Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][NH:5][C:6](=[NH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([Li])CCC.Cl[P:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][NH:5][C:6](=[N:13][P:21]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CN(C)CCNC(=N)c1ccccc1
Agent: [Li]CCCC
Product: CN(C)CCNC(=NP(c1ccccc1)c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
Procedure as described for NP Amidine I using the following amounts and modifications: 0.956 g of N1-(2-(dimethylamino)ethyl)benzamidine (Amidine XII, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.93 mL chlorodiphenylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, the oily product was treated with 20 mL of pentane. After 1 hour stiffing at room temperature, a white solid formed. The solution was concentrated to approximately 10 mL and filtered while cold, yielding 0.891 g (47%) after drying.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]([C:19]2[C:20]3[N:21]([N:26]=[CH:27][N:28]=3)[C:22](Br)=[CH:23][N:24]=2)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:6]=1)[CH3:2].CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][NH:41][CH:42]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:19]2[C:20]3[N:21]([N:26]=[CH:27][N:28]=3)[C:22]([C:38]3[CH:39]=[N:40][NH:41][CH:42]=3)=[CH:23][N:24]=2)[CH:6]=1)[CH3:2]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCOC(=O)c1cccc(N(C(=O)OC(C)(C)C)c2ncc(Br)n3ncnc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc(N(C(=O)OC(C)(C)C)c2ncc(-c3cn[nH]c3)n3ncnc23)c1
Temperature: 115 °C
Yield: 108.6 %

Procedure:
Nitrogen is bubbled through a mixture of 3-[(5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-tert-butoxycarbonyl-amino]benzoic acid ethyl ester (0.58 g, 1.25 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.49 g, 2.50 mmol), K2CO3 (0.35 g, 2.50 mmol) and Pd(dppf)Cl2DCM (102 mg, 0.125 mmol) in dioxane (37.5 mL) and water (9.6 mL). A condenser is fitted to the flask, the system is evacuated and purged with N2 (g) and then heated at 115° C. for 25 min. The heating bath is removed and CO2 (s) is added to cool and buffer the system. The solvent is removed under reduced pressure and the residue is purified by silica chromatography, eluting with 10% to 50% ethyl acetate in DCM, to afford the title compound as an orange oil (0.61 g, >100%) which is used without further purification.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Br)C(Cl)(Cl)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[CH2:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][Br:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(Cc2ccccc2)c1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: BrCc1cccc(Cc2ccccc2)c1
Reaction time: 0.17 h
Yield: 100.5 %

Procedure:
A solution of 3-benzylbenzyl alcohol (1.98 g) in diethyl ether (60 cm3) was cooled in an ice bath, and 1,1,2,2-tetrachloro-1,2-dibromoethane (3.90 g) added. When the addition was complete, triphenyl phosphine (3.14 g) was added to the cooled mixture. The reaction mixture was stirred for 10 minutes, then filtered and the solvent evaporated under reduced pressure. The resultant yellow oil was purified by column chromatography on a silica gel support, eluting with petroleum ether (boiling range 60°-80° C.) containing 10% by volume diethyl ether, to give 3-benzylbenzyl bromide (2.62 g).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[C:13]2[O:12][C:11]([CH:14]=[O:15])=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1>CO.O>[CH3:3][O:4][C:5]1[C:13]2[O:12][C:11]([CH2:14][OH:15])=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc2cc(C=O)oc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cccc2cc(CO)oc12
Reaction time: 3 h
Yield: 96.6 %

Procedure:
Sodium borohydride (0.462 g) was added in one portion to a stirred solution of 7-methoxybenzofuran-2-carbaldehyde (2.15 g) in methanol (50 ml) at room temperature and the reaction was stirred for 3 hours. The reaction mixture was then diluted with water (100 ml) and extracted with dichloromethane (3×30 ml). The organic extracts were combined, washed with water (30 ml), dried over magnesium sulphate, filtered and the solvent removed in vacuo to afford the title compound (2.10 g) as a pale orange liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([Cu])#[N:25]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:12]=[CH:11][C:10]=1[N:16]1[CH2:17][C:18](=[O:23])[NH:19][S:20]1(=[O:22])=[O:21])[C:24]#[N:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 110 °C

