Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH:15]3[CH2:17][CH2:16]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[N:28]1[C:32]([CH3:33])=[N:31][CH:30]=[N:29]1)[C:22](O)=[O:23]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH:15]3[CH2:17][CH2:16]3)[C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:27]([N:28]4[C:32]([CH3:33])=[N:31][CH:30]=[N:29]4)=[C:19]([F:18])[CH:20]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1ncnn1-c1ccc(C(=O)O)cc1F
Reactant: Clc1cnc(N2CCC(NC3CC3)CC2)nc1
Product: Cc1ncnn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3ncc(Cl)cn3)CC2)cc1F

Procedure:
The title compound is prepared from [1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-cyclopropyl-amine and 3-fluoro-4-(5-methyl-[1,2,4]triazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=3.90 min; Mass spectrum (ESI+): m/z=456 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(Br)ccn1
Reactant: Cc1cc(NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)cc(C)n2)ccn1
Product: Cc1cc(NC(=O)c2cc(-c3ccnc(C)c3)cc(C)n2)ccn1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide in accordance with the general method of example 131, step 2 using 4-Bromo-2-methylpyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a colorless amorphous, MS (ISP): m/e=319.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[C:15]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:15][O:1][C:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)c1ccc(C(C)(C)O)cc1
Solvent: CO
Product: COC(=O)c1ccc(C(C)(C)OC)cc1
Yield: 153.1 %

Procedure:
To a solution of methyl 4-(1-hydroxy-1-methylethyl)benzoate (340 mg, 1.75 mmol) in methanol (20 mL) was added p-toluenesulfonic acid (70 mg, 0.37 mmol). The mixture was refluxed for 48 h, concentrated in vacuo, and the residue chromatographed (silica gel, 10% ethyl acetate/90% hexanes to 30% ethyl acetate/70% hexanes) to give 118 mg (32%) of the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C@H:17]2[CH2:21][CH2:20][CH2:19][O:18]2)=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H].C(O)(=O)C(O)=O>C(O)C.C(O)(=O)C.[Pd].CC(O)C>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C@H:17]2[CH2:21][CH2:20][CH2:19][O:18]2)=[O:16])[CH2:10][CH2:9]1
Reactant: O=C(NC1CCN(Cc2ccccc2)CC1)[C@H]1CCCO1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: CC(C)O
Solvent: CC(=O)O
Product: O=C(NC1CCNCC1)[C@H]1CCCO1

Procedure:
(R)-Tetrahydro-furan-2-carboxylic acid (1-benzyl-piperidin-4-yl)-amide (128 g, 444 mmol) was dissolved in 300 mL ethanol and 50 mL acetic acid. Palladium on activated carbon (5 g) was added. A hydrogen pressure of 5 bars was applied, and hydrogenation was continued until no more hydrogen was consumed (about 5 days). The suspension was filtered through Celite, and the filtrate was evaporated to dryness under reduced pressure. The residue and oxalic acid (50 g, 555 mmol) were suspended in 500 mL 2-propanol and heated to dissolve the solids. Upon cooling, the oxalate salt of R-tetrahydro-furan-2-carboxylic acid piperidin-4-ylamide crystallized and was collected by filtration to yield (R)-Tetrahydro-furan-2-carboxylic acid piperidin-4-ylamide as an oxalate salt (99.0 g, 77%) as an off-white solid. 1H-NMR (300 MHz, DMSO-d6): δ 7.84 (d, J=7.8 Hz, 1H), 5.90 (bs, 2H), 4.18-4.14 (m, 1H), 3.89-3.67 (m, 3H), 3.25-3.20 (m, 2H), 2.94-2.71 (m, 2H), 2.13-2.00 (m, 1H), 1.56-1.58 (m, 6H) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[CH:28]1([CH2:34][NH2:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)[CH:16]=2)[C:11]([NH:35][CH2:34][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Reactant: NCC1CCCCC1
Product: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NCC3CCCCC3)c2)cc1
Yield: 105.5 %

