Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[CH2:13]([O:20][C:21](=[O:31])[C@@H:22]([O:27][C:28](Cl)=[O:29])[CH2:23][CH:24]([CH3:26])[CH3:25])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C>[CH2:13]([O:20][C:21](=[O:31])[C@@H:22]([O:27][C:28](=[O:29])[NH:2][C@H:3]([C:4](=[O:5])[N:6]([CH3:8])[CH3:7])[C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:23][CH:24]([CH3:25])[CH3:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)C[C@H](OC(=O)Cl)C(=O)OCc1ccccc1
Reactant: CN(C)C(=O)[C@@H](N)C(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](OC(=O)N[C@H](C(=O)N(C)C)C(C)(C)C)C(=O)OCc1ccccc1
Yield: 85.6 %

Procedure:
(2S)-2-Amino-3,3-dimethyl-N,N-dimethylbutyramide hydrochloride (0.25 g), (2S)-2-chlorocarbonyloxy-4-methylvaleric acid benzyl ester (0.36 g) and TEA (0.31 g) were reacted in ethyl acetate (10 ml) in a similar manner to that of Example 4-1) to give (2S)-2-[N-[(1S)-2,2-dimethyl-1-(N,N-dimethylcarbamoyl)propyl]-carbamoyloxy]-4-methylvaleric acid benzyl ester (0.44 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:10]=1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1cc(Cl)ccc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(Cl)ccc1OCc1ccccc1
Temperature: 10 °C

Procedure:
A mixture of 5-chlorosalicyclic acid (7.7 g), benzyl chloride (10.35 ml), anhydrous potassium carbonate (6.2 g), and dry sulpholane (100 ml) was stirred and heated in an oil bath at 120° C. for 20 hours. The yellow solution was cooled and poured into a mixture of ice and water (300 ml) and the mixture was acidified to pH 1 by treatment with concentrated hydrochloric acid. The brown oil which separated was extracted with diethyl ether (400 ml), the ether extract was washed with aqueous sodium carbonate solution (2N; 150 ml), dried over magnesium sulphate, and evaporated, to give a white solid (16 g), m.p 45°-50° C., consisting mainly of benzyl 2-benzyloxy-5-chlorobenzoate. This material was heated at reflux with aqueous sodium hydroxide solution (2N; 100 ml) for 3 hours. The mixture was then treated with methanol (40 ml) and heated at reflux for 6 hours. The resulting solution was neutralised to pH 7 by treatment with hydrochloric acid (2N), then concentrated under reduced pressure, acidified to pH 5 by treatment with hydrochloric acid (2N) and cooled to 10° C. The separated solid was filtered off and washed with a mixture of ice and water and recrystallized from acetic acid (100 ml) (filtering off some insoluble material ) to give 2-benzyloxy-5-chlorobenzoic acid (5.23 g), m.p. 113°-115° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:22]2([OH:28])[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1>>[OH:28][C:22]1([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[CH:17]=2)[CH2:27][CH2:26][CH2:25][N:24]([C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:12])[CH2:23]1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3ccc4ccccc4c3)C2)c1

Procedure:
The compound of Example 28 was prepared according to the general preparation protocol A from naphthalene-2-carbonyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [OH:1][C:2]([C:15]([F:18])([F:17])[F:16])([CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[C:3]([OH:5])=O.S(Cl)(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:29](=[O:30])[O:28][CH2:27]2.O>CC(N(C)C)=O>[OH:1][C:2]([C:15]([F:18])([F:17])[F:16])([CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[C:3]([NH:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:29](=[O:30])[O:28][CH2:27]2)=[O:5]
Reactant: CC(CC(O)(C(=O)O)C(F)(F)F)c1ccccc1
Reactant: Nc1ccc2c(c1)COC2=O
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CC(CC(O)(C(=O)Nc1ccc2c(c1)COC2=O)C(F)(F)F)c1ccccc1
Temperature: -15 °C
Reaction time: 3 h
Yield: 38.7 %

