Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.[C:23](Cl)(=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C(Cl)Cl>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C@@H:5]([NH:6][C:23](=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:4]([OH:3])=[O:15])=[CH:9][CH:10]=1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)N[C@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
To a solution of L-Tyrosine methyl ester hydrochloride (1 g, 4.3 mmol) in CH2Cl2 was added triethylamine (1.49 mL, 8.6 mmol) at room temperature. Palmitoyl chloride (1.53 g, 5.6 mmol) was then added to the reaction mixture at 0° C. After the reaction was completed, as judged by TLC, the reaction mixture was quenched and extracted with 1 N HCl (3×5 mL) then saturated sodium bicarbonate (1×5 mL). The combined organic layers were dried with Na2SO4 and evaporated under vacuum to a white solid (1.86 g, 4.3 mmol). The product was carried on without further purification. 1H NMR (300 MHz, CDCl3, 23° C., 6): 6.94 (d, 1H, J=8.5), 6.73 (d, 1H, J=8.5), 5.92 (d, 1, H, J=8.0), 4.90 (d, 1H, J=5.8), 4.85 (d, 1H, J=5.8), 3.73 (s, 3H), 3.04 (ddd, 1H, J=5.8, 14.0, 27.7), 2.26-2.12 (m, 1H), 1.58 (m, 2H), 1.25 (m, 24H), 0.90 (t, 3H, J=6.67).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])([CH3:24])[CH3:23])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[CH2:32](I)[CH3:33]>CN(C=O)C>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][C:22]([N:25]([CH2:32][CH3:33])[S:26]([CH3:29])(=[O:28])=[O:27])([CH3:23])[CH3:24])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CCI
Reactant: CC(C)(COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1)NS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(C)(C)COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Reaction time: 0.5 h

Procedure:
To a solution of N-boc-4-[2-(2-methanesulfonylamino-2-methyl-propoxy)-phenyl]-piperazine (197 mg, 0.46 mmol) in 4 mL of DMF was added NaH (55 mg of a 60% dispersion in oil, 1.38 mmol). After stirring for about 30 minutes, EtI (550 uL, 6.88 mmol) was added. After stirring at 45° C. for about an hour, the mixture was quenched with saturated aqueous sodium bicarbonate. The mixture was diluted with EtOAc, washed with water and brine, and then dried (Na2SO4), filtered and concentrated. The material was combined with 0.36 mmol of crude material from a previous reaction and purified by silica gel chromatography (35 g SiO2, 10 to 30% EtOAc/hexanes, over 30 minutes at 35 mL/min.) to afford about 323 mg (0.71 mmol, 86% combined yield) of the final compound. LRMS (electrospray): 456.2 [M+1]
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][CH:9]=2)[CH:4]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[O:3]1.[OH-:23].[Na+].Cl>CS(C)=O.CN(C=O)C>[OH:23][C:4]1([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2)[CH2:11][CH:2]([CH3:1])[O:3]1
Reactant: COc1ccc2c(c1)C(c1ccc([N+](=O)[O-])cc1)OC(C)C2
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(O)(c1ccc([N+](=O)[O-])cc1)OC(C)C2
Reaction time: 5 h

Procedure:
A solution of 16 (1.3 g) in 4 ml of DMSO and 24 ml of DMF was cooled to 8-12° C. and air was passed through the mixture. To the solution was added 1.2 ml of 50% aqueous sodium hydroxide in one portion and the resulting mixture was stirred for 5 hours. HCl (1 N) was added, and extracted with ethyl acetate three times. The combined organic phases were washed with water, dried over Na2SO4. Removal of the solvent afforded 17 as a syrup (1.6 g), which was used directly for the next step.
Reaction SMILES: [CH2:1]([N:8]1[C:18]2=[C:19]3C(=[CH:15][CH:16]=[CH:17]2)C=C[CH2:11][N:10]3[C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H+].[B-](F)(F)(F)F.CC1(C)N([Br:35])C(=O)N(Br)C1=O.[C:38]([O:42]C)([CH3:41])([CH3:40])C>C(#N)C.O>[CH2:1]([N:8]1[C:18]2=[C:19]3[C:40](=[CH:15][CH:16]=[CH:17]2)[C@@H:38]([OH:42])[C@H:41]([Br:35])[CH2:11][N:10]3[C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1n(Cc2ccccc2)c2cccc3c2n1CC=C3
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: COC(C)(C)C
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CC#N
Solvent: O
Product: O=c1n(Cc2ccccc2)c2cccc3c2n1C[C@@H](Br)[C@@H]3O
Reaction time: 3 h

