Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:27](=[O:28])[N:26]([CH:29]([CH3:31])[CH3:30])[C:5]2[N:6]=[C:7]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1B(O)O.C(N(CC)CC)C.COCCOC>O>[CH2:24]([N:21]1[CH2:20][CH2:19][N:18]([C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:7]3[N:8]=[C:9]([CH3:10])[C:4]4[CH:3]=[C:2]([C:33]5[S:32][CH:36]=[CH:35][CH:34]=5)[C:27](=[O:28])[N:26]([CH:29]([CH3:30])[CH3:31])[C:5]=4[N:6]=3)=[CH:17][CH:16]=2)[CH2:23][CH2:22]1)[CH3:25]
Reactant: CCN1CCN(c2ccc(Nc3nc(C)c4cc(Br)c(=O)n(C(C)C)c4n3)cc2)CC1
Reactant: OB(O)c1cccs1
Solvent: CCN(CC)CC
Solvent: O
Solvent: COCCOC
Product: CCN1CCN(c2ccc(Nc3nc(C)c4cc(-c5cccs5)c(=O)n(C(C)C)c4n3)cc2)CC1
Temperature: 100 °C
Reaction time: 24 h
Yield: 7 %

Procedure:
Pd(dppf) dichloromethane adduct (115 mg, 0.141 mmol) was added to a suspension of 6-bromo-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one (341 mg, 0.703 mmol), 2-thiophene boronic acid (99 mg, 0.77 mmol), and triethylamine (245 μL, 1.76 mmol) in 10:1 DME:water (6.6 mL). The reaction was heated to 100° C. After 24 h, the reaction was cooled to room temperature, diluted with water (50 mL) and filtered though a Celite plug and concentrated in vacuo. The residue was purified on reverse phase HPLC (25 mM ammonium acetate:acetonitrile, 30-80% gradient). The fractions containing product were collected and lyophilized to give 2-{[4-(4-Ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one. (23 mg, 7% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.63 (bd, J=3.2 Hz, 1H), 7.51 (m, 2H), 7.40 (bd, J=4.4 Hz, 1H), 7.11 (m, 2H), 6.97 (m, 2H), 5.90 (sept, 1H), 3.23 (m, 4H), 2.68 (s, 3H), 2.65 (m, 4H), 2.50 (q, J=7.2 Hz, 2H), 1.63 (d, J=6.8 Hz, 6H), 1.15 (t, J=7.2 Hz, 3H); MS (EI) for C27H32N6OS: 489.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([CH3:25])[C:5]([O:6][C:7]2[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([NH:17][CH:18]([CH2:21]O)[CH2:19][CH3:20])[C:8]=2C(O)=O)=[C:4]([CH3:26])[CH:3]=1.ClC(Cl)([O:30][C:31](=[O:37])OC(Cl)(Cl)Cl)Cl.C[CH2:40][N:41](CC)CC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:26])[C:5]([O:6][C:7]2[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([N:17]3[C@@H:18]([CH2:19][CH3:20])[CH2:21][O:30][C:31]3=[O:37])[C:8]=2[C:40]#[N:41])=[C:23]([CH3:25])[CH:24]=1
Reactant: CCC(CO)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)O
Reactant: CCN(CC)CC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC[C@H]1COC(=O)N1c1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C#N

Procedure:
The title compound was prepared by reacting with 2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hyroxymethyl-propylamino)-6-methyl-nicotinic acid with the triphosgene/NEt3 in THF. 1H NMR(CDCl3) d 7.18(s,1H), 7.06(s,2H), 5.00(m,1H), 4.64(t,1H), 4.23(dd,1H), 2.339s,3H), 2.08(s,6H), 1.5-1.8(m,2H), 0.949t,3H), ppm.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10](/[CH:14]=[CH:15]/[CH:16]([OH:18])[CH3:17])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][CH2:20][C:21](O)=[O:22].C1CCC(N=C=NC2CCCCC2)CC1.CCOCC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:19][CH2:20][C:21]([O:18][CH:16]([CH3:17])/[CH:15]=[CH:14]/[C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)=[O:22]
Reactant: O=C(O)CCl
Reactant: CC(O)/C=C/c1cccc(Oc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(/C=C/c1cccc(Oc2ccccc2)c1)OC(=O)CCl
Reaction time: 0.08 h
Yield: 99.2 %

