Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.[NH2:11][CH:12]1[CH2:16][O:15][CH:14]([CH3:17])[CH2:13]1.CC1CC(O)CO1.C(N(CC)CC)C>O>[Cl:8][C:7]1[C:2]([NH:11][CH:12]2[CH2:16][O:15][CH:14]([CH3:17])[CH2:13]2)=[N:3][CH:4]=[N:5][C:6]=1[CH2:9][CH3:10]
Reactant: CCc1ncnc(Cl)c1Cl
Reactant: CC1CC(N)CO1
Agent: CC1CC(O)CO1
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1ncnc(NC2COC(C)C2)c1Cl
Temperature: 85 °C

Procedure:
1.5 g of 4,5-dichloro-6-ethylpyrimidine (8.5 mmol), 0.86 g (8.5 mmol) of 4-amino-2-methyltetrahydrofuran (prepared from 2-methyltetrahydrofuran4-ol analogously to the route given for Example A) and 2 ml (14 mmol) of triethylamine were heated for 6 hours at 85° C. After cooling, the mixture was diluted with water and extracted with ether, and the organic phase was washed with saturated NaCl solution. After drying and concentrating, the residue was purified by column chromatography using petroleum ether/ethyl acetate (8:2, 7:3). This gave 1.73 g (84% of theory) of a colorless oil (diastereomers 2:1).
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].C([Li])CCC.C(#N)C.[F:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>C1COCC1.O>[NH2:22][C:21]([C:20]1[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=1)=[CH:2][C:1]#[N:4]
Reactant: CC(C)NC(C)C
Reactant: N#Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: N#CC=C(N)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of 0.390 ml (2.78 mmol) diisopropylamine in dry THF (2 ml) was cooled to −70° C. under inert gas atmosphere, and 1.74 ml (2.78 mmol) n-butyllithium solution (1.6 M in hexanes) were added dropwise. Then, a solution of 129 μl (2.45 mmol) acetonitrile in dry THF (2 ml) was slowly added over 10 min. The resulting solution was stirred for further 30 min at −70° C. before a solution of 200 mg (1.635 mmol) 4-fluorobenzonitrile in dry THF (2 ml) was added. The mixture was allowed to warm to room temperature and stirred for 1 h before water (4 ml) was added slowly. The mixture was extracted several times with dichloromethane (50 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to yield 244 mg (92% of th.) of the crude title compound which was used in the next step without further purification.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH:25]=[CH2:26]>CC#N>[Br-:23].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:26][CH:25]=[CH2:24])([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: C=CCBr
Solvent: CC#N
Product: C=CC[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 79.1 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0577 g, 0.197 mmol) and 3-bromo-1-propene (0.025 mL, 0.289 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0646 g, 79.8%). EI-MS m/z 334 (M+) Rt (1.54 min).
Reaction SMILES: [NH3:1].[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[O:26][C:27]([CH3:30])=[N:28][N:29]=4)[CH:20]=3)[C:9]=2[C:10](Cl)=[N:11][CH:12]=1)=[O:6])[CH3:3]>CC(O)C>[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[O:26][C:27]([CH3:30])=[N:28][N:29]=4)[CH:20]=3)[C:9]=2[C:10]([NH2:1])=[N:11][CH:12]=1)=[O:6])[CH3:3]
Reactant: N
Reactant: CCOC(=O)c1cnc(Cl)c2c(COc3cccc(-c4nnc(C)o4)c3)csc12
Solvent: CC(C)O
Product: CCOC(=O)c1cnc(N)c2c(COc3cccc(-c4nnc(C)o4)c3)csc12
Temperature: 140 °C

Procedure:
Ammonia gas was bubbled into a solution of 4-chloro-3-[3-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.12 g, 0.29 mmol) (from Example 8 supra) in 2-propanol (15 mL) for 20 minutes. The mixture was heated in a microwave reactor at 140° C. for 2 hours. The reaction mixture was concentrated. The residue washed with hot methanol, filtered and dried to give 4-amino-3-[3-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.07 g, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13]O)[CH:7]=1.S(Cl)([Cl:19])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][Cl:19])[CH:7]=1
Reactant: COc1ccc(Cl)cc1CCCOCCO
Reactant: O=S(Cl)Cl
Product: COc1ccc(Cl)cc1CCCOCCCl

