Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20](S(C2C=CC(OC)=CC=2)(=O)=O)[CH:19]=1.P([O-])([O-])(O)=O.[Na+].[Na+].[Cl-].[NH4+]>CO>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1
Reactant: COc1ccc(S(=O)(=O)n2cc(CCCCCCCCCCCCCCCCO)c3ccccc32)cc1
Agent: O=P([O-])([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: OCCCCCCCCCCCCCCCCc1c[nH]c2ccccc12
Reaction time: 12 h
Yield: 79.2 %

Procedure:
To a solution of 3-(16-hydroxyhexadecyl)-1-(4-methoxybenzenesulfonyl)indole (400 mg, 0.72 mmol) dissolved in 20 ml of dry methanol were added disodium hydrogen-phosphate(205 mg, 1.44 mmol) and amalgam chloride(6%, 4g) at 0° C. under argon gas. After the resulting mixture was allowed to stand at room temperature for 12 hours, 50 mL of ammonium chloride was added thereto. The resulting mixture was extracted three times with 60 ml of ethyl ether. The combined organic layer was washed with saline, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by chromatography on a silica gel column to give 3-(16-hydroxyhexadecyl)indole (Compound 1) as a white solid (204 mg, 75%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:11]=1)=O.[C:25]([CH2:27][C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[F:39])=[O:29])#[N:26].N12CCCN=C1CCCCC2>C1C=CC=CC=1>[F:39][C:33]1[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=1[CH2:31][N:30]1[C:5]([C:7]2[CH:8]=[N:9][N:10]([C:12]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:11]=2)=[CH:4][C:3]([C:2]([F:24])([F:23])[F:1])=[C:27]([C:25]#[N:26])[C:28]1=[O:29]
Reactant: O=C(CC(=O)C(F)(F)F)c1cnn(-c2ncccc2C(F)(F)F)c1
Reactant: N#CCC(=O)NCc1ccc(F)cc1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Product: N#Cc1c(C(F)(F)F)cc(-c2cnn(-c3ncccc3C(F)(F)F)c2)n(Cc2ccc(F)cc2F)c1=O
Temperature: 90 °C
Yield: 36.2 %

Procedure:
4,4,4-Trifluoro-1-[1-(3-trifluoromethyl-pyridin-2-yl)-1H-pyrazol-4-yl]-butane-1,3-dione (143 mg, 0.41 mmol) and 2-cyano-N-(2,4-difluoro-benzyl)-acetamide (86 mg, 0.41 mmol) were suspended in 1.5 mL anhydrous benzene. To the above reaction mixture was added 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU (31 mg, 0.21 mmol). The mixture was heated at 90° C. under nitrogen atmosphere for overnight. After this period of time, the mixture was evaporated in vacuo and the resulting residue was purified by column chromatography on silica gel (35% EtOAC/Hexane) to give 1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-6-[1-(3-trifluoromethyl-pyridin-2-yl)-1H-pyrazol-4-yl]-1,2-dihydro-pyridine-3-carbonitrile as a yellow solid (78 mg, 36% yield). 1H-NMR (400 MHz, CDCl3): δ 5.42 (s, 2H), 6.61 (s, 1H), 6.82 (m, 1H), 6.89 (m, 1H), 7.12 (m, 1H), 7.58 (dd, 1H, J=4.80, J=8.08), 7.73 (s, 1H), 8.28 (dd, 1H, J=1.77, J=8.08), 8.32 (s, 1H), 8.72 (dd, 1H, J=1.77, J=4.80).
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21]N)([CH3:14])[CH3:13].Cl>C(O)C>[CH:12]([C:15]1[C:16]2[NH:21][C:1]3[C:9]4[C:4]([CH2:3][C:2]=3[C:17]=2[CH:18]=[CH:19][CH:20]=1)=[CH:5][CH:6]=[CH:7][CH:8]=4)([CH3:14])[CH3:13]
Reactant: CC(C)c1ccccc1NN
Reactant: O=C1CCc2ccccc21
Agent: Cl
Solvent: CCO
Product: CC(C)c1cccc2c3c([nH]c12)-c1ccccc1C3

