Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[CH2:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH3:30][C:31]1[S:32][C:33]([CH:37]=O)=[C:34]([CH3:36])[N:35]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:37][C:33]4[S:32][C:31]([CH3:30])=[N:35][C:34]=4[CH3:36])[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1nc(C)c(C=O)s1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)CC(C(=O)OC)=CC=N3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2sc(C)nc2C)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 28.1 %

Procedure:
In 1,2-dichloroethane (21 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-benzazepine-4-carboxylate (0.70 g). To the solution were added 2,4-dimethyl-1,3-thiazole-5-carbaldehyde (0.62 g) and sodium triacetoxyborohydride (1.5 g), and the mixture was stirred at room temperature for 36 hours. After stirred at 60° C. for 12 hours, the mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=1/1) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(2,4-dimethyl-1,3-thiazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.26 g).
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[C@H:15]([O:16][CH2:17][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][CH3:32])[CH2:14][CH2:13][CH2:12][O:11]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:17]([O:16][C@@H:15]1[CH2:14][CH2:13][CH2:12][O:11][C@H:10]1[CH2:9][OH: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][CH3:32]
Reactant: CCCCCCCCCCCCCCCCO[C@@H]1CCCO[C@H]1COCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCCCCCCCCCCCCCO[C@@H]1CCCO[C@H]1CO
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.5 g of 10% w/w palladium-on-activated carbon was added to a solution of 3.757 g of dl-trans-2-benzyloxymethyl-3-hexadecyloxytetrahydropyran (prepared as described in Preparation 7) in 150 ml of methanol, and the whole was mixed with hydrogen by shaking in a Paar's apparatus at room temperature under a pressure of 4 atmospheres (about 4 bars). After 20 hours, the catalyst was removed by filtration, and the solvent was then removed by distillation to give 2.749 g of the title compound as a solid, melting at 41°-42° C. (cold hexane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[C:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]3[C:22](=[O:23])[C:21]4=[CH:24][S:25][CH:26]=[C:20]4[NH:19][C:18]3=[O:27])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:35][C:36]([CH3:41])([CH3:40])[C:37](Cl)=[O:38].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[C:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]3[C:22](=[O:23])[C:21]4=[CH:24][S:25][CH:26]=[C:20]4[N:19]([C:37](=[O:38])[C:36]([CH3:41])([CH3:40])[CH3:35])[C:18]3=[O:27])[CH2:11][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]c2cscc2c(=O)n1CCN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)n1c(=O)n(CCN2CCC(=C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(=O)c2cscc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.5 %

Procedure:
A mixture of 3-[2-[4-[bis(4-fluorophenyl)methylene]piperidin-1-yl]ethyl]thieno[3,4-d]pyrimidine-2,4-dione of Example 4 (0.80 g, 1.7 mmol), trimethylacetyl chloride (0.25 ml, 2.0 mmol) and triethylamine (0.84 ml, 6.0 mmol) in methylene chloride (20 ml) was stirred at room temperature for 16 hours. The reaction mixture was washed with water (2×30 ml) and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel 60 (80 g) using 1% methanol in methylene chloride as the eluant, to give the title compound (0.35 g, 37% yield) as a colorless solid, mp 69°-72° C. IR(KBr): 1595, 1660 and 1715 cm-1 ; MS (DCI), m/z 564 (MH+); 1H NMR (CDCl3): δ 1.44 (s, 9H), 2.34 (t, J=5 Hz, 4H), 2.61 (t, J=5 Hz, 4H), 2.67 (t, J=7 Hz, 2H), 4.17 (t, J=7 Hz, 2H), 6.58 (d, J=3 Hz, 1H), 6.96-7.08 (m, 8H) and 8.25 (d, J=3 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH2:16]Cl)[CH:15]=1.[H-].[Na+]>>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH2:16][N:5]2[CH2:6][CH2:7][CH2:8][C@H:4]2[CH2:3][O:2][CH3:1])[CH:15]=1
Reactant: ClCc1cncc(Br)c1
Reactant: COC[C@@H]1CCCN1
Agent: [H-]
Agent: [Na+]
Product: COC[C@@H]1CCCN1Cc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediates A-12 [B], (S)-2-(methoxymethyl)pyrrolidine was reacted with 3-bromo-5-chloromethyl-pyridine (intermediate A-12 [A]) in presence of NaH to give the title compound as a yellow oil. MS: 285.0, 286.9 (M+H+).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([NH2:20])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:22]1[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH:29][C@@H:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][CH2:31]2)[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Si:1]([O:8][CH2:9][C@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([NH:20][C:22]2[N:23]=[C:24]([NH:29][C@@H:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:32][CH2:31]3)[N:25]=[C:26]([CH3:28])[N:27]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: Cc1nc(Cl)nc(N[C@H]2CCc3ccccc32)n1
Reactant: CC1(C)O[C@@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@@H](N)[C@@H]2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1nc(N[C@H]2CCc3ccccc32)nc(N[C@@H]2C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H]3OC(C)(C)O[C@H]32)n1
Yield: 24.3 %

