Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][CH2:11][CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[F:22][C:23]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:24]=1[CH2:25]Br.C(Cl)Cl>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH2:10][CH2:11][CH2:12][O:13][CH2:25][C:24]1[CH:27]=[C:28]([Br:31])[CH:29]=[CH:30][C:23]=1[F:22])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(Br)cc1CBr
Reactant: CC(C)(CCCO)NC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(CCCOCc1cc(Br)ccc1F)NC(=O)OC(C)(C)C
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
A stirred solution of 4-(t-butoxycarbonylamino)-4,4-dimethylbutan-1-ol (1.11 g, 5.11 mmol) in tetrahydrofuran (49 ml) at −45° C. was treated with potassium t-butoxide (1 M in tetrahydrofuran, 5.62 ml, 5.62 mmol). The anion was stirred for 30 minutes at −45° C., then cooled to −78° C. and treated with a tetrahydrofuran solution of 2-fluoro-5-bromobenzyl bromide (1.23 g, 4.60 mmol). The resulting yellow mixture was slowly warmed to 0° C. and stirred for about four hours. The reaction mixture was diluted wtih methylene chloride (100 ml) and washed with 1 M potassium carbonate (20 ml). The organic fraction was dried over sodium sulfate, filtered, and the solvents were removed in vacuo. The residue was further purified by preparative high performance liquid chromatography to yield 1.53 grams (74%) of the title intermediate as a colorless oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@@:4]1([CH3:18])[C@@H:9]2[O:10][C@@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][CH2:30][C:31]1[NH:32][CH:33]=[CH:34][N:35]=1>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@@:4]1([CH3:18])[C@H:9]([OH:10])[C@@H:8]([N:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][CH3:21])[CH2:30][C:31]2[NH:35][CH:34]=[CH:33][N:32]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Reactant: COc1ccccc1NCc1ncc[nH]1
Product: COc1ccccc1N(Cc1ncc[nH]1)[C@H]1c2cc([N+](=O)[O-])ccc2O[C@@](C)(C(OC)OC)[C@@H]1O
Yield: 67.3 %

Procedure:
The title compound (580 mg, 67%) was prepared using (2R,3R,4R)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (500 mg, 1.78 mmol) and 2-methoxyphenyl-1H-imidazol-2-ylmethylamine (231 mg, 1.78 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:13])[CH:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[C:14](O)(=O)[CH:15]([CH3:17])[CH3:16]>>[CH:15]([C:17]1[O:13][C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[C:8]([C:9]([OH:11])=[O:10])[N:12]=1)([CH3:16])[CH3:14]
Reactant: NC(C(=O)O)C(O)c1ccccc1
Reactant: CC(C)C(=O)O
Product: CC(C)c1nc(C(=O)O)c(-c2ccccc2)o1

Procedure:
Prepared starting from DL-3-phenylserine hydrate following sequentially general procedures Y, Z with isobutyric acid, Z1 and Z2. LC-MS-conditions 02: tR=0.90 min; [M+H]+=232.51.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16]OS(C)(=O)=O)=[CH:12][C:11]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[CH:23]=3)=[N:10]2)=[CH:4][CH:3]=1.[N:33]1([CH2:39][CH2:40][OH:41])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16][N:36]3[CH2:37][CH2:38][N:33]([CH2:39][CH2:40][OH:41])[CH2:34][CH2:35]3)=[CH:12][C:11]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[CH:23]=3)=[N:10]2)=[CH:31][CH:32]=1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC=Cc3ccc(Cl)cc3)n2)cc1F
Reactant: OCCN1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(CCO)CC3)c(=O)n(CC=Cc3ccc(Cl)cc3)n2)cc1F
Yield: 65.1 %

Procedure:
Following the procedure of Example 1(10), 2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-piperazineethanol were reacted to yield the title compound as slightly-yellow needles (yield: 65.1%).
Reaction SMILES: CO[C:3]1[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH:4]=1.[CH2:10]([Mg]Br)[CH3:11].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH2:10]1[C:3]2([CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH2:4]2)[CH2:11]1
Reactant: CC[Mg]Br
Reactant: COC1=CC(=O)CCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Product: O=C1CCCC2(CC2)C1
Temperature: 25 °C
Yield: 32.6 %

