Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:28][CH2:29][C:30](Cl)=[O:31]>O>[Cl:28][CH2:29][C:30]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[CH:8]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=[CH:11][C:2]=1[CH3:1])=[O:31]
Reactant: Cc1ccc(C(F)(F)F)cc1NCC=O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(C(F)(F)F)cc1N(CC=O)C(=O)CCl
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2-methyl-5-trifluoromethylanilino)acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0° C. and α-chloroacetyl chloride (0.11 mole) is incrementally added with stirring. After the addition is completed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochloric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-chloroacetyl-2-methyl-5-trifluoromethylanilino)-acetaldehyde.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH:10]=[N:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=[N:13][OH:14])=[CH:4][CH:3]=1.ClN1C(=O)CCC1=O.[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])[CH:27]=[C:26]([Cl:36])[CH:25]=1.C(N(CC)CC)C>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH2:31][C:30]([C:28]3[CH:27]=[C:26]([Cl:36])[CH:25]=[C:24]([Cl:23])[CH:29]=3)([C:32]([F:33])([F:35])[F:34])[O:14][N:13]=2)=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2
Reactant: ON=Cc1ccc(Br)c2cnccc12
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(Br)c3cnccc23)=NO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 8-bromo-5-isoquinolinecarboxaldehyde oxime (i.e. the product from Step B) (70 mg, 0.28 mmol) in N,N-dimethylformamide (2.0 mL) was added N-chlorosuccinimide (64 g, 0.48 mmol). The reaction mixture was stirred for 0.5 h at room temperature, and then a solution of 1,3-dichloro-5-[1-(trifluoromethyl)ethenyl]benzene (135 mg, 0.56 mmol) (i.e. the product from Example 1, Step B) and triethylamine (0.12 mL, 0.86 mmol) in N,N-dimethylformamide (1.5 mL) was added. After stirring for an additional 12 h at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using hexanes/ethyl acetate as eluent to afford the title compound (20 mg) contaminated with some impurity.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18](O)=[O:19])=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:26][CH2:27][C@H:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[OH:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([NH:26][CH2:27][C@@H:28]([OH:29])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:19])=[O:14])[CH2:9][CH2:8]2)=[CH:24][CH:25]=1
Reactant: NC[C@@H](O)c1ccccc1
Reactant: O=C(O)c1cccc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)c1
Product: O=C(NC[C@@H](O)c1ccccc1)c1cccc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)c1
Yield: 51 %

Procedure:
The title compound was prepared in 51% yield (10.1 mg) prepared from 3-(4-(4-chlorophenoxy)piperidine-1-carbonyl)benzoic acid (Step-2) according to the procedure similar to that described in Step-2 of Example 349, using (S)-2-amino-1-phenylethanol instead of 25% ammonium water.
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([C:22]2[O:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:25][N:26]=2)=[N:20][C:19]([C:33]2[CH2:42][CH2:41][C:36]3(OCC[O:37]3)[CH2:35][CH:34]=2)=[CH:18][N:17]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.CC(O)=O.O.[OH-].[Na+]>CCOC(C)=O>[NH2:8][C:16]1[N:17]=[CH:18][C:19]([C:33]2[CH2:42][CH2:41][C:36](=[O:37])[CH2:35][CH:34]=2)=[N:20][C:21]=1[C:22]1[O:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:25][N:26]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(C2=CCC3(CC2)OCCO3)nc1-c1nnc(-c2ccccc2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Nc1ncc(C2=CCC(=O)CC2)nc1-c1nnc(-c2ccccc2)o1
Yield: 82 %

Procedure:
A solution of tert-butyl N-tert-butoxycarbonyl-N-[5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]carbamate in (40 mg, 0.069 mmol) AcOH (832 mg, 788 μL, 13.85 mmol) and H2O (50 mg, 50 μL, 2.8 mmol) was heated at 80° C. for 2 h. The reaction mixture was diluted with 10 ml of EtOAc and pH was adjusted to 8 with 1N NaOH. The reaction mixture was washed with 20 ml of NaHCO3. The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to obtain 4-[5-amino-6-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]cyclohex-3-en-1-one (19 mg, 82%), which was used as crude for the next step. LC/MS m/z 334.0 [M+H]+.
Reaction SMILES: C([O:4][CH2:5][C:6]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[N:23]=1)([OH:21])[CH2:7][N:8]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH3:20])[CH:14]=1)(=[O:12])=[O:11])[CH3:9])(=O)C.C(N(CC)CC)C.O>CO>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([S:10]([N:8]([CH2:7][C:6]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[N:23]=2)([OH:21])[CH2:5][OH:4])[CH3:9])(=[O:11])=[O:12])=[CH:14][C:15]=1[CH3:20]
Reactant: CC(=O)OCC(O)(CN(C)S(=O)(=O)c1ccc(Cl)c(C)c1)c1cccc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: Cc1cc(S(=O)(=O)N(C)CC(O)(CO)c2cccc(Cl)n2)ccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.1 %

