Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([CH3:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:19](=[NH:32])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC(C)([O-])C.[Na+].C1(P(C2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=C(C3C4C(=CC=CC=4)C=CC=3)C3C(C=2)=CC=CC=3)C2C=CC=CC=2)C=CC=CC=1>CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([CH3:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:32]=[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(Cc1cccc(Br)c1)NC(=O)OC(C)(C)C
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(Cc1cccc(N=C(c2ccccc2)c2ccccc2)c1)NC(=O)OC(C)(C)C

Procedure:
A suspension of [2-(3-bromo-phenyl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (750 mg, 2.39 mmol), benzophenone imine (0.44 mL, 2.63 mmol), sodium tert-butoxide (298 mg, 3.1 mmol), bis(diphenylphosphino)-1,1′-binaphthyl (45 mg, 0.07 mmol), palladium acetate (16 mg, 0.07 mmol), and toluene (7.5 mL) was heated to reflux for 3 h while stirring under an atmosphere of nitrogen. Reaction diluted with ether and organics washed with water and saturated sodium chloride. Product isolated as a viscous yellow oil after purification on silica. M+1=415.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3]([OH:5])=[O:4].[CH2:7](O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S(=O)(=O)(O)O.O>C(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([O:5][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: OCc1ccccc1
Reactant: CC(Br)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CC(Br)C(=O)OCc1ccccc1
Yield: 86 %

Procedure:
2-Bromopropionic acid (750 g, 4.90 moles) and benzyl alcohol (600 g, 3.55 moles) were dissolved in methylene chloride (1500 ml). To the resulting solution was added concentrated sulfuric acid (10 ml). The resulting solution was heated to a gentle reflux for two days, water separating during this time. Water (500 ml) was added and the layers were separated. The methylene chloride was washed with saturated sodium bicarbonate and the layers were separated. The organic layer was washed with water, dried over magnesium sulfate, filtered and evaporated to give a colorless oil which was vacuum distilled to give the pure product as a colorless oil (742 g, 86%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:7]1[C:24]([OH:26])=O)(=[O:3])[CH3:2].C(N(CC)C(C)C)(C)C.[OH:36][NH2:37].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl.C(OCC)(=O)C>[OH:36][NH:37][C:24]([CH:7]1[CH:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:26]
Reactant: NO
Reactant: COc1ccc(S(=O)(=O)N2CCCCC(COC(C)=O)C2C(=O)O)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)N2CCCCC(COC(C)=O)C2C(=O)NO)cc1
Temperature: 0 °C
Reaction time: 5.5 h

Procedure:
To a solution of 3-Acetoxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid (107 mg, 0.28 mmoL) in 5.6 mL dichloromethane was added N,N-Diisopropyl ethyamine (0.195 mL, 1.12 mmoL). This solution was cooled to 0° C. and Hydroxyl amine (58.4 mg, 0.84 mmoL) was added followed by PyBroP (155 mg, 0333 mmoL). The reaction was warmed to ambient temperature after 15 minutes and was stopped after 5.5 hours. The residue was diluted with ethyl acetate and washed sequentially with 0.5N HCl, and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (silica: 0.5% to 1.5% methanol in dichloromethane) to yield Acetic acid 2-hydroxycarbamoyl-1-(4-methoxy-benzene sulfonyl)-azepan-3-ylmethyl ester; MS: (M-H)- =399.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].[CH:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH2:17][CH3:18])[CH3:16]>[SH-].[C+4].[SH-].[SH-].[SH-]>[CH:15]([C:19]1[CH:24]=[CH:23][C:22]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])=[O:5])=[CH:21][CH:20]=1)([CH2:17][CH3:18])[CH3:16]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CCC(C)c1ccccc1
Agent: [Al+3]
Agent: [C+4]
Agent: [Cl-]
Product: CCC(C)c1ccc(C(=O)c2ccccc2F)cc1
Reaction time: 18 h
Yield: 76.1 %

Procedure:
A 3.17 g (0.02 mole) of 2-fluorobenzoic acid chloride was dissolved in 30 ml of carbon bisulfide and then, 3.99 g (0.03 mole) of anhydrous aluminum chloride was added to the solution. A 2.68 g (0.02 mole) of sec-butyl benzene was further added to the mixture with stirring and the reaction was carried out at room temperature for 18 hours. Carbon bisulfide was distilled off from the reaction mixture and water was added and the reaction product was extracted with benzene. The benzene phase was separated washed with 1N-NaOH and with water and was dried with anhydrous sodium sulfate. The solvent was distilled off to obtain a pale yellow oily product. The oily product was distilled under a reduced pressure to obtain 3.9 g of 4-sec-butyl-2'-fluorobenzophenone having a boiling point of 152° to 160° C./5 mmHg. (yield of 76.4%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[CH3:11][O:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])=[O:14]>C(Cl)Cl>[CH3:9][O:8][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:25]([NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:13]([O:12][CH3:11])=[O:14])(=[O:23])=[O:22])=[O:26])[N:7]=1
Reactant: COc1nc(C)nc(N)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Reaction time: 16 h

Procedure:
To an anhydrous suspension of 1.4 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine in 25 ml of methylene chloride was added with stirring at ambient temperatures and pressure 2.4 g of 2-methoxycarbonylbenzenesulfonylisocyanate. The mixture was thereafter stirred for 16 hours and filtered. The filtrate was evaporated to dryness, the residue was triturated with butyl chloride and the product removed by filtration. The product thus obtained melted at 165°, and had absorption peaks in the infrared at 1550, 1600, 1680 and 1700 cm-1 and in the NMR spectrum at 2.5, 3.65, 4.0 with an aromatic multiplet at 7.2-8 ppm.
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[F:16][C:17]([F:26])([F:25])[C:18]1[CH:19]=[C:20](O)[CH:21]=[CH:22][CH:23]=1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([C:17]([F:26])([F:25])[F:16])[CH:23]=2)=[O:14])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: N=C(N)N1CCC(CCC(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: N=C(N)N1CCC(CCC(=O)Oc2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 62.1 %

Procedure:
A mixture of 4.0 g of 1-amidino-4-piperidinepropionic acid hydrochloride and 2.75 g of m-trifluoromethylphenol was suspended in 27 ml of dry pyridine. To the suspension was added 3.5 g of dicyclohexylcarbodiimide, and the resulting mixture was stirred at room temperature for 6 hours. After removal of any insoluble materials, the solvent was removed. The residue was washed with ether, dissolved in chloroform and then stirred. After removal of any insoluble materials, the filtrate was washed twice with a saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 4.0 g (yield: 62.0%) of m-trifluoromethylphenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 97° to 100° C.
Reaction SMILES: O=[C:2]([CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][C:5](O)=[O:6].O.[NH2:22][NH2:23].O.CCOC(C)=O>C1(C)C=CC=CC=1>[C:9]1([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:2]2[CH2:3][CH2:4][C:5](=[O:6])[NH:22][N:23]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NN
Reactant: O=C(O)CCC(=O)C(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CCC(C(c2ccccc2)c2ccccc2)=NN1

Procedure:
A mixture of 4-oxo-5,5-diphenylpentanoic acid (2.47 g) and hydrazine monohydrate (1.4 mL) in toluene (49 mL) was refluxed for 3.5 hours. Water and EtOAc were poured into the reaction mixture. The organic layer was separated, washed with saturated NaHCO3 aqueous solution and brine, and dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was washed with MeCN to give 6-(diphenylmethyl)-4,5-dihydropyridazin-3(2H)-one (0.85 g) as white powder.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=4[O:24][CH3:25])=[N:11][C:10]=3[N:9]([CH3:26])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@@H:47]1[CH2:51][CH2:50][O:49][CH2:48]1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C.O1CCCC1>[CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([O:23][C@H:47]5[CH2:51][CH2:50][O:49][CH2:48]5)=[CH:19][C:18]=4[O:24][CH3:25])=[N:11][C:10]=3[N:9]([CH3:26])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Reactant: O[C@@H]1CCOC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(O[C@H]2CCOC2)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a 10 ml tetrahydrofuran suspension of 150 ml (0.423 mmol) of the compound obtained in Example 36, 133 mg (0.508 mmol) of triphenylphosphine, 51 μl (0.635 mmol) of (R)-(−)-3-hydroxytetrahydrofuran, and 80 μl (0.508 mmol) of diethyl azodicarboxylate were slowly added at room temperature, and the mixture was stirred at room temperature for 1 hour. Further, 44 mg (0.169 mmol) of triphenylphosphine, 17 μl (0.212 mmol) of (R)-(−)-3-hydroxytetrahydrofuran, and 27 μl (0.169 mmol) of diethyl azodicarboxylate were added, and the mixture was stirred at room temperature for 1.5 hours. Then, the reaction mixture was diluted with ethyl acetate, and the dilution was washed with water and a saturated aqueous solution of sodium chloride in this order. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1˜1/2) to obtain 124 mg (69%) of the captioned compound.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH2:2][CH3:3].[H-].[Na+].[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH2:15]Cl)[CH:14]=1.O>CN(C=O)C>[Br:8][C:9]1[CH:14]=[C:13]([CH2:15][NH:5][C:1](=[O:4])[CH2:2][CH3:3])[CH:12]=[N:11][CH:10]=1
Reactant: CCC(N)=O
Reactant: ClCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)NCc1cncc(Br)c1
Yield: 82 %

Procedure:
To a solution of propionamide (146 mg, 2.0 mmol) in DMF (10 mL) was added NaH (61 mg, 2.4 mmol) at 0° C. and reaction mixture was stirred for 10 min before the addition of 3-bromo-5-chloromethyl-pyridine (intermediate A-12 [A], 412 mg, 2.0 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour before water was added. Then, the reaction mixture was extracted with EtOAc and combined organic layers were dried by anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was then purified by flash chromatography to give title compound (400 mg, 82%) as a solid.
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([C@@H:12]2[N:17]3[C:18](=[O:31])[C@@H:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:16]3[S:15][CH:14]=[C:13]2[O:32][CH3:33])=[O:11])=CC=1)([O-])=O.[N+](C1C=CC(COC(C2N3C(=O)[C@@H](NC(=O)COC4C=CC=CC=4)[C@H]3SCC=2OC)=O)=CC=1)([O-])=O.[OH-].[K+].[Cl-].[Na+]>O1CCCC1.C(Cl)Cl>[O:23]([CH2:22][C:21]([NH:20][C@@H:19]1[C:18](=[O:31])[N:17]2[C@@H:12]([C:10]([OH:11])=[O:9])[C:13]([O:32][CH3:33])=[CH:14][S:15][C@H:16]12)=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC1=CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: COC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC1=CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution, prepared at 0° C., of 555 mg (1.11 mmols) of a crude mixture consisting of 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4α-carboxylic acid p-nitrobenzyl ester and 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester in the ratio of about 3:1, in 33 ml of tetrahydrofurane, is mixed, whilst stirring, with 16 ml of an 0.1 N potassium hydroxide solution which has been precooled to 0° C. The mixture is stirred for a further 5 minutes at 0° C., 100 ml of ice water and 100 ml of precooled methylene chloride are then added and the whole is stirred up briefly. Addition of 1 ml of saturated aqueous sodium chloride solution causes the two phases to separate. The organic phase is separated off, and the aqueous phase is again washed with 20 ml of methylene chloride, then covered with 50 ml of methylene chloride and acidified with 20 ml of 2 N hydrochloric acid. After shaking up, the organic phase is separated off and the hydrochloric acid solution is extracted twice more with 10 ml of methylene chloride at a time. The combined methylene chloride extracts are dried over sodium sulphate and evaporated in vacuo. The residue is recrystallised from methylene chloride/diethyl ether/pentane and gives 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4α-carboxylic acid of melting point 142°-145° C.
Reaction SMILES: COC1N=CC2N(C3SC(C(OC)=O)=C(OCC4C=CC=CC=4C(F)(F)F)C=3)C=NC=2C=1.[CH3:33][O:34][C:35]1[N:40]=[CH:39][C:38]2[N:41]=[CH:42][N:43]([C:44]3[S:48][C:47]([C:49]([O:51]C)=[O:50])=[C:46]([O:53][CH2:54][C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=4[C:61]([F:64])([F:63])[F:62])[CH:45]=3)[C:37]=2[CH:36]=1.[Li+].[OH-].[OH-].[Na+]>O1CCCC1.C(OCC)C>[CH3:33][O:34][C:35]1[N:40]=[CH:39][C:38]2[N:41]=[CH:42][N:43]([C:44]3[S:48][C:47]([C:49]([OH:51])=[O:50])=[C:46]([O:53][CH2:54][C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=4[C:61]([F:64])([F:62])[F:63])[CH:45]=3)[C:37]=2[CH:36]=1
Reactant: COC(=O)c1sc(-n2cnc3cnc(OC)cc32)cc1OCc1ccccc1C(F)(F)F
Agent: COC(=O)c1sc(-n2cnc3cc(OC)ncc32)cc1OCc1ccccc1C(F)(F)F
Agent: [Li+]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc2c(cn1)ncn2-c1cc(OCc2ccccc2C(F)(F)F)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1.2 g of an isomeric mixture of methyl 5-(6-methoxy-3H-imidazo[4,5-c]pyridin-3-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate and methyl 5-(6-methoxy-1H-imidazo[4,5-c]pyridin-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate (compounds B6a and B6b) in 30 ml tetrahydrofuran were added dropwise 30 ml of a 1N solution of LiOH. The reaction mixture was stirred for 12 h at room temperature and poured into a mixture of 200 ml diethylether and 0.1 N NaOH (1:1). The organic and aqueous layers were separated and the aqueous layer was acidified with HCl until pH 2 was reached. The aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic layers were dried with MgSO4 and concentrated to dryness under vacuum. The residue was purified by preparative HPLC to yield the title compound. The structural assignment of the title compound was unequivocally established by two-dimensional 1H NMR experiments (NOESY, COSY).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C@H:12]3[CH2:16][C@:5]([C:17]([N:19]4[CH2:24][CH2:23][CH:22]([CH2:25][C:26]5[C:27]([O:32]C)=[N:28][CH:29]=[CH:30][CH:31]=5)[CH2:21][CH2:20]4)=O)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.B(F)(F)F.CCOCC.O1CCCC1.B.CCCCCC>Cl.CO.C(OCC)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C@H:12]3[CH2:16][C@:5]([CH2:17][N:19]4[CH2:24][CH2:23][CH:22]([CH2:25][C:26]5[C:27]([OH:32])=[N:28][CH:29]=[CH:30][CH:31]=5)[CH2:21][CH2:20]4)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: COc1ncccc1CC1CCN(C(=O)[C@@]23C[C@@H](c4ccccc42)c2ccc(Cl)cc23)CC1
Agent: B
Agent: Cl
Agent: FB(F)F
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Oc1ncccc1CC1CCN(C[C@@]23C[C@@H](c4ccccc42)c2ccc(Cl)cc23)CC1

