Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([C@@H:7]2[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9][CH2:8]2)[C:5]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=2[N:3]=1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][CH:25]([CH:30]=O)[CH2:24]2>>[CH3:1][C:2]1[N:6]([C@@H:7]2[CH2:8][CH2:9][C@H:10]([NH:13][CH2:30][CH:25]3[CH2:24][C:23]4[C:27](=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:32])[F:33])[CH:22]=4)[CH2:26]3)[CH2:11][CH2:12]2)[C:5]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=2[N:3]=1
Reactant: O=CC1Cc2ccc(C(F)(F)F)cc2C1
Reactant: Cc1ccc2c(c1)nc(C)n2[C@H]1CC[C@@H](N)CC1
Product: Cc1ccc2c(c1)nc(C)n2[C@H]1CC[C@@H](NCC2Cc3ccc(C(F)(F)F)cc3C2)CC1

Procedure:
This compound was prepared from the hydrochloride salt of cis-4-(2,5-dimethyl-benzoimidazol-1-yl)-cyclohexylamine and 5-trifluoromethyl-indan-2-carbaldehyde. 1H-NMR is consistent with the assigned structure, LC-MS showed a single peak, C26H30F3N3 (m/e) calcd 441.2392, obsd 442.2 (M+H).
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH:7]([CH3:9])C)[CH:4]([CH3:6])C.N1CCCC1.BrC[C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=C[C:18]=1[F:26].CCOC(C)=O>C1COCC1>[F:26][C:18]1[CH:17]=[CH:22][C:21]([N+:23]([O-:25])=[O:24])=[CH:20][C:9]=1[CH2:7][N:3]1[CH2:2][CH2:1][CH2:6][CH2:4]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1ccc(F)c(CBr)c1
Solvent: C1CCNC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(F)c(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.9 %

Procedure:
A −20° C. mixture of DIEA (552 mg, 4.27 mmol) and pyrrolidine (152 mg, 2.137 mmol) in THF (5 mL) was treated drop-wise with a solution of 2-(bromomethyl)-1-fluoro-4-nitrobenzene (500 mg, 2.137 mmol) in THF (5 mL), allowed to warm to RT and stirred for 6 h. The mixture was treated with EtOAc, washed with water, then brine, dried over Na2SO4 and concentrated to dryness to afford 1-(2-fluoro-5-nitrobenzyl)pyrrolidine (450 mg, 94% yield). MS (ESI) m/z: 225.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][CH2:15][CH2:16][CH2:17][OH:18])([O-])=O.[H][H]>[Ni].CO>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][CH2:15][CH2:16][CH2:17][OH:18]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCCO
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Nc1cc(C(F)(F)F)ccc1NCCCO
Yield: 100 %

Procedure:
A mixture of 141 parts of 3-{[2-nitro-4-(trifluoromethyl)phenyl]amino}-1-propanol and 1200 parts of methanol is hydrogenated at normal pressure and at room temperature with 15 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from 2,2'-oxybispropane, yielding 110 parts (100%) of 3-{[2-amino-4-(trifluoromethyl)phenyl]amino}-1-propanol.
Reaction SMILES: NC1C=C(OC)C=CC=1O.[C:11]([O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)(=[O:13])[CH3:12].COC1C=CC(O)=C([N+]([O-])=O)C=1.C(OC1C=CC(NC(=O)CCl)=CC=1)(=O)C>>[C:11]([O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)Oc1ccc(NC(=O)CCl)cc1
Agent: COc1ccc(O)c(N)c1
Agent: COc1ccc(O)c([N+](=O)[O-])c1
Product: CC(=O)Oc1ccc(N)cc1

Procedure:
Compound 55 was prepared in the manner of compound 12 substituting 4-nitrophenyl acetate for compound 11 in part C-1 of Example 1. Synthesis of 4-(2-chloroacetylamino)phenyl acetate (56):
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:22][CH:6]2[C:7](=[O:21])[N:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)[CH2:9][CH:5]2[CH2:4]1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31].CCN(CC)CC>ClCCl>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH:2][CH:3]1[CH2:22][C@@H:6]2[C:7](=[O:21])[N:8]([C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=3)[CH2:9][C@@H:5]2[CH2:4]1)(=[O:32])=[O:31]
Reactant: NC1CC2CN(c3ccc(OC(F)(F)F)cc3)C(=O)C2C1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1[C@H]2CC(NS(=O)(=O)c3ccccc3Cl)C[C@H]2CN1c1ccc(OC(F)(F)F)cc1
Reaction time: 8 h
Yield: 35.1 %

