Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:27](O)=[O:28])=[CH:4][C:5]2[N:9]=[C:8]([NH:10][C:11]3[S:12][C:13]4[CH:19]=[C:18]([O:20][C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:16][C:14]=4[N:15]=3)[N:7]([CH3:25])[C:6]=2[CH:26]=1.[CH2:30]([NH2:32])[CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:30]([NH:32][C:27]([C:3]1[C:2]([F:1])=[CH:26][C:6]2[N:7]([CH3:25])[C:8]([NH:10][C:11]3[S:12][C:13]4[CH:19]=[C:18]([O:20][C:21]([F:23])([F:24])[F:22])[CH:17]=[CH:16][C:14]=4[N:15]=3)=[N:9][C:5]=2[CH:4]=1)=[O:28])[CH3:31]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)c(F)cc21
Reactant: CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1cc2nc(Nc3nc4ccc(OC(F)(F)F)cc4s3)n(C)c2cc1F

Procedure:
6-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid ethylamide (65 mg) was prepared by following General Procedure F starting from 6-fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), ethylamine (2 M in THF, 235 uL), HBTU (107 mg), and DIEA (62 uL). LC/MS: m/z 454.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.34 (bs, 1H), 8.17 (s, 1H), 7.93 (s, 1H), 7.85 (s, 1H), 7.73 (s, 1H), 7.48 (s, 1H), 7.36 (d, 1H), 3.61 (bs, 3H), 3.33-3.21 (m, 2H), 1.14 (t, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=1[CH3:15])[CH2:4][CH3:5])[CH3:2].[OH:16][CH2:17][C:18]([NH:20][CH2:21][C@H:22]([OH:36])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[NH:34])[NH:32]O)=[C:27]([CH3:35])[CH:26]=1)=[O:19]>>[CH2:4]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:14][N:34]=[C:31]([C:28]3[CH:29]=[CH:30][C:25]([O:24][CH2:23][CH:22]([OH:36])[CH2:21][NH:20][C:18](=[O:19])[CH2:17][OH:16])=[CH:26][C:27]=3[CH3:35])[N:32]=2)=[CH:9][C:8]=1[CH3:15])[CH2:1][CH3:2])[CH3:5]
Reactant: CCN(CC)Cc1sc(C(=O)O)cc1C
Reactant: Cc1cc(OC[C@@H](O)CNC(=O)CO)ccc1C(=N)NO
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(OCC(O)CNC(=O)CO)cc3C)no2)cc1C
Yield: 5.2 %

Procedure:
The title compound (3 mg) is prepared starting from 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (30 mg, 130 μmol) and (S)-2-hydroxy-N-(2-hydroxy-3-[4-(N-hydroxycarbamimidoyl)-3-methyl-phenoxy]-propyl)-acetamide (35 mg, 117 μmol) according to Method A; LC-MS: tR=0.50 min; [M+1]+=489.23.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH:14]=[CH2:15])[C:10](O)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C([Cl:19])=O>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH:14]=[CH2:15])[C:10]([Cl:19])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CC[C@H](C(=O)O)c1ccc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CC[C@H](C(=O)Cl)c1ccc(Cl)c(Cl)c1
Reaction time: 2 h