Procedure:
A mixture of 12.6 g (0.096 mol) of 1-indanone, 19.7 g (0.105 mol) of 2-isopropylphenylhydrazine hydrochloride, 150 ml of ethanol and 10 ml of conc. hydrochloric acid was refluxed for 2 hours. The solvent was removed by evaporation and the residue suspended in acidic water. Extraction with ether, drying (MgSO4) and evaporation gave the crude product, which was purified by column chromatography on silica gel using methylene chloride/light petroleum (2/8) as the eluant. The final purification was achieved by recrystallization from ethylacetate/light petroleum giving 14.0 g (59%) of the product. 1H NMR (CDCl3) 1.48 (6H, d), 3.37 (1H, septet), 3.77 (2H, s), 4.37 (1H, s), 7.1-7.3 (3H, m), 7.37 (1H, dd), 7.5-7.6 (3H, m), 8.03 (1H, s).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[CH:27]([NH:29][CH2:30][C:31](O)=O)=[O:28]>>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17]2[N:18]=[C:31]([CH2:30][NH:29][CH:27]=[O:28])[O:20][N:19]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: O=CNCC(=O)O
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CON=C1C[C@@H](c2noc(CNC=O)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and (formylamino)acetic acid, the title compound was obtained in 72% purity by HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:15]=2)=[CH:9][C:8]=1[Cl:30])[CH3:2].[N:32]1([CH2:38][CH2:39][CH2:40]O)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:40][CH2:39][CH2:38][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:17]=[C:16]([C:21]#[C:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[CH:15]=2)=[CH:9][C:8]=1[Cl:30])[CH3:2]
Reactant: OCCCN1CCOCC1
Reactant: CCOC(=O)COc1ccc(Sc2cc(O)cc(C#Cc3ccc(Cl)cc3)c2)cc1Cl
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(Cl)cc3)cc(OCCCN3CCOCC3)c2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (293 mg; 0.62 mmol) was dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. 3-morpholin-4-yl-propan-1-ol (75 mg; 0.52 mmol) and tributyl-phosphine (0.23 mL; 0.93 mmol) was added followed by 1,1′-(Azodicarbonyl)dipiperidine (0.38 g; 1.5 mmol) dissolved in THF (10 mL). The reaction mixture was stirred at room temperature for 16 h, filtered and evaporated in vacuo. The crude product was purified by prep. HPLC (method B). Yield: 200 mg. HPLC-MS: m/z: 600.4 (M+); Rt: 2.2 min.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=[CH:9][C:8]=2[N:7]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:6]=1)=[O:4].[BH4-].[Na+].C(=O)([O-])O.[Na+]>O1CCCC1>[Br:1][CH2:2][CH:3]([C:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:20])[CH3:21])[N:10]=[CH:9][C:8]=2[N:7]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:6]=1)[OH:4]
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(C(=O)CBr)cn2COCC[Si](C)(C)C)c1=O
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc2c(c(C(O)CBr)cn2COCC[Si](C)(C)C)c1=O
Reaction time: 2 h
Yield: 84.8 %

Procedure:
To 150 ml of dehydrated tetrahydrofuran solution containing 6.64 g (12.9 mmol) of 3-(2-bromoacetyl)-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 57-(b) was added dropwise 100 ml of tetrahydrofuran solution containing 486 mg (12.8 mmol) of sodium borohydride under cooling in ice-bath. After dropwise addition, the mixture was stirred at the same temperature for 2 hours. After completion of the reaction, to the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=7:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 5.67 g of the title compound as a white solid. (Yield: 85%)
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH3:16])[CH2:6][O:7][C:8]1[CH:12]=[C:11]([C:13]([OH:15])=O)[O:10][N:9]=1)(=[O:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]2[CH2:28][CH2:27]2)=[CH:20][C:19]=1[S:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH:36]([CH2:41][CH3:42])[CH2:37][CH2:38][CH2:39][CH3:40])=[O:33]>>[C:1]([NH:4][C@@H:5]([CH3:16])[CH2:6][O:7][C:8]1[CH:12]=[C:11]([C:13]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]3[CH2:27][CH2:28]3)=[CH:20][C:19]=2[S:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH:36]([CH2:41][CH3:42])[CH2:37][CH2:38][CH2:39][CH3:40])=[O:33])=[O:15])[O:10][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](C)COc1cc(C(=O)O)on1
Reactant: CCCCC(CC)COC(=O)CCSc1cc(OCC2CC2)ccc1N
Product: CCCCC(CC)COC(=O)CCSc1cc(OCC2CC2)ccc1NC(=O)c1cc(OC[C@H](C)NC(C)=O)no1

