Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH3:9])[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: C1CCNC1
Reactant: Cc1cc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Product: Cc1cc(N2CCCC2)nc(Cl)n1
Yield: 58.5 %

Procedure:
To a solution of 2,4-dichloro-6-methylpyrimidine (998 mg, 6.0 mmol) in tetrahydrofurane (30 mL) was added under stirring N,N-diisopropyl ethyl amine (853 mg, 6.6 mmol) and pyrrolidine (469 mg, 6.6 mmol) and the reaction was stirred over night at 20° C. The solvent was evaporated under reduced pressure and the residue was taken up in water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to dryness. The residue was purified by column chromatography on silica gel using heptane/ethyl acetate (9:1 to 7:3 v/v) as eluent to yield the title compound (694 mg, 58%) as white crystals. MS ISP (m/e): 198.1/200.1 (100/40) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=6.35 (s, 1H), 3.44 (m, 2H), 3.30 (m, 2H), 2.29 (s, 3H), 1.94 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[N+:13]([O-:24])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(OCc2ccccc2)cn1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(OCc2ccccc2)c[n+]1[O-]

Procedure:
A solution of 38.1 g. (0.1915 mol) of 5-benzyloxy-2-methylpyridine in 1 l. of chloroform is treated at 25°C. with 42.7 g. of 85% m-chloroperbenzoic acid. Ater one hour the solution is washed with 5% aqueous sodium carbonate, water, dried and evaporated to give 5-benzyloxy-2-methylpyridine-N-oxide, m.p. 87°-89°C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:4](=[O:16])[N:3]=1.C(N(CC)CC)C.[CH3:24][C:25]1([CH3:38])[C:29]([CH3:31])([CH3:30])[O:28][B:27]([C:32]2[CH2:33][CH2:34][NH:35][CH2:36][CH:37]=2)[O:26]1>C(Cl)(Cl)Cl.O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:5]2[CH:6]=[N:7][C:2]([N:35]3[CH2:34][CH2:33][C:32]([B:27]4[O:28][C:29]([CH3:31])([CH3:30])[C:25]([CH3:38])([CH3:24])[O:26]4)=[CH:37][CH2:36]3)=[N:3][C:4]2=[O:16])=[CH:10][CH:11]=1
Reactant: CC1(C)OB(C2=CCNCC2)OC1(C)C
Reactant: O=c1nc(Cl)ncn1Cc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC1(C)OB(C2=CCN(c3ncn(Cc4ccc(Cl)cc4)c(=O)n3)CC2)OC1(C)C
Yield: 40.1 %

Procedure:
To a chloroform solution (3.0 mL) of 4-chloro-1-(4-chlorobenzyl)-1,3,5-triazin-2(1H)-one (128 mg, 0.500 mmol) synthesized in Reference Synthesis Example 11, triethylamine (70.0 μL, 0.500 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (156 mg, 0.750 mmol) were added and the resultant mixture was stirred at room temperature for 4 hours. After completion of the reaction, water was added to the reaction solution and extraction from the resultant mixture with chloroform was performed. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0→4/1) to obtain the title compound (86.0 mg, yield 40%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.C(N(CC)CC)C.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[F:31])[C:25](Cl)=[O:26].C(OCC)(=O)C>O1CCOCC1>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:1][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:30]([F:31])=[C:22]([F:21])[CH:23]=2)=[CH:5][C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: NCCc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Nc1ccc(CCNC(=O)c2ccc(F)c(F)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
480 mg (2.649 mmol) of 4-(2-aminoethyl)-2-nitrophenylamine are dissolved in 30 ml of dioxane, and 1.102 ml (7.950 mmol) of triethylamine are added. 0.334 ml (2.650 mmol) of 3,4-difluorobenzoyl chloride are then added dropwise, and the mixture is stirred at room temperature for 30 min. Ethyl acetate is added to the reaction mixture, which is then washed 3× with water, dried using sodium sulfate, filtered and distilled off to dryness, giving N-[2-(4-amino-3-nitrophenyl)ethyl]-3,4-difluorobenzamide; EI-MS [M]+ 321, which is hydrogenated further under standard conditions, giving N-[2-(3,4-diaminophenyl)ethyl]-3,4-difluorobenzamide; HPLC-MS [M+H]+ 292.2.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([O:29][C:30]3[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=3)[C:23]=1[F:39])=[O:19])=[CH:12]2.[N:40]1[CH:45]=[CH:44][C:43]([C:46](O)=[O:47])=[CH:42][CH:41]=1.CCN(C(C)C)C(C)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:18]([C:13]2[NH:14][C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([NH:8][C:46]([C:43]2[CH:44]=[CH:45][N:40]=[CH:41][CH:42]=2)=[O:47])=[CH:17][CH:16]=3)=[O:19])=[C:23]([F:39])[C:24]=1[O:29][C:30]1[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=1
Reactant: O=C(O)c1ccncc1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(NC(=O)c5ccncc5)ccc4[nH]3)c2F)c1
Yield: 33.8 %

