Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][N:16]([S:19]([C:22]4[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.[CH2:38]([S:40](Cl)(=[O:42])=[O:41])[CH3:39]>ClCCl>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[O:29][C:5]1[CH:4]=[CH:3][C:2]([N:1]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[CH:7][C:6]=1[C:8]1[C:9]2[CH:18]=[CH:17][N:16]([S:19]([C:22]3[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=3)(=[O:20])=[O:21])[C:10]=2[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc(N)ccc4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Solvent: ClCCl
Product: CCS(=O)(=O)N(c1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3c2ccn3S(=O)(=O)c2ccc(C)cc2)c1)S(=O)(=O)CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 181.4 %

Procedure:
A solution of Example 36c (4.35 g, 8.34 mmol) in dichloromethane (50 mL) was cooled to 0° C. To this solution was added ethanesulfonyl chloride (2.37 mL, 25.0 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 80% ethyl acetate/hexanes) to provide the title compound (5.34 g, 91% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4]Br.[CH3:7][C:8]1[C:9]2[C:14]([CH:15]3[C:20]=1[CH2:19][CH2:18][NH:17][CH2:16]3)=[CH:13][CH:12]=[CH:11][CH:10]=2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:6])[CH2:4][N:17]1[CH2:18][CH2:19][C:20]2=[C:8]([CH3:7])[C:9]3[C:14]([CH:15]2[CH2:16]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CC1=C2CCNCC2c2ccccc21
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN1CCC2=C(C)c3ccccc3C2C1

Procedure:
A solution of 15.3 g of bromoacetic acid methyl ester in 50 cc of dimethyl formamide is added dropwise at 60° while stirring to a mixture of 18.5 g of 1,3,4,9b-tetrahydro-5-methyl-2H-indeno[1,2-c]pyridine and 41.4 g of potassium carbonate in 200 cc of dimethyl formamide. The reaction mixture is allowed to react at 60° for 1 hour, is poured on ice water and is extracted thrice with chloroform. The extracts are dried and completely concentrated by evaporation, the residue is dissolved in 50 cc of methanol, and the calculated amount of hydrochloric acid in ethanol is added. After the addition of ether, 1,3,4,9 b-tetrahydro-5-methyl-2H-indeno [1,2-c]pyridine-2-acetic acid methyl ester crystallizes as hydrochloride and is recrystallized twice from ethanol for further purification. The hydrochloride has a M.P. of 184°-185°.
Reaction SMILES: [CH2:1]=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[CH2:4][CH2:3]1.[H][H]>CO.CCOC(C)=O.[Pd]>[CH3:1][CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[CH2:4][CH2:3]1
Reactant: C=C1CCc2c(O)cccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1CCc2c(O)cccc21
Yield: 93579.3 %

Procedure:
A mixture of 1-methylene-indan-4-ol (200 mg, 1.37 mmol) and 10% Pd/C (60 mg, 10% weight) in methanol (6 ml) was hydrogenated under 50 psi hydrogen atmosphere for 1 hour. The mixture was dissolved in EtOAc, filtered through a celite pad. The filtrate was concentrated under reduced pressure, and dried to give 1-methyl-indan-4-ol (190 g, 94%)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:29][O:30][CH3:31])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:20]=[N:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15](=[S:17])[NH2:16])=[CH:11]2.[C:32]([O:37][CH2:38][CH3:39])(=[O:36])[C:33]#[C:34][CH3:35].C(P(CCCC)CCCC)CCC.O1CCCC1>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH:4]([CH2:29][O:30][CH3:31])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:20]=[N:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:17][CH:34]([CH2:33][C:32]([O:37][CH2:38][CH3:39])=[O:36])[CH2:35][N:16]=1)=[CH:11]2
Reactant: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=S)[nH]c12
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC(COC)COC)c3[nH]2)S1
Temperature: 60 °C
Reaction time: 0.83 h
Yield: 52 %

