Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[C:24](I)[CH:23]=2)[C:10]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:2].[NH:41]1[CH:45]=[CH:44][C:43](B(O)O)=[N:42]1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:45]3[CH:44]=[CH:43][NH:42][N:41]=3)[CH:25]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Reactant: OB(O)c1cc[nH]n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3cc[nH]n3)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Yield: 28.2 %

Procedure:
A similar procedure as described in Example 40, step 7 was used, starting from 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-iodo-5-methanesulfonyl-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (150 mg, 0.22 mmol), 1H-pyrazol-3-ylboronic acid (51.4 mg, 0.45 mmol), tetrakis(triphenylphosphine)palladium(0) (50.8 mg, 0.04 mmol), and potassium carbonate (30.2 mg, 0.22 mmol) to afford 4-(2-(2-ethoxycarbonyl-ethyl)-3-{6-[3-methanesulfonyl-5-(1H-pyrazol-3-yl)-phenoxy]-hexyl}-phenoxy)-butyric acid ethyl ester (39 mg, 28.5%) as a light brown viscous oil: ES(+)-HRMS m/e calcd for C33H44N2O8S (M+H)+ 629.2891, found 629.2894.
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][NH2:7])([CH3:3])[CH3:2].N[C:9](N)=[O:10]>>[CH:1]([N:4]1[CH2:5][CH2:6][NH:7][C:9]1=[O:10])([CH3:3])[CH3:2]
Reactant: CC(C)NCCN
Reactant: NC(N)=O
Product: CC(C)N1CCNC1=O
Temperature: 125 °C
Yield: 98.5 %

Procedure:
A five-liter three necked flask equipped with a thermometer, condenser, stirrer, and nitrogen inlet was charged with 2-isopropylaminoethylamine (2550 g, 25 moles) and urea (1500 g, 25 moles). The reaction mixture was heated to 125° C. for seven hours and then 170° C. until no more gas releasing was observed. About 3155 g of N-isopropyl-2-imidazolidone was obtained. The reaction is represented as follows: ##STR10##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:15])[N:6]([CH3:14])[C:7](=O)[NH:8]2.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:7]1[N:6]([CH3:14])[C:5](=[O:15])[C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc2[nH]c(=O)n(C)c(=O)c12
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2nc(Cl)n(C)c(=O)c12
Yield: 99.6 %

Procedure:
A mixture of 5-methoxy-3-methyl-1H-quinazoline-2,4-dione (165 mg, 0.800 mmol) and N,N-diisopropylethylamine (0.307 ml, 1.76 mmol) in phosphorus oxychloride (2.2 ml, 24.0 mmol) was refluxed for 18 h with stirring and concentrated to dryness under vacuum. The residue was diluted with water. The aqueous solution was extracted with dichloromethane. The extract was washed with water, dried over magnesium sulfate and concentrated under vacuum to afford 179 mg (99%) of the title compound. The residue was used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16]1([NH2:23])[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1>>[ClH:1].[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:17][CH:18]=1
Reactant: Nc1ccc(N)cc1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Product: COc1cc2ncnc(Nc3ccc(N)cc3)c2cc1OC
Product: Cl
Yield: 85 %

Procedure:
Using an analgous procedure to that described in Example 74, 4-chloro-6,7-dimethoxyquinazoline was reacted with 1,4-phenylenediamine to give 4-(4'-aminoanilino)-6,7-dimethoxyquinazoline hydrochloride in 85% yield, m.p. 274°-276° C. NMR Spectrum: (CD3SOCD3) 3.95 (s, 3H), 3.98 (s, 3H), 6.75 (d, 2H), 7.35 (s, 1H), 7.38 (d, 2H), 8.25 (s, 1H), 8.67 (s, 1H), 11.05 (broad s, 1H); Elemental Analysis: Found C, 57.6; H, 5.0; N, 16.9; C16H16N4O2. 1HCl requires C, 57.7; H, 5.15; N, 16.8%.
Reaction SMILES: C(OC([NH:8][CH:9]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([O:12][C:13]1[CH:14]=[N:15][C:16](/[CH:19]=[C:20]2\[NH:21][C:22](=[O:34])/[C:23](=[CH:27]/[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)/[NH:24][C:25]\2=[O:26])=[CH:17][CH:18]=1)=[O:11])=O)(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl>[F:41][C:42]([F:47])([F:46])[C:43]([O-:45])=[O:44].[CH:27](=[C:23]1/[NH:24][C:25](=[O:26])/[C:20](=[CH:19]/[C:16]2[N:15]=[CH:14][C:13]([O:12][C:10](=[O:11])[CH:9]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[NH3+:8])=[CH:18][CH:17]=2)/[NH:21][C:22]/1=[O:34])/[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)Oc1ccc(/C=c2\[nH]c(=O)/c(=C/c3ccccc3)[nH]c2=O)nc1)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C([O-])C(F)(F)F
Product: [NH3+]C(C(=O)Oc1ccc(/C=c2\[nH]c(=O)/c(=C/c3ccccc3)[nH]c2=O)nc1)c1ccccc1
Temperature: 0 °C
Yield: 71 %

Procedure:
Compound 8 (0.126 g) was dissolved in 10 mL of dichloromethane and then 2.5 mL of trifluoroacetic acid was added slowly at 0° C. The reaction mixture was stirred at 0° C. and monitored by TLC until the starting material disappeared. It was concentrated by rotary evaporator to a give a crude compound, which was recrystallized in acetonitrile to give Compound 9 as a yellow solid (71%). mp 280° C.; 1H-NMR (400 MHz, DMSO): δ 5.69 (s, 1H), 6.79 (s, 1H), 6.86 (s, 1H), 7.34-7.38 (m, 1H), 7.44 (dd, J=7.6 Hz, 7.6 Hz, 2H), 7.55-7.58 (m, 5H), 7.65-7.67 (m, 2H), 7.71-7.74 (m, 1H), 7.80-7.82 (m, 1H), 8.59 (s, 1H), 8.91 (br, 3H), 10.42 (br, 1H), 12.16 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:15][C:14]([OH:16])=[C:13]([CH2:17][C:18]3[N:28]=[C:21]4[N:22]=[C:23](C)[CH:24]=[C:25](C)[N:20]4[N:19]=3)[C:12](=[O:29])[O:11]2)[CH:5]=[CH:4][C:3]=1[C:35]1([C:38]#[N:39])[CH2:37][CH2:36]1.Cl[C:41]1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=C(CC)C=1OC.ClC1C=NC2N(N=C(C=O)N=2)C=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2([CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)[CH2:15][C:14]([OH:16])=[C:13]([CH2:17][C:18]3[N:28]=[C:21]4[N:22]=[CH:23][C:24]([CH3:41])=[CH:25][N:20]4[N:19]=3)[C:12](=[O:29])[O:11]2)[CH:5]=[CH:4][C:3]=1[C:35]1([C:38]#[N:39])[CH2:37][CH2:36]1
Reactant: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4ccc(C5(C#N)CC5)c(Cl)c4)(C4CCCC4)OC3=O)nc2n1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(Cl)c1OC
Agent: O=Cc1nc2ncc(Cl)cn2n1
Product: Cc1cnc2nc(CC3=C(O)CC(CCc4ccc(C5(C#N)CC5)c(Cl)c4)(C4CCCC4)OC3=O)nn2c1

Procedure:
The title compound was prepared analogously to Example B(97) (where 1-(2-Chloro-4-{2-[2-cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-phenyl)-cyclopropanecarbonitrile was substituted in place of 6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione in that example and 6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde in place of the 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde in that example. 1H NMR (400 MHz, CDCl3) δ: 1.38–1.42 (m, 2H), 1.47–1.73 (m, 8H), 1.73–1.77 (m, 2H), 2.01–2.21 (m, 2H)), 2.39–2.50 (m, 1H), 2.56 (d, J=16 Hz, 1H), 2.63–2.69 (m, 2H), 2.80 (d, J=16 Hz, 1H), 3.3 (s, 3H), 3.75 (d, J=16 Hz, 1H), 3.85 (d, J=16 Hz, 1H), 7.29 (dd, J=8, 1.6 Hz, 1H), 7.43–7.45 (m, 2H), 8.74 (d, J=2.3 Hz, 1H), 9.01 (dd, J=2.3, 1.1 Hz, 1H), 10.9 (s, 1H). C29H30ClN5O3.0.25: C, 64.68; H, 6.08; N, 13.00. Found: C, 64.78; H, 5.74; N, 12.65. MS (ESI): 532.2(M+H+).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=O)=[CH:6][CH:5]=1.C(O)(=O)C>O1CCOCC1>[ClH:3].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][NH2:10])=[CH:6][CH:5]=1
Reactant: NC(=O)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cl
Product: NCc1ccc(Cl)cc1

Procedure:
Into a mixture comprising 7.30 g of sodium borohydride, 6.00 g of 4-chlorobenzamide and 100 ml of 1,4-dioxane, a mixed solution of 11.58 g of acetic acid and 30 ml of 1,4-dioxane, was dropwise added under stirring and cooling with ice over a period of 30 minutes. After the dropwise addition, the reaction mixture was refluxed under stirring for two hours. After cooling, ice pieces were gradually added to decompose the excess reducing agent, and the solvent was distilled off under reduced pressure. Then, the residue was extracted with chloroform. The extract was washed with a saturated sodium chloride aqueous solution, and dried over sodium sulfate, and then the solvent was distilled off to a concentration of about 80 ml. The concentrated solution was cooled with ice, and 10 ml of a dioxane solution of 6N HCl was dropwise added thereto. The precipitated solid substance was treated with methanol-ether to obtain 3.16 g of the above identified compound as a colorless powder. The NMR spectrum of the free amine is as follows:
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].CO[C:7]([C:9]1[C:14]([F:15])=[CH:13][C:12]([O:16][C:17]2[C:22]3[CH2:23][C:24]([CH3:27])([CH3:26])[O:25][C:21]=3[CH:20]=[C:19]([C:28](=[O:36])[NH:29][C:30]3[CH:34]=[CH:33][N:32]([CH3:35])[N:31]=3)[CH:18]=2)=[CH:11][N:10]=1)=[O:8]>>[CH3:2][N:3]([CH3:4])[C:7]([C:9]1[C:14]([F:15])=[CH:13][C:12]([O:16][C:17]2[C:22]3[CH2:23][C:24]([CH3:27])([CH3:26])[O:25][C:21]=3[CH:20]=[C:19]([C:28](=[O:36])[NH:29][C:30]3[CH:34]=[CH:33][N:32]([CH3:35])[N:31]=3)[CH:18]=2)=[CH:11][N:10]=1)=[O:8]
Reactant: COC(=O)c1ncc(Oc2cc(C(=O)Nc3ccn(C)n3)cc3c2CC(C)(C)O3)cc1F
Reactant: CNC
Agent: Cl
Product: CN(C)C(=O)c1ncc(Oc2cc(C(=O)Nc3ccn(C)n3)cc3c2CC(C)(C)O3)cc1F

Procedure:
The title compound was prepared in a similar manner as described for Example 1, from dimethyl amine hydrochloride (278 mg, 3.41 mmol) and 5-[2,2-dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-3-fluoro-pyridine-2-carboxylic acid methyl ester (175b) (150 mg, 0.341 mmol) to give a white solid (74 mg, 48% yield). 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1 H) 8.22 (d, J=1.77 Hz, 1 H) 7.27-7.31 (m, 1 H) 7.01-7.13 (m, 3 H) 6.78 (d, J=2.02 Hz, 1 H) 3.81 (s, 3 H) 3.16 (s, 3 H) 3.00 (s, 3 H) 2.92 (s, 2 H) 1.50 (s, 6 H); LCMS for C23H24FN5O4 m/z 454.20 (M+H+); Anal. Calcd. for C23H24FN5O4: C, 60.92; H, 5.33; N, 15.44. Found: C, 60.66; H, 5.37; N, 15.26.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:9])[N:4]([CH3:8])[N:5]=[CH:6][CH:7]=1.[Cl:10][C:11]1[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[CH:20][C:12]=1[O:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.Cl.FC(F)(F)C1C=CC=C[C:30]=1[O:31]C1CCNCC1>>[CH3:8][N:4]1[C:3](=[O:9])[C:2]([NH:1][C:30]([N:17]2[CH2:18][CH2:19][CH:14]([O:13][C:12]3[CH:20]=[C:21]([Cl:25])[C:22]([Cl:24])=[CH:23][C:11]=3[Cl:10])[CH2:15][CH2:16]2)=[O:31])=[CH:7][CH:6]=[N:5]1
Reactant: Cn1nccc(N)c1=O
Reactant: Clc1cc(Cl)c(OC2CCNCC2)cc1Cl
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Agent: Cl
Product: Cn1nccc(NC(=O)N2CCC(Oc3cc(Cl)c(Cl)cc3Cl)CC2)c1=O
Yield: 46 %

Procedure:
Compound 70 is prepared from intermediate 4c and from 4-(2,4,5-trichloro-phénoxy)-piperidine (obtained following the method described for intermediate 1a) applying synthesis method 7 (yield: 46%).
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[CH2:42]([NH2:47])[CH2:43][CH2:44][CH2:45][CH3:46]>C1COCC1>[CH2:42]([NH:47][C:30]([C:28]1[CH:27]=[CH:26][C:12]2[N:13]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[C:9]([CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:10][C:11]=2[CH:29]=1)=[O:31])[CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: O=C(O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Reactant: CCCCCN
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CCCCCNC(=O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mmol of 2-phenoxymethyl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid were dissolved in 1 ml THF with 1 eq. DIC. After 15 min 1.5 eq of n-pentylamine were added and the reaction stirred at room temperature for 16 h. The crude material was purified via reversed phase preparative HPLC. MS(ISP): 512.3 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:17])([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>O>[NH2:1][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([CH3:17])([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=1
Reactant: COC(=O)C(C)(C)c1ccc(CN=[N+]=[N-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)c1ccc(CN)cc1
Yield: 68.8 %

Procedure:
A solution of methyl 2-(4-azidomethylphenyl)-2-methylpropionate (48.1 g)and triphenylphosphine (59.5 g) in a mixed solvent of tetrahydrofuran (480 ml) and water (24 ml) was refluxed for 30 min. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (developing solvent; chloroform:methanol=10:1, chloroform:methanol:aqueous ammonia=10:1:0.3) to give the title compound (29.4 g) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H][H]>CCOC(C)=O.[Pd]>[NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: [H][H]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(N)c1N

Procedure:
Methyl 2-amino-3-nitrobenzoate (117; 3.2 g) was dissolved in EtOAc (100 mL) and 10% Pd on C (200 mg) was added. The resulting reaction mixture was hydrogenated under 1 atm of hydrogen at room temperature for 2 days and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford essentially quantitative yield of methyl 2,3-diaminobenzoate 118.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][N:5]([CH3:19])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)(=[O:8])=[O:7].[Li].[N+:22]([CH:25]([CH3:27])[CH3:26])([O-:24])=[O:23]>CS(C)=O>[ClH:15].[CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][N:5]([CH3:19])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:25]([CH3:27])([N+:22]([O-:24])=[O:23])[CH3:26])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)(=[O:8])=[O:7]
Reactant: CC(C)[N+](=O)[O-]
Reactant: CN(C)CCN(C)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Li]
Solvent: CS(C)=O
Product: CN(C)CCN(C)S(=O)(=O)c1ccc(C(C)(C)[N+](=O)[O-])c([N+](=O)[O-])c1
Product: Cl
Reaction time: 72 h
Yield: 9.9 %

Procedure:
A solution of N-(2-dimethylaminoethyl)-N-methyl-4-chloro-3-nitrobenzenesulfonamide base (15.65 g, 49 mmol) and the lithium salt of 2-nitropropane (4.66 g, 49 mmol) in dimethylsulfoxide (100 mL) was stirred under nitrogen at 20°-25° for 3 days. An additional 0.35 g of the lithium salt was then added and stirring continued for three days more. After pouring the reaction mixture on ice, product was extracted into a 1:1 mixture of ethyl acetate and toluene which was washed with water, dried (Na2SO4), filtered and concentrated. Flash chromatography of the residue over silica gel and elution with 3% methanol-97% methylene chloride afforded 2.0 g of product. Treatment with anhydrous ethanolic hydrogen chloride and recrystallization from methanol-ethyl acetate hexane gave the hydrochloride salt, m.p. 231°-32.5° dec.
Reaction SMILES: [NH2:1][C:2]1[C:33]([Cl:34])=[CH:32][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:35][CH3:36])[CH:3]=1.[CH:37](=O)[CH3:38].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:33]([Cl:34])=[CH:32][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:37][CH3:38])[CH2:23][C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: CC=O
Reactant: COc1ccc(CNCCCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccc(OC)cc1

Procedure:
4-Amino-5-chloro-2-methoxy-N-((1-(6-(4-methoxybenzylamino)hexyl)-piperidin-4-yl)methyl)benzamide (0.9 g) as starting compound, acetaldehyde (0.12 ml) and sodium cyanoborohydride (0.26 g) were reacted and treated in the same manner as in Example 136 to give 0.55 g of 4-amino-5-chloro-N-((1-(6-(N-ethyl-N-(4-methoxybenzyl)amino)hexyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[Cl:22][CH2:23][C:24](Cl)=[O:25]>CC(C)=O>[C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:24](=[O:25])[CH2:23][Cl:22])=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)CCl)cc1
Reaction time: 1 h
Yield: 85 %

Procedure:
4-(tert-Butyl-dimethyl-silanyloxy)-phenylamine (2.23 g, 10 mmol) was dissolved in acetone (25 ml). After addition of Na2CO3 (3.2 g, 30 mmol), chloroacetylchloride (0.96 ml, 12 mmol) was added dropwise. After 1 hour at room temperature, the reaction mixture was quenched with H2O (100 ml) and the aqueous phase was extracted with CH2Cl2 (3×10 ml). Combined organic phases were dried over Na2SO4 and concentrated. The residue was chromatographed over silica gel (hexane-ethyl acetate 9:1 then hexane-ethyl acetate 4:1) to provide N-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-2-chloro-acetamide (2.55 g, 71%) as a colorless solid, m.p. 107°-108° C. and MS: m/e=299 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1>CN(C)C=O>[ClH:1].[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]2=[NH:10])=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: Nc1ccccn1
Solvent: CN(C)C=O
Product: Cl
Product: N=c1ccccn1Cc1ccc(Cl)nc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 44 %

Procedure:
2-chloro-5-chloromethylpyridine in an amount of 3.00 g (18.6 mmol) was dissolved in 20 mL of anhydrous dimethylformamide (DMF), 1.75 g (18.6 mmol) of 2-aminopyridine was added, and the mixture was stirred out at 80° C. for 8 hours and at room temperature for 5 hours. Following reaction completion, DMF was distilled off under reduced pressure and acetonitrile was added, whereupon a solid separated out. The solid was collected by filtration, thoroughly washed with acetonitrile, then dried, giving 2.07 g of 1-[(6-chloropyridin-3-yl)methyl]pyridin-2(1H)-imine hydrochloride (yield, 44%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH2:8][CH2:9][C:10]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](O)=[O:13])[CH:7]=1.C([N:25](C(C)C)CC)(C)C>CN(C=O)C.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH2:8][CH2:9][C:10]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH2:25])=[O:13])[CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(Br)cc1CCc1c(F)cccc1C(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(Br)cc1CCc1c(F)cccc1C(N)=O
Reaction time: 1.5 h

Procedure:
To a solution of 2-[2-(5-bromo-2-methoxyphenyl)-ethyl]-3-fluorobenzoic acid (1.78 g, 5.1 mol, 1 equiv) in DMF (6 mL) at room temperature were added diisopropylethylamine (DIPEA) (1.95 mL, 11.2 mmol, 2.2 equiv) and fluoro-N,N,N′-tetramethylformamidinium hexafluorophosphate (TFFH) (1.48 g, 5.6 mmol, 1.1 equiv). The homogeneous solution was allowed to stir for 1.5 hr, during which time the color changed to green. Ammonia gas was bubbled into the solution and the color changed to yellow and a precipitate was formed. The heterogeneous slurry was allowed to stir for 5 hr and then diluted with H2O and ethyl acetate. The phases were separated and the organic portion was washed with brine, dried over MgSO4, filtered and concentrated to give 2-[2-(5-bromo-2-methoxyphenyl)-ethyl]-3-fluorobenzamide in quantitative yield. The crude product was used without further purification. LCMS ES+ 352 (M+1), 354 (M+3).
Reaction SMILES: [CH:1]1([CH:7]([N:11]2[C:15]3[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C@@H:22]([O:29][CH3:30])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8](O)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.S(Cl)(Cl)=O.[NH2:41][C:42]1[CH:52]=[CH:51][C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:44][CH:43]=1>ClCCl>[CH2:49]([O:48][C:46](=[O:47])[C:45]1[CH:51]=[CH:52][C:42]([NH:41][C:8](=[O:9])[CH:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:11]2[C:15]3[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C@@H:22]([O:29][CH3:30])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:43][CH:44]=1)[CH3:50]
Reactant: CO[C@@H](c1ccccc1)c1nc2cc(F)c(F)cc2n1C(C(=O)O)C1CCCCC1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c([C@@H](OC)c3ccccc3)nc3cc(F)c(F)cc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cyclohexyl-[5,6-difluoro-2-((S)-methoxy-phenyl-methyl)-benzoimidazol-1-yl]-acetic acid (160 mg, 0.39 mmol, 1.0 equiv.) in dichloromethane (2 ml) was added pyridine (0.046 ml, 1.5 equiv.). Thionyl chloride (0.034 ml, 1.2 eq) was added dropwise. The mixture was stirred 1 h at room temperature. A solution of ethyl 4-amino-benzoate (64 mg, 0.95 equiv., [CAS RN 94-09-7]) and pyridine (0.031 ml, 1.1 equiv.) in dichloromethane (2 ml) was added and the mixture stirred overnight at room temperature. The mixture was applied to a 5 g silica gel column (Biotage) and the product eluted with EtOAc to afford the title compound as an orange solid that was used without further purification. MS (ISP): 562.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#N)=[CH:4][C:3]=1[F:11].[OH2:12].S(=O)(=O)(O)[OH:14]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:14])=[O:12])=[CH:4][C:3]=1[F:11]
Reactant: N#CCc1ccc(Cl)c(F)c1
Reactant: O
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(Cl)c(F)c1
Temperature: 25 °C
Yield: 79 %

Procedure:
A mixture of the product of example 26 (7.8 g, 0.046 mol), water (7.5 ml), concentrated sulfuric acid (7.5 ml) and acetic acid (7.5 ml) was heated at reflux for 2 hours. After being cooled to room temperature, the mixture was poured into ice-water. The resulting solids were collected by filtration and washed by diethyl ether to give the titled product (6.8 g, 79%)
Reaction SMILES: [NH2:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:20](OCC)=[O:21]>>[CH:20]([NH:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:21]
Reactant: CCOC=O
Reactant: Nc1[nH]c(-c2ccc(F)cc2)nc1-c1ccccc1
Product: O=CNc1[nH]c(-c2ccc(F)cc2)nc1-c1ccccc1

Procedure:
A mixture of 5-amino-2-(4-fluorophenyl)-4-phenylimidazole (1.00 g) and ethyl formate (10 ml) was refluxed for 15 hours. After cooling, the reaction mixture was concentrated under reduced pressure and crystallized from diethyl ether to obtain 5-formylamino-2-(4-fluorophenyl)-4-phenylimidazole (1.17 g) as colorless crystal.