Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH2:31])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:42](OC1C=CC([N+]([O-])=O)=CC=1)=[O:43].[CH2:54]([NH2:57])[CH2:55][NH2:56].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH:31][C:42]([NH:56][CH2:55][CH2:54][NH2:57])=[O:43])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCN
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)NCCN)c1
Reaction time: 1.7 h
Yield: 82.8 %

Procedure:
A solution of [4-(2′-amino-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 25: step c) 0.150 g, 0.290 mmol) in dry CH2Cl2 (10 mL) was treated with pyridine (0.026 mL, 0.319 mol) and p-nitrophenyl chloroformate (0.064 g, 0.319 mmol) and stirred 1.7 h. The reaction mixture was treated with ethylene diamine (0.194 mL, 2.90 mmol) and triethylamine (0.485 mL, 3.48 mmol) and stirred at room temperature 16 h. The reaction was diluted with CH2Cl2 and washed with water (3×50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the product [(4-{2′-[3-(2-amino-ethyl)-ureido]-6′-methyl-biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophen-2-yl)-imino-methyl]-carbamic acid tert-butyl ester (0.145 g, 82%) as a tan solid. 1H NMR (MeOD): δ 8.195 (s, 1H), 8.057 (d, 1H, J=8.0 Hz), 7.902 (t, 1H, J=1.6 Hz), 7.718 (t, 1H, J=8.0 Hz), 7.554 (d, 1H, J=8.0 Hz), 7.511 (d, 1H, J=8.0 Hz), 7.289 (t, 1H, J=7.6 Hz), 7.119 (d, 1H, J=7.2 Hz), 3.099 (m, 2H), 2.676 (s, 3H), 2.621 (m, 2H), 2.007 (s, 3H), 1.511 (s, 9H). C27H33N5O5S3: 604.16 (M+1) found 603.90.
Reaction SMILES: [OH:1][CH:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH3:21][C:22]1[C:23]([CH:32]2[CH2:34][O:33]2)=[CH:24][C:25]([O:30][CH3:31])=[C:26]([CH:29]=1)[C:27]#[N:28]>>[OH:33][CH:32]([C:23]1[C:22]([CH3:21])=[CH:29][C:26]([C:27]#[N:28])=[C:25]([O:30][CH3:31])[CH:24]=1)[CH2:34][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[C:10]2[CH:19]=[CH:18][C:13]3[C:14](=[O:17])[O:15][CH2:16][C:12]=3[C:11]=2[CH3:20])[CH2:5][CH2:6]1
Reactant: COc1cc(C2CO2)c(C)cc1C#N
Reactant: Cc1c(C(O)CN2CCNCC2)ccc2c1COC2=O
Product: COc1cc(C(O)CN2CCN(CC(O)c3ccc4c(c3C)COC4=O)CC2)c(C)cc1C#N

Procedure:
4-(1-hydroxy-2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-5-methyl-2-(methyloxy)benzonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLES 2C and 28˜29 starting from 5-(1-hydroxy-2-piperazin-1-ylethyl)-4-methyl-2-benzofuran-1(3H)-one and 5-methyl-2-(methyloxy)-4-oxiran-2-ylbenzonitrile. LC/MS (M+1)+=466.02.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[O:12]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>CO>[O:12]([C:19]1[CH:20]=[C:21]([CH:22]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:24]=[CH:25][CH:26]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1COc2cc(O)ccc21
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Agent: Cl
Solvent: CO
Product: O=C1C(=Cc2cccc(Oc3ccccc3)c2)Oc2cc(O)ccc21
Temperature: 25 °C

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-phenoxybenzaldehyde 1.27 ml were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.10 g.
Reaction SMILES: [CH:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:9]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:44][CH2:45][C@@H:46]([OH:51])[C:47]([O:49][CH3:50])=[O:48].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:21])([F:20])[F:22])=[CH:16][CH:17]=3)[N:9]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([NH:44][CH2:45][C@@H:46]([OH:51])[C:47]([O:49][CH3:50])=[O:48])=[O:29])=[CH:26][CH:25]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)[C@H](O)CN
Reactant: O=C(O)c1ccc(Cn2nc(C3CCCCC3)cc2-c2ccc(OC(F)(F)F)cc2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](O)CNC(=O)c1ccc(Cn2nc(C3CCCCC3)cc2-c2ccc(OC(F)(F)F)cc2)cc1

