Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[F:1][C:2]1[CH:11]=[C:10]([S:14]([Cl:13])(=[O:16])=[O:15])[C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=S(=O)(O)Cl
Reactant: Oc1ccc(F)c2cccnc12
Product: O=S(=O)(Cl)c1cc(F)c2cccnc2c1O
Temperature: 0 °C

Procedure:
A solution of 5-fluoro-8-hydroxyquinoline (0.50 g) in 4.0 mL of chlorosulfonic acid is stirred for 3 h at 90° C. and then 13 h at 105° C. The mixture is then cooled to 0° C. and poured onto 50 mL of finely divided −15° C. ice. The bright orange-red precipitate is collected by filtration, washed with four 10-mL portions of 0° C. distilled water and three 2 mL portions of diethyl ether, and dried in a stream of air to give 0.208 g of the title compound as a red-orange powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][CH2:18][C:19]([O:21]C)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCOc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCOc1cccnc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 0.815 g of methyl 8-(p-chlorophenylsulfonamido)-4-[2-(3-pyridyloxy)ethyl]-octanoate in 13 ml dioxane is added 3.5 ml of 1N aqueous sodium hydroxide. The solution is stirred at room temperature for 60 h and then the solvent is evaporated. The residue is dissolved in water, the solution is adjusted to pH=6.5 and extracted with methylene chloride (3×20 ml). The combined organic extracts are dried, filtered and evaporated to yield an oil which is crystallized from ether to obtain 8-(p-chlorophenylsulfonamido)-4-[2-(3-pyridyloxy)ethyl]-octanoic acid, m.p. 77°-79°. Two further crystallizations from acetonitrile raise m.p. to 89°-91°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([Li])CCC.C([O:22][B:23](OC(C)C)[O:24]C(C)C)(C)C.Cl>CCOCC.CCCCCC>[C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]([B:23]([OH:24])[OH:22])=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Brc1ccccc1-c1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OB(O)c1ccccc1-c1ccccc1
Temperature: -67 °C
Yield: 64.6 %

Procedure:
Under an atmosphere of argon, 2-bromobiphenyl (20 g, 86 mmole) was dissolved into anhydrous ether (200 ml) and the resultant solution was cooled at −35° C. in a dry ice/methanol bath. To the cooled solution, a hexane solution of n-butyllithium (1.50 mole/liter, 63 ml, 95 mmole) was added dropwise and the resultant mixture was stirred at −20° C. for 1 hour. After the reaction mixture was cooled at −67° C., a solution (50 ml) of triisopropoxyborane (50 ml, 0.22 mole, 2.5 eq) in anhydrous ether was added and the resultant mixture was stirred at −65° C. for 1 hour and at the room temperature for 2 hours and left standing for one night. To the obtained reaction mixture, a 10% hydrochloric acid (200 ml) was added. After the resultant mixture was stirred at the room temperature for 1 hour, the formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (50 ml) and dried with anhydrous magnesium sulfate. The solid obtained after removing the solvent by distillation was washed with hexane and a white solid (11 g, 62%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][CH:7]=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:20]1([CH2:23]Br)[CH2:22][CH2:21]1>C(#N)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH2:23][CH:20]3[CH2:22][CH2:21]3)[CH:7]=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1
Reactant: BrCC1CC1
Reactant: O=S1(=O)N=CNc2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=S1(=O)N=CN(CC2CC2)c2ccc(Cl)cc21

Procedure:
To a solution of 7-chloro-4H-1,2,4-benzothiadiazine 1,1-dioxide (1 g) in acetonitrile (40 mL) there is added potassium carbonate (2.5 g) and cyclopropylmethyl bromide (0.7 mL) and the mixture is heated at reflux for 24 hours. The reaction mixture is evaporated under reduced pressure and the residue is taken up in water (40 mL). The insoluble material is collected by filtration, washed with water and dried and is recrystallised from methanol.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7](=[N:21][O:22][S:23]([C:26]2[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:8][CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])[N:5]=[C:4]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:3]=1.[CH3:37][C:38](OC(C)=O)=[O:39]>>[C:38]([NH:1][C:2]1[N:6]([C:7](=[N:21][O:22][S:23]([C:26]2[CH:27]=[CH:28][C:29]([CH3:30])=[CH:31][CH:32]=2)(=[O:25])=[O:24])[CH2:8][CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])[N:5]=[C:4]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:3]=1)(=[O:39])[CH3:37]
Reactant: Cc1ccc(S(=O)(=O)ON=C(CCN2C(=O)c3ccccc3C2=O)n2nc(C(C)(C)C)cc2N)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(C(C)(C)C)nn1C(CCN1C(=O)c2ccccc2C1=O)=NOS(=O)(=O)c1ccc(C)cc1
Yield: 59 %

