Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:6](I)[C:5]2=[O:19].[C:20]([O:24][C:25](=[O:46])[NH:26][C:27]1([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH2:30][CH2:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[C:20]([O:24][C:25](=[O:46])[NH:26][C:27]1([C:31]2[CH:32]=[CH:33][C:34]([C:6]3[C:5](=[O:19])[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=4)[O:8][C:7]=3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:35][CH:36]=2)[CH2:28][CH2:29][CH2:30]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Reactant: O=c1c(I)c(-c2ccccc2)oc2ccc(F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Temperature: 125 °C
Yield: 30.2 %

Procedure:
To a microwave vial were added 6-fluoro-3-iodo-2-phenyl-chromen-4-one (55 mg, 0.15 mmol), {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (62 mg, 0.165 mmol, prepared as described in WO2008/070016), sodium carbonate solution (2M in water, 0.26 mL, 0.53 mmol), tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.015 mmol) and DME (3 mL). The reaction mixture was purged using argon and heated in a microwave reactor to 125° C. for 30 min. The mixture was partitioned between water (2 mL) and EtOAc (3 mL). The aqueous phase was extracted with ethyl acetate (3 mL). The combined organic extracts were washed with brine (5 mL), dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 30% ethyl acetate in cyclohexane) to afford the title compound (22 mg, 30%). 1H NMR (400 MHz, CDCl3): δ 7.95-7.90 (m, 1H), 7.57-7.52 (m, 1H), 7.46-7.30 (m, 6H), 7.28-7.22 (m, 2H), 7.21-7.16 (m, 2H), 5.03 (s, 1H), 2.64-2.31 (m, 4H), 2.14-2.00 (m, 1H), 1.89-1.77 (m, 1H), 1.48-1.18 (m, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[N:14]1[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20]C(=O)OC(C)(C)C)[CH2:15]1)([O-:3])=[O:2].[ClH:28]>>[ClH:28].[ClH:28].[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[N:14]1[CH2:19][CH2:18][CH2:17][C@H:16]([NH2:20])[CH2:15]1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1
Agent: Cl
Product: N[C@H]1CCCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of (S)-tert-butyl 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ylcarbamate (15.64 g, 40 mmol) was cooled to 7° C. and hydrochloric acid 4.0 M dioxane (80 ml, 321 mmol) was added and the mixture allowed to warm to ambient temperature. The orange solution was allowed to stir for 14 h, at which point it was concentrated in vacuo to give (S)-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-amine dihydrochloride as a yellow solid. MS m/z=290 [M+H]+. Calc'd for C12H14F3N3O2: 289.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C@:11]12[CH2:19][O:18][CH2:17][C@H:16]1[C:15](=[O:20])[N:14]([CH3:21])[C:13]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[N:12]2>[Zn]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@:11]23[CH2:19][O:18][CH2:17][C@H:16]2[C:15](=[O:20])[N:14]([CH3:21])[C:13]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[N:12]3)[CH:4]=1
Reactant: CN1C(=O)[C@@H]2COC[C@]2(c2cc([N+](=O)[O-])ccc2F)N=C1NC(=O)OC(C)(C)C
Agent: [Zn]
Product: CN1C(=O)[C@@H]2COC[C@]2(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 105.7 %

Procedure:
(±)-tert-Butyl ((4aS*,7aS*)-7a-(2-fluoro-5-nitrophenyl)-3-methyl-4-oxo-3,4,4a,5,7,7a-hexahydrofuro[3,4-d]pyrimidin-2-yl)carbamate (60 mg, 0.14 mmol) was transferred into the reaction vessel. Zinc (100 mg, 1.53 mmol) was transferred into the reaction vessel. The reaction was stirred at 0° C. for 30 mins. The reaction was filtered, concentrated and the residue was purified by flash chromatography (EtOAc/Hexane, 20-100%) to give the title compound (56 mg). LCMS (Method A) Rt 2.33 min, ESI-MS: m/z 279 [MH-BOC]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([C@H:19]([CH2:30][OH:31])[CH2:20][CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:13][C@H:12]1[CH3:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33]I>>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([C@H:19]([CH2:30][O:31][CH3:33])[CH2:20][CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:13][C@H:12]1[CH3:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: C[C@@H]1CN([C@H](CO)CCOCc2ccccc2)C(=O)CCN1C(=O)OCc1ccccc1
Product: COC[C@H](CCOCc1ccccc1)N1C[C@@H](C)N(C(=O)OCc2ccccc2)CCC1=O

