Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[CH2:43]([N:45]([CH2:49][CH3:50])[CH2:46][CH2:47][NH2:48])[CH3:44]>C(Cl)(Cl)Cl.O>[CH2:43]([N:45]([CH2:49][CH3:50])[CH2:46][CH2:47][NH:48][C:35]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][C:18]=1[CH3:23])=[O:41])[CH3:44]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(CC)CCN
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (142 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-diethyl-1,2-ethanediamine (56 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (49 mg, yield 34%).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13](=[O:24])[N:14]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:15]4=[N:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:25]S(O)(=O)=O>>[C:1]1([CH2:7][C:8]([C:9]2[CH:18]=[C:17]3[C:12]([C:13](=[O:24])[N:14]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:15]4=[N:16]3)=[CH:11][CH:10]=2)=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1c2ccc(C#Cc3ccccc3)cc2nc2n1CCCCC2
Reactant: O=S(=O)(O)O
Product: O=C(Cc1ccccc1)c1ccc2c(=O)n3c(nc2c1)CCCCC3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(phenylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one (400 mg, 1.3 mmol), HgSO4 (0.1 g, 0.3 mmol, 0.2 equiv) and H2SO4 (6 mL) was stirred at room temperature for 2 h. After quenching with water and basifying with saturated sodium carbonate, the solution was extracted with ethyl acetate (3×20 mL). The combined organic layers were concentrated. The residue was purified by silica gel chromatography to give the desired product (30 mg). MS (ESI): 333 (MH+); 1H NMR (300 MHz, CDCl3) δ 8.22-8.19 (d, J=8.16 Hz, 1H), 8.03-7.99 (d, J=7.14 Hz, 2H), 7.59-7.43 (m, 4H), 7.37-7.34 (d, J=8.19 Hz, 1H), 4.40 (s, 2H), 4.39-4.36 (t, J=5.34 Hz, 2H), 3.06-3.03 (t, J=3.60 Hz, 2H), 1.85-1.81 (m, 6H). mGluR5 PAM EC50: ++.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14]C(=O)OC(C)(C)C)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C([Cl:25])(=O)C>CO>[ClH:25].[ClH:25].[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][CH:10]([CH2:13][NH2:14])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2ccncc2)CC1
Reactant: CC(=O)Cl
Solvent: CO
Product: Cl
Product: NCC1CCN(c2ccncc2)CC1
Reaction time: 3 h

Procedure:
tert-Butyl (1-(pyridin-4-yl)piperidin-4-yl)methylcarbamate (7 g, 24.4 mmol) was dissolved in methanol and cooled in an ice bath; acetyl chloride (8.6 ml, 121.8 mmol) was added and stirring was carried out for 3 h at room temperature. The solvent was removed under reduced pressure and the residue was taken up in water/dichloromethane. The phases were separated, and the aqueous phase was washed with dichloromethane (2×) and dried by freeze drying. Yield: quantitative
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].C(N(CC)CC)C.Cl[C:19]([O:21][C:22]1[CH:27]=CC([N+]([O-])=O)=CC=1)=[O:20].[C:31](OCC)(=[O:34])[NH:32][NH2:33]>C1COCC1.O>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:31]([NH:32][NH:33][C:19]([O:21][CH2:22][CH3:27])=[O:20])=[O:34])=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)NN
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)NNC(=O)Nc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.7 %