Procedure:
The product from step (b) (12.01 g) and chloroacetic acid (5 g) were taken up in methylene chloride, DCC (15 g) was added, and the mixture stirred for 5 minutes. DMAP (0.5 g) was then added, causing the mixture to boil, and the mixture stirred for 1 hour. Ether (200 ml) was then added, the mixture filtered, and the filtrate washed with satd. aqu. NaHCO3, 2 M aqu. HCl, and satd. aqu. NaCl, dried over MgSO4 and stripped. The residue was taken up in ether/pet.ether (1:1, 100 ml). filtered, and stripped to give the desired product (15.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[C:8](=[O:14])[NH:9][C:10](=[S:13])[NH:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:17]I.[OH-].[Na+]>O.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:8](=[O:14])[NH:9][C:10]([S:13][CH3:17])=[N:11][CH:12]=2)=[CH:15][CH:16]=1
Reactant: CI
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1
Yield: 91.2 %

Procedure:
A solution of 5-(4-chlorobenzyl)-2-thiouracil (50.5 g), methyl iodide (28.4 g) and sodium hydroxide (8.2 g) in water (200 ml) and ethanol (400 ml) was stirred at 60° for 30 minutes then allowed to cool. The crystalline product was filtered and washed with water to give 5-(4-chlorobenzyl)-2-methylthio-4-pyrimidone (48.6 g), m.p. 193°-194° (methanol/ethanol).
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[F:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH3:17])[CH:11]=1.N1C=CN=C1>CN(C)C=O.CCOCC>[C:1]([Si:5]([O:16][C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][C:12]=1[CH3:17])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(F)ccc1O
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
t-Butyldimethylchlorosilane (14.34 g, 93.24 mmol) is combined with 4-fluoro-2-methylphenol (10.00 g, 77.70 mmol) and 1H-imidazole (13.32 g, 194.24 mmol) in dimethylformamide (100 mL) and stirred at room temperature overnight. The reaction is diluted with ether (200 mL) and washed with water (2×100 mL) and brine. The organic portion is dried with sodium sulfate, filtered, and concentrated to afford 18.9 g (100%) of the title compound. GC-ES m/z 240 [M]+, TR=4.06 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([OH:14])=O)[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[F:8].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:37]([O:44][C:45]1[CH:54]=[CH:53][C:48]([C:49]([NH:51][NH2:52])=[O:50])=[C:47]([CH2:55][CH3:56])[C:46]=1[CH3:57])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([NH:52][NH:51][C:49](=[O:50])[C:48]2[CH:53]=[CH:54][C:45]([O:44][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[C:46]([CH3:57])[C:47]=2[CH2:55][CH3:56])=[O:14])[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[F:8]
Reactant: COc1cc(CC(=O)O)cc(F)c1F
Reactant: CCc1c(C(=O)NN)ccc(OCc2ccccc2)c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(C(=O)NNC(=O)Cc2cc(F)c(F)c(OC)c2)ccc(OCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.7 %

Procedure:
340 mg of 2-(3,4-difluoro-5-methoxyphenyl)acetic acid (B2) are dissolved in 7.0 ml of N,N-dimethylformamide under a dry argon atmosphere. 484.3 mg of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 130.2 mg of N-hydroxybenzotriazole and 526.0 mg of 4-benzyloxy-2-ethyl-3-methylbenzohydrazide (B1) are subsequently added. The reaction solution is stirred at room temperature for 18 h overnight. When the reaction is complete (TLC check), 100 ml of water are added, and the mixture is stirred for 30 min and subsequently extracted three times with 75 ml of ethyl acetate each time. The combined organic phases are dried over Na2SO4, filtered off with suction, and the filtrate obtained is evaporated to dryness in vacuo. The residue is purified by flash column chromatography on silica gel (solvent gradient: dichloromethane/0-20% by vol. of ethanol), giving 321 mg of the title compound as a colourless oil; MS: 937.3 (2M+H+); TLC: Rf=0.50 (dichloromethane/methanol 95:5 parts by volume).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH2:8][NH2:9].CO[C:13]1[C:17](OC)=[N:16][S:15](=[O:21])(=[O:20])[N:14]=1.[CH2:22]([NH2:25])[C:23]#[CH:24]>>[CH2:22]([NH:25][C:13]1[C:17]([NH:9][CH2:8][CH2:7][CH2:6][C:5]#[C:4][CH2:3][N:2]([CH3:10])[CH3:1])=[N:16][S:15](=[O:21])(=[O:20])[N:14]=1)[C:23]#[CH:24]
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: C#CCN
Reactant: CN(C)CC#CCCCN
Product: C#CCNC1=NS(=O)(=O)N=C1NCCCC#CCN(C)C

