Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:9])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Br)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(Br)cc1
Yield: 59.3 %

Procedure:
To a suspension of 4-bromotoluene (60 g) and N-bromosuccinimide (69 g) in carbon tetrachloride (300 ml) was added 2,2'-azobis(isobutylonitrile) (0.1 g). The resulting mixture was heated under reflux for 2 hours. After the reaction mixture was cooled, succinimide so precipitated was removed by filtration, and the filtrate was washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous magnesium sulfate, followed by removal through distillation. The oily substance so obtained was crystallized from n-hexane, whereby 52 g of the title compound was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:15])[C:9]=2[CH:8]=[CH:7]1.OC(C)(C)CC(=O)C.[I-].[Na+].[F:26][C:27]([F:41])([F:40])[C:28]1[CH:29]=[C:30]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.ClCCl.C(OCC)(=O)C.ClCCl>[F:41][C:27]([F:26])([F:40])[C:28]1[CH:29]=[C:30]([N:34]2[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:14]4[CH2:13][CH2:12][CH2:11][C:10](=[O:15])[C:9]=4[CH:8]=[CH:7]3)[CH2:36][CH2:35]2)[CH:31]=[CH:32][CH:33]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: O=C1CCCc2c1ccn2CCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)(C)O
Solvent: ClCCl
Solvent: CC#N
Product: O=C1CCCc2c1ccn2CCCCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
A mixture of 1-(4-Chlorobutyl)-1,5,6,7-tetrahydroindol-4-one (6.0 g, 26.6 mmol, as a mixture with 3.0 g of 4-hydroxy-4-methyl-2-pentanone) and sodium iodide (4.38 g, 29.2 mmol) in acetonitrile (100 mL) was heated at reflux for 6 h. (3-Trifluoromethylphenyl)piperazine (5.81 g, 25.2 mmol) and potassium carbonate (3.67 g, 26.6 mmol) was then added and reflux continued for 16 h. TLC (ethyl acetate:dichloromethane 1:1) showed complete reaction. The reaction was poured into ice cold water (400 mL) and stirred for 0.5 h. An oil separated out and was isolated from the mixture. The oil was dissolved with dichloromethane (150 mL), washed with water and brine, then dried with sodium sulfate, filtered and the solvent removed under vacuum to yield the title compound as an oil (9.7 g, 91.5%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH3:14])=[C:8]([NH2:10])[CH:9]=1)([O-])=O>CC#N>[CH2:12]([O:11][C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][C:8]=1[NH2:10])[CH2:13][CH3:14]
Reactant: CCCOc1ccc([N+](=O)[O-])cc1N
Solvent: CC#N
Product: CCCOc1ccc(N)cc1N

Procedure:
4-Propoxybenzene-1,3-diamine (D-5) was synthesized following the general scheme above starting from 5-nitro-2-propoxy-phenylamine. Yield (79%). HPLC ret. time 0.54 min, 10-99% CH3CN, 5 min run; ESI-MS 167.5 m/z (MH+).
Reaction SMILES: [C:1]([C:4](=[CH:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[C:5]([O:7]CC)=O)(=[O:3])[CH3:2]>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:1]([C:4]1[C:5](=[O:7])[C:17]2[C:12](=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=CNc1ccccc1OC)C(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cccc2c(=O)c(C(C)=O)c[nH]c12
Yield: 30.6 %

Procedure:
Ethyl 2-acetyl-3-(2-methoxyphenylamino)acrylate (48 g) was added in portions to boiling diphenyl ether (250 ml) and the mixture heated under reflux for 1 hour. The mixture was cooled and crystallised from a 1:1 mixture of ether and petroleum ether. The solid was filtered off and triturated with boiling ethanol to give 3-acetyl-8-methoxy-4(1H)-quinolone as a brown solid (12.1 g, 31%), m.p. 287°-289°.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:17]([O:19]C(C)(C)C)=[O:18])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=2)O1>O.C1(C)C=CC=CC=1.C(O)C.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>[NH2:38][C:35]1[N:36]=[CH:37][C:32]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3([C:17]([OH:19])=[O:18])[CH2:15][CH2:16]3)=[CH:12][CH:13]=2)=[CH:33][N:34]=1
Reactant: CC(C)(C)OC(=O)C1(c2ccc(Br)cc2)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
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: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ncc(-c2ccc(C3(C(=O)O)CC3)cc2)cn1
Temperature: 120 °C
Yield: 60.3 %

