Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11](=[O:42])[N:12]([C:19]1([CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:24][CH2:23][C:22](=[O:25])[NH:21][C:20]1=[O:26])[C:13]2=[O:18]>N1C=CC=CC=1>[C:1]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11](=[O:42])[N:12]([C:19]1([CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:24][CH2:23][C:22](=[O:25])[NH:21][C:20]1=[O:26])[C:13]2=[O:18])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc2c1C(=O)N(C1(CCCCNC(=O)OCc3ccccc3)CCC(=O)NC1=O)C2=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc2c1C(=O)N(C1(CCCCNC(=O)OCc3ccccc3)CCC(=O)NC1=O)C2=O
Temperature: 70 °C
Reaction time: 12 h
Yield: 36.9 %

Procedure:
To a solution of acetic anhydride (0.098 mL, 1.04 mmol) in pyridine (1 mL) was added 6 (0.05 g, 0.104 mmol) and the mixture was stirred at 70° C. After 12 h, the mixture was quenched with 1% aqueous HCl and extracted with DCM. The organic layer was dried over MgSO4 and concentrated. Preparatory thin layer chromatography (1:1 EtOAc:hexanes) afforded 15 (0.02 g, 37%) as an impure product that was used in the subsequent reaction. Rf=0.16 (1:1 EtOAc:hexanes).
Reaction SMILES: O=[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:5][C:4]2[CH:13]=[N:14][NH:15][C:3]1=2.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]=[C:4]2[CH:13]=[N:14][NH:15][C:3]=12
Reactant: CCOC(=O)c1cc(=O)c2[nH]ncc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(Cl)c2[nH]ncc2n1
Yield: 83 %

Procedure:
Ethyl 4,7-dihydro-7-oxo-1H-pyrazolo[4,3-b]pyridine-5-carboxylate (5.0 g, 24 mmol) was heated under reflux in phosphoryl chloride (50 ml) for 25 min. Excess reagent was removed in vacuo and the residue was treated with water to give a yellow solid. After neutralisation with 10% sodium hydroxide solution, the solid was collected and dried to give the title compound (4.48 g, 83%), m.p. 276°-279° C. after recrystallisation from ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Br:15]N1C(=O)CCC1=O>C(#N)C>[Br:15][C:6]1[C:7]2[CH:8]=[C:9]([CH2:12][O:13][CH3:14])[O:10][C:11]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCc1cc2cccc(OC)c2o1
Solvent: CC#N
Product: COCc1cc2c(Br)ccc(OC)c2o1
Reaction time: 48 h
Yield: 110.7 %

Procedure:
A solution of 7-methoxy-2-methoxymethylbenzofuran (13.32 g) in acetonitrile (500 ml) was stirred at room temperature. N-bromosuccinimide (11.04 g) was added and stirring continued for 2 days after which the solvent was removed in vacuo. The resulting oil was partitioned between ethyl acetate (100 ml) and sodium metasulfite solution (50 ml), the organic extract washed with more sodium metasulfite solution (2×50 ml), followed by brine (50 ml). The organic layer was separated, dried over magnesium sulphate, filtered and the solvent removed in vacuo to afford the title compound as a yellow oil (18.61 g).
Reaction SMILES: [OH:1][C:2]1([CH2:16][C:17](O)=O)[CH2:7][CH:6]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5]2[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F:20][C:21]([F:41])([F:40])[C:22]1[C:30]2[N:29]=[C:28]([CH2:31][CH2:32][CH2:33][NH:34][CH3:35])[NH:27][C:26]=2[CH:25]=[C:24]([C:36]([F:39])([F:38])[F:37])[CH:23]=1>>[F:41][C:21]([F:20])([F:40])[C:22]1[C:30]2[N:29]=[C:28]([CH2:31][CH2:32][CH2:33][N:34]([CH3:35])[CH2:17][CH2:16][C:2]3([OH:1])[CH2:7][CH:6]4[CH2:8][CH2:9][CH:3]3[CH:4]=[C:5]4[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[NH:27][C:26]=2[CH:25]=[C:24]([C:36]([F:37])([F:38])[F:39])[CH:23]=1
Reactant: O=C(O)CC1(O)CC2CCC1C=C2c1ccccc1
Reactant: CNCCCc1nc2c(C(F)(F)F)cc(C(F)(F)F)cc2[nH]1
Product: CN(CCCc1nc2c(C(F)(F)F)cc(C(F)(F)F)cc2[nH]1)CCC1(O)CC2CCC1C=C2c1ccccc1

