Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18]O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:46]1(=[O:56])[NH:50][C:49](=[O:51])[C:48]2=[CH:52][CH:53]=[CH:54][CH:55]=[C:47]12.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:50]3[C:46](=[O:56])[C:47]4[C:48](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:49]3=[O:51])[CH2:11][CH2:10]2)=[CH:21][CH:22]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCCCC1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCCC1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
23.1 g (62.5 mmol) 4-{1-[bis(4-fluorophenyl)-methyl]-piperidin-4-yl}-butan-1-ol, 16.4 g (62.5 mmol) triphenylphosphine and 9.2 g (62.5 mmol) phthalimide are suspended in THF and 10.9 g (62.5 mmol) azodicarboxylic acid diethyl ester is added dropwise under a protective atmosphere and light cooling (ca. 15-25° C.). The mixture is stirred for three hours at RT and subsequently the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CH2Cl2/CH3OH (99.5/0.5) Yield: 27.6 g (90%).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].C([O:20][C@H:21]1[CH2:38][CH2:37][C@@:36]2([CH3:39])[C@@H:23]([CH2:24][CH2:25][C@:26]3([CH3:49])[C@@H:35]2[CH2:34][CH2:33][C@H:32]2[C@@:27]3([CH3:48])[CH2:28][CH2:29][C@@:30]3([CH:46]=O)[CH2:42][CH2:41][C:40]([CH:43]([CH3:45])[CH3:44])=[C:31]32)[C:22]1([CH3:51])[CH3:50])(=O)C>CN(C)C=O.O1CCCC1>[OH:20][C@H:21]1[CH2:38][CH2:37][C@@:36]2([CH3:39])[C@@H:23]([CH2:24][CH2:25][C@:26]3([CH3:49])[C@@H:35]2[CH2:34][CH2:33][C@H:32]2[C@@:27]3([CH3:48])[CH2:28][CH2:29][C@@:30]3(/[CH:46]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:42][CH2:41][C:40]([CH:43]([CH3:44])[CH3:45])=[C:31]32)[C:22]1([CH3:50])[CH3:51]
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)CC[C@]5(C=O)CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/[C@]12CCC(C(C)C)=C1[C@H]1CC[C@@H]3[C@@]4(C)CC[C@H](O)C(C)(C)[C@@H]4CC[C@@]3(C)[C@]1(C)CC2
Temperature: 0 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a suspension of ethyl 2-(diethoxyphosphoryl)acetate (7.80 g, 34.8 mmol) in anhydrous N,N-Dimethylformamide (DMF) (20 ml) and Tetrahydrofuran (THF) (10 ml) stirred under nitrogen at 0° C. was added NaH (1.288 g, 32.2 mmol) dropwise during 5 min and stirred for 10 mins. The solution was warmed to rt and stirred for 30 mins before (3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-formyl-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (4.2 g, 8.70 mmol) was added to above mixture. After sitting overnight, the reaction was quenched by water and washed with saturated NaHCO3, water and brine. The organic fraction was dried over sodium sulfate, filtered and concentrated to give a residue, which was purified on a silica gel column (petrol ether/EtOAc=10:1) to obtain the pure product (E)-ethyl 3-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)acrylate (3.1 g, 69%) as a white foam. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.01-6.84 (m, 2H), 5.64 (d, J=16.1 Hz, 1H), 4.20 (q, J=7.3 Hz, 2H), 3.26-3.07 (m, 3H), 2.40-2.11 (m, 5H), 2.08-1.91 (m, 2H), 1.89-0.61 (m, 43H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][O:13][C:14](=[O:17])[CH2:15][SH:16]>C(#N)C>[CH3:12][O:13][C:14]([C:15]1[S:16][C:8]2[CH:9]=[C:2]([Br:1])[CH:3]=[C:4]([F:11])[C:5]=2[CH:6]=1)=[O:17]
Reactant: COC(=O)CS
Reactant: O=Cc1c(F)cc(Br)cc1F
Solvent: CC#N
Product: COC(=O)c1cc2c(F)cc(Br)cc2s1
Yield: 62.1 %

