[C:3]([O-:5])=O.C([O-])([O-])=O.[K+].[K+].[Cl:28][C:29]1[CH:34]=[C:33]([CH2:35]Cl)[CH:32]=[CH:31][N:30]=1>CN(C=O)C>[Cl:28][C:29]1[CH:34]=[C:33]([CH2:35][N:7]2[C:2]([CH3:1])([CH3:6])[C:3](=[O:5])[N:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[C:8]2=[O:9])[CH:32]=[CH:31][N:30]=1
Reactant: ClCc1ccnc(Cl)c1
Reactant: CC(C)(NC(=O)Nc1ccc(SC(F)(F)F)cc1)C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(c2ccc(SC(F)(F)F)cc2)C(=O)N1Cc1ccnc(Cl)c1

Procedure:
5,5-Dimethyl-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione 3 (1 g, 3.29 mmol) is dissolved in 10 ml of DMF, 1.36 g of K2CO3 (3 eq, 9.87 mmol) and 909 mg of 2-chloro-4-chloromethylpyridine (3.95 mmol, 1.2 eq) are added, and the mixture is refluxed for 20 hours. The solvent is removed under vacuum and the residue is dissolved in CH2Cl2 and treated three times with active charcoal. After removing the solvent, the product 1-(2-chloropyrid-4-ylmethyl)-5,5-dimethyl-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione is obtained (3.2 g; 56%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:12]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[CH:14]=[C:13]([NH:23][C:24]3[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=3)[N:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(S)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1cccc(Sc2nc(Nc3cc(C)[nH]n3)cc3cc(OC)ccc23)c1

Procedure:
Similar procedure as described in example 305 was used, starting from 3-methoxy-benzenethiol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(3-methoxy-phenylsulfanyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 393 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C@@H:11]([OH:20])[CH2:10][CH2:9]4)[C@H:6]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH2:36][CH2:37][CH2:38][C:39]([F:45])([F:44])[C:40]([F:43])([F:42])[F:41])[C:31]([O:33]CC)=[O:32])[CH2:5][C:4]=2[CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C@@H:11]([OH:20])[CH2:10][CH2:9]4)[C@H:6]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH2:36][CH2:37][CH2:38][C:39]([F:44])([F:45])[C:40]([F:41])([F:42])[F:43])[C:31]([OH:33])=[O:32])[CH2:5][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C(CCCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12)CCCC(F)(F)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O)[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 60 °C
Yield: 96.5 %

Procedure:
Ethyl 11-[3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoate (660 mg, 1.03 mmol) was dissolved in a mixed solvent of ethanol (10 ml) and water (2.0 ml). To this solution, NaOH (820 mg, 20.5 mmol) was added, and the resulting mixture was heated for 4 hours at 60° C. After cooling, 2N aqueous hydrochloric acid was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then filtered. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/1) to give 11-[3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoic acid (613 mg, Yield 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([S:23][CH3:24])[CH:20]=[CH:19][C:3]=1[C:4]([C:6]1[C:7]([C:14]([O:16]CC)=[O:15])=[N:8][O:9][C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:22]=[C:21]([S:23][CH3:24])[CH:20]=[CH:19][C:3]=1[C:4]([C:6]1[C:7]([C:14]([OH:16])=[O:15])=[N:8][O:9][C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5]
Reactant: CCOC(=O)c1noc(C2CC2)c1C(=O)c1ccc(SC)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1ccc(C(=O)c2c(C(=O)O)noc2C2CC2)c(Cl)c1
Reaction time: 2 h
Yield: 94.8 %

