Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.Cl>>[OH:13][C@@H:12]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[C:11]1[CH:14]=[CH:15][C:8]([Cl:7])=[CH:9][CH:10]=1
Reactant: COP([O-])OC
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Product: COP(=O)(OC)[C@H](O)c1ccc(Cl)cc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
The solution of ALB in tetrahydrofuran (0.1 M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 μl, 0.40 mmol) at room temperature. After stirring for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then p-chlorobenzaldehyde (0.40 mmol) was added thereto. After reacting for 38 hours, 1N hydrochloric acid was added thereto to stop the reaction. The mixture was extracted with ethyl acetate (10 ml×three times), and the combined extracts were washed with brine and dried over Na2SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (S)-hydroxy(p-chlorophenyl)methylphosphonate as a final product in a yield of 90%. The chemical reaction in this Example is shown in chemical formula 28. ##STR22##
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[O:24][C:23](=[O:25])[C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[N:20]=1)=[O:11])=O)(C)(C)C.[ClH:30]>C(OCC)(=O)C>[ClH:30].[NH2:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[O:24][C:23](=[O:25])[C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[N:20]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccccc1-c1nc2ccccc2c(=O)o1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCC(=O)Nc1ccccc1-c1nc2ccccc2c(=O)o1

Procedure:
2-[2-(tert-butyloxycarbonyl)aminoethanoyl]aminophenyl-3,1-benzoxazin-4-one (45 mg) was reacted in ethyl acetate with hydrogen chloride under reaction conditions as described for the synthesis of compounds of Example 9, Method A, to afford the above-titled compound.
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:20])[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13](OC(C)(C)C)=O)[CH2:9][CH2:8]1)([CH3:3])[CH3:2].FC(F)(F)C(O)=O.ClC1[N:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]2[S:37][C:38]([C:41]#[N:42])=[CH:39][N:40]=2)[CH:30]=1.C(N(CC)CC)C>C(O)CCC>[C:41]([C:38]1[S:37][C:36]([NH:35][C:31]2[N:32]=[CH:33][N:34]=[C:13]([N:10]3[CH2:9][CH2:8][CH:7]([CH2:6][C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[O:20])[CH2:12][CH2:11]3)[CH:30]=2)=[N:40][CH:39]=1)#[N:42]
Reactant: N#Cc1cnc(Nc2cc(Cl)ncn2)s1
Reactant: CC(C)NC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CC(C)NC(=O)CC1CCN(c2cc(Nc3ncc(C#N)s3)ncn2)CC1

Procedure:
46-2 (0.21 g, 0.73 mmol) was treated with neat trifluoroacetic acid for 20 minutes and then the trifluoroacetic acid was evaporated off. This residue and 35-1 (0.17 g, 0.73 mmol) and triethylamine (0.37 g, 3.67 mmol) were heated at 150° C. for 3 hours in n-butanol. Upon cooling the precipitate was filtered off, washed with n-butanol and ethyl ether and then dried to afford 46-3. Hi-Res MS: calc: 386.1758 found: 386.1754. 1H-NMR (CD3OD): 8.36(s, 1H); 7.99(s, 1H); 6.14(s, 1H); 4.40(d, 2H); 3.98(m, 1H); 2.94(t, 2H); 2.10(complex, 3H); 1.77(d, 2H); 1.22(m, 2H); 1.13(d, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1>[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28][N:10]1[CH2:11][CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC1
Reactant: Clc1ccc(C2=NNCC2c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCN1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Yield: 34.1 %

