Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N+:12]=[N-:13].[CH2:14]([OH:17])[C:15]#[CH:16]>CCOCC>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:11])[N:12]3[N:13]=[C:15]([CH2:14][OH:17])[CH:16]=[C:5]3[C:4]=2[CH:3]=1
Reactant: C#CCO
Reactant: [N-]=[N+]=C1C(=O)Nc2ccc(F)cc21
Solvent: CCOCC
Product: O=c1[nH]c2ccc(F)cc2c2cc(CO)nn12
Reaction time: 0.25 h

Procedure:
2.0 g (0.0113 mole) of 5-fluoro-3-diazooxindole (part B) and 13.1 g (0.226 mole of 20 equivalents) of 97% propargyl alcohol are refluxed under argon for 4 hours. The reaction mixture is cooled, diluted with ether (200 ml) and stirred for 15 minutes. The beige-colored precipitates are filtered off and dried in vacuo overnight. Yield: 2.3 g, mp 295°-297°, 87.5% crude yield. The crude product is taken up in absolute ethanol (500 ml), treated with activated carbon, filtered through a Celite pad; the pad is washed with 50 ml of hot ethanol. The clear filtrate is concentrated down to a volume of 100 ml and cooled. The white precipitates are filtered off and dried in vacuo at 60° to yield the product (title compound) 1.16 g, mp 303°-304°.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5](S(C(F)(F)F)(=O)=O)[CH:4]=1)#[N:2].[Cl-].[Li+].C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)CCC.[F-].[K+]>O1CCOCC1.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(OCC)(=O)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:4]=1)#[N:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: N#Cc1ccc(C=O)c(S(=O)(=O)C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1ccc(C=O)c(-c2ccccc2)c1

Procedure:
Tetrakis(triphenylphosphine)palladium [0] (40 mg) was added to a stirred mixture of 4-cyano-2-trifluoromethylsulphonylbenzaldehyde (0.45 g, 1.6 mmol), lithium chloride (0.2 g, 4.8 mmol) and tri-n-butylphenylstannane (0.55 ml, 1.7 mmol) in dried dioxan (10 ml) under nitrogen atmosphere. The resulting suspension was heated under reflux for 24 hours. The dark mixture was cooled, and aqueous potassium fluoride solution (30 ml) and ethyl acetate (30 ml) were added. After vigorous stirring, the black precipitate was filtered and the filtrate layers separated. The ethyl acetate solution was washed with brine (30 ml), dried, filtered and evaporated to a yellow semi-solid (0.72 g). Chromatography on flash silica eluting with chloroform gave 4-cyano-2-phenylbenzaldehyde as a white solid, m.p. 75° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O1CCOCC1.Cl[C:14]1[C:19]([N:20]2[N:24]=[CH:23][CH:22]=[N:21]2)=[CH:18][C:17]([N+:25]([O-:27])=[O:26])=[CH:16][N:15]=1>O>[N+:25]([C:17]1[CH:18]=[C:19]([N:20]2[N:24]=[CH:23][CH:22]=[N:21]2)[C:14]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[N:15][CH:16]=1)([O-:27])=[O:26]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cnc(Cl)c(-n2nccn2)c1
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1cnc(N2CCOCC2)c(-n2nccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Morpholine (0.5 ml) was added to a 1,4-dioxane solution (1 ml) containing 2-chloro-5-nitro-3-(2H-1,2,3-triazol-2-yl)pyridine (30 mg), followed by stirring at room temperature for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and a yellow solid of 5-nitro-2-morpholino-3-(2H-1,2,3-triazol-2-yl)pyridine (33 mg) was thus obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:19]=[CH:18][C:11]([O:12][CH2:13][C:14]([O:16]C)=[O:15])=[CH:10][CH:9]=1)[CH2:5][CH2:6][Cl:7]>Cl>[Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:19]=[CH:18][C:11]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1)[CH2:5][CH2:6][Cl:7]
Reactant: COC(=O)COc1ccc(N(CCCl)CCCl)cc1
Agent: Cl
Product: O=C(O)COc1ccc(N(CCCl)CCCl)cc1
Temperature: 50 °C
Yield: 64.8 %