Procedure:
A solution of 24.6 mg product from Step A Example 6, 15.9 mg EDC, 11.2 mg HOBt, 17.2 mg methyl (2R)-3-amino-2-hydroxypropanoate hydrochloride from Step C Example 4 and 39 μL DIEA in 0.5 mL DMF was stirred at room temperature over night. The title compound was isolated by preparative HPLC using 55˜75% MeCN gradient over 10 minutes at 8.0 mL per minute with 0.1% TFA on a 9.4×250 mm SB-C18 Zorbax column as a white solid after lyophilization. LC-MS: 2.55 min. (M+H=546.3).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]3[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][C:14]=3[CH:15]=2)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:23].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[OH:46][CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]([N:52]4[CH2:53][CH2:54][N:49]([CH2:48][CH2:47][OH:46])[CH2:50][CH2:51]4)=[O:21])=[CH:16][C:14]=3[CH:15]=2)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:23]
Reactant: O=C(O)c1ccc2sc(-c3ccc(Cl)c4c3C(=O)NC4)cc2c1
Reactant: OCCN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1NCc2c(Cl)ccc(-c3cc4cc(C(=O)N5CCN(CCO)CC5)ccc4s3)c21
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
In a similar manner to Step 1 of Example 20, Compound 172 (25.0 mg, 0.0727 mmol) was dissolved in DMF (1 mL), and the solution was treated with EDCI (28 mg, 0.15 mmol), HOBT monohydrate (9.8 mg, 0.073 mmol) and 1-(2-hydroxyethyl)piperazine (38 mg, 0.29 mmol). The reaction mixture was added with water and ethyl acetate, and extracted with 1 mol/L hydrochloric acid. The aqueous layer was added with sodium carbonate to adjust the pH to 9 and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in chloroform, and the solution was added with diisopropylether and stirred for 30 minutes. The solid was collected by filtration, washed with diisopropylether and then dried under reduced pressure to obtain Compound 173 (22.9 mg, yield 69%).
Reaction SMILES: [CH2:1]([C:19]([OH:62])([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]/[CH:52]=[CH:53]\[CH2:54]/[CH:55]=[CH:56]\[CH2:57][CH2:58][CH2:59][CH2:60]C)[CH:20]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:21][CH2:22]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.[CH3:64][N:65]([CH3:72])[CH2:66][CH2:67][CH2:68][C:69]([OH:71])=[O:70].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:64][N:65]([CH3:72])[CH2:66][CH2:67][CH2:68][C:69]([O:71][CH2:22][CH2:21][CH:20]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:19]([OH:62])([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]/[CH:51]=[CH:52]\[CH2:53]/[CH:54]=[CH:55]\[CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:70]
Reactant: CN(C)CCCC(=O)O
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCCC(O)(CCCCCCCC/C=C\C/C=C\CCCCC)C(CCO)OCCCCCCCC/C=C\C/C=C\CCCCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC/C=C\C/C=C\CCCCCCCCOC(CCOC(=O)CCCN(C)C)C(O)(CCCCCCCC/C=C\C/C=C\CCCCC)CCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 64 h
Yield: 74.8 %

Procedure:
To a solution of (14Z,17Z)-4-((9Z,12Z)-octadeca-9,12-dienyl)-3-((9Z,12Z)-octadeca-9,12-dienyloxy)tricosa-14,17-diene-1,4-diol (450 mg, 0.52 mmol), 4-(dimethylamino)butanoic acid hydrochloride (105 mg, 0.62 mmol), EDCI hydrochloride (120 mg, 0.62 mmol), DIPEA (225 μL, 1.3 mmol) in anhydrous dichloromethane (10 mL) was added DMAP (5 mg). The solution was stirred at room temperature under nitrogen for 64 hours. Upon completion, the solution was concentrated in vacuo to dryness and purified by column chromatography on silica gel 60 (eluted with 1:1 hexanes/Ethyl acetate) to afford (13Z,16Z)-4-hydroxy-4-((9Z,12Z)-octadeca-9,12-dienyl)-3-((9Z,12Z)-octadeca-9,12-dienyloxy)docosa-13,16-dienyl 4-(dimethylamino)butanoate as a colorless oil (375 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 5.43-5.29 (m, 12H), 4.31-4.11 (m, 2H), 3.60-5.29 (m, 2H), 3.27-3.22 (m, 1H), 2.78 (t, 6H, J=6.4 Hz), 2.39-2.28 (m, 3H), 2.24 (s, 6H), 2.09-2.02 (m, 12H), 1.91-1.72 (m, 4H), 1.61-1.23 (m, 60H), 0.90 (t, 9H, J=7.0 Hz).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[CH:4][C:5]2[O:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[C:7](=[O:20])[C:6]=2[CH:21]=1.[CH3:23][NH2:24].O>CS(C)=O>[F:1][C:2]1[C:3]([NH:24][CH3:23])=[CH:4][C:5]2[O:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[C:7](=[O:20])[C:6]=2[CH:21]=1
Reactant: O=C1c2cc(F)c(F)cc2OCN1c1ccc([N+](=O)[O-])cc1
Reactant: CN
Solvent: O
Solvent: CS(C)=O
Product: CNc1cc2c(cc1F)C(=O)N(c1ccc([N+](=O)[O-])cc1)CO2
Temperature: 140 °C
Yield: 81 %