Procedure:
5-Amino-2-(4-trifluoromethoxy-phenyl)-hexahydro-cyclopenta[c]pyrrol-1-one, hydrochloride (60 mg, 0.18 mmol), 2-chlorobenzene-1-sulfonyl chloride (76 mg, 0.36 mmol) and Et3N (82 mg, 0.81 mmol) were added to dichloromethane (2 mL), the mixture was stirred for overnight. The solvent was removed, and the crude product was purified by prep-TLC (petroleum ether/ethyl acetate=1:1) to yield the title compound (30 mg, 33%). 1H NMR (300 MHz, CDCl3): δ 8.14-8.11 (m, 1H), 7.68-7.49 (m, 5H), 7.26-7.22 (m, 2H), 5.04 (d, 1H, J=6.6 Hz), 4.05 (t, 1H, J=9.0 Hz), 3.68-3.62 (m, 2H), 3.08-3.06 (m, 1H), 2.79-2.76 (m, 1H), 2.26-2.19 (m, 2H), 1.95-1.93 (m, 1H), 1.73-1.65 (m, 1H); LC-MS: 475.0 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][NH2:19]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:19][CH2:18][C:17]3[CH:20]=[CH:21][CH:22]=[C:15]([Br:14])[CH:16]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: NCc1cccc(Br)c1
Reactant: CSc1ncnc2cc(N)ncc12
Product: Nc1cc2ncnc(NCc3cccc(Br)c3)c2cn1
Temperature: 140 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (228 mg, 1.19 mmol) (described in a previous experimental) and 3-bromobenzylamine (0.84 g, 4.52 mmol) is stirred under N2 at 140° C. for 1 h. The resulting product is chromatographed on silica gel (2-10% EtOH/EtOAc) to give 7-amino-4-[(3-bromophenyl)methylamino]pyrido[4,3-d]pyrimidine (203 mg, 52%) as a light brown solid. 1H NMR (DMSO) δ 9.09 (1H, s), 8.86 (1H, t, J=5.8 Hz), 8.26 (1H, s), 7.54 (1H, s), 7.44 (1H, d, J=7.8 Hz,), 7.36 (1H, d, J=7.6 Hz), 7.29 (1H, t, J=7.7 Hz), 6.48 (2H, s), 6.37 (1H, s), 4.73 (2H, d, J=5.8 Hz).
Reaction SMILES: [NH:1]([CH:19]1[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]1.Cl[C:30]1[N:35]=[C:34]([NH:36][C:37]([CH2:40][C:41](C)(C)C)(C)C)[N:33]=[C:32]([NH:45][C:46]([CH2:49][C:50](C)(C)C)(C)C)[N:31]=1.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:25][C:23]1([CH3:26])[CH2:24][CH:19]([N:1]([C:30]2[N:31]=[C:32]([NH:45][CH2:46][CH:49]=[CH2:50])[N:33]=[C:34]([NH:36][CH2:37][CH:40]=[CH2:41])[N:35]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([C:30]2[N:31]=[C:32]([NH:45][CH2:46][CH:49]=[CH2:50])[N:33]=[C:34]([NH:36][CH2:37][CH:40]=[CH2:41])[N:35]=2)[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:17])([CH3:18])[CH2:10]2)[CH2:20][C:21]([CH3:28])([CH3:27])[NH:22]1
Reactant: CC1(C)CC(NCCCCCCNC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: CC(C)(C)CC(C)(C)Nc1nc(Cl)nc(NC(C)(C)CC(C)(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: C=CCNc1nc(NCC=C)nc(N(CCCCCCN(c2nc(NCC=C)nc(NCC=C)n2)C2CC(C)(C)NC(C)(C)C2)C2CC(C)(C)NC(C)(C)C2)n1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
A stirred mixture of 4,4'(hexamethylenediimino)bis(2,2,6,6-tetramethylpiperidine) (6.36 grams; 0.0161 mole), 2-chloro-4,6-bis(t-octylamino)-1,3,5-triazine (9.56 grams; 0.0322 mole), and powdered sodium hydroxide (1.29 grams; 0.0322 mole) in xylene (75 mls) is stirred and heated at reflux while removing water therein by means of a water trap. The reaction mixture is stirred and heated at reflux for 18 hours, cooled to 25° C., and treated with acetonitrile (200 mls). The reaction mixture is filtered to recover a precipitate, and the solid is washed successively with water and acetone, and dried to obtain 10.0 grams of product which melts at 208°-209° C. after recrystallization from xylene.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[SH:7][C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1.Br[CH2:15][CH2:16][CH:17]1[O:21][CH2:20][CH2:19][O:18]1.O>CC(C)=O>[O:18]1[CH2:19][CH2:20][O:21][CH:17]1[CH2:16][CH2:15][S:7][C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: BrCCC1OCCO1
Reactant: Sc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: c1cnc(SCCC2OCCO2)nc1