Procedure:
500 mg of 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid (Eur. Appl. 0 253 500 (Imperial Chemical Industries)) in 10 ml of dimethylacetamide is mixed at −15° C. with 0.14 ml of thionyl chloride. After 3 hours of stirring at −15° C., 600 mg of 5-aminophthalide (test) is added. The solution is stirred for 2 hours at −15° C. and then left for 18 hours at room temperature, then mixed with water and extracted with ethyl acetate. The ethyl acetate phase is dried (Na2SO4) and concentrated by evaporation. The residue is stirred with diethyl ether and suctioned off. 290 mg of 5-(2-hydroxy-4-phenyl-2-trifluoromethyl-valeroylamino)-phthalide, melting point 166-168° C., is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:11]1[C:19]2[C:14](=[CH:15][C:16]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[CH2:9][NH2:10].O=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C1(C)C=CC=CC=1.Cl>O1CCOCC1.C(OCC)(=O)C.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:11]2[C:19]3[C:14](=[CH:15][C:16]([N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:10][CH:9]=1
Reactant: NCC(c1ccccc1F)c1c[nH]c2cc(N3CCOCC3)ccc12
Reactant: CCOC(=O)C=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
To a solution of 2-(2-fluorophenyl)-2-(6-morpholino-1H-indol-3-yl)ethanamine (0.181 g, 0.533 mmol) and ethyl 2-oxoacetate in toluene (50%) (0.233 mL, 1.173 mmol) in 1,4-dioxane (18 mL) at room temperature was added hydrogen chloride (4 N in 1,4-dioxane) (0.267 mL, 1.067 mmol). The solution turned heterogeneous and it was stirred at room temperature for 16 hr. The volatiles were removed under vacuum. The residue was diluted with water (20 mL), basified with saturated NaHCO3 solution to pH 10, and extracted with ethyl acetate (3×30 mL). The combined extract was washed with brine (25 ml), dried over anhydrous MgSO4, and concentrated to dryness under vacuum. To the residue were added toluene (10 mL) and 10% Pd/C (0.3 g), and the mixture was heated at 140° C. under an ambient atmosphere for 4.5 hr. The solid phase was removed by suction filtration. The filtrate was diluted with ethyl acetate (100 ml), washed with brine (25 ml), and dried over anhydrous MgSO4. The desired product (94 mg, 0.222 mmol, 41.6% yield) was isolated with ISCO (24 g silica gel, 30-60% ethyl acetate/hexane) as a tan solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(OC([N:35]1[CH2:40][CH2:39][CH:38]([N:41]2[CH:45]=[C:44](B3OC(C)(C)C(C)(C)O3)[CH:43]=[N:42]2)[CH2:37][CH2:36]1)=O)(C)(C)C>>[F:27][C:14]1[C:13]([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:44]4[CH:43]=[N:42][N:41]([CH:38]5[CH2:39][CH2:40][NH:35][CH2:36][CH2:37]5)[CH:45]=4)[CH:3]=3)[NH:8][CH:9]=2)=[O:12])=[C:18]([F:19])[CH:17]=[CH:16][C:15]=1[NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cnn(C5CCNCC5)c4)cc23)c1F

Procedure:
Propane-1-sulfonic acid {2,4-difluoro-3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide P-1002 is prepared in two steps from propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide 9 and 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester 34 as shown in Scheme 4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:25]=[CH:24][C:15]([O:16][CH2:17][CH2:18][N:19]2[CH2:22][CH:21]([OH:23])[CH2:20]2)=[C:14]([C:26]2[N:27]([CH3:32])[N:28]=[CH:29][C:30]=2[Cl:31])[CH:13]=1>ClCCl.CN(C=O)C>[Cl:31][C:30]1[CH:29]=[N:28][N:27]([CH3:32])[C:26]=1[C:14]1[CH:13]=[C:12]([NH:11][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:10])[CH:25]=[CH:24][C:15]=1[O:16][CH2:17][CH2:18][N:19]1[CH2:22][CH:21]([OH:23])[CH2:20]1
Reactant: Cn1ncc(Cl)c1-c1cc(N)ccc1OCCN1CC(O)C1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1OCCN1CC(O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
4-Chlorophenylisocyanate (19.0 mg, 0.124 mmol) was added to a solution of 1-{2-[4-amino-2-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-azetidin-3-ol (40.0 mg, 0.124 mmol) in dichloromethane (2.0 mL) and DMF (0.1 mL), and the mixture stirred at room temperature overnight. The solution was concentrated and purified by RP-HPLC. The collected fractions were concentrated and 12% sodium hydroxide (aq) (0.2 mL) was added to give pH 9. The solution was extracted into ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to give a white solid (28 mg, 47%). LCMS m/z (%)=476 (M+H35Cl, 100), 478 (M+H37Cl, 67). 1H NMR (400 MHz, DMSO-d6) δ: 8.81 (bs, 1H), 8.71 (bs, 1H), 7.60 (s, 1H), 7.53-7.50 (m, 1H), 7.47 (d, J=2.08 Hz, 1H), 7.46 (d, J=2.10 Hz, 1H), 7.36 (d, J=2.71 Hz, 1H), 7.32 (d, J=2.11 Hz, 1H), 7.30 (d, J=2.04 Hz, 1H), 7.11 (d, J=9.06 Hz, 1H), 5.19 (d, J=8.00 Hz, 1H), 4.10-4.00 (m, 1H), 3.99-3.85 (m, 2H), 3.65 (s, 3H), 3.40-3.30 (m, 2H), 2.70-2.55 (m, 4H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[CH:12]([CH3:14])[CH3:13])=[O:3].[CH3:15][C:16]([CH3:21])([CH2:19][OH:20])[CH2:17][OH:18]>>[CH:12]([C:6]1[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=1[O:4][C:2]([O:18][CH2:17][C:16]([CH3:21])([CH3:15])[CH2:19][OH:20])=[O:3])([CH3:14])[CH3:13]
Reactant: Cc1ccc(C(C)C)c(OC(=O)Cl)c1
Reactant: CC(C)(CO)CO
Product: Cc1ccc(C(C)C)c(OC(=O)OCC(C)(C)CO)c1