Procedure:
3-Methoxy-cyclohex-2-enone (7.8 g, 61.83 mmol) was dissolved in Et2O (100 mL) and titanium tetraisopropoxide (20.1 mL, 68.01 mmol) was added. To the resulting brown solution ethylmagnesium bromide solution (3M, 60 mL, 180 mmol) was added dropwise over 70 minutes. A precipitate formed over the course of the addition. After 2 hours at RT the now dark brown/black reaction mixture was carefully quenched with saturated aqueous NH4Cl. A dark gray precipitate formed and was filtered off over Celite. The aqueous layer was extracted twice with Et2O. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and evaporated. The residue was taken up in Et2O (100 mL) and p-toluenesulfonic acid monohydrate (0.588 g, 3.091 mmol) was added. The resulting brown solution was stirred at RT over the weekend before being evaporated. The remaining brown oil was purified by SiO2 chromatography (330 g SiO2, hexanes/EtOAc 0 to 7% EtOAc) to give 2.5 g of spiro[2.5]octan-5-one as a light yellow liquid (32% yield).
Reaction SMILES: [CH2:1]([C:3]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH3:24])[CH:18]=1)([C:6]1[S:10][C:9]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:8]=2[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH3:30][O:29][C:27](=[O:28])[CH2:26][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:3]([CH2:4][CH3:5])([C:6]2[S:10][C:9]3[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:8]=3[CH:7]=2)[CH2:1][CH3:2])=[CH:18][C:19]=1[CH3:24]
Reactant: COC(=O)CBr
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1cc2ccc(OC)cc2s1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCC(CC)(c1ccc(OCC(=O)OC)c(C)c1)c1cc2ccc(OC)cc2s1
Yield: 48.9 %

Procedure:
To a mixture of 4-[1-ethyl-1-(6-methoxy-benzo[b]thiophen-2-yl)-propyl]-2-methyl-phenol (2.53 g, 7.43 mmol) and acetonitrile (25 mL) is added methyl bromoacetate (0.84 mL, 8.92 mmol), powdered potassium carbonate (4.10 g, 29.72 mmol), and potassium iodide (0.12 g, 0.74 mmol). The resulting slurry is stirred at reflux temperature for 2 h, filtered, and concentrated. The residue is dissolved in diethyl ether (100 mL), washed with water (75 ml), brine (75 mL), dried over MgSO4, filtered, and concentrated to give the title compound (1.5 g, 3.63 mmol, 49%). 1H NMR (CDCl3), δ 0.74 (t, J=7.2 Hz, 6H), 2.17 (q, J=14.7, 7.5 Hz, 4H), 2.25 (s, 3H), 2.30 (s, 2H), 3.80 (s, 3H), 3.86 (s, 3H), 3.60 (d, J=8.6 Hz, 1H), 6.89 (dd, J=8.6, 2.5 Hz, 1H), 7.04 (s, 1H), 7.07 (s, 1H), 7.16 (d, J=2.5 Hz, 1H), 7.55 (d, J=8.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17](Cl)=[O:18])[CH:13]=[N:14]2)=[CH:9][CH:8]=1.[NH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]([NH:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:18])[CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNC(=O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Reaction time: 14 h
Yield: 60 %

