Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N+:3]([C:6]1[C:7]([NH2:23])=[N:8][CH:9]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][NH:18][CH2:17][C:16]=3[CH:22]=2)[CH:11]=1)([O-:5])=[O:4].Cl[C:25]1[C:34]2[CH2:33][C:32]([CH3:36])([CH3:35])[CH2:31][CH2:30][C:29]=2[N:28]=[CH:27][N:26]=1.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CN1CCCC1=O>[CH3:35][C:32]1([CH3:36])[CH2:31][CH2:30][C:29]2[N:28]=[CH:27][N:26]=[C:25]([N:18]3[CH2:17][C:16]4[CH:22]=[C:12]([C:10]5[CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[C:7]([NH2:23])=[N:8][CH:9]=5)[CH:13]=[CH:14][C:15]=4[O:21][CH2:20][CH2:19]3)[C:34]=2[CH2:33]1
Reactant: Nc1ncc(-c2ccc3c(c2)CNCCO3)cc1[N+](=O)[O-]
Reactant: CC1(C)CCc2ncnc(Cl)c2C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc(N)c([N+](=O)[O-])c5)cc4C3)c2C1
Yield: 81.7 %

Procedure:
A solution of 3-nitro-5-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)pyridin-2-amine dihydrochloride (540 mg, 1.50 mmol), 4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazoline (270 mg, 1.37 mmol, reagent preparation 3), and diisopropylethylamine (970 mg, 7.49 mmol) in N-methylpyrrolidinone (3 mL) was stirred at 120° C. for 18 h. After cooling to room temperature ethyl acetate (100 mL) was added, the formed precipitate was filtered off, the organic filtrate was washed with saturated sodium bicarbonate (50 mL), water (2×50 mL), and brine (50 mL), dried over sodium sulfate, filtered and concentrated to afford crude 5-[4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-3-nitropyridine-2-amine (0.5 g) as a brown solid which was used in the next step without further purification. MS (EI) for C24H26N6O3: 447 (MH+).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)=[CH:10][C:9]=2[N+:19]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(=O)C1C=CC(NC2CCCCC2)=C(N)C=1)C>>[CH:1]1([NH:7][C:8]2[C:9]([NH2:19])=[CH:10][C:11]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1cc(-c2nnn[nH]2)ccc1NC1CCCCC1
Agent: CCOC(=O)c1ccc(NC2CCCCC2)c(N)c1
Product: Nc1cc(-c2nnn[nH]2)ccc1NC1CCCCC1

Procedure:
The title intermediate was prepared from 1.20 g (4.16 mmol) Compound 128 as described for Compound 11 to yield 0.9 g (83%). MS: 259.18 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:3]=1[C:22]([O:24]CC)=[O:23].[OH-].[K+]>O>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:15])=[CH:9][C:10]([Cl:14])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)[C:3]=1[C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)c1c(-c2ccncc2)nn(-c2c(Cl)cc(Cl)cc2Cl)c1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nc1c(C(=O)O)c(-c2ccncc2)nn1-c1c(Cl)cc(Cl)cc1Cl
Reaction time: 4 h

Procedure:
0.4 mmol of Ethyl 5-amino-3-(pyridin-4-yl)-1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-carb-oxylate (8) was dissolved in 20 ml and 10 ml H2O. 4 eq. (1.6 mmol) of KOH was added to the solution. The reaction was finished after 4 h reflux. The organic solvent was evaporated and the aqueous layer was neutralized in ice bath by adding conc. HCl. A colorless precipitate was filtered and recrystallized from hot ethanol.
Reaction SMILES: [C:1]([C:3]1([NH:9][S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)(=[O:12])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].O.S(=O)(=O)(O)[OH:26]>C(O)CO>[C:1]([C:3]1([NH:9][S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)(=[O:11])=[O:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)(=[O:26])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: C#CC1(NS(=O)(=O)Cc2ccc(S(C)(=O)=O)cc2)CCCCC1
Solvent: O
Solvent: OCCO
Product: CC(=O)C1(NS(=O)(=O)Cc2ccc(S(C)(=O)=O)cc2)CCCCC1
Temperature: 175 °C