Procedure:
To 6,7-difluoro-3-(4-nitrophenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (0.05 g, 0.16 mmol) in dimethyl sulfoxide (0.5 ml) was added methyl amine (0.3 ml, 2M solution in tetrahydrofuran) and the reaction heated to 140° C. for 1 hr. Water was added and product extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to give 0.42 mg (81%) of 6-fluoro-7-(methylamino)-3-(4-nitrophenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-one. RP-HPLC: 2.38 min; ES-MS (M+H)+=318.0; 1H-NMR (DMSO-d6) δ (ppm): 3.1 (s, 3 H), 5.73 (s, 2 H), 6.2 (d, 1 H), 7.38 (d, 1 H), 7.61 (d, 1 H), 8.2 (d, 2 H).
Reaction SMILES: C(O)C.[CH:4]([C:7]1[CH:20]=[CH:19][C:10]([O:11][CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].O.Cl.[NH2:23][C@H:24]([C:27]([OH:29])=[O:28])[CH2:25][SH:26].C([O-])(=O)C.[Na+]>O>[CH:4]([C:7]1[CH:20]=[CH:19][C:10]([O:11][CH:12]2[CH2:17][CH2:16][C:15]3([S:26][CH2:25][C@@H:24]([C:27]([OH:29])=[O:28])[NH:23]3)[CH2:14][CH2:13]2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CC(C)c1ccc(OC2CCC(=O)CC2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)c1ccc(OC2CCC3(CC2)N[C@H](C(=O)O)CS3)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.7 %

Procedure:
In a solvent mixture consisting of 21 ml of ethanol and 9 ml of water were dissolved 3.10 g of 4-(4-isopropylphenoxy)-1-cyclohexanone, 2.35 g of L-cysteine hydrochloride monohydrate and 1.10 g of sodium acetate. The mixture was stirred at ambient temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and water and ethyl ether were added to the concentrate. The deposited crystal was collected by filtration, and there was obtained 2.45 g of (3R)-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decan-3-carboxylic acid as a colorless crystalline product.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:8][C:9]1[C:18]([C:19]2[CH:23]=[CH:22][O:21][C:20]=2[CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:17][CH:16]=[C:15]([NH2:33])[C:10]=1[C:11]([O:13][CH3:14])=[O:12].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[NH2:8][C:9]1[C:18]([C:19]2[CH:23]=[CH:22][O:21][C:20]=2[CH2:24][O:25][Si:26]([C:29]([CH3:31])([CH3:30])[CH3:32])([CH3:27])[CH3:28])=[CH:17][CH:16]=[C:15]([NH:33][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1c(N)ccc(-c2ccoc2CO[Si](C)(C)C(C)(C)C)c1N
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc(-c2ccoc2CO[Si](C)(C)C(C)(C)C)c1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.8 %

Procedure:
Pivaloyl chloride (0.353 g) was added to a stirred, cooled mixture of methyl 2,6-diamino-3-[2-(tert-butyldimethylsilanyloxymethyl)furan-3-yl]benzoate (Intermediate 36, 1.0 g) and sodium bicarbonate (0.268 g) in ethyl acetate (20 mL) and water (7 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 1.5 hours. Further pivaloyl chloride (0.048 g) was added and the mixture was stirred for 1 hour. Ethyl acetate was added and the layers were separated. The organic layer was washed with aqueous sodium bicarbonate solution dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-20% to give methyl 2-amino-3-[2-(tert-butyldimethylsilanyloxymethyl)furan-3-yl]-6-(2,2-dimethylpropionylamino)benzoate (0.744 g) as an oil.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=O)[CH2:6]1)[CH:2]([CH3:4])[CH3:3].[C:12]([O:17]CC)(=[O:16])[C:13]([CH3:15])=O>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:13]([CH3:15])[C:12]([OH:17])=[O:16])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC1CCCC(=O)C1
Reactant: CCOC(=O)C(C)=O
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1

