Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]([OH:15])C)=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[CH:27]2[CH:22]([C:23]3([CH3:29])[O:28][CH:26]2[CH2:25][CH2:24]3)[C:21](=[O:30])[CH:20]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([CH2:13][O:15][C:19]3[CH:27]4[CH:22]([C:23]5([CH3:29])[O:28][CH:26]4[CH2:25][CH2:24]5)[C:21](=[O:30])[CH:20]=3)=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: CC12CCC(O1)C1C(Cl)=CC(=O)C12
Reactant: CC(O)c1cnc(-c2ccc(Cl)cc2)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC12CCC(O1)C1C(OCc3cnc(-c4ccc(Cl)cc4)s3)=CC(=O)C12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.1 %

Procedure:
To a solution of 1-[2-(4-chloro-phenyl)-thiazol-5-yl]ethanol (264 mg, 1.1 mmol) in tetrahydrofuran (5 ml) is added in one portion the sodium hydride (60% dispersion in mineral oil, 44 mg, 1.1 mmol). The reaction mixture is stirred for five minutes at room temperature and 5-Chloro-1-methyl-10-oxa-tricyclo[5.2.1.0*2,6*]dec-4-en-3-one (219 mg, 1.1 mmol) is added in one-portion. The reaction mixture is stirred at room temperature overnight. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give 5-[2-(4-chloro-phenyl)-thiazol-5-ylmethoxy]-1-methyl-10-oxa-tricyclo[5.2.1.0*2,6*]dec-4-en-3-one (410 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH:4]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[CH3:1][CH:2]([CH3:22])[CH2:3][CH:4]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(C(CC(C)C)Oc2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CC(Oc1ccccc1)c1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 100.5 %

Procedure:
A mixture of methyl 4-(3-methyl-1-phenoxybutyl)benzoate (25 mg, 0.084 mmol), lithium hydroxide monohydrate (42 mg, 1 mmol), tetrahydrofuran (6 mL), methanol (2 mL) and water (2 mL) was stirred at 20° C. for 4 hours. The mixture was acidified to pH=1 with concentrated hydrochloric acid and then extracted with dichloromethane (10 mL×3). The combined organic phase was dried by sodium sulfate and filtered. The filtrate was concentrated in vacuo to give 4-(3-methyl-1-phenoxybutyl)benzoic acid (24 mg, 99%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.[Li]CCCC.[C:13](=[O:15])=[O:14]>CCOCC>[Br:7][C:5]1[N:6]=[C:2]([C:13]([OH:15])=[O:14])[S:3][CH:4]=1
Reactant: Brc1csc(Br)n1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(O)c1nc(Br)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of 2,4-dibromothiazole (50 g, 207 mmol, 1.0 eq.) in Et2O (1000 mL) was added n-BuLi (90 mL, 2.5 M, 1.1 eq.) at −78° C. dropwise and it was stirred for one hour. The reaction solution was poured into dry CO2 at −78° C. and the reaction mixture was warmed to the room temperature. TLC and LCMS showed the reaction was complete. It was quenched with water (100 ml). The Et2O phase was removed. The aqueous phase was adjusted to pH to 2-3 and extracted with ethyl acetate. The organic phase was dried, filtered and concentrated to obtain 4-bromothiazole-2-carboxylic acid. 1HNMR (400 MHz, DMSO): δ 8.23 (1H, s).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH3:18])[CH2:4][CH2:3]1.O.NN>C(O)C.[Ni].O>[CH3:18][O:17][C:9]1[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:8]=1[N:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1
Reactant: COc1ccc([N+](=O)[O-])cc1N1CCN(C)CC1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(N)cc1N1CCN(C)CC1
Yield: 53 %

