Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:14])(=[O:13])[CH2:2][CH2:3]CCCCCCCCC.[C:15]([O-])(=[O:27])[CH2:16]CCCCCCCCCC.[CH2:29]([Sn+2]CCCC)CCC.C1CCCCC1>C1COCC1>[CH3:29][C:2]([C:1]([O:14][CH2:16][CH2:15][OH:27])=[O:13])=[CH2:3]
Reactant: CCCCCCCCCCCC(=O)[O-]
Reactant: CCCC[Sn+2]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCO
Temperature: 40 °C

Procedure:
A three-neck reaction flask fitted with a mechanical stirrer, condenser, dropping funnel, and thermometer was charged with 76 parts of a 32.4% THF solution of Polymer D followed by (0.25 parts) of dibutyltin dilaurate (Sigma-Aldrich) and 0.01 parts of BHT. A solution of IEM (4.77 parts) in THF (10 parts) was slowly added from the dropping funnel and the resulting solution heated at 40° C. for 30 minutes. The resulting polymer solution was cooled to room temperature, poured into a large excess of cyclohexane (approximately 5 times volume of reaction mixture), and the precipitated solid collected by filtration and dried in a 30° C. vacuum oven. The dried white solid was designated Example 2 and identified as the polymer of NIPAAM/HEMA with a plurality of the HEMA monomeric units derivatized with IEM to provide monomeric units of the following structure (Me=CH3):
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH3:16])[CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)(C)(C)C.Cl>CO>[CH3:16][C@H:8]([NH2:7])[CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: CC(CN1CCOCC1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: C[C@H](N)CN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 142.1 %

Procedure:
To a solution of (1-methyl-2-morpholin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.30 g, 1.22 mmol) in methanol (10 mL) was added 2N HCl (5 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The solvent was removed under vacuum to give (S)-1-Methyl-2-morpholin-4-yl-ethylamine as a light yellow solid (250 mg, 96%). MS (M+H)=145.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:17]=[C:16]3[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]3)=[N:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[N:10]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[CH:15]2
Reactant: COc1ccc(-n2cc3ccccc3n2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-n2cc3ccccc3n2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
To a solution of 2-(4-methoxyphenyl)-2H-indazole (50 mg, 0.22 mmol) in methylene chloride (3 mL) at −78° C. was added boron tribromide (62 μL, 0.66 mmol). The reaction was stirred at −78° C. for 1 hour and room temperature for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution. After the aqueous layer was extracted with methylene chloride, the combined organic layers were dried (MgSO4) and concentrated to give 28.4 mg of the desired indazole. LC-MS (C13H10N2O calculated 210) m/z 211 (M+H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([O:20][CH3:21])=[C:15](B(O)O)[CH:16]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:20][CH3:21])=[C:13]([C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=2)[CH:12]=1
Reactant: N#Cc1cccc(I)c1
Reactant: COc1ccc(Cl)cc1B(O)O
Product: COc1ccc(Cl)cc1-c1cccc(C#N)c1

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using 3-iodobenzonitrile and 5-chloro-2-methoxyphenyl boronic acid. Yield 0.465 g
Reaction SMILES: Cl[CH2:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][O:15][C:16](=[O:32])[C@H:17]([CH:29]([CH3:31])[CH3:30])[NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:7]=1)=[O:5].[I-:33].[Na+]>C(#N)C>[I:33][CH2:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][O:15][C:16](=[O:32])[C@H:17]([CH:29]([CH3:31])[CH3:30])[NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:7]=1)=[O:5]
Reactant: [I-]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCn1cc(C(=O)OCCl)ccc1=O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCn1cc(C(=O)OCI)ccc1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 94.7 %