Procedure:
The title compound (0.020 g, 34% yield) was prepared from 5-amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.060 g, 0.103 mmol), 4-pyridinecarboxylic acid (0.013 g, 0.103 mmol), DIPEA (0.090 ml, 0.514 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.079 g, 0.309 mmol) in a similar manner as described in the general procedure. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.64 (s, 1H), 10.39 (s, 1H), 8.90-9.22 (m, 1H), 8.76 (d, 8.09 (s, 1H), 7.86 (d, 2H), 7.81 (s, 1H), 7.52 (s, 1H), 7.43-7.51 (m, 3H), 7.36-7.43 (m, 2H), 7.16 (d, 1H), 4.56 (d, 2H). MS: m/z 574 (M+1).
Reaction SMILES: Cl[C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:10][C:11]1([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:13][O:12]1.C([O-])(=O)C.[Na+]>C(O)CC.C(Cl)Cl>[C:24]([O:23][C:21]([N:18]1[CH2:17][CH2:16][N:15]([CH2:14][C:11]2([CH3:13])[O:12][C:2]3=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]3[CH2:10]2)[CH2:20][CH2:19]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCN(CC2(C)CO2)CC1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Yield: 23.3 %

Procedure:
2-Chloro-4-nitro-1H-imidazole (3.19 g, 21.6 mmol) and tert-butyl 4-(2-methyloxiran-2-ylmethyl)-piperazine-1-carboxylate (5.53 g, 21.6 mmol) and sodium acetate (1.95 g, 23.8 mmol) were dissolved in 1-propanol (50 ml) followed by stirring under reflux for 48 hours. The reaction mixture was diluted with methylene chloride. The solution was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) and treated with methylene chloride-diisopropyl ether to afford 2-(4-tert-butoxycarbonylpiperazin-1-yl)methyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (1.85 g, yield 23%) as a white powder.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]([C:13]#[C:14][C:15](OC)=[O:16])=[O:12].N1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>C1COCC1.CCOC(C)=O>[O:16]=[C:15]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:8][C:13]([C:11]([O:10][CH3:9])=[O:12])=[CH:14]1
Reactant: COC(=O)C#CC(=O)OC
Reactant: NNc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(=O)n(-c2ccccc2)[nH]1
Temperature: 67 °C
Yield: 34.7 %

Procedure:
Phenylhydrazine (0.5 g; 4.62 mmol), acetylenedicarboxylic acid dimethyl ester (0.66 g; 4.62 mmol) and 4-toluenesulfonic acid pyridine salt (1.16 g; 4.62 mmol) were dissolved in 7 ml of dry THF under nitrogen atmosphere and the solution was stirred for 2 h at RT after which 7 ml of 10% HCl (g) in EtOAc was added and the mixture heated at 67° C. for 5 h. The reaction mixture evaporated to dryness and 6 ml of DCM added to the residue. The organic phase was washed with 8 ml of water and the combined water phases were extracted with 2×6 ml of DCM. The combined organic phases were once more washed with 12 ml of water, dried over Na2SO4, filtered and evaporated to dryness to give 0.35 g of the product which was used as such without further purification.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15]OS(C)(=O)=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[N:24](S(C)(=O)=O)[N:23]=2)[N:6]=1)([CH3:3])[CH3:2].[NH:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[C:37]([NH2:39])=[O:38].CCN(CC)CC>CC#N>[CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15][N:32]3[CH2:36][CH2:35][CH2:34][CH:33]3[C:37]([NH2:39])=[O:38])=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:6]=1)([CH3:2])[CH3:3]
Reactant: Cc1cc(Nc2cc3cc(COS(C)(=O)=O)ccc3c(OC(C)C)n2)nn1S(C)(=O)=O
Reactant: NC(=O)C1CCCN1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2cc3cc(CN4CCCC4C(N)=O)ccc3c(OC(C)C)n2)n[nH]1
Reaction time: 8 h

Procedure:
A mixture of 50 mg methanesulfonic acid 1-isopropoxy-3-(1-methanesulfonyl-5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ylmethyl ester, 50 mg pyrrolidine-2-carboxylic acid amide and 54 mg Et3N in 10 mL CH3CN was stirred at r.t overnight. After removal of solvent, the residue in MeOH was sent to prep-HPLC to give 1-[1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ylmethyl]-pyrrolidine-2-carboxylic acid amide as a yellow solid. LC-MS m/e 409 (MH+).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([O:11][CH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[CH3:20][NH:21]C.[C-]#N.[K+]>CO>[CH2:4]([O:11][CH:12]1[CH2:17][CH2:16][C:15]([N:2]([CH3:3])[CH3:1])([C:20]#[N:21])[CH2:14][CH2:13]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CNC
Reactant: O=C1CCC(OCc2ccccc2)CC1
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: CN(C)C1(C#N)CCC(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
A mixture of 130 ml of 7.9 molar aqueous dimethylamine solution, 16 ml of methanol, 20.0 g of 4-benzyloxycyclohexanone, 23.2 g of dimethylamine hydrochloride and 15.3 g of potassium cyanide was stirred for 65 hours at room temperature; extraction was carried out four times using 120 ml of diethyl ether each time, and the combined extracts were concentrated; 100 ml of dichloromethane were added to the residue, the phases were separated, and the organic phases were dried over sodium sulfate, filtered and concentrated. 24.5 g of 4-benzyloxy-1-dimethylaminocyclohexanecarbonitrile were obtained in the form of a yellowish oil which slowly solidified.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:22]([O:24][C:25]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1)[CH3:23]>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][O:18][C:25]3([O:24][CH2:22][CH3:23])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCOC1=CCCCCCC1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Product: CCOC1(OCCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)CCCCCCC1
Yield: 46.4 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the acetal with 1-ethoxycyclooctene (1.61 g, 10 mmol) in the same manner as the example 20 to give the compound 31 (232 mg, 46%). Rf 0.54 (Al2O3 hexane-EtOAc 4:1) PMR (CDCl3 -0.1% d5 -Py): δH1.06 (3 H, d, J 7 Hz), 1.37-1.80 (14 H, m), 3.00 (2 H, t, J 6 Hz, CH2 -Im), 3.00 (2 H, t, J 6 Hz, CH2 -Im), 3.07 (2 H, q, J 7 Hz, OCH2), 3.10 (1 H, s, J 7 Hz, (CH3)2CH), 3.51 (3 H, s, NCH.3), 3.68 (2 H, t, J 6.2 Hz, OCH2), 6.82 (2 H, d, J 1.8 Hz, arom-H), 7.11 (1 H, t-like, arom-H) Elementary analysis (for C25H36N2O2Cl2S) Calcd. : C, 60.11% H, 7.26% N, 5.61% S, 6.42% Cl, 14.19% Found: C, 59.91% H, 7.36% N, 5.74% S, 6.23% Cl, 13.88%
Reaction SMILES: Br[CH:2]1[C:8](=O)[C:7]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:6]=2[O:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[C:19]([NH2:22])(=[S:21])[CH3:20]>CN(C)C=O>[F:14][C:11]1[CH:12]=[CH:13][C:6]2[O:5][C:4]3[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=3[C:2]3[S:21][C:19]([CH3:20])=[N:22][C:8]=3[C:7]=2[CH:10]=1
Reactant: CC(N)=S
Reactant: O=C1c2cc(F)ccc2Oc2ccccc2C1Br
Solvent: CN(C)C=O
Product: Cc1nc2c(s1)-c1ccccc1Oc1ccc(F)cc1-2
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 11-bromo-8-fluoro-11H-dibenzo[b,f]oxepin-10-one (2.34 mmoles) in dry N,N-dimethylformamide (12 ml), thioacetamide (2.8 mmoles) was added. The reaction mixture was heated under stirring at 90° C. for 3 hours. Then the solvent was evaporated under reduced pressure and the remaining oily product was dissolved in ethyl acetate and water. After extraction the organic layers were washed with a saturated aqueous NaHCO3 solution, water and a saturated aqueous sodium chloride solution. After purification by chromatography on a silica gel column, a crystalline product was isolated.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:24]([CH3:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[C:21]3[C:17]=2[CH2:18][CH2:19][CH2:20]3)=[CH:11][C:10]=1[CH2:29]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:33])=O>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:24]([CH3:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[C:21]3[C:17]=2[CH2:18][CH2:19][CH2:20]3)=[CH:11][C:10]=1[CH2:29][Cl:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(OCc3ccccc3)c(CO)c1)CCC2
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(OCc3ccccc3)c(CCl)c1)CCC2

Procedure:
[2-benzyloxy-5-(5-methyl-7-nitroindan-4-yloxy)phenyl]methanol (2.48 g) was dissolved in diethyl ether. After adding dropwise thionyl chloride (5 mL) under ice-cooling with stirring, the mixture was stirred at room temperature for 6 hours. The reaction mixture was evaporated under reduced pressure to dryness. After adding water (10 mL), the residue was extracted with diethyl ether. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (2.04 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>>[CH3:13][C:7]1([CH3:14])[O:8][CH2:9][C:10](=[O:12])[NH:11][C:5]2[CH:4]=[CH:3][C:2]([C:18]3[C:17]([F:16])=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][C:6]1=2
Reactant: CC1(C)OCC(=O)Nc2ccc(Br)cc21
Reactant: OB(O)c1ccccc1F
Product: CC1(C)OCC(=O)Nc2ccc(-c3ccccc3F)cc21

Procedure:
Prepared from 7-bromo-5,5-dimethyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 2-fluoro benzeneboronic acid generally according to the coupling procedure described in example 1. 1H NMR (DMSO-d6): δ 10.01 (s, 1H), 7.63 (m, 1H), 7.51-7.57 (m, 1H), 7.36-7.43 (m, 2H), 7.25-7.30 (m, 2H), 7.19 (d, J=8.32 Hz, 1H), 4.27 (s, 2H), 1.59 (s, 6H); MS (ESI) m/z 286 ([M+H]+); MS (ESI) m/z 284 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:8](=O)[CH2:9][CH2:10][CH3:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>C(Cl)(Cl)Cl.C(O)(=O)C>[CH2:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCC=O
Reactant: Nc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCCNc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.8 %

