Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]([NH:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH:28]=[N:27][CH:26]=[CH:25]3)=[O:20])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][CH:4]=1.[CH3:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36].C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH3:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:10][NH:11][C:12]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:18])[C:19]([NH:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH:28]=[N:27][CH:26]=[CH:25]3)=[O:20])=[CH:7][CH:8]=1)=[O:36]
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)cc1
Reactant: Cc1ccccc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)OCc1ccc(C(CNC(=O)OC(C)(C)C)C(=O)Nc2ccc3cnccc3c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl 2-(4-(hydroxymethyl)phenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E139) in pyridine was added 2-methylbenzoyl chloride and the solution was stirred for 2 h at room temperature. The mixture was poured into NaHCO3 and extracted with EtOAc. The organics were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 5% MeOH/CH2Cl2) gave pure 4-(3-(tert-butoxycarbonylamino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2-methylbenzoate (E140).
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[N:13]=[C:12]2[CH2:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C.CS(O[CH2:45][CH2:46][C:47]1[S:48][CH:49]=[CH:50][CH:51]=1)(=O)=O>O>[ClH:1].[ClH:1].[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[N:13]=[C:12]2[CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:45][CH2:46][C:47]3[S:48][CH:49]=[CH:50][CH:51]=3)[CH2:23][CH2:22]2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(Cn2c(CC3CCNCC3)nc3cccnc32)cc1
Reactant: CS(=O)(=O)OCCc1cccs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: Fc1ccc(Cn2c(CC3CCN(CCc4cccs4)CC3)nc3cccnc32)cc1
Yield: 76 %

Procedure:
A mixture of 7.9 parts of 3-[(4-fluorophenylmethyl)-2-(4-piperidinylmethyl)-3H-imidazo[4,5-b]pyridine dihydrochloride, 8.5 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone was stirred and refluxed for 30 minutes using a water separator. 7.8 Parts of 2-thiopheneethanol methanesulfonate (ester) were added and the whole was stirred and refluxed for 4 hours using a water separator. After cooling, the salts were filtered off, washed with 4-methyl-2-pentanone and the filtrate was washed with water. The organic layer was dried, filtered and evaporated. The residue was converted into the hydrochloride salt in 2-propanol and 2-propanone. The salt was filtered off and dried in vacuo at 60° C., yielding 8.0 parts (76%) of 3-[(4-fluorophenyl)methyl]-2-[[1-[2-(2-thienyl)ethyl]-4-piperidinyl]methyl]-3H-imidazo[4,5-b]pyridine dihydrochloride. monohydrate; mp. 210.8° C. (117).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[O:13]1[CH:17]=[CH:16][C:15]([C:18]2[S:22][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:20][CH:19]=2)=[N:14]1>>[O:13]1[CH:17]=[CH:16][C:15]([C:18]2[S:22][C:21]([S:23]([NH:1][C:2]3[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=3)(=[O:25])=[O:24])=[CH:20][CH:19]=2)=[N:14]1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccon2)s1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(-c3ccon3)s2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 5-isoxazol-3-ylthiophene-2-sulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (15.9 mg) with purity >90%. MS (pos) m/z 400.3.
Reaction SMILES: CO[C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:6]=1)=[O:4].[F:26][C:27]([F:31])([F:30])[CH2:28][NH2:29]>>[F:26][C:27]([F:31])([F:30])[CH2:28][NH:29][C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2CO)no1
Reactant: NCC(F)(F)F
Product: O=C(NCC(F)(F)F)c1cc(OCc2c(-c3ccc(F)cc3)noc2CO)no1
Yield: 21 %

Procedure:
As described for example 43 g, 3-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-isoxazole-5-carboxylic acid methyl ester (100 mg, 0.29 mmol) was converted, using 2,2,2-trifluoroethylamine instead of isopropylamine, to the title compound (25 mg, 21%) which was obtained as a white solid after purification by chromatography (silica, dichloromethane:methanol=1:0 to 9:1). MS: m/e=414.0 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[O:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH2:9][N:10]([C:11]([N:13]3[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[O:12])[C:4]=2[CH:3]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][CH2:33][C:34](O)=[O:35])[CH:27]=1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[O:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH2:9][N:10]([C:11]([N:13]3[CH2:19][CH2:18][CH2:17][N:16]([C:34](=[O:35])[CH2:33][CH2:32][C:28]4[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=4)[CH2:15][CH2:14]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C(O)CCc1cccnc1
Reactant: O=C(N1CCCNCC1)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: O=C(CCc1cccnc1)N1CCCN(C(=O)N2Cc3ccccc3Oc3ccc(Cl)cc32)CC1
Yield: 61.1 %

Procedure:
The title compound of Example 60 (0.73 g, 2.0 mmol) was coupled to 3-(3-pyridyl) propanoic acid (0.31 g, 2.0 mmol) by the procedure of Example 55. Following chromatographic separation of the crude product, 0.60 g of the title compound was obtained as a white solid and used in Example 87 without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:17]=[CH:16][CH:15]=[N:14][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[NH2:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1>C1COCC1>[CH3:24][C:22]1[CH:23]=[C:19]([NH:18][C:2]2[C:3]3[CH:17]=[CH:16][CH:15]=[N:14][C:4]=3[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:7]=2)[NH:20][N:21]=1
Reactant: Clc1nc(-c2ccccc2)nc2ncccc12
Reactant: Cc1cc(N)n[nH]1
Solvent: C1CCOC1
Product: Cc1cc(Nc2nc(-c3ccccc3)nc3ncccc23)[nH]n1
Temperature: 65 °C
Yield: 50.7 %

Procedure:
To a solution of 4-chloro-2-phenyl-pyrido[2,3-d]pyrimidine (J. Pharm. Belg., 29, 1974, 145–148) (109 mg, 0.45 mmol) in THF (15 mL) was added 3-amino-5-methyl pyrazole (48 mg, 0.5 mmol) and the resulting mixture heated at 65° C. overnight. The mixture was cooled to room temperature and the resulting suspension was filtered and washed with Et2O. The solid was dissolved in a mixture EtOH:water and the pH adjusted to pH 7. The aqueous was extracted twice with ethyl acetate and the combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, DCM-MeOH gradient) to afford IV-31 as an off-white solid (69 mg, 50%): mp 234° C.; 1H NMR (DMSO) δ 2.14 (3H, s), 5.99 (1H, s), 7.20–7.40 (3H, m), 7.40–7.50 (3H, m), 8.60 (1H, d), 8.79 (1H, d), 12.82 (1H, br s); IR (solid) 2957, 2921, 2857, 1644, 1560, 1459, 1427; MS 303.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]>CCO.N.O.[Ni]>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][NH2:21])=[CH:18][CH:19]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(C#N)cc2)n1
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(CN)cc2)n1
Reaction time: 6 h

Procedure:
A suspension of [6-(4-cyano-phenyl)-pyridin-2-yl]carbamic acid tert-butyl ester (7.0 g, 24 mmol), Raney Ni (1.0 g) in EtOH (500 mL) and NH3.H2O (10 mL) was hydrogenated under H2 (50 psi.) at 50° C. for 6 h. The catalyst was filtered off and the filtrate was concentrated to dryness to give [6-(4-aminomethyl-phenyl)-pyridin-2-yl]-carbamic acid tert-butyl ester, which was used directly in next step. 1H NMR (300 MHz, CDCl3) δ 7.83-7.92 (m, 3 H), 7.70 (t, J=7.8 Hz, 1 H), 7.33-7.40 (m, 4 H), 3.92 (br s, 2 H), 1.53 (s, 9 H).
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([NH2:10])[CH:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3].[N:11]1([S:17](Cl)(=[O:19])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>N1C=CC=CC=1.CCOC(C)=O>[CH2:1]([C:4]1[N:9]=[C:8]([NH:10][S:17]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:19])=[O:18])[CH:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1cccc(N)n1
Reactant: O=S(=O)(Cl)N1CCCCC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCc1cccc(NS(=O)(=O)N2CCCCC2)n1
Yield: 32 %

Procedure:
A solution of 6-propyl-pyridin-2-ylamine (0.2 g) and piperidine-1-sulfonyl chloride (0.296 g, Bull. Soc. Chim. Fr.; 1936, 2143) in pyridine (7 mL) was heated to reflux for 15 h. After concentration of the reaction mixture in vacuo the residue was taken up in EtOAc, which was then washed with 1N aqueous HCl, saturated brine, dried over sodium sulphate and concentrated in vacuo. The residue was applied to a silica gel column with EtOAc/toluene (9:1 to 1:1) as eluent. Combination of the purified fractions and concentration in vacuo gave the desired piperidine-1-sulfonic acid (6-propyl-pyridin-2-yl)-amide (0.133 g) as a colorless amorphous solid. MS (ESI−): 282.0 ([M−H]−).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:3]1.O[N:30]=[C:31]([NH2:35])[CH2:32][O:33][CH3:34]>>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]3[O:28][N:35]=[C:31]([CH2:32][O:33][CH3:34])[N:30]=3)[CH2:10]2)=[O:8])[CH2:3]1
Reactant: COCC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)C2)C1
Product: COCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(O)C3)C2)n1

Procedure:
200 mg (0.497 mmol) of the compound from Example 112A and 77 mg (0.746 mmol) of N′-hydroxy-2-methoxyethanimidamide were reacted according to the General Method 2. Yield: 55 mg (24% of theory).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH:3]([CH3:5])[CH3:4].COCCOC[C:13]1[C:26]2[NH:27][N:28]=[C:24]3[C:25]=2[C:16]([C:17](=[O:30])[C:18]2[C:23]3=[CH:22][CH:21]=[CH:20][C:19]=2[OH:29])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:4][CH:3]([CH3:5])[CH2:2][CH2:1][O:29][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[C:17](=[O:30])[C:16]1[C:25]3[C:24]2=[N:28][NH:27][C:26]=3[CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)CCBr
Reactant: COCCOCc1ccc2c3c(n[nH]c13)-c1cccc(O)c1C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCOc1cccc2c1C(=O)c1cccc3[nH]nc-2c13
Temperature: 80 °C

Procedure:
Isopentyl bromide is added to a mixture of 3-(2-methoxyethoxymethyl)-7-hydroxyanthra[1,9cd]pyrazol-6(2H)-one and potassium carbonate in dimethylformamide at room temperature. After stirring the mixture for sixteen hours, water is added, and the mixture was extracted with ethyl acetate (×2). The combined organic layer is washed with aqueous sodium bicarbonate, water, 1N hydrochloric acid, and brine, dried and evaporated. The reside is taken in 6N hydrochloric acid and heated at 80° C. for 4 hours. After cooling, the mixture is extracted with ethyl acetate (×2), and the combined organic layer is washed with brine, dried, and evaporated. The residue is purified by column chromatography to afford the title compound as yellow solid.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[CH2:7][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)[CH2:5]1>CO>[OH:3][CH:4]1[CH2:5][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(=O)C2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC(O)C2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.89 g (23.57 mmol) of sodium borohydride is added portionwise at 0° C. to a solution of 3.54 g (15.71 mmol) of tert-butyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate (WO98/06720) diluted in 40 mL of methanol. The reaction mixture is stirred at room temperature for 1 hour 30 minutes. After evaporating off the solvent, water is added to the reaction medium, the aqueous phase is separated out and extracted several times with diethyl ether, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. After evaporating off the solvent, 3.10 g of product are obtained in the form of a brown oil, which is used without further purification in the following step.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:24](=[O:45])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[CH3:42])=[O:34])=[C:28]([O:43][CH3:44])[CH:27]=2)[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.[OH-].[Na+]>C1COCC1.CO>[CH3:44][O:43][C:28]1[CH:27]=[C:26]([CH2:25][C:24]([N:20]2[CH2:21][CH2:22][CH2:23][CH:19]2[CH2:18][NH:17][C@@H:14]2[CH2:15][CH2:16][C@H:11]([C:9]([OH:10])=[O:8])[CH2:12][CH2:13]2)=[O:45])[CH:31]=[CH:30][C:29]=1[NH:32][C:33]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH3:42])=[O:34]
Reactant: COc1cc(CC(=O)N2CCCC2CN[C@H]2CC[C@@H](C(=O)OCc3ccccc3)CC2)ccc1NC(=O)Nc1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(CC(=O)N2CCCC2CN[C@H]2CC[C@@H](C(=O)O)CC2)ccc1NC(=O)Nc1ccccc1C
Temperature: 70 °C
Reaction time: 18 h
Yield: 73.4 %

Procedure:
To a stirred solution of benzylcis-4-[[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenyl acetyl]-2-pyrrolidinyl]methylamino]cyclohexanecarboxylate (1.5 g, 2.45 mmol) in THF (10.0 ml) and MeOH (5.0 ml) was added 1N NaOH (3.68 ml, 3.68 mmol). The mixture was stirred at 70° C. for 18 hr. The mixture was concentrated in vacuo, water was added thereto, and neutralized with 1N HCl. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH—CH2Cl2 (1:5, v/v) as eluent to give cis-4-[[1-[3-methoxy-4-[N′-(2-methyl phenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methylamino]cyclohexanecarboxylic acid 171 (940 mg, 73%) as an amorphous solid. MW 522.64 IR (KBr) 3283, 2945, 2860, 1534, 1453, 1415 cm−1; 1H-NMR (DMSO-d6) δ1.38-2.00 (m, 12H), 2.45 (s, 3H), 2.30-3.95 (m, 4H), 3.22-3.75 (m, 2H), 3.58 (s, 2H), 3.86 (s, 3H), 4.12 (m, 1H), 6.73-7.16 (m, 5H), 7.77-7.79 (m, 1H), 7.98-8.02 (m, 1H), 8.51-8.52 (m, 1H), 8.57-8.59 (m, 1H); MS (FAB) m/z 523 (M++1); Anal. Calcd. for C29H38N4O5.0.5NaCl.2.2H2O: C, 58.89; H, 7.23; N, 9.47. Found: C, 59.21; H, 7.11; N, 9.11.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][O:18][C:19]1[CH:20]=[C:21](/[CH:25]=[CH:26]/[C:27](O)=[O:28])[CH:22]=[CH:23][CH:24]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:27](=[O:28])/[CH:26]=[CH:25]/[C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=3)=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Reactant: COc1cccc(/C=C/C(=O)O)c1
Product: COc1cccc(/C=C/C(=O)Nc2ccn(Cc3ccc(C(C)(F)F)o3)n2)c1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(3-methoxy-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.09 min; [M+H]+=388.21.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])[O:4]CC1>C(O)C.S(=O)(=O)(O)O.C(OCC)(=O)C>[N:13]1([C:11]([CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]2=[O:4])=[O:12])[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: O=C(C1CCCCC12OCCO2)N1CCOCC1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1CCCCC1C(=O)N1CCOCC1
Temperature: 80 °C
Yield: 35 %

Procedure:
To a solution of (1,4-dioxa-spiro[4.5]dec-6-yl)-morpholin-4-yl-methanone (59 mg, 0.23 mmol) in 60% aqueous ethanol (1.1 mL) were added 2 drops of conc. sulfuric acid (20 uL) and the mixture was heated to 80° C. for 2 h. The mixture was cooled to 20° C., diluted with ethyl acetate (20 mL) and washed with saturated aqueous sodium carbonate solution (10 mL), and with brine (10 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the title compound (17 mg, 35%) as a white solid. MS ISP (m/e): 211.9 (100) [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:18]([OH:20])=O)[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=1.Cl.[CH3:22][NH:23][O:24][CH3:25].CCN=C=NCCCN(C)C.Cl.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:25][O:24][N:23]([CH3:22])[C:18]([C:4]1[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=[C:2]([OH:1])[CH:3]=1)=[O:20]
Reactant: O=C(O)c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of acid 24 (0.35 g, 1.3 mmol), DMAP (0.5 g, 4.1 mmol), N,O Dimethylhydroxyl amine HCl (0.5 g, 5.1 mmol) in DMF (15 ml) was added EDCl (0.5 g, 2.6 mmol) and the reaction was stirred at rt for 1 hr. The reaction was then poured into 2N HCl and extracted with EtOAc, The EtOAc was dried, concentrated, and the resulting solid was triturated with CH2Cl2 and collected by filtration to give 119 as a white solid (0.22 g, 55%): Mp=125-127° C.; 1NMR (DMSO-d6) δ 9.88 (br s, 1 H), 9.44 (s, 1 H), 7.65(d, 2 H, 8.6 Hz), 7.08 (br s, 1 H), 6.97 (d, 1 H, J=2.3 Hz), 6.88 (d, 2 H, J=8.6 Hz), 6.71 (d, 1 H, J=2.6 Hz), 3.59 (s, 3 H), 3.30 (s, 3 H): MS 312 [M−H]−
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:25][CH3:26])(=O)=O>CN(C=O)C>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:8]([O:10][CH2:25][CH3:26])=[O:9])(=[O:3])[CH3:2]
Reactant: CCOS(=O)(=O)OCC
Reactant: CC(=O)Nc1cc(C(=O)O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Cl)c(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
120 g (562 mmol) of 3-acetamido-4-chlorobenzoic acid were dissolved in 77 ml of DMF and stirred with 93.16 g (674 mmol) of potassium carbonate at 60° C. for 30 min. The mixture was then cooled, admixed with 91 g (590 mmol) of diethyl sulfate, and left with stirring at RT for 7 h. The batch was concentrated, the residue was stirred with 2 l of water, and the precipitated crystals were isolated by filtration with suction. They were washed with water and dried in a vacuum cabinet at 70° C. for 3 h.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15](O)[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.S(Cl)([Cl:24])=O.CCCCCC>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=3[NH:13][C:14](=[O:17])[C:15]=2[Cl:24])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1ccc(C2=C(Cl)C(=O)Nc3ccccc3S2)cc1
Yield: 64.8 %

Procedure:
Under a nitrogen blanket, a 2.0 g sample of dl-cis-2-(4-methoxyphenyl)-2,3-dihydro-3-hydroxy-1,5-benzothiazepin-4(5H)-one (6.8 mmol) was refluxed neat with 20 mL of thionyl chloride (27.6 mmol) for approximately 2 hours. Then, 50 mL of hexane and about 20 mL of ether were added, and solid product was filtered off. The solid was dried under vacuum to obtain 1.4 g of 2-(4-methoxyphenyl)-3-chloro-1,5-benzothiazepin-4(5H)-one (66 percent yield of theory).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=2)[N:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:2]2[C:7]3[CH:8]=[CH:9][S:10][C:6]=3[CH:5]=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[N:3]=2)[CH2:22][CH2:21]1
Reactant: COc1ccc(-c2cc3sccc3c(Cl)n2)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(c2nc(-c3ccc(O)cc3)cc3sccc23)CC1

Procedure:
4-(4-Methylpiperazin-1-yl)-6-(4-hydroxyphenyl)thieno[3,2-c]pyridine (413 mg) obtained from 4-chloro-6-(4-methoxyphenyl)thieno[3,2-c]pyridine and N-methylpiperazine in the same manner as in Example 289-6 was dissolved in DMF (10 ml), followed by the addition of potassium carbonate (526 mg) and 2-bromoethanol (0.18 ml). The resulting mixture was stirred at 80° C. for 2 days, and then the resulting reaction mixture was partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried and evaporated. The resulting residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate system), to give a yellow oil (202 mg, yield; 43%). The resulting oil was converted into a hydrochloride in a conventional manner, to give the title compound as yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][C:5]1[CH:16]=[CH:15][C:8]([C:9](N(OC)C)=[O:10])=[CH:7][CH:6]=1.[CH3:21][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[C:9]([C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=2[OH:1])=[CH:16][CH:15]=1)(=[O:10])[CH3:21]
Reactant: CON(C)C(=O)c1ccc(Cc2ccccc2O)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Cc2ccccc2O)cc1
Reaction time: 0.25 h
Yield: 53 %

Procedure:
Next, 4-(2-hydroxybenzyl)-N-methoxy-N-methylbenzamide (250 mg, 0.921 mmol) was dissolved in tetrahydrofuran (10 mL), followed by addition of methylmagnesium bromide (12% in THF, 2.8 mL) at −20° C. After 15 minutes, a second addition of methylmagnesium bromide (12% in THF, 2.5 mL) was made, followed by a third addition of methylmagnesium bromide (12% in THF, 2.0 mL). After 10 minutes, saturated aqueous ammonium chloride was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After the solvent was concentrated, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the titled compound (110 mg, 53%) as a colorless powder.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[S:11][C:10]([NH:13][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:16]1([CH:14]([NH:13][C:10]2[S:11][C:12]3[C:4]([NH2:1])=[CH:5][CH:6]=[CH:7][C:8]=3[N:9]=2)[CH3:15])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(Nc1nc2cccc([N+](=O)[O-])c2s1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Nc1nc2cccc(N)c2s1)c1ccccc1
Yield: 10.8 %

Procedure:
To 0.165 g (0.55 mmol) of 7-nitro-N-(1-phenylethyl)-1,3-benzothiazol-2-amine in 10 mL of DMF was added 0.62 g (2.8 mmol) of stannous chloride dihydrate. The reaction was heated to 80° C. for 48 h and neutralized with saturated sodium bicarbonate. The mixture was filtered through celite and extracted with ethyl acetate. The extracts were dried in vacuo and purified by flash chromatography eluting with a 50-75% ethyl acetate/hexanes gradient mixture to give 0.016 g (11%) of the title compound as a light yellow solid.