Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][CH2:18][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:20][CH:21]=2)=[C:12]([F:25])[CH:11]=1.CN([CH:29]=[O:30])C>C1COCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][CH2:18][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:20][CH:21]=2)=[C:12]([F:25])[C:11]=1[CH:29]=[O:30]
Reactant: CN(C)C=O
Reactant: CCCC1CC=C(c2ccc(Br)cc2F)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC1CC=C(c2ccc(Br)c(C=O)c2F)CC1
Temperature: -70 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
First step Under a nitrogen atmosphere, LDA (93.6 mL, 103.9 mmol) was slowly added dropwise, at −70° C. or lower, to a THF (300 mL) solution of compound (69) (27.8 g, 93.54 mmol) prepared in Example 6. The reaction mixture was agitated at −70° C. or lower for 1 hour, and then DMF (11.2 g, 139.8 mmol) was slowly added dropwise thereto. The reaction mixture was returned to room temperature, and then quenched with 300 mL of 1N hydrochloric acid aqueous solution, and extracted with 100 mL of toluene three times. Combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was purified by silica gel column chromatography, and thus 4-bromo-2-fluoro-4′-propyl-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-3-carboaldehyde (72) (28.2 g, yield 92.7%) was obtained. Second Step
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(CC)CC.[Si:27]([O:34][C@@H:35]([CH3:61])[C@@H:36]([NH:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]#[N:58])=[C:53]([Cl:59])[C:52]=1[CH3:60])[C:37]([NH:39][NH:40][C:41](=[O:49])[C:42]1[CH:47]=[CH:46][C:45]([I:48])=[CH:44][CH:43]=1)=O)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>C(Cl)Cl>[Si:27]([O:34][C@@H:35]([CH3:61])[C@@H:36]([NH:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]#[N:58])=[C:53]([Cl:59])[C:52]=1[CH3:60])[C:37]1[O:49][C:41]([C:42]2[CH:43]=[CH:44][C:45]([I:48])=[CH:46][CH:47]=2)=[N:40][N:39]=1)([C:30]([CH3:32])([CH3:33])[CH3:31])([CH3:28])[CH3:29]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(I)cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(I)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of triphenylphosphine (7.2 g, 27.5 mmol) in DCM (300 mL) was added 12 (7.0 g, 27.5 mmol) at 0° C. After 12 was dissolved completely, Et3N (7.7 mL, 55.2 mmol) was added, followed by a solution of N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-4-iodobenzohydrazide (8.6 g, 13.7 mmol) in DCM (100 mL). The reaction mixture was allowed to warm to room temperature and stirred for an additional 60 min. The reaction was quenched with saturated sodium thiosulfate (50 mL) and diluted with DCM (500 mL). The organic layer was separated and washed with water, brine, dried over Na2SO4 and filtered. After the solvent was removed, the residue was purified by flash chromatography to provide the title compound (7.3 g, 88%). 1H NMR (400 MHz, CDCl3, δ in ppm) 8.06 (d, J=8.6 Hz, 2H), 7.88 (d, J=8.6 Hz, 2H), 7.55 (d, J=8.4 Hz, 1H), 6.66 (d, J=8.4 Hz, 1H), 5.56 (d, J=8.8 Hz, 1H), 5.00 (dd, J=2.0, 8.8 Hz, 1H), 4.74 (m, 1H), 2.59 (s, 3H), 1.62 (d, J=6.3 Hz, 3H), 1.07 (s, 9H), 0.28 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:26][CH:25]=3)[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[CH3:55][Si:56]1([CH3:74])[CH2:60][C@@H:59]([C:61]([NH:63][C@H:64]2[C:73]3[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=3)[CH2:67][CH2:66][CH2:65]2)=[O:62])[NH:58][CH2:57]1.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:20]([N:58]3[C@H:59]([C:61](=[O:62])[NH:63][C@H:64]4[C:73]5[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=5)[CH2:67][CH2:66][CH2:65]4)[CH2:60][Si:56]([CH3:74])([CH3:55])[CH2:57]3)=[O:21])[CH2:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][CH:29]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C[Si]1(C)CN[C@H](C(=O)N[C@@H]2CCCc3ccccc32)C1
Reactant: CC(C)(C)OC(=O)c1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2C[Si](C)(C)C[C@H]2C(=O)N[C@@H]2CCCc3ccccc32)cc1
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert-butoxycarbonyl)phenyl)propanoic acid (0.14 g, 0.29 mmol) in DMF (1.5 mL) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (86 mg, 0.31 mmol) at rt followed by a solution of (R)-3,3-dimethyl-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,3-azasilolidine-5-carboxamide, TFA (105 mg, 0.261 mmol) and DIEA (115 μL) in DMF (2 mL). After 2 h, the reaction mixture was directly purified by preparative HPLC to afford the title compound (165 mg, 83% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J=8.1 Hz, 2H), 7.75 (d, J=7.5 Hz, 2H), 7.52 (t, J=6.7 Hz, 2H), 7.39-7.06 (m, 10H), 6.51 (d, J=8.4 Hz, 1H), 5.76 (d, J=8.8 Hz, 1H), 5.18-5.00 (m, 3H), 4.38-4.30 (m, 1H), 4.25-4.10 (m, 1H), 3.18 (d, J=13.4 Hz, 1H), 3.08-3.00 (m, 1H), 2.85-2.71 (m, 4H), 2.10-2.02 (m, 1H), 1.91-1.81 (m, 3H), 1.56 (s, 9H), 1.33 (dd, J=14.9, 1.7 Hz, 1H), 1.06 (dd, J=14.7, 10.1 Hz, 1H), 0.46 (s, 3H), 0.29 (s, 3H); MS(ESI+) m/z 758.2 (M+H)+.
Reaction SMILES: [CH2:1]([CH:7]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:8][C:9]1[S:13][C:12]([C:14]2[C:25]3[S:24][CH:23]=[CH:22][C:21]=3[C:20]([C:26]3[S:27][C:28]([CH2:31][CH:32]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:29][CH:30]=3)=[C:19]3[C:15]=2[CH:16]=[CH:17][S:18]3)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1COCC1.C([Li])CCC.[CH3:65][Sn:66](Cl)([CH3:68])[CH3:67]>CCCCCC>[CH2:41]([CH:32]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:31][C:28]1[S:27][C:26]([C:20]2[C:19]3[S:18][C:17]([Sn:66]([CH3:68])([CH3:67])[CH3:65])=[CH:16][C:15]=3[C:14]([C:12]3[S:13][C:9]([CH2:8][CH:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:10][CH:11]=3)=[C:25]3[C:21]=2[CH:22]=[C:23]([Sn:66]([CH3:68])([CH3:67])[CH3:65])[S:24]3)=[CH:30][CH:29]=1)[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: C[Sn](C)(C)Cl
Reactant: CCCCCCCCC(CCCCCC)Cc1ccc(-c2c3ccsc3c(-c3ccc(CC(CCCCCC)CCCCCCCC)s3)c3ccsc23)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCC(CCCCCC)Cc1ccc(-c2c3cc([Sn](C)(C)C)sc3c(-c3ccc(CC(CCCCCC)CCCCCCCC)s3)c3cc([Sn](C)(C)C)sc23)s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
4,8-Bis-[5-(2-hexyldecyl)-thiophen-2-yl]-1,5-dithia-s-indacene (2.06 g, 2.56 mmol) was added into 200 mL flask. The system was vacuumed and backfilled with argon 3 times before 80 mL of anhydrous THF was injected. n-Butyl lithium (2.5 M in hexane, 2.3 mL, 5.6 mmol) was added after the mixture was cooled to −78° C. The mixture was stirred at −78° C. for 30 minutes and then at room temperature for one more hour. The system was cooled down to −78 ° C. again before trimethyltin chloride (0.5 g, 2.5 mmol) was added in portions. Stirring was continued overnight at room temperature. Hexane (200 mL) was added and the organic layer was washed with 150 mL of water. The aqueous layer was extracted with 100 mL of hexane twice. The combined organic layer was dried over anhydrous Na2SO4. Removal of the solvent under vacuum yielded a yellow liquid (2.2 g, 76.0% yield) as the final product after drying in vacuo overnight. 1H NMR (CDCl3, 500 MHz): δ 7.57 (s, 2H), δ 7.21 (d, 2H, J=3.0 Hz), δ 6.78 (d, 2H, J=3.5 Hz), δ 2.76 (d, 4H, J=6.5 Hz), δ 1.62 (s, 2H), δ 1.26-1.19 (m, 48H), δ 0.76 (m, 12H), δ 0.29 (m, 18H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:64][CH2:65][CH:66]1[CH2:68][CH2:67]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:66]1([CH2:65][NH:64][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[N:7][C:8]([CH3:12])=[N:9]3)=[CH:4][CH:3]=2)[CH2:68][CH2:67]1
Reactant: Cc1nc(N2CCCC2)c2ccc(Br)cc2n1
Reactant: NCC1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: Cc1nc(N2CCCC2)c2ccc(NCC3CC3)cc2n1
Yield: 46.9 %

