Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=O)[CH:18]=[CH:19][NH:20]2)=[CH:15][C:14]=1[C:24]([O:26][CH3:27])=[O:25])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O>[CH2:5]([O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]([Cl:3])=[CH:18][CH:19]=[N:20]2)=[CH:15][C:14]=1[C:24]([O:26][CH3:27])=[O:25])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(Cl)ccnc2cc1OCc1ccccc1

Procedure:
After adding thionyl chloride (70 ml) and a catalytic amount of dimethylformamide to methyl 7-(benzyloxy)-4-oxo-1,4-dihydro-6-quinolinecarboxylate (7.19 g, 23.2 mmol), the mixture was heated to reflux for 3 hours while stirring. The reaction solution was concentrated under reduced pressure, a 2N sodium hydroxide solution was gradually added for neutralization, extraction was performed with ethyl acetate, and the organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off, diethyl ether was added for crystallization, and the crystals were filtered out and blow-dried to obtain the title compound (4.067 g, 12.4 mmol) as light brown crystals.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:21]3[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=3[Cl:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: O=C(O)/C=C/c1ccc(F)cc1Cl
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)/C=C/c3ccc(F)cc3Cl)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and (E)-3-(2-chloro-4-fluoro-phenyl)-acrylic acid.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[NH:8])[CH3:7])[CH2:2][CH2:3][CH3:4].[N+:9](=[C:11]1[N:15]=[N:14][N:13]=[C:12]1[C:16]([NH2:18])=[O:17])=[N-:10].C>C(O)C>[CH2:1]([N:5]([C:6](=[NH:8])[CH3:7])[N:10]=[N:9][C:11]1[NH:15][N:14]=[N:13][C:12]=1[C:16]([NH2:18])=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(C)=N
Reactant: [N-]=[N+]=C1N=NN=C1C(N)=O
Solvent: CCO
Product: CCCCN(N=Nc1[nH]nnc1C(N)=O)C(C)=N

Procedure:
5.7 g. of N-butyl-acetamidine are dissolved in 300 ml of anhydrous ethanol, whereupon 7 g. of 5-diazo-1,2,3-triazole-4-carboxamide are added at 25° C. within half an hour. After 3 hours the solution is clarified with activated charcoal and evaporated in vacuo. The residual thick oil is admixed with 40 ml of anhydrous ethylacetate and the crude product (9.7 g. melting at 150° C. decomposition) is recrystallized from a mixture of 110 ml of acetone and 40 ml of anhydrous ethanol. Thus 6.1 g. of 5-[3-n-butyl-3-(alpha-iminoethyl)-1-triazeno]-1,2,3-triazole-4-carboxamide melting at 159°-160° C. (decomposition) are obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][NH:17][C:14]2=[CH:15][N:16]=1)[CH3:2].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C([O-])([O-])=O.[Cs+].[Cs+]>CO>[C:20]([O:24][C:25]([N:27]1[CH2:28][CH:29]=[C:30]([C:19]2[C:13]3[C:14](=[CH:15][N:16]=[C:11]([C:4]4[C:5]([CH2:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=4[CH2:1][CH3:2])[CH:12]=3)[NH:17][CH:18]=2)[CH2:31][CH2:32]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCc1cccc(CC)c1-c1cc2cc[nH]c2cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: CCc1cccc(CC)c1-c1cc2c(C3=CCN(C(=O)OC(C)(C)C)CC3)c[nH]c2cn1

