Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[CH3:10][NH2:11].Cl.[CH3:13][NH2:14].[C-]#N.[K+]>O>[CH3:1][O:2][N:3]1[CH2:8][CH2:7][C:6]([NH:14][CH3:13])([C:10]#[N:11])[CH2:5][CH2:4]1
Reactant: CON1CCC(=O)CC1
Reactant: CN
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: CNC1(C#N)CCN(OC)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 1-methoxy-piperidin-4-one [prepared according to Journal of Organic Chemistry (1961), 26, 1867-74] (100 g, 0.77 mol), aqueous methylamine (40 wt. % in H2O, 86 ml) and methylamine hydrochloride (57.5 g, 0.85 mol) in water (700 ml) at 0° C. was added a solution of potassium cyanide (55.5 g, 0.85 mol) in water (150 ml) dropwise over one hour. The reaction mixture was stirred at room temperature for two days. Over the next five days, the mixture was further treated with methylamine hydrochloride (5×2.6 g, total 13.0 g), aqueous methylamine (5×4.3 ml, total 21.5 ml) and potassium cyanide (5×2.5 g, total 12.5 g), and stirring continued at room temperature until the reaction was judged complete by thin layer chromatography. The aqueous reaction mixture was extracted with dichloromethane (1×500 ml, and 4×200 ml), the combined organic phases dried over sodium sulfate and evaporated. Yield: 113.0 g of 1-methoxy-4-methylamino-piperidine-4-carbonitrile (compound P5.1) as a red liquid. This material was used without further purification in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=O)[C:5]=2[S:4][CH:3]=1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:10]1[C:5]2[S:4][CH:3]=[C:2]([CH3:1])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: Cc1csc2c(=O)[nH]cnc12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1csc2c(Cl)ncnc12
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of 7-methyl-3H-thieno[3,2-d]pyrimid-4-one (3, 2.9 g, 18 mmol) in phosphorus oxychloride (18 mL) under N2 was heated at reflux for 1 hour. The resulting solution was allowed to cool to room temperature and then poured into a saturated aqueous solution of sodium bicarbonate to neutralize. The aqueous mixture was extracted with diethyl ether. The organic layer was washed with water followed by saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure to yield 4-chloro-7-methylthieno[3,2-d]pyrimidine (3.1 g, 96% yield) as a white solid.
Reaction SMILES: Cl[C:2](=[N:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C1C=CC=CC=1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:8]2)=[CH:11][CH:12]=1
Reactant: C=Cc1ccccc1
Reactant: CCOC(=O)C(Cl)=NNc1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=NN(c2ccc(Cl)cc2)C(c2ccccc2)C1
Temperature: 25 °C
Yield: 94 %

Procedure:
Part B: To a stirred boiling solution of ethyl 2-chloro[(4-chlorophenyl) hydrazono]acetate (22.95 gram, 0.088 mol) and styrene (30.3 ml, 0.264 mol) in benzene (140 ml) is added triethylamine (34.3 ml, 0.247 mol) and the resulting solution is heated at reflux temperature for 1 hour. The resulting solution is cooled to room temperature and the formed precipitate is removed by filtration and washed with toluene. The filtrate is concentrated in vacuo and purified by flash chromatography (silica gel, dichloromethane) to give ethyl 1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylate (27.2 gram, 94% yield) as a syrup which slowly solidifies on standing. 1H-NMR (200 MHz, CDCl3): 1.38 (t, J=7 Hz, 3H), 3.06 (dd, J=18 and 7 Hz, 1H), 3.73 (dd, J=18 and 13 Hz, 1H), 4.33 (q, J=7 Hz, 2H), 5.38 (dd, J=13 and 7 Hz, 1H), 7.02 (br d, J=8 Hz, 2H), 7.08-7.40 (m, 7H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22]O)[CH:17]=2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:25]([N:27](CC)CC)C.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[C-]#N.[Na+]>CN(C=O)C.N1C=CC=CC=1>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:25]#[N:27])[CH:17]=2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCN(CC)CC
Reactant: CCCCOc1nc(N)c2ncn(Cc3cccc(CO)c3)c2n1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2ncn(Cc3cccc(CC#N)c3)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.4 %