Procedure:
A suspension of 0.15 g (0.513 mmol) of 7-bromo-2-methyl-4-pyrrolidin-1-yl-quinazoline, 21.3 mg (0.034 mmol) racemic BINAP, 3.8 mg (0.017 mmol) of palladium(II)acetate and 65.8 mg (0.685 mmol) of sodium tert-butylate in toluene (8 ml) was treated at RT with 0.365 g (5.13 mmol) of aminomethyl cyclopropane and then heated to reflux under an argon atmosphere for 20 h. The reaction mixture was then filtered by suction over fiberglass filter paper and the filtrate was partitioned between EtOAc and water. The layers were separated, the organic layer dried over sodium sulphate and concentrated in vacuo. The residue was applied to silica gel column with CH2Cl2/MeOH/NH4OH (10:1:0.2) as eluent. Combination of the purified fractions and concentration in vacuo gave 68 mg (46.9%) of the desired cyclopropylmethyl-(2-methyl-4-pyrrolidin-1-yl-quinazolin-7-yl)-amine as brown viscous oil. ISP mass spectrum, m/e: 283.2 (M+1 calculated for C17H22N4: 283).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][CH:12]=[N:13][C:14]([NH2:15])=[C:9]3[C:8]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[C:18]([O:25]C)[CH:17]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)Cl>[NH2:15][C:14]1[N:13]=[CH:12][N:11]=[C:10]2[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[C:18]([OH:25])[CH:17]=3)[C:9]=12
Reactant: CCOc1ccc(-c2nn(C3CCCC3)c3ncnc(N)c23)cc1OC
Solvent: ClCCl
Product: CCOc1ccc(-c2nn(C3CCCC3)c3ncnc(N)c23)cc1O
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 13 %

Procedure:
1-cyclopentyl-3-(4-ethoxy-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (ZK359, 25 mg, 0,071 mmol) was dissolved in CH2Cl2 (5 ml) and stirred at −10° C. under an argon atmosphere. After 30 minutes, reaction was brought to 0° C. and stirred for 2.5 hours. Reaction was stirred for additional 4 hours at room temperature, then concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA98 (3 mg, 13% yield). ESI-MS (M+H)+ m/z calcd 340.1, found 340.1.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([O:19]C)[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br>C(Cl)Cl>[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([OH:19])[CH:11]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(S(=O)(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)c2ccccc2)cc1O
Temperature: 0 °C
Yield: 71.9 %

Procedure:
A solution of 4-benzenesulfonyl-2-methoxy-1-nitro-benzene (4.69 g, 16 mmol) was dissolved in 250 mL of methylene chloride and cooled to 0° C. BBr3 (64 mL, 1M in methylene chloride) was added dropwise to the reaction mixture over 30 minutes. Stirring was continued, and the reaction mixture was allowed to warm up to room temperature. Methylene chloride (200 mL) was added to the reaction mixture and the organic layer was washed twice with 450 mL of water, once with 200 mL of saturated NaHCO3, dried (MgSO4) and concentrated in vacuo. The residue was recrystallized from ethanol to afford 3.206 g (11.5 mmol, 72%) of 5-benzenesulfonyl-2-nitro-phenol as a yellow solid. MS: 280 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6][CH2:5]2.[CH2:13]([SH:16])[CH2:14][SH:15].[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([S:16][CH2:13][CH2:14][S:15]1)[CH2:7][CH2:6][CH2:5]2
Reactant: SCCS
Reactant: O=C1CCCc2cc(Br)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Brc1ccc2c(c1)CCCC21SCCS1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88 %

Procedure:
A solution of 6-bromo-3,4-dihydro-2H-naphthalen-1-one (CAS[66361-67-9]) (0.9 g, 4.00 mmol) in dichloromethane (8 ml) was cooled to 0° C. and treated with 1,2-ethandithiol (769 mg, 686 μl, 8.00 mmol) and boron trifluoro etherate (284 mg, 247 μl, 2.00 mmol). The reaction mixture was left to warm to room temperature and stirred for 15 hours. For the workup, the reaction mixture was poured into a solution of sodium hydroxide (1N) followed by extraction with dichloromethane (40 ml). The organic layer was dried over sodium sulphate and evaporated. The crude product was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 70:30 as the eluent. The 6′-bromo-3′,4′-dihydro-2′H-spiro[[1,3]dithiolane-2,1′-naphthalene] (1.06 g, 88% yield) was obtained as a light red oil.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][CH2:10][CH2:11][O:12]C2CCCCO2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:1]1([C:7]#[C:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(#Cc1ccccc1)CCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: OCCCC#Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-phenyl-5-tetrahydropyranyloxypent-1-yne (0.2 g), absolute ethanol (4 ml) and p-toluenesulphonic acid (20 mg) was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (40 ml) and extracted with ether (2×20 ml). The ether extracts were washed with saturated NaHCO3 solution, dried over MgSO4 and purified by chromatography on silica (20 g), eluting with 10% ether in hexane grading to 100% ether, followed by 10% ethyl acetate in ether. The solvent was removed to give 5-phenylpent-4-yn-1-ol as a colourless oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:4]=1[O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:20][C:18]1[CH:17]=[CH:16][C:4]([O:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)=[C:3]([CH:19]=1)[CH2:2][N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: Clc1ccc(Oc2cccc3ccccc23)c(CBr)c1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Clc1ccc(Oc2cccc3ccccc23)c(Cn2ccnc2)c1
Yield: 70.1 %