Procedure:
To a solution of the product of step (a) (5.07 g) in ethanol (70 ml) was added a paste of Raney Nickel in water (2 g). To the warmed suspension was added, with constant agitation, hydrazine hydrate (5 ml) dropwise during 20 min with occasional warming. After the main effervescence had ceased, the suspension was heated for 15 min and then filtered with the aid of ethanol under nitrogen. The residues were kept moist and washed with ethanol and the combined filtrate and washings were evaporated to dryness with the aid of ethanol. The dark residue was re-evaporated with ethanol (20 ml), resuspended in ether (40 ml) and the mixture filtered. The residue was washed with ether and dried to give a solid consisting of the title compound (2.365 g)
Reaction SMILES: C(O)(C)C.[CH3:5][NH:6][CH3:7].[C-]#N.[Na+].[C:11]1([C:17]2[C:23]3[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=3[N:21]3[C:29]([CH:32]=[O:33])=[N:30][N:31]=[C:20]3[CH2:19][N:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCOCC1.O1CCOCC1.C(O)(C)C.[O-2].[O-2].[Mn+4].C(Cl)Cl>[CH3:5][N:6]([CH3:7])[C:32]([C:29]1[N:21]2[C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[C:17]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:18][CH2:19][C:20]2=[N:31][N:30]=1)=[O:33]
Reactant: CNC
Reactant: O=Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: [Mn+4]
Agent: [C-]#N
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C)C(=O)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 0.17 h

Procedure:
80 ml of isopropanol is added to 120 ml of a 20% solution of dimethylamine in dioxane. After this has cooled to 0°, additions are made, with stirring, of 3.7 g (0.075 mole) of sodium cyanide and, after 5 minutes, of a solution of 4.8 g (0.015 mole) of 6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxaldehyde [see Example 1 a)] in 50 ml of dioxane/isopropanol (1:1), as well as of 13 g of manganese dioxide. After 10 minutes, a further addition is made of 13 g of manganese dioxide (total 0.3 mole), and the mixture subsequently stirred for 4 hours at 0°. After the addition of methylene chloride, the reaction mixture is filtered and the filtrate concentrated by evaporation. Crystallisation of the residue from ethyl acetate/petroleum ether yields N,N-dimethyl-6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxamide, M.P. 180°- 181° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:23])([CH3:22])[CH2:19][CH2:20][OH:21])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([CH3:23])([CH3:22])[CH2:19][CH:20]=[O:21])=[CH:16][CH:17]=1
Reactant: CC(C)(CCO)c1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CC=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.6 %

Procedure:
12 mL of a 2 M solution of oxalyl chloride in dichloromethane was diluted with 19 mL of dichloromethane and cooled on a dry ice/acetone bath. To this solution was added a dropwise a solution of 3.6 mL of DMSO in 16 mL of dichloromethane. After 10 minutes, a solution of 3-(4-fluorophenyl)-3-methylbutan-1-ol (3.6 g, 19.8 mmol) in 12 mL of dichloromethane was added and the mixture was stirred for 15 minutes. 14 mL of triethylamine was then added, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature and was quenched with water and diluted with hexanes. The organic layer was separated, washed with water, dried, filtered, and concentrated in vacuo. The residue was purified by chromatography over silica gel (eluent: hexanes to hexanes-dichloromethane (9:1), gradient) to give 1.2 g of 3-(4-fluorophenyl)-3-methylbutyraldehyde as an oil.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=2)[CH2:9][CH2:8]1.O1CCOCC1.[NH3:34]>O>[Cl:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH2:34])=[O:20])=[CH:17][CH:16]=2)[CH2:9][CH2:8]1
Reactant: N
Reactant: O=C(Cl)c1ccc(CCN2CCN(Cc3ccccc3Cl)CC2)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1ccc(CCN2CCN(Cc3ccccc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 14.2 g. (31.5 mmole) 4-{2-[1-(2-chlorobenzyl)-piperazin-4-yl]-ethyl}-benzoyl chloride dihydrochloride and 150 ml. dioxan, there is added dropwise, while stirring at ambient temperature, within the course of 30 minutes, a solution of 100 ml. concentrated aqueous ammonia in 50 ml. dioxan. The reaction mixture is stirred for a further 30 minutes and then sufficient water is added thereto to precipitate out the desired amide. After suction filtration, drying and recrystallisation from toluene, there are obtained 8.5 g. (75% of theory) of amide; m.p. 170°-173° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[CH3:11][C:12]([C:14]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=1[O:22][CH3:23])=[O:13].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[CH:11][C:12]([C:14]1[C:15]([O:22][CH3:23])=[CH:16][CH:17]=[CH:18][C:19]=1[O:20][CH3:21])=[O:13]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: COc1cccc(OC)c1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc(OC)c1C(=O)C=Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.5 %