Procedure:
Using 3-{[(2S)-2-(acetylamino)propyl]oxy}isoxazole-5-carboxylic acid and 2-ethylhexyl 3-{[2-amino-5-(cyclopropylmethoxy)phenyl]sulfanyl}propanoate, and in the same manner as in Example 2, step C, the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([OH:15])[O:10]2)=[C:5]([CH3:16])[O:4][N:3]=1.CC1C(C=CC2CCC=CO2)=C(C)[O:20]N=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(O)[O-].[Na+]>CC(C)=O>[CH3:1][C:2]1[C:6]([CH2:7][CH2:8][C:9](=[O:20])[CH2:14][CH2:13][CH2:12][C:11]([OH:15])=[O:10])=[C:5]([CH3:16])[O:4][N:3]=1
Reactant: Cc1noc(C)c1C=CC1CCC=CO1
Reactant: Cc1noc(C)c1CCC1CCCC(O)O1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Solvent: CC(C)=O
Product: Cc1noc(C)c1CCC(=O)CCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.5-dimethyl-4-(6-hydroxytetrahydropyran-2-ylethyl)-isoxazole, prepared as described in part B from 60.5 g. (0.294 mole) of racemic 3,5-dimethyl-4-(3,4-dihydro-2H-pyran-2-ylvinyl)-isoxazole, in 600 ml. of acetone was cooled in an ice bath as 400 ml. of Jones reagent was added dropwise over a 1.0 hr. period. The resulting suspension was stirred at room temperature overnight. Saturated sodium bisulfite solution was added to destroy the excess oxidizing agent and most of the acetone was removed at reduced pressure. The residue was diluted with water, saturated with sodium chloride, and extracted with ethyl acetate. The ethyl acetate solutions were washed with brine and then with excess saturated aqueous sodium bicarbonate solution. The sodium bicarbonate solutions were washed with ether, acidified with 3N hydrochloric acid, saturated with sodium chloride, and extracted with ethyl acetate. The ethyl acetate solutions were washed with brine and dried over anhydrous sodium sulfate. Solvent removal at reduced pressure gave a pale yellow resin. Crystallization of this material from ether gave two crops of racemic 7-(3,5-dimethyl-4 -isoxazolyl)-5-oxo-heptanoic acid as a fine white powder, m.p. 61.5°-63.5°.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][C:13]([O:15]CC)=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:26][NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[NH:36])[NH2:35])=[CH:30][CH:29]=1.[OH-].[Na+]>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([C:18](=[O:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:12][C:13]([OH:15])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:26][NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[NH:35])[NH2:36])=[CH:30][CH:29]=1
Reactant: CCOC(=O)CN(C(=O)c1ccccc1)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(N(CC(=O)O)C(=O)c3ccccc3)ccc21

Procedure:
Prepared analogously to Example 3 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-5-[N-(ethoxycarbonylmethyl)-benzoylamino]-benzimidazole and sodium hydroxide solution.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:13]=[S:14])=[CH:8][CH:7]=1>C(O)C>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH:3][C:2]#[N:1])=[S:14])=[CH:8][CH:7]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: N#CN
Agent: [Na]
Solvent: CCO
Product: N#CNC(=S)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
The suspension of monosodium cyanamide (1.9 g, 29.4 mmol) in absolute ethanol (5 mL) was slowly treated with 4-chlorophenylisothiocyanate (5.0 g, 29.4 mmol). The reaction was allowed to stir at room temperature for one hour and then heated at 75° C. for four hours. The reaction was cooled to room temperature and the colorless solid was filtered and washed with ethanol to give the title compound (5.4 g), mp>250° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1B(O)O.[CH2:17]([O:19][C:20]([C:22]1[CH:23]=[N:24][N:25]([C:27]2[N:36]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:35](=[O:45])[C:34]3[C:29](=[CH:30][CH:31]=[C:32](I)[CH:33]=3)[N:28]=2)[CH:26]=1)=[O:21])[CH3:18].C1COCC1>C(Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[CH2:17]([O:19][C:20]([C:22]1[CH:23]=[N:24][N:25]([C:27]2[N:36]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:35](=[O:45])[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[CH3:7])[CH:33]=3)[N:28]=2)[CH:26]=1)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Reactant: Cc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2nc3ccc(-c4ccccc4C)cc3c(=O)n2COCC[Si](C)(C)C)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 89.4 %