Procedure:
To a solution of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (108.4 mg, 0.243 mmol) in DMF (2 mL) is added KHCO3 (0.488 mL, 0.5M aqueous solution), CuCN (19 mg, 0.212 mmol) and resin-bound PPh3Pd (10 mol %) in DMF (2 mL) and the mixture is heated in a microwave apparatus at 110° C. for 20 min. The solvent is removed under reduced pressure and the residue purified by reverse phase MPLC to give the title compound.
Reaction SMILES: [ClH:1].[CH2:2]1[CH2:6][O:5][C:4]2[CH:7]=[CH:8][C:9]3[CH2:10][CH2:11]/[C:12](=[CH:14]\[CH2:15][NH2:16])/[C:13]=3[C:3]1=2.[OH-].[Na+]>C1(C)C=CC=CC=1>[ClH:1].[CH2:2]1[CH2:6][O:5][C:4]2[CH:7]=[CH:8][C:9]3[CH2:10][CH2:11][C@@H:12]([CH2:14][CH2:15][NH2:16])[C:13]=3[C:3]1=2
Reactant: NC/C=C1\CCc2ccc3c(c21)CCO3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: NCC[C@@H]1CCc2ccc3c(c21)CCO3
Yield: 73 %

Procedure:
To an aqueous solution of (E)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)ethylamine hydrochloride (1979 kg, Net 122 kg, 513 mol) were added toluene (532 L) and 5% aqueous solution of sodium hydroxide (456 L), and stirred. The layers were separated, and to the organic layer were added methanol (155 kg) and [RuCl(bebzene)(R)-BINAP]Cl (894 g) under nitrogen atmosphere, followed by stirring at 80° C. for 15 hrs under hydrogen atmosphere (4.9 MPa). The reaction solution was cooled, and water (330 L) and concentrated hydrochloric acid (52.3 kg) were added at below 30° C., followed by stirring for 30 minutes, then the layers were separated. The aqueous layer was washed with toluene (195 L), and pH was adjusted to about 6.0 by adding 5% aqueous solution of NaOH to the aqueous layer (containing 5.0% of compound III′). 5% Pd—C (50% wet, 9.7 kg) was added thereto, and stirred at 60° C. for 6 hrs under hydrogen atmosphere (4.9 MPa). The reaction mixture was filtered, and the filtrate was adjusted to around pH 6.0 with 5% aqueous solution of NaOH or dilute hydrochloric acid, followed by concentration under reduced pressure. The residue was recrystallized from mixed solution of n-butanol and water to give title compound (88.6 kg, yield 73.0%, compound (III′) is not detected, compound (IV′) is not detected).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:35][CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([NH:22][C:23]([C:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:28]=[CH:27][N:26]=4)=[O:24])[C:20](=[O:21])[N:13]3[CH:12]([C:36]([NH:38][CH:39]([CH2:54][C:55]([O:57]C(C)(C)C)=[O:56])[C:40](=[O:53])[CH2:41][O:42][C:43](=[O:52])[C:44]3[C:49]([CH3:50])=[CH:48][CH:47]=[CH:46][C:45]=3[CH3:51])=[O:37])[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([S:7]([N:10]2[CH2:35][CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([NH:22][C:23]([C:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:28]=[CH:27][N:26]=4)=[O:24])[C:20](=[O:21])[N:13]3[CH:12]([C:36]([NH:38][CH:39]([CH2:54][C:55]([OH:57])=[O:56])[C:40](=[O:53])[CH2:41][O:42][C:43](=[O:52])[C:44]3[C:45]([CH3:51])=[CH:46][CH:47]=[CH:48][C:49]=3[CH3:50])=[O:37])[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cccc(C)c1C(=O)OCC(=O)C(CC(=O)OC(C)(C)C)NC(=O)C1CN(S(=O)(=O)c2ccccc2)CC2CCCCC(NC(=O)c3nccc4ccccc34)C(=O)N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C)c1C(=O)OCC(=O)C(CC(=O)O)NC(=O)C1CN(S(=O)(=O)c2ccccc2)CC2CCCCC(NC(=O)c3nccc4ccccc34)C(=O)N21
Reaction time: 2 h

