Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([CH2:28][CH3:29])[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1)([CH3:4])([CH3:3])[CH3:2].[CH2:31]([O:33][C:34](=[O:43])[CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[C:40](Br)[CH:41]=1)[CH3:32]>>[CH2:31]([O:33][C:34](=[O:43])[CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[C:40]([C:10]2[CH:11]=[CH:12][C:13]([C:15]([F:16])([F:17])[F:18])=[CH:14][C:9]=2[CH2:8][N:7]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:30])[CH2:28][CH3:29])[CH:41]=1)[CH3:32]
Reactant: CCOC(=O)Cc1cncc(Br)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OC(C)(C)C
Product: CCOC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OC(C)(C)C)c1

Procedure:
Ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid tert-butyl ester and (5-bromo-pyridin-3-yl)-acetic acid ethyl ester were reacted as described in Example 8, Step 4 to provide (5-{2-[(N-tert-butoxycarbonyl-N-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid ethyl ester.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:22]([CH2:23][OH:24])=[C:21]([Cl:25])[CH:20]=[CH:19][N:18]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(N(CC)CC)C>[C:26]([O:24][CH2:23][C:22]1[C:17]([N:10]2[N:9]=[CH:8][C:7]3[C:12](=[C:13]([F:15])[CH:14]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=3)[C:11]2=[O:16])=[N:18][CH:19]=[CH:20][C:21]=1[Cl:25])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(Cl)c3CO)ncc2c1
Solvent: CCN(CC)CC
Product: CC(=O)OCc1c(Cl)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 116a (1.6 g, 4.4 mmol), acetic anhydride (10 mL), and triethylamine (1 mL). The reaction mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 116b as a brown solid (1.4 g, 82%). MS: [M+H]+ 404.3.
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15](O)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C1CCC(N=C=NC2CCCCC2)CC1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C1COCCN1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCOCC2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 8 %

Procedure:
To a solution of 2-(1, 2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetic acid (100 mg, 0.38 mmol) in DCM (10 ml) was added DCC (95 mg, 0.46 mmol), DMAP (56 mg, 0.46 mmol), and stirred for 5 min at RT, morpholine (1 ml, 11.5 mmol) was added and stirred at 25 deg C. for 14 h. The reaction mixture was concentrated to dryness and The resulting crude was purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) to obtain 10 mg (Yield 5.8%) of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-morpholino ethanone as TFA salt.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([C:22]2[CH:26]=[C:25]([C:27]3[CH:28]=[C:29]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)[CH:30]=[CH:31][CH:32]=3)[O:24][N:23]=2)[CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:61][CH2:62][CH2:63][S:64]([OH:67])(=[O:66])=[O:65]>CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([C:22]2[CH:26]=[C:25]([C:27]3[CH:28]=[C:29]([C:33]4[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=4)[CH:30]=[CH:31][CH:32]=3)[O:24][N:23]=2)[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:61][CH2:62][CH2:63][S:64]([OH:67])(=[O:66])=[O:65])=[O:18])=[CH:20][CH:21]=2)=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: NCCS(=O)(=O)O
Reactant: CC(C)(C)c1ccc([C@H](Cc2ccc(C(=O)O)cc2)c2cc(-c3cccc(-c4ccc(Cl)cc4)c3)on2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc([C@H](Cc2ccc(C(=O)NCCS(=O)(=O)O)cc2)c2cc(-c3cccc(-c4ccc(Cl)cc4)c3)on2)cc1
Reaction time: 14 h

Procedure:
To a mixture of (S)-4-{2-(4-tert-Butyl-phenyl)-2-[5-(4′-chloro-biphenyl-3-yl)-isoxazol-3-yl]-ethyl}-benzoic acid (0.25 g, 0.46 mmol), EDCI (133 mg, 0.69 mmol), HOBt (107 mg, 0.69 mmol), N,N-diispropylethylamine (0.25 mL, 1.95 mmol) in DMF (10 mL), and followed by taurine (116 mg, 0.093 mmol) was added. The resulting mixture was stirred for 14 h and monitored by LCMS after completion of the reaction the solvent was removed under reduced pressure. The resulting mixture was purified by column chromatography on C-18, eluting with H2O/Acetonitrile 40% to afford (4-{2-(4-tert-Butyl-phenyl)-2-[5-(4′-chloro-biphenyl-3-yl)-isoxazol-3-yl]-ethyl}-benzoylamino)ethane sulfonic acid (29) as a white solid. (125 mg, 42%): 1H NMR (300 MHz, MeOD): 8.01 (s, 1H), 7.78 (d, J=6.9 Hz, 2H), 7.70-7.47 (m, 6H), 7.35 (d, J=9.0 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H), 6.86 (s, 1H), 4.47 (t, J=6.9 Hz, 1H), 3.85-3.70 (m, 2H), 3.75 (dd, J=4.9, 13.2 Hz, 1H), 3.25-3.05 (m, 2H), 1.31 (s, 9H); LC-MS m/z=643 [C36H35ClN2O5S]+; HPLC conditions: Waters Atlantis C-18 OBD 4.6×150 mm; mobile phase=ACN/(H2O:0.1 TFA) flow rate=1.0 mL/min; detection=UV @ 254 and 220 nm retention time in min: 21.20; Anal Calcd: (MF:C36H35ClN2O5S+1.5H2O+0.2 CH2Cl2) Calcd: C, 63.27; H, 5.63; N, 4.08. Found: C, 63.24; H, 5.75; N, 3.96. αD[25] MeOH (4.66 mg in 1.0 mL)=+13.487.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.S(=O)(=O)(O)O.[CH3:15]O>>[CH3:15][O:8][C:7]([C:4]1[CH:3]=[C:2]([Br:1])[S:6][CH:5]=1)=[O:9]
Reactant: CO
Reactant: O=C(O)c1csc(Br)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1csc(Br)c1

Procedure:
5-Bromo-thiophene-3-carboxylic acid (13 g, 64 mmol) was dissolved in methanol (140 mL). Concentrated sulphuric acid (6.5 mL) was added and the mixture heated at reflux for 14 hours. The reaction was quenched by adding a solution of saturated aqueous sodium bicarbonate and most of the solvent was removed by evaporation under vacuum. The mixture was then diluted with a solution of saturated aqueous sodium bicarbonate and the product extracted with DCM. The organic solution was dried over sodium sulphate, filtered and the solvent removed by evaporation to give a white crystalline solid (13.2 g). 1H NMR (400 MHz, CDCl3): δ 8.0 (s, 1H), 7.5 (s, 1H), 3.85 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:24][O:25][C:26]([C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=[O:32])=[O:27].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:31]([C:30]5[CH:29]=[C:28]([CH:36]=[CH:35][CH:34]=5)[C:26]([O:25][CH3:24])=[O:27])=[O:32])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)c1
Yield: 70.7 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (250 mg, 0.81 mmol), 3-(methoxycarbonyl)benzoic acid (150 mg, 0.83 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (160 mg, 0.84 mmol), 1-hydroxybenzotriazole (110 mg, 0.81 mmol) and N,N-dimethylformamide (8.0 mL) as starting materials and in the same manner as in Example 318, the title compound (270 mg, 72%) was obtained as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C:17]3[CH2:16][CH2:15][C@@:13]4([CH3:14])[C@@H:9]([CH2:10][CH2:11][C@@H:12]4[OH:21])[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CC(O)C>CC(C)=O>[CH3:14][C:13]12[C:12](=[O:21])[CH2:11][CH2:10][CH:9]1[C:8]1[CH:7]=[CH:6][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[CH:19][C:18]=3[C:17]=1[CH2:16][CH2:15]2
Reactant: COc1ccc2c3c(ccc2c1)[C@@H]1CC[C@H](O)[C@@]1(C)CC3
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: COc1ccc2c3c(ccc2c1)C1CCC(=O)C1(C)CC3
Temperature: 0 °C

