Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@H:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>C(#N)C>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:9](=[O:11])[CH2:8][C@H:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:12]([O:14][CH3:15])=[O:13])=[CH:19][CH:18]=1
Reactant: COC(=O)[C@H](CC(=O)O)C1CCCCC1
Reactant: Nc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CC(=O)Nc1ccc(Cl)cc1)C1CCCCC1
Yield: 94.5 %

Procedure:
To a suspension of (3R)-3-cyclohexyl-4-methoxy-4-oxobutanoic acid (0.21 g), 4-chloroaniline (0.13 g) and HOBt (0.23 g) in acetonitrile (10 ml) were added WSC (0.29 g) and N-methylmorpholine (0.10 g), and mixed at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed sequentially with an aqueous sodium hydrogen carbonate solution, water, a 5% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a pale brown solid (0.30 g, 93%).
Reaction SMILES: [CH3:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[C:3]([O:5]CC)=[O:4].Br>C(O)(=O)C>[CH3:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)c1ccc(-c2ccc(OC)cc2)cc1
Agent: Br
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc(-c2ccc(O)cc2)cc1

Procedure:
A mixture containing α-methyl-4'-(methoxy)[1,1'-biphenyl]-4-acetic acid, ethyl ester (22.0 g, 77.4 mmol), acetic acid (400 mL) and 48% hydrobromic acid (80 mL) is refluxed for 18 hours. The solution is concentrated under reduced pressure to one-third the volume and the product crystallizes from the solution. The solid is filtered and dried to give a quantitative yield. A portion of this material is recrystallized from acetonitrile and a white solid is obtained, m.p. 205°-206° C. MS (El m/z): 242 (M)+, (b. p., M-CO2H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([Cl:18])=[C:12]([F:17])[CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=2)[CH:7]=1)=[O:5])C.O>C(O)(=O)C.Cl>[Cl:18][C:11]1[CH:10]=[C:9]2[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]2[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=2)=[CH:13][C:12]=1[F:17]
Reactant: CCOC(=O)c1cn(-c2ccc(F)cn2)c2cc(Cl)c(F)cc2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cn(-c2ccc(F)cn2)c2cc(Cl)c(F)cc2c1=O
Temperature: 90 °C

Procedure:
A suspension of 0.5 g 7-chloro-6-fluoro-1-(5-fluoro-pyridin-2-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (1.37 mmol) in a mixture of 1.5 ml acetic acid and 1.5 ml 25% HCl was stirred at 90° C. over night. The reaction was monitored by HPLC. The suspension was poured into 50 ml water, the colorless crystals filtered and dried.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][CH:7](Br)[CH:3]([CH2:4]2)[CH2:2]1.[Mg].Cl[C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]=[CH:13][N:12]=1.[Cl-].[NH4+].N1C=CC=NC=1>C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ni]Cl.O1CCCC1>[CH:3]12[CH2:4][CH:5]([CH2:1][CH2:2]1)[CH2:6][CH:7]2[C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]=[CH:13][N:12]=1
Reactant: Clc1cc(-c2ccccc2)ncn1
Reactant: BrC1CC2CCC1C2
Agent: Cl[Ni]Cl
Agent: [Cl-]
Agent: [Mg]
Solvent: c1cncnc1
Solvent: C1CCOC1
Product: c1ccc(-c2cc(C3CC4CCC3C4)ncn2)cc1
Temperature: -15 °C

