Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH:3]=[CH:4][C:5](O)=[O:6].[CH:10]1([CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:12][CH2:11]1>>[CH:10]1([CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:5](=[O:6])[CH:4]=[CH:3][C:2]([F:9])([F:8])[F:1])[CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:12][CH2:11]1
Reactant: O=C(O)C=CC(F)(F)F
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)C=CC(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 4,4,4-trifluorobut-2-enoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (19.6% yield). 1H NMR (500 MHz, CDCl3) δ 8.09, 8.00, 7.00, 6.81, 3.96-3.88, 3.78, 3.57, 1.53, 0.76, 0.48, 0.10. MS (ES+) m/z 398 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH:13]1[CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:13]2[CH2:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=S(=O)(c1ccc(F)cc1)N1CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.3 %

Procedure:
Commercially available 4-fluorophenylsulfonylchloride (225 mg, 1.15 mmol) was suspended in water (8 mL), and azetidine hydrochloride (90.0 mg, 0.96 mmol) and potassium carbonate (293 mg, 2.12 mmol) were added, followed by stirring at room temperature for 16 hours. To the reaction solution, water (15 mL) was added, followed by extraction twice with diethyl ether (15 mL), and washing was carried out with saturated brine (15 mL), followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, followed by vacuum drying, to afford the desired compound (170 mg, yield 82%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[NH:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7].Cl[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[N:13]([CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH2:12]2)[CH2:10][CH2:9]1)=[O:7]
Reactant: Cc1ccccc1N1C(=O)NCC12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: ClCCN1CCOCC1
Product: Cc1ccccc1N1C(=O)N(CCN2CCOCC2)CC12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=599.1 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-2-one and 4-(chloroethyl)morpholine.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH2:3]1.CC(C)([O-])C.[K+].[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Br)=[CH:26][CH:25]=1>>[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:5]2[C:4]3[CH2:3][N:2]([CH3:1])[CH2:14][CH2:13][C:12]=3[C:11]3[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:26][CH:25]=1
Reactant: CN1CCc2c([nH]c3ccccc23)C1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COC(=O)c1ccc(Cn2c3c(c4ccccc42)CCN(C)C3)cc1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 33.2 %

Procedure:
A round bottom flask fitted with reflux condenser containing 2-methyl-2,3,4,9-tetrahydro-1H-b-carboline (16) (0.30 g, 1.62 mmol) and potassium tert-butoxide (0.22 g, 1.92 mmol) was vacuum purged and filled with argon, followed by addition of DMSO (5 mL). After stirring at 120° C. for 20 min, 4-bromomethyl-benzoic acid methyl ester (0.37 g, 1.62 mmol) was added and the mixture was stirred at 120° C. for 3 h. The reaction was quenched by addition of water (30 mL), transferred to a separatory funnel and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (2×20 mL), dried (Na2SO4) and concentrated. The product was purified by MPCC (0 to 5% gradient of MeOH in CH2Cl2), which gave 180 mg (33%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 7.95 (d, 2H, J=8.2 Hz), 7.54 (m, 1H, J=7.6 Hz), 7.18-7.11 (m, 4H), 7.15 (d, 2H, J=8.1 Hz), 5.25 (s, 2H), 3.89 (s, 3H), 3.53 (s, 2H), 2.90 (m, 2H), 2.80 (m, 2H), 2.51 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 166.5, 141.9, 137.4, 130.4, 126.0, 122.8, 120.2, 118.6, 109.4, 106.7, 52.2, 51.3, 49.7, 46.6, 45.56, 42.1, 18.5. ESI-HRMS (m/z): [M+H]+ calcd. for C21H22N2O2, 335.1727. found, 335.1724.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][Br:17])=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2nc3ccccc3s2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2nc3ccccc3s2)cc1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
To a solution of 45 g (0.2 mol) of 4-(benzothiazol-2-yl) toluene in 1000 ml of dry carbon tetrachloride were added 35.6 g (0.2 mol) of N-bromosuccinimide and a catalytic amount of benzoyl peroxide. The mixture was refluxed for 12 hours, and then allowed to cool down to room temperature. The precipitated succinimide was filtered off and the filtrate evaporated to dryness in vacuo, whereupon 55 g of crude crystals were obtained. Recrystallization from 1500 ml of cyclohexane gave 41 g of purified 4-(benzothiazol-2-yl) bromomethylbenzene as colorless flakes.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([CH:23]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=2)[N:13]=1.[CH3:26][N:27]1[C:31]([C:32](Cl)=[O:33])=[CH:30][C:29]([CH3:35])=[N:28]1.C(N(CC)CC)C>O1CCCC1>[CH:20]1([C:18]([NH:17][C:15]2[N:16]=[C:11]3[CH:10]=[CH:9][C:8]([O:7][C:6]4[CH:23]=[C:2]([NH:1][C:32]([C:31]5[N:27]([CH3:26])[N:28]=[C:29]([CH3:35])[CH:30]=5)=[O:33])[CH:3]=[CH:4][C:5]=4[O:24][CH3:25])=[N:13][N:12]3[CH:14]=2)=[O:19])[CH2:21][CH2:22]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: COc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)c2cc(C)nn2C)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 70.9 %

Procedure:
Using N-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (129 mg, 0.379 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (78.3 mg, 0.493 mmol), triethylamine (115 mg, 1.14 mmol) and tetrahydrofuran (5.0 mL) as starting materials and in the same manner as in Example 96, the title compound (124 mg, 71%) was obtained as a white powder.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:12])[CH:8]=2)[CH:3]=1.[C:13]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[C:13]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:18]=[CH:17][CH:16]=[C:15]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Br:12])[CH:8]=3)[CH:3]=2)[CH:14]=1
Reactant: Brc1ccc2cc(Br)ccc2c1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
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: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc2cc(-c3cccc(-c4ccccc4)c3)ccc2c1
Yield: 51 %

Procedure:
Commercial 2,6-dibromonaphthalene in an amount of 12 g, 11 g of commercial 3-biphenylboronic acid and 180 ml of toluene were mixed together. Then, 5.7 g of tetrakis(triphenylphosphine)palladium and 90 ml of a 2 M aqueous solution of sodium carbonate were added, and the reaction system was purged with argon. After the reaction mixture was heated under the refluxing condition for 7.5 hours, the reaction mixture was cooled by leaving standing. The formed crystals were separated by filtration and subjected to extraction with toluene. The obtained organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried with anhydrous sodium sulfate, and the solvent was removed using an evaporator. The obtained residue was purified in accordance with the silica gel column chromatography (the developing solvent: hexane/toluene=5/1), and 7.8 g of 2-(biphenyl-3-yl)-6-bromonaphthalene was obtained as a white solid substance (the yield: 51%). 2-(Biphenyl-3-yl)-6-bromonaphthalene obtained above in an amount of 5.2 g, 6.4 g of 3-(9-phenylanthracen-10-yl)phenylboronic acid obtained in accordance with a conventional process, 60 ml of DME and 20 ml of toluene were mixed together. To the obtained solution, 0.67 g of tetrakis(triphenylphosphine)palladium and 60 ml of a 2 M aqueous solution of sodium carbonate were added, and the reaction system was purged with argon. After the reaction mixture was heated under the refluxing condition for 10 hours, the reaction mixture was cooled by leaving standing. The formed crystals were separated by filtration, washed with water and methanol and then with heated toluene, and 7.0 g of the object compound (AN-14) was obtained as a white solid substance (the yield: 74%). The obtained compound was examined in accordance with FD-MS (the field desorption mass analysis). Since it was found that m/z=658, which corresponded to C52H34=658, the obtained compound was identified to be AN-14.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH:16]([OH:18])[C:15](=[O:19])[NH:14][C:13]1=[O:20])[C:6]2=[O:11].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH:26]=O.[BH4-].[Na+]>C(O)(=O)C>[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH:16]([OH:18])[C:15](=[O:19])[NH:14][C:13]1=[O:20])[C:6]2=[O:11]
Reactant: Nc1cccc2c1CN(C1CC(O)C(=O)NC1=O)C2=O
Reactant: O=Cc1ccco1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=O)C(N2Cc3c(NCc4ccco4)cccc3C2=O)CC1O
Reaction time: 18 h

Procedure:
A solution of 3-(4-amino-1-oxoisoindolin-2-yl)-5-hydroxypiperidine-2,6-dione (0.82 g, 3.0 mmol) and 2-furaldehyde (0.34 g, 3.5 mmol) in acetic acid (10 mL) is heated at reflux for 4 hours. To the mixture is added sodium borohydride (130 mg, 3.5 mmol) at room temperature and kept for 18 hours. The mixture is worked up to give 3-(4-fur-2-ylmethylamino-1-oxoisoindolin-2-yl)-5-hydroxypiperidine-2,6-dione which is further purified by column chromatography.
Reaction SMILES: [C:1]1([NH:7][NH:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.CCOCC>[CH3:9][NH:8][NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CNNc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CNNc1ccccc1
Yield: 76.3 %

Procedure:
A solution of N'-phenylformohydrazide (20.59 g) in dry tetrahydrofuran (750 ml) was added dropwise under nitrogen to a stirred suspension of lithium aluminium hydride (10 g) in dry tetrahydrofuran (200 ml), then the mixture was stirred and heated under reflux for 4 hours. The mixture was quenched by the slow dropwise addition of water (10 ml), followed by 5M aqueous sodium hydroxide solution (10 ml), then water (20 ml), then it was filtered, dried (MgSO4) and the solvent removed in vacuo to yield an oil. The oil was dissolved in ether, redried (MgSO4) and the solvent removed in vacuo to yield 1-methyl-2-phenylhydrazine (14.1 g) as a yellow oil.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1)=[O:2].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19]>>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:1]([C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1)=[O:2]
Reactant: CCOC(=O)c1ccnc(C=O)c1
Reactant: NCCCCO
Product: CCOC(=O)c1ccnc(C(=O)NCCCCO)c1

Procedure:
By General Procedure A from ethyl 2-formylpyridine-4-carboxylate and 4-aminobutan-1-ol. Purification by column chromatography (5% MeOH/DCM) gave the target compound as greenish oil. 1H-NMR (300 MHz, CDCl3): δ 8.60 (d, 1H), 7.80 (s, 1H), 7.70 (d, 1H), 4.40 (q, 2H), 4.05 (s, 1H), 3.60 (m, 2H), 2.80 (m, 2H), 1.70 (m, 4H), 1.40 (t, 3H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:18]=1[C:19](Cl)=[O:20].[OH-].[Na+]>CC(C)=O>[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:18]=1[C:19]([NH:10][C@H:9]([C:11]([OH:13])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)=[O:20]
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O)c1c(Cl)cccc1Cl

Procedure:
Concretely, 4-nitro-L-phenylalanine and 2,6-dichlorobenzoylchloride are condensed in a mixed solvent of a sodium hydroxide aqueous solution and acetone with keeping the reaction temperature at 5 to 15° C., and then crystallization is conducted to obtain a corresponding condensed substance, Nα-(2,6-dichlorobenzoyl)-4-nitro-L-phenylalanine almost quantitatively.
Reaction SMILES: [S:1]=[C:2]1[NH:6][C@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH2:3]1.[CH3:14]I>C1COCC1>[CH3:14][S:1][C:2]1[CH2:3][CH2:4][C@@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:6]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=S)N1
Solvent: C1CCOC1
Product: CSC1=N[C@H](C(=O)OC(C)(C)C)CC1
Reaction time: 3.5 h
Yield: 90.5 %

Procedure:
To a solution of thiolactam 1b (10.50 g, 52.2 mmol) in 200 mL THF at rt, was added MeI (13.0 mL, 208.7 mmol). The mixture was stirred for 3.5 h, then concentrated. The residue was partitioned between CH2Cl2 and sat. NaHCO3 and the aqueous phase was extracted with CH2Cl2 (3×). The combined organic extract was dried (Na2SO4) and concentrated to afford 10.17 g (91%) of the title compound, 1c, as a brown oil. 1H NMR (300 MHz, CDCl3) δ4.60 (dd, J=6.2, 7.3, 1H), 2.83-2.58 (m, 2H), 2.49 (s, 3H), 2.37-2.22 (m, 1H), 2.17-2.03 (m, 1H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([O:4][C:5]([N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=[O:13])=[O:6])[CH3:3].C[Si]([N:19]([Si](C)(C)C)[C:20]1[CH:21]=[C:22]([Mg]Cl)[CH:23]=[CH:24][CH:25]=1)(C)C>C1COCC1>[CH3:3][C:2]([CH3:14])([O:4][C:5]([N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]([C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:19])[CH:25]=1)[OH:13])=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)n1cccc1C=O
Reactant: C[Si](C)(C)N(c1cccc([Mg]Cl)c1)[Si](C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cccc1C(O)c1cccc(N)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of N-(dimethylethoxycarbonyl)pyrrole-2-carboxaldehyde (10 g, 50 mmol) in THF (500 mL) at −30° C. under nitrogen was added dropwise to 3-[bis(trimethylsilyl)amino]phenylmagnesium chloride (55 mL of a 1M solution in THF, 55 mmol). After addition the reaction mixture was gradually warmed up and stirred at 0° C. for 1 hour, then at ambient temperature for 15 minutes. The reaction mixture was poured into ice water, and stirred for 30 minutes. The reaction mixture was extracted with ethyl ether (1 L). The combined organic layers were dried (Na2SO4) and concentrated. Chromatography on SiO2 (700 g) using 1:1 hexane/ethyl acetate afforded [N-(dimethylethoxycarbonyl)pyrrol-2-yl](3-aminophenyl)methanol (11.2 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:16])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=1.Br[C:18]1[CH:19]=[CH:20][C:21](N)=[N:22][CH:23]=1.N1C=CC=C([Sn](CCCC)(CCCC)CCCC)C=1>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:16]=[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([C:20]2[CH:21]=[N:22][CH:23]=[CH:18][CH:19]=2)=[CH:7][N:6]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: Nc1ccc(Br)cn1
Reactant: COC(=O)CCC(=O)Nc1ccc(Br)cn1
Agent: [Pd]
Agent: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)CCC(=O)Nc1ccc(-c2cccnc2)cn1
Temperature: 150 °C
Yield: 26 %

Procedure:
Methyl 4-[(5-bromo-2-pyridyl)amino]-4-oxo-butanoate (Commercially available or prepared as described in example II using as starting material the commercially available: 5-bromo-2-aminopyridine, 200 mg, 0.697 mmol) was dissolved in toluene in a microwave vial and 3-pyridyltributylstannane (0.836 mmol, 0.290 mL) and tetrakis(triphenylphosphine) palladium(0) (0.069 mmol) were added. Argon was bubbling through the mixture for ca. 5 min and the vial was heated under microwave irradiations for 10 min at 150° C. The solvent was evaporated and the residue was diluted with acetonitrile, washed with cyclohexane (2×) and evaporated. The product was purified by flash chromatography (RF-machine, AcOEt/cyclohexane: 0/100→100/0) to give methyl 4-oxo-4-[[5-(3-pyridyl)-2-pyridyl]amino]butanoate (compound A82) (0.051 g, 26% Yield). LC-MS (Method F) RT 0.50, 286 (M+H+). Compound A83, A84 and A85 from table A were prepared by the same method using the corresponding coupling reagent.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[NH:9][C:8](=[O:22])[C:7]=3[C:6]=2[C:23]=1[N+:24]([O-])=O.C(O)(=O)C.C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(O)C.[Fe].O>[NH2:24][C:23]1[C:6]2[C:7]3[C:8](=[O:22])[NH:9][C:10]([NH:15][C:16](=[O:21])[C:17]([CH3:19])([CH3:20])[CH3:18])=[N:11][C:12]=3[CH:13]=[CH:14][C:5]=2[CH:4]=[CH:3][C:2]=1[Br:1]
Reactant: CC(C)(C)C(=O)Nc1nc2ccc3ccc(Br)c([N+](=O)[O-])c3c2c(=O)[nH]1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)Nc1nc2ccc3ccc(Br)c(N)c3c2c(=O)[nH]1

Procedure:
A mixture of N-(9-bromo-1,2-dihydro-10-nitro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.8 g, 1.9 mmoles) and iron powder (0.44 g, mmoles) in ethanol:glacial acetic acid/1:1 (25 ml) was stirred and heated to reflux under a nitrogen atmosphere for 3 hours. The reaction mixture was poured into chloroform:water/2:1 (150 ml) and neutralized by addition of solid sodium bicarbonate. The chloroform layer was separated, and the aqueous phase was washed twice with chloroform (50 ml each). Combined chloroform layers were dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified on a silica gel column eluting with chloroform to give N-(10-amino-9-bromo-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide as a bright yellow solid. (0.66 g, 89%) 1H NMR (DMSO-d6, 200 MHz) δ: 1.27(s, 9H, t-butyl); 6.51(s, 2H, NH2); 7.22(d, J=8.4 Hz, 1H, Ar); 7.51(br d, J=9 Hz, 1H, Ar); 7.72(d, J=8.4 Hz, 1H, Ar); 8.12(d, J=9.0 Hz, 1H, Ar); 11.40(br s, 1H, NH); 12.45(br s, 1H, NH).
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[C:21]([O-])([O-])=O.[K+].[K+].CI>CO>[CH3:21][O:20][C:9]1[CH:8]=[CH:7][C:6]2[C@@H:5]3[C@H:14]([C@H:15]4[C@@:2]([CH2:3][CH2:4]3)([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [K+]
Solvent: CI
Solvent: CO
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 70 h
Yield: 99.8 %

Procedure:
Estrone (1, 100.0 g, 370 mmol) was dissolved in MeOH (1.5 L), followed by the addition of K2CO3 (300.0 g, 2.17 mol). MeI (310 mL, 4.98 mol) was added and the mixture stirred at room temperature for 70 h. The reaction mixture was concentrated in vacuo to remove some of the MeOH and was then poured into ice water forming a precipitate. The solid was collected and dried by partitioning into CH2Cl2. The organic layer was dried over MgSO4, and the solvent was removed in vacuo to yield compound 2 (105.0 g) as white crystals in quantitative yield. 1H NMR (250 MHz, CDCl3); δ 0.91 (s, 3, C-18 H), 3.78 (s, 3, MeO), 6.65 (s, 1, C-4 H), 6.72 (d, 1, J=8.57 Hz, C-2 H), 7.21 (d, 1, J=8.57 Hz, C-1 H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]C.CS(O)(=O)=O>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:7])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: COC(=O)c1ccsc1
Reactant: CCCCCCCCCCCCCCO
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCOC(=O)c1ccsc1
Yield: 92.4 %

Procedure:
To a 200 mL round bottom flask were added 10 g (70 mmol) of methyl 3-thiophenecarboxylate, 17 g (79 mmol) of 1-tetradecanol, 1 mL methanesulfonic acid, and 50 mL of toluene. This mixture was heated to reflux for 17 hours. After the solvent was removed, the remaining methyl 3-thiophenecarboxylate was removed by kugelrohr distillation. The remaining residue was filtered through a silica gel pad with 10% ethyl acetate in hexane. The solvents were removed from the filtrate to provide 21 g of the desired compound. The NMR data were obtained and were consistent with those of the desired compound.
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[Br:16][C:17]1[S:21][C:20](N)=[N:19][CH:18]=1>ClCCCl>[Br:16][C:17]1[S:21][C:20]([N:14]=[C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:19][CH:18]=1
Reactant: Nc1ncc(Br)s1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: Br
Solvent: ClCCCl
Product: Brc1cnc(N=C(c2ccccc2)c2ccccc2)s1
Yield: 82.9 %

Procedure:
26 g of benzophenone imine are added to 34 g of 5-bromo-1,3-thiazol-2-amine hydrobromide, in suspension in 300 ml of 1,2-dichloroethane. The mixture is kept under reflux for 18 hours. The precipitate formed is filtered and the filtrate is concentrated to give 37.2 g of solid.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+].Cl>CS(C)=O>[CH2:12]([O:19][C:3]1[C:2]([Br:1])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1cnc(OCc2ccccc2)c(Br)c1
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 23.6 %

Procedure:
A suspension of 5-bromo-6-chloro-nicotinic acid (CAS [29241-62-1], 1 g), benzylalcohol (0.686 g) and KOH (1.104 g) in DMSO (4 ml) was stirred at 140° C. for 15 min. DMSO (2 ml) was added and the mixture was stirred at 140° C. for 30 min. The mixture was cooled to room temperature. Ice was added and the mixture was acidified using 1 M HCl. The mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried, filtered and concentrated. The product was purified by flash chromatography (SiO2, CH2Cl2=>CH2Cl2/MeOH 4:1) to give 6-benzyloxy-5-bromo-nicotinic acid (0.308 g) as a white solid.