Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.ClC1C=CC=C(C(OO)=[O:19])C=1>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:19])=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1ccnc2[nH]ccc12
Solvent: CCOCC
Product: [O-][n+]1ccc(Br)c2cc[nH]c21
Reaction time: 2.5 h
Yield: 87 %

Procedure:
To a solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (25 mmol) in diethyl ether (400 mL) under nitrogen at room temperature was added m-chloroperbenzoic acid (40 mmol). The reaction was stirred for 2.5 h. The resultant precipitate was filtered and washed with cold ether (50 mL) to give the title compound as an off-white solid (87%). ESMS [M+H]+: 213.2
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[C:17](=O)(O)[O-].[Na+]>CO>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: O=C(O)c1cc(O)ccc1O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(O)ccc1O

Procedure:
2,5-Dihydroxybenzoic acid, 30 grams (0.195 moles), was heated to reflux with 10 ml conc'd. sulphuric acid in 500 ml methanol for 72 hours. Then it was neutralized with solid sodium bicarbonate and striped in vacuo. The product was extracted with ethyl acetate and the organic extract was dried and stripped in vacuo to give 29.8 grams of methyl 2,5-dihydroxybenzoate of >90% purity.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([CH2:25][OH:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([CH:25]=[O:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CO)ccc2c1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(C=O)ccc2c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.3 %

Procedure:
To a solution of tert-butyl(6-hydroxymethyl-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (4.58 g, 10.5 mmol) in tetrahydrofuran (50 mL) was added manganese dioxide (13.7 g) and the mixture was stirred at room temperature for 12 h. Manganese dioxide was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl(6-formyl-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (4.12 g, 90.4%) as crystals.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[C:6]([CH:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:7].Cl>ClCCCl>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[C:6](=[O:7])[CH:8]([C:9]([O:11][CH3:12])=[O:10])[CH2:13]2
Reactant: COC(=O)C(Cc1cccc(Cl)c1)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COC(=O)C1Cc2cc(Cl)ccc2C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
Under nitrogen atmosphere, 9.0 g of anhydrous aluminum chloride and 151.3 g of 1, 2-dichloroethane were stirred to yield a suspension, and the suspension was cooled to 0° C. A mixture of 7.98 g of methyl 2-chloroformyl-3-(3-chlorophenyl)-propionate prepared in Referential Example 1 and 151.3 g of 1,2-dichloroethane was added dropwise to the suspension while maintaining the temperature at 5° C. or below, followed by stirring under the same condition for 2 hours. The reaction mixture was added dropwise to 53.6 g of 1.7 percent by weight hydrochloric acid cooled to 5° C. or below, followed by stirring under the same condition for 1 hour. After separating the mixture into a 1,2-dichloroethane layer and an aqueous layer, the product in the aqueous layer was extracted with 15.1 g of 1,2-dichloroethane. This procedure was repeated a total of two times. The resulting 1,2-dichloroethane layers obtained by these procedures were collected and were washed with 33.0 g of water, followed by removal of 1,2-dichloroethane under reduced pressure. The concentrated residue was purified by silica gel column chromatography [mobile phase: hexane/ethyl acetate=4/1 (by volume)] to yield 5.21 g of methyl 5-chloro-1-oxo-2,3-dihydroindene-2-carboxylate as a beige solid in a yield of 70% on the basis of 3-(3-chlorophenyl)-2-methoxycarbonylpropionic acid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:30])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.Br[CH2:32][CH2:33][O:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1>CN(C=O)C>[CH3:3][O:4][C:5](=[O:30])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH2:32][CH2:33][O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)[CH:22]=2)[CH2:19][CH2:20]1
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1OCCN1CCC(c2cn(CCOC3CCCCO3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 0.29 g (7 mmol) of a dispersion of 60% NaH in 10 mL of anhydrous DMF under inert atmosphere, a solution of 1.5 g (4 mmol) of 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester, prepared in Example 1 (part D), in 5 mL of DMF was added. After 30 minutes at room temperature, a solution of 1.09 g (5.2 mmol) of 2-(2-bromoethoxy)tetrahydro-2H-piran in 2 mL of DMF was added. The reaction mixture was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure and the crude mixture was extracted between water and ethyl acetate. The organic phase was separated, dried and after filtering, the solvent was removed under reduced pressure. The crude mixture was purified by flash chromatography over silica affording 1.3 g (65% of yield) of the desired product.
Reaction SMILES: [CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:8]2[CH2:9][NH:10][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:55]([O:57][C:58]([CH2:60][C:61](Cl)=[O:62])=[O:59])[CH3:56]>>[CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[N:34]=[N:33][N:32]=3)=[CH:23][CH:24]=2)[C:8]2[CH2:9][N:10]([C:61](=[O:62])[CH2:60][C:58]([O:57][CH2:55][CH3:56])=[O:59])[CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)CNC(C(=O)OC)C2
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)CN(C(=O)CC(=O)OCC)C(C(=O)OC)C2

Procedure:
Methyl 2-n-butyl-3-{2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]-pyridine-6-carboxylate and ethoxycarbonylacetyl chloride are treated in the same manner as in Example 1-(2) to give methyl 2-n-butyl-5-ethoxycarbonylacetyl-3-{2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-6-carboxylate.
Reaction SMILES: Br[CH2:2][C:3]1[S:7][C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=3[N:12]=2)=[CH:5][CH:4]=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C1C=CC=CC=1>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:2][C:3]2[S:7][C:6]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=4[N:12]=3)=[CH:5][CH:4]=2)[CH2:23][CH2:22]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc2oc(-c3ccc(CBr)s3)nc2c1
Solvent: c1ccccc1
Product: CN1CCN(Cc2ccc(-c3nc4cc([N+](=O)[O-])ccc4o3)s2)CC1
Yield: 73.9 %

Procedure:
2-[5-(Bromomethyl)-2-thienyl]-5-nitrobenzoxazole (1.16 g, 0.0034 mole, prepared as described in Example 1) and N-methylpiperazine (1.4 g, 0.014 mole) are dissolved in 50 ml of benzene and heated at reflux for 24 hours. The precipitated N-methylpiperazine hydrobromide is removed by filtration and the benzene removed under vacuum yielding a solid. Crystallization from ethanol yields 0.9 g of the title compound, melting point 135°-137°C.
Reaction SMILES: N(CC)CC.CC([NH:10][CH2:11][CH:12]([OH:22])[C:13]1[CH:14]=[CH:15][C:16]([OH:21])=[C:17]([CH2:19][OH:20])[N:18]=1)(C)C>CO>[OH:20][CH2:19][C:17]1[C:16]([OH:21])=[CH:15][CH:14]=[C:13]([CH:12]([OH:22])[CH2:11][NH2:10])[N:18]=1
Reactant: CC(C)(C)NCC(O)c1ccc(O)c(CO)n1
Solvent: CCNCC
Solvent: CO
Product: NCC(O)c1ccc(O)c(CO)n1

Procedure:
A solution of 2.0 g., (0.005 mole) of 2-acetoxymethyl-3-acetoxy-6-(1-acetoxy-2-N-acetyl-tert-butylaminoethyl)pyridine in 50 ml. of methanol containing 1 ml. of concentrated hydrochloric acid was heated to reflux for 12 hours. The solvents were removed in vacuo and the residue recrystallized frcm ethyl acetate to give pirbuterol hydrochloride (900 mg., 58%) m.p. 172°-175° C. (dec.), NMR and tlc in 6:3:1 EtOAz: CH3OH: Et2NH identical to pirbuterol. Prolonged heating results in the formation of 2-hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-aminoethyl)pyridine, m.p. 184°-186° dec.
Reaction SMILES: [C:1]1([CH3:30])[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20](=[O:29])[N:21]([CH3:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:15][CH:14]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:31](=O)[CH3:32].C=O>>[CH3:31][CH:32]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][C:20](=[O:29])[N:21]([CH3:28])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:17]=2)[CH2:12][CH2:11][N:10]1[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:30])=[CH:6][CH:5]=1)(=[O:8])=[O:9]
Reactant: CC=O
Reactant: Cc1ccc(S(=O)(=O)NCCc2ccc(OC(=O)N(C)c3ccccc3)cc2)cc1
Agent: C=O
Product: Cc1ccc(S(=O)(=O)N2CCc3ccc(OC(=O)N(C)c4ccccc4)cc3C2C)cc1

Procedure:
The title compound was prepared using methyl-phenyl-carbamic acid 4-[2-(toluene-4-sulfonylamino)-ethyl]-phenyl ester as the sulfonamide and acetaldehyde in stead of formaldehyde. The crude product was purified by preparative HPLC (Gilson) (22%, brown oil).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])=[O:2].Br[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1>>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:4][C:3]=1[CH:1]=[O:2]
Reactant: Brc1cccnc1
Reactant: COc1ccc(B(O)O)cc1C=O
Product: COc1ccc(-c2cccnc2)cc1C=O

Procedure:
The title compound was prepared by employing the method described in Example 111, Step A with (3-formyl-4-methoxyphenyl)-boronic acid and the commercially available 3-bromopyridine. NMR (400 MHz, CDCl3): δ 10.53 (s, 1H), 8.89 (d, 1H, J=2 Hz), 8.63 (dd, 1H, J=5,1 Hz), 8.10 (dt, 1H, J=8,2 Hz), 8.09 (d, 1H, J=2 Hz), 7.83 (dd, 1H, J=9,2 Hz), 7.56 (dd, 1H, J=8,5 Hz), 7.17 (d, 1H, J=9 Hz), 4.02 (s, 3H). Mass spectrum (NH3 /CI): 214 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[C:26]([NH2:29])(=[O:28])[CH3:27]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:29][C:26](=[O:28])[CH3:27])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: CC(N)=O
Product: CC(=O)Nc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and acetamide. MS obsd. (ESI+) [(M+H)+] 396, 1H NMR (400 MHz, CD3OD) δ ppm 8.53 (s, 1 H), 8.10-8.06 (m, 2 H), 7.97-7.85 (d, J=8.4 Hz, 1 H), 7.82-7.80 (d, J=9.2 Hz, 1 H), 7.76-7.72 (m, 2 H), 7.58-7.54 (m, 2 H), 5.28 (s, 2 H), 4.60 (s, 2 H), 3.77-3.71 (m, 2 H), 2.52 (s, 3 H), 2.40 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:13](OC(Cl)(Cl)Cl)=[O:14]>O1CCOCC1>[N:1]([C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[C:13]=[O:14]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cccc(N=C=O)c1

Procedure:
To a vigorously stirred solution of 3-aminobenzenesulphonamide (1 g, 5.8 mmol) in dry dioxane (25 ml) is added trichloromethyl chloroformate (1.72 g, 8.7 mmol) and the reaction mixture is heated to reflux for 3 hours. The solvent is removed in vacuo to yield the title product which is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10]CC)=[O:9])=[C:5]([CH3:7])[N:6]=1.[Cl:13][C:14]1[S:18][C:17]([S:19](Cl)(=[O:21])=[O:20])=[CH:16][C:15]=1[C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[F:30]>>[Cl:13][C:14]1[S:18][C:17]([S:19]([NH:1][C:2]2[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=2)(=[O:21])=[O:20])=[CH:16][C:15]=1[C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[F:30]
Reactant: O=S(=O)(Cl)c1cc(-c2cc(F)ccc2F)c(Cl)s1
Reactant: CCOC(=O)c1sc(N)nc1C
Product: Cc1nc(NS(=O)(=O)c2cc(-c3cc(F)ccc3F)c(Cl)s2)sc1C(=O)O
Yield: 17 %

Procedure:
The product was prepared from ethyl 2-amino-4-methylthiazole-5-carboxylate (9.3 mg, 0.050 mmol) and 5-chloro-4-(2,5-difluorophenyl)thiophene-2-sulfonyl chloride (Intermediate 20) (17 mg, 0.050 mmol) according to the General Procedure 10, described in Example 128. The title compound was obtained in 17% yield (3.9 mg). 1H NMR (500 MHz, MeOH-d4) δ ppm 2.50 (s, 3 H) 7.18-7.23 (dddd, J=9.16, 7.57, 3.91, 3.05 Hz, 1 H) 7.26 (td, J=9.16, 4.60 Hz, 1H) 7.26 (ddd, J=8.70, 5.70, 3.05 Hz, 1 H) 7.57 (d, J=1.71 Hz, 1 H). MS (ESI+) m/z 451 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:4][C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.[O-:17][CH2:18][CH3:19].[Na+]>C(O)C>[CH2:18]([O:17][C:2]1[C:3]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:4][C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1)[CH3:19]
Reactant: CC[O-]
Reactant: CCN(CC)c1cc2nnc(N)n2nc1Cl
Agent: [Na+]
Solvent: CCO
Product: CCOc1nn2c(N)nnc2cc1N(CC)CC
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.9 %