Procedure:
4.39 g (8.6 mmol) of 5-amino-3-tert.butyl-1-(3-phthalimido-O-tosyl-propanehydroximoyl)pyrazole are reacted with acetanhydride in the same way as in example 1, synthesis step 3. The crude product which is obtained is recrystallised from methanol. 2.8 g (59%) of 5-acetamido-3-tert.butyl-1-(3-phthalimido-O-tosyl-propanehydroximoyl)-pyrazole with a m. pt. of 195°-201° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][N:14]([CH2:57][CH:58]=O)[C:15](=[O:56])[C:16]1[CH:55]=[CH:54][CH:53]=[C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:24][C:23]=2[C:34]2[CH:39]=[C:38]([C:40](=[O:52])[NH:41][C@@H:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:45][CH2:44][CH2:43]3)[CH:37]=[CH:36][N:35]=2)=[O:20])[CH:17]=1.CC(O)=O.C([BH3-])#N.[Na+]>C(O)C>[CH3:13][N:14]([CH2:57][CH2:58][N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:12])[C:15](=[O:56])[C:16]1[CH:55]=[CH:54][CH:53]=[C:18]([C:19](=[O:20])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:24][C:23]=2[C:34]2[CH:39]=[C:38]([C:40](=[O:52])[NH:41][C@@H:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:45][CH2:44][CH2:43]3)[CH:37]=[CH:36][N:35]=2)[CH:17]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: CN(CC=O)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CN(CCN1CCC[C@H]1C(=O)OC(C)(C)C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 47.8 %

Procedure:
To a solution of L-proline-t-butyl ester (0.096 mmol, 16 mg) in ethanol (0.2 mL) were added (S)—N1-methyl-N1-(2-oxoethyl)-N3-(4-(piperidin-1-yl)-2-(4-((1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)isophthalamide (0.032 mmol, 20 mg) and HOAc (0.064 mmol, 4 mg). The mixture was stirred at room temperature for 25 minutes, and then sodium cyanoborohydride (0.16 mmol, 10 mg) was added. The mixture was stirred for an additional 20 minutes and quenched with water. The yellow solid was collected via filtration and was purified by prep HPLC to give a yellow solid (12 mg, 37%). MS (ES, m/z): 786.1 [M+H]+.
Reaction SMILES: [CH:1]([CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=2)=[O:26])([CH2:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[O:15])[C:5]1=[O:36])=O.Cl.[CH3:38][NH:39][CH3:40].C([BH3-])#N.[Na+]>CO>[CH3:35][O:34][C:30]1[CH:29]=[C:28]([NH:27][C:25](=[O:26])[NH:24][C:6]2([CH2:13][C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[O:15])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]([CH2:3][CH2:1][N:39]([CH3:40])[CH3:38])[C:5]2=[O:36])[CH:33]=[CH:32][CH:31]=1
Reactant: COc1cccc(NC(=O)NC2(CC(=O)Nc3ccc(C)cc3)C(=O)N(CC=O)c3ccccc32)c1
Reactant: CNC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cccc(NC(=O)NC2(CC(=O)Nc3ccc(C)cc3)C(=O)N(CCN(C)C)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.2 %

Procedure:
To a solution of 0.386 g of (RS)-1-(formylmethyl)-3-(N'-(3-methoxyphenyl)ureido)-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-one in 50 ml of methanol was added 0.8 g of dimethylamine hydrochloride at room temperature, and 1.0 g of sodium cyanoborohydride was then added thereto. The mixture was stirred at room temperature for 1 day, followed by concentration. The concentrate was diluted with dichloromethane and washed with an aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was washed with dichloromethane to afford 0.107 g (26%) of the title compound.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14](Cl)[C:10]=1[C:11]([OH:13])=[O:12])(OC(C)(C)C)=[O:2].C(Cl)(=O)C([Cl:22])=O>C1(C)C=CC=CC=1>[Cl:22][C:15]1[CH:14]=[C:10]2[C:11]([O:13][C:1](=[O:2])[NH:8][C:9]2=[CH:17][CH:16]=1)=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cl)c1C(=O)O
Solvent: Cc1ccccc1
Product: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reaction time: 0.17 h

