Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11])#[CH:2].CCN(CC)CC.Cl[C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:53]=[CH:52][C:36]([C:37]([N:39]3[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]3)=[O:38])=[CH:35][CH:34]=2)[N:23]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CCOC(C)=O.[Cu]I>[CH3:13][O:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:26]1[C:27]([C:28]([F:30])([F:29])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([C:37]([N:39]3[CH2:40][CH2:41][N:42]([C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])[CH2:43][CH2:44]3)=[O:38])=[CH:52][CH:53]=2)[N:25]=1
Reactant: C#Cc1ccccc1CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A solution of methyl 2-(2-ethynylphenyl)acetate (K1) (0.129 g, 0.741 mmol) in DMF (3 mL) and Et3N (344 μL, 2.47 mmol) was added to a mixture of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoyl)piperazine-1-carboxylate (A22) (0.300 g, 0.617 mmol), PdCl2 (PPh3)2 (0.065 g, 0.093 mmol), CuI (0.018 g, 0.093 mmol) and PPh3 (0.016 g, 0.062 mmol) in DMF (3 mL). The resulting mixture was heated under microwave irradiation at 120° C. for 15 minutes, diluted with EtOAc and passed through a plug of Celite, washing with EtOAc (60 mL). The filtrates were combined and the volatiles were removed in vacuo to give a residue that was purified by silica gel column chromatography (Biotage Isolera, 25 g SiO2 cartridge, 0-80% EtOAc in petroleum benzine 40-60° C.) to give the title compound A23 as a yellow oil (0.337 g, 88%); 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 7.73 (d, J=8.6 Hz, 2H), 7.68 (dd, J=7.7, 1.0 Hz, 1H), 7.61 (s, 1H), 7.48-7.41 (m, 3H), 7.40-7.31 (m, 2H), 3.96 (s, 2H), 3.71 (s, 3H), 3.67-3.37 (m, 8H), 1.47 (s, 9H). LCMS-A: rt 6.393 min; m/z 624.1 [M+H]+.
Reaction SMILES: C([N:3](CC)CC)C.Cl.N=[C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=[CH:11]1.[CH3:22][N:23]=[C:24]=[S:25]>CC(C)=O>[CH3:22][NH:23][C:24]([CH:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:12][C:11]1=[NH:3])=[S:25]
Reactant: N=c1ccn(-c2ccccc2)nc1
Reactant: CN=C=S
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CC(C)=O
Product: CNC(=S)C1C=CN(c2ccccc2)NC1=N
Yield: 23.6 %

Procedure:
5.3 g (52.4 millimoles) of triethylamine were added dropwise to 10.0 g (48.2 millimoles) of 1,4-dihydro-4-imino-1-phenylpyridazine hydrochloride in 25 ml (26.7 g, 365 millimoles) of methyl isothiocyanate at room temperature, while stirring. After the addition was complete, the reaction mixture was diluted with 50 ml of acetone and stirred for a further 2 hours at room temperature. The product was filtered off under suction, washed with water and acetone and recrystallized from dimethylformamide/water. The crystals obtained were suspended in 25 ml of acetone, filtered off under suction, again suspended in 25 ml of acetone and filtered off under suction, and the product was recrystallized from isopropanol. 2.8 g (24% of theory) of 1,4-dihydro-4-(methylthiocarbamyl)-imino-1-phenylpyridazine were isolated as yellow crystals of melting point 177°-178° C. (decomposition).
Reaction SMILES: CO[C:3](=[C:10]([C:13]#[N:14])[C:11]#[N:12])[C:4]1[O:5][CH:6]=[CH:7][C:8]=1[CH3:9].[NH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>>[C:13]([C:10]([C:11]#[N:12])=[C:3]([NH:15][CH2:16][CH2:17][NH:18][C:19]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:25])[C:4]1[O:5][CH:6]=[CH:7][C:8]=1[CH3:9])#[N:14]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COC(=C(C#N)C#N)c1occc1C
Product: Cc1ccoc1C(NCCNC(=O)OC(C)(C)C)=C(C#N)C#N