Procedure:
This crude alcohol was dissolved in 10 ml of acetone and the resulting solution was stirred and cooled in an ice bath while 0.5 ml of Jones reagent (CrO3 --H2SO4) was added dropwise. After stirring for 5 min. the excess oxidant was decomposed with 1 ml of 2-propanol. The resulting mixture was treated with ice water and most of the acetone was evaporated at reduced pressure. Extraction of the residual suspension with three portions of chloroform followed by washing the extracts with saturated NaHCO3 solution then drying (MgSO4), filtration and concentration at aspirator pressure gave 0.262g of partially crystalline, crude equilenin methyl ether. A combination of preparative thin layer chromatography (silica gel; benzene:ethyl acetate, 95:5) and recrystallization from methanol gave 0.0775g (27.6%) of colorless needles, m.p. 192°-194° which was essentially pure equilenin methyl ether. Another recrystallization from methanol gave colorless solid, m.p. 195°-196°,[α]D25 + 88.72° (c 0.86, dioxane).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:28])=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[C:16]([O:23][CH2:24][C:25](O)=[O:26])=[CH:15][CH:14]=2)[N:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][C:2]1[NH:3][C:4]([CH3:28])=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[C:16]([O:23][CH2:24][CH2:25][OH:26])=[CH:15][CH:14]=2)[N:8]=1
Reactant: Cc1cc(-c2cccc(-c3ccc(OCC(=O)O)c4c3CCCC4)n2)c(C)[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(-c2cccc(-c3ccc(OCCO)c4c3CCCC4)n2)c(C)[nH]1

Procedure:
To a 100 mL round-bottomed flask equipped with condenser and nitrogen (N2) inlet were added 100 mg (0.27 mmol) 2-(2,5-dimethylpyrrolyl)6-[4-carboxymethoxy-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridine (from Example 1), 20 mL dry tetrahydrofuran, and 0.6 mL (0.53 mmol) of a 1 M solution of lithium aluminum hydride in tetrahydrofuran. The reaction was refluxed 16 hour, cooled, and quenched with 1 N hydrochloric acid. The mixture was adjusted to pH 10 with 1 N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue of 118 mg (100%), an oil, was used directly in the following step. 1H-NMR (δ, CDCl3): 1.69 (m, 2H), 1.78 (m, 2H), 2.16 (s, 6H), 2.7-2.9 (m, 4H), 3.95 (m, 2H), 4.08 (m, 2H), 5.885 (s, 2H), 6.73 (d, J=8, 1H), 7.13 (d, J=8, 1H), 7.20 (d, J=8, 1H), 7.35 (d, J=8, 1H), 7.83 (t, J=8, 1H); MS (%): 363 (parent+1, 100).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:36]=[CH:35][C:20]([CH2:21][N:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:24]([CH:33]=O)=[CH:23]2)=[CH:19][CH:18]=1.C(OP([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])(OCC)=O)C.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:36]=[CH:35][C:20]([CH2:21][N:22]2[CH:26]=[C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:24](/[CH:33]=[CH:45]/[C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:23]2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(C=O)c(-c3ccccc3)c2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
Sodium hydride (60%, oily, 222 mg) was added to a mixture of 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenylpyrrole-3-carbaldehyde (2.37 g), ethyl diethylphosphonoacetate (1.1 ml) and tetrahydrofuran (30 ml) at 0° C., and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and ethyl(E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propenoate (2.13 g, yield: 78%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 120–121° C.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([C:17](=[O:19])[CH3:18])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][C:21]([CH:23]([O:26][CH3:27])[O:24][CH3:25])=O.N1CCCC1>C1(C)C=CC=CC=1>[CH3:25][O:24][CH:23]([O:26][CH3:27])[C:21]1([CH3:20])[CH2:18][C:17](=[O:19])[C:12]2[CH:11]=[C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[CH:15]=[CH:14][C:13]=2[O:16]1
Reactant: CC(=O)c1cc(S(=O)(=O)c2ccccc2)ccc1O
Reactant: COC(OC)C(C)=O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: COC(OC)C1(C)CC(=O)c2cc(S(=O)(=O)c3ccccc3)ccc2O1

Procedure:
In 100 ml of toluene were dissolved 10 g of the compound obtained in step 4, 6.5 ml of pyruvic aldehyde dimethyl acetal and 1.5 ml of pyrrolidine. The resultant solution was heated to reflux for 16 hours and concentrated reduced pressure to obtain residue, which was purified by silica gel column chormatography using as an eluent a mixture of hexane and ethyl acetate (2:1) to obtain 11 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1>C1COCC1.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][CH2:16][C:11]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(C2=CCC3(CC2)OCCO3)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Fc1cccc(C2CCC3(CC2)OCCO3)c1

Procedure:
306.3 g of 8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene were dissolved in 3 l of THF, and 30 g of 5% Pd/C were added. The mixture was then hydrogenated at atmospheric pressure. The resultant solution was filtered and evaporated to a residue. The residue was recrystallized twice from 200 ml of hexane at -60° C., giving 8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]decane.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[CH2:6][C:7]([NH:30][C:31](=[O:43])[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]([F:18])([F:17])[F:16])[CH:9]=1.[N+](=[CH:46][Si](C)(C)C)=[N-]>C1COCC1.CO>[F:38][C:35]1[CH:36]=[CH:37][C:32]([C:31]([NH:30][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]([F:16])([F:17])[F:18])[CH:9]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:27])([F:28])[F:29])[CH:20]=2)[CH2:6][C:5]2[N:4]=[N:3][N:2]([CH3:46])[N:1]=2)=[O:43])=[CH:33][C:34]=1[C:39]([F:40])([F:41])[F:42]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(NC(Cc1nn[nH]n1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nnc(CC(NC(=O)c2ccc(F)c(C(F)(F)F)c2)(c2cccc(OC(F)(F)F)c2)c2cccc(OC(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
To a solution of N-(2-(2H-tetrazol-5-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-4-fluoro-3-(trifluoromethyl)benzamide (18 mg, 0.029 mmol) in THF (0.4 mL) and MeOH (0.1 mL) at rt was added (diazomethyl)trimethylsilane (0.02 mL, 2.0 M solution). The resulting solution was stirred at rt for 20 min. The solvents were evaporated and resulting residue was purified by ISCO flash chromatography (silica gel, hexane/EtOAc) to give 4-fluoro-N-(2-(2-methyl-2H-tetrazol-5-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(trifluoromethyl)benzamide (Example 281, 11 mg, yield: 60%). LCMS: RT=4.06 min [M+H] 638.23, [M+Na] 661.26 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].N.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=1/[N:20]=[C:21](\[C:31]#[N:32])/[C:22]1[S:30][C:25]2=[N:26][CH:27]=[CH:28][N:29]=[C:24]2[CH:23]=1>O.O1CCOCC1>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH3:10])=[C:12]([NH:20][CH:21]([C:22]2[S:30][C:25]3=[N:26][CH:27]=[CH:28][N:29]=[C:24]3[CH:23]=2)[C:31]#[N:32])[CH:13]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1/N=C(\C#N)c1cc2nccnc2s1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(N)cc1NC(C#N)c1cc2nccnc2s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
To a solution of sodium hydrosulfite (434 mg, 2.493 mmol) in water (3 mL) was added ammonia (0.561 mL, 3.64 mmol) and then compound 77 (62 mg, 0.192 mmol) in dioxane (3 mL). The reaction was stirred at rt. for 4 h. Quenched with water and extracted with EtOAc. Organic layer was washed with brine, dried and evaporated to give compound 2-(5-amino-2-methylphenylamino)-2-(thieno[2,3-b]pyrazin-6-yl)acetonitrile 78 (48 mg, 85%) which was used without further purification. (m/z)=296 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([OH:14])=O)[NH:9]2)=[CH:5][CH:4]=1)#[N:2].[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:17]1>>[C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([NH:15][C@H:16]3[CH2:21][CH2:20][C@H:19]([O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:17]3)=[O:14])[NH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](N)CC1
Reactant: N#Cc1ccc2cc(C(=O)O)[nH]c2c1
Product: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](NC(=O)c2cc3ccc(C#N)cc3[nH]2)CC1

Procedure:
In the same manner as in Example 1 (2), 6-cyano-2-indolecarboxylic acid (244 mg, 1.31mmol) and t-butyl trans-(4-aminocyclohexyloxy)acetate (300 mg, 1.3 mmol ) were condensed. The reaction mixture was purified by silica gel column chromatography (chloroform/methanol=50/1-1/1) to give 465 mg of t-butyl trans-[4-[(6-cyano-2-indolyl)carbonylamino]cyclohexyloxy]acetate as a brown solid (89%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([F:12])[CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:16]([C:29]([F:32])([F:31])[F:30])[CH:15]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([CH3:27])([CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:16]([C:29]([F:30])([F:31])[F:32])[CH:15]=2)=[O:11])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Reactant: CCOC(=O)C(C)(C)Cc1ccc(N)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Cc1ccc(NC(=O)Cc2ccc(Br)cc2F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.8 %

Procedure:
To a mixture of 2-(4-bromo-2-fluorophenyl)acetic acid (6 g, 25.7 mmol) in DCM (50 mL) was added ethyl 3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (7.45 g, 25.7 mmol), HATU (12.73 g, 33.5 mmol) and Et3N (10.74 mL, 77 mmol). Then the mixture was stirred at 25° C. for 12 h. The mixture was washed with brine and saturated NaHCO3 solution. The organic layer was dried over MgSO4, filtered and concentrated to yield a yellow oil of ethyl 3-(4-(2-(4-bromo-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (12 g, 19.99 mmol, 78.0% yield): 1H NMR (400 MHz, CD3OD) δ: 7.94 (d, J=2.0 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.36-7.25 (m, 3H), 7.22 (d, J=8.4 Hz, 1H), 4.14 (q, J=7.2 Hz, 2H), 3.73 (s, 2H), 3.07 (s, 2H), 1.22 (t, J=7.2 Hz, 3H), 1.15 (s, 6H); ES-LCMS m/z 504 (M).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[C:10](OCC)(=[O:16])[C:11](OCC)=[O:12]>>[OH:12][C:11]1[C:10]([OH:16])=[N:9][C:4]2[C:5](=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1ccc(Cl)cc1N
Product: Oc1nc2ccc(Cl)cc2nc1O
Temperature: 25 °C

Procedure:
A mixture consisting of 100 g. (0.07 mole) of 4-chloro-1,2-phenylenediamine and 750 ml. of diethyl oxalate was refluxed overnight and for a period of approximately 16 hours. Upon completion of this step, the reaction mixture was cooled to room temperature (~20° C.), filtered and the recovered product subsequently washed with ethanol and air-dried to constant weight to ultimately afford 140 g. of pure 2,3-dihydroxy-6-chloroquinoxaline, m.p.>260° C.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26]([O:28]CC)=O)[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][NH:39][C:38]1=[O:42]>>[F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26]([NH:34][CH2:35][CH2:36][N:37]4[CH2:41][CH2:40][NH:39][C:38]4=[O:42])=[O:28])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: NCCN1CCNC1=O
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Product: O=C(NCCN1CCNC1=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 1-(2-aminoethyl)-2-imidazolidinone using conditions similar to those employed in Example 563 to provide a white solid: ES+ MS: 537 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[C:21]([Cl:32])[N:20]=[C:19]2[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:13][CH:12]=1)=O.[NH2:37][NH2:38]>>[CH2:33]([C:19]1[N:18]([CH2:17][C:14]2[CH:13]=[CH:12][C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:3]([NH:37][NH2:38])=[O:2])=[CH:16][CH:15]=2)[C:22]([CH2:23][O:24][Si:25]([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:26])[CH3:27])=[C:21]([Cl:32])[N:20]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCc1nc(Cl)c(CO[Si](C)(C)C(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reactant: NN
Product: CCCCc1nc(Cl)c(CO[Si](C)(C)C(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)NN)cc1
Yield: 60 %

Procedure:
According to the procedure of Example 2, 4'-[[2-butyl-4-chloro-5-(t-butyldimethylsilyloxymethyl)-1H-imidazol-1-yl]methyl][1,1'-biphenyl-2-yl]carboxylic acid methyl ester was treated with hydrazine to give 4'-[[2-butyl-4-chloro-5-(t-butyldimethylsilyloxymethyl)-1H-imidazol-1-yl]methyl][1,1'-biphenyl-2-yl]carboxylic acid hydrazide (60%) .