Procedure:
Using analogous reaction condition and reagents as described in Example 25 for the preparation of I-25a, 4-bromo-2,6-difluoro-benzaldehyde (I-26a: 2.8 g, 12.8 mmol) was reacted with TEA (1.66 g, 16.47 mmol), mercapto-acetic acid methyl ester (1.47 g, 13.83 mmol) and acetonitrile (50 mL) to afford crude product. Purification by column chromatography on silica gel (2% ethyl acetate in hexane) afforded 2.3 g of the product (64% yield).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[C:11]([O:15][C:16](=[O:27])[NH:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([CH3:14])([CH3:13])[CH3:12]>C(#N)C>[C:11]([O:15][C:16](=[O:27])[NH:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:3][CH:2]=[CH2:1])=[CH:22][CH:21]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1ccc(CCNC(=O)OC(C)(C)C)cc1
Reaction time: 12 h

Procedure:
Allyl bromide (2.10 ml, 24.8 mmol) was added in one portion to a suspension of potassium carbonate (4.40 g, 31.8 mmol) and tert-butyl[2-(4-hydroxyphenyl)ethyl]carbamate (Prepared according to Journal of Organic Chemistry 1999, 64, 1074, 5.00 g, 21.1 mmol) in acetonitrile (50 ml) at room temperature. The reaction was stirred for 12 hours and the solvent removed in vacuo. Diethyl ether (50 ml) and water (20 ml) were added and the organics separated, washed with water (20 ml), dried (magnesium sulphate) and the solvent removed in vacuo to yield a clear oil. The oil was purified by column chromatography on silica gel eluting with ethyl acetate:pentane (25/75 by volume) to furnish the title compound as a white solid, 3.80 g.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[C:14]([O:15][C:16]2[CH:17]=[C:18]([CH:21]=[C:22]([Cl:24])[CH:23]=2)[C:19]#[N:20])=[C:13]([F:25])[C:12]([CH3:26])=[CH:11][CH:10]=1.[ClH:27].CCOC(C)=O>C(#N)C>[Cl:24][C:22]1[CH:21]=[C:18]([CH:17]=[C:16]([O:15][C:14]2[C:9]([Cl:27])=[CH:10][CH:11]=[C:12]([CH3:26])[C:13]=2[F:25])[CH:23]=1)[C:19]#[N:20]
Reactant: Cl
Reactant: Cc1ccc(N)c(Oc2cc(Cl)cc(C#N)c2)c1F
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To an oven dried flask was added CuCl2 (2.5 g, 18.0 mmol). The flask was placed under high vacuum, flushed with nitrogen and acetonitrile (10 ml) was added. t-Butyl nitrite (2.7 mL, 22.5 mmol) was added dropwise. The stirred solution was placed in a an oil bath at 50° C. under gentle stream of nitrogen and 3-[(6-amino-2-fluoro-3-methylphenyl)oxy]-5-chlorobenzonitrile dissolved in acetonitrile (15 mL) was added dropwise. The reaction was stirred for 0.5 h, cooled to RT and poured into ice cold, aqueous HCl (0.5 N, 100 mL). EtOAc (100 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×100 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated. Purification was accomplished by column chromatography (hexane/EtOAc) to afford the title compound (1.8 g, 67%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.79 (s, 1H), 7.48 (s, 1H), 7.44 (t, 1H), 7.41 (d, 1H), 7.31 (t, 1H), 2.27 (d, 3H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][CH2:11][CH2:10]2)#[N:2].[Cl:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21](/[CH:25]=[CH:26]/[C:27]3[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=3)[CH2:30]Cl)=[N:22]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[N:12]([CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[C:27](/[CH:26]=[CH:25]/[C:21]3[CH:20]=[CH:19][C:18]4[C:23](=[CH:24][C:15]([Cl:14])=[CH:16][CH:17]=4)[N:22]=3)[CH:28]=1)[CH2:11][CH2:10]2)#[N:2]
Reactant: ClCc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Reactant: N#CCCc1cccc2c1NCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCc1cccc2c1N(Cc1cccc(/C=C/c3ccc4ccc(Cl)cc4n3)c1)CC2
Temperature: 85 °C
Yield: 47 %

