Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1.[CH2:24]([Li])[CH2:25][CH2:26][CH3:27]>[Cl-].[Cl-].[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:24]([C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Reactant: [Li]CCCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Product: CCCCc1cc(C)c(-c2c(C)nc3c(C(CC)CC)cc(C)nn23)s1
Yield: 67.7 %

Procedure:
Using a procedure similar to Example 25 from 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.40 g, 0.1.02 mmol), 1.34 M n-Bu-Li (1.60 mL, 2.14 mmol), 0.5 M ZnCl2 (4.3 mL, 2.14 mmol) and PdCl2(dppf) (0.037 g, 0.051 mmol) furnishes the title compound (0.25 g, 0.69 mmol, 68%). 1H NMR (CDCl3), δ 0.88 (t, J=7.5 Hz, 6H), 0.97 (t, J=7.5 Hz, 3H), 1.40-1.51 (m, 2H), 1.67-1.92 (m, 6H), 2.07 (s, 3H), 2.46 (s, 3H), 2.51 (s, 3H), 2.83 (t, J=8.0 Hz, 2H), 3.30-3.38 (m, 1H), 6.64 (s, 1H), 6.70 (s, 1H) LC/MS (m/z): calcd. for C22H31N3S (M+H)+: 370.3; found: 370.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][CH:10]=[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=3)[C:14](=[O:22])[NH:13][C:12]2=[O:23])[CH:5]=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.IC1C=C2C(=CC=1)C(=O)NC(=O)C2=COC.NCC1C=C(O)C(C2C=CC=C([CH2:60][N:61]([CH3:63])[CH3:62])C=2)=CC=1>>[CH3:60][N:61]([CH2:63][C:26]1[CH:25]=[C:24]([C:3]2[CH:4]=[CH:5][C:6]([CH2:8][NH:9][CH:10]=[C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=4)[C:14](=[O:22])[NH:13][C:12]3=[O:23])=[CH:7][C:2]=2[OH:1])[CH:29]=[CH:28][CH:27]=1)[CH3:62]
Reactant: CN(C)Cc1cccc(-c2ccc(CN)cc2O)c1
Reactant: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Agent: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Product: CN(C)Cc1cccc(-c2ccc(CNC=C3C(=O)NC(=O)c4ccc(I)cc43)cc2O)c1
Yield: 24 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound (purified through chromatography) is prepared from 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (50 mg, 0.15 mmol) and 4-aminomethyl-3′-dimethylaminomethyl-biphenyl-2-ol (50 mg, 0.18 mmol) in 24% yield: MS (ESI): 554.0 (M+1)+1.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[C:11]([F:13])([F:12])[C:10]([F:15])([F:14])[C:9]([F:17])([F:16])[C:8]=2[O:18][C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[CH3:28][C:29]([OH:33])([C:31]#[CH:32])[CH3:30]>[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[OH:33][C:29]([CH3:30])([C:31]#[C:32][C:22]1[CH:21]=[CH:20][C:19]([O:18][C:8]2[C:9]([F:17])([F:16])[C:10]([F:14])([F:15])[C:11]([F:12])([F:13])[C:7]=2[O:6][C:5]2[CH:26]=[CH:27][C:2]([C:32]#[C:31][C:29]([CH3:30])([OH:33])[CH3:28])=[CH:3][CH:4]=2)=[CH:24][CH:23]=1)[CH3:28]
Reactant: FC1(F)C(Oc2ccc(Br)cc2)=C(Oc2ccc(Br)cc2)C(F)(F)C1(F)F
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1ccc(OC2=C(Oc3ccc(C#CC(C)(C)O)cc3)C(F)(F)C(F)(F)C2(F)F)cc1
Yield: 48.6 %