Procedure:
A mixture of 1.5 g of 1-acetoxy-3-[N-(4-chloro-3-methylbenzenesulfonyl)-N-methylamino]-2-(6-chloropyridin-2-yl)-2-hydroxypropane, 1 ml of triethylamine, 1 ml of water and 2 ml of methanol was stirred at room temperature for 4 hours. The reaction mixture was left to stand overnight, and the deposited crystals were filtered out and washed with water-containing methanol to obtain 1.17 g of the objective compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:29][CH3:30])=[C:15]([CH:17]3[CH2:22][CH2:21][N:20](C(=O)C(F)(F)F)[CH2:19][CH2:18]3)[CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:29][CH3:30])=[C:15]([CH:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)[CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)c2ccc(Cl)cc2)cc1C1CCN(C(=O)C(F)(F)F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(S(=O)(=O)c2ccc(Cl)cc2)cc1C1CCNCC1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 88.5 %

Procedure:
To a suspension of 1-{4-[5-(4-chloro-benzenesulfonyl)2-methoxyphenyl]piperidin-1-yl}-2,2,2-trifluoro-ethanone (31) (77 mg) in methanol (2 mL), a solution of 6N NaOH (0.5 mL) was added. After stirring at 80° C. for 10 min, water was added (10 ml) and the mixture was extracted into ethyl acetate (20 ml). The organic phase was dried (Na2SO4) and concentrated in vacuo to give 4-[5-(4-chloro-benzenesulfonyl)2methoxy-phenyl] piperidine (301) as a white solid (0.054 g ), MS, MH+ 365. The hydrochloride salt was prepared from ethanol-hydrogen chloride, m.p. 235.5-236.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20]2)=[CH:15][CH:14]=1.Cl([O-])=[O:29].[Na+].O.O.OP([O-])(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O.CC(=CC)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:29])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20]2)=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)N1CCC(c2ccc(-c3cc4c(C=O)c[nH]c4cc3Cl)cc2)C1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)(C)O
Solvent: O
Product: CS(=O)(=O)N1CCC(c2ccc(-c3cc4c(C(=O)O)c[nH]c4cc3Cl)cc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
To a solution of 6-chloro-5-{4-[1-(methylsulfonyl)pyrrolidin-3-yl]phenyl}-1H-indole-3-carbaldehyde (120 mg, 0.298 mmol) in acetonitrile (5 mL) and tert-butanol (5 mL) was added 2-methyl-2-butene (4 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (299.5 mg, 3.29 mmol) and sodium phosphate monobasic dihydrate (697 mg, 4.47 mmol) in water (2 mL) dropwise. After the reaction mixture was stirred for 2 h at room temperature, additional sodium chlorite (399.3 mg, 4.39 mmol) and sodium phosphate monobasic dihydrate (930 mg, 5.96 mmol) in H2O (2 mL) and 2-methyl-2-butene (1 mL) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated in vacuo and the aqueous residue was extracted with EtOAc (3×40 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in DMSO and purified via prep-HPLC to give 6-chloro-5-{4-[1-(methylsulfonyl)pyrrolidin-3-yl]phenyl}-1H-indole-3-carboxylic acid (56 mg) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:15]([CH2:19][CH:20]([OH:23])[CH2:21][F:22])[CH2:16][CH2:17][OH:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:22][CH2:21][CH:20]([O:23][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:19][N:15]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:16][CH2:17][O:18][S:25]([CH3:24])(=[O:27])=[O:26]
Reactant: OCCN(Cc1ccccc1)CC(O)CF
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCCN(Cc1ccccc1)CC(CF)OS(C)(=O)=O
Yield: 108.6 %

Procedure:
7.27 g (0.072 mole) of triethylamine were added to a solution of 6.75 g (0.03 mole) of N-benzyl-N-(3-fluoro-2-hydroxypropyl)ethanolamine [prepared as described in step (a) above] in 200 ml of ethyl acetate. Whilst stirring and ice-cooling the mixture, 8.24 g (0.072 mole) of methanesulfonyl chloride were added to it. After the resulting mixture had been stirred for 3 hours at the same temperature, an aqueous solution of sodium bicarbonate was added to it. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to give 12.49 g of N-(3-fluoro-2-methylsulfonyloxypropyl)-N-(2-methylsulfonyloxyethyl)benzylamine as a pale yellow oil.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH3:14].[NH2:15][C@H:16]([C:20]([OH:23])([CH3:22])[CH3:21])[C:17]([OH:19])=[O:18].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:15][C@H:16]([C:20]([OH:23])([CH3:22])[CH3:21])[C:17]([OH:19])=[O:18])=[C:3]([CH3:14])[C:4]=1[C:10]([F:13])([F:12])[F:11])#[N:7]
Reactant: CC(C)(O)[C@@H](N)C(=O)O
Reactant: Cc1c(F)ccc(C#N)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(N[C@@H](C(=O)O)C(C)(C)O)ccc(C#N)c1C(F)(F)F
Temperature: 85 °C
Reaction time: 18 h
Yield: 96.7 %

Procedure:
4-fluoro-3-methyl-2-(trifluoromethyl)benzonitrile (763 mg, 3.76 mmol) was mixed together with (R)-2-amino-3-hydroxy-3-methylbutanoic acid (500 mg, 3.76 mmol) in DMSO (25 mL). K2CO3 (1.56 g, 11.28 mmol) was added to the reaction mixture and the reaction mixture stirred at 85° C. for 18 h. The reaction mixture was allowed to cool to room temperature, quenched with H2O (25 mL) and extracted with EtOAc (2×30 mL). The aqueous layer was then acidified with solid citric acid and extracted with EtOAc (2×80 mL). The later organic extracts were combined, washed with H2O (2×30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provided the title compound as a yellow solid (1.15 g, 97%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 7.63 (d, J=9 Hz, 1H), 6.97 (d, J=9 Hz, 1H), 5.62 (d, J=9 Hz, 1H), 4.20 (d, J=9 Hz, 1H), 2.33 (s, 3H), 1.43 (s, 3H) and 1.42 (s, 3H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[O:8][C:7]([C:9]2[N:10]=[C:11]([NH:14][C:15]([NH2:17])=[S:16])[S:12][CH:13]=2)=[CH:6][CH:5]=1)#[N:2].[CH3:18][I:19]>CO.O1CCCC1>[IH:19].[NH2:17][C:15](=[N:14][C:11]1[S:12][CH:13]=[C:9]([C:7]2[O:8][C:4]([CH2:3][C:1]#[N:2])=[CH:5][CH:6]=2)[N:10]=1)[S:16][CH3:18]
Reactant: N#CCc1ccc(-c2csc(NC(N)=S)n2)o1
Reactant: CI
Solvent: CO
Solvent: C1CCOC1
Product: CSC(N)=Nc1nc(-c2ccc(CC#N)o2)cs1
Product: I

Procedure:
A mixture of 4-(5-cyanomethylfuran-2-yl)-2-thioureidothiazole (11.4 g) and methyl iodide (2.7 ml) in methanol (110 ml) and tetrahydrofuran (60 ml) was refluxed for 1.5 hours under stirring. Evaporation of the solvent gave a residue, which was triturated with ethyl acetate to give 2-[(amino)(methylthio)methyleneamino]-4-(5-cyanomethylfuran-2-yl)thiazole hydriodide (14.50 g).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].N([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=C=O>N1C=CC=CC=1>[O:10]=[C:2]1[NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1]1.[CH3:19][CH2:18][CH:17]([C:2]([NH2:3])=[O:10])[CH2:16][CH2:15][CH3:14]
Reactant: CCCCCCN=C=O
Agent: O=c1[nH]c2ccccc2s1
Solvent: c1ccncc1
Product: CCCC(CC)C(N)=O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
75 mg (0.45 mmol) of 3H-benzothiazol-2-one were dissolved in 10 ml of pyridine. Addition of 76 mg (0.59 mmol) of 1-isocyanatohexane was followed by stirring at 100° C. for 6 h, addition once again of the same amount of isocyanatohexane and stirring at 100° C. for 6 h. The reaction mixture was concentrated, and the residue was dissolved in water and extracted with ethyl acetate. The organic phase was concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 38 mg (28%), M+H+: 279.15.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.C1C(=O)N([Br:20])C(=O)C1.Cl.C(OCC)(=O)C>CC(C)=O>[Br:20][C:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Oc1ccc2cc(Br)ccc2c1Br

