Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[NH:10][CH:11]1[CH2:13][CH2:12]1.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH3:26])[C:23](O)=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:14]([O:18][C:19](=[O:20])[NH:21][C@H:22]([C:23](=[O:24])[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[C:3]=1[NH:10][CH:11]1[CH2:13][CH2:12]1)[CH3:26])([CH3:15])([CH3:16])[CH3:17]
Reactant: Nc1ccc(F)c(Br)c1NC1CC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)c(Br)c1NC1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
A mixture of 3-bromo-N2-cyclopropyl-4-fluorobenzene-1,2-diamine (759 mg, 3.10 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (644 mg, 3.41 mmol), HOAt (464 mg, 3.41 mmol) and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (654 mg, 3.41 mmol) in DCM (20 mL) was stirred at 0° C. for 1 h. The reaction mixture was then partitioned between DCM and a saturated solution of NaHCO3. The organic fraction was dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) to afford the title compound (1.05 g, 81%) as a pale beige solid. LCMS (Method C): RT 3.66 min [M+H]+ 416.05
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[F:28][C:29]([F:42])([F:41])[C:30]1[CH:31]=[C:32]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[NH2:33]>CCCCCCC.C(OCC)(=O)C>[F:28][C:29]([F:41])([F:42])[C:30]1[CH:31]=[C:32]([NH:33][C:11](=[O:12])[C:6]2[C:5]([O:4][C:3]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=3[Cl:1])=[CH:10][CH:9]=[N:8][CH:7]=2)[CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and 3,5-bis(trifluoromethyl)aniline (commercially available; CAS RN 328-74-5) and using a gradient of n-heptane:ethyl acetate (100:0 to 40:60) for the chromatographic purification. Light yellow foam (44%). MS (ESI): m/z=495.010 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[N:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][O:18][NH2:19])=[CH:15][CH:14]=1.Cl>CN(C)C=O>[CH3:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][O:18][NH:19][C:8](=[O:10])[CH2:7][N:6]2[C:2]([SH:1])=[N:3][N:4]=[N:5]2)=[CH:15][CH:14]=1
Reactant: O=C(O)Cn1nnnc1S
Reactant: COc1ccc(CON)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(CONC(=O)Cn2nnnc2S)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To an ice cold solution of 5-mercapto-1H-tetrazole-1-acetic acid (4.4 g) in N,N-dimethylformamide (40 ml) is added N,N'-carbonyldiimidazole (4.86 g), and the mixture is stirred under nitrogen for 1 hour. To this solution is added a solution of p-methoxybenzyloxyamine (7.9 g) in N,N-dimethylformamide (10 ml), and the mixture is stirred under ice cooling for 45 minutes. The reaction mixture is poured onto ice water containing hydrochloric acid and extracted with ethyl acetate. The extract solution is washed with water, dried and concentrated under reduced pressure. The residue is crystallized from a mixture of acetone and ether to give the title compound (7.3 g). mp. 167°-168° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Cl[C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1
Reactant: Clc1cnccn1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: Cc1onc(-c2ccccc2)c1C#Cc1cnccn1
Yield: 60 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-chloropyrazine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 78 mg, 60%) which was obtained as a light yellow solid. MS: m/e=262.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH2:30]([O:32][C:33](=[O:45])[C:34]([F:44])([F:43])[C:35]1[CH:40]=[CH:39][C:38]([CH:41]=O)=[CH:37][CH:36]=1)[CH3:31]>>[CH2:30]([O:32][C:33](=[O:45])[C:34]([C:35]1[CH:36]=[CH:37][C:38]([CH2:41][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[C:17]4[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[C:22](=[O:23])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:3]=2)=[CH:39][CH:40]=1)([F:43])[F:44])[CH3:31]
Reactant: CCOC(=O)C(F)(F)c1ccc(C=O)cc1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: CCOC(=O)C(F)(F)c1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and difluoro-(4-formyl-phenyl)-acetic acid ethyl ester according to the procedure of step 1, Example 66. MS (ES) m/z 605.3.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:14]1([CH3:23])[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>CN(C)C=O>[C:14]1([CH3:23])[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:22])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccc(C)cc2)n1