Procedure:
The process according to claim 8, by which 3-isobutyl-cyclohexanone and ethyl pyruvate are condensed without solvent and the condensate formed is heated at 220°-230° C. to give p-isobutyl-hydratropic acid.
Reaction SMILES: [CH2:1]([N:4]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)[C:2]#[CH:3].I[C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.C(N(CC)CC)C.C(OCC)(=O)C>C(#N)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:11]=[C:10]1[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]1[CH2:1][C:2]#[C:3][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1
Reactant: C#CCN1C(=O)c2ccccc2Oc2ccccc21
Reactant: COC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CCN2C(=O)c3ccccc3Oc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.9 %

Procedure:
The title compound 434 (0.310 g, 1.24 mmol) and the methyl 4-iodobenzoate (0.390 g, 1.48 mmol) were stirred in acetonitrile (10.0 mL). Copper iodide (24 mg, 0.124 mmol) and dichlorobis(triphenylphosphine)palladium (87 mg, 0.124 mmol) were added followed by triethylamine (0.44 mL, 3.11 mmol). The reaction mixture was stirred at room temperature for 4 hours. The mixture was poor into ethyl acetate and the organic layer was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography (10-30% ethyl acetate in hexanes) to afford title compound 435 (285 mg, 60%) as a light brown solid. MS (m/z): 384.3 (M+H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([CH3:13])=[C:10]([CH:12]=2)[NH2:11])=[CH:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][S:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][S:24][CH2:25][C:26]([NH:11][C:10]2[CH:12]=[C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[CH:7]=[CH:8][C:9]=2[CH3:13])=[O:27])=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: Cc1ccc(-c2ccoc2)cc1N
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CSCC(=O)O
Product: Cc1ccc(-c2ccoc2)cc1NC(=O)CSCC(=O)Nc1ccc(Cl)cc1C(=O)O

Procedure:
Using the same method as in Example 15-(i), 5-(furan-3-yl)-2-methylaniline was reacted with the [(2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethyl)sulfanyl]acetic acid obtained in Example 12-(i) to give 5-chloro-2-(([(2-([5-(furan-3-yl)-2-methylphenyl]amino)-2-oxoethyl)sulfanyl]acetyl)amino)benzoic acid.methyl ester (yield: 74%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C[Si](C=[N+]=[N-])(C)C.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.[CH3:29]CN(C(C)C)C(C)C>CO.C1(C)C=CC=CC=1>[CH3:29][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=1[NH:1][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=1
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C)ccc1NC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-5-methyl benzoic acid (1.0 mmol) dissolved in 10% MeOH in toluene (2.5 mL) is added dropwise trimethylsilyl-diazomethane (2.0 M in hexanes, 0.75 mL). The reaction mixture is stirred at room temperature for 1 hour and the solvent is removed under reduced pressure. The resulting methyl ester is dissolved in dichloromethane (3.0 mL) and then 4-chlorobenzoyl chloride (1.0 equivalent) and DIEA (1.0 equivalent) is added sequentially. The reaction mixture is stirred for 3 hours and the solvent is evaporated. The yellow residue is diluted with EtOAc, washed with 1 M NaHSO4, brine, dried, filtered and concentrated under reduced pressure to provide 2-(4-chloro-benzoylamino)-5-methyl-benzoic acid methyl ester (compound 11.1) which is used without purification in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1C(OC)=O.[CH3:12][Mg]Br.Cl.CC[O:18][CH2:19][CH3:20]>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:19]([OH:18])([CH3:20])[CH3:12]
Reactant: COC(=O)c1ccccc1Br
Reactant: CCOCC
Reactant: C[Mg]Br
Agent: Cl
Product: CC(C)(O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2-bromobenzoate (20.76 g, 96 mmol) in 120 mL of anhydrous ether under Argon at 0° C. was slowly added methylmagnesium bromide (77 mL, 3.26 M) at a rate that the internal temperature of the mixture was below 20° C. A white suspension resulted, and the mixture was stirred at room temperature for 2 h. The mixture was cooled in an ice-water bath. To the reaction mixture was very slowly added hydrochloric acid (400 mL, 0.5 M). The pH of the final mixture was adjusted to less than about 6 with few drops of 2M hydrochloric acid. The layers were separated, and the aqueous layer was extracted twice with ether. The organic layers were combined and dried over magnesium sulfate. The organic fraction was filtered, and the filtrate was concentrated to yield the title compound as a pale yellow liquid, which was distilled under vacuum to afford the title Compound 10d as a colorless liquid (16.9 g, 82%, b.p. about 65-70° C./0.3 mmHg). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.67 (dd, 1H, J=1.7, 7.9 Hz), 7.58 (dd, 1H, J=1.3, 7.9 Hz), 7.30 (ddd, 1H, J=1.4, 7.4, 7.9 Hz), 7.10 (ddd, 1H, J=1.7, 7.4, 7.8 Hz), 2.77 (br s, 1H), 1.76 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:25]=[C:26]([CH2:30]OS(C)(=O)=O)[CH:27]=[N:28][CH:29]=2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.[CH3:36][NH:37][CH3:38]>C1COCC1.O>[CH3:36][N:37]([CH2:30][C:26]1[CH:25]=[C:24]([C:4]2[CH:5]=[C:6]3[C:10](=[C:2]([CH3:1])[CH:3]=2)[C:9](=[O:11])[N:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=2)[CH2:7]3)[CH:29]=[N:28][CH:27]=1)[CH3:38]
Reactant: CNC
Reactant: Cc1cc(-c2cncc(COS(C)(=O)=O)c2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2cncc(CN(C)C)c2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 50 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
Methanesulfonic acid 5-[7-methyl-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindol-5-yl]-pyridin-3-ylmethyl ester (70 mg, 0.138 mmol) was dissolved in 2M dimethylamine in THF (5 mL) and stirred at 50° C. for 18 hrs. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (5% 2M N13 in MeOH/CH2Cl2) provided the title compound (37 mg, 59%) as a brown oil. 1H NMR (300 MHz, CDCl3): δ 8.75 (s, 1H), 8.53 (s, 1H), 7.89 (s, 1H), 7.44 (d, 2H), 7.37 (d, 2H), 7.20 (d, 2H), 4.81 (s, 2H), 4.31 (s, 2H), 3.52 (s, 2H), 2.84 (s, 3H), 2.30 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.C(N(CC)CC)C.[N+:15]([C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21](Cl)=[N:22][OH:23])([O-:17])=[O:16]>O1CCOCC1>[NH2:7][C:4]1[N:5]([C:21](=[N:22][OH:23])[C:20]2[CH:25]=[CH:26][CH:27]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=2)[N:6]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: O=[N+]([O-])c1cccc(C(Cl)=NO)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cc(N)n(C(=NO)c2cccc([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
4.85 g (0.05 mol) of 3(5)-amino-5(3)-methyl-pyrazole in 50 ml of absolute dioxan are treated with 8.3 ml (0,06 mol) of triethylamine and then, under stirring at room temperature, are treated dropwise with a solution of 10 g (0.05 mol) of 3-nitro-benzohydroximoyl chloride in 50 ml of absolute dioxan. Stirring is continued for 3 hours and then the mixture is evaporated to dryness. The residue is treated with water and ethyl acetate. The organic phase is dried over magnesium sulphate, evaporated under vacuum and the residue obtained in this way is recrystallised from dioxan. 9.8 g (48%) of 5-amino-1-(3-nitro-benzohydroximoyl)-3-methyl-pyrazole with a m. pt. of 224° to 226° C. are obtained.
Reaction SMILES: [S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:12]([F:13])=[CH:11][C:10]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:9][C:8]=2[F:26])[CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:28].[Na+]>CO.C(OCC)(=O)C.O>[F:13][C:12]1[CH:11]=[C:10]([N:14]2[CH2:18][C@H:17]([CH2:19][N:20]3[CH:24]=[CH:23][N:22]=[N:21]3)[O:16][C:15]2=[O:25])[CH:9]=[C:8]([F:26])[C:7]=1[C:4]1[CH2:5][CH2:6][S:1](=[O:28])[CH2:2][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1cc(F)c(C2=CCSCC2)c(F)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1cc(F)c(C2=CCS(=O)CC2)c(F)c1
Reaction time: 3 h
Yield: 76.1 %

Procedure:
(5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one (Example 86; 0.86 g, 2.3 mmol) was stirred in a mixture of methanol and ethyl acetate (1:1, 20 ml) at ambient temperature. Sodium periodate (0.50 g, 2.4 mmol) in water (10 ml) was added dropwise, and the mixture stirred for 3 hours. Precipitated salts were removed by filtration and washed with ethyl acetate. The filtrate was washed with brine, dried over magnesium sulfate and concentrated to dryness. The residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane to give the title product (0.69 g). MS (ESP): 395 (MH+) for C17H16F2N4O3S