Procedure:
11.2 g of 2-[3-(5-chloro-2-methoxyphenyl)propyloxy]-ethanol and 20 ml thionyl chloride are stirred at 50° C. for 3 hours; the excess thionyl chloride is distilled off in vacuo. 11.3 g of 2[3-(5-chloro-2-methoxyphenyl)propyloxy]ethyl chloride are obtained as a brown oil.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:10]([O-])([OH:12])=[O:11]>OS(O)(=O)=O>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[N:3]=1
Reactant: COc1cccnc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1ccc([N+](=O)[O-])nc1Br
Temperature: 60 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a solution of 2-bromo-3-methoxypyridine (7.0 g, 37 mmol) in H2SO4 (70 mL) was added fuming HNO3 (2.4 ml, 37 mmol) dropwise at 0° C. under N2 atmosphere. The mixture was stirred at 60° C. for 2 hours. After cooling to room temperature, the mixture was quenched with water (100 mL). The insoluble solid was collected by filtration and washed with water (100 mL). The solid was dissolved in ethyl acetate (100 mL) and basified to pH to 8 with saturated aqueous NaHCO3. The aqueous layer was extracted with ethyl acetate (150×3 mL). The combined organics layers were washed with brine, dried over anhydrous Na2SO4, evaporated in vacuo and purified by chromatography on silica gel (10% ethyl acetate in petroleum ether) to give 2-bromo-3-methoxy-6-nitropyridine (5.0 g, 55%). 1H-NMR (300 MHz, CDCl3) δ 8.27 (d, J=8.7, 1H), 7.32 (d, J=8.7, 1H), 4.06 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[O:12]1[CH2:16][CH:13]1[CH2:14][OH:15]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:16][CH:13]([OH:12])[CH2:14][OH:15])=[CH:7][CH:6]=1
Reactant: COCCc1ccc(O)cc1
Reactant: OCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: COCCc1ccc(OCC(O)CO)cc1
Yield: 86.2 %

Procedure:
39 g of 4-(2-methoxy-ethyl)-phenol are heated to about 120° C., after addition of 0.5 g of benzyl-tributylammonium chloride, and 20.4 g of 2,3-epoxypropanol are added dropwise in the course of 15 minutes. The mixture is allowed to cool, the syrup is dissolved in CHCl3, the solution is washed with water and the CHCl3 residue is purified by preparative HPLC. 50 g of 3-[4-(2-methoxyethyl)-phenoxy]-propane-1,2-diol are obtained.
Reaction SMILES: Cl[P:2]1[O:7][CH2:6][C:5]2([CH2:12][O:11][P:10](Cl)[O:9][CH2:8]2)[CH2:4][O:3]1.[CH3:14][NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C([N:36]([CH2:39]C)[CH2:37][CH3:38])C>C1(C)C=CC=CC=1>[CH3:14][N:15]([P:2]1[O:7][CH2:6][C:5]2([CH2:12][O:11][P:10]([N:36]([CH2:37][CH2:38][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[CH3:39])[O:9][CH2:8]2)[CH2:4][O:3]1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: ClP1OCC2(CO1)COP(Cl)OC2
Reactant: CCCCCCCCCCCCCCCCCCNC
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCN(C)P1OCC2(CO1)COP(N(C)CCCCCCCCCCCCCCCCCC)OC2
Yield: 60.2 %

Procedure:
The procedure of Example 1 is repeated using 18.4 g (70 mmol) of 3,9-dichloro-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane, 39.5 g (140 mmol) of N-methyl-N-octadecylamine and 19.5 mL (140 mmol) of triethylamine in 250 mL of toluene to give a crude reaction residue. The residue is purified by recrystallization from a mixture of toluene and acetonitrile to give 32 g (64% yield) of the title compound as an off-white solid melting at 70°-72° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:25])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6]1.Cl[C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([C:36]([CH3:43])([CH3:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38])[N:35]=2)[N:32]=1.[C:44]([O:47]CC)(=[O:46])[CH3:45].O1CCCC1>>[C:37]([OH:39])(=[O:38])/[CH:36]=[CH:45]/[C:44]([OH:47])=[O:46].[C:37]([OH:39])(=[O:38])/[CH:36]=[CH:45]/[C:44]([OH:47])=[O:46].[C:13]1([CH:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:11][CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH:3]([OH:25])[CH2:2][NH:1][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([CH:33]=[C:34]([C:36]([CH3:42])([CH3:43])[C:37]([O:39][CH2:40][CH3:41])=[O:38])[N:35]=4)[N:32]=3)[CH2:6][CH2:7]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Reactant: CCOC(C)=O
Reactant: NCC(O)CN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)c1cn2nc(NCC(O)CN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Product: O=C(O)/C=C/C(=O)O

