Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH:15]1([CH2:19][CH2:20][NH:21][C:22]([C:24]2[N:25]=[N:26][C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:28][CH:29]=2)=[O:23])[CH2:18][CH2:17][CH2:16]1>>[CH:15]1([CH2:19][CH2:20][NH:21][C:22]([C:24]2[N:25]=[N:26][C:27]([N:30]3[CH2:31][CH2:32][N:33]([C:7](=[O:8])[C:6]4[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[C:11]([F:14])([F:13])[F:12])[CH2:34][CH2:35]3)=[CH:28][CH:29]=2)=[O:23])[CH2:18][CH2:17][CH2:16]1
Reactant: O=C(Cl)c1cc(F)ccc1C(F)(F)F
Reactant: O=C(NCCC1CCC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CCC1)c1ccc(N2CCN(C(=O)c3cc(F)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 5-fluoro-2-(trifluoromethyl)benzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclobutylethyl)amide, the title compound was obtained as a white powder (71% yield).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][NH2:7].[CH3:13][CH2:14][CH2:15][C:16](=O)[CH2:17][CH2:18][CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.O.C(N(CC)CC)C>[Br:2][C:3]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][NH:7][CH:16]([CH2:17][CH2:18][CH3:19])[CH2:15][CH2:14][CH3:13]
Reactant: NCCc1ccc(F)cc1Br
Reactant: CCCC(=O)CCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCC(CCC)NCCc1ccc(F)cc1Br
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Added to a suspension of 1 g of 2-bromo-4-fluorophenethylamine hydrocloride in 25 cm3 of dichloromethane and under an inert atmosphere is 663 μL of triethylamine. After stirring for 30 min at a temperature close to 20° C., 5 cm3 of distilled water are added and the stirring is continued for 30 min. 15 cm3 of distilled water are added and the two phases are separated. The organic phase is washed with three lots of 10 cm3 of distilled water, then dried. Added to the solution obtained are successively 449 mg of 4-heptanone and 1.166 g of sodium triacetoxyborohydride. The reaction mixture is stirred for 15 h at a temperature close to 20° C. 20 cm3 of a saturated solution of sodium hydrogen carbonate are then added to the reaction medium. The organic phase is decanted and separated from the aqueous phase then washed successively with 15 cm3 of distilled water and 15 cm3 of a saturated solution of sodium chloride. The organic phase is dried then concentrated using a rotary evaporator under reduced pressure (5 kPa). 1.069 g of N-[2-(2-bromo-4-fluorophenyl)ethyl]heptan-4-amine are obtained in the form of a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:4]=1[CH2:5][N:6]([CH3:16])[C:7]2=[O:15].O[C:18]1C=CC([N+]([O-])=O)=C2C=1CN(C)C2=O>>[CH2:1]([O:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:4]=1[CH2:5][N:6]([CH3:16])[C:7]2=[O:15])[CH3:18]
Reactant: CN1Cc2c(O)ccc([N+](=O)[O-])c2C1=O
Reactant: COc1ccc([N+](=O)[O-])c2c1CN(C)C2=O
Product: CCOc1ccc([N+](=O)[O-])c2c1CN(C)C2=O

Procedure:
The title compound was prepare according to the procedure for 4-Methoxy-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (Compound 205B) using 4-Hydroxy-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one and iodoethane (Compound 205C, 28.8 uL, 0.360 mmol). 1H NMR (400 MHz, CD3OD) δ=1.47 (t, J=7.1 Hz, 3H), 3.17 (s, 3H), 4.27 (q, J=6.9 Hz, 2H), 4.43 (s, 2H), 7.23 (d, J=8.8 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H). MS (ES+): m/z 251.21 (100) [MH+]; HPLC: tR=1.06 min (UPLC, Analytical).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[C:32]#[N:33].O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:1][C:2]1[CH:7]=[C:6]([C:29]2[CH:36]=[CH:35][CH:34]=[C:31]([C:32]#[N:33])[CH:30]=2)[CH:5]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][N:19]=2)[CH:3]=1
Reactant: N#Cc1cccc(Br)c1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cccc(C#N)c2)c1
Temperature: 160 °C

Procedure:
A suspension of N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (1.00 g, 2.64 mmol), 3-bromobenzonitrile (0.492 g, 2.70 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.054 g, 0.066 mmol), 1,4-dioxane (10 mL), and aqueous sodium carbonate (2 M, 2.64 mL, 5.27 mmol) was placed under an argon atmosphere by performing 6 vacuum/argon cycles. The reaction mixture was then heated to 160° C. for 10 minutes using a microwave reactor. The resulting suspension was diluted with ethyl acetate (75 mL) and saturated aqueous sodium bicarbonate (25 mL). The layers were separated, and the organic layer was washed with water (10 mL) and then brine (25 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/hexanes) to afford 3′-methyl-5′-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-carbonitrile. MS ESI calc'd. for C19H14F3N4 [M+H]+ 355, found 355.
