Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[C:4]([NH:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[CH:9][C:8]=1[F:14])=O.S(Cl)([Cl:22])=O>>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[C:4]([Cl:22])=[N:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[CH:9][C:8]=1[F:14]
Reactant: O=C(Nc1c(F)cncc1F)c1c(F)cccc1Cl
Reactant: O=S(Cl)Cl
Product: Fc1cncc(F)c1N=C(Cl)c1c(F)cccc1Cl
Temperature: 100 °C

Procedure:
A stirred suspension of 2-chloro-N-(3,5-difluoropyridin-4-yl)-6-fluorobenzamide (11.4 g, 0.04 mol) in thionyl chloride (100 mL) was heated at 100° C. for 18 hours. After cooling to room temperature, the volatiles were removed under reduced pressure. The resulting residue was azeotroped with toluene (100 mL). The crude residue was triturated with diethyl ether to afford the title compound as an off-white solid (12.1 g, quantitative). LCMS (Method E): RT=3.88 min, m/z: 305 [M+H+].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:27][C:12]2=[CH:13][C:14]3[C:15](=[O:26])[N:16]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1.[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH3:39])=[C:33]([CH2:35][C@@H:36]([NH2:38])[CH3:37])[CH:34]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH3:39])=[C:33]([CH2:35][CH:36]([NH:38][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=2[C:9]2[NH:27][C:12]3=[CH:13][C:14]4[C:15](=[O:26])[N:16]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:17](=[O:20])[C:18]=4[CH:19]=[C:11]3[N:10]=2)[CH3:37])[CH:34]=1
Reactant: Cc1ccc(F)cc1C[C@H](C)N
Reactant: CN(C)CCN1C(=O)c2cc3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3cc2C1=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(CCN(C)C)C3=O
Yield: 84.3 %

Procedure:
2-(4-Chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(dimethylamino)ethyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (1.05 g, 2.72 mmol), (S)-1-(5-fluoro-2-methylphenyl)propan-2-amine (0.55 g, 3.26 mmol), n-butanol (50 mL) and N,N-diisopropylethylamine (5 mL) were mixed together in a flask. The reaction mixture was stirred and heated to reflux overnight under argon. Solvents were removed under reduced pressure. The residue solid was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a brown solid product, 1.18 g, 84.3% yield. MS: 517.2 [M+H]+. 1H NMR (DMSO-d6, 300 MHz): δ 13.42 (s, 1H), 11.23 (s, 1H), 10.86 (d, 1H, J=8.1 Hz), 8.13 (s, 1H), 8.00 (s, 1H), 7.31-7.10 (m, 3H), 6.90-6.83 (m, 1H), 6.14 (d, 1H, J=7.5 Hz), 4.22-4.13 (m, 1H), 3.68 (t, 2H, J=6.5 Hz), 3.00 (d, 2H, J=6.9 Hz), 2.51-2.47 (m, 2H), 2.42 (s, 3H), 2.18 (s, 6H), 1.34 (d, 3H, J=6.3 Hz).
Reaction SMILES: [NH:1]([C:5]1[S:6][C:7]2[CH2:8][NH:9][CH2:10][CH2:11][C:12]=2[N:13]=1)[C:2]([NH2:4])=[NH:3].[C:14]([N:16]=[C:17]([S-])[S-:18](C)[CH3:19])#[N:15]>C(O)C>[NH:1]([C:5]1[S:6][C:7]2[CH2:8][N:9]([C:17]([S:18][CH3:19])=[N:16][C:14]#[N:15])[CH2:10][CH2:11][C:12]=2[N:13]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc2c(s1)CNCC2
Reactant: C[S-](C)C([S-])=NC#N
Solvent: CCO
Product: CSC(=NC#N)N1CCc2nc(NC(=N)N)sc2C1
Reaction time: 30 h
Yield: 79.6 %