Procedure:
To a solution of 1-(2-N-CBz-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid chloromethyl ester (1.80 g, 3.87 mmol) in acetonitrile (30 mL), was added sodium iodide (2.32 g, 15.5 mmol). The solution was stirred for 4 h at 60° C. The resulting suspension was filtered and the filtrate was evaporated. The residue was dissolved in CH2Cl2 and washed with aqueous sodium thiosulfate (0.1 M). The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The crude product was column chromatographed (silica gel, 1% MeOH in CH2Cl2), to give 2.04 g 1-(2-N-CBz-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid iodomethyl ester.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12](O)=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:21]1([C:27]2[N:32]=[N:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.P(Cl)(Cl)(Cl)=O>CN(C=O)C.C(Cl)Cl.C1(C)C=CC=CC=1>[C:21]1([C:27]2[CH:28]=[CH:29][C:30]3[N:31]([C:12]([CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)=[N:34][N:33]=3)[N:32]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NNc1ccc(-c2ccccc2)nn1
Reactant: O=C(O)Cc1ccc2ncccc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(-c2ccc3nnc(Cc4ccc5ncccc5c4)n3n2)cc1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
To a 50 ml round-bottomed flask was added 2-(quinolin-6-yl)acetic acid (0.60 g, 3.2 mmol), CH2Cl2 (20 ml) and oxalyl chloride (4.0 ml, 8.0 mmol, 2 M in CH2Cl2) and DMF (0.2 mL of a solution of 1 drop DMF in 1 mL CH2Cl2). After 3 d, an additional 2.5 eq. of oxalyl chloride was added. After 4 h, toluene (1 mL) was added and the mixture was concentrated. Toluene (3 mL) was added and again concentrated. The residue was taken up in CH2Cl2 (20 mL) and 1-(6-phenylpyridazin-3-yl)hydrazine (0.60 g, 3.2 mmol) was added. The mixture was stirred for 17 h and then concentrated. The mixture was then taken up in phosphorous oxychloride (20 ml, 220 mmol) and heated at 100° C. for 15 h. Toluene (5 mL) was added and the solution was concentrated. Another 5 mL toluene was added to the residue and once again it was concentrated. The brown solid residue was taken up in sat. NaHCO3 and extracted with EtOAc (4×150 mL) and 25% iPrOH/CHCl3 (3×150 mL). The combined extracts were washed with brine, dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (0 to 5% MeOH (2M in NH3)/CH2Cl2) afforded the title compound as a tan solid. MS (ESI, pos. ion) m/z: 338 (M+1).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C@H:28]3[C@H:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[C:22](=[O:29])N(CCO)N=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>>[CH:9]1([O:10][C:11]2[CH:12]=[C:13]([C:19]3[C@H:28]4[C@H:23]([CH2:24][CH:25]=[CH:26][CH2:27]4)[C:22](=[O:29])[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH2:3][CH2:2][CH2:1][CH2:6]1
Reactant: NNc1ccccc1
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(c3ccccc3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC1CCCC1

Procedure:
Prepared from compound E (see starting compounds) and phenylhydrazine as described for compound 35. Crystallization from methanol. M.p. 134°-135° C.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH:22](OC)[O:23]C)[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2].Cl>>[C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH:22]=[O:23])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cnc(C#N)cn1)CCC2
Agent: Cl
Product: N#Cc1cnc(NC(=O)N2CCCc3ccc(C=O)nc32)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(5-cyanopyrazin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2A, 32 mg, 0.090 mmol) was treated with HCl (4M in dioxane, 2 ml, 65.8 mmol) and stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum to dryness. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, DCM/(DCM/MeOH 9:1) 100:0 to 0:100). The product containing fraction was collected and concentrated under vacuum to obtain the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([NH2:11])[CH2:6][CH2:5]2.[F:12][C:13]([F:24])([F:23])[C:14]([NH:16][C:17]1([C:20](O)=[O:21])[CH2:19][CH2:18]1)=[O:15]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([NH:11][C:20]([C:17]1([NH:16][C:14](=[O:15])[C:13]([F:12])([F:23])[F:24])[CH2:18][CH2:19]1)=[O:21])[CH2:6][CH2:5]2
Reactant: N[C@H]1CCc2cc(Br)ccc21
Reactant: O=C(NC1(C(=O)O)CC1)C(F)(F)F
Product: O=C(NC1(C(=O)N[C@H]2CCc3cc(Br)ccc32)CC1)C(F)(F)F