Procedure:
Combine (S)-2-(3,4-dichlorophenyl)pent-4-enoic acid (6.55 g, 26.7 mmol), dichloromethane (10 mL), and dimethylformamide (2 drops). Add a solution of oxalyl chloride (16 mL, 2 M, 32 mmol) in dichloromethane. After 2 hours, evaporate in vacuo to give (S)-2-(3,4-dichlorophenyl)pent-4-enoyl chloride. Combine with toluene (20 mL) and slowly add, with vigorous stirring, to a cooled (ice bath) aqueous solution of methylamine (4 mL, 40%) while maintaining the temperature of the reaction mixture at less than 10° C. When the addition is complete add toluene (40 mL). After 1 hour, partition the reaction mixture between water and dichloromethane. Separate the layers, extract the organic layer with a saturated aqueous sodium bicarbonate solution, dry over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 10% ethyl acetate/hexane, 20% ethyl acetate/hexane, and 30% ethyl acetate/hexane to give (S)-2-(3,4-dichlorophenyl)pent-4-enoic acid, N-methyl amide: Rf=0.50 (silica gel, 50% ethyl acetate/hexane).
Reaction SMILES: [Si]([O:8][C@H:9]([CH3:41])[C@@H:10]([NH:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[C:33]([Cl:39])[C:32]=1[CH3:40])[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][Si](C(C)(C)C)(C)C)[CH:17]=2)=[N:14][N:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[Cl:39][C:33]1[C:32]([CH3:40])=[C:31]([NH:30][C@@H:10]([C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)=[N:14][N:15]=2)[C@H:9]([OH:8])[CH3:41])[CH:38]=[CH:37][C:34]=1[C:35]#[N:36]
Reactant: Cc1c(N[C@@H](c2nnc(-c3cccc(O[Si](C)(C)C(C)(C)C)c3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: Cc1c(N[C@@H](c2nnc(-c3cccc(O)c3)o2)[C@@H](C)O)ccc(C#N)c1Cl

Procedure:
4-((1R,2R)-2-(tert-butyldimethylsilyloxy)-1-(5-(3-(tert-butyldimethylsilyloxy)phenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-chloro-3-methylbenzonitrile (intermediate 9c) (226 mg, 0.37 mmol) was deprotected using tetrabutylammonium fluoride (1.0 M solution in THF, 1.5 mL, 1.5 mmol) as described in the preparation of example 7. After column chromatography (80% EtOAc/hexanes) the title compound was isolated as a white solid (140 mg, quant.). 1H NMR (500 MHz, acetone-d6, δ in ppm) 8.87 (br s, 1H), 7.46 (m, 3H), 7.37 (at, J=8.1 Hz, 1H), 7.05 (m, 1H), 6.87 (d, J=8.7 Hz, 1H), 5.86 (d, J=8.8 Hz, 1H), 5.06 (dd, J=5.5, 8.8 Hz, 1H), 4.73 (br s, 1H), 4.53 (m, 1H), 2.35 (s, 3H), 1.42 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:24]([OH:25])[CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH:20]2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41]COCC[Si](C)(C)C)=[CH:37][CH:36]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(Cl)Cl>CO>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:24]([OH:25])[CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH:20]2[O:33][CH2:34][C:35]2[CH:36]=[CH:37][C:38]([OH:41])=[CH:39][CH:40]=2)=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc(OCOCC[Si](C)(C)C)cc2)C1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(O)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc(O)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
(β) A solution of 2.16 g (3.113 mmol) of tert-butyl (3RS,4SR,5SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-hydroxy-3-[4-(2-trimethylsilanyl-ethoxymethoxy)-benzyloxy]-piperidine-1-carboxylate in 50 ml of methanol was treated with 2.02 ml (4.046 mmol) of an anhydrous 2M hydrogen chloride solution in methanol and stirred at room temperature for 2 hours. Subsequently, the mixture was treated with 100 ml of a 95:5 mixture of methylene chloride and methanol (extracted against 5 volume % of a saturated aqueous ammonia solution) and the solution was evaporated on a rotary evaporator at 30° C. The white solid (2.17 g) was thereupon chromatographed on silica gel using a 4:1 mixture of methylene chloride and ethyl acetate as the eluent. There were obtained 780 mg (45% of theory) of tert-butyl (3RS,4SR,5SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-hydroxy-3-(4-hydroxy-benzyloxy)-piperidine-1-carboxylate in the form of a colourless oil; MS: 581 (M+NH4)+.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1B(O)O>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:14]3[CH:15]=[C:16]([C:19]([F:21])([F:22])[F:20])[CH:17]=[CH:18][C:13]=3[Cl:12])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1Cl
Reactant: Clc1nc2c(Br)cccn2n1
Product: FC(F)(F)c1ccc(Cl)c(-c2cccn3nc(Cl)nc23)c1

Procedure:
2-Chloro-8-(2-chloro-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.50 g, 2.15 mmol) and 2-chloro-5-trifluoromethylphenylboronic acid (0.72 g, 3.23 mmol) in a manner analogous to Example 2c (0.115 g, 16%). MP=156-158° C. MS=332 (MH)+.
Reaction SMILES: [F:1][C:2]1([F:13])[CH2:7][CH2:6][CH:5]([C:8](OCC)=[O:9])[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[F:1][C:2]1([F:13])[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1CCC(F)(F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCC(F)(F)CC1
Temperature: 0 °C

Procedure:
Under nitrogen atmosphere, 2.3 g of ethyl 4,4-difluorocyclohexanecarboxylate was dissolved in 50 ml of tetrahydrofuran. Thereto 0.46 g of lithium aluminum hydride was added at 0° C. and the mixture was stirred at 0° C. for an hour. Thereafter, 1N aqueous sodium hydroxide was added to the reaction mixture, and formed solids were filtered and then washed with ethyl acetate. The filtrate and the washing solution were combined, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain (4,4-difluorocyclohexyl)methanol.
Reaction SMILES: [CH2:1]([N:3]([CH3:15])[CH:4]=[N:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([OH:13])=[CH:8][C:7]=1[CH3:14])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:23]1[S:24][C:25]([Cl:30])=[C:26]([CH:28]=[O:29])[N:27]=1.[Na+].[Cl-]>CN(C=O)C.CO.ClCCl>[Cl:30][C:25]1[S:24][C:23]([O:13][C:9]2[C:10]([CH3:12])=[CH:11][C:6]([N:5]=[CH:4][N:3]([CH2:1][CH3:2])[CH3:15])=[C:7]([CH3:14])[CH:8]=2)=[N:27][C:26]=1[CH:28]=[O:29]
Reactant: O=Cc1nc(Cl)sc1Cl
Reactant: CCN(C)C=Nc1cc(C)c(O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CCN(C)C=Nc1cc(C)c(Oc2nc(C=O)c(Cl)s2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
To a solution of 3.57 g (17 mmol) of N-ethyl-N′-(4-hydroxy-2,5-dimethylphenyl)-N-methylimidoformamide in 60 ml of DMF were added 2.51 g (18 mmol) of potassium carbonate and the mixture was stirred at ambient temperature for 30 min. Then 3.00 g (16.5 mmol) of 2,5-dichloro-1,3-thiazole-4-carbaldehyde were added and the mixture was stirred at ambient temperature for 7 days. Then the reaction mixture was poured on water, dichloromethane and some NaCl was added, layers were separated, the water layer was extracted with dichloromethane, the organic phase was dried over sodium sulfate and evaporated. Column chromatographic (gradient: dichloromethane->methanol) yielded 4.40 g (12.5 mmol) 67% of N′-{4-[(5-chloro-4-formyl-1,3-thiazol-2-yl)oxy]-2,5-dimethylphenyl}-N-ethyl-N-methylimidoformamide log P (pH 2.3)=1.51
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[I:12]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[I:12]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1nc(Cl)c(I)cc1[N+](=O)[O-]
Yield: 89.6 %

Procedure:
To a suspension of 6-chloro-3-nitropyridin-2-amine (6.3 g, 36.3 mmol) in ethanol (110 mL), 9.2 g (36.3 mmol) of iodine and 11.32 g (36.3 mmol) of silver sulphate were added. The crude mixture was stirred at room temperature overnight and the precipitate formed was filtered off. The solid isolated was purified by flash chromatography (1:1 hexane/ethyl acetate) to give the title compound (9.74 g, 88% of yield).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].Cl[C:12]([CH3:20])([CH2:14][CH2:15][C:16](Cl)([CH3:18])[CH3:17])[CH3:13].C1(O)C=CC=CC=1>>[CH:1]([C:4]1[C:5]([OH:10])=[CH:6][C:7]2[C:12]([CH3:20])([CH3:13])[CH2:14][CH2:15][C:16]([CH3:18])([CH3:17])[C:8]=2[CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1O
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Solvent: Oc1ccccc1
Product: CC(C)c1cc2c(cc1O)C(C)(C)CCC2(C)C