Procedure:
(40) To a solution of 2,6-dichlorobenzaldehyde (485 mg, 2.77 mmol) and 2,6-dimethoxyacetophenone (500 mg, 2.77 mmol) in 4.1 ml of methanol was added 1.0 ml of 40% sodium hydroxide in water at 10° C. After stirring for 1.5 hours at room temperature, a solid appeared and was filtered. The precipitate was recrystallized from methanol to afford 481 mg (51.5%) of faint-yellow needles: mp 126.8-127.8° C. 1H NMR (250 MHz) δ 7.48-7.42 (d, 1 H), 7.37-7.31 (m, 3 H), 7.11-7.04 (d, 1 H), 6.63-6.60 (d, 2 H), 3.81 (s, 6 H); 13C NMR (62.7 MHz) 195.1, 158.0, 138.4, 136.5, 135.2, 132.6, 131.4, 130.0, 129.0, 117.9, 104.2, 56.1 ppm. Elemental Analysis. Calculated for C17H14Cl2O3: C, 60.55; H, 4.19. Found: C, 60.60; H, 4.18.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:10]([C:21](OC)=[O:22])[CH2:9]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:22][CH2:21][CH:10]1[CH2:9][CH:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: COC(=O)C1CC(OC2CCCCO2)CCN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OC2CCCCO2)CC1CO
Temperature: -20 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of the product of step E (5.0 g, 14.6 mmol) in tetrahydrofuran (50 mL) at −20° C. was added lithium aluminum hydride (1.14 g, 30 mmol). After stirring at −20° C. for 1 h, the reaction was quenched by slow addition of water (10 mL). The resulting suspension was filtered through Celite and the filtrate concentrated in vacuo to dryness. Water (60 mL) was added and the aqueous phase was extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash column chromatography (SiO2, 4:1 to 7:3, hexanes/ethyl acetate) afforded tert-butyl 2-(hydroxymethyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)piperidine-1-carboxylate (4.1 g, 81%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 4.73-4.63 (m, 1H), 4.44-4.23 (m, 1H), 4.02-4.00 (m, 1H), 3.90-3.70 (m, 4H), 3.50-3.48 (m, 1H), 3.21-2.42 (m, 1H), 2.09-1.93 (m, 1H), 1.82-1.71 (m, 5H), 1.54 (br s, 5H), 1.47 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:30])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([C@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1.[NH3:31]>O1CCOCC1>[NH2:31][C:2]1[C:7]2[C:8](=[O:30])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([C@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: N
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(N3CCOc4ncnc(Cl)c4C3=O)cc2)CC1
Solvent: C1COCCO1
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(N3CCOc4ncnc(N)c4C3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of methyl {trans-4-[4-(4-chloro-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6-(5H)-yl)phenyl]cyclohexyl}acetate, from Preparation 1, (5.29 g, 12.3 mmol) in 0.5M ammonia in p-dioxane (120 mL) was stirred at room temperature for 24 hours. The reaction mixture was concentrated in vacuo, diluted into EtOAc (1 L), washed with water, saturated aqueous brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound as an off-white solid, 5.04 g. 1H NMR (400 MHz, CDCl3): δ 8.22 (s, 1H), 8.16 (br s, 1H), 7.23 (d, 2H), 7.16 (d, 2H), 5.75 (br s, 1H), 4.63 (m, 2H), 3.98 (m, 2H), 3.64 (s, 3H), 2.44 (m, 1H), 2.21 (m, 2H), 1.81 (m, 5H), 1.42 (m, 2H), 1.10 (m, 2H). m/z=411.3 (M+1). IC50 34.5 nM (range 30-40 nM).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+]>>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[CH:7]=[N:6][C:5]([C:3]([NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Yield: 65.9 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (60 mg, 0.19 mmol), β-alanine (862 mg, 9.68 mmol) and NaOMe solution (14.5 mL, 7.26 mmol, 0.5 M in MeOH) was refluxed for 16 h. Solvent was evaporated in vacuo, and the residue was partitioned between water (50 mL) and EtOAc (50 mL). 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (10-80% EtOAc/hexanes+2% AcOH) to give 46 mg of the title compound as a light yellow solid. MS: (+) m/z 368.08 (M+1).
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)([Cl:17])=O>>[N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([Cl:17])=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1ccc(-n2ccnc2)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(-n2ccnc2)cc1

