Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C@H:23]([OH:44])[CH2:24][N:25]([CH2:33][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)CC2C=CC=CC=2)[CH:12]=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1.[C:45](O)(=[O:49])[C:46]([OH:48])=[O:47]>C(O)C>[C:46]([OH:48])(=[O:47])[C:45]([O:44][C@@H:23]([C:11]1[CH:12]=[CH:13][C:14]([OH:15])=[C:9]([OH:8])[CH:10]=1)[CH2:24][NH:25][CH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=1)=[O:49]
Reactant: O=C(O)C(=O)O
Reactant: COc1ccc(CCCN(Cc2ccccc2)C[C@@H](O)c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Solvent: CCO
Product: COc1ccc(CCCNC[C@@H](OC(=O)C(=O)O)c2ccc(O)c(O)c2)cc1
Reaction time: 8 h

Procedure:
To a solution of 1.50 g (2.6 mmole) of the above benzyl-protected amino alcohol (the product of step (c)) in 150 ml ethanol containing 10% dioxane, 400 mg of 10% Pd on carbon atom were added. The reaction mixture was hydrogenated overnight at 25 psi. To the resulting mixture, a solution of 0.23 g (2.60 m mole) of oxalic acid in 2 ml ethanol was added. After mixing, the solution was filtered and evaporated under reduced pressure. The residue was slurred in ether. The precipitate was collected by filtration, rinsed with ether and then acetone, and dried under vacuum to give 0.570 g of the above-identified product, melting point 158°-162° C. 1H NMR (CD3OD) δ7.0-6.5 (m, 7H, ArH), 4.8 (m, 1H, CHOH), 3.3 (S, 3H, CH3O), 3.00-2.90 (m, 4H, CH2N), 2.5-2.4 (m, 2H, ArCH2), 1.6-1.5 (m, 2H, CH2).
Reaction SMILES: [H-].[Na+].[CH:3]12[CH2:8][CH:7]1[C:6](=[O:9])[NH:5][C:4]2=[O:10].Br[CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C)C=O.O>[CH:14]1([CH2:13][CH2:12][N:5]2[C:6](=[O:9])[CH:7]3[CH:3]([CH2:8]3)[C:4]2=[O:10])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: BrCCC1CCCCC1
Reactant: O=C1NC(=O)C2CC12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C2CC2C(=O)N1CCC1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride (0.11 g) was added to a solution of 3-azabicyclo[3.1.0]hexane-2,4dione (0.3 g) and 1-bromo-2-cyclohexylethane (0.52 g) in dimethylformamide (5 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was diluted with water (15 ml) and then extracted with toluene (20 ml). The organic extract was washed with water (15 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by Kugelrohr distillation (boiling point 130-140° C. @ 0.1 mmHg) to give the title compound as a colourless oil.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].O1CCCCC1[N:34]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=[N:35]1>CCO.CC#N>[OH:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:36]3[NH:35][N:34]=[CH:38][CH:37]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](O)C2)c(Br)c1
Solvent: CC#N
Solvent: CCO
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](O)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in analogous fashion to that described in Example 8 using (S)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 34.1) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to afford an off-white powder. HPLC (Condition 4) tR=4.42 min, HPLC Chiral (CHIRALPAK® AD-H, 250×4.6 mm, eluent:EtOH/MeCN (98:2), 0.5 mL/min, UV 210 nm) tR=28.27 min, UPLC-MS (Condition 3) tR=0.91 min, m/z=434.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.63-1.88 (m, 2H) 2.92 (d, J=11.73 Hz, 1H) 3.19-3.29 (m, 2H) 3.34-3.47 (m, 1H) 4.18 (br. s, 1H) 4.80 (d, J=3.13 Hz, 1H) 6.37 (s, 1H) 7.31 (d, J=8.99 Hz, 2H) 7.75-7.89 (m, 3H) 8.00 (d, J=2.35 Hz, 1H) 8.71 (d, J=2.35 Hz, 1H) 10.16 (s, 1H) 12.85-13.12 (m, 1H).
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.C([Si](C)(C)[O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:31])=[CH:24][CH:23]=1)(C)(C)C>C1COCC1>[OH:4][C:3]1[CH2:5][C:30]([CH2:29][CH2:28][C:25]2[CH:24]=[CH:23][C:22]([OH:21])=[CH:27][CH:26]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[O:31][C:1](=[O:6])[CH:2]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCC(=O)c2ccccc2)cc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(CCc2ccc(O)cc2)(c2ccccc2)O1