Procedure:
In analogy to the procedure described in intermediate 6B, (R)-4-((S)-3-benzyloxy-1-hydroxymethyl-propyl)-2-methyl-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester and methyl iodide gave the title compound in quantitative yield as white oil. MS: 455.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[NH:16][C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:19])[O:3]1.[CH2:21](Br)[C:22]#[CH:23]>>[CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH2:23][C:22]#[CH:21])[C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:19])[O:3]1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Reactant: C#CCBr
Product: C#CCn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2

Procedure:
5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-2-carbonitrile (0.74 g, 2.8 mmol) and propargylbromide (0.5 g, 4.2 mmol) were reacted, according to General Method A, to afford the title compound, m.p. 222-224° C. (0.13 g, 15%); 1H-NMR (DMSO-d6): δ 1.65 (s, 6H), 3.64 (t, J=2.3 Hz, 1H), 4.85 (d, J=2.3 Hz, 2H), 6.37 (d, J=4 Hz, 1H), 7.01 (d, J=8.2 Hz, 1H), 7.11 (d, J=4 Hz, 1H), 7.43 (m, 2H), 10.45 (s, 1H), MS (APCI (−)) m/z 304 (M−H)−
Reaction SMILES: [CH2:1]([O:5][C:6]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])[CH3:7])[C:2](=C)[CH3:3].CC[O:16]C(C)=O>>[CH2:9]([O:8][C:6]([O:11][CH2:12][CH3:13])([O:5][CH2:1][C:2](=[O:16])[CH3:3])[CH3:7])[CH3:10]
Reactant: C=C(C)COC(C)(OCC)OCC
Reactant: CCOC(C)=O
Product: CCOC(C)(OCC)OCC(C)=O
Reaction time: 8 h
Yield: 82 %

Procedure:
To a cold (0° C.) suspension of NaH (2.68 g, 60%) in THF (150 mL) was added a solution of 1,1-diethoxyethanol [which was prepared according to the literature procedure of Zirkle, C. L. et. al. J. Org. Chem. 1961, 26, 395-407] (9.00 g) in THF (20 mL), and the reaction mixture was stirred at room temperature for 1 hour before adding methallyl chloride (8.0 mL). The reaction mixture was heated to reflux overnight, cooled and filtered through a plug of celite. Solvent was removed by rotary evaporation, and the residue purified by column chromatography (silica, 20% ether/hexane) to give 1,1-diethoxyethyl methallyl ether (11.5, 90%). ozonolysis of a chilled (−30° C.) solution of this ether (6.00 g) in EtOAc (80 mL) was carried out until no starting material was detectable by TLC (1 hour). At this time, the reaction was purged with oxygen, treated with Pd(OH)2 (150 mg) and stirred under an atmosphere of hydrogen overnight. The catalyst was filtered away, and the filtrate was concentrated by rotary evaporation. The resulting residue was purified by column chromatography (silica, 20% EtOAc/hexane) to afford the title compound (4.53 g, 82%).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:31](=[O:32])[C:30]5[CH:34]=[CH:35][C:27]([F:26])=[CH:28][CH:29]=5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)c1ccc(F)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)c1ccc(F)cc1

Procedure:
The title compound, white solid (17 mg, 60%), MS (ISP) m/z=453.2 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (24 mg, 0.0595 mmol) and 4-fluorobenzoic acid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[N:4][C:5]([CH:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1.S(Cl)(Cl)=O.[C:18]([O-])([O-])=O.[Na+].[Na+]>CO.CCOC(C)=O>[CH3:18][O:12][C:11]([C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([CH:8]([CH3:9])[CH3:10])[N:4]=1)=[O:13]
Reactant: CC(C)c1ncc(Br)c(C(=O)O)n1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(C(C)C)ncc1Br
Temperature: 25 °C
Reaction time: 17 h
Yield: 94 %