Procedure:
The crude 2,6-dimethyl-benzoic acid 3-({2-benzenesulfonyl-6-[(isoquinoline-1-carbonyl)-amino]-5-oxo-decahydro-2,4a-diaza-benzocyclooctene-4-carbonyl}-amino)-4-tert-butoxycarbonyl-2-oxo-butyl ester, 112, obtained above is treated with solution of trifluoroacetic acid (10 ml) and dichloromethane (10 ml). The mixture is stirred for 2 hours and solvent is removed in vacuo. The residue is purified by flash chromatography on silica gel (CH2Cl2/MeOH) to afford 120 mg of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br>CN(C)C=O.O>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: Fc1cccc(CBr)c1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCc2cccc(F)c2)cc1
Yield: 87.1 %

Procedure:
A mixture of 6.0 g of 4-hydroxy-benzaldehyde and 13.58 g of potassium carbonate in 60 ml of N,N-dimethylformamide was treated dropwise at room temperature with a solution of 11.14 g of 3-fluoro-benzylbromide in 30 ml of N,N-dimethylformamide. After 3 h the reaction mixture was diluted with water and extracted with ether. The organic layer was washed with water, dried over magnesium sulphate and evaporated to yield an oil (9.85 g) which crystallised on standing; MS: m/e=230 (M)+. The crude product was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1
Reactant: Nc1ccccc1B(O)O
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Product: CC(C)CNC(=O)C(C)(C)c1ccc(-c2ccccc2N)cc1
Yield: 65 %

Procedure:
Prepared in a similar manner to example 8 from 2-(4-Bromophenyl)-N-isobutyl-2-methylpropanamide (Example 1a) and 2-aminophenylboronic acid. Yield: 65%. 1H NMR (400 MHz, CDCl3): δ 0.8 (d, 6H), 1.65 (s, 6H), 1.67-1.70 (m,1H), 3 (t, 2H), 6.65-6.75 (m, 1H), 6.9 (m, 1H), 7.0 (m, 1H), 7.2 (m, 1H), 7.4 (d, 2H), 7.55 (d, 2H). MS (M+H, 311).
Reaction SMILES: [C:1]([O:5][C:6](=[O:53])[C:7]([O:10]/[N:11]=[C:12](/[C:40]1[N:41]=[C:42]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[S:43][CH:44]=1)\[C:13]([NH:15][C@@H:16]1[C:23](=[O:24])[N:22]2[C@@H:17]1[S@:18](=[O:39])[CH2:19][C:20]([CH2:37]Cl)=[C:21]2[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:26])=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[I-:54].[Na+]>CC(C)=O>[C:1]([O:5][C:6](=[O:53])[C:7]([O:10]/[N:11]=[C:12](/[C:40]1[N:41]=[C:42]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[S:43][CH:44]=1)\[C:13]([NH:15][C@@H:16]1[C:23](=[O:24])[N:22]2[C@@H:17]1[S@:18](=[O:39])[CH2:19][C:20]([CH2:37][I:54])=[C:21]2[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:26])=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: COc1ccc(COC(=O)C2=C(CCl)C[S@@](=O)[C@@H]3[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N23)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(CI)C[S@@](=O)[C@@H]3[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To the solution of (5R,6R,7R)-4-methoxybenzyl 7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 5-oxide (5 g, 6.28 mmol) in Acetone (50 mL) was added sodium iodide (1.176 g, 7.85 mmol) and the mixture was stirred at rt for 2 h. Solvent was removed under vacuum, the residue was chromatographed to give (5R,6R,7R)-4-methoxybenzyl 7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-3-(iodomethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 5-oxide (4.5 g, 5.07 mmol, 81% yield). LCMS: (M+H)+: 887.6
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][N:15](C(OC=C)=O)[CH2:14][C:13]=3[NH:12][C:11]3[CH2:25][N:26](C(OC=C)=O)[CH2:27][C:28](=[O:29])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].[ClH:35].CCOCC>C(O)C>[ClH:35].[ClH:35].[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][NH:15][CH2:14][C:13]=3[NH:12][C:11]3[CH2:25][NH:26][CH2:27][C:28](=[O:29])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C=COC(=O)N1CC(=O)C2=C(C1)NC1=C(C(=O)CN(C(=O)OC=C)C1)C2c1ccc(F)c(Br)c1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: O=C1CNCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CNCC1=O)N2
Temperature: 25 °C

