Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:6][CH:5]=1.[CH:21](=O)[C:22]1[O:26][CH:25]=[CH:24][CH:23]=1.C([BH3-])#N.[Na+].Cl>CO.C(O)(=O)C>[O:26]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:21][NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([S:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:8][CH:9]=1
Reactant: O=Cc1ccco1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1ccc(CCN)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)C(C)(C)Sc1ccc(CCNCc2ccco2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
4.0 g of 1,1-dimethylethyl 2-[[4-(2-aminoethyl)phenyl]thio]-2-methyl-propanoate [(P. J. Brown et al., J. Med. Chem. 42, 3785-88 (1999)] are dissolved in 100 ml of methanol and treated with 2.6 g of furfural. 9.3 ml of glacial acetic acid are added and the mixture is boiled briefly (10 min). The mixture is then cooled to 0° C., and 4.25 g of sodium cyanoborohydride are added a little at a time. The mixture is then stirred at room temperature overnight. 1 N HCl is added until the mixture is acidic, and the mixture is stirred for 30 min. The mixture is concentrated slightly and made basic using sat. NaHCO3 solution. The mixture is then extracted twice with ethyl acetate and the extracts are washed (sat. NaCl solution) and dried and concentrated. Chromatographic purification (dichloromethane/methanol 15+1) gives 2.4 g of the title compound as a colourless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]=[C:5]=[O:6].[CH2:7]([NH2:10])[C:8]#[CH:9]>C1COCC1>[CH2:7]([N:10]1[CH2:2][CH2:3][NH:4][C:5]1=[O:6])[C:8]#[CH:9]
Reactant: O=C=NCCCl
Reactant: C#CCN
Solvent: C1CCOC1
Product: C#CCN1CCNC1=O
Temperature: 25 °C
Yield: 81.3 %

Procedure:
Chloroetyl isocyanate (12.2 g, 0.11 mol) was added at 0° C. to a stirred solution of propargylamine (6.6 g, 0.12 mol) in THF (200 mL). The solution was allowed to warm to room temperature and sodium hydride (5.5 g of 50% in oil, washed with ether to remove the oil) was added. The reaction was quenched with acetic acid (6.0 mL), the THF was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water. The ethyl acetate was evaporated and the residual solid was crystallized from ethyl acetate:Skellysolve B to give 11.1 g of 1-(2-propynyl)-2-imidazolidinone, m.p. 110°-115° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[CH2:30]([NH:37][C@@H:38]([CH3:48])[CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([N:37]([C@@H:38]([CH3:48])[CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:17]([C:8]2[C:7]3[CH:26]=[C:27]([O:28][CH3:29])[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=3[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][N:13]([CH3:16])[CH2:14]3)[N:9]=2)=[CH:18][CH:19]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C[C@@H](COCc1ccccc1)NCc1ccccc1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(Cc3ccccc3)[C@@H](C)COCc3ccccc3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)benzoic acid and N-benzyl-N-((S)-2-benzyloxy-1-methyl-ethyl)-amine as described for example 1.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][O:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[CH3:11][N:12]([CH3:14])[CH:13]=[CH:2][C:1]([C:4]1[CH:8]=[CH:7][O:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccoc1
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1ccoc1

Procedure:
As in Example 1, Part A, 0.01 mol of 3-acetylfuran can be reacted with 0.02 mol of N,N-dimethylformamide dimethylacetal to produce 3-dimethylamino-1-(3-furyl)-2-propen-1-one.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[F:19])[CH:8]=[C:9](I)[CH:10]=1)=[O:4].[CH:20]([N:23]1[C:27](B(O)O)=[CH:26][CH:25]=[N:24]1)([CH3:22])[CH3:21].CC([O-])=O.[K+].COCCOC>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.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[F:19])[CH:8]=[C:9]([C:27]2[N:23]([CH:20]([CH3:22])[CH3:21])[N:24]=[CH:25][CH:26]=2)[CH:10]=1)=[O:4]
Reactant: CC(C)n1nccc1B(O)O
Reactant: COC(=O)c1cc(I)cc(-c2ccc(C)cc2F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2ccc(C)cc2F)cc(-c2ccnn2C(C)C)c1
Temperature: 130 °C
Yield: 52.5 %