Procedure:
A mixture of 5-(2,6-diethyl-phenyl)-1H-pyrrolo[2,3-c]pyridine (200 mg, 0.90 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (358 mg, 1.8 mmol), Cs2CO3 (586 mg, 1.8 mmol), and MeOH (6 mL) is refluxed for 18 h. MeOH is removed under reduced pressure. The residue is treated with acetic acid (0.5 mL) and water (3 mL) and is extracted with EtOAc. The combined organic extracts are washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Chromatography of the residue affords 4-[5-(2,6-Diethyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([CH2:14][CH2:15]Br)[N:11]=[C:10]([S:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:28])[CH2:26][CH3:27])=[CH:20][CH:19]=3)[N:9]=2)[CH:3]=1.[NH:29]1[CH2:32][CH2:31][CH2:30]1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][N:29]3[CH2:32][CH2:31][CH2:30]3)[N:11]=[C:10]([S:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:28])[CH2:26][CH3:27])=[CH:20][CH:19]=3)[N:9]=2)[CH:3]=1
Reactant: C1CNC1
Reactant: CCC(=O)Nc1ccc(Sc2nc(CCBr)cc(Nc3cc(C)[nH]n3)n2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(=O)Nc1ccc(Sc2nc(CCN3CCC3)cc(Nc3cc(C)[nH]n3)n2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of N-(4-(4-(5-methyl-1H-pyrazol-3-ylamino)-6-(2-bromoethyl)pyrimidin-2-ylthio)phenyl)propionamide (100 mg, 0.21 mmol) and azetidine (36 mg, 0.63 mmol) in dimethylformamide (2 ml) was stirred at room temperature under a nitrogen atmosphere for 24 hours. The reaction mixture was diluted with ethyl acetate (40 ml). The organic layer was washed with a saturated solution of sodium bicarbonate (10 ml) and brine (10 ml), then dried over magnesium sulfate. The residue was purified by Gilson HPLC to afford the title compound as a bis-trifluoro acetic acid salt (0.5 mg, 1%). 1H NMR (CD3OD): 1.30-1.37 (3H, m), 2.15-2.20 (3H, s), 2.40-2.50 (4H, m), 2.80-2.90 (2H, t), 3.50-3.55 (2H, t), 4.00-4.15 (4H, s), 6.50-6.55 (1H, s), 7.55-7.65 (2H, m), 7.75-7.80 (2H, m). ES+ 438
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH3:30])[C:21]=1[O:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[CH:17]=O.S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:30][C:20]1[CH:19]=[C:16]([C:17]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([F:11])=[CH:8][C:7]=3[F:12])[N:1]=2)[CH:15]=[C:14]([CH3:13])[C:21]=1[O:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NC(=O)c1c(N)cc(F)cc1F
Reactant: Cc1cc(C=O)cc(C)c1OCCN1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)cc(C)c1OCCN1CCCC1
Temperature: 145 °C
Reaction time: 16 h

Procedure:
To a solution of 2-amino-4,6-difluoro-benzamide (0.80 g, 4.60 mmol) and 3,5-dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (1.14 g, 4.60 mmol) in N,N-dimethylacetamide (60 mL) were added sodium hydrogen sulfite (58.5 wt %, 1.25 g, 6.9 mmol) and p-toluenesulfonic acid monohydrate (3.50 g, 18.4 mmol). The reaction mixture was stirred at 145° C. for 16 hours under nitrogen atmosphere, then cooled to room temperature. Solvent was evaporated under reduced pressure. Water (50 mL) was added, followed by saturated aqueous sodium bicarbonate solution (15 mL). The mixture was extracted with CH2Cl2 (2×100 mL) and washed with water. The organic phase was evaporated and the residue was washed with hexane/ether (90:10, 100 mL). The solid was filtered and dried under vacuum to give the title compound as a brown solid. Yield: 1.48 g (80%). MP 234-235° C. 1H NMR (400 MHz, DMSO-d6): δ 12.36 (s, 1H), 7.90 (s, 1H), 7.32 (m, 2H), 3.91 (t, J=4 Hz, 2H), 2.83 (t, J=4 Hz, 2H), 2.55 (s, 4H), 2.31 (s, 6H), 1.70 (s, 4H).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[OH:7][C:8]([CH3:41])([CH3:40])[CH2:9][C@@:10]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:24]=[CH:23][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:21][CH:20]=2)[CH3:18])[CH2:12][CH2:11]1.BrC1C=NC(C[CH:50]2[C:55](Br)=[CH:54][NH:53][C:52]([CH3:57])=[N:51]2)=NC=1>CN(C)C=O>[OH:7][C:8]([CH3:40])([CH3:41])[CH2:9][C@@:10]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:20]=[CH:21][C:22]([C:55]3[CH:54]=[N:53][C:52]([CH3:57])=[N:51][CH:50]=3)=[CH:23][CH:24]=2)[CH3:18])[CH2:12][CH2:11]1
Reactant: CC1=NC(Cc2ncc(Br)cn2)C(Br)=CN1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ncc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
2 M aqueous Na2CO3 solution (1.67 mL) was added to a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.80 g) and 5-bromo-2-(5-bromo-2-methyl-1,4-dihydro-pyrimidin-4-ylmethyl)-pyrimidine (0.40 g) in dimethylformamide (5 mL). The resulting mixture was sparged with argon for 5 min, before [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane complex (82 mg) was added. The mixture was heated to 100° C. and stirred at this temperature overnight. After cooling to ambient temperature, water was added, and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel (CH2Cl2/MeOH 95:5→80:20) followed by HPLC (MeCN/H2O/NH4OH) to afford the title compound (340 mg) which was crystallized from iPr2O. Yield: 0.25 g (34% of theory). Mass spectrum (ESI+): m/z=446 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:13][CH3:14])[C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]2[OH:20].[C:21](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:13][CH3:14])[C:11]=1[F:12])[N:8]([CH3:21])[CH:7]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2=[O:20]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cnc2c(OC)c(F)c(F)cc2c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2c(OC)c(F)c(F)cc2c1=O
Reaction time: 17 h
Yield: 94.4 %