Procedure:
Part A: A stirred solution of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (5.00 gram, 19.5 mmol) and N-(tert-butoxycarbonyl)aziridine (2.00 gram, 14.0 mmol) in toluene (100 ml) was heated at reflux temperature for 16 hours. After concentration in vacuo the residue was purified by flash chromatography (petroleum ether/diethyl ether=3/1 (v/v)), followed by petroleum ether/diethyl ether=1/1 (v/v)). After concentration in vacuo the remaining oily residue was crystallised from diisopropyl ether to afford 1-[2-((tert-butoxycarbonyl)amino)ethyl]-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (1.91 gram, 34%). Repeated crystallisations from the mother liquor afforded an additional amount of crystalline 1-[2-((tert-butoxycarbonyl)amino)ethyl]-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (1.19 gram).
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][N:10]=[C:9]([NH:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([C:26]([O:28]CC)=[O:27])[CH2:22][CH2:21]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[OH-].[Li+].S(=O)(=O)(O)O>O>[C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][N:10]=[C:9]([NH:19][C@H:20]3[CH2:21][CH2:22][C@H:23]([C:26]([OH:28])=[O:27])[CH2:24][CH2:25]3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](Nc2ncc(-c3ccccc3)c(-c3ccccc3)n2)CC1
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H]1CC[C@H](Nc2ncc(-c3ccccc3)c(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
70 mg (0.17 mmol) of ethyl trans-4-(4,5-diphenylpyrimidin-2-ylamino)-cyclohexanecarboxylate were mixed with 872 μl of tetrahydrofuran and 872 μl of 1N aqueous lithium hydroxide solution and stirred at room temperature for 48 hours. The reaction mixture was diluted with water and acidified with sulfuric acid, and the resulting precipitate was filtered off with suction. 64 mg (98%) of the desired product were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([OH:7])=O.[CH3:12][C:13](=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:14][NH:15][CH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH3:23].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(O)(C(F)(F)F)=O>C(#N)C.C(N(CC)CC)C>[Br:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Br:1])[CH:10]=1)[C:5]([N:15]([CH2:14][C:13]([CH3:12])=[CH:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH3:23])=[O:7]
Reactant: CC(=Cc1ccccc1)CNCCC1CCCN1C
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=Cc1ccccc1)CN(CCC1CCCN1C)C(=O)c1cc(Br)cc(Br)c1
Yield: 63 %

Procedure:
An analogous procedure to Example 2 was used with 3,5-dibromo-benzoic acid 0.16 g (0.38 mmol) and (2-methyl-3-phenyl-allyl)-[2-(1-methyl-pyrrolidine-2-yl)-ethyl]-amine 0.1 g (0.38 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride 0.11 g (0.57 mmol), 1-hydroxybenzotriazole 0.05 g (0.41 mmol) and triethylamine 0.08 ml. Reverse phase prep HPLC with a gradient 20-80% for the acetonitrile phase gavel 53 mg as a TFA salt. Yield: 63%.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][C:18]3[N:34]=[C:21]4[C:22]([C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=5)=[CH:23][CH:24]=[CH:25][N:20]4[N:19]=3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([NH:17][C:18]3[N:34]=[C:21]4[C:22]([C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=5)=[CH:23][CH:24]=[CH:25][N:20]4[N:19]=3)=[CH:12][CH:11]=2)[CH2:16][NH:8]1
Reactant: COc1cccc(-c2cccn3nc(Nc4ccc5c(c4)CN(C(=O)OC(C)(C)C)C5)nc23)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(-c2cccn3nc(Nc4ccc5c(c4)CNC5)nc23)c1

Procedure:
(2,3-Dihydro-1H-isoindol-5-yl)-[8-(3-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 5-[8-(3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino]-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid (0.500 mL) in a manner analogous to Example 312 to give product (0.025 g). MP=95-97° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.68 (s, 1H), 8.80 (d, 1H), 7.85 (d, 1H), 7.80 (s, 1H), 7.70 (m, 2H), 7.52 (m, 1H), 7.45 (m, 1H), 7.18 (d, 1H), 7.10 (t, 1H), 7.00 (d, 1H), 4.10 (br m, 4H), 3.86 (s, 3H), 3.40 (br m, 1H). MS=358 (MH)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:21][C:22]1([CH3:25])[CH2:24][O:23]1>C(#N)C>[CH3:21][C:22]([OH:23])([CH3:25])[CH2:24][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (514.3 mg, 2.65 mmol), cesium carbonate (1.295 g, 3.98 mmol) and 2,2-dimethyloxirane (0.589 mL, 6.63 mmol) in acetonitrile (5 mL) was heated at 130° C. under microwave for 1 h. The resulting mixture was concentrated. The residue was triturated with dichloromethane and stirred at room temperature for 30 min and filtered. The filtrate was concentrated to give 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (0.4289 g). This material was used in subsequent Suzuki coupling reactions without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.84 (d, J=0.4 Hz, 1H), 7.55 (d, J=0.7 Hz, 1H), 4.02 (s, 2H), 4.01 (s, 1H), 1.25 (s, 12H), 1.04 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[NH:5][C:6]1[S:7][C:8]2[C:14]([C:15]3[O:16][CH2:17][CH2:18][O:19][CH:20]=3)=[CH:13][CH:12]=[C:11]([O:21][CH3:22])[C:9]=2[N:10]=1)[CH3:2].[H][H]>O1CCOCC1.C(O)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[NH:5][C:6]1[S:7][C:8]2[C:14]([CH:15]3[CH2:20][O:19][CH2:18][CH2:17][O:16]3)=[CH:13][CH:12]=[C:11]([O:21][CH3:22])[C:9]=2[N:10]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)Nc1nc2c(OC)ccc(C3=COCCO3)c2s1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCOC(=O)Nc1nc2c(OC)ccc(C3COCCO3)c2s1
Yield: 62.1 %