Procedure:
The title compound was prepared as described in General Method 6 using 4.3 mL (40 mmol) of methyl acetoacetate, 1.64 g (41 mmol) of 60% sodium hydride, 25.6 mL (41 mmol) of 1.6 M n-butyllithium, 6.81 g (20 mmol) of 3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-1-phenyl-propan-1-one (from Example P) and 200 mL of THF. The product was carried on crude to the next step.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9](=[O:18])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCCC1.[Pd]>[C:12]1([CH2:11][CH2:10][C:9](=[O:18])[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(CCc1ccccc1)CCc1ccccc1
Yield: 49.3 %

Procedure:
A solution of 1,5-diphenyl-1,4-pentadien-3-one (50.9 g, 0.217 mole) in dry tetrahydrofuran (350 ml) was hydrogenated over 5% palladium on carbon (5.6 g) at room temperature under an atmosphere of hydrogen. After reduction, catalyst was filtered off, the filtrate was concentrated and the residue was distilled under reduced pressure to give 25.5 g of the title compound as a pale yellow oil having a boiling point of 160°-162° C./0.4 mmHg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[CH:15]=O>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:10])=[C:4]2[N:9]=[C:15]([C:14]3[CH:17]=[CH:18][C:19]([N+:20]([O-:22])=[O:21])=[C:12]([OH:11])[CH:13]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1c(Cl)cnc(N)c1N
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Solvent: CN(C)C=O
Product: Cc1c(Cl)cnc2[nH]c(-c3ccc([N+](=O)[O-])c(O)c3)nc12
Temperature: 100 °C
Reaction time: 16 h
Yield: 18 %

Procedure:
5-Chloro-4-methylpyridine-2,3-diamine (prepared by a method similar to Example 206a) (2.0 g, 12.7 mmol) was dissolved in DMF (40 ml) and heated to 100° C. 3-Hydroxy-4-nitrobenzaldehyde (2.10 g, 12.7 mmol) dissolved in DMF (10 ml) was added slowly (10 min). Air was bubbled through the reaction mixture. After 16 h, the DMF was evaporated off and the residue was purified by column chromatography (EtOAc/methanol, 10:1) giving the title compound (0.7 g, 18%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19](=[O:37])[C:20]4[C:25]([O:26][C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:24]3[NH:34][N:35]=[CH:36][C:23]3=[CH:22][CH:21]=4)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[I:41]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19](=[O:37])[C:20]4[C:25]([O:26][C:27]=3[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[C:24]3[NH:34][N:35]=[C:36]([I:41])[C:23]3=[CH:22][CH:21]=4)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: II
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5cn[nH]c54)c3=O)cc2)CCC1
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5c(I)n[nH]c54)c3=O)cc2)CCC1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 6.6 %

Procedure:
To a stirred ice-cooled solution of {1-[4-(6-oxo-8-phenyl-1,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (52 mg, 0.10 mmol) in DMF (0.5 mL), was added powdered potassium hydroxide (45 mg, 0.80 mmol). After 3 min, a solution of iodine (102 mg, 0.40 mmol) in DMF (0.5 mL) was added. The resulting mixture was stirred at RT for 16 hours. Aqueous sodium thiosulfate was added and the mixture was extracted twice with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 30 to 75% EtOAc in cyclohexane) to afford the title compound (4.2 mg, 7%) as a white solid. LCMS (Method H): RT=4.39 min, [M+H]+=634.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH3:24])[CH:19]=[CH:18]2.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:24][N:20]1[C:21]2[C:17](=[CH:16][C:15]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])=[CH:23][CH:22]=2)[CH:18]=[CH:19]1
Reactant: Cn1ccc2cc(Br)ccc21
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3c(ccn3C)c2)C1=O
Yield: 21.2 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847 mmol) was reacted with 5-bromo-1-methyl-1H-indole (215 mL, 1.016 mmol), 1,4-dioxane (20 mL), copper iodide (15 mg, 0.084 mmol), trans-1,2-diamino cyclohexane (0.03 mL, 0.254 mmol) and potassium carbonate (230 mg, 1.69 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3), followed by recrystallization using DCM and hexane afforded 55 mg of the product (27% yield).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[CH2:3][CH2:4][CH2:5][O:6][C:7]([N:9]1[CH2:15][C@H:14]([NH:16]C(OC(C)(C)C)=O)[C:13](=[O:24])[N:12]([CH2:25][CH2:26][CH2:27][C:28]([F:31])([F:30])[F:29])[C:11]2[CH:32]=[CH:33][CH:34]=[CH:35][C:10]1=2)=[O:8].[ClH:38]>O1CCOCC1>[ClH:38].[F:37][C:2]([F:1])([F:36])[CH2:3][CH2:4][CH2:5][O:6][C:7]([N:9]1[CH2:15][C@H:14]([NH2:16])[C:13](=[O:24])[N:12]([CH2:25][CH2:26][CH2:27][C:28]([F:30])([F:31])[F:29])[C:11]2[CH:32]=[CH:33][CH:34]=[CH:35][C:10]1=2)=[O:8]
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)OCCCC(F)(F)F)c2ccccc2N(CCCC(F)(F)F)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CN(C(=O)OCCCC(F)(F)F)c2ccccc2N(CCCC(F)(F)F)C1=O