Procedure:
N-(2-{[2,2-dicyano-1-(3-methyl(2-furyl))vinyl]amino}ethyl)(tert-butoxy)carboxamide was synthesized in the same manner using [methoxy(3-methyl(2-furyl))methylene]methane-1,1-dicarbonitrile and tert-butyl N-(2-aminoethyl)carbamate. The NMR and ESI/MS data for this compound are shown below.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.O=C1CCC(=O)N1[O:19][C:20](=O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].O>CN1C(=O)CCC1>[C:38]([O:37][C:35]([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)=[O:19])=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To 4-(Aminomethyl)benzoic acid (0.2 g, 1.32 mmol) was added in NMP (5 mL). Hexadecanedioic acid tert-butyl ester 2,5-dioxo-pyrrolidin-1-yl ester (0.58 g, 1.32 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was poured into water (100 mL), the precipitate was isolated by filtration and dried in vacuo. The crude material was recrystalized from toluene to give 4-[(15-tert-butoxycarbonylpentadecanoylamino)methyl]benzoic acid (413 mg).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2].CO.[CH3:17]CN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:17])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: CCc1n[nH]c2cc(C(=O)O)ccc12
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCc1n[nH]c2cc(C(=O)OC)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of 1.35 g (7.1 mmol) of 3-ethyl-1H-indazol-6-yl-carboxylic acid, [Marfat, A., et al., U.S. Pat. No. 6,262,040], 2.9 mL (71 mmol) of methanol, and 0.95 g (7.8 mmol) of DMAP in 60 mL of CH2Cl2 was added 1.5 g (7.8 mmol) of EDCI-HCl. This mixture was stirred at room temperature overnight, concentrated and the residue dissolved in 50 mL of ethyl acetate. The organic layer was successively washed with 40 mL of 1N HCl, 40 mL of water and 40 mL of brine, dried (Na2SO4), and concentrated. The residue was purified by chromatography over silica gel using a gradient of 35% to 50% ethyl acetate in hexanes over 20 minutes as eluant to yield 860 mg (4.2 mmol) of methyl 3-ethyl-1H-indazol-6-yl-carboxylate. 1H NMR (CDCl3) δ 11.7 (s, 1H), 8.18 (s, 1H), 7.73 (apparent q, 9.0 Hz, 2H), 3.94 (s, 3H), 3.03 (q, 7.5 Hz, 2H), 1.42 (t, 7.5 Hz, 3H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.[H-].[Na+].Br[CH2:20][CH2:21][CH:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27]>O1CCCC1>[CH3:29][CH:22]([CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:21][CH2:20][N:11]1[CH:10]=[CH:9][N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: CC(C)CCCC(C)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)CCCC(C)CCn1ccnc1-c1ccccc1
Temperature: 50 °C

Procedure:
To a solution of 21.5 g. (0.14 mole) of 2-phenylimidazole in 60 ml. dry dimethylformamide and 300 ml. dry tetrahydrofuran under nitrogen atmosphere there is added at room temperature 9.0 g. (0.19 mole) of 50% sodium hydride/mineral oil suspension. The resulting mixture is stirred and heated to 50° C. for about 3 hours. After cooling to room temperature the resulting mixture is treated dropwise with a solution of 40.5 g. (0.18 mole) of (±)-1-bromo-3,7-dimethyloctane in dry tetrahydrofuran. The reaction mixture is stirred over night at room temperature and the resulting mixture is filtered and the residue washed with tetrahydrofuran. The combined filtrate is concentrated in vacuo to an oil, the oil is then dissolved in methylene chloride, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield an oily product. Distillation gave (±)-1-(3,7-dimethyloctyl)-2-phenylimidazole; b.p. 150° to 157° C. at 0.2-0.16 mm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](I)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl-].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Zn+].O>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(I)c1
Reactant: [Zn+]c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(Br)cc(-c2ccccn2)c1
Reaction time: 8 h

Procedure:
To an argon purged solution of methyl 3-bromo-5-iodobenzoate (834 mg, 2.45 mmol) and Pd(PPh3)4 (142 mg, 0.12 mmol) in THF (20 mL) was added 2-pyridylzinc chloride (0.5 M, 7.4 mL, 3.7 mmol). The mixture was stirred overnight and then poured into a large volume of water (100 mL). The resulting solution was extracted with EtOAc (3×20 mL) and the combined organics were successively washed with water (1×20 mL), brine (1×20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified via automated flash chromatography (silica gel; 0 to 25% EtOAc in hexanes) to afford methyl 3-bromo-5-(pyridin-2-yl)benzoate. MS m/z=292, 294 [M+1]+; Calc'd for C13H10BrNO2: 292.
Reaction SMILES: C1(C[O:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH2:17][NH:18][CH2:19][CH2:20][NH:21][C:22]([C:24]45[CH2:33][CH:28]6[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]6)[CH2:25]4)[CH2:31]5)=[O:23])=[CH:14][C:13]=3[CH:34]=2)C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH2:17][NH:18][CH2:19][CH2:20][NH:21][C:22]([C:24]34[CH2:33][CH:28]5[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]5)[CH2:25]3)[CH2:31]4)=[O:23])=[CH:14][C:13]=2[CH:34]=1
Reactant: O=C(NCCNCc1cc2cc(OCc3ccccc3)ccc2o1)C12CC3CC(CC(C3)C1)C2
Agent: [Pd]
Solvent: CCO
Product: O=C(NCCNCc1cc2cc(O)ccc2o1)C12CC3CC(CC(C3)C1)C2
Yield: 57.9 %

