Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][CH3:12])[C:5]([OH:7])=[O:6].[N:13](OC(C)(C)C)=O.C([O-])(=O)C.[K+].C1OCCOCCOCCOCCOCCOC1>O1CCCC1.C(Cl)(Cl)Cl>[C:5]([C:4]1[CH:3]=[C:2]2[C:10]([C:11]([CH3:12])=[N:13][NH:1]2)=[CH:9][CH:8]=1)([OH:7])=[O:6]
Reactant: CC(C)(C)ON=O
Reactant: CCc1ccc(C(=O)O)cc1N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1n[nH]c2cc(C(=O)O)ccc12
Temperature: -12 °C
Reaction time: 0.33 h
Yield: 17.3 %

Procedure:
To chloroform (75 ml), which had been passed through an alumina column, was added boron trifluoride diethyl ether complex (3.75 g, 26.4 mmol) and the mixture was cooled at −12° C. A solution of 3-amino-4-ethylbenzoic acid (2.5 g, 15.1 mmol) in tetrahydrofuran (25 ml) was dropwise added thereto for 20 min. After the completion of the addition, t-butyl nitrite (1.87 g, 18.1 mmol) was added and the mixture was heated to 5° C. The mixture was stirred at 5° C. for 1.5 hr. Then potassium acetate (7.4 g, 75.4 mmol) and 18-crown-6-ether (400 mg, 1.51 mmol) were added and the mixture was stirred at room temperature for 40 hr. The brown reaction mixture was concentrated under reduced pressure. Ethyl acetate/acetone (7/3, 100 ml) and 1N hydrochloric acid (25 ml) was added to the residue and the mixture was stirred at room temperature for 1 hr. Saturated brine (25 ml) was added thereto. The insoluble matter was filtered off and the filtrate was partitioned. The water layers were extracted with ethyl acetate/acetone (7/3, 40 ml) and the combined organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained brown oil (4.3 g) was dissolved in ethyl acetate, and then hydrogen chloride-diethyl ether (61 of hydrogen chloride in 40 ml of ether) and diethyl ether (100 ml) were added. The precipitated solid was collected by filtration. The obtained solid was extracted with ethyl acetate/acetone (7/3, 100 ml) and saturated brine (25 ml), and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained solid was washed with diethyl ether to give the objective compound (0.46 g, 17%) as brown crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7](O)=[O:8])=[O:4].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C([O:46][P:47](=[O:74])([O:71]CC)[O:48][CH2:49][C@@H:50]([N:56]([S:61]([C:64]1[CH:69]=[CH:68][C:67]([NH2:70])=[CH:66][CH:65]=1)(=[O:63])=[O:62])[CH2:57][CH:58]([CH3:60])[CH3:59])[CH2:51][CH2:52][CH2:53][CH2:54][NH2:55])C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([C:7](=[O:8])[NH:55][CH2:54][CH2:53][CH2:52][CH2:51][C@H:50]([N:56]([S:61]([C:64]1[CH:65]=[CH:66][C:67]([NH2:70])=[CH:68][CH:69]=1)(=[O:62])=[O:63])[CH2:57][CH:58]([CH3:60])[CH3:59])[CH2:49][O:48][P:47]([OH:71])([OH:46])=[O:74])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Reactant: CCOP(=O)(OCC)OC[C@H](CCCCN)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)NCCCC[C@@H](COP(=O)(O)O)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 139.6 %

Procedure:
(2S)-2-methoxycarbonylamino-3,3-diphenyl-propionic acid (example 1A, step E) 0.9 g, 3 mmol) was activated in DMF (5 mL) with EDAC (1.7 g, 9 mmol) and HOBt (1.2 g, 9 mmol). To the solution was added 1.17 g of (2S)-phosphoric acid 6-amino-2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-hexyl ester diethyl ester (IX) (example 3, step B) and the mixture stirred for 3 h. 20 g of Amberlite XAD-2 resin was then added and the beads were left to soak for 10 min. The resin was transferred into a glass filter and washed thoroughly with distilled water (400 mL) and 200 mL of 1M NaHCO3. The beads were then washed with 4×50 ml portions of MeOH then EtOAc 200 mL. The organic phase was evaporated. The residue was adsorbed onto silica gel and passed through a short silica gel column (EtOAc) to yield 2.4 g (83%) of white solid after evaporation.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=13)=[O:10])[NH:2]2.[CH3:20][C:21]1[S:22][C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])=[C:24]([C:26](O)=[O:27])[N:25]=1>>[CH3:20][C:21]1[S:22][C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:36])[F:37])=[C:24]([C:26]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[O:19][CH:18]=[CH:17][C:16]=34)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:27])[N:25]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2C(F)(F)F)s1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2occc12
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4occc34)C[C@@H]3C[C@@H]32)c(-c2ccccc2C(F)(F)F)s1

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-methyl-5-(2-trifluoromethyl-phenyl)-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.43 min; [M+H]+=526.1.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([F:14])[CH:8]=1.CN(C)[CH:17]=[O:18].S(=O)(=O)(O)[O-].[K+]>C1(C)C=CC=CC=1.O1CCCC1>[F:14][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[CH3:13])[CH:17]=[O:18]
Reactant: Cc1ccc(Br)cc1F
Reactant: CN(C)C=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(C=O)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.9 %

Procedure:
tert-Butyllithium (31 ml of a 1.7 M solution in toluene, 52 mmol) was added slowly over 30 minutes to a cold (−70° C.), stirred solution of 4-bromo-2-fluorotoluene (5 g, 26 mmol) in tetrahydrofuran (25 ml). After addition was complete, the mixture was stirred for 15 minutes and a solution of dimethylformamide (2 g, 28 mmol) in tetrahydrofuran (10 ml) was then added over 10 minutes. After addition was complete, the reaction solution was warmed to room temperature over 30 minutes. The reaction was poured into 0.5N aqueous potassium bisulfate (125 ml) and extracted with ethyl ether. The combined organic extracts were dried over sodium sulfate and evaporated to give 3.3 g (90%) of the desired product as an oil. This material was suitable for use without further purification.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]3[N:14]([CH3:18])[C:13]4[CH2:19][CH:20]([C:22]([OH:24])=O)[CH2:21][C:12]=4[C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:25]>C(O)C>[C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]3[N:14]([CH3:18])[C:13]4[CH2:19][CH:20]([C:22]([NH2:25])=[O:24])[CH2:21][C:12]=4[C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cn1c2c(c3cc(OCc4ccccc4)ccc31)CC(C(=O)O)C2
Reactant: N
Solvent: CCO
Product: Cn1c2c(c3cc(OCc4ccccc4)ccc31)CC(C(N)=O)C2
Temperature: 100 °C

Procedure:
In a sealed tube was added a solution of 1,2,3,4-tetrahydro-7-phenylmethoxy-4-methylcyclopent[b]indole-2-carboxylic acid ecid ethyl ester (5.0 g, 0.014 mole) in 25 ml of absolute ethanol, followed by ammonia (30% aqueous solution, 10ml, 0.17 mole). After heating at 100° C. for five days, the mixture was cooled and the resultant tan precipitate collected and dried to give 3.0 g, m.p. 145°-148° C.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[NH2:23][CH2:24][C:25]([CH3:29])([OH:28])[CH:26]=[CH2:27]>C(Cl)Cl>[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:23][CH2:24][C:25]([CH3:29])([OH:28])[CH:26]=[CH2:27])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: C=CC(C)(O)CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(C)(O)CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12

Procedure:
Triethyl amine (6.2 mL, 0.045 mole) was added to a solution of 2,4-dichloro-3-nitroquinoline (10.9 g, 0.045 mole) in methylene chloride (60 mL). 4-Amino-3-methyl-1-butene-3-ol was added and the reaction mixture was heated at reflux for several hours before being concentrated under vacuum. The residue was chilled in an ice bath to give a solid. The solid was recrystallized from toluene to provide 17.1 g of the desired product as a yellow solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[CH:8]=[CH:7]2)([O-])=O.Cl.C([O:26][C:27](=[O:31])[CH2:28][CH2:29][NH2:30])C.[C:32]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>>[C:32]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:37]=[CH:36][C:35]([S:38]([NH:1][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[N:9]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:30][CH2:29][CH2:28][C:27]([OH:26])=[O:31])=[O:19])=[CH:21][CH:22]=2)[CH:8]=[CH:7]3)(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: CCOC(=O)CCN
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1ccc(Cn2ccc3cc([N+](=O)[O-])ccc32)cc1
Agent: Cl
Product: O=C(O)CCNC(=O)c1ccc(Cn2ccc3cc(NS(=O)(=O)c4ccc(-c5ccccc5)cc4)ccc32)cc1

Procedure:
The title compound was prepared from 4-[(5-nitro-1H-indol-1-yl)methyl]benzoic acid, β-alanine ethyl ester hydrochloride, and biphenyl 4-sulfonyl chloride following the procedure of Example 10: MS (ESI) m/z 554; MS (ESI) m/z 552.
Reaction SMILES: C(O[C:4]1[C:5](=[O:14])[C:6](=[O:13])[C:7]=1[NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])C.C(OC1C(=O)C(=O)C=1N[C@H](C)C(C)(C)C)C.[F:31][C:32]([F:43])([F:42])[O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH2:38].[K+].[Br-]>>[C:9]([NH:8][C:7]1[C:6](=[O:13])[C:5](=[O:14])[C:4]=1[NH:38][CH2:37][C:36]1[CH:39]=[CH:40][CH:41]=[C:34]([O:33][C:32]([F:31])([F:42])[F:43])[CH:35]=1)([CH3:10])([CH3:11])[CH3:12]
Reactant: NCc1cccc(OC(F)(F)F)c1
Reactant: CCOc1c(NC(C)(C)C)c(=O)c1=O
Agent: CCOc1c(N[C@H](C)C(C)(C)C)c(=O)c1=O
Agent: [Br-]
Agent: [K+]
Product: CC(C)(C)Nc1c(NCc2cccc(OC(F)(F)F)c2)c(=O)c1=O
Yield: 66 %

Procedure:
The title compound was prepared according to the procedure for example 1-step 2 except that 3-ethoxy-4-(tert-butylamino)-cyclobut-3-ene-1,2-dione was used in place of using (R)-3-ethoxy-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione and 3-trifluoromethoxy-benzylamine was used in place of 4-fluorobenzylamine. Yield: 66%; mp: 210-212° C.; 1H NMR (300 MHz, DMSO-d6): δ 1.36 (m, 9H), 4.76-4.81 (m 2H), 7.32-7.43 (m, 3H), 7.50-7.60 (m, 2H), 7.76-7.84 (brm, 1H); IR (KBr, cm-1): 3295m, 3239m, 3063w, 2973m, 1794m, 1655s, 1569s, 1542s, 1471s, 1446s, 1259-1168brs; MS (ES) m/z (relative intensity): 365 (M+ +Na, 50), 343 (M+ +H, 100); Anal. Calcd. for C16H17F3N2O3 : C, 56.14; H, 5.01; N, 8.18. Found: C, 55.91; H, 4.70; N, 7.99.
Reaction SMILES: [C:1]([OH:7])([C:3](F)(F)F)=[O:2].[CH3:8][C:9]([CH3:79])([CH3:78])[C@H:10]([NH:71][C:72](=[O:77])[C@@H:73]([NH:75][CH3:76])[CH3:74])[C:11]([N:13]1[C@H:17]([C:18](=[O:30])[NH:19][C@H:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22][CH2:21]2)[CH2:16][C@H:15]([C:31]2[CH:40]=[C:39]3[C:34]([CH2:35][C@@H:36]([C:58]([NH:60][C@H:61]4[C:70]5[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=5)[CH2:64][CH2:63][CH2:62]4)=[O:59])[N:37]([C:41](=[O:57])[C@@H:42]([NH:50][C:51](=[O:56])[C@@H:52]([NH:54][CH3:55])[CH3:53])[C:43]([S:46]CCO)([CH3:45])[CH3:44])[CH2:38]3)=[CH:33][CH:32]=2)[CH2:14]1)=[O:12]>>[CH3:79][C:9]([CH3:8])([CH3:78])[C@H:10]([NH:71][C:72](=[O:77])[C@@H:73]([NH:75][CH3:76])[CH3:74])[C:11]([N:13]1[C@H:17]([C:18](=[O:30])[NH:19][C@H:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22][CH2:21]2)[CH2:16][C@H:15]([C:31]2[CH:40]=[C:39]3[C:34]([CH2:35][C@@H:36]([C:58](=[O:59])[NH:60][C@H:61]4[C:70]5[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=5)[CH2:64][CH2:63][CH2:62]4)[N:37]([C:41](=[O:57])[C@@H:42]([NH:50][C:51](=[O:56])[C@@H:52]([NH:54][CH3:55])[CH3:53])[C:43]([S:46][CH2:3][C:1]([OH:7])=[O:2])([CH3:44])[CH3:45])[CH2:38]3)=[CH:33][CH:32]=2)[CH2:14]1)=[O:12]
Reactant: CN[C@@H](C)C(=O)N[C@H](C(=O)N1C[C@@H](c2ccc3c(c2)CN(C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)(C)SCCO)[C@H](C(=O)N[C@@H]2CCCc4ccccc42)C3)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C
Reactant: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1C[C@@H](c2ccc3c(c2)CN(C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)(C)SCC(=O)O)[C@H](C(=O)N[C@@H]2CCCc4ccccc42)C3)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.3 %

Procedure:
A solution of TFA (20% in CH2Cl2, 1.06 mmol) was added to Compound F of Example 28 (13 mg, 0.011 mmol). The resulting reaction mixture was stirred at room temperature for 1 h and then concentrated in vacuo. The crude oil was purified by preparative HPLC to give the title compound (2.5 mg, 18%) as a white solid after lyophilization. MS (ESI+) m/z 1021.6 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[C:10](=[O:24])[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([S:19](Cl)(=[O:21])=[O:20])=[C:14]([Cl:23])[CH:13]=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].Cl.C(OCC)(=O)C.[OH-].[NH4+:33]>>[CH2:1]([O:3][P:4]([C:9]1[C:10](=[O:24])[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([S:19]([NH2:33])(=[O:21])=[O:20])=[C:14]([Cl:23])[CH:13]=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)c1cc2cc(S(=O)(=O)Cl)c(Cl)cc2[nH]c1=O
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)c1cc2cc(S(N)(=O)=O)c(Cl)cc2[nH]c1=O

Procedure:
A suspension of the compound obtained in Step E of Example 1 (1.26 g, 3.0 mmol) in 18 ml of 28% ammonium hydroxide solution is stirred. After a few minutes the batch is observed to pass into solution. Stirring is maintained for 30 minutes and the reaction mixture is rendered acidic with 4N HCl. A few ml of ethyl acetate are added with stirring and precipitation occurs. The precipitate is filtered off and dried in vacuo to yield the title product in the form of a cream-coloured powder.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([OH:14])=[CH:3][CH:2]=1.[C:15](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.ClCCl>[CH3:15][O:14][C:4]1[C:5]2[S:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=[CH:2][CH:3]=1
Reactant: Oc1cccc2c1sc1ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: ClCCl
Product: COc1cccc2c1sc1ccccc12
Reaction time: 16 h

Procedure:
To a solution of dibenzothiophen-4-ol (i)(14.2 g, 71.0 mmol) in acetone (500 ml) was added powdered potassium carbonate (14.72 g, 106.5 mmol) and methyl iodide (4.43 ml, 71 mmol). The mixture was heated to reflux and stirred like this for 16 hours. The mixture was then cooled and filtered through a Celite™ pad. The resulting filtrant was concentrated in vacuo to give an oily residue that was diluted in dichloromethane (100 ml) and washed with 1M NaOH and saturated brine solution. The organic layer was dried using MgSO4, filtered and concentrated in vacuo to give a buff coloured solid that corresponded to the title compound and was used without any further purification. (15.2 g, 100%) m/z (LC-MS, ESP), RT=4.22 min, (M+H)=215.1
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3([OH:20])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[NH:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=2)=[O:23])=[CH:4][CH2:3]1.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35]O.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][O:20][C:14]1([C:12]2[CH:11]=[CH:10][C:9]([NH:21][C:22]([C:24]3[NH:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=3)=[O:23])=[C:8]([C:5]3[CH2:6][CH2:7][C:2]([CH3:31])([CH3:1])[CH2:3][CH:4]=3)[CH:13]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: CN(C)CCO
Reactant: CC1(C)CC=C(c2cc(C3(O)CCOCC3)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCOC1(c2ccc(NC(=O)c3ncc(C#N)[nH]3)c(C3=CCC(C)(C)CC3)c2)CCOCC1
Temperature: 50 °C
Yield: 20.3 %

Procedure:
To a suspension of 5-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(4-hydroxy-tetrahydro-pyran-4-yl)-phenyl]-amide (48.0 mg, 0.114 mmol)(prepared in Example 1, step (h)) in 1 mL of DCM was added 2-dimethylamino-ethanol (0.114 mL, 1.14 mmol), TFA (0.130 mL, 1.17 mmol), and the mixture heated to 50° C. for 8 h. The mixture was concentrated and the title compound purified by RP-HPLC on a C18 column eluting with a linear gradient of 30-50% CH3CN in 0.1% TFA/H2O over 12 min to give 14 mg (20%) of a white solid. 1H-NMR (400 MHz, CD3OD): δ 8.21 (d, J=8.6 Hz, 1H), 7.91 (s, 1H), 7.35 (dd, J=8.6, 2.2 Hz, 1H), 7.21 (d, J=2.2 Hz, 1H), 5.67 (m, 1H), 3.83-3.66 (m, 4H), 3.30-3.15 (m, 4H), 2.76 (s, 6H), 2.26-2.20 (m, 2H), 2.12-1.94 (m, 6H), 1.51 (t, J=6.3 Hz, 2H), 1.00 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C28H37N5O3, 492.3 (M+H). found 492.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5](N=C(C1C=CC=CC=1)C1C=C(Cl)C=CC=1O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(Cl)(=O)C1C=CC=CC=1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(N=C(c1ccccc1)c1cc(Cl)ccc1O)C(=O)OCC
Solvent: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 7.8 g. of [(5-chloro-2-hydroxy-α-phenylbenzyliden)amino] malonic acid diethyl ester in 15 ml. of pyridine is treated at 10°-15° C. with 3.5 ml. of benzoyl chloride. The mixture is stirred at room temperature for 1 hour and then poured on to 150 ml. of ice-water. The separated oily product is extracted with ether and the organic phase washed with water, then with 2-N sodium carbonate solution and finally with water. After drying over sodium sulfate and evaporation of the solvent, the oily residue is triturated with hexane, crystallization setting in. There is obtained [(2-benzoylloxy-5-chloro-α-phenylbenzyliden)amino] malonic acid diethyl ester in the form of colorless crystals, having a melting point of 108°-110° C. Recrystallization from ethanol increases the melting point to 109°-111° C.
Reaction SMILES: C[O-].[Na+].[CH:4]1([CH:7]=[O:8])[CH2:6][CH2:5]1.Cl[CH2:10][C:11]([O:13][CH3:14])=[O:12].C(O)(=O)C>CO.O>[CH:4]1([CH:7]2[O:8][CH:10]2[C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]1
Reactant: COC(=O)CCl
Reactant: O=CC1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C1OC1C1CC1
Temperature: -10 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
A 300-ml three-necked flask equipped with a thermometer and a stirrer was charged with 87 g (0.45 mole) of a 28% sodium methoxide solution in methanol and 21 g (0.30 mole) of cyclopropanecarbaldehyde and, after the contents had been cooled down to −10° C., 48.9 g (0.45 mole) of methyl chloroacetate was added dropwise over 3 hours. After completion of the addition, the reaction mixture was allowed to be warmed up to room temperature and was then stirred at room temperature for 5 hours. Thereafter, 12 g (0.20 mole) of acetic acid was added to neutralize remaining sodium methoxide and the resulting mixture was poured into 140 g of water. The reaction mixture thus obtained was extracted three times each with 50 ml of ethyl acetate and the extracts were washed with 50 ml of saturated salt water. The mixture thus washed was dried over anhydrous sodium sulfate and condensed. The residue was distilled under reduced pressure to yield, as distillates at 70 to 73° C. [6 mmHg (8.0 hPa)], 29.8 g (0.21 mole; yield: 70.0%) of methyl 3-cyclopropyl-2,3-epoxypropionate having the following properties.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[NH:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)=[CH:8][C:6]=1[NH2:7])([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CSCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1cc(N2CCSCC2)ccc1[N+](=O)[O-]
Temperature: 135 °C
Reaction time: 24 h
Yield: 91.4 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (5.6 g, 32 mmol), thiomorpholine (10.0 g, 97 mmol) and anhydrous potassium carbonate (4.98 g, 36 mmol) in N,N-dimethylacetamide (10 ml) was stirred at 135° C. under nitrogen for 1 day. Sample NMR analysis showed complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured into cold water and stirred vigorously for 3 hours. The resulting brown precipitate was collected by filtration, washed well with water then dried on the filter funnel. The resulting brown solid was washed with diethyl ether, filtered, washed with additional diethyl ether, dried to afford 2-Nitro-5-thiomorpholin-4-yl-phenylamine (7.0 g, 91.5%) as a brown powder, and used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:5]([NH:6][C:7]([C:9]2[S:17][C:16]3[CH2:15][CH2:14][S:13](=[O:18])[CH2:12][C:11]=3[C:10]=2[O:19][CH:20]([CH3:22])[CH3:21])=[O:8])=[N:4][N:3]=[N:2]1.S(S([O-])=O)([O-])(=O)=[O:24].[Na+].[Na+]>C(O)(=O)C.OO>[NH:1]1[C:5]([NH:6][C:7]([C:9]2[S:17][C:16]3[CH2:15][CH2:14][S:13](=[O:24])(=[O:18])[CH2:12][C:11]=3[C:10]=2[O:19][CH:20]([CH3:22])[CH3:21])=[O:8])=[N:4][N:3]=[N:2]1
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: CC(C)Oc1c(C(=O)Nc2nnn[nH]2)sc2c1CS(=O)CC2
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)Oc1c(C(=O)Nc2nnn[nH]2)sc2c1CS(=O)(=O)CC2
Reaction time: 72 h

Procedure:
To a stirred solution of 0.2 g (0.59 mmol) of 3-isopropoxy-5-oxo-6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-carboxylic acid (1H-tetrazol-5-yl)amide (from Example 5) in 15 mL of glacial acetic acid was added in one portion 0.19 g of 31.5% aqueous hydrogen peroxide. The reaction mixture stood at 24° C. for 3 days, and then was treated with 10% aqueous sodium metabisulfite. The solvent was removed by evaporation under reduced pressure to give a solid residue. The solid was crystallized from 20 mL of ethylacetate and 1 mL of water to provide 0.115 g of 3-isopropoxy-5,5-dioxo-6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-carboxylic acid (1H-tetrazol-5-yl) amide, mp 230°-232° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10](SC)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].Cl[C:15]1C=CC=C(C(OO)=O)C=1.[S:25]([O-:29])([O-])(=[O:27])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([S:25]([CH3:15])(=[O:29])=[O:27])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1cc(SC)ncn1
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC#CCOc1cc(S(C)(=O)=O)ncn1
Temperature: 0 °C
Reaction time: 10 h

Procedure:
To 14 ml of chloroform were added 4-(2-butynyloxy)-6-methylthiopyrimidine and 3.5 g of m-chloroperbenzoic acid (>65%), followed by stirring at 0° C. for 10 hours. The reaction mixture was then poured into a saturated aqueous sodium thiosulfate solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 1.4 g of 4-(2-butynyloxy)-6-methanesulfonylpyrimidine.