Procedure:
The reaction of 2-isopropyl-5-methylphenyl chloroformate with 2,2-dimethyl-1,3-propanediol is conducted on a 0.01 mole scale employing the same conditions as described in Example I. A 1.3 g yield of the pure product is obtained as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.Cl.[CH3:15]O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH3:15])=[O:12])=[CH:5]2
Reactant: CO
Reactant: O=C(O)c1cc2cc(Br)ccc2[nH]1
Agent: Cl
Product: COC(=O)c1cc2cc(Br)ccc2[nH]1
Temperature: 25 °C

Procedure:
A solution of 5-Bromo-1H-indole-2-carboxylic acid (commercial, 10.0 g, 41.6 mmol) in methanol (200 ml) was cooled to 0° C. and saturated with HCl(g). The resulting solution was allowed to warm gradually to room temperature overnight. The solvent was removed in vacuo and the residue treated with 0.88 ammonia (500 ml). The resulting solution was extracted with dichloromethane (3-fold 150 ml) and the combined organics dried (magnesium sulphate) and the solvent removed in vacuo to give the required product as a colourless oil (8.35 g).
Reaction SMILES: [NH2:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH2:12]([N:14]([CH2:43][C:44](O)=[O:45])[S:15]([C:18]([F:42])([F:41])[C:19]([F:40])([F:39])[C:20]([F:38])([F:37])[C:21]([F:36])([F:35])[C:22]([F:34])([F:33])[C:23]([F:32])([F:31])[C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])(=[O:17])=[O:16])[CH3:13].ON1C(=O)CCC1=O>O1CCCC1>[C:2]12([NH:1][C:44](=[O:45])[CH2:43][N:14]([CH2:12][CH3:13])[S:15]([C:18]([F:42])([F:41])[C:19]([F:39])([F:40])[C:20]([F:37])([F:38])[C:21]([F:35])([F:36])[C:22]([F:33])([F:34])[C:23]([F:31])([F:32])[C:24]([F:29])([F:30])[C:25]([F:28])([F:27])[F:26])(=[O:17])=[O:16])[CH2:3][CH:4]3[CH2:10][CH:8]([CH2:7][CH:6]([CH2:5]3)[CH2:11]1)[CH2:9]2
Reactant: CCN(CC(=O)O)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: CCN(CC(=O)NC12CC3CC(CC(C3)C1)C2)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
30.95 g (150 mmol) of N,N-dicyclohexylcarbodiimide is added at 0° C. to 15.12 g (100 mmol) of 1-aminoadamantane, 58.52 g (100 mmol) of N-(ethyl)N-(perfluorooctylsulfonyl)-aminoacetic acid and 11.51 g (100 mmol) of N-hydroxysuccinimide, dissolved in 300 ml of tetrahydrofuran. It is stirred for 2 hours at 0° C., then for 6 hours at room temperature. Precipitated urea is filtered out, the filtrate is evaporated to the dry state, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/acetone=30:1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]2)[C:3]=1[CH3:21].[H-].[Na+].I[CH3:25]>C1COCC1.O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([CH3:25])[C:16](=[O:20])[CH2:15]2)[C:3]=1[CH3:21]
Reactant: Cc1c(N2CCNC(=O)C2)nc2cc(F)cc(F)c2c1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(N2CCN(C)C(=O)C2)nc2cc(F)cc(F)c2c1Cl
Reaction time: 1.5 h