Procedure:
A mixture of 7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carbothioamide (940 mg), ethyl 2-butynoate (0.6 mL), tributylphosphine (0.5 mL), tetrahydrofuran (15 mL) and toluene (20 mL) was stirred at 60° C. for 50 min. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate/hexane=0/5/95 to 5/95/0, volume ratio) to give the title compound (610 mg, 52%) as a yellow amorphous solid. MS 578 (MH+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3[N:28]=[C:27]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[NH:26][C:25]=3[C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=3)=[CH:23][C:18]=2[O:17][CH2:16]1>C1COCC1>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3[N:28]=[C:27]([CH:29]4[CH2:30][CH2:31][N:32]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:33][CH2:34]4)[NH:26][C:25]=3[C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=3)=[CH:23][C:18]=2[O:17][CH2:16]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(-c2[nH]c(C3CCNCC3)nc2-c2ccc3c(c2)OCO3)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cccc(-c2[nH]c(C3CCN(S(C)(=O)=O)CC3)nc2-c2ccc3c(c2)OCO3)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
Methanesulfonyl chloride (0.009 mL, 0.12 mmol) and diisopropylethylamine (0.026 mL, 0.15 mmol) were added to a solution of 2-(5-benzo[1,3]dioxol-5-yl-2-piperidin-4-yl-3H-imidazol-4-yl)-6-methyl-pyridine (0.036 g, 0.10 mmol; see Example 9) in anhydrous THF (3 mL). The reaction mixture was stirred at room temperature for 3 hours. Solvent was removed under reduced pressure, and the residue was dissolved in 1 mL DMSO. The DMSO solution was filtered and injected onto preparative HPLC. HPLC purification eluting with acetonitrile:water gave 0.011 g (25%) of the title compound as a yellow solid. MS (ESP+) m/z 441.2 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.74 (t, 1H, J=7.9 Hz), 7.34 (m, 1H), 7.28 (m, 1H), 7.03 (m, 3H), 6.08 (s, 2H), 3.92 (m, 2H), 3.25 (m, 1H), 2.94 (m, 2H), 2.90 (s, 3H), 2.66 (s, 3H), 2.23 (m, 2H), 2.03 (m, 2H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][O:27][C:28](=[O:45])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][OH:44])=[O:24].N1C=CC=CC=1>C(Cl)Cl>[Cl:6][CH2:5][O:4][C:2]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][O:27][C:28](=[O:45])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:2]([O:4][CH2:5][Cl:6])=[O:3])=[O:24])=[O:3]
Reactant: O=C(CCCCCCCCCCCCCCCO)OCOC(=O)CCCCCCCCCCCCCCCO
Reactant: O=C(Cl)OCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCCCCCCCCCCCCCCOC(=O)OCCl)OCOC(=O)CCCCCCCCCCCCCCCOC(=O)OCCl
Temperature: 0 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
Chloromethyl chloroformate (0.93 g, 7.2 mmol) was added to an ice-cooled solution of methylene bis(16-hydroxyhexadecanoate) (2.0 g, 3.6 mmol) in methylene chloride (80 ml). Pyridine (0.57 g, 7.2 mmol) was added and the reaction mixture was stirred for 15 minutes at 0° C. and 4 hours at room temperature The reaction mixture was washed with hydrochloric acid (1M, 50 ml) saturated aqueous sodium bicarbonate (50 ml), water (50 ml) and dried (MgSO4). The solvent was evaporated and the residue was purified by flash chromatography (silica/methylene chloride). Yield: 84% 1H NMR (200 MHz, CDCl3): δ 1.25 (m, 44H), 1.72 (m, 8H), 2.31 (t, 4H), 4.20 (t, 4H), 5.72 (m, 6H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=1>O>[Cl:14][C:13]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Clc1cccnc1Cl
Reactant: C1CNCCN1
Solvent: O
Product: Clc1cccnc1N1CCNCC1
Temperature: 140 °C
Reaction time: 2 h
Yield: 102.5 %

