Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14][CH2:15][OH:16])=[CH:8][CH:7]=1)=[CH2:5])C.[Br:25]NC(=O)CCC(N)=O>O1CCCC1.O>[Br:25][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14][CH2:15][OH:16])=[CH:8][CH:7]=1)=[O:5]
Reactant: C=C(OCC)c1ccc(C[C@@H](CCO)NC(=O)OC(C)(C)C)cc1
Reactant: NC(=O)CCC(=O)NBr
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CCO)Cc1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a cooled (0° C.) solution of 1,1-dimethylethyl [(1S)-1-({4-[1-(ethyloxy)ethenyl]phenyl}methyl)-3-hydroxypropyl]carbamate (15 g, 44 mmol) in tetrahydrofuran (450 mL) and water (150 mL) was added N-bromosuccinamide. The resulting solution was allowed to warm to room temperature and maintained for 90 minutes. The reaction was then concentrated and diluted with ethyl acetate (1 L). The resulting solution was washed with water (1 L) and brine (500 mL), dried (MgSO4) and concentrated to give 19.5 g (˜100%) of 1,1-dimethylethyl ((1S)-1-{[4-(bromoacetyl)phenyl]methyl}-3-hydroxypropyl)carbamate as a slightly yellow solid. ESMS [M+H]+: 386.2.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH3:7][N:8]=[C:9]=[O:10]>CN(C)C=O>[NH2:1][C:2]1[N:3]([C:9]([NH:8][CH3:7])=[O:10])[N:4]=[CH:5][N:6]=1
Reactant: CN=C=O
Reactant: Nc1nc[nH]n1
Solvent: CN(C)C=O
Product: CNC(=O)n1ncnc1N
Yield: 81 %

Procedure:
The synthesis method of Example 1-(3) was applied. 3-Amino-1H-1,2,4-triazole (5.00 g), dimethylformamide (30 ml) and methyl isocyanate (4.0 ml) were used as reagents. The mixture was stirred at room temperature i:or 18 hours and 6.83 g of the resulting solid (yield 81%) was collected by filtration. The obtained solid was recrystallized from ethyl acetate to give colorless transparent crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:20]I>O1CCCC1.CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)[N:8]([CH3:20])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c(-c2ccnc(N)n2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccnc(N)n2)n(C)c1
Reaction time: 12 h
Yield: 82.3 %

Procedure:
To a solution of 5-(2-amino-pyrimidin-4-yl)-1H-pyrrole-3-carboxylic acid ethyl ester (5.1 g, 21.96 mmol) in tetrahydrofuran (70 mL) and dimethylsulfoxide (15 mL) cooled in a ice-water bath, NaH (0.96 g, 24.15 mmol) and methyl iodide (1.5 mL, 24.15 mmol) were added. The reaction was continued at room temperature for 12 h, tetrahydrofuran was removed under vacuo, then dichloromethane (200 mL) was added and the organic phase washed with water (100 mL). The aqueous fraction was extracted with dichloromethane (100 mL). The organic fractions were combined, dried over sodium sulfate, filtered, and concentered in vacuo. Purification by flash chromatography on silica gel (eluant: dichloromethane/ethanol 95/5) provided 4.45 g (82%) of the title compound as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][C:17](=[O:19])[NH:16][N:15]=3)[CH2:10][CH2:9]2)=[C:4]([F:20])[CH:3]=1.[N+:21]([C:24]1[O:28][C:27]([CH:29]=O)=[CH:26][CH:25]=1)([O-:23])=[O:22]>CC(O)=O.CO>[F:20][C:4]1[CH:3]=[C:2](/[N:1]=[CH:29]/[C:27]2[O:28][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:18][C:17](=[O:19])[NH:16][N:15]=2)[CH2:10][CH2:9]1
Reactant: Nc1ccc(N2CCC(c3n[nH]c(=O)o3)CC2)c(F)c1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Solvent: CC(=O)O
Solvent: CO
Product: O=c1[nH]nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3F)CC2)o1
Yield: 81 %

Procedure:
5-[1-(4-Amino-2-fluorophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (7e, 0.28 g, 1 mml) on reacting with 5-nitro2-furaldehyde in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 10 h and the obtained solid is filtered, washed with water and recrystallized in ethanol to obtain product 5-[1-(2-fluoro-4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9e, 324 mg, 81%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].[C:14](O)(=[O:21])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[Cl:8][C:7]1[C:6]([C:9]([F:12])([F:10])[F:11])=[CH:5][CH:4]=[C:3]([OH:13])[C:2]=1[NH:1][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccncc1
Reactant: Nc1c(O)ccc(C(F)(F)F)c1Cl
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1c(O)ccc(C(F)(F)F)c1Cl)c1ccncc1
Temperature: 80 °C
Yield: 59 %

Procedure:
A mixture of 0.17 g of 2-amino-3-chloro-4-trifluoromethylphenol, 0.99 g of isonicotinic acid, 0.19 g of WSC and 3 ml of pyridine was stirred while heating at 80° C. for two hours. The mixture was cooled to room temperature, and then water was poured, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.15 g of N-[2-chloro-6-hydroxy-3-(trifluoromethyl)pheny]isonicotinamide.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:21]1(OCC[O:24]1)[CH2:22][Br:23])[C:5]([NH:7][CH:8]1[C:19](=[O:20])[N:10]2[CH:11]([C:16]([OH:18])=[O:17])[CH:12]([OH:15])[CH2:13][S:14][C@H:9]12)=[O:6]>C(O)(=O)C>[CH3:1][O:2][N:3]=[C:4]([C:21](=[O:24])[CH2:22][Br:23])[C:5]([NH:7][CH:8]1[C:19](=[O:20])[N:10]2[CH:11]([C:16]([OH:18])=[O:17])[CH:12]([OH:15])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12)C1(CBr)OCCO1
Solvent: CC(=O)O
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Yield: 66.2 %

Procedure:
7-[2-Methoxyimino-3,3-ethylenedioxy-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 1 g.), 70% aqueous hydroperchloric acid (0.2 ml.) and acetic acid (2 ml.) were treated in a similar manner to that of Example 10 (4) to give 7-[2-methoxyimino-3-oxo-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 0.6 g.).
Reaction SMILES: [C:1]([Si:5]([CH3:42])([CH3:41])[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:9][C:8]=1[CH3:40])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Br[CH2:50][C:51]#[N:52].O>CN(C=O)C.C1COCC1.C(OCC)C>[C:1]([Si:5]([CH3:42])([CH3:41])[O:6][C:7]1[C:8]([CH3:40])=[CH:9][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([O:31][Si:32]([C:35]([CH3:36])([CH3:38])[CH3:37])([CH3:33])[CH3:34])=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:50][C:51]#[N:52])[C:15]2=[O:23])=[CH:11][C:12]=1[CH3:13])([CH3:2])([CH3:4])[CH3:3]
Reactant: N#CCBr
Reactant: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)N(CC#N)c3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 72.2 %

Procedure:
Under an N2 atmosphere, dissolve 3,3-Bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1,3-dihydro-indol-2-one (2.5 g, 4.15 mmol) in dry DMF (50 mL). Cool the reaction to 0° C. Add a solution of potassium t-butoxide (1.0 M) in THF (4.57 mL). Allow the reaction to stir at 0° C. for 10 minutes. Add bromoacetonitrile (0.32 mL, 4.57 mmol), and allow the reaction to warm to room temperature. Stir the reaction at room temperature overnight. Dilute the reaction with water (200 mL) and diethyl ether (200 mL). Separate the layers and wash the aqueous layer with diethyl ether (100 mL). Combine the organic layers. Wash the diethyl ether with brine (100 mL), and separate the layers. Dry the organic layer with sodium sulfate and concentrate in vacuo. Purify the crude oil by flash column chromatography. Elute the column with 20% ethyl acetate in hexanes to give 1.92 g (72%) of the title compound: 1H NMR(CDCl3): δ7.36 (td, 1H), 7.29-7.26 (m, 1H), 7.17 (td, 1H), 7.06 (d, 1H), 6.77 (s, 4H), 4.72 (s, 2H), 2.12 (s, 12H), 1.01 (s, 18H), 0.16 (s, 6H) 0.16 (s, 6H).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[C:4]([O:12][CH:13]([CH3:15])[CH3:14])[CH:3]=1.[OH:16][CH2:17][C@@H:18]1[C@:27]2([CH3:28])[C@H:22]([C:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][CH2:26]2)[CH2:21][CH2:20][C@@:19]1([CH3:32])[OH:31].C([O-])([O-])=O.[Cs+].[Cs+].COCCOCCOC>CCOC(C)=O.[Cu]I.C1(C)C=CC=CC=1>[CH3:14][CH:13]([O:12][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=1)[O:16][CH2:17][C@@H:18]1[C@:27]2([CH3:28])[C@H:22]([C:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][CH2:26]2)[CH2:21][CH2:20][C@@:19]1([CH3:32])[OH:31])[CH3:15]
Reactant: CC1(C)CCC[C@]2(C)[C@@H](CO)[C@](C)(O)CC[C@@H]12
Reactant: CC(C)Oc1cc(I)cc(OC(C)C)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOCCOC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(OC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]2(C)O)cc(OC(C)C)c1
Temperature: 120 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
In a sealed tube purged with nitrogen, compound (47) (1.85 g, 5.78 mmol), (1S,2R,4aS,8aS)-1-(hydroxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (3) (1.26 g, 5.25 mmol), Cs2CO3 (2.56 g, 7.87 mmol), 3,4,7,8-tetramethyl-[1,10]-phenylthroline (0.25 g, 1.0 mmol), CuI (0.10 g, 0.70 mmol), diglyme (5 mL) and toluene (20 mL) were placed. The reaction mixture was stirred at 120° C. for 18 h. The reaction was cooled to room temperature, diluted with EtOAc (600 mL) and washed with water (200 mL). The solid material was removed by filtration. The organic layer was separated, dried (Na2SO4) and concentrated. Purification by column chromatography on silica gel (Hexanes/EtOAc, 4:1) gave (1S,2R,4aS,8aS)-1-[3,5-bis(propan-2-yloxy)phenoxymethyl]-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (48) (1.50 g, 66%) as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[NH:17][C:16](=[S:18])[CH2:15][CH2:14][C@@H:13](OC(=O)C)[O:12][C:11](=[O:23])[C:10]2[C:24]([CH3:31])=[C:25]([O:29][CH3:30])[CH:26]=[C:27]([OH:28])[C:9]=2[CH:8](C)[S:7][CH2:6]1)=[O:4].[C:33](=O)([O-])[O-:34].[K+].[K+]>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C@H:5]1[NH:17][C:16](=[S:18])[CH2:15][CH2:14][C@@H:13]([CH2:33][OH:34])[O:12][C:11](=[O:23])[C:10]2[C:24]([CH3:31])=[C:25]([O:29][CH3:30])[CH:26]=[C:27]([OH:28])[C:9]=2[CH2:8][S:7][CH2:6]1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@@H]1CSC(C)c2c(O)cc(OC)c(C)c2C(=O)O[C@H](OC(C)=O)CCC(=S)N1
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CSCc2c(O)cc(OC)c(C)c2C(=O)O[C@H](CO)CCC(=S)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A mixture of 24 mg of the product of Example 11 and 8.3 mg of potassium carbonate in 0.5 ml of methanol was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate and washed successively with 1N hydrochloric acid and with water. The organic layer was dried over sodium sulfate, and the solvent was evaporated in vacuo. The residue was crystallized from ethyl acetate/hexane to yield 16 mg of (4R,9S)-15-hydroxy-9-hydroxymethyl-13-methoxy-12-methyl-11-oxo-6-thioxo-3,4,5,6,7,8,9,11-octahydro-1H-10,2,5-benzoxathiaazacyclotridecine-4-carboxylic acid methyl ester as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.C([Li])CCC.CCCCCC.Br[C:19]1[S:20][C:21]([C:25]2[N:29]3[N:30]=[C:31]([CH3:39])[CH:32]=[C:33]([CH:34]([CH2:37][CH3:38])[CH2:35][CH3:36])[C:28]3=[N:27][C:26]=2[CH3:40])=[C:22]([Br:24])[N:23]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].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]>[Br:24][C:22]1[N:23]=[C:19]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][N:5]=2)[S:20][C:21]=1[C:25]1[N:29]2[N:30]=[C:31]([CH3:39])[CH:32]=[C:33]([CH:34]([CH2:35][CH3:36])[CH2:37][CH3:38])[C:28]2=[N:27][C:26]=1[CH3:40]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)nc3Br)c(C)nc12
Reactant: Cn1cncn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ncnn4C)nc3Br)c(C)nc12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 57.9 %

Procedure:
82 mg of 1-methyl-1,2,4-triazole (0.99 mmol) is dissolved in 2 ml of dry THF and cooled to −78° C. and 0.4 ml of n-butyllithium 2.5 M in hexane (0.99 mmol) is added. The reaction mixture is stirred at −78° C. to room temperature for 10 min and cooled to −78° C. again. 1.98 ml of 0.5 M zinc chloride 0.5 M solution in THF (0.99 mmol) is added and stirred at −78° C. to room temperature for 15 min. 152 mg of 3-(2,4-dibromo-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.33 mmol) and 27 mg of PdCl2(dppf) (0.033 mmol) are added and the vial is capped with a Teflon cap and heated at 80° C. for 2 days. The reaction is cooled to room temperature and quenched with sat. NH4Cl1 and extracted with CH2Cl2. The separated CH2Cl2 layer is dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt:2M NH3 in MeOH=10:2:1) to give 88 mg of the title product. Yield 54%. mass spectrum (m/e): 461 (M+1). 1H-NMR (CDCl3): 7.98 (s, 1H), 6.77 (s, 1H), 4.44 (s, 3H), 3.35 (m, 1H), 2.59 (s, 3H), 2.55 (s, 3H), 1.88 (m, 4H), 0.92 (t, J=7.5 Hz, 6H).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([CH:14]([OH:30])[C:15]3[N:19]4[N:20]=[C:21]([C:24]5[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=5)[CH:22]=[CH:23][C:18]4=[N:17][CH:16]=3)=[CH:10][N:9]2[CH:31]=1)=O.C([O-])([O-])=O.[K+].[K+].O>C1COCC1.CO>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([CH:14]([C:15]3[N:19]4[N:20]=[C:21]([C:24]5[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=5)[CH:22]=[CH:23][C:18]4=[N:17][CH:16]=3)[OH:30])=[CH:10][N:9]2[CH:31]=1
Reactant: Cn1cc(-c2ccc3ncc(C(O)c4ccc5nc(NC(=O)C(F)(F)F)cn5c4)n3n2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc3ncc(C(O)c4ccc5nc(N)cn5c4)n3n2)cn1
Temperature: 90 °C

Procedure:
(rac)-2,2,2-Trifluoro-N-(6-{hydroxy-[6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]-methyl}-imidazo[1,2-a]pyridin-2-yl)-acetamide (Example 153, 120 mg, 0.263 mmol) was dissolved in THF/MeOH 1:1 (2 mL). K2CO3 was added (363 mg, 2.63 mmol) with water (1 mL) and the RM was heated over night at 90° C. After concentration under reduced pressure, the residue was purified by flash chromatography (CombiFlash® Companion System®, with 12 g RediSep® silica gel column, DCM/MeOH=8:2->DCM/MeOH/H2O/ammonia=80:19:0.5: 0.5) to afford the title compound (MH+=361, 1H NMR in DMSO-d6: .8.5 (s, 1H); 8.4 (s, 1H); 8.1 (s, 1H); 8.0 (d, 1H); 7.6 (s, 1H); 7.5 (d, 1H), 7.1 (q, 2H), 7.0 (s, 1H); 6.2 (s, 2H); 5.0 (s, 2H); 3.9 (s, 3H)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]2([C:30]([O:32]CC)=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]2([C:30]([OH:32])=[O:31])[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[C:7]=1[O:8][CH2:9][C:10]([F:11])([F:12])[F:13]
Reactant: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.6 %

Procedure:
A mixture of ethyl 4-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)tetrahydro-2H-pyran-4-carboxylate (400 mg, 0.78 mmol) and lithium hydroxide monohydrate (0.188 g, 7.8 mmol) in a MeOH/THF/Water solvent mixture (5 ml/5 ml5/ml) was stirred for 3 h at room temperature. After completion of reaction volatiles were removed under reduced pressure. Residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). Combined organic layer was washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 4-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)tetrahydro-2H-pyran-4-carboxylic acid (100 mg). 1H-NMR (CDCl3, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.56 (s, 1H); 7.34 (s, 1H); 3.98 (q, 2H); 3.61 (t, 2H); 2.53 (dd, 2H); 1.99 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26](O)(=[O:28])[CH3:27].C(OC(=O)C)(=O)C>O>[C:1]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:23][CH:24]=4)[CH2:17][CH2:18]3)=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(N2CCN(Cc3ncc(-c4ccccc4)o3)CC2)cc1
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(N2CCN(Cc3ncc(-c4ccccc4)o3)CC2)cc1