Procedure:
A solution of 1-((9S,10S)-2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylcarbonyl)-4-(2-methoxy-3-pyridylmethyl)piperidine (1.80 g. 3.92 mmol) in tetrahydroruran (50 mL) was treated with boron trifluoride etherate (612 mg, 4.31 mmol) and borane- tetrahydrofuran (14.9 mL of a 1.OH solution, 14.9 mmol). The resulting solution was heated to reflux for 3 h. The mixture was then concentrated on a rotary evaporator to give a colorless residue. The residue was dissolved in concentrated hydrochloric acid (50 mL, 12N) and heated to reflux for 3 h. The solution was concentrated to dryness on a rotary evaporator to give a glassy residue. This residue was dissolved in methanol (100 mL) and concentrated to dryness on a rotary evaporator (3X) to give a white foam. This foam was dissolved in methanol (5 mL) and added to rapidly stirred diethyl ether (200 mL) to give a white precipitate which was collected and washed with diethyl ether to give the hydrochloride salt of the title compound (1.3 g, 2.60 mmol, as an off-white powder, mp 211°-215° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][CH2:17][CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21].C(N(CC)CC)C>ClCCl>[CH2:20]([O:19][CH:18]([O:22][CH2:23][CH3:24])[CH2:17][CH2:16][NH:15][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH3:21]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CCOC(CCN)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(CCNc1c([N+](=O)[O-])cnc2ccccc12)OCC
Yield: 98.4 %

Procedure:
The general method described in Step 1 of Example 1 was used to react 4-chloro-3-nitroquinoline (20.3 g, 97.1 mmol), 1-amino-3,3-diethoxypropane (25.0 g, 116 mmol) and triethylamine (33.8 g, 333 mmol) in dichloromethane for 15 hours to provide (3,3-diethoxypropyl)-(3-nitroquinolin-4-yl)amine (30.5 g) as a yellow solid.
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8]Br)[C:3]([O:5][CH3:6])=[O:4].[S:10]1[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]1>>[S:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:8][CH2:7][CH:2]2[C:3]([O:5][CH3:6])=[O:4])[CH2:12][CH2:11]1
Reactant: NC1CCSCC1
Reactant: COC(=O)C(Br)CCBr
Product: COC(=O)C1CCN1C1CCSCC1
Yield: 35 %

