Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[N:11]=2)[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.Br[CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>CN(C=O)C.CS(C)=O>[C:46]([O:45][C:43](=[O:44])[CH2:42][NH:1][CH:2]1[CH2:3][CH2:4][CH:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:30])([F:31])[F:29])[N:11]=2)[CH2:6][CH2:7]1)([CH3:49])([CH3:48])[CH3:47]
Reactant: NC1CCC(CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CNC1CCC(CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a solution of N4-(4-amino-cyclohexylmethyl)-5-nitro-N2-(2-trifluoromethoxy-benzyl)-pyrimidine-2,4-diamine (88 mg, 0.20 mmol) in 2:1 DMF/DMSO (0.6 mL) was added N,N-diisopropylethylamine (35 μL, 0.30 mmol) followed by tert-butyl bromoacetate (22 μL, 0.15 mmol). The mixture was stirred at room temperature overnight then partitioned with EtOAc (15 mL) and water (5 mL). The layers were separated and the organics washed with water (2×5 mL) and brine. After concentration in vacuo, the residue was purified by column chromatography (silica gel, 97:3 DCM/MeOH) to afford (4-{[5-nitro-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexylamino)-acetic acid tert-butyl ester (51 mg, 61%) as a colorless oil, m/z 555 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([CH:14]=[CH2:15])[N:11]=[C:10]([CH3:16])[N:9]=2)[N:3]=1.Cl[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:9]=[C:10]([CH3:16])[N:11]=[C:12](/[CH:14]=[CH:15]/[C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH:13]=2)[N:3]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: C=Cc1cc(-n2nc(C)nc2C)nc(C)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(/C=C/c2ccc3ccccc3n2)cc(-n2nc(C)nc2C)n1
Temperature: 100 °C

Procedure:
To a solution of 4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methyl-6-vinylpyrimidine (1-3) (200 mg, 0.93 mmol, 1.0 eq.) in degassed DMF (4.0 mL) was added 2-chloroquinoline (148 mg, 0.93 mmol, 1.0 eq.) followed by palladium acetate (32.0 mg, 47.5 mol, 0.050 eq.) and triethylamine (1.20 mL, 4.65 mmol, 5.0 eq.). The reaction was heated at 100° C. for 48 hours and cooled to room temperature. The reaction was quenched by the addition of water (5.0 mL) and ethyl acetate (5.0 mL) was added and the mixture was filtered through Celite. The organic layer was separated and the aqueous layer was washed with ethyl acetate (2×5.0 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (10-40% ethyl acetate in hexanes) to afford (E)-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)vinyl)quinoline (1-4) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.19 (br d, 1H, J=8.5 Hz), 8.13 (d, 1H, J=16.0 Hz), 8.11 (br d, 1H, J=8.3 Hz), 7.87 (br s, 111), 7.81 (br dd, 1H, J=8.0, 1.0 Hz), 7.78-7.68 (m, 3H), 7.55 (ddd, 1H, J=8.0, 7.0, 1.0 Hz), 2.94 (s, 3H), 2.77 (s, 3H), 2.44 (s, 3H). LRMS mz (M+H+) 343 found, 343 required. m.p. 153-155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:7]([CH2:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][C:3]=1[OH:34].[CH2:35]([O:37][CH2:38][CH2:39]Cl)[CH3:36].[C:41](=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:7]([CH2:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[C:24]([F:25])([F:27])[F:26])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][C:3]=1[O:34][CH2:36][CH2:35][O:37][CH2:38][CH2:39][CH3:41]
Reactant: O=C([O-])[O-]
Reactant: CCOCCCl
Reactant: O=C(Cc1c(-c2ccccc2)c2cc(O)c(Cl)cc2oc1=O)Nc1ccc(Cl)cc1C(F)(F)F
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOCCOc1cc2c(-c3ccccc3)c(CC(=O)Nc3ccc(Cl)cc3C(F)(F)F)c(=O)oc2cc1Cl
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
A solution of 2-(7-chloro-6-hydroxy-2-oxo-4-phenyl-2H-chromen-3-yl)-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide (Example 208) (0.30 g) in DMF (5 ml) was combined with 2-chloroethyl ethyl ether (0.31 ml), potassium carbonate (0.23 g) and sodium iodide (0.15 g), and stirred at 120° C. for 30 minutes. The reaction solution was combined with water and extracted with ethyl acetate. The extract was washed with a saturated brine, and then dried over magnesium sulfate, and concentrated under reduced pressure. The resultant residue was recrystallized from ethyl acetate-diisopropyl ether to obtain the title compound as a colorless crystal (151 mg, 43%). Melting point: 170-171° C.
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][O:15][CH2:16][CH:9]1[CH2:10][N:11]([S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:12]2)C1C=CC=CC=1.[H][H]>CCO.CO.[Pd]>[C:20]1([S:17]([N:11]2[CH2:10][CH:9]3[NH:8][CH:13]([CH2:14][O:15][CH2:16]3)[CH2:12]2)(=[O:19])=[O:18])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=S(=O)(c1ccccc1)N1CC2COCC(C1)N2Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: O=S(=O)(c1ccccc1)N1CC2COCC(C1)N2
Yield: 89 %

Procedure:
To a solution of 112e (3.0g, 8.37 mmol) in EtOH (100 ml) was added Pd/C (0.5g) in MeOH (30 ml). The reaction mixture was hydrogenated at atmospheric hydrogen at 50° C. for overnight. Then, the catalyst was filtered off, washed with ethanol, and the solvent was evaporated to give 112f as a colorless solid (2.0g, 90%) MS: [M+H]+: 268
Reaction SMILES: C([Li])CCC.[CH2:6]([N:8]1[C:12]([CH3:13])=[N:11][N:10]=[N:9]1)[CH3:7].Cl[CH2:15][C:16]([CH3:18])=[CH2:17].O>C1COCC1>[CH2:6]([N:8]1[C:12]([CH2:13][CH2:17][C:16]([CH3:18])=[CH2:15])=[N:11][N:10]=[N:9]1)[CH3:7]
Reactant: CCn1nnnc1C
Reactant: C=C(C)CCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)CCc1nnnn1CC
Temperature: -70 °C
Yield: 80.2 %

Procedure:
n-Butyl lithium (1.53 M) hexane solution (6.5 ml, 9.98 mmol) was added dropwise to a solution of 1-ethyl-5-methyl-1H-tetrazole (0.80 g, 7.13 mmol) in THF (15 ml) while stirring at −70° C., and the mixture was further stirred for 1.5 hours. A solution of 3-chloro-2-methyl-1-propene (0.77 ml, 7.84 mmol) in THF (5 ml) was added to the mixture, and the resulting mixture was stirred for 2 hours. Water was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate, and the extract was dried over magnesium sulfate, and then concentrated under reduced pressure to afford 1-ethyl-5-(3-methyl-3-butenyl)-1H-tetrazole (0.95 g, yield 80%) as a brown oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]>>[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]
Reactant: COCCCN
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: COCCCNc1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using 3-methoxy-propylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. 1H NMR (DMSO) δ 1.81 (m, 2H); 2.98 (m, 2H); 3.24 (s, 3H); 3.41 (m, 4H); 3.56 (m, 2H); 7.19 (m, 2H); 7.28 (bs, 1H); 7.50 (m, 2H); 7.92 (m, 2H); 8.18 (m, 3H); 8.38 (bs, 1H); 8.68 (bs, 1H); 12.13 (bs, 1H). MS (ion spray) m/z 455 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:25](O)=[O:26])=[CH:9]2.[CH2:28]([S:35][CH:36]([CH:39]([O:42][CH3:43])[O:40][CH3:41])[CH2:37][NH2:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[CH2:28]([S:35][CH:36]([CH:39]([O:40][CH3:41])[O:42][CH3:43])[CH2:37][NH:38][C:25]([C:10]1[NH:11][C:12]2[C:8]([CH:9]=1)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=2[NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)(=[O:18])=[O:17])=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COCCOc1cc(NS(=O)(=O)c2ccccn2)c2[nH]c(C(=O)O)cc2c1
Reactant: COC(OC)C(CN)SCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cc(NS(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(SCc3ccccc3)C(OC)OC)cc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.5 %