Procedure:
The 4-aminophenyl compound of Example 36 (3.0 g; 0.009 mole) was warmed on a steam bath with glacial acetic acid (5 ml) and acetic anhydride (10 ml) for 1 hour. The mixture was poured into water (200 ml), stirred well and the collected precipitate washed with water and dried. After recrystallisation from methanol the product weighed 2.45 g and melted at 196°-7° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([N+:19]([O-:21])=[O:20])=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.[C:33]([CH:35](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:36])#[N:34]>O.[Cl-].[Na+].O.C(OCC)(=O)C>[C:33]([CH:35]([CH3:36])[N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=2)=[CH:11]1)#[N:34]
Reactant: Cc1ccc(S(=O)(=O)OC(C)C#N)cc1
Reactant: N#Cc1ccc(-c2c[nH]c3cc([N+](=O)[O-])ccc23)cc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C#N)n1cc(-c2ccc(C#N)c(F)c2)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.3 %

Procedure:
Method LL Add 2-Fluoro-4-(6-nitro-1H-indol-3-yl)-benzonitrile (1.24 mmoles; 350 mg), cesium carbonate (3.61 mmoles; 1.18 g) and dimethylformamide (10 mL) to a reaction vessel equipped with a stir bar. Stir this mixture for 10 minutes at room temperature then add toluene-4-sulfonic acid cyano-methyl-methyl ester (3.11 mmoles; 701 mg). Stir the resulting mixture for 5 hours at 55° C. Dilute this material with water (25 mL), brine (50 mL) and ethyl acetate (50 mL). Separate the organics and extract the resulting aqueous mixture with ethyl acetate (2×) and dichloromethane containing 10% methanol (2×). Combine the organics and concentrate in vacuo to about ½ volume. Wash the resulting mixture with water and evaporate the solvent in vacuo. Triturate the resulting yellow solids with hot dichloromethane. Collect the solids by vacuum filtration and rinse them with 50% dichloromethane/hexane to give the title compound (196 mg, 47%) yellow amorphous solid. MS (IS−) m/e 333.0 (M−1), 393.0 (M−1+OAc).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:23][C:24]([C:26]3[CH:27]=[C:28]([C:34]4[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=4)[CH:29]=[CH:30][C:31]=3[O:32][CH3:33])=[O:25])[C:17](=[O:22])N(OC)C)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].CC(C[AlH]CC(C)C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:23][C:24]([C:26]3[CH:27]=[C:28]([C:34]4[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:36][CH:35]=4)[CH:29]=[CH:30][C:31]=3[O:32][CH3:33])=[O:25])[CH:17]=[O:22])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)C(=O)N(C)OC
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)N[C@@H](C=O)Cc1ccc(-c2ccc(F)c(Cl)c2)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-formyl-ethyl]-amide was synthesized by the following procedure: To 4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(methoxy-methyl-carbamoyl)-ethyl]-amide (85 mg, 0.14 mmol) in THF (2 mL) was added DIBAL-H (0.64 mL, 0.64 mmol, 1.0 M in DCM) at −78° C. and the mixture was stirred at −78° C. for 2 h. After that potassium sodium tartrate was added and the mixture was stirred overnight, then the mixture was extracted with ethyl acetate (3×25 mL). Organic extracts were combined and concentrated in vacuo. The crude product was then purified with silica gel column chromatography by using ethyl acetate:hexanes (2:1) to afford the aldehyde intermediate(45 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27](Cl)=[C:26]([N+:31]([O-:33])=[O:32])[CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([O:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:26]([N+:31]([O-:33])=[O:32])[CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Cl
Reactant: COc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc(OCc3ccccc3)cc2[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
880 mg of 4-methoxyphenol was dissolved in 10 ml of N,N-dimethylformamide. 790 mg of potassium t-butoxide was added thereto. Then, 1.7 g of 4-benzyloxy-2-nitro-chlorobenzene was added thereto. The mixture was stirred for 1 hour at 110°-120° C. The reaction mixture was introduced into a mixture of 50 ml of ice water and 50 ml of ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: toluene) to obtain 1.92 g of 5-benzyloxy-2-(4-methoxyphenoxy)nitrobenzene.