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B] and A-1 [C], (S)-5-bromo-indan-1-ylamine has been coupled with 1-(2,2,2-trifluoroacetamido)cyclopropanecarboxylic acid (intermediate A-1 [A]) to give 1-(2,2,2-trifluoro-acetylamino)-cyclopropanecarboxylic acid ((S)-5-bromo-indan-1-yl)-amide, which was subsequently reacted with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) to yield the title compound as light brown solid. MS: 439.3 (MH+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[N:23][C:24]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:25][CH:26]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:13]=2)[CH:9]=[N:8]1.[CH3:46][C@H:47]1[CH2:49][O:48]1.CCN(C(C)C)C(C)C>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]5[CH2:32][CH2:31][N:30]([CH2:46][C@@H:47]([OH:48])[CH3:49])[CH2:29][CH2:28]5)=[N:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:37]=[CH:38][C:39]([CH3:40])=[CH:41][CH:42]=3)(=[O:34])=[O:35])[CH:13]=2)[CH:9]=[N:8]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)nc4)cnc32)cc1
Reactant: C[C@H]1CO1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1
Yield: 98 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperidin-4-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (85 mg. 0.132 mmol) was alkylated using (S)-2-methyloxirane (16 mg, 0.264 mmol), DIPEA (68 mg, 0.528 mmol) and ethanol (5 mL) to get 86 mg (97.8% yield) of the titled compound. MS: m/z=665.2 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=1.Cl[CH2:20][CH2:21][CH2:22][CH:23]([O:29]C(=O)C)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[OH:29][CH:23]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21][CH2:20][N:13]([CH2:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][C:3]([OH:2])=[O:18])[S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: CCCCCC(CCCCl)OC(C)=O
Reactant: COC(=O)COc1cccc(CNS(C)(=O)=O)c1
Product: CCCCCC(O)CCCN(Cc1cccc(OCC(=O)O)c1)S(C)(=O)=O

Procedure:
The title compound was prepared from [3-(methanesulfonylamino-methyl)-phenoxy]-acetic acid methyl ester (Preparation 10) and acetic acid 1-(3-chloropropyl)-hexyl ester using the alkylabon procedure described in U.S. Pat. No. 4,033,996. 1H NMR (CDCl3) δ 7.31-7.26 (m, 1H), 7.02-6.84 (m, 3H), 4.68 (s, 2H), 4.35 (s, 2H), 3.91-3.89 (m, 1H), 3.20-3.12 (m, 2H), 2.83 (s, 3H), 1.94-1.92 (m,1H), 1.79-1.24 (m, 12H), 0.87 (t, 3H); MS 400 (M+−1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][N:5]1[C:10]([C:11]2C=C[CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:8]=[C:7]([NH2:17])[C:6]1=[O:18].[K+].[Br-]>>[CH3:1][O:2][C:3](=[O:19])[CH2:4][N:5]1[C:10]([CH2:11][CH2:12][CH2:13][CH3:14])=[CH:9][CH:8]=[C:7]([NH2:17])[C:6]1=[O:18]
Reactant: COC(=O)Cn1c(-c2ccccc2)ccc(N)c1=O
Agent: [Br-]
Agent: [K+]
Product: CCCCc1ccc(N)c(=O)n1CC(=O)OC

