Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:21])[NH:11][C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:61][O:62][C:63]1[CH:68]=[C:67]([O:69][CH3:70])[CH:66]=[CH:65][C:64]=1[CH2:71]O>C(OCC)(=O)C.O1CCCC1>[CH3:61][O:62][C:63]1[CH:68]=[C:67]([O:69][CH3:70])[CH:66]=[CH:65][C:64]=1[CH2:71][N:11]1[C:10](=[O:21])[C:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:3][C:2]=2[F:1])=[C:14]([CH2:15][CH2:16][CH3:17])[N:13]2[N:18]=[CH:19][N:20]=[C:12]12
Reactant: COc1ccc(CO)c(OC)c1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)[nH]c2ncnn12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(Cc2ccc(OC)cc2OC)c2ncnn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.9 %

Procedure:
A mixture of 3′-fluoro-4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.3 g), tributylphosphine (1.6 mL), (2,4-dimethoxyphenyl)methanol (0.58 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.36 g, 26%).
Reaction SMILES: [O:1]=[C:2]([CH3:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:18])OCC(Cl)(Cl)Cl)=[CH:6][CH:5]=1.[C:20]1([C:26]2[N:30]=[C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[O:1]=[C:2]([CH3:19])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([N:34]2[CH2:35][CH2:36][N:31]([C:29]3[S:28][N:27]=[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:30]=3)[CH2:32][CH2:33]2)=[O:18])=[CH:8][CH:9]=1
Reactant: CC(=O)Cc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Cc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cc1

Procedure:
A solution of 2,2,2-trichloroethyl [4-(2-oxopropyl)phenyl]carbamate (200 mg, 0.616 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (152 mg, 0.616 mmol), diisopropylethylamine (0.107 ml, 0.616 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (45.2 mg, 17.4%) as a solid.
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]([F:29])([F:28])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]2[NH:23][O:24][C:25](=[O:27])[N:26]=2)[CH:17]=1.[CH3:30][C:31]([CH3:37])([CH2:35][CH3:36])[C:32](Cl)=[O:33]>N1C=CC=CC=1>[CH3:30][C:31]([CH3:37])([CH2:35][CH3:36])[C:32]([N:26]1[C:25](=[O:27])[O:24][N:23]=[C:22]1[C:18]1[CH:17]=[C:16]([O:15][CH2:14][C:13]([F:12])([F:28])[F:29])[CH:21]=[CH:20][N:19]=1)=[O:33]
Reactant: O=c1nc(-c2cc(OCC(F)(F)F)ccn2)[nH]o1
Reactant: CCC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(C)(C)C(=O)n1c(-c2cc(OCC(F)(F)F)ccn2)noc1=O
Reaction time: 2 h
Yield: 31.5 %

Procedure:
To 2 ml of pyridine were added 0.25 g of 1,8-diazabicyclo[5,4,0]undec-7-ene, and 0.3 g of 3-[4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-one, and 0.22 g of 2,2-dimethylbutanoyl chloride was added at room temperature. After stirring for 2 hours, the mixture was further stirred at 60° C. for 2 hours. The resultant solution was concentrated, and the residue was subjected to silica gel column chromatography to obtain 0.13 g of 4-(2,2-dimethylbutanoyl)-3-[4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-one (present compound (25)).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]=[O:8])[O:4][N:3]=1.[F-].[Cs+].C[Si](C)(C)[C:13]([F:16])([F:15])[F:14].Cl>C1COCC1.O>[F:14][C:13]([F:16])([F:15])[CH:7]([C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1)[OH:8]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1cc(C=O)on1
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(O)C(F)(F)F)on1
Temperature: -5 °C