Procedure:
1-Benzyl-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (II, XAMPLE 1, 240 g), acetonitrile (1.086 kg), water (227 ml) and fluoboric acid (48.5%, 13.4 g) are mixed and cooled to 0 to 5°. Dibromantin (163.5 g) is slurried into acetonitrile and is added to the reaction mixture. The reaction is carried out for about 3 hr at 0 to 5°. After the reaction is complete, methyl t-butyl ether is added over about 45 minutes keeping the reaction temperature in the pot below 10°. The slurry is cooled to −10 to −15°, stirred for an hour and then filtered. The product is washed with precooled methyl t-butyl ether, dried with 40° nitrogen to give the title compound, CMR (CDCl3) δ156.0, 137.8, 130.5, 129.6, 129.3, 129.1, 126.6, 123.6, 122.5, 119.6, 110.4, 69.9, 49.6, 47.7, 46.9 and 43.8.
Reaction SMILES: [Cl-:1].[Zn+2:2].[Cl-].[NH2:4][C@H:5]([C:10]([OH:12])=O)[CH2:6][CH2:7][S:8][CH3:9]>O>[NH2:4][C@H:5]([C:10]([Cl:1])=[O:12])[CH2:6][CH2:7][S:8][CH3:9].[Zn:2]
Reactant: [Cl-]
Reactant: [Zn+2]
Reactant: CSCC[C@H](N)C(=O)O
Solvent: O
Product: CSCC[C@H](N)C(=O)Cl
Product: [Zn]
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Zinc chloride (Zn Cl2, 68.0g, 0.5 mol) was dissolved in water (68.0 g) and the solution was heated to 90° C. Methionine (74.6 g, 0.5 mol) was added and the temperature was kept at 90° C. for 1 hour to provide zinc methionine chloride solution. The product contained 21.2% zinc and 53.9% methionine. Quantitative and instrumental analysis as previously described revealed the presence of a 1:1 complex salt of zinc methionine chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([OH:17])=O)[CH:11]=2)[C:6]1=[O:18].[N:23]1([CH2:28][CH2:29][CH2:30][NH2:31])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[Cl-:1].[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([NH:31][CH2:30][CH2:29][CH2:28][NH+:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:17])[CH:11]=2)[C:6]1=[O:18]
Reactant: O=C(O)c1ccc2c(c1)C(=O)N(Cc1ccccc1Cl)C2=O
Reactant: NCCCN1CCCC1
Product: O=C(NCCC[NH+]1CCCC1)c1ccc2c(c1)C(=O)N(Cc1ccccc1Cl)C2=O
Product: [Cl-]

