Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[CH3:9][N:10](C)C=O.[Cu](C#N)C#N.C(N(CC)CC)C>C(OCC)(=O)C.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]#[N:10])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc(Br)nc1
Agent: N#C[Cu]C#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1ccc(Cl)cn1
Reaction time: 4 h
Yield: 27 %

Procedure:
The compound (10.0g) obtained in (1) above, dimethylformamide (50 ml), copper cyanide (6.98 g), triethylamine (10.9 ml) and molecular sieves 4A (2 g, heat-treated) were placed in an autoclave. The outer temperature was set for 200° C. and the mixture was stirred for 4 hours. Water and ethyl acetate were added to the reaction mixture, and, after filtering off insoluble matters, extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled away under reduced pressure and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate) to give 1.92 g of a white solid (yield 27%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:17](I)([CH3:19])[CH3:18]>CC(C)=O.[Ag]=O>[CH:17]([N:13]1[CH2:14][CH2:15][CH2:16][CH:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:12]1)([CH3:19])[CH3:18]
Reactant: COc1ccc(C2CCCNC2)cc1OC
Reactant: CC(C)I
Agent: O=[Ag]
Solvent: CC(C)=O
Product: COc1ccc(C2CCCN(C(C)C)C2)cc1OC
Temperature: 20 °C
Reaction time: 24 h

Procedure:
2.5 g of silver oxide were added to a solution of 5 g of 3-(3',4'-dimethoxyphenyl)-piperidine in 25 ml of acetone and then 2.5 ml of isopropyl iodide were added dropwise. The mixture was stirred at 20° C for 24 hours and was filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 6-3-1 cyclohexane-chloroform-triethylamine mixture yielded 4.8 g of N-isopropyl-3-(3',4'-dimethoxyphenyl)-piperidine.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([CH:14]=1)[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH2:18]([SH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.Cl>O.CN(C=O)C>[CH2:18]([S:25][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([CH:14]=1)[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)COc1cc(F)ccc1[N+](=O)[O-]
Reactant: SCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1cc(SCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 68 %

Procedure:
A mixture of ethyl 2-(5-fluoro-2-nitrophenoxy)acetate (11 benzylmercaptan (5.2 g), triethylamine (5.08 g) and DMF (50 ml) was stirred and heated to 80° C. for 7 hours. The mixture was cooled, poured into water and acidified by the addition of dilute aqueous hydrochloric acid. The mixture was extracted with diethyl ether. The organic phase was washed with water and with brine, dried (MgSO4) and evaporated to give ethyl 2-(5-benzylthio-2-nitrophenoxy)acetate (10.6 g, 68%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:26])[C:9]2[CH:25]=[CH:24][C:12]3[N:13]([CH3:23])[C:14]([NH:16][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH3:38])=[C:32]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=1>>[ClH:1].[CH:17]1([NH:16][C:14]2[N:13]([CH3:23])[C:12]3[CH:24]=[CH:25][C:9]([N:8]([CH3:26])[C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:27][C:28]5[CH:29]=[CH:30][C:31]([CH3:38])=[C:32]([S:34]([NH2:37])(=[O:35])=[O:36])[CH:33]=5)[N:7]=4)=[CH:10][C:11]=3[N:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CN(c1ccc2c(c1)nc(NC1CCCCC1)n2C)c1ccnc(Cl)n1
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Product: Cc1ccc(Nc2nccc(N(C)c3ccc4c(c3)nc(NC3CCCCC3)n4C)n2)cc1S(N)(=O)=O
Product: Cl

Procedure:
The title compound was prepared following the procedure of example 1 with N5-(2-Chloro-pyrimidin-4-yl)-N2-cyclohexyl-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (92 mg, 0.25 mmol) and 5-amino-2-methyl-benzenesulfonamide (46 mg, 0.25 mmol) as a white solid (95 mg, 68%). 1H NMR (300 MHz, D6-DMSO) δ 9.51 (s, 1H), 8.56 (s, 1H), 8.18 (br s, 1H), 7.83 (d, J=6.0 Hz, 1H), 7.69 (dd, J=8.4 and 2.1 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.30 (s, 1H), 7.24 (s, 2H), 7.13-7.18 (M, 2H), 5.69 (d, J=6.0 Hz, 1H), 3.70 (m, 1H), 3.64 (s, 3H), 3.47 (s, 3H), 2.50 (s, 3H), 1.98-2.01 (m, 2H), 1.76-1.79 (m, 2H), 1.62—1.66 (m, 1H), 1.29-1.48 (m, 4H), 1.14-1.17 (m, 1H) ppm. MS (ESI) m/z=521 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1)#[N:2].[CH3:18][CH:19]([NH2:23])[C:20]([OH:22])=[O:21].[OH-].[Na+].O>CC(C)=O>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([NH:23][CH:19]([C:20]([OH:22])=[O:21])[CH3:18])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1)#[N:2]
Reactant: CC(N)C(=O)O
Reactant: N#Cc1nc(Cl)c(-c2ccccc2)nc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(Nc1nc(C#N)c(C#N)nc1-c1ccccc1)C(=O)O
Yield: 41.9 %

Procedure:
2,3-Dicyano-5-chloro-6-phenylpyrazine (4.82 g; 0.02 mole) was dissolved in 50 ml of acetone. The solution was cooled to 0° to 5° C., and with stirring, a solution prepared from 1.78 g (0.02 mole) of DL-α-alanine, 1.64 g (0.02 mole) of sodium hydroxide and 40 ml of water was added dropwise over the period of 30 minutes. The mixture was worked up in the same way as in Example 23, and recrystallized from benzene to afford 2.46 g (yield 42%) of 2,3-dicyano-5-(1-caroxyethyl)amino-6-phenylpyrazine.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[Li][CH2:13]CCC.[OH:17][C:18]1([CH3:25])[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1>COCCOC>[CH3:1][O:2][C:3](=[O:4])[CH:5]=[C:21]1[CH2:22][CH2:23][C:18]([O:17][CH3:13])([CH3:25])[CH2:19][CH2:20]1
Reactant: CC1(O)CCC(=O)CC1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: [Li]CCCC
Solvent: COCCOC
Product: COC(=O)C=C1CCC(C)(OC)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of trimethyl phosphonoacetate (9.11 mL, 56 mmol) and (40 mL, 64 mmol) of n-BuLi (1.6N) in DME (60 mL) is stirred for 10 minutes at 0° C. 4-Hydroxy-4-methyl-cyclohexanone (8 g, 56 mmol) was added and the mixture stirred 2.5 hours at 0° C. until TCL indicated complexion of the reaction. Product was obtained after extraction with dichloromethane (7.71 g, 69%).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25].C(Cl)Cl.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[CH:18]([O:17][CH:10]([CH3:9])[CH3:11])([CH3:19])[CH3:23].[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][C:24]1[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=1[Cl:22])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Cl
Reactant: Nc1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)OC(C)C
Product: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1Cl
Temperature: 90 °C
Reaction time: 3 h
Yield: 161.9 %

Procedure:
A mixture of 3-butyryl-4-chloro-8-(2-methylthioethoxy)quinoline (0.8 g, 2.5 mmol) and 2-chloroaniline (0.47 g, 3.7 mmol) in toluene (12 ml) was heated to 90° C. and stirred 3.0 h. After cooling to room temperature, methylene chloride and water were added. The mixture was neutralized with a saturated solution of sodium bicarbonate. The organic layer was dried over sodium sulfate and evaporated. Trituration with isopropyl ether gave 0.84 g (81%) of the desired product.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[H-].[Na+].[H][H].BrCCCC1C=CC=[C:22]2[C:23]([NH:25]C(=O)[C:21]=12)=O>C1COCC1.C(OCC)(=O)C.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:21][CH2:22][CH2:23][NH2:25]
Reactant: Oc1ccc2ccccc2c1
Reactant: [H][H]
Reactant: O=C1NC(=O)c2c(CCCBr)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NCCCOc1ccc2ccccc2c1
Temperature: 80 °C

Procedure:
2-Naphthol (2.9 g, 20 mmol) in dry THF (40 ml) was treated with 60% NaH suspension (0.96 g) at room temperature. After hydrogen evolution ceased, 3-bromopropylphthalimide (5.36 g, 20 mmol) was added and the mixture was heated at 80° C. overnight. The reaction was cooled, diluted with ethyl acetate and water. The layers were separated and the aqueous layer extracted 3 times with ethyl acetate. The combined organic layers were then extracted 5 times with 5% aqueous potassium carbonate, dried over sodium sulfate and concentrated in vacuo. The crude product (observed as a single spot by TLC) was taken up in methanol (60 ml), treated with anhydrous hydrazine (4 ml) and refluxed for 3.5 hours. The mixture was cooled to 4° C. for several hours, then filtered. The filtrate was concentrated to dryness, then partitioned between dichloromethane and 2.5 M aqueous sodium hydroxide. The organic layer was washed with saturated sodium chloride solution, dried and concentrated in vacuo to give 3-(2-naphthyloxy)propyl amine as a beige solid, 1.14 g. The amine (1.14 g, 5.7 mmol) was treated with benzotriazole carboxamidinium 4-methylbenzenesulfonate (1.89 g, 5.7 mmol) and DIEA (1.39 ml) in a mixture of acetonitrile (8 ml) and DMF (2 ml) with shaking at room temperature overnight. Precipitation with ether gave amino(3-(2-naphthyloxy)propyl)carboxamidinium 4-methylbenzenesulfonate as a white crystalline solid. This guanidine (100 mg) was reacted (65 hours, 105° C.) with resin (100 mg) in accordance with the method described in Example 10 (i.e., Resin Method C) to give the title compound.
Reaction SMILES: [CH2:1]=O.[CH2:3]([NH:7][CH3:8])[CH2:4][CH2:5][CH3:6].[Cl:9][C:10]1[C:11]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH2:31]2)=[N:12][CH:13]=[C:14]([C:16](=[O:29])[NH:17][C:18]2[S:19][CH:20]=[C:21]([C:23]3[S:24][CH:25]=[C:26]([Cl:28])[CH:27]=3)[N:22]=2)[CH:15]=1>C(O)(=O)C>[CH2:3]([N:7]([CH2:1][C:20]1[S:19][C:18]([NH:17][C:16]([C:14]2[CH:15]=[C:10]([Cl:9])[C:11]([N:30]3[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH2:31]3)=[N:12][CH:13]=2)=[O:29])=[N:22][C:21]=1[C:23]1[S:24][CH:25]=[C:26]([Cl:28])[CH:27]=1)[CH3:8])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCNC
Reactant: CCOC(=O)C1CCN(c2ncc(C(=O)Nc3nc(-c4cc(Cl)cs4)cs3)cc2Cl)CC1
Reactant: C=O
Solvent: CC(=O)O
Product: CCCCN(C)Cc1sc(NC(=O)c2cnc(N3CCC(C(=O)OCC)CC3)c(Cl)c2)nc1-c1cc(Cl)cs1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
3 ml of acetic acid, 24 μl of a formaldehyde aqueous solution (36%) and 47 μl of N-butyl-N-methylamine were added to 150 mg of ethyl 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)thiazol-2-yl]carbamoyl}-2-pyridyl)piperidine-4-carboxylate, and the mixture was stirred at 90° C. for 18 hours. After the solvent was distilled off under reduced pressure, a saturated sodium hydrogencarbonate aqueous solution was added. The mixture was extracted with chloroform, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography using hexane:EtOAc (7:1 to 5:1) as an elution solvent to obtain 147 mg of ethyl 1-(5-{[5-{[butyl(methyl)amino]methyl}-4-(4-chlorothiophen-2-yl)thiazol-2-yl]carbamoyl}-3-chloro-2-pyridyl)piperidine-4-carboxylate.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5]1.[C:25]([O:30][C:31](=[O:35])[CH2:32]CC)(=[O:29])[CH2:26][CH2:27][CH3:28].[OH-:36].[NH4+]>>[C:31]([OH:30])(=[O:35])[C:32]([OH:2])=[O:36].[CH3:1][O:2][CH2:3][C:4]1([N:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:25](=[O:29])[CH2:26][CH2:27][CH3:28])[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:5]1
Reactant: CCCC(=O)OC(=O)CCC
Reactant: COCC1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reactant: [OH-]
Agent: [NH4+]
Product: CCCC(=O)N(c1ccccc1)C1(COC)CCN(CCc2ccccc2)CC1
Product: O=C(O)C(=O)O

Procedure:
A mixture of 3 parts of 4-(methoxymethyl)-N-phenyl-1-(2-phenylethyl)-4-piperidinamine and 5 parts of butanoic acid, anhydride is stirred and refluxed for 8 hours. The reaction mixture is poured onto water and the whole is alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The oily residue is stirred in 1,1'-oxybisethane with activated charcoal. The latter is filtered off and the filtrate is evaporated. The residue is converted into the ethanedioate salt 2-propanol. The salt is filtered off and crystallized from 2-propanone, yielding 1.7 parts of N-[4-(methoxymethyl)-1-(2-phenylethyl)-4-piperidinyl]-N-phenylbutanamide ethanedioate; mp. 174.2° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([NH:13][CH2:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18])=[O:12].Cl[Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].N1C=CN=C1.Cl>CN(C)C=O.O>[Si:26]([O:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][CH2:10][C:11]([NH:13][CH2:14][C:15]2[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])=[O:12])=[C:2]([Cl:1])[CH:7]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1ccccc1CNC(=O)CCc1ccc(O)cc1Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1CNC(=O)CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of methyl 2-({[3-(2-chloro-4-hydroxyphenyl)propanoyl]amino}methyl)benzoate (380 mg) in N,N-dimethylformamide (4.00 mL) were added chloro tert-butyl dimethylsilane (215 mg) and imidazole (114 mg), followed by stirring at room temperature for 4 hours. To the reaction mixture were added water and 1 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain methyl 2-({[3-(4-{[tert-butyl(dimethyl)silyl]oxy}-2-chlorophenyl)propanoyl]amino}methyl)benzoate (500 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][C@H:8]([O:21]/[N:22]=[C:23](/[C:27]1[N:28]=[C:29]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[S:30][C:31]=1[Cl:32])\[C:24](O)=[O:25])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:43][C@@H:44]1[C:51](=[O:52])[N:50]2[C@@H:45]1[S:46][CH2:47][C:48]([CH2:69][Cl:70])=[C:49]2[C:53]([O:55][CH:56]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54].P(Cl)(Cl)(=O)OC1C=CC=CC=1.CN1CCOCC1>ClCCl>[CH:56]([O:55][C:53]([C:49]1[N:50]2[C@H:45]([S:46][CH2:47][C:48]=1[CH2:69][Cl:70])[C@H:44]([NH:43][C:24](=[O:25])/[C:23](=[N:22]\[O:21][C@@H:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:41])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:10])/[C:27]1[N:28]=[C:29]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[S:30][C:31]=1[Cl:32])[C:51]2=[O:52])=[O:54])([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: COc1ccc(COC(=O)[C@H](CC(=O)OC(C)(C)C)O/N=C(\C(=O)O)c2nc(NC(=O)OC(C)(C)C)sc2Cl)cc1
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(COC(=O)[C@H](CC(=O)OC(C)(C)C)O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)c2nc(NC(=O)OC(C)(C)C)sc2Cl)cc1
Reaction time: 3 h
Yield: 94.5 %