Procedure:
To a solution of 7-((3-chlorobenzyl)oxy)quinoline-3-carbonyl chloride in THF (1.5 mL) was added tert-butyl (2-aminoethyl)carbamate (38 mg, 0.23 mmol) and triethylamine (0.044 mL, 0.32 mmol). The reaction was stirred for 14 h. The crude reaction was loaded directly onto a column and purification (FCC, SiO2, 0-5%, MeOH/DCM) afforded the title compound as a white solid (44 mg, 60%). 1H NMR (400 MHz, CDCl3) δ 9.31-9.20 (m, 1H), 8.61-8.51 (m, 1H), 7.80 (d, J=9.0 Hz, 1H), 7.68-7.60 (m, 1H), 7.49 (s, 2H), 7.40-7.29 (m, 4H), 5.20 (s, 2H), 5.09-4.92 (m, 1H), 3.68-3.59 (m, 2H), 3.50-3.43 (m, 2H), 1.44 (s, 9H). [M+H]=456.3
Reaction SMILES: [Cl:1][C:2]1[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=3)=[CH:14][C:6]1=2.[CH3:28][N:29]1[CH2:34][CH2:33][N:32](C2C=C(B3OC(C)(C)C(C)(C)O3)C=CN=2)[CH2:31][CH2:30]1>>[Cl:1][C:2]1[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)[CH:16]=3)=[CH:14][C:6]1=2
Reactant: CN1CCN(c2cc(B3OC(C)(C)C(C)(C)O3)ccn2)CC1
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(-c4ccnc(Cl)c4)cc32)c1Cl
Product: CN1CCN(c2cc(-c3cnc4c(c3)N(Cc3c(F)ccc(F)c3Cl)CCN4)ccn2)CC1
Yield: 15 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-(2-chloropyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (88 mg) was coupled to 1-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4B to give the title compound as a light yellow solid (15% yield). LCMS: m/z=471.07 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.36 (3H, s), 2.56 (4H, t, J=4.9 Hz), 3.33 (2H, t, J=4.7 Hz), 3.55 (2H, m), 3.62 (4H, t, J=4.9 Hz), 4.53 (2H, s), 5.23 (1H, bs), 6.72 (1H, s), 6.78 (1H, dd, J=5.3, 1.3 Hz), 7.03 (2H, m), 7.12 (1H, m), 7.77 (1H, d, J=1.8 Hz), 8.18 (1H, d, J=5.1 Hz).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[O:6][CH:7]=1.[O:13]=[CH:14][C:15]1[CH:23]=[CH:22][C:20]([OH:21])=[C:17]([O:18][CH3:19])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:5]1[O:6][CH:7]=[C:3]([CH2:2][O:21][C:20]2[CH:22]=[CH:23][C:15]([CH:14]=[O:13])=[CH:16][C:17]=2[O:18][CH3:19])[N:4]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: ClCc1coc(-c2ccco2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OCc1coc(-c2ccco2)n1
Temperature: 80 °C
Reaction time: 15 h
Yield: 91.4 %

Procedure:
A mixture of 4-chloromethyl-2-(2-furyl)-1,3-oxazole (10.0 g), vanillin (8.29 g), potassium carbonate (7.53 g) and N,N-dimethylformamide (100 mL) was stirred at 80° C. for 15 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 4-{[2-(2-furyl)-1,3-oxazol-4-yl]methoxy}-3-methoxybenzaldehyde as brown crystals (14.90 g, yield 91%). Recrystallization from hexane-ethyl acetate gave pale-yellow prism crystals. melting point: 138-139° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11].C([O:15][C:16]([CH3:18])=[CH2:17])(=O)C.C[O-].C([Sn+](CCCC)CCCC)CCC.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>C1(C)C=CC=CC=1>[CH3:11][N:6]1[C:7]2[C:3](=[C:2]([CH2:17][C:16]([CH3:18])=[O:15])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: C=C(C)OC(C)=O
Reactant: Cn1ccc2c(Cl)cccc21
Agent: CCCC[Sn+](CCCC)CCCC
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[O-]
Solvent: Cc1ccccc1
Product: CC(=O)Cc1cccc2c1ccn2C
Temperature: 100 °C