Procedure:
Following the procedure of Example 9(e) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.5 g (1.26 mmol) and cyclohexylmethylamine (0.143 g, 1.26 mmol) were used to afford 0.60 g of the required product. Percentage purity (LCMS): 97.6%, (M+1)=451.1+1.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[N:9][NH:10][C:11]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C(#N)C>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[N:9][NH:10][C:11]2=[S:24])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=c1[nH]ncc2ccc([N+](=O)[O-])cc12
Solvent: CC#N
Product: O=[N+]([O-])c1ccc2cn[nH]c(=S)c2c1

Procedure:
13.9 g of 7-nitro-1(2H)-phthalazinone and 16.3 g of Lawesson reagent in 170 ml of acetonitrile are heated under reflux for 45 minutes. The reaction mixture is filtered while hot. The filtrate is cooled in an ice-bath and the crystals obtained are removed by filtration under suction. After drying in vacuo and recrystallization there is obtained 7-nitro-1(2H)-phthalazinethione as yellow crystals of m.p. 233°-234° (methanol/acetonitrile).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([O:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:12]([C:24]([O:26][CH3:27])=[O:25])=[N:11]2)=[CH:6][C:5]=1[F:28])#[N:3].CCN(C(C)C)C(C)C.Cl[C:39]1[N:44]=[CH:43][C:42]([CH2:45][CH2:46][CH3:47])=[CH:41][N:40]=1.CCOC(C)=O>CN1C(=O)CCC1>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([O:17][CH:18]3[CH2:19][CH2:20][N:21]([C:39]4[N:44]=[CH:43][C:42]([CH2:45][CH2:46][CH3:47])=[CH:41][N:40]=4)[CH2:22][CH2:23]3)[C:12]([C:24]([O:26][CH3:27])=[O:25])=[N:11]2)=[CH:6][C:5]=1[F:28])#[N:3]
Reactant: CCCc1cnc(Cl)nc1
Reactant: COC(=O)c1nn(-c2ccc(C#N)c(F)c2)c(=O)cc1OC1CCNCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCCc1cnc(N2CCC(Oc3cc(=O)n(-c4ccc(C#N)c(F)c4)nc3C(=O)OC)CC2)nc1
Temperature: 95 °C
Yield: 32.5 %

Procedure:
To a stirring solution of methyl 1-(4-cyano-3-fluorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carboxylate HCl (37.2 mg, 0.10 mmol) in NMP (3 mL) at room temperature under argon was added DIPEA (38.8 mg, 0.30 mmol) and 2-chloro-5-propylpyrimidine (23.5 mg, 0.15 mmol). The resulting reaction mixture was heated at 95° C. under argon overnight. 15 mL of EtOAc was added to the reaction mixture. The reaction mixture was washed with water (15 mL), and brine (15 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was directly purified by preparative HPLC (C18 column; 10-100% methanol in water without TFA) to give methyl 1-(4-cyano-3-fluorophenyl)-6-oxo-4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)-1,6-dihydropyridazine-3-carboxylate (16 mg, white solid, 32%). 1H NMR (400 MHz, CDCl3) δ ppm 0.56-1.12 (m, 3H) 1.37-1.67 (m, 2H) 1.70-2.20 (m, 4H) 2.39 (q, J=7.47 Hz, 2H) 3.64-4.09 (m, 7H) 4.02-4.40 (m, 1H) 4.40-4.95 (m, 1H) 6.31 (s, 1H) 7.45-7.91 (m, 3H) 7.91-8.46 (m, 2H). MS (ESI) 493 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH:17]([CH3:19])[CH3:18])=[C:12]([N+:20]([O-])=O)[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[H][H]>[Ni].C(O)C>[NH2:20][C:12]1[CH:11]=[C:10]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:9])[CH:15]=[CH:14][C:13]=1[NH:16][CH:17]([CH3:18])[CH3:19]
Reactant: [H][H]
Reactant: CC(C)Nc1ccc(C(=O)c2ccc(F)cc2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CC(C)Nc1ccc(C(=O)c2ccc(F)cc2)cc1N
Yield: 92.1 %