Procedure:
A mixture of (3aS,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-amine (141.8 mg, 0.0004703 mol), 4-chloro-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-6-methyl-1,3,5-triazin-2-amine (127.1 mg, 0.0004876 mol) and potassium carbonate (0.130 g, 0.000940 mol) in 1,4-dioxane (0.77 mL) was subjected to microwave irradiation (300 watts, 160° C.) for 30 minutes. The mixture was filtered with CH2Cl2 and concentrated. The residue was purified by flash chromatography (10 to 100% EtOAc/hexanes) to obtain 60 mg (24%) of the title compound. LC/MS: Rt=2.03 min, ES+ 279 (FA standard).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]2[C:30](=[O:31])[C:29]3[CH:32]=[C:33]([CH3:35])[S:34][C:28]=3[NH:27][C:26]2=S)[CH2:19][CH2:18]1.[OH-].[K+].C([OH:41])C.OO>O>[OH2:1].[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]2[C:30](=[O:31])[C:29]3[CH:32]=[C:33]([CH3:35])[S:34][C:28]=3[NH:27][C:26]2=[O:41])[CH2:19][CH2:18]1
Reactant: CCO
Reactant: Cc1cc2c(=O)n(CCN3CCC(Cc4nc5cccnc5n4Cc4ccco4)CC3)c(=S)[nH]c2s1
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cc2c(=O)n(CCN3CCC(Cc4nc5cccnc5n4Cc4ccco4)CC3)c(=O)[nH]c2s1
Reaction time: 8 h
Yield: 58 %

Procedure:
To a stirred mixture of 3 parts of 3-[2-[4-[[3-(2-furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperidinyl]ethyl]-2,3-dihydro-6-methyl-2-thioxothieno[2,3-d]pyrimidin-4(1H)-one, 4.3 parts of potassium hydroxide, 56 parts of ethanol and 5.5 parts of water were added dropwise 45 parts of a hydrogen peroxide solution 3%. The whole was stirred overnight. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanone. The product was filtered off and dried, yielding 1.7 parts (58%) of 3-[2-[4-[[3-(2-furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperidinyl]ethyl]-6-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione monohydrate; mp. 135.4° C. (496).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][C:17]=3Br)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[CH2:33]([Zn]CC)[CH3:34]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][C:17]=3[CH2:33][CH3:34])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC[Zn]CC
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(CC)c1
Reaction time: 4 h
Yield: 37 %