Procedure:
2-Butoxy-9-(3-hydroxymethylbenzyl)adenine (0.09 g, 0.27 mmol), triethylamine (0.20 g, 1.98 mmol), tosyl chloride (0.30 g, 1.57 mmol) and pyridine (0.4 ml) were added to DMF (10 ml), and the mixture was stirred at room temperature for 24 hours. To the reaction mixture was added sodium cyanide (0.40 g, 9.16 mmol), and the mixture was stirred at 80° C. for 18 hours. After removing the solvent, the residue was poured into water and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, concentrated and the residue was purified by column chromatography (SiO2 20 g, eluting solvent: CHCl3/MeOH=100/1) to give 2-butoxy-9-(3-cyanomethylbenzyl)adenine (0.04 g, 0.12 mmol, yield: 44%) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C:5]1[O:9][C:8]([CH2:10][N:11]2[C:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[S:19][C:15]=3[C:14](=[O:26])[N:13]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:12]2=[O:33])=[N:7][N:6]=1.[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][CH:50]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35].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>C(Cl)Cl>[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:50]=[CH:51][C:52]([C:53]([N:30]4[CH2:31][CH2:32][CH:27]([N:13]5[C:14](=[O:26])[C:15]6[S:19][C:18]([C:20]7[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=7)=[CH:17][C:16]=6[N:11]([CH2:10][C:8]6[O:9][C:5]([CH2:4][O:3][CH3:2])=[N:6][N:7]=6)[C:12]5=[O:33])[CH2:28][CH2:29]4)=[O:54])=[CH:56][CH:57]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35]
Reactant: COCc1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)o1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nnc(COC)o5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-{[5-(methoxymethyl)-1,3,4-oxadiazol-2-yl]methyl}-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (250 mg; compound B33) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (223 mg; compound C10) and HBTU (232 mg) in DCM (15 ml) in the presence of DIPEA (0.36 ml) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [silica gel, eluation gradient: DCM/MeOH, 1/0 to 3/2 (v/v)] and preparative HPLC as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]([CH3:31])=[C:21]([CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[CH3:30])[N:22]=2)=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]([CH3:31])=[C:21]([CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[CH3:30])[N:22]=2)=[CH:14][CH:13]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Reactant: OB(O)c1ccccc1F
Product: Cc1oc(-c2ccc(-c3ccccc3F)cc2)nc1CCN1CCC[C@H]1C

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 2-fluorobenzene boronic acid (201 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 61 mg (59%). MS (m/e) 365.2 (M+1)
Reaction SMILES: [CH3:1][Si:2]([CH2:5][N:6]1[CH:10]=[C:9]([CH2:11]O)[N:8]=[N:7]1)([CH3:4])[CH3:3].[N+:13]([C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[S:25]([NH:28][CH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=1)(=[O:27])=[O:26])([O-:15])=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>CCOC(C)=O.C1C=CC=CC=1>[N+:13]([C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[S:25]([N:28]([CH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=1)[CH2:11][C:9]1[N:8]=[N:7][N:6]([CH2:5][Si:2]([CH3:1])([CH3:3])[CH3:4])[CH:10]=1)(=[O:26])=[O:27])([O-:15])=[O:14]
Reactant: C[Si](C)(C)Cn1cc(CO)nn1
Reactant: COC(=O)c1ccc(CNS(=O)(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COC(=O)c1ccc(CN(Cc2cn(C[Si](C)(C)C)nn2)S(=O)(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1