Procedure:
To a microwave vessel was added 2′-fluoro-5-iodo-4′-methyl-biphenyl-3-carboxylic acid methyl ester (1.91 g, 5.4 mmol), 2-isopropyl-2H-pyrazole-3-boronic acid (1.08 g, 7.02 mmol), KOAc (1.59 g, 16.2 mmol), Pd(PPh3)4 (0.187 g, 0.16 mmol), dimethylglycol (15 mL) and water (3 mL). The mixture was flushed with N2 before submitting to microwave heating at 130° C. for 1 hour. After cooling down to room temperature, the reaction mixture was extracted with EtOAc and the combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column to afford 2′-fluoro-5-(2-isopropyl-2H-pyrazol-3-yl)-4′-methyl-biphenyl-3-carboxylic acid methyl ester as a viscous oil (1.0 g, 55.2%).
Reaction SMILES: COC1C=CC(CCC2C=CC(OC)=CC=2)=C(C=1)OC1C=CC(O)=CC=1.Cl.ClCCN1CCCCC1.C[O:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:61][CH2:62][C:63]2[CH:68]=[CH:67][C:66]([O:69]C)=[CH:65][CH:64]=2)=[C:43]([CH:60]=1)[O:44][C:45]1[CH:59]=[CH:58][C:48]([O:49][CH2:50][CH2:51][N:52]2[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]2)=[CH:47][CH:46]=1.Cl.N1C=CC=CC=1>O1CCCC1>[OH:69][C:66]1[CH:67]=[CH:68][C:63]([CH2:62][CH2:61][C:42]2[CH:41]=[CH:40][C:39]([OH:38])=[CH:60][C:43]=2[O:44][C:45]2[CH:59]=[CH:58][C:48]([O:49][CH2:50][CH2:51][N:52]3[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]3)=[CH:47][CH:46]=2)=[CH:64][CH:65]=1
Reactant: COc1ccc(CCc2ccc(OC)cc2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Agent: COc1ccc(CCc2ccc(OC)cc2Oc2ccc(O)cc2)cc1
Agent: Cl
Agent: ClCCN1CCCCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Oc1ccc(CCc2ccc(O)cc2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 170 °C
Reaction time: 0.17 h
Yield: 34.4 %

Procedure:
Synthesized from 4-{5-methoxy-2-[2-(4-methoxyphenyl)ethyl]phenoxy}phenol and 1-(2-chloroethyl)piperidine hydrochloride according to an analogous synthetic method to Preparation Example 40, to 1-{2-{4-{5-methoxy-2-[2-(4-methoxyphenyl)ethyl]phenoxy}phenoxy}ethyl}piperidine (344 mg) was added pyridine hydrochloride (1.2 g), and the solution was stirred for 3 hours and 10 minutes at 170° C. To the reaction solution were added tetrahydrofuran and an aqueous solution of 1N sodium hydroxide, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to provide the title compound (111 mg).
Reaction SMILES: [ClH:1].[CH:2]1[C:15]2[CH:14]=[C:13]([CH2:16][NH:17][C@@:18]([CH3:24])([C@@H:21]([OH:23])C)[CH2:19][OH:20])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C1C2C=[C:36]([CH:39]=[O:40])C3C(=CC=CC=3)C=2C=CC=1.Cl.NC(COCC)(CO)CO>>[ClH:1].[CH2:39]([O:40][CH2:24][C:18]([NH:17][CH2:16][C:13]1[C:12]2[C:7]([C:6]3[CH:5]=[CH:4][CH:3]=[CH:2][C:15]=3[CH:14]=1)=[CH:8][CH:9]=[CH:10][CH:11]=2)([CH2:21][OH:23])[CH2:19][OH:20])[CH3:36]
Reactant: O=Cc1cc2ccccc2c2ccccc12
Reactant: C[C@H](O)[C@@](C)(CO)NCc1cc2ccccc2c2ccccc12
Agent: CCOCC(N)(CO)CO
Agent: Cl
Product: CCOCC(CO)(CO)NCc1cc2ccccc2c2ccccc12