Procedure:
39 g (0.075 mol) of 1,2-bis-(4-bromophenoxy)-3,3,4,4,5,5-hexafluorocyclopent-1-ene (obtained according to Example 1), 32 g (0.38 mol) of 2-methyl-3-butin-2-ol, 211 mg of PdCl2 (PPh3)2, 230 mg of CuI and 630 mg of triphenylphosphine were added under nitrogen to 100 ml of triethylamine. After heating to reflux for 24 hours, the reaction mixture was filtered and the filtrate was concentrated in vacuo. Recrystallization of the residue resulting here from n-hexane/ethyl acetate gave 19.1 g of product, which corresponds to 48% of theory, having a melting point of 108° to 113° C. The 1H NMR spectrum showed characteristic bands at 1.59 ppm, 6.63 ppm and 7.2 ppm, measured against tetramethylsilane as internal standard.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:14]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)#[C:15][CH2:16][CH2:17][CH2:18][CH3:19].C(N(CC)CC)C>CN(C=O)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:20]1([CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[C:19][C:2]2[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[N:7]3)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1ccc(Br)c2cccnc12
Reactant: CCCCC#Cc1ccccc1
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=Cc1ccc(C#CCCCCc2ccccc2)c2cccnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
A solution of 5-bromo-8-quinolinecarboxaldehyde (987 mL, 418 mmol), 5-hexyn-1-yl-benzene [CAS 100848-88-2] (1.05 mL, 5.85 mmol), triethylamine (2 mL) and 1,3-bis(diphenylphosphino)propane (dppp, 59 mg) in DMF (10 mL) was heated to 90° C. with stirring for 2 h. After cooling to RT, the reaction mixture was extracted with ether and washed with water and brine, dried over magnesium sulfate and concentrated. Purification by MPLC (35% ethyl acetate in hexanes) gave rise to 1.04 g of Intermediate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:20])=[N:5][CH:6]=[C:7]([CH2:9][C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[NH:12][CH:11]=2)[CH:8]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:30]=O)[C:25]([O:28][CH3:29])=[N:26][CH:27]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[F:21][C:22]1[CH:23]=[C:24]([CH2:30][NH:20][C:4]2[C:3]([O:2][CH3:1])=[CH:8][C:7]([CH2:9][C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=4)[NH:12][CH:11]=3)=[CH:6][N:5]=2)[C:25]([O:28][CH3:29])=[N:26][CH:27]=1
Reactant: COc1cc(Cc2c[nH]c3ncc(C)cc23)cnc1N
Reactant: COc1ncc(F)cc1C=O
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cc2c[nH]c3ncc(C)cc23)cnc1NCc1cc(F)cnc1OC
Temperature: 80 °C

Procedure:
To 3-methoxy-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (128, 1 equivalent) in 2 mL of acetonitrile, 5-fluoro-2-methoxy-pyridine-3-carbaldehyde (37, 1 equivalent), triethylsilane (5 equivalents) and trifluoroacetic acid (6.9 equivalents) are added. The reaction is heated at 80° C. for 18 hours, then concentrated under vacuum and mixed with aqueous potassium carbonate and extracted with ethyl acetate. The organic layer is washed with water, brine, then dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].Cl[C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1>O>[OH:5][CH2:4][CH2:3][O:6][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cccnc1OCCO

Procedure:
Sodium hydride in oil (60%, 131 mg) is added to ethylene glycol (6.0 ml) and 2-chloro-3-nitropyridine (430 mg) is added. The mixture is stirred for 26 hours during which time additional sodium hydride in oil (60%, 100 mg) is added. Water is added, the pH is adjusted to 9 and the solution is extracted with methylene chloride (3×50 ml). The combined organic layers are dried with saline and sodium sulfate and concentrated. Chromatography on silica gel with a methanol/chloroform gradient affords the title compound, Rf =0.32 (TLC on silica gel, ethyl acetate/hexane [50/50]).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=2)[C:15]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[C:20]([O:27][CH3:28])[CH:19]=2)=[O:16])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:33]1C=C(S(Cl)(=O)=O)C=C[CH:38]=1>>[CH2:33]([O:23][C:22](=[O:24])[C:21]1[CH:25]=[CH:26][C:18]([NH:17][C:15](=[O:16])[C:14]2[CH:29]=[CH:30][CH:31]=[C:12]([NH:11][S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:9])=[O:10])[CH:13]=2)=[CH:19][C:20]=1[O:27][CH3:28])[CH3:38]
Reactant: COc1cc(NC(=O)c2cccc(NS(=O)(=O)c3cccc(Cl)c3)c2)ccc1C(=O)O
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3cccc(Cl)c3)c2)cc1OC

Procedure:
4-[3-(3-Chloro-benzenesulfonylamino)-benzoylamino]-2-methoxy-benzoic acid, MS (ISP): m/e=459.3 (M+H+), was prepared in analogy to example 17, steps A to D. Step C was performed using 3-chloro-benzenesulfonyl chloride and yielded 4-[3-(3-chloro-benzenesulfonylamino)-benzoylamino]-2-methoxy-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:24]2[O:23][CH2:22][CH2:21][C:20]([C:25]([NH:27][C:28]([NH2:30])=[NH:29])=[O:26])=[CH:19][C:18]=2[CH:17]=[CH:16][CH:15]=1)=[O:13])=O)(C)(C)C.[ClH:31].C(OC(C)C)(C)C>O1CCOCC1>[ClH:31].[ClH:31].[NH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:24]2[O:23][CH2:22][CH2:21][C:20]([C:25]([NH:27][C:28]([NH2:30])=[NH:29])=[O:26])=[CH:19][C:18]=2[CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1cccc2c1OCCC(C(=O)NC(=N)N)=C2
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Product: N=C(N)NC(=O)C1=Cc2cccc(C(=O)NCCN)c2OCC1
Reaction time: 18 h

Procedure:
To a solution of {2,3-dihydro-9-[2-(tert-butoxycarbonylamino)ethylaminocarbonyl]-1-benzoxepin-4-carbonyl}guanidine (0.8 g) in 1,4-dioxane (8 ml) was added 4N hydrogen chloride in 1,4-dioxane (8 ml) at ambient temperature and the mixture was stirred at the same temperature for 18 hours. Diisopropyl ether (10 ml) was added to the mixture and the precipitate was collected by filtration. The precipitate was recrystallized from a mixture of methanol and diisopropyl ether to give [2,3-dihydro-9-(2-aminoethylaminocarbonyl)-1-benzoxepin-4-carbonyl]guanidine dihydrochloride (0.57 g).
Reaction SMILES: [CH2:1]([Li])CCC.[I-].C[S+](C)C.[C:11]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)(=[O:14])[CH2:12][CH3:13].O>CCCCCC.C1COCC1>[CH2:12]([C:11]1([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH2:1][O:14]1)[CH3:13]
Reactant: CCC(=O)c1ccncc1
Reactant: [Li]CCCC
Agent: C[S+](C)C
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCC1(c2ccncc2)CO1
Temperature: 25 °C

Procedure:
n-Butyl lithium (7.3 cm3 of a 1.6M solution in hexane) was added at 0° to a stirred suspension of trimethyl sulphonium iodide (2.45 g) in THF (40 cm3) under nitrogen. After 5 minutes 4-propionylpyridine (1.35 g) in THF (5 cm3) was added, the mixture was allowed to warm to room temperature over 1.5 hours, water (20 cm3) was added and volatile material was removed in vacuo. The residue was partitioned between ether and water, the ethereal layer was dried (MgSO4) and evaporated and the residue was chromatographed on silica ("Merck" 60.9385) eluting with methanol:chloroform, 1:49, to give 2-ethyl-2-(4-pyridyl)oxirane as an oil (0.6 g). This material was taken without further purification into DMF (5 cm3) and treated with a solution of 2-sodioisothiazolidine-1,1-dioxide [made from isothiazolidine-1,1-dioxide (0.6 g) and sodium hydride (0.30 g of a 50% dispersion in oil)] in DMF (2 cm3) at 100° for 4 hours. Volatile material was removed in vacuo, the residue was partitioned between ethyl acetate (20 cm3) and water (10 cm3) and the aqueous phase was further extracted with ethyl acetate (2×20 cm3). The combined extracts were dried (MgSO4) and evaporated, and the residue was chromatographed on silica ("Merck" 60.9385) eluting with methanol:chloroform, 1:49, to afford 2-[2-(4-pyridyl)-2-hydroxy]but-1-ylisothiazolidine-1,1-dioxide as an oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:33])[C@H](OCC4C=CC=CC=4)C)[C@@H:18]([OH:34])[C@H:17]3[OH:35])=[C:9]([NH:36][CH2:37][CH:38]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:8]=2)[CH2:3]1.[C:51]([O:55]C(=O)N)(C)(C)[CH3:52]>>[NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:33])[CH2:52][CH2:51][OH:55])[C@@H:18]([OH:34])[C@H:17]3[OH:35])=[C:9]([NH:36][CH2:37][CH:38]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:8]=2)[CH2:3]1
Reactant: CC(C)(C)OC(N)=O
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Product: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CCO)[C@@H](O)[C@H]4O)c3n2)C1

