Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3]N(C)C=O.[OH:8][C:9]1[CH:10]=[C:11]([C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:12]=[CH:13][C:14]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CI>O>[CH3:3][O:8][C:9]1[CH:10]=[C:11]([C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:12]=[CH:13][C:14]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(OC)c1
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 0.01 moles of sodium hydride in 25 ml. of dry dimethylformamide which has been cooled to 0° C. is added dropwise a solution of 0.01 moles of ethyl 3-hydroxy-4-cyclohexylphenylglyoxylate in 10 ml. of dimethylformamide. The reaction mixture is stirred for 15 minutes and 0.015 moles of methyliodide is then added dropwise. The mixture is allowed to stir overnight at room temperature. 200 ml. of water is added and the resulting mixture is extracted well with ether. The ether extract is washed with water, dried over sodium sulfate, evaporated to dryness and distilled to obtain ethyl 3-methoxy-4-cyclohexylphenylglyoxylate.
Reaction SMILES: O[CH:2]1[CH2:6][N:5]([CH3:7])[C:4](=[O:8])[C:3]1([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.S(Cl)(Cl)=O.N1C=CC=CC=1.[CH:31](Cl)(Cl)[Cl:32]>>[Cl:32][CH2:31][CH:2]1[CH2:6][N:5]([CH3:7])[C:4](=[O:8])[C:3]1([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClC(Cl)Cl
Reactant: CN1CC(O)C(c2ccccc2)(c2ccccc2)C1=O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CN1CC(CCl)C(c2ccccc2)(c2ccccc2)C1=O
Yield: 59 %

Procedure:
To 25.0 g. (0.09 mole) of 4-hydroxy-1-methyl-3,3-diphenyl-2-pyrrolidinone, in 200 ml. of chloroform was added 21.4 g. (0.18 mole) of thionyl chloride. With stirring and ice bath cooling, 18.0 g. (0.23 mole) of pyridine was added dropwise. The solution was refluxed for two hours. After concentrating in vacuo, the residue was dissolved in chloroform and washed successively with dilute hydrochloric acid solution and dilute sodium hydroxide. The chloroform solution was dried, filtered, and concentrated in vacuo. The solid residue was recrystallized from a 50:50 ethyl acetate-isopropyl ether mixture. It weighed 16.0 g. (59% yield) and melted at 120°-122° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][C:5]2[N:10]=[C:9]([C:11]3[N:15]4[CH:16]=[CH:17][N:18]=[C:19]([N:20]5[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]5)[C:14]4=[N:13][CH:12]=3)[CH:8]=[CH:7][N:6]=2)=[CH:30][CH:29]=1
Reactant: CN1CCN(c2nccn3c(-c4ccnc(S(C)(=O)=O)n4)cnc23)CC1
Reactant: NCc1ccc(Cl)cc1
Product: CN1CCN(c2nccn3c(-c4ccnc(NCc5ccc(Cl)cc5)n4)cnc23)CC1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of 3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 46 supra) (150 mg, 0.402 mmol) and 4-chlorobenzylamine (228 mg, 1.608 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200˜300 mesh, eluting with dichloromethane:methanol, 30:1˜10:1) to afford the crude product (100 mg). The crude product was purified by prep-HPLC. Several drops of concentrated HCl were added to the fractions with product. After sonicating for several minutes, solution was concentrated under reduced pressure to afford (4-chloro-benzyl)-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine; hydrochloride. (Yield 38 mg, 21.8%). 1H NMR (300 MHz, CDCl3): δ 8.68 (s, 1H), 8.28 (s, 1H), 7.53 (d, 1H, J=6.9 Hz), 7.38-7.29 (m, 6H), 5.48-5.43 (m, 2H), 4.76 (brs, 2H), 3.68-3.61 (m, 4H), 3.34-3.27 (m, 4H), 2.89 (s, 3H). LC-MS: [M+H]+ 435.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](S)[O:8][C:4]=2[CH:3]=1.[K].[Cl:13]Cl>ClC1C=CC=CC=1>[Cl:13][C:7]1[O:8][C:4]2[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: Sc1nc2ccc(Cl)cc2o1
Reactant: ClCl
Agent: [K]
Solvent: Clc1ccccc1
Product: Clc1ccc2nc(Cl)oc2c1
Reaction time: 12 h
Yield: 91 %

