Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1/[CH:14]=[CH:15]/[C:16]([N:18]1[C@H:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][O:20][C:19]1=[O:29])=[O:17].[CH2:30]1[CH2:34]O[CH2:32][CH2:31]1>CSC>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[C@H:14]([C:30]1[CH:34]=[CH:9][C:8]2[C:32](=[CH:10][CH:11]=[CH:6][CH:7]=2)[CH:31]=1)[CH2:15][C:16]([N:18]1[C@H:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][O:20][C:19]1=[O:29])=[O:17]
Reactant: COc1ccc(/C=C/C(=O)N2C(=O)OC[C@H]2c2ccccc2)c(C2OCCO2)c1
Reactant: C1CCOC1
Solvent: CSC
Product: COc1ccc([C@@H](CC(=O)N2C(=O)OC[C@H]2c2ccccc2)c2ccc3ccccc3c2)c(C2OCCO2)c1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of copper(I) bromide-dimethyl sulfide complex (1.43 g, 6.9 mmol) in anhydrous THF (33 mL) and dimethyl sulfide (16.5 mL) at −78° C. was added 2-naphthylene magnesium bromide (27.3 mL, 0.5 M in THF) slowly via syringe. After the addition, the reaction solution was stirred at −40° C. for 30 min, and then re-cooled to −78° C. A solution of Compound 21 (1.8 g, 4.6 mmol) in THF (24 mL) was then added via syringe. The reaction mixture was slowly warmed to room temperature before it was quenched with aqueous ammonium chloride at 0° C. and extracted with ethyl acetate (2×). The combined organic extract was washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo. The residue obtained was purified by flash column chromatography (hexanes/ethyl acetate 95:5 to 55:45) to give Compound 22 (2.15 g, 85%) as an off-white foam: 1H NMR (CDCl3, 500 MHz) δ 7.72-7.70 (m, 2H), 7.69-7.63 (m, 2H), 7.46-7.40 (m, 2H), 7.37 (d, J=8.5 Hz, 1H), 7.24 (d, J=8.5 Hz, 1H), 7.17-7.11 (m, 2H), 7.04 (t, J=7.5 Hz, 2H), 6.99 (d, J=7.5 Hz, 2H), 6.81 (s, J=8.5 Hz, 1H), 6.09 (s, 1H), 5.34-5.30 (m, 2H), 4.59 (t, J=8.5 Hz, 1H), 4.16-4.14 (m, 3H), 4.06-4.01 (m, 3H), 3.79 (s, 3H), 3.60 (dd, J=16.5, 8.5 Hz, 1H).
Reaction SMILES: FC1C=CC(NC(=O)NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=CC=2)=CC=1.[C:35]([C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44](=[O:70])[NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([O:65]C)=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[CH:48][CH:47]=2)=[CH:39][CH:38]=1)#[N:36]>>[C:35]([C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44](=[O:70])[NH:45][C:46]2[CH:47]=[CH:48][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:68])[CH3:69])[C:63]([OH:65])=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[CH:50][CH:51]=2)=[CH:39][CH:38]=1)#[N:36]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(C#N)cc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(C#N)cc4)cc3)cc2C1=O
Yield: 94 %

Procedure:
The compound of example 40 was prepared analogous to compound of example 8 by hydrolysis of compound of example 39.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[CH2:10][OH:11].C([Cu])#N.CN([CH:18]=[O:19])C>O>[OH:8][C:5]1[C:4]([CH3:9])=[C:3]2[C:2](=[CH:7][CH:6]=1)[C:18](=[O:19])[O:11][CH2:10]2
Reactant: Cc1c(O)ccc(Br)c1CO
Reactant: CN(C)C=O
Agent: N#C[Cu]
Solvent: O
Product: Cc1c(O)ccc2c1COC2=O
Temperature: 145 °C
Reaction time: 2 h