Procedure:
A mixture of 5-(2-methoxyethoxy)-7-[(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylic acid (4.24 g), 2-(benzylthio)-3,3-dimethoxypropan-1-amine (2.88 g), 1H-1,2,3-benzotriazol-1-ol (1.80 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (2.70 g) and N,N-dimethylformamide (40 mL) was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (2:3-1:4, volume ratio) to give the title compound (6.03 g, yield 91%) as a colorless amorphous solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][C:6]=1[NH2:7].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH:19]=O)[CH:17]=O)=[CH:12][CH:11]=1>C(O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]2[CH:17]=[C:16]([C:13]3[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:15][CH:14]=3)[CH:19]=[N:7][C:6]=12
Reactant: Nc1[nH]ncc1I
Reactant: COc1ccc(C(C=O)C=O)cc1
Solvent: CCO
Product: COc1ccc(-c2cnc3c(I)cnn3c2)cc1
Temperature: 23 °C

Procedure:
A solution of 4-iodo-1H-pyrazol-5-amine (640 mg, 3.9 mmol, 1 equiv) and 2-(4-methoxyphenyl)malonaldehyde (700 mg, 3.9 mmol, 1.0 equiv) in ethanol (20 mL) was heated at 75° C. for 4 hours. The reaction mixture was allowed to cool to 23° C., and the precipitate was filtered, washed with cold methanol, and air dried to afford 3-iodo-6-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidine (2-1) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([N:21]1[CH2:24][C:23](=O)[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(O)(=O)C>CO.[Pd]>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH:23]2[CH2:22][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:24]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(N2CCN(Cc3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1-benzylpiperazine (0.500 ml) in methanol (25 ml) were added 1-Boc-azetidin-3-one (495 mg), acetic acid (0.182 ml), followed by stirring at room temperature for 5 min. 10% palladium on carbon (308 mg) was added thereto, followed by stirring at room temperature under a hydrogen atmosphere for 15 hr. The catalyst was removed by filtration. The residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. This was concentrated to provide a crude product of 4-benzyl-1-(1-Boc-azetidin-3-yl)piperazine (ESI-MS (m/z): 332 [M+H]+). This was dissolved in tetrahydrofuran (10 ml). Lithium aluminum hydride (219 mg) was added thereto while stirring in an ice bath. The mixture was stirred under a nitrogen atmosphere in an ice bath for 15 min, at room temperature for 15 min, and was heated to reflux at 100° C. for 3.5 hr. The reaction mixture was cooled in an ice bath. Water (0.22 ml), a 5N aqueous solution of sodium hydroxide (0.22 ml) and water (1.1 ml) were added thereto, followed by stirring in an ice bath for 1 hr. Insoluble matter was removed by filtration. To the filtrate was added a 4N solution of hydrochloric acid in ethyl acetate (2.17 ml), which was concentrated to provide a crude product of 4-benzyl-1-(1-methylazetidin-3-yl)piperazine trihydrochloride (ESI-MS (m/z): 246[M+H]+). This was dissolved in water (25 ml) and 2-propanol (25 ml). 10% palladium on carbon (615 mg) was added thereto, followed by stirring under a hydrogen atmosphere at room temperature for 12 hr. The catalyst was removed by filtration. Concentration of the filtrate provided a crude product of the titled compound as a white solid (382 mg).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>C(#N)C>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:13][CH:14]=3)[O:8][C:4]=2[CH:3]=1
Reactant: ClCCN1CCOCC1
Reactant: Oc1ccc(-c2nc3ccc(Br)cc3o2)cc1
Agent: Cl
Solvent: CC#N
Product: Brc1ccc2nc(-c3ccc(OCCN4CCOCC4)cc3)oc2c1

Procedure:
The preparation is carried out analogously to Example 40 from 4-(6-bromo-benzoxazol-2-yl)-phenol and N-(2-chloroethyl)morpholine hydrochloride with ACN as solv.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7](O)[CH2:8][N+:9]([O-:11])=[O:10].CCN(CC)CC.CS(Cl)(=O)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1/[CH:7]=[CH:8]/[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])CC(O)c1ccsc1Br
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])/C=C/c1ccsc1Br
Yield: 89 %

