Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:61][CH:62]=[CH:63][C:64]1[CH:69]=[CH:68][C:67]([O:70][CH3:71])=[CH:66][CH:65]=1.FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:61][CH:62]=[CH:63][C:64]3[CH:65]=[CH:66][C:67]([O:70][CH3:71])=[CH:68][CH:69]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: COc1ccc(C=CCOC(=N)C(Cl)(Cl)Cl)cc1
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccc(OC)cc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg in 6 ml 33% methylene chloride in cyclohexane), p-methoxycinnamyl trichloroacetimidate (117 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (3 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 20 minutes the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×20 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (16 mg).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[OH:27][CH2:28][CH2:29][C:30](O)=[O:31]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:28](=[O:27])[CH2:29][CH2:30][OH:31])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)CCO
Agent: Cl
Product: O=C(CCO)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (31 mg, 31%), MS (ISP) m/z=401.5 [(M+H)+], mp 158° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 3-hydroxy-propionic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7]=[O:8].C(N(CC)CC)C.[N+:16]([CH3:19])([O-:18])=[O:17]>>[N+:16]([CH2:19][CH:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)[OH:8])([O-:18])=[O:17]
Reactant: O=Cc1cnccn1
Reactant: C[N+](=O)[O-]
Solvent: CCN(CC)CC
Product: O=[N+]([O-])CC(O)c1cnccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To a round bottom flask was added 2-pyrazinecarboxaldehyde (770 mg, 7.12 mmol) in 10 mL of nitromethane, followed by the addition of triethylamine (721 mg, 7.12 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo. The residue was loaded onto a flash chromatography column. The column was eluted with 0–5% MeOH/CH2Cl2. The product fractions were collected and concentrated to afford 1124 mg (93.3%) of 2-nitro-1-pyrazin-2-yl-ethanol. (TLC: Rf=0.2, 5% MeOH/CH2Cl2, UV).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].CC([O-])(C)C.[K+].[CH3:30][O:31][C:32](=[O:35])[CH2:33]Br.O>C1COCC1>[CH3:30][O:31][C:32](=[O:35])[CH2:33][N:19]1[CH:20]=[CH:21][C:16]([C:10]([OH:15])([C:11]([F:14])([F:13])[F:12])[CH:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH3:23])=[CH:17][C:18]1=[O:22]
Reactant: COC(=O)CBr
Reactant: CC(c1ccc(Cl)cc1Cl)C(O)(c1cc[nH]c(=O)c1)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)Cn1ccc(C(O)(C(C)c2ccc(Cl)cc2Cl)C(F)(F)F)cc1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-[2-(2,4-Dichloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1H-pyridin-2-one (Example 119, 100 mg) was dissolved in THF (10 mL), and treated with t-BuOK (34 mg). After 5 minutes stirring, bromo-acetic acid methyl ester (0.03 mL) was added and the reaction mixture was stirred at 55° C. for 17 h. The reaction mixture was then cooled down to r.t., poured into water (50 mL) and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (10 g silica gel, ethyl acetate/heptane 30:70) to give the title compound as colorless waxy solid (49 mg). MS (m/e)=438.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[Cl:21])[C:6]([CH:12]=[O:13])=[N:7]2.[CH2:22]1COCC1.C[Mg]Br.C(OCC)C>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[Cl:21])[C:6]([CH:12]([OH:13])[CH3:22])=[N:7]2
Reactant: C1CCOC1