Procedure:
N-[2-[[(5-Phenylmethoxy-2-benzofuranyl)methyl]amino]ethyl]tricyclo[3.3.1.13,7 ]decane-1-carboxamide (0.70 g, 1.5 mmole) was dissolved in 100 ml of ethanol and 160 mg of 10% palladium on carbon was added. The mixture was hydrogenated at 50 psi on a Parr apparatus overnight. The mixture was then filtered through celite and concentrated in vacuum. The residue was crystallized from 25 ml of isopropanol with the addition of 7 ml of 4N HCl/isopropanol and 100 ml of diethyl ether to give 320 mg of the title compound as a white solid, monohydrochloride, hydrate, m.p. 140°-143° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:23](Br)[CH:24]=[CH2:25]>CN(C=O)C.C(OCC)(=O)C>[CH2:25]([O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:6]2[CH:15]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[Cl:16])=[CH:9][CH:10]=1)[CH:24]=[CH2:23]
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a solution of 4-(5-bromo-2-chlorobenzyl)phenol (6 g, 20.16 mmol, prepared as described in WO2006120208) in dry DMF (25 mL), was added Cs2CO3 (18.2 g, 60.6 mmol) and allyl bromide (4.2 mL, 50.6 mmol) at 0° C. and the reaction mixture was stirred at r.t. for 2 h. After the completion of the reaction as monitored by TLC, the reaction mixture was diluted with ethyl acetate (200 mL) and washed with water (3×30 mL). The combined organic layers were dried over Na2SO4 and the volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 0.4:9.6 Ethyl acetate:Pet. Ether) to afford the title compound (6.1 g, 89.6%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]([N:18]([CH3:20])[CH3:19])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[CH:21]1([CH2:27][S:28](Cl)(=[O:30])=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([CH2:27][S:28]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]([CH3:20])[CH3:19])[CH:13]=3)[CH2:8][CH2:7]2)(=[O:30])=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=S(=O)(Cl)CC1CCCCC1
Reactant: CN(C)c1cccc(N2CCN(CCCCN)CC2)c1
Product: CN(C)c1cccc(N2CCN(CCCCNS(=O)(=O)CC3CCCCC3)CC2)c1

Procedure:
Reaction of {3-[4-(4-amino-butyl)-piperazin-1-yl]-phenyl}-dimethyl-amine and cyclohexyl-methanesulfonyl chloride as described in Preparation 8 gave desired compound, C-Cyclohexyl-N-{4-[4-(3-dimethylamino-phenyl)-piperazin-1-yl]-butyl}-methanesulfonamide.
Reaction SMILES: ClC1C=C2C(=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.[I:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48](OCC)=[O:49])=[C:33]2[S:53](Cl)(=[O:55])=[O:54].Cl.CN.Cl.[CH3:61][O:62][NH:63][CH3:64]>>[I:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:48]([NH2:7])=[O:49])=[C:33]2[S:53]([N:63]([O:62][CH3:61])[CH3:64])(=[O:54])=[O:55]
Reactant: CNOC
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(I)ccc2n1S(=O)(=O)c1ccccc1
Agent: CN
Agent: Cl
Product: CON(C)S(=O)(=O)c1c(C(N)=O)[nH]c2ccc(I)cc12

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-iodo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and methylamine hydrochloride with N-methoxy-N-methylamine hydrochloride, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+ MS: 410.11 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]2[C:16]([C:18]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:21][N:20]([CH3:30])[N:19]=2)=[O:17])=[N:6][CH:7]=1.C([Sn](CC[CH2:42][CH3:43])CCCC)CCC.Cl.[OH2:45]>O1CCOCC1>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]2[C:18]([C:16]([N:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]3[CH2:9][NH:8][C:5]3[N:4]=[CH:3][C:2]([C:42](=[O:45])[CH3:43])=[CH:7][N:6]=3)=[O:17])=[N:19][N:20]([CH3:30])[CH:21]=2)=[CH:24][CH:25]=1
Reactant: CCCC[Sn](CCCC)CCCC
Reactant: Cn1cc(-c2ccc(F)cc2)c(C(=O)N2CCCC[C@H]2CNc2ncc(Br)cn2)n1
Reactant: O
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)c1cnc(NC[C@@H]2CCCCN2C(=O)c2nn(C)cc2-c2ccc(F)cc2)nc1
Reaction time: 1.5 h

Procedure:
A mixture of 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone (0.5 g) and 1-ethoxyvinyl)tributyltin (0.42 ml) tetrakis(triphenylphosphine)palladium[0} (0.06 g) was boiled in dioxane (8 ml) for 16 h. 2N Hydrochloric acid was added, the mixture stirred for 90 min, water was added and the mixture extracted (×3) with ethyl acetate. The combined ethyl acetate extracts were dried, solvent removed at reduced pressure and the residue column chromatographed (silica gel, ethyl acetate→2% methanol ethyl acetate to give the title compound (0.3 g) as a yellow foam.
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=1[NH:13][C:14]1[O:18][C:17]([C:19]([NH:21][C:22]2[CH:39]=[CH:38][C:25]([O:26][C@@H:27]3[CH2:32][CH2:31][C@H:30]([C:33]([O:35]CC)=[O:34])[CH2:29][CH2:28]3)=[CH:24][CH:23]=2)=[O:20])=[N:16][N:15]=1.O.CO>C1COCC1>[F:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=1[NH:13][C:14]1[O:18][C:17]([C:19]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([O:26][C@@H:27]3[CH2:28][CH2:29][C@H:30]([C:33]([OH:35])=[O:34])[CH2:31][CH2:32]3)=[CH:38][CH:39]=2)=[O:20])=[N:16][N:15]=1
Reactant: CCOC(=O)[C@H]1CC[C@@H](Oc2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(O[C@H]2CC[C@@H](C(=O)O)CC2)cc1)c1nnc(Nc2cc(F)c(F)cc2F)o1
Temperature: 35 °C
Reaction time: 3 h
Yield: 56.3 %

Procedure:
Lithium hydroxide monohydrate (184 mg, 4.38 mmol) was added in one portion to a solution of ethyl cis-4-{4-[({5-[(2,4,5-trifluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]-phenoxy}cyclohexanlecarboxylate (Example 645, 221 mg, 0.44 mmol) in a mixture of THF (4 mL), H2O (4 mL) and MeOH (8 mL) and the reaction mixture was stirred at 35° C. for 3 h. The reaction mixture was concentrated in vacuo and citric acid (40 mL) was added. The resulting mixture was filtered, washed with H2O and recrystallised from ethanol/H2O to give the title compound as a pale yellow solid (118 mg, 56%); 1H NMR δ 1.66-1.70 (4H, m), 1.75-1.83 (4H, m), 2.33-2.40 (1H, m), 4.50 (1H, s), 6.96 (2H, d), 7.67-7.74 (3H, m), 8.17 (1H, q), 10.95 (1H, s), 11.10 (1H, s), 12.05 (1H, s); MS m/e (M−H)− 475. The compound may be further recrystallised from EtOH, melting point 251-253° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:30][CH3:31])[CH:26]=3)[CH2:21]2)=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:39][CH2:40][N:41]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.O>CN(C)C=O>[N:41]1([CH2:40][CH2:39][O:19][C:16]2[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][NH:10][CH2:9][C:7]3[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[CH:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:30][CH3:31])[CH:26]=4)[CH2:21]3)=[CH:14][CH:15]=2)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1CNCCc1ccc(O)cc1)C2
Reactant: ClCCN1CCCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1CNCCc1ccc(OCCN3CCCCCC3)cc1)C2
Temperature: 60 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
To a solution of 4-{2-{[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]methylamino}ethyl}phenol (160 mg) in N,N-dimethylformamide (3 ml) were sequentially added potassium carbonate (100 mg) and 1-(2-chloroethyl)azepane (110 mg), and the solution was stirred for 2 hours at 60° C. Water was added thereto followed by stirring, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (157 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[NH2:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39]>>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[S:23]([NH:22][C:20]1[CH:21]=[C:16]([C:9]2[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[N:7]=2)[CH:17]=[CH:18][C:19]=1[F:34])(=[O:25])=[O:24]
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CS(=O)(=O)CCN
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(NCCS(C)(=O)=O)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (3.0 g, 5.71 mmol) and 2-aminoethyl-methyl-sulfone (2.82 g, 22.86 mmol), the title compound was obtained as a white solid (1.9 g, 53% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.93 (s, 1H), 8.14 (d, J=5.0 Hz, 1H), 7.67-7.77 (m, 1H), 7.48 (t, J=5.5 Hz, 1H), 7.38-7.46 (m, 2H), 7.28 (q, J=9.2 Hz, 3H), 6.22-6.31 (m, 1H), 3.62-3.73 (m, 2H), 3.34-3.40 (m, 2H), 3.25-3.30 (m, 1H), 3.02 (s, 3H), 1.36 (d, J=6.9 Hz, 6H). MS (ESI): 612.2 [M+H]+.
Reaction SMILES: Cl.Cl.[N:3]1([NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][CH:17]=2)=[O:11])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[H-].[Na+].Cl[CH2:27][C:28]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:29]>CN(C=O)C>[N:30]1([C:28](=[O:29])[CH2:27][N:6]2[CH2:5][CH2:4][N:3]([NH:9][C:10]([C:12]3[CH:17]=[N:16][C:15]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[N:14][CH:13]=3)=[O:11])[CH2:8][CH2:7]2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: O=C(NN1CCNCC1)c1cnc(-c2ccccc2)nc1
Reactant: O=C(CCl)N1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NN1CCN(CC(=O)N2CCOCC2)CC1)c1cnc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.6 %