Procedure:
The 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)piperazin-2-one (30 mg, 0.096 mmol) was dissolved in THF (1.0 mL) and sodium hydride (10.0 mg, 0.42 mmol) (60% suspension) was added followed by addition of iodomethane (17.0 μL, 0.27 mmol). The mixture was stirred for 1.5 h, then diluted with water. The mixture was extracted with EtOAc (2×15 mL). The combined organic layers were dried over magnesium sulfate. The filtrate was concentrated to give the desired product. Mass Spectrum (ESI) m/e=326.0 (M+1).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(#N)C>[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:13][CH2:12]2)=[O:16])=[CH:20][CH:19]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 54 h

Procedure:
1-BOC-piperidine-4-carboxylic acid (100 g, 437 mmol), 4-chloroaniline (61.2 g, 480 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100 g, 524 mmol) and triethylamine (182.6 mL, 1.31 mol) were dissolved in cold (10° C.) acetonitrile (1.75 L). The reaction mixture was stirred for 54 hours at room temperature and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and then partitioned with 2N hydrochloric acid. The resulting precipitate was filtered off, re-dissolved in dichloromethane, the solution was dried over MgSO4 and evaporated under reduced pressure. The residue was triturated with ether to afford the desired compound as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:24])[CH:9]=[CH:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[C:13]([CH3:23])[CH:12]=2)=[C:5]2[CH2:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH2:28][C:4]=12)[CH3:2].CCN(C(C)C)C(C)C>C(O)C.[Pd]>[CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:24])[CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[C:13]([CH3:23])[CH:12]=2)=[C:5]2[CH2:25][CH2:26][C:27]([CH3:29])([CH3:30])[CH2:28][C:4]=12)[CH3:2]
Reactant: CCc1sc(C(=O)C=Cc2cc(C)c(CCC(=O)O)c(C)c2)c2c1CC(C)(C)CC2
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCc1sc(C(=O)CCc2cc(C)c(CCC(=O)O)c(C)c2)c2c1CC(C)(C)CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.9 %

Procedure:
To a solution of 3-{4-[3-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propenyl]-2,6-dimethyl-phenyl}-propionic acid (610 mg, 1.44 mmol) and DIPEA (204 mg, 1.58 mmol) in ethanol (30 mL) is added Pd/C (300 mg, 10% Pd, moistened with 50% water). The slurry is stirred at rt for 18 h under 1 atm H2. The mixture is filtered and the filtrate is evaporated. The crude product is purified by prep. HPLC (Grom-Sil 120 ODS-4-HE, 30×75 mm, 10 μm, acetonitrile/water (0.5% HCOOH), 20% to 95% acetonitrile) to give 3-{4-[3-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propyl]-2,6-dimethyl-phenyl}-propionic acid (460 mg) as a colourless lyophilisate; LC-MS: tR=1.15 min; [M+1]=427.40; 1H NMR (CDCl3): δ 6.91 (s, 2H), 3.10-2.90 (m, 8H), 2.73 (q, J=7.6 Hz, 2H), 2.53-2.46 (m, 2H), 2.32 (s, 6H), 2.30 (s, 2H), 1.54 (t, J=7.0 Hz, 2H), 1.28 (t, J=7.6 Hz, 3H), 0.97 (s, 6H).
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH2:3][C@H:4]([NH:21][S@](C(C)(C)C)=O)[C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:9][CH:10]=1.[ClH:29].CCOCC>CO>[ClH:29].[CH3:1][CH:2]([CH3:28])[CH2:3][C@H:4]([NH2:21])[C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:9][CH:10]=1
Reactant: CC(C)C[C@H](N[S@@](=O)C(C)(C)C)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CC(C)C[C@H](N)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
(S)-2-methyl-propane-2-sulfinic acid {(S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butyl}-amide (38.83 g, 93.90 mmol) was dissolved in methanol and transferred to a 3-necked 1 L flask with overhead stirring and internal temperature. A total of 210 mL methanol was added to give a yellow solution. This was placed in an ice bath and at an internal temperature of 8° C., HCl in ether (188 mL, 2.0 M, 376 mmol) was added over 2 min. The temperature went up to 14° C. The ice bath was removed and the reaction stirred for ˜5 min as a yellow solution than as a white slurry. At 30 min, the reaction was rotovapped to dryness and the solid slurried in diethylether (200 mL) for 1 h. The solid was collected by Buchner filtration, washing with additional diethylether. This was suction dried for ˜1 h and then placed on the vacuum pump to give (S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylamine hydrochloride (31.58 g, 97%) as a white solid. 1H NMR (400 MHz, DMSO-d6, δ): 9.19 (s, 2H) 8.78 (br. s., 3H) 8.61 (d, J=8.2 Hz, 2H) 7.93 (d, J=8.4 Hz, 2H) 4.47 (br. s., 1H) 1.84-2.03 (m, 2H) 1.41 (m, 1H) 0.83-0.96 (m, 6H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[O:10]1[C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+].C(#N)C>O.CCOCC>[O:10]1[C:14]2([CH2:19][CH2:18][N:17]([C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: N#Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.5 %