Procedure:
1.60 g (0.0057 mole) of ethyl 6,7-difluoro-4-hydroxy-8-methoxyquinoline-3-carboxylate (IX) [prepared as described in step (B3) above] were dissolved in 20 ml of dimethylformamide, and 1.20 g (0.0085 mole) of potassium carbonate and 2.40 g (0.017 mole) of methyl iodide were added to the resulting solution. The mixture was then stirred at 60°-65° C. for 17 hours. At the end of this time, the solvent was distilled off under reduced pressure. The residue was extracted with methylene chloride, and the methylene chloride extract was washed with water, dried and concentrated by evaporation under reduced pressure to give 1.60 g of ethyl 6,7-difluoro-8-methoxy-1-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (X, R9' =methyl) as a pale brown powder.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:2]1.[Br:16][C:17]1[C:18](F)=[C:19]2[C:25]([NH:26][C:27]([CH:29]3[CH2:31][CH2:30]3)=[O:28])=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1>CCCCO>[Br:16][C:17]1[C:18]([N:1]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:2]2)=[C:19]2[C:25]([NH:26][C:27]([CH:29]3[CH2:30][CH2:31]3)=[O:28])=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCNC1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@H]1CCCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CC4)c23)C1
Yield: 9 %

Procedure:
(S)-tert-Butyl azepan-3-ylcarbamate (431 mg, 2.01 mmol; commercially available or Moon, Sung-Hwan, et al. “An Efficient Conversion of Chiral α-Amino Acids to Enantiomerically Pure 3-Amino Cyclic Amines.” Synthetic Communications. Vol. 28, No. 21 (1998): pp. 3919-3926) was added to N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (200 mg, 0.671 mmol) in n-BuOH (3 mL), and the reaction was heated for 18 hours to 160° C. in a sealed tube. After concentration, the residue was purified by chromatography (SP4, 25M, water/ACN 100/0→0/100, 40CV) to yield (S)-tert-butyl 1-(5-bromo-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)azepan-3-ylcarbamate (30 mg, 9% yield) as a solid.
Reaction SMILES: C1(NC(C2C(C(OCCCCCC)=O)=CSC=2)=O)C=CC=CC=1.[Br:24][C:25]1[S:26][C:27]([Br:48])=[C:28]([C:39](=[O:47])[NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:29]=1[C:30]([O:32]CCCCCC)=[O:31].C([O-])([O-])=O.[Cs+].[Cs+].O1CCCC1>[Pd].CO>[Br:24][C:25]1[S:26][C:27]([Br:48])=[C:28]([C:39](=[O:47])[NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:29]=1[C:30]([OH:32])=[O:31]
Reactant: CCCCCCOC(=O)c1c(Br)sc(Br)c1C(=O)Nc1ccccc1
Agent: [Pd]
Agent: CCCCCCOC(=O)c1cscc1C(=O)Nc1ccccc1
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1c(Br)sc(Br)c1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Hexyl 4-(phenylcarbamoyl)thiophene-3-carboxylate (4) (0.2949 g, 0.000890 mol), hexyl 2,5-dibromo-4-(phenylcarbamoyl)thiophene-3-carboxylate (7) (0.2952 g, 0.000890 mol), palladium catalyst (4% mol), ligand (8% mol) and Cs2CO3 (162.9 mg; 0.50 mmol) were put in a microwave vial with a magnetic stirring bar. Tetrahydrofuran (1 mL) was added and sealed. 5 cycles of freeze pump thaw was done and the reaction was kept at 120 degree Celsius for 48 hours. The whole mixture was cooled to room temperature and poured in 500 mL of cold methanol. The precipitate was filtered and dissolved in THF and precipitated again. This procedure was repeated 3 times to remove small molecules.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([C:9](=[O:11])N)=[C:6]([NH2:8])[N:7]=1.C.[OH-:13].[Na+]>O>[NH2:8][C:6]1[C:5]([C:9]([OH:11])=[O:13])=[N:4][CH:3]=[C:2]([NH2:1])[N:7]=1
Reactant: NC(=O)c1ncc(N)nc1N
Reactant: [OH-]
Agent: C
Agent: [Na+]
Solvent: O
Product: Nc1cnc(C(=O)O)c(N)n1