Procedure:
Prepared according to procedures P2.2 to P2.3 in Example 21 using rac-(1R*,2R*,4R*)-(2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-acetic acid and [3-(4,6-bis-trifluoromethyl-1H-benzoimidazol-2-yl)-propyl]-methyl-amine.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[H-].[Na+].Br[CH2:22][C:23]1([CH2:29][CH3:30])OCCC[O:24]1.BrCC(=O)CC.Cl>C1COCC1.C1(C)C=CC=CC=1.CN(C=O)C>[CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][CH:15]([O:18][CH2:22][C:23](=[O:24])[CH2:29][CH3:30])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCC1(CBr)OCCCO1
Reactant: CCCCCC1CCC(C2CCC(O)CC2)CC1
Agent: CCC(=O)CBr
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCCC1CCC(C2CCC(OCC(=O)CC)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
A solution of 25.2 g (0.1 mol) of 4-(4-pentylcyclohexyl) cyclohexanol in 50 ml of THF was added dropwise to a mixture of 5.2 g (0.11 mol) of sodium hydride and 20 ml of THF at a temperature of lower than 10° C. Then, 50 ml of DMF was further added and stirred for 1 hour at a room temperature. While keeping inside of the reaction system at a temperature of lower than 0°C., a solution of 21 g (0.1 mol) of 2-bromomethyl-2-ethyl-1,3-dioxane derived from commercially available 1-bromo-2-butanone in 50 ml of THF was added dropwise, and stirred for 2 hours at a room temperature and then for 2 hours at 50° C. This solution was added with 50 ml of 6N hydrochloric acid, stirred for 1 hour at 50° C., added with 200 ml of toluene, and extracted. The organic layer was washed once with an aqueous solution saturated with potassium carbonate and twice with water, and dried over anhydrous magnesium sulfate. After the anhydrous magnesium sulfate was separated, the solvent was distilled off under a reduced pressure, and the residue thus obtained was subjected to a silica gel column chromatography (eluate: toluene) to obtain 20.9 g (yield 65%) of 4-(4-pentylcyclohexyl)-(2-oxobutyloxy)cyclohexane.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:11][C:8]2([CH2:10][CH2:9]2)[CH2:7][N:6]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:4].[Li+].[OH-].Cl>C1COCC1.CO>[CH2:15]([O:14][C:12]([N:6]1[CH:5]([C:3]([OH:4])=[O:2])[CH2:11][C:8]2([CH2:9][CH2:10]2)[CH2:7]1)=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)C1CC2(CC2)CN1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CC2(CC2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester 6-methyl ester 603 (244 mg, 0.840 mmol) was dissolved in THF (2.0 mL)/MeOH (1.5 mL). An aqueous solution of LiOH (35.5 mg, 0.84 mmol) was added and stirring at room temperature was continued. After 3 hours, the reaction was neutralized with aqueous HCl (1 M) and the organic solvents were removed in vacuo. The crude mixture was diluted with water and EtOAc and the organic layer was collected. All volatiles were removed in vacuo and the crude acid 606 was used without further purification. LCMS-ESI+: calc'd for C15H17NO4: 275.3 (M+). Found: 276.3 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([NH:25][C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2.[CH3:31][N:32]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=[N:33]1.C([O-])([O-])=O.[K+].[K+].Cl>O1CCOCC1.O.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>[CH3:31][N:32]1[C:36]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=2[N:12]2[CH2:17][CH2:16][O:15][C:14]3[CH:18]=[C:19]([S:22]([NH:25][C:26]4[S:30][N:29]=[CH:28][N:27]=4)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]2=3)=[CH:35][CH:34]=[N:33]1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=S(=O)(Nc1ncns1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nccc1-c1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Nc3ncns3)ccc21
Temperature: 100 °C
Yield: 17.7 %