Procedure:
2-(2-chloro-benzyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-carboxylic acid (100 mg, 0.316 mmol) and 3-pyrrolidin-1-yl-propylamine (100 μL, 0.792 mmol) were reacted with each other. Target compound in the amount of 85 mg (58%) was obtained by following the procedure described in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.[H-].[Na+].[Br:13][C:14]1[CH:15]=[C:16]([O:21][CH2:22][CH3:23])[C:17](Cl)=[N:18][CH:19]=1>CN(C=O)C>[Br:13][C:14]1[CH:15]=[C:16]([O:21][CH2:22][CH3:23])[C:17]([O:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:18][CH:19]=1
Reactant: COc1ccc(CO)cc1
Reactant: CCOc1cc(Br)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(Br)cnc1OCc1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
To a mixture of (4-methoxyphenyl)methanol (16.71 g, 121 mmol) in DMF (300 mL) was added NaH (3.96 g, 165 mmol) at 0° C. dropwise. After the mixture was stirred for 30 min, 5-bromo-2-chloro-3-ethoxypyridine (26 g, 110 mmol) in DMF (100 mL) was added to above mixture and the mixture was stirred for 12 h at 80-90° C. The mixture was quenched by H2O (20 mL), extracted with DCM (400 mL×2), dried over Na2SO4, filtered, and concentrated to give the residue which was purified by column chromatography (10% EA: 90% PE, 360 g silica column). All fractions found to contain product by TLC (EA: PE=1:5, Rf=0.5) were combined and concentrated to yield a white solid of 5-bromo-3-ethoxy-2-((4-methoxybenzyl)oxy)pyridine (36 g, 74.5 mmol, 68% yield): 1H NMR (400 MHz, CD3OD) δ 7.71 (d, J=2.0 Hz, 1H), 7.36-7.31 (m, 3H), 6.89-6.87 (m, 2H), 5.27 (s, 2H), 4.05-4.00 (m, 2H) 3.77 (s, 3H), 2.37 (d, J=7.0 Hz, 3H); ES-LCMS m/z 338 (M+H).
Reaction SMILES: NC(N)=O.[Br:5][C:6]1[CH:10]=[N:9][N:8]([CH3:11])[C:7]=1[C:12]1[CH:13]=[C:14]([NH2:20])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[C:24]([C:31]([F:34])([F:33])[F:32])[CH:23]=1>C(Cl)Cl>[Br:5][C:6]1[CH:10]=[N:9][N:8]([CH3:11])[C:7]=1[C:12]1[CH:13]=[C:14]([NH:20][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][C:24]=2[C:31]([F:33])([F:32])[F:34])=[O:30])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1ccc(Cl)cc1C(F)(F)F
Agent: NC(N)=O
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2C(F)(F)F)cc1-c1c(Br)cnn1C
Yield: 56.9 %

Procedure:
Urea synthesis (General Procedure): To a stirred solution of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.034 g, 0.12 mol, Example 1.1) in CH2Cl2 (1 mL) was added 4-chloro-2-(trifluoromethyl)phenyl isocyanate (0.029 g, 20.0 μL, 0.13 mmol, 1.05 equiv.) at room temperature. White solid precipitated and was filtered and washed with cold CH2Cl2 to afford Compound 9 (0.037 g, 0.074 mmol, 60%) as a white solid. LCMS m/z (%)=503 (M+H79Br, 77), 439 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.82 (s, 1H), 8.22 (d, J=9.6 Hz, 1H), 7.62-7.72 (m, 4H), 7.49 (s, 1H), 7.43 (d, J=2.6 Hz, 1H), 7.15 (d, J=9.0 Hz, 1H), 3.83 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[N:10]=[CH:9][N:8]=[C:7]([N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[NH:20][C:19]4=O)[CH2:14][CH2:13]3)[C:6]=2[N:5]=[C:4]([O:28][CH3:29])[C:3]1=[O:30].N1CCC(N2C3C=CC=CC=3N[C:38]2=[O:46])CC1.C1(N2C3(CCNCC3)C(=O)NC2)C=CC=CC=1>>[CH3:29][O:28][C:4]1[C:3](=[O:30])[N:2]([CH3:1])[C:11]2[N:10]=[CH:9][N:8]=[C:7]([N:12]3[CH2:17][CH2:16][C:15]4([N:18]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:21]=5)[CH2:19][NH:20][C:38]4=[O:46])[CH2:14][CH2:13]3)[C:6]=2[N:5]=1
Reactant: COc1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n(C)c1=O
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: O=C1NCN(c2ccccc2)C12CCNCC2
Product: COc1nc2c(N3CCC4(CC3)C(=O)NCN4c3ccccc3)ncnc2n(C)c1=O

