Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)Cl>[CH:7]([CH:8]1[CH2:9][O:24]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(c1ccccc1)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: c1ccc(C(c2ccccc2)C2CO2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A flask was charged with 3,3-diphenylpropene (5.1 g, 26.3 mmol) in 100 ml CH2Cl2. It was followed by portionwise addition of mCPBA (9.1 g, 70% purity, 52.6 mmol) at 0° C. The mixture was stirred at room temperature for 24 h and the reaction was then quenched with 30 ml 1M Na2SO3. The aqueous layer was extracted with CH2Cl2 (2×100 ml). The combined organic phases were washed in turn with saturated NaHCO3, brine, and then dried over anhydrous Na2SO4. Purification by flash chromatography (Hexane/ether=9:1) gave pure 2-benzhydryl-oxirane, 4.7 g (85%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH:8]([CH3:15])[N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH3:33].C(O)C>Cl.O>[CH:16]1([N:7]2[CH:8]([CH3:15])[CH:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC1C(=O)N(C)c2cnc(Cl)nc2N(C2CCCC2)C1C
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)C(C)C(C)C(=O)N2C
Yield: 72.1 %

Procedure:
A mixture of 0.092 g (0.0003 mole) of (rac)-2-chloro-9-cyclopentyl-5,7,8-trimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-41), 0.1 g (0.00036 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.095 g of (rac)-4-(9-cyclopentyl-5,7,8-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-41a) as an off-white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@H:20]3[C@H:24]([OH:25])[C@H:23]([OH:26])[C@@H:22]([CH2:27][OH:28])[O:21]3)=[C:13]([NH2:29])[N:12]=2)[CH:10]=1)=O)C.[CH3:30][NH2:31]>>[OH:25][C@@H:24]1[C@H:23]([OH:26])[C@@H:22]([CH2:27][OH:28])[O:21][C@H:20]1[N:17]1[CH:16]=[N:15][C:14]2[C:18]1=[N:19][C:11]([N:9]1[CH:10]=[C:6]([C:4]([NH:31][CH3:30])=[O:3])[CH:7]=[N:8]1)=[N:12][C:13]=2[NH2:29]
Reactant: CN
Reactant: CCOC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Product: CNC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Temperature: 65 °C

Procedure:
Compound 12 (0.05 mg, 0.12 mmol) was added to 4 mL methylamine (40% sol. In water). The mixture was heated at 65° C. for 24 h. After concentration in vacuo, the residue was purified using prep. TLC (10% MeOH:DCM). 1HNMR (CD3OD) 62.90 (s, 3H), 3.78 (m, 1H), 3.91 (m, 1H), 4.13 (d, 1H), 4.34 (d, 1H), 4.64 (m, 1H), 6.06 (d, 1H), 8.11 (s, 1H), 8.38 (s, 1H), 9.05 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][NH2:13].C[O-].[Na+].C(O[CH:20]=[C:21]([C:24]#[N:25])[C:22]#[N:23])C>CO>[NH2:25][C:24]1[N:12]([C:3]2[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=2[F:1])[N:13]=[CH:20][C:21]=1[C:22]#[N:23]
Reactant: CS(=O)(=O)c1ccc(NN)c(F)c1
Reactant: CCOC=C(C#N)C#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)c1ccc(-n2ncc(C#N)c2N)c(F)c1
Yield: 87.6 %

Procedure:
(2-Fluoro-4-methanesulfonyl-phenyl)-hydrazine (1 g, 4.89 mmol) and sodium methoxide (30 mg, 0.489 mmol) were dissolved in methanol under N2 at room temperature. The mixture was stirred for 10. min and 2-ethoxymethylene-malononitrile (0.6 g, 4.91 mmol) was added. The reaction mixture was stirred for 30 min and then brought to reflux for 2 hours. The solvent was removed under reduced pressure; the residue was suspended in water and extracted with ethyl acetate. The organic layer was washed with water, brine and was dried over sodium sulfate. The solvent was concentrated, affording 5-amino-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazole-4-carbonitrile as a yellow solid (1.2 g, 87.5%). 1H NMR (400MHz DMSO-d6) δ (ppm): 7.96 (d, 1H); 7.93 (m, 1H); 7.80 (s, 1H); 7.74 (m, 1H); 6.89 (s, 2H); 3.24(s, 3H). Exact mass calculated for C11H9FN4O2S 280.04, found 281.30 (MH+, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCCCC1)C.C(Cl)(=O)C(C)(C)C.[CH3:35][O:36][C:37](=[O:47])[C@H:38]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[NH2:39].Cl>ClCCl.N1C=CC=CC=1>[CH3:35][O:36][C:37](=[O:47])[C@H:38]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[NH:39][C:17](=[O:19])[C@H:12]([CH2:13][C:14](=[O:16])[NH2:15])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: CCN1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.04 h
Yield: 68 %

Procedure:
A solution of benzyloxycarbonylasparagine (13.3 g; 50 mmoles), N-ethylpiperidine (7.0 ml) and pyridine (5.0 ml) in dichloromethane (100 ml) cooled to -20° C. is treated under constant stirring with pivaloylchloride (6.3 ml); the mixture is then stirred and cooled (0° C.) for 8 minutes. After that, within 2 to 3 minutes, a solution of phenylalanine methyl ester, liberated from its hydrochloride (10.7 g; 50 mmoles) by the addition of N-ethylpiperidine (7.0 ml), in dichlormethane (100 ml) is added. The reaction mixture is stirred for an additional 2 hours at room temperature, the precipitated crystalline substance is collected on filter and triturated successively with 1 M hydrochloric acid, water, 5% aqueous sodium hydrogencarbonate solution and water. Crystallization from methanol yields 14.5 g (68%) of the title product, melting at 196° -197° C. An analytical sample is crystallized from dimethylformamide and 2-propanol, and the m.p. remains unchanged. Chromatography: Rf 0.71/S1, 0.75/S2. Optical rotation [α]D20 -2.0° (c 0.2; dimethylformamide). The elemental composition corresponds to the summary formula C22H25N3O6.
Reaction SMILES: [C:1]1([NH:11][C:12]2[C:13]3[CH:20]=[C:19]([C:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=4)[NH:18][C:14]=3[N:15]=[CH:16][N:17]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:27]([N:31]=[C:32]=[O:33])([CH3:30])([CH3:29])[CH3:28].C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CN(C)C=O>[C:27]([NH:31][C:32]([N:24]1[CH2:23][CH:22]=[C:21]([C:19]2[NH:18][C:14]3[N:15]=[CH:16][N:17]=[C:12]([NH:11][C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)[C:13]=3[CH:20]=2)[CH2:26][CH2:25]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: C1=C(c2cc3c(Nc4cccc5ccccc45)ncnc3[nH]2)CCNC1
Reactant: CC(C)(C)N=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)N1CC=C(c2cc3c(Nc4cccc5ccccc45)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension containing naphthalen-1-yl-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine (120 mg, 0.35 mmol), tert-butyl isocyanate (35 mg, 0.35 mmol) and N,N-diisopropylethylamine (122 μL, 0.70 mmol) in anhydrous N,N-dimethylformamide (2 mL) was stirred overnight at rt. The reaction mixture was poured into saturated NaHCO3 solution (50 mL) and extracted with EtOAc (3×50 ml). The combined organics were washed with brine (3×50 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (2 to 4% MeOH in DCM) gave the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ=8.13 (1H, s), 8.08-8.02 (2H, m), 7.89 (1H, d, J=8.1 Hz), 7.74-7.71 (1H, m), 7.63-7.54 (3H, m), 6.55 (1H, d, J=8.3 Hz), 6.43 (1H, s), 5.83 (1H, s), 4.04 (2H, s), 3.55 (2H, t, J=5.6 Hz), 2.42 (2H, s), 1.34 (9H, s); MS (ES+): m/z 441.08 [MH+], HPLC: tR=2.59 min (MicromassZQ, polar—5 min).
Reaction SMILES: Br[C:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:9][CH:8]=1)([CH3:6])[CH2:3][CH2:4][OH:5].FC1C=C(F)C=CC=1C1C=CC(C(C)CCO)=CC=1.[C:40]([O-:43])(=[O:42])[CH3:41].[K+]>>[C:40]([O:43][C:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:9][CH:8]=1)([CH3:6])[CH2:3][CH2:4][OH:5])(=[O:42])[CH3:41]
Reactant: CC(=O)[O-]
Reactant: CC(Br)(CCO)c1ccc(-c2ccc(F)cc2F)cc1
Agent: CC(CCO)c1ccc(-c2ccc(F)cc2F)cc1
Agent: [K+]
Product: CC(=O)OC(C)(CCO)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
Analogously to Example 25 (a), 3-bromo-3-(2',4'-difluoro-4-biphenylyl)butan-1-ol, obtained by brominating 3-(2',4'-difluoro-4-biphenylyl)butan-1-ol, and potassium acetate are reacted to give 3-acetoxy-3-(2',4'-difluoro-4-biphenylyl)butan-1-ol.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.CCN(CC)CC.[OH:19][CH2:20][CH:21]1[O:25][C:24](=[O:26])[NH:23][CH2:22]1>ClCCl>[S:7]([O:19][CH2:20][CH:21]1[O:25][C:24](=[O:26])[NH:23][CH2:22]1)([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1NCC(CO)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CNC(=O)O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
p-Toluenesulphonyl chloride (2.74 g, 14.36 mmol) and Et3N (1.45 g, 14.36 mmol) were added to 5-hydroxymethyl-1,3-oxazolidine-2-one (1.40 g, 11.97 mmol) dispersed in 20 mL of dichloromethane and stirred overnight at room temperature under N2. After completion of the reaction (TLC), the solvent in the reaction mixture was evaporated and the residue was purified by column chromatography employing EtOAc-hexane (70:30) as eluent to afford 5-tosyloxymethyl-1,3-oxazolidine-2-one in 80% yield. m.p. 96-99° C.; [α]27D=+45.40 CHCl3); IR (KBr) 3302, 2980, 2925, 2871, 1757, 1694, 1357, 1184, 1090, 996, 965 cm1; 1HNMR (200 MHz, CDCl3) δ 2.47 (s, 3H), 3.40-3.50 (m, 1H), 3.64-3.74 (m, 1H), 4.14 (d, 2H, J=4.4 Hz), 4.71-4.82 (m, 1H), 7.35 (d, 2H, J=8.2 Hz), 7.78 (d, 2H, J=8.2 Hz); Mass (EI) 271, 207, 173, 155, 139, 91.
Reaction SMILES: [NH2:1][C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:11]=[C:12]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[C:24]1[CH:25]=[C:26]([CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1.Cl.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][N:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:1][C:28]4[CH:29]=[CH:24][CH:25]=[C:26]([CH:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[CH:27]=4)[N:22]=3)[CH:9]=[CH:8][CH:7]=2)[CH:11]=1)[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: CN1CCC(c2cccc(Br)c2)CC1
Reactant: CN(c1cccc(-c2cccn3nc(N)nc23)c1)S(C)(=O)=O
Agent: Cl
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCC(c2cccc(Nc3nc4c(-c5cccc(N(C)S(C)(=O)=O)c5)cccn4n3)c2)CC1

Procedure:
N-Methyl-N-(3-{2-[3-(1-methyl-piperidin-4-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-phenyl)-methanesulfonamide was prepared from N-[3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 4-(3-bromo-phenyl)-1-methyl-piperidine; hydrochloride (76.0 mg, 0.262 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.093 g, 80%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.46 (d, J=6.6 Hz, 1H), 8.10-8.07 (m, 1H), 7.98 (d, J=7.8 Hz, 1H), 7.61 (d, J=7.2 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.46-7.40 (m, 2H), 7.27 (t, J=7.9 Hz, 1H), 6.98 (t, J=7.1 Hz, 1H), 6.88 (d, J=7.7 Hz, 1H), 6.83 (s, 1H), 3.42 (s, 3H), 3.03-2.96 (m, 2H), 2.90 (s, 3H), 2.55-2.45 (m, 1H), 2.34 (s, 3H), 2.12-2.00 (m, 2H), 1.90-1.80 (m, 4H). MS=491 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[F:11][C:12]1[C:17]([CH:18]=[O:19])=[CH:16][CH:15]=[CH:14][C:13]=1[NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22].[OH-].[K+].O>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:18]([OH:19])[C:17]3[C:12]([F:11])=[C:13]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:14]=[CH:15][CH:16]=3)=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: CCCS(=O)(=O)Nc1cccc(C=O)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCS(=O)(=O)Nc1cccc(C(O)c2c[nH]c3ncc(Br)cc23)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
To 5-bromo-7-azaindole 67 (312 mg, 1.58 mmol) in methanol (28 mL) were added propane-1-sulfonic acid (2-fluoro-3-formyl-phenyl)-amide (503, 370 mg, 1.5 mmol) and potassium hydroxide (422.8 mg, 7.5 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the desired compound as white solid (504, 300 mg, 45.0%).
Reaction SMILES: N([O-])=O.[Na+].[F:5][C:6]1[CH:7]=[C:8](N)[C:9]2[O:14][CH2:13][CH2:12][O:11][C:10]=2[CH:15]=1.[BrH:17]>O>[Br:17][C:8]1[C:9]2[O:14][CH2:13][CH2:12][O:11][C:10]=2[CH:15]=[C:6]([F:5])[CH:7]=1
Reactant: Nc1cc(F)cc2c1OCCO2
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Fc1cc(Br)c2c(c1)OCCO2
Reaction time: 0.5 h

Procedure:
NaNO2 (2.69 g, 39.9 mmol) in water (20 mL) was added slowly at 0° C. to a solution of 7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-amine (4.5 g, 26 mmol) in aq. 47% HBr (20 mL) and continued stirring at same temperature for 30 min. The above diazonium salt solution was added slowly to a solution of CuBr (5.7 g, 39.9 mmol) in aq. 47% HBr (25 mL) at 0° C. and stirred at 25° C. for 30 min. Reaction mixture was quenched with ice water, extracted with ethyl acetate (3×50 mL), washed it with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude. The crude was purified by column purification (using silica gel and 0-5% ethyl acetate in Hexane as eluent) to afford 5-bromo-7-fluoro-2,3-dihydrobenzo[b][1,4]dioxine (Int-53) (5.9 g). 1H NMR (300 MHz, CDCl3) δ ppm 6.9-6.84 (1H, dd), 6.6-6.5 (1H, dd), 4.3-4.3 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][C@@H:23]2[CH2:25][O:24]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH2:26]([NH2:28])[CH3:27].Cl>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][C@@H:23]([OH:24])[CH2:25][NH:28][CH2:26][CH3:27])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(C[C@@H]2CO2)ccc1Cl
Reactant: CCN
Agent: Cl
Solvent: ClCCl
Product: CCNC[C@H](O)Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
2-Chloro-5-[(2R)-2-oxiranylmethyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 5c) (452mg), ethylamine (70% aqueous solution, 5 mL) and tetrahydrofuiran (15 mL) were heated together at 50° C. under nitrogen for 20 hours, cooled and concentrated to give an oil. This was purified by Waters' MCX resin (mixed-mode cation exchanger) and then by column chromatography eluting with 19:1:0.1 dichloromethane/methanol/ammonia. The oil obtained was dissolved in dichloromethane (5 mL) and one molar (1M) ethereal hydrogen chloride (4 mL) was added. The mixture was concentrated to give the sub-titled compound as a solid (415 mg).
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(OCC)(=O)C.Cl>O>[CH3:17][S:14]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:6]([OH:8])=[O:7])(=[O:16])=[O:15]
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of 4-chloro-3-methylsulfonyl-5-nitrobenzoic acid (5.0 g) and piperidine (25.0 ml) was stirred for 1 hour at ambient temperature. To the mixture was added a mixture of ethyl acetate and water and the mixture was adjusted to pH 1 with conc. hydrochloric acid. The separated organic layer was washed with water and dried over magnesium sulfate. The solvent was removed by concentration and the residue was triturated with a mixture of diisopropyl ether and n-hexane to give 3-methylsulfonyl-5-nitro-4-piperidinobenzoic acid (5.66 g).
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[OH:15][CH2:16][C@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[C:6]([C:5]1[C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=[CH:11][C:4]=1[O:15][CH2:16][C@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])#[N:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Yield: 87 %

Procedure:
Prepared as in Example 160d from 2,6-dinitrobenzonitrile and (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate in 87% yield as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 1.39 (s, 9H), 1.82 (m, 1H), 2.02 (m, 3H), 3.32 (m, 2H), 4.08 (m, 1H), 4.32 (m, 2H), 7.79 (d, J=8.0 Hz, 1H), 7.91 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][C:14]1[NH:18][N:17]=[C:16]([NH2:19])[CH:15]=1>C(O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:19][C:16]2[CH:15]=[C:14]([CH3:13])[NH:18][N:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: CCO
Product: Cc1cc(Nc2nc(Cl)nc3ccccc23)n[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2,4-dichloro-quinazoline (3.3 g, 16.6 mmol) in anhydrous ethanol (150 mL) is added 5-methyl-1H-pyrazol-3-yl amine (3.2 g, 32.9 mmol). The mixture is stirred at room temperature for 4 h, and the resulting precipitate is collected by filtration, washed with ethanol, and dried under vacuum to afford (2-chloro-quinazolin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=1[O:27][CH3:28]>>[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:22][C:21]=1[O:27][CH3:28]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: COc1cc(N)ccc1F
Agent: [Na+]
Product: COc1cc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)ccc1F
Yield: 75.5 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 520 mg of 4-fluoro-3-methoxyaniline in place of the 2,4-difluoroaniline. 262 mg of N-(4-fluoro-3-methoxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].[CH:9]1([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[C:18](Cl)=[O:19])[CH2:13][CH2:12][CH2:11][CH2:10]1>N1C=CC=CC=1.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:15]([O:14][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)[CH:16]=1
Reactant: COc1ccc(C(=O)Cl)cc1OC1CCCC1
Reactant: Nc1cnccc1Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: COc1ccc(C(=O)Nc2cnccc2Cl)cc1OC1CCCC1
Reaction time: 8 h
Yield: 59.2 %

Procedure:
A stirred solution of 4-chloropyrid-3-ylamine (1.94 g) and 3-cyclopentyloxy-4-methoxybenzoyl chloride (3.85 g) in pyridine (50 mL) is heated at 80° C. for 7 hours and then it is allowed to stand overnight. The reaction mixture is evaporated, to give a brown oil, which is subjected to mplc on silica gel, using diethyl ether as eluent, to give N-(4-chloropyrid-3-yl)-3-cyclopentyloxy-4-methoxybenzamide (3.1 g), m.p. 130°-132° C.
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH:21]([NH:26]S(C(C)(C)C)=O)[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO>[CH2:1]([C:8]1[O:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH:21]([NH2:26])[C:22]([CH3:24])([CH3:23])[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(NS(=O)C(C)(C)C)c1nc(-c2cc(F)ccc2F)oc1Cc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)C(N)c1nc(-c2cc(F)ccc2F)oc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of (±)-N-(1-(5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)-2,2-dimethylpropyl)-2-methylpropane-2-sulfinamide (340 mg, 0.738 mmol) in MeOH (10 mL) was added 4 M HCl in dioxane (369 μL, 1.476 mmol). The reaction mixture was stirred at room temperature for 1 h. After quenched with saturated NaHCO3 solution and diluted with EtOAc, the reaction mixture was stirred for 15 min and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude (±)-1-(5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)-2,2-dimethylpropan-1-amine was obtained in 91% yield (240 mg), which was used for the next step without further purification (a major side product, methyl 2-methylpropane-2-sulfinate, was completely removed under high vacuum). LC/MS (uplc): MH+ 340.2 (—NH2), 0.91 min.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH:23]=O)([CH3:18])([CH3:17])[CH3:16].[CH3:28][C:29]1[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=1[NH2:31].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][NH:31][C:30]1[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=1[CH3:28])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Reactant: Cc1ccccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccccc1NCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
2.5 g of sodium triacetoxyborohydride (12.0 mmol) was added to a solution of 1.87 g of (1,1-dimethyl-2-oxoethyl)carbamic acid t-butyl ester obtained in Reference Example 3 (10.0 mmol), 10.7 g of 2-methylaniline (10.0 mmol) and 0.57 ml of acetic acid (10.0 mmol) in methylene chloride (100 ml) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=5/1) to obtain 2.43 g of the title compound (yield: 87%).