Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:29]=[CH:28][C:12]([CH:13]([OH:27])[CH2:14][N:15]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:11][C:10]=1[N+:30]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Fe].C(O)(=O)C>[NH2:30][C:10]1[CH:11]=[C:12]([CH:28]=[CH:29][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:13]([OH:27])[CH2:14][N:15]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:16]([CH3:18])([CH3:19])[CH3:17]
Reactant: CC(C)(C)N(Cc1ccccc1)CC(O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(C)(C)N(Cc1ccccc1)CC(O)c1ccc(OCc2ccccc2)c(N)c1

Procedure:
In 150 ml. of a 50% aqueous acetic acid solution there was dissolved 30 g. of 4-benzyloxy-3-nitro-α-(N-benzyl-N-tert-butylaminomethyl) benzyl alcohol and after adding to the solution 12 g. of iron powder, the mixture was refluxed for 25 minutes, accompanied by heating. While the reaction mixture was still hot, it was filtered and the filtrate was concentrated under a reduced pressure. Then, after adding to the residue 50 ml. of a 10% aqueous sodium carbonate solution, the product was extracted with benzene. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crystalline residue. By recrystallizing the product from a mixture of 40 ml. of benzene and 60 ml. of n-hexane, 23 g. of 3-amino-4-benzyloxy-α-(N-benzyl-N-tert-butylaminomethyl) benzyl alcohol melting at 68°-69° C was obtained.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([CH3:9])[N:8]=1.[CH2:10]([O:12][CH:13]([S:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]2[N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[N:27]=[CH:28][C:21]=12)[C:14](OCC)=[O:15])[CH3:11].O>C1COCC1.C(Cl)Cl>[CH2:10]([O:12][CH:13]([S:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]2[N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[N:27]=[CH:28][C:21]=12)[C:14]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH3:9])[N:8]=1)=[O:15])[CH3:11]
Reactant: CCOC(=O)C(OCC)Sc1ncnc2c1cnn2-c1ccccc1OC
Reactant: Cc1csc(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CCOC(Sc1ncnc2c1cnn2-c1ccccc1OC)C(=O)Nc1nc(C)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 1.9 %

Procedure:
Sodium hydride (95%, 3.7 mg, 0.15 mmol) was added to a stirred solution of 2-amino-4-methylthiazol (17.6 mg, 0.154 mmol) in anhydrous THF (4 mL). The reaction mixture was kept at ambient temperature for 5 minutes before ethyl ethoxy{[1-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]thio}acetate (50 mg, 0.129 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 h. Water and DCM were added and the two phases were separated. The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was purified with column chromatography (silica gel, eluting with a gradient consisting of 40-100% EtOAc in heptane) to give the title compound as a colourless oil (1.1 mg), 1H NMR (300 MHz, CDCl3) δ 10.03 (br s, 1H), 8.74 (s, 1H), 8.26 (s, 1H), 7.47 (m, 2H), 7.12 (m, 2H), 6.91 (s, 1H), 6.58 (s, 1H), 4.02 (m, 1H), 3.81 (m, 4H), 2.38 (s, 3H), 1.34 (t, 3H), HRMS: calcd for (M+H+) C20H21N6O3S2: 457.1116. Found: 457.1116.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@H:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[C:19]([F:27])[CH:18]=1)[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:30][C@H:31]1[C:39]2[C:38]([N:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)=[N:37][CH:36]=[N:35][C:34]=2[C@H:33]([OH:46])[CH2:32]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[F:27][C:19]1[CH:18]=[C:17]([C@@H:13]([C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:14]([N:43]2[CH2:42][CH2:41][N:40]([C:38]3[C:39]4[C@H:31]([CH3:30])[CH2:32][C@@H:33]([OH:46])[C:34]=4[N:35]=[CH:36][N:37]=3)[CH2:45][CH2:44]2)=[O:15])[CH:22]=[CH:21][C:20]=1[C:23]([F:26])([F:24])[F:25]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)O)c1ccc(C(F)(F)F)c(F)c1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(C(F)(F)F)c(F)c4)[C@@H]4CCCN4C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
(S)-2-((S)-1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)-2-(3-fluoro-4-(trifluoromethyl)phenyl)acetic acid (0.036 g, 0.092 mmol) and (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol di-hydrochloride (0.028 g, 0.092 mmol) were slurried in dichloromethane (5 mL) and then treated with diisopropylethylamine (0.06 mL, 0.34 mmol). This was followed by treatment with HBTU (0.036 g, 0.095 mmol). The mixture was stirred at ambient temperature for 1 hour. The reaction was concentrated in vacuo and purified by column chromatography, eluting with ethyl acetate. (0.040 g, 72% yield). MS (APCI+) [M+H] 608.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][S:25]2(=[O:31])=[O:30])[CH:3]=1.[CH3:32][C@@H:33]1[CH2:37][O:36][C:35](=[O:38])[NH:34]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:34]4[C@H:33]([CH3:32])[CH2:37][O:36][C:35]4=[O:38])=[CH:3][C:4]=3[N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][S:25]3(=[O:31])=[O:30])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCCCS3(=O)=O)CC2)c(C)c1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3N3CCCCS3(=O)=O)CC2)c(C)c1
Yield: 31.6 %