Procedure:
A mixture of 7-(2-cyanoethyl)-2,3-dihydroindole (690 mg, 4.01 mmol), 3-[2-E-(7-chloroquinolin-2-yl)ethenyl]benzyl chloride (product of Example 3), 1.29 g, 4.10 mmol), and potassium carbonate (1.10 g, 7.97 mmol) in DMF (100 mL), was heated in an oil bath at 85° C. for 16 hours. The mixture was cooled and diluted with water and ethyl acetate. The organic solution was separated, washed once with water, once with saturated sodium chloride solution, then dried (over sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 70% hexane/30% ether) of the resulting residue provided 850 mg (47%) of the intermediate.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[CH2:12]([CH:14]1[O:16][CH2:15]1)Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[OH:11][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:12][CH:14]2[O:16][CH2:15]2)=[CH:9][C:4]=1[C:2]([CH3:1])=[O:3]
Reactant: BrCC1CO1
Reactant: CC(=O)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1cc(OCC2CO2)ccc1O

Procedure:
A solution containing 3.00 g (0.020 mole) of 2,5-dihydroxyacetophenone, 3.37 ml (0.040 mole) of epibromhydrine and 5.06 g (0.040 mole) of K2CO3 in 30 ml of acetone are heated for 8 hours under reflux. The solvent is evaporated off, 20 ml of a saturated solution of NaH2PO4 and 120 ml of water are added, and an extraction carried out with ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[OH:12].[CH3:13]N=NNC1C=CC(C)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[O:12][CH3:13]
Reactant: CN=NNc1ccc(C)cc1
Reactant: O=[N+]([O-])c1cc(F)c(O)c(F)c1
Solvent: c1ccccc1
Product: COc1c(F)cc([N+](=O)[O-])cc1F

Procedure:
Dissolve 2,6-difluoro-4-nitrophenol (J. Heterocyclic. Chem. 1976, 13, 1253; 10 g, 57.11 mmol) in 300 mL of benzene. Add dropwise a solution of 1-methyl-3-p-tolyltriazene (9.37 g, 62.82 mmol, 1.1 eq.) in benzene (150 mL). After TLC indicates absence of starting material, transfer the reaction mixture to a separator funnel and wash with 1N HCl, then saturated NaHCO3, and then water. Dry the organic layer over MgSO4, filter, and remove the solvent to give a residue. Crystallize the residue from MeOH/water to give 1,3-difluoro-2-methoxy-5-nitrobenzene as white needles: 1H NMR (300 MHz, CDCl3): 4.25 (t, 3H), 7.80 (d, 2H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][O:17][CH2:18][C@@H:19]1[O:23][C:22](=[O:24])[N:21]([C:25]2[C:29]3[CH:30]=[CH:31][C:32](O)=[CH:33][C:28]=3[O:27][CH:26]=2)[CH2:20]1.Cl>N1C=CC=CC=1>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:32]1[CH:31]=[CH:30][C:29]2[C:25]([N:21]3[CH2:20][C@H:19]([CH2:18][O:17][CH3:16])[O:23][C:22]3=[O:24])=[CH:26][O:27][C:28]=2[CH:33]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC[C@H]1CN(c2coc3cc(O)ccc23)C(=O)O1
Agent: Cl
Solvent: c1ccncc1
Product: COC[C@H]1CN(c2coc3cc(OS(=O)(=O)C(F)(F)F)ccc23)C(=O)O1