Procedure:
A suspension of 1.99 g (6.50 mmol) of methyl 4-[N,N-bis(2-chloroethyl)amino]phenoxyacetate in 60 ml of concentrated hydrochloric acid was heated at 50° C. for 30 minutes. The suspension was washed with methylene chloride, neutralized with sodium hydrogencarbonate, and then extracted with methylene chloride. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated, whereby 1.23 g of the title compound were obtained as colorless crystals (yield: 65%).
Reaction SMILES: [OH:1][CH:2]1[C@@H:6]2[CH2:7][C:8](=[O:9])[N:5]2[C:4]([C:10]([O:12][CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:11])=[C:3]1[CH3:21].C(Cl)(Cl)Cl.C(OCC)(=O)C>C(O)(=O)C.O1CCCC1.[Zn]>[OH:1][CH:2]1[C@@H:6]2[CH2:7][C:8](=[O:9])[N:5]2[CH:4]([C:10]([O:12][CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:18])([CH3:17])[CH3:19])=[O:11])[CH:3]1[CH3:21]
Reactant: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C[C@H]2C1O
Agent: [Zn]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1C(O)[C@@H]2CC(=O)N2C1C(=O)OCOC(=O)C(C)(C)C

Procedure:
By the method of Example 2, pivaloyloxymethyl 1-hydroxy-2-methylcarbapen-2-em-3-carboxylate is reduced with specially activated zinc powder in acetic acid-tetrahydrofuran, the reaction monitored by tlc (4:1 chloroform:ethyl acetate) and the product isolated to yield pivaloyloxymethyl 1-hydroxy-2-methylcarbapenam-3-carboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].Cl.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:23][CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=3[C:16]3[S:15][CH:19]=[CH:18][CH:17]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: NCc1ccccc1-c1cccs1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]nc(Cl)c2cc(NCc3ccccc3-c3cccs3)ccc12

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.58 mmol), 2-thiophen-2-yl-benzylamine hydrochloride (145 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (108 mg, 0.17 mmol) and NaOt-Bu (200 mg, 2.1 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2-thiophen-2-yl-benzylamino)-2H-phthalazin-1-one: 65 mg (30.5%): m/z (M+H)=368. 1H-NMR (DMSO-d6) δ: 12.34 (s, 1H), 7.91 (d, 1H), 7.64 (m, 2H), 7.47 (m, 2H), 7.37 (m, 2H), 7.25 (dd, 1H), 7.16 (m, 1H), 7.11 (m, 1H), 6.64 (s, 1H), 4.43 (d, 2H).
Reaction SMILES: [CH2:1]([C:3]1[S:21][C:6]2[N:7]=[CH:8][N:9]=[C:10]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[C:5]=2[CH:4]=1)[CH3:2].[Br:22]Br>CC(O)=O>[Br:22][C:4]1[C:5]2[C:10]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:19])[CH3:20])[CH2:14][CH2:13]3)=[N:9][CH:8]=[N:7][C:6]=2[S:21][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cc2c(NC3CCC(N(C)C)CC3)ncnc2s1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCc1sc2ncnc(NC3CCC(N(C)C)CC3)c2c1Br
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of 4-N-[6-ethylthieno[2,3-d]pyrimidin-4-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine (4.0 g, 13.14 mmol, 1.00 equiv) in AcOH (40 mL), dibromane (4.2 g, 26.28 mmol, 2.00 equiv). The resulting solution was stirred overnight at 70° C. The resulting mixture was concentrated under vacuum. The residue was diluted with 50 mL of water. The pH value of the solution was adjusted to 8.0 with saturated sodium carbonate. The resulting solution was extracted with 4×50 mL of chloroform and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 3.0 g (60%) of 4-N-[5-bromo-6-ethylthieno[2,3-d]pyrimidin-4-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine as a yellow solid. MS (ES, m/z): 383 [M+H]+ 1H-NMR (400 MHz, DMSO-d6, ppm): δ 8.36 (1H, s), 6.75-6.77 (1H, d), 4.01-4.07 (1H, m), 2.81-2.88 (2H, q), 2.27 (7H, s), 2.09-2.11 (2H, d), 1.86 (2H, d), 1.32-1.40 (4H, q),1.21-1.26 (3H, t).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](Cl)=[O:9].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=1)=[O:9]
Reactant: O=C(Cl)CCCCCCBr
Reactant: Clc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(CCCCCCBr)c1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
7-Bromoheptanoyl chloride (3.2 g) was added to chlorobenzene (30 ml), and aluminum chloride (1.6 g) was added under ice-cooling, which was followed by stirring for 3 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 2.2 g of 7-bromo-1-(4-chlorophenyl)-1-heptanone.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][CH2:5][CH2:6][CH2:7][Si:8]([CH3:19])([O:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[O:9][Si:10]([CH3:13])([CH3:12])[CH3:11].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)(C)C>[CH2:21]([NH:28][CH2:20][CH:2]([OH:1])[CH2:3][O:4][CH2:5][CH2:6][CH2:7][Si:8]([CH3:19])([O:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[O:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[Si](C)(C)O[Si](C)(CCCOCC1CO1)O[Si](C)(C)C
Reactant: NCc1ccccc1
Solvent: CC(C)O
Product: C[Si](C)(C)O[Si](C)(CCCOCC(O)CNCc1ccccc1)O[Si](C)(C)C
Temperature: 80 °C