Procedure:
A slurry consisting of 1.60 g of 3,5-diamino-6-carbamoylpyrazine, from Example 4, in 20 ml of 10% aqueous sodium hydroxide was heated at reflux for 2 hours, diluted to 100 ml with hot water and the resulting homogeneous solution was decolorized with Darco. Careful acidification to pH 1 gave a precipitate which was collected from the chilled solution by filtration. The collected material was washed twice, each time with small portions of water and methanol and dried yielding 0.92 g of 3,5-diaminopyrazinoic acid as a light powder, mp 169° (dec.).
Reaction SMILES: [O:1]1CCC[CH2:2]1.Br[C:7]1[CH:21]=[CH:20][C:10]([CH2:11][O:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.C([Li])CCC.CN(C)C=O>O>[CH3:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([O:12][CH2:11][C:10]2[CH:20]=[CH:21][C:7]([CH:2]=[O:1])=[CH:8][CH:9]=2)[CH:18]=1
Reactant: Cc1ccnc(OCc2ccc(Br)cc2)c1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccnc(OCc2ccc(C=O)cc2)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 55.4 %

Procedure:
To a tetrahydrofuran (150 mL) solution of 2-(4-bromo-benzyloxy)-4-methyl-pyridine (5.70 g, 20.5 mmol) described in Manufacturing Example 43-1-1 was added dropwise n-butyl lithium (2.67 M n-hexane solution, 9.21 mL, 24.6 mmol) on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere, which was stirred for 20 minutes at −78° C. N,N-dimethylformamide (3.16 mL, 41.0 mmol) was then added dropwise thereto and stirred for 10 minutes at −78° C. The reaction solution was allowed to room temperature, water was added, and the solution was extracted with ethyl acetate. The organic layer was separated and washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:3) to obtain the title compound (2.58 g, 55.4%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:10]=[C:11](O)[C:12]2[CH2:18][N:17]([C:19]3[N:23]([CH3:24])[N:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[CH:20]=3)[CH2:16][CH2:15][C:13]=2[N:14]=1.[Cl-].[Cl:30]C(=[N+](C)C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:30][C:11]1[C:12]2[CH2:18][N:17]([C:19]3[N:23]([CH3:24])[N:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[CH:20]=3)[CH2:16][CH2:15][C:13]=2[N:14]=[C:9]([C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[N:10]=1
Reactant: Cc1cccc(C)c1-c1nc(O)c2c(n1)CCN(c1cc(C(C)C)nn1C)C2
Reactant: CC(Cl)=[N+](C)C
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccc(C)c1-c1nc(Cl)c2c(n1)CCN(c1cc(C(C)C)nn1C)C2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-(2,6-dimethylphenyl)-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ol (2.38 g, 6.3 mmol) in DCM (50 mL) at 0° C., was added (1-chloro-ethylidene)-dimethylammonium chloride (Vilsmeier reagent) (2.421 g, 18.91 mmol). The reaction was stirred at 0° C. for 5 min, then at r.t. for 30 min. Saturated aqueous NaHCO3 was added to quench the reaction. The mixture was extracted with DCM three times. The combined organic layers was dried over Na2SO4. After filtration and concentration, the resulting residue was purified via silica gel FCC (0-100% EtOAc/heptane) to give 4-chloro-2-(2,6-dimethylphenyl)-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.19-7.27 (m, 1 H), 7.11 (d, J=7.6 Hz, 2 H), 5.80 (s, 1 H), 4.16 (s, 2 H), 3.72 (s, 3 H), 3.32 (t, J=5.9 Hz, 2 H), 3.16 (t, J=5.8 Hz, 2 H), 2.88 (dt, J=13.9, 6.9 Hz, 1 H), 2.11 (s, 6 H), 1.23 (d, J=6.8 Hz, 6 H). MS (ESI+) m/z 396.3 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[C:7]([CH3:14])[CH:8]=[CH:9][CH:10]=2)[C:5]=1[OH:15])([CH3:3])[CH3:2].[CH3:16][O:17]C(Cl)Cl.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH:1]([C:4]1[CH:13]=[C:12]([CH:16]=[O:17])[C:11]2[C:6]([C:5]=1[OH:15])=[C:7]([CH3:14])[CH:8]=[CH:9][CH:10]=2)([CH3:3])[CH3:2]
Reactant: COC(Cl)Cl
Reactant: Cc1cccc2ccc(C(C)C)c(O)c12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1cccc2c(C=O)cc(C(C)C)c(O)c12
Temperature: 0 °C