Procedure:
Using the reductive amination procedure outlined for 7G, phenanthrene-9-carbaldehyde (Aldrich) and 2-amino-2-ethoxymethyl-1,3-propanediol hydrochloride.1/4H2O (8B) gave 2-ethoxymethyl-2-(((9-phenanthrenyl)methyl)amino)-1,3-propanediol hydrochloride mp 173°-175°, (EtOH/Et2O), (C, H, Cl, N).
Reaction SMILES: [Br-].[CH2:2]([N+:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[CH2:2]([N:9]1[CH2:14][CH2:13][CH:12]=[C:11]([CH3:15])[CH:10]1[CH2:16][NH:17][C:18](=[O:19])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccc[n+](Cc2ccccc2)c1CNC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Product: CC1=CCCN(Cc2ccccc2)C1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of 1-benzyl-2-(((tert-butoxycarbonyl)amino)methyl)-3-methylpyridin-1-ium bromide (1.5 g) in MeOH (100 ml) was added NaBH4 (3 eq) in three portions at 0° C. The solution was then stirred for 3 h at rt and then concentrated in vacuo. The crude residue was taken up in EtOAc and washed with sat aq. NaHCO3, dried (MgSO4), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hex) to give the title compound as a pale yellow oil in 63% yield. MS (ESI) 317 (M+H).
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([NH2:7])=[O:6])#[N:3].[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([CH3:28])[C:18]=1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH2:12][N:13]=[N+:14]=[N-:15].C(O)(=O)C>C(O)C>[NH2:3][C:2]1[N:13]([CH2:12][C:11]2[CH:16]=[C:17]([CH3:28])[C:18]([C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[C:9]([Cl:8])[CH:10]=2)[N:14]=[N:15][C:4]=1[C:5]([NH2:7])=[O:6]
Reactant: Cc1cc(CN=[N+]=[N-])cc(Cl)c1C(=O)c1ccc(Cl)cc1
Reactant: N#CCC(N)=O
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(Cn2nnc(C(N)=O)c2N)cc(Cl)c1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67.3 %

Procedure:
A stirred, 60° C. solution of sodium (88.7 mg, 3.84 mmol) in absolute ethanol (9.6 ml) was treated with 2-cyanoacetamide (323 mg, 3.84 mmol), kept 5 min., and treated with 3-chloro-4-(4-chlorobenzoyl)-5-methylbenzyl azide (1.03 g, 3.20 mmol). The mixture was refluxed 1 hour, cooled to ambient temperature, acidified with glacial acetic acid (487 μl, 511 mg, 7.68 mmol), and evaporated to dryness at 30° C. under vacuum. The residue was chromatographed on a column of silica gel (150 g) eluted in 17 ml fractions with 19:1 (v/v) dichloromethane-methanol. Fractions 22-38 were combined and evaporated to dryness. The residual glass was kept 18 hours at ambient temperature with diethyl ether (25 ml), filtered, washed with diethyl ether, and dried to provide 870 mg (67%) crystalline 5-amino-1-(3-chloro-4-[4-chlorobenzoyl]-5-methylbenzyl)-1,2,3-triazole-4 -carboxamide, m.p. 205°-206° C.
Reaction SMILES: [CH2:1]([N:8]([CH3:22])[C:9]([CH2:11][CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]=[O:21])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([Mg]Cl)[CH3:24].[Cl-].[NH4+]>C1COCC1>[CH2:1]([N:8]([CH3:22])[C:9]([CH2:11][CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]([OH:21])[CH2:23][CH3:24])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[Mg]Cl
Reactant: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)[C@@H]1CCCN1C(=O)CCC(=O)N(C)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of (2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-al (700 mg) in THF (5 ml) was cooled to -25° C. A solution of ethyl magnesium chloride in THF (2M, 1.5 ml) was added dropwise to the solution. The mixture was stirred for 30 mins at the same temperature, and for 30 mins at 0° C. and further 1 hr. at room temperature. After reaction, a saturated aq. solution of ammonium chloride was added to the mixture. The oily layer separated was washed, dried and evaporated. The residue was purified by column chromatography on silica gel (EtOAc-CH3OH) to give the title compound (270 mg) having the following physical data:
Reaction SMILES: [F:1][C@H:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[CH2:7][CH2:6]1.FC(C1C=CC=CC=1F)CO[C@H]1CC[C@H](N)CC1.CS[C:39]1[N:44]=[C:43]([OH:45])[N:42]=[C:41]2[NH:46][N:47]=[CH:48][C:40]=12>CC(O)C.O>[F:1][C@H:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:39]2[N:44]=[C:43]([OH:45])[N:42]=[C:41]3[NH:46][N:47]=[CH:48][C:40]=23)[CH2:7][CH2:6]1
Reactant: CSc1nc(O)nc2[nH]ncc12
Reactant: N[C@H]1CC[C@H](OC[C@H](F)c2ccccc2F)CC1
Agent: N[C@H]1CC[C@H](OCC(F)c2ccccc2F)CC1
Solvent: CC(C)O
Solvent: O
Product: Oc1nc(N[C@H]2CC[C@H](OC[C@H](F)c3ccccc3F)CC2)c2cn[nH]c2n1

