Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[C:30]([C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([OH:38])[CH:32]=4)=[CH:29][N:28]=[C:27]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.[NH2:46][O:47][CH2:48][C:49]1[NH:50][CH:51]=[C:52]([OH:56])[C:53](=[O:55])[N:54]=1.CS(O)(=O)=O>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:46]/[O:47][CH2:48][C:49]2[NH:50][CH:51]=[C:52]([OH:56])[C:53](=[O:55])[N:54]=2)/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[C:30]([C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([OH:38])[CH:32]=4)=[CH:29][N:28]=[C:27]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[N:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: NOCc1nc(=O)c(O)c[nH]1
Reactant: Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4nc(-c5ccccc5)ncc4-c4ccc(O)c(O)c4)CS[C@H]23)cs1
Agent: CS(=O)(=O)O
Solvent: CC(=O)N(C)C
Product: Nc1nc(/C(=N/OCc2nc(=O)c(O)c[nH]2)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4nc(-c5ccccc5)ncc4-c4ccc(O)c(O)c4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[(5-(3,4-dihydroxyphenyl)-2-phenyl-4-pyrimidinyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (60 mg) (0.09 mmol), 20.5 mg (0.13 mmol) of 2-(aminooxy)methyl-5-hydroxy-4(1H)-pyrimidinone and 13 mg (0.13 mmol) of methanesulphonic acid are dissolved in 0.6 ml of absolute dimethylacetamide. After stirring at room temperature for 18 hours the mixture is concentrated in a high vacuum at room temperature and the residue is crystallized using ethanol. The product is washed with diethyl ether and dried in a high vacuum at room temperature. There are obtained 26 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyrimidinyl)methoxy]imino]acetamido]-3-[[[5-(3,4-dihydroxyphenyl)-2-phenyl-4-pyrimidinyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2 -carboxylic acid as a yellow powder. A further 28 mg of yellow crystals of the same compound can be obtained from the mother liquor after concentration.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][C:12]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([N+:26]([O-])=O)=[C:19]([O:24][CH3:25])[CH:20]=3)[CH2:15]2)=[O:13])[CH2:6][CH2:5]1)[CH3:3].[H][H]>C(O)C.[Pd]>[CH3:3][CH:2]([N:4]1[CH2:5][CH2:6][N:7]([CH2:10][CH2:11][C:12]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([NH2:26])=[C:19]([O:24][CH3:25])[CH:20]=3)[CH2:15]2)=[O:13])[CH2:8][CH2:9]1)[CH3:1]
Reactant: [H][H]
Reactant: COc1cc2c(cc1[N+](=O)[O-])CN(C(=O)CCN1CCN(C(C)C)CC1)CC2
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(cc1N)CN(C(=O)CCN1CCN(C(C)C)CC1)CC2
Yield: 98.5 %

Procedure:
A solution of 2-{3-[4-(1-methylethyl)-1-piperazinyl]propanoyl}-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (285 g, 0.731 mmol) in ethanol (10 mL) was treated with 10% palladium on carbon (30 mg, Aldrich), and stirred under 60 psi of hydrogen pressure for 16 h in a Fischer-Porter apparatus. The pressure was released, the reaction vessel evacuated, and back-filled with nitrogen twice. The mixture was filtered through celite and the filtrate was concentrated to provide 2-{3-[4-(1-methylethyl)-1-piperazinyl]propanoyl}-6-(methyloxy)-1,2,3,4-tetrahydro-7-isoquinolinamine (0.26 g, 0.72 mmol, 99%). 1H NMR (400 MHz, DMSO-d6) is complicated due to amide rotomers δ ppm 0.92-0.98 (m, 6 H), 2.30-2.71 (m, some signals underneath DMSO, 15 H), 3.56-3.63 (m, 2 H), 3.72 (s, 3 H), 4.37-4.47 (two singlets at 4.38 and 4.45, 2 H), 4.53-4.59 (two broad singlets at 4.55 and 4.58, 2 H), 6.38-6.42 (two singlets at 6.39 and 6.41, 1 H), 6.55-6.58 (two singlets at 6.56 and 6.57, 1 H); ESIMS (M+H)+=361.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][C:12]([C:18](O)=[O:19])=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:21])=[CH:4][CH:3]=1.[CH2:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][CH2:34][NH2:35])[CH3:25]>>[CH2:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][CH2:34][NH:35][C:18]([C:12]1[CH:11]=[C:10]2[C:15]([C:16](=[O:17])[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:23][CH:22]=3)[C:8](=[O:21])[NH:9]2)=[CH:14][CH:13]=1)=[O:19])[CH3:25]
Reactant: CCC1CCCCN1CCCN
Reactant: O=C(O)c1ccc2c(=O)n(Cc3ccc(Cl)cc3)c(=O)[nH]c2c1
Product: CCC1CCCCN1CCCNC(=O)c1ccc2c(=O)n(Cc3ccc(Cl)cc3)c(=O)[nH]c2c1

Procedure:
55 mg (42%) of the target compound was obtained in the same manner of Example 1, using 3-(4-chloro-benzyl)-2,4-dioxoquinazoline-7-carboxylic acid (90 mg, 0.272 mmol) obtained in Example 1 and 3-(2-ethyl-piperidine-1-yl)-propylamine (101 mL, 0.598 mmol).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=O)[CH2:5][CH2:6][C:7]([OH:9])=[O:8].C([O-])(=O)C.[Na+].[C:16]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:22]>O>[O:22]=[C:17]1[CH2:18][CH2:19][CH2:20][C:21]2[NH:2][CH:3]=[C:4]([CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:16]1=2
Reactant: O=C1CCCCC1=O
Reactant: NCC(=O)CCC(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)CCc1c[nH]c2c1C(=O)CCC2
Yield: 57.9 %

Procedure:
5-Aminolevulinic acid hydrochloride salt (13.7 g, 0.1 mol), sodium acetate (41 g, 0.2 mol), and 1,2-cyclohexanedione (11.2 g, 0.1 mol) were stirred for 20 hours in 200 ml of water at 50° C. The mixture was cooled and the solid product collected by vacuum filtration and washed with 50% ethanol in water. The product was slurry-washed in 100 ml of 50% ethanol in water, collected and dried under vacuum to give 3-(4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)propionic acid (12 g, 67% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10](=[NH:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.C([Li])CCC.Cl[P:24]([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26]>>[CH:25]([P:24]([CH:28]([CH3:30])[CH3:29])[N:17]=[C:10]([NH:9][CH2:8][CH2:7][N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:27])[CH3:26]
Reactant: CC(C)P(Cl)C(C)C
Reactant: N=C(NCCN1CCOCC1)c1ccccc1
Agent: [Li]CCCC
Product: CC(C)P(N=C(NCCN1CCOCC1)c1ccccc1)C(C)C

Procedure:
Procedure as described for NP Amidine XVII using the following amounts: 0.956 g of N1-(2-morpholinoethyl)benzamidine (Amidine XV, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.80 mL chlorodiisopropylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, a yellow oil was isolated (1.71 g, 98%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)[OH:4].Cl[CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+].OP([O-])(O)=O.[K+]>C(#N)C.C(OCC)(=O)C>[Br:11][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH2:2][NH:1][CH2:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH:10]=[CH:9][CH:8]=1
Reactant: NCC(O)c1cccc(Br)c1
Reactant: O=C(CCl)Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(CNCC(O)c1cccc(Br)c1)Nc1ccccc1
Temperature: 80 °C
Yield: 42.3 %

Procedure:
To a solution of 2-amino-1-(3-bromo-phenyl)-ethanol (example 33, step 1, 1.34 g) and crude 2-chloro-N-phenyl-acetamide (example 33, step 2, 1.0 g) in acetonitrile (15 mL) was added potassium carbonate (1.03 g). The mixture was heated to 80° C. overnight. A 1M solution of KH2PO4 was added, followed by ethyl acetate. The phases were separated, and the inorganic one was extracted with ethyl acetate (x2). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. Column chromatography (SiO2, CH2Cl2/MeOH 95:5) followed by precipitation from a mixture of diethylether/n-heptane (1:4) gave 2-[2-(3-bromo-phenyl)-2-hydroxy-ethylamino]-N-phenyl-acetamide (0.87 g, 42%) as a white solid, MS: 349.1 (M+H, 1Br)+.
Reaction SMILES: C(NC([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([O:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[CH:12][C:10]=2[N:11]=1)=O)C>CS(C)=O.CCOC(C)=O>[NH2:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([O:22][S:23]([C:26]([F:27])([F:29])[F:28])(=[O:25])=[O:24])=[CH:12][C:10]=2[N:11]=1
Reactant: CCNC(=O)Nc1nc2cc(OS(=O)(=O)C(F)(F)F)cc(-c3ccccn3)c2s1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Nc1nc2cc(OS(=O)(=O)C(F)(F)F)cc(-c3ccccn3)c2s1
Temperature: 160 °C
Reaction time: 16 h

Procedure:
[2-(ethylcarbamoylamino)-7-(2-pyridyl)-1,3-benzothiazol-5-yl]trifluoromethanesulfonate (1.34 g, 3.0 mmol) was dissolved in DMSO (10 mL) and stirred at 160° C. for 16 h. The mixture was diluted with EtOAc, washed with H2O, brine. The organic fraction was concentrated in vacuo to afford i (1.01 g, 90%). MS: 375.96 [M+H]+.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[CH:6][CH:5]=1>C(O)(=O)C.ClCCl>[Br:1][C:12]1[S:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=2)=[C:14]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH:13]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(-c2cc(Br)sc2-c2ccc(F)cc2)cc1
Temperature: 2 °C
Reaction time: 0.75 h

Procedure:
Bromine (1 ml) was added dropwise to a solution of 2-(4-fluorophenyl)-3-(4-nitrophenyl)thiophene (5.3 g) in acetic acid (53 ml) and dichloromethane (53 ml) at 2° C. The mixture was stirred at 2° C. for 45 minutes and concentrated to dryness. The residue was collected and washed with water and ethanol to give dark green crystals of 5-bromo-2-(4-fluorophenyl)-3-(4-nitrophenyl)thiophene (6.5 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=2)[CH:14]=[C:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[N:8][CH:9]=1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:30]=[CH:29][CH:28]=[C:13]([CH:14]=[C:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:12]=2)=[N:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(Oc2cccc(C=C3CCN(C(=O)OC(C)(C)C)CC3)c2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of tert-butyl 4-(3-(5-ethoxypyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.6 g, 1.46 mmol) in CH2Cl2 (5 mL) cooled to 0° C. under a N2 atmosphere was added TFA (1.1 mL, 14.6 mmol). The resulting mixture was stirred for 1 h at RT. The solution was concentrated and then quenched with saturated NaHCO3 solution. The mixture was extracted with CH2Cl2 and the organic layer was dried over Na2SO4, and concentrated under reduced pressure to give the title compound (0.45 g, 99%); m/z (311.5, M+ H+).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C@@H:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][CH3:8])[CH2:3][OH:4].C([O-])(=O)C.[Na+].[N:20]#[C:21]Br>CO>[C:9]1([C@@H:6]([CH2:7][CH3:8])[CH2:5][C@H:2]2[CH2:3][O:4][C:21]([NH2:20])=[N:1]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC[C@@H](C[C@H](N)CO)c1ccccc1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC[C@@H](C[C@H]1COC(N)=N1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred, cooled (0° C.) solution of (2S,4S)-2-amino-4-phenyl-hexan-1-ol (270 mg, 1.40 mmol) and sodium acetate (229 mg, 2.70 mmol) in methanol (20 ml) was added dropwise a solution of cyanogen bromide (180 mg, 1.68 mmol) in methanol (2 ml) over 10 min. The mixture was then allowed to warm to r.t. and stirring was continued for 16 h. The mixture was concentrated in vacuo and the residue was taken up in ethyl acetate and washed sequentially with saturated aqueous sodium bicarbonate solution and with saturated brine. The organic phase was dried over sodium sulphate and concentrated in vacuo. The residue was purified by chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: heptane/EtOAc/MeOH) to yield a light yellow solid. MS (ISP): 219.3 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6](O)=[O:7].C1([N:18]=C=NC2CCCCC2)CCCCC1.O.OC1C2N=NNC=2C=CC=1.[OH-].[NH4+]>CN(C)C=O>[NH2:11][C:4]1[CH:3]=[C:2]([Cl:1])[CH:10]=[CH:9][C:5]=1[C:6]([NH2:18])=[O:7]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: Oc1cccc2[nH]nnc12
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-chloroanthranilic acid (70 g, 0.41 mol) in hot (60° C.) dimethylformamide (700 mL), dicyclohexylcarbodiimide (93 g, 0.451 mol, 1.1 equiv), hydroxybenzotriazole hydrate (60.9 g, 0.451 mol, 1.1 eq) and 30% aqueous ammonium hydroxide solution (350 mL) were added. The resulting solution was stirred at room temperature for 18 h. The formed urea was filtered off and the filtrate concentrated. The resulting mixture was partitioned between ethyl acetate and 5% K2CO3 solution. The organic phase was separated, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness to give the desired product as a slightly yellow solid (58.1 g, 83%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)=[N:7][CH:8]=1.Cl.C(N=C=NCCCN(C)C)C.[NH2:34][C:35]1[CH:40]=[CH:39][N:38]=[C:37]([CH2:41][CH3:42])[C:36]=1[Cl:43]>ClCCl>[Cl:43][C:36]1[C:37]([CH2:41][CH3:42])=[N:38][CH:39]=[CH:40][C:35]=1[NH:34][C:17](=[O:19])[CH2:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:20])=[CH:8][N:7]=2)=[CH:15][CH:14]=1
Reactant: CCc1nccc(N)c1Cl
Reactant: O=C(O)Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCc1nccc(NC(=O)Cc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)c1Cl
Yield: 26.2 %

Procedure:
2.97 g (10.0 mmol) of 4-[(5-trifluoromethylpyridin-2-yl)oxy]phenylacetic acid was dissolved in 20 ml of dichloromethane, and the solution was cooled to a temperature of from -10° to 0° C. Then, 2.30 g (12.0 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added thereto, and the mixture was stirred at a temperature of from -10° to 0° C. 30 minutes later, 1.57 g (10.0 mmol) of 4-amino-3-chloro-2-ethylpyridine was added thereto, and the mixture was gradually returned to room temperature with stirring and further stirred for 16 hours at room temperature. Then, 10 ml of dichloromethane was added to the reaction solution. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. Then, dichloromethane was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate) to obtain 1.14 g of the desired product as colorless cotton-like crystals (melting point: 124.5° to 125° C.).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].CC(O[CH:25](N(C)C)[N:26]([CH3:28])[CH3:27])(C)C>C1(C)C=CC=CC=1>[CH3:25][N:26]([CH:28]=[C:7]1[CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:2]1=[O:1])[CH3:27]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CC(=CN(C)C)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2b (272 mg, 1.00 mmol) in dry toluene (4.0 mL) was added Bredereck's reagent (183 mg, 1.05 mmol) dropwise over 2 minutes. The mixture stirred at rt for 1 h and heated to 60° C. for 24 h. The mixture was concentrated and the residue purified on a SiO2 column (CH2Cl2, 50% EtOAc-hexanes then EtOAc for elution) to give a viscous oil. The oil was dissolved in 50% Et2O-hexanes and concentrated to give the title compound 3b as a waxy white solid; 243 mg, 74%. This material was used immediately without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1([CH3:14])[O:13]CCO1.[NH2:15][C:16]1[CH:17]=[C:18]2[C:22]3=[C:23]([CH2:25][S:26][CH2:27][CH2:28][N:21]3[C@H:20]3[CH2:29][CH2:30][N:31](C(OC(C)(C)C)=O)[CH2:32][C@@H:19]23)[CH:24]=1>>[CH2:28]1[N:21]2[C:22]3[C:18]([C@@H:19]4[CH2:32][NH:31][CH2:30][CH2:29][C@@H:20]42)=[CH:17][C:16]([NH:15][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9](=[O:13])[CH3:14])=[CH:24][C:23]=3[CH2:25][S:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Reactant: CC1(c2cc(Cl)ccc2Br)OCCO1
Product: CC(=O)c1cc(Cl)ccc1Nc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2

Procedure:
Using 2-(2-bromo-5-chlorophenyl)-2-methyl-1,3-dioxolane and following the procedures described in EXAMPLE 116, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 150. 1H NMR (CDCl3) δ: 10.26 (s, 1H), 7.72 (d, 1H, J=2.2 Hz), 7.20 (dd, 1H, J=9.2, 2.6 Hz), 6.96 (d, 1H, J=9.2 Hz), 6.84 (d, 1H, J=1.8 Hz), 6.77 (d, 1H, J=1.9 Hz), 6.87 (s, 1H), 3.74 (ABq, 2H, JAB=15.6 Hz), 3.63-3.57 (m, 1H), 3.50-3.42 (m, 1H), 3.40-3.30 (m, 1H), 3.20-3.02 (m, 5H), 2.98-2.90 (m, 1H), 2.66-2.58 (m, 1H), 2.61 (s, 3H), 2.05-1.97 (m, 2H). LRMS (ES)+: 391.4 (M+H)+. LRMS (ES)+: 414.4 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([O:15]C(=O)C2C=CC(OC)=CC=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(OCC)(=O)C>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:10][CH2:11][C@H:12]([OH:15])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(=O)O[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
A solution of Intermediate 118 (32.92 g) in methanol (400 ml) was added with 3 N aqueous sodium hydroxide (163 ml) at room temperature and stirred at 50° C. for 1.5 hours. The reaction mixture was cooled to room temperature, then added with ethyl acetate (400 ml) and washed 4 times with 0.5 N aqueous sodium hydroxide (50 ml each) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to obtain the title compound (7.94 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C)(C)C.[C:20]([O:24][C:25](OC([O-])=O)=[O:26])([CH3:23])([CH3:22])[CH3:21]>[OH-].[Na+]>[C:20]([O:24][C:25](=[O:26])[NH:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccccc2)CC1
Yield: 82.8 %

Procedure:
1-Benzylpiperidin-4-ylamine (3 g, 15.8 mmol), the starting material, was dissolved in 1M aqueous sodium hydroxide solution (35.8 ml) and t-butanol (32 ml) in a 250 ml vessel, and t-butyl-dicarbonate ((t-Boc)2O; 3.79 g, 17.38 mmol) was added thereto while stirring, and the resulting mixture was reacted at room temperature for 12 hrs. After the completion of reaction, the reaction mixture was extracted with ethyl acetate twice. Then, the organic layer was washed with 0.1N hydrochloric acid solution and brine in order, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified with a silica gel column chromatography to obtain 3.80 g of the title compound as a white solid (82.8%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([SH:12])[N:7]=1)=[O:5])[CH3:2].CN(C=O)C.[H-].[Na+].I[CH:21]([CH2:23][CH3:24])[CH3:22]>O>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH:21]([CH2:23][CH3:24])[CH3:22])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(S)n1
Reactant: CCC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(SC(C)CC)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
6-Mercapto-pyridine-2-carboxylic acid ethyl ester (0.25 g, 1.3 mmol) was added with DMF (7 mL), and the mixture was cooled to 0° C. NaH (0.065 g, 1.56 mmol) was added thereto, and the mixture was stirred for 30 minutes. 2-Iodobutane (0.2 mL, 1.56 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. The reactant was added with water and then extracted with EtOAc. The organic layer was separated, dried with MgSO4, and purified by column chromatography to obtain the title compound (0.17 g, 52%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[N:25][C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH:4]=1>CO.[Pd]>[CH3:1][O:2][CH:3]1[CH2:26][NH:25][C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[N:10]=[C:5]2[CH2:4]1
Reactant: COc1cnc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2c1
Agent: [Pd]
Solvent: CO
Product: COC1CNc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2C1
Temperature: 25 °C
Reaction time: 32 h

Procedure:
7-Methoxy-2,3-dip-tolylpyrido[2,3-b]pyrazine (94 mg, 0.275 mmol) in dry MeOH (4 ml), under nitrogen was treated with 10% Pd on Carbon (58.6 mg, 0.056 mmol). The suspension was stirred at RT under an atmosphere of hydrogen for 32 hours. The resulting mixture was loaded onto a 2.5 g Celite® column using MeOH and was flushed with 1:1 MeOH:DCM. The filtrate was concentrated in vacuo and the residue was dissolved in DCM (30 ml) and washed with water (×2). The organic portion was isolated and the solvent was removed in vacuo to afford the title compound; LCMS Rt 1.12 mins MS m/z 346 [ M+H]+ Method 2minLC_v003
Reaction SMILES: [CH:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)=[CH2:2].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(OCC)C>[CH:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=Cc1ccc(NS(C)(=O)=O)cc1
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of 500 g (4.2 moles) of 4-vinylaniline and 460 g (4.2 moles) of triethylamine in 1000 cc of anhydrous diethyl ether under a nitrogen atmosphere was added dropwise 478 g (4.2 moles) of methanesulfonyl chloride. The temperature of the reaction vessel was kept below 5° C. by an ice bath during the course of the reaction. When addition was complete (40 min.), the mixture was stirred for an additional 2 hours and the contents of the flask then brought to room temperature. The mixture was filtered and extracted with 500 cc of 1.0 M HCl solution. The etheral portion was separated, dried and the ether removed on a rotary evaporator. The resulting oily solid was extracted with 500 cc of ethanol and recrystallized from ethane/water and then from toluene. 70-75% yield after recrystallization. M.P. = 97° C.