Procedure:
The reaction of methyl 2,4-dibromobutanoate 17 with tetrahydro-thiopyran-4-ylamine 18J yielded methyl 1-(tetrahydro-2H-thiopyran-4-yl)azetidine-2-carboxylate as a light brown solid (35%). MS ISP (m/e): 216.3 (100) [(M+H)]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:42])([CH3:41])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:19][CH2:18]2)[CH:9]=1.C1C(=O)N([I:50])C(=O)C1>C(#N)C>[CH3:1][Si:2]([CH3:42])([CH3:41])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:50])=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])[CH2:19][CH2:18]2)[CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCN(C(=O)OCc3ccccc3)CC2)nc2ccnn12
Solvent: CC#N
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCN(C(=O)OCc3ccccc3)CC2)nc2c(I)cnn12
Reaction time: 1.5 h
Yield: 87.2 %

Procedure:
To a solution of benzyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (2.27 g, 3.7 mmol) in acetonitrile (15 mL) was added NIS (833 mg, 1 eq). After stirring 1.5 hour, solvent was removed and the residue was purified on silica gel. Elution with EtOAc/Hexanes (0-50%) gave the title compound (2.38 g, 86%) as gum.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:33])[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)=[C:17]([C:29]([F:32])([F:31])[F:30])[CH:16]=2)=[CH:9][C:3]=1[C:4](OCC)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.C(OCC)C>[OH:5][CH2:4][C:3]1[CH:9]=[C:10]([NH:13][C:14](=[O:33])[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]3)=[C:17]([C:29]([F:32])([F:30])[F:31])[CH:16]=2)[CH:11]=[CH:12][C:2]=1[CH3:1]
Reactant: CCOC(=O)c1cc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)ccc1C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution Ethyl 2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamido)benzoate (300 mg, 0.65 mmol) in dried THF (2.2 mL) was added Lithium aluminium hydride 2.0M THF solution (0.48 mL, 0.98 mmol) at 0° C. The reaction mixture was stirred for 2 hours at room temperature. When the reaction was completed, the reaction mixture was diluted with ethyl ether (2.0 mL) and added water very slowly to decompose the excess of the reagent. To a reaction mixture was added MgSO4, celite filtered and concentrated under reduced pressure. The title compound (230 mg, 84% yield) was used next step without further purification. MS m/z: 422 [M+1].
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:11](=[O:13])[NH:10][C@H:9]3[CH2:14][NH:15][CH2:16][C@@H:8]3[C:7]=2[CH:6]=[C:5]([CH2:17][CH3:18])[CH:4]=1.[CH:19](=O)[CH3:20].[BH4-].[Na+].Cl>CO.CCOCC.O1CCOCC1>[ClH:2].[Cl:2][C:3]1[C:12]2[C:11](=[O:13])[NH:10][C@H:9]3[CH2:14][N:15]([CH2:19][CH3:20])[CH2:16][C@@H:8]3[C:7]=2[CH:6]=[C:5]([CH2:17][CH3:18])[CH:4]=1
Reactant: CC=O
Reactant: CCc1cc(Cl)c2c(c1)[C@H]1CNC[C@@H]1NC2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCc1cc(Cl)c2c(c1)[C@H]1CN(CC)C[C@@H]1NC2=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 126.9 %

Procedure:
To a solution of (3aR,9bS)-6-chloro-8-ethyl-2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-one hydrochloride (Example 29) (10 mg, 0.035 mmol) in 2 mL of methanol was added acetaldehyde (0.006 mL, 0.10 mmol) followed by sodium borohydride (7 mg, 0.17 mmol). The reaction mixture was stirred at ambient temperature for 18 h. The reaction was concentrated and the residue was purified (ISCO, elution with 0-15% methanol/methylene chloride) to afford the free base. To the free base in 1 mL of ether was added 4N HCl in dioxane (0.05 mL). The mixture was concentrated in vacuo, triturated with ether, and dried in vacuo to afford 7 mg (64%) of the title compound of Example 65 as an off-white solid. 1H NMR (CD3OD): 7.27 (s, 1H), 6.95 and 6.91 (s, 1H), 4.30-4.25 and 3.93-3.85 (m, 2H), 3.70-52 (overlapping m, 3H), 3.42-3.27 (overlapping m, 3H), 2.61 (q, 2H), 1.33 (q, 3H), 1.16 (t, 3H). LRMS (ESI): 279.2/281.2 (M+H)+.