Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:12][S:13]([NH:16][C:17]([N:19]2[CH2:22][C@H:21]([NH:23]C(OCC3C=CC=CC=3)=O)[C:20]2=[O:34])=[O:18])(=[O:15])=[O:14])[CH:3]=1.C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O>>[NH2:23][C@H:21]1[CH2:22][N:19]([C:17]([NH:16][S:13]([NH:12][C:4]2[CH:3]=[C:2]([OH:1])[C:10]([OH:11])=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])(=[O:14])=[O:15])=[O:18])[C:20]1=[O:34]
Reactant: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)Nc2cc(O)c(O)cc2C(=O)O)C1=O)OCc1ccccc1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CN(C(=O)NS(=O)(=O)Nc2cc(O)c(O)cc2C(=O)O)C1=O
Temperature: 10 °C
Reaction time: 8 h
Yield: 159.6 %

Procedure:
4 Grams (0.008 mol) of (S)-4,5-dihydroxyl-2-[[[[[2-oxo-3-[[(phenylmethoxy)carbonyl]amino]-1-azetidinyl]carbonyl]amino]sulfonyl]amino]benzoic acid was added at 10° C. to a stirred mixture of 3.2 ml of thioanisole and 14 ml of trifluoroacetic acid. The mixture was stirred overnight at 10° C., evaporated and treated with ether to yield 4.6 g of crude (S)-2-[[[[(3-amino-2-oxo-1-azetidinyl)carbonyl]amino]sulfonyl]amino]-4,5-dihydroxybenzoic acid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:9]([C:26](=O)[CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:10][CH2:11][CH2:12][CH:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=1)[OH:14])[CH3:8].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1>[CH2:7]([N:9]([CH2:26][CH2:27][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1)[CH2:10][CH2:11][CH2:12][CH:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:23])=[O:24])=[CH:17][CH:16]=1)[OH:14])[CH3:8]
Reactant: CCN(CCCC(O)c1ccc(NS(C)(=O)=O)cc1)C(=O)CC1CCCC1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCN(CCCC(O)c1ccc(NS(C)(=O)=O)cc1)CCC1CCCC1
Temperature: 0 °C
Yield: 64 %

Procedure:
A 1M solution of LiAlH4 in THF (15.9 ml) was mixed with THF (15.9 ml) and cooled, under nitrogen in an ice bath. To this solution was added, dropwise, with stirring, a solution of the product from Step I (3.0 g, 0.0076 mol) in THF (30.7 ml). The mixture was kept in the ice bath for 1 hour and then treated cautiously with a saturated potassium sodium tartrate solution (16.1 ml). This mixture was stirred at ambient temperature for 45 minutes and extracted with EtOAc. The extract was washed with water, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel with 10-20% MeOH--CHCl3. A solution of the product in Et2O was washed with NaHCO3 and concentrated to give 1.86 g of the titled compound which is a compound of Formula I'. The mass spectrum had m/z 382 (M+). Theory for C20H34N2O3S: 382.2290; measured: 382.2291.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([NH:10][C:11](=[O:26])[CH:12]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH3:13])[CH2:9][CH2:8]1.[CH:27]1([CH2:30][O:31][C:32]2[CH:33]=[CH:34][C:35](F)=[C:36]([CH:39]=2)[C:37]#[N:38])[CH2:29][CH2:28]1>CC(N(C)C)=O>[C:37]([C:36]1[CH:39]=[C:32]([O:31][CH2:30][CH:27]2[CH2:29][CH2:28]2)[CH:33]=[CH:34][C:35]=1[N:23]1[CH2:22][CH2:21][CH:20]([C:17]2[CH:18]=[CH:19][C:14]([CH:12]([CH3:13])[C:11]([NH:10][CH:7]3[CH2:8][CH2:9]3)=[O:26])=[CH:15][CH:16]=2)[CH2:25][CH2:24]1)#[N:38]
Reactant: CC(C(=O)NC1CC1)c1ccc(C2CCNCC2)cc1
Reactant: N#Cc1cc(OCC2CC2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C(=O)NC1CC1)c1ccc(C2CCN(c3ccc(OCC4CC4)cc3C#N)CC2)cc1
Temperature: 150 °C
Reaction time: 6 h