Procedure:
A solution of sodium carbonate (0.56 g, 0.0052 mol) in water (5.0 mL) was added to a mixture of tert-butyl 1-(4-bromophenyl)cyclopropanecarboxylate (0.78 g, 0.0026 mol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.87 g, 0.0039 mol), and tetrakis(triphenylphosphine)palladium (0.2 g, 0.0001 mol) in toluene (10 mL) and ethanol (5 mL). The resulting mixture was heated at 120° C. for 15 min, quenched with water (5 mL), and washed with ether (3×10 mL). The precipitate in the aqueous layer was filtered, washed with water, and dried to afford the desired product (0.40 g, 60%). LCMS: (M+H)=256.1.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:36]2[N:37](C(OC(C)(C)C)=O)[CH:38]=[CH:39][CH:40]=2)O1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:36]3[NH:37][CH:38]=[CH:39][CH:40]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)n1cccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccc[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 6 using (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 22.1) and tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1-carboxylate to afford a grey solid. UPLC-MS (Condition 3) tR=1.06 min, m/z=449.2 [M+H]+, m/z=447.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.77 (m, 1H) 1.77-1.93 (m, 1H) 2.98 (d, J=12.23 Hz, 1H) 3.21-3.29 (m, 2H) 3.37-3.51 (m, 1H) 4.19 (d, J=2.20 Hz, 1H) 4.81 (d, J=3.42 Hz, 1H) 6.02-6.18 (m, 2H) 6.70-6.88 (m, 1H) 7.32 (d, J=9.05 Hz, 2H) 7.79-7.94 (m, 2H) 8.02 (d, J=2.45 Hz, 1H) 8.70 (d, J=2.45 Hz, 1H) 10.15 (s, 1H) 11.10 (d, J=1.47 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([CH:23]=O)=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:25][CH3:26].[Br-].[Cl:28][C:29]1[CH:54]=[C:53]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH:52]=[C:51]([F:60])[C:30]=1[CH2:31][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1CCN2C(=NCCC2)CC1>CC#N.O>[Cl:28][C:29]1[CH:54]=[C:53]([CH:52]=[C:51]([F:60])[C:30]=1[CH:31]=[CH:23][C:14]1[N:15]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[C:11]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:25][CH3:26])[CH:4]=2)([CH3:10])[CH3:9])=[CH:12][N:13]=1)[C:55]([O:57][CH2:58][CH3:59])=[O:56]
Reactant: CCOC(=O)c1cc(F)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1
Reactant: COc1cc(C(C)(C)c2cnc(C=O)n2-c2ccc(F)cc2)ccc1Cl
Agent: [Br-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCOC(=O)c1cc(F)c(C=Cc2ncc(C(C)(C)c3ccc(Cl)c(OC)c3)n2-c2ccc(F)cc2)c(Cl)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
To a mixture of 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-carbaldehyde (304 mg, 0.815 mmol) and (2-chloro-4-(ethoxycarbonyl)-6-fluorobenzyl)triphenylphosphonium bromide (454 mg, 0.815 mmol) in MeCN (5 mL) was added dropwise DBU (136 mg, 0.896 mmol). After stirring at 50° C. overnight, the mixture was diluted with H2O and extracted with DCM. The combined extracts were dried (MgSO4), filtered, concentrated and purified by flash chromatography (20-90% EtOAc/hexanes) to yield ethyl 3-chloro-4-(2-(5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)vinyl)-5-fluorobenzoate (0.241 g, 51%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 8.05-7.87 (m, 3H), 7.85-7.58 (m, 13H), 7.20 (tt, J=15.1, 7.1 Hz, 1H), 5.21 (d, J=15.0 Hz, 2H), 4.34 (dq, J=14.2, 7.1 Hz, 2H), 1.33 (dt, J=14.2, 7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][CH3:8])=[C:5]([C:9]2[CH:10]=[C:11]([C:14]([O:16]C)=[O:15])[S:12][CH:13]=2)[N:4]([CH3:18])[N:3]=1.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:6]([CH2:7][CH3:8])=[C:5]([C:9]2[CH:10]=[C:11]([C:14]([OH:16])=[O:15])[S:12][CH:13]=2)[N:4]([CH3:18])[N:3]=1
Reactant: CCc1c(Cl)nn(C)c1-c1csc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1c(Cl)nn(C)c1-c1csc(C(=O)O)c1
Yield: 87.2 %

Procedure:
A solution of methyl 4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (135 mg, 0.47 mmol) in 6N sodium hydroxide (1.6 ml, 9.48 mmol) and tetrahydrofuran (5.4 ml) was stirred at 70° C. in a sealed tube for 12 h. The resulting solution was cooled and then partitioned between H2O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated affording 4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (120 mg, 0.41 mmol, 87% yield) as a white foam: LCMS (ES) m/e 270, 272 (M, M+2)+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[N+:5]([O-:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:3]=1.[F:18][B-:19]([F:22])([F:21])[F:20].[CH3:23][O+](C)C>ClCCl>[F:18][B-:19]([F:22])([F:21])[F:20].[CH3:23][O:7][N+:5]1[N:4]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:17])[F:16])=[CH:12][CH:13]=2)[N:3]=[C:2]([CH3:1])[CH:6]=1
Reactant: C[O+](C)C
Reactant: Cc1c[n+]([O-])n(-c2ccc(C(F)(F)F)cc2)n1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CO[n+]1cc(C)nn1-c1ccc(C(F)(F)F)cc1
Temperature: 23 °C
Reaction time: 65 h

Procedure:
To a stirred solution of 4-methyl-2-[4-(trifluoromethyl)phenyl]-2H-1,2,3-triazole 1-oxide (i.e. the product of Step A, 5.22 g, 21.5 mmol) in dichloromethane (100 mL) was added trimethyloxonium tetrafluoroborate (4.13 g, 27.9 mmol). The reaction mixture was stirred at 23° C. for 65 h, then concentrated under reduced pressure to afford a crude mixture of the title compound as a brown oil which was used directly in the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:38]=[CH:37][C:8]([CH2:9][N:10]2[C:22]3[C:21]4[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:20]=4[CH2:19][CH2:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[C:14]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:15]=3)=[CH:7][CH:6]=1.[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.O>CN(C=O)C>[CH3:28][O:27][C:25]1[CH:24]=[CH:23][C:21]2[C:22]3[N:10]([CH2:9][C:8]4[CH:37]=[CH:38][C:5]([O:4][CH2:3][CH2:2][N:39]5[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]5)=[CH:6][CH:7]=4)[C:11]4[C:16]([C:17]=3[CH2:18][CH2:19][C:20]=2[CH:26]=1)=[CH:15][C:14]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:13][CH:12]=4
Reactant: COc1ccc2c(c1)CCc1c-2n(Cc2ccc(OCCCl)cc2)c2ccc(OCc3ccccc3)cc12
Reactant: C1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCc1c-2n(Cc2ccc(OCCN3CCCCC3)cc2)c2ccc(OCc3ccccc3)cc12
Temperature: 65 °C

Procedure:
Intermediate #18, 11-[4-(2-Chloroethoxy)-benzyl]-8-benzyloxy-3-methoxy-5,11-dihydro-6H-benzo[a]carbazole, (6 g, 11.5 mmol) in DMF was treated with KI (2.5 g, 15.0 mmol) and piperidine (12 mL) and heated to 65° C. for 18 hours. The reaction was worked up by pouring the crude reaction mixture into water and extracting with ethyl acetate. The ethyl acetate layer was washed with NaHCO3 aq., brine and dried over MgSO4. The resultant was chromatographed on silica gel using CH2Cl2 (100%), CH2Cl2 :MeOH (98:2), CH2Cl2 :MeOH (96:4) as the eluting solvents. The product (3.2 g) was isolated as an oil: 1H NMR (DMSO) 7.52-7.12 (m, 8 H), 6.98-6.82 (m, 5 H), 6.80 (dd, 1 H, J=8.4 Hz, 2.6 Hz), 6.73 (dd, 1 H, J=8.8 Hz, 2.4 Hz), 5.56 (s, 2 H), 5.11 (s, 2 H), 3.98 (t, 2 H, J=6.0 Hz), 3.70 (s, 3 H), 2.85-278 (m, 2 H), 2.75 (s, 2 H), 2.60 (t, 2 H, J=6.5 Hz), 2.42-2.38 (m, 4 H), 1.70-158 (m, 4 H), 1.58-1.35 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][NH2:16].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][C:26](Cl)=[O:27].Cl>O1CCCC1.O>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:13])([F:14])[F:12])=[CH:4][C:3]=1[N:15]1[CH:24]=[CH:25][C:26]([OH:27])=[N:16]1
Reactant: Cc1cc(F)c(NN)cc1SCC(F)(F)F
Reactant: O=C(Cl)CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(F)c(-n2ccc(O)n2)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.2 %