Procedure:
To a solution of 0.852 g (5.14 mmol) of 4-chloro-1-methylindole in 15 mL dry toluene, 0.85 mL (7.73 mmol) isopropenyl acetate and 2.3 mL (8 mmol) tributyltin methoxide were added. The solution was heated to 100° C. After 15 min 0.24 g (0.61 mmol) 2-dicyclohexylphospino-2′-(N,N-dimethylamino)biphenyl and 0.14 g (0.153 mmol) tris(dibenzylidineacetone)dipalladium were added and heating was continued. After 2 h the solution was cooled, filtered through a pad of CELITE diatomaceous earth and the filtrate was concentrated to ca. 5 mL. This solution was purified on a silica column using a gradient of 5-20% EtOAc/hexane to obtain the title compound. 1H NMR: (500 MHz, CDCl3): δ 2.14 (s, 3H), 3.84 (s, 3H), 3.97 (s, 2H), 6.51 (d, 1H), 7-7.3 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH:7](O)[C:6]=2[C:5]([CH3:14])=[C:4]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:3]=1[CH3:23].[CH3:24][NH:25][CH3:26]>C(OCC)(=O)C.CCCCCC>[Br:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH:7]([N:25]([CH3:26])[CH3:24])[C:6]=2[C:5]([CH3:14])=[C:4]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:3]=1[CH3:23]
Reactant: CNC
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)OC(C)(C)C)C(O)C(C)(C)O2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(Br)c2c(c(C)c1NC(=O)OC(C)(C)C)C(N(C)C)C(C)(C)O2
Yield: 89 %

Procedure:
Using tert-butyl (7-bromo-3-hydroxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 236 and dimethylamine, the title compound was synthesized in the same manner as in Example 297. Yield: 89%. Melting point: 111-112° C. (ethyl acetate-hexane).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:11]([C:13]2[C:14](Cl)=[N:15][CH:16]=[CH:17][CH:18]=2)=O)=[CH:9][CH:10]=1)=[O:5])[CH3:2].O.[NH2:21][NH2:22]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:11]2[C:13]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:22][N:21]=2)=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)c1ccc(C(=O)c2cccnc2Cl)[nH]1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2n[nH]c3ncccc23)[nH]1
Temperature: 80 °C
Yield: 33.9 %

Procedure:
A mixture of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-2-carboxylic acid ethyl ester (0.5 g) (from Example 30) and hydrazine hydrate (0.7 g) in ethanol was heated at 80° C. for 24 hours. The precipitate was filtered off and the filtrate was concentrated to give 156 mg of the titled compound.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.O.[NH2:10][NH2:11]>C(O)C>[CH3:8][C:5]1[N:4]=[N:3][C:2]([NH:10][NH2:11])=[CH:7][CH:6]=1
Reactant: NN
Reactant: Cc1ccc(Cl)nn1
Solvent: O
Solvent: CCO
Product: Cc1ccc(NN)nn1
Yield: 80 %