Procedure:
Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-bromophenyl)acetate (Example 46 step C; 30 mg, 0.058 mmol) was diluted with THF (1 mL) followed by the addition of 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (4.8 mg, 0.0058 mmol) and diethylzinc (0.13 ml, 0.15 mmol). After stirring for 4 hours, the reaction loaded directly onto a silica gel column, eluting with 5-50% ethyl acetate/hexane to yield ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-ethylphenyl)acetate (10 mg, 37% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C(Cl)Cl.[OH-].[Na+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>CCCCCCC>[CH2:20]([O:19][C:17](=[O:18])[NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cccc2cc[nH]c12
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCCCCCC
Product: O=C(Nc1cccc2cc[nH]c12)OCc1ccccc1
Temperature: 55 °C
Yield: 96.4 %

Procedure:
Equip a 12-L reaction flask with a cooling bath, air driven stirring apparatus, addition funnel, and thermometer probe. Thoroughly purge the flask with nitrogen, charge 7-aminoindole (352 g, 2.663 moles), CH2Cl2 (5.30 L, 15 volumes) and 2N NaOH (1.76 L, 3.515 moles). After cooling the biphasic solution to less than 10° C., benzyl chloroformate (500 g, 2.929 moles) add dropwise at such a rate so as to maintain the temperature at less than 10° C. over one hour. Stir the reaction vigorously for 1 hour until complete by TLC. Separate the layers and extract the aqueous layer with CH2Cl2 (1.7 L). Combine the organic layers, wash with 2N NaOH (2×2 L), and dry over Na2SO4. After filtering off the drying agent, concentrate the filtrate in vacuo to a volume of ˜1.5 L resulting in thin dark mixture. Gradually exchange the solvent using heptane (˜4 L) to form a thick sand-like slurry and increase the bath temperature to 50-60° C. Concentrate to a volume of ˜1.5 L, filter while hot (50-60° C.), wash with warm (45° C.) heptane (1 L) and RT heptane (1 L), and dry to yield 683.5 g (96.7%) of the title compound as light purple solid. 1H-NMR(DMSO-d6, 300 MHz), δ 10.79 (br s, 1H), 9.42 (br s, 1H), 7.20-7.56 (m, 8H), 6.92 (t, 1H), 6.41 (dd, 1H), 5.18(s, 1H).
Reaction SMILES: C(O)(=O)C1C=CC=CC=1.OC1C=CC([C:17](C2C=CC(O)=CC=2)([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=CC=1>>[F:19][C:18]([F:21])([F:20])[CH2:17][C:22]([F:25])([F:24])[F:23]
Reactant: Oc1ccc(C(c2ccc(O)cc2)(C(F)(F)F)C(F)(F)F)cc1
Agent: O=C(O)c1ccccc1
Product: FC(F)(F)CC(F)(F)F
Yield: 89 %

Procedure:
A reaction was conducted as described in Example 6 except that benzoic acid was replaced with 105 mmol of 2,2-bis(4-hydroxyphenyl)-1,1,1,3,3,3-hexafluoropropane and the amount of PGE was 200 mmol. Desired 2,2-bis[4-(2-hydroxy-3-phenoxypropyloxy)phenyl[-1,1,1,3,3,3-hexafluoropropane was formed in analytical yield of 89% and isolated in a yield of 83%.
Reaction SMILES: N[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[C:4]([O:14][CH3:15])[N:3]=1.N([O-])=O.[Na+].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[C:4]([O:14][CH3:15])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cnc(N2CCOCC2)c(N)n1
Agent: O=N[O-]
Agent: [Na+]
Product: COc1cnc(N2CCOCC2)c(Cl)n1

