Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[C:31]([CH3:38])[CH:32]=[C:33]([OH:37])[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39](=O)([O-:41])[O-:40].[K+].[K+].Cl.[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49]Cl>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[C:31]([CH3:38])[CH:32]=[C:33]([O:37][CH2:49][CH2:48][N:47]([CH3:51])[CH3:46])[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH:39]([O-:41])=[O:40]
Reactant: C=C(C)c1cc(C(=O)N2Cc3cc(O)cc(C)c3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CN(C)CCCl
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)c1cc(C(=O)N2Cc3cc(OCCN(C)C)cc(C)c3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Product: O=C[O-]
Temperature: 60 °C
Reaction time: 6 h
Yield: 256.8 %

Procedure:
A mixture of (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-(5-hydroxy-7-methyl-1,3-dihydro-isoindol-2-yl)-methanone (164 mg, 0.32 mmol), potassium carbonate (112 mg, 0.81 mmol) and 2-(dimethylamino)ethyl chloride hydrochloride (93 mg, 0.64 mmol) in DMF (5 mL) was heated at 60° C. for 17 hours then 90° C. for 6 hours. Further portions of potassium carbonate (112 mg, 0.81 mmol) and 2-(dimethylamino)ethyl chloride hydrochloride (93 mg, 0.64 mmol) were added and the mixture maintained at 60° C. for 72 hours and finally, a further 24 hours at 90° C. The mixture was concentrated in vacuo then the residue was partitioned between ethyl acetate and 0.5N aqueous sodium hydroxide. The organic phase was washed with brine (×2), dried (MgSO4) and concentrated to give a residue which was purified by preparative HPLC (acidic method) to afford the title compound as a formate salt (37 mg, 20%). 1H NMR (MeOH-d4) 8.51 (1H, br. s), 7.43-7.27 (7H, m), 7.24-7.20 (3H, m), 7.17 (0.5H, s), 7.16 (0.5H, s), 6.85 (0.5H, s), 6.84 (0.5H, s), 6.81 (0.5H, s), 6.77 (0.5H, s), 6.74 (0.5H, s), 6.62 (0.5H, s), 5.16 (1H, s), 5.14 (3H, s), 5.09 (1H, m), 5.06 (1H, m), 4.83 (1H, s), 4.74 (1H, s), 4.60 (1H, s), 4.48 (1H, s), 4.28 (1H, t), 4.23 (1H, t), 3.41 (1H, t), 3.37 (1H, t), 2.84 (3H, s), 2.81 (3H, s), 2.27 (1.5H, s), 2.09 (3H, s), 2.07 (1.5H, s). MS: [M+H]+ 577.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl.N1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:22](=[O:23])[O:21][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(-c2ccncc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2ccncc2)cc1)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a suspension of 4-(4-pyridinyl)aniline (50 mg) in dichloromethane (1.50 mL) and pyridine (356.4 μL) was added dropwise benzyloxycarbonyl chloride (75.5 μL) at ambient temperature and the mixture was stirred at the same temperature for 1 hour. The resulting mixture was concentrated in vacuo and water (10 mL) was added to the residue. The aqueous solution was extracted with ethyl acetate (15 mL) and the organic layer was washed successively with saturated sodium bicarbonate aqueous solution and brine, then dried and concentrated. The residual solid was triturated with diisopropylether (2.0 mL) to give benzyl [4-(4-pyridinyl)phenyl]carbamate (70.3 mg) as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:21][CH2:20][C:19](=[CH:22][C:23]([O:25]CC)=[O:24])[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11](C(OC(C)(C)C)=O)[C:10]=2[C:9]1=[O:35])=O)(C)(C)C.[Li+].[OH-]>CO.O>[O:35]=[C:9]1[C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:20][CH2:21][NH:8]1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)C(=O)c2c1c1ccccc1n2C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CC1=CCNC(=O)c2[nH]c3ccccc3c21

Procedure:
A solution of 5-ethoxycarbonylmethylene-1-oxo-1,3,4,5-tetrahydro-azepino[3,4-b]indole-2,10-dicarboxylic acid di-tert-butyl ester, (0.496 g, 1.02 mmol) and LiOH (0.246 g, 10.2 mmol) in MeOH—H2O (1:1 mixture, 50 mL) is stirred at room temperature for 2 days before it is concentrated. Water is added to the residue and it is acidified with NaHSO4 (2M). The solid that is precipitated is collected by vacuum filtration and dried to yield (1-oxo-1,2,3,10-tetrahydro-azepino[3,4-b]indol-5-yl)-acetic acid; 1H NMR (DMSO-d6) δ 2.50 (t, 2H, J=5.6 Hz), 2.82 (s, 1H), 5.00 (t, 1H, J=6.4 Hz), 6.18 (t, 1H, J=7.2 Hz), 6.34 (t, 1H, J=7.2 Hz), 6.56 (d, 1H, J=8.8 Hz), 6.90 (d, 1H, J=8.8 Hz), 7.21 (t, 1H, J=4.4 Hz), 10.98 (s, 1H); m/z [M++1] 257.0.
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]2[C:18]3[N:19]=[C:20]([CH3:26])[N:21]([CH2:22][O:23][CH2:24][CH3:25])[C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Br[CH2:40][CH:41]([CH3:44])[CH2:42][Cl:43]>O1CCCC1.C(OCC)C.O>[C:28]1([CH2:27][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]2[C:18]3[N:19]=[C:20]([CH2:26][CH2:40][CH:41]([CH3:44])[CH2:42][Cl:43])[N:21]([CH2:22][O:23][CH2:24][CH3:25])[C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(CCl)CBr
Reactant: CCOCn1c(C)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCOCn1c(CCC(C)CCl)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29.9 %

Procedure:
A solution of N,N-bis(phenylmethyl)-1-ethoxymethyl-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.8 g, 4.12 mmole, Example 1 Part E) in tetrahydrofuran (40 mL) was cooled to -78° C. Butyllithium (1.7 mL of 2.5M in hexanes, 4.2 mmole) was added and the reaction mixture was stirred for 20 minutes. 1-Bromo-3-chloro-2-methylpropane (4.8 mL, 41 mmole) was added and the reaction mixture was allowed to warm to ambient temperature over a period of 1 hour. The reaction mixture was diluted with diethyl ether and water. The ether layer was separated, dried over magnesium sulfate and then concentrated under vacuum. The resulting residue was purified by flash chromatography (silica gel eluting with 5-20% ethyl acetate in hexanes v/v) to provide 0.65 g of N,N-bis(phenylmethyl)-2-(4-chloro-3-methylbutyl)-1-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-])=O)=[C:9]([CH3:14])[C:8]([F:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O-]S(S([O-])=O)=O.[Na+].[Na+].Cl>COCCO.O>[NH2:11][C:10]1[C:2]([Cl:1])=[C:3]([CH:7]=[C:8]([F:15])[C:9]=1[CH3:14])[C:4]([OH:6])=[O:5]
Reactant: Cc1c(F)cc(C(=O)O)c(Cl)c1[N+](=O)[O-]
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCO
Product: Cc1c(F)cc(C(=O)O)c(Cl)c1N

Procedure:
18.5 g of 2-chloro-5-fluoro-4-methyl-3-nitro-benzoic acid and 51.5 g of Na2S2O4 are boiled in a mixture of 160 ml of glycol monomethyl ether and 160 g of water for 3 hours. 230 ml of 1/2-concentrated HCl are added to the still warm solution. The mixture is boiled up once more, cooled and poured into 560 ml of water. The solid which has precipitated is isolated and dried. Yield: 12.4 g, melting point: 182°-84°.
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]([O:25][CH3:26])=[CH:5][C:6]2[CH2:15][CH:14]3[N:9]([CH2:10][CH2:11][C:12]4[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:13]=43)[CH2:8][C:7]=2[CH:24]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[CH:32]=[CH:33][C:34](Cl)=[O:35]>N1C=CC=CC=1>[CH3:23][O:22][C:17]1[C:18]([O:20][CH3:21])=[CH:19][C:12]2[CH2:11][CH2:10][N:9]3[CH:14]([CH2:15][C:6]4[CH:5]=[C:4]([O:25][CH3:26])[C:3]([O:2][C:34](=[O:35])[CH:33]=[CH:32][C:31]5[CH:30]=[C:29]([O:28][CH3:27])[C:39]([O:40][CH3:41])=[C:38]([O:42][CH3:43])[CH:37]=5)=[CH:24][C:7]=4[CH2:8]3)[C:13]=2[CH:16]=1
Reactant: COc1cc(C=CC(=O)Cl)cc(OC)c1OC
Reactant: COc1cc2c(cc1O)CN1CCc3cc(OC)c(OC)cc3C1C2
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)C1Cc3cc(OC)c(OC(=O)C=Cc4cc(OC)c(OC)c(OC)c4)cc3CN1CC2
Yield: 46 %

Procedure:
1.9 g of 10-hydroxy-2,3,11-trimethoxy-5,6,13,13a-tetrahydro-8H-dibenzo[a, g]quinolizine hydrochloride was treated in the same manner as described in Example 6, using 2.0 g of 3,4,5-trimethoxycinnamoyl chloride and 20 ml of anhydrous pyridine and there was obtained 1.3 g (46.4% yield) of 5,6,13,13a-tetrahydro-2,3,11-trimethoxy-10-(3', 4', 5'-trimethoxycinnamoyloxy)-8H-dibenzo[a, g]quinolizine as a pale yellow powder. The methiodide derived from this compound was found to be in agreement with the methiodide of the compound obtained in Example 5 as determined from the melting point and IR spectrum.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=[O:11].[K+].[OH2:16]>>[Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:11])=[O:16])[C:5]([F:9])=[CH:4][CH:3]=1
Reactant: Cc1nc(Br)ccc1F
Reactant: O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: O=C(O)c1nc(Br)ccc1F
Temperature: 100 °C
Yield: 18 %

Procedure:
To 6-bromo-3-fluoro-2-methylpyridine (2.0 g, 10.58 mmoles) in H2O (200 mL) was added potassium permanganate (1.67 g, 10.58 mmoles). The solution was heated at 100° C. for 16 hours at which time upon cooling the material was filtered through celite (4 cm×2 inches) and rinsed with H2O (150 mL). The combined aqueous was acidified with 1N HCl to pH4, extracted with ethyl acetate (2×200 mL), washed with NaCl(sat.), dried over MgSO4, filtered and concentrated to yield 6-bromo-3-fluoropicolinic acid (18%) as a white solid. LCMS (m/z): 221.9 (MH+); LC Rt=1.71 min.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([Br:8])=[N:6][CH:7]=1.N([O-])=O.[Na+].[S:13](=[O:15])=[O:14].[ClH:16]>O.C(O)(=O)C.O.O.[Cu](Cl)Cl>[Br:8][C:5]1[N:6]=[CH:7][C:2]([S:13]([Cl:16])(=[O:15])=[O:14])=[CH:3][CH:4]=1
Reactant: Cl
Reactant: O=S=O
Reactant: Nc1ccc(Br)nc1
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)(Cl)c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.-5° C.) stirred solution of 5-amino-2-bromopyridine (1.5 g, 8.6 mmol) in 12 N hydrochloric acid (26.5 mL), was slowly added a solution of sodium nitrite (0.66 g, 7.76 mmol) in water (7 mL). In a separate flask, sulfur dioxide was bubbled through a stirred solution of copper(II) chloride dihydrate (0.63 g, 3.50 mmol) in glacial acetic acid at 0° C. for 30 minutes, and then the diazotized reaction mixture prepared above was added. The resulting mixture was slowly warmed to room temperature and stirred for 30 minutes, then was poured into ice water (100 mL), and extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude 6-bromo-pyridine-3-sulfonyl chloride, which was immediately used in the next step.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)[CH:5]=1.[OH-].[Na+]>C1COCC1.CO.O>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[S:11][C:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:23])=[O:2])=[N:14][CH:13]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1cccc(-c2ncc(-c3ccc(OC)cc3)s2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(-c2cnc(-c3cccc(C(=O)O)c3)s2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.6 %

Procedure:
A solution of 1.4 g (4.3 mmol) 3-[5-(4-Methoxy-phenyl)-thiazol-2-yl]-benzoic acid methyl ester from Preparation 10 in a 3:1:1 mixture of THF/methanol/water was added 10 mL (10 mmol) 1N NaOH. The mixture was stirred 14 hours at room temperature before concentrating on a rotary evaporator. The residue was treated with 6M HCl then filtered, washed with water (1×) and dried in a vacuum oven overnight at 70° C. to provide 1.2 g (88%) of desired product.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](Cl)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[O:19]=[C:20]1[CH2:25][NH:24][CH2:23][CH2:22][NH:21]1.N1C=CC=CC=1.C(O)(=O)C>[OH-].[Na+]>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:24]3[CH2:23][CH2:22][NH:21][C:20](=[O:19])[CH2:25]3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: O=C1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(=O)C3)cc21
Yield: 32.4 %

Procedure:
A mixture of 1-ethyl-7-chloro-1,4-dihydro-6-fluoro-4-oxoquinoline-3-carboxylic acid (0.80 g), 2-oxopiperazine (3.0 g) and 4 ml pyridine was heated for 18 hours. The reaction mixture was evaporated under vacuum, an aqueous solution of caustic soda was added to adjust the pH to 10, ice cooled and the undissolved matter was collected and washed with a small amount of an aqueous solution of NaOH. The filtered product was suspended in water, acidified with acetic acid, filtered and washed. The product obtained was dissolved in an aqueous solution of NaOH and acidified with acetic acid. The precipitate was filtered, washed and dried to obtain 0.32 g (32%) of 1-ethyl-1,4-dihydro-6-fluoro-7-(3-oxo-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: C(OC([NH:11][C:12]1[C:13](=[O:42])[N:14]([CH2:28][C:29]([NH:31][CH:32]([CH:39]([CH3:41])[CH3:40])[C:33](=[O:38])[C:34]([F:37])([F:36])[F:35])=[O:30])[C:15]([C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=2)=[CH:16][CH:17]=1)=O)C1C=CC=CC=1.[H][H]>>[NH2:11][C:12]1[C:13](=[O:42])[N:14]([CH2:28][C:29]([NH:31][CH:32]([CH:39]([CH3:40])[CH3:41])[C:33](=[O:38])[C:34]([F:36])([F:35])[F:37])=[O:30])[C:15]([C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=2)=[CH:16][CH:17]=1
Reactant: COc1cc(OC)cc(-c2ccc(NC(=O)OCc3ccccc3)c(=O)n2CC(=O)NC(C(=O)C(F)(F)F)C(C)C)c1
Reactant: [H][H]
Product: COc1cc(OC)cc(-c2ccc(N)c(=O)n2CC(=O)NC(C(=O)C(F)(F)F)C(C)C)c1

Procedure:
2-[3-Benzyloxycarbonylamino-6-(3,5-dimethoxyphenyl)-2-oxo-1,2-dihydro-1-pyridyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide was subjected to the conditions described in Example 159, except with shaking under a 2.7 bar hydrogen atmosphere, to give the title compound. Chromatography solvent: Dichloromethane:methanol (98:2, 95:5); TLC: Rf =0.35, dichloromethane:methanol (95:5); MS: m/z=456(M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][O:20][C:21]2[C:22]([C:27](OC)=[O:28])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1.[BH4-].[Na+].O1CCCC1.CO>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][O:20][C:21]2[C:22]([CH2:27][OH:28])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1ncccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2cccnc2CO)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a mixture of methyl 3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-2-pyridinecarboxylate (0.30 g), sodium borohydride (0.13 g) and tetrahydrofuran (10 mL) was dropwise added methanol (2 mL) at 50° C., and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give crystals (0.23 g, 82%) of [3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-2-pyridyl]methanol. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 118-119° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][NH:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1.C([Li])CCC.[CH3:19][Si:20]([CH3:59])([CH3:58])[CH2:21][CH2:22][O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[CH2:32][CH2:33][O:34][C:35]1[C:44]2[C:39](=[CH:40][C:41]([Cl:48])=[C:42]([N:45]=[C:46]=[O:47])[CH:43]=2)[NH:38][C:37](=[O:49])[C:36]=1[C:50]1[CH:55]=[C:54]([CH3:56])[CH:53]=[C:52]([CH3:57])[CH:51]=1)=[O:25]>>[CH3:58][Si:20]([CH3:19])([CH3:59])[CH2:21][CH2:22][O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[CH2:32][CH2:33][O:34][C:35]1[C:44]2[C:39](=[CH:40][C:41]([Cl:48])=[C:42]([NH:45][C:46]([N:5]([CH2:4][CH:3]([O:2][CH3:1])[O:12][CH3:13])[C:6]3[CH:11]=[N:10][CH:9]=[CH:8][N:7]=3)=[O:47])[CH:43]=2)[NH:38][C:37](=[O:49])[C:36]=1[C:50]1[CH:55]=[C:54]([CH3:56])[CH:53]=[C:52]([CH3:57])[CH:51]=1)=[O:25]
Reactant: COC(CNc1cnccn1)OC
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OCC[Si](C)(C)C)c3cc(N=C=O)c(Cl)cc3[nH]c2=O)c1
Agent: [Li]CCCC
Product: COC(CN(C(=O)Nc1cc2c(OCCC3CCCCN3C(=O)OCC[Si](C)(C)C)c(-c3cc(C)cc(C)c3)c(=O)[nH]c2cc1Cl)c1cnccn1)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9 %

Procedure:
To a solution of (2,2-dimethoxyethyl)-pyrazin-2-yl-amine (103 mg in 3 mL dry tetrahydrofuran) at -78° C. was added 0.23 mL of a 2.5M solution of butyllithium and the mixture stirred for 30 minutes. At this time, a solution of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-isocyanato-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid 2-trimethylsilanylethyl ester (94 mg in 2 mL tetrahydrofuran) was added via cannula and the mixture warmed to room temperature. After 20 hours, the reaction was quenched by the addition of saturated ammonium chloride and extracted with chloroform. The organic portion was washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification of the residue by preparative tlc on silica gel (ethyl acetate) gave the title compound (11 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]2[CH:21]=[N:20][CH:19]=[C:18]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:17]=2)=[CH:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.C(Cl)Cl.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C1COCC1>[Cl:1][C:2]1[C:3]([C:16]2[CH:21]=[N:20][CH:19]=[C:18]([NH:22][CH2:23][CH:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[N:17]=2)=[CH:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:33](=[O:35])[CH3:34])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3cncc(NCC4CCOCC4)n3)c(Cl)cn2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)N[C@H]1CC[C@H](Nc2cc(-c3cncc(NCC4CCOCC4)n3)c(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of trans-N1-(5-chloro-4-(6-((tetrahydro-2H-pyran-4-yl)methyl)aminopyrazin-2-yl)pyridin-2-yl)cyclohexane-1,4-diamine (example 85) (14 mg, 0.034 mmol), DCM (0.5 ml), THF (0.500 ml), TEA (0.014 ml, 0.101 mmol) and acetic anhydride (3.48 μl, 0.037 mmol) was stirred at ambient temperature for 1 hour, and the reaction progress was followed by LCMS. The solvent was concentrated off, added 1.0 ml of DMSO, filtered and purified by prep LC. After lyophilization 6.3 mg of title compound was obtained as a TFA salt. LCMS (m/z): 445.2 (MH+), retention time=0.59 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.21-1.55 (m, 6 H) 1.70 (d, J=12.89 Hz, 2 H) 1.92 (s, 3 H) 1.93-2.06 (m, 3 H) 2.10 (br. s., 2 H) 3.28-3.32 (dMeOH, 2H App.) 3.34-3.47 (m, 2 H) 3.55-3.73 (m, 2 H) 3.94 (dd, J=11.28, 3.08 Hz, 2 H) 7.00 (s, 1 H) 7.94 (s, 2 H) 8.01 (s, 1 H).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[C:8]2[NH:9][CH2:10][CH2:11][S:12][CH:13]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:7]=2[C:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[N:5]1.C(N(CC)C(C)C)(C)C.[C:35](Cl)(=[O:37])[CH3:36].O>C(Cl)Cl>[CH3:3][N:4]1[C:8]2[NH:9][CH2:10][CH2:11][S:12][CH:13]([CH:14]3[CH2:19][CH2:18][N:17]([C:35](=[O:37])[CH3:36])[CH2:16][CH2:15]3)[C:7]=2[C:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[N:5]1
Reactant: CC(=O)Cl
Reactant: Cn1nc(-c2ccccn2)c2c1NCCSC2C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCC(C2SCCNc3c2c(-c2ccccn2)nn3C)CC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a mixture of 1-methyl-4-(4-piperidyl)-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine dihydrochloride (0.10 g, 0.25 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.8 mmol) in DCM (20 mL) was added dropwise a solution of acetyl chloride (0.018 mL, 0.25 mmol) in DCM (2 mL), at about −10° C. The resulting mixture was stirred at about −10° C. for about 2 h and about 1 h at rt, then water (10 mL) and DCM (20 mL) were added. The layers were separated and the organic layer was washed with water (10 mL) and brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, DCM/methanol 95:5) to give 1-[4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]-1-piperidyl]ethanone (0.090 g, 97%) as a white solid: LC-MS (Table 1, Method a) Rt=1.60 min; m/z 372 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) (The spectrum is described as a 1:1 mixture of two compounds (‘rotamers’), each contributing 25 protons) δ 1.11 (1H, td, J=12.4, 4.3 Hz) 1.17-1.37 (4H, m) 1.38-1.50 (2H, m) 2.01 (3H, s) 2.07 (3H, s) 2.08-2.28 (4H, m) 2.39 (1H, td, J=12.7, 2.9 Hz) 2.65-2.74 (2H, m) 2.86 (1H, td, J=12.8, 2.9 Hz) 2.96-3.13 (5H, m) 3.39-3.54 (4H, m) 3.65 (1H, br. d, J=13.6 Hz) 3.77 (3H, s) 3.78 (3H, s) 3.84 (1H, br. d, J=13.6 Hz) 4.40 (1H, br. d, J=13.5 Hz) 4.63 (1H, br. d, J=13.7 Hz) 5.04 (1H, d, J=9.5 Hz) 5.06 (1H, d, J=9.9 Hz) 7.11-7.17 (2H, m) 7.63-7.69 (2H, m) 7.84-7.92 (2H, m) 8.50-8.56 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15](=[O:20])[CH2:16][C:17]([CH3:19])=O)[O:4][N:3]=1.[CH3:21][O:22][C:23](=[O:28])/[CH:24]=[C:25](\[NH2:27])/[CH3:26].[N+:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=O)([O-:31])=[O:30]>C(O)(C)C>[CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]([C:16]2[CH:35]([C:34]3[CH:37]=[CH:38][CH:39]=[C:32]([N+:29]([O-:31])=[O:30])[CH:33]=3)[C:24]([C:23]([O:22][CH3:21])=[O:28])=[C:25]([CH3:26])[NH:27][C:17]=2[CH3:19])=[O:20])[O:4][N:3]=1
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)CC(=O)OCCCCCCCc1cc(C)no1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCCc2cc(C)no2)C1c1cccc([N+](=O)[O-])c1
Yield: 60 %

Procedure:
7-(3-methylisoxazol-5-yl)heptylacetoacetate (1.967 g, 0.007 l mol) was added to a solution of methyl-β-aminocrotonate (0.805 g, 0.007 mol) and m-nitrobenzaldehyde (1.057 g, 0.007 mol) in isopropanol (35 mL). The reaction mixture was heated under reflux for 12 h and then concentrated under reduced pressure. The residual oil was purified by elution from a silica gel column using dichloromethane-hexane (9:1, v/v) as eluant to give 3-[7-(3-methylisoxazol-5-yl)heptyloxycarbonyl]-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine (60%) as a pale yellow thick oil. IR (neat) 3330 (NH) and 1701 and 1676 (CO2R)cm-1, NMR (CDCl3) 1.20-1.40 (m, 6H, --(CH2)3), 1.56-1.74 (m, 4H, --(CH2)2), 2.30 (S, 3H, Me), 2.39 (S, 3H, Me), 2.72 (t, J =9 Hz, 2H, CH2 -Het), 3.70 (S, 3H, CO2Me), 3.99-4.16 (m, 2H,--OCH2), 5.14 (S, 1H, H-4), 5.89 (S, 1H, Het-H), 7.06 (S, 1H, NH), 7.38-8.14 (m, 4H, H-2 , H-4', H-5', H-6'). Analysis found: C, 63.48; H, 6.45; N, 7.99. Required: C, 63.39; H, 6.50; N, 8.21 (C27H33N3O7). ##STR6##