Procedure:
In an analogous manner to that described in Example 1d), the treatment of the (S)-3-tert-butoxycarbonylamino-4-oxo-5-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-benzo[b][1,4]diazepine-1-carboxylic acid 4,4,4-trifluoro-butyl ester with hydrochlorid acid (37%) in dioxane yielded quantitatively the title compound as a white foam; MS (m/e): 442 (M+H)+.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Br:17][C:18]1[N:19]=[CH:20][C:21](N)=[N:22][CH:23]=1>>[Br:17][C:18]1[N:19]=[CH:20][C:21]([O:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:22][CH:23]=1
Reactant: Nc1cnc(Br)cn1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Product: Brc1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1

Procedure:
The title compound was prepared from 3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and 2,5-dibromopyrazine (D48) using the method of Example 257 (E257); MS (ES+) m/e 375 [M+H]+.
Reaction SMILES: [NH2:1][C@@:2]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([Br:16])[CH:8]=1)([CH3:6])[C:3](O)=[O:4].C1COCC1>C(OCC)(=O)C>[NH2:1][C@@:2]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([Br:16])[CH:8]=1)([CH3:6])[CH2:3][OH:4]
Reactant: C[C@](N)(C(=O)O)c1cc(Br)cc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@](N)(CO)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-2-Amino-2-(3-bromo-5-nitro-phenyl)-propionic acid (8.41 g, 25.8 mmol) was suspended in abs. THF (39 ml) and cooled to 0° C. BH3 in THF (103 ml, 103 mmol, 1M in THF) was added and the reaction was stirred at r.t. for 1 hr. The reaction was poured onto NaHCO3 (solid, 26 g, 12 eq.), 78 g ice and 155 ml ethyl acetate and stirred for 20 min. at r.t. Phases were separated. The organic phases were washed with water and brine, combined and dried over Na2SO4. Volatiles were removed under reduced pressure yielding the title compound as brown oil. 1H-NMR (360 MHz, DMSO-d6): 8.40 (s, 1H), 8.25 (s, 1H), 8.18 (s, 1H), 4.95 (t, 1H), 3.55 (m, 1H), 3.38 (m, 1H), 1.33 (s, 3H); MS: 275 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17](Cl)=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([C:27]#[N:28])=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccccc3)c(Cl)nn2)CC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccccc3)c(C#N)nn2)CC1
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
To a mixture of zinc cyanide (0.077 g, 0.66 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.1 g, 0.09 mmol) was added a solution of 4-(6-chloro-5-phenyl-pyridazin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (D13) (0.137 g, 0.36 mmol) in N,N-dimethylformamide (3.5 ml). The resulting mixture was stirred at 160° C. for 30 min, under microwave irradiation. The solvent was evaporated in vacuo to yield D14 (0.133 g, quant.). C20H23N5O2 requires 365. Found 366 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>CO>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(C#N)cc23)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N#Cc1ccc2[nH]cc(C3CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A stirred solution of 3-[1-(t-butoxycarbonyl)-4-piperidyl]-5-cyanoindole (8.4 g, 25.8 mmol) in methanol (260 mL) was treated with 4N hydrochloric acid in dioxane (64 mL, 256 mmol). After stirring at ambient temperature for 2 hours, the solution was concentrated. The residue was neutralized with 1N NaOH, extracted with ethyl acetate, dried, and concentrated to afford the product as a white solid (5.29 g, 91%). 1H-NMR δ(CDCl3) 8.59 (br s, 1 H), 8.00 (s, 1 H), 7.40 (s, 2 H), 7.09 (s, 1 H), 3.23 (br d, 1 H), 2.93 (m, 1 H), 2.81 (br t, 2 H), 2.01 (m, 2 H), 1.66 (m, 4 H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.[Cu]I>[Cl:1][C:2]1[N:3]=[N:4][C:5]([O:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccccc1
Reactant: Clc1ccc(Cl)nn1
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: Clc1ccc(Oc2ccccc2)nn1
Temperature: 90 °C
Yield: 93.5 %