Procedure:
To a suspension of 3-chloro-6-methyl-pyridazine (3 g, 23.3 mmol) in ethanol (45 mL) was added hydrazine hydrate (45 mL) and the resultant mixture was heated to reflux for 3 hrs. Most of the solvent was removed under reduced pressure and the white solid was collected by filtration and washed with ethanol. Upon drying 2.3 g of (6-methyl-pyridazin-3-yl)-hydrazine was obtained as a white crystalline solid (80% yield).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)([CH3:3])[CH3:2].C1C(=O)N([Br:22])C(=O)C1>C(#N)C>[Br:22][C:12]1[CH:13]=[CH:14][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: CC(C)Oc1cccc2ncccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)Oc1ccc(Br)c2ncccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of 5-isopropoxyquinoline (1.87 g, 10.0 mmol) in acetonitrile (100 mL) was added NBS (1.78 g, 10.0 mmol) at 0° C. The mixture was stirred at rt for 2 h before the solvent was removed. The residue was partitioned between EtOAc and H2O. The layers were separated and the organic layer was washed with brine, dried over MgSO4, and concentrated. The crude material was purified by column chromatography (0-10% EtOAc-Hex) to provide 8-bromo-5-isopropoxy-quinoline (92%) as a light brown solid. ESI-MS m/z calc 265.1, found 266.1 (M+1)+. Retention time: 1.44 minutes (3 min run).
Reaction SMILES: [C:1]1([CH3:8])[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.C=O.[O-:11][S:12]([O-:14])=[O:13].[Na+].[Na+]>O>[C:1]1([S:12]([OH:14])(=[O:13])=[O:11])([CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]1[CH3:7]
Reactant: O=S([O-])[O-]
Reactant: Cc1ccccc1C
Agent: C=O
Agent: [Na+]
Solvent: O
Product: CC1C=CC=CC1(C)S(=O)(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a similar reactor as described in Example 47, there was charged 106 grams of xylene (1.0 mole). There was added with fast stirring, 150 grams of fuming H1SO4 (20% SO3) at 20°-40° C. over a period of two hours. Next, the reaction was heated at 90°-95° C. for 2.25 hours. It was then cooled to room temperature and 138.0 grams of water was added at 30°-40° C. Then to 200 grams of sulfonation product (0.508 mole) was added 20.5 grams of 37% formaldehyde (0.254 mole) and heated to reflux (110° C.) for eight hours. At the end of this period, all formaldehyde was reacted as determined via standard Na2SO3 titration procedure.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1.C(N(CC)CC)C.I.[NH2:16][C:17]1[C:18]([C:25]([NH:27][C:28](=[NH:31])SC)=[O:26])=[N:19][C:20]([Cl:24])=[C:21]([NH2:23])[N:22]=1>O1CCCC1>[NH2:16][C:17]1[C:18]([C:25]([N:27]=[CH:28][NH:31][N:2]2[CH2:7][CH2:6][S:5][CH2:4][CH2:3]2)=[O:26])=[N:19][C:20]([Cl:24])=[C:21]([NH2:23])[N:22]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: C1CSCCN1
Agent: Cl
Agent: I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1nc(N)c(C(=O)N=CNN2CCSCC2)nc1Cl
Temperature: 0 °C

Procedure:
Thiomorpholine hydrochloride (2.10 g., 0.015 mole), triethylamine (2.1 ml., 0.015 mole), and 1-(3,5-diamino-6-chloropyrazinoyl)-2-methyl-2-thiopseudourea hydroiodide (1.94 g., 0.005 mole) are heated in tetrahydrofuran (50 ml.) at reflux for 4 hrs. The reaction mixture is added to ice-water to precipitate 590 mg. of 3,5-diamino-6-chloro-N-[(4-thiomorpholinyl)aminomethylene]-2-pyrazinecarboxamide which melts at 234°-6° C. after reprecipitation from dilute hydrochloric acid with sodium hydroxide.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1Br.[C:21]([O-:24])(=O)[CH3:22]>CN(C)P(=O)(N(C)C)N(C)C>[F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[N:8]1[CH2:9][CH2:22][C:21](=[O:24])[CH2:6][CH2:7]1
Reactant: CC1CCc2c(Br)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CC(=O)[O-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1CCc2c(N3CCC(=O)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 160 °C
Yield: 55.1 %

Procedure:
A mixture of 3 g of 9-fluoro-8-bromo-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 5 g of 4-piperidineethylene acetate and 30 ml of hexamethylphosphoric triamide was heated at 160° C. on an oil bath for 6 hours. After completion of reaction, hexamethylphosphoric triamide was distilled off under reduced pressure, and to the residue was added ethyl acetate to precipitate crystals which then were recrystallized from dimethylformamide containing a small amount of dilute hydrochloric acid to give 0.87 g of 9-fluoro-8-(4-oxo-1-piperidyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. m.p. not lower than 300° C., white rhombic crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([B:20]2[O:24][CH2:23]CO2)=[C:16](COCOC)[CH:15]=1.Cl>C1COCC1.O>[F:13][C:14]1[CH:15]=[CH:16][C:17]2[B:20]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[O:24][CH2:23][C:18]=2[CH:19]=1
Reactant: COCOCc1cc(F)ccc1B1OCCO1
Reactant: Brc1cccnc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc2c(c1)COB2c1cccnc1
Reaction time: 1 h
Yield: 7.7 %