Procedure:
A 500-ml, three-necked, round-bottomed flask equipped with a stirrer, addition funnel, and condenser was charged with 100 g (0.30 mole) of the epoxy trisiloxane (Compound I) of Example 1 dissolved in 200 ml of isopropanol. The addition funnel was charged with a solution of 42.8 g (0.4 mole) of benzylamine (Aldrich) in 100 ml of isopropanol; the solution was added drop-wise to the flask contents at room temperature. The resulting reaction solution was heated at 80° C. for eight hours, after which time the solvent was removed under reduced pressure using a rotary evaporator. The residue, an oil, was passed through a short silica column using 10% ethyl acetate in hexane as eluent. The yield of Compound V, a colorless oil, was 127.8 g (97%). The following elemental analysis was obtained:
Reaction SMILES: [C:1]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][C:10]([OH:12])=O)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].CC(C)=O.C(OC(=O)C)(=O)C.C([O-])(=O)C.[Mg+2].C([O-])(=O)C>C(O)(=O)C>[C:1]([NH:7][C@@H:8]1[C:13](=[O:14])[O:15][C:10](=[O:12])[CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)O
Agent: CC(=O)[O-]
Agent: [Mg+2]
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CC(=O)CC(=O)N[C@H]1CC(=O)OC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-acetoacetyl-L-aspartic acid, 21.7 parts, was slurried with 20 parts by volume of dry acetone and 10.7 parts acetic anhydride. Anhydrous magnesium acetate, 0.20 parts, was dissolved in 2.0 volumes glacial acetic acid and the solution was added to the stirred slurry of N-acetoacetyl-L-aspartic acid. The mixture was stirred for 3 hours at room temperature and the solid was then collected on a filter under nitrogen. The solid was rinsed with dry ethyl acetate and then dried at 0.1 mm to afford 17.3 parts of N-acetoacetyl-L-aspartic anhydride.
Reaction SMILES: [NH:1]1[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH3:16][O:17][C:18]([NH:20][C@H:21]([C:25](Cl)=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19]>ClCCl.[Ag]C#N>[CH3:16][O:17][C:18]([NH:20][C@H:21]([C:25]([N:1]1[C:5]2([CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)[CH2:4][CH2:3][CH:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:26])[CH:22]([CH3:23])[CH3:24])=[O:19]
Reactant: CCOC(=O)C1CCC2(CCOCC2)N1
Reactant: COC(=O)N[C@H](C(=O)Cl)C(C)C
Agent: N#C[Ag]
Solvent: ClCCl
Product: CCOC(=O)C1CCC2(CCOCC2)N1C(=O)[C@@H](NC(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.7 %

