Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].C[N+]1([O-])CC[O:19]CC1>C(#N)C>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[O:19])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=1)[CH3:11]
Reactant: C[N+]1([O-])CCOCC1
Reactant: CCOc1ccc(CBr)c([N+](=O)[O-])c1
Solvent: CC#N
Product: CCOc1ccc(C=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
A mixture of 1-(bromomethyl)-4-ethoxy-2-nitrobenzene (11.3 g), 4-methylmorpholine N-oxide (10.1 g), molecular sieves 4A (11 g) and acetonitrile (220 ml) was stirred under an argon atmosphere at room temperature for 1 hr. The reaction mixture was filtered through celite, and the solvent of the filtrate was evaporated under reduced pressure. The residue was diluted with ethyl acetate, and the mixture was washed twice with water. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a yellow solid (5.65 g).
Reaction SMILES: [C:1]1(=[O:17])[N:5]([CH2:6][CH2:7][S:8](Cl)(=[O:10])=[O:9])[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.[C:18]1(=O)[N:22](CC)[C:21](=O)C2=CC=CC=C12.CNS(=O)=O>>[C:4]1(=[O:12])[N:5]([CH2:6][CH3:7])[C:1](=[O:17])[C:2]2=[CH:16][CH:15]=[CH:14][CH:13]=[C:3]12.[CH3:21][N:22]([CH3:18])[SH:8](=[O:9])=[O:10]
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Agent: CCN1C(=O)c2ccccc2C1=O
Agent: CN[SH](=O)=O
Product: CN(C)[SH](=O)=O

Procedure:
2-Phthalimidoethanesulfonyl chloride (2.0 g) was used in a procedure similar to the one used for 2-phthalimidoethane-N-methylsulfonamide. Yield: 1.03 g (45%). 1H-NMR (CDCl3) δ (ppm) 7.87-7.79 (m, 2H), 7.75-7.66 (m, 2H), 4.11 (t, J=, 2H), 3.30 (t, J=Hz, 2H), 2.87 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:19]([OH:21])=O)[CH:9]=[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[N:3]=1.Cl.[CH3:23][NH:24][CH3:25].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.CO>[CH3:23][N:24]([CH3:25])[C:19]([C:8]1[CH:9]=[C:10]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:4]2[N:3]=[C:2]([CH3:1])[NH:6][C:5]=2[CH:7]=1)=[O:21]
Reactant: CNC
Reactant: Cc1nc2c(OCc3ccccc3)cc(C(=O)O)cc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc2c(OCc3ccccc3)cc(C(=O)N(C)C)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
A mixture of 2-methyl-4-[(phenylmethyl)oxy]-1H-benzimidazole-6-carboxylic acid (5.0 g, 17.7 mmol, STEP 4), dimethylamine hydrochloride (4.33 g, 53.1 mmol), 2-[1H-benzotriazole-1-yl]-1,1,3,3-tetramethyluronium hexafluorophosphate (10.1 g, 26.6 mmol), and triethylamine (10.7 g, 106 mmol) in N,N-dimethylformamide (80 mL) was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate/methanol (20:1), and washed with saturated ammonium chloride aqueous solution. The organic layer was dried over magnesium sulfate, and concentrated in vacuum. The residue was purified by column chromatography on silica gel (gradient elution from ethyl acetate only to ethyl acetate methanol 5:1) to afford the title compound as a white solid (4.90 g, 89%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9](=O)[C:8]2=O.B(F)(F)F.CCOCC.[BH4-].[Na+].Cl>C1COCC1.O>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2
Reactant: O=C1Nc2c(cccc2C(F)(F)F)C1=O
Agent: Cl
Agent: FB(F)F
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: FC(F)(F)c1cccc2cc[nH]c12
Temperature: -20 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 7-trifluoromethyl-1H-indole-2,3-dione (116 mg) in THF (5.00 mL) was added boron trifluoride etherate (0.205 mL, 1.62 mmol) followed by sodium borohydride (71.4 mg, 1.88 mmol). The resulting mixture was stirred at -20° C. for 2 hrs, then water (1 mL) was added and the mixture was stirred at 0° C. for 10 min. The solution was acidified to pH=1 with 2N HCl, warmed to r.t. and stirred at r.t. for 20 min prior to extraction with EtOAc. The extracts were dried over magnesium sulphate, concentrated in vacuo and the residue purified by chromatography over silica gel eluting with hexane to give 7-trifluoromethyl-1H-indole. 1H NMR (400 MHz, CDCl3) δ ppm 6.63-6.68 (1 H, m), 7.20 (1 H, t, J=7.71 Hz), 7.30-7.35 (1 H, m), 7.47 (1 H, d, J=7.33 Hz), 7.83 (1 H, d, J=8.08 Hz), and 8.56 (1 H, br. s.).