Procedure:
A solution of {1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}methanol (241 mg, 1.30 mmol), methyl 4-({[(2,4-dinitrophenyl)sulfonyl]amino}methyl)benzoate (514 mg, 1.30 mmol), triphenylphosphine (409 mg, 1.56 mmol) and benzene (4.34 mL) was treated with diethylazodicarboxylate (247 uL, 1.56 mmol). After one hour additional portions of triphenylphosphine (204 mg, 0.780 mmol) and diethylazodicarboxylate (124 uL, 0.780 mmol) The reaction was diluted with EtOAc and washed with 2M aq. HCl 2×, water, brine, dried (MgSO4) and concentrated to afford a brown oil used crude in the next reaction. MS: cal'd 563 (MH+), exp 563 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][N+:4]([O-:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH:14](O)([OH:19])[C:15]([F:18])([F:17])[F:16].O>C(OC)(C)(C)C>[CH3:1][CH:2]([CH3:7])[CH:3]([N+:4]([O-:6])=[O:5])[CH:14]([OH:19])[C:15]([F:18])([F:17])[F:16]
Reactant: CC(C)C[N+](=O)[O-]
Reactant: OC(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)C(C(O)C(F)(F)F)[N+](=O)[O-]
Temperature: 15 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
3A Molecular sieves (27.04 g) were heated at 120° C. under vacuum for 20 hours and added to a solution of 2-methyl-1-nitropropane (13.0 g) in methyl tert-butyl ether (420 ml). The mixture was stirred for 5 minutes, potassium carbonate (64.5 g) added and the mixture stirred a further 30 minutes. The mixture was cooled to 15° C. and fluoral hydrate (22.0 g) was added over 30 minutes. The reaction mixture was stirred at ambient temperature for 16 hours, then cooled to 15° C. and water (270 ml) added. After stirring for 5 minutes at ambient temperature, the organic phase was separated and washed with 10% aqueous potassium carbonate, 2M hydrochloric acid solution and water. Solvent was then removed by evaporation under reduced pressure at a temperature below 40° C. and the oil azeotroped dry with isopropyl alcohol at a temperature below 50° C. to give 4-methyl-3-nitro-1,1,1-trifluoro-2-pentanol (21.3 g) as an oil which was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:49]=[C:48]([CH3:50])[C:44]4[NH:45][CH:46]=[N:47][C:43]=4[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:32][CH2:31][N:30](CC5C=CC=CC=5)[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:51]=[CH:52][CH:53]=[CH:54][C:4]=2[NH:3]1.[H][H]>CO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:49]=[C:48]([CH3:50])[C:44]4[NH:45][CH:46]=[N:47][C:43]=4[CH:42]=3)[C:19]([N:21]3[CH2:22][CH2:23][CH:24]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH2:25][CH2:26]3)=[O:20])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:51]=[CH:52][CH:53]=[CH:54][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(Cc4ccccc4)CC3)CC2)cc2nc[nH]c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCNCC3)CC2)cc2nc[nH]c12
Reaction time: 2 h

Procedure:
75 mg (0.09 mmol) (R)-2-(1′-benzyl-4,4′-bipiperidinyl-1-yl)-1-(7-methyl-1H-benzimidazol-5-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate were dissolved in 10 mL MeOH and combined with 30 mg 10% Pd/C. The mixture was hydrogenated for 2 h in a Parr apparatus at 50° C. and 50 psi hydrogen pressure. Then the catalyst was filtered off and the filtrate was evaporated down i.vac.
Reaction SMILES: C(Cl)Cl.FC(F)(F)C([N:8]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)=O.[S:36]([OH:46])(=[O:45])([C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=1)=[O:37].[OH-].[Na+:48]>>[CH2:18]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:44][C:41]2[CH:42]=[CH:43][C:38]([S:36]([O-:46])(=[O:37])=[O:45])=[CH:39][CH:40]=2)=[O:14])=[CH:16][CH:17]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[Na+:48]
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Nc2ccc(S(=O)(=O)[O-])cc2)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A methylene chloride solution of N-trifluoroacetyl-4-(hexadecylamino)benzoyl chloride (4.8 g.) is added to a solution of 1.8 g. of sulfanilic acid in 1N sodium hydroxide at 0° C. After 3 hours, the solution is warmed to 60° C. briefly and the whole evaporated to dryness. The residue is extracted with a small amount of cold water and the resulting white solid crystallized from aqueous ethanol.
Reaction SMILES: [CH3:1][N:2]([C:9](=[O:11])[CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:12][S:13](O)(=[O:15])=[O:14].C(OC(C)C)(C)C>CCCCCC>[C:9]([N:2]([C:3]1[CH:8]=[CH:7][C:6]([S:13]([Cl:12])(=[O:15])=[O:14])=[CH:5][CH:4]=1)[CH3:1])(=[O:11])[CH3:10]
Reactant: CC(=O)N(C)c1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: CC(C)OC(C)C
Solvent: CCCCCC
Product: CC(=O)N(C)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 42 %