Procedure:
To a suspension of (S,Z)-2-(((4-(tert-butoxy)-1-((4-methoxybenzyl)oxy)-1,4-dioxobutan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)acetic acid (16.7 g, 27.2 mmol) and (6R,7R)-benzhydryl 7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, Hydrochloride (12.89 g, 28.6 mmol) in Dichloromethane (DCM) (210 mL) at −30° C. was added phenyl phosphorodichloridate (4.95 mL, 32.6 mmol), followed by dropwise N-methylmorpholine (8.97 mL, 82 mmol) over 15 mins. The mixture was stirred at the same temperature over 3 h. LCMS indicated completion of the reaction. The reaction was quenched by addition of 10% aq. citric acid (85 mL), the organic solution was separated and washed with 5% NaHCO3, brine, and dried (Na2SO4), filtered, and concentrated. The residue was purified by CombiFlash automated silica gel chromatography (330 g column, 0-50% EtOAc/Hexanes) to afford (S)-4-tert-butyl 1-(4-methoxybenzyl) 2-(((Z)-(2-(((6R,7R)-2-((benzhydryloxy)carbonyl)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)-2-oxoethylidene)amino)oxy)succinate (26 g, 25.7 mmol, 95% yield) as a light yellow foaming solid. LCMS: (M+H)+: 1010.6
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[N:8]([C:13](=[O:20])[CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=1)([O-])=O.O.NN>[Pd].C(O)C>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]2[N:8]([C:13](=[O:20])[CH2:14][N:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)[CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=1
Reactant: O=C(CN1CCCC1)N1CCCOc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)OCCCN2C(=O)CN1CCCC1
Yield: 95.7 %

Procedure:
10% Palladium on Carbon (50% Wet) (0.09 g), 1-(3-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-2-pyrrolidin-1-yl-ethanone (0.262 g, 0.858 mmol), and hydrazine hydrate (0.25 g, 5.0 mmol) in Ethanol (20 mL) was heated at 60° C. for 5 h. The mixture was cooled, filtered through Celite, washing with 50 mL methanol. The filtrate was conc. and azeotroped 3×30 mL toluene to afford 1-(3-Amino-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-2-pyrrolidin-1-yl-ethanone as a white solid (226 mg, 96%). 1H-NMR (CDCl3): 6.95 (d, 1H, J=8.4 Hz), 6.41 (s, 1H), 6.36 (d, 1H, J=8.4 Hz), 4.82 (d, 1H, J=13.2 Hz), 4.39 (d, 1H, J=12.1 Hz), 3.68 (m, 3H), 3.28 (m, 1H), 2.88 (m, 1H), 2.68 (m, 1H), 2.55 (m, 4H), 2.23 (m, 1H), 1.75 (m, 4H), 1.66 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:22])[CH2:11][C:12]1([S:15]([O:18][CH:19]([CH3:21])[CH3:20])(=[O:17])=[O:16])[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O.CC(OC)(C)C>CN(C=O)C.[Na+].[I-]>[CH2:23]([O:22][C@@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:11][C:12]1([S:15]([O:18][CH:19]([CH3:20])[CH3:21])(=[O:16])=[O:17])[CH2:13][CH2:14]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)OS(=O)(=O)C1(C[C@@H](O)COCc2ccccc2)CC1
Reactant: ClCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OS(=O)(=O)C1(C[C@H](COCc2ccccc2)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.1 %

Procedure:
Under a Nitrogen atmosphere was mixed NAH (91.5 g) in DMF (2 L) and (R)-isopropyl 1-(3-(benzyloxy)-2-hydroxypropyl)cyclopropane-1-sulfonate (715 g) in DMF (1 L) at a temperature between −5° C. and 5° C. for 140 minutes. After stirring for a further 5 minutes, NaI (5.1 g) was added. After BnCl (289.5 g) in DMF (300 mL) was added gradually, the reaction mixture was warmed slowly to room temperature and stirred for approximately 16 hours until HPLC analysis showed the reaction was complete. The reaction mixture was cooled to −5° C. and water (4 L) was added followed by MTBE (2 L (×2)) with stirring for 20 minutes. The organic layer was separated, washed with water (2 L (×2)), brine (2 L), dried over Na2SO4 and concentrated to give 830 g of product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH3:21][O:22][C:23]([CH2:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)=[O:24]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:30][C:29]3[CH:28]=[CH:27][C:26]([CH2:25][C:23]([O:22][CH3:21])=[O:24])=[CH:32][CH:31]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: COC(=O)Cc1ccc(N)cc1
Product: COC(=O)Cc1ccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)cc1
Yield: 81.2 %