Procedure:
To a solution of ethyl 8-oxa-1-azaspiro[4.5]decane-2-carboxylate (166) (125 mg, 0.59 mmol) in anhydrous dichloromethane (2 mL) was added silver cyanide (98 mg, 0.73 mmol) followed by N-[(methyloxy)carbonyl]-L-valyl chloride (142 mg, 0.73 mmol) as a solution in anhydrous dichloromethane (3.5 mL) and the solution stirred at room temperature for 18 h under nitrogen. The reaction is filtered and treated with methanol and stirred for 5 minutes. The reaction is concentrated in vacuo and the residue purified by silica gel chromatography eluting with 30-100% hexanes/EtOAc to afford the title compound as a white solid (43 mg, 20% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1>CS(C)=O.O>[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH:30][C:5]2[CH:4]=[C:3]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[N:10]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:26][CH2:25]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Fc1cc(-c2cccc(NCC3CCOCC3)n2)c(Cl)cn1
Solvent: O
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(-c3cccc(NCC4CCOCC4)n3)c(Cl)cn2)CC1
Temperature: 110 °C
Reaction time: 19 h

Procedure:
To a solution of 5′-chloro-2′-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine (500 mg, 1.55 mmol) in DMSO (7 mL) was added trans-1,4-diaminocyclohexane (710 mg, 6.22 mmol). The mixture was stirred at 110° C. for 19 hr. The cooled reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated to give 600 mg of N2′-(trans-4-aminocyclohexyl)-5′-chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine. LCMS (m/z): 416.1 (MH+), retention time=0.48 min.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][N:30]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c1
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CN(C(=O)COC)C[C@H]4O)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f51) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14]Br)[CH3:11].[OH-].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:14][CH:13]([O:16][CH2:17][CH3:18])[O:12][CH2:10][CH3:11])=[CH:4][C:3]=1[CH3:9]
Reactant: CCOC(CBr)OCC
Reactant: Cc1cc(O)ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOC(COc1ccc(Cl)c(C)c1)OCC

Procedure:
A mixture of 4-chloro-3-methylphenol (47 g), bromoacetaldehyde diethyl acetal (45 ml) and potassium hydroxide (33.6 g) in dimethyl sulphoxide (250 ml) was heated at 120° for 2 h. The cooled mixture was partitioned between water (750 ml) and toluene (3×500 ml) and the combined organic extracts washed with brine/water 1:1 (3×300 ml) and dried (Na2SO4). The solvent was evaporated to give the title compound as a pale yellow oil (67.9 g)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8](S)[O:9][C:5]=2[CH:4]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:14]>ClC1C=CC=CC=1>[Cl:14][C:8]1[O:9][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=2[N:7]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1ccc2nc(S)oc2c1
Solvent: Clc1ccccc1
Product: COc1ccc2nc(Cl)oc2c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A 100 mg portion of 6-methoxy-2-mercaptobenzoxazole and 172 mg of phosphorus pentachloride were dissolved in 35 ml of chlorobenzene to carry out 8 hours of heating under reflux. The reaction solution was poured into 300 ml of ice water and extracted three times with 100 ml of dichloromethane. The resulting organic layers were combined, dehydrated with sodium sulfate, concentrated under a reduced pressure and then purified by a silica gel column chromatography (n-hexane:chloroform=1:1), to obtain 79 mg of 2-chloro-6-methoxybenzoxazole.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:14][C:6]=1[CH:7]=[CH:8][C:9](OCC)=[O:10])([O-])=O.C(O)C.[OH-].[Na+]>[Ni].O>[N:18]1([C:15]2[CH:14]=[C:6]3[C:5](=[CH:17][CH:16]=2)[NH:2][C:9](=[O:10])[CH2:8][CH2:7]3)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)C=Cc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Agent: [Ni]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1CCc2cc(N3CCNCC3)ccc2N1
Temperature: 80 °C
Reaction time: 4 h
Yield: 54.9 %