Procedure:
By reaction and treatment in the same manner as in Example 201 and using [4-chloro-2-(1,1-dioxo-1,2-thiazinan-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (218 mg) described in Preparation Example 128 and (R)-4-methyloxazolidin-2-one (47.6 mg) described in Preparation Example 25, the title compound (78.5 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]([C:10](=O)[CH3:11])[C:7](=O)[CH3:8])[CH3:2].[CH3:14][NH:15][NH2:16]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[C:10]([CH3:11])=[N:16][N:15]([CH3:14])[C:7]=1[CH3:8])[CH3:2]
Reactant: CNN
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)Cc1c(C)nn(C)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.2 %

Procedure:
Dissolve 3-acetyl-4-oxopentanoic acid ethyl ester (3.35 g, 19.5 mmol) in glacial acetic acid (20 mL) and add methylhydrazine (1.13 mL, 21.4 mmol) dropwise. Stir the resulting mixture at room temperature for 16 hr. Concentrate and partition the residue between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (50 mL). Separate organic layer, dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 7:3 hexanes:ethyl acetate) to give (1,3,5-trimethyl-1H-pyrazol-4-yl)-acetic acid ethyl ester (2.8 g, 73%) as an oil. 1H NMR (CDCl3) δ 4.08 (q, 2H), 3.67 (s, 3H), 3.29 (s, 2H), 2.18 (s, 6H), 1.21 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:21])[CH:17]=2)[N:12]=1)[C:5]([OH:7])=[O:6].ClC1C=CC=C(C(OO)=[O:30])C=1>CC(O)=O>[C:5]([C:4]1[CH:8]=[CH:9][C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:21])[CH:17]=3)[N+:12]=2[O-:30])=[C:2]([Cl:1])[CH:3]=1)([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(-c2ccc3cc(O)ccc3n2)c(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-c2ccc3cc(O)ccc3[n+]2[O-])c(Cl)c1
Yield: 37.5 %

Procedure:
To a solution of 3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid (Compound 8) (620 mg) in HOAc (8 mL) was added 3-chloroperbenzoic acid (77% pure, 1.19 g). The resultant mixture was heated at 90° C. over 3 hour. After removal of HOAc under reduced pressure, the resultant mixture was trituated with DCM and recrystallized from EtOH/water twice to afford the desired product (245 mg) as colorless solids. 1H NMR (DMSO-d6 300 MHz TMS): δ 10.49 (1H, s), 8.43 (1H, d, J=9 Hz), 8.06 (1H, d, J=3 Hz), 8.01 (1H, dd, J=9 and 3 Hz), 7.82 (1H, d, J=6 Hz), 7.69 (1H, d, J=6 Hz), 7.47 (1H, d, J=9 Hz), 7.37 (1H, dd, J=9 and 3 Hz), 7.31 (1H, d, J=3 Hz) ppm; MS (ESI): m/z 316, [M+H+].
Reaction SMILES: C(=O)C1C=CC=CC=1.[O:9]1[C:13]2([CH2:18][CH2:17][N:16]([C:19]3[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1.[S:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33].N1CCCCC1>C(O)C>[O:9]1[C:13]2([CH2:18][CH2:17][N:16]([C:19]3[CH:26]=[CH:25][C:22]([CH:23]=[C:31]4[S:27][C:28](=[O:33])[NH:29][C:30]4=[O:32])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1
Reactant: O=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: O=C1CSC(=O)N1
Solvent: O=Cc1ccccc1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2ccc(N3CCC4(CC3)OCCO4)cc2)S1
Yield: 98.6 %