Procedure:
To 4-aminoacetophenone (676 mg, 5 mmol) in THF (25.000 mL) at 0° C. was added triethylamine (1.386 mL, 10.00 mmol) and 4-nitrophenyl chloroformate (1512 mg, 7.50 mmol). The mixture was stirred at room temperature for 2 hours. Then ethyl carbazate (1562 mg, 15.00 mmol) was added, followed by more triethylamine (2.079 mL, 15.00 mmol). The mixture was stirred at 55° C. for 2 hours. Water was then added, extracted with CH2Cl2 twice, washed with saturated sodium bicarbonate, dried over MgSO4, filtered, and concentrated in vacuo. The residue was triturated in ethyl acetate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography (10-80% ethyl acetate/heptane) giving ethyl 2-(4-acetylphenylcarbamoyl)-hydrazinecarboxylate (354 mg, 27%) as a light yellow solid. LC-MS (M+1) 266.1, t=0.79 minutes.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[C:13]([P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][S:11][C:10]=1I)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:28]1[S:29][CH:30]=[C:31]([P:41]([O:46][CH2:47][CH3:48])([O:43][CH2:44][CH3:45])=[O:42])[C:32]=1[P:33]([O:38][CH2:39][CH3:40])([O:35][CH2:36][CH3:37])=[O:34])CCC>C1COCC1.[Cu]Cl>[CH2:1]([O:3][P:4]([C:9]1[C:13]([P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][S:11][C:10]=1[C:28]1[S:29][CH:30]=[C:31]([P:41]([O:43][CH2:44][CH3:45])([O:46][CH2:47][CH3:48])=[O:42])[C:32]=1[P:33]([O:35][CH2:36][CH3:37])([O:38][CH2:39][CH3:40])=[O:34])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1scc(P(=O)(OCC)OCC)c1P(=O)(OCC)OCC
Reactant: CCOP(=O)(OCC)c1csc(I)c1P(=O)(OCC)OCC
Agent: Cl[Cu]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1csc(-c2scc(P(=O)(OCC)OCC)c2P(=O)(OCC)OCC)c1P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
In THF, 0.037 g (0.076 mmols) of the 2-iodo-3,4-bis(diethoxyphosphoryl)thiophene obtained in Example 4 and 0.049 g (0.076 mmols) of the 2-tributylstannyl-3,4-bis(diethoxyphosphoryl)thiophene obtained in Example 5 were dissolved, to which 0.009 g (0.091 mmols) of commercially available copper(I) chloride was added at room temperature. Thereafter, the reaction mixture was heated and stirred for 4 hours under reflex. After the reaction, the reaction mixture was cooled down to room temperature and the resulting solid was removed by celite filtration. The filtrate was distilled off under reduced pressure to remove the solvent, and the resulting crude product was purified with a silica gel column (ethyl acetate:methanol=15:1 to ethyl acetate:methanol=5:1) to obtain the specified substance in the form of a transparent oil at a yield of 0.049 g (yield: 91%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:15])[S:10][C:11]=1[CH3:12]
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1sc(C(=O)O)cc1-c1c(Br)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1sc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Br)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (191 mg, 0.63 mmol) [prepared according to the procedure of Example 159], 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (209 mg, 0.62 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g, 17.8 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (359 mg, 0.77 mmol) in chloroform (7 mL). DIEA (560 μL, 3.21 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (171 mg, 0.29 mmol, 46%): LC-MS (ES) m/z=583 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7][Br:8])=[CH:4][CH:3]=1.[CH:12](=[N:19][N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25][CH3:26])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)CCl>[Br-:8].[CH:12](=[N:19][N+:20]1[CH:24]=[CH:23][N:22]([CH2:7][C:6]([C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:9])[C:21]=1[CH2:25][CH3:26])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CCc1nccn1N=Cc1ccccc1
Solvent: ClCCCl
Product: CCc1n(CC(=O)c2ccc(Cl)cc2)cc[n+]1N=Cc1ccccc1
Product: [Br-]
Reaction time: 2 h

Procedure:
2.33 g (10 mmol) of p-chlorophenacyl bromide are added to a solution of 1.99 g (10 mmol) of 1-(benzylidene)amino-2-ethylimidazole in 30 ml of ethylene chloride. After stirring at 60° for 2 hours the product is filtered off and washed with ether. There is obtained 1-(benzylideneamino)-3-(p-chlorophenacyl)-2-ethylimidazolium bromide of melting point 236°-237°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[C:9]2[C:10](OS(C(F)(F)F)(=O)=O)=[CH:11][C:12]([O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])=[CH:13][C:8]=2[S:7][CH:6]=1.[CH3:34][N:35](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[C:9]2[C:10]([C:34]#[N:35])=[CH:11][C:12]([O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:16]([CH3:17])[CH3:18])[CH:19]([CH3:21])[CH3:20])=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: CN(C)C=O
Reactant: COC(=O)Cc1csc2cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(OS(=O)(=O)C(F)(F)F)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COC(=O)Cc1csc2cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(C#N)c12
Temperature: 100 °C
Reaction time: 20 h

