Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([O:24][C@@H:25]2[O:30][C@@H:29]([CH2:31]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:28][CH2:27][CH2:26]2)[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:11][CH:10]=1.[I-].[Na+]>CN(C)C=O.O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([O:24][C@@H:25]2[O:30][C@@H:29]([CH2:31][N:3]3[CH:7]=[CH:6][N:5]=[CH:4]3)[CH2:28][CH2:27][CH2:26]2)[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:13][CH:14]=1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@H](OC(c3ccc(Cl)cc3)c3ccc(Cl)cc3Cl)O2)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(C(O[C@H]2CCC[C@H](Cn3ccnc3)O2)c2ccc(Cl)cc2Cl)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
114 mg of 55% sodium hydride were added to a solution of 323 mg of imidazole in 10 ml of dimethylformamide, and, after the mixture had been stirred at 80° C. for 30 minutes, it was cooled to room temperature. There were then added 2.20 g of trans-6-[α-(4-chlorophenyl)-2,4-dichlorobenzyloxy]-2-tosyloxymethyltetrahydropyran, dissolved in 15 ml of dimethylformamide, and then 594 mg of sodium iodide were added to the mixture. The resulting mixture stirred under a stream of nitrogen at 90°-95° C. for 4 hours, after which it was cooled, diluted with water and extracted with diethyl ether. The ethereal extract was washed with water and dried over sodium sulphate, after which it was concentrated by evaporation under reduced pressure and the residue was purified by column chromatography through silica gel eluted with a 8:1:0.1 by volume mixture of ethyl acetate, benzene and triethylamine, to give 1.346 g of the title compound as a colourless oil.
Reaction SMILES: N[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[C:18]([C:21]1[CH:34]=[CH:33][C:24](OCC2C=CC=CC=2)=[CH:23][CH:22]=1)(O)=[O:19]>CCOCC.O>[CH2:9]([O:8][C:6]([C:5]1[CH:11]=[CH:12][C:2]([O:19][CH2:18][C:21]2[CH:34]=[CH:33][CH:24]=[CH:23][CH:22]=2)=[CH:3][CH:4]=1)=[O:7])[CH3:10]
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1ccc(OCc2ccccc2)cc1

Procedure:
Ethyl 4-aminobenzoate (8.25g) in a mixture of conc. hydrochloric acid (12.5ml) and water (12.5ml.) at 0° C was diazotised by the addition of sodium nitrite (3.45g). The solution of the diazo compound was added to benzyl alcohol (20g) at 35° C with stirring then stirred at this temperature for 3 hr. The reaction mixture was cooled and 4-ethoxycarbonylphenoxy phenyl methane isolated by extraction with ether, m.p. 45° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O-:23])=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([Cl:26])=[O:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C([O-])c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Product: O=C(Cl)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1

Procedure:
Methyl-4.-hydroxybiphenyl is reacted with benzyl bromide to obtain 4'-benzyloxybiphenyl-4-carboxylate, which is converted through hydrolysis to 4'-benzyloxybiphenyl-4-carboxylate, which is then reacted with thionyl chloride to obtain 4'-benzyloxybiphenyl-4-carboxylic acid chloride. The chloride is reacted with optically active 1-trifluoro-2-octanol 1-trifluoromethylheptyl-4'-benzyloxybiphenyl-4-carboxylate, which is subjected to catalytical hydrogenolysis to obtain 1-trifluoroheptyl-4'-hydroxybiphenyl-4-carboxylate (III).
Reaction SMILES: [C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:23])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1)(=[O:3])[CH3:2].[C:26](OC(C)=C)(=[O:29])[CH2:27][CH3:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16]([O:23][C:26](=[O:29])[CH2:27][CH3:28])=[CH:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Reactant: C=C(C)OC(=O)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Product: CCC(=O)OC1=CC[C@H]2[C@@H]3CCc4cc(OC)cc(OC(C)=O)c4[C@H]3CC[C@]12C