Procedure:
A mixture of potassium carbonate (85.4 mg 0.618 mmol), 2-methylphenylboronic acid (63.3 mg, 0.466 mmol), 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (110 mg, 0.204 mmol), and THF (1.5 ml) was degassed for 5 minutes with nitrogen in a sealable tube. The dichloromethane adduct of 1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium (20.2 mg, 0.0246 mmol) was added to the reaction mixture and the pressure tube was sealed. The reaction mixture was stirred at 80° C. for 18 h. The reaction mixture was cooled to 23° C., diluted with DCM (10 ml), and filtered. The filtrate was concentrated. The residue was purified by FCC (3-40% EtOAc/hexanes) to yield the titled compound (92.0 mg, 90%). MS (ESI): mass calcd. for C27H32N4O4Si, 504.22; m/z found, 446.6 [M−CH2OCH2CH2+H]+. 1H NMR (600 MHz, CDCl3): 8.68 (d, J=0.6 Hz, 1H), 8.31-8.30 (m, 1H), 8.18 (d, J=0.6 Hz, 1H), 7.79 (dd, J=8.3, 2.1 Hz, 1H), 7.76-7.74 (m, 1H), 7.33-7.28 (m, 4H), 5.91 (s, 2H), 4.39-4.35 (m, 2H), 4.37 (q, J=7.2 Hz, 2H), 2.31 (s, 3H), 1.39 (t, J=7.1 Hz, 3H), 0.83-0.79 (m, 2H), −0.08 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][CH3:10])[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=1.[CH3:23][NH:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1.CCN(C(C)C)C(C)C>CC#N.[OH-].[Na+].CCOC(C)=O>[CH2:9]([S:8][C:6]1[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=[C:2]([N:24]([CH3:23])[CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[N:7]=1)[CH3:10]
Reactant: CNCC1CCCCO1
Reactant: CCSc1nc(Cl)cc(C)c1C(=O)NCc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCSc1nc(N(C)CC2CCCCO2)cc(C)c1C(=O)NCc1cccc(F)c1
Yield: 37.3 %

Procedure:
A solution of 254 mg (0.75 mmol) 6-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide (synthesis is described in section b) of example 2), 322 mg (2.25 mmol) N-methyl-1-(tetrahydro-2H-pyran-2-yl)methanamine and 392 μl (2.25 mmol) DIPEA in MeCN (2 ml) was heated in the microwave at 150° C. for 4.5 h. Subsequently the RM was diluted with a 2M aq. NaOH sol and EtOAc and the layers were separated. The organic layer was washed with water and brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 1:1) provided 122 mg (0.28 mmol, 38%) 2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-[methyl-(tetrahydro-pyran-2-yl-methyl)-amino]-pyridine-3-carboxylic acid amide (example 5). [M+H]+ 432.2.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH3:26])[CH2:20][CH2:19]2)=[C:12]([F:27])[CH:11]=1.CN([CH:31]=[O:32])C>C1COCC1>[Br:9][C:10]1[C:11]([CH:31]=[O:32])=[C:12]([F:27])[C:13]([CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH3:26])[CH2:20][CH2:19]2)=[CH:14][CH:15]=1
Reactant: CCCC1CCC(CCc2ccc(Br)cc2F)CC1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC1CCC(CCc2ccc(Br)c(C=O)c2F)CC1
Temperature: -70 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Under a nitrogen atmosphere, LDA (299.0 mL, 328.9 mmol) was slowly added dropwise, at −70° C. or lower, to a THF (400 mL) solution of compound (76) (89.7 g, 274.1 mmol). The reaction mixture was agitated at −70° C. or lower for 1 hour, and then DMF (30.1 g, 411.1 mmol) was slowly added dropwise thereto. The reaction mixture was returned to room temperature, and then quenched with 400 mL of 1N hydrochloric acid aqueous solution, and extracted with 200 mL of toluene three times. Combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was purified by silica gel column chromatography, and thus 6-bromo-2-fluoro-3-(2-(4-propylcyclohexyl)ethyl)benzaldehyde (77) (61.4 g, yield 63.1%) was obtained.
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18](F)(F)F)[CH:15]=2)[CH:10]=[C:9]1B(O)O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].I[C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:36][CH2:35][CH2:34][S:33]2(=[O:38])=[O:37])=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH:10]=[C:9]1[C:26]1[CH:27]=[CH:28][C:29]([N:32]2[CH2:36][CH2:35][CH2:34][S:33]2(=[O:38])=[O:37])=[CH:30][CH:31]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=S1(=O)CCCN1c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccc(OC(F)(F)F)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc2cc(-c3ccc(N4CCCS4(=O)=O)cc3)n(C(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-Boc-6-trifluoromethoxyindole-2-boronic acid prepared above (0.74 g, 2.1 mmol), 2-(4-iodophenyl)isothiazolidine-1,1-dioxide (0.76 g, 2.4 mmol), and PdCl2(dppf) (0.08 g, 0.1 mmol) in DMF (6.0 mL), is added K2CO3 solution (3.2 mL, 2.0 M, 6.4 mmol). The mixture is stirred at room temperature overnight and then poured into ice-water (100 mL). The precipitate is collected and washed with water and purified by flash column chromatography (silica gel, DCM/EtOAc, 9/1) to furnish 1-Boc-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole, which is treated with 50% TFA in DCM (15 mL) at room temperature for 1 h. After the removal of the volatiles, the residue is carefully stirred with saturated NaHCO3 for 0.5 h. The precipitate is collected via filtration and washed thoroughly with water and dried to provide essentially pure 1-H-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-trifluoromethoxyindole.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]([CH3:46])([CH3:45])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[CH:21][C:20]=1[C:38]1[N:39]([CH3:44])[N:40]=[CH:41][C:42]=1[Cl:43].[CH:47](=O)[CH2:48][CH2:49][CH3:50].C(Cl)(=O)C>C1COCC1.CO>[CH2:47]([NH:15][C:16]([CH3:46])([CH3:45])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=2)=[CH:21][C:20]=1[C:38]1[N:39]([CH3:44])[N:40]=[CH:41][C:42]=1[Cl:43])[CH2:48][CH2:49][CH3:50]
Reactant: CCCC=O
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(C)(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCCCNC(C)(C)COc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.9 %

Procedure:
Sodium triacetoxyborohydride (34 mg, 161 μmol) was added to a solution of N-(4-(2-amino-2-methylpropoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)phenyl)-3-(trifluoromethyl)benzamide (53.8 mg, 115 μmol) and butyraldehyde (8 mg, 115 μmol) in THF (0.5 mL), and the mixture was stirred at room temperature. After 4 hours, the reaction was quenched with saturated sodium bicarbonate and extracted with dichloromethane. The extract was evaporated to dryness, the residue was redissolved in methanol, and the products were isolated by preparative HPLC. Product containing fractions were combined and concentrated in a vacuum centrifuge to one fourth of the original volume. The solution was made alkaline with saturated sodium bicarbonate, the product was extracted with dichloromethane, and the extract was evaporated to dryness. The residue was dissolved in a solution of acetyl chloride (16 μl, 230 μmol) in methanol (1 mL) and evaporated to dryness. The residue was dissolved in water and lyophilized to give the title compound (24 mg, 37%) as the hydrochloride salt. LCMS m/z (%)=553.6 (M+H, 37Cl 34.5), 551.6 (M+H, 35Cl 100.0%). 1H NMR (400 MHz, DMSO-d6) δ 0.88 (t, J=7.33 Hz, 3H) 1.21-1.34 (m, 2H) 1.26 (s, 6H) 1.40-1.54 (m, 2H) 2.55-2.71 (m, 2H) 3.65 (s, 3H) 4.05 (d, J=10.36 Hz, 1H) 4.15 (d, J=10.36 Hz, 1H) 7.32 (d, J=9.09 Hz, 1H) 7.68 (s, 1H) 7.72 (d, J=2.78 Hz, 1H) 7.80 (t, J=7.71 Hz, 1H) 7.93-8.01 (m, 2H) 8.27 (d, J=7.83 Hz, 1H) 8.30 (s, 1H) 8.58 (s, 2H) 10.58 (s, 1H).