Procedure:
To a stirred solution of 12.0 g (35.7 mmol) [7-(5,6-dihydro-[1,4]dioxin-2-yl)-4-methoxy-benzothiazol-2-yl]-carbamic acid ethyl ester in 600 ml dioxane and 12 ml acetic acid was added 12 g of 10% palladium on charcoal and the mixture was then stirred for 48 h at room temperature under a 10 bar atmosphere of hydrogen. The mixture was then filtered, washing with dioxane, and the filtrate concentrated in vacuo. Flash chromatography (1/1 acetone/dichloromethane) followed by trituration in ether and hexane afforded 7.50 g (62%) (±)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid ethyl ester as a white solid. ES-MS m/e (%): 339 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH:25]4[CH2:27][CH2:26]4)=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:28]1[CH2:32][CH2:31][CH2:30][C:29]1=[O:33]>>[CH:25]1([C:21]2[CH:22]=[C:23]([CH3:24])[C:18]([N:15]3[CH2:16][CH2:17][N:12]([C:10]([C:5]4[CH:4]=[CH:3][C:2]([N:28]5[CH2:32][CH2:31][CH2:30][C:29]5=[O:33])=[CH:9][C:6]=4[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]3)=[N:19][CH:20]=2)[CH2:27][CH2:26]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2C#N)CC1
Reactant: O=C1CCCN1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)cc2C#N)CC1

Procedure:
Using 5-bromo-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (723 mg) described in Preparation Example 189 and pyrrolidin-2-one (196 μL) and by the reaction and treatment in the same manner as in Example 20262, the title compound (668 mg) was obtained.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][C:29]1[O:33][N:32]=[C:31]([C:34]2[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=2)[C:37](O)=[O:38])[N:30]=1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:37](=[O:38])[C:36]5[CH:40]=[CH:41][CH:42]=[C:34]([C:31]6[N:30]=[C:29]([CH3:28])[O:33][N:32]=6)[CH:35]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: Cc1nc(-c2cccc(C(=O)O)c2)no1
Agent: Cl
Product: Cc1nc(-c2cccc(C(=O)N[C@H]3CC[C@H](CCN4CCN(c5nccc6c5OCC6)CC4)CC3)c2)no1