Procedure:
A solution of 1-acetoxy-3-methoxyestra-1,3,5(10)-trien-17-one (0.884 g, 26 mM), isopropenyl propionate (15.1 g, 123 mM) and p-toluenesulfonic acid monohydrate (0.134 g, 0.7 mM) is heated at 120° on a set-up employing a Vigreaux column as described in Example 9. After heating at 120° for 12 hrs, the temperature is raised to 150° for 1 hr. The pot residue is poured into ether. The ethereal solution is extracted with saturated sodium bicarbonate solution, cold H2O and dried over MgSO4. Evaporation of the solvent gives a residue which upon chromatography on neutral silica gel affords 1-acetoxy-3-methoxy-17-propionyloxyestra-1,3,5(10),16-tetraene.
Reaction SMILES: [Li+].[OH-].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:8]([CH:20]=1)[C:9]([O:11]CC1C=CC(F)=CC=1)=[O:10].Cl>O1CCCC1.O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)=[C:8]([CH:20]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(OCc1ccc(F)cc1)c1cc(Br)ccc1OCc1ccc(F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Br)ccc1OCc1ccc(F)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Solid LiOH (0.23 g, 9.58 mmol) was added to a stirred solution of (4-fluorophenyl)methyl 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}benzoate (may be prepared as described in Description 86; 1 g, 1.92 mmol) in tetrahydrofuran (30 ml) and water (10 ml) in air at room temperature. The reaction mixture was stirred at 70° C. overnight. After cooling to room temperature, the solvent was removed to obtain a solid, which was dissolved in water (20 ml) and stirred in an ice-water bath. 1N HCl (aq) was added to adjust the pH to 4. The solid was filtered, and dried in vacuo to yield the title compound as a grey solid. 674 mg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([OH:7])=[O:6].Cl.CN(C)CCCN=C=NCC.[C:24](O)([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:24]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([I:11])[CH:10]=[C:2]([Br:1])[CH:3]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C(O)c1cc(Br)cc(I)c1
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(Br)cc(I)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.3 %

Procedure:
To a solution of 3-bromo-5-iodo-benzoic acid (D7) (50 g, 153 mmol, 1 equiv) in CH2Cl2 (500 ml) was added 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (30.8 g, 160 mmol, 1.05 equiv), DMAP (14 g, 114 mmol, 0.75 equiv) and tert-butanol (90 ml, 917 mmol, 6 equiv). The resulting mixture was stirred at room temperature for 48 h. DMAP (4.67 g, 38 mmol, 0.25 equiv) was then added and the solution was stirred for another 24 h then concentrated in vacuo. The residue was dissolved in AcOEt and washed sequentially with 2N aqueous HCl solution, 1N aqueous NaOH solution and brine, dried over MgSO4 and concentrated in vacuo to give 3-bromo-5-iodo-benzoic acid tert-butyl ester (D8b) (50.6 g, 86%) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=3[CH3:28])=[C:10]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[OH-:29].[Na+].OO>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([C:26](=[O:29])[NH2:27])=[CH:22][C:21]=3[CH3:28])=[C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: CCOC(=O)CCc1scc(-c2ccc(Br)cc2)c1-c1ccc(C#N)cc1C
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C(N)=O)ccc1-c1c(-c2ccc(Br)cc2)csc1CCC(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 8.3 %