Procedure:
The title compound is prepared analogously to (R)-N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-propionamide (Example 181, step 4), by substituting {(R)-1-[9-[(1R,2S,3R,4S)-4-(3-tert-butoxy-propionylamino)-2,3-dihydroxy-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Intermediate ZG3) for {(R)-1-[9-[(1R,2S,3R,4S)-4-(R)-2-Benzyloxy-propionylamino)-2,3-dihydroxy-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Example 181, step 3).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]2[C:10]=1[CH2:9][N:8]([CH3:11])[C:7]2=[O:12]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:24]([O:23][C:21]([N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:5]1[C:6]2[C:7](=[O:12])[N:8]([CH3:11])[CH2:9][C:10]=2[C:2]([C:14]([O:16][CH3:17])=[O:15])=[CH:3][CH:4]=1)=[O:22])([CH3:26])([CH3:27])[CH3:25]
Reactant: CN1Cc2c(Br)ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2c1CN(C)C2=O
Temperature: 65 °C

Procedure:
A mixture of di-tert-butyl (7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)imidodicarbonate (Compound 118C, 500 mg, 1.13 mmol), Pd(PPh3)4 (131 mg, 0.113 mmol), in MeOH (5 mL) and THF (10 mL) was evacuated and refilled with carbon monoxide (3×), then heated at 65° C. overnight. The solvent was removed in vacuo and the crude product was taken up in EtOAc and washed successively with water then brine. The desired product was purified by column chromatography. MS (ES+): m/z 321.28 (100) [(M-Boc)H+]; HPLC: tR=1.32 min (UPLC, Analytical).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]1([N:24]=[C:25]=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([NH:24][C:25](=[O:26])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]3)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Reactant: O=C=NC1CCCCC1
Product: O=C(NC1CCCCC1)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (35.0 mg, 0.155 mmol) using the same procedure employed for Example 2 (2), but with cyclohexylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (14.8 mg, 27%) having the following characteristics.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][C:6]1[NH:11][C:10]2[S:12][CH:13]=[C:14]([CH2:15][O:16][CH2:17][O:18][CH3:19])[C:9]=2[S:8](=[O:21])(=[O:20])[N:7]=1)C.O.[OH-].[Li+]>O1CCCC1.O>[CH3:19][O:18][CH2:17][O:16][CH2:15][C:14]1[C:9]2[S:8](=[O:21])(=[O:20])[N:7]=[C:6]([CH2:5][C:4]([OH:22])=[O:3])[NH:11][C:10]=2[S:12][CH:13]=1
Reactant: CCOC(=O)CC1=NS(=O)(=O)c2c(COCOC)csc2N1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCOCc1csc2c1S(=O)(=O)N=C(CC(=O)O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
To a solution of (7-methoxymethoxymethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-acetic acid ethyl ester (0.54 g, 1.55 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was added lithium hydroxide monohydrate (0.33 g, 7.75 mmol). The reaction was stirred at 25° C. for 1 h before it was cooled to 0° C. The reaction was quenched via the addition of 6.0 M aqueous hydrochloric acid solution until a pH of 1-2 was reached. The resulting mixture was extracted with ethyl acetate (3×10 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude product, (7-methoxymethoxymethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-acetic acid (0.39 g, 1.21 mmol, 78%), which was used in the next step without further purification.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]1([C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10])[OH:8].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.Cl>CC(N(C)C)=O>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:8][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[OH:10])=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: Oc1ccccc1O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(Oc2ccccc2O)cc1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 53 %

Procedure:
Anhydrous DMA (50 ml) was added to t-BuOK (5.46 g, 48.7 mmol) and catechol (5.00 g, 45.4 mmol) at 0° C. under argon, the mixture was heated to 120° C. over 10 min. A solution of 1-fluoro-4-nitro-benzene (6.40 g, 45.4 mmol) in anhydrous DMA (10 ml) was added dropwise over 20 min. The reaction mixture was then stirred at 130° C. for 1.5 h, cooled, and poured into 1N HCl (200 ml), extracted with EtOAc (2×50 ml). The combined extract was washed H2O (3×150 ml), brine (150 ml), dried with Na2SO4, concentrated and purified by silica gel flash column chromatography to give desired product 388A (5.56 g, 53%) as a faintly yellow solid (0%-1% ethyl acetate-CH2Cl2).
Reaction SMILES: [Br-].Br[C:3]1[CH:4]=[C:5]2[C:10](=[N:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7][CH2:6]2.C(N(C(C)C)CC)(C)C.[C:23]([O:27][C:28](=[O:31])[CH:29]=[CH2:30])([CH3:26])([CH3:25])[CH3:24].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C>O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C(Cl)Cl.CO.CN(C)C=O.C(#N)C>[O:13]=[C:8]1[NH:9][C:10]2[N:11]=[CH:12][C:3](/[CH:30]=[CH:29]/[C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:31])=[CH:4][C:5]=2[CH2:6][CH2:7]1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=C1CCc2cc(Br)cnc2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Temperature: 77.5 °C
Reaction time: 20 h
Yield: 81.7 %