Procedure:
A solution of 14.7 parts of (4-fluorophenyl) [4-[(1-methylethyl)amino]-3-nitrophenyl]methanone in 120 parts of ethanol was hydrogenated at 2.105Pa with 3 parts of Raney nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over diatomaceous earth and the filtrate was evaporated, yielding 12.3 parts (92.1%) of [3-amino-4-[(1-methylethyl)amino]phenyl](4-fluorophenyl)methanone as a residue (int. 2).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]3([CH2:27][O:26][C:25]4[CH:28]=[C:29]5[C:33](=[CH:34][C:24]3=4)[CH2:32][CH2:31][O:30]5)[C:16]2=[O:35])[CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C>CO.[OH-].[OH-].[Pd+2]>[CH3:1][N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]3([CH2:27][O:26][C:25]4[CH:28]=[C:29]5[C:33](=[CH:34][C:24]3=4)[CH2:32][CH2:31][O:30]5)[C:16]2=[O:35])[CH2:9]1
Reactant: O=C1N(CC2CN(Cc3ccccc3)CCO2)c2ccccc2C12COc1cc3c(cc12)CCO3
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1CCOC(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)C1
Yield: 9.3 %

Procedure:
1′-[(4-Benzylmorpholin-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.19 g, 0.41 mmol) was suspended in methanol (20 mL) and ethyl acetate (20 mL) in a steel bomb, then 20% palladium hydroxide on carbon (0.03 g, 0.04 mmol) was added. Hydrogenation was done at 120 psi in the steel bomb for 16 h. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (ethyl acetate/methanol/ammonia, 10:1:0.1) to afford 1′-[(4-methylmorpholin-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1H)-one (0.015 g, 10%) as a colorless foam as the first fraction: 1H NMR (300 MHz, CDCl3) δ7.34-7.25 (m, 1H), 7.17-6.99 (m, 3H), 6.48 (s, 0.5H), 6.44 (s, 0.5H), 6.39 (s, 1H), 4.94-4.88 (m, 1H), 4.69-4.63 (m, 1H), 4.52 (t, J=8.7 Hz, 2H), 4.00-3.55 (m, 5H), 2.97 (t, J=8.7 Hz, 2H), 2.76 (d, J=8.4 Hz, 1H), 2.60 (d, J=8.4 Hz, 1H), 2.26 (s, 3H), 2.18-1.88 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 178.1, 178.0, 161.8, 161.7, 161.2, 161.18, 142.7, 142.67, 132.7, 132.6, 128.7, 128.6), 123.7, 123.6, 123.3, 123.2, 120.4, 120.3, 119.8, 119.7, 118.9, 118.8, 109.6, 109.4, 93.2, 93.16, 80.5, 80.4, 73.7, 73.6, 72.3, 66.8, 66.6, 58.3 58.0, 57.6, 54.7, 54.6, 46.4, 46.3, 43.2, 43.17, 29.0; MS (ES+) m/z 393.0 (M+1), and 1-(morpholin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.04 g, 26%) as a colorless foam as the second fraction: MS (ES+) m/z 379.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[NH:15]1[CH2:20][CH2:19][S:18][CH2:17][CH2:16]1>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N:15]1[CH2:20][CH2:19][S:18][CH2:17][CH2:16]1)=[O:14])[CH:6]=[CH:5]2
Reactant: C1CSCCN1
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Product: O=C(c1ccc2cc(O)ccc2c1)N1CCSCC1