Procedure:
Next, into a reaction container were put 2.99 g of exo-2-bromonorbornane, 0.50 g of magnesium, and 10 mL of tetrahydrofuran (THF), and this reaction container was heated by irradiation with microwaves (2.45 GHz, 100 W) for 10 minutes so that Grignard reagent was prepared. 5.02 g of 4-chloro-6-phenylpyrimidine obtained in Step 1 and 30 mL of THF were mixed, and while the mixture was being stirred at −15° C., the obtained Grignard reagent was added thereto, 30 mg of [1,2-bis(diphenylphosphino)ethane]nickel(II) dichloride (abbreviation: Ni(dppe)Cl2) was also added, then the temperature of the mixture was increased to room temperature. To this reaction solution was added an aqueous solution of ammonium chloride, and an organic layer was extracted with ethyl acetate. The obtained organic layer was dried with magnesium sulfate. After the drying, the solution was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by flash column chromatography (silica gel) using a mixed solvent of hexane and ethyl acetate as a developing solvent in a volume ratio of 5:1, to give Hnbppm, which is the objective substance and a pyrimidine derivative (yellow oily substance, 43% in yield). A synthetic scheme of Step 2 is shown by a following (b-2).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([NH:13][CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[N:10]3[N:23]=[CH:24][C:25]([C:26]4[CH:27]=[N:28][C:29]5[C:34]([CH:35]=4)=[CH:33][CH:32]=[CH:31][CH:30]=5)=[C:9]3[N:8]=2)[CH2:3][CH2:2]1.Cl>O1CCOCC1>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:12]=[C:11]([NH:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[N:10]3[N:23]=[CH:24][C:25]([C:26]4[CH:27]=[N:28][C:29]5[C:34]([CH:35]=4)=[CH:33][CH:32]=[CH:31][CH:30]=5)=[C:9]3[N:8]=2)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)CCNc1cc(N2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CCNc1cc(N2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12

Procedure:
NaH (25.1 mg, 60%, 0.63 mmol) and then tert-butyl 3-bromopropanoate (69.7 uL, 0.42 mmoL) was added to 5-morpholino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine (72.3 mg, 0.21 mmoL) in DMF (3 mL). The mixture was stirred at room temperature until LCMS indicated complete conversion. The reaction mixture was diluted with Sat. NH4Cl and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation of solvent afforded the crude tert-butyl 3-(5-morpholino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)propanoate. The crude ester was heated with 4N HCl (4 mL) and 1,4-dioxane (4 mL) at 50° C. for 3 h. Concentration provided 3-(5-morpholino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-ylamino)propanoic acid. LCMS tR=1.10 Min (5 min run, UV254nm). Mass calculated for, M+ 418.1, observed LC/MS m/z 419.2 (M+H).
Reaction SMILES: O[N:2]=[CH:3][C:4]1[C:5]([F:17])=[C:6]([CH:12]=[C:13]([F:16])[C:14]=1[F:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8]>ClC(Cl)(Cl)C#N>[C:3]([C:4]1[C:5]([F:17])=[C:6]([CH:12]=[C:13]([F:16])[C:14]=1[F:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:2]
Reactant: CCOC(=O)c1cc(F)c(F)c(C=NO)c1F
Solvent: N#CC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(F)c(F)c(C#N)c1F
Temperature: 90 °C
Reaction time: 16 h

Procedure:
Ethyl 3-hydroxyiminomethyl-2,4,5-trifluorobenzoate (5.5 g, 24.0 mmol) was dissolved in trichloroacetonitrile (25 g), and the solution was stirred at 90° C. for 16 hours. The reaction mixture was left to cool, and the solid matter that precipitated was separated through filtration. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography (eluent; n-hexane ethyl acetate=10:1), to thereby yield the title compound as a colorless oily substance (3.35 g, 61%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[CH:34]=[CH:33][C:21]([CH2:22][NH:23][C@@H:24]4[CH2:27][C@H:26]([C:28]([O:30]CC)=[O:29])[CH2:25]4)=[CH:20][CH:19]=3)[O:15][N:14]=2)=[CH:9][CH:8]=1)[CH:4]([CH3:6])[CH3:5].[ClH:35]>C(O)C>[ClH:35].[CH2:3]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:17]=[C:16]([C:18]3[CH:34]=[CH:33][C:21]([CH2:22][NH:23][C@@H:24]4[CH2:27][C@H:26]([C:28]([OH:30])=[O:29])[CH2:25]4)=[CH:20][CH:19]=3)[O:15][N:14]=2)=[CH:11][CH:12]=1)[CH:4]([CH3:6])[CH3:5]
Reactant: CCOC(=O)[C@H]1C[C@@H](NCc2ccc(-c3nc(-c4ccc(CC(C)C)cc4)no3)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Cc1ccc(-c2noc(-c3ccc(CN[C@H]4C[C@@H](C(=O)O)C4)cc3)n2)cc1
Temperature: 100 °C