Procedure:
223.5 g (1 mole) of potassium 6-chloro-2-mercaptobenzoxazole are suspended in 500 ml of chlorobenzene and 180 g (2.5 moles) of chlorine gas are added in the course of 3 hours at a temperature of approx. 25° C. Stirring is continued for 12 hours at room temperature and excess chlorine is blown out of the mixture by means of nitrogen. The precipitated potassium chloride is filtered off and rinsed with approx. 200 ml of chlorobenzene. The filtrate is then distilled. When the sulfur dichloride and chlorobenzene have been distilled off, 171 g (91% of theory) of 2,6-dichlorobenzoxazole are obtained, having a melting point of 49°-51° C. and a boiling point of 124°-128.5° C. under approx. 25 mbars.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>CCOCC>[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1
Reactant: C1=COCCC1
Reactant: CCOC(=O)C=Cc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCOC(=O)C=Cc1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 30 ml of anhydrous ether solution containing 5 g of ethyl 4-hydroxycinnamate was added 7.1 ml of dihydropyran and 50 mg of p-toluenesulfonic acid were added, the mixture was stirred at a room temperature for 2 hours, the reaction mixture was neutralized with 1%-sodium hydroxide solution, washed with water, and dried with anhydrous sodium sulfate. The solvent was removed by evaporation to yield 6.8 of ethyl 4-(2-tetrahydropyranyloxy)cinnamate. Colorless indefinite form crystals. Melting point: 52°-53° C.
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[CH:8]=[C:9]3[C:14](=[C:15]4[CH:20]=[CH:19][N:18]=[CH:17][C:16]=24)[N:13]=[CH:12][N:11]([C@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]2[OH:27])[C:10]3=[O:28])=[CH:4][CH:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:27][C@H:22]1[CH2:23][CH2:24][CH2:25][CH2:26][C@@H:21]1[N:11]1[C:10](=[O:28])[C:9]2[C:14](=[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]3=[C:7]([CH2:6][C:5]3[CH:29]=[CH:30][C:2]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[CH:3][CH:4]=3)[CH:8]=2)[N:13]=[CH:12]1
Reactant: O=c1c2cc(Cc3ccc(Br)cc3)c3cnccc3c2ncn1[C@H]1CCCC[C@@H]1O
Reactant: C1COCCN1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=c1c2cc(Cc3ccc(N4CCOCC4)cc3)c3cnccc3c2ncn1[C@H]1CCCC[C@@H]1O
Temperature: 100 °C

Procedure:
To a solution of 6-(4-bromobenzyl)-3-[(1S,2S)-2-hydroxycyclohexyl]pyrido[3,4-h]quinazolin-4(3H)-one (0.050 g, 0.11 mmol) in 1 mL of toluene under an atmosphere of nitrogen was added morpholine (0.038 g, 0.43 mmol), bis(tri-tert-butylphosphine)palladium(0) (2.8 mg, 0.0054 mmol), and potassium tert-butoxide (0.030 g, 0.27 mmol). The mixture was heated to 100° C. for 18 h, cooled to rt, and diluted with ethyl acetate. The organic solution was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 471.0 for [M+H]+: 1H NMR (400 MHz, d6-DMSO) δ 9.70 (s, 1H), 9.20 (d, J=6.1 Hz, 1H), 8.77 (d, J=6.2 Hz, 1H), 8.65 (s, 1H), 8.28 (s, 1H), 7.22 (d, J=8.6 Hz, 2H), 7.02 (d, J=8.6 Hz, 2H), 4.64 (s, 2H), 4.22 (br s, 1H), 3.84 (t, J=4.8 Hz, 4H), 3.18 (t, J=4.6 Hz, 4H), 2.20 (br s, 1H), 2.03-1.87 (m, 1H), 1.87-1.72 (m, 4H), 1.56-1.47 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=O.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][N:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]1
Reactant: CN1CCNCC1
Reactant: O=Cc1cc(F)cc(Br)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCN(Cc2cc(F)cc(Br)c2)CC1
Reaction time: 1 h
Yield: 51 %

