Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:16]>>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH2:12])=[O:16])=[CH:13][CH:14]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Reactant: O=S(=O)(O)O
Product: NC(=O)c1ccc(N2CCNCC2)cc1
Yield: 19.5 %

Procedure:
To 8.0 g (0.04 mole) of 4-(1-piperazinyl)benzonitrile was added, with stirring, 50.0 ml (0.87 mole) of 93% sulfuric acid over a 15 min period. The mixture was stirred overnight and the resulting suspended amide was collected by filtration, rinsed with water, and allowed to air dry. The solid was recrystallized from absolute ethanol to give 1.6 g (20%) of white solid, m.p. 240°-243° C.
Reaction SMILES: Cl.[CH3:2][C:3]1([NH2:9])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[I-].C([N+]1(C)[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)C.C([O-])(O)=O.[Na+]>C(O)C.O.C(O)C.O>[CH3:2][C:3]1([N:9]2[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: CC1(N)CCOCC1
Reactant: CC[N+]1(C)CCC(=O)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: CC1(N2CCC(=O)CC2)CCOCC1
Temperature: 85 °C
Yield: 39.7 %

Procedure:
A stirred solution of 4-methyltetrahydro-2H-pyran-4-amine hydrochloride (D11) (640 mg, 4.22 mmol) in ethanol (20 mL) and H2O (10 mL) at room temperature was treated with potassium carbonate (417 mg, 3.02 mmol) and the stirring was maintained for 10 min under argon. The mixture was then heated to 85° C. and a solution of 1-ethyl-1-methyl-4-oxopiperidinium iodide (D13, 1.11 g, 4.11 mmol) in a mix of ethanol/H2O (8 mL, 1:1) was added over 15 min. The mixture was then refluxed for 2 extra hours. The mixture was then cooled to room temperature and poured onto an aqueous saturated solution of NaHCO3. The aqueous obtained was extracted with DCM (3×). Organics were combined and washed with H2O (1×), dried over Na2SO4, filtered and concentrated under vacuum. The crude product was then purified via chromatography (silica, DCM to 5% MeOH/95% DCM). The title compound (D12) (322 mg, 37%) was obtained as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C@H:15]1[CH2:20][C@@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C@@H:18]([NH2:29])[C@@H:17]([CH3:30])[CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:31](=O)C1C=CC=CC=1.[B-]C#N.[Na+].C=O>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C@H:15]1[CH2:20][C@@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C@@H:18]([NH:29][CH3:31])[C@@H:17]([CH3:30])[CH2:16]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccccc1
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N
Agent: [Pd+2]
Agent: C=O
Agent: [B-]C#N
Solvent: CO
Product: CN[C@H]1[C@@H](C)C[C@@H](c2ccncc2NC(=O)OC(C)(C)C)C[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a solution of (+/−)-tert-butyl ((1R,2S,3S,5R)-5-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-2-amino-3-methylcyclohexyl)carbamate (1.0 equiv.) in MeOH (0.10 M) was added benzaldehyde (1.3 equiv.). After 3 hrs, sodium cyanotrihydroborate (2.5 equiv.) was added and the mixture was stirred at rt for 16 hrs. The reaction mixture was quenched by the addition of water, and volatiles were removed in vacuo. The mixture was extracted with ethyl acetate. The combined organic phases were