Procedure:
A microwave vial was charged with INTERMEDIATE D (0.100 g, 0.192 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Sigma Aldrich, St. Louis, Mo., 0.060 g, 0.288 mmol), tetrakis(triphenylphosphine)palladium(0) (0.022 g, 0.019 mmol), and K2CO3 (0.133 g, 0.959 mmol). The solids were diluted with dioxane (1.279 mL) and water (0.639 mL), and the reaction was heated under microwave irradiation at 100° C. for 60 minutes (starting material remained, but the reaction was moved forward). The reaction mixture was diluted with water, and washed with DCM. Equal partitioning between both layers was observed, so the organic and aqueous layers were combined and concentrated. The material was taken up in methanol, and acidified with HCl (1N) (3.84 mL, 3.84 mmol), and then re-concentrated under a vacuum. The solids were taken up in DCM, and washed with water. The organic layer was then dried using a phase separator, concentrated under a vacuum and purified by reverse-phase preparative HPLC (Column: Phenomenex 150×30 mm, 5 micron, C18 column; 0.1% TFA in CH3CN/H2O, gradient 25% to 90% over 20 min (Phenomenex, Torrance, Calif.)) to provide 4-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.018 g, 0.034 mmol) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.66 (s, 3 H) 4.14 (br. s., 2 H) 6.31 (d, J=1.66 Hz, 1 H) 6.68 (d, J=8.51 Hz, 1 H) 7.07-7.16 (m, 2 H) 7.42 (d, J=1.76 Hz, 1 H) 7.72 (d, J=8.41 Hz, 1 H) 7.86 (s, 1 H) 7.90 (d, J=8.61 Hz, 1 H) 8.44 (s, 1 H). m/z (ESI) 523.0 (M+H)+.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH2:25][CH:26]2[CH2:29][CH2:28][CH2:27]2)[C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH2:4]1)=O.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][CH:40]2[CH2:41][CH2:42][N:43]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:6][N:5]([C@H:14]([CH2:25][CH:26]4[CH2:29][CH2:28][CH2:27]4)[C:15]([OH:17])=[O:16])[CH2:4]3)[CH2:44][CH2:45]2)=[CH:35][CH:36]=1
Reactant: Fc1ccc(CCCC2CCNCC2)cc1
Reactant: O=C[C@H]1CN([C@H](CC2CCC2)C(=O)OCc2ccccc2)C[C@@H]1c1ccccc1
Product: O=C(O)[C@@H](CC1CCC1)N1C[C@H](CN2CCC(CCCc3ccc(F)cc3)CC2)[C@@H](c2ccccc2)C1
Yield: 85.5 %

Procedure:
The title compound was prepared from 25 mg (0.06 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-3-(cyclobutyl)propanoic acid, benzyl ester (from EXAMPLE 25, Step B) and 16 mg (0.06 mmol) of 4-(3-(4-fluorophenyl)propyl)piperidine.HCl (from EXAMPLE 96, Step B) using procedures analogous to those described in EXAMPLE 95, Steps F and G. 26 mg (81%) of the title compound was obtained: ESI-MS 507 (M+H); HPLC A: 2.69 min.
Reaction SMILES: [CH3:1]OS(OC)(=O)=O.C(=O)(O)[O-].[K+].[C:13]1([CH:19]([O:26][C:27](=[O:59])/[C:28](/[N:32]2[CH:35]([S:36][S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[CH:34]([NH:47][C:48](=[O:57])[CH2:49][O:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:33]2=[O:58])=[C:29](\[OH:31])/[CH3:30])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:13]1([CH:19]([O:26][C:27](=[O:59])/[C:28](/[N:32]2[CH:35]([S:36][S:37]([C:40]3[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=3)(=[O:38])=[O:39])[CH:34]([NH:47][C:48](=[O:57])[CH2:49][O:50][C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:33]2=[O:58])=[C:29](/[O:31][CH3:1])\[CH3:30])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COS(=O)(=O)OC
Reactant: C/C(O)=C(/C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [I-]
Solvent: Cc1ccccc1
Product: CO/C(C)=C(/C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(avi) 3.78 g (30 mmols) of dimethylsulphate and 30 ml of 20 percent strength aqueous potassium bicarbonate solution are added to a suspension of 6.72 g (10 mmols) of 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonic acid diphenylmethyl ester (crystalline) and 0.36 g (1 mmol) of tetra-n-butylammonium iodide in 100 ml of toluene and the mixture is stirred vigorously for 4 hours at room temperature. During the first 15 minutes, the solid dissolves. The mixture is diluted with toluene and washed with saturated aqueous sodium chloride solution. After drying the organic phase with sodium sulphate, and concentrating it, crystallisation from ethyl acetate/diethyl ether gives 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonic acid diphenylmethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[I:17]Cl.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([I:17])=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1
Reactant: ClI
Reactant: Clc1ccc2nc(-c3ccccc3)cn2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Clc1ccc2nc(-c3ccccc3)c(I)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a solution, cooled to 0° C., of 10.4 g (45.4 mmol) of 6-chloro-2-phenylimidazo[1,2-b]pyridazine (CAS No.: 1844-53-7) in 500 mL of chloroform is rapidly added dropwise a solution of 11.1 g (68.1 mmol) of iodine monochloride in 100 mL of chloroform. After cooling to room temperature and stirring for 1 hour, the mixture is treated with aqueous 5% sodium thiosulfate solution. The product is extracted with dichloromethane and the organic phase is dried over sodium sulfate and concentrated under reduced pressure. The residue is triturated in 150 ml of acetonitrile containing a few mL of isopropyl alcohol and the solid is isolated after filtration. 15 g of a yellow powder are isolated after drying under vacuum.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[OH:15])(=[O:3])[CH3:2].[N+](C1C=C(S(O[CH2:29][C@@H:30]2[CH2:32][O:31]2)(=O)=O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[O:15][CH2:29][C@@H:30]1[CH2:32][O:31]1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: COC(=O)c1ccc(NC(C)=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(C)=O)c(OC[C@@H]2CO2)c1
Yield: 36.2 %