Procedure:
To a stirred, cooled (0° C.) solution of 5-bromo-2-isopropyl-pyrimidine-4-carboxylic acid (3 g, 12.2 mmol) in methanol (50 ml) under an argon atmosphere was added dropwise thionyl chloride (4.37 g, 2.68 ml, 36.7 mmol). When the addition was complete, the mixture was allowed to warm to rt and stirring at rt was continued for 17 h. The orange mixture was concentrated to leave a paste which was taken up in EtOAc (50 ml)/saturated aqueous Na2CO3 solution (50 ml). The aqueous phase was extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried over MgSO4, filtered and concentrated to leave the product (2.98 g, 94%) as a light brown oil which was used in the next reaction step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:16][C:17]1[CH:30]=[CH:29][C:20]2[C:21]([C:25]([NH:27][CH3:28])=[O:26])=[C:22]([CH3:24])[O:23][C:19]=2[CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[O:16][C:17]1[CH:30]=[CH:29][C:20]2[C:21]([C:25]([NH:27][CH3:28])=[O:26])=[C:22]([CH3:24])[O:23][C:19]=2[CH:18]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: CNC(=O)c1c(C)oc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(=O)c1c(C)oc2cc(Oc3ncnc4cc(OC)c(OC)cc34)ccc12
Reaction time: 10 h
Yield: 85 %

Procedure:
To a solution of 4-chloro-6,7-dimethoxyquinazoline (1 equiv.) in 2 ml CH3CN were added 6-hydroxy-N,2-dimethylbenzofuran-3-carboxamide (1 equiv.) and K2CO3 (1.5 equiv.). The mixture was refluxed under stirring for 10 hr. After the solvent was evaporated, the residue was washed with water, dried over MgSO4, filtered, concentrated, and purified by column chromatography to give the title compound in a yield of 85%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[O:13][CH:12]=[CH:11][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=2)[O:25][C:26]=1[CH3:27].COC1C=C(C=C(OC)C=1)C=O.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[O:13][CH:12]=[CH:11][C:10]=2[C:9]([O:15][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:8][CH:7]=1
Reactant: CCOC(Cc1ccc(O)c2ccoc12)C(=O)OC
Reactant: COc1cc(OC)cc(-c2nc(CCl)c(C)o2)c1
Agent: COc1cc(C=O)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(Cc1ccc(OCc2nc(-c3cc(OC)cc(OC)c3)oc2C)c2ccoc12)C(=O)OC

Procedure:
In analogy to the procedure described in example 120 f], [rac]-2-ethoxy-3-(4-hydroxy-benzofuran-7-yl)-propionic acid methyl ester (example 120 e]) was reacted with 4-chloromethyl-2-(3,5-dimethoxy-phenyl)-5-methyl-oxazole (prepared from 3,5-dimethoxy-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 21 a] and b]) in the presence of potassium carbonate and potassium iodide to yield [rac]-3-{4-[2-(3,5-dimethoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzofuran-7-yl}-2-ethoxy-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-3-{4-[2-(3,5-dimethoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzofuran-7-yl}-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)/[C:8](=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1)/[C:7]([CH3:21])=[C:6]2[CH2:22][C:23]([OH:25])=O.C(Cl)(=O)C([Cl:29])=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)/[C:8](=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1)/[C:7]([CH3:21])=[C:6]2[CH2:22][C:23]([Cl:29])=[O:25]
Reactant: COc1ccc2c(c1)C(CC(=O)O)=C(C)/C2=C/c1ccc(SC)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(CC(=O)Cl)=C(C)/C2=C/c1ccc(SC)cc1

Procedure:
(Z)-5-methoxy-2-methyl-1-(p-methylthiobenzylidene)-3-indenylacetic acid (70 mmol) in absolute THF (500 ml) is heated with oxalylchloride (2 M in CH2Cl2 ; 70 mmol) at reflux (24 hours). The solvent is evaporated to yield the title compound, which is used as such in the next step.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([CH3:22])[NH:21][C:14]=23)[CH2:3][CH2:2]1.Cl[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([CH3:22])[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:14]=23)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C)ccc3OCC3CC3)ccnc12
Reactant: C[Si](C)(C)CCOCCl
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(C)ccc3OCC3CC3)ccnc12

Procedure:
Starting from ethyl 7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (example D.a6) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is prepared as pale yellow viscous oil.
Reaction SMILES: [Cl-].C[O:3][C:4]([C@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH2+:7]1)=O.C(OCC)(=O)C.[OH-].[Na+].[NH3:20]>>[NH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C@@H:6]1[C:4]([NH2:20])=[O:3]
Reactant: N
Reactant: COC(=O)[C@H]1CCCC[NH2+]1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: NC(=O)[C@H]1CCCCN1
Temperature: 60 °C