dried with sodium sulfate, filtered and concentrated. The residue was dissolved in MeOH (0.10 M) and paraformaldehyde (5.0 equiv.) was added. After 16 hrs, sodium cyanotrihydroborate (5.0 equiv.) was added and the mixture was left stirred at rt for 16 hrs. The reaction was quenched by the addition of water, and volatiles were removed in vacuo. The mixture was extracted with DCM. The combined organic phases were dried with sodium sulfate, filtered, concentrated and purified by ISCO Chromatography. The product was dissolved in MeOH (0.10 M) and treated with Pd(OH)2 (0.50 equiv.) under H2 for 5 hrs at RT. The reaction was filtered through a pad of celite and the cake was washed with MeOH. The organics were concentrated to yield (+/−)-tert-butyl ((1R,2S,3S,5R)-5-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-3-methyl-2-(methylamino)cyclohexyl)carbamate in 75% yield. LC/MS (m/z)=435.2 (MH+), Rt=0.64 min.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>P(=O)(O)(O)O>[C:11]([C:5]1[S:1][C:2]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)=[CH:3][CH:4]=1)(=[O:13])[CH3:12]
Reactant: c1csc(-c2cccs2)c1
Reactant: CC(=O)OC(C)=O
Agent: O=P(O)(O)O
Product: CC(=O)c1ccc(-c2cccs2)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.40 g of 2,2'-bithiophene was dissolved in 8 ml of acetic anhydride and refluxed under nitrogen gas atmosphere. 6 drops of phosphoric acid (85%) was added and reacted for 5 hours. The reaction mixture was poured onto 200 g of crushed ice cubes and stirred for 1 h. The solid deposited was collected and vacuum distilled, 5-acetyl-2,2'-bithiophene 1.98 g was obtained at 148° C./0.8 mm-Hg and the melting point was 112°-113° C. The residue was recrystallized from dioxane and 0.25 g of 5,5'-diacetyl-2,2'-bithiophene with melting point of 236°-9° C. was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=3)[CH2:10][C:9]2=[O:25])=[CH:4][CH:3]=1.[CH2:26](Br)[CH:27]([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:26]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=3)[CH2:10][C:9]2=[O:25])=[CH:4][CH:3]=1)[CH:27]([CH3:29])[CH3:28]
Reactant: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(O)cc3)C2)cc1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(OCC(C)C)cc3)C2)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Methyl 4-[1-(4-hydroxyphenyl)-2-pyrrolidon-4-yl]methoxybenzoate (2.00 g), isobutyl bromide (2.58 ml) and potassium carbonate (3.24 g) are dissolved and suspended in dimethylformamide (20 ml) and the mixture is heated with stirring at 80° C. for 24 hours. The solvent is distilled off under reduced pressure and water is added to the resulting residue. The resulting precipitate is collected by filtration and recrystallized from about 20% aqueous methanol to give the desired product (2.11 g}, m.p. 117.5°-118.5° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:8]2[C:9]([C:13](OCC)=[O:14])=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[CH3:18]>CN(C=O)C>[CH3:18][C:5]1[N:6]=[C:7]2[N:8]3[C:4]=1[NH:3][C:13](=[O:14])[C:9]3=[CH:10][CH:11]=[CH:12]2
Reactant: CCOC(=O)c1cccc2nc(C)c(N)n12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2cccc3c(=O)[nH]c1n23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.1 %