Procedure:
To a solution of 1-(2-bromothiophen-3-yl)-2-nitroethanol (3 g, 12.0 mmol), DMAP (146 mg, 1.2 mmol) and Et3N (2.4 g, 24.0 mmol) in DCM (30 mL) was added MsCl (2.4 g, 24.0 mmol) dropwise. The resulting mixture was then refluxed for 3 h. After cooling, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (2.5 g, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Br:12])[CH:11]=1)[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2.[CH2:14]([O:16][P:17]([O-:21])[O:18][CH2:19][CH3:20])[CH3:15].CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([P:17](=[O:21])([O:18][CH2:19][CH3:20])[O:16][CH2:14][CH3:15])[CH:11]=1)[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2.[Br:12][C:10]1[CH:11]=[C:2]([P:17](=[O:21])([O:18][CH2:19][CH3:20])[O:16][CH2:14][CH3:15])[CH:3]=[C:4]2[C:9]=1[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2
Reactant: CCOP([O-])OCC
Reactant: Cc1ccc2cc(Br)cc(Br)c2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1cc(Br)c2nc(C)ccc2c1
Product: CCOP(=O)(OCC)c1cc(Br)cc2ccc(C)nc12
Temperature: 100 °C
Yield: 13 %
Yield: 4 %

Procedure:
To a degassed solution of 6,8-dibromo-2-methylquinoline (3.01 g, 10 mmol, prepared according to Song et al. J. Heterocyclic Chem. 1993, 39, 17.), diethylphosphite (1.65 g, 12 mmol) and Et3N (1.21 g, 12 mmol) in toluene (3 mL) was added Pd(OAc)2 (224.5 mg, 1 mmol). The mixture was degassed and Ph3P (1.049 g, 4 mmol) was added. The mixture was heated to 100° C. for 7 h, cooled, diluted with EtOAc (200 mL) and filtered through celite. The filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel to give 475 mg (13%) of diethyl 6-bromo-2-methyl-8-quinolylphosphonate and 150 mg (4%) of diethyl 8-bromo-2-methyl-6-quinolylphosphonate.
Reaction SMILES: [F:1][CH2:2][C:3]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][NH:5][CH2:4]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O1CCOCC1.O>[F:1][CH2:2][C:3]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][N:5]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:4]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1(CF)CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C1(CF)CCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
To a solution of ethyl 3-(fluoromethyl)pyrrolidine-3-carboxylate (1.86 g, 10.62 mmol) in a 1:1 mixture of 1,4-dioxane/water (18 mL) was added sodium carbonate (1.35 g, 12.74 mmol) and the mixture cooled to 0° C. in an ice bath. Benzyl chloroformate (1.79 mL, 12.74 mmol) was added dropwise and the resulting mixture was stirred at 0° C. for 30 minutes, then at ambient temperature for 18 hours. The mixture was partitioned between water and ether, and the layers separated. The organic layer was washed sequentially with water, saturated sodium bicarbonate solution and brine, then dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by chromatography (Biotage 25M; 15% ethyl acetate/hexanes) to afford 1-benzyl 3-ethyl 3-(fluoromethyl)pyrrolidine-1,3-dicarboxylate (3.3 g, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=1)[NH:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:40][C:41]([CH3:46])([CH3:45])[C:42](Cl)=[O:43]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=1)[N:14]([C:42](=[O:43])[C:41]([CH3:46])([CH3:45])[CH3:40])[CH2:13][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3c(c2)CCNC3c2ccc(OCCN3CCCC3)cc2)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)N1CCc2cc(OCc3ccccc3)ccc2C1c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.5 %