Procedure:
6-Chloro-N*7*,N*7*-diethyl-[1,2,4]triazolo[4,3-b]pyridazine-3,7-diamine (W2.021, 38 mg) were initially charged in ethanol (7 ml) and admixed with sodium ethoxide (24 mg). The reaction mixture stirred at RT for 4 h. It was then stirred at 45° C. for another 2 h. Subsequently, the mixture was dried, the residue was admixed with water and extracted three times with EA, and the combined EA phases were dried with magnesium sulfate, filtered and concentrated. 30 mg of the title compound were obtained as a crude product, which was clean enough for the next reaction.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]([CH3:35])[C:27]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1.[C:36](Cl)(=[O:39])[CH:37]=[CH2:38]>C(Cl)Cl>[C:36]([NH:10][CH:11]1[CH2:12][CH2:13][N:14]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([N:26]([CH3:35])[C:27]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])=[CH:24][CH:25]=2)(=[O:18])=[O:19])[CH2:15][CH2:16]1)(=[O:39])[CH:37]=[CH2:38]
Reactant: C=CC(=O)Cl
Reactant: CN(C(=O)C1CCOCC1)c1ccc(S(=O)(=O)N2CCC(N)CC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)NC1CCN(S(=O)(=O)c2ccc(N(C)C(=O)C3CCOCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.4 %

Procedure:
Diisopropylethylamine (0.34 ml, 2.1 mmol) was added in one portion to a stirred solution of tetrahydro-pyran-4-carboxylic acid [4-(4-amino-piperidine-1-sulfonyl)-phenyl]-methyl-amide (0.17 g, 0.4 mmol) in DCM (10 ml), followed by the drop wise addition of acryloyl chloride (0.04 ml, 0.42 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the mixture was diluted with DCM (20 ml) and washed sequentially with HCl (1M solution, 10 ml), NaOH (1M solution, 10 ml) and brine (10 ml). The organic layer was separated, dried (MgSO4), filtered, concentrated and the resulting residue was purified by flash column chromatography (elution: 97% EtOAc, 3% Methanol) to give the title compound (0.032 g, 18% yield) as a white solid.
Reaction SMILES: C(O)C.C(O)(=O)C.[Cl:8][C:9]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][N:30]([C:33]3[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[CH2:29][CH2:28]2)[C:24]([N+:41]([O-])=O)=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22])=[O:12]>[Fe]>[NH2:41][C:24]1[C:25]([N:27]2[CH2:28][CH2:29][N:30]([C:33]3[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[CH2:31][CH2:32]2)=[CH:26][C:9]([Cl:8])=[C:10]([CH:23]=1)[C:11]([NH:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22])=[O:12]
Reactant: Cc1ccc(C)c(N2CCN(c3cc(Cl)c(C(=O)NCCCN4CCCC4=O)cc3[N+](=O)[O-])CC2)c1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(C)c(N2CCN(c3cc(Cl)c(C(=O)NCCCN4CCCC4=O)cc3N)CC2)c1
Temperature: 75 °C
Reaction time: 4 h
Yield: 80.5 %

Procedure:
In a 250 ml round bottom flask equipped with a magnetic stir bar and fitted with a septum with a nitrogen inlet, the iron powder (578.30 mg, 10.36 mmol) was suspended in clean, dry, reagent-grade ethanol (50.00 ml, 856.34 mmol) and was stirred vigorously at room temperature under nitrogen as the acetic acid (5.00 ml, 87.34 mmol) was added. The 2-chloro-4-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-5-nitro-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-benzamide 12c (212.90 mg, 0.41 mmol) was added in one portion and the reaction was warmed to 75° C. The reaction was allowed to stir for 4 h. After 4 h, the reaction was cooled to room temperature and filtered through Celite, eluting with methanol. The solvent was then removed under reduced pressure and the ruby red oil was taken up in 100 ml of ethyl acetate. 100 ml of saturated NaHCO3 was added to the solution. The layers were separated and the aqueous layer was extracted twice with 75 ml of ethyl acetate. The organic phases were combined and washed with brine (1×100 ml) and dried over Na2SO4. The product solution was decanted and the solvent was removed under reduced pressure. The crude product, 5-amino-2-chloro-4-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-benzamide 12d (158.70 mg, 0.33 mmol), was isolated as a brown solid and was carried on without further purification. LCMS (m/e)=485 (M+H).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[S:16][C:7]2[CH2:8][CH2:9][N:10]([CH:13]([CH3:15])[CH3:14])[CH2:11][CH2:12][C:6]=2[CH:5]=1.[S-:17][C:18]#[N:19].[K+].BrBr>>[ClH:1].[ClH:1].[NH2:19][C:18]1[S:17][C:5]2[C:6]3[CH2:12][CH2:11][N:10]([CH:13]([CH3:14])[CH3:15])[CH2:9][CH2:8][C:7]=3[S:16][C:4]=2[N:3]=1
Reactant: CC(C)N1CCc2cc(N)sc2CC1
Reactant: N#C[S-]
Agent: BrBr
Agent: Cl
Agent: [K+]
Product: CC(C)N1CCc2sc3nc(N)sc3c2CC1

Procedure:
This compound was prepared from 2-amino-5,6,7,8-tetrahydro-6-isopropyl-4H-thieno[2,3-d]azepine dihydrochloride, potassium thiocyanate and bromine analogous to Example 1.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=1)[C@H:3]([OH:6])[CH2:4][OH:5].[O:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O>C1COCC1>[F:15][C:10]1[CH:9]=[C:8]([CH:13]=[C:12]([F:14])[CH:11]=1)[CH2:7][C@H:2]([NH:1][C:17](=[O:16])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:3]([OH:6])[CH2:4][OH:5]
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CO
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CO
Reaction time: 8 h

Procedure:
Aminodiol 27 was dissolved in THF and BOC2O was added and stirred overnight. Solvent removal afforded 28, which was carried directly into the next step; analytical sample m.p.=122°.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[C:13](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/3)[CH:12]=[C:11]([O:23][CH3:24])[N:10]=2)[CH2:5][CH2:4]1.[S:25]1[CH:29]=[CH:28][C:27]([C:30]2[N:35]=[C:34]([CH:36]=O)[CH:33]=[CH:32][CH:31]=2)=[CH:26]1>>[CH3:24][O:23][C:11]1[N:10]=[C:9]([N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][CH2:36][C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([C:27]4[CH:28]=[CH:29][S:25][CH:26]=4)[N:35]=3)[CH2:4][CH2:5]2)[N:14]=[C:13](/[CH:15]=[C:16]2/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/2)[CH:12]=1
Reactant: COc1cc(/C=C2\SC(=O)NC2=O)nc(N2CCC(CN)CC2)n1
Reactant: O=Cc1cccc(-c2ccsc2)n1
Product: COc1cc(/C=C2\SC(=O)NC2=O)nc(N2CCC(CNCc3cccc(-c4ccsc4)n3)CC2)n1

Procedure:
(Z)-5-((6-methoxy-2-(4-((((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using (Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)-6-methoxypyrimidin-4-yl)methylene)thiazolidine-2,4-dione (Example 153), the general reductive amination procedure and 6-(thiophen-3-yl)picolinaldehyde (34.3 mg, 65 mg theoretical, 52.8%). LC-MS m/z 523 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[C:11]([C:19]([N:21]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@H:22]2[CH2:27][C@@H:26]([CH:28]=[O:29])[CH2:25][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:23]2)=[O:20])[N:10]=[N:9]1.S([CH2:51][N+:52]#[C-:53])(C1C=CC(C)=CC=1)(=O)=O.C[O-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[C:11]([C:19]([N:21]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@H:22]2[CH2:27][C@@H:26]([C:28]3[O:29][CH:53]=[N:52][CH:51]=3)[CH2:25][N:24]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:23]2)=[O:20])[N:10]=[N:9]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C=O)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](c3cnco3)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.2 %

Procedure:
tert-Butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-formylpiperidine-1-carboxylate (235 mg) and tosylmethyl isocyanide (125 mg) were dissolved in methanol (4 ml), sodium methoxide (28% methanol solution, 325 mg) was added and the mixture was heated under reflux with stirring for 2 hr. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (5:95-100:0) was concentrated under reduced pressure to give the object product (98.5 mg).