Procedure:
101 mg (0.73 mmol) potassium carbonate are added to a mixture of 80 mg (0.29 mmol) N-cyclopropyl-2-(4-piperidin-4-yl-phenyl)-propionamide (XI.1) and 56 mg (0.29 mmol) 5-cyclopropylmethoxy-2-fluoro-benzonitrile (1.8) in 2 mL DMA. The mixture is stirred for 6 h at 150° C. under microwave irradiation. Subsequently the solvent is removed in vacuo and the residue is purified using reversed phase HPLC (water, 0.3% NH4OH/MeOH) to yield the desired product.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[N:10][N:11]2[C:16]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[N:15][C:14]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=3)=[N:13][C:12]=12.[OH-].[Na+]>CO.O>[NH2:28][C:24]1[CH:23]=[C:22]([NH:21][C:14]2[N:15]=[C:16]([NH:17][CH:18]3[CH2:19][CH2:20]3)[N:11]3[N:10]=[CH:9][C:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:29])=[O:2])=[C:12]3[N:13]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)CCCCc1cnn2c(NC3CC3)nc(Nc3cccc(N)c3)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1cccc(Nc2nc(NC3CC3)n3ncc(CCCCC(=O)O)c3n2)c1
Yield: 87.4 %

Procedure:
To a solution compound (9a) (0.12 g, 0.3 mmol) in 10 mL of MeOH and 0.5 mL of H2O was added NaOH (40 mg, 1 mmol). The reaction mixture was refluxed for 1 h, concentrated to re-move MeOH. The reaction solution was adjusted to pH 4 with HCl and the solid was collected by filtration, washed with water, and dried in vacuum over P2O5 to give 5-[2-(3-amino-phenylamino)-4-cyclopropylamino-pyrazolo[1,5-a][1,3,5]triazin-8-yl]-pentanoic acid (10a) (0.1 g, 90%).
Reaction SMILES: C1(P(CC)C2C=CC=CC=2)C=CC=CC=1.[CH3:16][C:17]1([CH3:24])[C:21]([CH3:23])([CH3:22])[O:20][BH:19][O:18]1.[C:25]([NH:28][C:29]([CH:41]1[CH2:44][C:43]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=2)([NH:45][CH:46]=[O:47])[CH2:42]1)([CH2:37][CH2:38][CH:39]=[CH2:40])[C:30]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:27])[CH3:26]>ClCCl>[C:25]([NH:28][C:29]([CH:41]1[CH2:42][C:43]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=2)([NH:45][CH:46]=[O:47])[CH2:44]1)([CH2:37][CH2:38][CH2:39][CH2:40][B:19]1[O:20][C:21]([CH3:23])([CH3:22])[C:17]([CH3:24])([CH3:16])[O:18]1)[C:30]([NH:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])(=[O:27])[CH3:26]
Reactant: C=CCCC(NC(C)=O)(C(=O)NC(C)(C)C)C1CC(Cc2ccc(Cl)cc2)(NC=O)C1
Reactant: CC1(C)OBOC1(C)C
Agent: CCP(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CC(Cc2ccc(Cl)cc2)(NC=O)C1
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
While under argon, bis(1,5-dicyclooctadiene)diiridium(I)dichloride (15 mg, 0.022 mmol) and diphenylphosphinoethan (18 mg, 0.044 mmol) in dichloromethane (3 mL) was cooled to 0° C. and treated with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.430 mL, 2.95 mmol). After 30 min, a solution of 2-acetamido-N-tert-butyl-2-(3-(4-chlorobenzyl)-3-formamidocyclobutyl)hex-5-enamide (330 mg, 0.738 mmol) in dichloromethane (10 mL) was added and the cooling bath was removed. After 16 h, the solution was diluted with dichloromethane (20 mL) and washed with water and saturated aqueous sodium chloride. The organic layer was dried over MgSO4, filtered and concentrated to give the crude product (420 mg, 99%), which was used in the next step without further purification. ESI MS found for C30H47BClN3O5 m/z [576.8 (M+1), 574.7 (M−1)].
Reaction SMILES: [CH:1]([CH:4]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5]1)=[C:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].CO>C(Cl)Cl>[CH:1]([C@H:4]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5]1)=[C:2]=[CH2:3]
Reactant: C=C=CC1CCC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C=C=C[C@@H]1CCC(=O)N1
Yield: 97.1 %