Procedure:
A solution of 3-bromo-5-fluorobenzaldehyde (CI) (2.12 g, 10.42 mmol) in MeOH (200 mL) was added 1-methylpiperazine (2.3 mL, 20.84 mL). The pH was adjusted to 6 using HOAc and stirred for 1 h. NaCNBH3 (917 mg, 14.59 mmol) was added and stirred at room temperature overnight. The MeOH was removed under vacuum and the residue was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and evaporated under vacuum. The crude product was purified on a silica gel column (100% CHCl3→3:97 MeOH[7N NH3]:CHCl3) to produce 1-(3-bromo-5-fluorobenzyl)-4-methylpiperazine (CII) as a yellow oil (1.52 g, 5.29 mmol, 51% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.14 (s, 3H), 2.28-2.40 (m, 8H), 3.46 (s, 2H), 7.15-7.17 (m, 1H), 7.35 (s, 1H), 7.40-7.42 (m, 1H); ESIMS found C12H16BrFN2 m/z 287 (M+H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:2]1.Br[CH2:17][CH2:18][C:19]1[CH:28]=[CH:27][C:22]2[NH:23][C:24](=[O:26])[O:25][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C(C)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:17][CH2:18][C:19]3[CH:28]=[CH:27][C:22]4[NH:23][C:24](=[O:26])[O:25][C:21]=4[CH:20]=3)[CH2:14][CH2:15]2)=[N:2]1
Reactant: O=c1[nH]c2ccc(CCBr)cc2o1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccc(CCN3CCN(c4nsc5ccccc45)CC3)cc2o1

Procedure:
To a 125 ml round-bottomed flask equipped with condenser were added 4.82 grams (0.022 mol) of N-(3-benzisothiazolyl)piperazine (prepared according to the procedure given in U.S. Pat. No. 4,411,901), 5.32 grams (0.022 mol) of 6-(2-bromoethyl)benzoxazolone, 2.33 grams (0.022 mol) of sodium carbonate, and 50 ml of methyl isobutyl ketone. The mixture was refluxed for 18 hours. The reaction was cooled and partitioned between ethyl acetate and water. The ethyl acetate layer was isolated, washed with water and saturated aqueous sodium chloride solution dried over sodium sulfate, and evaporated to an oil. The oil was chromatographed on silica gel using ethyl acetate as eluent, and the product fractions collected, concentrated to dryness and triturated with methylene chloride/isopropyl ether to give a white solid, 1 m.p. 185°-187° C. NMR (δ, CDCl3): 1.7 (bs, 1H), 2.8 (m, 8H), 3.6 (m, 4H), 6.9-8.0 (m, 7H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)=[C:20]([C:38]([F:41])([F:40])[F:39])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:43]>C(O)C>[ClH:43].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)=[C:20]([C:38]([F:39])([F:40])[F:41])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3cccc4ccccc34)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2cccc3ccccc23)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
Compound 73-3 (620 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (490 mg) as a white powder.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH3:34])[C:23](O)=[O:24]>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]([N:29]3[CH:33]=[CH:32][N:31]=[C:30]3[CH3:34])=[C:20]([F:19])[CH:21]=2)[CH2:2][CH2:3]1
Reactant: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1
Reactant: Cc1nccn1-c1ccc(C(=O)O)cc1F
Product: Cc1nccn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3nc(C(C)C)no3)CC2)cc1F

Procedure:
The title compound is prepared from cyclopropyl-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine and 3-fluoro-4-(2-methyl-imidazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 90. LC (method 19): tR=3.98 min; Mass spectrum (ESI+): m/z=453 [M+H]+.
Reaction SMILES: Br.Br.[NH2:3][C:4]1[C:8]([NH2:9])=[CH:7][S:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[Cl:19][C:20]1[S:21][CH:22]=[C:23]([CH3:28])[C:24]=1[N:25]=[C:26]=[S:27]>C1COCC1>[NH2:9][C:8]1[C:4]([NH:3][C:26]([NH:25][C:24]2[C:23]([CH3:28])=[CH:22][S:21][C:20]=2[Cl:19])=[S:27])=[CH:5][S:6][CH:7]=1
Reactant: Cc1csc(Cl)c1N=C=S
Reactant: Nc1cscc1N
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1csc(Cl)c1NC(=S)Nc1cscc1N
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
0.55 g of 3,4-diaminothiophene dihydrobromide was added to a solution of 0.51 g of N-ethyl-N,N-diisopropylamine in 30 ml of anhydrous THF, the mixture was stirred at room temperature for approx. 5 minutes and the solution was then admixed with a mixture of 0.4 g of 2-chloro-4-methyl-3-thienyl isothiocyanate in 5 ml of THF. The mixture was stirred at room temperature for 3 hours and at 40° C. for 10 minutes. After it had been left to stand overnight, the solvent was distilled off, and the residue was treated with water and extracted with ethyl acetate. The insoluble fraction was filtered off, and the organic phase was washed with water and dried over sodium sulfate. After the solvent had been distilled off, the product was purified by column chromatography on silica gel using a mixture of 1 part by volume of toluene and 1 part by volume of ethyl acetate and, after the solvent had been distilled off, the N-(4-amino-3-thienyl)-N′-(2-chloro-4-methylthienyl)thiourea was obtained as a crystalline solid.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16]OS(C)(=O)=O)[CH2:10][C@H:9]1[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:7].[NH:41]1[CH2:46][CH2:45][C:44]2([C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[CH2:48][CH2:47]2)[CH2:43][CH2:42]1>C(#N)C>[F:36][C:35]([F:38])([F:37])[C:33]1[CH:32]=[C:5]([CH:4]=[C:3]([C:2]([F:39])([F:1])[F:40])[CH:34]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:41]2[CH2:46][CH2:45][C:44]3([C:54]4[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=4)[CH2:48][CH2:47]3)[CH2:43][CH2:42]2)[CH2:10][C@H:9]1[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:7]
Reactant: c1ccc2c(c1)CCC21CCNCC1
Reactant: CS(=O)(=O)OCCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Solvent: CC#N
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCCN2CCC3(CCc4ccccc43)CC2)C[C@H]1Cc1c[nH]c2ccccc12
Yield: 90.1 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (200 mg) and spiro[indan-1,4'-piperidine] (70 mg) in acetonitrile (3 ml) was refluxed for 1.5 hours. The reaction mixture was evaporated under reduced pressure and then the residue was purified by column chromatography on silica gel using dichloromethane-methanol (10:1) as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[3-(spiro[indan-1,4'-piperidine]-1'-yl)propyl]-2-(1H-indol-3-ylmethyl)piperazine (208 mg) as a powder.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[N:12](OC(C)(C)C)=[O:13].Cl>O1CCCC1>[C:6]1([C:1](=[O:5])[C:2](=[N:12][OH:13])[CH2:3][CH3:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)ON=O
Reactant: CCCC(=O)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CCC(=NO)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
To a stirred solution of the butyrophenone (300 mg, 2.0 mmol) in tetrahydrofuran (8 mL) was added t-butyl nitrite (0.475 mL, 4.0 mmol) and hydrochloric acid (4N in dioxane, 0.65 mL, 2.6 mmol). The reaction was stirred at RT for 3 hours, then the solvent was evaporated and the residue was purified by Prep HPLC (ammonium acetate/water/acetonitrile) to give the title material (0.200 g, 56%). HPLC 91% (220 nm), LCMS (+ESI, M+H+) m/z 178; 1H NMR (400 MHz, methanol-d4) δ (ppm): 1.13 (3H, t, J=7.6 Hz), 2.71 (2H, qa, J=7.6 Hz), 7.45 (2H, br t), 7.57 (1H, br t), 7.90 (2H, d, J=7.0 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@H:9]1[C:14]1[NH:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28](B4OC(C)(C)C(C)(C)O4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:41]1[CH:67]=[CH:66][C:44]2[NH:45][C:46]([C@@H:48]3[CH2:52][C@H:51]([CH3:53])[CH2:50][N:49]3[C:54]([CH:56]([N:60]([CH3:65])[C:61](=[O:64])[O:62][CH3:63])[CH:57]([CH3:59])[CH3:58])=[O:55])=[N:47][C:43]=2[CH:42]=1.C(Cl)Cl.C([O-])(O)=O.[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH3:13])[CH2:10][CH:9]1[C:14]1[NH:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:41]4[CH:67]=[CH:66][C:44]5[NH:45][C:46]([C@@H:48]6[CH2:52][C@H:51]([CH3:53])[CH2:50][N:49]6[C:54](=[O:55])[C@@H:56]([N:60]([C:61]([O:62][CH3:63])=[O:64])[CH3:65])[CH:57]([CH3:59])[CH3:58])=[N:47][C:43]=5[CH:42]=4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[N:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)N(C)C(C(=O)N1C[C@@H](C)C[C@H]1c1nc2cc(I)ccc2[nH]1)C(C)C
Reactant: C[C@H]1C[C@@H](c2nc(-c3ccc(-c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)N(C)[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2cc(-c3ccc(-c4ccc(-c5c[nH]c(C6CC(C)CN6C(=O)OC(C)(C)C)n5)cc4)cc3)ccc2[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 18 h
Yield: 37.3 %