Procedure:
(2R)-2-(Methoxycarbonyl)piperidinium chloride (2.6 g, 14.5 mmol) was dissolved in ammonia (0.88M, 30 ml). The reaction mixture was heated at 60° C. for 1.5 hr. The mixture was partitioned between ethyl acetate (100 ml) and sodium hydroxide (1N, 100 ml, 100 mmol), the aqueous was washed with ethyl acetate (3×100 ml). The combined organic layers were dried over sodium sulphate and the solvent evaporated under reduced pressure. Aqueous layer was acidified with hydrochloric acid and evaporated to dryness under reduced pressure. The resultant white solid was triturated with dichloromethane:methanol (9:1), the remaining solid was removed by filtration and the filtrate evaporated under reduced pressure to afford the title compound as a white solid, 1.14 g, (61%). LRMS: m/z=129 (MH+).
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=2[CH:14]([NH:17][S@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[CH:15]=[CH2:16])[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:34](Br)[CH:35]=[CH2:36]>CN(C=O)C>[CH2:36]([N:17]([CH:14]([C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[S:4][CH:1]1[CH2:3][CH2:2]1)[CH:15]=[CH2:16])[S@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[CH:35]=[CH2:34]
Reactant: C=CCBr
Reactant: C=CC(N[S@@](=O)C(C)(C)C)c1cc([N+](=O)[O-])ccc1SC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=CCN(C(C=C)c1cc([N+](=O)[O-])ccc1SC1CC1)[S@@](=O)C(C)(C)C
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 80.2 %