Procedure:
A solution of (5S)-N-((2S)-2-(1,1-dimethylethyl)dimethylsilyloxy)propanoyl)-5-(1,2-propadienyl)pyrrolidin-2-one (2.70 g, 8.7 mmol), K2CO3 (0.6 g, 4.4 mmol), and MeOH (40 mL) was stirred at room temperature for 1.5 hours. The solvent was removed by rotary evaporation (≤30° C.) to give a yellow gum. This gum was dissolved in CH2Cl2 (20 mL), filtered to remove salts and applied to a silica gel plug (50 g). This plug was rinsed with 10% MeOH/CH2Cl2, discarding the initial eluent which contains the chiral auxiliary, to give (5S)-5-(1,2-Propadienyl)pyrrolidin-2-one (1.04 g, 97%) as a clear oil: TLC (Eluent A) Rf =0.45; 1H NMR: δ6.6 (br s, 1 H, NH); 5.17 (ddd, 3J64 ≃4J68 ≃4J68 ≃6.6 Hz, 1 H, H6); 4.88 (d, 4J68 ≃6.7 Hz, 1 H, H8); 4.88 (d, 4J68' =6.4, 1 H, H8'); 4.21 (m, 1 H, H5); 2.35 (m, 3 H, H3, H4, H4'); 1.93 (m, 1 H, H3'); Cl Mass spec: m/z 124 (MH+), 84 (MH+ --C3H4).
Reaction SMILES: [C:1]([C:9]1[C:18]([CH2:19][O:20]C(=O)C)=[N+:17]([O-:24])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:27]O>>[CH3:27][O:8][C:1]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]2=[N+:10]([O-:25])[C:11]3[C:16]([N+:17]([O-:24])=[C:18]2[CH2:19][O:20]1)=[CH:15][CH:14]=[CH:13][CH:12]=3
Reactant: CO
Reactant: CC(=O)OCc1c(C(=O)c2ccccc2)[n+]([O-])c2ccccc2[n+]1[O-]
Agent: Cl
Product: COC1(c2ccccc2)OCc2c1[n+]([O-])c1ccccc1[n+]2[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 61 %

Procedure:
A stirred suspension of 0.50 g. (1.47 mmol.) of 2-benzoyl-3-acetoxymethylquinoxaline 1,4-dioxide in 10 ml. of methanol was saturated with dry hydrogen chloride. The reaction mixture was stirred at room temperature for three days and then the suspended solid was removed by filtration. The solid was washed with methanol, and dried, to give 0.28 g. (61% yield) of 1-methoxy-1-phenyl-1,3-dihydrofuro[3,4-b]quinoxaline 4,9-dioxide, m.p. 153 °-155° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:11])[C:9]=1[OH:10])[CH:5]=O.[CH3:12][C:13](=[O:18])[CH2:14][C:15](=[O:17])[CH3:16].N1CCCCC1.C(O)(=O)C>C(OCCCC)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:14]([C:13](=[O:18])[CH3:12])[C:15](=[O:17])[CH3:16])[CH:7]=[C:8]([Cl:11])[C:9]=1[OH:10]
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1cc(O)c(O)c(Cl)c1
Solvent: C1CCNCC1
Solvent: CCCCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)C(=Cc1cc(O)c(O)c(Cl)c1)C(C)=O