Procedure:
The title compound, white solid (120 mg, 93%), MS (ISP) m/z=517.5 [(M+H)+], mp 227.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzoic acid.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][CH2:15][C:5]([C:6]=23)=[CH:4]1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[C:23]1([S:29]([N:3]2[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]4[CH2:12][NH:13][CH2:14][CH2:15][C:5]([C:6]=34)=[CH:4]2)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2c[nH]c3cccc(c23)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc2c3c(cccc31)CNCC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
NaH (60% in mineral oil, 66 mg, 0.4 mmol) was added to a solution of tert-butyl 1,3,4,6-tetrahydro-5H-azepino[5,4,3-cd]indole-5-carboxylate, Intermediate 12 (51 mg, 0.2 mmol) in 800 of dry DMF). The reaction mixture was shaken at room temperature for 10 minutes and phenylsulfonyl chloride (66.2 mg, 0.4 mmol, in 600 uL of dry DMF) was added. The reaction mixture was shaken at room temperature for 10-20 minutes. The reaction was quenched by adding 4 mL of mixture a mixture of methanol and acetic acid (1:1). Boc-deprotection was carried out by adding 4 mL of solution of TFA/DCM (1:1). 2M NH3 in MeOH was added to the crude reaction (2×10 mL) and the solvent was removed under vacuum. The crude product was purified by preparative HPLC using System B, 100 mM NH4HCO3/MeCN (10-50% MeCN). 50 mg of the pure product was isolated as an off-white solid. MS m/z 313 [M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:19]([C:23]([CH3:29])=[C:24]1[CH:28]=[CH:27][CH:26]=[CH:25]1)=[CH:20][CH2:21][CH3:22].C1([Li])C2CC3C(=CC=CC=3)C=2C=CC=1>C1COCC1.CCCCCC.O>[CH:24]1([C:23]([CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)([CH3:29])[CH2:19][CH2:20][CH:21]=[CH2:22])[CH:28]=[CH:27][CH:26]=[CH:25]1
Reactant: CCC=CC(C)=C1C=CC=C1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Agent: [Li]c1cccc2c1Cc1ccccc1-2
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: C=CCCC(C)(C1C=CC=C1)C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution was prepared by dissolving 10 g of fluorene in 100 mL of THF and then this was slowly reacted with 37.6 mL of a 1.6 molar solution of n-butyllithium in hexane. This dark red solution was stirred overnight at room temperature. Then a solution was prepared by combining 8.8 g of 6-(butenyl)-6-methylfulvene with 50 mL of THF. This solution was then added dropwise over a period of one half hour to the solution of the fluorenyl lithium salt. That reaction mixture was stirred overnight at room temperature and then 100 mL of water was added. The organic phase was dried overnight over sodium sulfate and the solvent was evaporated in a vacuum. The yellow residue was dissolved in pentane and filtered using silica gel. The solvent was concentrated by means of evaporation. Crystallization took place at about -18° C. to give 5-cyclopentadienyl-5-(9-fluorenyl)-1-hexene in a form of a white solid.
Reaction SMILES: Br[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[CH3:19].[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[C:30]([CH3:37])[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=2[CH3:19])=[C:30]([CH3:37])[CH:29]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1c(Br)n(C)c(=O)n(COCC[Si](C)(C)C)c1=O
Reactant: Cc1cc(OCc2ccccc2)ccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(OCc2ccccc2)ccc1-c1c(C)c(=O)n(COCC[Si](C)(C)C)c(=O)n1C

Procedure:
To a mixture of C3 (10 g, 29 mmol), [4-(benzyloxy)-2-methylphenyl]boronic acid (10.4 g, 43.0 mmol) and cesium carbonate (28 g, 86 mmol) in 1,4-dioxane (400 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.2 g, 3.0 mmol). The reaction mixture was heated at reflux for 4 hours, then filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography (Gradient: 10% to 20% ethyl acetate in petroleum ether) to provide the product as a light yellow solid. Yield: 10 g, 21 mmol, 72%. 1H NMR (400 MHz, CDCl3) δ 7.34-7.49 (m, 5H), 7.00 (d, half of AB quartet, J=8.3 Hz, 1H), 6.91-6.97 (m, 2H), 5.50 (AB quartet, JAB=9.2 Hz, ΔνAB=4.1 Hz, 2H), 5.10 (s, 2H), 3.73-3.79 (m, 2H), 3.03 (s, 3H), 2.15 (s, 3H), 1.65 (s, 3H), 1.00-1.06 (m, 2H), 0.03 (s, 9H).
Reaction SMILES: [CH2:1]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]([NH2:14])=O)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[NH2:14][CH2:12][CH:9]1[CH2:10][CH2:11][N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]1
Reactant: CCCCCN1CCC(C(N)=O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCCN1CCC(CN)CC1
Yield: 79 %

Procedure:
Prepared from 1-pentyl-piperidine-4-carboxamide (3.0 g, 15.1 mmol) and LAH (1.14 g, 30.2 mmol) according to general the procedure used for Example 8 (Step B) to give 2.2 g of title compound as an oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].C1(NC2CCCCC2)CCCCC1.[OH:22][N:23]1[C:27](=[O:28])[CH2:26][CH2:25][C:24]1=[O:29]>C(Cl)(Cl)Cl>[C:2](=[O:3])([O:22][N:23]1[C:27](=[O:28])[CH2:26][CH2:25][C:24]1=[O:29])[O:4][CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)COC(=O)Cl
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClC(Cl)Cl
Product: CC(C)COC(=O)ON1C(=O)CCC1=O
Reaction time: 8 h
Yield: 61.8 %