Procedure:
0.511 g of 1-amino-3-[4-(diphenylmethoxy)piperidino]-2-propanol and 0.268 g of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate were stirred at 190-200° C. for 3 hours. After cooling, ethyl acetate-tetrahydrofuran (2:1) was added; the mixture was washed with aqueous sodium bicarbonate and saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (90:10:1). The desired fraction was collected, dissolved in 5 ml of ethyl acetate; a solution of 82 mg of fumaric acid in 5 ml of methanol was added, followed by concentration. Ethyl ether was added to the residue; the resulting powder was collected by filtration, washed with ethyl ether and dried to yield 0.223 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[N:5][C:6]([S:9][C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:8]=1.[Cl:19]N1C(=O)CCC1=O>CO>[CH3:1][O:2][C:3]1[N:4]=[N:5][C:6]([S:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[Cl:19])=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:8]=1
Reactant: COc1ccc(Sc2cc3ccccc3[nH]2)nn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CO
Product: COc1ccc(Sc2[nH]c3ccccc3c2Cl)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A mixture of 3-methoxy-6-(indole-2-sulfenyl)-pyridazine) (2.92 mmol, 750 mg), N-chloro-succinimide (2.92 mmol, 390 mg) and methanol (15 mL) was stirred overnight at room temperature. Excess methanol was removed and the residue was extracted with EtOAc (3×10 mL). The EtOAc extract was collected, dried, filtered and evaporated to dryness to obtain a residue, which was purified by silica gel chromatography (eluent:hexanes:EtOAc::19:5) to yield 3-methoxy-6-(3-chloro-indole-2-sulfenyl)-pyridazine (40%, 338 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1.[Br:13]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][Br:13])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1cccc(C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Cc1cccc(CBr)c1
Temperature: 25 °C

Procedure:
A solution of m-tolyl-acetic acid methyl ester (11.41 g, 69.49 mmol), N-bromosuccinimide (12.59 g, 70.73 mmol), AIBN (100 mg) in CCl4 (200 mL) was heated at reflux for 16 h. The reaction was cooled to room temperature and aqueuos NaHCO3 (satd) was added. The aqueous solution was extracted with CH2Cl2 (2×) and the organic solution was dried (MgSO4), filtered, and concentrated. Purification by flash chromatography (hexanes to 9:1 hexanes:EtOAc) provided the title compound as a clear and colorless liquid (11.99 g). 1H NMR (CDCl3 400 MHz) δ7.27 (m, 4H), 4.47 (s, 2H), 3.69 (s, 3H), 3.62 (s, 2H).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([CH3:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[CH3:34][NH:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[CH3:34][NH:35][CH:36]1[CH2:39][N:38]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([CH3:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:37]1
Reactant: CNC1CNC1
Reactant: Cc1cc(F)c(N)nc1-n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(Cl)c21
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: CNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4C)c3c2Cl)C1
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 68.2 %

Procedure:
To 90 mg of N,N-dimethylformamide were added 25 mg of 1-(6-amino-5-fluoro-3-methylpyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 25 mg of 3-(methylamino)azetidine dihydrochloride, and 70 mg of N-methylpyrrolidine, and the mixture was stirred at 85° C. for 45 minutes. After adding 0.2 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 20 mg of the title compound as a colorless powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14]O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14][Br:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCc1ccc(OCc2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: BrCCc1ccc(OCc2ccccc2)cc1
Reaction time: 3 h

Procedure:
To a solution of 4-benzyloxyphenethyl alcohol (8.29 g) and carbon tetrabromide (24.1 g) in ether (150 ml) is portionwise added triphenylphosphine (19.0 g) and the resulting mixture stirred for about 3 hours. The supernatent is decanted, the solid washed with ether and the combined organic solution concentrated in vacuo. The crude product is purified by passing it through a silica plug to give 4-benzyloxyphenethyl bromide.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([NH:16][CH3:17])=[S:15])[CH2:3][CH2:2]1.[CH3:18][I:19]>CC(C)=O>[IH:19].[CH3:18][S:15][C:14](=[N:16][CH3:17])[NH:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: CI
Reactant: CNC(=S)Nc1ccccc1N1CCOCC1
Solvent: CC(C)=O
Product: CN=C(Nc1ccccc1N1CCOCC1)SC
Product: I

