Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]1[S:6][C:7]([C:10]2[NH:14][N:13]=[CH:12][CH:11]=2)=[N:8][N:9]=1)=[N+]=[N-].[Sn](Cl)Cl>CO>[NH:14]1[C:10]([C:7]2[S:6][C:5]([CH2:4][NH2:1])=[N:9][N:8]=2)=[CH:11][CH:12]=[N:13]1
Reactant: [N-]=[N+]=NCc1nnc(-c2ccn[nH]2)s1
Agent: Cl[Sn]Cl
Solvent: CO
Product: NCc1nnc(-c2ccn[nH]2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a 3 mL methanol solution of 2-(azidomethyl)-5-(1H-pyrazol-5-yl)-1,3,4-thiadiazole (50 mg, 0.24 mmol) was added Tin (II) chloride, anhydrous (82 mg. 0.43 mmol) and the resulting yellow solution was stirred at rt overnight. The reaction mixture was concentrated and purified by HPLC (acetonitrile-water-ammonium hydroxide eluent) to give the title compound (37 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C1COCC1.CC([O-])(C)C.[K+].C1(CS([C:37]2[CH:42]=[CH:41][C:40]([S:43]([CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)(=[O:45])=[O:44])=[CH:39][N:38]=2)(=O)=O)C=CC=CC=1>O.C1(C)C=CC=CC=1>[C:9]1([C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][C:37]3[CH:42]=[CH:41][C:40]([S:43]([CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)(=[O:44])=[O:45])=[CH:39][N:38]=3)=[CH:7][CH:6]=2)=[O:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: O=S(=O)(Cc1ccccc1)c1ccc(S(=O)(=O)Cc2ccccc2)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)c1ccc(Oc2ccc(S(=O)(=O)Cc3ccccc3)cn2)cc1
Yield: 44 %

Procedure:
To 4.96 g of p-hydroxybenzophenone in a 25 ml THF/25 ml DMSO mixture was added 3.1 g of t-BuOK and then 9.69 g of 2.5-bis((phenylmethyl)sulfonyl)pyridine and the resulting mixture heated at 60° C. for 11/2 hrs. The reaction mixture was allowed to cool overnight, diluted with 4 volumes of water, and the golden-brown precipitate which formed removed by filtration. Recrystallization from CH2Cl2 /ethanol and then from toluene gave the product, phenyl(4-((5-((phenylmethyl)sulfonyl)-2-pyridinyl)oxy)phenyl)methanone, (44% yield), as tan prisms, m.p. 146°-147° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].Cl[C:11]([C:13]([O:20][CH3:21])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:12].C(N(CC)CC)C>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:11](=[O:12])[C:13]([O:20][CH3:21])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)C(C)(OC)C(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(OC)C(=O)Nc1cc(Cl)cc(Cl)c1
Yield: 50 %

Procedure:
3,5-Dichloroaniline (3.33 grams, 0.02 mole), ethyl 2-(chlorocarbonyl)-2-methoxypropionate (4.0 grams, 0.02 mole), prepared in Example LXII Part C, and triethylamine (2.08 grams, 0.02 mole) were reacted in a manner similar to the procedure described in Example I to give 4.40 grams (0.01 mole) of ethyl 3-[(3,5-dichlorophenyl)amino]-2-methoxy-2-methyl-3-oxopropanoate having a melting point of 72° C.-75° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:12]([C:17]([N:19]2[CH2:23][C@H:22]([OH:24])[CH2:21][C@H:20]2[CH2:25][NH:26][C:27]([C:29]2[CH:30]=[CH:31][CH:32]=[C:33]3[C:38]=2[N:37]=[CH:36][CH:35]=[CH:34]3)=[O:28])=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=1.CCN(CC)CC>C(Cl)Cl>[C:11]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:12]([C:17]([N:19]2[CH2:23][C:22](=[O:24])[CH2:21][C@H:20]2[CH2:25][NH:26][C:27]([C:29]2[CH:30]=[CH:31][CH:32]=[C:33]3[C:38]=2[N:37]=[CH:36][CH:35]=[CH:34]3)=[O:28])=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(NC[C@@H]1C[C@@H](O)CN1C(=O)c1ccccc1-c1ccccc1)c1cccc2cccnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C1C[C@@H](CNC(=O)c2cccc3cccnc23)N(C(=O)c2ccccc2-c2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 52.7 %