Procedure:
After suspending 2-(Boc)amino-6-chlorobenzoic acid (1.51 g, 5.56 mmol) in toluene (20 mL), the mixture was heated to reflux. Oxalyl chloride (0.572 mL, 6.67 mmol) was added dropwise thereto, and the mixture was vigorously stirred for 10 minutes. After cooling the reaction mixture on ice, the precipitated crystals were filtered out, washed with n-hexane and dried in a desiccator to obtain 5-chloroisatoic anhydride.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl[C:6]1[C:14]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[N+:19]([O-:21])=[O:20]>O>[CH:1]([NH:4][C:6]1[C:14]([S:15](=[O:17])(=[O:18])[NH2:16])=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[N+:19]([O-:21])=[O:20])([CH3:3])[CH3:2]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: CC(C)N
Solvent: O
Product: CC(C)Nc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Isopropylamine (120 ml) and water 8 ml) were added to 4-chloro-3-nitro-5-sulphamyl-benzoic acid (22.4 g), while cooling. Then the reaction mixture was stirred for 5 days at room temperature. After evaporation in vacuo, the residue was triturated with 4N hydrochloric acid, after which the resulting 4-isopropylamino-3-nitro-5-sulphamyl-benzoic acid was collected by suction. After recrystallization from aqueous ethanol, the acid was obtained with a melting point of 206°C (decomp.).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].F[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19]>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19]
Reactant: Oc1ccccc1Cl
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Oc1ccccc1Cl
Temperature: 65 °C

Procedure:
Sodium hydride (1.00 g) was added in portions to a solution of 2-chlorophenol (5.00 g) in N,N-dimethylformamide (100 mL) under nitrogen. To the resulting solution was added 2-fluoro-1-nitrobenzene (5.00 g). The mixture was heated at 65° C. overnight, and then was evaporated under vacuum. The residue was partitioned between chloroform and 1 N NaOH, and the layers were separated. The aqueous layer was extracted once more with chloroform, and the combined chloroform layers were washed with water and brine, dried over magnesium sulfate, and evaporated under vacuum to a yellow oil. The oil was crystallized from ethyl ether/hexane at -78° C. to yield the title compound as a light yellow solid. Mp: 48°-49° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:32]C)=[C:6]([C:8]([CH3:31])([CH3:30])[CH2:9][C:10]([C:26]([F:29])([F:28])[F:27])([OH:25])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([CH2:23][OH:24])=[N:18]3)[CH:7]=1.B(Br)(Br)Br.CO>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:32])=[C:6]([C:8]([CH3:30])([CH3:31])[CH2:9][C:10]([C:26]([F:27])([F:28])[F:29])([OH:25])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([CH2:23][OH:24])=[N:18]3)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2nc(CO)ccc12)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC(C)(CC(O)(CNc1cccc2nc(CO)ccc12)C(F)(F)F)c1cc(F)ccc1O
Reaction time: 20 h

Procedure:
290 mg (0.62 mmol) of 4-(5-fluoro-2-methoxyphenyl)-1-(2-(hydroxymethyl)quinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol in 7.0 ml of dichloromethane is mixed at room temperature with 12.5 ml (12.5 mmol) of a 1 M boron tribromide solution. After 20 hours at room temperature, the reaction is brought to a halt by adding methanol. The solvent is removed in a vacuum, the residue is taken up in saturated sodium bicarbonate solution and ethyl acetate, extracted with ethyl acetate, and the combined organic phases are dried on sodium sulfate. After the solvent is removed and after purification on silica gel with hexane-ethyl acetate (0–70%) as well as with ethyl acetate-methanol (0–10%), 160 mg (51% of theory) of the product is obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:9](=[NH:14])[O:10][CH2:11][CH2:12][CH3:13])[CH:6]=[N:7][CH:8]=1)[CH3:2].[N:15]#[C:16]N>C(#N)C>[C:16]([N:14]=[C:9]([C:5]1[CH:6]=[N:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=1)[O:10][CH2:11][CH2:12][CH3:13])#[N:15]
Reactant: CCCOC(=N)c1cncc(CC)c1
Reactant: N#CN
Solvent: CC#N
Product: CCCOC(=NC#N)c1cncc(CC)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 44 %

