Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([F:21])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:22])[CH2:4]1.[Cl:23][C:24]1[C:33]([CH:34]=O)=[N:32][C:31]2[NH:30][C:29](=[O:36])[CH2:28][O:27][C:26]=2[CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>CO.CCOCC.C(Cl)Cl>[Cl:23][C:24]1[C:33]([CH2:34][NH:1][CH2:2][C@@H:3]2[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([F:21])[CH:19]=4)[CH:14]=[CH:13][C:12]3=[O:22])[CH2:4]2)=[N:32][C:31]2[NH:30][C:29](=[O:36])[CH2:28][O:27][C:26]=2[CH:25]=1
Reactant: NC[C@@H]1CCCN(CCn2c(=O)ccc3ccc(F)cc32)C1
Reactant: O=Cc1nc2c(cc1Cl)OCC(=O)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: O=C1COc2cc(Cl)c(CNC[C@@H]3CCCN(CCn4c(=O)ccc5ccc(F)cc54)C3)nc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-{2-[(3S)-3-(aminomethyl)-1-piperidinyl]ethyl}-7-fluoro-2(1H)-quinolinone (90 mg; 0.3 mmol) and 7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (for a synthesis see WO2003064421, Example 15(c)) (64 mg, 0.3 mmol) in methanol (2 ml), DCM (4 ml) was stirred at rt overnight. Sodium triacetoxyborohydride (0.127 g; 0.6 mmol) was added and the mixture was stirred at room temperature for 1 h. The reaction was evaporated and chromatographed on silica gel, eluting with 0-15% methanol-DCM-1% NH4OH to give an oil. The oil was treated with 1M HCl in Et2O to give the title compound (14 mg) as the dihydrochloride salt. 1H NMR (400 MHz, CD3OD) δ ppm 1.07 (s, 1H) 1.59-1.69 (m, 1H) 1.71-1.83 (m, 2H) 1.83-1.94 (m, 2H) 2.15-2.23 (m, 1H) 2.56-2.61 (m, 21H) 2.63-2.75 (m, 3H) 2.97 (s, 1H) 3.13-3.20 (m, 1H) 3.90 (s, 2H) 4.49 (td, J=14.21, 7.71 Hz, 2H) 6.67 (d, J=9.60 Hz, 1H) 7.11 (td, J=8.46, 2.27 Hz, 1H) 7.38-7.50 (m, 2H) 7.75 (dd, J=8.72, 6.19 Hz, 1H) 7.91 (d, J=9.60 Hz, 1H)
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[Br:28][C:29]1[CH:42]=[CH:41][C:32]([CH2:33][C:34]2[O:35][C:36]([CH3:40])=[C:37]([CH3:39])[CH:38]=2)=[CH:31][CH:30]=1>CN(C)C=O.C(Cl)Cl>[Br:28][C:29]1[CH:42]=[CH:41][C:32]([CH2:33][C:34]2[O:35][C:36]([CH3:40])=[C:37]([CH3:39])[C:38]=2[C:9]([C:8]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]=2)=[O:11])=[CH:31][CH:30]=1
Reactant: COc1ccc(C(=O)O)cc1C1CCCC1
Reactant: Cc1cc(Cc2ccc(Br)cc2)oc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2c(Cc3ccc(Br)cc3)oc(C)c2C)cc1C1CCCC1
Yield: 78.5 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3-cyclopentyl-p-anisic acid (2.04 g, 9.24 mmol, RN-59216-82-9), oxalyl chloride (0.887 mL, 10.2 mmol), N,N-dimethylformamide (2 drops), tin (IV) chloride (1.19 mL, 10.2 mmol) and 2-(4-bromo-benzyl)-4,5-dimethyl-furan (2.45 g, 9.24 mmol) in CH2Cl2. Purification on Biotage KP-Sil eluting with 4% EtOAc/pet. ether gave 3.39 g (78%) of the title compound. 1H NMR (DMSO-d6) δ 1.38-1.47 (m, 2 H), 1.60-1.73 (m, 4 H), 1.79 (s, 3 H), 1.90-1.94 (m, 2 H), 2.18 (s, 3 H), 3.21 (quintet, 1 H), 3.82 (s, 2 H), 3.88 (s, 3 H), 7.02-7.08 (m, 3 H), 7.44 (d, 2 H), 7.55-7.61 (m, 2 H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC(C([O:16][C@H:17]([CH3:36])[C@H:18]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)=O)=CC=1)([O-])=O.C1COCC1.C(OCC)(=O)C>CO>[OH:16][C@H:17]([CH3:36])[C@H:18]([NH:28][C:29](=[O:30])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[C:19]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=1
Reactant: C[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
Potassium carbonate powder (6.43 g) was added to a mixed solution of (1R,2R)-2-tert-butoxycarbonylamino-1-methyl-2-(3,4,5-trifluorophenyl)ethyl 4-nitrobenzoate (7.03 g) in methanol (90 ml)-THF (10 ml), and the reaction solution was stirred at room temperature for one hour. Ethyl acetate was added to the reaction solution, which was then sequentially washed with water and brine (twice). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diethyl ether was added to the resulting residue, and the insoluble matter was removed by filtration. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (toluene:ethyl acetate=6:1) to obtain 4.49 g of the title compound.
Reaction SMILES: B.O1CCCC1.[CH:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([CH2:17][C@@H:18]([NH2:22])[C:19](O)=[O:20])[CH:8]=1>O1CCCC1>[NH2:22][C@H:18]([CH2:17][C:9]1[CH:8]=[CH:7][CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=1)[CH2:19][OH:20]
Reactant: N[C@H](Cc1cccc(C(F)(F)F)c1)C(=O)O
Agent: B
Solvent: C1CCOC1
Product: N[C@@H](CO)Cc1cccc(C(F)(F)F)c1
Reaction time: 3 h
Yield: 84.1 %