Procedure:
From trans-4-[(2R)-2-fluoro-2-(2-fluorophenyl)ethoxy]cyclohexanamine, the resolved product of Example 11, Step 8, and 4-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-6-ol [R. K. Robins, J. Am. Chem. Soc. 79, (1957), 6407-15] in refluxing 2-propanol/water for several days: MS (m+1)=390.4; 1H NMR (400 MHz, CDCl3-CD3OD) 8.2 (s, 1H), 8.0 (s, 1H), 7.5 (m, 1H), 7.4 (dd, 1H), 7.2 (t, 1H), 7.1 (t, 1H), 5.85 (dd, JHF=47 Hz, 1H), 4.2 (m, 1H), 3.75 (m, 2H), 3.4 (m, 1H), 2.7 (m, 1H), 2.1 (m, 2H), 1.4 (m, 2H).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[Li]C(C)(C)C.Cl([O-])(=O)(=O)=O.[CH2:19]1[C:26]2[CH2:25][CH2:24][CH2:23][N+:22]=2[CH2:21][CH2:20]1>CCOCC.CCCCC>[CH3:8][C:5]1[N:6]=[CH:7][C:2]([C:26]23[CH2:25][CH2:24][CH2:23][N:22]2[CH2:21][CH2:20][CH2:19]3)=[CH:3][CH:4]=1
Reactant: Cc1ccc(I)cn1
Reactant: C1CC2=[N+](C1)CCC2
Agent: [Li]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: CCCCC
Product: Cc1ccc(C23CCCN2CCC3)cn1
Temperature: -95 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
5-Iodo-2-methylpyridine (345 mg, 1.39 mmol) was dissolved in Et2O and cooled to -95° C. A solution of 2.5M t-BuLi (1.7M in pentane, 1.8 mL, 3.06 mmol) in pentane was added dropwise. 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (435 mg, 2.1 mmol) was added, and the reaction mixture was allowed to warm to -10° C. with stirring for 2 hours. The cold bath was removed, 2N HCl was added, and the phases were separated. The aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2×). The CH2Cl2 fractions were combined, dried (MgSO4) and concentrated, and the residue was chromatographed (silica gel; CHCl3 /MeOH, 95:5) to afford the title compound as an oil (126 mg, 45%): 1H NMR (CDCl3, 300 MHz) δ1.57-1.71 (m, 2H), 1.77-2.05 (m, 6H), 2.52 (s, 3H), 2.64-2.72 (m, 2H), 3.12-3.19 (m, 2H), 7.05 (d, J=8.1 Hz, 1H), 7.71 (dd, J=8.1, 2.6 Hz, 1H), 8.56 (d, J=2.6 Hz, 1H); MS (CI/NH3) m/z: 203 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([NH2:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O-])([O-])=O.[K+].[K+].ClC(OCC)=O.B>C1COCC1.O>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([NH:21][CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: B
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CNC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 77.9 %

Procedure:
To a solution of (3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylamine (9.2 g, 0.028 mol) in THF (100 ml) was added a solution of K2CO3 (7.91 g, 0.057 mol) in H2O (35 ml). After 10 minutes, ethyl chloroformate (2.86 ml, 0.030 mol) was added and stirring was continued at RT for an additional 4 h. The intermediate carbamate was then extracted with Et2O, dried over Na2SO4 and concentrated under vacuo to give viscous oil. The oil was taken up in THF (100 ml) and a solution of borane in THF (1M) was added (114.5 ml). The reaction mixture was then heated at 65° C. over night, cooled to RT and carefully quenched with conc. HCl (100 ml). The mixture was then heated at 80° C. for 2 h, cooled to RT, concentrated under vacuo, diluted with Et2O (100 ml) and neutralized with an aqueous solution of NaHCO3. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, CH2Cl2/MeOH 9:1) to afford 7.31 g (76%) of the title compound as a colorless oil. ES-MS m/e: 335.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][C:20]3[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:21]=3[N:22]=2)=[CH:14][CH:13]=1>C1COCC1.CCOCC>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[CH:16][CH:17]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(Br)nc4)cc3)sc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 29.4 %

Procedure:
To a solution of 6-bromonicotinic acid (0.16 g, 0.78 mmol) in dry THF (5 ml) was added under an atmosphere of argon 1,1′-carbonyldiimidazole (0.13 g, 0.78 mmol) and the reaction mixture stirred at room temperature for 5 h. To the reaction mixture was added 2-(4-aminophenyl)-6-methoxybenzothiazole (0.2 g, 0.78 mmol) over 2 mins, stirring continued at room temperature for 1 h, then heated under reflux for 18 h. After cooling to room temperature, the reaction mixture was diluted with Et2O (30 ml) and the precipitate was collected by filtration, washed with Et2O (50 ml) and dried under high vacuum to give the title compound (0.101 g, 29%) as an orange solid.
Reaction SMILES: [Mg].[CH2:2]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11][CH3:12])[C:5]=1Br)[CH3:3].[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>C1(C)C=CC=CC=1.BrC(Br)C.O1CCCC1>[CH2:2]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11][CH3:12])[C:5]=1[C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:3]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCc1cc(C)cc(CC)c1Br
Agent: CC(Br)Br
Agent: Cl
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c(CC)cc(C)cc1CC
Temperature: 33 °C
Reaction time: 0.33 h
Yield: 118.4 %

Procedure:
To a 2 L volume four-necked flask, magnesium (cutting chip) (66.2 g), tetrahydrofuran (anhydrous) (494 g), and toluene (549 g) were added under a nitrogen atmosphere at room temperature. After starting to stir the mixture, dibromoethane (26.9 g) was added dropwise over 10 minutes at about 20° C., and then the internal temperature was raised to 33° C. The resulting mixture was stirred at 30° C. for 20 minutes. 2,6-diethyl-4-methylbromobenzene (10-a) (549.0 g) was added dropwise thereto at 40° C. over 1 hour. The resulting mixture was stirred at 50° C. for 51 hours, and diethyl oxalate (389.1 g) dissolved in toluene (550.1 g) was added dropwise thereto at about 0° C. over 1 hour. The resulting mixture was stirred at about 5° C. for 1 hour. Then, to the mixture, 3.5 w/w % of hydrochloric acid (832 g) was added dropwise at the same temperature. Then the mixture was warmed to room temperature, and the organic layer was separated. The aqueous layer was extracted with toluene (548.3 g). The organic layers were combined, washed with water (1098 g) and concentrated under reduced pressure to give 710.8 g of ethyl 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetate (9-a).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2O.C(Cl)(=O)C([Cl:18])=O.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[Cl:18][C:5]1[C:4]2[C:9](=[CH:10][N:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[CH:7][C:6]=1[C:12]#[N:13]
Reactant: N#Cc1cnc2cnc(F)cc2c1O
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cnc2cnc(F)cc2c1Cl
Temperature: 0 °C
Yield: 92 %

Procedure:
To 10 g of 6-fluoro-4-hydroxy-[1.7]naphthyridine-3-carbonitrile under an inert atmosphere in 150 mL of methylene chloride was added 24 mL of oxalyl chloride followed by 0.4 mL of N,N-dimethyl formamide. After two hours at reflux, an additional 5 mL of oxalyl chloride and 0.3 mL of N,N-dimethyl formamide was added. After an additional hour at reflux, the reaction was poured into ice-water and solid potassium carbonate was added carefully to a pH of about 8. The chloroform layer was washed with brine, dried with sodium sulfate, and stripped to give a crude product. This material was further purified by passing it through a plug of silica gel with chloroform and recrystallizing from a mixture of chloroform and hexanes to give 10 g (92%) of 4-chloro-6-fluoro-[1.7]naphthyridine-3-carbonitrile as a yellowish solid: melting point 150-155° C.; mass spectrum (m/e): M+H2O-Cl 190.0.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([N:15]=[C:16]=[O:17])[CH2:13][CH3:14]>C1(C)C=CC=CC=1>[C:1]1([N:7]2[CH2:8][C:9](=[O:11])[N:15]([CH2:12][CH2:13][CH3:14])[C:16]2=[O:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCN=C=O
Reactant: O=C(O)CNc1ccccc1
Solvent: Cc1ccccc1
Product: CCCN1C(=O)CN(c2ccccc2)C1=O
Yield: 59.6 %

Procedure:
In a similar manner, N-phenyl glycine (0.1 mole), n-propyl isocyanate (0.12 mole) and toluene (30 ml) was refluxed for about 51/2 hours producing 13 grams (59% yield) of 1-phenyl-3-n-propyl hydantoin having a melting point of about 97° C. and the structure: ##STR7##
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[C:11]([CH2:23][OH:24])[C:10]=2[CH2:25][OH:26])[CH:6]=[CH:5][N:4]=1)[NH2:2].[C:27](O)(=[O:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:27]([NH:2][NH:1][C:3]1[CH:8]=[C:7]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[C:11]([CH2:23][OH:24])[C:10]=2[CH2:25][OH:26])[CH:6]=[CH:5][N:4]=1)(=[O:29])[CH3:28]
Reactant: COc1cc2cc(CO)c(CO)c(-c3ccnc(NN)c3)c2cc1OC
Reactant: CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cc2cc(CO)c(CO)c(-c3ccnc(NNC(C)=O)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 1-(2-hydrazino-4-pyridyl)-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (2.0 g) and acetic acid (20 ml) is stirred at room temperature for 96 hours. After the reaction is complete, to the mixture are added methylene chloride and an aqueous potassium carbonate solution. The methylene chloride layer is separated, concentrated under reduced pressure, and the residue is crystallized from chloroform to give 1-[2-(2-acetylhydrazino)pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (0.84 g), which is listed in Table 10.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[N:16][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[N+:18]([C:15]1[CH:14]=[CH:13][C:12]([O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:17][N:16]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc(Oc2ccc([N+](=O)[O-])nc2)c1
Temperature: 50 °C
Reaction time: 15 h
Yield: 33 %

Procedure:
A mixture of 3-nitrophenol (7.76 g, 55.8 mmol), 5-bromo-2-nitropyridine (10.3 g, 50.7 mmol), cesium carbonate (24.8 g, 76.1 mmol) and N,N-dimethylformamide (150 mL) was stirred at 50° C. for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, hexane/ethyl acetate=100/0→0/100) to give the title compound (4.37 g, 33%) as a yellow solid.