Procedure:
To 85B (2.46 g, 6.95 mmol) in DMF (20 mL) at −20° C. was added lithium bis(trimethylsilyl)amide (1.0 M in THF, 12.2 mL, 12.2 mmol) dropwise. The mixture was stirred at −20° C. for 20 min followed by addition of allyl bromide (3.0 mL, 34.8 mmol). After 1.0 h stirring at −20° C., the reaction was quenched with sat. NH4Cl and warmed to rt. It was extracted with EtOAc (3×50 mL), the organic layer was washed with brine and dried over Na2SO4. After removal of solvent, the crude was purified by silica gel column chromatography using gradient EtOAc in hexanes to give 85C (2.2 g, 80% yield). HPLC and 1H NMR indicated 85C is a mixture of two diastereoisomers in a ratio of 5:1. Major isomer: 1H NMR (400 MHz, CDCl3) δ ppm 0.67-0.76 (m, 2H) 1.15-1.20 (m, 2H) 1.25 (s, 9H) 2.12-2.20 (m, 1H) 3.02 (dd, J=17.14, 6.59 Hz, 1H) 4.05 (dd, J=17.14, 4.83 Hz, 1H) 5.06-5.26 (m, 5H) 6.00 (ddd, J=17.03, 10.22, 7.03 Hz, 1H) 7.70 (t, J=8.13 Hz, 1H) 8.10 (dd, J=8.79, 2.64 Hz, 1H) 8.49 (d, J=2.64 Hz, 1H), LC-MS 395 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:28]2[CH2:37][CH2:36][C:31]3(OCC[O:32]3)[CH2:30][CH2:29]2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([O:26][CH3:27])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].Cl>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:28]2[CH2:29][CH2:30][C:31](=[O:32])[CH2:36][CH2:37]2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([O:26][CH3:27])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(C2CCC3(CC2)OCCO3)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC)CC1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1sc(C2CCC(=O)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
The product of step III was dissolved in THF (40 mL), 3N HCl (20 mL) was added to this solution, and the mixture was heated for 3 h at 50° C., then for an additional 3 h at 60° C. The mixture was brought to room temperature, extracted with CH2Cl2, washed with sodium bicarbonate and brine, organic fraction was separated, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography on silica gel using hexanes-EtOAc gradient to afford 726 mg (85%) of 3-[(trans-4-methoxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(4-oxocyclohexyl)-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH2:1]([CH:3]1[C:12]2[C:7](=[N:8][C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=2)[N:6]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[CH2:5][CH2:4]1)[CH3:2].[Li+].[OH-].Cl>C1COCC1.O>[CH2:1]([CH:3]1[C:12]2[C:7](=[N:8][C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=2)[N:6]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCOC(=O)CCCCCCN1CCC(CC)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC1CCN(CCCCCCC(=O)O)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of rac-ethyl 7-(8-ethyl-2,3-diphenyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 1) (15 mg, 0.032 mmol) in THF (4.5 ml) and water (1.5 ml) was added LiOH (4.57 mg, 0.191 mmol). The reaction mixture was heated to reflux for 3.5 hours and stirred at RT overnight. The pH of the reaction mixture was adjusted to pH<5 by addition of 2M HCl. The volatile solvent was removed in vacuo and the crude residue was dissolved in water (10 ml) and extracted with EtOAc (3×10 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to afford the title compound;
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=1N)([CH3:3])[CH3:2].N([O-])=O.[Na+].CCCCCC.[BrH:22]>O.[Cu]Br>[Br:22][C:5]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: Cc1cccc(C(C)C)c1N
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: Cc1cccc(C(C)C)c1Br
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
2-isopropyl-6-methylanilin (14.9 g, 0.1 mol) was solved in conc hydrobromic acid (40 ml) and the mixture was cooled to 5° C. Sodium nitrite (7.0 g, 0.1 mol) in water (15 ml) was added so that the temperature was below 10° C. A solution of copper(I)bromide in conc hydrobromic acid (10 ml) was added to the reaction mixture and the temperature was allowed to raise to room temperature. The mixture was stirred for 1 h. at room temperature and 30 min at 40° C. Hexane was added and the organic layer was separated and evaporated under reduced pressure. Purification by column chromatography on silica gel using hexane as eluent gave 6.9 g (32%) of the title compound as an oil.
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.[NH:17]1[C:21]2[CH:22]=[C:23]([N:26]3[CH:30]([C:31]4[CH:32]=[N:33][C:34]5[C:39]([CH:40]=4)=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:29]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[C:28]([OH:47])[C:27]3=[O:48])[CH:24]=[CH:25][C:20]=2[N:19]=[CH:18]1>CO.O>[NH:19]1[C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]([C:31]4[CH:32]=[N:33][C:34]5[C:39]([CH:40]=4)=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:29]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)=[C:28]([O:47][CH3:3])[C:27]3=[O:48])=[CH:22][C:21]=2[N:17]=[CH:18]1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: O=C1C(O)=C(c2ccccc2)C(c2cnc3ccccc3c2)N1c1ccc2nc[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC1=C(c2ccccc2)C(c2cnc3ccccc3c2)N(c2ccc3[nH]cnc3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (10 eq in water), diazald (5 eq) ethylene glycol/Et2O (3/1 v/v), 1-(1H-benzo[d]imidazol-6-yl)-5-(quinolin-3-yl)-3-hydroxy-4-phenyl-1H-pyrrol-2(5H)-one (0.230 g, 0.5 mmol, 1 eq) and MeOH/H2O (90/10 v/v); yield: 0.003 g (1.4%); MS m/z: 433.4 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 4.17 (s, 3H), 6.85, 6.87 (2s, 1H), 7.19-7.22 (m, 1H), 7.30-7.34 (m, 2H), 7.37-7.41 (m, 1H), 7.45-7.53 (m, 2H), 7.60-7.63 (m, 1H), 7.69-7.71 (m, 2H), 7.78-7.80 (m, 1H), 7.84-7.86 (m, 2H), 8.11 (s, 1H), 8.35 (s, 1H), 8.84 (s, 1H); HPLC (METHOD [A]): rt 12.26 min (100%)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:16]2[C:17]([CH2:28][OH:29])=[N:18][N:19]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[C:20]=2[CH3:21])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1>ClCCl.O=[Mn]=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:16]2[C:17]([CH:28]=[O:29])=[N:18][N:19]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[C:20]=2[CH3:21])[CH:9]=[C:10]([C:12]([F:13])([F:15])[F:14])[CH:11]=1
Reactant: COCCOc1cc(-c2c(CO)nn(C3CCCCO3)c2C)cc(C(F)(F)F)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COCCOc1cc(-c2c(C=O)nn(C3CCCCO3)c2C)cc(C(F)(F)F)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 124.1 %

Procedure:
A mixture of (R/S) (4-(3-(2-methoxyethoxy)-5-(trifluoromethyl)phenyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methanol (70 mg, 0.17 mmol, 1.00 equiv) and MnO2 (147 mg, 1.69 mmol, 10.01 equiv) in dichloromethane (20 mL) was stirred at 40° C. for 1 h. The solid was removed by filtration. The filtrate was concentrated under vacuum to give 87 mg of crude (R/S) 4-(3-(2-methoxyethoxy)-5-(trifluoromethyl)phenyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carbaldehyde as a brown oil.