Procedure:
2-aminopyridine (5.0 g) was dissolved in chloroform (40 mL) and acetic acid (10 mL), and n-butyraldehyde (4.2 g) was added, then stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (16.9 g) was added and stirred at room temperature for three hours. Ethyl acetate (300 mL) was added to the reaction solution, and the organic layer was washed with saturated aqueous solution of sodium hydrogen carbonate (200 mL) and saturated sodium chloride solution (50 mL). After drying on anhydrous sodium sulfate, filtration, and vacuum concentration, the residue was purified by silica gel flash column chromatography (developing solvent: n-hexane:ethyl acetate=2:1) to give the above-identified compound (2.7 g, yield 34%).
Reaction SMILES: [CH3:1][CH:2]1[CH:11]([CH3:12])[CH2:10][CH:9]2[C:4]([CH3:13])([CH2:5][CH:6]=[CH:7][CH2:8]2)[C:3]1=[O:14]>C(OCC)(=O)C.[Pd]>[CH3:1][CH:2]1[CH:11]([CH3:12])[CH2:10][CH:9]2[C:4]([CH3:13])([CH2:5][CH2:6][CH2:7][CH2:8]2)[C:3]1=[O:14]
Reactant: CC1CC2CC=CCC2(C)C(=O)C1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1CC2CCCCC2(C)C(=O)C1C
Yield: 98.1 %

Procedure:
2,3,8a-trimethyl-3,4,4a,5,8,8a-hexahydro-1(2H)-naphthalenone (10 g, 52 mmol) was hydrogenated, at room temperature and atmospheric pressure, in ethyl acetate (100 ml) in presence of 5% Pd—C (1.0 g). The crude product was purified by bulb-to-bulb distillation (78° C./0.035 mbar) to give desired compound (9.88 g, 51 mmol, 98%) as a 3:2 mixture of diastereoisomers.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([NH2:19])[CH:13]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1cccc(N)c1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Nc1cccc(Nc2ccc(Br)cc2[N+](=O)[O-])c1
Temperature: 120 °C
Yield: 63.2 %

Procedure:
A mixture of 4-bromo-1-fluoro-2-nitro-benzene (1.14 ml, 9.25 mmol), benzene-1,3-diamine (1.96 g, 18.1 mmol) and DIPEA (1.93 ml, 11.1 mmol) in dry NMP (5 ml) was deoxygenated by evacuate/fill N2 (×3), then stirred and heated at 120° C. under N2 for 18 hours. After cooling to RT the mixture was partitioned between EtOAc and 0.5N HCl. The organic layer was washed with H2O (×1), brine (×1) then dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica (10→40% EtOAc/petrol) to give the title compound (1.8 g) as a red solid. 1H NMR (400 MHz, DMSO-d6): 9.28 (1H, s), 8.20 (1H, d), 7.63 (1H, dd), 7.14 (1H, d), 7.07 (1H, t), 6.49 (1H, s), 6.48-6.39 (2H, m), 5.24 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:21])[C:4](=[O:20])[C:5]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:8]([O:10]C)=O)[N:7]=1.[CH3:22][NH2:23].C1COCC1>>[CH3:22][NH:23][C:8]([C:6]1[N:7]=[C:2]([NH2:1])[N:3]([CH3:21])[C:4](=[O:20])[C:5]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10]
Reactant: COC(=O)c1nc(N)n(C)c(=O)c1OCc1ccccc1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1nc(N)n(C)c(=O)c1OCc1ccccc1
Temperature: 140 °C
Yield: 100 %

Procedure:
To a mixture of methyl 2-amino-5-(benzyloxy)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.907 g, 3.14 mmol, Eq: 1.00), methylamine 2M in THF (12 ml, 24.0 mmol) was added. The mixture was heated in a microwave oven at 140° C. for 2 h. The crude reaction mixture was concentrated in vacuo to give the title product as an off-white solid (0.90 g; 100%). LCMS: m/z=289 (MH+).
Reaction SMILES: C([O:3][C:4]1[CH2:9][O:8][CH2:7][C:6]([C:11]2[CH:12]=[C:13]([NH:17][C:18]([C:20]3[C:25]([F:26])=[CH:24][C:23]([F:27])=[CH:22][N:21]=3)=[O:19])[CH:14]=[CH:15][CH:16]=2)([CH3:10])[N:5]=1)C.[Cl-].[NH4+]>CO>[CH3:10][C:6]1([C:11]2[CH:12]=[C:13]([NH:17][C:18]([C:20]3[C:25]([F:26])=[CH:24][C:23]([F:27])=[CH:22][N:21]=3)=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH2:7][O:8][CH2:9][C:4](=[O:3])[NH:5]1
Reactant: CCOC1=NC(C)(c2cccc(NC(=O)c3ncc(F)cc3F)c2)COC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC1(c2cccc(NC(=O)c3ncc(F)cc3F)c2)COCC(=O)N1
Temperature: 100 °C
Yield: 24.3 %