Procedure:
A mixture of 0.1 g (0.9 mmol) 3-Methyl-isoxazole-5-carbaldehyde and 14 mg (0.09 mmol) CsF and THF is cooled to −5° C. 540 μl (1.1 mmol) trimethyl(trifluormethyl)-silane 2 M in THF is added dropwise and after 30 min the mixture is allowed to reach RT. After cooling with ice and addition of 5 ml 1 N aq. HCl, the mixture is stirred at RT over night, diluted with water and extracted with DCM. The combined organic layers are dried and evaporated giving rise to 2,2,2-trifluoro-1-(3-methylisoxazol-5-yl)ethanol.
Reaction SMILES: C(N(CCC)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][C:22]3[NH:23][CH:24]=[CH:25][N:26]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)CC.[CH2:31]([N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=O)[CH2:32][CH3:33].[C:41]([BH3-])#[N:42].[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:6]([N:42]([CH2:41][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][N:20]([CH2:21][C:22]3[NH:26][CH:25]=[CH:24][N:23]=3)[CH2:39][C:35]3[N:34]([CH2:31][CH2:32][CH3:33])[CH:38]=[CH:37][N:36]=3)=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)[CH2:7][CH2:8][CH3:9])[CH2:5][CH3:10]
Reactant: [BH3-]C#N
Reactant: CCCN(CCC)c1ccc(NC(=O)c2ccc(CNCc3ncc[nH]3)cc2)cc1
Reactant: CCCn1ccnc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3nccn3CCC)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The compound (120 mg) obtained in Example 47-3 was dissolved in methanol (5.0 ml) and then added with the compound (57.0 mg) obtained in Example 91-1 and sodium cyanoborohydride (18.0 mg). Then, the solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 2 days. After completion of the reaction, a 1 mol/l sodium hydroxide aqueous solution was added to the reaction solution, followed by separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol) and then treated with hydrochloric acid, thereby obtaining hydrochloride (201 mg) of the subject compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[NH:4][C:3]1=[O:14]>CO.[Pd]>[NH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:2]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH3:1])[C:3](=[O:14])[NH:4]2
Reactant: CCOC(=O)CC1(C)C(=O)Nc2cccc([N+](=O)[O-])c21
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC1(C)C(=O)Nc2cccc(N)c21
Reaction time: 3 h

Procedure:
A mixture of (±)-ethyl (3-methyl-4-nitro-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate from Step A (2.66 g, 9.56 mmol) and 10% Pd/C (500 mg) was stirred vigorously in MeOH (50 mL) under an atmosphere of hydrogen (ca. 1 atm). After 3 h, the mixture was filtered through a pad of Celite, washing with MeOH, and the filtrate was concentrated in vacuo to give the title compound. MS: m/z=249 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[C:7](Cl)(=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[C:7]([NH:1][C@@H:2]([CH3:3])[C:4]([OH:6])=[O:5])(=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCC(=O)Cl
Reactant: C[C@H](N)C(=O)O
Product: CCCCCC(=O)N[C@@H](C)C(=O)O

Procedure:
L-Alanine (10 mmol) and hexanoyl chloride (11 mmol) were reacted using the method described in Example 5 Part A to give the title compound as a white crystalline material (1.091 g, 58%) after recrystallization from isopropyl ether (~6 ml).
Reaction SMILES: [OH-].[Na+].[CH3:3][NH:4][C@H:5]([C:10]([OH:12])=[O:11])[CH2:6][CH:7]([CH3:9])[CH3:8].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20](=[O:22])[C:19]([CH2:29][C:30](Cl)=[O:31])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]=2[CH:33]=1.Cl>O.O1CCCC1>[CH3:3][N:4]([C:30](=[O:31])[CH2:29][C:19]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:18]2[CH:33]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]=2[O:21][C:20]1=[O:22])[C@H:5]([C:10]([OH:12])=[O:11])[CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: O=C(Cl)CC1(c2ccccc2)C(=O)Oc2ccc(Cl)cc21
Reactant: CN[C@@H](CC(C)C)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)N(C)C(=O)CC1(c2ccccc2)C(=O)Oc2ccc(Cl)cc21
Temperature: 5 °C
Reaction time: 3 h

Procedure:
0.9 g of sodium hydroxide is added to a solution of 3 g of N-methylleucine in 70 ml of water and 40 ml of tetrahydrofuran. The medium is then cooled to 5° C. and a solution of 7.3 g of 2-(5-chloro-2,3-dihydro-2-oxo-3-phenyl-3-benzofuranyl)acetyl chloride in 50 ml of tetrahydrofuran and a solution of 0.9 g of sodium hydroxide in 22.7 ml of water are then added simultaneously in small portions so as to maintain the pH at 12. The mixture is stirred for 3 hours at room temperature and 22.7 ml of N hydrochloric acid are added. The medium is concentrated and the precipitate obtained is filtered off and dissolved hot in an ethanol/methanol (50:50) mixture. The solution is filtered and the filtrate evaporated. A crystalline product is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:35]=[CH:36][CH:37]=1)[CH:26](Cl)[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.C(OCC)C>[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:35]=[CH:36][CH:37]=1)[CH:26]([N:9]1[CH2:8][CH2:7][N:6]([CH2:5][C:4]2[CH:12]=[CH:13][CH:14]=[C:2]([CH3:1])[CH:3]=2)[CH2:11][CH2:10]1)[C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cccc(CN2CCNCC2)c1
Reactant: Clc1ccc(C(Cl)c2cccc(OCc3ccccc3)c2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1cccc(CN2CCN(C(c3ccc(Cl)cc3)c3cccc(OCc4ccccc4)c3)CC2)c1
Temperature: 25 °C
Yield: 53 %

Procedure:
The crude piperazine derivative from above (11.0 g, 56 mmole) was dissolved in 150 ml of toluene and added to 19.2 g (56 mmole) of 3-benzyloxy-4'-chlorobenzhydryl chloride (see U.S. Pat. No. 4,757,074) and heated to reflux for 40 hours. The reaction was cooled to room temperature, diluted to 600 ml with diethyl ether, and washed with 100 ml of 1.0M sodium hydroxide followed by three 200 ml portions of water and 100 ml of saturated sodium chloride. The product was dried over sodium sulfate and the solvent removed to give 27.0 g of crude product as a dark oil. The material was purified by chromatography on silica gel (Waters Prep 500) with 0.1% triethylamine in dichloromethane to give 14.7 g (53%) of 1-(3-benzyloxy-4'-chlorobenzhydryl)-4-(3-methylbenzyl)piperazine as a dark oil. A 5.0 g portion of the oil was dissolved in 300 ml of 2:1 ethanol:methanol and treated with an excess of ethanolic hydrochloric acid to produce the dihydrochloride salt of the product. Addition of 150 ml diethyl ether and cooling provided 1.74 g of the salt as white crystals, mp. 204°-208° C. Calc. for C32H33ClN2O 2HCl: C, 67.43; H, 6.19; N, 4.91; Cl, 18.66. Found: C, 67.15; H, 6.14; N, 4.87; Cl, 18.58.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Br:11]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[C:3]=1[CH2:10][Br:11]
Reactant: Cc1c(Cl)cccc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: N#Cc1cccc(Cl)c1CBr
Yield: 46 %

Procedure:
To a refluxing solution of 3-chloro-2-methylbenzonitrile (2.0 g, 13.2 mmol) in 20 mL of CCl4 was added 2.6 g (14.4 mmol, 1.1 eq) of N-bromosuccinimide and 0.2 g of AIBN. The solution was refluxed for 3 hours and then cooled, diluted with 500 mL of CH2Cl2 and washed with 200 mL of H2O and 200 mL of brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The resultant oil was flash chromatographed with 5:1 hexane/ethyl acetate to yield the titled compound (1.4 g, 46%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:41][C@H:42]([OH:52])[C@@H:43]([NH2:51])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][CH:34]=2)=[CH:31][N:30]=[CH:29]1>CN(C=O)C>[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:41][C@H:42]([OH:52])[C@@H:43]([NH:51][C:11](=[O:13])[C@H:6]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][CH:34]=2)=[CH:31][N:30]=[CH:29]1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2cncs2)cc1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, 1.36 g (7.2 mmol) of N-methoxycarbonyl-(L)-iso-leucine, 2.59 g (13.5 mmol) of EDC and 1.22 g (9 mmol) of HOBT are dissolved in 20 ml of DMF. After 30 min, 3.79 ml (27 mmol) of TEA are added and a solution of 2.11 g (4.5 mmol) of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexane (Example 2b) in 40 ml of DMF are added dropwise. After 3 hours, the reaction mixture is worked up analogously to Example 2c to form the title compound: m.p: 163-166° C.; Anal. (C33H45N5O6S (0.14 H2O)) calc. C 61.71, H 7.11, N 10.90, S 4.99, H2O 0.39: found C 61.61, H 7.10, N 10.79, S 4.76, H2O 0.4; HPLC20-100 : tRet =16.0; FAB MS (M+H)+ =640.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:20]([OH:22])=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][N:11]=1.CN(C(O[N:31]1N=N[C:33]2[CH:34]=[CH:35]C=C[C:32]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:45]([O:48][CH2:49]C)(=[O:47])[CH3:46]>CN(C=O)C>[CH3:49][O:48][C:45]([C@@H:46]1[CH2:35][CH2:34][CH2:33][CH2:32][N:31]1[C:20]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][N:11]=1)=[O:22])=[O:47]
Reactant: O=C(O)c1nccc2ccccc12
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCOC(C)=O
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCCN1C(=O)c1nccc2ccccc12
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A stirred solution of (S)-1-Piperidine-carboxylic acid methyl ester hydrochloride (1.00 g, 5.57 mmol), in DMF (20 ml) at room temperature was treated with DIPEA (2.12 ml, 12.25 mmol). The resulting mixture was allowed to stir for 30 min before being treated with 1-isoquinolinecarboxylic acid (964 mg, 5.57 mmol) and TBTU (1.79 g, 5.57 mmol). The mixture stirred at room temperature for 4 hr, diluted with ethyl acetate, washed with saturated aq. NaHCO3, saturated aq. NaCl, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (67% ethyl acetate in hexane) to afford the sub-title compound as a colourless gum (1.05 g, 63%): 1H NMR (400 MHz, CDCl3) δ 1.00-2.51 (6H, m), 3.05-3.38 (2H, m), 3.60-3.95 (3H, m), 4.35-4.95 (1H, m), 5.70-5.80 (1H, m), 7.55-7.95 (3H, m), 8.13-8.29 (1H, m), 8.48-8.61 (1H, m).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8]1.[O:19]1[CH2:24][CH2:23][CH:22]([C:25](Cl)=[O:26])[CH2:21][CH2:20]1.N1C=CC=CC=1.N.CO>C(Cl)Cl>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:25]([CH:22]3[CH2:23][CH2:24][O:19][CH2:20][CH2:21]3)=[O:26])=[CH:14][CH:13]=2)[CH2:8]1
Reactant: O=C(Cl)C1CCOCC1
Reactant: C[C@H]1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Agent: N
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: C[C@H]1CCCN1C1CC[C@H](c2ccc(NC(=O)C3CCOCC3)cc2)C1
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
4-[(S)-3-((S)-2-Methyl-pyrrolidin-1-yl)-cyclopentyl]-phenylamine (Intermediate 14) (40 mg, 0.16 mmol) was dissolved in DCM (2 mL). To this solution was transferred a solution of tetrahydro-pyran-4-carboxylic acid chloride (71.3 mg, 0.5 mmol, 3.0 equiv.) in DCM (1 mL), followed by pyridine (0.5 mL). The solution was stirred at r.t. for 2 h when TLC (5% of 7N NH3 MeOH in DCM) and LC/MS showed that the reaction was complete. The reaction was quenched by addition of polymer bound diethylenetriamine (4 mmol/g) (0.1 g) and the suspension was stirred for 30 min. Then, 10 mL of DCM was added to the suspension and the suspension was filtered through a celite pad, rinsed with DCM and 10% MeOH in DCM. The crude product was purified on a silica gel column eluted with 5% of 7N NH3 MeOH in DCM to obtain 50 mg (87% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)[C:5]2=O.O.[NH2:25][NH2:26]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)=[CH:7][NH:26][N:25]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: NN
Reactant: COc1ccc(-c2coc3cc(O)c(Cl)cc3c2=O)cc1OC
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2c[nH]nc2-c2cc(Cl)c(O)cc2O)cc1OC
Yield: 65.1 %

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-3-(3,4-dimethoxy-phenyl)-7-hydroxy-chromen-4-one (0.2 g, 0.62 mmol), hydrazine hydrate (4 ml), ethanol (10 ml). The crude solid product was columned to give 4-Chloro-6-[4-(3,4-dimethoxy-phenyl)-1H-pyrazol-3-yl]-benzene-1,3-diol as a white solid (0.139 g, 65.1%); Rf 0.36 Cf SM 0.56 ethyl acetate/hexane (75/25).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][CH:12]=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[I:20]I.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O.CO>[CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([I:20])=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: II
Reactant: CC(C)c1c[nH]c(COCc2ccccc2)n1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(C)c1nc(COCc2ccccc2)[nH]c1I
Reaction time: 0.08 h

Procedure:
In 250 ml of methylene chloride was dissolved 70 g (304 mmol) of 2-(benzyloxymethyl)-4-isopropyl-1H-imidazole (3c). Then, an aqueous solution prepared by dissolving 13 g of sodium hydroxide in 160 ml of water was added at 0° C. and the mixture was stirred for 5 minutes. Then, a solution of iodine (49 g, 386 mmol) in methylene chloride (350 ml)-methanol (150 ml) was added at 0° C. and the mixture was then stirred at room temperature for 20 minutes. To this reaction mixture was added an aqueous solution of sodium sulfite and the mixture was extracted with methylene chloride. The extract was washed with saturated brine, dried over dry sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to provide 2-benzyloxymethyl-5-iodo-4-isopropylimidazole (4c). Yield 93 g (85.5%).
Reaction SMILES: [CH:1]1([N:4]2[C:9]3[N:10]=[C:11]([S:14][CH3:15])[N:12]=[CH:13][C:8]=3[CH:7]=[CH:6][C:5]2=[O:16])[CH2:3][CH2:2]1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:24])C=CC=CC=1>C(Cl)Cl>[CH:1]1([N:4]2[C:9]3[N:10]=[C:11]([S:14]([CH3:15])=[O:24])[N:12]=[CH:13][C:8]=3[CH:7]=[CH:6][C:5]2=[O:16])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1ncc2ccc(=O)n(C3CC3)c2n1
Solvent: ClCCl
Product: CS(=O)c1ncc2ccc(=O)n(C3CC3)c2n1
Yield: 74.1 %

Procedure:
A solution of 8-cyclopropyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.5 g, 2.1 mmol) and 2-benzenesulfonyl-3-phenyl-oxaziridine (0.84 g, 3.2 mmol) in CH2Cl2 (5 mL) was stirred at room temperature for 20 hours. The white solid formed was collected by filtration and washed with hexane, then dried to give 8-cyclopropyl-2-methylsulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.388 g, 74%). 1H NMR: δ (400 MHz, DMSO) 9.15 (s, 1H), 8.0 (d, J=9.5 Hz, 1H), 6.74 (d, J=9.5 Hz, 1H), 2.92 ( s, 1H), 1.18˜1.14 ( m, 2H), 0.83˜0.79 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9]O)[CH:6]=[CH:5][N:4]=1)[CH3:2].[Br:11]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][Br:11])[CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1cc(CO)ccn1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCc1cc(CBr)ccn1
Temperature: 20 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
A solution of 0.3 g of 2-ethyl-4-(hydroxymethyl)pyridine in 3.5 ml of dichloromethane is added dropwise to a solution of 1.25 g of dibromotriphenylphosphorane in 4 ml of dichloromethane, under an inert atmosphere of argon at a temperature in the region of 0° C. The mixture is stirred to a temperature in the region of 20° C. over about 1 hour. The reaction medium is taken up in 50 ml of dichloromethane and then washed with 3×50 ml of water. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. The residue thus obtained is purified by flash chromatography using a cartridge 20 mm in diameter packed with 10 g of 20-40 μm conditioned silica, and then eluted with a mixture (cyclohexane/ethyl acetate)(9/1)(v/v), at a flow rate of 8 ml/minute. The fractions between 80 and 120 ml are concentrated under reduced pressure. 0.062 g of 2-ethyl-4-(bromomethyl)pyridine is thus obtained.
Reaction SMILES: [OH:1][C@H:2]([CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:16][CH3:17].[C:24](OC(=O)C)(=[O:26])[CH3:25].O>>[C:24]([O:1][C@H:2]([CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:16][CH3:17])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(=O)[nH]cnc2cc1OC[C@H](O)CN1CCCC1
Solvent: O
Product: COc1cc2c(=O)[nH]cnc2cc1OC[C@@H](CN1CCCC1)OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
A mixture of (2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (803 mg, 2.51 mmol) in acetic anhydride (1.2 ml, 12.5 mmol) was stirred at ambient temperature for 1 hour. Water (360 μl, 20 mmol) was added and stirring was continued for 90 minutes. The mixture was partitioned between aqueous sodium hydrogen carbonate and methylene chloride. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The residue was triturated with ether, filtered and dried under vacuum to give (2R)-7-(2-acetoxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (595 mg, 65%).