Procedure:
A mixture containing 3.45 g of 3,4-dihydroxy-5-chlorobenzaidehyde, 3.0 ml of 2,4-pentanedione, 0.3 ml of piperidine and 1.0 ml of acetic acid in 100 ml of 1-butyl acetate was refluxed for 2 h with Dean-Stark separator. The solution was filtered and the solvent was evaporated in vacuo. The residue was crystallized from 1-propanol. Yield 0.46 g, mp 167°-171° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:11][N:10]=[C:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[S:8]1)=[N+:2]=[N-:3].[C:26]([N:34]=[C:35]=[S:36])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]([C:35]([NH:34][C:26](=[O:33])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[S:36])[N:10]=[C:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[S:8]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=S)NC(=O)c1ccccc1
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a solution of 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole (1.00 g, 2.79 mmol) in 20 mL of anhydrous THF was added benzoyl isothiocyanate (0.45 mL, 3.34 mmol). The reaction mixture was stirred overnight at reflux, then cooled and concentrated in vacuo. The residue was purified by flash column chromatography (5-35% ethyl acetate/hexanes) to afford the desired product as a yellow gum (1.45 g, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Br:9][CH2:10][CH2:11][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: OCCBr
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(OCCBr)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Chlorophenol (500 mg, 3.89 mg), 2-bromoethanol (0.28 ml, 3.89 mmol), triphenylphosphine (1.02 g, 3.89 mmol) were dissolved in tetrahydrofuran (8 ml). The solution was added dropwise with diisopropylazodicarboxylate (0.84 ml, 3.89 mmol) and stirred at room temperature for 3 hours. The solvent of the reaction mixture was evaporated, and then solids were precipitated by using diethyl ether-hexane and removed by filtration. The filtrate was evaporated under reduced pressure to obtain the title compound as crude product (1.18 g). The crude product was used for the next reaction without purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH2:12])=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[C:23]1[C:28]([I:29])=[C:27]([CH:30]([Cl:32])[CH3:31])[N:26]=[CH:25][N:24]=1>C1(C)C=CC=CC=1>[Cl:32][CH:30]([C:27]1[N:26]=[CH:25][N:24]=[C:23]([NH:12][CH2:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=2)[C:28]=1[I:29])[CH3:31]
Reactant: NCCc1ccc(OC(F)(F)F)cc1
Reactant: CC(Cl)c1ncnc(Cl)c1I
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(Cl)c1ncnc(NCCc2ccc(OC(F)(F)F)cc2)c1I
Temperature: 60 °C

Procedure:
In toluene (50 ml) were dissolved 2-(4-trifluoromethoxyphenyl)ethylamine (1.0 g) and triethylamine (1.0 g), then, 4-chloro-6-(1-chloroethyl)-5-iodopyrimidine (1.5 g) was added to the solution, and the mixture was heated at about 60° C. for 3 hours while stirring.
Reaction SMILES: [NH2:1][C@@H:2]([C@@H:5]([CH3:8])[CH2:6][CH3:7])[CH2:3][OH:4]>O1CCOCC1>[CH:5]([CH:2]1[NH:1][C:3](=[O:4])[CH:2]([CH:5]([CH2:6][CH3:7])[CH3:8])[NH:1][C:3]1=[O:4])([CH2:6][CH3:7])[CH3:8]
Reactant: CC[C@H](C)[C@H](N)CO
Solvent: C1COCCO1
Product: CCC(C)C1NC(=O)C(C(C)CC)NC1=O
Yield: 72 %

Procedure:
Upon refluxing a dioxane solution containing 2 mmol of (2S,3S)-2-amino-3-methylpentan-1-ol and 0.02 mmol of catalyst 1 for 19 hrs and cooling the reaction mixture, the solid product precipitated and was filtered off and dried under vacuum to give pure 3-(sec-butyl)-6-(sec-butyl)piperazine-2,5-dione 7c in 72% yield (Table 31, entry 2). The structure was confirmed by NMR and MS spectroscopies. Under the same conditions, cyclic peptidation of (S)-2-amino-3-methylbutan-1-ol led to 3,6-diisopropylpiperazine-2,5-dione 7d as an insoluble solid which separated from the reaction mixture and was isolated by filtration and dried under vacuum to give 78% of (3S,6S)-3,6-diisopropylpiperazine-2,5-dione 7d (Table 31, entry 3). The optical rotation of the pure product)(−52° was essentially the same as reported in the literature)(−54°). Thus, under these experimental condition, no racemization took place.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:44][O:45][C:46]1[C:47]2[N:60]=[C:59]([NH2:61])[S:58][C:48]=2[C:49]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[N:50][CH:51]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([NH:61][C:59]1[S:58][C:48]2[C:49]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)=[N:50][CH:51]=[C:46]([O:45][CH3:44])[C:47]=2[N:60]=1)=[O:8]
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: COc1cc(C(=O)O)ccc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cc(C(=O)Nc2nc3c(OC)cnc(N4CCOCC4)c3s2)ccc1C

