Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([CH:14]=[N:15][O:16][CH2:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)[C:4]([CH3:27])=[N:3]1.[OH-].[Na+:29]>O>[CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:5]([CH:14]=[N:15][O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([O-:24])=[O:23])=[CH:25][CH:26]=2)[C:4]([CH3:27])=[N:3]1.[Na+:29]
Reactant: Cc1nn(C)c(Oc2ccccc2)c1C=NOCc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nn(C)c(Oc2ccccc2)c1C=NOCc1ccc(C(=O)[O-])cc1
Reaction time: 2 h

Procedure:
1.0 Gram (0.0027 mole) of 4-[(1,3-dimethyl-5-phenoxypyrazol-4-yl)methyleneaminooxymethyl]benzoic acid and 0.07 g (0.0028 mole) of sodium hydroxide were added to 10 ml of water, and the resulting mixture was stirred for 2 hours. After completion of the reaction, water was removed by evaporation under reduced pressure to obtain the desired compound in a quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:5]=[C:6]([Cl:23])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1.CI.[C:32](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:5]=[C:6]([Cl:23])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:32])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=1
Reactant: FC(F)(F)c1ccc(NCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(CCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)c1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
A mixture of 0.37 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(4-(trifluoromethyl) phenylamino)propyloxy)benzene, 0.1 ml of methyl iodide, 0.12 g of potassium carbonate and 10 ml of N,N-dimethylformamide was stirred at 50° C. for 3 hours. After cooling to room temperature, the reaction mixture was poured into ice-water, and extracted twice with 50 ml of ethyl acetate. The combined ethyl acetate layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.26 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(methyl(4-(trifluoromethyl)phenyl)amino)propyloxy)benzene (68% yield), nD25.5 1.5593.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][NH:9][C:8]=2[C:12]([NH:14][NH:15][C:16]([O:18]C)=O)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O>[C:1]1([C:7]2[CH:11]=[CH:10][N:9]3[C:8]=2[C:12](=[O:13])[NH:14][NH:15][C:16]3=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)NNC(=O)c1[nH]ccc1-c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=c1[nH][nH]c(=O)n2ccc(-c3ccccc3)c12
Temperature: 85 °C
Yield: 88 %

Procedure:
To a solution of methyl 2-(3-phenyl-1H-pyrrole-2-carbonyl)hydrazinecarboxylate (4.00 g, 15.0 mmol) in ethanol (60 mL) was added potassium hydroxide (4.33 g, 770 mmol) at room temperature and heated to 85° C. for 30 min. The reaction mixture was evaporated under reduced pressure to give a brown solid, which was redissolved in water (100 mL) and acidified with saturated citric acid solution to pH 7. The solid obtained was filtered through the Buchner funnel and further it was triturated with hexane to yield 8-phenyl-2,3-dihydropyrrolo[1,2-d][1,2,4]triazine-1,4-dione (3.00 g, 86.0%) as a white solid. LCMS method B-3: retention time 1.59 min, [M+1]=228.0. 1H NMR (400 MHz, DMSO-d6) δ ppm: 6.88 (d, J=2.8 Hz, 1H), 7.29-7.39 (m, 3H), 7.64-7.66 (m, 2H), 7.76 (d, J=2.8 Hz, 1H), 11.43 (br s, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:22])[CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:19](=[O:20])[C:14]2[N:15]=[C:16]([CH3:18])[S:17][C:13]=2[C:12](=[O:21])[CH:11]=1.CO[C:25]1[C:44](=[O:45])[C:29]2[N:30]=[C:31]([C:33]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)=[O:34])[S:32][C:28]=2[C:27](=[O:46])[CH:26]=1>C(O)C>[CH3:43][O:42][C:39]1[CH:38]=[CH:37][C:36]([NH:35][C:33]([C:31]2[S:32][C:28]3[C:27](=[O:46])[CH:26]=[C:25]([NH:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:22])[CH2:6][CH2:7][CH2:8][NH:9][C:10]4[C:19](=[O:20])[C:14]5[N:15]=[C:16]([CH3:18])[S:17][C:13]=5[C:12](=[O:21])[CH:11]=4)[C:44](=[O:45])[C:29]=3[N:30]=2)=[O:34])=[CH:41][CH:40]=1
Reactant: Cc1nc2c(s1)C(=O)C=C(NCCCN(C)CCCN)C2=O
Reactant: COC1=CC(=O)c2sc(C(=O)Nc3ccc(OC)cc3)nc2C1=O
Solvent: CCO
Product: COc1ccc(NC(=O)c2nc3c(s2)C(=O)C=C(NCCCN(C)CCCNC2=CC(=O)c4sc(C)nc4C2=O)C3=O)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 9 %

