Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:7]([OH:9])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.Cl.[Cl:43][C:44]1[C:45]([NH:73][C:74](=[O:95])[C:75]2[CH:80]=[CH:79][C:78]([N:81]3[CH2:86][CH2:85][N:84]([C:87](=[O:93])[C:88]([CH3:92])([CH3:91])[CH2:89][OH:90])[CH2:83][C@H:82]3[CH3:94])=[N:77][CH:76]=2)=[CH:46][C:47]([O:68][C:69]([F:72])([F:71])[F:70])=[C:48]([C:50]2[CH:55]=[CH:54][C:53]([C:56]3[N:57]=[C:58]([C@@H:61]4[CH2:65][C@H:64]([O:66][CH3:67])[CH2:63][NH:62]4)[NH:59][CH:60]=3)=[CH:52][CH:51]=2)[CH:49]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@@H:6]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:7]([N:62]1[CH2:63][C@@H:64]([O:66][CH3:67])[CH2:65][C@H:61]1[C:58]1[NH:59][CH:60]=[C:56]([C:53]2[CH:52]=[CH:51][C:50]([C:48]3[CH:49]=[C:44]([Cl:43])[C:45]([NH:73][C:74]([C:75]4[CH:76]=[N:77][C:78]([N:81]5[CH2:86][CH2:85][N:84]([C:87](=[O:93])[C:88]([CH3:91])([CH3:92])[CH2:89][OH:90])[CH2:83][C@H:82]5[CH3:94])=[CH:79][CH:80]=4)=[O:95])=[CH:46][C:47]=3[O:68][C:69]([F:71])([F:72])[F:70])=[CH:55][CH:54]=2)[N:57]=1)=[O:9]
Reactant: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Reactant: CO[C@@H]1CN[C@H](c2nc(-c3ccc(-c4cc(Cl)c(NC(=O)c5ccc(N6CCN(C(=O)C(C)(C)CO)C[C@H]6C)nc5)cc4OC(F)(F)F)cc3)c[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](OC)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(=O)C(C)(C)CO)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C1CCOCC1
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
To a solution of (S)-methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (37.6 mg, 0.17 mmol) in DMA (1 mL) was added HATU (65.9 mg, 0.17 mmol). The reaction mixture was stirred for 15 min and N-{5-chloro-4′-[2-((2S,4S)-4-methoxy-pyrrolidin-2-yl)-1H-imidazol-4-yl]-2-trifluoromethoxy-biphenyl-4-yl}-6-[(R)-4-(3-hydroxy-2,2-dimethyl-propionyl)-2-methyl-piperazin-1-yl]-nicotinamide 3HCl (100 mg, 0.12 mmol; Preparation 34) was added followed by DIPEA (0.10 mL, 0.58 mmol) and the reaction mixture was stirred at RT overnight, concentrated by rotary evaporation, dissolved in 1:1 acetic acid:water (4 mL) and purified by reverse phase HPLC. Fractions containing the desired compound were combined and lyophilized to provide the di-TFA salt of the title compound (65.2 mg) as a white powder. Impure fractions were lyophilized, dissolved in 1:1 acetic acid:water (1.5 mL) and purified by reverse phase HPLC to provide additional di-TFA salt of the title compound (75 mg total, 55% yield). (m/z): [M+H]+ calcd for C46H54ClF3N8O9 955.37. found 955.8.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=O)[CH3:20])=[C:14]([NH2:22])[CH:13]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CO.C(=O)([O-])O.[K+]>O>[C:1]1([S:7]([NH:10][C:11]([C:12]2[CH:17]=[CH:16][C:15]3[N:18]=[C:19]([CH3:20])[NH:22][C:14]=3[CH:13]=2)=[O:23])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)cc2[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
A mixture of 0.500 g of N-benzenesulfonyl-4-acetylamino-3-aminobenzamide, 3.9 g of 35% hydrochloric acid, 15 ml of methanol and 12 ml of water was stirred at 60° C. for 1 hour. The reaction mixture was neutralized with a potassium hydrogencarbonate aqueous solution. The crystals precipitated were separated through filtration, and were dried to give 0.404 g of 5-benzenesulfonylcarbamoyl-2-methylbenzimidazole (272).
Reaction SMILES: [Br:1][C:2]1[C:3](I)=[N:4][C:5]([I:8])=[N:6][CH:7]=1.[S-:10][C:11]#[N:12].[K+]>C(O)=O>[Br:1][C:2]1[C:3]([S:10][C:11]#[N:12])=[N:4][C:5]([I:8])=[N:6][CH:7]=1
Reactant: Brc1cnc(I)nc1I
Reactant: N#C[S-]
Agent: [K+]
Solvent: O=CO
Product: N#CSc1nc(I)ncc1Br
Yield: 82.4 %

Procedure:
In 30 ml of formic acid, a reaction of 4.11 g of 5-bromo-2,4-diiodopyrimidine and 1.17 g of potassium thiocyanate was conducted at room temperature (20° C.) for 5 hours in a similar manner as Synthesis Example 1. Then, the reaction mixture was treated in a similar procedure as Synthesis Example 1, there was obtained a 82.4% yield of 5-bromo-2-iodo-4 thiocyanopyrimidine, m.p. 199°-202° C.
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13]([C:17]#[C:18]/[CH:19]=[CH:20]/[C:21]([OH:23])=O)[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>O>[OH:29][NH:28][C:21](=[O:23])/[CH:20]=[CH:19]/[C:18]#[C:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([S:8](=[O:10])(=[O:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=1
Reactant: NO
Reactant: O=C(O)/C=C/C#Cc1cccc(S(=O)(=O)Nc2ccccc2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(/C=C/C#Cc1cccc(S(=O)(=O)Nc2ccccc2)c1)NO
Reaction time: 0.17 h

Procedure:
To a solution of (E)-5-(3-phenylsulfamoylphenyl)pent-2-en-4-ynoic acid (56a) (0.25 g 0.77 mmol) in methylene chloride (5 ml) oxalyl chloride (0.42 g 3.1 mmol) was added. The resultant mixture was stirred for 1 hour at ambient temperature and the solvents were removed under reduced pressure. The crude product (57a) was dissolved in acetonitrile (5 ml) and the obtained solution to a mixture of hydroxylamine hydrochloride (0.3 g, 4.3 mmol) and NaHCO3 (0.3 g, 3.6 mmol) in water (8 ml) was added. The reaction mixture was stirred for 10 min. and the product was extracted with ethyl acetate (30 ml). The extract was washed with 10% Na2CO3, and the aqueous phase was acidified with 3% HCl. The precipitate was filtered and dried to give the title compound (0.12 g, (46%). M.p 88-90° C. 1H NMR (DMSO-d6, HMDSO) δ: 6.41 (1H, d, J=15.8 Hz, CH); 6.82 (1H, d, J=15.8 Hz, CH); 6.92-7.41 (5H, m, C6H5); 7.47-8.01 (4H, m, C6H4); 8.94-11.21 (3H, br s, NH, NH, OH). Anal. Calcd for C17H14N2O4S*0.4H2O: C 58.58, H 4.27, N 8.01. Found: C 58.12, H 4.03, N 7.80.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:13])[CH:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[CH3:14][O:15][CH2:16][CH2:17][C:18](O)=O>>[CH3:14][O:15][CH2:16][CH2:17][C:18]1[O:13][C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[C:8]([C:9]([OH:11])=[O:10])[N:12]=1
Reactant: COCCC(=O)O
Reactant: NC(C(=O)O)C(O)c1ccccc1
Product: COCCc1nc(C(=O)O)c(-c2ccccc2)o1

Procedure:
Prepared starting from DL-3-phenylserine hydrate following sequentially general procedures Y, Z with 3-methoxy-propionic acid, Z1 and Z2. LC-MS-conditions 02: tR=0.77 min; [M+H]+=247.96.
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(N(CC)CC)C>CCO>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][N:22]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:9]2[C:14]([N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]2=[O:20])=[CH:15]1)[CH3:30]
Reactant: CCOC(=O)CCCN
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CCCn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Temperature: 25 °C