Procedure:
A solution of 2-phenyl-pyrimidine-5-carboxylic acid piperazin-1-ylamide dihydrochloride (0.43 mmol) and NaH (60%, 2.15 mmol) in DMF (10 mL) is stirred under N2 at rt for 20 min. 2-Chloro-1-morpholin-4-yl-ethanone (0.65 mmol)) is added and the reaction mixture is stirred at rt overnight. The reaction mixture is quenched with water, and extracted with EtOAc. The organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-4% methanol in DCM to afford 2-phenyl-pyrimidine-5-carboxylic acid [4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazin-1-yl]-amide (24 mg, 14%) as a solid. MS: 411 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.85-3.10 (m, 2H), 3.60-4.00 (m, 12H), 4.46 (d, 2H), 4.84 (s, 2H), 7.44-7.62 (m, 3H), 8.34-8.58 (m, 2H), 9.20-9.38 (d, 2H). IC50=831.5 nM.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1.[CH3:14][NH2:15].CO>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:15][CH3:14])=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1
Reactant: CN
Reactant: CS(=O)(=O)c1cc(Br)ccc1CBr
Solvent: CO
Product: CNCc1ccc(Br)cc1S(C)(=O)=O
Yield: 80 %

Procedure:
A solution of 4-bromo-1-bromomethyl-2-methanesulfonyl-benzene (300 mg, 0.9 mmol) in ˜40% MeNH2/MeOH (10 mL) was stirred at room temperature for 3 hours. TLC (petroleum ether:EtOAc 3:1) showed the reaction was complete. The reaction mixture was concentrated in vacuo to give crude title compound (200 mg, 80%) as a yellow oil, which was used for next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10][C@H:9]1[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:19]#[N:20].[Na+].O.C(OCC)(=O)C>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:19]#[N:20])[CH2:10][C@H:9]1[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H]1C[C@H](C#N)CN1C(=O)OC(C)(C)C
Yield: 71.6 %

Procedure:
A solution of (2R,4R)-1-(tert-butoxycarbonyl)-4-methanesulfonyloxy-2-methylpyrrolidine (2.3 g) and sodium cyanide (1.37 g) in dimethyl sulfoxide (25 ml) was heated for two and a half hours at 90° C. The reaction mixture was poured into a mixture of water (100 ml) and ethyl acetate (100 ml). The organic layer was separated, washed with brine, and dried over magnesium sulfate. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (100 ml) eluting with a mixture of hexane and ethyl acetate (4:1, V/V) to give (2R,4S)-1-(tert-butoxycarbonyl)-4-cyano-2-methylpyrrolidine (1.24 g).