Procedure:
Following a procedure similar to that described in Preparation 1. the desired compound was prepared from 12 g of ethyl 2-aminothiazol-4-ylglyoxylate. 10 g of p-tolyl isocyanate and 80 ml of dimethylformamide. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:3]=1.CS(O[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:26]=1)(=O)=O.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:23][CH2:24][C:25]3[CH:26]=[C:27]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])[CH:28]=[CH:29][CH:30]=3)[CH2:14][CH2:13]2)[N:3]=1
Reactant: CS(=O)(=O)Nc1cccc(CCOS(C)(=O)=O)c1
Reactant: Cc1ncc2c(N3CCNCC3)cccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ncc2c(N3CCN(CCc4cccc(NS(C)(=O)=O)c4)CC3)cccc2n1
Temperature: 100 °C
Reaction time: 24 h
Yield: 37.6 %

Procedure:
A mixture of 2-methyl-5-(1-piperazinyl)quinazoline (50 mg), 2-{3-[(methylsulfonyl)amino]phenyl}ethyl methanesulfonate (65 mg), diisopropylethylamine (192 μL) and DMF (0.5 mL) was heated to 100° C. in a sealed tube and stirred for 24 hours. The mixture was cooled to room temperature and partitioned between aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed (water, brine), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography [SiO2; DCM-MeOH: (100:0)→(95:5)] to give the title compound as a beige foam (35 mg).
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13](=[O:24])[CH2:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=2[F:23])=[C:10](CC)[CH:9]=[CH:8][N:7]=1)=[O:5])C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:21][C:20]1[CH:19]=[C:18]([F:22])[CH:17]=[C:16]([F:23])[C:15]=1[CH:14]1[C:4](=[O:5])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][N:7]=2)[NH:12][C:13]1=[O:24]
Reactant: CCOC(=O)c1nccc(CC)c1NC(=O)Cc1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2cccnc2C(=O)C1c1c(F)cc(F)cc1F
Reaction time: 18 h

Procedure:
The product from Step 2 (0.80 g) and potassium carbonate (0.40 g) were stirred in dry DMF (10 ml) at 100° C. for 6 hours. The reaction mixture was cooled, stood for 18 hours and the DMF was evaporated to give a solid. This was diluted with water (1 ml), acidified to neutrality and the water was evaporated to give a solid, which was then extracted with methanol. The methanol was evaporated to give 3-(2,4,6-trifluorophenyl)-1H-[1,5]naphthyridine-2,4-dione as a peach coloured solid (0.15 g), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][O:9]2)=[CH:4][N:3]=1.[NH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:28])[C:22]=3[C:21]3=[N:29][O:30][C:31]([CH3:32])=[C:20]3[C:19]2=[O:33])[CH2:13]1>C(O)C>[Cl:28][C:23]1[C:22]2[C:21]3[C:20](=[C:31]([CH3:32])[O:30][N:29]=3)[C:19](=[O:33])[N:18]([CH:14]3[CH2:15][CH2:16][CH2:17][CH:12]([NH:11][CH2:10][CH:8]([C:5]4[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[OH:9])[CH2:13]3)[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: Clc1ccc(C2CO2)cn1
Reactant: Cc1onc2c1c(=O)n(C1CCCC(N)C1)c1cccc(Cl)c21
Solvent: CCO
Product: Cc1onc2c1c(=O)n(C1CCCC(NCC(O)c3ccc(Cl)nc3)C1)c1cccc(Cl)c21

Procedure:
To a stirred solution of 6-chloronicotinic acid (900 mg, 5.7 mmol) in THF (7 mL) was added BH3 (16 mL, 17.1 mmol, 1M in THF) under N2 atmosphere. The reaction mixture was stirred for 5 h. It was quenched with methanol (5 mL) and then concentrated. The crude was dissolved in EtOAc (30 mL), washed with 1N NaOH (15 mL×3), brine, dried and concentrated. Yield: 615 mg (75%) of 6-chloro-pyridin-3-yl-methanol. To this alcohol (615 mg, 4.28 mmol) solution in CH2Cl2 (8 mL) was added Dess-Martin reagent (5.4 mg, 12.8 mmol). It was stirred at rt. for 2 h and then diluted with CH2Cl2. The resulting solution was washed with NaOH (1N, 2×5 mL), brine, dried and concentrated. 516 mg (85%) of yellow solid as the desired 6-chloro-pyridine-3-carbaldehyde. To a solution of above aldehyde (401 mg, 2.82 mmol) in CH2Cl2 (10 mL) was added 50% NaOH solution (9.3 mL), trimethylsulfonium iodide (1.15 g, 5.64 mmol) and tetrabutylammonium iodide (11 mg). It was refluxed for 48 h and poured onto ice water. The organic layer was extracted with CH2Cl2, washed with brine, dried and concentrated. The crude epoxide was chromatographed (gradient, hexanes: EtOAc) and 190 mg (43%) yellow oil was yielded as desired 2-Chloro-5-oxiranyl-pyridine. To the solution of 2-chloro-5-oxiranyl-pyridine (118.4 mg, 0.76 mmol) in absolute ethanol (40 mL) was added a compound from Example 660 (252 mg, 0.76 mmol). The reaction mixture was refluxed for 24 h and concentrated.
Reaction SMILES: [CH:1]([N:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][C:5](O)=O)=O.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[C:15]#C.C(OC(=O)C)(=O)C>>[C:8]1([N:3]2[CH:4]=[CH:5][C:15]([C:14]([O:18][CH2:19][CH3:20])=[O:17])=[CH:1]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C#CC(=O)OCC
Reactant: O=CN(CC(=O)O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1ccn(-c2ccccc2)c1
Yield: 89.6 %