Procedure:
5.8 ml (0.035 mol) of trifluoromethanesulphonic anhydride are added slowly to a solution, maintained at -20° C., of 7.6 g (0.029 mol) of (R)-5-(methoxymethyl)-3-(6-hydroxybenzofuran-3-yl)oxazolidin-2-one in 60 ml of pyridine. After returning to room temperature, the mixture is poured into ice and is brought to a pH of 6 by means of 2N hydrochloric acid. The product is then extracted with ethyl acetate, the solvent is evaporated under reduced pressure and the product is purified by chromatography on silica gel with a 10/90 mixture of cyclohexane and dichloromethane.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH3:36])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.CC(C)([O-])C.[K+]>C1COCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:34][CH2:35][CH3:36])=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Reactant: CCOc1cc2ncnc(Cl)c2cc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A (0.2 g 0.73 mmol), 4-chloro-7-ethoxy-6-methoxyquinazoline from the previous step (0.18 g, 0.75 mmol), and potassium tert-butoxide (0.252 g, 2.25 mmol) in THF was stirred at room temperature overnight, and then was heated at 60° C. for 5 hours. The reaction was still found to be incomplete and additional 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea (0.07 g, 0.025 mmol) was added. The mixture was heated further at 60° C. overnight. The reaction was quenched with water and extracted with EtOAc. Extracts were dried over MgSO4 and concentrated under reduced pressure. It was purified by silica gel chromatography with EtOAc/hexane as eluant to afford 1-(5-tert-butylisoxazol-3-yl)-3-[3-(7-ethoxy-6-methoxyquinazolin-4-yloxy)phenyl]urea as a solid (0.078 g). 1H NMR (300 MHz, CDCl3) δ 9.12 (br and s, 2H), 8.61 (s, 1H), 7.64 (s, 1H), 7.54 (s, 1H), 7.31 (m, 3H), 7.0 (d, 1H), 6.05 (s, 1H), 4.29 (q, 2H), 4.05 (s, 3H), 1.58 (t, 3H), 1.30 (s, 9H); LC-MS (ESI) m/z 478 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([P:13](=[O:30])([O:22]CC2C=CC=CC=2)[O:14]CC2C=CC=CC=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]>C(OCC)(=O)C.[Pd]>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([P:13](=[O:14])([OH:30])[OH:22])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(P(=O)(OCc2ccccc2)OCc2ccccc2)cc(OC)c1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(P(=O)(O)O)cc(OC)c1OC
Reaction time: 16 h

Procedure:
To a solution of dibenzyl 3,4,5-trimethoxyphenylphosphonate 2 (1 mmol) in 30 mL of ethyl acetate is added 10% Pd on carbon (0.10 g). The mixture is stirred under an atmosphere of hydrogen for 16 hours. Mixture is filtered through celite and washed with methanol (3×10 mL). All washings and filtrate are combined and concentrated to give 3,4,5-trimethoxyphenylphosphonic acid 3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:15])([CH3:14])[C:10]([O:12]C)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C1COCC1.O.O.[OH-].[Li+].Cl>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:15])([CH3:14])[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)C(C)(C)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
To methyl 2-(3,4-dichlorophenyl)-2-methylpropanoate (22.03 g, 89.1 mmol) was added THF/water (4:1) (178 mL) and lithium hydroxide hydrate (22.4 g, 535 mmol). The reaction was then stirred at 50° C. for 3 days. The reaction mixture was acidified with 3N HCl, diluted with 200 mL of diethyl ether, added to a separatory funnel, partitioned with water, washed 2 times with 100 mL of water, separated, dried over Na2SO4, and concentrated in vacuo to give the title compound which was used without further purification. MS (m/z)=233 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([Cl:16])=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Yield: 96.8 %