Reaction SMILES: [N:1]([C:4]1[S:8][C:7]2[CH2:9][CH2:10][CH2:11][CH2:12][C:6]=2[C:5]=1[C:13]([O:15]CC)=O)=[C:2]=[S:3].[CH3:18][C:19]1[N:23]([CH2:24][CH2:25][CH2:26][NH2:27])[CH:22]=[N:21][CH:20]=1>>[CH3:18][C:19]1[N:23]([CH2:24][CH2:25][CH2:26][N:27]2[C:13](=[O:15])[C:5]3[C:6]4[CH2:12][CH2:11][CH2:10][CH2:9][C:7]=4[S:8][C:4]=3[NH:1][C:2]2=[S:3])[CH:22]=[N:21][CH:20]=1
Reactant: Cc1cncn1CCCN
Reactant: CCOC(=O)c1c(N=C=S)sc2c1CCCC2
Product: Cc1cncn1CCCn1c(=S)[nH]c2sc3c(c2c1=O)CCCC3

Procedure:
The compound was synthesized starting from ethyl 4,5,6,7-tetrahydro-2-isothiocyanatobenzo[b]thiophene-3-carboxylate (0.175 g. 0.66 mmol) and 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (5) (0.09 g, 0.66 mmol) as described above.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][NH:21][CH2:22][CH3:23])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(ON1C(=O)C2C=CC=CC=2N=N1)(OCC)(OCC)=O.CCN(C(C)C)C(C)C.[C:53]1([S:59][CH2:60][C@H:61]([NH:66][C:67]2[CH:72]=[CH:71][C:70]([S:73](=[O:76])(=[O:75])[NH2:74])=[CH:69][C:68]=2[S:77]([C:80]([F:83])([F:82])[F:81])(=[O:79])=[O:78])[CH2:62][C:63]([OH:65])=O)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C1COCC1>[Si:1]([O:18][CH2:19][CH2:20][N:21]([CH2:22][CH3:23])[C:63](=[O:65])[CH2:62][C@@H:61]([NH:66][C:67]1[CH:72]=[CH:71][C:70]([S:73](=[O:75])(=[O:76])[NH2:74])=[CH:69][C:68]=1[S:77]([C:80]([F:81])([F:82])[F:83])(=[O:79])=[O:78])[CH2:60][S:59][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)O)c(S(=O)(=O)C(F)(F)F)c1
Reactant: CCNCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
2-(tert-Butyldiphenylsilyloxy)-N-ethylethanamine (INTERMEDIATE 23, 0.263 g, 0.80 mmol) in THF (2.5 ml), diethyl 4-oxobenzo[d][1,2,3]triazin-3(4H)-yl phosphate (0.480 g, 1.60 mmol) and DIPEA (0.280 ml, 1.60 mmol) were added sequentially to a solution of (R)-4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)butanoic acid (INTERMEDIATE 8, 0.4 g, 0.80 mmol) in THF (5.0 ml) and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was then concentrated under reduced pressure, diluted with EtOAc and the organic layer was washed with 1N aq. NaHSO4 and saturated aq. NaHCO3. The organic layer was dried (Na2SO4), concentrated under reduced pressure to give a residue, which was purified by column chromatography (ISCO, 40 g silica gel column, eluting with 0→100% EtOAc/hexanes) to provide the title product (590 mg, yield: 91%).
