Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:4]=1[C:5]#[N:6].[OH2:15].NN>C(O)C.[Ni]>[NH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:3]([N:2]([CH3:14])[CH3:1])[C:4]=1[C:5]([NH2:6])=[O:15]
Reactant: O
Reactant: CN(C)c1cccc([N+](=O)[O-])c1C#N
Agent: [Ni]
Agent: NN
Solvent: CCO
Product: CN(C)c1cccc(N)c1C(N)=O
Temperature: 65 °C

Procedure:
2-Amino-6-dimethylaminobenzamide is prepared by adding a suspension of 2-dimethylamino-6-nitrobenzonitrile and hydrazine hydrate in ethanol to a suspension of Raney nickel in ethanol while maintaining the reaction temperature at about 65° C. The mixture is then heated to reflux for about half an hour, filtered through Celite and evaporated to dryness. The solid product may be recrystallized from ethanol or used neat in the reaction with ethyl oxalyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][C:10]1([CH3:24])[C:15]2[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:14]=2[NH:13][C:12](=[O:23])[O:11]1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:17]2[CH:18]=[CH:19][C:14]3[NH:13][C:12](=[O:23])[O:11][C:10]([CH3:24])([CH3:9])[C:15]=3[CH:16]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(N)nc3)cc21

Procedure:
Prepared according to procedure B from 2-amino-5-bromopyridine and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. White crystals, mp 257-259° C. 1H-NMR (DMSO-d6) δ10.20 (s, 1H), 8.22 (d, 1H, J=2.38 Hz) 7.69, 7.66 (dd, 1H, J=2.5, 2.5 Hz), 7.42 (m, 2H), 6.89 (d, 1H, J=8.8 Hz), 6.49(d, 1H, J=8.64 Hz), 6.02 (s, 2H), 1.64 (s, 6H); MS m/z 269 M+. Anal. Calcd. For C15H5N3O2.17H2O: C, 66.15; H, 5.68; N, 15.43. Found: C, 66.10; H, 5.81; N, 15.02.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[CH2:5]1[CH2:10][CH2:9][CH:8]([CH:11]=[O:12])[CH2:7][CH2:6]1>O1CCCC1>[CH:8]1([CH:11]([OH:12])[CH:1]=[CH2:2])[CH2:9][CH2:10][CH2:5][CH2:6][CH2:7]1
Reactant: C=C[Mg]Br
Reactant: O=CC1CCCCC1
Solvent: C1CCOC1
Product: C=CC(O)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99.1 %

Procedure:
To 140 ml of dry tetrahydrofuran, degassed and flushed with nitrogen (3×) and cooled to 0° C. under nitrogen, was added 1.3M vinyl magnesium bromide (195 ml, 253.5 mmol) in tetrahydrofuran rapidly and dropwise over 5 minutes. The resulting solution was stirred for 5 minutes at 0° C. under nitrogen after which a solution of 24.0 g (223 mmol) of cyclohexylcarboxaldehyde in 40 ml of dry tetrahydrofuran was added via syringe at 0° C. The resulting mixture was stirred for 3.75 hours at 0° to 5° C. under a nitrogen atmosphere after which the reaction was quenched at 0° C. by careful addition of saturated aqueous ammonium chloride. The resulting suspension was poured into 1 L of ice cold, saturated, aqueous ammonium chloride and extracted with three 600 ml portions of ethyl acetate. The ethyl acetate extracts were combined and washed with 1 L of saturated aqueous ammonium chloride, 1 L of saturated aqueous sodium bicarbonate, then twice with 1 L each of brine. The ethyl acetate extract was dried thoroughly over magnesium sulfate, filtered, and concentrated at room temperature via rotovap to give 31.0 g of 1-cyclohexylprop-2-enol.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[N:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O>C(O)(=O)C>[C:13]1([N:11]=[N:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Nc1ccccc1
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: CC(=O)O
Product: O=C(O)c1ccc(N=Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.3 %