Procedure:
5-({3-[(3-aminopropyl)(methyl)amino]propyl}amino)-2-methyl-1,3-benzothiazole-4,7-dione is solubilized in 250 ml of ethanol and 2.12 g (6.16 mmol; 0.8 equivalent) of 5-methoxy-N-(4-methoxyphenyl)-4,7-dioxo-4,7-dihydro-1,3-benzothiazole-2-carboxamide is added. The reaction mixture is maintained under stirring at 60° C. for 4 hours, then the solvent is evaporated off under reduced pressure. The residue is then purified by chromatography on a silica column (eluent: dichloromethane/methanol: 95/5) and 450 mg (yield=9%) of N-(4-methoxyphenyl)-5-{[3-(methyl{3-[(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol-5-yl)amino]propyl}amino)propyl]amino}-4,7-dioxo-4,7-dihydro-1,3-benzothiazole-2-carboxamide is obtained in the form of red powder.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:11][C:12]1[CH:25]=[CH:24][C:15]([O:16][C:17]2[S:21][C:20]([CH2:22][NH2:23])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1.F[P-](F)(F)(F)(F)F.N1([P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CS(C)=O.C(#N)C.O.FC(F)(F)C(O)=O>[NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:23][CH2:22][C:20]1[S:21][C:17]([O:16][C:15]2[CH:24]=[CH:25][C:12]([Cl:11])=[CH:13][CH:14]=2)=[CH:18][CH:19]=1)=[O:6]
Reactant: Nc1ncccc1C(=O)O
Reactant: NCc1ccc(Oc2ccc(Cl)cc2)s1
Agent: CN(C)[P+](N(C)C)(N(C)C)n1nnc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1ncccc1C(=O)NCc1ccc(Oc2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 24.9 %

Procedure:
A solution of 2-amino-nicotinic acid (21 mg, 0.15 mmol), C-(5-(4-chloro-phenoxy)-thiophen-2-yl)-methylamine described in Preparation Example 157 (36 mg, 0.15 mmol), benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate (86 mg, 0.195 mmol) and triethylamine (0.065 mL, 0.45 mmol) in dimethylsulfoxide (1 mL) was stirred under nitrogen atmosphere for 17 hours at room temperature. This reaction solution was purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), and trifluoroacetic acid salt of the title compound (17.7 mg, 0.037 mmol, 24.9%) was obtained as a pale yellow solid.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl[CH2:11][C:12]#[N:13]>ClCCl>[O:7]1[C:1]2([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:11]1[C:12]#[N:13]
Reactant: N#CCCl
Reactant: O=C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: N#CC1OC12CCCCC2
Reaction time: 0.75 h
Yield: 46 %

Procedure:
To a stirred mixture of cyclohexanone (5.39 g, 0.055 mol), 50% sodium hydroxide solution (10 ml) and compound 1 (1 mmol) was added dropwise chloroacetonitrile (3.8 g, 0.05 mol) and stirring was continued for further 45 minutes. After that time, the resulting reaction mixture was diluted with dichloromethane (15 ml), the organic layer was separated and the aqueous phase extracted with dichloromethane (3×15 ml). The combined organic portions were dried over magnesium sulphate and evaporated to give a residue which upon distillation under reduced pressure gave 1-oxaspiro[2,5]octane-2-carbonitrile.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH2:8][C:9]3[CH:22]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH:20]=[CH:19][C:10]=3[CH2:11][CH:12]([CH2:13][C:14]([O:16]CC)=[O:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1NCCCOC1C=CC2C[C@H](CC(OCC)=O)C3C=CC=CC=3CC=2C=1>>[CH3:1][C:2]1[C:7]2[CH2:8][C:9]3[CH:22]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH:20]=[CH:19][C:10]=3[CH2:11][CH:12]([CH2:13][C:14]([OH:16])=[O:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1Cc2ccc(OCCCNc3ccccn3)cc2Cc2c(C)cccc21
Agent: CCOC(=O)C[C@H]1Cc2ccc(OCCCNc3ccccn3)cc2Cc2ccccc21
Product: Cc1cccc2c1Cc1cc(OCCCNc3ccccn3)ccc1CC2CC(=O)O