Procedure:
To a 2 L 3 neck flask equipped with overhead stirrer, N2 inlet, and condenser were charged 4-bromo-3-hydroxymethyl-2-methyl phenol (100 g, 461 mmol), CuCN (83.0 g, 921 mmol), and DMF (500 mL). The solution was sparged with N2 for 15 min then heated to 145° C. to obtain a homogeneous solution. The solution was aged at 145° C. for 2 h, then the reaction mixture was cooled to 95° C. 41.5 mL water was added (sparged with N2), and the reaction aged for 20 h. The reaction was cooled to RT then the solids filtered through solka flok and the cake washed with 50 mL DMF. To a 3 L flask containing 1 L EtOAc was added the DMF filtrate. A precipitate coating formed in bottom of flask. The DMF/EtOAc suspension was filtered through solka flok and the cake was washed with 250 mL EtOAc. The resulting filtrate was washed with 5% brine solution (3×500 mL). The aqueous layers were extracted with 500 mL EtOAc and the combined organics were dried over MgSO4, filtered and evaporated. The solids were slurried in 250 mL MTBE at RT then filtered and washed with 100 mL MTBE. The solids were dried under vacuum at RT, providing 5-hydroxy-4-methyl-3H-isobenzofuran-1-one.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[CH:16]1([NH2:19])[CH2:18][CH2:17]1>>[CH:16]1([NH:19][CH:12]2[CH2:13][CH2:14][N:9]([C:6]3[N:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=3)[CH2:10][CH2:11]2)[CH2:18][CH2:17]1
Reactant: CCc1cnc(N2CCC(=O)CC2)nc1
Reactant: NC1CC1
Product: CCc1cnc(N2CCC(NC3CC3)CC2)nc1

Procedure:
The title compound is prepared from 1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-one and cyclopropylamine following a procedure analogous to that described in Intermediate 4. LC (method 12): tR=2.53 min; Mass spectrum (ESI+): m/z=247 [M+H]+.
Reaction SMILES: [CH3:1][Mg+].[Br-].[CH3:4][C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([N+:14]([O-])=O)=[CH:9][CH:8]=2>[Pd]>[NH2:14][C:10]1[C:11]([CH3:1])=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5]([CH3:4])=[CH:13]2
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: C[Mg+]
Agent: [Pd]
Agent: [Br-]
Product: Cc1cc2c(C)c(N)ccc2[nH]1

Procedure:
Addition of MeMgBr to 2-methyl-5-nitroindole followed by hydrogenation over Pd/C provided 5-amino-2,4-dimethylindole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: O=C1Cc2c(cccc2-c2ccccc2F)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccccc4F)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.9 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3)triazol-1-yl-ethyl)amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (52.8 mg, 45%).
Reaction SMILES: [OH:1][CH2:2][C:3](=[CH2:8])[C:4]([O:6][CH3:7])=[O:5].N12CCN(CC1)CC2.[CH2:17](O)[CH:18]=[CH2:19]>>[CH2:19]([O:1][CH2:2][C:3](=[CH2:8])[C:4]([O:6][CH3:7])=[O:5])[CH:18]=[CH2:17].[OH:1][CH2:2][C:3](=[CH2:8])[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=CCO
Agent: C1CN2CCN1CC2
Agent: C=C(CO)C(=O)OC
Product: C=CCOCC(=C)C(=O)OC
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A 100 mL 4-neck flask equipped with a stirrer, condenser, thermometer, gas inlet and oil bath was charged with 34.8 g of methyl α-(hydroxymethyl)acrylate, 3.4 g of 1,4-diazabicyclo[2.2.2]octane, and 0.02 g of 4-hydroxy-2,2,6,6-tetramethyl-1-oxyl as the polymerization inhibitor. Next, the temperature was raised to 95° C. and 26.2 g of allyl alcohol was added dropwise over 8 hours while stirring and blowing air into the reaction mixture, after which the reaction was continued for another 8 hours. Conversion of the methyl α-(hydroxymethyl)acrylate was 86 mol %, and the yields of methyl α(allyloxymethyl)acrylate and allyl ester with respect to the methyl α-(hydroxymethyl)acrylate were respectively 52.2 mol % and 1.0 mol %. The allyl ester content was 2.2 wt % per 100 wt % of methyl α-(allyloxymethyl)acrylate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][NH2:10].[N-:11]=[C:12]=[O:13].[K+].Cl>O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][NH:10][C:12]([NH2:11])=[O:13]
Reactant: NCCOC1CCCCO1
Reactant: [N-]=C=O
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NCCOC1CCCCO1
Temperature: 0 °C
Yield: 92 %

Procedure:
A mixture of 33.2 g of 2-(tetrahydropyran-2-yloxy) ethylamine, 50 g of ice, and a solution of 35 g of potassium isocyanate in 80 ml of water is stirred well as 45.6 ml of 5N hydrochloric acid (cooled to -40°C) is added in one portion. The resulting solution is refluxed for 90 minutes, cooled, and extracted with four 150 ml portions of chloroform. The chloroform extract is dried and evaporated in vacuo to give 39.6 g of oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]3)[CH:5]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:3]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OC1CCN(c2cc(-c3ccccc3)nc(Cl)n2)CC1
Reactant: OB(O)c1ccccc1
Product: OC1CCN(c2cc(-c3ccccc3)nc(-c3ccccc3)n2)CC1
Yield: 61 %

Procedure:
1-(2,6-Diphenyl-pyrimidin-4-yl)-piperidin-4-ol was prepared from compound 1-(2-chloro-6-phenyl-pyrimidin-4-yl)-piperidin-4-ol and phenyl boronic acid by a procedure analogous to that disclosed in Examples 39 and 95, as described above. Yield: 61%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[NH:23][C:22]3[C:21](=[O:24])[N:20]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:19](=[O:32])[N:18]([CH2:33][CH2:34][CH2:35][CH3:36])[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(C)(C)C.Cl.O.C(=O)(O)[O-].[Na+]>O1CCOCC1.[Cl-].[Na+].O>[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]2[NH:23][C:22]3[C:21](=[O:24])[N:20]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:19](=[O:32])[N:18]([CH2:33][CH2:34][CH2:35][CH3:36])[C:17]=3[N:16]=2)=[CH:12][CH:13]=1
Reactant: CCCCn1c(=O)n(Cc2ccccc2)c(=O)c2[nH]c(Cc3ccc(NC(=O)OC(C)(C)C)cc3)nc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: O
Product: CCCCn1c(=O)n(Cc2ccccc2)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Yield: 99.3 %

Procedure:
[4-(1-Benzyl-3-butyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl)-phenyl]-carbamic acid tert-butyl ester (303 mg) was suspended in p-dioxane (3 mL) and 4M HCl in p-dioxane (Aldrich, 5 mL) added. After 17 h the reaction mixture was poured into water and the mixture cautiously neutralized with saturated aqueous sodium bicarbonate. Brine was added to the mixture which was then thoroughly extracted with dichloromethane. The combined organic extracts were dried (sodium sulfate) and concentrated in vacuo to give the desired product as an orange solid (241 mg).
Reaction SMILES: [O-:1]Cl=O.[Na+].[Cl:5][C:6]1[N:7]=[C:8]([S:21]([NH:24][CH3:25])(=[O:23])=[O:22])[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:10]=1[CH:11]=[O:12].CC(=CC)C>O.C1COCC1.CC(O)(C)C>[Cl:5][C:6]1[N:7]=[C:8]([S:21]([NH:24][CH3:25])(=[O:23])=[O:22])[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:18])[CH3:19])[C:10]=1[C:11]([OH:1])=[O:12]
Reactant: CNS(=O)(=O)c1nc(Cl)c(C=O)n1COCC[Si](C)(C)C
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1nc(Cl)c(C(=O)O)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of NaClO2 (0.21 g, 2.34 mmol) and NaH2PO4.H2O (0.19 g, 1.41 mmol) in H2O (0.5 mL) was added to a solution of 4-chloro-5-formyl-N-methyl-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-2-sulfonamide (0.083 g, 0.23 mmol) and 2-methyl-2-butene (1.41 mL of a 2M solution in THF, 2.81 mmol) in THF (0.70 mL) and t-BuOH (0.16 mL). The reaction mixture was stirred at RT for 1 h and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and dried to provide 4-chloro-2-[(methylamino)sulfonyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid as a clear oil that was assumed to be quantitative and used without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([OH:28])=O)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:34][C:35]1[CH:36]=[C:37]([CH2:42][NH2:43])[CH:38]=[CH:39][C:40]=1[CH3:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:34][C:35]1[CH:36]=[C:37]([CH2:42][NH:43][C:26]([C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[CH:24]=2)=[O:28])[CH:38]=[CH:39][C:40]=1[CH3:41]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Reactant: Cc1ccc(CN)cc1Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(Br)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[({[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (0.451 g, 1 mmol), [(3-bromo-4-methylphenyl)methyl]amine (0.2 g, 1 mmol, HBTU (0.379 g, 1 mmol), and TEA (0.278 mL, 2 mmol) were combined in CH2Cl2 (25 mL). The mixture was stirred overnight at room temperature. Aqueous workup gave the crude product which was CombiFlashed on a 40 g column eluted with 0-10% MeOH/CH2Cl2 to give the title compound as a white solid. LC-MS m/z 633.8 (M+H)+, 1.85 min (ret time); mp 175-176° C.; analytical HPLC shows 97.5% purity, (ret time 13.568 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:11])=[N:5][CH:6]=[C:7]([CH:9]=[CH2:10])[N:8]=1>C(O)C.[Pd]>[CH2:9]([C:7]1[N:8]=[C:3]([O:2][CH3:1])[C:4]([NH2:11])=[N:5][CH:6]=1)[CH3:10]
Reactant: C=Cc1cnc(N)c(OC)n1
Agent: [Pd]
Solvent: CCO
Product: CCc1cnc(N)c(OC)n1

Procedure:
A solution of 3-methoxy-5-vinylpyrazin-2-amine (490 mg, 3.08 mmol; see step 1) in 50 mL ethanol was hydrogenated under atmospheric hydrogen pressure using an H-cube employed with a Pd/C-cartridge. Complete conversion were observed and the volatile components were removed using a rotary evaporator to deliver 500 mg (95%) of the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:11]=[CH:12][N:13]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]CCCC.CN([CH:31]=[O:32])C>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[N:11]=[C:12]([CH:31]=[O:32])[N:13]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:20])([CH3:21])[CH3:22])[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cn(COCC[Si](C)(C)C)cn1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cn(COCC[Si](C)(C)C)c(C=O)n1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (See WO03/022274) (1 eq) in THF at 40° C. was added dropwise a solution of BuLi (2 eq.) in hexanes and the mixture was stirred at 40° C. for a further 30 min. DMF (4 eq.) was then added and the cooling bath was removed and the reaction mixture was allowed to warm to RT and stirred for 30 min, after which time it was quenched by addition of a sat. aq. NH4Cl solution. The organics were extracted with EtOAc (2×), washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The material was purified by column chromatography on silica eluting with 15% EtOAc/petroleum ether. 1H NMR (300 MHz, CDCl3) δ: 9.81 (1H, s), 7.30 (1H, s), 5.95 (2H, s), 4.87, (2H, s), 3.58 (2H, t, J=7.7 Hz), 1.05-0.85 (20H, m), 0.05 (6H, s).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][C@H:47]1[CH2:52][CH2:51][CH2:50][NH:49][CH2:48]1.[CH3:55][C:56]1[O:60][N:59]=[C:58]([C:61](Cl)=[O:62])[CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][C@H:47]1[CH2:52][CH2:51][CH2:50][N:49]([C:61]([C:58]2[CH:57]=[C:56]([CH3:55])[O:60][N:59]=2)=[O:62])[CH2:48]1
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: O=C(C[C@H]1CCCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCC[C@H](CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)C2)no1
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-piperidin-3-yl]acetamide tris(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as the starting materials in 60% yield. LCMS for C29H30ClN8O3 (M+H)+: m/z=573.1.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH4+].[Cl-]>CN(C)C=O>[CH2:8]([O:7][C:5]([CH:4]1[CH2:3][CH2:2][N:1]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH2:10]1)=[O:6])[CH3:9]
Reactant: CCOC(=O)C1CCNCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl isonipecotate (40.0 mL, 0.26 mol), K2CO3, (55 g, 0.4 mol) and N,N-dimethylformamide (200 mL) were combined under nitrogen. The resulting mixture was cooled in an ice bath and benzyl bromide (31.0 mL, 0.26 mol) was added. The reaction mixture was allowed to stir overnight with warming to ambient temperature. A saturated aqueous solution of NH4Cl (500 mL) was added, and the product was extracted twice with ethyl acetate (1 L and 0.5 L). The combined organic layers were washed with saturated aqueous NH4Cl (500 mL) and brine (500 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude product was purified by flash chromatography on silica gel (400 g) eluting with hexane/ethyl acetate (1:0 to 4:1) to obtain 1-benzyl-piperidine-4-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ ppm 1.24 (t, J=7.07 Hz, 3 H) 1.69-1.82 (m, 2 H) 1.82-1.92 (m, 2 H) 1.96-2.10 (m, 2 H) 2.20-2.34 (m, 1 H) 2.79-2.91 (m, 2 H) 3.48 (s, 2 H) 4.12 (q, J=7.14 Hz, 2 H) 7.20-7.32 (m, 5 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([C:28](O)=[O:29])=[CH:25][CH:26]=3)[C:21]([CH3:31])=[C:20]2[CH3:32])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[C:33]1([CH:39]([NH2:42])[CH2:40][CH3:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:32][C:20]1[N:19]([CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=2)[C:27]2[C:22]([C:21]=1[CH3:31])=[CH:23][C:24]([C:28](=[O:29])[NH:42][CH:39]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:40][CH3:41])=[CH:25][CH:26]=2
Reactant: CCOC(=O)c1ccc(-c2ccccc2Cn2c(C)c(C)c3cc(C(=O)O)ccc32)cc1
Reactant: CCC(N)c1ccccc1
Product: CCOC(=O)c1ccc(-c2ccccc2Cn2c(C)c(C)c3cc(C(=O)NC(CC)c4ccccc4)ccc32)cc1