Procedure:
A solution of the product from Example 4B (0.22 g, 0.41 mmol) in ethyl alcohol (5 mL) was treated with concentrated hydrochloric acid (0.10 mL) refluxed for 3 hours, allowed to cool to ambient temperature and treated with ether. The resulting solid precipitate was collected and dried to provide the title compound (0.12 g).
Reaction SMILES: Cl.[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)=[O:9])([CH3:5])([CH3:4])[CH3:3].[CH3:18][C:19]([CH3:26])([CH2:23][CH2:24][CH3:25])[C:20](Cl)=[O:21].FC(F)(F)C(O)=O.[OH-].[NH4+]>>[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:20](=[O:21])[C:19]([CH3:26])([CH3:18])[CH2:23][CH2:24][CH3:25])=[C:12]([OH:17])[CH:11]=1)=[O:9])([CH3:5])([CH3:3])[CH3:4]
Reactant: CCCC(C)(C)C(=O)Cl
Reactant: CC(C)(C)NCC(=O)c1ccc(O)c(O)c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C)(C)C(=O)Oc1ccc(C(=O)CNC(C)(C)C)cc1O

Procedure:
By insteracting 13 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride with 8.0 g. of 2,2-dimethylpentanoyl chloride in 30 ml. of trifluoroacetic acid on a steam bath for 1 hour and treating the resulting product with ammonium hydroxide there was obtained 3-hydroxy-4-(2,2-dimethylpentanoyloxy)phenyl tert-butylaminomethyl ketone. This product was converted to the acetate salt (10.5 g.) and this salt was converted to the corresponding methanesulfonate salt [8.3 g., m.p. 250° C. (dec.)(uncorr.)], by treatment with a slight excess of methanesulfonic acid. When this methanesulfonate (8.0 g.) was catalytically hydrogenated in the presence of palladium-on-charcoal catalyst, there was obtained 5.8 g. of 3-hydroxy-4-(2,2-dimethylpentanoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate as a white crystalline solid which melted at 128°-130° C. (uncorr.).
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([O:6][C:7]2[CH:12]=[C:11]([O:13][CH2:14][CH2:15][NH2:16])[CH:10]=[CH:9][N:8]=2)=[C:4]([I:20])[CH:3]=1.CCN(CC)CC.Cl[CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([O:6][C:7]2[CH:12]=[C:11]([O:13][CH2:14][CH2:15][NH:16][S:31]([CH:30]=[CH2:29])(=[O:33])=[O:32])[CH:10]=[CH:9][N:8]=2)=[C:4]([I:20])[CH:3]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: NCCOc1ccnc(Oc2cc(Cl)c(Cl)cc2I)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)NCCOc1ccnc(Oc2cc(Cl)c(Cl)cc2I)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 155.3 %

Procedure:
To a mixture of 2-(2-(4,5-dichloro-2-iodophenoxy)pyridin-4-yloxy)ethanamine (30 mg, 0.07 mmol), Et3N (35.7 mg, 0.35 mmol) in DCM (5 mL), 2-chloroethanesulfonyl chloride (11.5 mg, 0.07 mmol) was added and the resulting mixture was stirred at room temperature for 1 h. Then solvent was removed under reduced pressure. The residue was taken in THF (2 mL) and H2O (2 mL), then K2CO3 (100 mg) was added and the resulting mixture was stirred at room temperature for 1 h. The mixture was partitioned between DCM and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/ethyl acetate=5:1) to afford the desired product (56 mg, 56% yield). 1H NMR (400 MHz, CDCl3) δ: 7.98 (d, J=5.6 Hz, 1H), 7.92 (s, 1H), 7.25 (s, 1H), 6.61-6.57 (m, 2H), 6.47 (d, J=2.0 Hz, 1H), 6.32 (d, J=16.4 Hz, 1H), 6.00 (d, J=10.0 Hz, 1H), 4.77 (t, J=5.2 Hz, 1H), 4.18 (t, J=5.2 Hz, 2H), 3.51-3.47 (m, 2H). ESI-MS m/z: 515.0[M+H]+.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH:6]([C:10](=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18])[C:7]([NH2:9])=[O:8]>C(O)C>[C:2]([S:3][CH:6]([C:10](=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:18])([F:19])[F:20])[C:7]([NH2:9])=[O:8])(=[NH:4])[NH2:1]
Reactant: NC(=O)C(Br)C(=O)c1ccccc1C(F)(F)F
Reactant: NC(N)=S
Solvent: CCO
Product: N=C(N)SC(C(N)=O)C(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.4 %

Procedure:
To a solution of 2.80 g (0.37 mole) of thiourea in 1200 mL of ethanol was added 11.40 g (0.37 mole) of 2-bromo-3-oxo-3-(2-trifluoromethyl-phenyl)-propionamide. After stirring at room temperature overnight, the mixture was concentrated under reduced pressure. Purification of the residue by silica gel chromatography, eluting with dichloromethane-methanol (gradient 100:0-80:20) gave 11.80 g of 2-carbamimidoylsulfanyl-3-oxo-3-(2-trifluoromethyl-phenyl)-propionamide as a yellow solid.
Reaction SMILES: [CH3:1][O:2][Si:3]([CH2:6][CH2:7][CH2:8]Cl)([CH3:5])[CH3:4].[CH3:10][NH:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15]>CO>[CH3:1][O:2][Si:3]([CH2:6][CH2:7][CH2:8][N:11]([CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[CH3:10])([CH3:5])[CH3:4]
Reactant: CNCCN(C)C
Reactant: CO[Si](C)(C)CCCCl
Solvent: CO
Product: CO[Si](C)(C)CCCN(C)CCN(C)C

Procedure:
Under Ar, a solution of CH3OSi(CH3)2(CH2)3Cl (10.0 g, 59.3 mmol), CH3NHCH2CH2N(CH3)2 (10.0 g, 98.2 mmol) and methanol (5.0 mL) is refluxed for 22 h and then concentrated with a rotary evaporator (about 10 Torr, about 45 ° C.). The concentrate is diluted with ether (50 mL) and filtered. The solid is washed with ether (50 mL), the washings and the filtrate are combined, and the resulting solution is concentrated with a rotary evaporator (about 60 Torr, about 30 ° C.). The concentrate is filtered and the solid is washed with ether (10 mL). The washings and the filtrate are combined, and the resulting solution is concentrated with a rotary evaporator (about 60 Torr, about 30° C.). The resultant ligand, CH3OSi(CH3)2(CH2)3N(CH3)(CH2)2N(CH3)2, having the form of a light yellow liquid, is weighed (8.46 g, 36.4 mmol, 61%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:8]=2)[C@@H:4]([C:21]([OH:23])=O)[O:3]1.S(Cl)([Cl:26])=O>ClCCl>[O:1]=[C:2]1[NH:6][C@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:8]=2)[C@@H:4]([C:21]([Cl:26])=[O:23])[O:3]1
Reactant: O=S(Cl)Cl
Reactant: O=C1N[C@H](c2cccc(C#Cc3ccccc3)c2)[C@@H](C(=O)O)O1
Solvent: ClCCl
Product: O=C1N[C@H](c2cccc(C#Cc3ccccc3)c2)[C@@H](C(=O)Cl)O1
Yield: 94.9 %