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[Cl:57][C:58]1[CH:63]=[C:62](I)[C:61]([F:65])=[CH:60][N:59]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[Cl:57][C:58]1[CH:63]=[C:62]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[C:61]([F:65])=[CH:60][N:59]=1
Reactant: Fc1cnc(Cl)cc1I
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1cc(Cl)ncc1F
Temperature: 100 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
tert-Butyl carbamate (960 mg), cesium carbonate (5.06 g), Pd2(dba)3 (1.07 g), and Xantphos (1.35 g) were added to a toluene solution (40 ml) containing 2-chloro-5-fluoro-4-iodopyridine (2 g), followed by stirring at 100° C. for 3 hours. The reaction solution was adjusted to room temperature and water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=9:1 to 4:1). A yellow oily matter of tert-butyl (2-chloro-5-fluoropyridin-4-yl)carbamate (1.53 g) was thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH:23]=[C:24]([CH:32]([CH3:34])[CH3:33])[CH:25]=[C:26]3[C:31]=2[N:30]=[CH:29][CH:28]=[CH:27]3)[CH:17]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1.[CH3:36]C(C)([O-])C.[K+].CI>C1COCC1.CN(C=O)C.[Cl-].[NH4+].C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:35])[C:4]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH:23]=[C:24]([CH:32]([CH3:33])[CH3:34])[CH:25]=[C:26]3[C:31]=2[N:30]=[CH:29][CH:28]=[CH:27]3)[CH:17]=1)([CH3:36])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)c1cccc(-c2cc(C(C)C)cc3cccnc23)c1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)C(C)(Cc1ccc(S(C)(=O)=O)cc1)c1cccc(-c2cc(C(C)C)cc3cccnc23)c1
Temperature: 21 °C
Reaction time: 18 h

Procedure:
To a solution of Example 92 (90 mg, 0.185 mmol) in THF/DMF (1:1, 2 mL) at −78° C. was added potassium tert-butoxide (1M, 0.19 mL, 0.19 mmol) dropwise followed by MeI (0,014 mL, 0.22 mmol) after 15 min. The resulting reaction mixture was stirred 18 h at 21° C., then diluted with a saturated ammonium chloride solution and ethyl acetate. The organic extracts were washed (H2O, brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with hexane/ethyl acetate, 50:50) provided the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]2/[CH:17]=[CH:18]/[N+:19]([O-:21])=[O:20].C(O)C.[BH4-].[Na+].C(O)(=O)C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]2[CH2:17][CH2:18][N+:19]([O-:21])=[O:20]
Reactant: CCOC(=O)c1[nH]c2ccc(OC)cc2c1/C=C/[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1[nH]c2ccc(OC)cc2c1CC[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
To a mixture of ethyl 5-methoxy-3-[(E)-2-nitrovinyl]-1H-indole-2-carboxylate (4.92 g) and ethanol (100 mL) was added sodium borohydride (1.92 g), followed by stirring at room temperature for 2 hours. To the mixture were added acetic acid and then water under ice-cooling, and the precipitated solid was collected by filtration and dried to obtain ethyl 5-methoxy-3-(2-nitroethyl)-1H-indole-2-carboxylate (4.01 g) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][C:10]2[C:15]([CH:16]([CH3:18])[CH3:17])=[CH:14][C:13]([OH:19])=[C:12]([I:20])[CH:11]=2)=[CH:4][N:3]=1.[CH2:21](Br)[CH3:22]>CN(C=O)C>[CH2:21]([O:19][C:13]1[C:12]([I:20])=[CH:11][C:10]([O:9][C:5]2[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[C:15]([CH:16]([CH3:18])[CH3:17])[CH:14]=1)[CH3:22]
Reactant: CCBr
Reactant: CC(C)c1cc(O)c(I)cc1Oc1cnc(N)nc1N
Solvent: CN(C)C=O
Product: CCOc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Yield: 78.9 %

Procedure:
To a solution of 4-(2,4-Diamino-pyrimidin-5-yloxy)-2-iodo-5-isopropyl-phenol (0.2 g, 0.52 mmol) in anhydrous DMF (2 ml) was added EtBr (57 mg, 0.52 mmol) in portions. The reaction mixture was partitioned between EtOAc and H2O. The organic extract was dried over Na2SO4, filtered and a concentrated. Flash chromatography on silica (3% MeOH in methylene chloride with 1% NH4OH) gave 5-(4-Ethoxy-5-iodo-2-isopropyl-phenoxy)-pyrimidine-2,4-diamine (0.17 g, 28%) as a yellow solid. (M+H)=415.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:32][C:33]1[C:38]([F:39])=[CH:37][CH:36]=[C:35]([F:40])[C:34]=1B(O)O>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:34]3[C:35]([F:40])=[CH:36][CH:37]=[C:38]([F:39])[C:33]=3[F:32])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: OB(O)c1c(F)ccc(F)c1F
Product: Cn1ncc(NC(=O)c2csc(-c3c(F)ccc(F)c3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,3,6-trifluorophenyl)boronic acid gave 243. 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.67 (s, 1H), 7.83 (s, 1H), 7.73 (qd, J=9.5, 5.0 Hz, 1H), 7.38 (tdd, J=9.5, 3.9, 2.1 Hz, 1H), 4.83 (dd, J=10.7, 3.6 Hz, 1H), 4.45-4.23 (m, 1H), 4.17 (ddd, J=21.9, 15.0, 1.8 Hz, 1H), 4.08-3.89 (m, 1H), 3.77 (s, 3H), 3.29-3.13 (m, 1H), 2.12-2.01 (m, 1H), 1.87-1.72 (m, 1H), 1.72-1.60 (m, 4H). LCMS (ES+) m/z 470 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH:33][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:27])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: CN(C)CCN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-dimethylamino-ethyl)-amide (42 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (41 mg), N,N-dimethyl-ethylenediamine (0.29 ml), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 480. 1H NMR (DMSO-d6, 400 MHz): δ 8.16 (t, 1H), 7.81 (s, 1H), 7.61 (d, 1H), 7.49 (d, 1H), 7.29 (d, 1H), 7.15 (d, 1H), 7.07 (d, 1H), 3.56 (s, 3H), 3.32 (m, 2H), 2.85 (m, 2H), 2.41 (t, 1H), 2.17 (s, 6H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([CH3:16])=[C:6]([Cl:15])[CH:7]=[C:8]([CH:12](Cl)[CH3:13])[C:9]=1[O:10][CH3:11].[CH3:17][C:18]1[C:26]2[C:21](=[N:22][CH:23]=[N:24][C:25]=2[NH2:27])[NH:20][N:19]=1>CN(C)C=O.C(Cl)Cl>[Br:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([CH:12]([N:20]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:27])=[C:26]3[C:18]([CH3:17])=[N:19]2)[CH3:13])[CH:7]=[C:6]([Cl:15])[C:5]=1[CH3:16]
Reactant: COc1c(C(C)Cl)cc(Cl)c(C)c1Br
Reactant: Cc1n[nH]c2ncnc(N)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Sodium hydride (36 mg, 0.91 mmol) was added to a mixture of 3-bromo-1-chloro-5-(1-chloroethyl)-4-methoxy-2-methylbenzene (150 mg, 0.503 mmol), 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (110 mg, 0.76 mmol) in N,N-dimethylformamide (8 mL) and the reaction was stirred at 30° C. overnight. The mixture was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with 0 to 70% EtOAc in CH2Cl2 (103 mg, 50%). LCMS calculated for C16H18BrClN5O (M+H)+: m/z=410.0; Found: 410. The racemic products were applied on a Phenomenex Lux-Cellulose 1 column (21.1×250 mm, 5 micron particle size), eluting with 5% ethanol in hexanes at a flow rate of 18 mL/min, ˜13 mg/injection, to provide two enantiomers.
Reaction SMILES: [Mg].[CH3:2][O-:3].[Mg+2].C[O-].[CH2:7]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C=O>O.C(O)(=O)C.C1(C)C=CC=CC=1.CO>[CH2:7]([C:16]1[CH:17]=[C:18]([CH:2]=[O:3])[C:19]([OH:22])=[CH:20][CH:21]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCc1ccc(O)cc1
Reactant: C[O-]
Agent: C=O
Agent: [Mg+2]
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCCc1ccc(O)c(C=O)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
A 2-liter round-bottomed flask was charged with magnesium (12 g, 0.49 mol), methanol (285 ml), toluene (120 ml) and magnesium methoxide (10 ml solution of 7.4% by weight magnesium methoxide in methanol). The reaction mixture was heated to reflux and the magnesium dissolved. Para-nonyl phenol (112.4 g) was added in one portion to the reaction mixture. The flask was then rigged for a fractional vacuum distillation and an azeotrope of methanol/toluene was distilled off an internal temperature of 70° C. at a pressure of 350 mm Hg. Glacial acetic acid (28.5 ml, 0.5 mole) was added to the reaction mixture over a 1-hour period while maintaining the reaction temperature at 70° C. and the pressure at 350 mm Hg. When the addition of glacial acetic acid was complete, solid paraformaldehyde (46 g, a commercial sample containing 5-7% by weight water) was added over a 105-minute period. The reaction mixture was maintained at a temperature of 65° C. and a pressure of 350 mm Hg, during the addition of paraformaldehyde, and the volatile reaction by-products were continually removed. When the paraformaldehyde addition was complete, the reaction temperature was increased to 75° C. and maintained at that temperature for an additional 3 hours. Sulphuric acid (300 ml, 10% w/w) was added to the reaction mixture, which was then stirred for 1 hour. After phase separation, the organic phase was washed twice with 200 portion of water. The washed organic phase was then separated, dried and rendered free of the solvent to yield crude 5-nonyl salicylaldehyde. A 67% yield was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]([NH:15]C(C)(C)C)=[O:14])=[NH:11]>Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]([NH2:15])=[O:14])=[NH:11]
Reactant: CC(C)(C)NC(=O)NC(=N)Nc1c(Cl)cccc1Cl
Agent: Cl
Product: N=C(NC(N)=O)Nc1c(Cl)cccc1Cl

Procedure:
A mixture of 32.1 g. (0.106 moles) of 1-(2,6-dichlorophenylamidino)-3-(t-butyl)urea and 200 ml of conc. hydrochloric acid is refluxed for 1/2 hour. The reaction mixture is cooled, filtered and washed with 10 ml of 1:1 HCl/H2O and dried. The product is then recrystallized from ethanol-ether to obtain (2,6-dichlorophenylamidino)urea hydrochloride.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[C:3]=1[O:21][CH3:22].[Br:23][C:24]1[N:29]=[C:28]([CH3:30])[C:27]([NH2:31])=[C:26]([CH3:32])[CH:25]=1.C(N1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2)C(C)C.O(C(C)(C)C)[Na]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].O>[Br:23][C:24]1[N:29]=[C:28]([CH3:30])[C:27]([NH:31][C:2]2[N:7]=[CH:6][N:5]=[C:4]([O:8][CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)[C:3]=2[O:21][CH3:22])=[C:26]([CH3:32])[CH:25]=1
Reactant: COc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reactant: Cc1cc(Br)nc(C)c1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(Nc2c(C)cc(Br)nc2C)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 150 °C

Procedure:
To a solution of isopropyl 4-(6-chloro-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxylate (2.0 g, 6.1 mmol) in 10 ml of dioxane, were added 6-bromo-2,4-dimethylpyridin-3-amine (1.0 g, 5.1 mmol), 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (0.35 g, 1.0 mmol), Pd(OAc)2 (0.11 g, 0.51 mmol), and NaO-t-Bu (1.2 g, 12 mmol) at an ambient temperature. The reaction was heated to 150° C. for 3 hrs. The reaction was cooled to room temperature and poured into H2O. The organics were extracted with ethyl acetate and dried over MgSO4. The ethyl acetate was concentrated under vacuum and purified over SiO2 to give isopropyl 4-(6-(6-bromo-2,4-dimethylpyridin-3-ylamino)-5-methoxy pyrimidin-4-yloxy)piperidine-1-carboxylate. 1HNMR (CDCl3, 400 MHz) δ 1.24-1.25 (d, J=6.2 Hz, 6H), 1.72-1.77 (m, 2H), 1.95-2.01 (m, 2H), 2.22 (s, 3H), 2.52 (s, 3H), 3.37-3.44 (m, 2H), 3.73-3.79 (m, 2H), 4.91-4.97 (m, 1H), 5.30-5.35 (m, 1H), 6.01 (s, 1H), 7.34-7.36 (d, J=8.5 Hz, 1H), 8.14-8.16 (d, J=8.5 Hz, 1H), 8.37 (s, 1H). Exact mass calculated for C21H28BrN5O4 494.31. found 495.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:11](=[O:21])[N:10]([CH2:22][C:23](O)=[O:24])[N:9]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[F:40][C:41]([F:52])([F:51])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH2:48][CH2:49][NH2:50]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:11](=[O:21])[N:10]([CH2:22][C:23]([NH:50][CH2:49][CH2:48][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[C:41]([F:40])([F:51])[F:52])=[O:24])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O
Reactant: NCCc1ccccc1C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O)NCCc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The carboxylic acid from Example 156A (60 mg, 0.14 mmol) and HOBt (27.0 mg, 0.20 mmol) are placed in 0.86 ml DMF and treated at RT with 38.2 mg (0.20 mmol) of EDC. After 20 mins, 27 mg of 2-(2-trifluoromethyl-phenyl)ethylamine (0.14 mmol) are added and the mixture is stirred overnight at RT. The mixture is then directly separated by preparative HPLC (Method 20). 69 mg (91% of theory) of the title compound are obtained.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[N:12]=[CH:11][C:10]3[O:13][C:14]4[C:19]([C@:20]5([N:25]=[C:24]([NH2:26])[CH2:23][O:22][CH2:21]5)[C:9]=3[CH:8]=2)=[CH:18][C:17]([C:27]2[C:28]([F:33])=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:16][CH:15]=4)[CH2:3][CH2:2]1>CO>[F:33][C:28]1[C:27]([C:17]2[CH:18]=[C:19]3[C@:20]4([N:25]=[C:24]([NH2:26])[CH2:23][O:22][CH2:21]4)[C:9]4[CH:8]=[C:7]([CH:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[N:12]=[CH:11][C:10]=4[O:13][C:14]3=[CH:15][CH:16]=2)=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(C3=CCOCC3)cc12
Solvent: CO
Product: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(C3CCOCC3)cc12
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A 10-mL round-bottom flask was charged with (S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (82.8 mg, 0.186 mmol) and MeOH (2.5 mL). The flask was flushed with Ar (g), then 10% Pd/C (ca. 35 mg) was added. H2 (g) was bubbled through the mixture for 1 min, then the reaction mixture was stirred under an H2 (g) atmosphere overnight. An additional portion of 10% Pd/C (21 mg) was added, and H2 (g) was bubbled through for 1 min. After stirring overnight, the mixture was filtered through celite, and the filter cake was washed with methanol. The filtrate was concentrated, and the residue was purified by chromatography (10-40% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM) to give (S)-7-(2-fluoropyridin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (72 mg) as an off-white solid. [M+H]+=447.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]#N)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(C2(C=[O:27])CCCC2)C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:13]=[O:27])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#CC1(c2ccc(Cl)cc2)CCCC1
Reactant: O=CC1(c2ccccc2)CCCC1
Product: O=CC1(c2ccc(Cl)cc2)CCCC1
Yield: 98.23 %

Procedure:
1-(4-chlorophenyl)-cyclopentanecarbaldehyde (22-02) (66 g, 98.23%) was synthesized from (4-chlorophenyl)-acetonitrile (21-02) (66 g, 321.95 mmol) as a white solid as a crude product following the procedure as described for 1-phenyl-cyclopentanecarbaldehyde (22-01).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][NH:5][C:6]1[C:11]([C:12]#[N:13])=[C:10]([CH3:14])[CH:9]=[C:8]([CH3:15])[N:7]=1.Cl[C:18]([O:20][CH3:21])=[O:19]>C1C=CC=CC=1>[C:12]([C:11]1[C:6]([N:5]([CH2:4][CH2:3][N:2]([CH3:16])[CH3:1])[C:18](=[O:19])[O:20][CH3:21])=[N:7][C:8]([CH3:15])=[CH:9][C:10]=1[CH3:14])#[N:13]
Reactant: Cc1cc(C)c(C#N)c(NCCN(C)C)n1
Reactant: COC(=O)Cl
Solvent: c1ccccc1
Product: COC(=O)N(CCN(C)C)c1nc(C)cc(C)c1C#N

Procedure:
To a solution of N,N-dimethyl-N'-(3-cyano-4,6-dimethyl-2-pyridyl)-1,2-diaminoethane (13.5 g, 62 mmol) in dry benzene (150 ml) is added methyl chloroformate (7.1 ml, 92 mmol) and then the resulting mixture is refluxed for 11/2 hours. This mixture is evaporated to dryness and the residue dissolved in water, washed with methylene chloride, made basic with sodium carbonate and the product extracted into methylene chloride. Upon evaporation of the solvent there is obtained 16.6 g of oily title B product.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]#[N:14])=[CH:7][CH:6]=1.Cl.Cl.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][N:20]=1>>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[N:25]([C:22]3[CH:21]=[N:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=3)[N:26]=[C:13]([NH2:14])[CH2:12]2)=[CH:7][CH:6]=1
Reactant: COCOc1ccc(C=CC#N)cc1
Reactant: COc1ccc(NN)cn1
Agent: Cl
Product: COCOc1ccc(C2CC(N)=NN2c2ccc(OC)nc2)cc1
Yield: 41.2 %

Procedure:
The title compound (1.63 g, 41.2%) was prepared as a powder from 3-(4-methoxymethoxyphenyl)acrylonitrile and 2-methoxy-5-pyridinylhydrazine dihydrochloride in a similar manner to that of Example 14-1.