Procedure:
A 22-L three-necked round-bottomed flask with a mechanical stirrer, a thermocouple, a reflux condenser and a nitrogen inlet was flushed with N2. The flask was charged with acetonitrile (8 L, 5 v), dimethylformamide (93.2 L, 2 v) and 6-bromo-3,4-dihydro-1,8-naphthyridin-2(1H)-one bromide (1.6 kg, 7.05 mol, 1 eq.). To the suspension were added diisopropylethylamine (1.33 kg, 10.57 mol, 1.5 eq.) and tert-butylacrylate (1.33 kg, 10.57 mol, 1.5 eq.). The suspension was then purged with a slow stream of N2 for 10 min. Trio-tolylphosphine (0.214 kg, 0.705 mol, 0.1 eq) and palladium diacetate (0.079 kg, 0.352 mol, 0.05 eq) were added to the reaction mixture. The reaction mixture was heated to 75-80° C. and stirred at 75-80° C. for 20 h. The reaction mixture was cooled to 20-25° C., diluted with water (10 v) and stirred for one hour. The solid was collected by vacuum filtration using a Buchnner funnel with a cloth filter and 20-L glass receiver flask. The solids were then washed with water (3×1 v) followed by heptane (2×1v). The light brown damp solid was dried under vacuum at 30-35° C. with a slow N2 bleed for 48 h to a constant weight to give 2.11 kg of light brown solid. This solid was then suspended DCM/MeOH (10v/1v) under N2 in two 22-L three necked RBFs with a mechanical stirrer, a thermocouple and a reflux condenser. To each of these RBFs charcoal (100 g, ALDRICH Activated Darco G 60-100 mesh) was added and the mixture allowed to stir at 20-25° C. for 20 h. The suspensions were filter through a pad of celite (500 g)/silica gel (500 g) using a cintered glass funnel and a 20-L glass filter flask. The solid cake was rinsed with DCM (3×1 v). The combined filtrate was concentrated under vacuum ˜30-35° C. and the residue was diluted with heptane/ethyl acetate (3v/3v) and further concentrated to a suspension. The solid product was collected under vacuum by filtration using a Buchnner funnel with a cloth filter. The solids were rinsed with heptane (3×1.25 v) and the damp solid was dried under vacuum at 30-35° C. with a slow N2 bleed for 90 h to a constant weight to give 1.58 kg (82%) of the desired product as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O:29][C:30]([NH:32][CH2:33][CH2:34][NH2:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N=C=NCCCN(C)C)C>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][C:14](=[O:15])[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[NH:35][CH2:34][CH2:33][NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)CCCCCNC(=O)CCNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNC(=O)CCCCCNC(=O)CCNC(=O)OCc1ccccc1
Yield: 72.5 %

Procedure:
The compound 37 was prepared using General Procedure B with the acid 36 2.23 g, 6.63 mmol), 2-t-butoxycarbonylamino-ethylamine (1.27 g, 7.95 mmol), 1-hydrobenzotriazole (HOBt) (1.25 g, 9.28 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (1.79 g, 9.28 mmol) in DMF (20 mL). Recrystallization of the crude product from EtOAc afforded 2.30 g (73%) of the desired product (37) as a white solid. 1H NMR (CDCl3): δ 7.32 (m, 5H, ArH), 6.44 (s, 1H, NH), 6.23 (s, 1H, NH), 5.67 (s, 1H, NH), 5.19 (s, 1H, NH), 5.06 (s, 2H, OCH2Ar), 3.45 (dt, J=6.4, 12.4 Hz, 2H, CH2NHCO), 3.31 (dt, J=5.2, 10.4 Hz, 2H, CH2NHCO), 3.21 (m, 4H, CH2NHCO), 2.39 (dt, J=6.0, 6.4 Hz, 2H, CH2CO), 2.14 (dt, J=7.0, 7.2 Hz, 2H, CH2CO), 1.60 (m, 2H, CH2), 1.47 (m, 2H, CH2), 1.41 (s, 9H, t-Bu), 1.30 (m, 2H, CH2); ESI-MS m/z 513[N+Cl]−; 501[M+Na]+, 479[M+H]+.