Procedure:
In a manner similar to Example 7(a) above, by the reaction of 30 g (0.22 mol) of 2-isopropylphenol with 40.3 g (0.22 mol) of 2,5-dichloro-2,5-dimethylhexane, 48.9 g (90%) of the expected phenol of melting point 79°-80° C. were obtained after chromatography on a silica column eluted with a mixture of dichloromethane and hexane (40/60).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=S)=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[OH:19].O=O.[K+].O>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:19][C:13]3[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=3[N:11]=2)=[CH:4][CH:3]=1
Reactant: S=C=Nc1ccc(Br)cc1
Reactant: Nc1cc(Cl)ccc1O
Agent: O=O
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Clc1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
4-Bromophenyl isothiocyanate (3.639 g, 17.00 mmol) was added to a solution of 2-amino-4-chlorophenol (2.441 g, 17.00 mmol) in acetonitrile (20 mL) and the reaction was stirred at room temperature for 2 h. The resulting brown solution was then added dropwise, via a dropping funnel, to a suspension of potassium superoxide (6.04 g, 85.0 mmol) in acetonitrile (20 mL) pre-cooled to 0° C. in an ice bath. After 20 minutes the initial exotherm had subsided and the reaction was allowed to warm to room temperature for 40 minutes. Water (120 mL) was added dropwise and the resulting off-white solid was collected by filtration, washed with additional water (60 mL) and dried overnight on a lyophilizer to afford N2-(4-bromophenyl)-5-chloro-1,3-benzoxazol-2-amine as an off-white solid (4.06 g, 74%);
Reaction SMILES: [N+:1]([O-:15])([O:3][CH2:4][CH:5]([O:11][N+:12]([O-:14])=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][OH:10])=[O:2].[CH2:16]([O:18][C:19]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[N:41]([C:42]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[N:40]=[N:39][N:38]=3)=[CH:27][CH:26]=2)[C:22]2[C:61]([C:65]([O:67][C:68]([CH3:83])([O:70][C:71](OC3C=CC([N+]([O-])=O)=CC=3)=[O:72])[CH3:69])=[O:66])=[CH:62][CH:63]=[CH:64][C:21]=2[N:20]=1)[CH3:17]>ClCCl>[CH2:16]([O:18][C:19]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[N:41]([C:42]([C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[N:40]=[N:39][N:38]=3)=[CH:27][CH:26]=2)[C:22]2[C:61]([C:65]([O:67][C:68]([O:70][C:71]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([O:11][N+:12]([O-:14])=[O:13])[CH2:4][O:3][N+:1]([O-:15])=[O:2])=[O:72])([CH3:83])[CH3:69])=[O:66])=[CH:62][CH:63]=[CH:64][C:21]=2[N:20]=1)[CH3:17]
Reactant: O=[N+]([O-])OCC(CCCCO)O[N+](=O)[O-]
Reactant: CCOc1nc2cccc(C(=O)OC(C)(C)OC(=O)Oc3ccc([N+](=O)[O-])cc3)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOc1nc2cccc(C(=O)OC(C)(C)OC(=O)OCCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6-Hydroxyhexane-1,2-diyl dinitrate (intermediate 1, 0.082 g, 0.36 mmol) and N,N-dimethylaminopyridine (0.029 g, 0.11 mmol) were added to a stirred dichloromethane (3.5 mL) solution of 1-methyl-1-{[(4-nitrophenoxy)carbonyl]oxy}ethyl 2-ethoxy-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate (intermediate 9, 0.220 g, 0.24 mmol). The solution was stirred at room temperature for 18 hours. Then it was washed with a 5% solution of sodium dihydrogenphosphate (2×10 mL) and brine (10 mL). The organic layer was dried over sodium sulfate, concentrated and purified by flash chromatography (Biotage SP1, 25+M column, TLC method n-hexane/EtOAc 6/4, Rf 0.4), affording the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.04-8.01 (m, 1H), 7.63-7.61 (m, 2H), 7.46-7.18 (m, 12H), 6.98-6.90 (m, 8H), 6.91 (t, 1H), 6.81 (d, 3H), 6.68 (d, 2H), 5.62 (s, 2H), 5.25-5.23 (m, 1H), 4.72 (dd, 1H), 4.28-4.26 (m, 2H), 4.05 (t, 2H), 1.78-1.52 (m, 10H), 1.49-1.42 (m, 6H).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Cl:5][C:6]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:7]=1[CH:8]=[C:9]1[NH:13][C:12](=[O:14])[CH:11]=[C:10]1[OH:15]>C(O)(=O)C>[Cl:5][C:6]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:7]=1[CH:8]=[C:9]1[NH:13][C:12](=[O:14])[C:11](=[N:1][OH:3])[C:10]1=[O:15]
Reactant: O=N[O-]
Reactant: O=C1C=C(O)C(=Cc2cccc(Cl)c2Cl)N1
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=Cc2cccc(Cl)c2Cl)C(=O)C1=NO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An aqueous solution of 1.1 mmol (0.075 g) sodium nitrite was added dropwise to an ice-cooled solution of 2 mmol 5-(2,3-dichlorobenzylidene)-4-hydroxy-1,5-dihydropyrrol-2-one (prepared in accordance with H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, 331, 389-394) and H.-D. Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199) and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in 5 ml glacial acetic acid, while stirring. The resulting solution was then stirred at room temperature for 30 minutes and concentrated in vacuo. The residue is purified by recrystallization from ethanol. The yield of 5-(2,4-dichlorobenzylidene)-pyrrolidine-2,3,4-trione 3-oxime was 55%, with a melting point of 180° C.
Reaction SMILES: [NH2:1][C:2]([C:28]1[NH:32][C:31]2[CH:33]=[CH:34][C:35]([C:37]#[N:38])=[CH:36][C:30]=2[N:29]=1)([C:7]1[C:15]([Br:16])=[CH:14][C:13]([CH3:17])=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2S(C1C=CC(C)=CC=1)(=O)=O)[C:3]([F:6])([F:5])[F:4].[O-]CC.[Na+]>CCO>[NH2:1][C:2]([C:28]1[NH:32][C:31]2[CH:33]=[CH:34][C:35]([C:37]#[N:38])=[CH:36][C:30]=2[N:29]=1)([C:7]1[C:15]([Br:16])=[CH:14][C:13]([CH3:17])=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[C:3]([F:5])([F:4])[F:6]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(N)(c4nc5cc(C#N)ccc5[nH]4)C(F)(F)F)c(Br)cc(C)c32)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Br)c(C(N)(c2nc3cc(C#N)ccc3[nH]2)C(F)(F)F)c2cc[nH]c12
Temperature: 60 °C