Procedure:
6-methoxy-8-methyl-4-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)pteridin-7(8H)-one was prepared in an analogous fashion to 8-methyl-6-(methyloxy)-4-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]pteridin-7(8H)-one, in which the 1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one was replaced with commercially available 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one. 1H NMR (400 MHz, DMSO-d6): δ 8.82 (s, 1H), 8.37 (s, 1H), 7.08 (t, 2H), 6.66 (t, 1H), 6.61 (d, 1H), 4.99 (d, 2H), 4.60 (s, 2H), 3.81 (s, 3H), 3.57 (s, 3H), 2.63 (m, 2H), 1.76 (d, 2H); MS (EI) for C21H23N7O3; 422 (MH+).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:11].[Br:12]Br>C(Cl)(Cl)(Cl)Cl>[Br:12][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:11].[Br:12][C:3]1[C:2]([OH:11])=[CH:1][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: Oc1ccc2c(c1)CCCC2
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1cc2c(cc1Br)CCCC2
Product: Oc1ccc2c(c1Br)CCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46 %
Yield: 9 %

Procedure:
An oven dried 1 L round bottom flask was charged with 5,6,7,8-tetrahydro-2-naphthol (4 g, 26.8 mmol) and CCl4 (536 mL). The solution was cooled to 0° C. with an ice bath for 30 minutes, followed by the slow addition of a solution of Br2 (4.28 g, 26.8 mmol) in CCl4 (27 mL). The reaction was stirred at 0° C. for 30 minutes then placed in the freezer at −10° C. for 18 hours. The reaction was then allowed to warm to ambient temperature. TLC shows the reaction complete. The reaction was concentrated in vacuo to give 6.16 g of an ivory laced with dark brown solid. The crude was purified in four batches by Biotage MPLC (120 g columns, 2.5% ethyl acetate). Purification gave 2.83 g (46%) of 1-bromo-5,6,7,8-tetrahydronaphthalen-2-ol as a white solid, 2.28 g (37%) of a mixed fractions (1-bromo-5,6,7,8-tetrahydronaphthalen-2-ol and 3-bromo-5,6,7,8-tetrahydronaphthalen-2-ol) and 0.56 g (9%) of 3-bromo-5,6,7,8-tetrahydronaphthalen-2-ol as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10]([NH:21][CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([OH:33])=O)=[CH:26][CH:25]=1>>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([N:21]([CH3:22])[C:31](=[O:33])[CH2:30][C:27]2[CH:26]=[CH:25][C:24]([F:23])=[CH:29][CH:28]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CN[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)Cc1ccc(F)cc1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound N-[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide was prepared from [(3R,4S)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amine using 4-fluorophenylacetic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light yellow oil. MS m/e: 471.2 [M]+.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:7]=[CH:6][N:5]=[CH:4]1.[OH-].[K+].[Br:15][C:16]1[C:17]2[C:18]3[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20](S)[C:19]=3[CH:26]=[CH:27][CH:28]=2>C(O)C>[Br:15][C:16]1[C:17]2[C:18]3[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)[C:19]=3[CH:26]=[CH:27][CH:28]=2
Reactant: SC1=Nc2ccc(Br)c3cccc1c23
Reactant: NCCCCn1ccnc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Brc1ccc2c3c(cccc13)C(NCCCCn1ccnc1)=N2
Reaction time: 18 h