Procedure:
A solution of methyl 4-(acetylamino)-3-hydroxybenzoate (0.209 g, 1 mmol), (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (0.26 g, 1 mmol) and caesium carbonate (0.39 g, 1.2 mmol) in dimethylformamide (5 mL) was stirred at room temperature overnight. The mixture was partitioned between water and ethyl acetate, and the organic phase was washed twice with water and once with brine, and finally concentrated. The crude material was purified by flash chromatoghrphy on silica gel (eluent:ethyl acetate/n-heptane), yielding the subtitle compound (96 mg, 36%) as colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:34][C@H:35]([OH:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C:24](O)=[O:25])=[C:19]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:55][S:56]([NH2:59])(=[O:58])=[O:57].C1CCN2C(=NCCC2)CC1.Cl>CN(C)C=O>[CH:28]1([O:27][C:19]2[CH:18]=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][N:8]([CH2:34][C@H:35]([OH:42])[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:12][CH:13]=3)[CH:22]=[CH:21][C:20]=2[CH2:23][C:24]([NH:59][S:56]([CH3:55])(=[O:58])=[O:57])=[O:25])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(CC(=O)O)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1ccccc1
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(CC(=O)NS(C)(=O)=O)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1ccccc1
Reaction time: 1.5 h
Yield: 23.6 %

Procedure:
To a solution of [4′-[2-[(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-(cyclohexyloxy)-4-biphenylyl]acetic acid (228 mg) in N,N-dimethylformamide (2.5 ml) was added 1,1′-carbonyldiimidazole (77 mg) at room temperature under nitrogen, and the mixture was stirred at the same temperature for 1.5 hours. To this one were added methanesulfonamide (76 mg) and 1,8-diazabicyclo[5.4.0]-7-undecene (91 mg) at 5° C., and the mixture was stirred at the same temperature for 5 hours. The resulting mixture was poured into 1N hydrochloric acid and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid (twice) and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/ethyl acetate=10:1 to 5:1) to give tert-butyl [2-(3′-(cyclohexyloxy)-4′-[2-[(methylsulfonyl)amino]-2-oxoethyl]-4-biphenylyl]ethyl]-[(2R)-2-hydroxy-2-phenylethyl]carbamate (61 mg).
Reaction SMILES: [P:1]([Cl:5])(Cl)(Cl)=[S:2].[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[OH:14]>C(N(CC)CC)C>[P:1]([Cl:5])([O:14][C:8]1[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=1[CH3:6])([O:14][C:8]1[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=1[CH3:6])=[S:2]
Reactant: S=P(Cl)(Cl)Cl
Reactant: Cc1ccc(O)c(C)c1
Solvent: CCN(CC)CC
Product: Cc1ccc(OP(=S)(Cl)Oc2ccc(C)cc2C)c(C)c1
Temperature: 20 °C
Yield: 89.9 %