Procedure:
Potassium carbonate (0.766 g) was added to a stirred solution of 2-mercaptopyrimidine (0.622 g) in acetone (10 cm3) at ambient temperature. 2-(2-Bromoethyl)-1,3-dioxolane (1 g) was added to the resulting mixture and the reaction heated under reflux for 3.5 hours. The reaction mixture was left to cool overnight, then poured into water and extracted with diethyl ether. The organic phase was dried with magnesium sulfate and evaporated under reduced pressure to give a yellow oil. This material was used in step 2 without further purification. M+ =212; 1H NMR (CDCl3): δ2.25 (2H,m); 3.25(2H,t); 3.90 (2H,m); 4.00 (2H,m); 5.05 (1H,t); 6.96 (1H,t); 8.52 (2H,d).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:6]2=[CH:5][CH:4]=1.[Br:16]Br>C(O)(=O)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[Br:16]
Reactant: COc1ccc2c(n1)C(C)(C)C(=O)N2C
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1nc2c(cc1Br)N(C)C(=O)C2(C)C
Temperature: 60 °C
Yield: 567.4 %

Procedure:
To a solution of 0.14 g (0.853 mmol) 5-methoxy-1,3,3-trimethyl-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one dissolved in 2 ml of acetic acid was added 0.136 g (0.0853 mmol) of bromine. The solution was heated to 60° C. for 1 hour. The reaction was cooled to room temperature and quenched with 5 ml of water. The pH was adjusted to 7.5 and the mixture extracted with ethyl acetate. The ethyl acetate extracts were combined, dried (Na2SO4) and evaporated. The residue was chromatographed on silica using chloroform as the elutant. Appropriate fractions were combined and evaporated to yield 138 mg of 5-methoxy-6-bromo-1,3,3-trimethyl-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one. Mass spectrum: m/e=285,287.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([CH2:13][OH:14])=[CH:12][C:5]=2[O:4][CH2:3]1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:14][CH2:13][C:11]2[CH:10]=[CH:9][C:6]3[O:7][CH2:8][C:2]([CH3:15])([CH3:1])[CH2:3][O:4][C:5]=3[CH:12]=2)=[CH:20][CH:19]=1
Reactant: CC1(C)COc2ccc(CO)cc2OC1
Reactant: COc1ccc(O)cc1
Product: COc1ccc(OCc2ccc3c(c2)OCC(C)(C)CO3)cc1

Procedure:
According to the method described in example 23, the title compound is prepared from (3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-methanol (31) and 4-methoxyphenol. MS (ESI) 332.3 (M+NH4)+.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:36][O:37][CH2:38][CH2:39][CH3:40])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:21]([O:23]CC4C=CC([N+]([O-])=O)=CC=4)=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].CO.O>[C].[Pd].O1CCCC1>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:36][O:37][CH2:38][CH2:39][CH3:40])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Yield: 85.7 %

Procedure:
A suspension of 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-n-propoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 2.4 g.), 10% palladium carbon (1.0 g.), methanol (24 ml.), water (3.6 ml.) and tetrahydrofuran (48 ml.) was subjected to catalytic reduction under ordinary pressure at room temperature. After removing insoluble substance by filtration, the filtrate was concentrated in vacuo. Water and ethyl acetate were added to the residue, and adjusted to pH 8 with a saturated aqueous solution of sodium bicarbonate. The insoluble substance was removed by filtration, and the aqueous layer was separated. Ethyl acetate was added to the solution, adjusted to pH 2.0 with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution and extract were combined together, washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solution was concentrated in vacuo, and the residue was triturated with diethyl ether and collected by filtration to give 7-[2-(2-formamidothiazol-4-yl)-2-n-propoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.6 g.).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[N:9]=[CH:10][C:3]=12.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]1([C:2]2[N:7]=[CH:6][N:5]=[C:4]3[N:8]([CH2:11][CH2:12][N:13]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[N:9]=[CH:10][C:3]=23)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Clc1ncnc2c1cnn2CCN1CCCCC1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1ccc(-c2ncnc3c2cnn3CCN2CCCCC2)cc1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
A mixture of 4-chloro-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine (50 mg, 0.19 mmol), phenylboronic acid (73 mg, 0.60 mmol) and anhydrous K2CO3 (82 mg, 0.59 mmol) in toluene (3 mL) was introduced in a microwave vial. It was degassed by argon for 30 minutes followed by the addition of Pd(PPh3)4 (4.0 mg, 0.003 mmol) after which the mixture was degassed for 10 additional minutes. The mixture was stirred at 150° C. for 30 min under microwave irradiation (150 W). After cooling to rt, the mixture was filtered on decalite and the solvent was removed at reduced pressure. The crude was purified by flash chromatography to provide 4-phenyl-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine as a white solid (19.1 mg, 0.06 mmol, 33%).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=1.[CH2:31]([Mg]Br)[CH3:32]>O1CCOCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:31]([C:2]1[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=1)[CH3:32]
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Reactant: CC[Mg]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1COCCO1
Product: CCCn1c(CC)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Temperature: 50 °C
Yield: 9.7 %

Procedure:
To a solution of 2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (0.1 g, 0.239 mmol) in dioxane (5 ml) under argon was added ethyl magnesium bromide (0.05 g, 1.146 mmol, 1M solution) and 1M zinc chloride (0.031 g, 2.39 mmol, 1M). To this solution Pd(PPh3)4 (0.026 g, 0.0239 mmol) was added. The reaction mixture was heated at 50° C. for overnight. The reaction mixture was filtered through celite pad and the solvents were removed under reduced pressure. The residue was purified by column chromatography to obtain 2-Ethyl-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (0.01 g, 10%) as a white solid.
Reaction SMILES: C1([C@H]([N:9]2[CH:13]3[CH2:14][N:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH:12]3[CH2:11][CH2:10]2)C)C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH:9]1[CH2:10][CH2:11][CH:12]2[CH2:16][N:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][CH:13]12
Reactant: CCOC(=O)N1CC2CCN([C@H](C)c3ccccc3)C2C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)N1CC2CCNC2C1
Temperature: 50 °C

Procedure:
5% palladium hydroxide on activated carbon (13.9 g, 50% w/w in water) was added to a pressure reactor. The product of Example A3 (as 506.8 g of a 25.9 wt % solution of ethyl 1-((R)-1-phenylethyl)hexahydropyrrolo[2,3-c]pyrrole-5(1H)-carboxylate (131.3 g) in MeOH was added, followed by a MeOH rinse (37 g). The mixture was heated to 50° C. under an atmosphere of hydrogen (40 psi) for 4 hours. The mixture was filtered through HYFLO Filter Aid (HYFLO is a registered trademark of Celite Products Company of Los Angeles, Calif.) and rinsed with 200 mL of MeOH to provide a solution containing 78.9 g of the title compound.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].F[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].Cl>CN(C=O)C.O>[Cl:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:19]([O-:21])=[O:20])[C:12]=1/[C:2](=[C:3](\[OH:4])/[CH3:5])/[C:1]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(C)=O
Reactant: O=[N+]([O-])c1cccc(Cl)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)/C(=C(\C)O)c1c(Cl)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51 %

Procedure:
Methyl acetoacetate (59.82 mmol, 2.1 equiv.) was added dropwise at 0° C. to a suspension of NaH (65.52 mmol, 2.3 equiv.) in DMF (40 ml). Then the mixture was stirred for 10 min and subsequently heated to 25° C. 2-Fluoro-3-chloronitrobenzene (28.49 mmol, 1.0 equiv.) was cooled with an ice bath in a reaction flask, and the NaH suspension was added. Then stirring was carried out for 16 h at 25° C. 2 M HCl (5 ml) and water (10 ml) were then added, and extraction with diethyl ether (3×20 ml) was carried out. The combined organic phases were washed with water (10 ml) and sat. NaCl solution (20 ml), dried over Na2SO4 and reduced under reduced pressure. The residue was purified by column chromatography (5% ethyl acetate in hexane). Yield: 51%
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[CH3:16][C:17]1[N:18]=[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:20][CH:21]=1>>[OH:14][CH:3]1[CH:4]([N:20]2[CH:21]=[C:17]([CH3:16])[N:18]=[C:19]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=2)[O:11][C:2]1([CH3:15])[CH3:1]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: Cc1c[nH]c(-c2ccccc2)n1
Product: Cc1cn(C2c3cc(C#N)ccc3OC(C)(C)C2O)c(-c2ccccc2)n1

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 4-methyl-2-phenyl-1H-imidazole as starting materials, the title compound was prepared as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:23][CH:22]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][N:31]4[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]4)=[CH:23][CH:22]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1cccc([C@@H]2COc3cc(OC)ccc3[C@@H]2c2ccc(OCCCN3CCCCC3)cc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1cccc([C@@H]2COc3cc(O)ccc3[C@@H]2c2ccc(OCCCN3CCCCC3)cc2)c1

Procedure:
In an manner analogous to that described in step 5 for Example 10, (±)-cis-7-methoxy-3-(3-methoxyphenyl)-4-(4-(3-piperidinopropoxy)phenyl)chromane (0.49 g, 1.0 mmol) was de-methylated by heating with pyridine hydrochloride to give the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[O:5][C:4](=O)[CH:3]=1.C([O-])(=O)C.[NH4+:17]>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[NH:17][C:4](=[O:5])[CH:3]=1
Reactant: [NH4+]
Reactant: Cc1cc(C(F)(F)F)oc(=O)c1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1cc(C(F)(F)F)[nH]c(=O)c1
Temperature: 120 °C

Procedure:
To a solution of crude 4-methyl-6-(trifluoromethyl)-2H-pyran-2-one (28.8 g, 162 mmol) in acetic acid (330 mL) was added ammonium acetate (25.0 g, 324 mmol). The reaction solution was heated at 120° C. over weekend. The solvent was removed in vacuo. The residue was diluted with ethyl acetate and washed with saturated NaHCO3 and brine, dried over Na2SC4, filtered and concentrated. The crude was purified with pad silica gel. The solvent was removed. The solid was washed with 10:1 hexanes/ethyl acetate to give the desired product as white solid. LCMS (M+H)+: 178.0.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.C([Li])(CC)C.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[N:4][CH:3]=2)([OH:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1cncc2ccccc12
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cncc3ccccc23)CC1
Reaction time: 1.5 h
Yield: 39 %

Procedure:
A solution of 6.46 gm (31.1 mMol) 4-bromoisoquinoline in 80 mL tetrahydrofuran was cooled to −100° C. under a nitrogen atmosphere. To this solution was added dropwise 28.7 mL (37.3 mmol) sec-butyllithium (1.3 M in hexanes) and the reaction mixture was allowed to stir for 1.5 hours. To the reaction mixture was then added dropwise a solution of 1-tert-butoxycarbonyl-4-piperidone in 20 mL tetrahydrofuran dropwise. The reaction mixture was then stirred for 18 hours at room temperature. The reaction mixture was then partitioned between ethyl acetate and 2N sodium hydroxide. The phases were separated and the aqueous phase extracted well with ethyl acetate. The organic phases were combined, washed saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 9:1 dichloromethane:methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 3.95 gm (39%) 1-tert-butoxycarbonyl-4-(isoquin-olin-4-yl)-4-hydroxypiperidine as a yellow solid.
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: BrCCOC1CCCCO1
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
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.