Procedure:
In a manner similar to Example 1, reaction of 6-dimethylaminohex-4-ynylamine and 3,4-dimethoxy-1,2,5-thiadiazole-1,1-dioxide followed by treatment with propargylamine gives the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:5][C:6](=[O:13])[C@H:7]([CH2:9][C:10](=[O:12])[OH:11])[NH2:8].[C:22](=[O:25])(O)[O-].[Na+].Cl.[C:28]([O:31][CH2:32][CH3:33])(=[O:30])C>O.O1CCOCC1>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH:5][C:6](=[O:13])[C@H:7]([CH2:9][C:10](=[O:11])[OH:12])[NH:8][C:22](=[O:25])[C@@H:4]([CH3:3])[NH:5][C:28]([O:31][CH2:32][C:33]1[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1)=[O:30]
Reactant: O=C([O-])O
Reactant: CCOC(C)=O
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In 50 ml of water were dissolved 2.4 g of α-L-aspartyl-L-phenylalanine methyl ester and 0.7 g of sodium bicarbonate. A solution of 1.9 g of N-benzyloxycarbonyl-D-alanine N-hydroxysuccinimide ester in 50 ml of dioxane was added to the solution. The mixture was stirred at room temperature for 5 hours. After the pH was adjusted to 2.5 with 6N hydrochloric acid, 150 ml of ethyl acetate was added to the mixture. The separated ethyl acetate layer was wahsed with water and a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Sodium sulfated was removed, and ethyl acetate was distilled off under reduced pressure. The residue was reprecipitated from ethyl acetate/hexane. Yield 2.1 g.
Reaction SMILES: [OH:1][C:2]1([CH3:13])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(N(CC)CC)C>[C:14]([O:1][C:2]1([CH3:13])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC1C(=O)C=CC1(C)O
Solvent: CCN(CC)CC
Product: CCCCCC1C(=O)C=CC1(C)OC(C)=O

Procedure:
Into the same flask as used in Example 1, dl-3-hydroxy-2-n-pentyl-3-methyl-4-cyclopentenone (18.2 g), triethylamine (0.1 g) and acetic anhydride (36 g) were charged, and the resultant mixture was stirred at 60°-80° C. for 3 hours. After completion of the reaction, the reaction mixture was subjected to the same work-up as in Example 1 to give 21.9 g of dl-3-acetoxy-2-n-pentyl-3-methyl-4-cyclopentenone. Yield, 98%. B.P., 100°-110° C./0.1-0.3 mmHg).
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][NH2:9])=[C:6]([F:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[F:13].[F:14][C:15]([F:33])([F:32])[C:16]([N:18]([CH2:25][P:26]([O:30]Cl)([O:28]Cl)=[O:27])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17]>O1CCCC1>[F:14][C:15]([F:33])([F:32])[C:16]([N:18]([CH2:25][P:26]([O:30][NH:9][NH:8][C:7]1[C:6]([F:10])=[C:5]([F:11])[C:4]([F:12])=[C:3]([F:13])[C:2]=1[F:1])([O:28][NH:9][NH:8][C:7]1[C:2]([F:1])=[C:3]([F:13])[C:4]([F:12])=[C:5]([F:11])[C:6]=1[F:10])=[O:27])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17]
Reactant: CCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Reactant: NNc1c(F)c(F)c(F)c(F)c1F
Solvent: C1CCOC1
Product: CCOC(=O)CN(CP(=O)(ONNc1c(F)c(F)c(F)c(F)c1F)ONNc1c(F)c(F)c(F)c(F)c1F)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of pentafluorophenylhydrazine (3.96 g, 0.02 mole) in 40 ml. of tetrahydrofuran at 0° C. was added over 1/2 hour ethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (1.65 g, 0.005 mole) in 40 ml. of tetrahydrofuran. The reaction mixture was allowed to warm to room temperature and stir for 2 hours, then filtered. The filtrate was washed with water, dried, and concentrated in vacuo to yield a dark red-brown solid. This solid was washed several times with 70% ether in petroleum ether to yield ethyl N-trifluoroacetyl-N-(bis(pentafluorophenylhydrazino)phosphonomethyl)glycinate, m.p. 100°-110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[C:12](OC(=O)C)(=O)[CH3:13].[CH2:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)(=O)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:8])[N:27]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]([CH3:13])=[N:11]2)=[CH:9][CH:10]=1
Reactant: NCCc1ccccc1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(Cl)ccc1C(=O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1nc2cc(Cl)ccc2c(=O)n1CCc1ccccc1
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 50.8 %