Procedure:
N-Methylacetanilide (25.0 g, 188.0 mmol) was added to chlorosulfonic acid (62.8 ml) under cooling with ice in portions at such a rate as not to raise the temperature of the resulting mixture to 50° C. or above, which took about 10 minutes. The obtained mixture was stirred at 80° C. for 2.5 hours and poured into a mixture comprising ice (200 ml), hexane (30 ml) and isopropyl ether (30 ml) under cooling with ice at 20° C. or below in portions to decompose excess chlorosulfonic acid. The precipitated crystal was recovered by filtration, washed with water and dissolved in ethyl acetate. The obtained solution was washed with water and a saturated aqueous solution of common salt. The organic layer was dried over magnesium sulfate and concentrated to give the title compound as a white crystal (19.4 g, yield: 42%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[I:16][C:17]1[CH:21]=[CH:20][NH:19][N:18]=1.[F:22][CH:23]([F:26])[CH2:24]I>CN(C=O)C>[F:22][CH:23]([F:26])[CH2:24][N:19]1[CH:20]=[CH:21][C:17]([I:16])=[N:18]1
Reactant: Ic1cc[nH]n1
Reactant: FC(F)CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: FC(F)Cn1ccc(I)n1
Reaction time: 1.25 h
Yield: 50.5 %

Procedure:
A stirred solution of NaHMDS in THF (1.0 M, 3.1 mL, 3.1 mmol) was cooled in an ice water bath under Ar. 3-iodo-1H-pyrazole (500 mg, 2.6 mmol) was added as a solution in DMF (1 mL), washing with additional DMF (2×1 mL). 1,1-difluoro-2-iodoethane (0.47 mL, 5.2 mmol) was added in one portion and the mixture was removed from the cold bath. After 1.25 h, the reaction mixture was diluted with water and EtOAc. The phases were separated, and the organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel (0-15% EtOAc in hexanes) to provide 1-(2,2-difluoroethyl)-3-iodo-1H-pyrazole 7.02 (339 mg). Regiochemistry was assigned by NOE studies. LCMS-ESI+ (m/z): [M+H]+ calcd for C5H6F2IN2: 259.0; found: 258.2. 1H NMR (400 MHz, Chloroform-d) δ 7.29 (d, J=2.4 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 6.06 (tt, J=55.4, 4.3 Hz, 1H), 4.45 (td, J=13.4, 4.3 Hz, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([N+:36]([O-])=O)=[C:7]([OH:35])[C:8]([NH:12][C:13](=[O:34])[CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:27][CH3:28])([CH3:26])[CH3:25])=[CH:20][C:19]=2[C:29]([CH2:32][CH3:33])([CH3:31])[CH3:30])[CH2:15][CH3:16])=[CH:9][C:10]=1[Cl:11])(=[O:3])[CH3:2].[OH-].[Na+].O.[C:42](O)(=[O:44])C>CO>[Cl:11][C:10]1[C:5]2=[N:4][C:1](=[O:3])[CH2:2][C:42](=[O:44])[N:36]=[C:6]2[C:7]([OH:35])=[C:8]([NH:12][C:13](=[O:34])[CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:27][CH3:28])([CH3:25])[CH3:26])=[CH:20][C:19]=2[C:29]([CH2:32][CH3:33])([CH3:30])[CH3:31])[CH2:15][CH3:16])[CH:9]=1
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(Cl)c(NC(C)=O)c([N+](=O)[O-])c1O
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(Cl)c2c(c1O)=NC(=O)CC(=O)N=2
Temperature: 25 °C

Procedure:
In 200 ml of methanol was dispersed 40 g of the 3-acetylamino-4-chloro-2-nitro-6-[2-(2,4-di-t-amylphenoxy)butanoylamino]phenol, and the dispersion was stirred while refluxing for 5 hours together with 9 g of sodium hydroxide and 40 ml of water. The reaction mixture was cooled to room temperature and then poured into 300 ml of water. Upon dropwise addition of 15 ml of acetic acid, red crystals were precipitated. The crystals were collected by filtration, recrystallized from acetonitrile, and dried to provide 21 g of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:12][CH2:13]/[C:14](/[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[CH:15]\[CH:16]1[CH2:21][CH2:20][CH:19]=[CH:18][CH2:17]1>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:12][CH2:13]/[C:14](/[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[CH:15]\[CH:16]2[CH2:21][CH2:20][CH:19]=[CH:18][CH2:17]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OC/C(=C\C1CC=CCC1)c1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC/C(=C\C2CC=CCC2)c2ccc(F)cc2)cc1
Reaction time: 24 h
Yield: 87.9 %

Procedure:
32.5 g of 4-methylbenzenesulfonyl chloride are added, at room temperature, to a solution of 34 g of Z-1-hydroxymethyl-1-(4-fluorophenyl)-2-(3-cyclohexenyl)ethene in 200 ml of methylene chloride and 29 g of triethylamine. After 24 hours, the reaction mixture is washed with aqueous sodium bicarbonate solution and water, dried over sodium sulfate and evaporated down under reduced pressure. 49.7 g (95%) of Z-1-(4-methylphenylsulfonyloxymethyl)-1-(4-fluorophenyl)-2-(3-cyclohexenyl)-ethene are obtained from the residue.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@H:4]([OH:41])[C@@H:5]([NH:13][C:14](=[O:40])[C@@H:15]([NH:22][C:23](=[O:39])[C@@H:24]([CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:16][C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[C:42]1(=O)[O:47][C:45](=[O:46])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12>C(#N)C>[CH:7]1([CH2:6][C@H:5]([NH:13][C:14](=[O:40])[C@@H:15]([NH:22][C:23](=[O:39])[C@@H:24]([CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:35])[CH3:36])[CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:16][C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)[C@@H:4]([OH:41])[CH2:3][N:2]2[C:45](=[O:46])[C:44]3=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]3[C:42]2=[O:47])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CC(C)(C)C(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CN
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Solvent: CC#N
Product: CC(C)(C)C(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CN1C(=O)c2ccccc2C1=O
Yield: 56.7 %

Procedure:
50 mg (0.08 mmol) of (S)-N-[(1S,2S)-3-amino-1-(cyclohexylmethyl)-2-hydroxypropyl]-α-[(R)-α-(3,3-dimethyl-2-oxobutyl)hydrocinnamamido]imidazole-4-propionamide hydrochloride and 1.5 g (10 mmol) of phthalic anhydride were suspended in 15 ml of acetonitrile and heated to reflux overnight. Thereafter, the reaction mixture was evaporated to dryness under reduced pressure and the residue was chromatographed on 10 g of silica gel with a mixture of methylene chloride, methanol and ammonia as the eluting agent, whereby there were obtained 31 mg of (S)-N[(1S,2S)-1-(cyclohexylmethyl)-2-hydroxy-3-phthalimidopropyl]-α-[(R)-α-(3,3-dimethyl-2-oxobutyl)hydrocinnamamido]imidazole-4-propionamide as a foam, MS: 684 (M+H)+.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[NH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:14]=[CH:15][N:16]3[C:21]=2[C:20]([NH:22][C:23]2[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=2)[N:28]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)[N:27]=[CH:26]4)=[N:19][CH:18]=[N:17]3)[CH2:8][CH2:7]1>CO>[F:39][C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][CH:36]=1)[CH2:32][N:28]1[C:29]2[C:25](=[CH:24][C:23]([NH:22][C:20]3[C:21]4=[C:13]([CH2:12][N:9]5[CH2:8][CH2:7][CH:6]([NH:5][CH2:3][CH2:2][C:1]#[N:4])[CH2:11][CH2:10]5)[CH:14]=[CH:15][N:16]4[N:17]=[CH:18][N:19]=3)=[CH:31][CH:30]=2)[CH:26]=[N:27]1
Reactant: NC1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Reactant: C=CC#N
Solvent: CO
Product: N#CCCNC1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Yield: 76 %

Procedure:
Acrylonitrile (0.2 mL, 30 equiv.) was added to a solution of [5-(4-amino-piperidin-1-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (47 mg, 0.1 mmole) in MeOH (3 mL) at RT. Removal the solvent followed by radial chromatography (1 mm silica gel plate, gradient elution with DCM containing 0 to 2% MeOH) afforded 40 mg (76%) of the title compound as a solid. MS: 524 (M+H)+; HPLC Ret Time: 0.99 min (Xterra 3.0×50 mm S7 C18 column, 2 min gradient, 5 mL/min).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[C:39]([CH:44]3[CH2:46][CH2:45]3)=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[C:39]([CH:44]3[CH2:45][CH2:46]3)=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2C2CC2)c1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3C3CC3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(2-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K29) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow foam (210 mg, 48%).