Procedure:
1N NaOH (3.00 g, 3.00 mmol) was added to a solution of ethyl cis-3-({4-[3-(4-isobutylphenyl)-1,2,4-oxadiazol-5-yl]benzyl}amino)cyclobutanecarboxylate (0.260 g, 0.600 mmol) and ethanol (2 mL) and heated to 100° C. in a microwave for 5 minutes. The reaction mixture was adjusted to pH of 7 with 1N HCl causing a white precipitate to form. The reaction mixture was filtered and the solid was slurried in ethyl acetate and treated with 1 N HCl in ether. The slurry was filtered and washed with petroleum ether to give the title compound (0.100 g, 41% yield) as a white solid.
Reaction SMILES: B(O)(O)[OH:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1O>>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:2])=[CH:9][CH:8]=1
Reactant: COc1ccccc1O
Reactant: OB(O)O
Product: COc1ccc(O)cc1

Procedure:
The reaction was carried out in the same manner as in Example 4 except that orthoboric acid was replaced by 1.2 g. of anhydrous boric acid and 2.60 g. (21.0 m.moles) of o-methoxyphenol and 1.74 g. (14.0 m.moles) of p-methoxyphenol were obtained. The yield of these hydroxyphenyl ethers was 49.4 %.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Br[C:29]1[CH:30]=[N:31][CH:32]=[N:33][CH:34]=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:29]4[CH:30]=[N:31][CH:32]=[N:33][CH:34]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: Brc1cncnc1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2cncnc2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 5-bromopyrimidine in Step 4. LC-MS Method 2 tR=1.332, m/z=436.1; 1H NMR (CD3OD) 1.49 (d, 3H), 1.83 (m, 2H), 2.14-2.28 (m, 4H), 2.42 (m, 1H), 3.08 (m, 1H), 3.49 (m, 2H), 5.52 (m, 1H), 6.99 (t, 2H), 7.08 (d, 2H), 7.23 (m, 2H), 7.42 (d, 2H), 8.91 (s, 2H), 9.06 (s, 1H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[N:9]2[C:10](=[O:17])[CH:11]([NH2:16])[CH2:12][CH:13]=[CH:14][CH2:15][CH:8]2[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[NH2:16][C@@H:11]1[C:10](=[O:17])[N:9]2[C@H:5]([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][C@H:8]2[CH2:15][CH:14]=[CH:13][CH2:12]1
Reactant: COC(=O)C1CCC2CC=CCC(N)C(=O)N21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N[C@H]1CC=CC[C@@H]2CC[C@@H](C(=O)O)N2C1=O
Reaction time: 8 h

Procedure:
To a solution of 6-amino-5-oxo-1,2,3,5,6,7,10,10a-octahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid methyl ester, 8, (1.4 g, 5.2 mmol) in THF/water (3:1) is added LiOH (1.1 eq) and the solution is stirred overnight. The reaction is treated with 1 N HCl to pH 4. The mixture is then frozen and lyophilized to a pale yellow powder, which can be used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=[O:10])[CH:4]=1.[CH3:11][O:12][CH:13]([O:17][Si](C)(C)C)[CH:14]([CH3:16])[CH3:15]>ClCCl.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH3:11][O:12][C:13](=[O:17])[C:14]([CH3:16])([CH3:15])[CH:9]([OH:10])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=1
Reactant: COC(O[Si](C)(C)C)C(C)C
Reactant: COc1ccnc(C=O)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(O)c1cc(OC)ccn1
Reaction time: 18 h

Procedure:
A solution of 0.58 g of 4-methoxypyridine-2-carbaldehyde (Ashimori et al., Chem. Pharm. Bull. 38, 2446-2458 (1990)) and 21 mg of scandium trifluoromethanesulfonate in 14 ml of dichloromethane is treated dropwise with 0.9 ml of 1-methoxy-2-methyl-1-trimethylsilyloxypropane under ice-cooling. After 10 min the cooling bath is removed and the mixture is stirred for 18 h. Thereafter, 12 ml of methanol and 12 ml of aqueous hydrochloric acid (3 M) are added and stirring is continued for further 14 h. The solvents are removed in vacuo, the residue is dissolved in dichloromethane and washed with saturated aqueous sodium hydrogencarbonate solution. The organic layer is dried using sodium sulfate and concentrated to give 0.845 g of the title compound as a colorless oil. MS: 240.0 (MH+). TLC: Rf=0.46 (toluene/acetone 2:1).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][C:9]2[N:10]=[N:11][N:12]([CH2:14][CH2:15][OH:16])[N:13]=2)[CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[S:19][C:20]([C:26]2[C:31]([F:32])=[CH:30][C:29]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:28][C:27]=2[F:37])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24]>>[F:37][C:27]1[CH:28]=[C:29]([C:33]([OH:36])([CH3:35])[CH3:34])[CH:30]=[C:31]([F:32])[C:26]=1[C:20]1[S:19][C:18]([NH:17][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][C:9]3[N:10]=[N:11][N:12]([CH2:14][CH2:15][OH:16])[N:13]=3)[N:7]=2)=[C:22]([C:23]([NH2:25])=[O:24])[CH:21]=1
Reactant: OCCn1nnc(Cc2cccc(Br)n2)n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(Cc4nnn(CCO)n4)n3)s2)c(F)c1

Procedure:
The title compound was synthesized from 2-{5-[(6-bromopyridin-2-yl)methyl]-2H-tetrazol-2-yl}ethanol (114 mg, 0.40 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (125 mg, 0.40 mmol) according to the general procedure in Example 1.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:19]=1[C:20](O)=[O:21]>>[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:23][C:19]=1[C:20]([N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)=[O:21]
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(Cl)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1

Procedure:
The title compound was prepared according to the procedure E described for example 9 from 1-(4-trifluromethylphenyl)piperazine (ABCR F07741NB, [30459-17-7] and 2-chloro-5-(methylsulfonyl)-benzoic acid (CAS: 89938-62-5); MS (m/e): 464.3 (M+NH4+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](O)=O.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:39][C:40]1[C:61]([NH2:62])=[CH:60][C:43]2[CH2:44][C@@H:45]3[C:50]([CH3:52])([CH3:51])[C@:49]([CH3:53])([C:42]=2[CH:41]=1)[CH2:48][CH2:47][N:46]3[C:54](=[O:59])[C:55]([F:58])([F:57])[F:56]>CN(C)C=O.CCOC(C)=O>[F:58][C:55]([F:56])([F:57])[C:54]([N:46]1[CH2:47][CH2:48][C@:49]2([CH3:53])[C:50]([CH3:52])([CH3:51])[C@H:45]1[CH2:44][C:43]1[CH:60]=[C:61]3[N:62]=[C:7]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)[NH:39][C:40]3=[CH:41][C:42]=12)=[O:59]
Reactant: O=C(O)c1cnccn1
Reactant: CC1(C)[C@H]2Cc3cc(N)c(N)cc3[C@]1(C)CCN2C(=O)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)[C@H]2Cc3cc4nc(-c5cnccn5)[nH]c4cc3[C@]1(C)CCN2C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of pyrazine-2-carboxylic acid (152 mg), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (397 mg), and triethylamine (0.5 mL) in dimethylformamide (5 mL) is stirred at room temperature for 30 min, before 1-[(2R,6S)-8,9-diamino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone (300 mg) is added. The solution is stirred at room temperature overnight. Then, the solution is diluted with EtOAc and washed with water and 2 M aqueous K2CO3 solution and dried (MgSO4). The solvent is removed under reduced pressure and the residue is taken up in acetic acid (5 mL). The resulting solution is heated at 80° C. overnight. Then, the solvent is removed under reduced pressure and the residue is evaporated twice with toluene to give the crude title compound that is used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)=[O:23]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][CH2:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[O:23])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CC(N)c1cccc(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(NCC(=O)c1ccc(Cl)cc1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
To an ice-cooled mixture of the product from Step A (4.6 g, 23 mmol) and diisopropylethylamine (4.46 g, 34.5 mmol) in dichloromethane (50 mL) was added 2-bromo-4′-chloroacetophenone (5.48 g, 23 mmol). The reaction mixture was stirred at room temperature for 3 hours and then diluted with dichloromethane (100 mL). The mixture was washed with water and brine, dried over sodium sulfate, and concentrated. Flash chromatography (silica gel, 20 to 40% ethyl acetate/hexanes) purification provided the 2-(1-(3-bromophenyl)ethylamino)-1-(4-chlorophenyl)ethanone (6.0 g, 74%): 1H NMR (CDCl3, 300 MHz) δ 7.80 (dd, J=6.7, 2.0 Hz, 2H), 7.52 (t, J=1.7 Hz, 1H), 7.43-7.37 (m, 3H), 7.29-7.17 (m, 2H), 3.93 (d, J=1.4 Hz, 2H), 3.80 (q, J=6.6 Hz, 1H), 1.42 (d, J=6.6 Hz, 3H). ESI MS m/z=352 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:22][CH2:23][OH:24])[CH2:10][C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(CC)CC.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:22][CH2:23][O:24][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:10][C:11]([N:13]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C(=O)CC(CCO)c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)CC(CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1
Yield: 91.1 %

Procedure:
3,4-Dichloro-beta-(2-hydroxyethyl)-N-(4-chlorophenyl)-N-methylbenzenepropanamide (2.1 g) in CH2Cl2 (40 mL) was cooled to -5° to -10° C. and treated sequentially with Et3N (0.69 g), and methanesulfonyl chloride (0.78 g). After two hours the reaction mixture was washed with water(3×50 mL) and the organic layer separated, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (2.3 g).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]([N:18]4[CH2:21][CH:20]([OH:22])[CH2:19]4)=[O:17])[S:15][C:8]=23)=[C:4]([F:25])[CH:3]=1.CSC1SC2C(=NC=CC=2OC2C=CC(NC(NC(=O)CC3C=CC=CC=3)=S)=CC=2F)C=1.[CH3:58][O:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=1[CH2:66][C:67]([N:69]=[C:70]=[S:71])=[O:68]>>[F:25][C:4]1[CH:3]=[C:2]([NH:1][C:70]([NH:69][C:67](=[O:68])[CH2:66][C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=2[O:59][CH3:58])=[S:71])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]([N:18]3[CH2:19][CH:20]([OH:22])[CH2:21]3)=[O:17])[S:15][C:8]=12
Reactant: COc1ccccc1CC(=O)N=C=S
Reactant: Nc1ccc(Oc2ccnc3cc(C(=O)N4CC(O)C4)sc23)c(F)c1
Agent: CSc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Product: COc1ccccc1CC(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(C(=O)N4CC(O)C4)sc23)c(F)c1
Yield: 39 %