Procedure:
According to the procedure of Example 6 (c), except substituting ethyl (±)-10,11-dihydro-6-methyl-3-[3-(pyridin-2-ylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate for the ethyl (R)-10,11-dihydro-3-[3-(pyridin-2-ylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate, the title compound was obtained as a white solid: MS (ES) m/e 417.3 (M+H)+. Anal. Calcd for C26H28N2O3.1.25 H2O: C, 71.13; H, 7.02; N, 6.38. Found: C, 71.33; H, 6.67; N, 6.01.
Reaction SMILES: [Li+].[F:2][C:3]([F:30])([F:29])[C:4]1[CH:28]=[CH:27][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]([O-:26])=O)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[CH3:65][O:66][C:67]1[CH:68]=[C:69]([CH:77]=[CH:78][C:79]=1[N+:80]([O-:82])=[O:81])[O:70][CH:71]1[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]1>CN(C)C=O.ClCCl.O1CCCC1>[CH3:65][O:66][C:67]1[CH:68]=[C:69]([CH:77]=[CH:78][C:79]=1[N+:80]([O-:82])=[O:81])[O:70][CH:71]1[CH2:72][CH2:73][N:74]([C:24](=[O:26])[CH2:23][CH2:22][N:19]2[CH2:20][CH2:21][N:16]([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][C:7]4[CH:6]=[CH:5][C:4]([C:3]([F:29])([F:2])[F:30])=[CH:28][CH:27]=4)=[CH:11][CH:12]=3)[CH2:17][CH2:18]2)[CH2:75][CH2:76]1
Reactant: O=C([O-])CCN1CCN(c2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)CC1
Reactant: COc1cc(OC2CCNCC2)ccc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC2CCN(C(=O)CCN3CCN(c4ccc(OCc5ccc(C(F)(F)F)cc5)cc4)CC3)CC2)ccc1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
3-{4-[4-(4-Trifluoromethyl-benzyloxy)-phenyl]-piperazin-1-yl}-propionic acid lithium salt (41 mg; 0.10 mmol, prepared in accordance with Example 37), diisopropylethyl amine (35 μL; 0.20 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (38 mg; 0.10 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution of 4-(3-methoxy-4-nitro-phenoxy)-piperidine hydrochloride (32 mg; 0.11 mmol) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 4 hours at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (3×5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (17 mg; 0.03 mmol). The structure was confirmed using Protocol I-B. Calculated mass=643; observed mass=643; HPLC retention time=4.66 min.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][SH:4].[CH2:7]([OH:10])[C:8]#[CH:9].[OH-].[K+].CN(C)C=O>O>[OH:10][CH2:7][CH:8]=[CH:9][S:4][CH2:3][C:2]([F:6])([F:5])[F:1]
Reactant: FC(F)(F)CS
Reactant: C#CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: OCC=CSCC(F)(F)F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 2.32 g 2,2,2-trifluoroethanethiol, 1.12 prop-2-yne-1-ol, 300 mg potassium hydroxide and 40 ml dimethylformamide is stirred at ambient temperature for 20 hours. The mixture is poured into 150 ml of water and extracted with 100 ml ethyl acetate (3 times). The organic phase is washed with water, dried and concentrated. The crude product is purified by column chromatography to obtain 75 mg of pure 1-hydroxy-3-(2,2,2-trifluoroethylthio)-prop-2-ene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@H:35]([C:37](O)=[O:38])[CH3:36])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:49]1([CH2:55][C@H:56]([NH2:65])/[CH:57]=[CH:58]\[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@@H:35]([CH3:36])[C:37]([NH:65][C@H:56](/[CH:57]=[CH:58]\[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[CH2:55][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:38])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Reactant: N[C@H](/C=C\c1ccccc1)Cc1ccccc1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C\c1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C

Procedure:
First, N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S,3Z)-1,4-diphenylbut-3-en-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]-pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide was synthesized by analogy with the synthesis of intermediate 17 by reacting 20 mg (29 μmol) N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-2-carboxy-1-methoxypropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (intermediate 7) with 7.1 mg (32 μmol) (2S,3Z)-1,4-diphenylbut-3-en-2-amine (intermediate 12).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][CH2:5][C:6]1(O)[C:12]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2.C([O-])=O.[NH4+]>[Pd].C(O)(=O)C>[CH3:18][O:17][C:15]1[CH:14]=[CH:13][C:12]2[CH:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:24])[C:7]3[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=3[CH2:9][CH2:10][C:11]=2[CH:16]=1
Reactant: COc1ccc2c(c1)CCc1ccccc1C2(O)CCCN(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCc1ccccc1C2CCCN(C)C
Temperature: 60 °C
Yield: 84.2 %