Reactant: O=Cc1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(O)c1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a stirring hetereogeneous mixture of 5-chloro-3-(2-chloro-5-fluorophenyl)-quinoxaline-2-carbaldehyde (0.1650 g, 0.514 mmol) in THF (5.00 mL, 0.514 mmol) was added methylmagnesium bromide 3 M in diethyl ether (0.257 mL, 0.771 mmol) dropwise at 0° C., and the mixture was then allowed to warm to room temperature and stirred at room temperature. After 5.5 h, the reaction was quenched with NH4Cl (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with water (50 mL×1), brine (50 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 14 min and then 50% isocratic of EtOAc for 10 min as eluent to give 1-(5-chloro-3-(2-chloro-5-fluorophenyl)quinoxalin-2-yl)ethanol as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.17 (1 H, dd, J=8.4, 1.4 Hz), 8.09 (1 H, dd, J=7.8, 1.2 Hz), 7.88-7.96 (1 H, m), 7.72 (1 H, dd, J=9.0, 5.1 Hz), 7.61 (1 H, br. s.), 7.44-7.53 (1 H, m), 5.36 (1 H, d, J=6.3 Hz), 4.83 (1 H, br. s.), 1.49 (3 H, br. s.); LC-MS (ESI) m/z 337.0 [M+H]+.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[C:28]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)#[N:29]>>[C:28]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:8]4[C:7]5[CH2:6][CH2:5][O:4][C:12]=5[CH:11]=[CH:10][N:9]=4)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:35])=[CH:32][CH:31]=1)#[N:29]
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: Cl
Product: N#Cc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4CCO5)CC3)CC2)cc1

Procedure:
The title compound, off-white solid (110 mg, 96%), MS (ISP) m/z=460.5 [(M+H)+], mp 243.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 4-cyano-benzoic acid.
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[O:11][C:12]([CH2:15][NH:16][C:17]([NH:21][CH3:22])=[N:18][C:19]#[N:20])=[CH:13][CH:14]=2)[N:9]=1)[NH2:3].[ClH:23].C[OH:25]>>[ClH:23].[ClH:23].[NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[O:11][C:12]([CH2:15][NH:16][C:17]([NH:21][CH3:22])=[N:18][C:19](=[O:25])[NH2:20])=[CH:13][CH:14]=2)[N:9]=1)[NH2:3]
Reactant: CNC(=NC#N)NCc1ccc(-c2csc(N=C(N)N)n2)o1
Reactant: CO
Agent: Cl
Product: CNC(=NC(N)=O)NCc1ccc(-c2csc(N=C(N)N)n2)o1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture of 2-(diaminomethyleneamino)-4-[5-(2-cyano-3-methylguanidino)methylfuran-2-yl]thiazole (2.28 g) and 4M-dioxanic hydrogen chloride (10 ml) in methanol (20 ml) was stirred at ambient temperature for 19 hours and further at 50° C. for 5 hours. The resulting precipitate was collected by filtration, washed with methanol, and recrystallized from a mixture of methanol and water to afford 2-(diaminomethyleneamino)-4-[5-(2-carbamoyl-3-methylguanidino)methylfuran-2-yl]thiazole dihydrochloride (1.65 g).
Reaction SMILES: [C:1](Cl)(=O)[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:16][CH:15]=[CH:14][CH:13]=2.Cl.N1C=CC=CC=1>ClCCl>[CH2:2]([C:1]1[N:19]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Cl
Reactant: CCOC(=O)CCCNc1c(N)cnc2cccnc12
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1nc2cnc3cccnc3c2n1CCCC(=O)OCC
Reaction time: 1 h
Yield: 88.3 %

Procedure:
Valeryl chloride (1.8 mL, 15.3 mmol, 1.1 eq) was added dropwise to a solution of ethyl 4-[(3-amino[1,5]naphthyridin-4-yl)amino]butyrate (3.8 g, 13.9 mmol, 1 eq) in dichloromethane (55 mL) and stirred for one hour. The reaction mixture was concentrated under reduced pressure and was dissolved in pyridine (55 mL). Pyridine hydrochloride (0.16 g, 1.39 mmol, 0.1 eq) was added and the reaction mixture was heated to reflux for 18 hours. The reaction mixture was concentrated under reduced pressure and diluted with dichloromethane (100 mL) and saturated aqueous sodium bicarbonate (75 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2×30 mL). The combined organics were dried over magnesium sulfate, stirred over decolorizing charcoal, filtered through CELITE filter aid, concentrated under reduced pressure, and dried at 35° C. under high vacuum to afford 4.18 g of ethyl 4-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyrate as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.[N:21](OC(C)(C)C)=[O:22].Cl>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8](=[N:21][OH:22])[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)ON=O
