Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][CH:13]=[C:12]([CH3:15])[C:11]=2[CH:16]=1.CN([CH:20]=[O:21])C>C1COCC1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([CH:20]=[O:21])=[C:12]([CH3:15])[C:11]=2[CH:16]=1
Reactant: Cc1coc2ccc(Cl)cc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(C=O)oc2ccc(Cl)cc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
n-Butyl lithium (2.5 M in hexane, 6.6 mmol, 2.6 mL) was added dropwise over 15 minutes to a solution of 5-chloro-3-methyl benzofuran (6.0 mmol, 1 g) in THF (8 mL) cooled to −78° C. To this was added DMF (12 mmol, 0.6 mL) and stirred for one hour. The reaction mixture was allowed to come to room temperature overnight and then quenched with EtOAc (20 mL) and H2O (10 mL). The organic portion was collected, dried, filtered and the filtrate was evaporated to dryness to obtain 5-chloro-3-methyl benzofuran-2-carboxaldehyde (96%, 1.12 g), which-was carried on without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH:17][O:18][CH3:19].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:13](=[O:15])[N:17]([O:18][CH3:19])[CH3:16])[CH2:10][CH2:11][CH2:12]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC1
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1(NC(=O)OC(C)(C)C)CCC1
Yield: 87 %

Procedure:
To a solution of 1-tert-butoxycarbonylamino-cyclobutanecarboxylic acid (3 g, 13.94 mmol) in dry DMF (50 mL) was added N,O-dimethylhydroxylamine x HCl (1.36 g, 13.94 mmol) and DIEA (9.21 mL, 55.75 mmol). The reaction flask was cooled to 0° C. and after 10 minutes HATU (5.30 g, 13.94 mmol) was added to the solution (which turned yellow on addition). After 2 hrs the DMF was removed by rotary evaporation at reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed twice with 10% citric acid (aq) and saturated NaHCO3(aq) solution. The organic phase was dried with Na2SO4, filtered and evaporated on silica. The product was purified by flash chromatography (heptane: ethyl acetate (1:1) to give the product as a colourless oil that slowly crystallizes (3.13 g) in 87% yield.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([CH2:12][C:13]([NH2:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCOC(C)=O>CN1CCCC1=O>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:2]2[N:11]=[C:10]([CH2:12][C:13]([NH2:15])=[O:14])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: NC(=O)Cc1nc(Cl)nc2ccccc12
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CN1CCN(c2nc(CC(N)=O)c3ccccc3n2)CC1
Temperature: 50 °C

Procedure:
2-(2-chloro-quinazolin-4-yl)-acetamide (221 mg, 1.0 mmol) is dissolved in 1-methyl-2-pyrrolidinone (2.0 mL) and N-methylpiperazine (555 μL, 5.0 eq.) is added. The mixture is heated 45 min. at 50° C. AcOEt is added and the suspension is filtered to afford 2-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-acetamide as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]=O)=[C:6]2[CH2:7][CH2:8][CH2:9][O:10][C:5]2=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=1.[BH4-].[Na+].Cl>CO.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:11]=1[CH2:12][NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=1
Reactant: CC(=O)c1ccc(N)cc1
Reactant: O=Cc1c(O)ccc2c1CCCO2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)c1ccc(NCc2c(O)ccc3c2CCCO3)cc1
Temperature: 25 °C
Yield: 33 %

Procedure:
A mixture of 6-hydroxy-3,4-dihydrobenzopyran-5- carboxaldehyde (308 mg, 1.73 mmol) and p-aminoacetophenone (236 mg, 1.73 mmol) in methanol (8 mL) was heated at reflux for one hour. The mixture was cooled to 15° at which time the intermediate Schiff's base crystallized. After filtration and drying a light orange product (221 mg, 43.3%) was obtained. This material was suspended in methanol (8 mL) and sodium borohydride (28 mg, 0.74 mmol) was added. After stirring at room temperature for ten minutes the mixture was poured into water (75 mL) and the resulting suspension neutralized (pH=7) with 2.5 N HCl. The product was collected by filtration and dried to afford 6-hydroxy-5-(4-acetylphenyl) aminomethyl-3,4-dihydrobenzopyran (170 mg, 76.6%), m.p. 213°-215° C.
Reaction SMILES: [Cl:1]C1([N:8]=[O:9])CCCCC1.[CH2:10]([O:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[C:20](\[CH3:24])/[CH:21]=[CH:22]/[CH3:23])=[CH:15][CH:14]=1)[CH3:11]>C(O)C.C(OCC)C>[ClH:1].[CH3:23][CH:22]1[CH:21]=[C:20]([CH3:24])[CH:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:10][CH3:11])=[CH:14][CH:15]=2)[O:9][NH:8]1
Reactant: C/C=C/C(C)=C/c1ccc(OCC)cc1
Reactant: O=NC1(Cl)CCCCC1
Solvent: CCOCC
Solvent: CCO
Product: CCOc1ccc(C2ONC(C)C=C2C)cc1
Product: Cl

Procedure:
To a solution of 1-chloro-1-nitrosocyclohexane (3.22 g, 21.86 mmol) in ethanol (2.31 ml) and diethyl ether (8 ml) cooled in an ice bath was added a solution of 1-(4-ethoxyphenyl)-2-methylpent-1E,3E-diene (4.0 g, 19.88 mmol) in diethyl ether (4 ml). The reaction vessel was sealed and kept in a fridge at 0° C. over a period of 4 weeks yielding three crops of 3,6-dihydro-3,5-dimethyl-6-(4-ethoxyphenyl)-2H-1,2-oxazine hydrochloride as white crystals.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH2:12][O:13][CH3:14])[CH2:3][CH2:2]1.[NH2:18][C@@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH2:22])=[O:21]>>[C:20]([C@@H:19]([NH:18][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH2:12][O:13][CH3:14])[N:8]=1)=[O:17])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:21])[NH2:22]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: COCCOc1nc(C(=O)O)ccc1C1CC1
Product: COCCOc1nc(C(=O)N[C@@H](CC(C)C)C(N)=O)ccc1C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=350.2 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)[CH2:12][CH2:11]2)=[N:2]1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([NH:25][S:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[F:26])(=[O:35])=[O:34])=[CH:23][CH:24]=3)[CH2:14][CH2:15]2)=[N:2]1
Reactant: Nc1ccc(CCCN2CCN(c3nsc4ccccc34)CC2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1F
Product: O=S(=O)(Nc1ccc(CCCN2CCN(c3nsc4ccccc34)CC2)cc1)c1ccccc1F

Procedure:
N-{4-[3-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-propyl]-phenyl}-2-fluoro-benzenesulfonamide was prepared according to the procedure outlined in Example 44 starting with 4-[3-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-propyl]-phenylamine (100 mg) and 2-fluorobenzenesulfonyl chloride (55 mg). The resultant white solid was purified using an ISCO autocolumn eluting with 100% ethyl acetate to afford N-{4-[3-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-propyl]-phenyl}-2-fluoro-benzenesulfonamide. MS (APCI): 511 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([C@@H:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])[C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].ClCCl.Cl>CO.CCOCC>[CH3:1][N:2]([C@@H:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])[C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:4]
Reactant: C[C@H](c1ccccc1)N(C)C(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N(C)C(=O)c1cnc(N2CCNCC2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl 4-[5-[[methyl[(1R)-1-phenylethyl]amino]carbonyl]-2-thiazolyl]-1-piperazinecarboxylate (i.e. the product of Example 4, Step C) (0.75 g, 1.7 mmol) in 10 mL of methanol and 10 mL of dichloromethane was treated with 15 mL of 1 N HCl in ether. The reaction mixture was stirred at ambient temperature overnight, concentrated under reduced pressure, dissolved in water and brine, basified with 1. N aqueous NaOH solution and extracted with dichloromethane. The extract was dried over MgSO4 and concentrated under reduced pressure to give 0.48 g of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH3:9][N:10]([CH3:25])[C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[C:16]2[S:21](Cl)(=[O:23])=[O:22]>>[CH3:9][N:10]([CH3:25])[C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[C:16]2[S:21]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:23])=[O:22]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2cccc3c(N(C)C)cccc23)c1Br
Yield: 68 %

Procedure:
5-Dimethylamino-N-(4-bromo-3-methyl-5-isoxazolyl)-1-naphthalenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 5-dimethylaminonaphthalenesulfonyl chloride according to the procedures described in Example 5. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 87°-89° C., yield 68%.
Reaction SMILES: [OH:1][C@H:2]([CH3:9])[CH2:3][C:4]([O:6]CC)=O.[CH2:10]([Mg]Br)[CH3:11].[CH2:14](OCC)C>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[OH:6][C@H:4]([CH2:10][CH3:11])[CH2:3][C:2]1([OH:1])[CH2:9][CH2:14]1
Reactant: CCOC(=O)C[C@@H](C)O
Reactant: CCOCC
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Product: CC[C@@H](O)CC1(O)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (3R)-ethyl 3-hydroxybutanoate (2.5 g, 18.9 mmol) in THF (100 mL) under nitrogen was added a solution of titanium(IV) isopropoxide (6.02 mL, 19.9 mmol) in THF (15 mL) followed by a solution of ethyl magnesium bromide in diethyl ether (3 M, 30.2 mL, 90.7 mmol) dropwise over a period of 2 hr. The reaction mixture was stirred for a further 2 hr, before being cooled to 0° C. and quenched by the slow addition of a saturated aqueous ammonium chloride (75 mL). The solution was filtered and the filtrate extracted with DCM (3×20 mL). The combined organic layers were washed with brine (75 mL), separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 1-[(2R)-2-hydroxybutyl]-cyclopropanol as a yellow oil (1.50 g). To a solution of this oil (900 mg, 7.76 mmol) in DCM (15 mL) cooled to 0° C. was added 2,6-lutidine (2.26 mL, 19.40 mmol) followed by trimethylsilyl trifluoromethanesulfonate (3.1 mL, 17.10 mmol). The reaction mixture was stirred at 0° C. for 2 hr before additional 2,6-lutidine (2.26 mL, 19.40 mmol) and trimethylsilyl trifluoromethanesulfonate (3.1 mL, 17.10 mmol) were added. The reaction mixture was allowed to warm to room temperature and stirred for 18 hr. The mixture was cooled to 0° C., quenched with 0.1 M aqueous HCl (15 mL) and extracted with DCM (50 mL). The organic layer was washed with 0.1 M aqueous HCl (2×15 mL) and passed through a phase separation cartridge. To this solution was added 2-methyl-4-nitro-pyrazole-3-carbaldehyde (1.90 g, 7.13 mmol) and the resulting solution was cooled to −78° C. before trimethylsilyl trifluoromethanesulfonate (0.64 mL, 3.56 mmol) was added dropwise. The mixture was warmed to 0° C. and stirred for 3 hr before being cooled to −78° C. and additional trimethylsilyl trifluoromethanesulfonate (1 mL, 5.49 mmol) was added. After stirring at 0° C. for 3 hr the procedure was repeated. The reaction mixture was stirred at 0° C. for a further 2 hr before solid sodium carbonate (2.5 g) was added. The reaction mixture was stirred for 10 min and a saturated solution of NaHCO3 (10 mL) was added. The organic layer was washed with water (10 mL) and brine (10 mL), separated, dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 1-methyl-5-(5-ethyl-6,8-dioxaspiro[2.5]octan-7-yl)-4-nitro-pyrazole as a colourless solid (655 mg, 4% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 6.58 (s, 1H), 4.13 (s, 3H), 4.00-3.92 (m, 1H), 2.29 (t, J=12.4 Hz, 1H), 1.75-1.47 (m, 3H), 1.00-0.87 (m, 5H), 0.67-0.53 (m, 2H).
Reaction SMILES: [O-:1][Mo:2]([O-:5])(=[O:4])=[O:3].[Na+].[Na+].[P:8](O)([O-:11])([O-:10])=[O:9].[Na+].[Na+].Cl>O>[OH:10][PH:8]([OH:11])=[O:9].[OH:4][Mo:2]([OH:5])(=[O:3])=[O:1]
Reactant: O=P([O-])([O-])O
Reactant: O=[Mo](=O)([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=[Mo](=O)(O)O
Product: O=[PH](O)O

Procedure:
Separately, a heteropoly acid solution of phosphomolybdic acid (PMA) is prepared by adding 47.5 parts of anhydrous sodium molybdate and 5 parts of anhydrous disodium phosphate to 2100 parts of water at 75° C., stirring to solution, and then adding 58 parts of 31.5% hydrochloric acid to a pH of about 1.8.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:29])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=2[CH:18]=[C:19]([CH3:29])[CH:20]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)cc(-c4ccccc4F)c3O2)cc1
Product: CNCC1Cc2cc(C)cc(-c3ccccc3F)c2O1

Procedure:
The title compound was prepared (0.03 g, 28%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2-fluorophenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.14 g, 0.34 mmol) and methylamine (0.105 g, 3.4 mmol). mp 153-155° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][C@H:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[C:5](=[O:14])[N:4]2[C@H:15]([C:19]([OH:21])=O)[CH2:16][CH2:17][CH2:18][N:3]12.C(OC([NH:28][C@H:29]([CH:38]([OH:50])[C:39]1[O:40][C:41]2[C:47]([Cl:48])=[CH:46][C:45]([Cl:49])=[CH:44][C:42]=2[N:43]=1)[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=O)C=C.C(NC1C(=O)N2C(C(NC(C(O)COCC3C(Cl)=CC=CC=3Cl)CC(OC(C)(C)C)=O)=O)CCCN2C(=O)CC1)(=O)C1C=CC=CC=1>>[Cl:49][C:45]1[CH:46]=[C:47]([Cl:48])[C:41]2[O:40][C:39]([CH:38]([OH:50])[CH:29]([NH:28][C:19]([CH:15]3[N:4]4[C:5](=[O:14])[CH:6]([NH:9][S:10]([CH3:13])(=[O:11])=[O:12])[CH2:7][CH2:8][C:2](=[O:1])[N:3]4[CH2:18][CH2:17][CH2:16]3)=[O:21])[CH2:30][C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])=[N:43][C:42]=2[CH:44]=1
Reactant: C=CCOC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(O)c1nc2cc(Cl)cc(Cl)c2o1
Reactant: CS(=O)(=O)N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)O)N2C1=O
Agent: CC(C)(C)OC(=O)CC(NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)C(O)COCc1c(Cl)cccc1Cl
Product: CC(C)(C)OC(=O)CC(NC(=O)C1CCCN2C(=O)CCC(NS(C)(=O)=O)C(=O)N12)C(O)c1nc2cc(Cl)cc(Cl)c2o1

Procedure:
was prepared from the acid 212b and (3S,4RS) t-butyl N-(allyloxycarbonyl)-3-amino-4-hydroxy-4-(5,7-dichlorobenzoxazol-2-yl)butanoate (204) by an analogous method as that used for compound 215e to afford a mixture of diastereomers (460 mg, 70%) as a glass: IR (film) 3325, 1725, 1664, 1453, 1399, 1373, 1327, 1274, 1256, 1155; 1H NMR (CDCl3) δ7.57 (1H, m), 7.36 (2H, m), 6.06 (1H, t), 5.29 (2H, m), 4.79 (1H, m), 4.47 (1H, m), 3.23 (1H, m), 2.97 and 2.94(3H combined, 2×s), 2.9-2.4 (4H, m), 2.30 (1H, m), 1.96 (4H, m), 1.41 and 1.37 (9H combined, 2×s). MS ES Da/e 660 (M−1)− Cl35 100%, 662 (M−1) Cl37.
Reaction SMILES: [O:1]=[C:2](C)[CH2:3]CC(OCC)=O.BrBr.[C:13]([O:19]CC)(=[O:18])[CH2:14][C:15]([CH3:17])=O.C(OC)(=O)C=C>C(O)(=O)C>[O:1]=[C:2]([CH3:3])[CH2:17][CH2:15][CH2:14][C:13]([OH:19])=[O:18]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCOC(=O)CCC(C)=O
Agent: BrBr
Solvent: CC(=O)O
Solvent: C=CC(=O)OC
Product: CC(=O)CCCC(=O)O

Procedure:
Appropriate α-bromoketone 21b was prepared by bromination of ethyl 4-oxopentanoate by bromine in acetic acid. α-bromoketone 21c was prepared according to literature (Lugtenburg J. et. al., Eur. J. Org. Chem. 2002, 189-2202) from ethyl acetoacetate and methyl acrylate in 1,4-addition reaction and subsequent decarboxylation under acidic conditions to give 5-oxohexanoic acid. Esterification and bromination gave α-bromoketone 21c (methyl 6-bromo-5-oxohexanoic acid) in 4 step procedure. α-Chloroketone 21a
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11](=O)([O-])[O-].[K+].[K+].IC>O.CCOC(C)=O>[Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cccc(O)c1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: O
Product: COc1cccc(C=O)c1Br
Reaction time: 0.08 h

Procedure:
To a solution of 2-bromo-3-hydroxybenzaldehyde (0.5 g, 2.4 mmol) was added potassium carbonate (0.77 g, 5.6 mmol), and the mixture was stirred for 5 minutes. Iodomethane (0.17 mL, 2.7 mmol) was added, and the reaction was stirred at room temperature for 2 hours. The mixture was diluted with H2O (30 mL) and EtOAc (30 mL), and the organic layer was washed with 1N aqueous NaOH, then brine, dried over Na2SO4, decanted, and concentrated. The residue was purified by silica gel chromatography (0-60% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.Cl.C(O)CCCCCCC.[Sn]>O>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([OH:11])=[CH:3][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: Cl
Agent: [Sn]
Solvent: CCCCCCCCO
Solvent: O
Product: Nc1ccc(O)cc1F
Yield: 95.3 %

Procedure:
The 14 g (0.09 mol) of 3-fluoro-4-nitrophenol from above was combined with 55 mL (0.66 mol) of concentrated HCl, 55 mL of H2O, and 0.5 mL of octanol and stirred mechanically. To this mixture was added 33 g (0.28 mol) of mossy tin and the mixture was heated on a steam bath to initiate the reaction. After the reaction had subsided (8-10 minutes), 92 mL of concentrated HCl in 160 mL of water was added. The reaction was stirred on the steam bath for 1/2 hour and filtered hot. The filtrate was cooled and made basic with solid sodium bicarbonate. The resulting salts were filtered off and washed with ethyl acetate. The filtrate was extracted three times with ethyl acetate; all of the ethyl acetate extracts were combined, washed twice with saturated sodium chloride solution, and dried over magnesium sulfate. The solvent was stripped in vacuo and the resulting residue dissolved and stripped twice with toluene then ethanol then acetonitrile. The solid residue was triturated in hexane, filtered and washed to yield 10.9 g (96%) of 4-amino-3-fluorophenol, mp 138°-140° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:22]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=3[Cl:31])=[C:21]([F:32])[C:12]3[N:13]=[CH:14][N:15]([CH2:16][CH2:17][CH2:18][CH2:19]Cl)[C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1.[I-].[Na+].[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>C(OCC)(=O)C>[CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:22]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=3[Cl:31])=[C:21]([F:32])[C:12]3[N:13]=[CH:14][N:15]([CH2:16][CH2:17][CH2:18][CH2:19][N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]4)[C:11]=3[CH:10]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: O=C(NOCC1CC1)c1cc2c(ncn2CCCCCl)c(F)c1Nc1ccc(Br)cc1Cl
Reactant: CN1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN1CCN(CCCCn2cnc3c(F)c(Nc4ccc(Br)cc4Cl)c(C(=O)NOCC4CC4)cc32)CC1
Yield: 73.1 %

Procedure:
A solution of 6-(4-bromo-2-chloro-phenylamino)-3-(4-chloro -butyl)-7-fluoro-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide 18ee (10 mg, 0.018 mmol), sodium iodide (14 mg, 0.092 mmol), and 1-methyl-piperazine (10 μL, 0.092 mmol) are stirred at 85° C. for three hours. The reaction mixture is diluted with ethyl acetate and washed three times with water, washed twice with saturated aqueous potassium carbonate, dried (Na2SO4) and concentrated under reduced pressure to a yellow oil. Flash column chromatography (1:1 dichloromethane/methanol followed by methanol followed by 20:1 methanol/triethylamine) yields clean product (8 mg, 72%) as an off-white foam. MS ESI (+) m/z 607, 609 (M+, Br pattern) detected. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.71 (s, 1H), 7.49 (d, 1H), 7.18 (dd, 1H), 6.40 (dd, 1H), 4.38 (t, 2H), 3.62 (d, 2H), 2.45 (broad, 8H), 2.41 (t, 2H), 2.28 (s, 3H), 1.96 (m, 2H), 1.54 (m, 2H), 1.07 (m, 1H), 0.50 (d, 2H), 0.22 (d, 2H).
Reaction SMILES: O1CCCC1.[CH3:6][CH:7]([OH:10])[CH2:8][CH3:9].[H-].[Na+].[Br:13][C:14]1[N:31]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:17]2[CH:18]=[N:19][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21](=[O:22])[C:16]=2[C:15]=1[CH2:40]Br>O>[Br:13][C:14]1[N:31]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:17]2[CH:18]=[N:19][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21](=[O:22])[C:16]=2[C:15]=1[CH2:40][O:10][CH:7]([CH2:8][CH3:9])[CH3:6]
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CBr)c(Br)n2COCC[Si](C)(C)C)c1=O
Reactant: CCC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(C)OCc1c(Br)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To 4 ml of dehydrated tetrahydrofuran solution containing 0.96 ml of 2-butanol was added 0.30 g of sodium hydride (60% dispersed material in mineral oil), and the mixture was stirred at room temperature for 3 hours. Then, 0.85 g (1.50 mmol) of 2-bromo-3-bromomethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 25-(a) was added to the mixture under cooling in ice-bath, and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed successively with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1→4:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 0.46 g of the title compound as a colorless oil. (Yield: 55%)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)(=[O:25])=[O:24].[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][NH2:40])[CH:34]=1>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:40][CH2:39][C:35]3[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=3)=[O:19])=[CH:20][CH:21]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)(=[O:24])=[O:25]
Reactant: NCc1cccnc1
Reactant: Cc1cccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)c1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1cccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4cccnc4)cc3)oc2C)c1
Yield: 39.8 %

Procedure:
Reaction of oxalyl chloride (56 λL, 0.64 mmol) and benzoic acid 32 (158 mg, 0.43 mmol) with subsequent coupling to 3-pyridinylmethylamine (48 λL, 0.47 mmol) gave benzamide 33 (79 mg, 40%) as a white powder: mp (EtOAc) 179-181° C.; 1H NMR δ 9.20 (t, J=5.8 Hz, 1H, CONH), 8.57 (d, J=1.8 Hz, 1H, H-2′), 8.47 (dd, J=4.7, 1.6 Hz, 1H, H-6′), 8.00 (d, J=8.5 Hz, 2H, H-2, H-6), 7.90 (br d, J=8.5 Hz, 2H, H-3, H-5), 7.74 (dt, J=7.9, 1.9 Hz, 1H, H-4′), 7.63 (br s, 1H, H, H-2″) 7.53-7.60 (m, 2H, H-4″, H-6″), 7.50 (t, J=7.6 Hz, 1H, H-5″), 7.36 (ddd, J=7.9, 4.7, 0.5 Hz, 1H, H-5′), 4.65 (s, 2H, CH2SO2), 4.51 (d, J=5.8 Hz, 2H, CH2N), 2.37 (s, 3H, CH3), 2.16 (s, 3H, CH3); 13C NMR δ 165.4, 157.9, 149.9, 148.8, 148.0, 139.0, 138.3, 135.3, 135.1, 134.8, 134.3, 128.9, 128.7, 128.3, 128.0 (2), 125.8, 125.3 (2), 125.2, 123.3, 52.8, 40.4, 20.6, 9.67; MS m/z 462.8 (MH+, 100%). Anal. calcd for C25H23N3O4S: C, 64.06, 5.02; N, 9.10. Found: C, 64.76; H, 5.06; N, 9.05%.