Procedure:
A procedure similar to that described in Example 52 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (340 mg, 1 mmol) and p-methoxycarbonylmethylaniline (215 mg, 1.3 mmol) to give 395 mg of the title compound (81%): mp 262° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ10.02 (s, 1H), 7.50 (d, 2H, J=8.3 Hz), 7.23 (bs, 1H), 7.18 (d, 2H, J=8.3 Hz), 7.17 (bs, 1H), 5.17~5.26 (m, 1H), 3.61~3.62 (m, 5H), 3.06 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.84 (dm, 1H, J=17.1 Hz),2.56~2.66 (m, 2H), 2.11 (dm, 1H, J=13.5 Hz), 1.76~1.94 (m, 1H).
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].[Li]CCCC.[CH3:13][C:14]1([C:17]([O:19]C)=O)[CH2:16][CH2:15]1>C1COCC1>[CH3:13][C:14]1([C:17](=[O:19])[CH2:2][C:1]#[N:4])[CH2:16][CH2:15]1
Reactant: COC(=O)C1(C)CC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C(=O)CC#N)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
To a solution of diisopropylamine (7.43 mL, 52.6 mmol) in 60 mL of THF was added n-BuLi (2.5M) (21.03 mL, 52.6 mmol) at −78° C. The reaction was stirred at −78° C. for 30 min, then acetononitrile (2.76 mL, 52.6 mmol) was added at −78° C. and the reaction was stirred for 30 min, then methyl 1-methylcyclopropanecarboxylate (3 g, 52.6 mmol) was added at −78° C. The reaction was stirred at −78° C. for 1 h and then allowed to warm up at rt overnight. The solvent was evaporated and the solid dissolved in water. The aqueous layer was washed with ether and then acidified with 6N HCl to pH 2-3. The aqueous layer was extracted with ether. The organic layer was dried with MgSO4 and concentrated to afford the title compound (2.89 g, 89%). MS (DCI/NH3) m/z 124 (M+H)+.
Reaction SMILES: C(O[C:5]([C:7]1[N:8]=[CH:9][C:10]2[N:11](S(C3C=CC(C)=CC=3)(=O)=O)[C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([O:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1)=[CH:14][CH:13]=3)=[O:6])(C)C.[C:44]1([Li])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(O)(=O)C>O1CCCC1.C1C=CC=CC=1>[C:24]1([O:23][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH:9]=[N:8][C:7]([C:5](=[O:6])[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[C:19]([CH2:20][O:21][CH3:22])[C:18]3=2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1
Reactant: COCc1c(C(=O)OC(C)C)ncc2c1c1cc(Oc3nccc4ccccc34)ccc1n2S(=O)(=O)c1ccc(C)cc1
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COCc1c(C(=O)c2ccccc2)ncc2[nH]c3ccc(Oc4nccc5ccccc45)cc3c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
476 mg of 6-(1-isoquinolyloxy)-4-methoxymethyl-9-tosyl-β-carboline-3-carboxylic acid isopropyl ester is mixed in 10 ml of tetrahydrofuran under argon at -60° C. with 0.79 ml of a 0.9 m solution of phenyllithium in benzene. After 1 hour at -60° C., it is stirred for 16 hours at room temperature. The batch is acidified with glacial acetic acid and concentrated by evaporation. The residue is dispersed in ethyl acetate/water and the organic phase is washed, dried, filtered and concentrated by evaporation in succession with respectively saturated sodium bicarbonate and common salt solution. The residue is chromatographed on silica gel with methylene chloride: ethanol=10:1. The corresponding fractions are combined, concentrated by evaporation and recrystallized. 30 mg of 6-(1-isoquinolyloxy)-4-methoxymethyl-3-benzoyl-β-carboline of melting point 159°-160° C. (ethyl acetate/hexane) is obtained.