Procedure:
N-(1-Ethynylcyclohexyl)-4-methanesulfonyl-phenylmethane sulfonamide (19.6 g, 55 mmol) was suspended in ethylene glycol (250 ml). 10 ml Water, 2 g HgO and 2 ml conc. sulfuric acid were added and the mixture was heated at 175° C. for 3 hours, then poured warm into 1 l crushed ice, decanted from mercury salts, stirred and the precipitate was filtered off, washed with water and dried under vacuum at 70° C. to yield N-(1-acetylcyclohexyl)-4-methanesulfonyl-phenylmethanesulfonamide, shown below, as a solid (14.4 g, 70%). 1H-NMR (CDCl3) δ 7.95 (d, 2H), 7.68 (d, 2 H), 4.68 (s, 1 H), 4.42 (s, 2 H), 3.06 (s, 3 H), 2.29 (s, 3 H), 2.00-1.25 (m, 10 H); MS (IS): 372.1 [M−H]−
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][C:15]2=[O:16])=[CH:10][CH:9]=1)=[O:6].[H-].[Na+].[CH3:33]I>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[C:5]([N:7]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][C:15]2=[O:16])=[CH:10][CH:9]=1)[CH3:33])=[O:6]
Reactant: COc1ccc(C(=O)Nc2ccc(N3C(=O)CCc4ccccc43)cc2)c(OC)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N(C)c2ccc(N3C(=O)CCc4ccccc43)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
To a solution of 1-[4-(2,4-dimethoxybenzoylamino)phenyl]-3,4-dihydrocarbostyril (0.19 g) in dimethylformamide (8 ml) is added with stirring 60% sodium hydride (0.02 g) under ice cooling. The mixture is stirred at room temperature for 0.5 hour and thereto is added a solution of methyl iodide (0.08 g) in dimethylformamide (6 ml). The mixture is stirred at room temperature for 3 hours. The solvent is distilled off under reduced pressure and water is added to the residue. The mixture is extracted with dichloromethane, washed with water and dried with magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography to give 1-{4-[N-(2,4-dimethoxybenzoyl)-N-methylamino]phenyl}-3,4-dihydrocarbostyril (70 mg).
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OC([N:24]([C:32]1[S:41][CH2:40][C@H:39]2[C@:34]([C:46]3[CH:51]=[C:50](Br)[CH:49]=[CH:48][C:47]=3[F:53])([CH2:35][O:36][C@@H:37]([C:42]([F:45])([F:44])[F:43])[CH2:38]2)[N:33]=1)C(OC(C)(C)C)=O)=O)(C)(C)C>CN(C=O)C.C(OCC)(=O)C.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>[F:53][C:47]1[CH:48]=[CH:49][C:50]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:51][C:46]=1[C@@:34]12[N:33]=[C:32]([NH2:24])[S:41][CH2:40][C@@H:39]1[CH2:38][C@H:37]([C:42]([F:45])([F:43])[F:44])[O:36][CH2:35]2
Reactant: OB(O)c1cccnc1F
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@@]2(c3cc(Br)ccc3F)CO[C@@H](C(F)(F)F)C[C@H]2CS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC1=N[C@@]2(c3cc(-c4cccnc4F)ccc3F)CO[C@@H](C(F)(F)F)C[C@H]2CS1
Temperature: 85 °C
Reaction time: 7 h
Yield: 14.5 %

Procedure:
2-Fluoropyridine-3-boronic acid (63.9 mg), tetrakis(triphenylphosphine)palladium (26.2 mg) and a 1 N sodium carbonate solution (453 μl) were added to a solution of (±)-N,N-di(tert-butyloxycarbonyl)-[(4aR*,6R*,8aS*)-8a-(5-bromo-2-fluorophenyl)-6-trifluoromethyl-4,4a,5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl]amine (138 mg) in DMF (9.9 ml), and the mixture was stirred in a nitrogen atmosphere at 85° C. for seven hours. The reaction solution was cooled to room temperature and then diluted with ethyl acetate. The organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Dichloromethane (4.0 ml) and TFA (1.0 ml) were added to the residue, and the mixture was stirred at room temperature for four hours. When the reaction was completed, the reaction solution was diluted with dichloromethane and ice was added, followed by neutralization with a sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by NH-silica gel column chromatography. The resulting white solid was washed with diethyl ether to obtain the title compound (14.0 mg).
Reaction SMILES: C1COCC1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:13]1[CH:18]=[C:17]([Cl:19])[N:16]=[C:15]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:14]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=2)O1>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].O.CCOC(C)=O>[Cl:19][C:17]1[N:16]=[C:15]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:14]=[C:13]([C:34]2[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=2)[CH:18]=1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cl)nc(N3CCOCC3)n2)cn1
Temperature: 85 °C
Yield: 44.3 %

