Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]([OH:15])[CH3:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.Cl[C:17]1[CH:23]2[O:24][C:20]([CH3:25])([CH2:21][CH2:22]2)[C:19](=[O:26])[CH:18]=1.[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([CH:13]([O:15][C:17]3[CH:23]4[O:24][C:20]([CH3:25])([CH2:21][CH2:22]4)[C:19](=[O:26])[CH:18]=3)[CH3:14])=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: CC12CCC(O1)C(Cl)=CC2=O
Reactant: CC(O)c1cnc(-c2ccc(Cl)cc2)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(OC1=CC(=O)C2(C)CCC1O2)c1cnc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
To a solution of 1-[2-(4-Chlorophenyl)thiazol-5-yl]ethanol (129 mg, 0.54 mmol) and 4-chloro-1-methyl-8-oxabicyclo[3.2.1]oct-3-en-2-one (93 mg, 0.54 mmol) in dry THF (5 ml) is added in one portion the sodium hydride, 60% dispersion in mineral oil, (21 mg, 0.54 mmol). The reaction mixture is stirred at room temperature overnight. Silica gel is added to the crude reaction mixture, and the solvent is evaporated under reduced pressure. The residue is purified by flash chromatography on silica gel to give 4-{1-[2-(4-Chlorophenyl)thiazol-5-yl]-ethoxy}-1-methyl-8-oxabicyclo[3.2.1]oct-3-en-2-one (160 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH2:12][CH2:13][CH2:14][CH2:15]O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[F:24])[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(CCCCO)c1cc(F)ccc1F
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C1(c2cc(F)ccc2F)CCCC1

Procedure:
In toluene (10 ml) was dissolved 5-[(4-chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-1-pentanol (100 mg, 0.267 mmol). After addition of cyanomethylenetri-n-butylphosphorane (130 mg, 0.539 mmol), the mixture was heated under reflux for 2 days under an argon atmosphere. The reaction mixture was allowed to cool down and then, added with cyanomethylenetri-n-butylphosphorane (130 mg, 0.539 mmol). The mixture was heated under reflux for 3 days under an argon atmosphere. The reaction mixture was allowed to cool down and then concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=15:1) to yield a white solid. The resulting white solid was washed with hexane, whereby the title compound (35 mg, 37%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[S:18][CH:17]=[C:16]([CH:19]=[CH2:20])[C:11]=2[N:12]=[C:13](Cl)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]1>>[CH2:1]([NH:8][C:9]1[C:10]2[S:18][CH:17]=[C:16]([CH:19]=[CH2:20])[C:11]=2[N:12]=[C:13]([NH:29][CH2:28][CH2:27][N:24]2[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1csc2c(NCc3ccccc3)nc(Cl)nc12
Reactant: NCCN1CCOCC1
Product: C=Cc1csc2c(NCc3ccccc3)nc(NCCN3CCOCC3)nc12
Yield: 78.5 %

Procedure:
The target compound of Example 46 (36 mg, 78% yield) was prepared in the same manner as Step 3 of Example 44 using N-benzyl-2-chloro-7-vinylthieno[3,2-d]pyrimidin-4-amine (35 mg, 0.116 mmol) and 2-morpholinoethanamine (75 mg, 0.58 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH3:13])[CH3:12].C(Cl)Cl.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>C(N(CC)CC)C>[CH3:12][C:5]1([CH3:13])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[O:25])[CH:3]=2)[NH:7][C:6]1=[O:11]
Reactant: CC1(C)C(=O)Nc2ccc(N)cc21
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C(=O)Nc2ccc(NC(=O)c3ccncc3)cc21

Procedure:
A suspension of 5.0 g. (0.028 mol) 5-amino-3,3-dimethylindolin-2-one in 100 ml. methylene chloride containing 14 ml. triethylamine is mixed, while cooling, with 7.0 g. (0.04 mol) isonicotinic acid chloride hydrochloride. Subsequently, the reaction mixture is evaporated and the residue is digested with water, filtered with suction and recrystallised from ethanol. Yield: 5.8 g. (73% of theory); m.p.>300° C.
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[NH:9]1[C:17]2[C:12](=[CH:13][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([C:2]3[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Reactant: O=C1C=C(Br)CCC1
Product: O=C1C=C(c2ccc3[nH]ccc3c2)CCC1
Yield: 83 %

Procedure:
Synthesized from 3-bromocyclohex-2-enone and indole-5-boronic acid pinacol ester according to the general procedure described for the Suzuki coupling. Purification by automated flash chromatography using gradient elution yielded the product (151 mg, 83%) as a pale yellow solid. 1H NMR (300 MHz, CDCl3): δ 8.68 (bs, 1H), 7.86 (d, J=0.3 Hz, 1H), 7.37-7.44 (m, 2H), 7.25 (dd, J=3.3, 2.5 Hz, 1H), 6.59 (t, J=2.5 Hz, 1H), 6.51 (t, J=1.1 Hz, 1H), 2.88 (td, J=6.3, 1.4 Hz, 2H), 2.51 (t, J=6.3 Hz, 2H), 2.18 (quintet, J=6.0 Hz, 2H). 13C (75 MHz, CDCl3): 200.1, 161.5, 136.7, 130.1, 127.9, 125.4, 123.7, 120.2, 119.1, 111.3, 103.3, 37.3, 28.5, 23.0. HRMS (LCT Electrospray): mass calcd for (C14H13NO+Na) m/z 234.0895; measured [M+Na]+: m/z 234.0897.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:17])[C:3]=1[C:18](=O)[CH3:19].[CH3:21][O:22][C:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH2:32])=[O:30])=[CH:27][CH:26]=1)=[O:24]>>[CH3:17][C:4]1[C:3](=[C:18]([NH:32][NH:31][C:29](=[O:30])[C:28]2[CH:33]=[CH:34][C:25]([C:23]([O:22][CH3:21])=[O:24])=[CH:26][CH:27]=2)[CH3:19])[C:2](=[O:1])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:15])([F:16])[F:14])=[CH:9][CH:8]=2)[N:5]=1
Reactant: CC(=O)c1c(C)nn(-c2ccc(C(F)(F)F)cc2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)cc1
Product: COC(=O)c1ccc(C(=O)NNC(C)=C2C(=O)N(c3ccc(C(F)(F)F)cc3)N=C2C)cc1

Procedure:
From 1-(5-hydroxy-3-methyl-1-(4-trifluoromethylphenyl)-1H-pyrazol-4-yl)-ethanone and 4-methoxycarbonylbenzhydrazide, 58.9 mg of the desired product was obtained in the same manner as in Synthetic Example 4 as a yellow solid (yield 65%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[Cu][C:14]#[N:15].CN1C(=O)CCC1>C(OCC)(=O)C>[C:14]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6])#[N:15]
Reactant: N#C[Cu]
Reactant: COC(=O)c1ccc(O)c(Br)c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(O)c(C#N)c1
Temperature: 200 °C
Yield: 46.2 %

Procedure:
To a mixture of methyl 3-bromo-4-hydroxybenzoate (1.78 g, 7.70 mmol) and copper(I) cyanide (0.897 g, 10.02 mmol) was added NMP (10 mL). The mixture was heated to 200° C. for 2 h under microwave irradiation. The mixture was diluted with ethyl acetate and quenched with 1 N aqueous HCl solution. After the addition of brine, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography. The combined fractions were concentrated under reduced pressure and triturated with cold water to provide the title compound as an off-white solid (0.63 g). LCMS m/z=178.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 3.92 (s, 3H), 6.55 (bs, 1H), 7.04 (d, J=8.72 Hz, 1H), 8.15 (dd, J=8.72, 2.15 Hz, 1H), 8.23 (d, J=1.89 Hz, 1H).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][CH2:12][C:11]=2[CH:17]=1.S(Cl)([Cl:20])=O>N1C=CC=CC=1>[Cl:20][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][CH2:12][C:11]=2[CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1Nc2ccc(OCCCCO)cc2CO1
Solvent: c1ccncc1
Product: O=C1Nc2ccc(OCCCCCl)cc2CO1
Temperature: 25 °C

Procedure:
Sixty grams (0.253 mol) of 6-(4-hydroxy-butoxy)-4H-3,1-benzoxazin-2-one and 5 ml of pyridine are added to 300 ml of thionyl chloride, under stirring, at ambient temperature. After refluxing for two hours, the excess thionyl chloride is distilled off in a rotary evaporator, and the residue is taken up in chloroform and is stirred with the same volume of ice water for 30 minutes. Then, the chloroform phase is removed, washed twice with water, and dried with sodium sulfate, and the chloroform is distilled off. The residue is recrystallized from toluene/diisopropylether (3:1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]1([NH2:21])[CH2:20][CH2:19]1.Cl.CN(C)CCCN=C=NCC>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15](=[O:17])[NH:21][CH:18]2[CH2:20][CH2:19]2)[CH2:13][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)NC2CC2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred mixture of trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (6.1 g, 25.0 mmol) and cyclopropylamine (1.9 mL, 27.5 mmol) in dichloromethane (125 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.3 g; 27.5 mmol) is added in one portion. The reaction is stirred at ambient temperature for 48 hours. The solvent is evaporated and the crude is stirred in ice-cold 1N hydrochloric acid (100 mL) for 30 min. The solid product is isolated by suction filtration, washed with small portions of water and recrystallized from ethanol/water to deliver 5.2 g of the title compound as colorless solid.
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].[CH3:16][C:17]1[N:22]=[C:21]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:20]=[CH:19][CH:18]=1>>[C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:29]1[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][O:23][C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:16])[N:22]=2)[CH2:27][CH2:28]1)#[N:2]
Reactant: Cc1cccc(OCCN2CCNCC2)n1
Reactant: CC(C)C(C#N)(CCCI)c1cccs1
Product: Cc1cccc(OCCN2CCN(CCCC(C#N)(c3cccs3)C(C)C)CC2)n1

Procedure:
The title compound was synthesized in accordance with Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and 1-[2-(6-methyl-2-pyridyloxy)ethyl]piperazine. The physico-chemical data of the compound was as below.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])([O:3][CH3:4])=[O:2].[NH2:17][C:18]1[N:23]=[C:22]([NH:24][CH3:25])[N:21]=[C:20]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:19]=1>C(Cl)Cl>[CH3:25][NH:24][C:22]1[N:21]=[C:20]([O:26][CH2:27][C:28]([F:31])([F:29])[F:30])[N:19]=[C:18]([NH:17][C:15]([NH:14][S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:1]([O:3][CH3:4])=[O:2])(=[O:12])=[O:13])=[O:16])[N:23]=1
Reactant: CNc1nc(N)nc(OCC(F)(F)F)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: CNc1nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OC)nc(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
2-Carbomethoxybenzenesulfonyl isocyanate (0.5 g) was dissolved in 5 ml of methylene chloride. The aminoheterocycle (0.46 g) prepared in Example 2 was added and the mixture was stirred overnight under nitrogen at room temperature. The resulting solids were filtered of, washed with methylene chloride and dried to give 0.54 g of ~80% pure subject compound; m.p. 195°-197° C. decomp. No attempt was made at further purification. The resulting product named above had the following characteristics: IR (nujol) showed carbonyl bands at 1723 cm-1 and 1740 cm-1. NMR (CDCl3, DMSO-d6): δ2.9, m, (NHCH3); 3.8, s, (CO2CH3); 4.9, m, (OCH2CF3); 7.7-8.4 m, (aromatic H's) plus ~20% heterocycle.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][CH2:12][CH:13]=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1.[OH:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[OH:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:13][CH2:12][CH2:11][C:7]2[N:6]=[C:5]3[CH2:4][O:3][C:2](=[O:1])[C:10]3=[CH:9][CH:8]=2)[CH2:23][CH2:22]1
Reactant: O=CCCc1ccc2c(n1)COC2=O
Reactant: OCCOCCN1CCNCC1
Product: O=C1OCc2nc(CCCN3CCN(CCOCCO)CC3)ccc21
Yield: 78.7 %

Procedure:
In a process similar to that described in Preparation 8, 3-(5-Oxo-5,7-dihydro-furo[3,4-b]pyridin-2-yl)-propionaldehyde (76 mg, 0.4 mmol) and 1-[2-(2-hydroxyethoxy)ethyl]-piperazine (66 μL, 0.4 mmol) are reacted to provide the title compound as an oil (110 mg, 79%).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40](OC)=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].OC(C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)(C1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.Cl.[CH3:87][O:88][C:89](=[O:93])[C@@H:90]([CH3:92])[NH2:91]>>[OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40]([NH:91][C@H:90]([CH3:92])[C:89]([O:88][CH3:87])=[O:93])=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Reactant: COC(=O)[C@@H](C)N
Agent: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Product: COC(=O)[C@@H](C)NC(=O)c1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Yield: 143.3 %