Procedure:
To a solution of isobutyl chloroformate (26 ml, 200 mmole) in 600 ml of chloroform was added in portions the dicyclohexylamine (DCHA) salt of N-hydroxysuccinimide (HOSu, 49.28 g, 200 mmole). After stirring the resulting suspension overnight, the precipitated DCHA hydrochloride was filtered off and washed with chloroform. The concentrated filtrate (ca. 50 ml) and washings were diluted with 400 ml of ethyl acetate (EtOAc) and washed with 10% citric acid (4×100 ml), brine (2×100 ml), 10% sodium bicarbonate (3×100 ml), and brine (4×100 ml) and then dried (magnesium sulfate), filtered, and concentrated to ca. 100 ml. On diluting with ether and precipitating with hexane, 26.6 g (62% yield) of iBuOCO-OSu was obtained, mp 33°-35° C.
Reaction SMILES: [C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]\[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].II>CC(C)=O>[C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[C:6]([OH:8])=[O:7]
Reactant: O=C(O)/C=C\C=C\C(=O)O
Agent: II
Solvent: CC(C)=O
Product: O=C(O)/C=C/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 13.8 %

Procedure:
cis,trans-Muconic acid (109 mg, 0.767 mmol) is dissolved in acetone (10 mL) at room temperature and a crystal of iodine (13 mg, 0.05 mmol) was added. The reaction mixture is allowed to stir at room temperature for 24 hour. The precipitate is filtered, washed with ice-cold acetonitrile and dried under reduced pressure to yield 15 mg of trans,trans-muconic acid, a 13 percent yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])/[C:5](/[O:22][CH2:23][CH3:24])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][C:8]=1[CH3:21])[CH3:2].B(F)(F)F.O(CC)CC.CSC>ClCCl>[CH2:1]([O:3][C:4](=[O:25])/[C:5](/[O:22][CH2:23][CH3:24])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:21])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccc(OCc2ccccc2)cc1C)OCC
Agent: FB(F)F
Solvent: CSC
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)/C(=C/c1ccc(O)cc1C)OCC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (Z)-3-(4-benzyloxy-2-methyl-phenyl)-2-ethoxy-acrylic acid ethyl ester (46.1 g, 135.4 mmol) in dichloromethane (500 ml) was added BF3-OEt2 (186 ml, 677 mmol, 46%) and dimethyl sulfide (149 ml, 2.03 mol). The reaction mixture was stirred at ambient temperature for 14 h, poured onto ice water and extracted two times with dichloromethane. The combined extracts were washed with ice water/brine 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, n-heptane/AcOEt) to give 23.1 g (92.3 mmol, 68% over three steps) of the title compound as yellow crystals.
Reaction SMILES: C(OC([NH:8][CH:9]([CH:17]([OH:44])[CH:18]([NH:26][C:27](=[O:43])[C@H:28]([CH:40]([CH3:42])[CH3:41])[NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)(C)C.CO.C(N)(C)C.C(Cl)(Cl)Cl>>[NH2:8][CH:9]([CH:17]([OH:44])[CH:18]([NH:26][C:27](=[O:43])[C@H:28]([CH:40]([CH3:42])[CH3:41])[NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(C)N
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Yield: 100 %

Procedure:
Using the procedure of Example 56 with the resultant compound of Example 55 gave, after silica gel chromatography using methanol/isopropylamine/chloroform, the desired compound (RF 0.3; 2.5% methanol/2% isopropylamine/chloroform) in 100% yield, m.p. 158°-160° C. Mass spectrum (M+H)+ =504.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:21])=[C:4]([S:8]([NH:11][C:12]2[S:13][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:15][N:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[CH:40]([NH:43][CH:44]([CH3:46])[CH3:45])([CH3:42])[CH3:41]>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:3]([CH3:21])=[C:4]([S:8]([NH:11][C:12]2[S:13][C:14]([CH2:17][C:18]([N:43]([CH:44]([CH3:46])[CH3:45])[CH:40]([CH3:42])[CH3:41])=[O:20])=[CH:15][N:16]=2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)NC(C)C
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1ncc(CC(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ncc(CC(=O)N(C(C)C)C(C)C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.3 %

Procedure:
To a solution of (2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)acetic acid (Example 3) (0.09 g, 0.25 mmol) in CH2Cl2 (5.0 mL) and DMF (0.5 mL) were added EDCI (0.05 g, 0.27 mmol), DMAP (0.02 g, 0.12 mmol), triethylamine (0.1 mL, 0.75 mmol) and diisopropylamine (0.04 mL, 0.30 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then washed with 1 M HCl (2×15 mL) and the organic layer was collected. The organic phase was dried (MgSO4) and concentrated under reduced pressure. Purification using preperative HPLC afforded the desired product (0.01 g) in 9% yield.