Procedure:
A solution of 6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline (0.015 g, 0.04 mmol) and Et3N (0.01 ml, 0.07 mmol) in anhydrous THF (0.35 ml) was added to a solution of trimethylacetyl chloride (0.04 mmol) in anhydrous THF (0.4 ml) at rt in a sealed reaction vessel. The resulting suspension was stirred at rt for 20 hr, then evaporated to dryness. The product was suspended in a mixture of H2O (0.4 ml) and saturated NaHCO3 solution (0.4 ml), then extracted with CH2Cl2 (3×0.75 ml). The combined extracts were evaporated to dryness to give the crude product. Purification by reverse-phase HPLC, eluting first with gradient. Purification by reverse-phase HPLC on a Primesphere (Phenomenex 2320 West 205th St. Torrance, Calif. 90501) C-18HC (50.0 mm×10.0 mm column with 5 m particle size) column, eluting with a linear gradient starting at time 0 min. of H2O:CH3CN:1% TFA/H2O (85:10:5), increasing to H2O:CH3CN:1% TFA/H2O (5:90:5) at 8 min., detected on a Micromass Platform 2 mass spectrometer (DAD 190-600 nM) gave material which, after evaporation to dryness, was purified by reverse-phase HPLC on a Primesphere C-18HC (3.0 mm×2.0 mm column with 5 m particle size) column, eluting with a linear gradient starting at time 0 min. of H2O:CH3CN:TFA (99.9:0:0.1), increasing to H2O:CH3CN:TFA (0:99.9:0.1) at 4 min., detected with a UV detector (300 nM +/−90 nM and 254 nM +/−25 nM), gave an eluent that was evaporated to dryness to give 0.012 g (56% yield) of the pure product. MS 513 m/e (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:28][CH2:29][CH2:30][O:31][Si](C(C)(C)C)(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:28][CH2:29][CH2:30][OH:31])[C:16]3[C:11](=[CH:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: N#Cc1ccc2c(c1)COC2c1ccc(F)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)COC2(CCCO)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
A solution of 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (13.4 g, 60 mmol) in THF (450 mL) was added to a solution of LDA (76 mmol) in THF (30 mL) at −78° C. under an atmosphere of nitrogen. After stirring at −78° C. for 30 min, a solution of (3-bromopropoxy)-tert-butyldimethylsilane (16.8 mL, 72 mmol) in THF (30 mL) was added and the resulting mixture was allowed to warm to room temperature and stirred for 2 h. Then the mixture was poured into ice/H2O (400 mL), and extracted with Et2O (3×500 mL). The organic extracts were washed with H2O (500 mL) and brine (500 mL), dried and evaporated. The residue was dissolved in methanol (400 mL) and was added 1M HCl (200 mL). The resulting solution was stirred at room temperature for 1 h and evaporated. Silica gel chromatography (heptane, EtOAc 5:1) of the residue gave the title product as an oil (14.4 g, 81%). 1H NMR (DMSO-d6) δ1.25 (2H, m); 2.18 (2H, t, J=8.8 Hz); 3.31 (2H, q, J=6.2 Hz); 4.34 (1H, t, J=6.2 Hz); 5.12 (1H, d, J=13.2 Hz); 5.17 (1H, d, J=13.2 Hz); 7.15 (2H, t, J=8.8 Hz); 7.58 (2H, dd, J=6.0 and 8.8 Hz); 7.72 (1H, s); 7.78 (2H, br d, J=6.0 Hz.). 13C NMR (DMSO-d—6) δ27.4; 37.3; 59.8; 71.0; 90.7; 110.5; 114.8; 115.2; 118.8; 123.2; 125.6; 126.9; 127.1; 132.0; 139.9; 140.6; 149.5; 160.9; 162.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:15])[CH:9]=2)=[O:5])[CH3:2].P(Cl)(Cl)(Cl)=O.O.[OH-].[Na+].CN([CH:27]=[O:28])C>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH:27]=[O:28])=[CH:12][CH:11]=[C:10]([Cl:15])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)c1[nH]c2cc(Cl)ccc2c1C=O
Temperature: 60 °C

Procedure:
To a stirred solution of 2.36 g (0.011 mol) of 6-chloro-1H-indole-2-carboxylic acid ethyl ester in DMF (20 ml) was added phosphorus oxychloride (1.08 ml, 0.012 mol) at RT. The solution was heated at 60° C. for 2 hours, then cooled to RT, and poured into water. The ph was adjusted to 7 by careful addition of aq. NaOH 2N. The resulting brown precipitate was collected by filtration and dried over night in a vacuum oven (50° C.). The title compound was obtained as light brown solid, 2.05 g (77%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][N:26]=2)=[N:10]1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH:32]1[C:37]([OH:39])=[O:38]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH:32]2[C:37]([OH:39])=[O:38])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncc(C(F)(F)F)s2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2ncc(C(F)(F)F)s2)=NC1c1ccc(F)cc1Br
Yield: 64.4 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(5-(trifluoromethyl)thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.37 g, 0.65 mmol) was reacted with morpholine-3-carboxylic acid (0.1 g, 0.71 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.26 g, 65%). The compound was characterized by the following spectroscopic data: