Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19](Br)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.COCCOC.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.O>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
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: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3cncc(-c4ccccc4)c23)C1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
Intermediate 1 (228 mg) obtained in Example 1, Step A is added with phenylboronic acid (122 mg, Aldrich), tetrakis(triphenylphosphine)palladium(0) (116 mg), 1,2-dimethoxyethane (5 ml) and 2 N aqueous sodium carbonate (2 ml), and the mixture is refluxed by heating for 5 hours under a nitrogen gas atmosphere. The reaction mixture is cooled to room temperature, then added with water (25 ml), and extracted 3 times with ethyl acetate (20 ml for each time), and the combined organic layer is washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel chromatography (n-hexane:ethyl acetate=2:1) to obtain the title compound (158 mg (predictive yield)).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26]CC)=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:35][C:36]1[CH:37]=[CH:38][C:39]([O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])=[C:40]([CH2:42][OH:43])[CH:41]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:6][CH2:7][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:43][CH2:42][C:40]4[CH:41]=[C:36]([F:35])[CH:37]=[CH:38][C:39]=4[O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[C:24]([OH:26])=[O:25])[CH2:9][CH2:10]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Reactant: C=CC[C@H](C)Oc1ccc(F)cc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)O)c(C)nc3cc(COCc4cc(F)ccc4O[C@@H](C)CC=C)nn23)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 36 %

Procedure:
To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.05 g, 0.086 mmol) and (S)-(5-fluoro-2-(pent-4-en-2-yloxy)phenyl)methanol (0.022 g, 0.103 mmol) in DMF (1 ml) was added sodium hydride (5.13 mg, 0.128 mmol) and the resulting yellow mixture was stirred at rt. After 5 h, the mixture was diluted with EtOAc and washed with 1N HCl followed by water and brine. The organic phase was dried (Na2SO4), filtered and concentrated. The oil was purified by flash chromatography (Biotage; 0%-10% MeOH/DCM; 10 CV) to give (S)-2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((5-fluoro-2-((S)-pent-4-en-2-yloxy)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid (20 mg, 0.031 mmol, 36.6% yield) was obtained as an amber oil. 1H NMR (400 MHz, CDCl3) δ 7.22 (dd, J=9.0, 2.9 Hz, 1H), 6.89 (dd, J=8.1, 3.2 Hz, 1H), 6.84-6.75 (m, 1H), 6.60 (s, 1H), 6.10-5.95 (m, 1H), 5.89-5.75 (m, 1H), 5.52-5.38 (m, 1H), 5.23-4.99 (m, 4H), 4.80 (s, 2H), 4.66 (s, 2H), 4.45-4.28 (m, 1H), 4.06-3.93 (m, 2H), 2.71-2.54 (m, 3H), 2.47 (d, J=5.9 Hz, 1H), 2.40-2.30 (m, 1H), 2.08-1.56 (m, 4H), 1.49-1.01 (m, 15H). LCMS (M+H) calcd for C35H48FN4O6: 639.35. found: 639.2.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]=O)=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1.[CH2:14]([NH2:18])[CH:15]([CH3:17])[CH3:16].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)(Cl)Cl>[O:1]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][NH:18][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)CN
Reactant: O=Cc1ccc2c(c1)OCCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CC(C)CNCc1ccc2c(c1)OCCCO2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice cold mixture of 15 g of 3,4-dihydro-2H-1,5-benzodioxepine-7-carbaldehyde and 67 mL (8 equiv) of isobutylamine in 100 mL of 1,2-dichloroethane was added 50 mL (10 equiv) of acetic acid and 25 g (1.4 equiv) of sodium triacetoxyborohydride. The mixture was allowed to warm and stir overnight then diluted with 500 mL of chloroform and washed with 500 mL of 5N NaOH. The aqueous layer was extracted with 4 additional 100 mL portions of chloroform and the combined extracts dried over magnesium sulfate and concentrated under reduced pressure. After drying under vacuum the product was obtained as clear oil: MS (m+1)=236.2; 1H NMR (400 MHz, CDCl3) 7.0-6.8 (m, 3H), 4.2 (q, 4H), 3.65 (s, 2H), 2.42 (d, 2H), 2.2 (m, 2H), 1.8 (m, 1H), 0.9 (d, 6H).