Procedure:
To a suspension of 3.95 g (20 mmol) of 2-guanidino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine in 40 ml of absolute ethanol, 3.51 g (24 mmol) of N-cyano-S,S-dimethyldithioimidocarbonate (IV: X"=NR8, R8 =CN) was added at room temperature. After standing for 30 hours, the reaction mixture was evaporated to dryness and the crude residue was chromatographed on a silica gel column using ethyl acetate with increasing methanol as eluant. 4.7 g (80% yield) of 2-guanidino-5-(methylthio-N-cyano-imino-methyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (V: ##STR15## R2 =R6 =R7 =H, n=0, X"=NR8, R8 =CN), m.p. 224°-227° C., were obtained. This compound was treated with a 33% solution of methylamine in 93 ml of ethanol at room temperature. After standing for 24 hours the solid compound was filtered and crystallized from methanol. 2.21 g (50% yield) of the title compund (m.p. 243°-246° C. with decomposition) were obtained.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:17])[CH:3]=1.[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=1[CH:22]=O.C([O-])(=O)C.[NH4+]>C(O)C>[NH4+:5].[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=1[CH:22]=[C:3]1[C:2](=[O:1])[N:6]([C:7]2[CH:8]=[CH:9][C:10]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:11][CH:12]=2)[N:5]=[C:4]1[CH3:17]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: Cc1cc(O)n(-c2ccc(S(=O)(=O)O)cc2)n1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc(C=C2C(=O)N(c3ccc(S(=O)(=O)[O-])cc3)N=C2C)c(OC)c1
Reaction time: 5 h

Procedure:
2.55 g of 5-hydroxy-3-methyl-1-(4-sulfophenyl)-1H-pyrazole, 1.83 g 2,4-dimethoxybenzaldehyde and 0.8 g of ammonium acetate in 25 mL of ethanol were heated at 70° C. After 5 hours, the mixture was cooled and filtered.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Oc1ccc(Br)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(Oc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.6 %

Procedure:
To a solution of 4-(trifluoromethoxy)phenylboronic acid (10.0 g, 48.6 mmol) and 4-bromophenol (4.20 g, 24.3 mmol) in dichloromethane (250 ml) over 4 A molecular sieves was added copper (II) acetate (4.41 g, 24.3 mmol), diisopropylethylamine (21 ml, 121 mmol) and pyridine (10 ml, 121 mmol). The reaction mixture was stirred 12 hours at room temperature under positive pressure of dry air and concentrated in vacuo. The resulting residue was resuspended in ethyl acetate and 0.5 M HCl. The organic layer was extracted with water and brine, dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography (ethyl acetate/hexanes) provided 5.07 g 1-bromo-4-(4-(trifluoromethoxy)phenoxy)benzene (63% yield) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=9.3 Hz, 1H), 7.19 (d, J=8.9 Hz, 1H), 6.99 (d, J=9.3 Hz, 1H), 6.89 (d, J=8.9 Hz, 1H).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([OH:23])(=[O:22])[C@@:11]1([CH2:21][CH2:20][C@H:16]([C:17]([OH:19])=O)[C:13]1([CH3:15])[CH3:14])[CH3:12].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[C:10]1(=[O:22])[O:23][C:17](=[O:19])[CH:16]2[CH2:20][CH2:21][C@@:11]1([C:13]2([CH3:14])[CH3:15])[CH3:12]
Reactant: CC1(C)[C@@H](C(=O)O)CC[C@@]1(C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C2CC[C@@]1(C)C(=O)OC2=O
Reaction time: 4 h
Yield: 90.1 %