Reactant: O=C(Cc1ccnc(F)c1)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Product: O=C(C(=NO)c1ccnc(F)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To a mixture of 2-(2-fluoropyridin-4-yl)-1-(3-trifluoromethylphenyl)ethanone (10.80 g, 0.038 mol) in ethanol (200 mL), at −10° C., under argon, was added tert-butyl nitrite (5.0 mL, 0.042 mol) and hydrogen chloride (12.2 mL, 2.5M in ethanol, 0.031 mol) dropwise while maintaining the temperature below −5° C. Upon completion of addition, the reaction was allowed to warm to RT for 2 hrs. The reaction mixture was then concentrated in vacuo, diluted with water (100 mL), basified with saturated sodium bicarbonate (200 ml), and extracted with ethyl acetate (3×400 mL). The combined organic layers were washed with water (300 mL), dried with brine (300 mL) and anhydrous sodium sulfate, filtered and concentrated to yield 11.4 g of the title compound, as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[NH:8][C:9]1[C:13](OCC)=[N:12][S:11](=[O:18])(=[O:17])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[CH3:31][C:32]1[CH:33]=[C:34]([NH:38][C:39]([NH:41][CH2:42][CH2:43][NH2:44])=[O:40])[CH:35]=[CH:36][CH:37]=1.C(N(CC)CC)C>C(O)C>[C:1]([O:5][C:6](=[O:27])[C@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[NH:8][C:9]1[C:13]([NH:44][CH2:43][CH2:42][NH:41][C:39]([NH:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([CH3:31])[CH:33]=2)=[O:40])=[N:12][S:11](=[O:17])(=[O:18])[N:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cccc(NC(=O)NCCN)c1
Reactant: CCOC1=NS(=O)(=O)N=C1N[C@@H](Cc1ccc(O)cc1)C(=O)OC(C)(C)C
Agent: O=C[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cccc(NC(=O)NCCNC2=NS(=O)(=O)N=C2N[C@@H](Cc2ccc(O)cc2)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a solution of N-(4-ethoxy-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-tyrosine tert-butyl ester from Step A (150 mg, 0.38 mmol) and the formate salt of 2-(3-methylphenylaminocarbonylamino)eth-1-ylamine from Step B (210 mg, 0.89 mmol) in ethanol (10 mL) was added triethylamine (133 mg, 1.44 mmol). The reaction was stirred at room temperature overnight. Solvent was removed under reduced pressure and the residue purified by flash column chromatography (silica, 5% MeOH in EtOAc)to give the title compound (130 mg, 91%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH2:17][CH2:18][CH3:19].[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[CH2:16]([O:15][C@H:3]1[C@@H:2]([NH:1][C:28]([C:23]2[NH:24][C:25]([CH2:26][CH3:27])=[C:21]([Cl:20])[N:22]=2)=[O:29])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4]1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 117.1 %

Procedure:
The same operation as in Example (106d) was performed using tert-butyl cis(±)-4-amino-3-butoxypiperidine-1-carboxylate obtained in Example (119d) (1.26 g, 4.6 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 1.03 g, 5 mmol), WSC hydrochloride (2.88 g, 15 mmol), HOBt (1.01 g, 7.5 mmol), DMA (15 mL) and dichloromethane (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 2.31 g of the title compound as a colorless solid (100%).