Procedure:
A mixture of 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzaldehyde benzaldehyde (Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) (15 g, 60 mol), 2,4-thiazolidinedione (7.0 g, 60 mmol), and piperidine (8.0 mL, 81.2 mmol) in 450 mL of ethanol was refluxed for 6 hours. The solid which was formed on cooling the solution was collected to give the title compound as an orange solid (20.5 g, 99%); 1H NMR (300 MHz, DMSO-d6) δ 1.67 (t, J=5.6 Hz, 4H), 3.47 (t, J=5.6 Hz, 4H), 3.92 (s, 4H), 7.07 (d, J=9.0 Hz, 2H), 7.43 (d, J=9.0 Hz, 2H), 7.67 (s, 1H), 12.40 (brs, 1H); MS (ES) m/z: 346.8 (MH+); HRMS Calcd. for C17H19N2O4S(MH+): 346.0987. Found: 346.0994. Anal. Calcd. for C17H18N2O4S: C, 58.94; H, 5.24; N, 8.09. Found: C, 58.92; H, 5.11; N, 7.96.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][O:16][CH:17]([O:19][CH2:20][CH3:21])[CH3:18])=[O:8])[O:4][N:3]=1.[BH4-].[Na+].[CH3:24]I.[H-].[Na+]>[Cl-].[Na+].O.CCOCC.CN(C)C=O.CO.O1CCCC1>[CH2:20]([O:19][CH:17]([O:16][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:7]([C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1)[O:8][CH3:24])[CH3:18])[CH3:21]
Reactant: CI
Reactant: CCOC(C)OCc1ccccc1C(=O)c1cc(C)no1
Agent: [BH4-]
Agent: [Cl-]
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(C)OCc1ccccc1C(OC)c1cc(C)no1
Temperature: 25 °C
Yield: 94.7 %

Procedure:
To a mixture of 3.18 g (11 mmol) of 2-(1-ethoxyethyl)oxymethylphenyl 3-methylisoxazol-5-yl ketone, 11 ml of tetrahydrofuran and 11 ml of methanol was added 0.42 g (11 mmol) of sodium borohydride under ice-cooling and stirred at room temperature for an hour. After completion of the reaction, 300 ml of brine was added and extracted twice with 100 ml of dichloromethane. The extract was dried over anhydrous magnesium and concentrated under reduced pressure to give 3.30 g of a crude product of 5-[2-(1-ethoxyethyl)oxymethyl-α-hydroxybenzyl]-3-methylisoxazole. To the crude product, 22 ml of N,N-dimethylformamide and 1.03 ml (16.5 mmol) of methyl iodide was added and then 0.57 g (14.3 mmol) of 60% sodium hydride was added under ice-cooling and stirred at the same temperature for an hour. After completion of the reaction, 200 ml of ether was added and washed twice with 200 ml of brine. The ether layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 5-[2-(1-ethoxyethyl)oxymethyl-α-methoxybenzyl]-3-methylisoxazole (3.18 g, 94.7%) as colorless oil.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[N:6][C:5]2[N:8]=[CH:9][CH:10]=[C:11]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])OC(C)(C)C)=[CH:15][CH:14]=3)[C:4]=2[NH:3]1.[C:27]([C:31]1[CH:35]=[C:34]([N:36]=C=O)[N:33]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)[N:32]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([C:31]1[CH:35]=[C:34]([NH:36][C:20]([NH:19][C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]3[C:4]4[NH:3][C:2](=[O:1])[CH:7]=[N:6][C:5]=4[N:8]=[CH:9][CH:10]=3)=[CH:18][CH:17]=2)=[O:26])[N:33]([C:39]2[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=2)[N:32]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N=C=O)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3ncc(=O)[nH]c23)cc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc4ncc(=O)[nH]c34)cc2)cc1
Yield: 64 %

