Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[C:24]([O:27][CH2:28][CH3:29])[C:25]=1F)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[O:16])[CH2:10][CH2:9]1)[CH3:2].C(OC1C=C(C=C(OCC)C=1[N:41]1[CH:45]=[CH:44][CH:43]=[CH:42]1)C=O)C.C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[C:24]([O:27][CH2:28][CH3:29])[C:25]=1[N:41]1[CH:45]=[CH:44][CH:43]=[CH:42]1)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[O:16])[CH2:10][CH2:9]1)[CH3:2]
Reactant: CCOc1cc(C=O)cc(OCC)c1-n1cccc1
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cncnc3)CC2)cc(OCC)c1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1cc(CN2CCC(NC(=O)c3cncnc3)CC2)cc(OCC)c1-n1cccc1

Procedure:
In analogy to the procedure described in example 50k), pyrimidine-5-carboxylic acid piperidin-4-ylamide (example 56) was reacted with 3,5-diethoxy-4-pyrrol-1-yl-benzaldehyde (example 40b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as light yellow solid. MS: 450.2 (MH+).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2([CH3:43])[O:42][CH2:41][CH2:40][NH:39][CH2:38]2)=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([N:39]3[CH2:40][CH2:41][O:42][C:37]([C:34]4[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=4)([CH3:43])[CH2:38]3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC1(c2ccc(Cl)cc2)CNCCO1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCOC(C)(c4ccc(Cl)cc4)C3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A mixture of (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate, 2-(4-chlorophenyl)-2-methylmorpholine and iPr2NEt (20.1 mg, 0.156 mmol) in DMF was heated at 100° C. for 10 hours. The mixture was evaporated to dryness and separated on CombiFlash, eluting with 0-70% EtOAc/Hex to give title compound. LCMS-ESI+: calc'd for C33H36Cl2N2O4S: 627.2, 629.2 (M+H+); found: 627.3, 629.3 (M+H+).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=1)[C:10](O)=[O:11]>C1(C)C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=1)[C:10]([Cl:3])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C(=O)O)ccn1
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)Cl)ccn1
Temperature: 80 °C
Yield: 45.8 %

Procedure:
Thionyl chloride (30.0 mL, 0.39 mol) was added to a suspension of 2-methoxy-isonicotinic acid (15.0 g, 97.9 mmol) in anhydrous toluene (150 mL). The mixture was heated at 80° C. under nitrogen for 3 hours, cooled to room temperature and filtered. The filtrate was concentrated in vacuo to afford the title compound 7.7 g (46% yield).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([N:12]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38]C)=[C:34]([Br:40])[CH:33]=2)=[CH:28][CH:27]=1)[C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH3:24])[CH:16]=1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)=O.CC(C)=O.O>C(Cl)Cl>[CH2:5]([N:12]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([Br:40])[CH:33]=2)=[CH:28][CH:27]=1)[C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH3:24])[CH:16]=1)=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COc1ccc(-c2ccc(CN(Cc3ccccc3)C(=O)c3cn(C)c4ccccc34)cc2)cc1Br
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cn1cc(C(=O)N(Cc2ccccc2)Cc2ccc(-c3ccc(O)c(Br)c3)cc2)c2ccccc21
Reaction time: 3 h
Yield: 78.8 %

Procedure:
Boron tribromide (22.0 mL of a 1 M solution in methylene chloride; 22.0 mmol) was added under nitrogen dropwise over 30 minutes to a solution of N-benzyl-N-[(3′-bromo-4′-methoxy-1,1′-biphenyl-4-yl)methyl]-1-methyl-1H-indole-3-carboxamide (4.3 g, 7.97 mmol), prepared in the previous step, in 150 mL of methylene chloride at dry ice-acetone temperature. After the addition the dry ice-acetone bath was replaced with an ice bath and the stirring continued for 3 h. At ice bath temperature water (100 mL) was added dropwise. The aqueous layer was separated and extracted two times with methylene chloride. The extracts were combined, extracted with saturated NaCl, dried (MgSO4) and the solvent removed under reduced pressure to give N-benzyl-N-[(3′-bromo-4′-hydroxy-1,1′-biphenyl-4-yl)methyl]-1-methyl-1H-indole-3-carboxamide (3.3 g, 76%) as a white solid, MS (ESI) m/z 525 [M+H]+. Elemental Analysis for C30H25BrN2O2: Calc'd: C, 68.58; H, 4.80; N, 5.33; Found: C, 67.54; H, 4.92; N, 5.17.
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:24]Br.O>ClCCl>[Br:24][C:19]1[CH:18]=[C:17]([C:14]2[N:15]=[CH:16][C:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:12][N:13]=2)[CH:22]=[CH:21][C:20]=1[OH:23]
Reactant: BrBr
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCc1cnc(-c2ccc(O)c(Br)c2)nc1
Reaction time: 2 h
Yield: 76.6 %

Procedure:
A solution of 5 g of 4-(5-decyl-2-pyrimidinyl)phenol in 50 ml of dichloromethane was treated at 0° C. while gassing with argon with a solution of 2.6 g of bromine in 50 ml of dichloromethane. The reaction mixture was stirred for a further 2 hours and then treated with water. The organic phase was separated and the aqueous phase was back-extracted three times with 50 ml of dichloromethane each time. The combined organic phases were washed with water, sodium hydrogen carbonate solution and again with water, dried over magnesium sulfate0 filtered and subsequently concentrated. The residue was purified by chromatography on silica gel with toluene/ethyl acetate (vol. 4;1). Recrystallization from hexane gave 4.8 g of 2-bromo-4-(5-decyl-2-pyrimidinyl)phenol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[N:16][C:17]([CH:20]([NH:22][C:23]([C:25]3[CH:29]=[CH:28][O:27][CH:26]=3)=O)[CH3:21])=[CH:18][N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[O:27]1[CH:28]=[CH:29][C:25]([C:23]2[N:16]3[C:17]([CH:18]=[N:19][C:14]([NH:13][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=4)=[N:15]3)=[C:20]([CH3:21])[N:22]=2)=[CH:26]1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccoc3)nn2)cc(OC)c1OC
Agent: c1nc[nH]n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccoc4)n3n2)cc(OC)c1OC
Yield: 50.5 %

Procedure:
In a similar manner as described for Example 9, N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)-3-furamide (Intermediate 37) (211 mg, 0.53 mmol), and 1,2,4-triazole (220 mg, 3.18 mmol) in pyridine (4 mL) and phosphorous oxychloride (0.15 mL, 1.60 mmol) gave 7-(3-furyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (102 mg, 51%) as a yellow solid. 1H NMR (CDCl3): δ8.78 (s, 1H), 8.56 (s, 1H), 7.52 (t, J=1.65 Hz, 1H), 7.20 (d, J=1.65, 1H), 6.87 (s, 2H), 6.82 (s, 1H), 3.90 (s, 6H), 3.87 (s, 3H), 2.60 (s, 3H). MS m/z 381 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C([O-])([O-])=O.[Cs+].[Cs+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH:26]([CH3:30])[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:26]([CH3:30])[CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1-Bromo-2-nitrobenzene (2.00 mmol, 404 mg), Pd(OAc)2 (0.100 mmol, 22.5 mg), Palucki-Phos (0.120 mmol, 45.8 mg) and Cs2CO3 (3 mmol, 1 g) were loaded into a Schlenk tube containing a stir bar. The tube was capped with a rubber septum, evacuated and refilled with nitrogen. 3-Methyl-piperazine-1-carboxylic acid tert-butyl ester (0.48 mL, 2.5 mmol) and toluene (3 mL) were added to the reaction through the septum via syringe and the tube was sealed with a Teflon screw cap under a flow of nitrogen, and put into an oil bath at 100° C. The reaction was allowed to stir at this temperature for about 15 hours and was then was cooled to room temperature and filtered through celite. The filtrate was concentrated in vacuo and the resulting residue was purified using flash column chromatography on silica gel (eluent: Hexane/EtOAc (5:1) to provide 3-methyl-4-(2-nitro-phenyl)-piperazine-carboxylic acid tert-butyl ester.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]1>CC(C)=O>[CH2:8]([N:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH:29]1[CH2:28][CH2:27][OH:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: OCCC1CCCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCN1CCCCC1CCO
Temperature: 40 °C
Reaction time: 18 h

Procedure:
Potassium carbonate (2.312 g) and 1-bromooctadecane (2.80 ml) were added to a solution of 2-(2-hydroxyethyl)piperidine (1.057 g) in acetone. The solution was stirred for 18 hours at 40° C. and was further stirred for 23 hours at 60° C. After the insoluble matter was filtrated out under a vacuum, the filtrate was concentrated. The residue was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 60 g, chloroform:methanol=30:1~10:1), thereby yielding the entitled compound (1.935 g) as white solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:26](Cl)[C:27]2[CH:32]=[C:31]([CH2:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[C:28]=2[F:37])[N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.CCN(C(C)C)C(C)C.[NH2:48][C:49]1[CH:50]=[C:51]2[C:56](=[CH:57][CH:58]=1)[C:55]([N:59]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])=[N:54][CH:53]=[CH:52]2>CC#N.C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[N:3]=[C:4]([CH:26]([NH:48][C:49]2[CH:50]=[C:51]3[C:56](=[CH:57][CH:58]=2)[C:55]([N:59]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[C:67]([O:69][C:70]([CH3:71])([CH3:72])[CH3:73])=[O:68])=[N:54][CH:53]=[CH:52]3)[C:27]2[CH:32]=[C:31]([CH2:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[C:28]=2[F:37])[N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1
Reactant: CCc1cc(OC)c(F)c(C(Cl)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cc(OC)c(F)c(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 40 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
To a solution of the chloro intermediate (350 mg, 0.594 mmol) in 5 mL CH3CN and 2 mL CH2Cl2 at rt, was added DIEA (0.207 mL, 1.19 mmol), di-tert-butyl (6-aminoisoquinolin-1-yl)imidodicarbonate (235 mg, 0.653 mmol). The mixture was stirred at rt for 18 h and at 40° C. for 3 h, then was diluted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 60% EtOAc/hexanes gradient) to afford 425 mg of Intermediate 206.4 as a colorless residue.
Reaction SMILES: Cl.[NH2:2][OH:3].[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12]1[N:17]=[C:16]([C:18]([NH:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][C:26]=2[C@H:27]2[CH2:32][C@@H:31]([NH:33]C(=O)OC(C)(C)C)[C:30](=O)[C@@H:29]([CH3:42])[CH2:28]2)=[O:19])[CH:15]=[CH:14][C:13]=1[F:43]>CCO.N1C=CC=CC=1>[NH2:33][C@@H:31]1[CH2:32][C@H:27]([C:26]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[NH:20][C:18](=[O:19])[C:16]2[CH:15]=[CH:14][C:13]([F:43])=[C:12]([C:6]3[C:5]([F:4])=[CH:10][CH:9]=[CH:8][C:7]=3[F:11])[N:17]=2)[CH2:28][C@H:29]([CH3:42])/[C:30]/1=[N:2]/[OH:3]
Reactant: NO
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](N)/C1=N\O
Reaction time: 16 h
Yield: 14 %

Procedure:
A solution of hydroxylamine-HCl (4.0 equiv.) and tert-butyl (1R,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-oxocyclohexylcarbamate (1.0 equiv.) in EtOH/pyridine (1/1, 0.01 M) was capped and left standing at rt for 16 hrs. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and Na2CO3(sat.). The organic layer was washed with NaCl(sat.), dried over MgSO4, filtered, concentrated. The Boc group was removed with 25% TFA/CH2Cl2. After 45 minutes, the volatiles were removed in vacuo and after pumping the residue was dissolved in DMSO and purified by RP-HPLC to yield N-(4-((1R,3R,5S,Z)-3-amino-4-(hydroxyimino)-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 14% yield. LC/MS (m/z)=470.3 (MH+), Rt=0.60 min. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.94 (s, 1H), 10.49 (s, 1H), 8.60 (s, 1H), 8.48 (d, J=4.0, 1H), 8.35 (dd, J=8.0, 4.0, 1H), 8.20 (t, J=8.0, 1H), 8.02 (broad doublet, J=4.0, 2H), 7.67-7.74 (m, 1H), 7.42 (d, J=4.0, 1H), 7.36 (t, J=8.0, 2H), 4.24 (m, 1H), 3.82-3.86 (m, 1H), 3.21-3.27 (m, 1H), 2.50-2.55 (m, 1H), 2.24 (d, J=12.0, 1H), 1.86 (d, J=16.0, 1H), 1.68 (q, J=12.0, 1H), 1.59 (q, J=12.0, 1H), 1.40 (d, J=8.0, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[C:11]2[CH3:28])=[CH:4][CH:3]=1.[F:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34]>>[F:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:29])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[C:11]2[CH3:28])=[CH:6][CH:7]=1)=[O:34]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(N)cc1
Product: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(NC(=O)c2ccccc2F)cc1

Procedure:
Synthesis in analogy to Example 8 starting from 3-[2-(4-amino-phenyl)-2-oxo-ethyl]-2-methyl-5,5-diphenyl-3,5-dihydro-imidazol-4-one and 2-fluoro-benzoyl chloride to yield 2-fluoro-N-{4-[2-(2-methyl-5-oxo-4,4-diphenyl-4,5-dihydro-imidazol-1-yl)-acetyl]-phenyl}-benzamide. LC/MS at 254 nm; [M+H] 506; Rt 3.438 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:16])[CH:9]([NH2:15])[CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.Cl.[CH2:18]([O:20][C:21]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:22]=1[C:23](=N)OCC)[CH3:19].ClC1C=CC(C2NC(C3C=CC(OC)=CC=3OCC)=NC2CC2CCCC2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:16][C:23]([C:22]3[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:21]=3[O:20][CH2:18][CH3:19])=[N:15][CH:9]2[CH2:10][CH2:11][CH:12]([CH3:13])[CH3:14])=[CH:6][CH:7]=1
Reactant: CCOC(=N)c1ccc(OC)cc1OCC
Reactant: CC(C)CCC(N)C(N)c1ccc(Cl)cc1
Agent: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1
Agent: Cl
Product: CCOc1cc(OC)ccc1C1=NC(CCC(C)C)C(c2ccc(Cl)cc2)N1

Procedure:
5-(4-Chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-(3-methyl-butyl)-4,5-dihydro-1H-imidazole was prepared from 1-(4-chloro-phenyl)-5-methyl-hexane-1,2-diamine and ethyl 2-ethoxy-4-methoxy-benzimidate hydrochloride in an analogous manner as described for the preparation of 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (Example 9). HR-MS (ES, m/z) observed 401.1994, calculated for C23H30N2O2Cl [(M+H)+]401.1991.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[Cl:7][C:8]1[C:13]([CH2:14]Cl)=[CH:12][N:11]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>C(#N)C>[Cl:7][C:8]1[CH:9]=[C:10]([C:16]([F:19])([F:17])[F:18])[N:11]=[CH:12][C:13]=1[CH2:14][C:5]#[N:6]
Reactant: FC(F)(F)c1cc(Cl)c(CCl)cn1
Reactant: C[Si](C)(C)C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#CCc1cnc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
Trimethylsilylcyanid (TMSCN) (69.3 g, 0.7 mol) was added to a solution of 4-chloro-5-(chloromethyl)-2-(trifluoromethyl)pyridine (Int-13) (80 g, 0.348 mol) and Tetra-n-butylammoniumfluoride (129.5 g, 0.7 mol) in acetonitrile (1.5 L) slowly. Then the mixture was stirred at 20-30° C. for 2 hours. Thin layer chromatography (petroleum ether: EtOAc=3:1) showed all of starting material was consumed. The mixture was concentrated and the residue was purified by silica gel chromatography eluted with petroleum ether: EtOAc=20:1˜3:1 to yield [4-chloro-6-(trifluoromethyl)pyridin-3-yl]acetonitrile (Int-14) (50 g, 60% from NMR, 39% of yield) as yellow syrup.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[O:11]1[CH2:16][CH2:15][CH:14]([C:17]#[N:18])[CH2:13][CH2:12]1.[Cl:19][CH2:20][CH2:21][CH2:22]I>C1COCC1.CCOCC>[Cl:19][CH2:20][CH2:21][CH2:22][C:14]1([C:17]#[N:18])[CH2:15][CH2:16][O:11][CH2:12][CH2:13]1
Reactant: ClCCCI
Reactant: N#CC1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#CC1(CCCCl)CCOCC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 99.6 %

Procedure:
To a stirred solution of 1 M LiHMDS (25 mL, 25 mmol) in THF (10 mL) at −78° C. was added dropwise a solution of tetrahydro-2H-pyran-4-carbonitrile (2.23 g, 20 mmol) in THF (15 mL) over 10 minutes. After 40 min, 1-chloro-3-iodopropane (2.7 mL, 25 mmol) was added at once, stirred at −78° C. for 1 h and 4 h room temperature. Then the reaction mixture was diluted with ether (100 mL), washed with water (20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated to give yellow oil which was purified by flash column chromatography using 10-30% EtOAc/Hexanes to afford the title compound as a colorless liquid (3.74 g, 99%). 1H NMR (500 MHz, CDCl3) δ: 3.97 (2H, dd, J=11.3, 3.7 Hz), 3.71 (2H, td, J=12.2, 1.8 Hz), 3.61 (2H, t, J=6.3 Hz), 2.05-1.98 (2H, m), 1.88 (2H, dd, J=13.4, 1.8 Hz), 1.77-1.74 (2H, m), 1.65-1.59 (2H, m).
Reaction SMILES: [NH:1]([C:8](=[O:29])[C:9]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=1)([C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[CH:41]1[CH:42]=[CH:43][C:44]2[N:49](O)N=[N:47][C:45]=2[CH:46]=1.C1(N)C=CC=CC=1N>CN(C=O)C>[NH2:47][C:45]1[CH:46]=[CH:41][CH:42]=[CH:43][C:44]=1[NH:49][C:24]([C:23]1[CH:27]=[CH:28][C:20]([C:9]([OH:10])([C:8]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:29])[C:11]([NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:12])=[CH:21][CH:22]=1)=[O:26]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(C(O)(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1ccc(C(O)(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
To a solution of 4-[2-anilino-1-(anilinocarbonyl)-1-hydroxy-2-oxoethyl]benzoic acid (31 mg, 0.079 mmol) in DMF (1.5 mL) at room temperature was added EDCI (18 mg, 0.094 mmol) and HOBT (13 mg, 0.096 mmol). The solution was stirred for 30 min and 1,2-phenylenediamine (31 mg, 0.29 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 18 h and purified by reverse phase HPLC (30% to 95% MeCN in water) to give 2-(4-{[(2-aminophenyl)amino]carbonyl}phenyl)-2-hydroxy-N,N′-diphenylmalonamide (26 mg, TFA salt, 55%) as a white solid: 1H NMR (600 MHz, DMSO-d6) δ 10.10 (s br, 2H), 9.64 (s br, 1H), 7.97 (d, J=8.5 Hz, 2H), 7.82 (d, J=8.5 Hz, 2H), 7.70 (s, 1H), 7.69 (d, J=7.6 Hz, 2H), 7.32 (td, J=7.3, 2.1 Hz, 4H), 7.15 (d, J=7.3 Hz, 1H), 7.09 (t, J=6.4 Hz, 2H), 6.95 (td, J=8.2, 1.8 Hz, 1H), 6.76 (dd, J=7.9, 1.5 Hz, 1H), 6.58 (t, J=7.6 Hz, 1H), 4.89 (s br, 2H); ESIMS calcd 481.2 (M++H), found 481.1 (M++H).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][C:8](=[O:10])[O:7][C:5]1=[O:6])[CH:2]=[CH2:3].[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[NH2:15].C(N(CC)CC)C.C1(C)C(C)=CC=CC=1>O>[Cl:11][C:12]1[CH:13]=[C:14]([N:15]=[C:5]([OH:6])[CH:4]([CH2:1][CH:2]=[CH2:3])[CH2:9][C:8]([OH:7])=[O:10])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: C=CCC1CC(=O)OC1=O
Reactant: Nc1cc(Cl)cc(Cl)c1
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCC(CC(=O)O)C(O)=Nc1cc(Cl)cc(Cl)c1
Reaction time: 4 h
Yield: 89.4 %

Procedure:
28 g (0.2 moles) of allylsuccinic acid anhydride, 32.4 g (0.2 moles) of 3,5-dichloroaniline, 0.6 g of triethylamine and 150 ml of xylene are reacted at 125° C., with stirring. The water produced during the reaction is removed azeotropically by way of a water separator. The duration of the reaction is 4 hours. The solvent is subsequently drawn off and the residue is recrystallized from ethyl acetate with the addition of active carbon. The product has a melting point of 121° C. The yield is 89.4% of the theoretical yield.