Procedure:
Ethyl 2-nitro-5-piperazinylcinnamate hydrochloride (3.5 g) was dissolved in a mixed solvent consisting of 150 ml of ethanol and 45 ml of water and the solution was adjusted to pH of about 7 with an aqueous sodium hydroxide. The solution was added 2 g of Raney nickel catalyst and placed in a glass autoclave followed by stirring at 80° C. under hydrogen gas pressure of 5 kg/cm2 for 4 hours. After removing hydrogen gas the reaction mixture was taken out and the catalyst was removed. The solution was concentrated to dryness and methanol was added to the residue to precipitate crystals, which then were collected by filtration and recrystallized from methanol to give 1.3 g of 6-(1-piperazinyl)-3,4-dihydrocarbostyril, m.p. 224°-231.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][C:3]=1[N+:13]([O-])=O.Cl>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][C:3]=1[NH2:13]
Reactant: CCCCSc1ccc(N)c([N+](=O)[O-])c1
Agent: Cl
Product: CCCCSc1ccc(N)c(N)c1
Reaction time: 0.17 h

Procedure:
4 G. of 1-amino-2-nitro-4-n-butylthiobenzene is treated in 12 ml. concentrated hydrochloric acid with a solution of 24 g. stannous chloride in 12 ml. concentrated hydrochloric acid. The mixture is kept on the steam bath for 10 minutes, then cooled and the gummy product is washed with 12 ml. 6N hydrochloric acid. The salt is dissolved in water, treated with sodium hydroxide, and the mixture extracted with chloroform. Evaporation of the extracts followed by crystallation of the crude product from benzene yields 1,2-diamino-4-n-butylthiobenzene.
Reaction SMILES: [Br-:1].O([CH2:9][CH2:10][P+:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C1C=CC=CC=1.[CH3:30][NH2:31]>C(O)C>[Br-:1].[CH3:30][NH:31][CH2:9][CH2:10][P+:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN
Reactant: c1ccc(OCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCO
Product: CNCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The required β-methylaminoethyltriphenylphosphonium bromide was prepared by heating a mixture of β-phenoxyethyltriphenyl phosphonium-bromide (46.2 g.) dissolved in ethanol (80 ml.) and 33% ethanolic methylamine (130 ml.) in an autoclave at 100° C for 3 hours. After cooling, the produce was precipitated by addition of dry ether (2 l.) filtered, washed with ether and dried, and had a melting point of 226° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:19](=O)[CH2:20][CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][OH:24].Cl.N1C=CC=CC=1>CCO>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:19](=[N:23][OH:24])[CH2:20][CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: CCC(=O)c1ccc(-c2ccccc2)c(-c2ccccc2)n1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCC(=NO)c1ccc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure P, 1-(5,6-diphenyl-pyridin-2-yl)-propan-1-one (Compound 76, 90 mg, 0.31 mmol), NH2OH—HCl (87 mg, 1.25 mmol) and pyridine (272 mg, 0.27 mmol) in EtOH (2 ml) were reacted to give title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].O=[C:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1.O.CC1C=CC(S(O)(=O)=O)=CC=1.ClC(Cl)C.Cl>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]2[C:15]3([O:13][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[C:3]1=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3
Reactant: Cn1cccc1-c1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: O
Product: Cn1ccc2c1-c1ccccc1OC21CCNCC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(1-methylpyrrol-2-yl)phenol (1.20 g, 6.90 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (1.38 g, 6.93 mmol), 4-methylbenzenesulfonic acid hydrate (264 mg, 1.39 mmol), and dichloroethane (24 mL) was heated at 80° C. for 2 h. To the mixture was added HCl (1.7 mL of 4.0 M, 6.9 mmol) and the mixture was allowed to stir at 50° C. for 1 h. The mixture was cooled to 25° C. and was concentrated in vacuo. The residue was taken up in dichloromethane and was washed with saturated aqueous NaHCO3. The organic layer was dried over sodium sulfate and concentrated. Column chromatography (0-100% ethyl acetate/hexanes) on the residue gave 1-methyl-1H-spiro[chromeno[4,3-b]pyrrole-4,4′-piperidine]. ESI-MS m/z calc. 254.3. found 255.2 (M+1)+; Retention time: 1.51 minutes (3 min run).