Procedure:
Methyl[3-amino-1,2-dihydro-2-oxo-6-phenyl-1-pyridyl]acetate (50f), was isolated (86%) as a grey solid: mp. 207°-9° C.; IR (KBr) 3473, 3345, 1750, 1644, 1600, 1536, 1443, 1366, 1309, 1212, 1184, 1156; 1H NMR (d6 -DMSO) δ 7.30 (5H, m), 6.54 (1H, d), 6.03 (1H, d), 5.25 (2H, s), 4.49 (2H, s), 3.61 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH:13]([CH3:15])[CH3:14])[NH:5][C:6]([O:8]C(C)(C)C)=[O:7].N1C(C)=CC=CC=1C.[Si:25](OS(C(F)(F)F)(=O)=O)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].[Cl-].[NH4+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH:13]([CH3:14])[CH3:15])[NH:5][C:6]([O:8][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[O:7]
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)[C@@H](NC(=O)O[Si](C)(C)C(C)(C)C)C(C)C
Reaction time: 0.25 h

Procedure:
To a methylene chloride solution (1.0 ml) of N-t-butoxycarbonyl-L-valine methyl ester (115.5 mg, 0.5 mmol) and 2,6-lutidine (0.116 ml, 1.0 mmol) was added dropwise t-butyldimethylsilyltrifluoromethane sulfonate (0.172 ml, 0.75 mmol) at room temperature in a nitrogen atmosphere. After the mixture was stirred for 15 minutes, a saturated aqueous solution of ammonium chloride (2 ml) was added to quench the reaction and extraction with ether was conducted. The organic layer was dried over anhydrous magnesium sulfate and filtered. By distilling off the solvent under vacuum, the titled compound was obtained in an amount of 153.2 mg.
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2C=C1)[CH2:7]3.C([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])C=C>>[C:15]([NH:14][CH2:1][CH:5]1[CH2:4][CH:8]2[CH2:7][CH:6]1[CH:10]=[CH:9]2)([CH3:18])([CH3:17])[CH3:16]
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C=CCNC(C)(C)C
Product: CC(C)(C)NCC1CC2C=CC1C2
Temperature: 185 °C
Reaction time: 15 h
Yield: 64.7 %

Procedure:
5-(t-butylanfinomethyl)norbomene. 14 g of dicyclopentadiene and 60 g of the N-allyl-N-t-butylamine were placed neat in a Parr High-Pressure Reactor. The reaction was heated to 185° C. with stirring for 15 h. The reaction was then cooled down and the reaction solution was distilled under vacuum (0.5 torr). The desired product distilled over at 35°-36 ° C. 24.6 g of product was collected in this way (64.7% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][C:24]=1[O:31][CH2:32][O:33][CH3:34])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[K+].Cl>CCO.CCOCC>[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26](/[CH:27]=[CH:13]/[C:12]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:9][O:10][CH3:11])=[CH:7][C:2]=2[OH:1])=[O:14])=[CH:25][C:24]=1[O:31][CH2:32][O:33][CH3:34])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COCOc1ccc(C(C)=O)c(O)c1
Reactant: COCOc1cc(C=O)ccc1OCc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: COCOc1ccc(C(=O)/C=C/c2ccc(OCc3ccccc3)c(OCOC)c2)c(O)c1
Temperature: 25 °C
Reaction time: 144 h
Yield: 57.7 %

Procedure:
To 1-(2-hydroxy-4-(methoxymethoxy)phenyl)ethanone (618 mg, 3.15 mmol) and 4-(benzyloxy)-3-(methoxymethoxy)benzaldehyde (816 mg, 3 mmol) in a 25-mL round-bottom flask under Ar atmosphere was added 2.5 mL of a freshly made 5% KOH in EtOH solution. The mixture was vigorously stirred at rt until it solidified and kept at rt for 6 days. It was taken up in ether (100 mL) and added 0.5 M HCl to pH=5, and stirred for 3 min. The mixture was washed with water (2×100 mL) and dried over MgSO4 and concentrated. The residue was chromatographed (hexane/EtOAc) to afford (E)-3-(4-(benzyloxy)-3-(methoxymethoxy)phenyl)-1-(2-hydroxy-4-(methoxymethoxy)phenyl)prop-2-en-1-one as a clear oil (780 mg, 58%). MS (ESI) m/z 451 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]#[N:8].[F:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=[O:14]>N1C=CC=CC=1>[C:7]([C:6]1[NH:5][CH:4]=[N:3][C:2]=1[NH:1][C:13](=[O:14])[C:12]1[CH:16]=[CH:17][CH:18]=[C:10]([F:9])[CH:11]=1)#[N:8]
Reactant: N#Cc1[nH]cnc1N
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: c1ccncc1
Product: N#Cc1[nH]cnc1NC(=O)c1cccc(F)c1

Procedure:
Under a nitrogen atmosphere a stirred solution of 4-amino-1H-imidazole-5-carbonitrile (1.1 g, 0.01 mole) and 3-fluorobenzoyl chloride (1.8 g, 0.011 mole) in 25 ml of dry pyridine was heated at reflux for one hour. The reaction mixture was cooled and the pyridine removed under reduced pressure. The residue was washed with saturated aqueous sodium bicarbonate and water. The residual solid was collected by filtration and washed sequentially with two portions of water, diethyl ether, and ethyl acetate. The solid was dried under reduced pressure; mp, 222°-240°. The solid was dissolved in ethanol and precipitated with petroleum ether, then collected by filtration and washed with diethyl ether to give after drying N-(5-cyano-1H-imidazol-4-yl)-3-fluorobenzamide (2.0 g; mp, 242°-46°).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[CH2:19][OH:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[O:36][CH:37]=[CH:38][N:39]=2)=[CH:31][CH:30]=1.ClC1C=CC(S(N(CC2C=CC(C#N)=CC=2)[C@@H]2CCCCC[C@H]2CO)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[CH2:19][OH:20])[CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]3[O:36][CH:37]=[CH:38][N:39]=3)=[CH:33][CH:34]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: BrCc1ccc(-c2ncco2)cc1
Reactant: O=S(=O)(N[C@@H]1CCCCC[C@@H]1CO)c1ccc(Cl)cc1
Agent: N#Cc1ccc(CN([C@@H]2CCCCC[C@H]2CO)S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncco2)cc1)[C@@H]1CCCCC[C@@H]1CO
Yield: 53.7 %