Procedure:
100.00 g (0.50 mol) of 5-chloro-2-nitrobenzoic acid were mixed with 72.20 g (0.61 mol) of thionyl chloride and the mixture was heated under reflux for 2 h. The excess thionyl chloride was removed in vacuo. 106.50 g (ca. 98%) of crude 5-chloro-2-nitro-benzoyl chloride were obtained as an oil.
Reaction SMILES: C1(C)C(C(N)=O)=CC=CC=1.C(OC(=O)[NH:17][CH2:18][CH2:19][CH2:20][N:21]([CH:31]([C:35]1[N:44]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:43](=[O:52])[C:42]2[C:37](=[N:38][CH:39]=[CH:40][N:41]=2)[N:36]=1)[CH:32]([CH3:34])[CH3:33])[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)(C)(C)C>C(O)(C(F)(F)F)=O.O.ClCCl>[NH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH:31]([C:35]1[N:44]([CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:43](=[O:52])[C:42]2[C:37](=[N:38][CH:39]=[CH:40][N:41]=2)[N:36]=1)[CH:32]([CH3:34])[CH3:33])[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2nc3nccnc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Agent: Cc1ccccc1C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C(=O)N(CCCN)C(c2nc3nccnc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Formula I where R2 and R3 are H; R5 is Benzyl; R6 is Isopropyl; R6′ is H; R7 is 3-Amino-propyl-; R8 is —C(O)—R9 where R9 is p-Methyl-phenyl-; X and Y are —C═; and W and Z are —N═: The toluamide, {3-[[1-(3-benzyl-4-oxo-3,4-dihydro-pteridin-2-yl)-2-methyl-propyl]-(4-methyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester, was then dissolved in TFA/H2O (95/5) (50 mL) and stirred at room temperature for 1 hour, after which it was diluted with dichloromethane, washed with saturated sodium bicarbonate, water and brine, and dried over sodium sulfate. Concentration of the dichloromethane solution gave the title product (±)-N-(3-amino-propyl)-N-[1-(3-benzyl-4-oxo-3,4-dihydro-pteridin-2-yl)-2-methyl-propyl]-4-methyl-benzamide as a white solid (150 mg, 98.0%). MS (Cl) M/E: 485.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([I:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH2:14][CH2:15]Cl.[NH2:17][CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20]>>[CH2:19]([CH:18]([N:17]1[C:2]2[C:11]3[CH:10]=[CH:9][C:8]([I:12])=[CH:7][C:6]=3[N:5]=[C:4]([C:13]3[C:3]([CH3:4])=[CH:2][C:11]([CH3:6])=[CH:10][C:9]=3[CH3:8])[C:3]=2[CH2:14][CH2:15]1)[CH2:21][CH3:22])[CH3:20]
Reactant: Cc1nc2cc(I)ccc2c(Cl)c1CCCl
Reactant: CCC(N)CC
Product: CCC(CC)N1CCc2c(-c3c(C)cc(C)cc3C)nc3cc(I)ccc3c21

Procedure:
A solution of 4-chloro-3-(2-chloroethyl)-7-iodo-2-methylquinoline (300 mg, 0.82 mmol) in 3-aminopentane (10.0 mL) was stirred at 200° C. for eight hours in a sealed tube. The mixture was evaporated, and the residue was purified by silica gel column chromatography (10-70% ethyl acetate/hexane), to give the title compound (39 mg) as a pale yellow oil.
Reaction SMILES: [ClH:1].C1C=C[C:5]2N(O)N=[N:8][C:6]=2C=1.CCN(C(C)C)C(C)C.[N:21]1[CH:26]=C[C:24]([N:27]2[CH2:32]CC3(CCNCC3)C[CH2:28]2)=[CH:23][CH:22]=1>C1COCC1.C(Cl)Cl>[CH3:5][CH2:6][N:8]=[C:26]=[N:21][CH2:22][CH2:23][CH2:24][N:27]([CH3:28])[CH3:32].[ClH:1]
Reactant: c1cc(N2CCC3(CCNCC3)CC2)ccn1
Reactant: On1nnc2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN=C=NCCCN(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
HCl (939 mg, 4.9 mmol), HOBT (660 mg, 4.9 mmol) and DIPEA (2.2 ml, 12.69 mmol) were added to a solution of the product just obtained in step 4 (1 g, 3.2 mmol) in THF (20 ml). The reaction mixture was stirred at 25° C. for 30 min, a solution of 3-pyridin-4-yl-3,9-diaza-spiro[5.5]undecane (3.2 mmol, 1 eq.) in THF (20 ml) was then added and the mixture was stirred further at 25° C. for 12 h. The reaction mixture was diluted with methylene chloride and washed with sat. NH4Cl solution and NaHCO3 solution. The organic phase was washed with water and sat. NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]([CH3:11])[O:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].CN1C(=O)CCC1>O.CCOC(C)=O>[CH3:11][CH:10]1[C:3]2[C:2]([N:22]3[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:24][CH2:23]3)=[N:7][CH:6]=[N:5][C:4]=2[CH2:8][O:9]1
Reactant: CC1OCc2ncnc(Cl)c21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC1OCc2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 90 °C
Yield: 82.1 %