Procedure:
12 g of 2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenylhydrazine was dissolved in 200 mL of tetrahydrofuran, and 100 mL of water was added. To this solution, 16 g of potassium carbonate and 8.1 g of 3-bromopropionyl chloride were added, followed by stirring at room temperature for 5 hours. The aqueous layer was neutralized to the vicinity of pH 2 with 6N hydrochloric acid. Then, the solvent was distilled off under reduced pressure, and the residue was subjected to extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a solid, which was washed with hexane. Then, this solid was dissolved in 200 mL of toluene, and 100mL of water was added. Then, 3.7 g of potassium permanganate and tetra n-butyl ammonium bromide in a catalytic amount were added, followed by stirring at room temperature for 10 minutes. Then, an insoluble solid was removed by filtration, and the organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the solid was washed with hexane to obtain 8.7 g of pale yellow crystals (melting point: 166-168° C.).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[NH:15][C:14](=[O:18])[C:13](C(O)=O)=[N:12]2)=[C:7]([F:22])[CH:6]=1)([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>SCC(O)=O>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[NH:15][C:14](=[O:18])[CH:13]=[N:12]2)=[C:7]([F:22])[CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(-n2nc(C(=O)O)c(=O)[nH]c2=O)c(F)c1
Agent: O=C(O)CS
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(-n2ncc(=O)[nH]c2=O)c(F)c1
Yield: 14.9 %

Procedure:
A solution of 4.70 g (0.0152 mole) of 2-(4-isopropoxy-2-fluorophenyl)-1,2,4-triazine-3,5-dion-6-carboxylic acid in 5 mL of mercaptoacetic acid was heated at 140°-145° C. for two hours under a nitrogen atmosphere. After this mixture had cooled, it was poured into 250 mL of a saturated aqueous solution of sodium bicarbonate with vigorous stirring. An equal volume of ethyl acetate was added to this mixture, and the resulting layers were separated. The organic layer was washed twice with 150 mL of a saturated aqueous solution of sodium bicarbonate and once with 150 mL of a saturated aqueous solution of sodium chloride. The organic solution was then dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, leaving a syrup which slowly crystallized to a yellow-orange solid upon standing. This solid was recrystallized from ethyl acetate/petroleum ether (1:1), yielding 0.60 g of 2-(4-isopropoxy-2-fluorophenyl)-1,2,4-triazine-3,5-dione as a yellow solid. The NMR was consistent with the proposed structure. This reaction was repeated to obtain additional material for subsequent reactions.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].NC1C=CC=CC=1C(N)=O.[CH3:21][O:22][CH2:23][CH2:24]O>[Ni]>[CH3:21][O:22][CH2:23][CH2:24][NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6]
Reactant: COCCO
Reactant: NC(=O)c1cccc(N)c1
Agent: [Ni]
Agent: NC(=O)c1ccccc1N
Product: COCCNc1cccc(C(N)=O)c1

Procedure:
10 g of 3-aminobenzamide and 30 g of rainy nickel were mixed with 150 ml of 2-methoxy ethanol and refluxed for 15 hours. (Molar ratio of aminobenzamide:solvent=1:26.) Celite was added to the reaction mixture and the debris removed by filtration. The filtrate was then evaporated under reduced pressure and the product, 3-(2-methoxyethylamino)benzamide crystallized on cooling, mp 89°-91° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)([CH3:22])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)O)[CH3:2].B(F)(F)F.CCOCC.C([SiH](CC)CC)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)([CH3:22])[CH2:6][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Oc1cccc(F)c1)C(O)c1ccc(OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(4Benzyloxyphenyl)-3-hydroxy-2-(3-fluorophenoxy)-2-methylpropionic acid ethyl ester (9.5 mmol) in anhydrous CH2Cl2 (30 mL) was cooled to 0° C. and treated with BF3-Et2O (1.16 mL, 9.5 mmol) and triethylsilane (1.51 mL 9.5 mmol). The mixture was stirred for 2 h and gradually warmed to ambient temperature. Saturated aqueous Na2CO3 (15 mL) was added and the mixture was stirred vigorously. The solution was partitioned and the organic layer was washed twice with water and brine, dried over Na2SO4, and concentrated in vacuo to produce 3-(4-benzyloxyphenyl)-2-(3-fluorophenoxy)-2-methylpropionic acid ethyl ester as an oil.
Reaction SMILES: [OH:1][C:2]([CH3:14])([CH3:13])[CH2:3][CH2:4][CH2:5][C@H:6]([CH3:12])[CH2:7][CH2:8][CH2:9][CH:10]=[O:11].C(Cl)Cl.[Si:18](Cl)([CH3:21])([CH3:20])[CH3:19]>CN(C1C=CN=CC=1)C.CCN(CC)CC>[CH3:12][C@@H:6]([CH2:5][CH2:4][CH2:3][C:2]([CH3:13])([O:1][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[CH2:7][CH2:8][CH2:9][CH:10]=[O:11]
Reactant: C[C@H](CCCC=O)CCCC(C)(C)O
Reactant: C[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](CCCC=O)CCCC(C)(C)O[Si](C)(C)C
Reaction time: 0.5 h