Procedure:
The 2-amino substituent of Step A product when treated with sodium nitrite as described in Step E of Preparation 81 is converted to the 2-hydroxy group. Treatment of the 2-hydroxy-3-morpholino-6-methopxypyrazine with phosphorus oxychloride by Preparation 13, Step B method, gives 2-chloro-3-morpholino-6-methoxypyrazine.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH3:16][CH:17]1[CH2:26][CH2:25][C:24]2[C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[CH:21]=[CH:20][C:19]=2[NH:18]1>O>[CH3:16][CH:17]1[CH2:26][CH2:25][C:24]2=[C:23]3[C:22](=[CH:21][C:20]4=[C:19]2[N:18]1[CH2:4][CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]4=[O:13])[CH:30]=[CH:29][CH:28]=[CH:27]3
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC1CCc2c(ccc3ccccc23)N1
Solvent: O
Product: CCOC(=O)C1CN2c3c(cc4ccccc4c3CCC2C)C1=O
Temperature: 200 °C

Procedure:
A mixture of diethyl ethoxymethylenemalonate (17.3 g., 0.08 mole) and 3-methyl-1,2,3,4-tetrahydrobenzo[f]quinoline (prepared by reduction of 1-chloro-3-methylbenzo[f]quinoline with rhodium on carbon) (15.8 g., 0.08 mole) was heated to 200° C., then slowly cooled to about 170° C. and maintained at that temperature for about three hours. After cooling to ambient temperature, polyphosphoric acid (100 g.) was added and the mixture was heated at 90° C. with manual stirring. The temperature was permitted to rise gradually to about 110° C. and the mixture was observed to foam. After the foam subsided, the mixture was poured into hot water with stirring. An oil formed which became a yellow solid when cooled. Recrystallization from methanol provided ethyl 1,2-dihydro-3-methyl-7-oxo-3H,5H-naphtho[1,2,3-ij]quinolizine-6-carboxylate as a pale yellow solid, m.p. 178°-180° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:11]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C1([O:33][C:34]([NH:36][OH:37])=O)C=CC=CC=1>C1COCC1>[OH:37][NH:36][C:34]([N:24]1[CH2:23][CH2:22][CH:21]([N:10]([CH2:9][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=2)[CH:11]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)[CH2:26][CH2:25]1)=[O:33]
Reactant: O=C(NO)Oc1ccccc1
Reactant: Cc1cnc(CN(C2CCNCC2)C2CCCc3cccnc32)c(C)c1
Solvent: C1CCOC1
Product: Cc1cnc(CN(C2CCN(C(=O)NO)CC2)C2CCCc3cccnc32)c(C)c1
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 33.7 %

Procedure:
To a solution of (3,5-dimethyl-pyridin-2-ylmethyl)-piperidin-4-yl-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (150.0 mg, 0.428 mmol) in THF (5 mL) was added hydroxylamine carboxylic acid phenyl ester (75 mg, 0.449 mmol) and stirred for 17.5 h at reflux. The mixture was cooled to ambient temperature and concentrated in vacuo. Purification by flash chromatography on silica gel using CH2Cl2/MeOH/NH4OH (89:10:1) followed by purification by radial chromatography using CH2Cl2/MeOH/NH4OH (94:5:1) afforded COMPOUND 369 (59 mg, 34%) as white solid. 1H NMR (CDCl3) δ1.54-1.72 (m, 3H), 1.81-2.05 (m, 5H), 2.23 (s, 3H), 2.37 (s, 3H), 2.53-2.79 (m, 5H), 3.85-4.07 (m, 5H), 6.95-7.00 (m, 2H), 7.14 (s, 1H), 7.25 (d, 1H, J=4.2 Hz), 8.10 (s, 1H), 8.40 (d, 1H, J=3.7 Hz); 13C NMR (CDCl3) δ 17.90, 18.58, 21.71, 29.04, 29.37, 30.08, 31.25, 43.84, 53.30, 57.64, 60.19, 121.29, 131.51, 133.03, 134.11, 136.25, 138.92, 145.97, 146.88, 158.41, 160.63; ES-MS m/z 410 (M+H). Anal Calcd. For C23H31N5O200.1(H2O)90.3CH2Cl2): C, 64.07; H, 7.34; N, 16.03. Found: C, 64.13; H, 7.44; N, 15.69.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[CH3:12].[N:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][N:13]=3)=[CH:24][N:23]=2)=[O:11])=[CH:4][C:3]=1[CH3:12]
Reactant: Nc1ccc(-c2cnccn2)cn1
Reactant: Cc1cc(CC(=O)O)cnc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cc(CC(=O)Nc2ccc(-c3cnccn3)cn2)cnc1Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 2-(6-chloro-5-methylpyridin-3-yl)acetic acid 86-7 (3.0 g, 16.2 mmol), 5-(pyrazin-2-yl)pyridin-2-amine 86-3 (2.80 g, 16.2 mmol), 1,3-dicyclohexylcarbodiimide (4 g, 19.44 mmol) and 4-(dimethylamino)pyridine (324 mg, 3.24 mmol) in DMF (45 mL) was stirred at room temperature for 10 hours. The reaction mixture was filtered to remove the solid and the filtrate was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 5% methanol in dichloromethane to give 2-(6-chloro-5-methylpyridin-3-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide 86-8 as pale yellow solid. MS m/z 340.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 11.09(s 1H), 9.31(d, 1H, J=1.6 Hz), 9.11(d, 1H, J=1.6 Hz), 8.72(m, 1H), 8.63(m, 1H), 8.51(dd, 1H, J1=8.6 Hz, J2=2.4 Hz), 8.21(m, 2H), 7.76(d, 1H, J=1.6 Hz), 3.82(s, 2H), 2.33(s, 3H).
Reaction SMILES: [C:1]([C@@H:3]([NH:22][C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1C(OC(C)(C)C)=O)=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([S:19]([CH3:21])=[O:20])[CH:12]=2)=[CH:7][CH:6]=1)#[N:2].C(O)=[O:39]>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C@H:3]([NH:22][C:23]([C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]3)=[O:24])[C:1]#[N:2])=[CH:6][CH:7]=2)=[CH:12][C:13]=1[S:19]([CH3:21])=[O:20])(=[O:39])[NH2:18]
Reactant: CS(=O)c1cc(-c2ccc(C[C@@H](C#N)NC(=O)[C@@H]3CCCCN3C(=O)OC(C)(C)C)cc2)ccc1C#N
Reactant: O=CO
Product: CS(=O)c1cc(-c2ccc(C[C@@H](C#N)NC(=O)[C@@H]3CCCCN3)cc2)ccc1C(N)=O
Temperature: 50 °C

Procedure:
A solution of (2S)-tert-butyl 2-((1S)-1-cyano-2-(4′-cyano-3′-(methylsulfinyl)biphenyl-4-yl)ethylcarbamoyl)piperidine-1-carboxylate (0.08 g) in formic acid (2 mL) was stirred and heated at 50° C. for 10 min. The mixture was evaporated and applied to a 10 g SCX column. The column was washed with methanol then eluted with 10% ammonia in methanol. The eluate was evaporated and the residue dissolved in isopropanol and precipitated with diethyl ether. The solid was collected, washed with diethyl ether and dried over magnesium sulfate. Purification by RPHPLC using aqueous 0.1% TFA afforded the major product as a colourless solid (0.027 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([C:6]([OH:8])=[O:7])[CH2:2]1.C(N(CC)C(C)C)(C)C.CO.[C:20]([CH:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:32]=[CH:33][C:34]3[S:38][C:37]([CH:39]=O)=[N:36][C:35]=3[CH:41]=2)[CH2:26][CH2:25]1)([CH3:23])([CH3:22])[CH3:21].C([BH3-])#N.[Na+]>>[C:20]([CH:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:32]=[CH:33][C:34]3[S:38][C:37]([CH2:39][N:1]4[CH2:5][CH2:4][C@@H:3]([C:6]([OH:8])=[O:7])[CH2:2]4)=[N:36][C:35]=3[CH:41]=2)[CH2:26][CH2:25]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)C1CCC(Oc2ccc3sc(C=O)nc3c2)CC1
Reactant: O=C(O)[C@@H]1CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(C)C1CCC(Oc2ccc3sc(CN4CC[C@@H](C(=O)O)C4)nc3c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(R)-Pyrrolidine-3-carboxylic acid (100 mg, 0.9 mmol) (HCl salt) was combined with N,N-Diisopropylethylamine (300 uL, 2 mmol) in Methanol (4.0 mL, 98 mmol) and stirred for 15 min. 5-(4-tert-Butyl-cyclohexyloxy)-benzothiazole-2-carbaldehyde (10.0E2 mg, 0.33 mmol) was then added and the mixture was stirred at RT for 30 minutes. After 30 minutes the reaction was cooled to 0° C. and Sodium cyanoborohydride (100 mg, 2 mmol) was added in two portions. The reaction was then allowed to warm to RT while stirring overnight. The reaction was then purified directly on the Gilson (10-90% CH3CN/H2O (0.1% TFA), 19×150 cm C18, RT=8.6 min) The product was then dried on the highvac to give the title compound as a white solid. 1H NMR (400 MHz, MeOD) Shift=8.00-7.78 (m, 1H), 7.69-7.51 (m, 1H), 7.27-7.05 (m, 1H), 5.09-4.93 (m, 3H), 4.39-4.21 (m, 1H), 4.01-3.39 (m, 4H), 2.65-2.18 (m, 3H), 2.01-1.80 (m, 2H), 1.53-1.04 (m, 6H), 0.92 (s, 9H). MS (ESI, M+1): 417.30.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[CH:9][C:8]([CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.C(O[CH:21]=[C:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>N1C=CC=CC=1>[CH:1]1([N:4]([CH:21]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:5]2[CH:6]=[CH:7][C:8]([CH2:11][N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)=[CH:9][CH:10]=2)[CH2:3][CH2:2]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: c1cc(NC2CC2)ccc1CN1CCOCC1
Solvent: c1ccncc1
Product: CCOC(=O)C(=CN(c1ccc(CN2CCOCC2)cc1)C1CC1)C(=O)OCC
Temperature: 145 °C

Procedure:
To a flask containing N-cyclopropyl-4-(4-morpholinylmethyl)aniline (0.55 g) from Preparation No. 23 is added diethyl ethoxymethylenemalonate (0.45 mL) and pyridine (0.33 mL). The flask is tightly capped and heated to 145° C. for 2 hours. The reaction is cooled to room temperature and azeotroped under reduced pressure with toluene (3×). The residue is dissolved in dichloromethane and washed with brine, dried and concentrated under reduced pressure. The residue is chromatographed on silica eluting with 2% to 6% methanol in dichloromethane. The product-containing fractions are evaporated to give 0.77 g of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[S:20][C:21]([C:25](O)=[O:26])=[C:22]([CH3:24])[N:23]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN.[CH3:30][N:31](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[S:20][C:21]([C:25]([NH:31][CH3:30])=[O:26])=[C:22]([CH3:24])[N:23]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1nc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)sc1C(=O)O
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1sc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)nc1C
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A mixture of 2-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-4-methyl-1,3-thiazole-5-carboxylic acid (Example 16) (0.15 g, 0.35 mmol), methylamine (96 μL, 2.46 mmol), HATU (0.268 g, 0.70 mmol) and DIPEA (80 μL, 0.46 mmol) in DMF was stirred at 40° C. overnight. The solvent was evaporated and the residue was washed with water and extracted with DCM (large volume). The organic phase was dried over sodium sulphate, filtered and concentrated. The residue was twice purified by flash chromatography eluting with DCM/MeOH (95/5) to give after crystallisation from ether the title compound as a white solid (33 mg, 21%). HRMS calculated for C17H16Cl2N6O2S (M+H)+439.0511, found: 439.0548, Rt: 2.69 min. MP: 218.5° C.