Procedure:
A dried pressure tube was charged under an argon atmosphere with a dispersion of (RS)-3,5-difluoro-pyridine-2-carboxylic acid [3-(5-ethoxy-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide (0.348 g, 0.9 mmol) and ammonium chloride (0.182 g, 3.4 mmol) in methanol (10 ml). The sealed pressure tube was heated at 100° C. for 16 hours. After cooling, the reaction mixture was evaporated to dryness and directly purified by chromatography on an Isolute flash NH2 column using a gradient of dichloromethane/methanol=100/0 to 95/5 as the eluent. There were obtained 0.076 g (38% of theory) of (RS)-3,5-difluoro-pyridine-2-carboxylic acid [3-(3-methyl-5-oxo-morpholin-3-yl)-phenyl]-amide (=3,5-difluoro-pyridine-2-carboxylic acid [3-((RS)-3-methyl-5-oxo-morpholin-3-yl)-phenyl]-amide) as a white solid; mass (calculated) C17H15F2N3O3 [347.324]; (found) [M+H]+=348, and 0.113 g (57% of theory) of (RS)-3,5-difluoro-pyridine-2-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide (1) as a light yellow foam; mass (calculated) C17H16F2N4O2 [346.340]; (found) [M+H]+=347.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([S:7]([C:10]1[CH:14]=[CH:13][O:12][C:11]=1[CH3:15])(=[O:9])=[O:8])[CH3:6])[CH3:2].Cl[CH2:18][C:19]1[CH:33]=[CH:32][C:22]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:21][CH:20]=1>>[CH2:1]([O:3][C:4](=[O:16])[C:5]([CH3:6])([S:7]([C:10]1[CH:14]=[CH:13][O:12][C:11]=1[CH3:15])(=[O:8])=[O:9])[CH2:18][C:19]1[CH:33]=[CH:32][C:22]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:21][CH:20]=1)[CH3:2]
Reactant: CCOC(=O)C(C)S(=O)(=O)c1ccoc1C
Reactant: ClCc1ccc(OCCN2CCCCC2)cc1
Product: CCOC(=O)C(C)(Cc1ccc(OCCN2CCCCC2)cc1)S(=O)(=O)c1ccoc1C

Procedure:
2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-(2-methyl-furan-3-sulfonyl)-propionic acid ethyl ester (2.4 g, 9.8 mmol) and 1-[2-(4-chloromethylphenoxy)-ethyl]-piperidine (2.96 g, 10.7 mmol); Yield 2.4 g (92%); amber oil; MS 464.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[N:8](CC3C=CC=CC=3)[CH:7]=[N:6][C:5]=2[N:4]2[C@H:19]3[CH2:24][CH2:23][CH2:22][C@H:20]3[N:21]=[C:3]12>CCO.[OH-].[OH-].[Pd+2]>[CH3:1][N:2]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]2[C@H:19]3[CH2:24][CH2:23][CH2:22][C@H:20]3[N:21]=[C:3]12
Reactant: CN1C(=O)c2c(ncn2Cc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CN1C(=O)c2[nH]cnc2N2C1=N[C@@H]1CCC[C@@H]12

Procedure:
Hydrogenate cis-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylmethyl)cyclopenta[4,5]imidazo[2,1-b]purin-4-one (0.3 g=0.93 mmol) at room temperature/60 psi in EtOH (125 ml) containing 0.4 g Pearlman catalyst. Filter catalyst, remove solvent, and recrystallize to give the title compound as a white solid. FAB MS: M+1=232.