Reaction SMILES: [CH3:1][N:2](C(OC(C)(C)C)=O)[C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].[NH2:18][CH:19]([CH2:24][CH:25]=[CH2:26])[CH2:20][C:21]([O-:23])=[O:22].C(O)(C(F)(F)F)=O>O>[CH3:1][NH:2][C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].[NH2:18][CH:19]([CH2:24][CH:25]=[CH2:26])[CH2:20][C:21]([O-:23])=[O:22]
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: C=CCC(N)CC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN[C@@H](CC(C)C)C(=O)O
Reaction time: 0.5 h

Procedure:
Methyl N-(t-butoxycarbonyl)leucine-3-amino-5-hexenoate (10 g) was treated with 90% TFA in water(100 ml). The mixture was stirred for 30 min and the TFA and water were then removed by evaporation. The residue was purified by preparative HPLC on a C18 silica column eluting with acetonitrile/water/0.1% TFA to give a gummy solid on evaporation of appropriate fractions. This was dissolved in ethyl acetate (50 ml) and washed twice with saturated sodium bicarbonate solution(10 ml), once with saturated brine(10 ml), dried (MgSO4) and evaporated to give 1.6 g of a single diastereoisomer of methyl leucine-3-amino-5-hexenate as a pale blue oil. HPLC Dynamax 60A C18 column; acetonitrile/water/0.1%TFA 10-70% over 20 min Rt 10.7 min; 1H NMR (DMSO-d6, 300 MHz, ppm): 0.9(6H, m), 1.4-1.5 (2H, m), 1.5-1.7 (1H, m), 2.1-2.3(2H, m), 2.3-2.5(2H, m), 3.5 (3H, s), 3.6-3.7(1H, m), 4.1-4.2(1H, m), 4.4-4.6 (2H, b), 5.0-5.1 (2H, dd), 5.6-5.8 (1H, m), 8.4 (1H, d): m/Z 257 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=1[NH2:11].Cl>N1C=CC=CC=1>[Cl:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=1[NH:11][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC(=O)Nc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C

Procedure:
Valeryl chloride (12.06 g., 0.10 mole) is added dropwise to a cooled stirred solution of 2-chloro-4-nitroaniline (17.26 g., 0.10 mole) in pyridine (100 ml.). The mixture is warmed to ambient temperature, then heated (80°-100° C.) for 24 hours. The cooled solution is poured into cold 1 N hydrochloric acid (500 ml.) with stirring. The precipitated solid is collected, washed well with water and dried, 25.1 g., m.p. 80°-95° C. Recrystallization from cyclohexane yeilds mater al (19.75 g.) of m.p. 95°-97° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]([CH3:13])=[C:6]2[C:10]=1[CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7]2.[CH3:15][O:16]C(Cl)Cl>ClCCl>[Cl:1][C:2]1[C:3]([CH:15]=[O:16])=[C:4]([CH3:14])[C:5]([CH3:13])=[C:6]2[C:10]=1[CH2:9][C:8]([CH3:11])([CH3:12])[CH2:7]2
Reactant: COC(Cl)Cl
Reactant: Cc1cc(Cl)c2c(c1C)CC(C)(C)C2
Solvent: ClCCl
Product: Cc1c(C)c2c(c(Cl)c1C=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
To a solution of 17.0 g of the 7-chloro-2,2,4,5-tetramethylindane in 100 ml of dry dichloromethane was continuously added 18.5 ml of α,α-dichloromethyl methyl ether and 11 ml of TiCl2 at 0° C. The reaction mixture was stirred at room temperature for 2 hours, quenched with 200 ml of water, and separated the organic layer. The aqueous layer was extracted with dichloromethane. The combined organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 14.7 g of the title compound as yellow solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=2)[CH:5]1[N:17]1[CH2:22][CH2:21][N:20]([C:23]2([CH3:36])[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)[CH2:19][C@@H:18]1[CH3:37])[CH3:2].[ClH:38].[CH3:39][C:40]1[C:45]([C:46]([OH:48])=O)=[C:44]([CH3:49])[N:43]=[CH:42][N:41]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>O1CCOCC1.C(Cl)Cl>[ClH:38].[ClH:38].[CH2:1]([O:3][C@@H:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:10]=2)[C@H:5]1[N:17]1[CH2:22][CH2:21][N:20]([C:23]2([CH3:36])[CH2:28][CH2:27][N:26]([C:46]([C:45]3[C:40]([CH3:39])=[N:41][CH:42]=[N:43][C:44]=3[CH3:49])=[O:48])[CH2:25][CH2:24]2)[CH2:19][C@@H:18]1[CH3:37])[CH3:2]
Reactant: Cc1ncnc(C)c1C(=O)O
Reactant: CCOC1Cc2cc(C(F)(F)F)ccc2C1N1CCN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)C[C@@H]1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCO[C@@H]1Cc2cc(C(F)(F)F)ccc2[C@H]1N1CCN(C2(C)CCN(C(=O)c3c(C)ncnc3C)CC2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
t-Butyl 4-{(3S)-4-[2-ethoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidine-1-carboxylate (48.4 g, 0.0921 mol) was treated with a 4.0 M solution of hydrogen chloride in 1,4-dioxane (230 mL) at room temperature for 1 h. The reaction mixture was concentrated to dryness and the residue was further dried under high vacuum. The formed amine hydrochloride was mixed with 4,6-dimethyl-pyrimidine-5-carboxylic acid (16.80 g, 0.110 mol) in methylene chloride (100 mL), and then 1-hydroxybenzotriazole (16.80 g, 0.1243 mol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (25.00 g, 0.1304 mol) and triethylamine (65.0 mL, 0.466 mol) were added. The resulting reaction mixture was stirred at room temperature overnight before it was diluted with methylene chloride and washed with aqueous sodium hydroxide (1 M) and brine. The organic layer was collected and dried over magnesium sulfate. After removal of the solvent, the residue was dissolved in methylene chloride (50 mL) and the solution was passed through a silica plug with ethyl acetate containing 1% triethylamine. The solution was concentrated and the residue was dissolved in 900mL of isopropyl acetate. To the above solution, 185 mL of 1.0 N HCl in isopropyl acetate was slowly added. The mixture slowly turned cloudy, and was stirred overnight. The formed white solid was collected, washed with 40 mL of isopropyl acetate. The cake was air-dried to give 47.0 g (80.7%) of product. MS (EI) 560.3 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.[OH-].[Na+].[N:14]#[C:15]Cl>C(Cl)Cl.O>[C:15]([N:5]1[C:4]([CH3:11])([CH3:10])[CH2:3][CH:2]([OH:1])[CH2:7][C:6]1([CH3:9])[CH3:8])#[N:14]
Reactant: N#CCl
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)CC(O)CC(C)(C)N1C#N

Procedure:
62.8 g (0.4 mole) of 4-hydroxy-2,2,6,6-tetramethyl piperidine are dissolved in 250 ml of methylene chloride a solution of 16 g (0.4 mole) of sodium hydroxide in 250 ml of water is introduced and 20.5 ml of cyanogen chloride are added dropwise to the mixture at 0° to 5° C. The mixture is stirred until it reaches room temperature, after which the organic phase is separated off, dried with sodium sulphate, filtered and the methylene chloride distilled off, leaving 31 g (42.5% of the theoretical) of 1-cyano-4-hydroxy-2,2,6,6-tetramethyl piperidine. Bp 0.5 = 135° C; melting point 96°-98° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[NH2:21]>CCOC(C)=O.C1CCCCC1>[CH3:28][O:27][C:23]1[CH:22]=[C:20]([NH:21][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])[N:3]=2)[CH:19]=[C:18]([O:17][CH3:16])[C:24]=1[O:25][CH3:26]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Clc1cncc(Oc2ccccc2Cl)n1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(Oc3ccccc3Cl)n2)cc(OC)c1OC
Yield: 71 %

Procedure:
Using Method EE with 2-chloro-6-(2-chlorophenyloxy)-pyrazine (200 mg, 0.83 mmol) and 3,4,5-trimethoxyaniline (183 mg, 1.00 mmol), and purification by column chromatography (AcOEt:cyclohexane, 1:1), the title compound was obtained (227 mg). Yield: 71%. 1H NMR (250 MHz, DMSO-d6) δ 3.43 (s, 6H, [CH3O]3+5), 3.54 (s, 3H, [CH3O]4), 6.68 (s, 2H, Harom2′+6′), 7.26-7.30 (m, 1H, Harom 4), 7.37-7.40 (m, 2H, Harom 5+6), 7.59 (d, 1H, Harom 3, J=7.8 Hz), 7.82 (s, 1H, HPz 5), 7.95 (s, 1H, HPz 3), 9.56 (s, 1H, NH). m/z: 388.1 [(M+H)+, calcd for C19H18ClN3O4 387.1].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[C:13]=2[O:19]C)[N:8]([CH3:21])[C:7]=1[CH3:22])=[O:5])[CH3:2].B(Br)(Br)[Br:24]>ClCCl>[BrH:24].[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[C:13]=2[OH:19])[N:8]([CH3:21])[C:7]=1[CH3:22])=[O:5])[CH3:2]
Reactant: BrB(Br)Br
Reactant: CCOC(=O)c1c(C)c(-c2cccc(N)c2OC)n(C)c1C
Solvent: ClCCl
Product: Br
Product: CCOC(=O)c1c(C)c(-c2cccc(N)c2O)n(C)c1C
Yield: 64.8 %

Procedure:
5-(3-Amino-2-methoxy-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6g (210 mg, 0.69 mmol) was dissolved in 5 mL of dichloromethane followed by addition of boron tribromide (1.39 mL, 2.78 mmol). The reaction mixture was reacted at room temperature for 0.5 hours and monitored by TLC until the disappearance of the starting materials. The reaction was quenched with methanol, and the mixture was concentrated under reduced pressure followed by addition of 50 mL of ethyl acetate and 15 mL of saturated aqueous sodium bicarbonate. The mixture was mixed well and the layers were separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain the title compound 5-(3-amino-2-hydroxy-phenyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester hydrobromide 6h (165 mg, yield 82.5%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:18][O:19][CH2:20][C:21]1[C:26]([C:27](O)=[O:28])=[CH:25][N:24]=[C:23]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[N:22]=1.COC(=O)CC(=O)COC>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH:16][C:27]([C:26]2[C:21]([CH2:20][O:19][CH3:18])=[N:22][C:23]([C:30]3[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=3)=[N:24][CH:25]=2)=[O:28])=[CH:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: COCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1C(=O)O
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)cc1
Agent: COCC(=O)CC(=O)OC
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2COC)cc1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester [PCT Int. Appl. (2002), WO 2002/096895A1] was reacted with 4-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (prepared from 4-methoxy-3-oxo-butyric acid methyl ester, in analogy to the procedures described in examples 27C] and 27D] followed by saponification in analogy to the procedure described in example 53B]) to give 2-[4-({[4-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow foam.
Reaction SMILES: [CH2:1]1[NH:5][CH:4]([C:6]([OH:8])=[O:7])[CH:3]=[CH:2]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1>C([O-])(O)=O.[Na+]>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:5]2[CH2:1][CH:2]=[CH:3][CH:4]2[C:6]([OH:8])=[O:7])=[O:18])=[CH:12][CH:11]=1
Reactant: O=C(O)C1C=CCN1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)C1C=CCN1C(=O)Nc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
0.250 g (2.21 mmol) 3,4-dehydro-DL-proline are dissolved in 15 ml of 5% NaHCO3 solution, combined with 0.678 ml (4.42 mmol) 4-chlorophenylisocyanate and stirred for 16 h at 80° C. Then the mixture is cooled, filtered and the residue is washed with water. The filtrate is adjusted to pH 1 with semi-concentrated HCl, extracted 2× with ethyl acetate, dried on sodium sulphate and concentrated i. vac.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:19][CH3:20]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([O:7][CH2:19][CH3:20])=[O:6]
Reactant: CCI
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Yield: 104.3 %

Procedure:
To a solution of 3-bromo-4-chlorobenzoic acid (3.00 g, 12.74 mmol) and cesium carbonate (6.23 g, 19.11 mmol) in acetonitrile (70 mL) was added iodoethane (5.1 mL, 63.7 mmol). The reaction mixture was heated at reflux overnight. After cooling to room temperature, the solution was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. Chromatography on silica gel (biotage, 5% EtOAc in hexane) afforded 3.5 g of ethyl 3-bromo-4-chlorobenzoate (97%). 1H NMR (300 MHz; CDCl3) 1.40 (t, 3H); 4.37 (q, 2H); 7.52 (d, J=8.1 Hz, 1H); 7.91 (dd, J1=8.4 Hz, J2=1.8 Hz, 1H); 8.28 (d, J=1.8 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][C:14]1=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:16]1[CH2:17][CH2:18][NH:13][C:14](=[O:19])[CH2:15]1)=[N:7][N:6]=[CH:5]2