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate C) (996 mg, 2.95 mmol), ethyl 4-aminobutanoate hydrochloride (489 mg, 2.95 mmol) and triethylamine (0.823 ml, 5.91 mmol) were combined in EtOH (15 ml) and heated at reflux for 2.5 hours. The reaction mixture was cooled to RT and evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with water (1×) and brine (1×). The organic phase was dried over sodium sulphate and evaporated under reduced pressure to afford the title compound as an off-white solid;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:10][C:11]([C:17]([F:20])([F:19])[F:18])=[C:12]([C:14]([OH:16])=O)[N:13]=1.[CH3:21][O:22][CH2:23][CH2:24][N:25]([CH3:33])[C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][N:27]=1>>[CH3:21][O:22][CH2:23][CH2:24][N:25]([CH3:33])[C:26]1[N:27]=[CH:28][C:29]([NH:32][C:14]([C:12]2[N:13]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[O:10][C:11]=2[C:17]([F:20])([F:19])[F:18])=[O:16])=[CH:30][CH:31]=1
Reactant: COCCN(C)c1ccc(N)cn1
Reactant: COc1ccccc1-c1nc(C(=O)O)c(C(F)(F)F)o1
Product: COCCN(C)c1ccc(NC(=O)c2nc(-c3ccccc3OC)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-(2-methoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-(2-methoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C21H21F3N4O4 (m/e) 504. obsd 505 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19]Br)[CH:6]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:34]=[C:35]([F:37])[CH:36]=1)[O:26][C@H:27]1[O:31][C:30](=[O:32])[NH:29][C@@H:28]1[CH3:33]>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][N:29]2[C@H:28]([CH3:33])[C@@H:27]([O:26][C:25]3[CH:24]=[C:23]([F:22])[CH:36]=[C:35]([F:37])[CH:34]=3)[O:31][C:30]2=[O:32])[CH:6]=1
Reactant: C[C@H]1NC(=O)O[C@@H]1Oc1cc(F)cc(F)c1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CBr)c1
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2C(=O)O[C@H](Oc3cc(F)cc(F)c3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-phenyl]-acetic acid methyl ester and (4R,5S)-5-(3,5-difluoro-phenoxy)-4-methyl-oxazolidin-2-one.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:11](C(OC(C)(C)C)=O)[NH:12]C(OC(C)(C)C)=O)[CH:8]=2)[CH2:3]1.FC(F)(F)C(O)=O.C[O:36][C:37](=O)[CH2:38][C:39](=O)[CH3:40]>C(O)(=O)C>[CH3:1][C:2]1([CH3:27])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:11]3[C:37](=[O:36])[CH2:38][C:39]([CH3:40])=[N:12]3)[CH:8]=2)[CH2:3]1
Reactant: CC1(C)Cc2ccc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2C1
Reactant: COC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC1=NN(c2ccc3c(c2)CC(C)(C)C3)C(=O)C1
Temperature: 90 °C
Reaction time: 2 h
Yield: 21.8 %