Procedure:
Borane-tetrahydrofuran complex (1 M in tetrahydrofuran, 21.4 ml, 21.4 mmol) was added at 0° C. to a solution of D-3-trifluoromethylphenylalanine (2.00 g, 8.57 mmol) in tetrahydrofuran (45 ml). The reaction mixture was allowed to reach room temperature over 3 h, then partitioned between sat. aq. sodium carbonate solution and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) afforded the title compound (1.58 g, 84%). Colorless oil, MS (ISP)=220.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:12])[C:6]2=[O:11].[BH4-].[Na+].[OH-].[K+].Br[C:18]1C=CC=C2C=1CC(C)C2O>C1COCC1.CO.CS(C)=O.O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:12])[CH:6]2[O:11][CH3:18]
Reactant: CC1Cc2c(Br)cccc2C1=O
Reactant: CC1Cc2c(Br)cccc2C1O
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COC1c2cccc(Br)c2CC1C
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
To a solution of 149.5 g (0.664 mol) of 4-bromo-2-methyl-1-indanone in 900 ml of THF-methanol (2:1, vol.), 37.6 g (0.995 mol) of NaBH4 was added in small portions with vigorous stirring over 1.5 hours at 5° C. This mixture was stirred at room temperature for 12 hours and then added to 2 L of cold water. The hydrogenation product was extracted with 5×200 ml of dichloromethane, and the combined extract was evaporated to dryness. To 149 g (2.65 mol) of KOH in 420 ml of DMSO, 188 g (82.5 ml, 1.33 mol) of Mel, and a solution of the crude 4-bromo-2-methylindan-1-ol in 220 ml of DMSO were added. This mixture was stirred for 2 hours at ambient temperature; then, 92.0 g (40.4 ml, 0.664 mol) of Mel was added, and the mixture was additionally stirred for 2 hours. The resulting mixture was added to 2.5 L of cold water. The crude product was extracted with 5×200 ml of dichloromethane. The combined extract was dried over Na2SO4, and then evaporated to dryness. Fractional distillation gave a mixture of two diastereomeric compounds, b.p. 108° C./3 mm Hg. Yield, 148.5 g (93%) of a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N-:11]=[C:12]=[S:13].[K+]>C(O)(=O)C>[N:11]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)=[C:12]=[S:13]
Reactant: [N-]=C=S
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [K+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccnc1N=C=S

Procedure:
A 10 g sample of 2-chloro-3-nitropyridine, an 8 g sample of potassium isothiocyanate, and 75 ml of acetic acid were combined and refluxed for 2 h. The reaction mixture was then cooled and poured into 400 ml of ice/H2O. The resulting solid was washed with water, redissolved in ethyl acetate and washed (4x) with water. The ethyl acetate solution was then treated with activated carbon, dried over anhydrous Na2SO4, filtered and evaporated to dryness to provide 3.72 g of the title compound. m.p.=115°-118° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])=O)[S:5][CH:6]=1.[NH2:18][NH2:19]>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:7]2[C:9]3[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11](=[O:12])[NH:19][N:18]=2)[S:5][CH:6]=1
Reactant: NN
Reactant: Cc1csc(C(=O)c2ccccc2C(=O)O)n1
Solvent: CCO
Product: Cc1csc(-c2n[nH]c(=O)c3ccccc23)n1
Temperature: 25 °C

Procedure:
A RBF set up with stirring bar and reflux condenser was charged with 2-(4-methylthiazole-2-carbonyl)benzoic acid (1.9 g, 7.7 mmol), hydrazine (1.3 mL, 226.9 mmol), and ethanol (40 mL, 0.2 M) while kept under nitrogen atmosphere. The reaction mixture was stirred under reflux overnight, then cooled to RT. The resulting precipitate was filtered off and washed with DCM to afford 4-(4-methylthiazol-2-yl)phthalazin-1(2H)-one. MS m/z=244 [M+H]+. Calc'd for C12H9N3OS: 243.2.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>CCOCC>[CH:4]1[CH:3]=[CH:2][C:1]([NH:7][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C=Nc1ccccc1
Solvent: O
Solvent: CCOCC
Product: O=C(Nc1ccccc1)Nc1ccccc1
Yield: 94 %

Procedure:
20 parts freshly distilled ether, 1.19 parts (0.01 mole) phenyl isocyanate and 0.19 part (0.01 mole) of water were combined and reacted as described in Example 1. The isolation techniques described in Example 2 were conducted. 0.70 part (94% yield) diphenylurea was recovered having a melting point of 253° C. An isocyanate and water produce urea in the absence of a boron complexing agent.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:35][C:34]1[C:25]([NH:24][C:22]2[C:21]([Cl:36])=[CH:20][N:19]=[C:18]([NH:16][C:13]3[CH:14]=[CH:15][C:8]4[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=4[CH:12]=3)[N:23]=2)=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27]([NH:29][CH3:30])=[O:28]
Reactant: CNC(=O)c1cccc(Cl)c1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: CNC(=O)c1cccc(Cl)c1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
3-Chloro-2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidine-4-ylamino}-N-methyl-benzamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-chloro-N-methyl-benzamide in an analogous manner to Example 308c. Product isolated as a yellow foam (25 mg, 14%). LCMS (m/e) 515 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.06 (s, 1H), 7.82 (s, 1H), 7.58 (d, 1H, J=8.0 Hz), 7.44 (d, 1H, J=7.7 Hz), 7.31-7.25 (m, 1H), 7.10 (s, 1H), 6.99 (d, 1H, J=8.0 Hz), 6.96 (s, 1H), 6.86 (d, 1H, J=8.0 Hz), 6.03-5.93 (m, 1H), 3.56-3.52 (m, 2H), 3.37 (s, 3H), 2.88-2.82 (m, 2H), 2.76-2.60 (m, 12H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:11]=[C:10]([CH2:12][NH2:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:20][CH:21]([CH3:25])[C:22](O)=[O:23].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:5]2[N:11]=[C:10]([CH2:12][NH:13][C:22](=[O:23])[CH:21]([CH3:25])[CH3:20])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)C(=O)O
Reactant: NCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Reaction time: 8 h

Procedure:
(2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methanamine from Example 145 (0.1 g) was added to a pre-stirred (15 minutes) solution of 2-methylpropanoic acid (1.2 eq), 1-hydroxybenzotriazole (1.1), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.1), triethylamine (2 eq) in N,N-dimethylformamide (2.77 mL). The reaction was stirred overnight then extracted with Ethyl Acetate and brine. The organic layer was dried (Mg2SO4), filtered and concentrated to give quantitative yield of N-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)isobutyramide.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][N:35]4C(=O)C5=CC=CC=C5C4=O)[CH:28]=3)[C:15](=[O:26])[N:16]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:25])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:35][CH2:34][CH2:33][C:29]1[CH:28]=[C:27]([N:14]2[C:12]3=[N:13][C:8]([NH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:9][CH:10]=[C:11]3[CH2:17][N:16]([C:18]3[C:19]([CH3:25])=[CH:20][CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]2=[O:26])[CH:32]=[CH:31][CH:30]=1
Reactant: Cc1cccc(C)c1N1Cc2cnc(Nc3ccccc3)nc2N(c2cccc(CCN3C(=O)c4ccccc4C3=O)c2)C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cccc(C)c1N1Cc2cnc(Nc3ccccc3)nc2N(c2cccc(CCN)c2)C1=O
Yield: 2.5 %

Procedure:
A solution of 500 mg (0.86 mmol) of 7-anilino-3,4-dihydro-3-(2,6-dimethylphenyl)-1-[3-(2-phthalimidoethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one in 30 ml of ethanol was treated with 0.8 ml of hydrazine hydrate. After 18 hours the mixture was evaporated and the product purified by column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined, evaporated and the residue evaporated with toluene. The residue was then dissolved in 50 ml of dichloromethane, washed with 50 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. Trituration of the residue with hexane followed by filtration afforded 10 mg (3%) of 1-[3-(2-aminoethyl)phenyl]-7-anilino-3,4-dihydro-3-(2,6-dimethylphenyl)-pyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 128° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9](B(O)O)[S:8][C:7]=2[CH:14]=1.[CH2:15]([C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:15]([C:21]1[CH:26]=[CH:25][C:24]([C:9]2[S:8][C:7]3[CH:14]=[C:3]([O:2][CH2:1][CH2:5][CH2:4][CH2:3][CH2:14][CH2:7][CH2:6][CH3:10])[CH:4]=[CH:5][C:6]=3[CH:10]=2)=[CH:23][CH:22]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: COc1ccc2cc(B(O)O)sc2c1
Reactant: CCCCCCc1ccc(Br)cc1
Product: CCCCCCCCOc1ccc2cc(-c3ccc(CCCCCC)cc3)sc2c1

Procedure:
is prepared analogously to Reference 14 (p. 16) from 6-methoxybenzo[b]thiophene-2-boronic acid and 4-hexylbromobenzene in a Suzuki reaction. The 2-(4-hexylphenyl)-6-methoxybenzo[b]thiophene obtained as the primary product is subjected to ether cleavage by means of hydrobromic acid/glacial acetic acid. The resultant hydroxyl compound gives the target compound in a Williamson ether synthesis using octyl bromide in 2-butanone in the presence of potassium carbonate.
Reaction SMILES: C(=[N:14][C:15]1[CH:16]=[C:17]([C:21]2([CH3:28])[NH:26][C:25](=[O:27])[CH2:24][O:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:29]>O1CCOCC1>[ClH:29].[NH2:14][C:15]1[CH:16]=[C:17]([C:21]2([CH3:28])[NH:26][C:25](=[O:27])[CH2:24][O:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1
Reactant: CC1(c2cccc(N=C(c3ccccc3)c3ccccc3)c2)COCC(=O)N1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(c2cccc(N)c2)COCC(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of (RS)-5-[3-(benzhydrylidene-amino)-phenyl]-5-methyl-morpholin-3-one (5.62 g, 15 mmol) in dioxane (75 ml) was cooled to 15° C. and treated dropwise with 1 N hydrochloric acid (18 ml). The reaction mixture was stirred at room temperature overnight. For the workup, the reaction mixture was evaporated at reduced pressure, and the residue was portioned between diethylether (120 ml) and 1 N hydrochloric acid (20 ml). The aqueous phase was separated and washed with diethylether (120 ml). This procedure was repeated twice. The combined aqueous layers were evaporated at reduced pressure, and 3.27 g (88% of theory) of (RS)-5-(3-amino-phenyl)-5-methyl-morpholin-3-one hydrochloride were obtained as a yellowish solid used in the next step without further purification. Mass (calculated) C11H15ClN2O2 [242.707]; (found) [M+H]+=207.
Reaction SMILES: C([O:5][C:6](=[O:35])[CH:7]([NH:18][C:19](=[O:34])[CH:20]([C:22](=[O:33])[NH:23][CH2:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1)[CH3:21])[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:32][C:27]1[CH:26]=[C:25]([CH:30]=[C:29]([F:31])[CH:28]=1)[CH2:24][NH:23][C:22]([CH:20]([CH3:21])[C:19]([NH:18][CH:7]([CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[C:6]([OH:35])=[O:5])=[O:34])=[O:33]
Reactant: CC(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[2-(3,5-Difluoro-benzylcarbamoyl)-propionylamino]-3-(1H-indol-3-yl)-propionic acid tert-butyl ester (5.99 g, 12.3 mmol) was dissolved in dichloromethane (15 ml), and trifluoroacetic acid (15 ml) was added at 0° C. The mixture was stirred overnight at r.t. until all starting material was consumed (analytical HPLC). The volatiles were evaporated, the residue was taken up in ethyl acetate and washed with water. The organic layers were dried (Na2SO4). After evaporation of the solvent, the title compound, MS: m/e=429.4 (M+H+), (3.5 g, 66%) was obtained by chromatographic purification of the residue (silica gel, MeOH, CH2Cl2).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[CH3:8].[NH:11]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]([C:20](O)=O)=[N:12]1.C(OCC)(=O)C>CCCCCC>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[NH:9][C:20]([C:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[NH:11][N:12]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Cc1cc(N)c(N)cc1C
Reactant: O=C(O)c1n[nH]c2c1CCCC2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc2nc(-c3n[nH]c4c3CCCC4)[nH]c2cc1C
Reaction time: 0.03 h
Yield: 17 %

Procedure:
4,5-Dimethylbenzene-1,2-diamine (90 mg) and 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid [110 mg, Reference Example 17(a)] were mixed in a glass vial then subjected to microwave radiation (900 W, domestic oven) twice for two minutes. The resulting solid was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (85:15, v/v) to give 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-indazole (30 mg) as a pale brown solid. LC-MS (METHOD B): RT=2.28 minutes; 267 (M+H)+. (b) 2-(5-Isopropyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=1)=O.C([SiH](CC)CC)C.B(F)(F)F>ClCCl.C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[CH2:9][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH3:18])=[CH:15][CH:16]=1
Reactant: CCc1ccc(C(=O)c2cc(I)ccc2Br)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CC#N
Solvent: ClCCl
Product: CCc1ccc(Cc2cc(I)ccc2Br)cc1
Temperature: 47.5 °C
Reaction time: 4 h

Procedure:
A solution of (2-bromo-5-iodo-phenyl)-(4-ethyl-phenyl)-methanone (32 g) and triethylsilane (50 mL) in dichloromethane (30 mL) and acetonitrile (100 mL) is cooled in an ice-bath. Then, boron trifluoride diethyletherate (20 mL) is added dropwise over 5 min. The cooling bath is removed and the solution is heated to 45-50° C. and stirred at this temperature for 4 h. After cooling to ambient temperature, 4 M aqueous KOH solution is added and the resulting mixture is extracted with ethyl acetate. The combined organic phases are washed with 2 M potassium hydroxide solution and brine and then dried (sodium sulphate). After the solvent is evaporated, the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:0->9:1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:18]4[C:17]5[CH:19]=[C:20]([NH:23][C:24](=[O:33])[C:25]6[C:30]([Cl:31])=[CH:29][N:28]=[C:27](Cl)[CH:26]=6)[CH:21]=[CH:22][C:16]=5[CH2:15][CH2:14][C:13]=4[C:12]([C:34]([NH2:36])=[O:35])=[N:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:18]4[C:17]5[CH:19]=[C:20]([NH:23][C:24](=[O:33])[C:25]6[C:30]([Cl:31])=[CH:29][N:28]=[C:27]([N:41]7[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]7)[CH:26]=6)[CH:21]=[CH:22][C:16]=5[CH2:15][CH2:14][C:13]=4[C:12]([C:34]([NH2:36])=[O:35])=[N:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN1CCNCC1
Reactant: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3cc(Cl)ncc3Cl)cc1-2
Product: CN1CCN(c2cc(C(=O)Nc3ccc4c(c3)-c3c(c(C(N)=O)nn3-c3ccc5c(c3)OCO5)CC4)c(Cl)cn2)CC1
Temperature: 100 °C
Yield: 46 %

Procedure:
A mixture of the title compound of Example 211 (1.2 g, 0.0023 mol) and N-methylpiperazine (4.6 mL, 0.046 mol) was heated at 100° C. in a sealed tube for 24 h. The completion of the reaction was checked by HPLC. After removal of the volatiles under vacuum, the residue was partitioned between water and CH2Cl2. The organic layer was washed an additional time with water and dried over MgSO4. The crude product mixture was purified by chromatography on silica gel using CH2Cl2/MeOH: 12/1 to 10/2 to give 0.62 g of the title product, yield: 46%. Mp: 305-307° C. 1H NMR (400 MHz, d6-DMSO): δ 2.18 (s, 3H), 2.34-2.35 (d, 2H, J=5 Hz), 2.89-2.91 (m, 4H), 3.49 (d, 2H, J=5 Hz), 6.08 (s, 2H), 6.91-7.03 (m, 3H), 7.1 (d, 1H, J=2 Hz), 7.24-7.3 (m, 3H), 7.38-7.41 (dd, 1H, J=8.3 Hz, 2 Hz), 7.49 (s, 1H), 8.13 (s, 1H), 10.33 (s, 1H). M+1=587.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:8](OCC)=[O:9])[S:6][CH:7]=1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:8][OH:9])[S:6][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)c1nc(CC)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCc1csc(CO)n1
Reaction time: 3 h
Yield: 107.7 %

Procedure:
Ethyl 4-ethylthiazole-2-carboxylate (500 mg 2.27 mmol) was stirred in methanol (20 mL) under nitrogen. Sodium borohydride (230 mg 6.07 mmol) was added in portions and the resulting solution stirred for a further 3 hours. The methanol was removed under vacuum and the residue dissolved in ethyl acetate (40 mL), washed with water, dried over sodium sulfate and concentrated to give the title product as a colorless oil (350 mg, 91%).
Reaction SMILES: [F:1]/[C:2](=[C:5](/[C:7]1[CH:16]=[C:15]2[C:10]([C:11]([CH3:22])([CH3:21])[CH2:12][CH:13]=[C:14]2[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:9][C:8]=1[O:23][CH2:24][CH2:25][CH3:26])\[CH3:6])/[CH2:3][OH:4].C[N+]1([O-])CCOCC1.ClCCl>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1]/[C:2](=[C:5](/[C:7]1[CH:16]=[C:15]2[C:10]([C:11]([CH3:22])([CH3:21])[CH2:12][CH:13]=[C:14]2[C:17]([CH3:19])([CH3:18])[CH3:20])=[CH:9][C:8]=1[O:23][CH2:24][CH2:25][CH3:26])\[CH3:6])/[CH:3]=[O:4]
Reactant: CCCOc1cc2c(cc1/C(C)=C(/F)CO)C(C(C)(C)C)=CCC2(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CCCOc1cc2c(cc1/C(C)=C(/F)C=O)C(C(C)(C)C)=CCC2(C)C

Procedure:
As described in General Procedure H-1, (2E)-2-fluoro-3-(4,4 - dimethyl-6-n-propoxy-1-tert-butyl-3,4-dihydronaphthalen-7-yl)-2-butenol (Compound A-57, 0.027 g, 0.075 mmol), tetrapropylammonium perruthenate (12 mg, 0.038 mmol) and 4-methylmorpholine N-oxide (22 mg, 0.19 mmol) were reacted in acetonitrile (0.2 mL) and dichloromethane (1 mL) to produce the title compound as an oil.