Procedure:
A mixture of 3,6-dichloropyridazine (1.0 g, 5.23 mmol), phenol (0.50 g, 5.31 mmol), potassium carbonate (2.90 g, 20.98 mmol), and copper(I) iodide (0.59 g, 3.09 mmol) in dimethylsulfoxide (3.6 mL, 1.45 M) was heated to 90° C. overnight. After this time, the reaction was cooled to 25° C. and then poured into a 2N aqueous hydrochloric acid solution (75 mL) rinsing with water. The resulting mixture was filtered through filter paper and diluted with a saturated aqueous sodium chloride solution followed by extraction with ethyl acetate (150 mL). The organics were washed with a saturated aqueous sodium chloride solution (1×75 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 80 g, 5-24% ethyl acetate/hexanes) afforded 3-chloro-6-phenoxy-pyridazine (1.01 g, 93%) as a yellow solid. 1H-NMR (300 MHz, DMSO-d6) δ ppm 7.14-7.35 (m, 3H), 7.47 (t, J=7.5 Hz, 2H), 7.59 (d, J=9.2 Hz, 1H), 7.96 (d, J=9.2 Hz, 1H).
Reaction SMILES: C[N:2]1[CH:7]2[CH:8]([O:10][CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[CH2:9][CH:3]1[CH2:4][C:5](=[O:17])[CH2:6]2.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>CCOCC.[OH-].[Na+]>[CH2:22]([O:21][C:19]([N:2]1[CH:7]2[CH:8]([O:10][CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[CH2:9][CH:3]1[CH2:4][C:5](=[O:17])[CH2:6]2)=[O:20])[CH3:23]
Reactant: CN1C2CC(=O)CC1C(OC1CCCCO1)C2
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C2CC(=O)CC1C(OC1CCCCO1)C2
Reaction time: 2 h

Procedure:
A mixture of 0.5 g of 8-methyl-6-(tetrahydro-pyran-2-yloxy)-8-aza-bicyclo[3.2.1]octan-3-one, 1 mL of ethyl chloroformate, 25 mg of potassium carbonate, and 10 mL of toluene was heated to reflux overnight. After cooling the mixture was diluted with 500 mL of ether and 50 mL of 3N NaOH and stirred for 2 hours. The organic layer was dried over MgSO4 and concentrated under reduced pressure. Drying under vacuum gave 0.60 g of the ethyl carbamate.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH:28]=O)[CH:24]=[N:23][CH:22]=[N:21]1>>[N:20]1([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH2:28][N:1]2[CH:2]([C:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=3[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])[CH:24]=[N:23][CH:22]=[N:21]1
Reactant: O=Cc1cccc(-n2cncn2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-n2cncn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 3-(1H-1,2,4-triazol-1-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.70 min.; [M+H]+: 393.15 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2[CH2:19]O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Br:21]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:21][CH2:19][C:10]1[CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=[CH:14][C:9]=1[C:3]1([O:2][CH3:1])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC1(c2ccc(C(F)(F)F)cc2CO)CCCCC1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC1(c2ccc(C(F)(F)F)cc2CBr)CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.8 %