Procedure:
In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (622 mg) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with D-alanine methyl ester hydrochloride (283 mg) in a similar manner as described in Example 24-(i) to give the titled compound (622 mg) as a colorless powder.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([C:18]1([C:25]([OH:27])=[O:26])[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH2:19]1)#[N:17].[CH2:28]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=2)=[CH:36][CH:35]=1)[CH2:29]CCCC.C(N(CC)C1C=CN=CC=1)C>C(Cl)Cl>[C:16]([C:18]1([C:25]([O:27][C:43]2[CH:44]=[CH:45][C:40]([C:37]3[CH:36]=[CH:35][C:34]([CH2:28][CH3:29])=[CH:39][CH:38]=3)=[CH:41][CH:42]=2)=[O:26])[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH2:19]1)#[N:17]
Reactant: CC1CCCC(C#N)(C(=O)O)C1
Reactant: CCCCCCc1ccc(-c2ccc(O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN(CC)c1ccncc1
Solvent: ClCCl
Product: CCc1ccc(-c2ccc(OC(=O)C3(C#N)CCCC(C)C3)cc2)cc1
Reaction time: 2 h

Procedure:
A solution of 23 g of dicyclohexylcarbodiimide in 50 ml of CH2Cl2 is added to a mixture of 16 g of 1-cyano-3-methyl-cyclohexanecarboxylic acid, 25 g of 4'-hexyl-biphenyl-4-ol, 1.2 g of 4-diethylaminopyridine and 200 ml of methylene chloride at room temperature and the mixture is stirred for 2 hours. Customary working up and separation by column chromatography (silica gel/toluene) gives 4'-hexylbiphenyl-4-yl 1-cyano-3-methylcyclohexanecarboxylic as the pure product by recrystallization, m.p. 51°, [α]D20 =+2.2°.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].[C:11](O)(=[O:14])[CH2:12][CH3:13]>O>[C:11]([C:7]1[CH:8]=[CH:9][C:4]2[NH:3][C:2](=[O:10])[O:1][C:5]=2[CH:6]=1)(=[O:14])[CH2:12][CH3:13]
Reactant: CCC(=O)O
Reactant: O=c1[nH]c2ccccc2o1
Solvent: O
Product: CCC(=O)c1ccc2[nH]c(=O)oc2c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
1000 g polyphosphoric acid are taken at 50° C., 100 g (740 mmol) 2-benzoxazolinone and 80 mL (1.07 mol) propionic acid are added and then the mixture is stirred for 2 h at 90° C. The reaction mixture is cooled to 50° C. and while being cooled it is combined with 1500 mL cold H2O. H2O phase is decanted off and the whole process is repeated twice more with 1500 mL H2O. Then the solid is suction filtered, triturated with diethyl ether/EtOH, suction filtered and washed with diethyl ether.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14]O.S(=O)(=O)(O)O>ClC(Cl)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:14])=[O:10])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The reactant ester, methyl p-(t-butyl)-benzoate is prepared by refluxing a mixture of 178 g (1 mol) p-t-butyl benzoic acid, 96 g (3 mol) methanol, 300 ml dichloroethane, and 15 ml concentrated sulfuric acid for a 21 hour period. This mixture is washed four times with 500 ml water and 500 ml of a 10% sodium carbonate solution. The product is dried over calcium chloride and distilled, yielding 161 g of the ester boiling at 258°-262° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[CH:8]([OH:19])[C@H:9]([OH:18])[C@H:10]1[O:15][C:13](=[O:14])[C:12]([OH:16])=[C:11]1[OH:17].[C:20]1(O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>O.[N+](C)([O-])=O>[O:19]([CH2:8][C@H:9]([OH:18])[C@H:10]1[O:15][C:13](=[O:14])[C:12]([OH:16])=[C:11]1[OH:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1ccccc1
Reactant: O=C1O[C@H]([C@@H](O)C(O)Br)C(O)=C1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: O=C1O[C@H]([C@@H](O)COc2ccccc2)C(O)=C1O
Reaction time: 6 h

Procedure:
To a stirred solution of 7.44 g (0.06 mol) sodium carbonate in 25 ml of water was added 4.76 g (0.02 mol) of 6-bromo-L-ascorbic acid in small portions, followed by 3.8 g (0.04 mol) of phenol. The solution thickened to a white mobile paste, gradually turning yellow after stirring 6 hours under a nitrogen atmosphere. The reaction mixture was then adjusted to pH 0.5 with 6 N aqueous hydrochloric acid the aqueous solution extracted with ethyl acetate (3×100 ml), the ethyl acetate layer washed with water, brine and dried over anhydrous magnesium sulfate. On removal of solvent in vacuo the residue was triturated with benzene, the resulting crystals collected by filtration and dried under vacuum overnight affording 1.54 g of crude title compound. A sample for analysis was obtained by recrystallization from nitromethane followed by drying under vacuum overnight: mp 160°-161°; VmaxKBr 5.68 (s) 6.00 (s); 1H-nmr (D2O): 7.54-6.75 (m, 5, arom.), 4.93 (broad s, l), 7.20 (m, 3, --CH2 --O and --CH--OH); mass spectrum (70 eV): m/e 252.0563 (parent, C12H12O6, 136 (--O--CH2 --C+H--OH), 116 ##STR4## 107 (--O+ =CH2), 94 (base, --OH); [α]D24 79.3° (C 1.09, CH3OH).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([C:8]([CH3:11])=[CH:9][CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:17])=O.N1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([C:8]([CH3:11])=[CH:9][CH:10]=1)[C:5]([Cl:17])=[O:6]
Reactant: Cc1ccc(C)c([N+](=O)[O-])c1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(C)c([N+](=O)[O-])c1C(=O)Cl

Procedure:
3,6-Dimethyl-2-nitrobenzoic acid in an amount of 9.6 g (51 mmol) was dissolved in 100 ml benzene and then followed by an addition of thionyl chloride in an amount of 8.8 g (74 mmol) and pyridine in an amount of 0.1 lg. The mixture was then heated for 2 hours under reflux, and the solvent therein was distillated out under reduced pressure to obtain 3,6-dimethyl-2-nitrobenzoyl chloride in an amount of 10.3 g.
Reaction SMILES: [F:1][CH:2]1[CH2:7][NH:6][CH:5]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][CH2:3]1.[CH3:17][C:18]1[S:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O.CCOC(C)=O>[F:1][CH:2]1[CH2:7][N:6]([C:23]([C:21]2[N:22]=[C:18]([CH3:17])[S:19][C:20]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:24])[CH:5]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)NCC1CCC(F)CN1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)N2CC(F)CCC2CNC(=O)OC(C)(C)C)c(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl (5-fluoropiperidin-2-yl)methylcarbamate (0.43 mmol, 0.1 g), 2-methyl-5-phenyl-1,3-thiazole-4-carboxylic acid (made as described in the literature: see for instance, WO2008/020405, 0.47 mmol, 0.1 g), diisopropyl ethyl amine (0.47 mmol, 0.08 mL) and HATU (0.47 mmol, 0.18 g) in dimethyl acetamide (2 mL) was stirred at rt overnight. The reaction mixture was diluted with EtOAc and washed with 1N NaOH and brine successively. The organic layer was separated, dried with MgSO4 and concentrated in vacuo to provide desired tert-butyl (5-fluoro-1-(2-methyl-5-phenylthiazole-4-carbonyl)piperidin-2-yl)methylcarbamate which was used for next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)O)[C:10]([CH3:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=1>>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=2)[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:10]([CH3:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: Cc1nn(Cc2ccccc2)cc1C(O)C1CCCCC1
Product: Cc1nn(Cc2ccccc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 1.6 %

Procedure:
Using (1-benzyl-3-methyl-1H-pyrazol-4-yl)(cyclohexyl)methanol (0.65 g) synthesized in Example 41(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.65 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (18.2 mg, 2%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([S:8][CH:9]1[N:12]([CH2:13][C:14](=[O:23])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11](=[O:24])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:33])C=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([S:8]([CH:9]1[N:12]([CH2:13][C:14](=[O:23])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11](=[O:24])[CH2:10]1)=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCc1ccccc1)CN1C(=O)CC1SCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CCc1ccccc1)CN1C(=O)CC1S(=O)Cc1ccccc1
Reaction time: 0.5 h
Yield: 24.5 %

Procedure:
A solution of 4-(benzylthio)-1-(4-phenyl-2-oxobutyl)azetidin-2-one (3.1 g, 9.2 mmol) in dichloromethane (100 ml) was cooled to -50 to -60° C. and a solution of m-chloroperbenzoic acid (1.9 g, 11 mmol) in dichloromethane (80 ml) added dropwise with stirring over 30 min. After a further 30 min at -50 to -60° C. the reaction mixture was shaken with a mixture of saturated aqueous sodium sulphite and saturated sodium hydrogen carbonate and the organic layer separated, dried (MgSO4) and evaporated to a solid. Two recrystallisations from ethyl acetate gave (4R,SR/4S,SS) 4-(benzylsulphinyl)-1-(4-phenyl-2-oxobutyl)azetidin-2-one (0.8 g, 27%), mp 147-9° C.