Reaction SMILES: O.[I-:2].[I-].[I-].[I-].[CH:6]1[C:19]2[C:10](=[S+:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:8][CH:7]=1.[CH:20]1[C:33]2[C:24](=[S+:25][C:26]3[C:31]([N:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:22][CH:21]=1.[CH:34]1[C:47]2[C:38](=[S+:39][C:40]3[C:45]([N:46]=2)=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:37]=[CH:36][CH:35]=1.C1[C:61]2C(=[S+]C3[C:59]([N:60]=2)=CC=CC=3)C=CC=1.[CH3:62][NH:63][CH3:64]>CO>[I-:2].[I-:2].[I-:2].[CH3:31][N:32]([CH3:33])[C:8]1[CH:7]=[CH:6][C:19]2[C:10]([CH:9]=1)=[S+:11][C:12]1[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:18]=2.[CH3:59][N:60]([C:36]1[CH:35]=[CH:34][C:47]2[C:38]([CH:37]=1)=[S+:39][C:40]1[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=1)[N:46]=2)[CH3:61].[CH3:62][N:63]([C:22]1[CH:21]=[CH:20][C:33]2[C:24]([CH:23]=1)=[S+:25][C:26]1[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=1)[N:32]=2)[CH3:64]
Reactant: c1ccc2[s+]c3ccccc3nc2c1
Reactant: CNC
Agent: [I-]
Solvent: O
Solvent: CO
Product: CN(C)c1ccc2nc3ccccc3[s+]c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of phenothiazine-5-ium tetraiodide hydrate (0.417 g, 0.57 mmol) in methanol (10 ml) was stirred at room temperature and treated dropwise with a solution of dimethylamine (1.14 mmole) in methanol (2 ml). The mixture was stirred at room temperature for 3 hrs until the starting materials was consumed, as monitored by TLC (silica, CH3OH/TEA). The precipitate was filtered and washed with small amount of methanol, afforded a black solid, 0.30 g (84%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:14])=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[C:66]1([CH2:72][SH:73])[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:72]([S:73][C:2]1[C:3]([CH3:14])=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: SCc1ccccc1
Reactant: Cc1c(Br)cccc1-c1cccnc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1c(SCc2ccccc2)cccc1-c1cccnc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
Intermediate 73 (3 g, 12.09 mmol) in dioxane (50 ml) was stirred under argon, then DIPEA (3.82 ml, 24.18 mmol), xantphos (0.42 g, 0.73 mmol) and Pd2(dba)3 (0.33 g, 0.36 mmol) were added and the reaction was heated to 100° C. Phenyl-methanethiol (1.56 ml, 13.3 mmol) was slowly added and the reaction stirred for 16 h. The reaction was quenched by addition of 150 ml of H2O. After extraction (three times) with ethyl acetate the combined organic layers were washed with water, dried with Na2SO4, evaporated to dryness and the compound was obtained and used without further purification in step 22.3.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[N:2]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1([C:6]2[CH:13]=[CH:12][C:9](/[CH:10]=[CH:22]/[CH:23]=[O:24])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: O=Cc1ccc(-n2ccnn2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1ccc(-n2ccnn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(1H-1,2,3-triazol-1-yl)-benzaldehyde (prepared as described in J. Med Chem. 1998, 41, 2390) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 200 (M+H)+.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[OH:18])[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2.C(=O)([O-])[O-].[K+].[K+].[CH2:37]([CH:39]1[O:41][CH2:40]1)Br>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:37][CH:39]1[CH2:40][O:41]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2
Reactant: BrCC1CO1
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCC1CO1
Temperature: 80 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
N,N-Dimethylformamide (3 ml) was added to 6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (100 mg), potassium carbonate (125 mg), and epibromohydrin (124 mg), and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (62 mg, yield 53%).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([B:9]2[O:13][C:12]([CH3:15])(C)[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:2].C1CCN2C(=NCCC2)CC1.[C:35]([O:39][CH2:40][CH3:41])(=[O:38])[CH:36]=[CH2:37]>C(#N)C>[CH2:1]([C:3]1[C:8]([B:9]2[O:10][C:11]([CH3:16])([CH3:17])[CH:12]([CH3:15])[O:13]2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH:18]1[CH2:23][CH2:22][N:21]([CH2:37][CH2:36][C:35]([O:39][CH2:40][CH3:41])=[O:38])[CH2:20][CH2:19]1)[CH3:2]
Reactant: CCc1c(B2OC(C)(C)C(C)(C)O2)cccc1C1CCNCC1
Reactant: C=CC(=O)OCC
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CCN1CCC(c2cccc(B3OC(C)C(C)(C)O3)c2CC)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
To a solution of 4-[2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (D119) (80 mg, 0.186 mmol) and DBU (0.034 mL, 0.224 mmol) in Acetonitrile (8 mL) was added ethyl 2-propenoate (57 mg, 0.499 mmol). The solution was sealed and stirred at 80° C. for 2 h. The solution was evaporated in vacuo to afford ethyl 3-{4-[2-ethyl-3-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-piperidinyl}propanoate (D123) (46 mg). MS (ES): C24H38BNO4 requires 415.3. found 416.3 (M+H+).