Procedure:
From 2.69 g (15 mmol) of N-formyl-N-phenylglycine, 5.47 g (55.8 mmol) of ethyl propiolate and 15 ml of acetic anhydride, 2.894 g of the title compound were obtained in a similar manner as in Referential Example 3 (yield: 89.6%).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][CH2:22][O:23][Si](C(C)(C)C)(C)C)[C:11]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=2[F:40])([C:31]#[N:32])[CH:10]([CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])[NH:9]1)=[O:7])(C)(C)C.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>ClCCl>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C:11]2([C:31]#[N:32])[CH:10]([CH2:41][C:42]([CH3:43])([CH3:44])[CH3:45])[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]2[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][CH2:22][OH:23])=[C:34]([F:40])[CH:35]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cc(Cl)ccc2OCCO[Si](C)(C)C(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cc(Cl)ccc2OCCO)C1(C#N)c1ccc(Cl)cc1F
Yield: 98 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl}-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 84b (1.0 g, 1.5 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-[5-chloro-2-(2-hydroxy-ethoxy)-phenyl]-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.9 g, 98%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:5]=[C:6]2[C:12]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.[CH3:19][Si:20]([CH2:23][CH2:24][O:25][CH2:26]Cl)([CH3:22])[CH3:21]>CN(C=O)C.O>[Br:3][C:4]1[N:5]=[C:6]2[C:12]([C:13](=[O:18])[C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:11][N:10]([CH2:26][O:25][CH2:24][CH2:23][Si:20]([CH3:22])([CH3:21])[CH3:19])[C:7]2=[N:8][CH:9]=1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.3 %

Procedure:
To a 100 ml three necked round bottom flask, sodium hydride (60% in paraffin) (0.744 g, 0.0186 mole) was taken in DMF (10.0 ml). To this, 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-yl)-2,2-dimethyl propan-1-one (5.0 g, 0.1773 mole) in DMF (15 ml) was slowly added at 0° C. over 15 min under nitrogen atmosphere. After addition was complete, the reaction mixture was stirred for 10 min at same temperature followed by dropwise addition of SEM chloride (3.1 g, 0.0186 mole) at 0° C. After completion of the addition, the reaction mixture was warmed up to RT and stirred for 30 min. After completion of the reaction, the reaction mixture was poured in water and the aq. Layer was extracted with ethyl acetate. Organic layers were combined, washed with brine solution, dried over Na2SO4, filtered and concentrated to afford crude product which was subjected for the column purification. The crude compound was purified using column purification by eluting the compound with 10-15% ethyl acetate in hexanes to yield 7.0 g of 1-(2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl)-2,2-dimethylpropane-1-one.
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][CH:6]=1.[NH:20]1[C:30]2[C:25](=[C:26]([O:31][CH2:32][CH:33]3[O:35][CH2:34]3)[CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][C:21]1=[O:22]>C(O)(C)C>[NH:20]1[C:30]2[C:25](=[C:26]([O:31][CH2:32][CH:33]([OH:35])[CH2:34][NH:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]3[CH:6]=[CH:7][C:8]([C:11]4[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=4)=[CH:9][CH:10]=3)[CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][C:21]1=[O:22]
Reactant: O=C1CCc2c(cccc2OCC2CO2)N1
Reactant: CC(C)(N)CNc1ccc(C2=NNC(=O)CC2)cc1
Solvent: CC(C)O
Product: CC(C)(CNc1ccc(C2=NNC(=O)CC2)cc1)NCC(O)COc1cccc2c1CCC(=O)N2
Reaction time: 20 h
Yield: 49.9 %

Procedure:
3.1 g of 6-[4-(2-amino-2-methylpropylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone obtained in Example 1, (3) and 2.2 g of 1-(3,4-dihydrocarbostyril-5-yloxy)-2,3-epoxypropane were dissolved in 30 ml of isopropyl alcohol and heated with stirring for 20 hours. After the end of the reaction, the reaction solution was concentrated under reduced pressure. The residue was separated by silica gel chromatography (chloroform-methanol=10:1). Recrystallization from dichloro-methane-isopropanol gave 2.4 g of 6-[4-[2-[3-(3,4-di hydrocarbostyril-5-yloxy)2-hydroxypropylamino]-2-methyl-propylamino]phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([I:13])=[CH:9][C:8]=2[Cl:14])=[N:5][N:6]=1.[CH3:15][N:16]1[CH2:23][C@@H:22]2[C@@H:18]([CH2:19][NH:20][CH2:21]2)[CH2:17]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[Cl:14][C:8]1[CH:9]=[C:10]([I:13])[CH:11]=[CH:12][C:7]=1[C:4]1[S:3][C:2]([N:20]2[CH2:21][C@@H:22]3[C@@H:18]([CH2:17][N:16]([CH3:15])[CH2:23]3)[CH2:19]2)=[N:6][N:5]=1
Reactant: CN1C[C@H]2CNC[C@H]2C1
Reactant: Clc1cc(I)ccc1-c1nnc(Br)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CN1C[C@@H]2CN(c3nnc(-c4ccc(I)cc4Cl)s3)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of 2-bromo-5-(2-chloro-4-iodophenyl)-1,3,4-thiadiazole (600 mg, 1.49 mmol) and (3aR,6aS)-2-methyloctahydropyrrolo[3,4-c]pyrrole (377 mg, 2.99 mmol) in NMP (4 mL) was heated at 120° C. for ˜18 hours. The reaction mixture was cooled to room temperature then saturated NaHCO3(aq) (30 mL) was added. The resulting suspension was left to slurry for 1 hour before filtering under vacuum to afford the title compound as a pale brown solid which was used in the next step without further purification. LC-MS: Rt 1.06 min; MS m/z 446.8 [M]+ 1H NMR (400 MHz, DMSO-d6) δ ppm 8.03 (s, 1H), 7.77-7.86 (m, 2H), 3.71 (t, J=8.84 Hz, 2H), 3.36 (br. s., 2H), 2.97 (br. s., 2H), 2.40-2.54 (m, 4H), 2.22 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][CH2:10][C:11]([CH3:13])=[CH2:12].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:11]([CH3:13])([CH3:12])[CH2:10][Cl:9])[CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: C=C(C)CCl
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(CCl)c1cc(Cl)ccc1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-chlorophenol (12.6 g, 0.1 mol) and 3-chloro-2-methyl-propene (10.8 g, 0.12 mol) was added concentrated sulfuric acid (5 g, 0.05 mol) and stirred at 0° C. for 1 hour. The mixture was diluted with cold water and extracted with ether. The ethereal extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel to afford 4-chloro-2-(1-chloro-2-methylpropan-2-yl)phenol (721).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:14])([CH3:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[CH2:15][CH:16]([CH3:19])[CH2:17]Cl.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:14])([CH3:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[CH2:15][CH:16]([CH3:19])[CH2:17][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCCCC(C)(C)c1ccc(CC(C)CCl)c(Br)c1
Reactant: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: CCCCC(C)(C)c1ccc(CC(C)CN2CCCCC2)c(Br)c1
Temperature: 150 °C
Yield: 47.3 %

Procedure:
A mixture of 50 g of XIII and 38.3 g of piperidine was heated at 150° C. for 7 hours. The mixture was cooled and then taken up in CHCl3, and the solution was washed with dilute NaOH and then with water, dried over Na2SO4 and concentrated. Distillation of the residue gave 27 g of (XIV) of boiling point 170°-171° C./0.1 mbar.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@@H:9]([O:10][C:11]3[N:44](COCC[Si](C)(C)C)[C:14]4=[N:15][C:16]([C:20]5[CH:25]=[CH:24][C:23]([C:26]6[CH:31]=[CH:30][C:29]([S:32]([N:41]([CH3:43])[CH3:42])(=[O:40])=[N:33]C(=O)C(F)(F)F)=[CH:28][CH:27]=6)=[CH:22][CH:21]=5)=[C:17]([Cl:19])[CH:18]=[C:13]4[N:12]=3)[C@H:5]2[O:4][CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@@H:9]([O:10][C:11]3[NH:44][C:14]4=[N:15][C:16]([C:20]5[CH:21]=[CH:22][C:23]([C:26]6[CH:27]=[CH:28][C:29]([S:32](=[NH:33])([N:41]([CH3:42])[CH3:43])=[O:40])=[CH:30][CH:31]=6)=[CH:24][CH:25]=5)=[C:17]([Cl:19])[CH:18]=[C:13]4[N:12]=3)[C@H:5]2[O:4][CH2:3]1
Reactant: CN(C)S(=O)(=NC(=O)C(F)(F)F)c1ccc(-c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)S(=N)(=O)c1ccc(-c2ccc(-c3nc4[nH]c(O[C@@H]5CO[C@H]6[C@@H]5OC[C@H]6O)nc4cc3Cl)cc2)cc1
Temperature: 25 °C

Procedure:
A mixture of N-({4-[4-(2-{[(3R,3aR,6R,6aR)-6-hydroxy-hexahydrofuro[3,2-b]furan-3-yl]oxy}-6-chloro-3-{[2-(trimethylsilyl)ethoxy]methyl}imidazo[4,5-b]pyridin-5-yl)phenyl]-phenyl}(dimethylamino)oxo-λ6-sulfanylidene)-2,2,2-trifluoroacetamide (22 mg) and trifluoroacetic acid (0.30 mL) in dichloromethane (1.00 mL) is stirred over night at room temperature. The reaction mixture is concentrated in vacuo and the residue is dissolved in methanol. Aqueous Na2CO3 solution (2 N; 60 μL) is added and the mixture is stirred for 1 h. The reaction mixture is filtered and the crude product is purified by preparative HPLC to give the title compound. LC (method 1): tR=0.86 min; Mass spectrum (ESI+): m/z=556 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][N:5]1[C:9](=[O:10])[N:8](/[CH:11]=[CH:12]/[C:13]([F:16])([F:15])[F:14])[C:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[N:6]1.[OH-].[Li+].Cl>CO.CS(C)=O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:7]2[N:8](/[CH:11]=[CH:12]/[C:13]([F:15])([F:14])[F:16])[C:9](=[O:10])[N:5]([CH2:4][C:3]([OH:24])=[O:2])[N:6]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
260 mg (0.72 mmol) of the compound of Example 10A were dissolved in 5 ml of methanol, and 2.87 ml (2.87 mmol) of a 1M aqueous lithium hydroxide solution were added. The mixture was stirred at RT for 1 h and then acidified with 1N hydrochloric acid and diluted with DMSO. The entire solution was purified by preparative HLPC [Method 9]. This gave 215 mg (86% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[CH:10]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3)CC2)c1
Reactant: Oc1ccc(Br)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3ccc(Br)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-bromophenol and N-{3-[1-(6-hydroxy-6-phenylhexyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 577.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2[C:27]#[N:28])=[CH:4][C:5](=[O:19])[N:6]([CH:8]([CH2:12][CH2:13][O:14][C:15]([F:18])([F:17])[F:16])[C:9](O)=[O:10])[CH:7]=1.[NH2:29][C:30]1[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:32][CH:31]=1>>[Cl:1][C:2]1[C:3]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2[C:27]#[N:28])=[CH:4][C:5](=[O:19])[N:6]([CH:8]([CH2:12][CH2:13][O:14][C:15]([F:16])([F:17])[F:18])[C:9]([NH:29][C:30]2[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])=[CH:32][CH:31]=2)=[O:10])[CH:7]=1
Reactant: N#Cc1ccc(Cl)cc1-c1cc(=O)n(C(CCOC(F)(F)F)C(=O)O)cc1Cl
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)C(CCOC(F)(F)F)n2cc(Cl)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1

Procedure:
237 mg (purity 84%, 0.46 mmol) of 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-(trifluoromethoxy)butanoic acid (racemate) and 97 mg (0.50 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 142 mg (purity 81%, 41% of theory)