Reactant: O=C1CNCCN1
Reactant: Clc1nncc2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CN(c2nncc3cc(Br)ccc23)CCN1
Temperature: 190 °C
Yield: 83.2 %

Procedure:
A glass microwave reaction vessel was charged with 6-bromo-1-chlorophthalazine (Example 1, 0.11 g, 0.45 mmol), piperazin-2-one (0.090 g, 0.90 mmol), potassium carbonate (0.062 g, 0.45 mmol) and 5 mL acetonitrile. The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 190° C. for about 12 min (watts, Powermax feature on, ramp time 1 min). The mixture was purified directly via flash chromatography (silica gel) eluting with 5% 2 M ammonia methanol/DCM to give the 4-(6-bromophthalazin-1-yl)piperazin-2-one (0.115 g) as a pale yellow solid. Found MS (ES+): 307, 309(M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3]/[CH:4]=[CH:5]/[C:6]1([OH:12])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[S:15]1[C:19]2=[CH:20][CH:21]=[CH:22][C:23]([S:24]([NH:27][C:28]3[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=3)(=[O:26])=[O:25])=[C:18]2[N:17]=[CH:16]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:12][C:6]1(/[CH:5]=[CH:4]/[CH2:3][C:2]([F:1])([F:13])[F:14])[CH2:7][CH2:8][N:9]([C:32]([C:31]2[CH:30]=[CH:29][C:28]([NH:27][S:24]([C:23]3[CH:22]=[CH:21][CH:20]=[C:19]4[S:15][CH:16]=[N:17][C:18]=34)(=[O:26])=[O:25])=[CH:36][CH:35]=2)=[O:33])[CH2:10][CH2:11]1
Reactant: O=C(O)c1ccc(NS(=O)(=O)c2cccc3scnc23)cc1
Reactant: OC1(/C=C/CC(F)(F)F)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(NS(=O)(=O)c2cccc3scnc23)cc1)N1CCC(O)(/C=C/CC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round-bottom flask was added with (E)-4-(4,4,4-trifluorobut-1-enyl)piperidin-4-ol (50 mg 0.24 mmol), 4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (80 mg, 0.24 mmol), DIPEA (155 mg, 1.2 mmol), HATU (110 mg, 0.29 mmol), and DCM (5 mL). The mixture was stirred at r.t. for 16 hours. After washing with brine, the combined organic layer was dried over anhy. Na2SO4 and concentrated in vacuo. Purification by a standard method gave the desired compound. 1H NMR (CHLOROFORM-d) δ: 9.31 (s, 1H), 8.19 (d, J=8.1 Hz, 1H), 8.10 (d, J=7.5 Hz, 1H), 7.99 (s, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.17-7.24 (m, J=8.3 Hz, 2H), 7.08-7.15 (m, J=8.1 Hz, 2H), 5.78-5.94 (m, 1H), 5.64-5.76 (m, 1H), 4.28-4.47 (m, 1H), 3.51 (s, 1H), 3.32-3.48 (m, 1H), 3.27 (br. s., 1H), 2.84 (dd, J=10.5, 7.0 Hz, 1H), 1.66 (br. s., 4H), 1.46 (d, J=9.7 Hz, 2H). LC-MS: m/z 526.7 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[F:12]F.C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(O)(=O)C>[NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][C:5]([F:12])=[CH:6][N:7]=1
Reactant: COC(=O)c1nccnc1N
Reactant: FF
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(F)cnc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 10 mL of acetic acid was dissolved 0.5 g of methyl 3-amino-2-pyrazinecarboxylate. At room temperature, 10% fluorine gas (a fluorine gas diluted with nitrogen gas) was introduced into the solution at a rate of 23 mL per minute for a period of 32 minutes. After stirring the solution for 30 minutes at room temperature, the reaction mixture was added to a mixture of 50 mL of saturated aqueous solution of sodium hydrogen carbonate and 50 mL of ethyl acetate, and the organic layer was separated. The organic layer thus obtained was washed successively with 10 mL of water and 10 mL of saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=3:1] to obtain 0.01 g of methyl 3-amino-6-fluoro-2-pyrazinecarboxylate as a light yellow-colored solid product.