Procedure:
THF (130 mL) and aq. Na2CO3 (2M, 40 mL, 80 mmol) were added to a glass pressure vessel containing 4,6-dichloro-2-morpholinopyrimidine (prepared as in Method 22; 4.5 g, 19.2 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (4.7 g, 21.2 mmol). The resulting mixture was stirred and sparged with argon for 1-2 minutes. The catalyst, dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (1.26 g, 1.54 mmol), was then added in one portion. After sealing the reaction vessel, the reaction was heated at 85° C. for 1 hour with stirring. Upon cooling to RT, the THF was removed under reduced pressure to leave a viscous residue. EtOAc (450 mL) and water (50 mL) were added. After vigorously stirring for 1-2 minutes, the solids were filtered off and washed with EtOAc (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were washed with saturated NaCl solution (1×50 mL), dried with Na2SO4, filtered and evaporated under reduced pressure. The crude material was further purified by silica gel chromatography to give 5-(6-chloro-2-morpholin-4-yl-pyrimidin-4-yl)-pyridin-2-ylamine (2.48 g, 44%). LC/MS (m/z): 292.1 (MH+), Rt 2.06 minutes.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10]CC)=O)[CH2:4][CH2:3]1.[NH2:13][NH2:14]>CO>[OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([NH:13][NH2:14])=[O:10])[CH2:4][CH2:3]1
Reactant: NN
Reactant: CCOC(=O)C1CCC(O)CC1
Solvent: CO
Product: NNC(=O)C1CCC(O)CC1
Temperature: 55 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 4-hydroxycyclohexanecarboxylate (2.0 g, 12 mmol) and hydrazine (1.5 g, 46 mmol) in methanol (20 mL) was stirred at 55° C. for 4 h and then cooled to room temperature (about 25° C.). After cooling, the solvent and excess hydrazine were removed by distillation under reduced pressure to provide a residue. The residue was co-evaporated with methanol (2×), and was then dried under high vacuum to provide the crude product 4-hydroxycyclohexanecarbohydrazide, which was used in the next synthesis step without further purification. LCMS: (M+H)+=155.2.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1.[CH3:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1B1OC(C)(C)C(C)(C)O1)[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[C:7]([C:5]1[N:6]=[C:2]([C:21]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=2[CH3:11])[S:3][CH:4]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1csc(Br)n1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2nc(C(C)(C)C)cs2)c(C)c1
Yield: 92.4 %

Procedure:
To a suspension of 2-bromo-4-(1,1-dimethylethyl)thiazole (6 g, 27.3 mmol), methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (9.78 g, 35.4 mmol), and potassium carbonate (11.30 g, 82 mmol) in 1,4-dioxane (20 mL) and water (5 mL), was added 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.113 g, 1.363 mmol). It was degassed and refilled with nitrogen, and was heated to reflux for 1 hour to see complete conversion of the 2-bromothiazole, by LCMS. It was distributed between water (50 mL) and ethyl acetate (200 mL). The organic layer was collected, dried over sodium sulfate, filtered and the filtrate concentrated. The crude isolate was purified on silica gel, eluting with 30% of ethyl acetate in hexanes, to get methyl 4-(4-tert-butylthiazol-2-yl)-3-methylbenzoate as a white solid (7.3 g, 93% yield). LCMS (M+H)+: 290.1. 1H NMR (CDCl3, 500 MHz): δ 8.00 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.02 (s, 1H), 3.97 (s, 3H), 2.70 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(N(C(C)C)C(C)C)C>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C#N)cn2)CC1
Yield: 63 %

Procedure:
A mixture of 6-chloro-nicotinonitrile (2.1 g, 15.16 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.86 g, 24.25 mmol, 1.6 equiv; commercially available) in N-ethyl diisopropylamine (5 mL) and anhydrous DMF (10 mL) was stirred at 60° C. for 3 d. To the reaction mixture was added a sat. solution of Na2CO3 (100 mL) and the crude extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with silica column chromatography eluting with toluene/ethyl acetate (4:1) to provide 2.90 g (63%) of the title compound. 1H NMR (300 MHz, DMSO): δ1.24-1.42 (m, 2H), 1.41 (s, 9H), 1.84-1.89 (m, 2H), 2.85-2.94 (m, 2H), 3.87-3.91 (m, 2H), 3.98 (br s, 1H), 6.54 (d, J=8.9 Hz, 1H), 7.53 (d, J=7.5 Hz, 1H), 7.66 (dd, J=8.9 Hz, J=2.1 Hz, 1H), 8.38 (d, J=2.1 Hz, 1H). 13C NMR (75 MHz, DMSO): δ28.04, 31.19, 42.25, 47.12, 78.58, 94.49, 108.62, 118.91, 138.53, 153.00, 153.89, 159.17. MS (ISP): 303.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([NH:17][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([F:12])[C:9]([F:11])=[CH:10][C:2]=1[F:1])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1cc(F)c(F)cc1F
Product: CC(C)(C)NC(=O)c1cc(F)c(F)cc1F

Procedure:
The title compound was prepared by the same method as that described in Example 26, using 2,4,5-trifluorobenzoic acid and t-butylamine.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19]([C:21]2[C:22]([C:27]3[C:32](Cl)=[CH:31][N:30]=[CH:29][C:28]=3[Cl:34])=[N:23][O:24][C:25]=2[CH3:26])=[O:20])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:35])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]2[C:32]3[C:27](=[C:28]([Cl:34])[CH:29]=[N:30][CH:31]=3)[C:22]3=[N:23][O:24][C:25]([CH3:26])=[C:21]3[C:19]2=[O:20])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2c(Cl)cncc2Cl)c1C(=O)NC1CCCC(CNC(=O)OCc2ccccc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)OCc3ccccc3)C1)c1cncc(Cl)c21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57.2 %

Procedure:
Dissolve (3-{[3-(3,5-dichloro-pyridin-4-yl)-5-methyl-isoxazole-4-carbonyl]amino}-cyclohexylmethyl)-carbamic acid benzyl ester (0.60 g, 0.0012 mol) in N,N-dimethylformamide (5 mL) at ambient temperature under a nitrogen atmosphere. Add a solution of potassium bis(trimethylsilyl)amide (0.5 M in toluene, 2.32 mL, 0.0012 mol) and stir for 20 min. at ambient temperature. Quench the dark mixture with water and follow by the adding solid sodium chloride. Extract with ethyl acetate and dry over sodium sulfate. Concentrate and elute over silica gel with methanol/dichloromethane to give 0.33 g (58%) of the desired product. MS(ES): (M+1)+ 481.0 m/z.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([N:11]=[N+]=[N-])=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23]>CC(O)=O.C(Cl)Cl.C(Cl)Cl.[Zn]>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([NH2:11])=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23]
Reactant: COC(=O)c1cc(Br)c(N=[N+]=[N-])c(F)c1Nc1ccc(Cl)cc1Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c(N)c(F)c1Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a mixture of 4-azido-5-bromo-2-(2,4-dichlorophenylamino)-3-fluorobenzoic acid methyl ester (2.05 g, 4.72 mmol) in AcOH-CH2Cl2 (10-30 mL) was added Zn dust (1.59 g, 24.3 mmol) at 0° C. The reaction mixture was warmed to room temperature. The resulting mixture was stirred for 1 hour. The reaction mixture was diluted with CH2Cl2, and washed with water, saturated aqueous NaHCO3 (2×), water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give the crude material which was purified by silica gel flash column chromatography(3 to 5% EtOAc in hexanes) to afford the desired product (1.24 g, 64%).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[N:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([CH2:16][N:17]4[C:21]5[CH:22]=[CH:23][C:24]([OH:26])=[CH:25][C:20]=5[N:19]=[CH:18]4)[CH:13]=[CH:12][C:10]=3[N:11]=2)[C@@H:5]2[CH2:27][CH2:28][CH2:29][CH2:30][C@H:4]2[O:3]1.I[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C([O-])([O-])=O.[Cs+].[Cs+].CN1C(=O)CCC1>CCOC(C)=O>[CH3:1][C:2]1([CH3:31])[N:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([CH2:16][N:17]4[C:21]5[CH:22]=[CH:23][C:24]([O:26][CH2:33][CH2:34][N:35]6[CH2:40][CH2:39][O:38][CH2:37][CH2:36]6)=[CH:25][C:20]=5[N:19]=[CH:18]4)[CH:13]=[CH:12][C:10]=3[N:11]=2)[C@@H:5]2[CH2:27][CH2:28][CH2:29][CH2:30][C@H:4]2[O:3]1
Reactant: ICCN1CCOCC1
Reactant: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(Cn3cnc4cc(O)ccc43)cc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(Cn3cnc4cc(OCCN5CCOCC5)ccc43)cc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
A mixture of 1-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-ol (100 mg, 0.23 mmol) from Step 1 of this Example, 4-(2-iodoethyl)morpholine (111 mg, 0.46 mmol) from Step 2 of this Example, Cs2CO3 (250 mg, 0.69 mmol), and NMP (2 mL) was stirred at rt for 3 h. The mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with a gradient of 33% DCM in THF to 100% THF, to afford (3aR,7aR)-2,2-dimethyl-3-(6-((5-(2-morpholinoethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)octahydrobenzo[d]oxazole (84 mg, 67%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.90 (s, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.40 (s, 1H), 7.29 (s, 1H), 7.14-7.19 (m, 2H), 6.90 (m, 1H), 5.35 (s, 2H), 4.11-4.17 (m, 2H), 3.70-3.75 (m, 4H), 3.65 (m, 1H), 3.08 (m, 1H), 2.76-2.84 (m, 3H), 2.57-2.60 (m, 4H), 2.17 (m, 1H), 1.82-1.92 (m, 2H), 1.78 (s, 3H), 1.46 (s, 3H), 1.33-1.39 (m, 4H); LCMS (ESI) m/z 548 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[C:10]([CH3:14])([CH3:13])[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:15])[C:10]([CH3:14])([CH3:13])[CH2:11][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C=O)C(=O)OCc1ccccc1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(CN1CCCCC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of benzyl-2,2-dimethyl-3-oxopropanoate (200 mg, 1.0 mmol) in DCM (30 mL) were added piperidine (0.10 mL, 1.1 mmol) and sodium triacetoxyborohydride (400 mg, 2.0 mmol). The reaction mixture was left to stir at rt for 16 h. The mixture was partitioned between DCM and water and treated with saturated NaHCO3. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Purification via silica gel chromatography (5% EtOAc in Hexane) afforded the title compound as a yellow oil. MS (ES+): m/z: 276.18 (100) [MH+]. HPLC: tr=1.97 min (ZQ2000: polar—5 min). 1H NMR (400 MHz, CDCl3): δ=1.17 (s, 6H), 1.28-1.37 (m, 2H), 1.40-1.46 (m, 4H), 2.34-2.36 (m, 4H), 2.44 (s, 2H), 5.09 (s, 2H), 7.25-7.34 (m, 5H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])[CH3:27].C(N(CC)CC)C>C(O)C>[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][N:34]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:6]3[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ccc(-n2c(-c3ccc(Cl)cc3Cl)nc3c(Cl)ncnc32)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2ncnc3c2nc(-c2ccc(Cl)cc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 70 °C

Procedure:
6-chloro-9-(4-chlorophenyl)-8-(2,4-dichlorophenyl)-9H-purine I-(1A-1)d (30 mg, 0.07 mmol), piperidine-4-carboxylic acid ethyl ester (34 mg, 0.22 mmol), and triethylamine (20 μl, 0.29 mmol) were combined in ethanol (1 ml) and heated at 70° C. for 2 hours. The reaction mixture was concentrated under a stream of N2 and then extracted into ethyl acetate from saturated NaHCO3 solution. The organic layers were combined, dried (Na2SO4), filtered, evaporated to dryness, and then purified by preparative TLC using 4% methanol in methylene chloride as eluant to obtain title compound 7A-1. A solution of the material in methylene chloride was treated with excess 1 N HCl in diethyl ether, stirred and evaporated to dryness to afford the hydrochloride salt of compound 7A-1 (24 mg, 65%) as a solid: +ESI MS (M+1) 530.1; 1H NMR (400 MHz, CD3OD) δ 8.35 (s, 2H), 7.60 (d, J=8.3 Hz, 1H), 7.56 (d, J=2.1 Hz, 1H), 7.50–7.45 (m, 3H), 7.34 (d, J=8.7 Hz, 2H), 4.15 (q, J=7.1 Hz, 2H), 3.68 (v br s, 2H), 2.85 (m, 1H), 2.16 (m, 2H), 1.89 (m, 2H), 1.25 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:21]=[CH:22]/[C:23]([OH:25])=O)[CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[CH:10]=2)[CH:8]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:21]=[CH:22]/[C:23]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:25])[CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[CH:10]=2)[CH:8]=1
Reactant: Nc1ccccc1
Reactant: COc1cc(/C=C/C(=O)O)cc(-c2ccc3cc(OC)ccc3c2)c1
Product: COc1cc(/C=C/C(=O)Nc2ccccc2)cc(-c2ccc3cc(OC)ccc3c2)c1
Yield: 62 %

Procedure:
The compound was prepared by reaction of (E)-3-[3-methoxy-5-(6-methoxy-naphthalene-2-yl)phenyl]acrylic acid (300 mg, 0.89 mmol, 1 eq) with aniline (1 eq) according to method D. Purification by column chromatography with hexane/ethyl acetate 2/1 as the eluent yielded the desired product in a yield of 62%, 227 mg.