Procedure:
From 3-methoxy-4-methylbenzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 415 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][S:10]([C:13]1[N:17]=[CH:16][NH:15][N:14]=1)(=[O:12])=[O:11].C1(C)C=CC(S([C:27]2[N:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[N:28]=2)(=O)=O)=CC=1.N12CCCN=C1CCCCC2>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][S:10]([C:13]1[N:17]=[CH:16][N:15]([C:27]2[N:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[N:28]=2)[N:14]=1)(=[O:11])=[O:12]
Reactant: O=S(=O)(Nc1c(Cl)cccc1Cl)c1nc[nH]n1
Reactant: Cc1ccc(S(=O)(=O)c2nc(C)cc(C)n2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(-n2cnc(S(=O)(=O)Nc3c(Cl)cccc3Cl)n2)n1
Yield: 79.4 %

Procedure:
N-(2,6-dichlorophenyl)-1,2,4-triazole-3-sulphonamide (2.051 g) was heated for 1 hour at 125° C. with 1.82 g of 2-p-toluenesulphonyl-4,6-dimethylpyrimidine in the presence of 1,8-diazabicyclo(5,4,0)undec-7-ene (2.128 g) in dimethylformamide (35 ml). After distillation of the solvent, the residue was poured into a mixture of water (80 ml) and 1N hydrochloric acid (20 ml), and was then filtered off. This crude product was chromatographed on silica gel using methylene chloride/methanol (95/5) as eluent, to give 2.2 g of the desired product, mp 274°-275° C.
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][C:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:6]=1[O:12][CH2:13][CH:14]([OH:28])[CH2:15][NH:16][CH2:17][CH2:18][NH:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27].Cl.[CH4:30]>C(O)=O>[ClH:1].[ClH:1].[N:11]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([O:12][CH2:13][CH:14]([OH:28])[CH2:15][NH:16][CH2:17][CH2:18][NH:19][C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:27])[C:5]=2[NH:4][CH:30]=1
Reactant: C
Reactant: Cc1cccc(C)c1NCCNCC(O)COc1cccc(N)c1N
Agent: Cl
Solvent: O=CO
Product: Cc1cccc(C)c1NCCNCC(O)COc1cccc2nc[nH]c12

Procedure:
A solution of 21.5 g. 2,3-diamino-1-{2-hydroxy-3-[2-(2,6-dimethylphenylamino)-ethylamino]-propoxy}-benzene trihydrochloride in 150 ml. formic acid is boiled under reflux for 6 hours. After evaporating the reaction mixture in a vacuum, the residue obtained is taken up in 200 ml. 2N hydrochloric acid, boiled under reflux for 4 hours, mixed with active charcoal and filtered while hot. The filtrate is evaporated to dryness and the residue then recrystallized. There are obtained 3.5 g. (17.4% of theory) of the desired compound: m.p. 128°-131° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:26]3[CH2:27][CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][C:25]=3[S:24][C:10]=2[N:11]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12](=[O:15])[CH2:13][N:14]=1.ClC1C=C(C=CC=1)C(OO)=[O:43].C(OC(C)C)(C)C.CCC(C)C>[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:26]3[CH2:27][CH2:28][NH:29][CH2:30][C:25]=3[S:24][C:10]=2[N:11]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12](=[O:15])[CH:13]([OH:43])[N:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3c2C(c2ccccc2Cl)=NCC(=O)N3CCc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: CCC(C)C
Product: O=C1C(O)N=C(c2ccccc2Cl)c2c(sc3c2CCNC3)N1CCc1ccccc1
Reaction time: 24 h

Procedure:
t-butyl 5-(2-chlorophenyl)-1,2,3,6,7,9-hexahydro-2-oxo-1-(2-phenylethyl)-8H-pyrido[4′,3′:4.5]thieno[2,3-e]-1,4-diazepine-8-carboxylate (22 g, 41 mmol) is dissolved a 23° C. in 1,2-chloro ethane (320 ml). Meta-chloroperoxybenzoic acid at 85% (21.6 g, 0.1 mol) is added. Agitation is carried out for 24 hours at 23° C. then a solution of 5N sodium hydroxide (400 ml) is added. After decanting, the organic phase is washed with water, dried over magnesium sulphate, filtered and concentrated with a rotary evaporator. After purification by chromatography on a silica column (eluent: ethyl acetate-heptane: 50-50 to 80-20), the fractions containing only the product ae evaporated. The solid obtained is agitated in a mixture of solvents: isopropyl ether-isopentane (20-80). After filtration on frit and washing with isopentane, the desired product is obtained in the form of a white powder (5.9 g, 26%).
Reaction SMILES: [ClH:1].FC1C=CC=C(F)C=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][C:22]([C:24]4C=NC=CC=4)=[CH:23][C:16]=23)=[C:10]([F:30])[CH:9]=1)=[O:6].Cl.FC1C=C(NC(=O)[CH2:66][C:67]([NH:69][C:70]2[CH:75]=[CH:74][C:73]([F:76])=[CH:72][CH:71]=2)=[O:68])C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[ClH:1].[F:30][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[CH2:66][C:67]([NH:69][C:70]2[CH:75]=[CH:74][C:73]([F:76])=[CH:72][CH:71]=2)=[O:68])[CH:13]=[CH:12][C:11]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[NH:21][C:22]([CH3:24])=[CH:23][C:16]=12
Reactant: O=C(Nc1ccc(Oc2ccnc3[nH]c(-c4cccnc4)cc23)c(F)c1)c1c(F)cccc1F
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)ccnc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.9 %

Procedure:
To a mixture of 3-fluoro-4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yloxy)benzenamine (20 mg, 0.078 mmol, Compound E of Example 292), 3-(4-fluorophenylamino)-3-oxopropanoic acid (20 mg, 1 mmol, Compound A of Example 25), and HATU (44 mg, 0.12 mmol) in DMF (0.5 mL) was added DIPEA (0.1 mL). The reaction mixture was stirred at rt for 2 h and concentrated in vacuo. The residue was purified by preparative HPLC to give the desired product (HCl salt, 12.5 mg, 34%) as a white solid. 1H NMR (CD3OD) δ 8.05 (d, 1H, J=7.2 Hz), 7.79 (dd, 1H, J=12.7, 2.8 Hz), 7.50-7.53 (m, 2H), 7.27-7.36 (m, 2H), 6.97 (m, 2H), 6.70 (d, 1H, J=6.6 Hz), 6.20 (s, 1H), 3.47 (s, 2H), 2.40 (s, 3H); LC/MS(ESI+) m/z 437 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([OH:14])=[O:13].S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14][CH2:20][CH3:21])=[O:13]
Reactant: O=C(O)Cc1ccccc1CCCO
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccccc1CCCO

Procedure:
A solution of [2-(3-hydroxypropyl)phenyl]acetic acid (48.6 g., 0.25 mole) and sulfuric acid (3 ml.) in ethanol (400 ml.) is heated at reflux for 6 hours. Workup as described in Example 25, Step A(3) yields the title compound.
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:41][O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:16][S:17][CH2:18][C@@H:19]([C:38](O)=[O:39])[NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:90][C:91]1([CH2:94][OH:95])[CH2:93][CH2:92]1>C(Cl)Cl>[C:43]([O:42][CH2:41][C@@H:15]([O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:16][S:17][CH2:18][C@H:19]([NH:20][C:21]([O:22][CH2:23][CH:24]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=2[C:31]2[C:36]1=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:37])[C:38]([NH:90][C:91]1([CH2:94][OH:95])[CH2:93][CH2:92]1)=[O:39])(=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCC
Reactant: NC1(CO)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NC1(CO)CC1)OC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5R,9R)-9-(dodecanoyloxy)-1-(9H-fluoren-9-yl)-3,12-dioxo-2,11-dioxa-7-thia-4-azatricosane-5-carboxylic acid (6, 1 eq) and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (3.5 eq), followed by (1-aminocyclopropyl)methanol hydrochloride (1.2 eq). The reaction was stirred at room temperature for 2 hours. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 30-50% EtOAc/Hex to give (R)-3-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1-(hydroxymethyl)cyclopropylamino)-3-oxopropylthio)propane-1,2-diyl didodecanoate.