Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17](Cl)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2].[Br:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH2:37].NC1C=C(O)C(C)=CC=1>>[Br:33][C:34]1[CH:35]=[C:36]([NH:37][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:22]([S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[C:14]([NH:13][C:12]3[C:7]4[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[N:32][C:8]=4[N:9]=[CH:10][N:11]=3)[CH:15]=2)[CH:38]=[CH:39][CH:40]=1
Reactant: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Reactant: Nc1cccc(Br)c1
Agent: Cc1ccc(N)cc1O
Product: COc1ccc(Sc2ccc(C(=O)Nc3cccc(Br)c3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1

Procedure:
The product from Example 137B was reacted with 3-bromoaniline according to the procedure from Example 137C substituting 3-bromoaniline for 5-amino-o-cresol to provide the title compound as an off white solid after silica gel chromatography (50 mg, 38%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.99 Hz, 6H), 3.16-3.30 (m, 1H), 3.77 (s, 3H), 7.00 (d, J=8.82 Hz, 2H), 7.40 (d, J=8.82 Hz, 2H), 7.53 (d, J=8.82 Hz, 2H), 7.64 (d, J=8.82 Hz, 1), 7.74 (d, J=8.82 Hz, 2H), 7.81 (dd, J=8.46, 1.84 Hz, 1H), 7.99 (d, J=1.47 Hz, 1H), 8.59 (s, 1H), 8.86 (d, J=8.82 Hz, 1H), 10.21 (s, 1H), 10.33 (s, 1H); MS (APCI) m/z 602 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C=O)C>[CH2:1]([N:8]([CH3:26])[C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)c1ccn(CCc2ccc(CBr)cc2)c(=O)c1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)c1ccn(CCc2ccc(CN3CCCC3)cc2)c(=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 150 mg (0.37 mmol) 4-(benzyl-methyl-amino)-1-[2-(4-bromomethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 14d) in 2.0 mL DMF is added 152 μL (1.82 mmol) pyrrolidine at RT. The reaction mixture is stirred for 1 h at RT and is directly transferred to a reverse HPLC for purification (Waters symmetry, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [C:1]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.[CH3:16][N:17]([CH2:19][CH2:20][CH2:21][O:22][NH2:23])[CH3:18].C(O)(=O)/C=C/C([O-])=O>>[CH3:16][N:17]([CH2:19][CH2:20][CH2:21][O:22][N:23]=[C:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:18]
Reactant: O=C1CCCCCCCCCCC1
Reactant: CN(C)CCCON
Agent: Cl
Agent: O=C([O-])/C=C/C(=O)O
Product: CN(C)CCCON=C1CCCCCCCCCCC1

Procedure:
Starting from 18.23 g. (0.1 moles) of cyclododecanone and 21.0 g. (0.11 moles) of dimethylaminopropoxyamine dihydrochloride the title compound is prepared as in Example 13. Yield: 20.9 g. (74%). Hydrogen fumarate, m.p.: 117°-118° C.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:12][CH2:13][C@@H:14]1[CH2:19][NH:18][CH2:17][C@H:16]([N:20]2[CH:28]=[N:27][C:26]3[C:25](=[O:29])[NH:24][C:23]([NH:30][C:31](=[O:40])[CH2:32][O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:22][C:21]2=3)[O:15]1.C(N(CC)CC)C.[C:48](Cl)([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>ClCCl>[OH:12][CH2:13][C@@H:14]1[CH2:19][N:18]([C:48]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH2:17][C@H:16]([N:20]2[CH:28]=[N:27][C:26]3[C:25](=[O:29])[NH:24][C:23]([NH:30][C:31](=[O:40])[CH2:32][O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:22][C:21]2=3)[O:15]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(COc1ccccc1)Nc1nc2c(ncn2[C@H]2CNC[C@@H](CO)O2)c(=O)[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COc1ccccc1)Nc1nc2c(ncn2[C@H]2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@@H](CO)O2)c(=O)[nH]1
Temperature: 25 °C
Yield: 82 %