Procedure:
To a suspension of (2S,4S)-4-methyl-2{-4-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (211 mg, 0.3985 mmol), methyl N-[1-[(2S,4S)-2-(5-iodo-1H-benzimidazol-2-yl)-4-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl]-N-methyl-carbamate (198.6 mg, 0.3985 mmol), Pd(DPPF)(Cl)2.CH2Cl2 (32.54 mg, 0.03985 mmol) in 2-propnaol (2.1 mL) is added 1M aqueous NaHCO3 (2 mL, 2 mmol). The reaction mixture is stirred at 80° C. for 18 hours, cooled to RT, filtered on a bed of Celite and concentrated to dryness. The residue is purified by flash column chromatography on silica gel (12 to 100% EtOAc in hexanes) to give 2S,4S)-2-{4-[4′-(2-{(2S,4S)-1-[(S)-2-(methoxycarbonyl-methyl-amino)-3-methyl-butyryl]-4-methyl-pyrrolidin-2-yl}-1H-benzoimidazol-5-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (115 mg, 37%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][N:25]=1>C1(C)C=CC=CC=1.CN(C=O)C>[OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][N:25]=2)=[CH:14][CH:15]=1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: Oc1ccc(CCNC2CCCC2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc(CCN[C@@H]3CCC[C@H]3O)cc2)nc1
Yield: 18.2 %

Procedure:
Heat a mixture of 4-[2-(2-hydroxycyclopentylamino)ethyl]phenol (210.5 mg, 0.95 mmol), K2CO3 (395 mg, 2.85 mmol) and 6-chloronicotinamide (223.4 mg, 1.43 mmol) in 1:3 toluene/DMF (6 mL) at 165° C. for 2 hours, while removing H2O azeotropically with toluene. Remove DMF azeotropically with xylenes and take up the residue in H2O (50 mL) and 10% MeOH in CH2Cl2 (50 mL). Shake and separate the layers. Extract the aqueous layer with 10% MeOH in CH2Cl2 (2× 50 mL) and 10% MeOH in EtOAc (50 mL). Combine the organic layers, dry over MgSO4 and concentrate. Concentrate the aqueous layer, which still contains the product by TLC, to dryness and extract the product out with MeOH. Dry the solution with Na2SO4, filter and combine with the organic concentrate above. Concentrate, re-dissolve in MeOH and filter through a Na2SO4 pad. Concentrate and purify by flash chromatography, eluting with 10:15:75 2.0 M NH3 in MeOH/CH2CL2/EtOAc to afford the title compound (137.4 mg) along with the (cis)-isomer of the starting phenol (59.0 mg) recovered: MS ES+ 342.0 (M+H)+, HRMS calcd for C19H24N3O3 342.1818 (M+H)+, found 342.1812, time 0.34 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 5-95% over 19 min], tR=16.76 min, 100% purity; Anal. Calcd for C19H23N3O3.0.1CH2Cl2 0.1EtOAc: C, 65.29; H, 6.74; N, 11.71. Found: C, 65.35; H, 6.61; N, 11.98.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Sn]([N:26]=[N+:27]=[N-:28])(C)C>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[N:26]=[N:27][NH:28][N:21]=3)=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)cc2)CC1
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nn[nH]n3)cc2)CC1
Temperature: 110 °C
Reaction time: 24 h
Yield: 83.7 %

Procedure:
The intermediate 1A (6.0 g; 20.8 mmol) in solution in xylene (76 ml), under nitrogen, is treated with trimethyltin azide (6.25 g; 31.3 mmol). After stirring for 24 h at 110° C., the reaction medium is brought to room temperature and the precipitate formed is filtered on sintered glass and then washed with toluene and with petroleum ether. This solid is purified by chromatography on a silica gel column eluted with a dichloromethane/methanol/ammonium hydroxide mixture in the proportions 80/19/1 to give compound 1B (5.75 g; 87%) in the form of a white solid.
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[C:14]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=4)[CH:16]=3)=[CH:13][N:12]=[C:11]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[N:10]=2)=CC=1.F[C:39](F)(F)[C:40](O)=O>C(Cl)Cl>[OH:8][C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH2:39][CH3:40])=[O:25])=[CH:22][CH:21]=3)[CH:16]=2)=[CH:13][N:12]=[C:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-c2cc(-c3cnc(-c4ccccn4)nc3OCc3ccc(OC)cc3)on2)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-c2cc(-c3cnc(-c4ccccn4)nc3O)on2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 37-k (300 mg, 0.61 mmol) in DCM (5 mL) was added trifluoroactic acid (2.5 mL) dropwise. The mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness to give compound 37-m, which was used in the next step without further purification.