Procedure:
To (±)-2-(1-amino-1-(5-bromo-7-methyl-1-tosyl-1H-indol-4-yl)-2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-5-carbonitrile (203 mg, 0.337 mmol) in EtOH (3.3 mL) was added sodium ethoxide (22% solution in EtOH) (2.5 mL, 6.74 mmol) and the mixture was stirred at 60° C. After 3 hours the reaction mixture was purified directly by flash chromatography (0-100% EtOAc in heptanes) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.61 (br. s., 1H) 11.37 (br. s., 1H) 8.25 (m) 7.94 (m) 7.83-7.90 (m) 7.51-7.61 (m) 7.33 (br. s., 1H) 7.16 (s, 1H) 6.92 (br. s., 1H) 3.22 (s, 2H) 2.46 (d, J=0.51 Hz, 3H). HRMS calcd. for C19H13BrF3N5 (M+H)+ 448.0379. found 448.0389.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=O)=[CH:5][CH:4]=1.[CH2:13]([NH:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])[CH3:14].[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:13]([NH:15][C:16]([N:18]1[CH2:19][CH2:20][N:21]([CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=3)[CH2:7][CH2:8]2)[CH2:22][CH2:23]1)=[O:17])[CH3:14]
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: CCNC(=O)N1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Product: CCNC(=O)N1CCN(C2CCc3ccc(OC)cc32)CC1