Procedure:
The title compound was synthesised from 6-hydroxy-2-naphtoic acid (commercially available) and thiomorpholine (commercially available) according to the procedure described for Example A. MS (m/e): 272.0 (MH−, 100%)
Reaction SMILES: [ClH:1].[CH2:2]([C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1)[CH2:3][CH2:4][C:5]#[CH:6].[N:13]([CH2:16][C:17]1[CH:21]=[CH:20][S:19][CH:18]=1)=[N+:14]=[N-:15]>>[ClH:1].[S:19]1[CH:20]=[CH:21][C:17]([CH2:16][N:13]2[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][C:7]3[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=3)[N:15]=[N:14]2)=[CH:18]1
Reactant: [N-]=[N+]=NCc1ccsc1
Reactant: C#CCCCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(CCCc2cn(Cc3ccsc3)nn2)c[nH]1
Yield: 46.1 %

Procedure:
4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.090 g, 0.486 mmol) was reacted with 3-Azidomethyl-thiophene (0.081 g, 0.582 mmol) following the general procedure for click reactions outlined above to produce 4-[3-(1-Thiophen-3-ylmethyl-1H-[1,2,3]triazol-4-yl)-propyl]-1H-imidazol-2-ylamine hydrochloride (0.0727 g, 46%) as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.61 (s, 1H), δ 7.24 (s, 1H), δ 7.23 (d, 1H), δ 6.87 (d, 1H), δ 6.29 (s, 1H), δ 2.54 (t, 2H), 2.33 (t, 2H), δ 1.75 (m, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 147.6, 147.4, 147.3, 136.1, 127.9, 127.0, 126.9, 124.2, 122.2, 109.1, 53.1, 27.9, 24.3; HRMS (ESI) calcd for C13H16N6S (M+) 289.1229. found 289.1234.
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([C:10]2[S:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:16][C:17]1[O:21][N:20]=[C:19]([CH3:22])[C:18]=1[Br:23]>>[Br:23][C:18]1[C:19]([CH3:22])=[N:20][O:21][C:17]=1[NH:16][S:2]([C:5]1[S:6][C:7]([C:10]2[S:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: Cc1noc(N)c1Br
Reactant: Cc1ccc(-c2ccc(S(=O)(=O)Cl)s2)s1
Product: Cc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)s2)s1
Yield: 90.4 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(5-methyl-2-thienyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 2-chlorosulfonyl-5-(5-methyl-2-thienyl)thiophene (200 mg, 0.72 mmol) with 5-amino-4-bromo-3-methylisoxazole (127 mg, 0.72 mmol) yielded 273 mg (90%) of the crude sulfonamide. After passing through a small plug of silica gel, a portion of the product was further purified by preparative HPLC to give the pure sulfonamide as a white powder, m.p. 161°-162° C.
Reaction SMILES: C(O)C.[Na].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[C:13]([CH2:15][CH2:16][NH:17][C:18](=[O:23])[C:19](Br)([CH3:21])[CH3:20])#[N:14]>C1(C)C=CC=CC=1>[C:13]([CH2:15][CH2:16][NH:17][C:18](=[O:23])[C:19]([O:12][C:9]1[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=1)([CH3:21])[CH3:20])#[N:14]
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(Br)C(=O)NCCC#N
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)NCCC#N

Procedure:
Into a 25 liter reactor fitted with cooling and stirring means there were poured 3 liters of ethanol, 60 g of sodium and 250 g of p-chlorophenol (1.944 mol). After stirring for 1 hour there were added 3 liters of toluene and the ethanol/toluene azeotrope was removed by distillation; 2 more liters of toluene were added and also 425 g of N-cyanoethyl α -bromo-isobutyramide, (1.944 mol).
Reaction SMILES: [C:1]([N:9]1[CH2:18][CH2:17][C@H:16]2[C@@H:11]([CH2:12][CH2:13][C:14]([OH:27])([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH2:15]2)[CH2:10]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(Cl)(Cl)Cl.CO>C1COCC1>[CH2:1]([N:9]1[CH2:18][CH2:17][C@H:16]2[C@@H:11]([CH2:12][CH2:13][C:14]([OH:27])([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[CH2:15]2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C2(O)CC[C@H]3CN(C(=O)c4ccccc4)CC[C@@H]3C2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CC[C@H]3CN(Cc4ccccc4)CC[C@@H]3C2)cc1