Procedure:
1-(2-Bromomethyl-4-chlorophenoxy)naphthalene (400 mg) from Example 3 was dissolved in acetonitrile (20 ml), followed by addition of imidazole (235 mg) and cesium carbonate (1.1 g) under reflux for 10 minutes. After leaving the solution to stand at room temperature, the solvent was removed under reduced pressure. The residue was purified by chromatography on a silica gel column (methylene chloride:methanol=99:1) to give the title compound (270 mg; 70%). The purity of the compound was determined by HPLC, which was of 99.9%.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([N:27]2[C:32]3=[N:33][C:34](S(C)(=O)=O)=[N:35][CH:36]=[C:31]3[CH2:30][N:29]([C:41]3[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][C:42]=3[Cl:48])[C:28]2=[O:49])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>Cl>[NH:50]([C:34]1[N:33]=[C:32]2[N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:22]=3)[C:28](=[O:49])[N:29]([C:41]3[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][C:42]=3[Cl:48])[CH2:30][C:31]2=[CH:36][N:35]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)[Si](OCCc1cccc(N2C(=O)N(c3c(Cl)cccc3Cl)Cc3cnc(S(C)(=O)=O)nc32)c1)(c1ccccc1)c1ccccc1
Agent: Cl
Product: CC(C)(C)[Si](OCCc1cccc(N2C(=O)N(c3c(Cl)cccc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 96 %

Procedure:
A mixture of 980 mg (1.22 mmol) of 1-[3-(2-t-butyldiphenylsilyloxyethyl)phenyl]-3-(2,6-dichlorophenyl)-7-methanesulfonyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one and 5 ml of aniline was heated at 100° C. for 30 minutes. The reaction was allowed to cool then poured into 50 ml of 2M hydrochloric acid. The product was collected by filtration, washed with water (50 ml), then hexane (50 ml) and dried to give 960 mg (96%) of 7-anilino-1-[3-(2-tert-butyldiphenylsilyloxyethyl)phenyl]-3-(2,6-dichlorophenyl)-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one as a fawn solid. [Mass spectrum (ESI) MH+ =744].
Reaction SMILES: [N:1]1([C:5]2[CH:6]=[CH:7][C:8]([O:11][C:12]3[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=3)[CH:15]=[C:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[N:9][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1([C:5]2[CH:6]=[CH:7][C:8]([O:11][C:12]3[CH:31]=[CH:30][CH:29]=[C:14]([CH:15]=[C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]4)[CH:13]=3)=[N:9][CH:10]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(N4CCC4)cn3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C(=C1CCNCC1)c1cccc(Oc2ccc(N3CCC3)cn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 952.8 %