Procedure:
Piperazine (20.0 g) was melted by heating at 140° C. and 2,3-dichloropyridine (3.42 g) was added thereto. The mixture was stirred at 120° C. for 2 hr. Water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with brine, dried and concentrated under reduced pressure to give 1-(3-chloro-2-pyridyl)piperazine (4.68 g) as a dark-brown oil.
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[N:7]([CH2:10][CH:11]=[CH2:12])[N:6]([CH2:13][CH:14]=[CH2:15])[C:5]1=[O:16])[CH:2]=[CH2:3].CCC(OO)=[O:20].C1C=CC=CC=1>>[CH2:1]([N:4]1[C:5](=[O:16])[N:6]([CH2:13][CH:14]2[O:20][CH2:15]2)[N:7]([CH2:10][CH:11]=[CH2:12])[C:8]1=[O:9])[CH:2]=[CH2:3]
Reactant: CCC(=O)OO
Reactant: C=CCn1c(=O)n(CC=C)n(CC=C)c1=O
Solvent: c1ccccc1
Product: C=CCn1c(=O)n(CC=C)n(CC2CO2)c1=O

Procedure:
6.895 kg (35 mol) of trisallylurazole were reacted with 31.5 kg of a 22% strength solution of perpropionic acid in benzene (77 mol) at 60° C. in a manner analogous to that described in Example 1. After a reaction time of 10 hours, the percarboxylic acid conversion was 97.2% and the conversion of trisallylurazole was 94.6%. Diallylglycidylurazole was formed in a selectivity of 28.3%, allyldiglycidylurazole was formed in a selectivity of 41.2% and trisglycidylurazole was formed with a selectivity of 20.1%, in each case based on the trisallylurazole reacted.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C@@H:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17]2)[CH2:11][C@@H:10]1[NH2:24])=O)(C)(C)C.C(O)C.[ClH:35]>ClCCl>[ClH:35].[CH2:22]([O:21][C:19]([C:16]1([NH:15][CH:12]2[CH2:13][CH2:14][C@@H:9]([NH2:8])[C@@H:10]([NH2:24])[CH2:11]2)[CH2:17][CH2:18]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)C1(NC2CC[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)[C@@H](N)C2)CC1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C1(NC2CC[C@@H](N)[C@@H](N)C2)CC1
Reaction time: 1.5 h

Procedure:
(1R*,2S*)-N,N-Bis(tert-butoxycarbonyl)-4-[(1-ethoxycarbonyl)cyclopropan-1-yl]amino-1,2-cyclohexane-diamine (Stereoisomer A) (1.34 g) was dissolved in dichloromethane (20 ml), a saturated ethanol solution (20 ml) of hydrochloric acid was added, and the mixture was stirred for 90 minutes. The solvent was distilled off under reduced pressure to obtain (1R*,2S*)-4-[(1-ethoxycarbonyl)cyclopropan-1-yl]amino-1,2-cyclohexane-diamine hydrochloride (Stereoisomer A) (1.07 g) as a colorless solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][SH:4].O.CS([C@H:11]1[NH:14][C:13](=[O:15])[C@H:12]1[NH:16][C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)=O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH2:3]([S:4][C@H:11]1[NH:14][C:13](=[O:15])[C@H:12]1[NH:16][C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH:2]([CH3:5])[CH3:1]
Reactant: CC(C)CS
Reactant: CS(=O)(=O)[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)CS[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 90 °C