Procedure:
The propyl 5-ethyl-3-pyridinecarboximidate were then dissolved in acetonitrile (5 ml), and an aqueous solution (30 ml) of cyanamide (1.13 g, 26.9 mmol), Na2HPO4 (1.29 g, 9.1 mmol) and NaH2PO4 ·2H2O (8.45 g, 54.2 mmol) was added to the solution. The mixture was stirred at room temperature for 19 hours. After reaction, the mixture was extracted with chloroform (50 ml×2). The chloroform layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to silica gel column chromatography (Wako Gel C-200, 50 g; eluted with hexane:ethyl acetate=5:1) to give 1.51 g (7.0 mmol) of propyl N-cyano-5-ethyl-3-pyridinecarboximidate (yield, 44%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[CH3:18][C:19]1([C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=2[OH:32])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.Br[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][C:41]([O:43][CH3:44])=[O:42]>>[CH3:18][C:19]1([C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=2[O:32][CH:40]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:34]=2)[C:41]([O:43][CH3:44])=[O:42])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: COC(=O)Cc1ccccc1Br
Reactant: Cc1ccc(O)c(C2(C)CCCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: COC(=O)C(Oc1ccc(C)cc1C1(C)CCCCC1)c1ccccc1
Yield: 91.1 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 30, 0.496 g (2.43 mmol) of 2-(1-methylcyclohex-1-yl)-4-methylphenol was alkylated with 0.834 g (3.64 mmol) of methyl 2-bromophenylacetate to afford 0.780 g (91%) of the title compound.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([CH2:27][C:28]#[N:29])([N:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([Cl:26])[N:21]=3)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.F[Si-2](F)(F)(F)(F)F.[H+].[H+]>C(#N)C>[Cl:26][C:22]1[N:21]=[C:20]([C:18]2[CH:17]=[N:16][N:15]([C:12]3([CH2:27][C:28]#[N:29])[CH2:13][CH2:14][CH:9]([OH:8])[CH2:10][CH2:11]3)[CH:19]=2)[CH:25]=[CH:24][N:23]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(CC#N)(n2cc(-c3ccnc(Cl)n3)cn2)CC1
Agent: [H+]
Solvent: CC#N
Product: N#CCC1(n2cc(-c3ccnc(Cl)n3)cn2)CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-(tert-butyl(dimethyl)silyl)oxy-1-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)cyclohexylacetonitrile (1.8 g, 0.0042 mol) in acetonitrile (69.74 mL) was added fluorosilicic acid (2.0 M in water, 4.17 mL). The mixture was stirred at room temperature overnight. After evaporation of most of the solvent, the mixture was neutralized with aqueous sodium bicarbonate, extracted with ether. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated to dryness. The residue (a 1:3.5 mixture of cis- and trans-isomers) was used directly in next step (1.20 g, 90.6%). LCMS (M+H) 318.3.
Reaction SMILES: FC(F)(F)C([O-])=O.C([NH:10][C@@H:11]1[C:32](=[O:33])[N:13]2[C:14]([C:29]([OH:31])=[O:30])=[C:15](/[CH:18]=[CH:19]/[CH2:20][N+:21]([C@@H:24]([C:26](=[O:28])[NH2:27])[CH3:25])([CH3:23])[CH3:22])[CH2:16][S:17][C@H:12]12)=O.C(#N)C.[ClH:37].CO>>[ClH:37].[NH2:10][C@@H:11]1[C:32](=[O:33])[N:13]2[C:14]([C:29]([O-:31])=[O:30])=[C:15](/[CH:18]=[CH:19]/[CH2:20][N+:21]([C@@H:24]([C:26](=[O:28])[NH2:27])[CH3:25])([CH3:23])[CH3:22])[CH2:16][S:17][C@H:12]12
Reactant: C[C@H](C(N)=O)[N+](C)(C)C/C=C/C1=C(C(=O)O)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: CC#N
Solvent: CO
Product: C[C@H](C(N)=O)[N+](C)(C)C/C=C/C1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 1 h

Procedure:
The compound (0.5 g) of Example 23 was dissolved at room temperature in a 4% (w/v) hydrochloric acid-methanol solution (5 ml), followed by stirring for 1 hour. Acetonitrile (50 ml) was added, and a precipitate thus formed was collected by filtration. The precipitate was washed with acetonitrile and acetone to obtain the target product (0.31 g). Infrared spectrum (cm-1, Nujol): 1780, 1690.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].O([CH2:33][C:34]([F:37])([F:36])[F:35])S(C(F)(F)F)(=O)=O>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[CH2:33][C:34]([F:37])([F:36])[F:35])=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2CC(F)(F)F)CC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was alkylated with 2,2,2-trifluoroethyl triflate in analogy to experiment L37 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(2,2,2-trifluoro-ethyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 436.2 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([C:13]2([CH2:19][CH:20]=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:22][CH2:23][O:24][C:25]([CH3:27])=[O:26]>C1COCC1>[C:7]1([C:13]2([CH2:19]/[CH:20]=[CH:27]/[C:25]([O:24][CH2:23][CH3:22])=[O:26])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(C)=O
Reactant: O=CCC1(c2ccccc2)CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/CC1(c2ccccc2)CCCCC1
Reaction time: 0.5 h

