Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:35]=[C:36]([NH2:40])[CH:37]([CH3:39])[CH3:38]>ClCCl>[CH:15]1([CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]2[O:11][N:40]=[C:36]([CH:37]([CH3:39])[CH3:38])[N:35]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)C(N)=NO
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
A solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 1) (500 mg, 1.70 mmol) in dichloromethane (30 ml) was treated with 1,1′-carbonyldiimidazole (272 mg, 1.70 mol) and the solution was stirred at room temperature for 1 hour. The N′-hydroxy-2-methylpropanimidamide (Monatsh.Chem.; 113; 1982; 781-792) (174 mg, 1.70 mmol) was then added and the mixture was stirred for 30 minutes. The solvent was removed under reduced pressure and the residue was heated neat at 120° C. under a nitrogen atmosphere for 18 hours. The crude product was then purified by column chromatography on silica gel eluting with dichloromethane to afford the title compound as a colourless oil (250 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:48][C:49]1[S:50][C:51]([CH3:54])=[CH:52][N:53]=1.Cl>C(Cl)Cl.O.C(OCC)(=O)C>[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([NH:48][C:49]2[S:50][C:51]([CH3:54])=[CH:52][N:53]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Cc1cnc(N)s1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1
Agent: Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 56.2 %

Procedure:
A solution of triphenylphosphine (345 mg, 1.31 mmol) in methylene chloride (4 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (234 mg, 1.31 mmol). The reaction mixture was stirred at 0° C. for 15 min and then treated with 3-cyclopentyl-2(R)-(4-methanesulfonylphenyl)propionic acid (prepared as in Example 128, 300 mg, 1.01 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 25 min. The reaction mixture was then treated with 2-amino-5-methylthiazole (288 mg, 2.52 mmol). The resulting reaction mixture was allowed to stir at 25° C. for 20 h. The reaction mixture was then diluted with water (30 mL), a 1N aqueous hydrochloric acid solution (5 mL), and ethyl acetate (30 mL). The layers were separated, and the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-N-(5-methyl-thiazol-2-yl)-propionamide (223 mg, 56%) as a pale yellow foam: mp 81–85° C. (foam to gel); [α]23589=−40.4° (c=1.01, chloroform); EI-HRMS m/e calcd for C19H24N2O3S2 (M+) 392.1228, found 392.1225.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5].C[CH:8]([C@@H:12]1[CH2:17][CH2:16][NH:15][C@H:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH2:13]1)[C:9]([O-:11])=[O:10].[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([C@H:33]([N:15]2[CH2:16][CH2:17][C@@H:12]([CH2:8][C:9]([OH:11])=[O:10])[CH2:13][C@H:14]2[C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5])=[CH:31][CH:30]=1
Reactant: CC(C)CCBr
Reactant: CC(C(=O)[O-])[C@@H]1CCN[C@H](c2ccc(C(F)(F)F)cc2)C1
Reactant: O=Cc1ccc(Cl)cc1
Product: CC(C)CC[C@H](c1ccc(Cl)cc1)N1CC[C@@H](CC(=O)O)C[C@H]1c1ccc(C(F)(F)F)cc1

Procedure:
The compound was prepared analogously to Example 160 using the Grignard reagent derived from 1-bromo-3-methylbutane, starting with the chiral piperidine of Example 114 Step 1 and replacing 4-(trifluoromethyl)benzaldehyde with 4-chlorobenzaldehyde. M/Z (ES+) 482 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH:14]([CH3:16])[CH2:13][CH:12]([CH3:17])[CH2:11]2)=C([CH:9]=1)C#N.[OH-].[K+].O.[C:21]([O:24]CC)(=[O:23])[CH3:22]>COCCOCCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:11][CH:12]([CH3:17])[CH2:13][CH:14]([CH3:16])[CH2:15]2)=[C:22]([CH:9]=1)[C:21]([OH:24])=[O:23]
Reactant: CCOC(C)=O
Reactant: CC1CC(C)CN(c2ccc(Cl)cc2C#N)C1
Agent: [K+]
Agent: [OH-]
Solvent: COCCOCCO
Solvent: O
Product: CC1CC(C)CN(c2ccc(Cl)cc2C(=O)O)C1
Temperature: 25 °C
Yield: 75 %