Procedure:
In 30 mL of dichloromethane was suspended 2.0 g of N9-{(2R,6S)-6-(hydroxymethyl)morpholin-2-yl}-N2-(phenoxyacetyl)guanine p-toluenesulfonate (REFERENCE EXAMPLE 1), and 13.9 g of triethylamine and 18.3 g of trityl chloride were added to the suspension under ice cooling. The mixture was stirred at room temperature for an hour. The reaction solution was washed with saturated sodium bicarbonate aqueous solution and then with, water, and dried over sodium sulfate. The organic layer was concentrated under reduced pressure. To the residue was added 40 mL of 0.2 M sodium citrate buffer (pH 3)/methanol (1:4 (v/v)), and the mixture was stirred. Subsequently, 40 mL of water was added and the suspension mixture was stirred for an hour under ice cooling. The precipitates were taken out by filtration, washed with cold methanol and dried to give 1.84 g of the objective compound (yield: 82.0%).
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24](F)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl.Cl.[NH:32]1[C:36]2=[N:37][C:38]([CH2:41][NH2:42])=[CH:39][CH:40]=[C:35]2[CH2:34][CH2:33]1>>[NH:32]1[C:36]2=[N:37][C:38]([CH2:41][NH:42][C:24]3[N:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:21]([NH:20][C:12]3[CH:11]=[C:10]4[C:15]([C:16]([CH3:19])([CH3:18])[CH2:17][NH:8][CH2:9]4)=[CH:14][CH:13]=3)=[O:22])=[CH:39][CH:40]=[C:35]2[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3F)ccc2C(C)(C)C1
Reactant: NCc1ccc2c(n1)NCC2
Agent: Cl
Product: CC1(C)CNCc2cc(NC(=O)c3cccnc3NCc3ccc4c(n3)NCC4)ccc21

Procedure:
The titled compound was prepared from 7-[(2-fluoro-pyridine-3-carbonyl)-amino]-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester and C-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-6-yl)-methylamine dihydrochloride by the method described in Example 1. MS (ES+): 429 (M+H). Calc'd. for C25H28N6O—428.54.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(NC(C)C)(C)C.ClC(OC)=O.[NH2:33][C:34]1[CH:50]=[CH:49][C:37]([CH2:38][S:39]([CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])(=[O:41])=[O:40])=[CH:36][CH:35]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:33][C:34]3[CH:35]=[CH:36][C:37]([CH2:38][S:39]([CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])(=[O:41])=[O:40])=[CH:49][CH:50]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Reactant: CCOC(=O)CCS(=O)(=O)Cc1ccc(N)cc1
Agent: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CCOC(=O)CCS(=O)(=O)Cc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxylic acid (Intermediate 13, 130 mg; 0.47 mmol) in DCM was treated with diisopropylamine (90 mL; 0.52 mmol) and methyl chloroformate (40 mL; 0.52 mmol). After stirring at 0° C. for 15 minutes, ethyl 3-(4-aminobenzylsulfonyl)propanoate (Intermediate 42, 130 mg; 0.48 mmol) was added. After stirring at 0° C. for 30 minutes and RT for 1 hour, saturated sodium bicarbonate solution was added and the mixture stirred for 15 minutes. DCM was added and the layers separated. The organic extract was filtered through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].[C:12](O)(=[O:15])[CH:13]=[CH2:14]>CS(O)(=O)=O>[OH:11][C:3]1[C:2]([CH3:1])=[C:8]2[C:6](=[C:5]([CH3:9])[C:4]=1[CH3:10])[O:7][C:12](=[O:15])[CH2:13][CH2:14]2
Reactant: C=CC(=O)O
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: CS(=O)(=O)O
Product: Cc1c(C)c2c(c(C)c1O)CCC(=O)O2
Temperature: 100 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a mixture of trimethyl-hydroquinone (3.04 g) and acrylic acid (1.44 g) was added methyl-sulfonic acid (30 mL). The mixture was heated slowly up to 100° C. under nitrogen. The reaction mixture was stirred at 100° C. for 1 hour. The solution was poured into ice, and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate water solution, water and brine. Evaporation and chromatography (silica gel, hexane-ethyl acetate 10% to 25%) gave 1.77 g of 6-hydroxy-5,7,8-trimethyl-chroman-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH2:12][CH2:13][Cl:14])[CH2:9][N:8]([CH3:15])[C:7](=O)[C:6]=2[CH:17]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19].[S-2].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH2:12][CH2:13][Cl:14])[CH2:9][N:8]([CH3:15])[C:7](=[S:19])[C:6]=2[CH:17]=1
Reactant: CN1CC(CCCl)Oc2ccc(Cl)cc2C1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [K+]
Agent: [S-2]
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Oc2ccc(Cl)cc2C1=S
Yield: 86.1 %

Procedure:
To a solution of 20 g (0.07 mole) of 7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-one in 200 ml of toluene was added a mixture of 9.55 g (0.05 mole) of phosphorus pentasulfide and 9.5 g of potassium sulfide which had been ground together. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give a yellow solid. Recrystallization from absolute ethanol gave 12.5 g (68%) of the product, m.p. 102°-104° C.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:8]([O:18][CH2:19][CH2:20][OH:21])=[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH:6]=1)C.[OH-].[K+]>C1COCC1.CCO>[Cl:17][C:13]1[CH:12]=[C:11]([C:9]2[CH:10]=[C:5]([CH:6]=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:8]=2[O:18][CH2:19][CH2:20][OH:21])[C:4]([OH:29])=[O:3])[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Reaction time: 18 h

Procedure:
To a stirred solution of 3,5-bis-(m-chlorophenyl)-4-(2-hydroxyethoxy)benzoic acid ethyl ester (0.620 g, 1.44 mmol) in THF:EtOH (3:2, 30 mL) at room temperature was added 1 N KOH (7.20 mL, 7.20 mmol) dropwise. After 18 h at this temperature, the reaction mixture was concentrated and diluted with H2O (100 mL). The aqueous solution was acidified to pH 1 with 2 N HCl. The solid [3,5-bis-(m-chlorophenyl)-4-(2-hydroxyethoxy)benzoic acid] that formed was filtered off, washed with excess H2O, and then dried on the high vacuum pump (0.450 g, 78%).
Reaction SMILES: [C:1]([NH:8][CH:9]([CH2:21][OH:22])[CH:10]=[CH:11][CH:12]1[C:16]([CH3:18])([CH3:17])[CH2:15][CH2:14][C:13]1([CH3:20])[CH3:19])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:23]OS(OC)(=O)=O.O>C(Cl)Cl>[C:1]([NH:8][CH:9]([CH2:21][O:22][CH3:23])[CH:10]=[CH:11][CH:12]1[C:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][C:16]1([CH3:18])[CH3:17])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)OC(=O)NC(C=CC1C(C)(C)CCC1(C)C)CO
Solvent: ClCCl
Solvent: O
Product: COCC(C=CC1C(C)(C)CCC1(C)C)NC(=O)OC(C)(C)C

Procedure:
A solution of 2,2,5,5-tetramethylcyclopentylmethyl bromide in ether is added slowly to magnesium turnings until the Grignard begins to form. The remainder of the alkyl bromide is then added and the mixture stirred until all the magnesium dissolved. At 0° C. a solution of N-Boc-0-methyl-D-serinal is quenched with 1M HCl, and extracted with ether, and the extracts are evaporated. The residue is dissolved in dioxane and 2M H2SO4 is added. The mixture is heated until the alcohol is dehydrated as shown by thin layer chromatography. Water is added and the mixture is extracted with ether. The organic layer is dried over MgSO4 and is evaporated to give N-Boc-3-amino-4-methoxy-1-(2,2,5,5-tetramethylcyclopentyl)--butene and some N-Boc-3-amino-4-hydroxy-1-(2,2,5,5-tetramethylcyclopentyl)-1-butene. This mixture is dissolved in methylene chloride and is methylated with dimethylsulfate. Water is added and the mixture is extracted with ether. The organic layer is dried over MgSO4 and is evaporated to give N-Boc-3-amino-4-methoxy-1-(2,2,5,5-tetramethylcyclopentyl)-1-butene.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:15]=[C:14]1[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OO)(=[O:29])C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:18]([O-:29])=[CH:17][C:16]=2[N:15]=[C:14]1[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)OO
Reactant: Cc1nc2cnc3ccccc3c2n1CCCCNC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1nc2c[n+]([O-])c3ccccc3c2n1CCCCNC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
0.15 g (0.423 mmol) of 1-[4-(tert-butoxycarbonylamino)butyl]-2-methyl-1H-imidazo[4,5-c]quinoline) was dissolved in a mixed solvent of 5 ml of ethyl acetate and 5 ml of chloroform and 0.11 ml (0.508 mmol) of 32% peracetic acid was added thereto. The mixture was heated at 50° C. and stirred for 3 hours. After the reaction mixture was poured into a sodium hydrogencarbonate aqueous solution, the resulting solution was extracted with chloroform, dried (Na2SO4), then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1 (v/v)) to obtain 0.13 g (0.351 mmol) of 1-[4-(tert-butoxycarbonylamino)butyl]-2-methyl-1H-imidazo[4,5-c]quinoline-5-oxide shown below as a white solid. ##STR59## Its spectroscopic data are as follows: IR (KBr) cm-1 : 3230, 2980, 1710, 1540, 1440, 1370, 1280, 1170, 880, 770.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[C:20]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])=[O:11])[S:7][CH:8]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29].N1C=CC=CC=1>C(Cl)Cl>[CH:22]1([C:20]([C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:10](=[O:11])[NH:9][C:6]2[S:7][CH:8]=[C:4]([CH2:3][CH2:2][NH:1][S:28]([CH3:27])(=[O:30])=[O:29])[N:5]=2)=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: Cc1ccc(NC(=O)Nc2nc(CCN)cs2)c(C(=O)C2CCCC2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)Nc2nc(CCNS(C)(=O)=O)cs2)c(C(=O)C2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To 1-[4-(amino-ethyl)-thiazol-2-yl]-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (0.05 g, 0.13 mmol) in 10 mL DCM at 0° C. was added methanesulfonyl chloride (0.02 g, 0.13 mmol) followed by pyridine (0.02 g, 0.21 mmol). The reaction was stirred at ambient temperature overnight, concentrated and purified by flash chromatography on silica gel with 20-50% EtOAc/hexane to obtain the product as white solid in 75% yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: FC(F)(F)c1ccc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)c(Cl)n2)CC1
Yield: 65.2 %

Procedure:
tert-Butyl 4-[6-chloro-5-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxylate (1.67 g, yield 65%, off-white solid) was synthesized from 2,6-dichloro-3-(trifluoromethyl)pyridine (1.51 g, 7.0 mmol) and tert-butyl piperazine-1-carboxylate (1.56 g, 8.38 mmol) by a method similar to Production Example 96, step 2.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.Cl.[Cl:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(OCCCCC)(=O)C>[ClH:13].[N:16]1([CH2:15][CH2:14][O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: ClCCN1CCCCC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCOC(C)=O
Product: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Temperature: 125 °C

Procedure:
To a 125 mL 3 neck flask with mechanical stirring, condenser, and a heating apparatus consisting of an RTD probe in the flask hooked via a temperature controller to a heating mantle, the following were added: 7.61 g methyl 4-hydroxybenzoate, 11.05 g β-chloroethylpiperidine hydrochloride, 16.59 g powdered potassium carbonate, and 60 mL amyl acetate. The mixture was heated overnight under nitrogen in an oil bath to 125° C., and was allowed to proceed until HPLC indicated complete consumption of the methyl 4-hydroxybenzoate. The mixture was cooled to ambient temperature and 40 mL deionized water was added to dissolve the solids. The aqueous layer was separated and discarded. The water wash was repeated. 25 mL of 8N hydrochloric acid were added to extract intermediate. The layers were separated and the acid layer returned to the reaction flask. The acid solution was heated to 95° C. for about 24 hours as a "stress" test; (after 6 hours 1% of the uncleaved ester remained.) The mixture was cooled to 40° C. and 25 mL acetone added. The mixture was cooled to 0° C.-5° C. for 1 hour. The mixture was filtered and the cakes rinsed with approx. 25 mL acetone and dried. Yield=12.0 g (84.1% of theoretical).
Reaction SMILES: Cl[C:2]1[C:3]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[CH:4][C:5]([NH:8]C(=O)C(C)(C)C)=[N:6][CH:7]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[CH3:22][N:19]1[CH2:18][CH2:17][CH:16]([NH:15][C:3]2[C:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:7][N:6]=[C:5]([NH2:8])[CH:4]=2)[CH2:21][CH2:20]1
Reactant: CN1CCC(Nc2cc(NC(=O)C(C)(C)C)ncc2Cl)CC1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CN1CCC(Nc2cc(N)ncc2-c2ccccc2)CC1
Temperature: 130 °C
Yield: 238.6 %

Procedure:
A solution of the N-(5-chloro-4-(1-methylpiperidin-4-ylamino)pyridin-2-yl)pivalamide (Synthesis 153-C) (0.187 g, 0.57 mmol), phenyl boronic acid (0.140 g, 1.15 mmol), sodium carbonate (0.153 g, 1.43 mmol) and Bedford catalyst (0.003 g, 0.005 mmol) in a mixture of acetonitrile/water (4/1, 3.1 mL) was heated under microwave irradiation for 30 min at 130° C. The crude reaction mixture was purified by ion exchange on SCX-II acidic resin (1 g) eluting with methanol/dichloromethane (1/1), then 2M ammonia-methanol. The basic fractions were combined and the solvent was removed in vacuo. The crude mixture was used without further purification. A solution of the protected amine in 6 M HCl (3 mL) was heated under microwave irradiation at 105° C. for 50 min. The solution was basified with Na2CO3 and extracted with ethyl acetate (3×10 mL). The crude mixture was purified by flash chromatography on silica, eluting with methanol and dichloromethane (1/9), to give the title compound as a colourless solid (0.384 g, 73%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C@@H:41]([CH2:58][CH3:59])[C@H:42]([NH:46][C:47]([N:49]([CH3:57])[CH2:50][C:51]1[N:52]=[C:53]([CH3:56])[S:54][CH:55]=1)=[O:48])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:30][O:29][C:28](=[O:31])[NH:27][C@@H:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20](=[O:21])[NH:19][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:4][C@H:3]([OH:32])[C@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:1][C:43](=[O:44])[C@H:42]([CH:41]([CH2:58][CH3:59])[CH3:40])[NH:46][C:47](=[O:48])[N:49]([CH3:57])[CH2:50][C:51]1[N:52]=[C:53]([CH3:56])[S:54][CH:55]=1
Reactant: CC[C@H](C)[C@H](NC(=O)N(C)Cc1csc(C)n1)C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(C)[C@H](NC(=O)N(C)Cc1csc(C)n1)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
A solution containing the product from Example 2C (0.025 g, 0.047 mmol) in THF (0.5 mL) was treated with the product from Example 109E (0.018 g, 0.061 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine (0.041 mL, 0.235 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by 0-10% methanol in ethyl acetate, to give the title compound (0.030 g, 78% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.78 (m, 16 H), 1.01 (m, 1 H), 1.36 (m, 1 H), 1.50 (m, 2 H), 1.70 (m, 1 H), 2.61 (s, 3 H), 2.73 (m, 3 H), 2.86 (s, 3 H), 3.49 (s, 3 H), 3.62 (m, 1 H), 3.83 (d, J=9.93 Hz, 1 H), 3.98 (t, J=7.91 Hz, 1 H), 4.11 (m, 2 H), 4.43 (m, 2 H), 4.86 (d, J=5.88 Hz, 1 H), 6.19 (d, J=8.09 Hz, 1 H), 6.62 (d, J=9.56 Hz, 1 H), 7.16 (m, 8 H), 7.31 (m, 1 H), 7.42 (d, J=9.19 Hz, 1 H), 7.77 (d, J=8.09 Hz, 1 H), 7.85 (m, 4 H), 8.63 (d, J=4.78 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([S:22][C:19]2[CH:20]=[CH:21][C:16]([NH2:15])=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Sc2ccnc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.6 %

Procedure:
2,4-Dichloropyridine (4.44 g, 30.0 mmol) and potassium carbonate (8.28 g. 60.0 mmol) in dimethylformamide (60 mL) was purged with nitrogen for 10 min. 4-Aminothiophenol (3.76 g, 30.0 mmol) was added and the mixture stirred under nitrogen at room temperature for 18 h. Water (300 mL) was added and the slurry stirred for 30 min. The resulting solid was filtered, washed with water and vacuum dried at room temperature. Recrystallization from ethyl acetate (35 mL), filtered hot, then cooled gave 4-(2-Chloro-pyridin-4-ylsulfanyl)-phenylamine (3.946 g, 56% yield).