Procedure:
To a solution of triethyl phosphonoacetate (0.601 mL, 3.00 mmol) in THF (10 mL) at 0° C. was added 1 M potassium tert-butoxide (3.00 mL, 3.00 mmol) in THF dropwise and the mixture was stirred for 30 mins at the same temperature. Then a solution of 2-(1-phenylcyclohexyl)acetaldehyde (405 mg, 2 0 mmol) in 4 ml of THF was added dropwise and the mixture was stirred for 0.5 hrs at 0° C. and for 1.5 hrs at room temperature. The mixture was added to EtOAc and washed with water (2×) and saturated NH4Cl. The resulting material was dried over Na2SO4 and evaporated to give an oily residue. It was purified by Combiflash (80 g silica gel) eluting with 5:95 EtOAc-hexane to give (E)-ethyl 4-(1-phenylcyclohexyl)but-2-enoate (213.7 mg). 1H NMR (400 MHz, CDCl3) δ ppm 7.27-7.37 (4 H, m), 7.15-7.23 (1 H, m), 6.60 (1 H, ddd, J=15.49, 7.91, 7.80 Hz), 5.66 (1 H, dt, J=15.60, 1.32 Hz), 4.12 (2 H, q, J=7.18 Hz), 2.39 (2 H, dd, J=7.80, 1.21 Hz), 2.11 (2 H, dd, J=13.07, 5.60 Hz), 1.33-1.66 (8 H, m), 1.24 (3 H, t, J=7.18 Hz).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:18]([CH3:29])[C:17]=3[CH3:30])=[C:12]([C:31]([CH3:33])=[CH2:32])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:18]([CH3:29])[C:17]=3[CH3:30])=[C:12]([CH:31]([CH3:33])[CH3:32])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: [H][H]
Reactant: C=C(C)c1snc(-c2ccc(CC)cc2)c1COc1ccc(CCC(=O)OCC)c(C)c1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(OCc2c(-c3ccc(CC)cc3)nsc2C(C)C)c(C)c1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of ethyl 3-(4-[[3-(4-ethylphenyl)-5-(prop-1-en-2-yl)-1,2-thiazol-4-yl]methoxy]-2,3-dimethylphenyl)propanoate (76.3 mg, 0.16 mmol, 1.00 equiv) in ethanol (5 mL) and palladium on carbon (10%, 76 mg). The mixture was then subject to an atmosphere of hydrogen and stirred for 12 h at 25° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 73.1 mg (95%) of ethyl 3-(4-[[3-(4-ethylphenyl)-5-(propan-2-yl)-1,2-thiazol-4-yl]methoxy]-2,3-dimethylphenyl)propanoate as white oil.
Reaction SMILES: Cl[C:2]1([CH:8]=[N:9][OH:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH2:3]1.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=[CH2:24])[CH:20]([CH3:25])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)Cl.C(N(CC)CC)C>O>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]2([O:10][N:9]=[C:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:24]2)[CH:20]([CH3:25])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=C1CCN(Cc2ccccc2)CC1C
Reactant: ON=CC1(Cl)C=CC=CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC1CN(Cc2ccccc2)CCC12CC(c1ccccc1)=NO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Compound C (4.49 g, 28.9 mmol, dissolved in abs. DCM (25 ml)) was added dropwise to a solution of compound S (2.5 g, 14.45 mmol) in abs. DCM (25 ml) at 0° C. within 10 min. A solution of triethylamine (16 ml, 11.7 g, 115.6 mmol) in abs. DCM (25 ml) was added to this mixture within 10 min at 0° C. As the reaction was highly exothermic, cooling was carried out in a mixture of ice/sodium chloride. The reaction mixture was stirred for 16 h at RT. For working up the mixture, DCM (50 ml) and water (70 ml) were added. The phases were separated. The aqueous solution was extracted with DCM (2×20 ml). The combined organic phases were washed successively with water (50 ml) and sat. NaCl solution (50 ml) and then dried and concentrated (4.9 g, yellow oil). The residue was purified by column chromatography [silica gel 60 (500 g); EtOAc/cyclohexane 1:2 (3 l)]. The desired product was obtained as a diastereomer mixture in a yield of (2.28 g, 50%) having a melting point of 101-108° C.