Procedure:
A mixture of 4-chloro-5-methyl-5,7-dihydrofuro[3,4-d]pyrimidine (0.97 g, 5.7 mmol), N-Bocpiperazine (1.3 g, 6.8 mmol), TEA (1.6 mL, 11.4 mmol) and NMP (3 mL) was heated to 90° C. for 4 hours. The reaction was cooled to room temperature and diluted with H2O and EtOAc. The organic layer was separated and the aqueous layer extracted with EtOAc (3×20 mL). The combined organics were dried with MgSO4 and concentrated. The residue was purified by column chromatography (EtOAc) to give tert-butyl 4-(5-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (1.5 g, 83%) as an off white solid. 1H NMR (CDCl3, 400 MHz) δ 8.54 (s. 1H), 5.57-5.52 (m, 1H), 4.93 (d, J=2.0 Hz, 2H), 3.67-3.45 (m, 8H), 1.48 (s, 9H), 1.41 (d, J=6.0 Hz, 3H). LCMS (APCI+) m/z 321 [M+H+].
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])[CH2:11][C:12]([CH3:25])([C:14]2[C:19](=[O:20])[C:18]([CH3:21])=[C:17]([CH3:22])[C:16](=[O:23])[C:15]=2[CH3:24])[CH3:13])=[CH:5][CH:4]=1.[OH:27][C:28]1[CH:38]=[CH:37][C:31]2[N:32]=[C:33]([C:35]#[N:36])[S:34][C:30]=2[CH:29]=1.N1C(C)=CC(C)=CC=1C>C1COCC1>[C:35]([C:33]1[S:34][C:30]2[CH:29]=[C:28]([O:27][CH2:2][C:3]3[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])[CH2:11][C:12]([CH3:25])([C:14]4[C:19](=[O:20])[C:18]([CH3:21])=[C:17]([CH3:22])[C:16](=[O:23])[C:15]=4[CH3:24])[CH3:13])=[CH:5][CH:4]=3)[CH:38]=[CH:37][C:31]=2[N:32]=1)#[N:36]
Reactant: CC1=C(C)C(=O)C(C(C)(C)CC(=O)Nc2ccc(CBr)cc2)=C(C)C1=O
Reactant: N#Cc1nc2ccc(O)cc2s1
Solvent: C1CCOC1
Solvent: Cc1cc(C)nc(C)c1
Product: CC1=C(C)C(=O)C(C(C)(C)CC(=O)Nc2ccc(COc3ccc4nc(C#N)sc4c3)cc2)=C(C)C1=O
Temperature: 25 °C
Yield: 40 %

Procedure:
A mixture of N-(4-(bromomethyl)phenyl)-3-methyl-3-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)butanamide (0.23 g, 0.57 mmol), 6-hydroxy-2-cyanobenzothiazole (0.15 g, 0.86 mmol), 2,4,6-collidine (0.125 ml) and Ag2CO3 (0.24 g, 0.86 mmol) in 15 ml of dry THF was stirred at room temperature over night. After removal of solid by filtration, the compound was purified by silica chromatography using heptane and ethyl acetate as eluent to give a yield of 40%. The product was further purified by HPLC to remove small contamination of 2-cyano-6-hydroxybenzothiazole. 1H NMR (300 MHz, CD2Cl2) δ 7.4-7.5 (m, 3H), 7.35-7.42 (m, 2H), 7.32 (dd, 1H), 7.25 (s, br, 1H, NH), 7.18 (dd, 1H), 5.15 (s, 2H, CH2O), 2.99 (s, 2H, CH2), 2.14 (s, 3H, CH3), 1.92 (s, 6H, CH3), 1.47 (s, 6H, CH3). MS (m/e): 514.2 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10]([O-])([O-])=O.[K+].[K+].IC>C(#N)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:10])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CC#N
Product: COc1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-3-methyl-phenol (500 mg, 2.67 mmol, 1 eq.) in acetonitrile (5 mL) is added K2CO3 (1.47 g, 10.6 mmol, 4 eq.). The mixture is stirred for 30 minutes at room temperature. Iodomethane (493 mg, 1.3 eq) is then added dropwise via syringe and the mixture is stirred for 12 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The combined organic layers are washed with brine and dried over Na2SO4. After concentration, the residue is purified by silica gel column chromatography (5% EtOAc in hexanes) to give 1-Bromo-4-methoxy-2-methyl-benzene.