Procedure:
To a solution of (2-(1-methoxycyclohexyl)-5-(trifluoromethyl)phenyl)methanol (27 mg; 0.094 mmol) in methylene chloride (1 mL) was added N-bromosuccinimide (28 mg; 0.157 mmol) followed by triphenylphosphine (40 mg; 0.152 mmol). The reaction was stirred at room temperature for 4 hours. The reaction was directly loaded onto silica and purified over 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-40% ethyl acetate in heptane) to give 26 mg (79%) of a gum. MS-GC (El): Calc: 351.2, Found; 352 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 7.81 (d, J=1.66 Hz, 1H), 7.48 (td, J=8.30, 1.66 Hz, 1H), 7.39 (d, J=8.30 Hz, 1H), 5.12 (s, 2H), 3.00 (s, 3H), 2.25 (d, J=12.45 Hz, 2H), 1.84-1.71 (m, 3H), 1.65 (m, 4H), 1.27(m, 1H).
Reaction SMILES: [NH2:1][C:2](=O)[CH:3]([NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=1)[CH3:4].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17]>C1(C)C=CC=CC=1>[CH3:4][C:3]1[N:5]=[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=2)[S:17][C:2]=1[NH2:1]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1cc(C(=O)NC(C)C(N)=O)ccn1
Solvent: Cc1ccccc1
Product: Cc1cc(-c2nc(C)c(N)s2)ccn1
Yield: 47.9 %

Procedure:
A mixture of N-(1-amino-1-oxopropan-2-yl)-2-methylisonicotinamide (1.00 g, 4.83 mmol) and phosphorus pentasulfide (2.15 g, 9.65 mmol) in 10 mL of toluene was allowed to reflux overnight. The mixture was concentrated and the residue was purified by CombiFlash using 0-10% methanol/DCM to give 0.475 g of 4-methyl-2-(2-methylpyridin-4-yl)thiazol-5-amine 22C. LCMS (ES+) m/z 206.
Reaction SMILES: [CH3:1][N:2]([C@H:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH2:24]1)[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[S:8][CH:9]=1)=[O:4].[ClH:33]>ClCCl.CO.O1CCOCC1>[ClH:33].[CH3:1][N:2]([C@H:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH2:24]1)[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[S:8][CH:9]=1)=[O:4]
Reactant: CN(C(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1)[C@@H]1CCCc2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: CN(C(=O)c1csc(C2CCNCC2)n1)[C@@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl 4-[4-[(methyl[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-carbonyl]-2-thiazolyl]-1-piperidinecarboxylate (i.e. the product of Example 6, Step B) (2.4 g, 5.26 mmol) was dissolved in 20 mL of a mixture of dichloromethane and methanol (1:1), and 13.15 mL (52.6 mmol) of 1 N HCl in dioxane was added. The reaction mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was dissolved in 20 mL of methanol and concentrated under reduced pressure (this procedure was repeated 3 times) resulting in 1.7 g of the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[NH2:12][C:13]1[N:18]=[C:17]([NH2:19])[C:16]([CH:20]=O)=[CH:15][N:14]=1>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([NH2:11])=[N:19][C:17]2[N:18]=[C:13]([NH2:12])[N:14]=[CH:15][C:16]=2[CH:20]=1
Reactant: Cc1cccc(CC#N)c1C
Reactant: Nc1ncc(C=O)c(N)n1
Product: Cc1cccc(-c2cc3cnc(N)nc3nc2N)c1C

Procedure:
The title compound was prepared according to Example 1, starting from 2,3-dimethylphenylacetonitrile and 2,4-diamino-5-pyrimidine-carboxaldehyde; mp 330°-333° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=O.Cl.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[C@@H:31]3[C@@H:26]([CH2:27][CH:28]=[CH:29][CH2:30]3)[C:25](=[O:32])[N:24]([CH:33]3[CH2:38][CH2:37][N:36](CC4C=C5C(C=CC(=O)O5)=CC=4)[CH2:35][CH2:34]3)[N:23]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[ClH:1].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[C@@H:31]3[C@@H:26]([CH2:27][CH:28]=[CH:29][CH2:30]3)[C:25](=[O:32])[N:24]([CH:33]3[CH2:38][CH2:37][N:36]([CH:3]([N:5]4[CH2:10][CH2:9][O:8][CH2:7][CH2:6]4)[CH3:2])[CH2:35][CH2:34]3)[N:23]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(C2=NN(C3CCN(Cc4ccc5ccc(=O)oc5c4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Reactant: O=C(CCl)N1CCOCC1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(C)N4CCOCC4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from 4-(2-chloroacetyl)morpholine and starting compound A1 as described for compound 18. M. p. 159-162° C.