Procedure:
To 65 mg (0.19 mmol) of 4 was added 5 ml of glacial acetic acid. The mixture was heated to 60° C. and allowed to stir until the mixture was homogeneous. The reaction mixture was cooled to room temperature and 300 mg of 10% Pd/C was added followed by 1 g of ammonium formate. The mixture was heated to 70° C. and allowed to stir at that temperature for 4 hours. The reaction mixture was cooled to room temperature and filtered. The residue was washed with 50 ml of dichloromethane. The combined filtrate was concentrated. The residue was dissolved in 100 ml of dichloromethane and washed with 2×50 ml of saturated NaHCO3 followed by 2×50 ml of brine. The organic part was dried (Na2SO4) and concentrated to give 50 mg (0.16 mmol, 82%) of 5.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:12][CH:11]=1>C(O)CCC>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:28][CH2:29][N:30]([CH2:2][CH2:1][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:31][CH2:32]2)=[CH:12][CH:11]=1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Reactant: C=Cc1ccccn1
Solvent: CCCCO
Product: Fc1ccc(Cn2c(NC3CCN(CCc4ccccn4)CC3)nc3ccccc32)cc1
Yield: 23 %

Procedure:
A mixture of 2.1 parts of 2-(ethenyl)pyridine, 3.25 parts of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine and 80 parts of 1-butanol is stirred and refluxed overnight. The reaction mixture is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2,2'-oxybispropane, yielding 1 part (23%) of 1-[(4-fluorophenyl)methyl]-N-{1-[2-(2-pyridinyl)ethyl]-4-piperidinyl}-1H-benzimidazol-2-amine; mp. 133.4° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21]O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:25][CH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1
Reactant: OCc1ccccc1-c1cccc(OCc2ccccc2)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1ccccc1-c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3′-benzyloxybiphenyl-2-yl)methanol from Example 4, Step E (247 mg, 0.851 mmol) in dry CH2Cl2 (5 mL) was added thionyl chloride (1.01 g, 8.51 mmol). The reaction mixture was stirred at ambient temperature for 2 hours, then concentrated to dryness in vacuo. The residue was concentrated twice from cyclohexane in vacuo to yield the titled compound.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1(C)C=CC=C[CH:18]=1.OS(O)(=O)=O.O>CCO.CCOC(C)=O>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([O:10][CH2:17][CH3:18])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(c1ccccc1)c1ccccc1

Procedure:
To a solution of diphenylacetic acid (20 g, 0.094 mol) in EtOH (70 mL), was added toluene (70 mL). Next, H2SO4 (3 mL) was added dropwise and the reaction mixture was refluxed for 18 h. Then, H2O and EtOAc were added, the layers were separated, and the organic phase was washed with saturated NaHCO3 solution (3×), dried and concentrated to a white solid (23.2 g), which was directly used in the next step as obtained.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:32][C@@H:33]([NH2:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([NH:13][C:14]([NH:38][C@H:33]([CH3:32])[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:19])=[O:20])[C:16]#[N:17])[CH:4]=[C:3]([C:2]([F:31])([F:1])[F:30])[CH:8]=1
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Reactant: C[C@@H](N)C(C)(C)C
Product: C[C@@H](NC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1)C(C)(C)C
Yield: 39 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chloro-phenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.300 g, 0.6 mmol) was stirred in (R)-1,2,2-trimethylpropylamine (1 ml) for 17 h at 75° C. under nitrogen. Work-up as described in Example 17, 2) gave 131 mg (39%) of the title compound. Mp 164-165° C. 1H NMR (200 MHz, CDCl3): δ=0.9 (s, 9H), 1.0 (d, 3H), 3.0 (m, 1H), 7.37 (s, 2H), 7.50 (d, 2H), 7.68 (s, 1H), 7.80 (d, 2H); Analysis: calc. for C23H22ClF6N3O2S: C, 49.87%; H, 4.00%; N, 7.59%. Found: C, 49.95%; H, 4.15%; N, 7.48%.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([OH:26])=O)[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:57][N:58]1[CH2:63][CH2:62][CH:61]([N:64]2[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]2)[CH2:60][CH2:59]1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:67]3[CH2:66][CH2:65][N:64]([CH:61]4[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]4)[CH2:69][CH2:68]3)=[O:26])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)O)co2)C2CC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCN(C4CCN(C)CC4)CC3)co2)C2CC2)c(C)c1
Reaction time: 0.25 h