Procedure:
The title compound was synthesized from 4-chloro-N-(cis-2-(hydroxymethyl)cycloheptyl)benzenesulfonamide (119 mg, 0.38 mmol), cesium carbonate (244 mg, 0.75 mmol), and 2-(4-(bromomethyl)phenyl)oxazole (98 mg, 0.41 mmol) according to the procedure described for 4-chloro-N-(4-cyanobenzyl)-N-(trans-2-(hydroxymethyl)cyclopentyl)benzenesulfonamide (Example 40) to give 4-chloro-N-(cis-2-(hydroxymethyl)cycloheptyl)-N-(4-(oxazol-2-yl)benzyl)benzenesulfonamide (97 mg, 54%). 1H NMR (400 MHz, CDCl3) δ ppm 7.95 (2H, d, J=8.31 Hz), 7.71 (1H, s), 7.66 (2H, d, J=8.56 Hz), 7.43 (4H, t, J=9.06 Hz), 7.26 (1H, s), 4.64 (1H, d, J=16.62 Hz), 4.41 (1H, d, J=16.62 Hz), 4.24-4.31 (1H, m), 3.57 (1H, dd, J=11.33, 8.31 Hz), 3.33 (1H, dd, J=11.33, 5.54 Hz), 1.90-2.05 (1H, m), 1.40-1.78 (6H, m), 1.11-1.34 (5H, m). LC/MS R.T.=2.21 min; [M+H]+=475.11. HRMS [M+H]+ calc'd 475.1458, found 475.1437.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17](OC(C)(C)C)=[O:18])=[C:15]([NH2:24])[N:14]=[C:13]([C:25]3[C:30]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)=[CH:29][CH:28]=[CH:27][C:26]=3[O:41][CH2:42][CH:43]3[CH2:45][CH2:44]3)[CH:12]=2)=[CH:7][C:6]=1[OH:46])(=O)[CH3:2].[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1COCC1>[NH2:24][C:15]1[C:16]([CH2:17][OH:18])=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([NH:4][CH2:1][CH3:2])=[C:6]([OH:46])[CH:7]=2)[CH:12]=[C:13]([C:25]2[C:30]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=3)=[CH:29][CH:28]=[CH:27][C:26]=2[O:41][CH2:42][CH:43]2[CH2:44][CH2:45]2)[N:14]=1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(-c3ccc(NC(C)=O)c(O)c3)c(C(=O)OC(C)(C)C)c(N)n2)cc1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNc1ccc(-c2cc(-c3c(OCc4ccc(OC)cc4)cccc3OCC3CC3)nc(N)c2CO)cc1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a cold (0° C.) solution of tert-butyl 4-[4-(acetylamino)-3-hydroxyphenyl]-2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}nicotinate (1.00 g, 1.60 mmol) in THF (15.0 mL) under argon atmosphere was added a solution of sodium bis(2-methoxyethoxy)aluminum hydride (3.7 N in toluene, 1.25 mL, 6.39 mmol) in THF (2 mL) dropwise. After being stirred for 5 hrs., a solution of sodium bis(2-methoxyethoxy)aluminum hydride (3.7 N in toluene, 0.833 mL, 4.26 mmol) in THF (1 mL) was added to the mixture at 0° C., then the mixture was allowed to warm to room temperature, and the stirring was continued overnight. The mixture was quenched with ethyl acetate and poured into saturated aqueous sodium potassium tartarate. The extracted organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 5-[2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-3-(hydroxymethyl)-4-pyridinyl]-2-(ethylamino)phenol.; LC-MS (m/z=542 M+1)
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH2:11]([CH2:13][NH2:14])[OH:12].C([O-])(O)=O.[Na+]>ClCCl>[OH:12][CH2:11][CH2:13][NH:14][S:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:9])=[O:8]
Reactant: NCCO
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(NCCO)c1ccc(Br)s1
Yield: 65.2 %

Procedure:
A mixture of 5-bromo-thiophene-2-sulfonyl chloride (1.5 g, 4. mmol) and ethanolamine (0.72 mL, 12 mmol) in dichloromethane (8 mL)/sat. NaHCO3 solution (8 mL) was stirred at 20° C. for 28 h. The mixture was partitioned between AcOEt (50 mL) and H2O (150 mL). The organic layer was dried (Na2SO4) and evaporated to give the title compound (1.07 g, 93%) as a pale-yellow oil. MS (ISP) 284.0 [(M−H)−].
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:31])[N:10]([C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][CH3:29])=[O:27])=[CH:20][C:19]=2[OH:30])[CH:15]=[CH:16][CH:17]=1)[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)(=O)C>CO.C(OCC)(=O)C.[Pd]>[CH2:1]([NH:8][C:9](=[O:31])[N:10]([C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][C:19]=2[OH:30])[CH:15]=[CH:16][CH:17]=1)[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C/C(=O)OC)cc2O)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Yield: 50.7 %

Procedure:
A solution of 5.89 g (13.87 mmol, 1 eq) of methyl (E)-3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]acrylate in 10 ml of methanol and 10 mL of ethyl acetate in the presence of 3 mL of acetic acid and 1.0 g (17% by mass) of 10% palladium-on-charcoal is stirred for 12 hours at room temperature under a hydrogen atmosphere. The palladium is filtered off through Celite and the solvents are evaporated off. The residue is chromatographed on silica gel (7/3 heptane/ethyl acetate) and crystallized from pentane. 3.0 g of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate are obtained in solid form. Yield=60%