Procedure:
4-chloroanthranilic acid (6 g, 34.27 mmol) suspended in acetic anhydride (25 mL, 264.47 mmol) was refluxed for 3 h. The resulting solution was cooled to rt to give crystal formed. The solution was filtered and washed with excess of hexane to get light yellow needle crystal. The crystal was mixed with phenethylamine (4.6 mL, 36.15 mmol) in acetic acid (25 mL) and refluxed for 18.5 h. After 18.5 h, the reaction mixture was diluted with dichloromethane (50 mL) and washed with water (3×50 mL) and saturated aqueous NaHCO3 solution (7×40 mL). The organic layer dried over MgSO4 was concentrated to around 20 mL and added with excess of MeOH to get crystal formed. The solution was filtered to give title compound as white crystal (5.2 g, 50.8%). Rf=0.3 (ethyl acetate/hexane=1:2); mp 133-135° C. (recrystallized from methanol); 1H NMR (400 MHz, DMSO-d6) δ 2.46 (s, 3H, CH3), 2.96 (t, J=8 Hz, 2H, CH2), 4.20 (t, J=8 Hz, 2H, CH2), 7.23-7.25 (m, 3H, ArH), 7.28-7.32 (m, 2H, ArH), 7.49 (dd, 1H, J=8.4, 2 Hz, 7.60 (d, J=2 Hz, 1H, ArH), 8.09 (d, J=8.4 Hz, 1H, ArH); 13C NMR (50 MHz, DMSO-d6) δ 23.2, 33.9, 46.2, 119.2, 126.1, 127.0, 127.1, 128.7, 129.1, 129.3, 138.7, 139.4, 148.6, 157.1, 160.9; ESIMS(+) m/z 299.0 [M+1]+. Anal. (C17H15ClN2O) C, H, N. Calcd: 68.34, 5.06, 9.38. Found: 68.56, 5.07, 9.57.
Reaction SMILES: [Na].[O-]CC.[Na+].[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=1[CH3:16].[C:17](OCC)(=[O:23])[C:18]([O:20]CC)=[O:19]>CCO.O>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=1[CH2:16][C:17](=[O:23])[C:18]([OH:20])=[O:19]
Reactant: Cc1c(F)cccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C(O)C(=O)Cc1c(F)cccc1[N+](=O)[O-]
Yield: 21.3 %

Procedure:
Sodium (2.30 g, 100 mmol) was added to anhydrous EtOH (80 mL) at 0-5° C. for 10 min to prepare a fresh sodium ethoxide solution. A solution of 1-fluoro-2-methyl-3-nitrobenzene (14.4 g, 93.0 mmol) and diethyl oxalate (15.3 g, 105 mmol) in EtOH (80 mL) was added to the above solution, and the resulting mixture was then refluxed for 45 min. After cooling down, the red dark solution was diluted with water (100 mL). After removal of the ethanol, the residue was extracted with EtOAc. The aqueous layer was acidified with 2N HCl to pH around 3 to 4, and extracted with DCM. The organic layers were washed with water, dried, and concentrated to afford 4.5 g (21%) of 3-(2-fluoro-6-nitrophenyl)-2-oxopropanoic acid (32) as red oil. LCMS (ESI) m/z: 245.1 [M+NH4]+.
Reaction SMILES: O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:22]([O:29][CH2:30][C:31](=[O:41])[CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[F:42][C:43]([Si](C)(C)C)([F:45])[F:44].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C1(C)C=CC=CC=1>[F:42][C:43]([F:45])([F:44])[C:31]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([OH:41])[CH2:30][O:29][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(COCc1ccccc1)COCc1ccccc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: OC(COCc1ccccc1)(COCc1ccccc1)C(F)(F)F
Reaction time: 0.05 h
Yield: 101.8 %

Procedure:
Tetrabutylammonium fluoride trihydrate (TBAF 3H2O) (2.9 g, 0.5 equivalent) was dissolved in THF (5 ml). This was added cautiously to a stirred and cooled (+15° C.) solution of 1,3-dibenzyloxy-2-propanone in toluene (24.65 g, equivalent to 5 g of the ketone) and (trifluoromethyl)trimethylsilane (7.5 ml). There was an exotherm and a lot of gas evolution on addition of the first 1 ml of TBAF solution. The temperature rose from 18 to 40° C. The TBAF addition was carried out over 3 minutes and then the mixture was stirred at 15-30° C. for a further 2 minutes and then cooled to +10° C. while carrying out an HPLC analysis. The reaction mixture was sequentially washed with 1M aqueous hydrochloric acid (50 ml), 1% aqueous sodium chloride solution (2×25 ml) and a mixture of 1% sodium chloride (25 ml) and saturated sodium bicarbonate (5 ml) solution. The separated organic extract was concentrated in vacuo to give 6.41 g of the desired product as dark brown oil in 101.8% yield. The NMR spectrum showed the presence of residual toluene (8.8%) and starting material (ca 3%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)=[CH:13][C:12]2=[O:24])=[CH:5][CH:4]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>C(#N)C>[N:25]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:23]=[CH:22][S:21][CH:20]=4)=[CH:13][C:12]3=[O:24])=[CH:5][CH:4]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CCNC1
Reactant: O=c1cc(OCc2ccsc2)ccn1CCc1ccc(CBr)cc1
Solvent: CC#N
Product: O=c1cc(OCc2ccsc2)ccn1CCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 150 mg (0.37 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-(thiophen-3-ylmethoxy)-1H-pyridin-2-one (example 4.1b) in 1.5 mL acetonitrile is added at RT 122 μL (1.48 mmol) pyrrolidine. The reaction mixture is stirred for 2 h at RT and is directly transferred to a reverse HPLC for purification (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:22])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:5](=[O:13])[N:6]([CH2:9][CH2:10][CH2:11][CH3:12])[C:7]=1[NH2:8].[CH3:23][N:24]1[C:28]([CH3:29])=[C:27]([NH:30][S:31]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=O)=[CH:36][CH:35]=2)(=[O:33])=[O:32])[C:26]([CH3:44])=[N:25]1>>[CH2:9]([N:6]1[C:7]2[N:8]=[C:41]([CH2:40][C:37]3[CH:38]=[CH:39][C:34]([S:31]([NH:30][C:27]4[C:26]([CH3:44])=[N:25][N:24]([CH3:23])[C:28]=4[CH3:29])(=[O:32])=[O:33])=[CH:35][CH:36]=3)[NH:1][C:2]=2[C:3](=[O:22])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:5]1=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: Cc1nn(C)c(C)c1NS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: CCCCn1c(N)c(N)c(=O)n(Cc2ccccc2F)c1=O
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(S(=O)(=O)Nc4c(C)nn(C)c4C)cc3)nc21

Procedure:
Prepared from 5,6-diamino-1-butyl-3-(2-fluoro-benzyl)-1H-pyrimidine-2,4-dione (30.6 mg, 0.1 mmol) and [4-(1,3,5-trimethyl-1H-pyrazol-4-ylsulfamoyl)-phenyl]-acetic acid. 4-[3-Butyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzenesulfonamide was obtained as a colorless solid; 1H NMR (DMSO-d6, 300 MHz) δH 13.48 (s, 1H), 8.94 (s, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.38 (d, J=7.7 Hz, 2H), 7.30–6.90 (m, 4H), 5.03 (s, 2H), 4.10 (s, 2H), 3.88 (t, J=7.1 Hz, 2H), 3.45 (s, 3H), 1.71 (s, 3H), 1.60–1.45 (m, 2H), 1.42 (s, 3H), 1.25–1.10 (m, 2H), 0.79 (t, J=7.5 Hz, 3H); FAB-HRMS m/e calculated for C29H32FN7O4S (M+H)+ 594.2299, found 594.2281.
Reaction SMILES: [S:1]([NH:17][CH2:18][CH2:19][C:20]([OH:22])=O)([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].C(Cl)(=O)C([Cl:26])=O>ClCCl.CN(C)C=O>[S:1]([NH:17][CH2:18][CH2:19][C:20]([Cl:26])=[O:22])([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: CN(C)c1cccc2c(S(=O)(=O)NCCC(=O)O)cccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)c1cccc2c(S(=O)(=O)NCCC(=O)Cl)cccc12
Temperature: 0 °C

Procedure:
970 mg(3 mmol) dansyl beta alanin were dissolved in 5 mL dried dichloromethane and stirred under argon flux at 0° C. Then 0.6 mL (6.6 mmol) oxalyl chloride was added drop wise at 0° C., and subsequently, a few drops of dried dimethylformamide were added which lead to gas development. The mixture was stirred at room temperature for 100 min. The solvents were removed by using a rotary evaporator and then the remainder was twice evaporated with dichloromethane. The crude product was used directly in the next step.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1)=O.O1CCN([C:22]2[CH2:26][CH2:25][CH2:24][CH:23]=2)CC1.Cl.[OH2:28]>C1C=CC=CC=1>[O:28]=[C:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1
Reactant: C1=C(N2CCOCC2)CCC1
Reactant: CCOC(=O)C(C)c1ccc(C=O)cc1
Reactant: O
Agent: Cl
Solvent: c1ccccc1
Product: CCOC(=O)C(C)c1ccc(C=C2CCCC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5.15 g of ethyl 2-(p-formylphenyl)propionate and 4.5 g of morpholinocyclopentene in 10 ml of benzene was heated under reflux for 10 hours. After cooling, a mixture of 5 ml of conc. hydrochloric acid and 5 ml of water was added to the reaction mixture under ice-cooling and the resulting mixture was stirred at room temperature overnight. After addition of 100 ml of benzene, an organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to leave an oily substance, which was then distilled under reduced pressure to give 5.3 g of the desired product having a boiling point of 160°-165° C./0.25 mmHg.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.[CH3:16][N:17]([CH:19]=[C:20]1[S:24][C:23](=[O:25])[NH:22][C:21]1=[O:26])[CH3:18].C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[CH3:18][N:17]([CH:19]=[C:20]1[S:24][C:23](=[O:25])[N:22]([CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]2[N:12]3[CH:13]=[CH:14][N:15]=[C:11]3[CH:10]=[CH:9][CH:8]=2)[C:21]1=[O:26])[CH3:16]
Reactant: CN(C)C=C1SC(=O)NC1=O
Reactant: ClCCCCSc1cccc2nccn12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 241 mg (1.0 mmol) of 5-(4-chlorobutylthio)imidazo[1,2-a]pyridine and 173 mg (1.0 mmol) of 5-(dimethylamino)methylene-thiazolidine-2,4-dione in 10 ml of N,N-dimethylformamide, 0.15 ml (1.0 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added, followed by stirring at 80°C. for 3 hours. After the reaction mixture was cooled, water was added; the mixture was extracted with ethyl acetate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4→ethyl acetate→chloroform/ethanol=10/1) to yield 310 mg (82.3%, yellow oily substance) of the desired product.