Procedure:
6-Bromo-2-naphthol (500 mg, 2.242 mmol, 1 eq) and NBS (558.7 mg, 3.319 mmol, 1.4 eq) are stirred at RT in 4.4 ml of acetone and 22 μl of 1 N HCl for 15 min. Ethyl acetate is added, and this organic phase is washed three times with 1 N HCl. After drying over magnesium sulfate, filtering and concentrating in vacuum on a rotary evaporator, the desired product is obtained in quantitative yield (677 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([C:20]2[CH:29]=[C:28]3[C:23]([CH:24]=[CH:25][C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:27]3)=[CH:22][CH:21]=2)[N:9]2C(=O)C3C(=CC=CC=3)C2=O)=[N:4][CH:5]=[CH:6][N:7]=1.NN.C(Cl)Cl>CCO>[Cl:1][C:2]1[C:3]([CH:8]([NH2:9])[C:20]2[CH:29]=[C:28]3[C:23]([CH:24]=[CH:25][C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:27]3)=[CH:22][CH:21]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C1c2ccccc2C(=O)N1C(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Agent: NN
Solvent: ClCCl
Solvent: CCO
Product: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl

Procedure:
A solution of 2-[(3-chloropyrazin-2-yl)-(2-phenylquinolin-7-yl)-methyl]-isoindole-1,3-dione (1.536 g, 3.22 mmol) and anhydrous hydrazine (335 μL, 342 mg, 10.7 mmol) in EtOH (2 mL)/CH2Cl2 (12 mL) is stirred at rt overnight. The white precipitate formed is filtered off and washed with CH2Cl2. The combined filtrate and washings are concentrated in vacuo, the residue is suspended in CDCl3 and filtered (0.45 μM pore size), and the filtrate is concentrated in vacuo to obtain the title compound as yellow foam, which is used for the next step without further purification; 1H NMR (CDCl3, 400 MHz): δ2.4 (brs, 2H), 5.79 (s, 1H), 7.43-7.55 (m, 3H), 7.61 (dd, J=1.8, 8.6 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 8.06 (d, J=1.2 Hz, 1H), 8.10-8.15 (m, 2H), 8.19 (d, J=8.8 Hz, 1H), 8.31 (d, J=2.4 Hz, 1H), 8.60 (d, J=2.4 Hz, 1H); MS (ES+):m/z347.0/349.0(30/10) [MH+], 330.0/332.0 (18/6) [MH+-NH3]; HPLC: tR=2.1 min (MicromassZQ, polar—5 min).
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH3:4][C:5]([CH3:11])([C:9]#[CH:10])[C:6]([OH:8])=[O:7]>CCOCC>[CH3:4][C:5]([CH3:11])([C:9]#[CH:10])[C:6]([O:8][CH3:3])=[O:7]
Reactant: C#CC(C)(C)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: C#CC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.4 %

Procedure:
To a solution of diazomethane (˜10 g) in ether (400 mL) was added dropwise 2,2-dimethyl-but-3-ynoic acid (10.5 g, 93.7 mmol) at 0° C. The mixture was warmed to room temperature and stirred overnight. The mixture was distilled under atmospheric pressure to give crude methyl 2,2-dimethylbut-3-ynoate (14 g), which was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ 3.76 (s, 3H), 2.28 (s, 1H), 1.50 (s, 6H).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([S:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)[C:9]2[CH:10]=[N:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:42][O:43][C:44](=[O:48])[CH2:45][CH2:46][NH2:47].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:42][O:43][C:44](=[O:48])[CH2:45][CH2:46][NH:47][C:30](=[O:31])[C:29]1[CH:28]=[CH:27][C:26]([S:25][CH:8]([C:9]2[CH:10]=[N:11][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:34][CH:33]=1
Reactant: COC(=O)CCN
Reactant: O=C(O)c1ccc(SC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1ccc(SC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a mixture of 4-{2-cyclohexyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethylsulfanyl}-benzoic acid (100 mg, 0.5 mmol) in methylene chloride (5 mL) are added triethyl amine (0.09 mL, 0.62 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl ester (86.2 mg, 0.62 mmol) and EDCI (118.7 mg, 0.62 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving 3-(4-{2-cyclohexyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethylsulfanyl}-benzoylamino)-propionic acid methyl ester (90 mg).
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:9][CH2:8]2)[S:4][N:3]=1.Cl.[F:24][C:25]1([F:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CN1CCCC1=O>[F:24][C:25]1([F:31])[CH2:30][CH2:29][N:28]([C:2]2[N:6]=[C:5]([N:7]3[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[CH2:9][CH2:8]3)[S:4][N:3]=2)[CH2:27][CH2:26]1
Reactant: COc1ccc(CCN2CCN(c3nc(Br)ns3)CC2)cc1
Reactant: FC1(F)CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1ccc(CCN2CCN(c3nc(N4CCC(F)(F)CC4)ns3)CC2)cc1
Temperature: 200 °C