Procedure:
A mixture of 10 g (0.0825 mol) p-fluorobenzonitrile, 47 g (0.3282 mol) of 1,4-dioxa-8-azaspiro[4.5]decane, 17 g (0.123 mol) of K2CO3, and 100 ml of acetonitrile is stirred at 90°-100° C. for three days. The reaction mixture is allowed to cool to ambient temperature, diluted with water and extracted with methylene chloride. The combined extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo to give a pasty solid. Trituration with ether furnishes 13.4 g (67%) of title compound: IR (KBr) 2210 and 1600 cm-1 ; NMR (CDCl3) δ 7.48 (d, 2H), 6.88 (d, 2H), 4.0 (s, 4H), 3.58-3.40 (m, 4H), and 1.90-1.70 (m, 4H).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1.Cl>N1C=CC=CC=1>[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH:12][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:10][CH:9]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
A mixture of ethanesulfonyl chloride (2.1 mL, 22 mmol), and 4-bromoaniline (3.44 g, 20 mmol) in pyridine (35 mL) was stirred at room temperature for 2 hours. The reaction mixture was acidified with 1N HCl solution and extracted with ether. The combined organic layers were dried over magnesium sulfate, and concentrated. The solid was triturated with hexane to afford the title compound (4.85 g, 92%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:33]=[CH:32][C:11]3[N:12]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:13]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=4[N:23]4[CH:27]=[N:26][CH:25]=[N:24]4)[C:18]#[N:19])=[N:14][C:10]=3[CH:9]=2)=[CH:4][N:3]=1.[NH4+].[OH-:35].OO>CO.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:33]=[CH:32][C:11]3[N:12]([C:28]([CH3:29])([CH3:30])[CH3:31])[C:13]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=4[N:23]4[CH:27]=[N:26][CH:25]=[N:24]4)[C:18]([NH2:19])=[O:35])=[N:14][C:10]=3[CH:9]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)n1c(-c2cc(C#N)ccc2-n2cncn2)nc2cc(-c3cnc(N)nc3)ccc21
Reactant: [OH-]
Agent: OO
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)n1c(-c2cc(C(N)=O)ccc2-n2cncn2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
To a round bottom flask is added 3-[5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-4-1,2,4-triazol-1-yl-benzonitrile (Example 7) (200 mg, 0.46 mmol) in MeOH (5 mL), followed by the addition of NH4OH (2 mL) and H2O2 (1 mL) (30% in water). The reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with EtOAc (20 mL), washed with water (10 mL), brine (5 mL), dried under anhydrous Na2SO4 (500 mg), filtered and concentrated. The residue is purified by silica gel flash column chromatography with 10% MeOH in CH2Cl2 as the eluent to afford the title compound (89 mg, 42%) as a white solid. LCMS (ESMS): m/z 454.73 (M++1)
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][OH:26])[CH:19]=1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:27])[N:7]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH:25]=[O:26])[CH:19]=1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCCc1ccccn1)Cc1cccc(CCO)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CCCc1ccccn1)Cc1cccc(CC=O)c1
Reaction time: 1.5 h
Yield: 100.5 %

Procedure:
A solution of [3-(2-hydroxy-ethyl)-benzyl]-(3-pyridin-2-yl-propyl)-carbamic acid tert-butyl ester (90 mg) in anhydrous dichloromethane (8 mL) under nitrogen was treated with Dess-Martin periodinane (123 mg) and the mixture stirred for 90 minutes. Ethyl acetate (8 mL) was added followed by saturated aqueous sodium thiosulphate (8 mL) and saturated aqueous sodium bicarbonate (8 mL), the resultant mixture was stirred vigorously for 10 minutes before being extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium bicarbonate, dried and the solvent removed under reduced pressure to yield the sub-titled compound (90 mg).