Procedure:
To a solution of (4R,5S)-2-oxo-4-(3-(phenylethynyl)phenyl)oxazolidine-5-carboxylic acid (120 mg, 0.390 mmol) in dichloromethane (5 mL) was added thionyl chloride (0.285 mL, 3.90 mmol) and the solution was heated to reflux for 3 h. The reaction mixture was concentrated in vacuo providing (4R,5S)-2-oxo-4-(3-(phenylethynyl)phenyl)oxazolidine-5-carbonyl chloride (127 mg, 0.370 mmol, 95% yield) as a light brown wax.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:42][C@H:43]1[C:48]([CH3:50])([CH3:49])[S:47][C@H:46]2[CH2:51][CH2:52][CH2:53][N:45]2[C:44]1=[O:54]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([NH:42][C@H:43]1[C:48]([CH3:49])([CH3:50])[S:47][C@H:46]2[CH2:51][CH2:52][CH2:53][N:45]2[C:44]1=[O:54])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC1(C)S[C@H]2CCCN2C(=O)[C@H]1N
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Agent: Cl
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@@H]3C(=O)N4CCC[C@@H]4SC3(C)C)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((3R,8aS)-2,2-dimethyl-4-oxohexahydro-2H-pyrrolo[2,1-b][1,3]thiazin-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (15 mg, 0.026 mmol) and Intermediate 29 (8.0 mg, 0.040 mmol) to give a white solid (15 mg, 72% yield). Anal. Calcd. for C40H52N4O6S2 m/z 748.4. found: 749.3 (M+H)+; 1H NMR (500 MHz, CD3OD) δ ppm 8.14 (d, J=7.70 Hz, 1H), 7.95 (d, J=9.35 Hz, 1H), 7.28-7.08 (m, 10H), 5.56 (dd, J=6.05, 2.75 Hz, 1H), 5.21-5.12 (m, 1H), 5.07-4.99 (m, 2H), 4.79 (d, J=9.35 Hz, 1H), 3.69-3.57 (m, 4H), 3.43-3.35 (m, 1H), 3.12-3.04 (m, 1H), 2.94 (br. s., 1H), 2.88-2.77 (m, 3H), 2.75-2.66 (m, 3H), 2.43 (dd, J=13.20, 6.60 Hz, 1H), 2.36 (d, J=13.75 Hz, 1H), 2.16-1.88 (m, 4H), 1.88-1.68 (m, 5H), 1.68-1.57 (m, 5H), 0.87 (s, 3H), 0.84 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([Cl:14])=[CH:6][CH:5]=1)(=[O:3])C.Cl[O-:16].[Na+]>Cl>[Cl:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([C:1]([OH:3])=[O:16])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Cl)c2ccccc12
Reactant: [O-]Cl
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1ccc(Cl)c2ccccc12
Temperature: 25 °C
Yield: 23 %

Procedure:
The compound (8.33 g) obtained in (1) above and a 5% sodium hypochlorite solution (380 ml) were stirred with refluxing for 44 hours. The reaction mixture was cooled to room temperature and concentrated hydrochloric acid (10 ml) was dropwise added. The resulting solid was collected by filtration. The obtained solid was subjected to silica gel column chromatography (hexane-ethyl acetate) to give 1.96 g of a red-brown solid (yield 23%).