Procedure:
DIEA (8.0 g) was added to a suspension of (1R,3S)-camphoric acid (5.0 g) and BOP Reagent (11.1 g) in THF (50 ml) at room temperature. The mixture was stirred for 4 hr. and the solvent was removed in vacuo. The residue was extracted with AcOEt and the extract was washed with 5% HCl, sat. NaHCO3, and sat. LiCl, and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (eluent; CHCl3) to give (1R)-camphoric anhydride (4.1 g) as a colorless powder.
Reaction SMILES: C[N:2]([C:4]([S-:6])=[S:5])[CH3:3].[CH3:7][N:8]([C:10]([S-:12])=[S:11])C.[Zn+2:13].CCC(NC(C1C=C(Cl)C(C)=C(Cl)C=1)=O)(C(CCl)=O)C>>[CH2:7]([NH:8][C:10]([S-:12])=[S:11])[CH2:3][NH:2][C:4]([S-:6])=[S:5].[Zn+2:13]
Reactant: CN(C)C(=S)[S-]
Agent: CCC(C)(NC(=O)c1cc(Cl)c(C)c(Cl)c1)C(=O)CCl
Agent: [Zn+2]
Product: S=C([S-])NCCNC(=S)[S-]

Procedure:
ziram; zoxamide;
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][N:24]([C:38]([CH:35]4[CH2:37][CH2:36]4)=[O:39])[CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C(Cl)C1CC1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(C(=O)C3CC3)CC2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=554.2 (M+H+), was prepared in accordance with the general method of example 38 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone and cyclopropane carboxylic acid chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH3:12])[N:8]=[CH:7][C:6](C(OCC)=O)=[C:5]2[OH:18].[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH3:12])[N:8]=[CH:7][CH:6]=[C:5]2[OH:18]
Reactant: CCOC(=O)c1cnc2nc(C)c(Br)cc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc2nccc(O)c2cc1Br
Temperature: 180 °C

Procedure:
A mixture of ethyl 6-bromo-4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylate (6.7 g), sodium hydroxide pellets (1.7 g) and water (50 ml) was heated at 180° C. in a pressure vessel for 18 hours. The mixture was cooled and filtered to give 6-bromo-7-methyl-1,8-naphthyridin-4-ol, m.p. >250° C.
Reaction SMILES: CN(C)C=O.[CH2:6]([C:8]1[NH:9][C:10]2[C:11]([N:18]=1)=[N:12][C:13]([CH3:17])=[CH:14][C:15]=2[CH3:16])[CH3:7].[H-].[Na+].[Cl:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH2:32]Br)[CH:30]=2)[N:25]=[C:24]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[N+:40]([O-:42])=[O:41])[CH:23]=1>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[Cl:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH2:32][N:18]3[C:11]4=[N:12][C:13]([CH3:17])=[CH:14][C:15]([CH3:16])=[C:10]4[N:9]=[C:8]3[CH2:6][CH3:7])[CH:30]=2)[N:25]=[C:24]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[N+:40]([O-:42])=[O:41])[CH:23]=1
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Reactant: O=[N+]([O-])c1ccccc1-c1cc(Cl)c2cc(CBr)ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2nc(-c3ccccc3[N+](=O)[O-])cc(Cl)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
To 61 ml of N,N-dimethylformamide (DMF) containing 7.45 g (42.5 mmol) of 2-ethyl-5,7-dimethyl-1H-imidazo[4,5-b]pyridine, 1.79 g (44.6 mmol) of sodium hydride (60%) was added and stirred at room temperature for 30 minutes. To the thus-prepared mixture, 15.3 g of 4-chloro-6-(bromomethyl)-2-(2-nitrophenyl)quinoline was added and stirred at room temperature for 12 hours. After adding 120 ml of toluene thereto, the thus-prepared mixture was poured into a mixture of 60 ml of toluene with 300 ml of water. After adding 120 ml of ethyl acetate thereto, the mixture was separated out and the resulting aqueous layer was extracted with a mixture of 90 ml of toluene with 90 ml of ethyl acetate. The resulting organic layers were combined and evaporated to 117.82 g in an evaporator. Then, 90 ml of toluene was added thereto and the thus-prepared mixture was washed with 90 ml of water twice. The resulting insolubles were filtered off and the organic layer was concentrated to 58.3 g in an evaporator. After allowing to stand at 5° C., the crystals precipitated were collected, washed with 10 ml of toluene twice and dried to obtain 8.12 g of 4-chloro-6-[(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-2-(nitrophenyl)quinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1.N1C=CC=CC=1>O>[C:18]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(Oc1ccc(Cl)cc1C(=O)c1ccccc1)c1cccnc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
15 g (64,5 mmol) of p-chlorobenzoylphenol and 12 g (68 mmol) of nicotinic acid chloride hydrochloride was mixed with 200 ml dry pyridine and stirred for 24 hours at 40° C. After cooling 200 ml water were added and the precipitated product washed twice with 80 ml of water and recrystallized from methanol.
Reaction SMILES: [CH2:1]([C:3]1([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([O:15]C)[CH:10]=2)OCCC[O:4]1)[CH3:2].[I-].[Na+].[Cl-].C[SiH](C)C.O>C(#N)C>[O:15]=[C:11]1[CH:10]=[C:9]([C:3](=[O:4])[CH2:1][CH3:2])[CH:14]=[CH:13][NH:12]1
Reactant: CCC1(c2ccnc(OC)c2)OCCCO1
Agent: C[SiH](C)C
Agent: [Cl-]
Agent: [I-]
Solvent: O
Solvent: CC#N
Product: CCC(=O)c1cc[nH]c(=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxypyridine (prepared according to the method described in the Patent Application PCT/FR96/00980, 57 g, 255 mmol) and sodium iodide (88 g, 580 mmol) in acetonitrile (1 l) is treated with trimethylsilane chloride (74 ml, 586 mmol), taken to reflux for 3 hours, then agitated at ambient temperature for 16 hours. The reaction medium is then treated with water (100 ml) and concentrated to dryness after elimination of the insolubles by filtration. The residue is taken up in ethyl acetate and washed successively with water and with an aqueous solution saturated in sodium chloride. The organic phase is dried, concentrated under reduced pressure, and the residue is taken up in diethyl ether in order to produce after filtration and drying 30 g (88%) of a white solid, m.p. 168° C.
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@:9]3([O:38][CH3:39])[CH2:10][CH2:11][C@H:12]2[N:20](C(OC(C)(C)C)=O)[C:21]([NH:23]C(OC(C)(C)C)=O)=[NH:22])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([OH:40])[CH:4]=[CH:5]2.[ClH:41]>CCOCC.O>[ClH:41].[ClH:41].[O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@:9]3([O:38][CH3:39])[CH2:10][CH2:11][C@H:12]2[NH:20][C:21]([NH2:23])=[NH:22])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([OH:40])[CH:4]=[CH:5]2
Reactant: CO[C@@]12CC[C@@H](N(C(=N)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)[C@@H]3Oc4c(O)ccc5c4[C@@]31CCN(C)[C@@H]2C5
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CO[C@@]12CC[C@@H](NC(=N)N)[C@@H]3Oc4c(O)ccc5c4[C@@]31CCN(C)[C@@H]2C5

Procedure:
A solution of Compound 16 (50 mg, 0.089 mmol) in Et2O (3 ml) was mixed through to a clear acidic reaction with ethereal HCl and with 4 drops of H2O. The mixture was subjected to ultrasound for one hour at room temperature and then evaporated. The residue (40 mg of white foam resin) was dissolved in H2O and freeze dried. Yield: 30 mg (79%) 17.2 HCl as white lyophilisate: 1H-NMR (CDCl3): δ 9.59 (s, OH—C(3)); 9.29 (s, br, NH+); 8.53 (d, J=8.0, C(6)-NH—); 7.29 (s, br, C(6)-NH—C(NH2)2+), 6.78 (d, J=8.1, 1 arom. H); 6.69 (d, J=8.1, 1 arom. H); 4.49 (d, J=7.2, H—C(5)); 3.26 (s, CH3O—C(14)); 2.84 (s, CH3N).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15](=[O:17])[CH3:16])[CH:8]=[C:9]([O:11][CH2:12][CH2:13][F:14])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br-:18].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.O>CO.C1COCC1>[Br:18][CH2:16][C:15]([C:7]1[CH:8]=[C:9]([O:11][CH2:12][CH2:13][F:14])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)=[O:17]
Reactant: [Br-]
Reactant: CC(=O)c1cc(OCCF)cc(C(C)(C)C)c1
Agent: C[N+](C)(C)c1ccccc1
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(OCCF)cc(C(=O)CBr)c1
Yield: 120.5 %