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(O)[CH2:16][CH2:17][CH2:18][OH:19]>>[C:6]([O:8][CH2:9][CH2:16][CH2:17][CH2:18][OH:19])(=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([C:1]([O:13][CH2:14][CH2:4][CH2:5][CH2:6][OH:7])=[O:12])=[CH:3][CH:4]=1
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Reactant: OCCCCO
Product: O=C(OCCCCO)c1ccc(C(=O)OCCCCO)cc1

Procedure:
This example demonstrates the transesterification reaction of dimethyl terephthalate with 1,4-butanediol using lanthanum tris(acetylacetonate) hydrate as the transesterification catalyst (150 ppm La based on final polymer) to form bis(4-hydroxybutyl) terephthalate.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][CH:8]([NH2:11])[CH2:9][CH3:10].N1C=CC=CC=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.C(OCC)C>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C@H:8]([NH:11][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:9][CH3:10]
Reactant: CCC(N)Cc1sccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC[C@H](Cc1sccc1Cl)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Five grams of 3-chloro-2-(2-aminobutyl)thiophene is dissolved in 10 ml of methylene chloride in a 3-neck round bottomed flask blanketed with an inert atmosphere at 0° C. Pyridine (2.2 ml) is added in one portion followed by 2.05 ml of methanesulfonyl chloride. After warming to room temperature, the mixture is stirred for 4 hours before diluting with 100 ml of diethyl ether. The solution is poured into a separatory funnel and washed with water, dilute 2N HCl, saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to provide (R)-N-[1-[(3-chlorothien-2-yl)methyl]propyl]methanesulfonamide (5.5 g) as an orange oil which solidifies upon standing in a refrigerator overnight. MS: m/z (EI, 70EV) 267 (5%). 1H NMR (200 MHz; CDCl3): δ 1.0 (3H, t, CH3), 1.6 (2H, m, CH2), 2.65 (3H, s, CH3), 3.0 (2H, m, CH2), 3.6 (1H, m, CH), 6.9 (1H, d, CH), 7.2 (1H, d, CH).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>C(O)C.O1CCOCC1>[ClH:24].[ClH:24].[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:16]=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][N:20]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(C(=O)O)cn2)CC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(O)c1cnc(NC2CCNCC2)nc1

Procedure:
A solution of 2-(1-tert-butoxycarbonyl-piperidin-4-ylamino)-pyrimidine-5-carboxylic acid (0.18 g, 0.56 mmol) in ethanol (5 mL) and 4 M HCl in dioxane (10 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 223.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[Li+].CC([N-]C(C)C)C.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33](=[O:38])N(OC)C)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.C1COCC1>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33](=[O:38])[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:8]([F:9])([F:10])[F:11])[C:2]=2[F:1])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Fc1ccccc1C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2cccc(C(F)(F)F)c2F)CC1
Temperature: -78 °C
Reaction time: 2.75 h
Yield: 52.4 %

Procedure:
To a stirred solution of 2-fluorobenzotrifluoride (19.4 g, 118 mmol) and anhydrous THF (300 mL) at −78° C. under nitrogen was added was added LDA (65.0 mL of a 2.0 M solution in heptane/tetrahydrofuran/ethylbenzene, 130 mmol) dropwise over 25 min. After 165 min, a solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (40.1 g, 147 mmol) in anhydrous THF (100 mL) was added dropwise over 50 min and the reaction stirred at −78° C. for 20 min and at room temperature for 85 min. The reaction was quenched with saturated ammonium chloride (40 mL) and the mixture concentrated. The residue was taken up in ethylacetate (400 mL) and washed successively with 1 N HCl (200 mL), 5% aqueous potassium carbonate, water (200 mL), and brine (200 mL). The organic phase was dried over magnesium sulfate, filtered, and the solvent removed to give an amber oil. The product was chromatographed on silica gel (300 g), using a step gradient elution of 20% ethyl acetate/heptane to 60% ethyl acetate/heptane, to afford 23.2 g (52%) of the desired product as an off-white solid.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].Cl.[C:7]([O:11][C:12](=[O:15])[CH2:13][NH2:14])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.Cl>C(Cl)Cl>[C:7]([O:11][C:12](=[O:15])[CH2:13][NH:14][C:3](=[O:4])[CH2:2][Br:1])([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C(Br)CBr
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNC(=O)CBr

Procedure:
77.8 g (385.5 mmol) of bromoacetic acid bromide is added in drops at 0° C. to 50 g (296.5 mmol) of glycine-tert-butyl ester hydrochloride salt and 90 g (889.5 mmol) of triethylamine in 500 ml of methylene chloride. In this case, the temperature remains between 0° C.-5° C. 1000 ml of 5% aqueous hydrochloric acid is added, and the organic phase is separated. The organic phase is extracted once more with 500 ml of 5% aqueous hydrochloric acid, dried on magnesium sulfate and evaporated to dryness in a vacuum. The residue is recrystallized from diisopropyl ether/n-hexane.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([NH:15][CH2:16][C:17]([OH:19])=[O:18])(=O)[CH3:13].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>>[CH3:13][C:12]1[O:19][C:17](=[O:18])[C:16](=[CH:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:15]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)NCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC1=NC(=Cc2ccc([N+](=O)[O-])cc2)C(=O)O1
Temperature: 120 °C
Reaction time: 6 h
Yield: 66.5 %

Procedure:
4-Nitrobenzaldehyde (53.7 g, 0.356 mol), N-acetylglycine (49.9 g, 0.427 mol) and sodium acetate (37.9 g, 0.463 mol) were mixed with acetic anhydride (168 g, 1.78 mol) and the resulting mixture heated with stirring to 120° C. for 6 hrs, giving a dark suspension. The mixture was then cooled to RT overnight, resulting in the formation of a precipitated solid. The reaction mixture was poured into ice-water (150 g) and the resulting suspended solid was collected by filtration. The crude solid product was washed with acetone (100 ml) then recrystallized from hot acetone (650 ml) to give a crystalline solid that was washed with 50% aqueous ethanol, then dried in vacuo to give 2-methyl-4-(4-nitrobenzylidene)oxazol-5(4H)-one (55.0 g, 66%) as pale yellow needles. The crystallisation mother liquors and washes were combined and evaporated to give a solid residue that was recrystallized from acetone to give a second crop of 2-methyl-4-(4-nitrobenzylidene)oxazol-5(4H)-one (8 g, 10%). The combined yield of 2-methyl-4-(4-nitrobenzylidene)oxazol-5(4H)-one was 63 g (76%)
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:3]1=2.S(Cl)(Cl)=O.[CH3:26]O>>[CH3:26][O:1][C:2]1[C:3]2[CH:16]=[C:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:14]=[CH:13][C:4]=2[CH2:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1
Reactant: COC(=O)Cc1ccc2c(c1)C(=O)Cc1ccccc1C2
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc2c(c1)C(OC)=Cc1ccccc1C2

Procedure:
In 50 ml of dry methanol was dissolved 6.3 g of methyl 10,11-dihydro-11-oxo-5H-dibenzo[a,d]cycloheptene-2-acetate obtained in Example 10. Thionyl chloride (7 g) was added, and the solution was heated under reflux for 2 hours with stirring. After the reaction, the reaction mixture was cooled, and methanol was distilled off. The residue was dissolved in 200 ml of benzene. The benzene solution was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The benzene was then distilled off. The residue was chromatographed on a silica gel column using benzene as an eluent. A slightly yellow solid was obtained from the eluate. Recrystallization from n-hexane afforded 4.6 g of methyl 11-methoxy-5H-dibenzo[a,d]cycloheptene-2-acetate as colorless needle-like crystals having a melting point of 72° to 73° C.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[C:5]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]([CH:23]=[O:24])[NH:14][C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=3)=[CH:10][C:4]2=[N:3]1.[BH4-].[Na+]>CO>[CH3:1][N:2]1[N:6]=[C:5]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]([CH2:23][OH:24])[NH:14][C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=3)=[CH:10][C:4]2=[N:3]1
Reactant: Cc1cccc(-c2[nH]c(C=O)nc2-c2ccc3nn(C)nc3c2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(-c2[nH]c(CO)nc2-c2ccc3nn(C)nc3c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
4-(2-methyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazole-2-carbaldehyde (20 mg, 0.063 mmol) was dissolved in 2 ml anhydrous methanol. Sodium borohydride (3 mg, 0.069 mmol) was added and the reaction stirred at room temperature for 1 hour. The reaction was quenched with water and solvent was removed by rotary evaporation. The residue was purified on Biotage Flash 12S silica gel column using chloroform/methanol gradient system (97:3 to 95:5, respectively) as eluent to afford [4-(2-methyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazol-2-yl]-methanol (13 mg, 64% yield) as a white solid. HPLC tR=3.18 min, LC-MS=321 (M+1).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]([O:30]C(=O)[C@H](C1C=CC=CC=1)C)([C:8]1[CH:9]=[CH:10][C:11]2[N:17]([C:18](=[O:27])[C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[CH2:16][C@@H:15]([OH:28])[CH2:14][CH2:13][C:12]=2[CH:29]=1)[C:4]([F:7])([F:6])[F:5].FC(F)(F)C(OC(=O)[C@H](C1C=CC=CC=1)C)(C1C=CC2N(C(=O)[C@H](C3C=CC=CC=3)C)C[C@@H](OC3C=CC=C(CC(OC)=O)C=3)CCC=2C=1)C(F)(F)F.[OH-].[Na+]>CO>[OH:28][C@H:15]1[CH2:14][CH2:13][C:12]2[CH:29]=[C:8]([C:3]([OH:30])([C:2]([F:1])([F:41])[F:42])[C:4]([F:7])([F:5])[F:6])[CH:9]=[CH:10][C:11]=2[N:17]([C:18](=[O:27])[C@H:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH3:20])[CH2:16]1
Reactant: C[C@H](C(=O)OC(c1ccc2c(c1)CC[C@H](O)CN2C(=O)[C@@H](C)c1ccccc1)(C(F)(F)F)C(F)(F)F)c1ccccc1
Agent: COC(=O)Cc1cccc(O[C@H]2CCc3cc(C(OC(=O)[C@@H](C)c4ccccc4)(C(F)(F)F)C(F)(F)F)ccc3N(C(=O)[C@@H](C)c3ccccc3)C2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](C(=O)N1C[C@@H](O)CCc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (S)-2-phenyl-propionic acid 2,2,2-trifluoro-1-[(S)-3-hydroxy-1-((S)-2-phenyl-propionyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-7-yl]-1-trifluoromethyl-ethyl ester (15.0 mg, 0.025 mmol), which was prepared from Example 81 by a similar procedure as that used to prepare 101A, in MeOH (0.5 mL) was added 1N NaOH (0.05 mL, 0.05 mmol) and the mixture was stirred at rt for 5 h. The solvent was removed in vacuo and the residue was dissolved in THF and neutralized with 1N HCl. Volatiles were removed under vacuum and the product was purified by prep-HPLC. The fraction containing the title compound was neutralized with 1N NaOH and evaporated. The residue was dissolved in EtOAc, washed with water, and dried over anhydrous Na2SO4. The solvent was removed under vacuum to give Example 126. LC/MS m/z 462.2 (M+H)+. 1H NMR (500 MHz, Methanol) δ 7.74 (d, 1H), 7.49 (d, 1H), 7.38 (s, 1H), 7.10 (m, 1H), 7.03 (m, 2H), 6.55 (d, 2H), 4.70 (dd, 1H), 3.91 (m, 1H), 3.59 (m, 1H), 2.36 (t, 1H), 2.07 (m, 1H), 1.89 (m, 1H), 1.35 (d, 3H), 1.31 (m, 1H), 1.12 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1.[OH-:13].[Na+]>O1CCOCC1>[NH2:1][C:2]1[C:7]([S:8]([OH:13])(=[O:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)cc1S(=O)(=O)Cl