Reaction SMILES: CS([Br:5])(=O)=O.[CH3:6][O:7][C:8](=[O:35])[CH2:9][C@H:10]1[C:14]2[CH:15]=[CH:16][C:17]([O:19][C@H:20]3[C:28]4[C:23](=[C:24]([CH2:33]O)[C:25]([C:29]([F:32])([F:31])[F:30])=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)=[CH:18][C:13]=2[O:12][CH2:11]1.C(N(CC)CC)C>ClCCl>[CH3:6][O:7][C:8](=[O:35])[CH2:9][C@H:10]1[C:14]2[CH:15]=[CH:16][C:17]([O:19][C@H:20]3[C:28]4[C:23](=[C:24]([CH2:33][Br:5])[C:25]([C:29]([F:32])([F:31])[F:30])=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)=[CH:18][C:13]=2[O:12][CH2:11]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CO)ccc21
Reactant: CS(=O)(=O)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CBr)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methylsulfonyl bromide (0.96 mL) is added to a solution of {(S)-6-[(R)-4-hydroxymethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (2.00 g) and triethylamine (1.98 mL) in dichloromethane (20 mL) chilled in an ice bath. The cooling bath is removed, and the solution is stirred at room temperature overnight. More dichloromethane is added, and the resulting solution is washed with aqueous NaHCO3 solution and brine, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate) to give the title compound. LC (method 4): tR=1.24 min.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH2:8]([O:15][C:16]1[CH:32]=[CH:31][C:19]2[N:20]([CH2:29][CH3:30])[C:21](=[O:28])[CH:22]([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]=2[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:33](I)[CH2:34][CH2:35][CH3:36]>C(OCC)(=O)C>[CH2:8]([O:15][C:16]1[CH:32]=[CH:31][C:19]2[N:20]([CH2:29][CH3:30])[C:21](=[O:28])[C:22]([CH2:33][CH2:34][CH2:35][CH3:36])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]=2[CH:17]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCCCI
Reactant: CCN1C(=O)C(C)C(=O)N(C)c2cc(OCc3ccccc3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCC1(C)C(=O)N(C)c2cc(OCc3ccccc3)ccc2N(CC)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Under ice cooling, sodium hydride (60% in oil) (129 mg, 3.23 mmol) was added to a N,N-dimethylformamide (5 mL) solution of 7-benzyloxy-1-ethyl-3,5-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (500 mg, 1.48 mmol), and the mixture was stirred at 0° C. for 30 minutes. Thereafter, butyl iodide (0.336 mL, 2.95 mmol) was added. The reaction solution was stirred at 0° C. for 30 minutes, and then stirred at room temperature for 2 hours. The reaction solution was poured into ice water, and ethyl acetate (20 mL) extraction was performed. The resulting organic layer was washed with water, and the solvent was distilled off. The resulting residue was subjected to silica gel column chromatography (elution solvent: 1:2=ethyl acetate:n-hexane). The solvent was distilled off, thereby obtaining 520 mg of a colorless, liquid target compound (yield: 89%).