Procedure:
1-[3-tert-Butyl-5-(2-fluoroethoxy)phenyl]ethanone (O2.105; 600 mg) was dissolved in methanol/THF (15/15 ml). While stirring, phenyltrimethylammonium tribromide (950 mg) was added. After stirring at RT for 3 h, water (5 ml) was added and the mixture was dried. The residue was admixed with DCM (200 ml) and saturated sodium hydrogencarbonate solution (100 ml). The DCM phase was removed and the aqueous phase was extracted three times more with DCM. The combined DCM phases were dried over sodium sulfate, filtered and concentrated. The residue was purified using silica gel (50 g cartridge, n-heptane/EA gradient of 0-60% within 40 min). 560 mg of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:12][CH2:11]3)=[C:7]([C:13]([NH:15][CH3:16])=[O:14])[C:6]=2[CH:17]=1.[C:23]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:3]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:20])=[O:21])=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:11][CH2:12]3)=[C:7]([C:13]([NH:15][CH3:16])=[O:14])[C:6]=2[CH:17]=1
Reactant: CNC(=O)c1c(C2CC2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNC(=O)c1c(C2CC2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 63.9 %

Procedure:
To a suspension of compound 5-bromo-2-cyclopropyl-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (1.5 g, 3.9 mmol) and K2CO3 (1.6 mg, 7.8 mmol) in DMF (15 mL) was added dropwise CH3I (1.1 mg, 7.8 mmol) at 0° C. under N2, and then the mixture was stirred at 80° C. for 2 hours. After concentration in vacuum, the residue was suspended in H2O and extracted with DCM. The combined organic layer was washed with H2O, brine and dried over Na2SO4. The mixture was filtered and concentrated to give the product of compound 5-bromo-2-cyclopropyl-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (1 g, yield: 65%). 1H-NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 6.98 (s, 1H), 5.63 (s, 1H), 3.05 (s, 3H), 2.79 (s, 6H), 2.39˜2.43 (m, 1H), 0.95˜0.97 (m, 2H), 0.89˜0.91 (m, 2H). MS (M+H)+: 401/403.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[H-].[Na+].[Cl-].[NH4+].[CH2:20]([OH:23])[CH2:21][OH:22]>>[NH2:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([O:22][CH2:21][CH2:20][OH:23])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1
Reactant: OCCO
Reactant: Cc1ccc(-c2c(N)ncnc2Cl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Product: Cc1ccc(-c2c(N)ncnc2OCCO)cc1

Procedure:
A mixture of 4-amino-6-chloro-5-(4-methylphenyl)pyrimidine (500 mg), ethylene glycol (10 ml) and sodium hydride (60% dispersion, 0.46 g) is reacted at 70° C. for two hours, and then reacted at 90° C. for five hours. The reaction mixture is treated with a saturated ammonium chloride solution, and extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated under reduced pressure to remove the solvent. The residue is crystallized from hexane-ethyl acetate to give 2-{6-amino-5-(4-methylphenyl)-pyrimidin-4-yloxy}ethanol (422 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH3:26])[CH2:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].[CH2:27]([Sn](CCCC)(CCCC)C(C)=C)[CH2:28][CH2:29]C>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([C:28]([CH3:29])=[CH2:27])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH3:26])[CH2:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10]
Reactant: CCCN1CC[C@@H](c2ccc(NS(=O)(=O)c3ccc(Br)cc3F)cc2)C1
Reactant: C=C(C)[Sn](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: C=C(C)c1ccc(S(=O)(=O)Nc2ccc([C@@H]3CCN(CCC)C3)cc2)c(F)c1
Temperature: 150 °C
Reaction time: 0.67 h
Yield: 97.2 %