Procedure:
Di-tert-butyl 1-(2,2-dimethyl-1H-inden-5-yl)hydrazine-1,2-dicarboxylate 45c (3.3 g, 8.78 mmol) was dissolved in 12 mL of acetic acid followed by addition of 6 mL of trifluoroacetic acid and 3-oxo-butanoic acid methyl ester (1.5 mL, 13.8 mmol). Upon completion of the addition, the reaction mixture was stirred at 90° C. for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure and the residue was diluted with 30 mL of water and 30 mL of ethyl acetate. After mixing well, the separated organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2-(2,2-dimethyl-indan-5-yl)-5-methyl-2,4-dihydro-pyrazol-3-one 45d (464 mg, yield 22.1%) as a yellow oil.
Reaction SMILES: [H-].[Na+].[C:3]1([C@H:9]2[NH:19][C:18](=[O:20])[C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[NH:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C1COCC1>[O:20]=[C:18]1[C:13]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[NH:12][CH2:11][CH2:10][C@@H:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:19]1[CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C1N[C@H](c2ccccc2)CCNC12CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CN1C(=O)C2(CCCC2)NCC[C@H]1c1ccccc1)OCc1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (0.147 g, 6.14 mmol) in THF (10 mL) was added (9S)-9-phenyl-6,10-diazaspiro[4.6]undecan-11-one (0.300 g, 1.23 mmol) at ambient temperature. The reaction was warmed to 60° C. for 2 h, then cooled to ambient temperature. Benzyl bromoacetate (0.309 g, 1.35 mmol) was added dropwise to the reaction. After 1 h, the mixture was quenched with a saturated aqueous ammonium chloride solution. The mixture was concentrated in vacuo then partitioned between H2O and CH2Cl2. The aqueous phase was then extracted several times with CH2Cl2. The combined organic extracts were washed with saturated brine, then dried over MgSO4, filtered and concentrated in vacuo The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc:hexane—0:100 to 100:0, to yield the title compound. MS: m/z=393 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19].C(=O)([O-])O.[Na+]>CC(C)=O.O>[CH2:1]([O:8][C:9]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCCCCO
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(NCCCCCCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
7.06 ml (47 mmol) of chloroformic acid benzyl ester are added dropwise to a solution of 5.52 g (47 mmol) of 6-aminohexan-1-ol and 3.95 g (47 mmol) of sodium hydrogen carbonate in 100 ml of acetone and 50 ml of water. The mixture is stirred at room temperature for 18 hours and concentrated to approximately 70 ml, and the white precipitate is filtered off, washed with approximately 20 ml of water, taken up in 250 ml of methylene chloride and dried over magnesium sulfate; the magnesium sulfate is filtered off and the residue is concentrated to dryness by evaporation. 6-(N-benzyloxycarbonylamino)hexan-1-ol is obtained in the form of white crystals having a melting point of 58°-60°.
Reaction SMILES: [C:1]([C:3](=[C:8]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[CH3:18])SC)[C:4]([O:6]C)=O)#[N:2].Cl.[CH:20]1([CH2:25][C:26]([NH2:28])=[NH:27])[CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:20]1([CH2:25][C:26]2[NH:28][C:4](=[O:6])[C:3]([C:1]#[N:2])=[C:8]([NH:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:17]=3[CH3:18])[N:27]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)C(C#N)=C(Nc1cnccc1C)SC
Reactant: N=C(N)CC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccncc1Nc1nc(CC2CCCC2)[nH]c(=O)c1C#N
Temperature: 90 °C
Reaction time: 72 h

Procedure:
0.2 g (0.76 mmol) of methyl 2-cyano-3-[(4-methyl-3-pyridinyl)amino]-3-(methylsulfanyl)-2-propenoate are dissolved with 0.13 g (0.85 mmol) of 2-cyclopentylethanamidine hydrochloride and 0.23 g (1.67 mmol) of potassium carbonate in 4 ml of DMF and stirred at 90° C. for 3 days. After cooling, the product is purified by preparative HPLC (YMC Gel ODS-AQ S 5/15 μm; eluent A: water, eluent B: aceto-nitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95% B) purified. 60 mg (25% of theory) of the product are obtained.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][C@@H:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]([O:5][N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22])=[O:4]
Reactant: C[C@@H](CCCc1ccccc1)C(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C[C@@H](CCCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture consisting of (S)-2-methyl-5-phenylpentanoic acid (20mb(i), 290 mg, 1.51 mmol) in dichloromethane (20 mL) was added N-hydroxysuccinimide (191 mg, 1.66 mmol), 4-dimethylaminopyridine (203 mg, 1.66 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (318 mg, 1.66 mmol). The resulting reaction mixture was stirred for two hours at room temperature. The reaction mixture comprising 18mb(i) was carried on directly to the next step.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[CH2:9]([N:11]([CH2:19][CH3:20])[C:12]1[S:16][C:15]([CH:17]=O)=[CH:14][CH:13]=1)[CH3:10].C(O)(C(F)(F)F)=O>C(O)(C)C>[CH2:19]([N:11]([CH2:9][CH3:10])[C:12]1[S:16][C:15]([CH:17]=[N:1][C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7]#[N:8])=[CH:14][CH:13]=1)[CH3:20]
Reactant: N#Cc1ccsc1N
Reactant: CCN(CC)c1ccc(C=O)s1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: CCN(CC)c1ccc(C=Nc2sccc2C#N)s1

Procedure:
In a round bottom flask (50 mL), 30 mg of 2-amino-thiophene-3-carbonitrile was added to 20 mL isopropanol to which was further added 5-diethylamino-thiophene-2-carbaldehyde (48 mg) and a catalytic amount of TFA. The mixture was refluxed for 3 hours. Complete removal of the solvent leads to an orange oil which was purified by flash chromatography (SiO2). The title compound was isolated as an orange solid (63%). 1H-NMR (300 MHz, [D] acetone): δ=8.44 (s, 1H), 7.54 (d, 1H, 3J=4.5 Hz), 7.09 (s, 2H), 6.13 (d, 1H, 3J=4.5 Hz), 3.54 (q, 4H, 3J=7.1 Hz), 1.27 (t, 6H, 3J=7.1 Hz). 13C-NMR (300 MHz, [D] acetone): δ=166.1, 153.2, 141.2, 131.9, 127.9, 123.3, 118.8, 116.0, 104.5, 101.5, 48.2, 12.4.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([F:25])=[CH:19][C:18]=3[OH:26])[C:9]2=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:35]I.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[C:28]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[CH:22]=[C:21]([O:23][CH3:24])[C:20]([F:25])=[CH:19][C:18]=4[O:26][CH2:35]3)[C:9]2=[O:27])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: ClCI
Reactant: COc1cc(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)c(O)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1F)OCC21C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.4 %

Procedure:
A suspended mixture of 1-(diphenylmethyl)-3-(4-fluoro-2-hydroxy-5-methoxyphenyl)-1,3-dihydro-2H-indol-2-one (1.10 g, 2.5 mmol), chloroiodomethane (0.70 g, 4.0 mmol) and cesium carbonate (2.60 g, 8.0 mmol) in tetrahydrofuran (50 mL) was stirred at ambient temperature for 24 h. The reaction mixture was filtered. The solid was washed with acetone (50 mL). The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography with a 20% to 70% gradient of ethyl acetate in hexanes to afford 1′-(diphenylmethyl)-6-fluoro-5-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.49 g, 43%) as a colorless solid: MS (ES+) m/z 452.0 (M+1).
Reaction SMILES: [S:1]1[C:5]([CH2:6][C:7]2[C:8]([CH3:25])=[C:9]([CH3:24])[C:10]([OH:23])=[C:11]([CH:13]3[CH:18]([OH:19])[CH:17]([OH:20])[CH2:16][CH:15]([CH2:21][OH:22])[O:14]3)[CH:12]=2)=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:36](Br)[CH:37]=[CH2:38]>CC(C)=O>[CH2:38]([O:23][C:10]1[C:9]([CH3:24])=[C:8]([CH3:25])[C:7]([CH2:6][C:5]2[S:1][C:2]3[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=3[CH:4]=2)=[CH:12][C:11]=1[CH:13]1[CH:18]([OH:19])[CH:17]([OH:20])[CH2:16][CH:15]([CH2:21][OH:22])[O:14]1)[CH:37]=[CH2:36]
Reactant: C=CCBr
Reactant: Cc1c(Cc2cc3ccccc3s2)cc(C2OC(CO)CC(O)C2O)c(O)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C=CCOc1c(C2OC(CO)CC(O)C2O)cc(Cc2cc3ccccc3s2)c(C)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.1 %

Procedure:
A 20 ml vial was charged with 22 (33.3 mg, 0.08 mmol) and Cs2CO3 (39.3 mg, 0.12 mmol) and to which was added 1 ml of dry acetone, followed by allyl bromide (19.4 mg, 0.16 mmol). The resulting mixture was stirred at room temperature for 16 h and the solid was filtered of, washed with acetone. The solvent was evaporated and the crude residue was purified by flash column chromatography on silica gel (4 g column, EtOAc/heptane: 0>>>100%) to afford 17.5 mg (43.1%) of 24 as a white solid. 1H NMR (CD3OD) δ 7.71 (d, J=8.08 Hz, 1H), 7.60 (d, J=7.58 Hz, 1H), 7.13-7.28 (m, 3H), 6.87 (s, 1H), 6.14 (m, 1H), 5.47 (dd, J=17.18, 2.02 Hz, 1H), 5.24 (dd, J=10.61, 1.52 Hz, 1H), 4.51 (d, J=9.60 Hz, 1H), 4.47 (dd, J=12.63, 5.05 Hz, 1H), 4.35 (dd, J=12.63, 5.05 Hz, 1H), 4.23 (s, 2H), 3.47-3.73 (5H), 2.23 (s, 3H), 2.20 (s, 3H), 2.01 (m, 1H), 1.48 (q, J=11.12 Hz, 1H). MS (ES) 477.1 (M+Na+).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([Br:29])[CH:28]=1)[CH2:24]Br>>[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([Br:29])[CH:28]=1)[CH2:24][N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: BrCc1cc(Br)cc(Br)c1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2cc(Br)cc(Br)c2)c(=O)[nH]c1=O
Yield: 73.9 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3,5-dibromobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (375 mg, yield: 73.9%).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]3[CH2:15][CH2:14][C@H:13]([N:16]([C:20]4[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=4)[CH2:17][C:18]#[CH:19])[C:7]=3[CH:8]=2)[N:3]=1.[F:29][C:30]1[C:35](O)=[C:34]([F:37])[C:33]([F:38])=[C:32]([F:39])[C:31]=1[F:40]>CC(N(C)C)=O>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]3[CH2:15][CH2:14][C@H:13]([N:16]([C:20]4[CH:21]=[CH:22][C:23]([C:24]([O:26][C:35]5[C:34]([F:37])=[C:33]([F:38])[C:32]([F:39])=[C:31]([F:40])[C:30]=5[F:29])=[O:25])=[CH:27][CH:28]=4)[CH2:17][C:18]#[CH:19])[C:7]=3[CH:8]=2)[N:3]=1
Reactant: C#CCN(c1ccc(C(=O)O)cc1)[C@H]1CCc2cc3nc(C)[nH]c(=O)c3cc21
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CC(=O)N(C)C
Product: C#CCN(c1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1)[C@H]1CCc2cc3nc(C)[nH]c(=O)c3cc21

Procedure:
A solution of p-[N-((6S)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta-[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoic acid (0.7 g) in DMA (25 ml) was added to a stirred mixture of pentafluorophenol (1.2 g), N,N-dicyclohexylcarbodiimide (0.45 g) and DMA (50 ml). The resultant mixture was stirred at 50° C. for 18 hours. The mixture was evaporated and the residue was purified by column chromatography using initially a 40:1 and then a 20:1 mixture of methylene chloride and methanol as eluant. There was thus obtained pentafluorophenyl p-[N-((6S)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)-amino]benzoate as a solid (0.57 g);
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[N:13]=2)[C:8](=[O:16])[C:7]([C:17]([OH:19])=O)=[CH:6]1.[NH2:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[N:13]=2)[C:8](=[O:16])[C:7]([C:17]([NH:20][C:21]2[NH:25][N:24]=[N:23][N:22]=2)=[O:19])=[CH:6]1
Reactant: COCCn1cc(C(=O)O)c(=O)c2ccc(C)nc21
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Product: COCCn1cc(C(=O)Nc2nnn[nH]2)c(=O)c2ccc(C)nc21
Reaction time: 2 h

Procedure:
1,4-Dihydro-1-(2-methoxyethyl)-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (0.5 g) and N,N'-carbonyldiimidazole (0.31 g) in dimethylformamide (50 ml) were warmed at 60° for 1 hour. 5-Amino-1H-tetrazol (0.16 g) was added and the solution was stirred at 60° for 2 hours and cooled. The solid was collected and crystallised from dimethylformamide and had m.p. 245°-246° (d).