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1ncc(Br)cc1S(=O)(=O)O
Temperature: 75 °C

Procedure:
2-Amino-5-bromopyridine-3-sulfonyl chloride (100 mg, 0.37 mmol) was taken into 1:1 aqueous dioxane (3 mL) and the mixture was basified to pH 14 by drop wise addition of 50% aqueous sodium hydroxide solution. The mixture was warmed to 75° C. for 0.5 h then cooled to room temperature and concentrated. The residue was taken into water (2 mL) and carefully acidified to pH 1-2 by concentrated aqueous hydrochloric acid addition and cooled to 0° C. After 1 h at 0° C. the crystalline solid obtained was collected by filtration and dried to give 2-amino-5-bromopyridine-3-sulfonic acid as a solid. 1H NMR (DMSO-d6): 8.24 (d, 1H), 8.06 (d, 1H). MS (EI) for C5H5N2SO3Br: 253, 255 (MH+, Br pattern).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[N:17]=[CH:16][C:15]([C:18]2[S:22][C:21]([NH:23][C:24](=[O:26])[CH3:25])=[N:20][C:19]=2[CH3:27])=[CH:14][N:13]=1>N1C=CC=CC=1>[CH3:27][C:19]1[N:20]=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[S:22][C:18]=1[C:15]1[CH:16]=[N:17][C:12]([NH:11][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[N:13][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(=O)Nc1nc(C)c(-c2cnc(N)nc2)s1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(C)c(-c2cnc(NS(=O)(=O)c3ccccc3)nc2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzenesulfonyl chloride (0.192 mL) was added to a stirred mixture of N-[5-(2-aminopyrimidin-5-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (195 mg) and pyridine (10 mL) and the reaction mixture was heated to reflux for 18 hours. Additional benzenesulfonyl chloride (0.384 mL) was added and the mixture was heated to reflux for 2 hours. The reaction mixture was evaporated. A 7M methanolic ammonia solution (10 mL) was added to the residue and the mixture was stirred at room temperature for 1 hour. The resultant mixture was evaporated and the residue was purified by preparative HPLC. There was thus obtained the title compound (55 mg); 1H NMR Spectrum: (DMSOd6) 2.13 (s, 3H), 2.27 (s, 3H), 7.61 (m, 3H), 8.02 (m, 2H), 8.60 (s, 2H), 12.00 (br s, 1H), 12.20 (s, 1H); Mass Spectrum: M+H+ 390.
Reaction SMILES: [C:1]([C:3]([OH:6])([CH3:5])[CH3:4])#[N:2].[Cl:7][CH2:8][C:9](Cl)=[O:10].Cl>O>[Cl:7][CH2:8][C:9]([O:6][C:3]([C:1]#[N:2])([CH3:5])[CH3:4])=[O:10]
Reactant: CC(C)(O)C#N
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: O
Product: CC(C)(C#N)OC(=O)CCl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
0.85 g of 2-cyano-2-propanol and solution F were mixed and stirred for 15 minutes at 0° C. To the mixture was added 0.8 ml of chloroacetic chloride and the solution was stirred for 5 minutes at 0° C., additional 2 hours at room temperature and further 1 hour at 70° C. Then, to the reaction mixture was added 1N hydrochloric acid and water, and extracted with ethyl acetate. The organic layer was washed successively with water and aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography to give 0.25 g of (1-cyano-1-methylethyl) chloroacetate.