Procedure:
Lastly, Step 5 of Scheme II was followed: A mixture of crude ethyl 3-(4-(4-bromophenyl)-3-(4-cyano-2-methylphenyl)thiophen-2-yl)propanoate (210 mg, 0.46 mmol) in DMSO (3 mL) was added aqueous solution of NaOH (2M, 1 mL), followed by the addition of H2O2 (0.2 mL). The mixture was stirred at room temperature for 10 minutes. The mixture was quenched with saturated aqueous Na2SO3 and extracted with a mixture of DCM/iPrOH (3/1). The combined organic layer was dried over Na2SO4, concentrated in vacuo. The residue was purified by HPLC (48-78% acetonitrile+0.15% trifluoroacetic acid in water, over 15 min.) to afford 3-(4-(4-bromophenyl)-3-(4-carbamoyl-2-methylphenyl)thiophen-2-yl)propanoic acid (17.0 mg, yield 8.3%). 1H NMR (CD3OD 400 MHz): δ 7.66 (d, J=8.0 Hz, 1H), 7.62 (s, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.20-7.19 (m, 3H), 7.11-7.08 (m, 2H), 2.62-2.81 (m, 2H), 2.50 (t, J=7.6 Hz, 2H), 1.98 (s, 3H). MS (ESI): m/z 446.0 [M+3]+.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([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)[C:7]=2[O:6][CH2:5]1.[OH:28][C:29]1([CH2:35][C:36](O)=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([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:36](=[O:37])[CH2:35][C:29]5([OH:28])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)CC1(O)CCCCC1
Agent: Cl
Product: O=C(CC1(O)CCCCC1)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, off-white solid (13.4 mg, 40%), MS (ISP) m/z=472.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and 2-(1-hydroxycyclohexyl)acetic acid.
Reaction SMILES: C12[N:8]([C:9]3C=N[C:16]4[C:11](=CC=[CH:14][CH:15]=4)[N:10]=3)CC1CCNC2.[C:19]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:27]1[CH2:33][CH:32]2[CH:29]([CH2:30][NH:31]2)[CH2:28]1)=[O:26].ClC1N=C(C)C=CN=1>>[C:19]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:27]1[CH2:33][CH:32]2[CH:29]([CH2:30][N:31]2[C:9]2[N:8]=[C:15]([CH3:14])[CH:16]=[CH:11][N:10]=2)[CH2:28]1)=[O:26]
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNC2C1
Agent: Cc1ccnc(Cl)n1
Product: Cc1ccnc(N2CC3CN(C(=O)c4ccccc4-c4ccccc4)CC32)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 19 and 2-chloro-4-methylpyrimidine. MS (ESI) mass calcd. for C23H22N4O, 370.46; m/z found, 371.2 [M+H]+.
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].F[C:16](F)(F)[C:17](O)=[O:18].[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:53]=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:52])[CH2:46][CH:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.C(Cl)(=O)C>>[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].[C:17]([N:49]1[CH2:50][CH2:51][CH:47]([CH2:46][C:45]([NH:44][C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[N:42]=[C:26]([NH:27][C:28]5[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=5)[CH2:33][CH2:34][C:35]=2[CH:43]=3)[N:25]=[CH:24][C:23]=4[Cl:22])=[O:52])[CH2:48]1)(=[O:18])[CH3:16]
Reactant: O=C(CC1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Product: CC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)C1
Yield: 39 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, 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-pyrrolidin-3-ylacetamide tris(trifluoroacetate) and acetyl chloride as starting materials in 39% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.08 (s, 1H), 9.40 (m, 2H), 9.07 (s, 1H), 8.32 (m, 2H), 8.21 (s, 1H), 7.67 (m, 1H), 7.30 (m, 1H), 7.07 (m, 1H), 3.50 (m, 4H), 3.17 (m, 1H), 2.99 (m, 4H), 2.08 (m, 2H), 1.91 (s, 3H), 1.60 (m, 2H). LCMS for C25H27ClN7O2 (M+H)+: m/z=492.2.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:29]1([CH:35]2[O:40][C@H:39]3[CH2:41][C@@H:42](O)[CH2:43][O:44][C@@H:38]3[CH2:37][O:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:20]([O:28][C@@H:42]1[CH2:43][O:44][C@H:38]2[C@@H:39]([O:40][CH:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:36][CH2:37]2)[CH2:41]1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O[C@H]1CO[C@@H]2COC(c3ccccc3)O[C@H]2C1
Reactant: O=C(O)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@@H]1CO[C@@H]2COC(c3ccccc3)O[C@H]2C1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of triphenylphosphine (560 mg, 2.134 mmol) and benzoic acid (261 mg, 2.134 mmol) under nitrogen in anhydrous THF (8.0 mL) was added (4aR,7R,8aS)-2-phenylhexahydro-pyrano[3,2-d][1,3]dioxin-7-ol (500 mg, 2.134 mmol), then DIAD (0.41 mL, 428 mg, 2.116 mmol) dropwise over 10 minutes. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure. The resultant oil was dissolved in DCM, then loaded directly onto a Biotage™ 50 g (2×25 g in series) silica gel cartridge and eluted with 0-100% EtOAc in 1:1 Hexane/DCM over 25 column volumes. The product fractions were combined and concentrated under reduced pressure to provide the desired product as a white solid. LC-MS: calculated for C20H20O5 340.13, observed m/e: 341.13 (M+H)+ (Rt 2.21/4 min).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[NH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccccc2)c1C#N
Reactant: NCCc1ccc(O)cc1
Solvent: COCCOC
Product: N#Cc1c(NCCc2ccc(O)cc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-methanesulfonyl-6-phenyl-pyrimidine-5-carbonitrile and tyramine in DME. ES-MS m/e (%): 332 (M+H+, 100).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][OH:20])([CH3:18])[CH2:13]1.[H-].[Na+].[CH3:23]I.O>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][O:20][CH3:23])([CH3:18])[CH2:13]1
Reactant: CC1(CO)CCCN(CC2COc3ccccc3O2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC1(C)CCCN(CC2COc3ccccc3O2)C1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of [1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]methanol (0.1 g, 0.36 mmol) in THF (5 ml) was added to NaH (60% in oil, 79.0 mg, 1.79 mmol) which was previously washed with heptane. The reaction mixture was stirred at 70° C. for 1 h and then cooled to RT followed by dropwise addition of a solution of methyl iodide (0.034 ml, 0.54 mmol) in THF (1 ml). Stirring was continued for 1 h. Water was slowly added and the reaction mixture extracted with DCM (3×20 ml). The combined organic phases were dried over Na2SO4, filtered and the filtrate was evaporated to give the title compound, which was purified by column chromatography (DCM/MeOH, 90:10).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:9]=2)[C:4]([NH2:15])=[N:3]1.[C:16]([OH:20])(=[O:19])[CH:17]=O>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([F:12])([F:13])[F:14])=[CH:8][CH:9]=2)[C:4]([NH:15][CH2:17][C:16]([OH:20])=[O:19])=[N:3]1
Reactant: Cn1nc(N)c2cc(C(F)(F)F)ccc21
Reactant: O=CC(=O)O
Product: Cn1nc(NCC(=O)O)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as white solid from reductive amination of 1-methyl-5-trifluoromethyl-1H-indazol-3-ylamine (as prepared in the previous step) and glyoxylic acid using the procedure described in Step B of Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH:9]=[CH:10][N:11](C)C)[S:5][C:6]=1[Br:7].O.[NH2:16]N>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][NH:11][N:16]=2)[S:5][C:6]=1[Br:7]
Reactant: CN(C)C=CC(=O)c1cc(Br)c(Br)s1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Brc1cc(-c2cc[nH]n2)sc1Br
Temperature: 25 °C
Yield: 99.4 %

Procedure:
A mixture of 1-(4,5-dibromo-2-thienyl)-3-(dimethylamino)prop-2-en-1-one (9.6 mmol) and hydrazine hydrate (14.3 mmol) in 22 mL ethanol was refluxed for 15 h and then allowed to cool to room temperature. The solvent was evaporated under reduced pressure and dried in vacuum to afford 2.94 g (100% yield) 3-(4,5-dibromo-2-thienyl)-1H-pyrazole which was used in the next step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]([C:19]3([OH:27])[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21][CH2:20]3)=[N:16][CH:15]=2)=[CH:10][C:9]=1[F:28])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]([C:19]3([OH:27])[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21][CH2:20]3)=[N:16][CH:15]=2)=[CH:10][C:9]=1[F:28]
Reactant: CCN1CCC(O)(c2ncc(-c3ccc(NC(=O)OC(C)(C)C)c(F)c3)s2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN1CCC(O)(c2ncc(-c3ccc(N)c(F)c3)s2)CC1
Reaction time: 2 h

Procedure:
To an ambient solution of Example 8A (0.20 g, 0.48 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred for 2 h, and was then concentrated under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 (5 mL) and ethyl acetate (5 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×5 mL). The combined organics were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield the title compound, which was used without further purification. MS (ESI) m/z 322 [M+H]+.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH2:28]([O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)[CH2:29][CH2:30][CH3:31]>C1COCC1>[CH2:28]([O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[CH:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:35][CH:34]=1)[CH2:29][CH2:30][CH3:31]
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCOc1ccc(C=O)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCOc1ccc(C=CCCCC(=O)O)cc1
Yield: 72.8 %