Procedure:
A suspension of 4-(imidazol-1-yl)benzoic acid (0.90 g) in thionyl chloride (2.0 ml) was heated on a steam bath under argon for one hour. Evaporation of the volatile material under reduced pressure afforded a residue which crystallized upon the addition of hexane to yield the 4-(imidazol-1-yl)benzoyl chloride as the hydrochloride salt (1.17 g), m.p. 242-247° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]2[N:9]=[C:10]([NH2:15])[N:11]=[C:12]([NH:24][C:21]3[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=3)[CH:13]=2)[CH:7]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Product: Cc1ccc(Br)cc1-c1cc(Nc2ccc(Cl)cc2)nc(N)n1
Yield: 76 %

Procedure:
Following the method described in Example 26, 4-(5-bromo-2-methyl-phenyl)-6-chloro-pyrimidin-2-ylamine and 4-chloro-phenylamine provided the title compound (76% yield). 1H NMR (DMSO-d6) δ 2.35 (s, 3H, CH3), 6.39 (s, 1H, Ar), 7.40 (d, 1H, J=8.4 Hz, Ar), 7.47 (d, 2H, J=8.5 Hz, Ar), 7.70-7.71 (m, 2H, Ar), 7.84-7.89 (m, 2H, Ar), 10.95 (br s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17](Cl)=[O:18])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([S:27]([F:30])(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17]([NH:20][C:21]3[CH:22]=[C:23]([S:27]([F:30])(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=3)=[O:18])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Reactant: Nc1cccc(S(=O)(=O)F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cccc(S(=O)(=O)F)c1)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (3.00 g, 9.70 mmol) was added to 3-amino-benzenesulfonyl fluoride (1.87 g, 10.6 mmol) in CH2Cl2 (50 ml) containing pyridine (2.35 ml, 29.1 mmol). Reaction mixture stirred overnight at room temperature, concentrated under reduced pressure and crude product purified by column chromatography to give 3-{[1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-benzenesulfonyl fluoride (3.23 g, 74%).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[N+](C1C=CC=CC=1C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O-])=O.C([C@@H]1COC(C)(C)N1C(OC(C)(C)C)=O)=O.[CH3:53][C:54]1([CH3:77])[N:58]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[C@H:57]([CH:66]=[CH:67][C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=2[N+:74]([O-])=O)[CH2:56][O:55]1>O1CCOCC1.CCOC(C)=O.[Pd].O>[NH2:74][C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][C:68]=1[CH2:67][CH2:66][C@@H:57]1[CH2:56][O:55][C:54]([CH3:77])([CH3:53])[N:58]1[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60]
Reactant: CC(C)(C)OC(=O)N1[C@H](C=Cc2ccccc2[N+](=O)[O-])COC1(C)C
Agent: [Pd]
Agent: CC(C)(C)OC(=O)N1[C@H](C=O)COC1(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@H](CCc2ccccc2N)COC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium tert-butoxide (498 mg, 4.44 mmol) was added to a solution of (2-nitrobenzyl)triphenylphosphonium chloride (2.04 g, 4.89 mmol) in 1,4-dioxane (10 mL) under an atmosphere of argon. The mixture was stirred for 30 min at room temperature and then at 80° C. for 40 min. A solution of tert-butyl (4S)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylate (510 mg, 2.22 mmol) in 1,4 dioxane (3.0 mL) was added with a syringe. The resulting mixture was refluxed for 4 h and then allowed to come to room temperature overnight. The reaction mixture was poured into water and extracted with EtOAc (×3). The organic phases were combined and washed with brine and dried with MgSO4. The crude product was purified by flash chromatography eluting with petroleum ether/EtOAc 9:1 to afford a (Z)/(E) mixture of tert-Butyl (4R)-2,2-dimethyl-4-[2-(2-nitrophenyl)vinyl]-1,3-oxazolidine-3-carboxylate as a yellow oil. 288 mg of the obtained product was dissolved in EtOAc (10 ml), added Pd/C (40 mg, 10%) and then stirred under an atmosphere of hydrogen (1 atm) for 4 h. The reaction mixture was filtered through a pad of decalite and concentrated in vacuo. The crude product was purified by flash chromatography eluting with petroleum ether/EtOAc 2:1 to afford the title compound as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:23][C:24](=[O:39])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]#[C:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:26]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([N:34]5[CH:38]=[CH:37][N:36]=[CH:35]5)[CH:29]=4)[CH2:25][C:24](=[O:39])[NH:23][C:9]=3[CH:10]=2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1NC(=O)CC(=O)c1ccnc(-n2ccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2ccnc(-n3ccnc3)c2)=Nc2ccc(C#Cc3ccc(F)cc3)cc2N1