Procedure:
0.2 g of 2-fluoro-4-bromo-N-[4-((S)-1-propyl-pyrrolidin-3-yl)-phenyl]-benzenesulfonamide (0.45 mmol), 1.05 g of tributyl-isopropenyl-stannane (3.17 mmol) and 0.026 g of tetrakistriphenylphosphinpalladium(0) (0.02 mmol) were dissolved in 3 ml of tetrahydrofuran and stirred for 40 minutes at 150° C. in the microwave (CEM). The reaction mixture was filtered over celite, washed with methanol, and the filtrate evaporated to dryness under reduced pressure. The residue was purified via silica gel chromatography with cyclohexane/ethyl acetate (20%), ethyl acetate, and ethyl acetate/methanol (15%). Fractions containing the product were combined, the solvent evaporated to yield 0.176 g of the title product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][CH:6]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:7]([O:9]C)=O.[Li].Cl.[NH2:20][CH2:21][C:22]#[N:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O.Cl.CN(C=O)C.C(OCC)(=O)C.O1CCCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][CH:6]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:7]([NH:23][CH2:22][C:21]#[N:20])=[O:9]
Reactant: N#CCN
Reactant: COC(=O)C(CC(C)C)Oc1cccc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)CC(Oc1cccc(Br)c1)C(=O)NCC#N
Reaction time: 0.02 h

Procedure:
Methyl 2-(3-bromophenoxy)-4-methylpentanoate, in a mixture of water (42 mL), methanol (8 mL) and tetrahydrofuran (4 mL) was treated with lithium hydroxyde monohydrate (1.3 g, 31.6 mmoles) until disappearance of the starting material was observed by TLC. The reaction was diluted with 1.2 N hydrochloric acid until pH 1. The aqueous phase was extracted 3 times with dichloromethane. The organic phase was concentrated under reduced pressure to provide a residue that was used as such in the next reaction. To a solution of the resulting crude 2-(3-bromophenoxy)-4-methylpentanoic acid in DMF (30 mL) was added aminoacetonitrile hydrochloride (2.9 g, 31.5 mmoles) and HATU (6.3 g, 16.5 mmoles). After stirring for 1 minute, triethylamine (8.75 mL, 63 mmoles) was added in one portion. The reaction was stirred overnight, diluted with ethyl acetate and water. The organic phase was separated and washed twice with 1.2 N hydrochloric acid, brine and dried over magnesium sulfate. After concentration under reduced pressure, the solid 2-(3-bromophenoxy)-N-(cyanomethyl)-4-methylpentanamide obtained was sufficiently pure.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11](Cl)[CH3:12].[SH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=1[O-:21].[Na]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=1[O-:21])[CH3:12]
Reactant: CC(Cl)c1ccc2ccccc2c1
Reactant: [O-][n+]1ccccc1S
Agent: [Na]
Product: CC(Sc1cccc[n+]1[O-])c1ccc2ccccc2c1

Procedure:
The intermediate 2-(1-[2-naphthyl]ethylthio)pyridine N-oxide is prepared from 1-(2-naphthyl)ethyl chloride and 2-mercapto pyridine N-oxide, sodium salt by the procedure described in Example 2. Melting point 112° - 115° C. Structure confirmed by IR and NMR.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[Cl:14][C:15]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:16]=1[CH2:17][NH2:18].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:18][CH2:17][C:16]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:15]=3[Cl:14])[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: NCc1cc(Cl)ccc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]nc(Cl)c2cc(NCc3cc(Cl)ccc3Cl)ccc12

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.58 mmol), 2,5-dichloro-benzylamine (0.085 mL, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (108 mg, 0.17 mmol) and NaOt-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2,5-dichloro-benzylamino)-2H-phthalazin-1-one: 6 mg (2.9%): m/z (M+H)=354. 1H-NMR (DMSO-d6) δ: 12.39 (s, 1H), 7.96 (d, 1H), 7.66 (m, 1H), 7.53 (d, 1H), 7.47 (m, 1H), 7.40 (dd, 1H), 7.16 (dd, 1H), 6.82 (s, 1H), 4.50 (d, 2H).