Procedure:
To a suspension of 610 mg (15.3 mmol) of 60% sodium hydride (dispersion in oil) in 5 ml of DMF was added, while stirring at room temperature, a solution of 1.67 g (7.62 mmol) of 3-amino-5-ethoxycarbonyl-2-methyl-imidazo[1,2-a]pyridine in 5 ml of DMF. The mixture was stirred for 10 minutes, then for 30 minutes at 100° C. After cooling, the reaction mixture was poured into ice-water, and washed with chloroform. To the aqueous layer was added 6N-HCl to adjust the pH to 5-6. The resulting precipitates were collected by filtration, washed with water and diethyl ether, successively, and dried to afford 357 mg of the desired compound (27.0%, a brown solid).
Reaction SMILES: [O:1]1[CH2:5][C@@H:4]([NH2:6])[C@H:3]([NH2:7])[CH2:2]1.C([Li])CCC.[C:13](OC([O-])=O)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[Cl-].[Na+]>O1CCCC1>[C:16]([O:15][C:13](=[O:14])[NH:6][C@@H:4]1[CH2:5][O:1][CH2:2][C@H:3]1[NH2:7])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: N[C@@H]1COC[C@H]1N
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1COC[C@H]1N
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 26.2 %

Procedure:
A flame-dried round bottom flask under nitrogen was charged with dry tetrahydrofuran (17 mL) and ((3S,4S)-tetrahydro-3,4-furandiamine (170 mg, 1.70 mmol) prepared according to the procedures of Skarzewski, J., et al. Tetrahedron: Asymmetry 1997, 8 (11), 1861. The solution was cooled to −78° C., and 2.5 M n-butyl lithium in hexanes (700 μL, 1.75 mmol) was added. The resulting cloudy white suspension was warmed to 23° C., and the suspension became orange. After 10 min, tert-butyl dicarbonate (371 mg, 1.70 mmol) was added in one portion. An additional 100 mg-portion of tert-butyl dicarbonate was added after 10 min. The reaction was then poured into saturated aqueous sodium chloride (50 mL), and the aqueous layer was washed with ethyl acetate (4×20 mL). The combined organic layers were dried over sodium sulfate, concentrated, and the resulting residue was purified by flash chromatography (5-10% methanol in dichloromethane) to yield the desired amine (90 mg, 26%) as a yellow oil. MS (ESI) 203 (M+H).
Reaction SMILES: [O:1]1[CH:5]=[C:4](/[CH:6]=[N:7]/[S:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])[N:3]=[CH:2]1.[CH3:14][Mg]Br>ClCCl>[O:1]1[CH:5]=[C:4]([CH:6]([NH:7][S:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])[CH3:14])[N:3]=[CH:2]1
Reactant: CC(C)(C)S(=O)/N=C/c1cocn1
Reactant: C[Mg]Br
Solvent: ClCCl
Product: CC(NS(=O)C(C)(C)C)c1cocn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
In a round-bottomed flask, 2-methyl-propane-2-sulfinic acid 1-oxazol-4-yl-meth-(E)-ylideneamide (548 mg, 2.74 mmol) was dissolved in dichloromethane (9 ml). The reaction mixture was cooled to 0° C. and methylmagnesium bromide (3.0 M in diethyl ether, 1.0 ml, 3.0 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h then quenched with saturated aqueous NH4Cl and extracted with ethyl acetate (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to afford 588 mg of 2-methyl-propane-2-sulfinic acid (1-oxazol-4-yl-ethyl)-amide as a light yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]N3C4C=CC=CC=4N=N3)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43]([NH2:49])[CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([NH:49][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:22])([CH2:14][CH2:13]1)[CH2:16][CH2:17]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: CCCCCCN
Product: CCCCCCNC(=O)C12CCC(N(CC(=O)N3C[C@@H](F)C[C@H]3C#N)C(=O)OCc3ccccc3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and hexylamine (15.0 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-hexylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (42.7 mg).
Reaction SMILES: [Mg].[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1Br.[C:11]([O:16][CH2:17][C:18]([CH2:20][O:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[O:19])(=[O:15])[CH:12]([CH3:14])[CH3:13].S(=O)(=O)(O)O>C1COCC1>[C:11]([O:16][CH2:17][C:18]([C:4]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=1[F:2])([OH:19])[CH2:20][O:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])(=[O:15])[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)C(=O)OCC(=O)COC(=O)C(C)C
Reactant: Fc1ccc(Br)c(F)c1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)C(=O)OCC(O)(COC(=O)C(C)C)c1ccc(F)cc1F
Reaction time: 1 h
Yield: 84.6 %

Procedure:
Under an atmosphere of argon, 5 ml of THF was slowly added to 925 mg of magnesium turnings, and then thereto was added dropwise 7 g of 2,4-difluorobromobenzene dissolved in 30 ml of THF with keeping the temperature at 20° C. After the reaction mixture was stirred for 1 hour with keeping the temperature at 20° C., 7.9 g of 1,3-diisobutyryloxyacetone dissolved in 10 ml of THF was added dropwise thereto with keeping the temperature at 0° C. After the dropping, the reaction mixture was stirred for 4 hours and then the reaction was stopped by adding 35 ml of 1N sulfuric acid. The obtained liquid was extracted twice with 35 ml of ethyl acetate. The organic layer was washed with saturated aqueous solution with sodium bicarbonate and with saturated aqueous solution with sodium chloride, in turn. The solvent was removed under reduced pressure. Thus obtained concentrate was distilled under reduced pressure to give 10 g of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]2[CH:17]=[C:16]([N:18]3[C@@H:22]4[CH2:23][CH2:24][C@@H:25]([O:26][Si](C(C)(C)C)(C)C)[C@@H:21]4[O:20][C:19]3=[O:34])[N:15]=[C:14]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:13]=2)=[CH:4][N:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]2[CH:17]=[C:16]([N:18]3[C@@H:22]4[CH2:23][CH2:24][C@@H:25]([OH:26])[C@@H:21]4[O:20][C:19]3=[O:34])[N:15]=[C:14]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:13]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@@H]2[C@H]1OC(=O)N2c1cc(-c2cnc(N)nc2C(F)(F)F)nc(N2CCOCC2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Nc1ncc(-c2cc(N3C(=O)O[C@H]4[C@H](O)CC[C@H]43)nc(N3CCOCC3)n2)c(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
To a solution of (3aR*,6R*,6aR*)-3-(2′-amino-2-morpholino-4′-(trifluoromethyl)-[4,5′-bipyrimidin]-6-yl)-6-((tert-butyldimethylsilyl)oxy)hexahydro-2H-cyclopenta[d]oxazol-2-one (810 mg, 1.253 mmol) in THF (12 mL), was added dropwise 1M TBAF in THF (1.0 mL, 1.0 mmol) at 0° C. The reaction mixture was stirred for 30 min at 0° C. and 2 h at RT before evaporation. The residue was purified by flash chromatography (hexane-THF 60:40→0:100). The residue was triturated in Et2O, filtered and dried. The residue was purified by preparative HPLC (Waters Sun Fire C18, 30×100 mm, 5 um; 0.1% TFA-water/acetonitrile; gradient acetonitrile 5-100% in 20 min) to afford the title compound (430 mg, 72%); tR=0.93 min (UPLC 1), tR=0.81 min (LC-MS 3); ESI-MS: 468 [M+H]+ (LC-MS 3).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6](F)[C:3]=1[CH:4]=O.C(=O)([O-])[O-].[K+].[K+].Cl.CON.[NH2:22][NH2:23]>COCCOC.O>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]2[C:3]=1[CH:4]=[N:22][NH:23]2
Reactant: NN
Reactant: O=Cc1c(F)cc(F)cc1F
Agent: CON
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Fc1cc(F)c2cn[nH]c2c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
To a solution of 2,4,6-trifluorobenzaldehyde (0.80 g, 5.0 mmol) in 1,2-dimethoxyethane (10 mL) were added potassium carbonate (1.04 g, 7.5 mmol) and O-methylhydroxylamine hydrochloride (438 mg, 5.25 mmol). The reaction mixture was heated at 50° C. for 5 h then cooled to room temperature and filtered, rinsing with dichloromethane. The filtrate was concentrated. The residue was dissolved in 1,2-dimethoxyethane (10 mL) and hydrazine (0.17 mL, 5.5 mmol) was added. The reaction mixture was heated at 100° C. for 1.5 h. Additional hydrazine (0.17 mL, 5.5 mmol) was added and heating was continued for 30 min. Thereaction was cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with sat LiCl and brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 20% to 50% EtOAc/heptane to provide 358 mg (47%) of 4,6-difluoro-1H-indazole as a light yellow solid. 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 13.47 (br. s., 1H), 8.19 (s, 1H), 7.22 (d, J=9.1 Hz, 1H), 6.96 (td, J=10.0, 1.9 Hz, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13](CC3C=C(F)C=CC=3Br)[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1.[Cl:26][C:27]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:28]=1[CH2:29]Br>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:29][C:28]3[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:27]=3[Cl:26])[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1
Reactant: Clc1ccc(Cl)c(CBr)c1
Reactant: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2cc(F)ccc2Br)c1=O
Product: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2cc(Cl)ccc2Cl)c1=O

Procedure:
The title compound was prepared from compound 1 using the same procedures as in the preparation of compound 10, except that 2,5-di-chloro-benzyl bromide was used in the place of 2-bromo-5-fluoro-benzyl bromide. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1): 8 ppm 7.50 (d, J=8.6 Hz, 1 H), 7.39 (dd, J=8.3, 2.526 Hz, 1 H), 7.22 (d, J=2.5 Hz, 1 H), 5.41 (s, 1 H), 5.01-4.93 (ABq, J=41.9, 16.2 Hz, 2H), 3.25 (m, 2 H), 3.10 (s, 3H), 2.85 (m, 1 H), 2.76 (m, 1 H), 2.67 (m, 1 H), 1.91 (m, 1H), 1.75 (m, 1 H), 1.45 (m, 2 H). MS (ES) [m+H] calc'd for C17H21Cl2N4O2, 383.1; found 383.1.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]([Cl:16])=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(Cl)C(C)=CN(Cl)N=C1.[Br-].[F:28]C1C=CC(C[Zn+])=CC=1>>[Cl:16][C:11]1[N:10]=[N:9][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][C:5]([F:28])=[CH:6][CH:7]=2)=[C:13]([CH3:14])[C:12]=1[CH3:15]
Reactant: Cc1c(Cl)nnc(Cc2ccccc2)c1C
Reactant: Fc1ccc(C[Zn+])cc1
Agent: CC1=CN(Cl)N=CC1(C)Cl
Agent: [Br-]
Product: Cc1c(Cl)nnc(Cc2ccc(F)cc2)c1C

Procedure:
Analogous to compound 42 above, 3-chloro-6-(4-fluoro-benzyl)-4,5-dimethyl-pyridazine is prepared from 4,5-dimethyl-1,4-dichloro-pyridazine and para-fluoro benzyl zinc bromide.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[I:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([OH:18])=[O:17].[CH3:19]O>C(Cl)Cl>[CH3:19][O:17][C:16](=[O:18])[CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[I:8]
Reactant: CO
Reactant: O=C(O)Cc1ccccc1I
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Product: COC(=O)Cc1ccccc1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Trimethylsilyl diazomethane (15.3 ml, 30.6 mmol, 2.0 M in diethyl ether) was added dropwise to a stirred, cooled 0° C. solution of (2-iodophenyl)acetic acid (4.0 g, 15.3 mmol) and MeOH (10 ml) in CH2Cl2 (50 ml) and the solution was stirred at 0° C. for 1 hour. The yellow solution was purged with nitrogen for 10 minutes. The solvent removed in vacuo and the residue was azeotroped with THF (3×25 ml) to afford 4.2 g, 100% of 23-1 as a yellow oil.
Reaction SMILES: CC([O-])(C)C.[K+].CC1C=CC(S([CH2:17][N+:18]#[C-])(=O)=O)=CC=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH:24]=O.CO>C1COCC1.O>[Cl:20][C:21]1[CH:22]=[C:23]([CH2:24][C:17]#[N:18])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc(C=O)cc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CC#N)cc1Cl
Reaction time: 0.17 h
Yield: 82.6 %

Procedure:
To a suspension of t-BuOK (4.8 g, 40 mmol) in THF (30 mL) was added a solution of TosMIC (3.9 g, 20 mmol) in THF (10 mL) at −78° C. The mixture was stirred for 10 minutes, treated with a solution of 3-chloro-4-methoxy-benzaldehyde (1.65 g, 10 mmol) in THF (10 mL) dropwise, and continued to stir for 1.5 hours at −78° C. To the cooled reaction mixture was added methanol (10 mL). The mixture was heated at reflux for 30 minutes. Solvent of the reaction mixture was removed to give a crude product, which was dissolved in water (20 mL). The aqueous phase was extracted with EtOAc (20 mL×3). The combined organic layers were dried and evaporated under reduced pressure to give crude product, which was purified by column chromatography (Petroleum Ether/EtOAc 10:1) to afford 2-(3-chloro-4-methoxyphenyl)acetonitrile (1.5 g, 83%). 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=2.4 Hz, 1H), 7.20 (dd, J=2.4, 8.4 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 3.91 (s, 3H), 3.68 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 154.8, 129.8, 127.3, 123.0, 122.7, 117.60, 112.4, 56.2, 22.4.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[N:32]1[CH:36]=[N:35][CH:34]=[N:33]1)[C:26](O)=[O:27]>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:20])([F:19])[F:21])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:31]([N:32]3[CH:36]=[N:35][CH:34]=[N:33]3)=[C:23]([F:22])[CH:24]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(-n2cncn2)c(F)c1
Reactant: Fc1cc(C(F)(F)F)cnc1N1CCC(NC2CC2)CC1
Product: O=C(c1ccc(-n2cncn2)c(F)c1)N(C1CC1)C1CCN(c2ncc(C(F)(F)F)cc2F)CC1

Procedure:
The title compound is prepared from cyclopropyl-(3′-fluoro-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amine and 3-fluoro-4-[1,2,4]triazol-1-yl-benzoic acid following a procedure analogous to that described in Example 90. LC (method 19): tR=4.44 min; Mass spectrum (ESI+): m/z=493 [M+H]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[S:5]1(=[O:14])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1.[Br:15][CH2:16][C:17](Cl)=[O:18]>CN(C)C=O>[Br:15][CH2:16][C:17]([C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[CH:6][S:5](=[O:14])[C:9]=2[CH:10]=1)=[O:18]
Reactant: O=S1C=Nc2ccccc21
Reactant: O=C(Cl)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C(CBr)c1ccc2c(c1)S(=O)C=N2

Procedure:
210 g (1.60 mol) of aluminum chloride are introduced into a 500-cm3 ground-necked flask surmounted by a condenser, and 43 cm3 of dimethylformamide are then added dropwise and with magnetic stirring via a dropping funnel. 30.2 g (0.2 mol) of benzothiazolinone are then added and, while the reaction medium homogenizes, the temperature is stabilized at 70° C. using an oil bath. 19.8 cm3 (0.24 mol) of bromoacetyl chloride are then introduced gradually. After the addition, the mixture is left stirring for one hour at a temperature of 70° C. The reaction medium is hydrolyzed by pouring it onto crushed ice and the precipitate obtained is drained, washed copiously with water and dried. The product is recrystallized in dioxane.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:20](=[O:21])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C.[F:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[CH:40][CH:39]=1.[I-].[K+]>CN(C=O)C>[F:37][C:38]1[CH:39]=[CH:40][C:41]([N:44]2[CH2:49][CH2:48][N:47]([CH2:2][CH2:3][CH2:4][CH:5]3[C:20](=[O:21])[C:9]4[C:10]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[F:19])=[N:11][O:12][C:8]=4[CH2:7][CH2:6]3)[CH2:46][CH2:45]2)=[CH:42][CH:43]=1
Reactant: O=C1c2c(-c3ccccc3F)noc2CCC1CCCCl
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2c(-c3ccccc3F)noc2CCC1CCCN1CCN(c2ccc(F)cc2)CC1
Temperature: 80 °C
Yield: 47 %

Procedure:
To a solution consisting of 5-(3-chloropropyl)-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one (5.8 g) and DMF (100 ml) was added anhydrous potassium carbonate (1.3 g), diisopropylethyl amine (4.9 ml), 1-(4-fluorophenyl)piperazine (4.1 g) and potassium iodide (0.3 g) at room temperature with stirring. The flask was flushed with nitrogen and warmed to 80° C. for 13.5 hours. Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous phase was extracted 3 times with ethyl acetate. The combined organic layers were washed with water twice, brine, and then dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, 2% triethylamine/ether) afforded 4.0 g of 6,7-dihydro-5-[3-(4-(4-fluorophenyl)-1-piperazinyl)-propyl]-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one as an oil. The product was flushed thru alumina with ether. The hydrochloride was prepared in ether with ethereal HCl. The precipitate was filtered and washed with pentane, m.p. 161°-164° C.