Procedure:
0.65 g of 2-isopropyl-8-methyl-1-naphthol was dissolved in 50 ml of dichloromethane and cooled down to 0° C. 1.3 ml of titanium tetrachloride was gradually dropped in the solution for reaction at 0° C. for 5 minutes, after which 0.9 ml of dichloromethyl methyl ether was gradually dropped and reacted at 0° C. for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate. The resultant organic phase was washed with a saturated saline solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were collected by filtration to obtain 0.7 g of the captioned compound as black crystals.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])C1=S)[CH:2]=[CH2:3].[CH2:19](N)C(C)C>O>[Cl:16][C:15]1[C:10]([NH:6][CH2:7][CH2:8][CH2:9][NH:4][CH2:1][CH:2]([CH3:3])[CH3:19])=[C:11]([CH3:17])[CH:12]=[CH:13][CH:14]=1
Reactant: C=CCN1CCCN(c2c(C)cccc2Cl)C1=S
Reactant: CC(C)CN
Solvent: O
Product: Cc1cccc(Cl)c1NCCCNCC(C)C
Temperature: 85 °C

Procedure:
Under cooling the hydrobromide salt of Example 12, Step B (6.82 g) was mixed with isobutylamine (5.85 g). The mixture was warmed to 85° C. under nitrogen until homogeneous and then refluxed for 2.5 hours. After cooling, it was diluted with water and the basic solution extracted with dichloromethane. The extracts were washed with 20% aqueous sodium chloride, dried over anhydrous potassium carbonate and evaporated to a brown oil which was flash chromatographed (on Merck-60 flash silica gel). The less polar impurities were eluted with 1:1 hexane- EtOAc and the desired material with 95:5:0.1 dichloromethane-methanol-ammonium hydroxide. The low melting material (3.82 g, 75%) was used as such in the next step.
Reaction SMILES: Br[CH:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[C:16]([C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=1)#[CH:17]>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].[Cu]I.O>[F:24][C:22]1[CH:23]=[C:18]([C:16]#[C:17][CH:2]=[C:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH:19]=[C:20]([F:25])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=CBr)CC1
Reactant: C#Cc1cc(F)cc(F)c1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=CC#Cc2cc(F)cc(F)c2)CC1
Temperature: 80 °C

Procedure:
A mixture of the Compound 49a (0.110 g, 0.40 mmol), palladium tetrakis(triphenylphosphine) (0.023 g, 0.02 mmol), copper(I) iodide (0.0078 g, 0.04 mmol) and 1-ethynyl-3,5-difluorobenzene (49 μL, 0.4 mmol) and TEA (2.5 mL) was heated for 3 h at 80° C. Afterwards, the reaction mixture was cooled, poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue (0.062 g.), used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].Br[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:8][C:6]1[CH:5]=[CH:4][C:3]([C:9](=[O:11])[CH3:10])=[C:2]([OH:1])[CH:7]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1O
Product: CC(=O)c1ccc(OCC(=O)OCc2ccccc2)cc1O

Procedure:
1-(2,4-Dihydroxy-phenyl)-ethanone was treated with 1 equivalent of benzyl 2-bromoacetate and processed as described in the synthesis of example 20a to obtain the title compound. The crude was purified using flash chromatography (silica gel, 3% CH3CN in chloroform) and crystallization was effected using ether-PE 60-80° C. Yield, 75%, white solid; mp, 66-67° C.; MS (EI): 300 (M+), 285, 165, 91 (100%); analysis: C17H16O5 requires C, 67.99; H, 5.37. found: C, 67.99; H, 5.53%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10]Br)=[CH:4][CH:3]=1.C([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=O>CC(O)C>[O:8]([CH2:9][CH2:10][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: BrCCOc1ccc(Br)cc1
Reactant: O=CN1CCNCC1
Solvent: CC(C)O
Product: c1ccc(OCCN2CCNCC2)cc1

Procedure:
The procedure of Example 6 was repeated, substituting 57.0 g (0.27 moles) of 2-bromoethyl phenyl ether for 2-bromoethyl p-bromophenyl ether, using 61.6 g (0.54 moles) of 1-formylpiperazine in 300 ml of 2-propanol and refluxing the mixture for 8 hours. Evaporation of the final dried chloroform extracts gave 35 g of 1-[2-phenoxyethyl]piperazine as an oil.