Procedure:
A mixture of 3-bromo-5-(4-(4-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole (55 mg, 143 μmol), 4,4-difluoropiperidine hydrochloride (67.8 mg, 430 μmol) and DIPEA (185 mg, 251 μl, 1.43 mmol) in N-Methyl-2-pyrrolidinone (1 mL) was heated with microwave at 200° C. for 2.5 h. The amber reaction solution was purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3 to yield after evaporation of the product containing fractions 41.8 mg (69%) of the title compound as off-white solid. MS (m/e): 424.2 (MH+).
Reaction SMILES: C[C:2]1[C:3]([Cl:10])=[N:4][C:5]([Cl:9])=[N:6][C:7]=1Cl.[F:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH2:14][NH2:15].C(N(CC)CC)C>CO>[Cl:9][C:5]1[N:6]=[C:7]([NH:15][CH2:14][C:13]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:12]=2[F:11])[CH:2]=[C:3]([Cl:10])[N:4]=1
Reactant: Cc1c(Cl)nc(Cl)nc1Cl
Reactant: NCc1ccc(F)cc1F
Solvent: CO
Solvent: CCN(CC)CC
Product: Fc1ccc(CNc2cc(Cl)nc(Cl)n2)c(F)c1
Reaction time: 1 h
Yield: 37.97 %

Procedure:
A suspension of methyl 2,4,6-trichloropyrimidine (1 g, 4.87 mmol) in methanol (20 ml) was cooled −20° C., to this 2,4-difluoro benzylamine (0.627 mg, 4.39 mmol) and triethylamine (0.98 mg, 9.74 mmol) were added. RM was stirred at same temperature for 1 hr then at room temperature for 4 hrs. Methanol was removed under vacuum. The residue was purified by column chromatography to get the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:29])[CH2:18][N:19]3[C:23]([CH3:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[N:20]3)[CH2:13][CH2:12]2)[S:9][CH:10]=1)=[O:5])C.[OH-].[Na+].Cl>CO>[CH3:24][C:23]1[N:19]([CH2:18][C:17]([N:14]2[CH2:15][CH2:16][CH:11]([C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=3)[CH2:12][CH2:13]2)=[O:29])[N:20]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:22]=1
Reactant: CCOC(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.1 %

Procedure:
A solution of ethyl-2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarboxylate (13.0 g, 30.2 mmol) (i.e. the product of Example 19, Step B) in 60 mL of methanol was cooled to 0° C. and treated with a 1 N aqueous NaOH solution (36.3 mL, 36.3 mmol). The reaction mixture was allowed to warm to room temperature, and stirred for 5 h. The reaction mixture was cooled again to 0° C. and treated with 1 N aqueous hydrochloric acid (36.3 mL, 36.3 mmol). The resulting precipitate was filtered, washed with water and dried in a vacuum oven at 100° C. to give 10.95 g of the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[CH3:32][O-:33].[Na+]>CO>[CH3:32][O:33][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6]
Reactant: C[O-]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: [Na+]
Solvent: CO
Product: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Yield: 44 %

Procedure:
The mixture of 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (46.0 mg, 0.1 mmol), 0.1 M NaOMe (4 ml) in methanol (2 mL) was refluxed overnight. The reaction mixture was concentrated and purified by reverse phase HPLC (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (20.0 mg, 44%).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[CH:4][C:3]=1[F:19].C([N-]C(C)C)(C)C.[Li+].CN(C)[CH:30]=[O:31].C(O)(=O)C>O1CCCC1.O>[Br:1][C:2]1[C:3]([F:19])=[C:4]([C:5]([O:6][CH2:7][CH2:8][O:9][Si:10]([C:13]([CH3:15])([CH3:14])[CH3:16])([CH3:11])[CH3:12])=[CH:17][CH:18]=1)[CH:30]=[O:31]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(Br)c(F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Br)c(F)c1C=O
Yield: 64.5 %

Procedure:
In a manner similar to the method described in example 52a, 1 [2-(4-bromo-3-fluoro-phenoxy)-ethoxy]-tert-butyl-dimethyl-silane (17.2 g, 49.3 mmol) prepared in example 183a was reacted with lithium diisopropyl amide (32.8 mL, 2.0 M in THF, 59.1 mmol), N,N-dimethyl-formamide (4.57 mL, 59.1 mmol) and quenched with acetic acid (12.1 g, 197.2 mmol) and water (61.8 mL) in tetrahydrofuran to give 3-bromo-6-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-2-fluoro-benzaldehyde as white solid (Yield: 12 g, 67%).