Procedure:
Thiophosphoryl chloride (17.0 g) was dissolved in tuoluene (250 cm3) and triethylamine (21.5 g) was added. The solution was stirred at 20° C. and 2,4-dimethylphenol (24.4 g) was added in portions during 1 hr. The mixture was stirred for 2 hr. and then heated and stirred at 80° C. for a further 2 hr. and then cooled and filtered to remove thriethylamine hydrochloride. The toluene was distilled under reduced pressure leaving bis(2,4-dimethylphenyl) chlorothiophosphate (oil, 30.6 g. 31P NMR in CDCl3, singlet 54.57 ppm downfield of H3 PO4).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[C:5]([C:18]([F:21])([F:20])[F:19])=[CH:4][N:3]=1.[CH2:22]([O:29][C:30](=[O:40])[C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[C:33]([O:38][CH3:39])[CH:32]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C[Si](Cl)(C)C>CC(O)C>[CH2:22]([O:29][C:30](=[O:40])[C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:2]2[N:7]=[C:6]([O:8][C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=3)[C:5]([C:18]([F:21])([F:20])[F:19])=[CH:4][N:3]=2)=[C:33]([O:38][CH3:39])[CH:32]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=[N+]([O-])c1ccc(Oc2nc(Cl)ncc2C(F)(F)F)cc1
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1N
Agent: C[Si](C)(C)Cl
Solvent: CC(C)O
Product: COc1cc(C(=O)OCc2ccccc2)ccc1Nc1ncc(C(F)(F)F)c(Oc2ccc([N+](=O)[O-])cc2)n1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
b-3.) 1.0 g of 2-chloro-4-(4-nitrophenyloxy)-5-trifluoromethylpyrimidine and 0.77 g of 4-amino-3-methoxy-benzoic acid benzyl ester are suspended in 15 mL of 2-propanol. The suspension is heated to 50° C. and 0.08 mL trimethylsilylchloride (TMSCl) are added. The suspension is stirred for 16 hours at 50° C. The suspension is cooled to ambient temperature and stirred for 3 hours. The precipitate is filtered and washed with 2-propanol. After drying in a vacuum drying oven 1.38 g (85% of theory) of the corresponding 2-amino pyrimidine derivative product, i.e. 3-methoxy-4-[4-(4-nitro-phenoxy)-5-trifluoromethyl-pyrimidin-2-ylamino]-benzoic acid benzyl ester is obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][C@H:12]([CH3:29])[C@:13]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])([OH:20])[CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:37][C:38]([F:49])([F:48])[C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1>C(Cl)Cl>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C@:13]([OH:20])([C@H:12]([N:11]([C:43](=[O:44])[C:42]1[CH:46]=[CH:47][C:39]([C:38]([F:37])([F:48])[F:49])=[CH:40][CH:41]=1)[CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:29])[CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: C[C@@H](NCCOCc1ccccc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](N(CCOCc1ccccc1)C(=O)c1ccc(C(F)(F)F)cc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 140 %

Procedure:
To a solution of (2R*,3R*)-3-[(2-benzyloxyethyl)amino]-2-[2,4-difluorophenyl]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (4.40 g, 11.4 mmol) (obtained as described in reference example 2) in CH2Cl2 (40 mL) was added triethylamine (1.74 mL, 12.5 mmol). The resulting mixture was cooled in an ice bath and a solution of 4-(trifluoromethyl)benzoyl chloride (2.61 g, 12.5 mmol) in CH2Cl2 (5 mL) was carefully added and the mixture was stirred for 1 h at 0° C. and then for 18 h at room temperature. The resulting solution was diluted with CH2Cl2 and washed with 5% aqueous NaHCO3 solution. The organic phase was separated, dried over Na2SO4 and the solvent was removed, to afford a thick oil (9.17 g) that was purified by chromatography on silica gel (EtOAc: hexane 1:1). The title compound of the example was obtained as a white foam.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.C[C@@]12[C@@H]([OH:40])CC[C@H]1[C@H]1[C@@H](C3C=CC(O)=CC=3CC1)CC2>>[CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH2:21][OH:40])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CC[C@@H]2O

Procedure:
This compound is the postulated reaction intermediate of the first hydroxylation step of testosterone-to-estradiol conversion by Aromatase.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24]C2C=CC(C(F)(F)F)=CN=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(C#C)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.Br[C:60]1[CH:61]=[N:62][CH:63]=[C:64]([C:66]([F:69])([F:68])[F:67])[CH:65]=1>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:60]2[CH:61]=[N:62][CH:63]=[C:64]([C:66]([F:69])([F:68])[F:67])[CH:65]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cncc(Br)c1
Reactant: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)nc1
Agent: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: FC(F)(F)c1cncc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Yield: 31 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 3-bromo-5-(trifluoromethyl)pyridine in 31% yield.