Procedure:
Following the general procedure described in Example 49, trans-2-benzoyl-6-hydroxy-6-(4'-methoxyphenyl)decahydroisoquinoline (219 mg, 0.6 mmol) and lithium aluminum hydride (0.14 g, 3.6 mmol) were reacted in anhydrous THF (10 mL). Column chromatography (chloroform: methanol::9:1) afforded the product, a solid (158 mg): mp 38°-40° C.; NMR (CDCl3, 200 MHz): 7.4 (d, 2H, J=8), 7.35-7.2 (m, 5H), 6.85 (d, 2H, J=8), 3.8 (s, 3H), 3.55 (s, 2H), 2.95 (br d, 1H, J=10), 2.85 (br d, 1H, J=10), 2.05 (br t, 1H, J=8), 1.85-1.7 (m, 4H), 1.6-1.3 (m, 7H); HRMS: Calcd: 351.2198, Found: 351.2193.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].[C:18](Cl)(=[O:22])[C:19]([CH3:21])=[CH2:20].Cl.[Cl-].[Na+]>O>[C:18]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:22])[C:19]([CH3:21])=[CH2:20]
Reactant: NCCCCCCCCCCCC(=O)O
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: C=C(C)C(=O)NCCCCCCCCCCCC(=O)O
Temperature: -5 °C
Yield: 67.8 %

Procedure:
To a 5000 mL beaker, 1700 mL of water was added and then 11 g of sodium hydroxide was added, followed by stirring to dissolve the sodium hydroxide completely. Then, 26.9 g of 12-aminododecanoic acid (produced by Wako Pure Chemical Industries, Ltd.) was added to the reaction system, followed by stirring for 30 minutes to obtain a homogeneous solution. Subsequently, the internal temperature of the reaction system was cooled to −5° C. with an ice-salt bath. After the cooling treatment, 14.3 g of methacryloyl chloride (produced by Wako Pure Chemical Industries, Ltd.) was dropped over 15 minutes with a dropping funnel while stirring the reaction system. During the dropping, cooling was continued so that the internal temperature of the reaction system might not exceed 0° C. After the end of the dropping, the bath was changed to an ice bath and the reaction system was stirred at 0° C. for 1 hour. After stirring for 1 hour, a 6 mol/L aqueous hydrochloric acid solution was added to adjust the pH of the reaction solution at 3 or less. With the addition of the aqueous hydrochloric acid solution, white precipitate formed in the reaction system. To the solution was added 600 g of sodium chloride, and then extraction was carried out three times using 800 mL of ethyl acetate. The resulting ethyl acetate solution was washed with saturated aqueous sodium chloride solution and then magnesium sulfate was added to the ethyl acetate layer to dehydrate it. After the dehydration, ethyl acetate was distilled off under reduced pressure with a rotary evaporator to give white crude crystals. The resulting crude crystals were recrystallized from ethyl acetate to give 24 g of white crystals of N-methacryloyl-12-aminododecanoic acid (melting point: 73 to 74° C.). The chemical reaction formula of this Example is shown below.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][NH:6][C:7](=[O:32])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22][C:23]2[CH:28]=[C:27]([CH3:29])[C:26](Br)=[C:25]([CH3:31])[CH:24]=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.[F:34][C:35]([F:46])([F:45])[C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>>[CH3:31][C:25]1[CH:24]=[C:23]([O:22][CH:14]([C:11]2[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:33])=[O:32])=[CH:13][CH:12]=2)[CH2:15][CH2:16][CH2:17][C:18]([F:20])([F:21])[F:19])[CH:28]=[C:27]([CH3:29])[C:26]=1[C:39]1[CH:40]=[CH:41][C:36]([C:35]([F:46])([F:45])[F:34])=[CH:37][CH:38]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2cc(C)c(Br)c(C)c2)cc1
Product: Cc1cc(OC(CCCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(C(F)(F)F)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 128 starting from 3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic acid methyl ester and 4-trifluoromethyl phenyl boronic acid. MS: 580.3 [M−H]−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](OC(N1CCCC1C(O)=O)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH:9]([C:13]2[NH:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([Br:24])=[CH:22][CH:23]=3)=[CH:16][N:17]=2)[CH2:10][CH:11]2[CH:12]1[CH2:25]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1
Product: CC(C)(C)OC(=O)N1C(c2ncc(-c3ccc(Br)cc3)[nH]2)CC2CC21
Yield: 60 %

Procedure:
3-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (0.16 g, 60%) was prepared following the procedure for 2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester, substituting 2-Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester for Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester. LCMS-ESI+: calc'd for C19H22BrN3O2: 403.09 (M+); Found: 404.76 (M+H+).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([NH:9][C:10]([NH:12][C:4]2=[CH:3][CH:2]=1)=[O:11])=[O:8].Cl[CH2:14][CH2:15][CH2:16][S:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[N:21]1[CH:22]=[CH:23][C:18]([S:17][CH2:16][CH2:15][CH2:14][N:9]2[C:7](=[O:8])[C:5]3[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=3)[NH:12][C:10]2=[O:11])=[CH:19][CH:20]=1
Reactant: O=c1[nH]c(=O)c2ccccc2[nH]1
Reactant: ClCCCSc1ccncc1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2c(=O)n1CCCSc1ccncc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 31 %

Procedure:
To a solution of 1.62 g (10 mmol) of benzoylene urea and 1.88 g (10 mmol) of 4-(3-chloropropylthio)pyridine in 50 ml of dimethylformamide, 1.65 ml (11 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added, and the mixture was stirred at 80° C. for 16 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried and the solvent was distilled off. The residue was purified by column chromatography (eluent:ethyl acetate/ethanol=25:1 to 10:1 to 2:1). First, 0.973 g of 3-[3-(4-pyridylthio)propyl]quinazoline-2,4-(1H,3H)-dione (31.1% yield, pale yellow crystals) was obtained, and then, 0.487 g of the desired product was obtained (10.4% yield, yellow oil).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1>>[CH:22]([C:21]1[CH:24]=[CH:25][C:18]([O:17][CH2:16][CH2:15][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=3)[CH:3]=[CH:2]2)=[CH:19][CH:20]=1)=[O:23]
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Product: COC(=O)c1ccc2ccn(CCOc3ccc(C=O)cc3)c2c1

Procedure:
Methyl 1H-indole-6-carboxylate was alkylated with 4-(2-bromoethoxy)benzaldehyde as described in Example 3, Step 1 to provide methyl 1-(2-(4-formylphenoxy)ethyl)-1H-indole-6-carboxylate.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[NH:11][CH:12]=2)=[CH:4][CH:3]=1.[O-:18][CH2:19][CH3:20].[Na+]>C(O)C>[CH2:19]([O:18][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[NH:11][CH:12]=2)=[CH:4][CH:3]=1)[CH3:20]
Reactant: CC[O-]
Reactant: NCCCCc1nc(-c2ccc(Cl)nc2)c[nH]1
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccc(-c2c[nH]c(CCCCN)n2)cn1
Temperature: 130 °C
Yield: 87 %

Procedure:
To a solution of 4-[4-(6-chloro-3-pyridyl)imidazolyl]butylamine (825 mg, 3.3 mmoles) in ethanol (15 ml) was added sodium ethoxide (2.24 g, 33 mmoles). The reaction mixture was heated in a sealed vessel in a 130° C. oil bath for 48 hours; upon cooling more sodium ethoxide was added (1.0 g) and the closed vessel was heated at 150° C. for 48 hours more. Upon cooling the reaction mixture was concentrated and than was taken up in dichloromethane (200 ml) and was washed with water (50 ml). The aqueous layer was extracted further with dichloromethane (2×200 ml), the combined organics were dried over MgSO4, filtered, and concentrated yielding 4-[4-(6-ethoxy-3-pyridyl)imidazolyl]butylamine (747 mg, 87%). MH+(261)