Procedure:
The title compound was prepared by the above procedure using 6-methoxy-1-indanone (2.4 g, 15 mmol), N-ethyl-1-piperazinecarboxamide (2.4 g, 15 mol), titanium(IV) isopropoxide (6 mL, 18 mmol) and sodium borohydride (2.7 g, 67 mmol) to give 2.8 g of product as the fumarate salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]=[C:12]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([Cl:25])=[CH:19][C:18]=2[Cl:26])[NH:11]1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:34]([S:46]SC(=N)N)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].C(OCC)(=O)C>C(O)C>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([S:46][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:12]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([Cl:25])=[CH:19][C:18]=2[Cl:26])=[N:11]1
Reactant: COc1cc(Nc2cc(=O)n(-c3c(Cl)cc(Cl)cc3Cl)[nH]2)c(Cl)cc1Cl
Reactant: CCCCCCCCCCCCSSC(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCCCCCCCCCSC1C(=O)N(c2c(Cl)cc(Cl)cc2Cl)N=C1Nc1cc(OC)c(Cl)cc1Cl
Reaction time: 0.17 h

Procedure:
15.1 g of 1-(2,4,6-trichlorophenyl)-3-(2,4-dichloro-5-methoxyanilino)-5-pyrazolone was dissolved in 500 ml of 80% ethanol (ratio by volume of ethanol:water=4:1), and 2.5 g of potassium carbonate was added thereto. A solution prepared by dissolving 10.4 g of S-(n-dodecylthio)isothiourea hydrochloride in 100 ml of ethanol was added dropwise thereto over 10 minutes with stirring while heating on a steam bath, and the mixture was stirred for another 10 minutes. After cooled rapidly under a water stream, 300 ml of ethyl acetate was added thereto, and the mixture was washed twice with water. After drying the ethyl acetate layer with anhydrous sodium sulfate, sodium sulfate was removed and the solvent was removed by condensing under a reduced pressure. The residue was crystallized with acetonitrile. The resulting crystals were recrystallized with acetonitrile-ethyl acetate (ratio by volume: 10:1) to obtain 18 g of the coupler having a melting point of 100° to 102° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:14]([CH3:34])[C:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=3[F:25])[N:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:16]=2[CH3:33])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+].[NH:75]1[CH2:80][CH2:79][O:78][CH2:77][CH2:76]1>C1(C)C=CC=CC=1.O.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]>[N:8]1([C:5]2[C:4]([N:14]([CH3:34])[C:15]3[C:24]4[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=4[F:25])[N:18]=[C:17]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[C:16]=3[CH3:33])=[CH:3][C:2]([N:75]3[CH2:80][CH2:79][O:78][CH2:77][CH2:76]3)=[CH:7][N:6]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1N(C)c1cc(Br)cnc1N1CCOCC1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1N(C)c1cc(N2CCOCC2)cnc1N1CCOCC1
Temperature: 100 °C
Reaction time: 21 h

Procedure:
A stirred mixture of N-(5-bromo-2-morpholinopyridin-3-yl)-5,7-difluoro-N,3-dimethyl-2-(pyridin-2-yl)quinolin-4-amine (12.0 mg, 0.023 mmol), tris(dibenzylideneacetone)dipalladium (0) (2.1 mg, 2.280 μmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl (2.2 mg, 4.56 μmol), and sodium tert-butoxide (15 mg, 0.153 mmol) in toluene (2 mL) was purged three times with argon and placed under vacuum three times. Before heating, morpholine (9.93 μL, 0.114 mmol) was added and the mixture was heated to 100° C. Stirring continued for 21 h. After which the reaction was cooled to rt, diluted with water and extracted with EtOAc (3×10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was dissolved in MeOH and purified by HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution) to yield N-(2,5-di-4-morpholinyl-3-pyridinyl)-5,7-difluoro-N,3-dimethyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, CD3OD) δ ppm 8.66 (1H, d, J=4.7 Hz), 8.01 (1H, m), 7.78 (1H, d, J=7.8 Hz), 7.61-7.67 (1H, m), 7.60 (1H, d, J=2.7 Hz), 7.51 (1H, m), 7.23 (1H, m), 7.10 (1H, br. s.), 3.82-3.92 (4H, m), 3.35-3.44 (4H, m), 3.31 (4H, m), 3.17-3.28 (4H, m), 2.46 (3H, br. s.), 1.94-2.04 (3H, s); Mass Spectrum (ESI) m/e=533.2 (M+1).