Procedure:
Method E1 was used with tert-butyl 4-(2-oxo-1,2-dihydropyrido[2,3-b]pyrazin-8-yloxy)phenylcarbamate and 3-tert-butyl-5-isocyanato-1-p-tolyl-1H-pyrazole to obtain the title compound (yield 64%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:23](OCC)=[O:24])[N:12]=[N:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[O:24])[N:12]=[N:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: O=Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
Ethyl 5,6-bis(benzyloxy)pyridazine-3-carboxylate (Intermediate 62; 3.8 g, 10.43 mmol) was dissolved in THF (95 ml) and cooled to 0-5° C. under nitrogen atmosphere. A solution of di-isobutyl-aluminium hydride in THF (1 M, 21 ml, 20.8 mmol) was added at 0-5° C. and reaction mixture was stirred at room temperature for 2 hours. Upon completion the reaction was quenched by the addition of ethyl acetate and then saturated aqueous ammonium chloride solution. The resulting mass was filtered and extracted into ethyl acetate (3×50 ml) and the combined organics were washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, eluting with dichloromethane) to afford 5,6-bis(benzyloxy)pyridazine-3-carbaldehyde (2.9 g, 87% yield).
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][CH2:10][Mg+].[Br-].B(F)(F)F.CCOCC>C(Cl)Cl.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:2]1([C:1]2([NH2:8])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[Mg+]
Reactant: N#Cc1ccccc1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: FB(F)F
Agent: [Br-]
Solvent: CCOCC
Solvent: ClCCl
Product: NC1(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
To a solution of benzonitrile (1.03 g, 10 mmol) in DCM (50 mL) at −60° C. was added Ti(OiPr)4 (3.22 mL, 11 mmol) and EtMgBr (3M in ether, 7.34 mL, 22 mmol), the resulting dark brown solution was slowly warmed up to room temperature over 1 h. BF3.OEt2 (2.47 mL, 20 mmol) was added, and the solution was further stirred at room temperature for 2 h. The mixture was quenched with Sat. NH4Cl and 1N HCl, aqueous layer was separated and extracted with ether, and then neutralized with 5N NaOH to pH=10. The resulting precipitate was filtered off and the filtrate was extracted with EtOAc, EtOAc layer was combined, dried and concentrated to give 1-phenylcyclopropanamine as oil (600 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8](Br)[C:7]([O:11][CH3:12])=[N:6][CH:5]=1.[CH:14]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)([CH3:16])[CH3:15].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[K+]>O1CCOCC1.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]>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:14]([CH3:16])[CH3:15])[CH:22]=2)[C:7]([O:11][CH3:12])=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(OC)c(Br)c1
Reactant: CC(C)c1cccc(B(O)O)c1
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Product: COC(=O)c1cnc(OC)c(-c2cccc(C(C)C)c2)c1
Temperature: 45 °C
Yield: 54.4 %

Procedure:
Under an atmosphere of argon, a mixture of 5-bromo-6-methoxy-nicotinic acid methyl ester (W. J. Thompson and J. Gaudino, J. Org. Chem. 49 (1984), 5237-5243) (100 mg, 0.406 mmol), 3-isopropylphenylboronic acid (73 mg, 0.447 mmol), tri-(tert-butyl)phosphonium tetrafluoroborate (7 mg, 0.024 mmol), tris(dibenzylideneacetone)dipalladium(0) (11 mg, 0.012 mmol) and potassium fluoride (78 mg, 1.34 mmol) in a flask was suspended in dioxane (1.5 ml) and heated to 45° C. for 3 h. After cooling, it was filtered over a small plug of silica gel and evaporated to dryness. Purification of the residue by silica gel chromatography (HEP/EA gradient) and subsequent RP HPLC (water/ACN gradient) yielded 63 mg of the title compound.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=1.C([O-])(O)=O.[Na+]>CCO>[Cl:14][C:15]1[N:20]=[C:19]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH:18]=[CH:17][N:16]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccnc(Cl)n2)CC1