Procedure:
A mixture of 1-(2-morpholinophenyl)-3-methylthiourea (5 g) and methyliodide (2.8 g) in acetone (30 ml) was heated at reflux for 4 hours to yield 2-methyl-1-(2-morpholinophenyl)-3-methyl-2-thiopseudourea hydroiodide (m.p. 163°-164° C.) which was recrystallised from a 1:3 mixture of methanol and ether.
Reaction SMILES: [ClH:1].[C:2]1([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[C:23](=[O:29])[CH2:22][CH2:21][CH2:20]2.C=O.[CH2:32](O)C>C(O)(C)C>[ClH:1].[C:2]1([C:8]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:32][CH:22]3[CH2:21][CH2:20][C:19]4[C:24](=[CH:25][C:26]([O:27][CH3:28])=[C:17]([O:16][CH3:15])[CH:18]=4)[C:23]3=[O:29])[CH2:10][CH2:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(cc1OC)C(=O)CCC2
Reactant: CCO
Reactant: OC1(c2ccccc2)CCNCC1
Agent: C=O
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(cc1OC)C(=O)C(CN1CCC(O)(c3ccccc3)CC1)CC2

Procedure:
A mixture of 21.35 g. of 4-phenylpiperidin-4-ol hydrochloride, 20.6 g. of 6,7-dimethoxy-1-tetralone and 8 g. of paraformaldehyde in 200 ml. of ethanol (or isopropanol) is heated under reflux for 4 hours. The solvent is evaporated and the residue is made into a slurry with acetone/ether and is filtered off. 2-(4-phenyl-4-hydroxypiperidinomethyl)-6,7-dimethoxy-1-tetralone hydrochloride, m.p. 175°-177°, is obtained.
Reaction SMILES: 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.[C:47](=[O:50])([O-])[O-:48].[Cs+].[Cs+].Br[C:54]1[CH:55]=[CH:56][C:57]([Cl:64])=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:59]=1.[CH3:65][NH:66][C:67]([C:69]1[CH:74]=[C:73]([O:75][C:76]2[CH:86]=[CH:85][C:79]3[N:80]=[C:81]([NH2:84])[N:82]=[N:83][C:78]=3[CH:77]=2)[CH:72]=[CH:71][N:70]=1)=[O:68]>CN(C)C=O>[F:61][C:60]([F:63])([F:62])[C:47]([OH:48])=[O:50].[CH3:65][NH:66][C:67]([C:69]1[CH:74]=[C:73]([O:75][C:76]2[CH:86]=[CH:85][C:79]3[N:80]=[C:81]([NH:84][C:54]4[CH:55]=[CH:56][C:57]([Cl:64])=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:59]=4)[N:82]=[N:83][C:78]=3[CH:77]=2)[CH:72]=[CH:71][N:70]=1)=[O:68]
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1cc(Oc2ccc3nc(N)nnc3c2)ccn1
Reactant: FC(F)(F)c1cc(Br)ccc1Cl
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc3nc(Nc4ccc(Cl)c(C(F)(F)F)c4)nnc3c2)ccn1
Product: O=C(O)C(F)(F)F
Temperature: 120 °C
Reaction time: 18 h

Procedure:
To a vial with 2 mL of anhydrous dimethylformamide under argon atmosphere were added 15.4 mg (0.0168 mmol, 0.05 equivalent) of tris(dibenzyllideneatone) dipalladium(0), 21.0 mg (0.033 mmol, 0.1 equivalent) of BINAP, 220.0 mg (0.675 mmol, 2.0 equivalent) of anhydrous cesium carbonate, 175.1 mg (0.675 mmol, 2.0 equivalent) of 5-bromo-2-chlorobenzotrifluoride, and 100 mg (0.337 mmol, 1.0 equivalent) of 4-(3-amino-benzo[1,2,4]triazin-7-yloxy)-pyridine-carboxylic acid methylamide, in that particular order. Argon gas was bubbled through the mixture for 5 min. Then the vial was capped and the reaction mixture was heated to 120° C. with stirring under argon atmosphere for 18 hours. At this point LC/MS indicated about 40% conversion to the product. As pointed out in the previous examples, the longer reaction times result in the formation of the by-product and partial decomposition. So, the reaction mixture was allowed to cool down to ambient temperature, filtered through 0.3 μm syringe filter and purified by reverse-phase prep-HPLC using acetonitrile/water mixture with 0.1% of TFA.
Reaction SMILES: Cl.[C:2]1([CH2:8][N:9]2[CH2:16][CH2:15][CH2:14][C@H:10]2[C:11]([OH:13])=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1[CH:18]=CC2N(O)N=[N:23][C:21]=2[CH:22]=1.[CH3:27]N1CCOCC1.N1CCCCC1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:2]1([CH2:8][N:9]2[CH2:16][CH2:15][CH2:14][CH2:27][C@H:10]2[C:11]([N:23]2[CH2:18][CH2:17][CH2:22][CH2:21]2)=[O:13])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)[C@@H]1CCCN1Cc1ccccc1
Reactant: CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCNCC1
Solvent: ClCCl
Product: O=C([C@@H]1CCCCN1Cc1ccccc1)N1CCCC1
Reaction time: 8 h
Yield: 40.1 %

Procedure:
1-(Phenylmethyl)-L-proline hydrochloride (2.0 g, 8.247 mmol) and HOBt (1.34 g, 9.928 mmol) were dissolved in CH2Cl2 (50 mL), and 4-methylmorpholine (2.72 mL, 24.822 mmol), piperidine (0.981 mL, 9.929 mmol), and EDCI (1.906 g, 9.928 mmol) were added to this solution. After stirring overnight, the solution was washed with water (50 mL), and the aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo to provide (2S)-1-(phenylmethyl)-2-(1-pyrrolidinylcarbonyl)piperidine (0.901 g, 40%). LCMS: (M+H)+: 273.1.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH2:9])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18].[OH-].[Na+]>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:9][C:17](=[O:19])[CH3:18])[CH:5]=[CH:4][CH:3]=1
Reactant: NCc1cccc(Br)n1
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1cccc(Br)n1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of C-(6-Bromo-pyridin-2-yl)-methylamine (5440 mg, 29.08 mmol) in dichloromethane (100 mL) at room temperature was added triethylamine (5886 mg, 58.17 mmol) and acetyl chloride (2511 mg, 31.99 mmol). The reaction mixture was heated at 40° C. for 3 h and cooled down to room temperature. A solution of sodium hydroxide (1N) was added and the reaction was stirred for 1 h at room temperature. The layers were separated and the organic phase was concentrated under reduced pressure. The crude mixture was dissolved in EtOH (50 mL) and concentrated hydrochloric acid (10 mL) was added. The mixture was stirred for 30 min and benzene was added followed by sodium hydroxide pellets until pH 10 was reached. The phases were separated and the organic layer was washed with an aqueous solution of ammonium chloride and the volatiles were removed in vacuo. The crude material was purified by column chromatography with a gradient of 0 to 5% methanol/dichloromethane to give N-(6-Bromo-pyridin-2-ylmethyl)acetamide as viscous orange oil. MS ES (MH+ 229.1/231.0).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[CH2:15]O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:19][CH2:15][C:11]1[N:10]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:17])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH:14]=[CH:13][N:12]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccnc2CO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccnc2CBr)cc1
Yield: 45.3 %

Procedure:
To a solution of the above alcohol (0.55 g, 2.17 mmol) and CBr4 (1.08 g, 3.26 mmol) in CH2Cl2 (25 mL) at 0° C. was added a solution of triphenylphosphine (0.68 g, 2.60 mmol) in CH2Cl2 (10 mL) as described in J. Med. Chem. (1997) 40, 14:2196. Purification by flash column chromatography using 25% EtOAc/hexanes afforded 2-bromomethyl-1-(toluene-4-sulfonyl)-1H-imidazole as a yellow oil (0.31 g, 45%). 1H NMR (CDCl3) δ 2.45 (s, 3H), 4.81 (s, 2H), 7.04 (s, 1H), 7.37 (d, 2H, J=9.0 Hz), 7.42 (s, 1H), 7.92 (d, 2H, J=9.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]3[CH:23]=[C:22]([Sn](CCCC)(CCCC)CCCC)[N:21]=[CH:20]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:37][C:38]([NH:41][S:42]([C:45]1[S:49][C:48](Br)=[CH:47][CH:46]=1)(=[O:44])=[O:43])([CH3:40])[CH3:39].CCCCCC>C1(C)C=CC=CC=1.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>[C:38]([NH:41][S:42]([C:45]1[S:49][C:48]([C:22]2[N:21]=[CH:20][N:19]([C:11]3[N:10]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[N:12]=3)[CH:23]=2)=[CH:47][CH:46]=1)(=[O:43])=[O:44])([CH3:40])([CH3:37])[CH3:39]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(Cl)c(Cl)c3)cc(C(F)(F)F)n2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A stirred mixture of 4-(3,4-dichloro-phenyl)-2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (Example G.6) (0.46 g, 0.71 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.23 g, 0.78 mmol), tetrakis(triphenylphosphine)palladium (0.049 g, 0.042 mmol) in toluene (8 mL) was heated under reflux conditions for 15 h, hexane (10 mL) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and dried to yield 5-{1-[4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.34 g) as a white solid.