Procedure:
9.18 g (0.067 mol) of 4-aminobenzoic acid (Merck, purum) was placed in a 250 mL one-necked round flask with a magnetic stirring bar and 100 mL of glacial acetic acid was added causing a light yellow solution. After 20 minutes 7.21 g (0.067 mol) of nitrosobenzene (Fluka, purum) was added in one portion immediately forming a green solution with particles. Stirring at room temperature was continued for 16 h. The formed metal shining precipitate was filtered off and washed once with 50 mL of cold glacial acetic acid and twice with 100 mL of cold water. The orange precipitate was dissolve in a hot mixture of 200 mL of ethanol and 20 mL of water. After cooling, filtration and 15 h drying under vacuum at 60° C. 10.96 g (72% yield) of [4-(phenylazo)phenyl]-methanoic acid was obtained.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][S:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]([CH3:40])[C:30]4[C:35]([NH:36][CH:37]([CH3:39])[CH3:38])=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)(=[O:10])=[O:9])C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH2:6][CH2:7][S:8]([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]([CH3:40])[C:30]3[C:35]([NH:36][CH:37]([CH3:38])[CH3:39])=[CH:34][CH:33]=[CH:32][N:31]=3)[CH2:25][CH2:24]1)=[O:22])=[CH:15]2)(=[O:9])=[O:10]
Reactant: CC(C)Nc1cccnc1N(C)C1CCN(C(=O)c2cc3cc(NS(=O)(=O)CCN4C(=O)c5ccccc5C4=O)ccc3[nH]2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)Nc1cccnc1N(C)C1CCN(C(=O)c2cc3cc(NS(=O)(=O)CCN)ccc3[nH]2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-[5-(2-phthalimidoethanesulfonamido)indole-2-carbonyl]-4-[N-methyl-N-(3-(1-methylethylamino)-2-pyridinyl)amino]piperidine (EXAMPLE 31, 675 mg) in 95% ethanol (10 ml) under nitrogen is added hydrazine monohydrate (53 μl). The mixture is stirred at 70°-750° for 20 hrs during which additional hydrazine monohydrate (10 μl) is added, concentrated to remove ethanol, diluted with water (10 ml), acidified to pH 2 with 1M hydrochloric acid and stirred for 10 min. The mixture is then filtered, the filtrate is adjusted to pH 10-11, and the resulting precipitate is isolated by filtration to give the title compound, NMR (CDCl3) 9.86, 7.70, 7.56, 7.29, 7.10, 6.94, 6.84, 6.68, 4.60, 4.50, 3.56, 3.44, 3.40-2.80, 2.62, 1.93, 1.65 and 1.22 δ. The b&sic filtrate is extracted with methylene chloride (2×15 ml) which is then washed with saline (10 ml), dried over sodium sulfate, and concentrated under reduced pressure to give an additional amount of the title compound.
Reaction SMILES: C([CH2:4][C:5]1[C:6]([F:19])=[C:7]([C:16]([OH:18])=[O:17])[C:8](=[C:12]([F:15])[C:13]=1[F:14])C(O)=O)(O)=O>CS(C)=O>[CH3:4][C:5]1[C:6]([F:19])=[C:7]([CH:8]=[C:12]([F:15])[C:13]=1[F:14])[C:16]([OH:18])=[O:17]
Reactant: O=C(O)Cc1c(F)c(F)c(C(=O)O)c(C(=O)O)c1F
Solvent: CS(C)=O
Product: Cc1c(F)c(F)cc(C(=O)O)c1F

Procedure:
The thus obtained 4-carboxymethyl-3,5,6-trifluorophthalic acid is heated in dimethyl sulfoxide in the presence of a base to give 3-methyl-2,4,5-trifluorobenzoic acid.
Reaction SMILES: [OH:1][C@@H:2]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])/[CH:3]=[CH:4]/[C@H:5]1[C@H:12]([O:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:28])[O:9]2.[O:36]1[CH:41]=[CH:40][CH2:39][CH2:38][CH2:37]1>C(Cl)Cl>[C:21]1([C:18]2[CH:17]=[CH:16][C:15]([C:14]([O:13][C@@H:12]3[CH2:11][C@H:10]4[C@H:6]([CH2:7][C:8](=[O:28])[O:9]4)[C@H:5]3/[CH:4]=[CH:3]/[C@@H:2]([O:1][CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41][O:36]3)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:27])=[CH:20][CH:19]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C1=COCCC1
Reactant: CCCCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccc(-c2ccccc2)cc1)OC1CCCCO1

Procedure:
The 3S-hydroxy compound (4a) (4.58 g) was dissolved into methylene chloride (100 ml), and reacted with dihydropyran in the presence of a catalytic amount of p-toluenesulfonic acid-1H2O. After a usual work-up, the reaction mixture was column-chromatographed to give the title compound (5). Yield: 5.03 g
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.CN(C)C=O.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([Cl:19])=[O:11]
Reactant: O=C(O)Cc1ccccc1F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccccc1F
Temperature: 22.5 °C
Reaction time: 0.33 h

Procedure:
A solution of 50.0 g of o-fluorophenylacetic acid in 150 mL of toluene and 2.2 g of N,N-dimethylformamide is added to 50.2 g (31.7 mL) of thionyl chloride with efficient stirring over a period of 20 minutes while maintaining an internal temperature of 20-25° C. After addition, the mixture is stirred for 3 hours at 20-25° C., and concentrated to dryness under reduced pressure (66-76 mm Hg, bath temperature 65-70° C.) to obtain 2-fluorobenzenacetyl chloride as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:33]=1>>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)=[CH:22][CH:23]=2)[S:38]([C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)(=[O:40])=[O:39])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3cnccn3)cc2)c1
Agent: Cl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3cnccn3)cc2)S(=O)(=O)c2cccnc2)c1

Procedure:
The title compound of Step B was prepared from {3-[(4-pyrazin-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester of Step A and pyridine-3-sulfonyl chloride hydrochloride, of Preparation 2, following the method described in Example 3, Step B. 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.97 (m, 1H), 8.78 (m, 1H), 8.60 (m, 1H), 8.50 (d, 1H), 8.03 (m, 1H), 7.88 (m, 2H), 7.42 (m, 1H), 7.23 (m, 2H), 7.13 (m, 1H), 6.66 (m, 1H), 6.65 (m, 2H), 4.43 (s, 2H), 4.39 (s, 2H), 4.35 (s, 2H), 1.47 (s, 9H); MS 547 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][Si](C(C)(C)C)(C)C)[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.CC1(C)[C@@]2(CS(O)(=O)=O)C(C[C@@H]1CC2)=O.O>CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][OH:25])[CH2:21][CH2:22]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)cn2)c1=O
Agent: CC1(C)[C@H]2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Solvent: O
Solvent: CO
Product: Cn1cc(Br)cc(Nc2ccc(N3CCN(CCO)CC3)cn2)c1=O
Reaction time: 8 h
Yield: 139.6 %

Procedure:
To a suspension of 123b (300 mg, 0.57 mmol) at room temperature in MeOH (20 mL) was added L(−)-camphorsulfonic acid (199 mg, 0.86 mmol). The reaction mixture was stirred overnight. Water (20 mL) was added and the mixture was extracted with ethyl acetate (50 mL×2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford 123c (325 mg, 95%) as a yellow solid. MS: [M+H]+ 408.7.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([CH:11]=[O:12])=[C:5]1[C:13]([O:15][CH3:16])=[O:14].N12CCCN=C1CCCCC2>O1CCCC1>[CH:11]([C:6]1[C:7]([CH3:10])=[C:8]([CH3:9])[N:4]([CH:3]=[CH2:2])[C:5]=1[C:13]([O:15][CH3:16])=[O:14])=[O:12]
Reactant: COC(=O)c1c(C=O)c(C)c(C)n1CCBr
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: C=Cn1c(C)c(C)c(C=O)c1C(=O)OC
Temperature: 25 °C
Yield: 74.2 %

Procedure:
A solution of 0.15 g (0.00052 mole) of methyl 1-(2-bromoethyl)-3-formyl-4,5-dimethylpyrrole-2-carboxylate and 0.08 g (0.00052 mole) of 1,8-diazabicyclo[5.4.0]undec-7-ene dissolved in 2 ml of tetrahydrofuran was heated under reflux for 6 hours. The reaction mixture was allowed to cool at room temperature and purified by column chromatography through silica gel using a 9:1 mixture of toluene and ethyl acetate as an eluent to give 0.080 g (74% yield) of methyl 3-formyl-4,5-dimethyl-1-vinylpyrrole-2-carboxylate as pale yellow crystals.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:8][CH:7]=1.Cl.[F:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>>[F:25][CH:26]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]3=[O:23])=[CH:8][CH:7]=2)[CH2:27]1
Reactant: FC1CCNC1
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCI)cc1
Agent: Cl
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCCN2CCC(F)C2)cc1

Procedure:
In a manner similar to that described in Example 217, 3-{[4-(3-Iodo-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one and 3-fluoro-pyrrolidine hydrochloride (226 mg, 1.2 equiv.) (prepared by the method of Giardina, G et al, Synlett (1995), (1), 55–7) are converted to the named compound as a slightly brownish yellow solid (258 mg, 45%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22].Cl>CCCCCC.ClCCl.C(COC)OC>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([C:9]2[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:15])=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=2)=[O:29])=[CH:31][CH:32]=1)([O-:23])=[O:22]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Temperature: 60 °C

Procedure:
To a stirred solution of 2,6-di(t-butyl)phenol in 150 ml. of glyme under nitrogen is added 52 ml. of 2.04 M n-butyl lithium in hexane. The reaction causes an exotherm and the product is heated to 60° C. About 20 g. of 4-nitrobenzoyl chloride is added, and the resulting solution is stirred without heating for about 16 hours. The mixture is then acidified with 10 percent hydrochloric acid and washed with dichloromethane, then with 10 percent sodium hydroxide solution and finally with water. The solution is then reacted in ethanol with 50 percent sodium hydroxide solution by heating at reflux for about two hours, mixed with dichloromethane, then washed several times with water. The organic layer is separated, dried and evaporated to provide an orange oil which solidifies in cold hexane. This solid is recrystallized from a benzene-hexane mixture to provide 4-(4-nitrobenzoyl)-2,6-di(t-butyl)phenol, m.p. 178°-179.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:18]3[C:17]=1[C:16](=[O:19])[C:15]1[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:9]=3[CH:8]=[CH:7][CH:6]=2.[Cl-].[Al+3:21].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[Al+3:21].[O-:1][C:2]1[CH:3]=[CH:4][C:5]2[C:18]3[C:17]=1[C:16](=[O:19])[C:15]1[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:9]=3[CH:8]=[CH:7][CH:6]=2.[O-:1][C:2]1[CH:3]=[CH:4][C:5]2[C:18]3[C:17]=1[C:16](=[O:19])[C:15]1[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:9]=3[CH:8]=[CH:7][CH:6]=2.[O-:1][C:2]1[CH:3]=[CH:4][C:5]2[C:18]3[C:17]=1[C:16](=[O:19])[C:15]1[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:9]=3[CH:8]=[CH:7][CH:6]=2
Reactant: O=C1c2ccccc2-c2cccc3ccc(O)c1c23
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2-c2cccc3ccc([O-])c1c23
Temperature: 110 °C

Procedure:
6-Hydroxy benzanthrone (1.0 g) was placed in a 100 mL round-bottom flask. Dry toluene (50 mL) was added to the flask together with aluminum chloride (0.113 g). The solution turned yellow-orange, and a precipitate began to form. The mixture was refluxed at 110° C. overnight. The flask was then cooled and the contents filtered. Crude yield 0.62 g, mp>300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:47]=[CH:46][C:5]([CH2:6][C@@H:7]([NH:32][CH:33]2[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]2)[C:8]([N:10]2[CH:15]3[CH2:16][CH2:17][CH:11]2[CH2:12][CH:13]([N:18]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])[CH2:14]3)=[O:9])=[CH:4][CH:3]=1>Cl.C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:47]=[CH:46][C:5]([CH2:6][C@H:7]([C:8]([N:10]2[CH:15]3[CH2:16][CH2:17][CH:11]2[CH2:12][CH:13]([N:18]([CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[C:19]([N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])=[O:20])[CH2:14]3)=[O:9])[NH:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@@H](Cc1ccc(Cl)cc1)NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOCC
Product: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@@H](Cc1ccc(Cl)cc1)NC1CCNCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 161.2 %

Procedure:
0.37 g of tert-butyl 4-{[(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl[(diethylamino)carbonyl]amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]amino}-piperidine-1-carboxylate is solubilized in 2.74 ml of 2N hydrochloric acid in diethyl ether. The reaction medium is stirred at ambient temperature for 16 h. After evaporation to dryness, the crude is chromatographed on silica gel, elution being carried out with a 95/5/0.5 mixture of dichloromethane, methanol and aqueous ammonia. 0.27 g of N-[8-(4-chloro-N-piperidin-4-yl-D-phenylalanyl)-8-azabicyclo-[3.2.1]oct-3-yl]-N-cyclohexyl-N′,N′-diethylurea hydrochloride is then obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:18][C:19]([OH:21])=O)[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:22][N:23](C)C=O.S(Cl)(Cl)=O.CN>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:18][C:19]([NH:23][CH3:22])=[O:21])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2nc3ccc(Cl)nc3n2CC(=O)O)cc1
Reactant: CN(C)C=O
Agent: CN
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CNC(=O)Cn1c(-c2ccc(C)cc2)nc2ccc(Cl)nc21
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A slurry of 5-chloro-2-(4-methylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (2.8 g, 0.0093 mole) in tetrahydrofuran (11.3 ml) and dimethylformamide (0.68 g, 0.0093 mole) was cooled in an ice bath under nitrogen. Thionyl chloride (1.22 g, 0.0102 mole) was added dropwise to the stirred suspension. After stirring at room temperature for twenty minutes, the solution was cooled again in an ice bath and a solution of methylamine in tetrahydrofuran (21.5 ml of a 2.59M solution, 0.056 mole) was added dropwise. The suspension was stirred at room temperature under nitrogen for one hour and then the solvents were removed under reduced pressure. The residue was triturated in water (100 ml) and the resulting solid was collected by filtration and rinsed three times with water. The solid was dissolved in hot isopropyl alcohol, filtered while hot, and brought to the cloud point with isopropyl ether. Upon cooling, a solid precipitated which was collected by filtration, rinsed with isopropyl ether, and dried under high vacuum at 70° C. to give 1.86 g(64% yield) of title compound, mp >250° C.
Reaction SMILES: [CH2:1]([C:3]1[NH:12][C:6]2=[CH:7][N:8]=[C:9](Cl)[CH:10]=[C:5]2[CH:4]=1)[CH3:2].[NH3:13].O>CCO>[CH2:1]([C:3]1[NH:12][C:6]2=[CH:7][N:8]=[C:9]([NH2:13])[CH:10]=[C:5]2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2cc(Cl)ncc2[nH]1
Reactant: N
Solvent: O
Solvent: CCO
Product: CCc1cc2cc(N)ncc2[nH]1
Temperature: 200 °C
Reaction time: 10 h
Yield: 16 %

Procedure:
A suspension of 2-ethyl-5-chloro-1H-pyrrolo[2,3-c]pyridine (1.3 g, 7.19 mmol) in EtOH (20 mL), CuSO4.5H2O (179 mg, 0.72 mmol) and NH3—H2O (60 ml) was added into an autoclave (100 mL). The reaction was stirred at 200° C. and 2 MPa for 10 h. The reaction was cooled to 25° C. and was quenched with water and extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 10/1) to give 2-ethyl-1H-pyrrolo[2,3-c]pyridin-5-amine (190 mg, 16%). 1H-NMR (CDCl3, 300 MHz) δ 10.71 (brs, H), 8.00 (s, 1H), 6.39 (s, 1H), 5.87 (s, 1H), 4.89 (br s, 2H), 2.65 (q, J=7.5 Hz, 2H), 1.22 (t, J=7.5 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:37]=[C:38]([Cl:40])[CH:39]=1)[O:28][C:29]1[O:33][C:32]([C:34](Cl)=[O:35])=[CH:31][CH:30]=1>C1COCC1.C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([CH:37]=[C:38]([Cl:40])[CH:39]=1)[O:28][C:29]1[O:33][C:32]([C:34]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:13]=3)[CH2:10][CH2:11]2)=[O:35])=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccc(Oc2cc(Cl)cc(Cl)c2)o1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN)CC2)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCNC(=O)c3ccc(Oc4cc(Cl)cc(Cl)c4)o3)CC2)c1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-{3-[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 5-(3,5-dichlorophenoxy)-2-furoyl chloride: ESMS m/e: 572.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[F:23])[C:16]([O:18]C)=O)(=[O:11])=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:34][C:35]1[N:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=1>C1COCC1>[Cl:34][C:35]1[N:40]=[C:39]([CH2:41][C:16]([C:15]2[CH:20]=[CH:21][C:22]([F:23])=[C:13]([NH:12][S:9]([C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])(=[O:10])=[O:11])[CH:14]=2)=[O:18])[CH:38]=[CH:37][N:36]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: COC(=O)c1ccc(F)c(NS(=O)(=O)c2cc(F)ccc2F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1ccnc(Cl)n1)c1ccc(F)c(NS(=O)(=O)c2cc(F)ccc2F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a solution of methyl 3-(2,5-difluorophenylsulfonamido)-4-fluorobenzoate (40 g, 116 mmol) in dry THF (500 mL) at −10° C., LiHMDS (1M in THF, 406 mmol, 406 mL) was added dropwise and the solution was allowed to stir for 1 h at 0° C. A solution of 2-chloro-4-methylpyrimidine (17.8 g, 139 mmol) in THF (50 mL) was then added dropwise to the solution of ester and base at 0° C. over 20 min. The solution was allowed to stir 1 h at rt. TLC showed the reaction was complete. The reaction was quenched by addition of the saturated aqueous NH4Cl (300 mL) at 0° C. The reaction mixture was extracted with EtOAc (500 mL×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash column on silica gel, eluting with DCM. This solution was evaporated to obtain a solid. The orange solid was triturated with a small amount of EtOAc and filtered, rinsing with diethyl ether to give the title compound of Step B (31 g, 60.8% yield). 1H NMR (400 MHz, CDCl3) δ ppm 13.72-13.77 (br, 1H), 8.57-8.61 (m, 0.4H), 8.38-8.42 (m, 1H), 8.13-8.19 (m, 0.4H), 7.97-8.02 (m, 1H), 7.78-7.82 (m, 0.4H), 7.57-7.63 (m, 1H), 7.52-7.57 (1.4H), 7.02-7.30 (m, 4.2H), 6.91-6.93 (m, 1H), 5.93 (s, 1H), 4.40 (s, 1H). MS (ES+): 442 [M+H]+.