Procedure:
This compound was synthesized from 4-carboxybutyltriphenylphosphonium bromide (8.86 g, 20 mmol) and p-butoxybenzaldehyde (3.56 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Crystallization (petroleum ether) afforded the product (3.82 g, 73%) as white crystals (mp: 56-57° C.). IR: 3350-2500, 1700 cm-1 ; 1H-NMR: 1.00 (t, 3H), 1.50 (m, 2H), 1.80 (m, 4H), 2.40 (m, 4H), 3.90 (t, 2H), 5.50+6.00 (m, 1H), 6.38 (q, 1H), 7.05 (q, 4H), 11.00 (bs, 1H). Anal. Calcd. for C16H22O3 : C, 73.25, H, 8.45%; Found: C, 73.32, H, 8.46%. Z:E=37:63.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[C:6]([S:19]([NH:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])(=[O:21])=[O:20])([C:9]([C:12]([C:15]([F:18])([F:17])[F:16])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.C(OCCOCCO)CCC>O>[C:6]([S:19]([N:22]([CH2:23][CH2:24][CH2:25][N:26]([CH3:27])[CH3:28])[CH2:3][CH2:2][C:1]([OH:5])=[O:4])(=[O:20])=[O:21])([C:9]([C:12]([C:15]([F:16])([F:17])[F:18])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7]
Reactant: C=CC(=O)O
Reactant: CN(C)CCCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: O
Solvent: CCCCOCCOCCO
Product: CN(C)CCCN(CCC(=O)O)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 125 °C

Procedure:
An acrylic acid Michael addition reaction was then run according to the general procedure given in U.S. Pat. No. 5,144,069 (Stern et al.). 50 g (0.12 mole) of the purified C4F9SO2N(H)C3H6N(CH3)2, 16.4 g (0.23 mole) of acrylic acid and 0.2 g of phenothiazine (free radical polymerization inhibitor) were added to a 250-mL three-neck flask equipped with an air stirrer and thermometer. The resulting mixture was heated to 125° C. and was allowed to react for 6 hours. After this reaction period, a positive solubility check of the product in water of pH 7 indicated that the Michael addition reaction was essentially complete. While still mixing, a solvent blend of 18 g of diethylene glycol monobutyl ether and 42 g of deionized water was added and the mixture was allowed to cool to room temperature. The water solubility test was run again with the same positive result, showing good conversion to the desired Michael addition product, C4F9SO2N(C2H4COOH)C3H6 (CH3)2.
Reaction SMILES: [O:1]([CH2:19][C:20]1([CH2:28][N:29]2[CH:33]=[C:32]([CH:34]=C)[N:31]=[C:30]2[N+:36]([O-:38])=[O:37])[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22][CH2:21]1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I([O-])(=O)=[O:40].[Na+]>[Os]=O.O.O1CCOCC1>[O:1]([CH2:19][C:20]1([CH2:28][N:29]2[CH:33]=[C:32]([CH:34]=[O:40])[N:31]=[C:30]2[N+:36]([O-:38])=[O:37])[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22][CH2:21]1)[Si:2]([C:15]([CH3:16])([CH3:18])[CH3:17])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [O-][I+2]([O-])[O-]
Reactant: C=Cc1cn(CC2(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)COC(C)(C)OC2)c([N+](=O)[O-])n1
Agent: O=[Os]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)OCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)(Cn2cc(C=O)nc2[N+](=O)[O-])CO1
Temperature: 25 °C
Reaction time: 120 h
Yield: 66.7 %

Procedure:
2.0 mL of a mixed solution of water/1,4-dioxane=3/1 was added to 163 mg (0.30 mmol equivalents) of 5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-5-[(4-vinyl-2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane, 38 mg (microcapsules, Wako Pure Chemical Industries, Ltd., 0.015 mmol equivalents) of osmium oxide and 130 mg (0.60 mmol equivalents) of sodium iodate were added thereto, and the mixture was stirred at room temperature (25° C.) for 5 days. After completion of the reaction, the osmium oxide was taken out, and the reaction liquid was extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, then dried with anhydrous magnesium sulfate, and subsequently concentrated under vacuum. The obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=5/1) to give 107 mg (0.20 mmol equivalents) of 5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-5-[(4-formyl-2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane.