Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][CH:2]=1.[H-].[Na+].Br[CH2:13][CH2:14][Cl:15].CCCCCCC>CN(C=O)C>[Cl:15][CH2:14][CH2:13][N:3]1[C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[N:1]=[CH:2]1
Reactant: c1cnc2[nH]cnc2c1
Reactant: ClCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: ClCCn1cnc2cccnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
6.5 g (54.56 mmol) 3H-imidazo[4,5-b]pyridine were dissolved under argon in 100 ml DMF and cooled to 0° C. in an ice bath. 4.6 g (109.1 mmol) sodium hydride were added and the mixture was stirred for 1 hour at room temperature. Then a solution of 9 ml (109.1 mmol) 1-bromo-2-chloroethane in 30 ml DMF was added over the period of an hour and the solution was stirred at room temperature during 20 hours. The brownish solution was poured onto ice water and extracted 3 times with ethyl acetate. The organic layers were combined, washed once with brine, dried over Na2SO4 and evaporated in vacuo to give a yellow oil. The oil was stirred with three times 50 ml warm heptane. Heptane was decanted, the tree fractions pooled and evaporated to give 2.08 g of light yellow crystals. MS(ISP): 182.2 [MH]+; 1H-NMR (CDCl3): 3.99 (t, 2H), 4.66 (t, 2H), 7.28-7.32 (m, 1H), 8.11-8.17 (m, 2H), 8.40-8.42 (m, 1H).
Reaction SMILES: [H-].[Li+].[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([NH:8][CH:9]=[N:10]2)=[C:6]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:5]=1.[CH2:18]([O:20][P:21]([CH2:26][O:27][CH2:28][CH2:29][CH2:30]Br)([O:23][CH2:24][CH3:25])=[O:22])[CH3:19].O>CN(C)C=O>[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[CH2:30][CH2:29][CH2:28][O:27][CH2:26][P:21]([O:23][CH2:24][CH3:25])([O:20][CH2:18][CH3:19])=[O:22])=[C:6]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:5]=1
Reactant: CCOP(=O)(COCCCBr)OCC
Reactant: COCCOc1nc(N)nc2nc[nH]c12
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(COCCCn1cnc2c(OCCOC)nc(N)nc21)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of lithium hydride (560 mg, 60 mmol) in dry dimethylformamide (DMF, 200 ml) was added 2-amino-6-methoxyethoxy purine (8.0 g, 40 mmol) (prepared according to the literature procedure: J. Kjellberg, M. Liljenberg and N. G. Johansson, Tetrahedron Lett. 877, 1986]and stirred for 60 min at 25° C. To this solution was added over 3 min a solution of 3-(diethylphosphonomethoxy)-1-bromopropane (12.0 g, 41.5 mmol) in DMF (5 mL) and the solution was heated at 55° C. for 4 h. The reaction mixture was then cooled to room temperature and water (50 mL) was added dropwise. Insoluble material was removed by filtration. The filtrate was concentrated in vacuo to give a viscous oil which was purified by column chromatography on silica gel (5% methanol in CH2Cl2) to afford 2-amino-9-(3-(diethylphosphonomethoxy)propyl]-6-methoxyethoxy purine as a white crystalline solid: yield 3.45 g (21%); mp 78°-79° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([C:16]#[N:17])[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O)(C(F)(F)F)=O.[H][H]>[Pd].CO>[NH2:17][CH2:16][CH:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C(C#N)c1ccc(OC)c(OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(CN)c1ccc(OC)c(OC)c1
Yield: 32.8 %

Procedure:
A MeOH solution (100 mL) containing methyl 3,4-dimethoxyphenylcyanoacetate (1.2 g, 5.1 mmol), TFA (1 mL), and 50 mg of 10% Pd/C was shaken on a Parr shaker for 20 hours under 30 psi of hydrogen. The reaction was filtered, concentrated, dissolved in H2O, and extracted 2× with Et2O. The pH was adjusted to ~10 and the mixture extracted 3× with EtOAc. The EtOAc fractions were dried over Na2SO4 and concentrated to yield 400 mg (32%) of the title compound.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:12]([NH2:22])[CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:23]I>N1C=CC=CC=1>[OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:12]([NH:22][CH3:23])[CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CI
Reactant: CCOC(=O)C(O)CCc1ccc(C2CCCCC2)c(N)c1
Solvent: c1ccncc1
Product: CCOC(=O)C(O)CCc1ccc(C2CCCCC2)c(NC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.01 moles of ethyl α-hydroxy-γ-(3-amino-4-cyclohexylphenyl)butyrate in 100 ml. of pyridine is added 0.1 moles of methyl iodide. The reaction mixture is stirred overnight at room temperature, filtered and concentrated. The residue is distilled to obtain ethyl α-hydroxy-γ-(3-methylamino -4-cyclohexylphenyl)butyrate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[OH:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[CH3:19][O:18][C:16](=[O:17])[C:15]1[CH:20]=[CH:21][C:12]([O:11][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=2[CH:7]=[O:8])=[CH:13][CH:14]=1
Reactant: O=Cc1cc(Cl)ccc1F
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(Oc2ccc(Cl)cc2C=O)cc1
Yield: 80.7 %

Procedure:
In a manner similar to the method described in Example 50a, 5-chloro-2-fluorobenzaldehyde (4.2 g, 26 mmol) (Alfa) was reacted with methyl 4-hydroxybenzoate (4 g, 28 mmol)(Aldrich) and K2CO3 in N,N-dimethylacetamide to give 4-(4-chloro-2-formyl-phenoxy)-benzoic acid methyl ester as a white solid (Yield 6.1 g, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O-:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Na+].Cl[C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17]>CN(C)C=O>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10])[O:13][C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17]
Reactant: COc1cc([O-])cc(OC)c1OC
Reactant: O=C(Cl)N1CCOCC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC(=O)N2CCOCC2)cc(OC)c1OC

Procedure:
To a solution of 10.15 g (0.049 mole) sodium 3,4,5-trimethoxyphenolate in 100 ml anhydrous dimethylformamide are added gradually, with stirring, 7.5 g (0.050 mole) N-chloroformyl-morpholine.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[IH:12].CS[C:15](=[NH:17])[NH2:16]>C(O)C>[IH:12].[C:1]([N:8]([CH2:9][CH2:10][NH2:11])[C:15]([NH2:17])=[NH:16])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CSC(=N)N
Agent: I
Solvent: CCO
Product: CC(C)(C)OC(=O)N(CCN)C(=N)N
Yield: 72.8 %

Procedure:
A solution of commercial N-BOC-ethylendiamine (1 g) in dry ethanol (100 ml) and 2-methyl-2-thiopseudourea hydroiodide (1.5 g) was refluxed for 8 hours. The solvent was removed at reduced pressure and the crude residue purified by flash chromatography (methylene chloride/methanol:9/1) to yield 1.5 g of N-BOC-2-aminoethylguanidine hydroiodide as a yellow oil which was dissolved in methanolic hydrochloric acid solution 5N (20 ml) and stirred at room temperature for 3 hours. The white precipitate was collected and washed with dry ethanol, affording 700 mg of the intermediate.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:16]=[CH:15][C:14]=3[S:23]([NH2:26])(=[O:25])=[O:24])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N1(C2C=CC=CN=2)CCCC1.Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:40].N1(CC2C=CC(C3C=C(CC(C)C)C=CC=3S(NC(C)(C)C)(=O)=O)=CC=2)C=CN=C1>N1C=CC=CC=1>[CH2:42]([O:41][C:39]([NH:26][S:23]([C:14]1[CH:15]=[CH:16][C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:18][C:13]=1[C:10]1[CH:9]=[CH:8][C:7]([CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:12][CH:11]=1)(=[O:24])=[O:25])=[O:40])[CH2:43][CH2:44][CH3:45]
Reactant: CC(C)Cc1ccc(S(N)(=O)=O)c(-c2ccc(Cn3ccnc3)cc2)c1
Reactant: CCCCOC(=O)Cl
Agent: CC(C)Cc1ccc(S(=O)(=O)NC(C)(C)C)c(-c2ccc(Cn3ccnc3)cc2)c1
Agent: c1ccc(N2CCCC2)nc1
Solvent: c1ccncc1
Product: CCCCOC(=O)NS(=O)(=O)c1ccc(CC(C)C)cc1-c1ccc(Cn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 68 %

Procedure:
The crude product from step (d) above was dissolved in pyridine (2 mL, dried over 4 Å molecular sieve). Pyrrolidinopyridine (36 mg, 0.024 mmol) and butyl chloroformate (276 μL, 2.23 mmol) were added to the mixture, which was then stirred for 30 h under N2 (g) at room temperature. The solvent was removed in vacuo and then co-evaporated with acetonitrile. Purification using column chromatography with CHCl3: MeOH (10:1) as eluent yielded the title compound (66.7 mg, 0.142 mmol) in 68% yield (from 2-(4-imidazol-1-ylmethylphenyl)-4-iso-butyl-N-tert-butylbenzene-sulfonamide).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([O:25][CH3:26])(=[O:24])/[CH:18]=[CH:19]\[C:20]([O:22][CH3:23])=[O:21]>C(N(CC)CC)C>[C:1]([C:5]1[CH:10]=[C:9]([S:11][CH:19]([CH2:18][C:17]([O:25][CH3:26])=[O:24])[C:20]([O:22][CH3:23])=[O:21])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)/C=C\C(=O)OC
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Product: COC(=O)CC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)OC
Yield: 79.6 %

Procedure:
The procedure of Example 1 is repeated using 23.84 grams of 2,6-di-tert-butyl-4-mercaptophenol, 14.41 grams of dimethyl maleate, and 0.5 grams of triethylamine. The product is recrystallized from heptane to give 30.44 grams (80% yield) of white solid, m.p. 94°-96° C.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]([N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22]3[CH:27]=[C:26]([N:28]4[C:36]5[C:31](=[CH:32][C:33]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:34][CH:35]=5)[CH2:30][CH2:29]4)[N:25]=[CH:24][N:23]=3)[CH2:17][CH2:16]2)=[O:14])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([O:12][C:13]([N:15]2[CH2:16][CH2:17][CH:18]([O:21][C:22]3[CH:27]=[C:26]([N:28]4[C:36]5[C:31](=[CH:32][C:33]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:34][CH:35]=5)[CH2:30][CH2:29]4)[N:25]=[CH:24][N:23]=3)[CH2:19][CH2:20]2)=[O:14])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(OC(=O)N2CCC(Oc3cc(N4CCc5cc(S(C)(=O)=O)ccc54)ncn3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)OC3CNC3)CC2)ncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Half of 22a was dissolved in 2.5 mL of DCM and 2.5 mL of TFA was added. The mixture was stirred at room temperature for 2 h then evaporated. The crude material was purified by preparative HPLC to afford 22-1, LCMS 474.1 (MH+).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[OH:41][C@H:42]([C@@H:65]1[CH2:69][C@H:68]([SH:70])[CH2:67][N:66]1[C:71]([O:73][CH2:74][C:75]1[CH:80]=[CH:79][C:78]([N+:81]([O-:83])=[O:82])=[CH:77][CH:76]=1)=[O:72])[CH2:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:52]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=2)=[O:53])[CH2:48][CH2:47]1)=[O:45]>>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:8]([S:70][C@@H:68]3[CH2:67][N:66]([C:71]([O:73][CH2:74][C:75]4[CH:80]=[CH:79][C:78]([N+:81]([O-:83])=[O:82])=[CH:77][CH:76]=4)=[O:72])[C@H:65]([C@@H:42]([OH:41])[CH2:43][C:44]([N:46]4[CH2:47][CH2:48][N:49]([C:52]([O:54][CH2:55][C:56]5[CH:57]=[CH:58][C:59]([N+:62]([O-:64])=[O:63])=[CH:60][CH:61]=5)=[O:53])[CH2:50][CH2:51]4)=[O:45])[CH2:69]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: O=C(C[C@H](O)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H]([C@@H](O)CC(=O)N4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 75.5 %

Procedure:
By using 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (461.1 mg) and (2S,4S)-2-[(1S)-1-hydroxy-2-[4-(4-nitrobenzyloxycarbonyl)piperazin-1-ylcarbonyl]ethyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (456.2 mg), reaction and purification were carried out in a similar manner to that described in Example 40-(1), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(2S,4S)-2-[(1S)-1-hydroxy-2-[4-(4-nitrobenzyloxycarbonyl)piperazin-1-ylcarbonyl]ethyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate (536.7 mg) was obtained.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH3:15])=[C:7]([C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[C:8]#[N:9])=[O:4].[OH:16][CH2:17][C@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]1.CCN(C(C)C)C(C)C>C1COCC1>[C:8]([C:7]1[C:6]([CH3:15])=[C:5]([C:3](=[O:4])[CH2:2][N:23]2[CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:19][C@H:18]2[CH2:17][OH:16])[CH:12]=[CH:11][C:10]=1[O:13][CH3:14])#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Reactant: COc1ccc(C(=O)CBr)c(C)c1C#N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)c(C)c1C#N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the 3-(bromoacetyl)-6-methoxy-2-methylbenzonitrile (2.25 g, 8.40 mmol) in THF was added tert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (2.18 g, 10.8 mmol) and Hunig's Base (2.93 mL, 16.8 mmol). The reaction was allowed to stir at RT for 16 hours. TLC showed good reaction at that point. The crude reaction was adsorbed onto silica gel, and purified by silica gel flash chromatography to afford the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:9]=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[C:12]([OH:14])[CH:13]=1.COC(=O)[C:21](Cl)([F:23])[F:22].O>CN(C)C=O>[F:22][CH:21]([F:23])[O:14][C:12]1[CH:13]=[C:8]([F:7])[CH:9]=[CH:10][C:11]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1OC(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71.9 %

Procedure:
Potassium carbonate (2.42 g, 17.5 mmol) was added to a solution of 5-fluoro-2-nitrophenol (785 mg, 5.00 mmol) in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 20 min. Chlorodifluoroacetic acid methyl ester (1.33 mL, 12.5 mmol) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 30 min and then stirred at an external temperature of 90° C. for 3 hr. After cooling, water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→4:1) to afford 2-(difluoromethoxy)-4-fluoro-1-nitrobenzene as a pale yellow oil (745 mg).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]=1[S:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.[OH:20]O>C(O)(=O)C>[OH:10][C:4]1[CH2:5][C:6]([CH3:8])([CH3:9])[CH2:7][C:2](=[O:1])[C:3]=1[S:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[O:20]
Reactant: OO
Reactant: Cc1ccc(CSC2=C(O)CC(C)(C)CC2=O)cc1
Solvent: CC(=O)O
Product: Cc1ccc(CS(=O)C2=C(O)CC(C)(C)CC2=O)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 3-hydroxy-5,5-dimethyl-2-(p-methylbenzylthio)-2-cyclohexen-1-one (10 g., 0.036 mole), 30 percent hydrogen peroxide (4.11 g., 0.0362 mole), and 100 ml. of glacial acetic acid was allowed to stand at room temperature for 24 hours. The solution was poured into ice water, and the resulting pink solid was filtered and dried to give pure product (9.9 g., m.p. 89°-90.5°C.).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:3]1.[OH-].[K+].Br[CH2:21][CH2:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1>CS(C)=O.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:21][CH2:22][O:23][C:24]3[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)=[CH:3]1
Reactant: Cn1cc(CN2CCNCC2)c2ccccc21
Reactant: O=Cc1ccc(OCCBr)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cn1cc(CN2CCN(CCOc3ccc(C=O)cc3)CC2)c2ccccc21
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
A suspension of 1-(1-methylindole-3-ylmethyl)piperazine (1.3 g) in dimethylsulfoxide (15 ml) and potassium hydroxide (0.63 g) was stirred for 30 min under nitrogen at 22° C. and then a solution of 4-[2-bromoethoxy]benzaldehyde (1.3 g) was added and stirring was continued for further 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate and the organic layer was washed with water, brine, dried (Na2SO4) and solvent was evaporated under reduced pressure. The crude product was chromatographed on silica gel using mixture of methanol: chloroform (1:9) as eluent to afford the pure product (0.76 g, 51%) as an oil.
Reaction SMILES: I[C:2]1[CH:20]=[CH:19][C:5]2[O:6][CH2:7][C:8]([OH:18])([CH3:17])[C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1.[C:21]([C@:23]1([OH:30])[CH2:27][CH2:26][N:25]([CH3:28])[C:24]1=[O:29])#[CH:22]>>[OH:18][C:8]1([CH3:17])[CH2:7][O:6][C:5]2[CH:19]=[CH:20][C:2]([C:22]#[C:21][C@:23]3([OH:30])[CH2:27][CH2:26][N:25]([CH3:28])[C:24]3=[O:29])=[CH:3][C:4]=2[N:10]2[N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=[C:9]12
Reactant: C#C[C@]1(O)CCN(C)C1=O
Reactant: CC1(O)COc2ccc(I)cc2-n2nc(C(N)=O)cc21
Product: CN1CC[C@@](O)(C#Cc2ccc3c(c2)-n2nc(C(N)=O)cc2C(C)(O)CO3)C1=O

Procedure:
Similar to as described in General Procedure G, racemic 9-iodo-4-hydroxy-4-methyl-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxamide was reacted with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one to give a diasteromeric mixture of the titled compound after purification by prep HPLC.
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.[NH2:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=1[C:15]([O:17][CH3:18])=[O:16].C(N(CC)CC)C>O1CCOCC1>[N:9]([C:10]1[CH:14]=[CH:13][S:12][C:11]=1[C:15]([O:17][CH3:18])=[O:16])=[C:2]=[O:1]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1sccc1N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)c1sccc1N=C=O
Temperature: 25 °C

Procedure:
Diphosgene (4.6 mL) was added dropwise to a solution of methyl 3-amino-2-thiophenecarboxylate (5.0 g) in p-dioxane (100 mL) at room temperature under N2. Triethylamine (5.3 mL) was then added with concomitant formation of a white precipitate. The resulting reaction mixture was heated at reflux overnight. The reaction was allowed to cool to room temperature and then filtered to remove solid impurities. The precipitate was rinsed with diethyl ether (about 250 mL) and the filtrate was concentrated under reduced pressure to yield 6.4 g of crude title compound of Step A as a brown solid. 1H NMR (CDCl3): δ 7.43 (d,1H), 6.78 (d,1H), 3.92 (s,3H).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:5][C:4]=1[CH3:12])[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([N:21]=[C:22]=[O:23])[CH:17]=[CH:18][C:19]=1[Cl:20].[OH-].[Na+].Cl>CC(C)=O>[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]([NH:11][S:8]([C:6]2[S:7][C:3]([CH2:1][CH3:2])=[C:4]([CH3:12])[CH:5]=2)(=[O:9])=[O:10])=[O:23])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CCc1sc(S(N)(=O)=O)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCc1sc(S(=O)(=O)NC(=O)Nc2ccc(Cl)c(Cl)c2)cc1C
Yield: 27.4 %

Procedure:
The procedure of Example 4B was followed with 5-ethyl-4-methyl-2-thiophenesulfonamide (1.5 g, 7.3 mmole), 3,4-dichlorophenyl isocyanate (1.38 g, 7.3 mmole), acetone (7 0 ml), 1H NaOH (7.3 ml), concentrated HCl to give the named product as a white solid (2.17 g, 5 2 mmole).
Reaction SMILES: [C:1](=[O:20])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1>CN(C=O)C>[CH3:30][C:31]1[CH:32]=[CH:33][C:34]([N:37]2[CH2:42][CH2:41][N:40]([C:1]([O:2][CH:3]3[CH2:4][CH2:5][N:6]([CH3:9])[CH2:7][CH2:8]3)=[O:20])[CH2:39][CH2:38]2)=[CH:35][CH:36]=1
Reactant: CN1CCC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: Cc1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCN(C(=O)OC3CCN(C)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution of 1-methylpiperidin-4-yl 4-nitrophenyl carbonate (1.81 g, 6.44 mmol) and DIPEA (0.76 mL, 4.4 mmol) in DMF (20 mL) was added 4-(4-methylphenyl)piperazine (1.53 g, 6.14 mmol). The reaction mixture was stirred at room temperature for 3 hours, the reaction mixture was then concentrated in vacuo. The resulting residue was dissolved in EtOAc (250 mL) and washed with 1M aq Na2CO3 (5×150 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 90:10 mixture of DCM:MeOH) to give 1-methyl-piperidin-4-yl 4-(4-methylphenyl)piperazine-1-carboxylate (1.54 g, 79%) as a cream solid.