Procedure:
To a solution of tert-butyl 4-(3-(5-(azetidin-1-yl)pyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.135 g, 0.32 mmol) in CH2Cl2 (5 mL) cooled to 0° C. under a N2 atmosphere was added TFA (0.24 mL, 3.2 mmol). The resulting mixture was stirred for 1 h at RT. The solution was concentrated and then quenched with saturated NaHCO3 solution. The mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (0.98 g, 96%). 1H NMR (500 MHz, DMSO-d6): δ 7.46 (s, 1H), 7.28 (s, 1H), 6.91 (d, J=7.5 Hz, 1H), 6.85 (m, 4H), 6.28 (s, 1H), 3.87 (t, J=7 Hz, 4H), 3.02 (m, 2H), 2.90 (m, 2H), 2.53 (m, 2H), 2.39 (m, 4H).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21]O)(=[O:16])[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][O:11][C:10]([CH:7]1[CH2:8][CH2:9][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]1)=[O:12])(=[O:16])[CH:14]=[CH2:15]
Reactant: CCCC1CCC(C(=O)O)CC1
Reactant: C=CC(=O)OCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCCCOC(=O)C1CCC(CCC)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Propyl-cyclohexanecarboxylic acid (10.0 g, 58.0 mmol), 4-hydroxybutyl acrylate (8.0 g, 57.0 mmol) and a catalytic amount of para-toluene sulphonic acid are stirred under reflux in toluene (100 ml) in a flask equipped with Dean-Stark apparatus. The reaction is shown to be complete by GCMS after 1 hour. The solution is allowed to cool to room temperature, is washed with aqueous sodium carbonate and water, dried and evaporated to dryness. Purification is achieved by flash column chromatography using petrol as eluant. Evaporation of the appropriate fractions gives a colourless oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([O:8]/[N:9]=[C:10](/[NH2:36])\[C:11]1[CH:12]=[N:13][C:14]([C:17]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:29]=[N:30][CH:31]=[C:32]([O:34][CH3:35])[CH:33]=3)=[CH:24][CH:23]=2)([CH3:21])[CH:18]([CH3:20])[CH3:19])=[CH:15][CH:16]=1)=O)(=[O:3])[CH3:2]>C1(C)C(C)=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1[O:8][N:9]=[C:10]([C:11]2[CH:12]=[N:13][C:14]([C:17]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:29]=[N:30][CH:31]=[C:32]([O:34][CH3:35])[CH:33]=4)=[CH:24][CH:23]=3)([CH3:21])[CH:18]([CH3:19])[CH3:20])=[CH:15][CH:16]=2)[N:36]=1)(=[O:3])[CH3:2]
Reactant: COc1cncc(-c2ccc(C(C)(c3ccc(/C(N)=N\OC(=O)COC(C)=O)cn3)C(C)C)cc2)c1
Solvent: Cc1ccccc1C
Product: COc1cncc(-c2ccc(C(C)(c3ccc(-c4noc(COC(C)=O)n4)cn3)C(C)C)cc2)c1
Temperature: 25 °C

Procedure:
A solution of 1b (0.896 mmol) in xylene (6.00 mL) was heated to 110° C. for approximately 1 h. After cooling to rt, the reaction mixture was concentrated in vacuo to afford the title compound 1c, which was used without further purification in the subsequent reaction. m/z (ES) 473 (MH)+.
Reaction SMILES: C([Al:3](CC)CC)C.[C:8]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([O-:16])=[O:15])(=[O:10])[CH3:9].O>O1CCCC1>[C:8]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([O-:16])=[O:15])(=[O:10])[CH3:9].[C:8]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([O-:16])=[O:15])(=[O:10])[CH3:9].[C:8]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([O-:16])=[O:15])(=[O:10])[CH3:9].[Al+3:3]
Reactant: CC[Al](CC)CC
Agent: CC(=O)Oc1ccccc1C(=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: [Al+3]

Procedure:
3.8 g of triethyl aluminum were dissolved in 70 ml of tetrahydrofuran. Under ice cooling, a solution of 10.8 g of o-acetoxybenzoate dissolved in 200 ml of tetrahydrofuran was added dropwise little by little to the above solution in nitrogen gas current. After completion of the dropwise addition, the temperature of the mixture was returned to room temperature, and it was thrown into a great quantity of water. The precipitated crude crystals were recovered by filtration and dried under reduced pressure to yield 10 g of white aluminum tris-(o-acetoxybenzoate) having a molecular weight of about 545 and an average degree of polymerization of about 1. The infrared absorption spectrum of the resulting salt was as follows:
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)#[N:2].O1CCCC1.C(O[K])(C)(C)C.[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][CH2:33]Br)[CH:27]=1>O.CN(C)C=O>[Br:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33][CH:3]([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[C:1]#[N:2])[CH:29]=[CH:30][CH:31]=1
Reactant: BrCCc1cccc(Br)c1
Reactant: COC(=O)c1ccc(CC#N)cc1
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C(C#N)CCc2cccc(Br)c2)cc1
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a mixed solution of methyl 4-(cyanomethyl)benzoate (3.50 g, 20.0 mmol), tetrahydrofuran (25 mL) and N,N-dimethylformamide (10 ml) was added tert-butoxy potassium (2.69 g, 24.0 mmol) at −78° C., and the mixture was stirred for 30 min. To the reaction mixture was added 1-bromo-3-(2-bromoethyl)benzene (3.37 mL, 22.0 mmol) at the same temperature, and the mixture was stirred under ice-cooling for 4 hr. The reaction mixture was diluted with water, extracted with ethyl acetate, washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (3.94 g, 55%) as a colorless oil.