Procedure:
Prepared from {4-(4-fluoro-phenylethynyl)-2-[3-(2-imidazol-1-yl-pyridin-4-yl)-3-oxo-propionylamino]-phenyl}-carbamic acid tert.-butyl ester (Example K43) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light brown solid (189 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH3:9])[C:5](F)=[CH:4][N:3]=1.[NH2:12][NH2:13]>C(O)CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:8]([CH3:9])=[N:13][NH:12][C:5]2=[CH:4][N:3]=1
Reactant: NN
Reactant: CC(=O)c1cc(Br)ncc1F
Solvent: OCCO
Product: Cc1n[nH]c2cnc(Br)cc12
Temperature: 165 °C
Reaction time: 3.5 h

Procedure:
To a 150 mL sealed flask containing 50 mL dry ethylene glycol was dissolved 1-(2-bromo-5-fluoro-4-pyridinyl)ethanone (8.2 g, 37.6 mmol). Added dropwise via syringe next was anhydrous hydrazine (1.24 mL, 39.5 mmol). The stirred light yellow mixture was sealed, and heated at 165° C. After 3.5 h, the orange-tan reaction mixture was removed from heating. After cooling to room temperature, the contents were poured onto a stirring mixture of 300 g ice/water (1:1), wherein solid precipitation occurred. After stirring for 10 min, the off-white precipitate was collected. This solid was dried in vacuo and collected 5-Bromo-3-methyl-1H-pyrazolo[3,4-c]pyridine as an off-white solid (7.9 g, 99%). ESI MS m/z=212 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:26]2[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[O:11])=[C:13]([C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)[CH:14]=1
Reactant: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2-c2ncccn2)[C@@H]1CN
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2-c2ncccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(4-fluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 475 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 9.00-6.70 (m, 9H), 4.95-2.75 (m, 5H), 2.00-0.65 (m, 8H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[NH:17][C:18]([CH3:23])=[C:19]([CH:21]=O)[N:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCCl.C(O)(=O)C>[CH3:15][C:16]1[NH:17][C:18]([CH3:23])=[C:19]([CH2:21][NH:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)[N:20]=1
Reactant: Cc1nc(C=O)c(C)[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1nc(CNC2CCN(C(=O)OC(C)(C)C)CC2)c(C)[nH]1
Yield: 108.2 %

Procedure:
N-(tert-butoxycarbonyl-4-piperidinyl)amine (4.8 g), 2,5-dimethylimidazole-4-carbaldehyde (3.0 g) and acetic acid (1.7 ml) were dissolved in 1,2-dichloroethane (50 ml), under ice-cooling, sodium triacetoxyborohydride (7.7 g) was added thereto, and mixed at room temperature for 15 hours. The reaction solution was poured into an aqueous potassium carbonate solution, and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and then the residue was purified with silica gel column to obtain a pale yellow oily title compound (8.0 g, quantitative).