Procedure:
2-({Cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3-oxazole-4-carboxylic acid (100 mg, 0.26 mmol) was dissolved in DCM (15 mL) and EDCI (70 mg, 0.36 mmol), HOBt (53 mg, 0.39 mmol) and DIPEA (0.057 mL, 0.33 mmol) were added. The resulting solution was stirred for 15 min prior to the addition of 1-(1-methylpiperidin-4-yl)piperazine (57 mg, 0.31 mmol) dissolved in DCM (2 mL) and stirred at ambient temperature for 12 h. The reaction was diluted with DCM (20 mL) and washed with water (10 mL), saturated aqueous NaHCO3 (10 mL), saturated brine (5 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by FCC with 0-2% MeOH in DCM to afford the title compound as pale yellow oil.
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[CH:28]=[C:29]([O:33][C:34]2[N:39]=[CH:38][C:37]3[N:40]=[C:41]([C:45]4[C:46]([NH2:50])=[N:47][O:48][N:49]=4)[N:42]([CH2:43][CH3:44])[C:36]=3[CH:35]=2)[CH:30]=[CH:31][CH:32]=1>C(Cl)Cl.N1C=CC=CC=1.CN(C=O)C>[NH2:50][C:46]1[C:45]([C:41]2[N:42]([CH2:43][CH3:44])[C:36]3[CH:35]=[C:34]([O:33][C:29]4[CH:28]=[C:27]([NH:26][C:15](=[O:17])[C:14]5[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][N:2]6[CH2:3][CH2:4][O:5][CH2:6][CH2:7]6)=[CH:19][CH:18]=5)[CH:32]=[CH:31][CH:30]=4)[N:39]=[CH:38][C:37]=3[N:40]=2)=[N:49][O:48][N:47]=1
Reactant: CCn1c(-c2nonc2N)nc2cnc(Oc3cccc(N)c3)cc21
Reactant: O=C(O)c1ccc(OCCN2CCOCC2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCn1c(-c2nonc2N)nc2cnc(Oc3cccc(NC(=O)c4ccc(OCCN5CCOCC5)cc4)c3)cc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Under argon, to a suspension of the HCl salt of 4-{[2-(4-morpholinyl)ethyl]oxy}benzoic acid (3.98 g, 13.8 mmol) in CH2Cl2 (100 ml) was added DMF (40 μl), followed with oxalylchloride (3.6 ml, 41.4 mmol). This mixture was then heated to reflux until a clear solution resulted. The reaction mixture was then concentrated, added CH2Cl2 (20 mL) and reconcentrated. A suspension of the above product in CH2Cl2 (100 mL), was added to a suspension of the product of Example 3 (3.96 g, 11.7 mmol) in pyridine (30 mL). This mixture was then heated to 70° C., the CH2Cl2 was distilled off, then stirred for 1 h. CH2Cl2 (200 mL) was added to the cooled reaction mixture, stirred for 15 min and then filtered to provide a first crop of product (crop 1). The filtrate was concentrated in vacuo and the residue taken up in EtOAc, washed with water (4×), brine, dried over Na2SO4, filtered and concentrated to provide Crop 2. Crops 1 and 2 were combined and recrystallized from MeOH to afforded a off white solid (5.54 g, 83%). 1H NMR (400 MHz, DMSO) δ ppm 11.35 (bs, 1H), 10.22 (s, 1H), 8.79 (d, 1H, 0.8 Hz), 7.99 (d, 2H, 8.8 Hz), 7.58-7.64 (m, 3H), 7.37 (t, 1H, 8.0 Hz), 7.12 (d, 2H, 8.8 Hz), 6.95 (s, 2H), 6.84-6.87 (m, 1H), 4.70 (q, 2H, 7.2 Hz), 4.53 (bs, 2H), 3.81-3.98 (m, 4H), 3.49-3.58 (m, 4H), 3.18-3.36 (m, 2H), 1.41 (t, 3H, 7.2 Hz). MS (ES+) m/e 571 [M+H]+.