Procedure:
To a solution of 3-bromopyridine (731 mg, 4.63 mmol) in THF (5 mL) was added isopropylmagnesium chloride (1 M in THF; 2.3 mL) at room temperature under nitrogen atmosphere, and the mixture was stirred for 1 h. To the mixture was added compound 6 (1.11 g, 4.63 mmol) in THF (4 mL), and the mixture was stirred at room temperature overnight. Water was added and the pH was adjusted to 7 with 1 N HCl. Then the mixture was extracted with ethyl acetate. The solvent was removed under reduced pressure, and the residue was dissolved in THF (30 mL). To the mixture was added 1 N HCl (10 mL), and the mixture was refluxed overnight. The pH was adjusted to 7 with aqueous NaHCO3 and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue was recrystallized from i-Pr2O to afford compound 15 (76 mg, 7.7%): mp 210-212° C.; 1H NMR (300 MHz, DMSO-d6) δ 4.94 (s, 2H), 6.9-7.1 (m, 2H), 7.36 (br s, 1H), 7.66 (dd, J=6.7, 5.3 Hz, 1H), 8.19 (d, J=6.7 Hz, 1H), 8.24 (br s, 1H), 8.64 (d, J=5.3 Hz, 1H): ESI-MS m/z 214 (M+H)+; Anal (C12H9BFNO.0.6H2O)C, H, N.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@@H:9]([OH:12])[C@H:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38]1([CH3:45])[C:43](O)=[CH:42][CH:41]=[CH:40][CH:39]=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[CH3:45])[C@H:8]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1ccccc1O
Reactant: CCOC(=O)N1CC[C@@H](O)[C@H](c2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)N1CC[C@H](Oc2ccccc2C)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6.23 g of trans-1-ethoxycarbonyl-3-phenyl-4-piperidinol, 7.21 g of triphenylphosphine, 2.97 g of o-cresol and 250 ml of anhydrous benzene is added, dropwise at 5° C. under nitrogen over a 90 minute period, a solution of 4.79 g of diethyl azodicarboxylate in 250 ml of benzene. After the addition is complete the mixture is stirred overnight at room temperature. The solid is then filtered and washed with benzene and the filtrate concentrated in vacuo to an oil. The oil is triturated overnight in a stoppered flask with 250 ml of hexane. The hexane is decanted and the gummy solid is triturated with more hexane and the hexane solution is filtered. The hexane filtrate is washed with 10% aqueous sodium hydroxide solution (3×75 ml), 2 N hydrochloric acid (100 ml), water (100 ml), saturated sodium chloride solution (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to a yellow gum. The gummy solid previously obtained is washed with ether. The ether filtrate is concentrated in vacuo and the residue is partitioned between 150 ml of hexane and 50 ml of 10% sodium hydroxide solution. The phases are separated. The hexane phase is washed with 10% sodium hydroxide solution, followed by 2 N hydrochloric acid solution (50 ml), water (100 ml), saturated sodium chloride solution (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting gum is combined with the previously obtained gum. Trituration of the gum with a 2:1 mixture of petroleum ether:ether affords a colorless solid. A second crop is obtained from the filtrate. Filtration through a silica gel plug using dichloromethane as solvent, followed by trituration with 2:1/petroleum ether:ether solution and filtration affords product as a colorless solid, mp 119.5°-121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[N+:11]([O-])([OH:13])=[O:12].S(=O)(=O)(O)O.O>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Solvent: O
Product: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
78.25 g of 4-chlorobenzoic acid were suspended in 400 ml of 1,2-dichloroethane. 99.0 g of a mixed acid containing 35.2% of nitric acid and 64.2% of sulphuric acid were added dropwise with stirring over a period of 3 hours at 40° C. After stirring for 2 hours at that temperature, the reaction mixture was poured on to 300 ml of water. The 1,2-dichloroethane was then distilled off and the reaction product filtered off from the residual aqueous suspension, washed with water and dried at 90° C., giving 97.8 g (96.8% of the theoretical) of 4-chloro-3-nitrobenzoic acid melting at 182.9° to 184.0° C. with a purity of 99.5%. The content of unreacted 4-chlorobenzoic acid amounted to only about 0.1%.