Procedure:
Starting from the amine 299, following the procedure described above for the synthesis of compound 232a (scheme 50, example 203) but replacing 2-phenylacetyl isothiocyanate with (2-methoxy-phenyl)-acetyl isothiocyanate and title compound 300 was obtained in 39% yield as a creamy solid. 1HNMR: (CD3OD) δ (ppm): 12.58 (s, 1H), 11.77 (s, 1H), 8.62 (m, 1H), 8.09 (d, J=12.3 Hz, 1H), 7.95 (s, 1H), 7.56 (m, 2H), 7.26 (m, 2H), 7.00 (m, 1H), 6.92 (m, 1H), 6.77 (m, 1H), 6.50 (d, J=5.9 Hz, 1H), 4.81 (m, 1H), 4.59 (m, 1H), 4.35 (m, 2H), 3.87-3.78 (m, 6H). MS (m/z): 567.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:11][N:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[O:36][CH:37]=[CH:38][CH:39]=5)[O:32][C:33]=4[CH3:34])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:11][N:10]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[O:36][CH:37]=[CH:38][CH:39]=5)[O:32][C:33]=4[CH3:34])=[CH:25][CH:26]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccco2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(-c3ccc(F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
A mixture of ethyl 3-[3-(4-fluorophenyl)-1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (350 mg), 1N aqueous sodium hydroxide solution (2 ml), ethanol (4 ml), and tetrahydrofuran (4 ml) was stirred at room temperature for 2 hours. The reaction mixture was acidified with dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[3-(4-fluorophenyl)-1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (150 mg, yield: 45%). This was recrystallized from ethyl acetate-hexane. Melting point: 125–126° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9][C@H:8]1[CH2:17][OH:18])=[O:6])[CH:2]=[CH2:3].[C:19]([O-:22])(=[S:21])[CH3:20].[K+].C(OCC)(=O)C>CN(C)C=O>[C:19]([S:21][C@@H:10]1[CH2:11][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C@H:8]([CH2:17][OH:18])[CH2:9]1)(=[O:22])[CH3:20]
Reactant: CC([O-])=S
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CO
Temperature: 65 °C
Reaction time: 5 h
Yield: 85.5 %

Procedure:
A solution of (2S,4R)-1-allyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (19.32 g: 69.17 mmole) and 90% potassium thioacetate (10.73 g: 89.9 mmole) in dimethylformamide (217 ml) is heated with stirring at 65° C. for 5 hours. To the reaction mixture ethyl acetate (200 ml) and ice water (200 ml) are added. The organic layer is taken, successively washed with aqueous 0.05N-sodium hydroxide, 0.1N-hydrochloric acid, water and saturated brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel chromatography to give (2S,4S)-4-acetylthio-1-allyloxycarbonylpyrrolidine-2-methanol (15.34 g). Yield: 90%.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1.[CH3:24][O:25][CH2:26][CH2:27][CH:28]([NH2:30])[CH3:29]>>[OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:30][CH:28]([CH2:27][CH2:26][O:25][CH3:24])[CH3:29])=[O:13])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: COCCC(C)N
Reactant: COc1cc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccn1
Product: COCCC(C)NC(=O)c1ccc(-n2ncc(-c3ccnc(OC)c3)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(5-hydroxy-4-(2-methoxypyridin-4-yl)-1H-pyrazol-1-yl)nicotinic acid and 4-methoxybutan-2-amine. 1H NMR (400 MHz, methanol-d4) δ ppm 1.28 (d, J=6.32 Hz, 3H) 1.86 (dd, J=6.95, 5.43 Hz, 2H) 3.33 (s, 3H) 3.44-3.57 (m, 2H) 4.18 (s, 3H) 4.22-4.34 (m, 1H) 7.77 (d, J=5.31 Hz, 1H) 7.86 (s, 1H) 8.04 (d, J=6.57 Hz, 1H) 8.44 (br. s., 3H) 8.68-9.15 (m, 1H). MS m/z [M+H]+ 398.2.