Procedure:
The title compound was prepared following the same protocol as described in Step 8, Example 1, using the 1-((4′-(ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid and the 1-phenylpropan-1-amine instead of the (S)-1-(4-bromophenyl)ethanamine.
Reaction SMILES: C(OCCCC)(=O)CC[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15]C)=[O:11].C([OH:39])CCCCCCCCCCCCCCC>O>[CH2:13]([O:12][C:10]([C:9]1[CH:4]=[CH:5][C:6]([OH:39])=[CH:7][CH:8]=1)=[O:11])[CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: CCCCOC(=O)CCCCCCCCC(=O)OCCCC
Solvent: O
Product: CCCOC(=O)c1ccc(O)cc1

Procedure:
The SQ 30,741 and parabens are mixed with dibutyl sebacate with gentle heat, not over 50° C., and melted together and Polysorbate 60 and cetyl alcohol added. Water is heated to 80° C. to dissolve the sodium carboxymethyl cellulose forming an aqueous phase which is added with vigorous agitation to the oil phase to emulsify. Agitation is continued until the temperature drops down to 48° C. Sufficient 50° C. water is added to make 100 gm. Mixing is continued at a slow rate to congeal the mixture, until the lotion drops down to room temperature.
Reaction SMILES: O=[C:2]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].Cl.[CH2:21]([O:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1C=CC=CC=1>CCOCC>[CH2:21]([O:28][N:29]=[C:2]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NOCc1ccccc1
Reactant: COC(=O)CCC1CCCCCCCCCCC1=O
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: COC(=O)CCC1CCCCCCCCCCC1=NOCc1ccccc1
Temperature: 140 °C
Yield: 92.4 %

Procedure:
A heavy walled reaction tube was charged with 3-(2-oxocyclododecyl)-propionic acid, methyl ester (6.0 g, 22.3 mmol), benzyloxyamine hydrochloride (3.99 g, 25 mmol), and pyridine (30 mL). The tube was sealed and heated in an oil bath at 140° C. for 2 hours. Upon cooling, the reaction mixture was diluted with ether (1L) and extracted with 2NN HCl until the aqueous layer was acidic, followed by extraction with water (2×50 mL). The organic phase was dried over magnesium sulfate, filtered through a silica gel plug, and the solvent removed in vacuo to afford 8.1 g (97%) of a crude oil. Purification by flash column chromatography on silica gel (100:1 ratio) and by elution with hexane/ethyl acetate (95/5) afforded 7.7 g (92% yield) of the title compound as a colorless oil with a 4:1 (E/Z) isomer ratio. 1H NMR (CDCl3, 400 Mhz) δ: 7.23-7.36 (m, 5H), 5.03 (s, 2H, (E) major isomer), 5.02 (s, 2H, (Z) minor isomer), 3.63 (s, 2.4H, (E) major isomer), 3.61 (s, 0.6H, (Z) minor isomer), 2.63 (ddd, J=13.3, 9.8, 4.8 hz, 1H), 2.36 (m, 1H), 2.24 (m, 2H), 2.05 (m, 1H), 1.75 -1.84 (m, 2H), 1.69 (m, 2H), 1.52-1.62 (m, 1H), 1.40-1.51 (m, 1H), 1.26 (m, 14H)