Procedure:
A mixture of 4.2 g of 4-(1H-imidazol-l-yl)butanamine dihydrochloride in 75 ml of ethanol was treated with 2.2 g of potassium hydroxide and stirred for 18 hours. A 5.2 g portion of 6-bromo-benz(cd)indole-2-thiol and 6.4 g of mercuric acetate were added and the reaction proceeded as described in Example 1, giving 3.7 g of the desired product, mp 145° C.-147° C.
Reaction SMILES: Cl.Cl.[C:3]([O:7][C:8]([N:10]([C@@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[C:11]1[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:38])=[CH:33][CH:32]=1.C1COCC1>CCN(CC)CC>[C:37]([C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:26]2[CH2:27][CH2:28][C@@H:24]([N:10]([C:8]([O:7][C:3]([CH3:4])([CH3:5])[CH3:6])=[O:9])[C:11]3[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=3)[CH2:25]2)=[CH:36][CH:35]=1)(=[O:38])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCNC2)nc1
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(Cc3ccc(C(=O)c4ccccc4)cc3)C2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a mixture of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate dihydrochloride (150 mg), [4-(bromomethyl)phenyl](phenyl)methanone (143 mg), and THF (3.5 mL) was added Et3N (0.168 mL). After stirring for 2 hours at room temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-{6-[[(3R)-1-(4-benzoylbenzyl)-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylate (149 mg).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[F:13][C:14]1[C:19]2[NH:20]C(=O)O[C:23](=[O:24])[C:18]=2[CH:17]=[CH:16][CH:15]=1>C(O)C.O>[NH2:20][C:19]1[C:14]([F:13])=[CH:15][CH:16]=[CH:17][C:18]=1[C:23]([N:3]([O:4][CH3:5])[CH3:2])=[O:24]
Reactant: CNOC
Reactant: O=c1[nH]c2c(F)cccc2c(=O)o1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cccc(F)c1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.4 %

Procedure:
To a suspension of N,O-dimethylhydroxylamine hydrochloride (703 mg, 7.21 mmol) in ethanol (5.4 ml) and water (0.6 ml) was added triethylamine (729 mg, 1.00 ml, 7.21 mmol) and the mixture was stirred for 10 min at room temperature. Then 8-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (870 mg, 4.8 mmol) and additional ethanol (2 ml) were added and the reaction mixture was heated to reflux for 3.5 h. After cooling to room temperature, the mixture was poured onto ice/saturated NaHCO3-solution, extracted with EtOAc and the combined extracts were washed with water and brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, heptane/EtOAc 80:20-70:30) to afford the title compound (765 mg, 80%) as light brown oil. MS (ESI): 199.2 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([NH:12][C:13]([NH:15][CH2:16][CH2:17]Cl)=[O:14])[C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C>O>[F:9][C:8]([F:11])([F:10])[CH:7]([NH:12][C:13]1[O:14][CH2:17][CH2:16][N:15]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NCCCl)NC(c1ccccc1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Product: FC(F)(F)C(NC1=NCCO1)c1ccccc1
Yield: 95 %

Procedure:
7.6 g of N-(α-phenyl trifluoroethyl) N'-(β-Chloroethyl) Urea are suspended in 60 ml water, then 4.3 ml triethylamine are added and the whole mixture is heated to reflux under stirring for 30 mn. The reaction mixture is let to revert to about 20°, the precipitate is separated which is dried, washed with water until the washings are neutral and dried under vacuum-6.3 g 2-[α-trifluoromethyl) benzylamino] oxazoline are obtained i.e. a yield of 95%. For analytical purpose the compound is recrystallized from isopropanol with a yield of 73%. The analytical sample melts at 162°-168° (sublim).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:16]3[CH2:22][CH:21]4[N:23](C)[CH:18]([CH2:19][CH2:20]4)[CH2:17]3)[C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.ClC(OC(Cl)C)=O.C(N(C(C)C)CC)(C)C>ClCCCl>[CH:21]12[NH:23][CH:18]([CH2:19][CH2:20]1)[CH2:17][CH:16]([N:6]1[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:15][C:14]=3[S:13][C:12]3[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:22]2
Reactant: CN1C2CCC1CC(N1c3ccccc3Sc3cc(Br)ccc31)C2
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Brc1ccc2c(c1)Sc1ccccc1N2C1CC2CCC(C1)N2
Temperature: 25 °C