Procedure:
To a solution of 5-chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzonitrile (1.05 g, 4.220 mmol) in Diethylene glycol monomethyl ether (2.50 mL) was added KOH (0.947 g, 16.883 mmol) and water (0.750 ml). The reaction was heated at 130–135° C. overnight. Upon cooling to rt, water and ethyl acetate was added the organic layer was discarded and the aqueous layer is acidified to pH˜6–7. The aqueous layer was then extracted with ethyl acetate three times. The combined organic layer was washed with water, brine, dried (Na2SO4), and concentrated to give required 5-chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzoic acid (0.850 g, 75%) as an off white solid. LCMS 268(M+1)+.
Reaction SMILES: [C:1]([C:4]([C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1)(C(=O)C)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2].C(OCC)(=O)C.O>FC(F)(F)C(O)=O>[C:25]([C:22]1[CH:21]=[CH:20][C:19]([C:18]([CH:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:27])=[CH:24][CH:23]=1)#[N:26]
Reactant: CCOC(=O)CCCCCC(C(C)=O)(C(C)=O)C(=O)c1ccc(C#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCC(C(C)=O)C(=O)c1ccc(C#N)cc1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
Ethyl 7-acetyl-7-(4-cyanobenzoyl)-8-oxononanoate (3.5 g) was dissolved in trifluoroacetic acid (12.6 ml) and the mixture was stirred at 20° C. for 15 minutes. The mixture was partitoned between ethyl acetate and water. The organic layer was separated, washed with water, aqueous sodium bicarbonate and brine, dried over MgSO4 (magnesium sulfate), and evaporated to give ethyl 7-(4-cyanobenzoyl)-8-oxononanoate (2.25 g) as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][N:17]([S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])(=[O:22])=[O:21])[CH2:16][CH2:15]3)[C:11]2=[O:30])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[F:31][C:32]([Si](C)(C)C)([F:34])[F:33].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.Cl>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[S:20]([N:17]1[CH2:18][CH2:19][C:12]2([C:11](=[O:30])[N:10]([C:7]3[CH:6]=[CH:5][C:4]([C:1]([OH:3])([CH3:2])[C:32]([F:34])([F:33])[F:31])=[CH:9][CH:8]=3)[CH2:14][CH2:13]2)[CH2:15][CH2:16]1)(=[O:22])=[O:21]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(=O)c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CC(O)(c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 60.5 %

Procedure:
2-(4-Acetyl-phenyl)-8-(2-chloro-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one (0.13 g), product of example 151), dissolved in THF (12 ml) under an argon atmosphere was treated at RT with (trifluoromethyl)trimethylsilane (0.062 g) then with tetra-n-butylammonium fluoride (1M solution in THF, 0.29 ml) and the reaction mixture was stirred overnight at RT. The mixture was made acidic with 3M aqueous HCl (a few drops) and stirred further 15 minutes. The solvent was removed in vacuo and the residue adsorbed on silica gel and chromatographed over silica gel (AcOEt/heptane, gradient from 0 to 40%) to give the desired product as white solid (0.091 g). MS (ESI): 517.1 MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:15]1([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.O>CN(C=O)C>[N:15]1([CH:21]2[CH2:26][CH2:25][N:24]([CH2:13][C@:11]([CH3:14])([OH:12])[CH2:10][N:3]3[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]3[Cl:1])[CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@](O)(CN1CCC(N2CCCCC2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 70 °C
Reaction time: 5 h
Yield: 74.2 %

Procedure:
(R)-2-Chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (0.500 g, 2.29 mmol) and 4-piperidinopiperidine (0.425 g, 2.53 mmol) were dissolved in DMF (5 ml), and the solution was stirred at 70° C. for 5 hours. The reaction mixture was added water and extracted with ethyl acetate twice. The organic phases were combined, washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/2) using basic silica gel to afford (S)-1-(4-piperidinopiperidin-1-yl)-3-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-propan-2-ol (0.656 g, yield 74%) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:26])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[C:13]([Cl:23])[CH:12]=3)[O:8][C:7](=O)[C:6]=2[CH:25]=1.[CH:27]([NH2:30])([CH3:29])[CH3:28].[O:31]1CCCC1>>[Cl:23][C:13]1[CH:12]=[C:11]([C:9]([NH:10][C:5]2[C:6]([C:7]([NH:30][CH:27]([CH3:29])[CH3:28])=[O:31])=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:26])=[O:8])[N:15]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[N:14]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Cl)nn3-c3ncccc3Cl)nc12
Reactant: CC(C)N
Reactant: C1CCOC1
Product: Cc1cc(Cl)cc(C(=O)NC(C)C)c1NC(=O)c1cc(Cl)nn1-c1ncccc1Cl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 6-chloro-2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one (e.g, the benzoxazinone product of Step E) (6.21 g, 15.21 mmol) in tetrahydrofuran (100 mL) was added isopropylamine (4.23 g, 72.74 mmol) and the reaction mixture was then heated to 60° C., stirred for 1 hour and then cooled to room temperature. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford the title compound, a compound of the present invention, as a white solid (5.05 g) melting at 173-175° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)=[N:11][C:10]=2[C:23](O)=[O:24])=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH2:30][C:31]1[S:32][CH:33]=[N:34][N:35]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)=[N:11][C:10]=2[C:23]([NH:30][C:31]2[S:32][CH:33]=[N:34][N:35]=2)=[O:24])=[CH:7][CH:8]=1
Reactant: Nc1nncs1
Reactant: COc1ccc(-c2[nH]c(-c3cccc([N+](=O)[O-])c3)nc2C(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: COc1ccc(-c2[nH]c(-c3cccc([N+](=O)[O-])c3)nc2C(=O)Nc2nncs2)cc1

Procedure:
5-(4-Methoxyphenyl)-2-(3-nitrophenyl)imidazole-4-carboxylic acid, 1 M hydrochloric acid—ether solution, thionyl chloride and 2-amino-1,3,4-thiadiazole are reacted and treated in the same manner as in Example 1 to give 5-(4-methoxyphenyl)-2-(3-nitrophenyl)-N-(1,3,4-thiadiazol-2-yl)imidazole-4-carboxamide.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:5][C:6]1[NH:10][C:9]2[CH:11]=[CH:12][C:13]([C:15]3[CH:16]=[CH:17][C:18]4[O:24][CH2:23][CH2:22][NH:21][CH2:20][C:19]=4[CH:25]=3)=[CH:14][C:8]=2[N:7]=1)[CH3:4].Cl[C:27]1[N:36]=[C:35](Cl)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1.[CH3:38][NH2:39]>>[CH2:3]([NH:5][C:6]1[NH:7][C:8]2[CH:14]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]4[O:24][CH2:23][CH2:22][N:21]([C:35]5[C:34]6[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=6)[N:28]=[C:27]([NH:39][CH3:38])[N:36]=5)[CH2:20][C:19]=4[CH:25]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1)[CH3:4]
Reactant: CCNc1nc2cc(-c3ccc4c(c3)CNCCO4)ccc2[nH]1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CN
Agent: Cl
Product: CCNc1nc2ccc(-c3ccc4c(c3)CN(c3nc(NC)nc5ccccc35)CCO4)cc2[nH]1

Procedure:
Prepared according to the method of example 25 by using N-ethyl-5-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazol-2-amine dihydrochloride (example 11, step 3) and 2,4-dichloroquinazoline in step 1 and methylamine in step 2. 1H NMR (400 MHz, DMSO-d6) δ 7.80 (d, 1H), 7.51 (d, 2H), 7.43 (d, 1H), 7.33 (s, 1H), 7.15 (t, 2H), 7.06-6.96 (m, 2H), 6.74-6.61 (m, 2H), 4.94 (s, 2H), 4.43 (s, 2H), 4.07 (s, 2H), 3.31 (q, 2H), 2.77 (s, 3H), 1.87 (s, 6H), 1.18 (t, 3H); MS (EI) for C27H27N7O: 466.
Reaction SMILES: Br[CH:2]([CH3:17])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1)=O.[NH2:18][C:19]1[C:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH2:26]([O:25][C:24]1[C:19]2[N:20]([C:2]([CH3:17])=[C:3]([C:5]3[CH:6]=[CH:7][C:8]4[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=4[CH:16]=3)[N:18]=2)[CH:21]=[CH:22][CH:23]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: CC(Br)C(=O)c1ccc2c(c1)NC(=O)C(C)O2
Product: Cc1c(-c2ccc3c(c2)NC(=O)C(C)O3)nc2c(OCc3ccccc3)cccn12
Yield: 80.9 %

Procedure:
6-(8-Benzyloxy-3-methylimidazo[1,2-a]pyridin-2-yl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (2.6 g) was prepared in substantially the same manner as that of Example 16 from 6-(2-bromopropionyl)-2-methyl-3-oxo-3,4-dihydro- 2H-1,4-benzoxazine (2.4 g) and 2-amino-3-benzyloxypyridine (4.8 g). mp. 261°-262° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[C:16]([C:18]1[CH:19]=[C:20]([NH:25]N)[CH:21]=[CH:22][C:23]=1[F:24])#[N:17]>>[F:24][C:23]1[CH:22]=[C:21]2[C:20](=[CH:19][C:18]=1[C:16]#[N:17])[NH:25][C:9]1[C:10]([CH3:14])([CH3:13])[C:11]3[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[CH2:7][C:8]2=1
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Reactant: N#Cc1cc(NN)ccc1F
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)c(F)cc3c1C2

Procedure:
Under the same conditions as the method for synthesizing Compound A3-1, the title compound was prepared from Compound A2 and 3-cyano-4-fluorophenylhydrazine.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[CH:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][C:34]1=[O:39])([CH3:32])[CH3:31].CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:36]4[CH2:37][CH2:38][N:33]([CH:30]([CH3:32])[CH3:31])[C:34](=[O:39])[CH2:35]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CC(C)N1CCNCC1=O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)C)C(=O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.8 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.15 g, 0.39 mmol), 1-isopropylpiperazin-2-one (0.082 g, 0.58 mmol) and 4 Å molecular sieves (0.718 g) in DCE (5 mL) and MeOH (1 mL) was stirred for 5 h at room temperature. Sodium triacetoxyborohydride (0.163 g, 0.77 mmol) was added and the reaction mixture was stirred for 72 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:EtOAc, gradient 0:100 to 5:95) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 469 as an off-white solid (0.044 g, 22%). LCMS (Method I): RT=3.31 min, [M+H]+ 518.3. 1H NMR (400 MHz, DMSO-d6): δ 8.04-8.00 (m, 1 H); 7.65-7.61 (m, 1 H); 7.28-7.21 (m, 2 H); 4.64-4.58 (m, 1 H); 4.28-4.25 (m, 4 H); 3.86 (s, 2 H); 3.81 (s, 3 H); 3.80-3.77 (m, 4 H); 3.27 (q, 7.5 Hz, 2 H); 3.17 (t, J=5.3 Hz, 2 H); 3.13 (s, 2 H); 2.73 (t, J=5.3 Hz, 2 H); 1.34 (t, J=7.5 Hz, 3 H); 1.05 (d, J=6.8 Hz, 6 H)
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[NH2:15]/[C:16](/[CH3:23])=[CH:17]\[C:18]([O:20][CH2:21][CH3:22])=[O:19].[F:24][C:25]([F:33])([F:32])[C:26](=O)[CH2:27][C:28](=[O:30])[CH3:29].C(O)(=O)C>CC(O)C>[C:28]([C:27]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16]([CH3:23])[NH:15][C:26]=1[C:25]([F:33])([F:32])[F:24])(=[O:30])[CH3:29]
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C)NC(C(F)(F)F)=C(C(C)=O)C1c1cccc2c(=O)cc(C)oc12

Procedure:
A solution of 2.1 g (11.16 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde in 60 ml of 2-propanol is mixed with 1.44 g (11.16 mmol) of ethyl 3-aminocrotonate, 17.2 g (111.6 mmol) of 1,1,1-trifluoro-2,4-pentanedione and 0.96 ml (16.74 mmol) of acetic acid and stirred under reflux for 12 h. After cooling, the reaction mixture is concentrated and the residue is taken up in 30 ml of acetic acid and again stirred under reflux for 12 h. After cooling, the reaction mixture is concentrated, and the residue is purified by preparative HPLC. The product fractions are concentrated and purified again on an Analogix cartridge (mobile phase: cyclohexane/ethyl acetate 2:1). 0.212 g (4.4% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[N+:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N+:18]#[C-:19])#[C-:11].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=O>Cl(O)(=O)(=O)=O>[CH3:8][C:6]1[N:7]2[C:11]([NH:10][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N+:18]#[C-:19])=[C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)[N:1]=[C:2]2[N:3]=[C:4]([CH3:9])[CH:5]=1
Reactant: Cc1cc(C)nc(N)n1
Reactant: [C-]#[N+]CCCCCC[N+]#[C-]
Reactant: O=Cc1ccccn1
Agent: [O-][Cl+3]([O-])([O-])O
Product: [C-]#[N+]CCCCCCNc1c(-c2ccccn2)nc2nc(C)cc(C)n12

Procedure:
Compound (2) was prepared according to the general synthesis instructions from 1.0 ml of 2-amino-4,6-dimethylpyrimidine solution (0.1 M, DCM), 0.575 ml of 1,6-diisocyanhexane solution (0.2 M, DCM), 0.500 ml of pyridine-2-carbaldehyde solution (0.3 M, DCM), and 10 μl of perchloric acid (w=20%).
Reaction SMILES: [CH3:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)=[N:11][C:10]=2[C:25]([NH2:27])=[O:26])=[O:7])=[CH:4][C:3]=1[N+:30]([O-])=O>CO.C1COCC1.[Pd]>[NH2:30][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:2]=1[CH3:1])[C:6]([NH:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[N:11][C:10]=1[C:25]([NH2:27])=[O:26])=[O:7]
Reactant: Cc1ccc(C(=O)Nc2sc(Nc3ccc4ccccc4c3)nc2C(N)=O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(=O)Nc2sc(Nc3ccc4ccccc4c3)nc2C(N)=O)cc1N
Reaction time: 16 h
Yield: 51.1 %

Procedure:
To a mixture of 5-(4-methyl-3-nitrobenzamido)-2-(naphthalen-2-ylamino)thiazole-4-carboxamide (0.07 g, 0.15 mmol) in MeOH-THF (10 mL, 1:1) was added 10% Pd/C (0.014 g) under N2-atmosphere. The mixture was stirred for 16 hrs under hydrogen atmosphere. The insoluble material was then filtered off, and the filtrate was concentrated under reduced pressure to give 0.032 g (49% yield) of the titled compound.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:27][C:28]1[CH:44]=[CH:43][C:31]([O:32][C:33]2[CH:38]=[CH:37][N:36]=[C:35]3[NH:39][C:40](=[O:42])[NH:41][C:34]=23)=[CH:30][CH:29]=1>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([O:32][C:33]3[CH:38]=[CH:37][N:36]=[C:35]4[NH:39][C:40](=[O:42])[NH:41][C:34]=34)=[CH:43][CH:44]=2)=[O:19])[N:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)[nH]c23)cc1
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccc(F)cc2)n1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)[nH]c34)cc2)n(-c2ccc(F)cc2)n1
Temperature: 50 °C
Yield: 86.4 %

Procedure:
Method I1. A mixture of phenyl 3-tert-butyl-1-(4-fluorophenyl)-1H-pyrazol-5-yl-carbamate (66 mg, 0.18 mmol) and 7-(4-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one (30 mg, 0.12 mmol) in anhydrous THF (1.5 mL) containing 4 Angstrom molecular sieves was heated at 50° C. for 14 hours. After dilution with EtOAc (10 mL) and filtration to remove the molecular sieves, the solution was washed with 0.5 M citric acid (aqueous), saturated NaHCO3 (aqueous) and brine. The organic layer was dried over MgSO4 and the solvent was evaporated under reduced pressure. The orange solid residue was washed with Et2O to afford the title compound (52 mg, 85%) as a slightly orange solid. 1H-NMR (6, ppm, DMSO-d6): 1.28 (s, 9H, t-Bu), 6.31 (d, 1H, HPy,5, J=6.0 Hz), 6.35 (s, 1H, HPyz,4), 7.09 (d, 2H, Harom,Ph,3+5, J=8.9 Hz), 7.37 (t, 2H, Harom,4-F-Ph,3+5 J=8.8 Hz), 7.47 (d, 2H, Harom,Ph,2+6, J=8.9 Hz), 7.57 (dd, 2H, Harom,4-F-Ph,2+6 J=8.8 Hz and J=5.0 Hz), 7.74 (d, 1H, HPy,6, J=6.0 Hz), 8.37 (bs, 1H, NHurea), 9.06 (bs, 1H, NHurea), 11.16 (bs, 1H, NHPy3) 11.34 (bs, 1H, NHPy2). LC-MS (m/z): 502 (M+H, 100).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:28]=[CH:27][C:8]2[N:9]=[C:10]([C:12]3[CH:26]=[CH:25][C:15]([CH2:16]P(=O)(OCC)OCC)=[CH:14][CH:13]=3)[S:11][C:7]=2[CH:6]=1.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][C:31]=1[N+:38]([O-:40])=[O:39]>C1COCC1>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[CH:16][C:15]2[CH:14]=[CH:13][C:12]([C:10]3[S:11][C:7]4[CH:6]=[C:5]([O:4][CH3:3])[CH:28]=[CH:27][C:8]=4[N:9]=3)=[CH:26][CH:25]=2)=[CH:32][C:31]=1[N+:38]([O-:40])=[O:39]
Reactant: CCOP(=O)(Cc1ccc(-c2nc3ccc(OC)cc3s2)cc1)OCC
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2nc(-c3ccc(C=Cc4ccc(Cl)c([N+](=O)[O-])c4)cc3)sc2c1
Yield: 46.4 %

Procedure:
Prepared as described in the Alkene Formation section using sodium hydride (60% dispersion in mineral oil, 0.077 g, 1.92 mmol), diethyl 4-(6-methoxybenzothiazol-2-yl)benzylphosphonate (0.5 g, 1.28 mmol) and 4-chloro-3-nitrobenzaldehyde (0.26 g, 1.41 mmol) in dry THF (20 ml) to give the title compound (0.251 g, 46%) as pale orange needles after work-up and recrystallisation from 1,2-dichloroethane.