Procedure:
3.10 g of (S)-9-hydroxy-5,9-dimethyl-decanal was dissolved in 60 ml of abs. CH2Cl2 and treated successively at 0° with 57 mg of DMAP, 7.0 ml of NEt3 and 3.1 ml of TMS-Cl. The reaction mixture was kept for 30 minutes at RT and then poured onto crushed ice, extracted twice with ether, washed twice with water and brine, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=95/5) yielded 3.90 g of (S)-5,9-dimethyl-9-trimethylsilanyloxy-decanal as colorless oil, 98.6% pure according to GC.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[CH2:12][N:11]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][C@@H:25]([CH3:30])[C:26]([F:29])([F:28])[F:27])=[O:17])[CH2:10]3)[CH2:3][CH2:2]1.[Cl:31][S:32](O)(=[O:34])=[O:33]>ClCCCl>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[CH2:12][N:11]([C:16]([C:18]2[CH:23]=[C:22]([S:32]([Cl:31])(=[O:34])=[O:33])[CH:21]=[CH:20][C:19]=2[O:24][C@@H:25]([CH3:30])[C:26]([F:29])([F:27])[F:28])=[O:17])[CH2:10]3)[CH2:3][CH2:2]1
Reactant: C[C@H](Oc1ccccc1C(=O)N1Cc2ccc(C3CCOCC3)cc2C1)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Solvent: ClCCCl
Product: C[C@H](Oc1ccc(S(=O)(=O)Cl)cc1C(=O)N1Cc2ccc(C3CCOCC3)cc2C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
A solution of 0.2 g (0.47 mmol) [5-(tetrahydro-pyran-4-yl)-1,3-dihydro-isoindol-2-yl]-[2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone in 2 ml of 1,2-dichloroethane was added dropwise to 0.32 ml (4.7 mmol) chlorosulfonic acid under ice bath cooling. The mixture was stirred at room temperature for 30 minutes and then at 55° C. for 30 minutes. The mixture was cooled in an ice bath and quenched by dropwise addition of 2 ml water. The mixture was diluted with dichloromethane. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined dichloromethane extracts were dried over Na2SO4, filtered and concentrated in vacuo. The obtained foam was stirred with ethylacetate. The solid was filtrated. The filtrate was washed twice with a saturated solution of NaHCO3, dried over Na2SO4, filtered and concentrated in vacuo to provide 0.12 g (51%) of the title compound as light yellow foam. MS (m/e): 517.1 [M]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[N:14][N:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C:12](=[O:22])[CH:11]=2)=[N:6][CH:7]=1.OC1C=NN(C2CCCCO2)C(=O)C=1.Br.BrCC1C=CC=CN=1>>[N:6]1[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=1[CH2:8][O:9][C:10]1[CH:15]=[N:14][N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:12](=[O:22])[CH:11]=1
Reactant: O=c1cc(OCc2ccc(Br)cn2)cnn1C1CCCCO1
Agent: Br
Agent: BrCc1ccccn1
Agent: O=c1cc(O)cnn1C1CCCCO1
Product: O=c1cc(OCc2ccccn2)cnn1C1CCCCO1

Procedure:
5-(Pyridin-2-ylmethoxy)-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one is prepared following preparation 25a from 2.00 g (10.2 mmol) 5-hydroxy-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (preparation 5a) and 2.58 g (10.2 mmol) 2-bromomethyl-pyridine hydro-bromide.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[BH4-].[Na+].[Cl-].[NH4+].O>CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[CH:4]=[O:5]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
43.3 g of 2-fluoro-4-nitrobenzoic acid was dissolved in 600 ml of dimethylformamide, and 1,1′-carbodiimide was added to it, and stirred at room temperature for 2 hours. 11.1 g of sodium borohydride was added thereto, and further stirred for 30 minutes. Aqueous saturated ammonium chloride solution was added to it, 800 ml of water was added thereto, extracted with 1.2 liters of ethyl acetate, and the organic layer was washed with saturated saline water. The solvent was evaporated away under reduced pressure, the residue was again diluted with ethyl acetate, and the organic layer was washed with water and saturated saline water. This was dried with anhydrous sodium sulfate, and the solvent was evaporated away to obtain 32.7 g of a brown oil.