Procedure:
A solution of zinc acetate (0.7 g, 3 mmol) in toluene (15 mL) and 2-methyl-propanethiol (0.72 g, 8 mmol) was refluxed for 45 min in an apparatus equipped with a Dean-Stark trap to azeotrope water. (3R,4R)-4-(Methylsulfonyl)-3-(triphenylmethylamino)azetidin-2-one (1.5 g, 36 mmol) was added and the mixture was heated to 90° C. for 2 h. The mixture was concentrated and the residue was triturated with ethyl acetate and the insoluble material was removed by filtration. The filtrate was concentrated and the residue was chromatographed on silica gel eluted with 20% ethyl acetate:hexane. The fractions containing the product were combined, concentrated to give the title compound. MS(ES) m/e 417 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20][NH:21][S:22]([C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:17][CH:18]=2)[CH:13]=[CH:12]1>>[Cl:1][C:2]1[C:3]([N:21]([CH2:20][C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[N:11]([CH3:10])[CH:12]=[CH:13]3)[S:22]([C:25]2[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=2)(=[O:23])=[O:24])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(ccn3C)c2)cc1
Reactant: Fc1ncc(Cl)cc1Cl
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(ccn3C)c2)c2ncc(Cl)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 3,5-dichloro-2-fluoropyridine and methyl 4-(N-((1-methyl-1H-indol-5-yl)methyl)sulfamoyl)benzoate (step-1 of Example 6).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]([CH:14]=[C:15]1[CH:21]=[CH:20][CH:19]=[C:17]([NH2:18])[CH2:16]1)=[O:13]>>[CH3:10][O:11][C:12]([CH:14]=[C:15]1[CH:21]=[CH:20][CH:19]=[C:17]([NH:18][C:2]2[N:7]=[C:6]([NH:18][C:17]3[CH2:16][C:15](=[CH:14][C:12]([O:11][CH3:10])=[O:13])[CH:21]=[CH:20][CH:19]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH2:16]1)=[O:13]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COC(=O)C=C1C=CC=C(N)C1
Product: COC(=O)C=C1C=CC=C(Nc2ncc(F)c(NC3=CC=CC(=CC(=O)OC)C3)n2)C1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-(methoxycarbonylmethylene)aniline were reacted to produce the desired N2,N4-bis(3-methoxycarbonylmethylenephenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.23 (br s, 1H), 10.05 (br s, 1H), 8.26 (d, 1H, J=4.6 Hz), 7.64 (d, 1H, J=8.2 Hz), 7.51 (br s, 1H), 7.46 (d, 1H, J=8.2 Hz), 7.33 (br s, 1H), 7.29 (t, 1H, J=7.6 Hz), 7.20 (t, 1H, J=7.6 Hz), 7.06 (d, 1H, J=7.6 Hz), 6.93 (d, 1H, J=7.6 Hz), 3.63 (s, 2H), 3.58 (s, 3H), 3.57 (s, 3H), 3.56 (s, 2H); LCMS: ret. time: 21.74 min.; purity: 92%; MS (m/e): 425 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:14])([C:11](=[O:13])[CH3:12])[CH3:10])=[CH:5][CH:4]=1.[O:15]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[F:30])[CH:25]=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[K+]>CO>[O:15]([C:22]1[CH:23]=[C:24]([CH:25]=[CH:12][C:11](=[O:13])[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)([CH3:14])[CH3:10])[CH:27]=[CH:28][C:29]=1[F:30])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Reactant: COc1ccc(C(C)(C)C(C)=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(C)(C)C(=O)C=Cc2ccc(F)c(Oc3ccccc3)c2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 32.6 %

Procedure:
A mixture of 7.6 g of 2-(4-methoxyphenyl)-2-methyl-3-butanone, 8.5 g of 3-phenoxy-4-fluorobenzaldehyde, 30 ml of methanol and 2 g of KOH was stirred at 60° C. for two hours. In the same manner as described in (a) of (1) of Synthesis Example 1, the reaction mixture was treated to give 5 g of 1-(3-phenoxy-4-fluorophenyl)-4-(4-methoxyphenyl)-4-methyl-1-penten-3-one.
Reaction SMILES: [NH:1]([C:6]([O:8][CH2:9][CH:10]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH2:2][C:3](O)=[O:4].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.[CH3:52][O:53][C:54](=[O:74])[CH:55]([NH2:73])[CH:56]([C:61]1[CH:66]=[CH:65][C:64]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)=[CH:63][CH:62]=1)[C:57]([O:59][CH3:60])=[O:58]>CN(C)C=O>[CH3:60][O:59][C:57](=[O:58])[CH:56]([C:61]1[CH:62]=[CH:63][C:64]([C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)=[CH:65][CH:66]=1)[CH:55]([NH:73][C:3](=[O:4])[CH2:2][NH:1][C:6]([O:8][CH2:9][CH:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[C:17]2[C:22]1=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:7])[C:54]([O:53][CH3:52])=[O:74]
Reactant: COC(=O)C(N)C(C(=O)OC)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(NC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21)C(C(=O)OC)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 54 %

Procedure:
A solution of Fmoc-Gly-OH (from Bachem) (1.66 g., 5.6 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (from Aldrich, 39391) (1.1 g., 5.7 mmol), 1-hydroxybenzotriazole (from Aldrich, 54804) (0.76 g., 5.6 mmol) and triethylamine (0.4 mL, 2.8 mmol) in dimethylformamide (50 mL) was stirred at room temperature for 1 hour. A solution of 2-amino-3-biphenyl-4-yl-succinic acid dimethyl ester hydrochloride (0.98 g., 2.8 mmol) in dimethylformamide (10 mL) was added and the reaction mixture was stirred at room temperature for a further 14 hours. The solvent was removed in vacuo and the residue partitioned between ethylacetate (100 mL) and sodium bicarbonate (100 mL, saturated solution in water). The aqueous layer was washed with ethylacetate (2×100 mL), the organics combined, dried over magnesium sulphate and concentrated in vacuo to afford a crude residue. The crude product was purified using flash chromatography (SiO2) eluting with ethylacetate/isohexane (3:1) to afford 2-biphenyl-4-yl-3-[2-(9H-fluoren-9-ylmethoxycarbonylamino)-acetylamino]-succinic acid dimethyl ester as a white crystalline solid (0.89 g., 54% yield). 1HNMR (CDCl3) δH(ppm); 3.71-3.73 (m, 7H), 3.81 0.2H (d, CH J=5.6 Hz), 3.86, 0.3H (d, CH J=5.8 Hz), 3.9, 0.3H (d, CH J=5.3 Hz), 3.94, 0.2H (d, CH J=5.8 Hz), 4.13-4.24 (m, 1H), 4.28-4.44 (m, 2.5H), 4.5 (d, 0.5H J=4.4 Hz), 5.1-5.4 (m, 2H), 6.4 (d, NH J=8.5 Hz), 7.19 (d, NH J=9.4 Hz), 7.23-7.34, 5H (m, Ar—H), 7.35-7.42, 4H (m, Ar—H), 7.47-7.60, 6H (m, Ar—H), 7.74, 2H (d, Ar—H J=7.6 Hz); LCMS analysis (solvent MeCN/H2O/0.1% HCO2H, 5-95% gradient/H2O 2.5 min, 95% 4 min., Phenomenex C18 reverse phase, flow rate 1 mL/min.) HPLC retention times 5.33 and 5.47 min. (diastereoisomers).; mass found 593 (M+H).
Reaction SMILES: [CH2:1]([NH:5][N:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1)[CH2:2][CH2:3][CH3:4].[CH2:11]([O:13][C:14](=[O:26])[CH:15]([C:21](OCC)=[O:22])[C:16](OCC)=[O:17])[CH3:12]>>[CH2:11]([O:13][C:14]([C:15]1[C:16](=[O:17])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]2[CH:10]=[CH:9][CH:8]=[C:7]2[C:21]=1[OH:22])=[O:26])[CH3:12]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: CCCCNn1cccc1
Product: CCCCn1c(=O)c(C(=O)OCC)c(O)c2cccn21
Temperature: 170 °C