Procedure:
To a solution of oxalyl chloride (39 μL, 0.45 mmol) in DCM (7 mL) at −78° C., was added a solution of DMSO (64 μL, 0.90 mmol) in DCM (4 mL). After stirring at −78° C. for 15 min, a solution of N-(((2S,4R)-1-(biphenylcarbonyl)-4-hydroxypyrrolidin-2-yl)methyl)quinoline-8-carboxamide (0.135 g, 0.30 mmol) in DCM (4 mL) was added. The resulting mixture was stirred at −78° C. for 1 h, treated with Et3N (0.25 mL, 1.8 mmol) dropwise and then allowed to warm to rt gradually over 1.5 h. The mixture was then concentrated in vacuo to a beige solid and purified by column chromatography on silica gel (70% MeOH in EtOAc) to provide (S)—N-((1-(biphenylcarbonyl)-4-oxopyrrolidin-2-yl)methyl)quinoline-8-carboxamide as a white solid (0.071 g, 53% yield). MS (ESI) 450.12 (M+H).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[NH:5][C:6]([C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[N:14]=[C:15]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]([CH3:22])=[N:17]3)=[CH:7][C:8]=1[C:9]([OH:11])=[O:10].C(OC(NCC1NC(C2C=CC=C3C=2N=C(NC2(C)CC2)C(C)=N3)=CC=1C(OCC)=O)=O)(C)(C)C>>[ClH:1].[NH2:2][CH2:3][C:4]1[NH:5][C:6]([C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[N:14]=[C:15]([NH:23][C:24]2([CH3:27])[CH2:26][CH2:25]2)[C:16]([CH3:22])=[N:17]3)=[CH:7][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: Cc1nc2cccc(-c3cc(C(=O)O)c(CN)[nH]3)c2nc1NC(C)(C)C
Agent: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC4(C)CC4)nc23)[nH]c1CNC(=O)OC(C)(C)C
Agent: Cl
Product: Cc1nc2cccc(-c3cc(C(=O)O)c(CN)[nH]3)c2nc1NC1(C)CC1

Procedure:
This compound was prepared according to the procedures described for Intermediate (334c), using ethyl 24(tert-butoxycarbonyl)amino)methyl)-5-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylate (357b) (0.25 g, 0.53 mmol) as starting material. Crude material was used without further purification. Assumed theoretical conversion. m/z (ESI, +ve) 352.0 (M+H)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.FC(F)(F)C(O)=O.[Cl:27][CH2:28][CH2:29][CH2:30]/[C:31](=[CH:35]\[C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]2)=[C:38]([O:48][CH3:49])[CH:37]=1)/[C:32]([OH:34])=O.[F:50][C:51]1[CH:59]=[C:58]2[C:54]([CH2:55][CH2:56][CH:57]2[NH2:60])=[CH:53][C:52]=1[N:61]1[CH2:66][CH2:65][O:64][CH2:63][CH2:62]1>CN(C=O)C.C(Cl)CCl>[F:50][C:51]1[CH:59]=[C:58]2[C:54]([CH2:55][CH2:56][CH:57]2[NH:60][C:32](=[O:34])/[C:31](=[CH:35]/[C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]3)=[C:38]([O:48][CH3:49])[CH:37]=2)/[CH2:30][CH2:29][CH2:28][Cl:27])=[CH:53][C:52]=1[N:61]1[CH2:66][CH2:65][O:64][CH2:63][CH2:62]1
Reactant: NC1CCc2cc(N3CCOCC3)c(F)cc21
Reactant: COc1cc(/C=C(\CCCCl)C(=O)O)ccc1-n1cnc(C)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(/C=C(\CCCCl)C(=O)NC2CCc3cc(N4CCOCC4)c(F)cc32)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