Procedure:
A mixture of 9.55 g of tert-butyl 1-piperazinecarboxylate, 7.64 g of 2,4-dichloropyrimidine and 8.6 g of NaHCO3 in 50 ml of EtOH is heated at reflux for 1 hour. It is concentrated under vacuum, the residue is taken up in water and extracted with DCM, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/AcOEt (90/10 to 60/40; v/v) mixture. Two compounds are separated:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8](=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:21])[C:9](O)=[O:10].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[NH2:27]>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH:27][C:9](=[O:10])[C:8]([C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])=[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:21])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COc1ccc(N)cc1OC
Reactant: Cc1cc(C)c(C(C(=O)O)=C2C(=O)Nc3ccccc32)[nH]1
Product: COc1ccc(NC(=O)C(=C2C(=O)Nc3ccccc32)c2[nH]c(C)cc2C)cc1OC
Yield: 37.6 %

Procedure:
(3,5-Dimethyl-1H-pyrrol-2-yl)-(2-oxo-1,2-dihydro-indol-3-ylidene)-acetic acid (90 mg) was reacted with 3,4-dimethoxyaniline (110 mg) using method B to give 50 mg (37%) of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([O:17][CH3:18])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[CH:10][CH:9]=2)=[O:4].[OH-].[Na+]>CO>[CH3:18][O:17][C:7]1[C:8]2[C:13](=[CH:12][C:11]([O:15][CH3:16])=[CH:10][CH:9]=2)[CH:14]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=1
Reactant: COC(=O)c1cc2cc(OC)ccc2c(OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(OC)nc(C(=O)O)cc2c1

Procedure:
500 mg (2.02 mmol) 1,6-dimethoxy-isoquinoline-3-carboxylic acid methyl ester was dissolved in 20 mL MeOH and treated with 2.50 mL 4 M aqueous NaOH solution at RT for 12 h. The solvent was removed by distillation, the residue taken up in water and acidified with 4 M aqueous hydrochlorid acid. The precipitate was filtered off, washed with water and purified by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[Cl:42])[CH3:35]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:33]=[C:34](/[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])\[CH3:35])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(=CBr)c1ccccc1Cl
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (220 mg, 1 mmol) was dissolved in DMF. Copper (I) iodide (19 mg, 0.1 mmol), L-proline (23 mg, 0.2 mmol) and potassium phosphate (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-2-chlorobenzene (277 mg, 1.2 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-5% MeOH-DCM. The product was further purified by HPLC. Yield: 20 mg. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.58 (s, 1H), 7.50 (m, 2H), 7.40 (m, 3H), 7.22 (d, 1H), 6.60 (s, 1H), 4.40 (m, 2H), 3.70 (m, 2H), 3.22 (m, 2H), 3.15 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>CN(C)C=O>[Cl:18][C:13]1[C:14]2[C:5]([N:6]=[C:7]3[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]3)=[CH:4][CH:3]=[CH:2][CH:1]=2
Reactant: O=S(Cl)Cl
Reactant: O=c1c2ccccc2[nH]c2ccccc12
Solvent: CN(C)C=O
Product: Clc1c2ccccc2nc2ccccc12
Reaction time: 0.5 h
Yield: 97 %

Procedure:
0.488 g (2.5 mmol) of 9-(10H)acridone, 2.5 ml of thionyl chloride and a catalytic amount (a few drops) of dimethylformamide were mixed at 80° C. After 30 min of stirring, the reaction mixture was evaporated, the residue was dissolved in chloroform and poured into cold aqueous ammonia. The ammonia solution was extracted several times with chloroform. The combined organic phases were washed with 2M ammonia solution, dried over sodium sulfate and evaporated to obtain 0.517 g (97%) of 9-chloroacridine.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[OH:24][CH2:25][C@H:26]([NH:29][C:30]1[CH2:34][S:33][C:32](=[O:35])[N:31]=1)[C:27]#[CH:28].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:34]2/[C:30]([NH:29][C@@H:26]([CH2:25][OH:24])[C:27]#[CH:28])=[N:31][C:32](=[O:35])[S:33]/2)[CH2:8][CH2:7]1
Reactant: C#C[C@H](CO)NC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C#C[C@H](CO)NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Yield: 41.3 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (135 mg) in 2-propanol (5 mL) were added (R)-4-[(1-hydroxybut-3-yn-2-yl)amino]thiazol-2(5H)-one (110 mg) and piperidinium acetate (59 mg). The reaction mixture was heated under reflux overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (83 mg).