Procedure:
A mixture of butyl-pyrrol-1-yl-amine (943 mg) and 2-ethoxycarbonyl-malonic acid diethyl ester (3.15 mL) in a test tube was heated for 30 min at 170° C. and then 30 min at 200° C.; then cooled, the residue was directly column-purified to give the desired product (778 mg) as brown liquid. ESI (m/z): 279 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[CH2:12](O)[CH2:13][OH:14].O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:14][CH2:13][CH2:12][O:6]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: OCCO
Reactant: COc1ccc(C=O)cc1F
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C2OCCO2)cc1F
Yield: 92.5 %

Procedure:
A solution of 3-fluoro-4-methoxy-benzaldehyde (463 mg, 3 mmol), ethylene glycol (0.86 mL, 15 mmol) and PPTs (75 mg, 0.3 mmol) in toluene (15 mL) was heated at reflux with aceotropic removal of water for 6 hours. The solvent was evaporated and the residue was diluted with methylene chloride (20 mL), washed with water (2×10 mL) and dried (MgSO4). Concentration produced 2-(3-Fluoro-4-methoxy-phenyl)-[1,3]-dioxolane as a colorless oil (550 mg, 92%). 1H-NMR (CDCl3, 200.15 MHz): δ 7.24–7.15 (m, 2H), 6.92 (t, 1H, J=8.5), 5.71 (s, 1H), 4.10–3.98 (m, 4H), 3.86 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[N:10][N:11]([CH2:17][C:18]([O-:20])=O)[C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:33]1C=CN=C1)=O.[OH-].[NH4+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:21]3[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)=[N:10][N:11]([CH2:17][C:18]([NH2:33])=[O:20])[C:12]=2[C:13]([F:14])([F:16])[F:15])=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CS(=O)(=O)c1ccc(-c2nn(CC(=O)[O-])c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2nn(CC(N)=O)c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.9 %

Procedure:
To a solution of [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (Example 10) (0.24 g, 0.54 mmol) in THF (6 mL) was added 0.10 g of 1,1'-carbonyldiimidazole at 25° C. under nitrogen. After gas evolution had ceased (approx. 30 minutes), 6 mL conc. ammonium hydroxide was added and the mixture stirred at 25° C. for 18 hours. The reaction mixture was diluted with water, extracted with two portions ethyl acetate and the organic layer washed successively with dilute aqueous HCl and brine, dried over MgSO4 and concentrated in vacuo. Recrystallization from chloroform/acetone gave [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetamide as a white crystalline solid (0.15 g, 34%). Elemental analysis for C19H15N3F4SO3Calc'd: C, 51.70, H, 3.42, N, 9.52. Found: C, 51.46, H, 3.35, N, 9.39.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C@H:12]([CH2:13][OH:14])[C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:25]([N:27]=C=O)=[O:26].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][N:9]1[C@H:12]([CH2:13][O:14][C:25](=[O:26])[NH2:27])[C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:10]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(OCc2ccccc2)[C@@H]1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(OCc2ccccc2)[C@@H]1COC(N)=O
Yield: 72.4 %

Procedure:
In 6 ml of chloroform dried with molecular sieve is dissolved 390 mg (1.21 mmole) of (3S,4S)-1-benzyloxy-3-(tert-butoxycarbonylamino)-4-hydroxymethyl-2-azetidinone, and a solution of 0.11 ml (1.33 mmole) of chlorocarbonyl isocyanate in 2 ml of dried chloroform is added dropwise to the solution under ice-cooling with stirring. After the stirring under ice-cooling for 30 minutes, the same amount of chlorocarbonyl isocyanate is furthermore added to the reaction solution in the same manner. After the stirring under ice-cooling for further 30 minutes, 10 ml of saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution. The chloroform is distilled off under reduced pressure, and 10 ml of 3N hydrochloric acid and ethyl acetate are added to the residue, followed by thorough shaking. The ethyl acetate layer is separated, while the aqueous layer is extracted again with ethyl acetate, and the ethyl acetate layers are combined, washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ether and n-hexaneare added to the residue, and the resulting crystals are recovered by filtration to give 320 mg of (3S,4S)-1benzyloxy-3-(tert-butoxycarbonylamino)-4-carbamoyloxymethyl-2azetidinone.