IPEA (165 μL), EDC (90.9 mg) and HOBT (64.0 mg) were sequentially added to a solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (138 mg) and 6-fluoro-5-morpholin-4-ylindan-1-ylamine (56.0 mg) in DMF (3.0 mL), and the reaction solution was stirred at room temperature for 1 hour. After confirming that the raw materials disappeared, the solvent was concentrated under reduced pressure, and water and ethyl acetate were added to the residue and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent:heptane-ethyl acetate system, ethyl acetate-methanol system) to obtain 123 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=2)[C:23]([O:25]C)=[O:24])=[O:19])=[CH:4][CH:3]=1.[OH-].[Li+].C1COCC1.Cl>O>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=2)[C:23]([OH:25])=[O:24])=[O:19])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CO)c3)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CO)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 3-[({[6-fluoro-3′-(hydroxymethyl)-3-biphenylyl]methyl}amino)-carbonyl]benzoate (0.309 g, 0.786 mmol), lithium hydroxide (0.0282 g, 1.2 mmol), THF (6 mL), and water (2 mL) were combined and stirred under argon at room temperature overnight. Solvents were pumped off, the residue adjusted to pH 2 with 1N HCl, and extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford the title compound as a white solid. LC-MS m/z 379.8 (M+H)+, 1.69 min (ret time); mp 169-171° C.; analytical HPLC shows 93.2% purity, (ret time 7.059 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27](O)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.[N:37]1([CH2:42][CH2:43][CH2:44][NH2:45])[CH:41]=[CH:40][N:39]=[CH:38]1.C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([NH:45][CH2:44][CH2:43][CH2:42][N:37]3[CH:41]=[CH:40][N:39]=[CH:38]3)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Reactant: NCCCn1ccnc1
Agent: CCOP(=O)(C#N)OCC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)NCCCn4ccnc4)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-{2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and 3-(1H-imidazol-1-yl)propylamine using diethyl cyanophosphonate as a coupling reagent Mass: 616.15 (M+H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:21].[Na+]>CO>[CH2:1]([CH:8]1[CH2:13][CH2:12][CH:11]([NH2:21])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(Cc2ccccc2)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC1CCC(Cc2ccccc2)CC1
Reaction time: 0.17 h

Procedure:
A mixture of 2 g of 4-benzylcyclohexanone, the product of Example 1, Step 3, 16 g of ammonium acetate, 100 mL of methanol and 2.5 g of sodium cyanoborohydride was stirred for 5 days at room temperature. After cooling in an ice bath, the reaction was carefully quenched in an efficient fume hood by dropwise addition of 25 mL of 1N HCl. After stirring for 10 min, sodium hydroxide pellets were added to the cold solution until the pH (indicator paper) was about 10. The mixture was concentrated under reduced pressure, diluted with 100 mL of water, made basic by addition of more sodium hydroxide pellets and extracted into 4×100 mL portions of chloroform. After drying over magnesium sulfate, the extracts were concentrated under reduced pressure and then dried under vacuum overnight. Analysis by TLC (silica gel, elution with 90:10:1 chloroform:methanol:conc. ammonium hydroxide) indicated no 4-benzylcyclohexanone or 4-benzylcyclohexanol was present, only 2 new bands which correspond to a mixture of cis- and trans 4-benzyl-cyclohexylamine, which was an oil.
Reaction SMILES: Br[C:2]1[C:3](=[O:34])[N:4]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:33]=[CH:32][C:19]3[N:20]([CH2:30][CH3:31])[C:21](=[O:29])[C:22]([CH3:28])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]=3[CH:17]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[CH2:30]([N:20]1[C:21](=[O:29])[C:22]([CH3:28])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]2[CH:17]=[C:16]([O:15][CH2:14][CH2:13][CH2:12][N:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:11]=[C:2]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:3]3=[O:34])[CH:33]=[CH:32][C:19]1=2)[CH3:31]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCn3c(=O)c(Br)cc4ccccc43)ccc21
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCn3c(=O)c(-c4ccccc4)cc4ccccc43)ccc21
Temperature: 25 °C
Yield: 68.4 %

Procedure:
7-[3-(3-Bromo-2-oxo-2H-quinolin-1-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.5 g), phenylboronic acid (0.12 g), tetrakis(triphenyl phosphine)palladium (0) (0.11 g), and potassium carbonate (0.39 g) were added to dioxane (5 ml). The mixture was heated under reflux for 2 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature. Water was added thereto, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1→3:1). The purified product was condensed to dryness under reduced pressure, thereby obtaining the title compound (0.34 g) as a white amorphous solid.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].O.[F:7][C:8]([F:20])([F:19])[C:9]1[CH:10]=[C:11]([C:15]#[C:16][C:17]#[N:18])[CH:12]=[CH:13][CH:14]=1>CO>[F:7][C:8]([F:19])([F:20])[C:9]1[CH:10]=[C:11]([C:15]2[O:3][N:2]=[C:17]([NH2:18])[CH:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: N#CC#Cc1cccc(C(F)(F)F)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1cc(-c2cccc(C(F)(F)F)c2)on1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Hydroxylamine hydrochloride (1.6 grams), and sodium hydroxide (1.6 grams) were dissolved in 32 ml. of a 1:1 mixture of water and methanol at 0°-5° C. 3-(3-(Trifluoromethyl)phenyl)propiolonitrile (2.8 grams) in 10 ml. of methanol was added portionwise, and the reaction mixture was stirred overnight (about 18 hours) at 25° C. Solvent was evaporated; water was added to the residue and the product extracted with ether, washed with water, dried and evaporated, yield 1.4 grams. The identity of the desired product was confirmed by NMR.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:41]=[CH:40][C:27]([O:28][CH2:29][C:30]([NH:32][C@@H:33]([C:37]([OH:39])=O)[CH:34]([CH3:36])[CH3:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.Cl.[NH2:43][C@H:44]([C:49]([O:51]C(C)(C)C)=[O:50])[CH2:45][CH2:46][S:47][CH3:48].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[BH4-].[Na+].C([O-])(=O)C.[NH4+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[OH:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][C@@H:33]([C:37]([NH:43][C@H:44]([C:49]([OH:51])=[O:50])[CH2:45][CH2:46][S:47][CH3:48])=[O:39])[CH:34]([CH3:35])[CH3:36])=[O:31])=[CH:40][CH:41]=2)=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](NC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Reactant: CSCC[C@H](N)C(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: CN1CCOCC1
Product: CSCC[C@H](NC(=O)[C@H](NC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(C)C)C(=O)O
Reaction time: 0.08 h

Procedure:
N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-D-valine (13.3 mg, 0.023 mmol), tert-butyl L-methioninate hydrochloride (7.4 mg, 0.031 mmol) and N-methylmorpholine (10 μl, 0.091 mmol) were dissolved in 1 ml. After 5 minutes, TBTU (8.9 mg, 0.028 mmol) was added and the resulting suspension was stirred overnight. Additional tert-butyl L-methioninate hydrochloride (2.1 mg, 0087 mmol), N-methylmorpholine (5 μl, 45 μmol) and TBTU (2.1 mg, 6.54 μmol) were added and the mixture was stirred for 2 h. The formation of the ester was confirmed. MHz 768.1 (M−H) and 770.0 (M+H). The yellow suspension was purified on silica gel (1 g) and eluted with EtOAc:DCM (15:85). The pure fractions were concentrated and formic acid (1.5 ml) was added. The solution was stirred at 50° C. overnight. The solvent was removed under reduced pressure. Toluene was added and removed under reduced pressure. The residue was dissolved in methanol (1 ml) and sodium borohydride (9.9 mg, 0.26 mmol) was added. The resulting reaction mixture was stirred for 10 minutes. Ammonium acetate (18.9 mg) was added and the solvent was removed under reduced pressure. The residue was purified with preparative HPLC on a C8 column. A gradient from 20% to 40% MeCN in 0.1 M ammonium acetate buffer was used as eluent. After lyophilisation, the title compound was obtained as a white solid was obtained (4.6 mg, 28%). 1H-NMR (400 MHz, DMSO-d6): 0.75 (d, 3H), 0.79 (d, 3H), 1.79-1.97 (m, 3H), 1.99 (s, 3H), 2.36-2.44 (m, 2H), 2.86-2.92 (m, 2H), 2.24-4.35 (m, 3H), 4.58 (d, 2H), 4.67-4.76 (m, 1H), 5.03 (d, 0.5H), 5.5 (d, 0.5H), 5.63 (t, 1H), 6.95 (d, 2H), 7.05-7.16 (m, 4H), 7.18-7.24 (m, 2H), 7.30-7.38 (m, 2H), 7.82 (d, 1H), 7.37 (d, 1H). M/z: 714.0 (M−1) and 716.1 (M+H).
Reaction SMILES: C([N:4]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[C:9]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:8]=2[CH2:7][CH2:6][C:5]1=[O:20])(=O)C.C[O-].[Na+]>CO>[Cl:19][C:17]1[CH:16]=[CH:15][C:9]2[C:10](=[O:14])[CH2:11][CH2:12][CH2:13][NH:4][C:5](=[O:20])[CH2:6][CH2:7][C:8]=2[CH:18]=1
Reactant: CC(=O)N1CCCC(=O)c2ccc(Cl)cc2CCC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCc2cc(Cl)ccc2C(=O)CCCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.05 g (7 mmol) of 4-acetyl-11-chloro-1,2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione in 30 ml of methanol was treated with 0.85 g (15.4 mmol) of sodium methanolate, stirred at room temperature for 2 hours, the reaction mixture was concentrated in vacuo, treated with water and extracted at pH 14 with chloroform. After drying the chloroform phase with sodium sulphate and distillation of the solvent in vacuo there was obtained 11-chloro-1,2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione of melting point 142°-144°.
Reaction SMILES: [Al].[CH2:2](Br)[C:3]#[CH:4].[F:6][C:7]([F:27])([F:26])[C:8](=[O:25])[CH2:9][C:10]1([CH3:24])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:18]=2)[O:13][CH2:12][CH2:11]1>C1COCC1.C1(C)C=CC=CC=1>[F:27][C:7]([F:6])([F:26])[C:8]([CH2:9][C:10]1([CH3:24])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([S:20]([CH3:23])(=[O:21])=[O:22])[CH:18]=2)[O:13][CH2:12][CH2:11]1)([OH:25])[CH2:4][C:3]#[CH:2]
Reactant: CC1(CC(=O)C(F)(F)F)CCOc2ccc(S(C)(=O)=O)cc21
Reactant: C#CCBr
Agent: [Al]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C#CCC(O)(CC1(C)CCOc2ccc(S(C)(=O)=O)cc21)C(F)(F)F
Temperature: 40 °C
Reaction time: 0.33 h

Procedure:
A mixture of 70 mg (2.75 mmol) of aluminum foil and 0.8 mg (0.003 mmol) of mercuric chloride in 3 mL of anhydrous THF was vigorously stirred. After 20 minutes, 0.31 mL (2.75 mmol) of a 80% solution of propargyl bromide in toluene was added and the reaction was warmed at 40° C. for one hour. The dark grey solution was then added to a chilled (0° C.) solution of 300 mg (0.88 mmol) of 1,1,1-trifluoro-3-(6-methanesulfonyl-4-methylchroman-4-yl)propan-2-one in 10 mL of dry tetrahydrofuran. The reaction was warmed to room temperature overnight, concentrated in vacuo, quenched with ice and extracted with diethyl ether. The combined organic fractions were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 330 mg of crude 1,1,1-trifluoro-2-(6-methanesulfonyl-4-methylchroman-4-ylmethyl)pent-4-yn-2-ol as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7](/[C:8](/O)=[CH:9]\[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[N:11]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:18][S:19]([C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29])(=[O:21])=[O:20].[CH3:30][C:31]([CH3:36])([CH3:35])[C:32](=[S:34])[NH2:33]>>[Cl:1][C:2]1[C:7]([C:8]2[N:33]=[C:32]([C:31]([CH3:36])([CH3:35])[CH3:30])[S:34][C:9]=2[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[N:11]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:18][S:19]([C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29])(=[O:21])=[O:20]
Reactant: O=S(=O)(Nc1cccc(/C(O)=C\c2ccnc(Cl)n2)c1Cl)c1c(F)cccc1F
Reactant: CC(C)(C)C(N)=S
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2Cl)c(-c2ccnc(Cl)n2)s1
Yield: 43.7 %

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step A using N-{2-chloro-3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide (4.03 g, 8.80 mmol) and 2,2-dimethylpropanethioamide (1.03 g, 8.80 mmol), the title compound was obtained as a bright yellow solid (2.25 g; 43.7% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.87 (s, 1H), 8.54 (d, J=5.3 Hz, 1H), 7.63-7.73 (m, 1H), 7.42-7.57 (m, 3H), 7.22 (t, J=9.2 Hz, 2H), 6.53 (d, J=5.3 Hz, 1H), 1.42 (s, 9H).
Reaction SMILES: Cl.Cl.Cl.Cl.[NH2:5][CH2:6][CH2:7][CH2:8][S:9][CH2:10][CH2:11][O:12][C@@H:13]1[C@@H:21]([O:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][CH2:28][NH2:29])[C@@H:20]([O:30][CH2:31][CH2:32][S:33][CH2:34][CH2:35][CH2:36][NH2:37])[C@@H:19]([CH2:38][O:39][CH2:40][CH2:41][S:42][CH2:43][CH2:44][CH2:45][NH2:46])[O:18][C@@H:14]1[O:15][CH2:16][CH3:17].COC([C:51]1[C:52](N[C:55](=[O:57])[CH:56]=1)=[O:53])=O>C([O-])(O)=O.[Na+].O.C(#N)C.C(Cl)Cl>[C:19]1(=[O:18])[N:5]([CH2:6][CH2:7][CH2:8][S:9][CH2:10][CH2:11][O:12][C@@H:13]2[C@@H:21]([O:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][CH2:28][N:29]3[C:52](=[O:53])[CH:51]=[CH:56][C:55]3=[O:57])[C@@H:20]([O:30][CH2:31][CH2:32][S:33][CH2:34][CH2:35][CH2:36][N:37]3[C:52](=[O:53])[CH:51]=[CH:56][C:55]3=[O:57])[C@@H:19]([CH2:38][O:39][CH2:40][CH2:41][S:42][CH2:43][CH2:44][CH2:45][N:46]3[C:52](=[O:53])[CH:51]=[CH:56][C:55]3=[O:57])[O:18][C@@H:14]2[O:15][CH2:16][CH3:17])[C:13](=[O:12])[CH:21]=[CH:20]1
Reactant: CCO[C@H]1O[C@H](COCCSCCCN)[C@H](OCCSCCCN)[C@H](OCCSCCCN)[C@H]1OCCSCCCN
Reactant: COC(=O)C1=CC(=O)NC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CCO[C@H]1O[C@H](COCCSCCCN2C(=O)C=CC2=O)[C@H](OCCSCCCN2C(=O)C=CC2=O)[C@H](OCCSCCCN2C(=O)C=CC2=O)[C@H]1OCCSCCCN1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 351 %

Procedure:
A solution of amine 8 (23.9 mg, 29.0 μmol) dissolved in 1 M aqueous solution of NaHCO3 (1 mL) was treated with methoxycarbonylmaleimide (27.03 mg, 17.4 μmol) at 0° C. After 5 min, the mixture was diluted with water (1 mL) and acetonitrile (2 mL), and then stirred at room temperature for 1 h. The mixture was diluted with CH2Cl2 (50 mL) and washed with brine (3×10 mL). The organic phase was dried over Na2SO4, filtered and concentrated. The oily residue was purified by flash chromatography (CH2Cl2/MeOH 96:4) to give maleimide 9 (20.3 mg, 71%); Rf 0.45 (CH2Cl2/MeOH 96:4); 1H-NMR (CDCl3/TMS): δ6.72 (s, 8H, CH═CH), 4.94 (d, 1H, J=3.4 Hz, H-1), 3.95-3.82 (m, 2H, H-4, and OCHHCH2CH2N), 3.80˜3.45 (m, 22H, H-2, H-3, H-5, H-6, H-6′, OCH2CH2CH2S, SCH2CH2N, and OCH2CH3), 2.90-2.60 (m, 16H, OCH2CH2CH2SCH2CH2N), 1.96-1.82 (m, 8H, OCH2CH2CH2S), 1.23 (t, 3H, J=7.1 Hz, OCH2CH3); ES-MS: 1019.49 (M+Na)+, 951(M-OEt)+.