Procedure:
To a mixture of methyl(4-(((trifluoromethyl)sulfonyl)oxy)-6-((triisopropylsilyl)oxy)-1-benzothiophen-3-yl)acetate (5.8 g) and DMF (dry) (80 mL) were added zinc cyanide (2.095 mL) and Pd(Ph3P)4 (1.273 g) at room temperature, and the mixture was stirred at 100° C. for 20 h. The mixture was cooled to room temperature. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (1.920 g).
Reaction SMILES: CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([OH:30])=O.Cl.[CH3:32][NH:33][O:34][CH3:35]>CN(C)C=O.C(N(CC)CC)C>[CH3:35][O:34][N:33]([CH3:32])[C:28](=[O:30])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=1
Reactant: O=C(O)c1ccccn1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccccn1
Reaction time: 0.25 h

Procedure:
EDCI (2.30 g, 0.012 mol) and 1-hydroxy benztriazole (1.36 g, 0.009 mol) were added o a stirred solution of pyridine-2-carboxylic acid (1.0 g, 0.008 mol) in N,N-dimethyl formamide (16 mL) at 0° C. The reaction mixture was allowed to stir for 15 min then triethyl amine was added followed by addition of N,O-dimethyl hydroxyl amine hydrochloride at 0° C. The resulting mixture was stirred at RT overnight. The reaction mixture was partitioned between water (30 mL) and ethyl acetate (2×30 mL). The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography using 100-200 mesh silica gel and 0-20% EtOAc: Hexane as eluant to obtain product.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:35]([CH2:44][C:45]2[CH:54]=[CH:53][C:48]([C:49]([NH:51]O)=[NH:50])=[CH:47][CH:46]=2)[CH:36]2[CH2:42][CH2:41][CH2:40][CH2:39][NH:38][C:37]2=[O:43])(=[O:34])=[O:33])=[CH:28][CH:27]=1.O>CN(C)C=O>[CH2:1]([O:8][CH2:9][C:10]1[O:12][N:50]=[C:49]([C:48]2[CH:53]=[CH:54][C:45]([CH2:44][N:35]([CH:36]3[CH2:42][CH2:41][CH2:40][CH2:39][NH:38][C:37]3=[O:43])[S:32]([C:29]3[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][CH:30]=3)(=[O:34])=[O:33])=[CH:46][CH:47]=2)[N:51]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)COCc1ccccc1
Reactant: N=C(NO)c1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCCCCC1N(Cc1ccc(-c2noc(COCc3ccccc3)n2)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.8 %

Procedure:
To a solution of benzyloxyacetic acid (162 μl, 1.10 mmol) in 5 ml dimethylformamide were added 1,1′-carbonyl-diimidazole (0.18 g, 1.10 mmol). The mixture was stirred at room temperature for 10 minutes, heated to 40° C. for a few minutes and cooled to room temperature. 4-{[(4-Chloro-benzenesulfonyl)-(2-oxo-azepan-3-yl)-amino]-methyl}-N-hydroxy-benzamidine (0.45 g, 1.00 mmol) was added and the mixture was stirred at 100° C. for 5 hours and then poured into water. Filtration and chromatography on silicagel with ethylacetate/heptane (1/1 to 4/1) yielded 0.51 g (87%) N-[4-(5-benzyloxymethyl-[1,2,4]oxadiazol-3-yl)-benzyl]-4-chloro-N-(2-oxo-azepan-3-yl)-benzenesulfonamide as white solid, MS: m/e (%)=581.1 (MH+, 100).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([C@H:14]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:16]2[CH:28]=[C:29]([C:33]([F:36])([F:35])[F:34])[C:30]([CH3:32])=[CH:31][C:15]1=2)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH2:46]([O:48][C:49](=[O:52])[CH2:50]Br)[CH3:47].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:46]([O:48][C:49](=[O:52])[CH2:50][N:25]1[CH2:24][CH2:23][CH:22]([CH2:21][N:17]2[CH2:18][CH2:19][CH2:20][C@H:14]([N:7]([CH2:6][C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:39]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:37]=3)[C:8]3[N:9]=[N:10][N:11]([CH3:13])[N:12]=3)[C:15]3[CH:31]=[C:30]([CH3:32])[C:29]([C:33]([F:34])([F:35])[F:36])=[CH:28][C:16]2=3)[CH2:27][CH2:26]1)[CH3:47]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc2c(cc1C(F)(F)F)N(CC1CCNCC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1CCC(CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)CC1
Temperature: 50 °C

Procedure:
To a solution of (S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-piperidin-4-ylmethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (Example 120) (0.18 mmol) in DMF (3 mL), add bromo-acetic acid ethyl ester (0.54 mmol) and cesium carbonate (0.90 mmol). After heating the mixture at 50° C. for 30 minutes, cool to room temperature and dilute the reaction with water (15 mL) and extract with ethyl acetate (3×10 mL). Dry the combined organic phases over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the product over silica gel, eluting with ethyl acetate/hexane (5-50%), to give the title compound as a colorless foam. MS (ES+): 736 (M+H).
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[CH:15]1([CH2:21][C:22](Cl)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>O1CCCC1>[CH:15]1([CH2:21][C:22]([NH:14][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[C:9]=3[CH:1]=2)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCc2oc3ccccc3c2C1
Reactant: O=C(Cl)CC1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CC1CCCCC1)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 20.6 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol), cyclohexylacetyl chloride (0.80 g, 6.0 mmol), and triethylamine (2.1 mL, 15 mmol) in tetrahydrofuran (24 mL) provided 2-cyclohexyl-N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-acetamide (0.32 g). Mp 189-191° C.; MS m/z 312 ([M+H]+); Anal. Calcd. for C20H25NO2: C, 77.14; H, 8.09; N, 4.50; Found: C, 77.44; H, 8.08; N, 4.59.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([CH:15]=[C:16](Br)Br)[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.Br[CH2:26][CH2:27][CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1.[NH4+].[Cl-]>C1COCC1.CN1C(=O)N(C)CCC1>[C:1]([O:5][C:6](=[O:19])[N:7]([CH3:8])[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:26][CH2:27][CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCCCOC1CCCCO1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C=C(Br)Br)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCCCOC2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3.97 g (10 mmol) of trans-[4-(2,2-Dibromo-vinyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 160 ml THF was treated at −78° C. with 13.13 ml (21 mmol) of BuLi (ca 1.6 M in hexane) and stirred for 2 h. 11 ml DMPU were added and 10 min later 4.60 g (20 mmol) of 1-bromo-3-tetrahydropyranyloxypropane in 15 ml THF were added over a period of 20 min. The reaction mixture was warmed up to RT for 16 h, cooled, poured into cooled aqueous saturated NH4Cl and extracted (Et2O 3×). The organic phase was washed with aqueous 10% NaCl, water, dried over Na2SO4, evaporated and purified by flash silica gel column (Hexane/EtOAc 98:2 to 90:10) to yield 1.61 g (42%) of trans-Methyl-{4-[5-(tetrahydro-pyran-2-yloxy)-pent-1-ynyl]-cyclohexyl}-carbamic acid tert-butyl ester, MS: 378 (M−H).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[N:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]=1[CH3:22].B(Br)(Br)Br.COC1C=C2C(=CC=1)N(CC1C=CC=CC=1)C(C)=C2CC(O)=O.Cl>C(Cl)Cl.CCO>[OH:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:6]([CH3:22])=[C:5]2[CH2:4][C:3]([OH:23])=[O:2]
Reactant: COC(=O)Cc1c(C)n(Cc2ccccc2)c2ccc(O)cc12
Agent: BrB(Br)Br
Agent: COc1ccc2c(c1)c(CC(=O)O)c(C)n2Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: Cc1c(CC(=O)O)c2cc(O)ccc2n1Cc1ccccc1
Reaction time: 17 h
Yield: 100 %

Procedure:
5-Hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid methyl ester. Three mL (30 mmol) of BBr3 was added to 3.1 g (10 mmol) of 5-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid in 250 mL of CH2Cl2 and the mixture stirred for 17 hours. After stirring with 1N HCl, some EtOH was added, the organic layer separated, washed with saturated NaCl solution, dried and concentrated at reduced pressure to give 2.95 g(100% yield) of crude 5-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid. A methanol solution of 1.7 g of the material was treated with sulfuric acid as described in Part A to give after silica gel chromatography (30% ether/hexane→60% ether/hexane) 1.5 g of 5-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid methyl ester.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[C:12]=1[NH2:13].[CH:22]([C:34]1[CH:35]=[N:36][N:37]([CH:39]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:40](O)=[O:41])[CH:38]=1)=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1.ClCCl>[CH:22]([C:34]1[CH:35]=[N:36][N:37]([CH:39]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:40]([NH:13][C:12]2[C:14]([O:20][CH3:21])=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:11]=2[O:10][CH3:9])=[O:41])[CH:38]=1)=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: CCCCCCCCCCC=Cc1cnn(C(C(=O)O)c2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC=Cc1cnn(C(C(=O)Nc2c(OC)cc(OC)cc2OC)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
Triethylamine (18 mL, 130 mmol) was added to a suspension of 2,4,6-trimethoxyaniline hydrochloride (28.48 g, 130 mmol) in 500 mL THF and stirred for 1 hour before filtering to remove triethylamine hydrochloride. The filtrate was concentrated and redissolved in 500 mL dichloromethane along with (±)-4-(1-dodecenyl)-α-phenyl-1H-pyrazole-1-acetic acid (43.43 g, 118 mmol) at -15° C. Dicyclohexylcarbodiimide (25.53 g, 124 mmol) was added in one portion and the resulting suspension was warmed to room temperature and stirred for 16 hours. Filtered to remove a white solid and partitioned the filtrate between dichloromethane and 1N HCl. The organic layer was dried over MgSO4, filtered, and concentrated to give an oily tan solid. Recrystallized from hexanes to give the title compound as a tan solid (45.43 g, 72%); mp 82°-85° C.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12].CCN=C=NCCCN(C)C.Cl.[CH:30]1[CH:31]=[CH:32][C:33]2[N:38](O)[N:37]=[N:36][C:34]=2[CH:35]=1.CN([CH:43]=[O:44])C>C(OCC)(=O)C>[NH2:1][C:2]1[S:10][C:5]2[CH2:6][N:7]([C:43]([C:30]3[CH:31]=[CH:32][C:33]4[NH:38][N:37]=[N:36][C:34]=4[CH:35]=3)=[O:44])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12]
Reactant: CN(C)C=O
Reactant: Nc1sc2c(c1C(=O)N1CCCC1)CCNC2
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1sc2c(c1C(=O)N1CCCC1)CCN(C(=O)c1ccc3[nH]nnc3c1)C2
Temperature: 25 °C
Yield: 10 %

Procedure:
Starting material 12 (1.6 g, 6.4 mmol) was dissolved in 20 ml DMF. Then EDCl (1.46 g, 7.6 mmol) and HOBt (1.3 g, 9.5 mmol) were added. Now, one half of 1.04 g (6.4 mmol) 1H-1,2,3-benzothiazole-5-carboxyllic acid was added. The reaction mixture was stirred at ambient temperature over night. Then the other half of the 1H-1,2,3-benzothiazole-5-carboxyllic acid was added and the reaction mixture was again stirred at ambient temperature over night. The reaction mixture was now concentrated in vacuo yielding 7 g crude product. Those were taken up in ethyl acetate and water and the phases were separated. The organic phase was washed with water and the combined aqueous phases were washed with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The desired product 13 was isolated as a brown oil (1.2 g, 20% content, 10% yield).