Procedure:
To a solution of 3-bromo-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine, 3i (1.0 g, 2.49 mmol) in 1,2-dichloroethane (15 mL) were added 1-chloroethyl chloroformate (807 μL, 7.5 mmol) and N,N-diisopropyl-N-ethylamine (1.4 mL, 7.97 mmol). The mixture was heated to reflux for 2.5 h, allowed to cool to rt, and evaporated. The mixture was evaporated and the residue was dissolved dissolved in methanol (15 mL) and heated to reflux for 1 h. After work-up, the residue was purified via flash column chromatography (eluent gradient: 0 to 30% MeOH in EtOAc containing 1% triethylamine) to yield 150 mg of recovered starting material 3i and 382 mg (66%) of title compound 3-bromo-10-piperidin-4-yl-10H-phenothiazine, 4i as a mixture of endo and exo isomers. MS m/z (MH+) 387.1/389.1.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][CH2:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:8][C:7]([C:18]([NH2:20])=O)=[N:6]1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:9]([CH2:10][CH2:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:8][C:7]([C:18]#[N:20])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nc(C(N)=O)cc1CCS(=O)(=O)CCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCn1nc(C#N)cc1CCS(=O)(=O)CCC
Temperature: 25 °C
Yield: 101 %

Procedure:
1-Butyl-5-[2-(propylsulfonyl)ethyl]-1H-pyrazole-3-carboxamide (4.00 g, 13.27 mmol) in toluene (66 mL) was treated with phosphorous oxychloride (2.50 mL, 26.5 mol). The solution was heated at reflux for 1 hour. The reaction mixture was allowed to cool to ambient temperature and the volatiles were removed under reduced pressure. The resulting oil was diluted with water (50 mL) and saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane (2×50 mL). The organic layers were combined, washed with saturated aqueous sodium bicarbonate (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 3.8 g of 1-butyl-5-[2-(propylsulfonyl)ethyl]-1H-pyrazole-3-carbonitrile as a brown oil.
Reaction SMILES: [CH2:1]([C:8]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][C:17]#[N:18]>>[CH2:1]([C:8]1([OH:14])[CH2:13][CH2:12][N:11]([CH2:16][C:17]#[N:18])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: OC1(Cc2ccccc2)CCNCC1
Product: N#CCN1CCC(O)(Cc2ccccc2)CC1

Procedure:
The title compound is synthesized by coupling of 4-Benzyl-4-hydroxy-piperidine (commercially available from ABCR GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=231.2: AtRet=1.81.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2C3=N[CH:13]=[C:14]([S:16][CH3:17])[N:15]=[C:10]3[CH:9]=[C:8]2[CH:18]=[O:19])=[CH:4][CH:3]=1.[C-:22]#[N:23].[Na+].[CH3:25][OH:26]>[O-2].[O-2].[Mn+4]>[CH3:25][O:26][C:18]([C:8]1[N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:21][CH:20]=2)[C:22]2=[N:23][CH:13]=[C:14]([S:16][CH3:17])[N:15]=[C:10]2[CH:9]=1)=[O:19]
Reactant: CO
Reactant: CSc1cnc2c(cc(C=O)n2Cc2ccc(F)cc2)n1
Reactant: [C-]#N
Agent: [Mn+4]
Agent: [Na+]
Agent: [O-2]
Product: COC(=O)c1cc2nc(SC)cnc2n1Cc1ccc(F)cc1
Temperature: 22.5 °C
Reaction time: 15 h
Yield: 66.4 %

Procedure:
To the compound obtained in Example 34 (6) (15 mg), methanol (2.8 ml), manganese dioxide (22 mg) and sodium cyanide (13 mg) were added at 0° C. and the mixture was stirred at 15 to 30° C. for 15 hours. The reaction solution was then filtered through Celite, extracted with chloroform, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (chloroform methanol=100:1) to obtain 11 mg (66.4%) of the desired product as a white powder.