Procedure:
Ethyl 4-(2-chloro-4-methylsulphenylbenzoyl]-5-cyclopropylisoxazole-3-carboxylate (2.4 g) was added to a stirred solution of sodium hydroxide (2.2 g) in ethanol and water while maintaining the temperature below 0° C. The mixture was stirred at below 0° C. for 2 hours. The mixture was carefully acidified to pH1 at 0° C. and the solid was filtered off and dried to give 4-(2-chloro-4-methylsulphenylbenzoyl)-5-cyclopropylisoxazole-3-carboxylic acid (2.1 g) as an off-white solid, m.p. 106°-108° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[CH:6]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3.[CH3:23][C:24]([CH3:39])([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][C:36](O)=[O:37])[CH2:31][CH2:30]1)=[O:28])[CH3:25]>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[CH:6]([N:15]3[CH2:16][CH2:17][N:18]([C:36](=[O:37])[CH2:35][CH:32]4[CH2:33][CH2:34][N:29]([C:27]([O:26][C:24]([CH3:25])([CH3:23])[CH3:39])=[O:28])[CH2:30][CH2:31]4)[CH2:19][CH2:20]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Reactant: Clc1ccc2c(c1)SCc1cccnc1C2N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4SCc4cccnc43)CC2)CC1
Yield: 83.5 %

Procedure:
The title compound (563 mg) was prepared similarly from 1-(8-chloro-5,11-dihydro-[1]benzothiepino[4,3-b]pyridin-11-yl)-piperazine (400 mg, 1.21 mmol) and 1-(1,1-dimethylethoxycarbonyl)-4-piperidine-acetic acid (589 mg, 2.42 mmol); MS (CI, M+H)=557; HRMS: calc.: 557.2353; found: 557.2351.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([C:15]2[C:16]([C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=3)[C:24]([O:26]C)=[O:25])=[N:17][CH:18]=[CH:19][N:20]=2)[CH2:12]1.O.[OH-].[Li+:33].O>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:12][CH:13]([C:15]2[C:16]([C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=3)[C:24]([O-:26])=[O:25])=[N:17][CH:18]=[CH:19][N:20]=2)[CH2:14]1.[Li+:33]
Reactant: COC(=O)c1cccc(-c2nccnc2C2CN(c3ccc4ccccc4n3)C2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])c1cccc(-c2nccnc2C2CN(c3ccc4ccccc4n3)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.9 %

Procedure:
A mixture of methyl 3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzoate (0.079 g, 0.198 mmol, SCHEME 5), lithium hydroxide hydrate (0.017 g, 0.397 mmol), water (0.4 mL) and THF (1.2 mL) was stirred at RT overnight. The mixture was concentrated in vacuo. The product was obtained as an off-white solid (83 mg, 108%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](OCCCCCCC)=[C:6]([CH:32]=1)[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24](OC(F)(F)F)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[F:41][C:42]([F:54])([F:53])[O:43][C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1>>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@H:10]([NH:9][C:7]([C:6]2[CH:32]=[CH:2][C:3]([C:47]3[CH:46]=[CH:45][C:44]([O:43][C:42]([F:41])([F:53])[F:54])=[CH:49][CH:48]=3)=[CH:4][CH:5]=2)=[O:8])[C:11]([OH:13])=[O:12])=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCCCCCCOc1ccc(Cl)cc1C(=O)N[C@@H](Cc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1)C(=O)O
Product: O=C(N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Yield: 86.9 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(5-bromo-benzoyl-amino)-propionic acid (100 mg, 0.23 mmol) was reacted with 4-trifluoromethoxy phenyl boronic acid (145 mg, 0.69 mmol) by following general procedure D yielding the title compound (101 mg) as a white solid:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][NH:6][N:5]=1.Br[CH2:15][C:16](=[O:20])[CH2:17][CH2:18][CH3:19]>CN(C=O)C>[NH2:3][C:4]1[N:5]([CH2:15][C:16](=[O:20])[CH2:17][CH2:18][CH3:19])[N:6]=[CH:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCCC(=O)CBr
Reactant: CCOC(=O)c1c[nH]nc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(=O)Cn1ncc(C(=O)OCC)c1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.4 %

Procedure:
To a mixture of sodium hydride (60% dispersion in mineral oil, 0.8 g) in DMF (50 ml) was added ethyl 3-amino-pyrazol-4-carboxylate (2.0 g) and the reaction mixture was stirred at room temperature for 15 minutes. After addition of 1-bromo-2-pentanone (4.0 g), the mixture was stirred at room temperature for 13 hours. The reaction mixture was concentrated to dryness, and the residue was dissolved in ethyl acetate-water. The organic layer was washed with water, dried and concentrated to dryness. The resulting yellow syrup was purified by column chromatography on silica gel to give pale yellow prisms (1.4 g, 45%).